Toshiyuki Yasui, Minoru Irahara and Toshihiro Aono : 排卵障害治療の実際 漢方療法, Nakayama-Shoten Co., Ltd., Tokyo, Jan. 2000.
34.
Toshiyuki Yasui, Minoru Irahara and Toshihiro Aono : The Management of the Menopause:The Millennium Review 2000, --- Effects of oral and transdermal hormone replacement therapy in relation to serum estrogen levels ---, The Parthenon publishing Group, London, Oct. 1999.
Yohei Takahashi, Takashi Kaji, Toshiyuki Yasui, Atsuko Yoshida, Naoto Yonetani, Naoto Suzue, Shinsuke Katoh, Kazuhisa Maeda, Koichi Sairyo, Minoru Irahara and Takeshi Iwasa : Ultrasonographic changes in quadriceps femoris thickness in women with normal pregnancy and women on bed rest for threatened preterm labor., Scientific Reports, Vol.12, No.1, 17506, 2022.
(Summary)
This study aimed to evaluate the changes in quadriceps femoris muscle thickness during the pregnancy and postpartum periods and to elucidate the effect of bed rest for threatened preterm labor on muscle thickness. In 26 women with normal pregnancy, quadriceps femoris thickness was measured at 11-13, 26, 30, and 35 weeks' gestation, and at 3-5 days and 1 month postpartum using ultrasonography. In 15 pregnant women treated with bed rest for threatened premature labor, quadriceps femoris thickness was measured at 30 and 35 weeks' gestation and postpartum. In women with normal pregnancy, quadriceps femoris thickness increased, peaking at 35 weeks' gestation, followed by a postpartum decrease. In women on bed rest, quadriceps femoris thickness showed no significant change during the pregnancy and postpartum periods, and the muscle was significantly thinner at 35 weeks' gestation than that in women with normal pregnancy. In conclusion, a significant increase in quadriceps femoris muscle thickness during normal pregnancy was found using ultrasonography. Meanwhile, in pregnant women on bed rest treatment, the quadriceps femoris was significantly thinner in the late third trimester than that in normal pregnant women. Prolonged bed rest can affect normal changes in the quadriceps femoris muscle thickness during the pregnancy and postpartum periods.
(Keyword)
Infant, Newborn / Humans / Female / Pregnancy / Bed Rest / Quadriceps Muscle / Obstetric Labor, Premature / Gestational Age / Pregnancy Trimester, Third
Shuhei Kamada, Yuri Yamamoto, Hidenori Aoki, Kou Tamura, Asuka Takeda, Saki Minato, Rie Masaki, Rie Yanagihara, Noriko Hayashi, Yuya Yano, Junki Imaizumi, Tomohiro Kagawa, Atsuko Yoshida, Takako Kawakita, Minoru Irahara and Takeshi Iwasa : A novel PCOS rat model and an evaluation of its reproductive, metabolic, and behavioral phenotypes., Reproductive Medicine and Biology, Vol.21, No.1, e12416, 2021.
(Summary)
Although animal models of PCOS have been used in many studies, none of them can reproduce both the reproductive and metabolic phenotypes of PCOS. In addition, behavioral parameters have not been evaluated in PCOS animal models. We tried to produce an improved rat model of PCOS, and the reproductive, metabolic, and behavioral phenotypes of the model rats were evaluated. Female rats were implanted with silicon tubes containing oil-dissolved dihydrotestosterone (Oil-DHT) as a new PCOS model. Their phenotypes were compared with those of conventional PCOS model rats (DHT), into which tubes containing crystalline DHT were implanted, and non-DHT-treated rats (control). Both the Oil-DHT and DHT rats showed greater body weight gain, food intake, and fat depot weight than the control rats. Furthermore, these groups showed fewer estrous stages and increased numbers of cystic follicles. The DHT rats exhibited lower ovarian and uterine weights than the control rats, whereas no such changes were observed in the Oil-DHT rats. The Oil-DHT and DHT rats showed less locomotor activity in the light phase than the control rats. Our proposed PCOS model reproduced both the reproductive and metabolic phenotypes of PCOS and may have potential for PCOS research.
Natsumi Yamaguchi, Toshiyuki Yasui, Takashi Kaji, Eishi Sogawa, Atsuko Yoshida, Naoto Yonetani and Minoru Irahara : Usefulness of measurement of proximal phalanx length by using ultrasonography in newborn infants., Journal of Obstetrics and Gynaecology, Vol.41, No.5, 739-745, 2020.
(Summary)
The purpose of this study was to compare digit lengths and proximal phalanx lengths in newborn infants by using ultrasonography (USG) and to examine sex differences between the ratio of the second digit (2D) and fourth digit (4D) of digit length and that of proximal phalanx length and the associations of digit length and proximal phalanx length with birth weight and birth height. Sixty newborn infants (28 males and 32 females) were recruited. Digit lengths were measured by using a transparent ruler and proximal phalanx lengths were measured by using USG. There were significant correlations between digit length and proximal phalanx length in the left and right hands. There was no significant correlation between 2D:4D ratios of digit lengths and 2D:4D ratios of proximal phalanx lengths measured by using USG. In males, birth height was significantly associated with right fourth proximal phalanx length and with left second and fourth proximal phalanx lengths. Birth weight was significantly associated with proximal phalanx length in males. Proximal phalanx length measured by using USG was significantly associated with digit length in newborn infants. Hormonal exposure before birth may be involved in the associations of proximal phalanx length with birth weight and height in males.Impact statement The ratio of the second digit (2D) and fourth digit (4D) has been used postnatally to provide a retrospective indication of the foetal hormonal environment. Digit lengths have been measured by using a direct method, photocopies, digital scans and radiographs, but the results of a study on measurement of digit lengths by using ultrasonography (USG) have not been reported. Proximal phalanx length measured by using USG was significantly associated with digit length in newborn infants. In males, birth height was significantly associated with right fourth proximal phalanx length and with left second and fourth proximal phalanx lengths. Birth weight was significantly associated with proximal phalanx length in males. Measurement of proximal phalanx length by using USG may be useful for a study on gender differences in foetal development and the foetal hormonal environment. Hormonal exposure before birth may be involved in the associations of proximal phalanx length with birth weight and height in males.
Midori Fukui, Toshihiko Tsutsumi, Aimi Yamamoto-Mikami, Katsuya Morito, Naoko Takahashi, Tamotsu Tanaka, Tekeshi Iwasa, Akira Kuwahara, Minoru Irahara and Akira Tokumura : Distinct contributions of two choline-producing enzymatic activities to lysophosphatidic acid production in human amniotic fluid from pregnant women in the second trimester and after parturition, Prostaglandins & Other Lipid Mediators, Vol.150, 106471, 2020.
Yiliyasi Mayila, Toshiya Matsuzaki, Takeshi Iwasa, Altankhuu Tungalagsuvd, Munkhsaikhan Munkhzaya, Kiyohito Yano, Rie Yanagihara, Takako Tokui, Saki Minato, Asuka Takeda, Sachiko Endo, Takaaki Maeda and Minoru Irahara : The reduction in sexual behavior of adult female rats exposed to immune stress in the neonatal period is associated with reduced hypothalamic progesterone receptor expression., General and Comparative Endocrinology, Vol.288, 113360, 2020.
(Summary)
We examined the mechanism by which neonatal immune stress reduces the sexual behavior of female rats in adulthood. Neonatal female rats were randomly divided into 3 groups: control (n = 11), postnatal day 10 lipopolysaccharide (PND10LPS) (n = 23), and PND25LPS (n = 11) groups, which received intraperitoneal injections of LPS (100 μg/kg) or saline on PND10 and 25. Daily inspections of the vaginal opening (VO) were performed from PND27 to PND37. Thereafter, the frequency of estrus was assessed for 15 days. Female rats (at 11-12 weeks of age) were placed in a cage with male rats, and their sexual behavior was monitored for 30 min. The hypothalamic mRNA expression levels of factors related to sexual behavior were examined via real-time PCR. VO occurred later and the frequency of estrus was lower in the PND10LPS group compared to the control group. The number of lordosis behaviors and the total number of mounts performed by male partners were lower in the PND10LPS and PND25LPS groups than in the control group. Acceptability: The lordosis quotient and lordosis rating were lower in the PND10LPS group than in the control group. Proceptive behavior: the number of ear wiggling events was lower in the PND10LPS group than in the other groups, and the number of hops/darts was lower in the PND10LPS group than in the control group. The hypothalamic mRNA expression level of progesterone receptors (PR)A + B was lower in the PND10LPS group than in the control group, and the hypothalamic PRB mRNA expression level was lower in the PND10LPS and PND25LPS groups than in the control group. Neonatal immune stress impeded sexual behavior and hypothalamic PR mRNA expression in female rats. Decreased progesterone activity in the hypothalamus might explain the reduction in sexual behavior seen in these rats.
(Keyword)
Age Factors / Animals / Animals, Newborn / Down-Regulation / Drug Administration Schedule / Female / Gene Expression / Hypothalamus / Immune System / Lipopolysaccharides / Male / Pregnancy / Rats / Rats, Sprague-Dawley / Receptors, Progesterone / Sexual Behavior, Animal / Stress, Physiological / Time Factors
Kiyohito Yano, Toshiya Matsuzaki, Takeshi Iwasa, Yiliyasi Mayila, Rie Yanagihara, Altankhuu Tungalagsuvd, Munkhsaihan Munkhzaya, Takako Tokui, Shuhei Kamada, Aki Hayashi, Rie Masaki, Hidenori Aoki, Kou Tamura and Minoru Irahara : The influence of psychological stress in early life on sexual maturation and sexual behavior in male and female rats., Reproductive Medicine and Biology, Vol.19, No.2, 135-141, 2019.
(Summary)
We studied the influence of psychological stress during the early neonatal period on sexual maturation and sexual behavior in rats. Neonatal male and female rats were divided into control (C) and maternal separation (MS) groups (n = 20-24 per group). The pups in the MS groups were placed in isolation cages for 240 minutes/d from postnatal days 2-11. Vaginal opening (VO) in females and preputial separation (PS) in males (indicators of sexual maturation) were monitored, as was the estrous cycle in females. Thereafter, sexual behavior was monitored twice at 13 and 15 weeks of age. As for sexual maturation, the onset of PS occurred significantly earlier in the MS group than in the C group, whereas the onset of VO did not differ between the groups. The length of the estrous cycle did not differ between the groups. The frequencies of sexual behaviors did not differ between the groups in either sex. In conclusion, early-life psychological stress induced by MS advanced sexual maturation in male rats, whereas it did not affect sexual maturation in female rats. On the other hand, early-life psychological stress might not affect sexual behavior in adulthood in either sex.
Takeshi Iwasa, Toshiya Matsuzaki, Yiliyasi Mayila, Rie Yanagihara, Yuri Yamamoto, Takako Kawakita, Akira Kuwahara and Minoru Irahara : Oxytocin treatment reduced food intake and body fat and ameliorated obesity in ovariectomized female rats., Neuropeptides, Vol.75, 49-57, 2019.
(Summary)
Recent studies have shown that oxytocin reduces food intake and body weight gain and promotes lipolysis in some species, including humans. Interestingly, these effects of oxytocin are more marked in obese individuals. Although the menopausal loss of ovarian function induces increased visceral adiposity and some metabolic disorders, no safe medical interventions for these conditions have been established. In this study, we evaluated the effects of oxytocin on appetite, body weight, and fat mass in ovariectomized rats. Six-day oxytocin treatment attenuated cumulative food intake and body weight gain, and reduced visceral and subcutaneous fat weight and adipocyte cell area in ovariectomized rats. Blood examinations indicated that 6-day oxytocin treatment did not alter renal or hepatic functions. Instead, it might prevent ovariectomy-induced liver damage. In addition, acute oxytocin treatment did not affect body temperature or locomotor activity. These results indicate that oxytocin might be useful for treating or preventing menopause-induced metabolic disorders, without causing any adverse effects.
Eishi Sogawa, Takashi Kaji, Soichiro Nakayama, Atsuko Yoshida, Naoto Yonetani, Kazuhisa Maeda, Toshiyuki Yasui and Minoru Irahara : Seasonal variation of serum 25(OH)vitamin D levels in maternal and umbilical cord blood in Japanese women, The Journal of Medical Investigation : JMI, Vol.66, No.1.2, 128-133, 2019.
(Summary)
We aimed to demonstrate that the serum 25-hydroxyvitamin D (25(OH)D) level in maternal and umbilical cord blood has a seasonal variation in Japanese women. The study cohort comprised 256 healthy Japanese women with a singleton pregnancy who delivered after 36 gestational weeks between 2012 and 2015. The season at delivery was categorized for 3 months and recorded as "spring", "summer", "autumn" and "winter". Subjects were divided into four groups according to season. A sample of peripheral venous blood at 35-36 gestational weeks and blood from the umbilical vein at delivery were taken. The mean serum 25(OH)D concentra tion (ng/mL) in maternal blood for each season (spring, summer, autumn and winter) was 18.0 (?6.7), 17.1 (?5.1), 21.6 (?8.0) and 16.0 (?5.1), whereas that for umbilical cord blood was 8.8 (?3.6), 8.6 (?2.6), 10.7 (?3.5) and 8.6 (?2.1), respectively. The mean serum 25(OH)D concentration of maternal and umbilical cord blood in autumn was higher than that for the other three seasons. In pregnant Japanese women, the mean serum 25(OH)D concentration in maternal and umbilical cord blood was affected by the season of delivery, with both being highest in autumn. Regardless of the season, the maternal serum concentration of 25(OH)D was low in Japan. J. Med. Invest. 66 : 128-133, February, 2019.
Kana Kasai, Takeshi Katou, Yuri Kadota, Otgontsetseg Erdenebayar, Kaoru Keyama, Takako Kawakita, Kanako Yoshida, Akira Kuwahara, Toshiya Matsuzaki and Minoru Irahara : Intraperitoneal administration of activin A promotes development of endometriotic lesions in a mouse model of endometriosis., The Journal of Medical Investigation : JMI, Vol.66, No.1.2, 123-127, 2019.
(Summary)
This study aimed to investigate the effect of intraperitoneal administration of activin on the occurrence of endometriosis using a mouse model of endometriosis. A mouse model of endometriosis was prepared by intraperitoneally administering endometrial tissue and blood collected from donor mice to C57BL/6J 7-8- week-old recipient mice. A total of 400 μg of activin A was intraperitoneally administered to model mice in the activin group for 5 days. Intraperitoneal endometriotic lesions were confirmed macroscopically and IL-6 and TNF-α levels in washed ascites were measured by ELISA. Endometriotic lesions were observed in all mice. In the activin group, the maximum diameter of endometriotic lesions was significantly larger than that in control group (4.7?1.3 vs 2.9?0.9 mm, p?0.01). The total area of the lesion was also significantly higher in the activin group than in the control group (21.1?9.9 vs 8.8?5.4 mm,p?0.01). Furthermore, IL-6 and TNF-α levels in ascites were significantly higher in the activin group than in the control group (IL-6 : 85.8?15.3 vs 75.1?19.3 pg/ml, p?0.05 ; TNF-α : 629.8?15.4 vs 605.9?11.4 pg/ml, p?0.05). Activin promotes occurrence of endometriosis. Inflammatory cytokines are also elevated by activin administration,suggesting that they may contribute to progression of endometriosis J. Med. Invest. 66 : 123-127, February, 2019.
Yuu Tanaka, Toshiya Matsuzaki, Naoko Tanaka, Takeshi Iwasa, Akira Kuwahara and Minoru Irahara : Activin effects on follicular growth in in vitro preantral follicle culture., The Journal of Medical Investigation : JMI, Vol.66, No.1.2, 165-171, 2019.
(Summary)
As the follicular environment transits from being activin dominant to inhibin dominant during folliculogenesis, it is assumed that activin plays an important role in the early stage of follicular growth. We examined the effects of activin on morphological, biochemical and molecular changes in isolated preantral follicles. Preantral follicles were mechanically isolated from 14-day old female C57BL/6 mice. Each follicle was cultured and observed for 14 days usingan in vitro follicle culture system containing FSH, FSH + activin A and FSH + inhibin in the culture medium. We subsequently examined FSH receptor (FSH-R) mRNA expression in isolated follicle cultures with or without activin on days 0 and 2. Activin was observed to significantly stimulate follicle enlargement on days 2, 4, 6 and 8, accelerate morphological changes and increase estradiollevels in culture medium on days 4, 12 and 14. In contrast, inhibin did not alter follicular growth. Additionally, activin stimulated the expression of FSH-R mRNA in isolated granulosa cells. It was demonstrated that activin stimulated the growth of preantral follicles, mainly during the early stage of folliculogenesis, by inducing FSH-R expression, in an isolated follicle culture system. J. Med. Invest. 66 : 165-171, February, 2019.
Atsuko Yoshida, Takashi Kaji, Hirotsugu Yamada, Naoto Yonetani, Eishi Sogawa, Masami Yamao, Kazuhisa Maeda, Masataka Sata and Minoru Irahara : Measurement of hemodynamics immediately after vaginal delivery in healthy pregnant women by electrical cardiometry., The Journal of Medical Investigation : JMI, Vol.66, No.1.2, 75-80, 2019.
(Summary)
Few reports have focused on hemodynamics around delivery in pregnant women because of the difficulty of continuous and noninvasive measurement. Electrical cardiometry allows noninvasive continuous monitoring of hemodynamics and has recently been used in non-pregnant subjects. We compared the use of electrical cardiometry versus transthoracic echocardiography in healthy pregnant women and evaluated hemodynamics immediately after vaginal delivery. In Study 1, electrical cardiometry and transthoracic echocardiography were used to measure cardiac output in 20 pregnant women with threatened premature delivery. A significant correlation was found between the two methods, with electrical cardiometry showing the higher cardiac output. In Study 2, heart rate, stroke volume, and cardiac output were continuously measured in 15 women during vaginal delivery up to 2 h postpartum. Cardiac output increased markedly because of an increased heart rate and stroke volume at the time of newborn delivery. The heart rate then immediately returned to baseline, while cardiac output remained elevated for at least 2 h after delivery because of a sustained high stroke volume. Electrical cardiometry was as readily available as transthoracic echocardiography for evaluating hemodynamics and allowed for continuous measurement during labor. High intrapartum cardiac output was sustained for at least 2 h after vaginal delivery. J. Med. Invest. 66 : 75-80, February, 2019.
Ayuka Mineda, Masato Nishimura, Tomohiro Kagawa, Eri Takiguchi, Takako Kawakita, Akiko Abe and Minoru Irahara : Resveratrol suppresses proliferation and induces apoptosis of uterine sarcoma cells by inhibiting the Wnt signaling pathway., Experimental and Therapeutic Medicine, Vol.17, No.3, 2242-2246, 2019.
(Summary)
Resveratrol, a natural product and peroxisome proliferator-activated receptor (PPAR) agonist, has been reported to exert anti-cancer effects in several tumor models. A previous study by our group reported that prostaglandin J2, a PPARγ ligand, inhibited cell proliferation in a uterine sarcoma cell line. The aim of the present study was to investigate the role of the Wnt signaling pathway in resveratrol-induced apoptosis and inhibition of cell proliferation in the MES-SA human uterine sarcoma cell line. A WST-1 assay demonstrated that resveratrol inhibited cell proliferation in the MES-SA cell line, and flow cytometry revealed that the number of apoptotic cells increased in a resveratrol dose-dependent manner. The mechanisms underlying these effects of resveratrol were speculated to involve the expression of β-catenin and its target gene, c-myc, which were examined using western blot analysis. The results revealed a dose-dependent downregulation of this β-catenin and c-myc. This effect was blunted by a pharmacological inhibitor of glycogen synthase kinase 3β. Therefore, it is likely that resveratrol inhibited the cell proliferation and increased the number of apoptotic cells, at least partially, via the Wnt signaling pathway. The present results suggest that resveratrol is a potential candidate for the treatment of uterine sarcoma.
Sumika Matsui, Toshiyuki Yasui, Hirokazu Uemura and Minoru Irahara : Variation in follicle-stimulating hormone level and different associations of follicle-stimulating hormone level with body mass index over the menopausal transition in Japanese wome, The Journal of Japan Society for Menopause and Women's Health, Vol.27, No.2, 311-317, 2019.
Kaoru Keyama, Takeshi Katou, Yuri Kadota, Otgontsetseg Erdenebayar, Kana Kasai, Takako Kawakita, Anna Tani, Sumika Matsui, Takeshi Iwasa, Kanako Yoshida, Masahiko Maegawa, Akira Kuwahara, Toshiya Matsuzaki and Minoru Irahara : Lipopolysaccharide promotes early endometrial-peritoneal interactions in a mouse model of endometriosis., The Journal of Medical Investigation : JMI, Vol.66, No.1.2, 70-74, 2019.
(Summary)
The aims of this study were to clarify the effects of lipopolysaccharide (LPS) on the early development of endometriosis and on the production of cytokines and chemokines in the murine peritoneal cavity. Endometriotic lesions were induced in C57BL/6J adult female mice by intraperitoneal injection of endometrial fragments plus blood or endometrial fragments plus blood with LPS. On day 7, endometriotic lesions were assessed by gross and microscopic evaluations. Time-dependent changes in the secretion of TNF-α,IL-6,and CXCL2/MIP-2 in peritoneal lavage fluid after the intraperitoneal injection of LPS (50 µg/body) were measured by their respective enzyme-linked immunosorbent assays. The areas of endometriotic lesions in the LPS group (10.8 8.6 mm) were significantly larger than those in the control group (3.1 3.7 mm).The levels of TNF-α and IL-6 peaked within 2 hours and the level of MIP-2 reached a maximum on day 1 after the injection of LPS. LPS promotes development of the early stages of murine endometriotic lesions. J. Med. Invest. 66 : 70-74, February, 2019.
Takeshi Iwasa, 谷口 友香, 中山 聡一朗, Naoto Yonetani, Atsuko Yoshida, Akiko Abe, Yuri Yamamoto, Takashi Kaji, Akira Kuwahara, Toshiya Matsuzaki and Minoru Irahara : Current status of chromosomal analysis in couples with recurrent miscarriage at Tokushima University Hospital, Modern Trends in Obstetrics & Gynecology, Vol.67, No.1, 21-24, 2018.
Osamu Ishihara, Seung Chik Jwa, Akira Kuwahara, Tomonori Ishikawa, Koji Kugu, Rintaro Sawa, Kouji Banno, Minoru Irahara and Hidekazu Saito : Assisted reproductive technology in Japan: A summary report for 2016 by the Ethics Committee of the Japan Society of Obstetrics and Gynecology., Reproductive Medicine and Biology, Vol.18, No.1, 7-16, 2018.
(Summary)
The Japan Society of Obstetrics and Gynecology started an online cycle-based assisted reproductive technology (ART) registry system in 2007. This report presents the characteristics and treatment outcomes of ART registered for the cycles practiced during 2016. Cycle-specific information for all ART cycles implemented in participating ART facilities were collected. A descriptive analysis was conducted for the registry database of 2016. In total, 447 790 treatment cycles and 54 110 neonates (one in 18.1 neonates born in Japan) were reported in 2016. The mean patients' age was 38.1 years (SD = 4.5). Among the egg retrieval cycles, 104 575 of 251 399 (41.6%) were freeze-all cycles without fresh embryo transfers (ET), while fresh ET was performed in 64 497 cycles (58.4%). A total of 187 132 frozen-thawed ET cycles were reported, resulting in 62 432 pregnancies and 44 484 neonates born. Single ET was selected for 81.0% of fresh transfers and 82.7% of frozen cycles, resulting in singleton pregnancy/live birth rates of 97.0%/96.4% and 96.7%/96.4%, respectively. The total ART cycles and subsequent live births continued to increase in 2016. Single ET was performed more than 80%, and ET has shifted from using fresh embryos to frozen ones.
Toshiya Matsuzaki, Munkhsaikhan Munkhzaya, Takeshi Iwasa, Altankhuu Tungalagsuvd, Kiyohito Yano, Yiliyasi Mayila, Rie Yanagihara, Takako Tokui, Takeshi Katou, Akira Kuwahara, Sumika Matsui and Minoru Irahara : Prenatal undernutrition suppresses sexual behavior in female rats., General and Comparative Endocrinology, Vol.269, 46-52, 2018.
(Summary)
Infectious, psychological and metabolic stresses in the prenatal and early neonatal period induce long-lasting effects in physiological function and increase the risk of metabolic disorders later in life. We examined the sexual behavior of female rats that were subjected to undernutrition in the prenatal period. Eight pregnant rats were divided into two groups: a maternal normal nutrition group (mNN; n = 4) and a maternal undernutrition group (mUN; n = 4), which received 50% of the daily food intake amount of the mNN group from gestation day 13 to delivery. Nine and seven female offspring were randomly selected from the mNN and mUN groups, respectively. Vaginal opening (VO), estrous cycle length, sexual behavior and mRNA expression levels of the factors that regulate sexual behavior were observed. In the mUN group, VO day was later, the estrous cycle was longer, and the lordosis quotient and lordosis rating were lower than in the mNN group; such differences were not seen in other sexual performances, such as ear wiggles, darts, kick bouts and box. The hypothalamic mRNA expression level of progesterone receptor (PR) A + B and oxytocin (OT) were significantly lower in the mUN group than in the mNN group. These findings indicated that prenatal undernutrition disrupted puberty onset, the estrous cycle, sexual behavior and hypothalamic mRNA expression of PR and OT in female rat pups.
Kanako Yoshida, Masato Nishimura, Akiko Abe, Takeshi Katou, Hiroyuki Furumoto and Minoru Irahara : Can systematic lymphadenectomy be omitted for low-risk endometrial cancer?, The Journal of Medical Investigation : JMI, Vol.65, No.3,4, 221-224, 2018.
(Summary)
The objective of this study was to identify pathological indicators that could be used to identify a subgroup of patients with apparent stage I endometrial cancer who do require retroperitoneal lymphadenectomy. 188 T1 endometrial cancer patients underwent primary surgery at Tokushima University Hospital. We retrospectively evaluated their clinical records and histopathological factors. Systematic lymphadenectomy was performed for 149 patients, and 39 patients (grade 1 with < 5 mm of myometrial invasion) were treated without lymphadenectomy. Lymph node metastases were found in 19 (12.8%) of the lymphadenectomy cases. Twenty-four patients with a T1a endometrium-limited lesion did not exhibit lymph node metastasis. Three (3.1%) of the 95 patients with a T1a lesion exhibited lymph node metastasis, and these 3 cases exhibited approximately 50% myometrial invasion. The 39 low-risk patients who did not undergo systematic lymphadenectomy remain alive without recurrence. Systematic lymphadenectomy could be omitted for patients with a grade 1 tumor and minor myometrial invasion of less than 5mm. J. Med. Invest. 65:221-224, August, 2018.
Tomoko Yoshida, Toshiya Matsuzaki, Mami Miyado, Kazuki Saito, Takeshi Iwasa, Yoichi Matsubara, Tsutomu Ogata, Minoru Irahara and Maki Fukami : 11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome., Endocrine Journal, Vol.65, No.10, 979-990, 2018.
(Summary)
11-oxygenated C19 steroids (11oxC19s) are newly specified human androgens. Although median serum levels of 11oxC19 were reported to be higher in patients with polycystic ovary syndrome (PCOS) than in unaffected women, inter-individual variations in androgen levels among PCOS patients have poorly been investigated. Here, we quantified four 11oxC19s, i.e., 11-ketotestosterone (11KT), 11β-hydroxytestosterone (11OHT), 11β-hydroxyandrostenedione (11OHΔ4A), and 11-ketoandrostenedione (11KΔ4A), in blood samples of 28 PCOS patients and 31 eumenorrheic women using liquid chromatography-tandem mass spectrometry. We referred to our previous data of classic androgens in these individuals. We found that 11OHT levels were higher in the PCOS group than in the eumenorrheic group. Moreover, although the median values of 11KT, 11KΔ4A, and 11OHΔ4A were comparable between the two groups, these steroids were markedly increased in some patients. Of the 28 patients, 8 had high levels of both 11oxC19s and classic androgens, whereas 4 had an increase only in 11oxC19 levels, and 12 had an increase only in classic androgen levels. Intragroup variations in androgen levels were relatively large in the PCOS group. Levels of 11OHT and 11KT were significantly higher in overweight/obese patients than in normal weight patients and correlated with body mass indexes. These results highlight the clinical significance of 11oxC19s as circulating androgens in PCOS patients and indicate that the accumulation of 11oxC19s and/or classic androgens is an essential feature of PCOS. The profiles of circulating androgens appear to vary among patients. In particular, overweight/obesity likely enhances the 11oxC19s accumulation in PCOS, although this notion awaits further validation.
(Keyword)
Adult / Androgens / Body Mass Index / Chromatography, Liquid / Female / Humans / Obesity / Polycystic Ovary Syndrome / Tandem Mass Spectrometry / Young Adult
Takeshi Iwasa, Toshiya Matsuzaki, Kiyohito Yano, Rie Yanagihara, Yiliyasi Mayila and Minoru Irahara : The effects of chronic testosterone administration on hypothalamic gonadotropin-releasing hormone regulatory factors (Kiss1, NKB, pDyn and RFRP) and their receptors in female rats., Gynecological Endocrinology, Vol.34, No.5, 437-441, 2018.
(Summary)
The effects of androgens on gonadotropin-releasing hormone (GnRH) secretion in females have not been fully established. To clarify the direct effects of androgens on hypothalamic reproductive factors, we evaluated the effects of chronic testosterone administration on hypothalamic GnRH regulatory factors in ovariectomized (OVX) female rats. Both testosterone and estradiol reduced the serum luteinizing hormone levels of OVX female rats, indicating that, as has been found for estrogen, testosterone suppresses GnRH secretion via negative feedback. Similarly, the administration of testosterone or estradiol suppressed the hypothalamic mRNA levels of kisspeptin and neurokinin B, both of which are positive regulators of GnRH, whereas it did not affect the hypothalamic mRNA levels of the kisspeptin receptor or neurokinin-3 receptor. On the contrary, the administration of testosterone, but not estradiol, suppressed the hypothalamic mRNA expression of prodynorphin, which is a negative regulator of GnRH. The administration of testosterone did not alter the rats' serum estradiol levels, indicating that testosterone's effects on hypothalamic factors might be induced by its androgenic activity. These findings suggest that as well as estrogen, androgens have negative feedback effects on GnRH in females and that the underlying mechanisms responsible for these effects are similar, but do not completely correspond, to the mechanisms underlying the effects of estrogen on GnRH.
Toshiya Matsuzaki, Altankhuu Tungalagsuvd, Munkhsaikhan Munkhzaya, Takeshi Iwasa, Kiyohito Yano, Yiliyasi Mayila, Takako Tokui, Rie Yanagihara, Sumika Matsui, Takeshi Katou, Akira Kuwahara and Minoru Irahara : Neurokinin B receptor agonist and Dynorphin receptor antagonist stimulated luteinizing hormone secretion in fasted male rodents., Endocrine Journal, Vol.65, No.4, 485-492, 2018.
(Summary)
Kisspeptin/neurokinin B (NKB)/dynorphin (Dyn) (KNDy) neuron in hypothalamic arcuate nucleus plays a key role in GnRH/LH pulsatile secretion. We aimed to determine whether stimulation of NKB/neurokinin 3 receptor (NK3R) signaling and inhibition of Dyn/kappa-opioid receptor (KOR) signaling recover LH secretion that is suppressed by acute fasting in male rats. Furthermore, we determined dose dependent effect of NKB/NK3R signaling on serum LH level under acute fasting condition in male mice. Mature male rats were injected saline (0.1 mL) and senktide (20 μg/kg), a NK3R agonist, or nor-BNI (800 μg/kg), a KOR antagonist intraperitoneally (ip) after 72 h fasting. And mature male mice were injected multiple doses of senktide, ip after 48 h fasting. Blood and brain sample were collected 90 min after injections for LH measurement and hypothalamic mRNA expressions. All three studies showed significantly lower LH concentration in fasted groups than non-fasted groups. Senktide did not recover LH suppressed by acute fasting in male rats, whereas nor-BNI injected male rats showed significantly higher LH than 72 h fasted male rats (p < 0.05). Mice study showed significantly higher LH concentration in higher doses senktide groups than 48 h fasted group and one of lower doses senktide group. These results suggest that stimulation of NKB/NK3R signaling and attenuation of Dyn/KOR signaling could recover suppressed LH secretion under acute fasting condition in male rodents.
Masaharu Kamada, Hiroaki Inui, Tomohiro Kagawa, Ayuka Mineda, Takao Tamura, Tomohito Fujioka, Takahiro Motoki, Hiroki Hirai, Eiichi Ishii and Minoru Irahara : What information can change the attitude of teachers toward the human papillomavirus vaccine?, The Journal of Obstetrics and Gynaecology Research, Vol.44, No.4, 778-787, 2018.
(Summary)
We conducted a self-administered survey on the perception of teachers toward human papillomavirus (HPV) vaccine to determine the ways to increase their willingness to encourage its use. Answers were obtained both prior to and after having the teachers read five brief information articles: (i) cervical cancer knowledge, (ii) vaccine knowledge, (iii) result of a survey in Nagoya, (iv) news report of the World Health Organization statement and (v) articles written by Dr Muranaka, a journalist. Most of the respondents (180/247) did not know about the natural history of cervical cancer. Only 36% knew that HPV is the cause of cervical cancer, although 63% knew that HPV vaccine would prevent cervical cancer. Few respondents had knowledge regarding adverse events following immunization and the survey results from Nagoya. Among those who were initially negative for the HPV vaccine, only 43% revealed that they fully understood its safety and only 29% reversed their opinion to recommend vaccination to their daughters and/or students, even after reading our informational material. The most useful information for changing their attitudes was to increase their understanding of vaccines and informing them about Nagoya city survey results. They mostly wanted a proof of the preventive effects of the vaccine on cervical cancer in Japan. Gynecologists and pediatricians must proactively communicate accurate scientific information to the government and the media to spread awareness among people in Japan. Also, we must try to demonstrate the capabilities of this vaccine to prevent cervical cancer and/or its precancerous lesions.
Takeshi Iwasa, Toshiya Matsuzaki, Kiyohito Yano, Yiliyasi Mayila and Minoru Irahara : Effects of dihydrotestosterone administration on the expression of reproductive and body weight regulatory factors in ovariectomized and estradiol-treated female rats., Gynecological Endocrinology, Vol.34, No.1, 73-77, 2018.
(Summary)
To clarify the direct effects of androgens, the changes in the hypothalamic levels of reproductive and appetite regulatory factors induced by chronic dihydrotestosterone (DHT) administration were evaluated in female rats. DHT treatment increased the BW and food intake of the ovariectomized rats, but not the estradiol (E2)-treated rats. DHT administration suppressed the expression of a hypothalamic anorexigenic factor. Although the kisspeptin (Kiss1) mRNA levels of the anterior hypothalamic block (the anteroventral periventricular nucleus, AVPV) were increased in the E2-treated rats, DHT administration did not affect the Kiss1 mRNA levels of the AVPV in the ovariectomized or E2-treated rats. Conversely, DHT administration reduced the Kiss1 mRNA levels of the posterior hypothalamic block (the arcuate nucleus, ARC) in the ovariectomized rats. Although the Kiss1 mRNA levels of the posterior hypothalamic block (ARC) were decreased in the E2-treated rats, DHT administration did not affect the Kiss1 mRNA levels of the ARC in these rats. Serum luteinizing hormone levels of these groups exhibited similar patterns to the Kiss1 mRNA levels of the ARC. These results showed that DHT affects the production of hypothalamic reproductive and appetite regulatory factors, and that these effects of DHT differ according to the estrogen milieu.
Takeshi Iwasa, Toshiya Matsuzaki, Kiyohito Yano, Yiliyasi Mayila and Minoru Irahara : The roles of kisspeptin and gonadotropin inhibitory hormone in stress-induced reproductive disorders., Endocrine Journal, Vol.65, No.2, 133-140, 2018.
(Summary)
Several kinds of stress suppress the hypothalamic-pituitary-gonadal (HPG) axis and reproductive behavior in humans and animals. These changes can eventually cause diseases and disorders, such as amenorrhea and infertility. In previous studies, it has been shown that stress-related factors, e.g., corticotropin-releasing hormone, cortisol, and pro-inflammatory cytokines, promote the stress-induced suppression of the HPG axis. However, these mechanisms are not sufficient to explain how stress suppresses HPG axis activity, and it has been suggested that some other factors might also be involved. In the early 21st century, novel neuroendocrine peptides, kisspeptin and gonadotropin inhibitory hormone (GnIH)/RFamide-related peptide 3 (RFRP-3), which directly regulate GnRH/gonadotropin synthesis and secretion, were newly discovered. Growing evidence indicates that kisspeptin and GnIH/RFRP-3 play pivotal roles in the stress-induced disruption of the HPG axis and reproductive behavior in addition to their physiological functions. This review summarizes what is currently known about the roles of kisspeptin and GnIH/RFRP-3 in stress-induced reproductive disorders.
Akiko Abe, Masato Nishimura and Minoru Irahara : See and treat LEEP biopsy for cervical intraepithelial neoplasia grade 2/3, European Journal of Gynaecological Oncology, Vol.39, No.6, 958-962, 2018.
Aya Shirakawa, Takashi Kaji, Yasunobu Hayabuchi, Souichiro Nakayama, Kazuhisa Maeda and Minoru Irahara : Prenatal three-dimensional color Doppler imaging showing crossover of the inflow streams of two ventricles in a case of criss-cross heart., Journal of Echocardiography, Vol.15, No.4, 191-193, 2017.
Hidekazu Saito, Seung Chik Jwa, Akira Kuwahara, Kazuki Saito, Tomonori Ishikawa, Osamu Ishihara, Koji Kugu, Rintaro Sawa, Kouji Banno and Minoru Irahara : Assisted reproductive technology in Japan: a summary report for 2015 by The Ethics Committee of The Japan Society of Obstetrics and Gynecology., Reproductive Medicine and Biology, Vol.17, No.1, 20-28, 2017.
(Summary)
The Japan Society of Obstetrics and Gynecology (JSOG) implemented an assisted reproductive technology (ART) registry system in 1986. Here are reported the characteristics and treatment outcomes of ART cycles that were registered in 2015. JSOG has requested all participating ART facilities to register cycle-specific information for all ART cycles since 2007. A descriptive analysis was performed by using the registry database for 2015. In total, 424 151 cycles and 51 001 neonates (1 in 19.7 neonates born in Japan) were registered in 2015. The patients' mean age was 38.2 years (standard deviation = 4.5). Among the fresh cycles, 94 158 of 244 718 (38.5%) egg retrieval cycles were cycles with freeze-all embryos or oocytes, while fresh embryo transfer (ET) was performed in 70 254 cycles, signaling a decrease from 2014. There were 169 898 frozen-thawed ET cycles, resulting in 56 355 pregnancies and 40 599 neonates. Single ET was performed at a rate of 79.7% for fresh and 81.8% for frozen cycles and the singleton pregnancy/live birth rates were 96.9%/96.5% and 96.8%/96.4% for the respective cycles. The total ART cycles and live births resulting from ART has been increasing in Japan. Single ET was performed at a rate of almost 80% and ET cycles have shifted from fresh to frozen cycles.
Takeshi Iwasa, Toshiya Matsuzaki, Kiyohito Yano and Minoru Irahara : The effects of ovariectomy and lifelong high-fat diet consumption on body weight, appetite, and lifespan in female rats., Hormones and Behavior, Vol.97, 25-30, 2017.
(Summary)
In females, ovarian hormones play pivotal roles in metabolic, appetite, and body weight regulation. In addition, it has been reported that ovarian hormones also affect longevity in some species. Recently, it was found that the consumption of a high-fat diet aggravates ovariectomy-associated metabolic dysregulation in female rodents. The aim of this study was to investigate the hypothesis that long-term high-fat diet consumption and ovariectomy interact to worsen body weight regulation and longevity in female rats. At 21days of age, female rats were weaned and randomly divided into two groups, one of which was given the high-fat diet, and the other was supplied with standard chow. At 23weeks of age, each group was further divided into ovariectomized and sham-operated groups, and then their body weight changes, food intake, and longevity were measured until 34months of age. The sham - high-fat diet rats exhibited greater body weight changes and higher feed efficiency than the sham - standard chow rats. On the other hand, the ovariectomized - high-fat diet and ovariectomized - standard chow rats displayed similar body weight changes and feed efficiency. The sham - high-fat diet and ovariectomized - standard chow rats demonstrated similar body weight changes and feed efficiency, indicating that the impact of ovariectomy on the regulation of body weight and energy metabolism might be similar to that of high-fat diet. Contrary to our expectations, ovariectomy and high-fat diet consumption both had small favorable effects on longevity. As the high-fat diet used in the present study not only had a high fat content, but also had a high caloric content and a low carbohydrate content compared with the standard chow, it is possible that the effects of the high-fat diet on body weight and longevity were partially induced by its caloric/carbohydrate contents. These findings indicate that the alterations in body weight and energy metabolism induced by ovariectomy and high-fat diet might not directly affect the lifespan of female rats.
Yoshimasa Asada, Yoshiharu Morimoto, Yoshiharu Nakaoka, Takahiro Yamasaki, Yutaka Suehiro, Hikaru Sugimoto, Masayuki Yoshida and Minoru Irahara : Age-specific serum anti-Müllerian hormone concentration in Japanese women and its usefulness as a predictor of the ovarian response., Reproductive Medicine and Biology, Vol.16, No.4, 364-373, 2017.
(Summary)
To compare the ovarian response predictive ability of anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), and estradiol (E2) and to determine the age-specific distribution of serum AMH concentrations of Japanese women. This was a multicenter (four-site), observational, analytic, cross-sectional Japanese study consisting of two parts: Study 1 (the prediction of the ovarian response of 236 participants who were undergoing controlled ovarian stimulation [COS]) and Study 2 (the distribution of the AMH concentration with an assay of 417 healthy women who were aged 20-49 years and who had normal menstrual cycles). The AMH had a significantly higher predictive value for the normal and high responders than FSH and E2 as a stronger correlation between the ovarian response and AMH was observed than for FSH and E2. The serum AMH concentration decreased proportionally with age. The AMH concentration correlated well with the oocyte count in the patients who were undergoing COS for in vitro fertilization and was shown to predict the risk of ovarian hyperstimulation syndrome among these patients.
Toshiya Matsuzaki, Munkhsaikhan Munkhzaya, Altankhuu Tungalagsuvd, Yiliyasi Mayila, Takeshi Iwasa, Kiyohito Yano, Rie Yanagihara, Takako Tokui, Takeshi Katou, Akira Kuwahara, Sumika Matsui and Minoru Irahara : Prenatal undernutrition disrupted the sexual maturation, but not the sexual behavior, in male rats., Reproductive Medicine and Biology, Vol.16, No.4, 325-329, 2017.
(Summary)
Exposure to various stressors, including psychological, metabolic, and immune, in the perinatal period induces long-lasting effects in physiological function and increase the risk of metabolic disorders in later life. In the present study, sexual maturation and sexual behavior were assessed in prenatally undernourished mature male rats. All the pregnant rats were divided into the maternal normal nutrition (mNN) group and the maternal undernutrition (mUN) group. The mUN mothers received 50% of the amount of the daily food intake of the mNN mothers. Preputial separation and sexual behavior were observed in randomly selected pups of the mNN and mUN groups. The body weight of the mothers was significantly lighter in the mUN group than in the mNN group. Similarly, the pups in the mUN group showed a significantly lower body weight than those in the mNN group from postnatal day (PND) 1 to PND 15. The preputial separation day was significantly delayed in the mUN group, compared to the mNN group. Sexual behavior did not show any significant difference between the two groups. These findings indicated that prenatal undernutrition delayed sexual maturation, but did not suppress sexual behavior, in mature male rats.
Yuka Taniguchi, Akira Kuwahara, Ayaka Tachibana, Yuya Yano, Kiyohito Yano, Yuri Yamamoto, Mikio Yamasaki, Takeshi Iwasa, Kenji Hinokio, Toshiya Matsuzaki and Minoru Irahara : Intra-follicular kisspeptin levels are related to oocyte maturation and gonadal hormones in patients who are undergoing assisted reproductive technology., Reproductive Medicine and Biology, Vol.16, No.4, 380-385, 2017.
(Summary)
To assess the kisspeptin concentrations in follicular fluid and their relationship with clinical outcomes during assisted reproductive technology. Thirty-nine patients who were aged 24-40 years and underwent oocyte retrieval for in vitro fertilization/intracytoplasmic sperm injection participated in this study In 65 follicular fluid samples that had been obtained from 30 patients and their blood samples, the kisspeptin levels were measured in order to investigate the correlations with their gonadal hormone levels. Venous blood samples were collected from 14 patients to investigate their plasma kisspeptin levels across different phases of assisted reproductive technology. The follicular fluid kisspeptin level was significantly higher than that of the plasma level and was positively associated with the follicular fluid estradiol concentration and with the serum estradiol and number of mature oocytes. In the plasma, the maximum concentration of kisspeptin was observed on the day of ovum pick-up and on the day of embryo transfer during ovarian stimulation for assisted reproductive technology. Kisspeptin was present in the follicular fluid and the plasma kisspeptin concentration was affected by ovarian stimulation. Kisspeptin appears to affect oocyte maturation and ovulation.
Sumika Matsui, Toshiyuki Yasui, Kana Kasai, Kanako Yoshida, Takeshi Katou, Hirokazu Uemura, Akira Kuwahara, Toshiya Matsuzaki and Minoru Irahara : Circulating dehydroepiandrosterone-sulphate decreases even with a slight change in oestradiol., Journal of Obstetrics and Gynaecology, Vol.38, No.2, 231-235, 2017.
(Summary)
The aim of this study was to determine the effect of hormone replacement therapy (HRT) on changes in circulating dehydroepiandrosterone-sulphate (DHEA-S) with focus on the relationship between oestrogen level and change in DHEA-S. Forty-two women were enrolled in this longitudinal study. Nineteen women received oral oestradiol and twenty-three women received transdermal oestradiol continuously. Twenty women received progesterone continuously except for women who had undergone hysterectomy. Circulating oestradiol, follicle-stimulating hormone, luteinising hormone and DHEA-S levels before and at 3 months after commencement of HRT were measured. Circulating DHEA-S level was significantly decreased at 3 months (p < .001). Oestradiol level at 3 months ranged from 6.5 pg/ml to 159 pg/ml. There was no significant correlation of ΔDHEA-S (DHEAS level at 3 months-DHEA-S level at baseline) with Δoestradiol (r = 0.114, p = .471). Circulating DHEA-S level was significantly decreased at 3 months in all the four quartiles and divided according to Δoestradiol, and ΔDHEA-S did not show significant differences. In conclusion, circulating DHEA-S decreases even with a slight increase in oestradiol level. Impact statement What is already known on this subject: A transient increase in DHEA-S in women during the menopausal transition may be involved in the occurrence of menopausal symptoms and/or unfavourable metabolic changes. Hormone replacement therapy decreases circulating DHEA-S level. However, dose dependency of the change in DHEA-S on oestrogen has not been reported. What the results of this study add: Circulating DHEA-S decreases even with a slight increase in oestradiol level. What the implications are of these findings for clinical practice and/or further research: Adrenal function may respond to a small change in oestrogen.
Takeshi Iwasa, Toshiya Matsuzaki, Mayila Yiliyasi, Kiyohito Yano and Minoru Irahara : The effects of chronic testosterone administration on body weight, food intake, and fat weight were age-dependent., Steroids, Vol.127, 18-23, 2017.
(Summary)
Previously, we showed that chronic testosterone administration increased body weight (BW) and food intake (FI), but did not alter fat weight, in young female rats. To examine our hypothesis that the effects of androgens on BW, FI and body composition might be age-dependent, the effects of chronic testosterone administration were evaluated in rats of different ages; i.e., young and middle-aged rats. Although chronic testosterone administration increased BW gain, FI, and feed efficiency in both young and middle-aged rats, it increased visceral fat weight in middle-aged rats, but not in young rats. Therefore, it is possible that testosterone promotes the conversion of energy to adipose tissue and exacerbates fat accumulation in older individuals. In addition, although the administration of testosterone increased the serum leptin level, it did not alter hypothalamic neuropeptide Y mRNA expression in middle-aged rats. On the contrary, the administration of testosterone did not affect the serum leptin levels of young rats. Thus, testosterone might induce hypothalamic leptin resistance, which could lead to fat accumulation in older individuals. Testosterone might disrupt the mechanisms that protect against adiposity and hyperphagia and represent a risk factor for excessive body weight and obesity, especially in older females.
Takeshi Iwasa, Toshiya Matsuzaki, Yiliyasi Mayila, Kiyohito Yano and Minoru Irahara : Developmental changes in hypothalamic SF-1, POMC, and ERα mRNA expression and their sensitivity to fasting in male and female rats., Endocrine Journal, Vol.64, No.12, 1157-1163, 2017.
(Summary)
Estrogen plays pivotal roles in body weight regulation through its effects on central estrogen receptor-α (ERα) expression. ERα is found on neurons that express the hypothalamic anorexigenic factors steroidogenic factor-1 (SF-1) and pro-opiomelanocortin (POMC) mediate these effects of estrogen. As the gonadal hormonal milieu is drastically altered during the developmental period, the expression levels of SF-1 and POMC might also change during this period. In this study, we showed that hypothalamic SF-1 and ERα mRNA expression did not change during the neonatal to pre-pubertal period (from postnatal day 10 to 30), and there were no significant differences in the hypothalamic mRNA expression levels of these molecules between males and females at any examined age. On the other hand, hypothalamic POMC mRNA expression and the serum estradiol (E2) level increased during development in both males and females. Significant positive correlations were detected between the serum E2 level and hypothalamic POMC mRNA expression in both males and females. Hypothalamic ERα and POMC mRNA expression were decreased by fasting in male rats at all examined ages, whereas fasting had no effect on hypothalamic ERα or POMC mRNA expression in the female rats. These results indicate that the regulatory system involving E2 and hypothalamic POMC expression might already be established in the neonatal period and that the roles of POMC and ERα in body weight regulation during development might differ slightly between males and females.
Eri Takiguchi, Masato Nishimura, Ayuka Mineda, Takako Kawakita, Akiko Abe and Minoru Irahara : Growth inhibitory effect of the Src inhibitor dasatinib in combination with anticancer agents on uterine cervical adenocarcinoma cells., Experimental and Therapeutic Medicine, Vol.14, No.5, 4293-4299, 2017.
(Summary)
Uterine cervical adenocarcinoma has a poor clinical prognosis when compared with squamous cell carcinoma. Therefore, the development of new treatment strategies for uterine cervical adenocarcinoma is necessary. Src is a proto-oncogene that is important in cancer progression. Dasatinib is a Src inhibitor that has been reported to be effective when used in combination with anticancer drugs. The present study aimed to confirm Src expression in human cervical adenocarcinoma cell lines and to determine the mechanism underlying the inhibitory effect of dasatinib on Src signaling . Western blot analysis was performed to investigate Src expression in cervical adenocarcinoma cell lines (HeLa and TCO-2 cells). The cells were cultured for 48 h with the addition of different concentrations of anticancer drugs (paclitaxel or oxaliplatin). Viable cell count was measured using a colorimetric (WST-1) assay. The concentrations of anticancer agents were fixed according to the results obtained, and the same experiments were performed using the drugs in combination with dasatinib at various concentrations to determine the concentrations that significantly affected the number of viable cells. The presence or absence of apoptosis was investigated using a caspase-3/7 assay. Signal transduction in each cell line was examined using western blotting. Src was activated in the two cell lines, and cell proliferation was significantly suppressed by each anticancer drug in combination with 10 µM dasatinib. Caspase-3/7 activity was also increased and Src signaling was suppressed by each anticancer drug in combination with dasatinib. In conclusion, Src is overexpressed in cervical adenocarcinoma cell lines, and dasatinib inhibits intracellular Src signaling and causes apoptosis. The results of the present study suggest that Src may be targeted in novel therapeutic strategies for cervical adenocarcinoma.
Minoru Irahara, Tadashi Kimura and Hironori Sugino : Japan Society for Reproductive Medicine RMB Best Paper Award., Reproductive Medicine and Biology, Vol.16, No.3, 239, 2017.
Toshiya Matsuzaki, Tsutomu Douchi, Toshimichi Oki, Osamu Ishihara, Ryugo Okagaki, Takeshi Kajihara, Midori Tamura, Fumikazu Kotsuji, Kimihisa Tajima, Mika Kawano, Bunpei Ishizuka and Minoru Irahara : Weight reduction using a formula diet recovers menstruation in obese patients with an ovulatory disorder., Reproductive Medicine and Biology, Vol.16, No.3, 268-275, 2017.
(Summary)
To determine the effectiveness of a formula diet in weight reduction and the recovery of menstruation in obese patients with ovulatory disorders. After the enrollment of 39 obese women with ovulatory disorders, they replaced one or two of their three normal meals with a microdiet (MD) (240 kcal/meal) for 24 weeks. Physical, endocrinological, and biochemical tests were conducted before and at 12 and 24 weeks of the study. Of the 39 women enrolled, 26 were not taking clomiphene. They were divided into three groups according to their body weight outcomes and then analyzed for menstruation recovery. A weight reduction of ≥5% was observed in 31 (81.5%) of the 39 women. There were significant decreases in the body weight and Body Mass Index during the study. Menstruation returned in 18 (69%) of the 26 patients without clomiphene treatment, with the recovery being significantly more prevalent in the groups (totally 81.0%) that exhibited a 5%-10% weight reduction and ≥10% weight reduction, compared to the group with a <5% weight reduction. The use of a formula diet effectively reduced the patients' body weight and led to the recovery of menstruation in these obese patients with ovulatory disorders.
T Tatsumi, S C. Jwa, Akira Kuwahara, Minoru Irahara, T Kubota and H Saito : Pregnancy and neonatal outcomes following letrozole use in frozen-thawed single embryo transfer cycles., Human Reproduction, Vol.32, No.6, 1244-1248, 2017.
(Summary)
Are pregnancy and neonatal outcomes following letrozole use comparable with natural and HRT cycles in patients undergoing single frozen-thawed embryo transfer (FET)? Letrozole use was significantly associated with higher rates of clinical pregnancy, clinical pregnancy with fetal heart beat and live birth, and with a lower rate of miscarriage, compared with natural and HRT cycles. Letrozole is the most commonly used aromatase inhibitor for mild ovarian stimulation in ART. However, the effect of letrozole on pregnancy and neonatal outcomes in FET are not well known. A retrospective cohort study was conducted using data from the Japanese national ART registry between 2012 and 2013. A total of 110 722 single FET cycles with letrozole (n = 2409), natural (n = 41 470) or HRT cycles (n = 66 843) were included. The main outcomes were the rates of clinical pregnancy, clinical pregnancy with fetal heart beat, miscarriage and live birth. Adjusted odds ratios and relative risks (RRs) were calculated using a generalized estimating equation adjusting for correlations within clinics. The rates of clinical pregnancy, clinical pregnancy with fetal heart beat, and live birth were significantly higher, while the rate of miscarriage was significantly lower in the letrozole group compared with the natural and HRT groups. In blastocyst stage transfers, the adjusted RRs for clinical pregnancy with fetal heart beat of letrozole compared with natural and HRT cycles were 1.48 (95% CI: 1.41-1.55) and 1.62 (95% CI: 1.54-1.70), respectively. Similarly, the adjusted RRs of letrozole for miscarriage compared with natural and HRT cycles were 0.91 (95% CI: 0.88-0.93) and 0.84 (95% CI: 0.82-0.87), respectively. Neonatal outcomes were mostly similar in letrozole, natural and HRT cycles. Important limitations of this study included the lack of information concerning the reasons for selecting the specific FET method, parity, the number of previous ART failures, embryo quality and the dose and duration of letrozole intake. These results suggest that letrozole use may improve clinical pregnancy, clinical pregnancy with fetal heart beat, and live births and reduce the risk of miscarriage in patients undergoing single FET cycles. No external funding was used for this study. There are no conflicts of interest. Not applicable.
Mikio Yamasaki, Akira Kuwahara, Takeshi Iwasa, Yuri Yamamoto, Yuka Taniguchi, Yuya Yano, Sumika Matsui, Toshiya Matsuzaki and Minoru Irahara : Development-related changes in the expression of the ovarian Kiss1 and Kiss1r genes and their sensitivity to human chorionic gonadotropin in prepubertal female rats., The Journal of Reproduction and Development, Vol.63, No.4, 409-414, 2017.
(Summary)
Kisspeptin, which is encoded by the Kiss1 gene, and its receptor, the G protein-coupled receptor 54 (Kiss1r), play important roles in the regulation of reproductive functions in mammals. Several studies have shown that the Kiss1 and Kiss1r genes are expressed in the rat, primate, and human ovaries, and that the ovarian kisspeptin system plays a pivotal role in ovulation at the proestrous stage in adulthood. The purpose of this study was to evaluate development-related changes in the expression of ovarian Kiss1 and Kiss1r genes and in kisspeptin levels, and to identify the regulatory factors for these genes during the prepubertal period. The serum kisspeptin level was also measured to examine whether ovarian kisspeptin affects serum kisspeptin levels. Variations in the ovarian Kiss1 and Kiss1r mRNA levels were observed during the prepubertal period in female rats, with levels peaking around postnatal days 20 and 15, respectively. Nevertheless, the ovarian kisspeptin content per total protein level was stably maintained. Serum kisspeptin levels at postnatal days 30 and 35 were higher than those at earlier postnatal days. The pattern of the ovarian Kiss1 mRNA levels was similar to that of the serum luteinizing hormone (LH) levels, and the ovarian Kiss1 mRNA level increased after injection with human chorionic gonadotropin (HCG) on postnatal day 20, but not on postnatal days 10 and 30. These data indicate that ovarian Kiss1 and Kiss1r mRNA levels are increased on postnatal days 20 and 15, respectively, and that changes in the serum LH level and the ovarian sensitivity to LH may be involved in the alteration of ovarian Kiss1 mRNA levels.
Takeshi Iwasa, Toshiya Matsuzaki, Kiyohito Yano, Rie Yanagihara, Altankhuu Tungalagsuvd, Munkhsaikhan Munkhzaya, Yiliyasi Mayila, Akira Kuwahara and Minoru Irahara : The effects of chronic testosterone administration on body weight, food intake, and adipose tissue are changed by estrogen treatment in female rats., Hormones and Behavior, Vol.93, 53-61, 2017.
(Summary)
In females, estrogens play pivotal roles in preventing excess body weight (BW) gain. On the other hand, the roles of androgens in female BW, appetite, and energy metabolism have not been fully examined. We hypothesized that androgens' effects on food intake (FI) and BW regulation change according to the estrogens' levels. To evaluate this hypothesis, the effects of chronic testosterone administration in ovariectomized (OVX) female rats with or without estradiol supplementation were examined in this study. Chronic testosterone administration decreased BW, FI, white adipose tissue (WAT) weight, and adipocyte size in OVX rats, whereas it increased BW, WAT weight, and adipocyte size in OVX with estradiol-administered rats. In addition, chronic testosterone administration increased hypothalamic CYP19a1 mRNA levels in OVX rats, whereas it did not alter CYP19a1 mRNA levels in OVX with estradiol-administered rats, indicating that conversion of testosterone to estrogens in the hypothalamus may be activated in testosterone-administered OVX rats. Furthermore, chronic testosterone administration decreased hypothalamic TNF-α mRNA levels in OVX rats, whereas it increased hypothalamic IL-1β mRNA levels in OVX with estradiol-administered rats. On the other hand, IL-1β and TNF-α mRNA levels in visceral and subcutaneous WAT and liver were not changed by chronic testosterone administration in both groups. These data indicate that the effects of chronic testosterone administration on BW, FI, WAT weight, and adipocyte size were changed by estradiol treatment in female rats. Testosterone has facilitative effects on BW gain, FI, and adiposity under the estradiol-supplemented condition, whereas it has inhibitory effects in the non-supplemented condition. Differences in the responses of hypothalamic factors, such as aromatase and inflammatory cytokines, to testosterone might underlie these opposite effects.
Takako Kawakita, Masato Nishimura, Eri Takiguchi, Akiko Abe and Minoru Irahara : Cytotoxic effects of 15-deoxy-Δ12,14-prostaglandin J2 alone and in combination with dasatinib against uterine sarcoma ., Experimental and Therapeutic Medicine, Vol.13, No.6, 2939-2945, 2017.
(Summary)
Effective chemotherapeutic strategies for uterine sarcoma are lacking; existing therapies achieve poor response rates. Previous studies have identified the prostaglandin 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) as a potential anticancer treatment; however, its effectiveness in uterine sarcoma has not been examined. Furthermore, the molecular mechanisms underlying the cytotoxic mechanism of 15d-PGJ2 remain unclear. Here, we evaluated the effects of 15d-PGJ2 alone and in combination with the tyrosine kinas inhibitor (TKI) dasatinib in uterine sarcoma cell lines (MES-SA, MES-SA/DX5 and SKN). 15d-PGJ2 inhibited cell growth and increased apoptosis. Western blotting demonstrated that 15d-PGJ2 treatment increased MEK and ERK phosphorylation, and decreased levels of phosphorylated AKT. Dasatinib in combination with 15d-PGJ2 significantly reduced cell proliferation compared with 15d-PGJ2 alone, and repressed both the AKT and MAPK pathways. The cell growth inhibition rate in the PGJ2 was 21.5±12.0, 35.3±5.4 and 28.3±4.2%, respectively (MES-SA, MES-SA/DX5 and SKN cell lines) and the cell growth inhibition rate in the combination therapy was significantly higher compared with 15d-PGJ2 alone (MES-SA; 64.2±0.8, MES-SA/DX5;23.9±8.2 and SKN; 41.4±17.6%). The PGJ2 IC determined by MTT assay was 27.41,10.46 and 17.38 µmol/l, respectively (MES-SA, MES-SA/DX5 and SKN cell lines) and the dasatinib IC was 6.68,17.30 and 6.25 µmol/l, respectively. Our findings demonstrate that 15d-PGJ2 suppresses proliferation by inactivating the AKT pathway in uterine sarcoma. Furthermore, combining 15d-PGJ2 with dasatinib produced a synergistic effect on cancer cell inhibition by repressing 15d-PGJ2-mediated activation of MAPK signaling, and further repressing AKT signaling. These results suggest that 15d-PGJ2 could be used in combination with dasatinib as a potential therapeutic approach for uterine sarcoma.
Minoru Irahara, Akira Kuwahara, Takeshi Iwasa, Tomonori Ishikawa, Osamu Ishihara, Koji Kugu, Rintaro Sawa, Kouji Banno and Hidekazu Saito : Assisted reproductive technology in Japan: a summary report of 1992-2014 by the Ethics Committee, Japan Society of Obstetrics and Gynecology., Reproductive Medicine and Biology, Vol.16, No.2, 126-132, 2017.
(Summary)
The Japan Society of Obstetrics and Gynecology implemented a registry report system for the clinical practice of assisted reproductive technology in 1986. The aggregated results from 1992 to 2014 are reported herein. The total number of registered treatments was 393 745 cycles, of which 66 550 were pregnancy cycles and 46 008 were cycles with a live birth. Compared to the number of registered treatments in 2008, when the cycle-based registry was newly introduced, there was a 2.07-fold increase in the total number of treatments and a 2.25-fold increase in the number of cycles with a live birth. As the average age of patients who receive assisted reproductive technology has become markedly higher year by year, the most common age of those patients who received assisted reproductive technology in 2014 was 40 years. The total numbers of both assisted reproductive technology treatments and assisted reproductive technology live births are likely to be higher in the future. In addition, the trend toward aging patients seems to be continuing into the future.
Takeshi Iwasa, Toshiya Matsuzaki, Kiyohito Yano and Minoru Irahara : Gonadotropin-Inhibitory Hormone Plays Roles in Stress-Induced Reproductive Dysfunction., Frontiers in Endocrinology, Vol.8, 62, 2017.
(Summary)
Physical and psychological stressors suppress hypothalamic-pituitary-gonadal axis activity and sexual behavior and consequently induce reproductive dysfunction. Recently, it has been shown that gonadotropin-inhibitory hormone (GnIH), also called RFamide-related peptide 3 (RFRP) in mammals, which is a potent inhibitory regulator of gonadotropin-releasing hormone (GnRH) and gonadotropin, is involved in stress-induced reproductive dysfunction. GnIH/Rfrp (the gene coding RFRP-3) expression and activity are increased by psychological and immune stress, and this alteration suppresses GnRH and gonadotropin secretion. Glucocorticoid acts as a mediator that interacts between stress and hypothalamic GnIH/RFRP-3. GnIH/RFRP-3 also plays important roles in stress-induced suppression of sexual behavior and infertility, and genetic silencing of GnIH/Rfrp completely recovers sexual behavior and fertility. This review summarizes what is currently known about the roles of GnIH in stress-induced reproductive dysfunction.
Toshiya Matsuzaki, Altankhuu Tungalagsuvd, Takeshi Iwasa, Munkhsaikhan Munkhzaya, Kiyohito Yano, Yiliyasi Mayila, Takako Tokui, Rie Yanagihara, Sumika Matsui, Takeshi Katou, Akira Kuwahara and Minoru Irahara : Clinical outcome of various metformin treatments for women with polycystic ovary syndrome., Reproductive Medicine and Biology, Vol.16, No.2, 179-187, 2017.
(Summary)
Polycystic ovary syndrome (PCOS) is an ovulatory disorder and insulin resistance and diabetes are involved in its pathophysiology. Metformin, an anti-diabetic agent, has been reported to be useful to induce ovulation. Metformin treatment was classified into four types: (1) clomiphene-metformin combination treatment for clomiphene-resistant patients; (2) clomiphene-metformin combination for clomiphene-sensitive patients; (3) clomiphene-metformin combination for naïve patients; and (4) metformin monotherapy. The patients underwent physical, endocrinological, and clinical examinations for their ovulation rates, pregnancy rates, and follicular development. The ovulation rates, pregnancy rates, and single follicular development were not significantly different among the clomiphene-metformin combination treatment groups. In the Body Mass Index (BMI) subanalysis, the pregnancy rate was higher in the BMI≥30 kg/m group than in the other three groups with a BMI of ≤30 kg/m in both cycles and cases. The ovulation rates and pregnancy rates were significantly higher in the group with a fasting insulin of ≥15 μU/mL than in the groups with a fasting insulin of <15 μU/mL in both cycles and cases. Clomiphene-metformin combination treatment appears to be useful, at least for clomiphene-resistant patients, and a BMI of >30 kg/m and a fasting insulin of ≥15 μU/mL appear to be predictors of a good result with this treatment.
Polycystic ovary syndrome (PCOS) is an ovulatory disorder that affects 6-10% of women of reproductive age. Serum AMH level may be an additional factor, or surrogate of PCOM, in the diagnostic criteria of PCOS. We evaluated the correlations between the serum AMH level and various endocrine and metabolic features in PCOS using the latest fully automated assay. Serum AMH level was compared between 114 PCOS patient (PCOS group) and 95 normal menstrual cycle women (Control group). Correlations between serum AMH level and various endocrine and metabolic factors were analysed in PCOS group. The serum AMH level was significantly higher in the PCOS group (8.35±8.19 ng/mL) than in the Control group (4.99±3.23 ng/mL). The serum AMH level was independently affected by age and the presence of PCOS on multiple regression analysis. Ovarian volume per ovary (OPVO) showed the strongest positive correlation (r=0.62) with the serum AMH level among related factors. On receiver operating characteristic (ROC) curve analysis, the cut-off value of AMH for the diagnosis of PCOS was 7.33 ng/mL, but this value did not have high efficacy (sensitivity 44.7%, specificity 76.8%). A cut-off value of 10 ng/mL had a high specificity of 92.6%, although the sensitivity was low (24.6%). The serum AMH level was elevated and reflected ovarian size in PCOS patients. The serum AMH level could be a surrogate for ultrasound findings of the ovaries in PCOS and might be useful for estimating ovarian findings without transvaginal ultrasound in the diagnosis of PCOS.
(Keyword)
Adolescent / Adult / Age Factors / Anti-Mullerian Hormone / Female / Humans / Organ Size / Ovary / Polycystic Ovary Syndrome / Sensitivity and Specificity / Ultrasonography / Young Adult
Sumika Matsui, Toshiyuki Yasui, Kana Kasai, Kaoru Keyama, Kanako Yoshida, Takeshi Katou, Hirokazu Uemura, Akira Kuwahara, Toshiya Matsuzaki and Minoru Irahara : Sex hormone-binding globulin and antithrombin III activity in women with oral ultra-low-dose estradiol., Journal of Obstetrics and Gynaecology, Vol.37, No.5, 627-632, 2017.
(Summary)
Oral oestrogen increases the risk of venous thromboembolism (VTE) and increases production of sex hormone-binding globulin (SHBG) in a dose-dependent manner. SHBG has been suggested to be involved in venous thromboembolism. We examined the effects of oral ultra-low-dose oestradiol on circulating levels of SHBG and coagulation parameters, and we compared the effects to those of transdermal oestradiol. Twenty women received oral oestradiol (500 g) every day (oral ultra-low-dose group) and 20 women received a transdermal patch (50 g) as a transdermal group. In addition, the women received dydrogesterone continuously (5g) except for women who underwent hysterectomy. Circulating SHBG, antithrombin III (ATIII) activity, d-dimer, thrombin-antithrombin complex and plasmin- 2 plasmin inhibitor complex were measured before and 3 months after the start of treatment. SHBG was significantly increased at 3 months in the oral ultra-low-dose group, but not in the transdermal group. However, percent changes in SHBG were not significantly different between the two groups. In both groups, ATIII was significantly decreased at 3 months. In conclusion, even ultra-low-dose oestradiol orally increases circulating SHBG level. However, the magnitude of change in SHBG caused by oral ultra-low-dose oestradiol is small and is comparable to that caused by transdermal oestradiol. Impact statement Oral oestrogen replacement therapy increases production of SHBG which may be related to increase in VTE risk. However, the effect of oral ultra-low-dose oestradiol on SHBG has not been clarified. Even ultra-low-dose oestradiol orally increases circulating SHBG levels, but the magnitude of change in SHBG caused by oral ultra-low-dose oestradiol is small and is comparable to that caused by transdermal oestradiol. VTE risk in women receiving oral ultra-low-dose oestradiol may be comparable to that in women receiving transdermal oestradiol.
Takeshi Iwasa, Toshiya Matsuzaki, Kiyohito Yano, Altankhuu Tungalagsuvd, Munkhsaikhan Munkhzaya, Yiliyasi Mayila, Akira Kuwahara and Minoru Irahara : The effects of prenatal undernutrition and a high-fat postnatal diet on central and peripheral orexigenic and anorexigenic factors in female rats., Endocrine Journal, Vol.64, No.6, 597-604, 2017.
(Summary)
Prenatal undernutrition and postnatal overnutrition increase the risk of some peripheral and central metabolic disorders in adulthood. We speculated that disturbances of appetite/metabolic regulatory factors might already have been established in the early stages of life and contribute to obesity later in life. The effects of a high-fat diet on the levels of peripheral and central appetite/metabolic regulatory factors were compared between the offspring of normally nourished dams and those of undernourished dams in the peri-pubertal period. In the offspring of the normally nourished dams (control), the consumption of the high-fat diet resulted in lower hypothalamic mRNA levels of orexigenic factors (neuropeptide Y (NPY) and prepro-orexin (pporexin)), whereas no such changes were seen in the offspring of the undernourished dams (subjected to intrauterine growth restriction). These results indicate that in high-energy conditions either the adaptive response does not function properly or has not been established in the offspring of undernourished dams. Because NPY and pporexin are negatively regulated by leptin, these findings suggest that in the intrauterine growth restriction group, the leptin resistance of hypothalamic functions, which is usually caused by diet-induced obesity in adulthood, had already been established in the peri-pubertal period.
Yuu Tanaka, Akira Kuwahara, Kenjiro Ushigoe, Yuya Yano, Yuka Taniguchi, Yuri Yamamoto, Toshiya Matsuzaki, Toshiyuki Yasui and Minoru Irahara : Expression of cytokine-induced neutrophil chemoattractant suppresses tumor necrosis factor alpha expression and thereby prevents the follicles from undergoing atresia and apoptosis., Reproductive Medicine and Biology, Vol.16, No.2, 157-165, 2017.
(Summary)
Cytokine-induced neutrophil chemoattractant (CINC/gro) is a CXC family chemokine, similar to interleukin-8 in rats, and is one of the factors that regulates ovulation. However, the mechanism that regulates atresia of the ovaries postovulation is not clearly defined. Whether antibody-blocking of CINC/gro can alter the number of ovulated oocytes and modulate neutrophil infiltration was investigated. The effect of the antibody on the level of inflammatory cytokine production and follicular atresia was examined. Apoptosis was measured by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method and via analysis of the messenger RNA expression of Bcl-2 and Bcl2-associated X (Bax). The anti-CINC/gro antibody treatment decreased the number of ovulated oocytes. The messenger RNA levels of cyclooxygenase-2 and interleukin-1 beta were decreased by the antibody treatment, whereas that of tumor necrosis factor (TNF) alpha was increased. The TUNEL analysis revealed a larger number of apoptotic cells in the antibody group, compared with those in the control group, as well as a significant increase in the Bax/Bcl-2 ratio 24 hours after human chorionic gonadotropin administration. These findings suggest that ovulation is accelerated by neutrophil infiltration into the theca layer. The CINC/gro appears to synergize with interleukin-1 beta for ovulation. By contrast, the data suggest that CINC/gro expression suppresses TNF alpha expression and that CINC/gro expression therefore prevents the follicles from undergoing atresia and apoptosis.
Mikio Sugano, Homare Yoshida, Hirotsugu Kurobe, Hiroki Arase, Hajime Kinoshita, Takashi Kitaichi, Noriko Sugasawa, Soichiro Nakayama, Kazuhisa Maeda, Minoru Irahara and Tetsuya Kitagawa : Effects of Transplanted Human Cord Blood- Mononuclear Cells on Pulmonary Hypertension in Immunodeficient Mice and Their Distribution., The Journal of Medical Investigation : JMI, Vol.64, No.1,2, 43-49, 2017.
(Summary)
To investigate the effects of human umbilical cord blood-derived mononuclear cell (hUCB-MNC) transplantation on pulmonary hypertension (PH) induced by monocrotaline (MCT) in immunodeficient mice and their distribution. MCT was administered to BALB/c Slc-nu/nu mice, and PH was induced in mice 4 weeks later. Fresh hUCB-MNCs harvested from a human donor after her delivery were injected intravenously into those PH mice. The medial thickness of pulmonary arterioles, ratio of right ventricular to septum plus left ventricular weight (RV/S+LV), and ratio of acceleration time to ejection time of pulmonary blood flow waveform (AT/ET) were determined 4 weeks after hUCB-MNC transplantation. To reveal the incorporation into the lung, CMTMR-labeled hUCB-MNCs were observed in the lung by fluorescent microscopy. DiR-labeled hUCB-MNCs were detected in the lung and other organs by bioluminescence images. Medial thickness, RV/S+LV and AT/ET were significantly improved 4 weeks after hUCB-MNC transplantation compared with those in mice without hUCB-MNC transplantation. CMTMR-positive hUCB-MNCs were observed in the lung 3 hours after transplantation. Bioluminescence signals were detected more strongly in the lung than in other organs for 24 hours after transplantation. The results indicate that hUCB-MNCs are incorporated into the lung early after hUCB-MNC transplantation and improve MCT-induced PH. J. Med. Invest. 64: 43-49, February, 2017.
Takashi Kaji, Yasunobu Hayabuchi, Kazuhisa Maeda, Soichiro Nakayama and Minoru Irahara : Prenatal assessment of coronary artery anatomy using color Doppler in cases of D-transposition of the great arteries: Case reports, The Journal of Obstetrics and Gynaecology Research, Vol.43, No.2, 397-402, 2017.
(Summary)
Abnormal coronary artery (CA) anatomy is common in cases of D-transposition of the great arteries (TGA) and can be a significant risk factor during the arterial switch operation. Here, we report three cases of TGA in which CA anatomy was assessed prenatally using color Doppler imaging. All CA, except the left circumflex CA in one case, were identified. CA anatomy was completely correctly diagnosed in one of our three cases. In the two remaining cases, the left circumflex CA could not be visualized in one patient, and the origin of the left anterior descending CA was not correctly diagnosed in the other. We found that prenatal assessment of CA anatomy using color Doppler in TGA was feasible, but the diagnostic accuracy was limited. We anticipate that more experience with the advancing technology will improve accuracy.
Kazuhisa Maeda, Takashi Kaji, Souichiro Nakayama, Daichi Nakaoku, M Murakami, A Kondo, M Morine, Kenji Hinokio and Minoru Irahara : Pregnancies with factor V deficiency: a case report and review of the literature., Clinical and Experimental Obstetrics & Gynecology, Vol.44, No.2, 299-300, 2017.
(Summary)
A 30-year-old Japanese nulliparous woman visited for pregnancy at 33 weeks with a massive ovarian tumor located in the pouch of Douglas. By preoperative screening, her prothrombin time (PT) and activated partial thromboplastin time (APTT) were prolonged, and her FV activity was significantly decreased to 4.8%. After prophylactic FFP 20 ml/kg was administered and her FV factor was 19.3%, cesarean delivery was performed, and her perioperative course was uneventful. One year later, she underwent a dilatation and evacuation because of a missed abortion, although prophylactic FFP was not administered. During a third pregnancy, after prophylactic FFP 20 ml/kg was administered and FV activity increased to 21.1%, elective cesarean delivery was performed, and her postoperative course was uneventful. For surgical therapy or delivery, the goal of therapy is to maintain FV activity above 20%. It is particularly useful to administer prophylactic FFP.
T Tatsumi, S C. Jwa, Akira Kuwahara, Minoru Irahara, T Kubota and H Saito : No increased risk of major congenital anomalies or adverse pregnancy or neonatal outcomes following letrozole use in assisted reproductive technology., Human Reproduction, Vol.32, No.1, 125-132, 2016.
(Summary)
Does letrozole use increase the risk of major congenital anomalies and adverse pregnancy and neonatal outcomes in fresh, single-embryo transfer? Letrozole significantly decreases the risk of miscarriage and does not increase the risk of major congenital anomalies or adverse pregnancy or neonatal outcomes compared with natural cycles in patients undergoing ART. Letrozole is the most commonly used aromatase inhibitor for mild ovarian stimulation in ART. However, its safety in terms of pregnancy and neonatal outcomes is unclear. This retrospective cohort study used data from the Japanese national ART registry from 2011 to 2013. A total of 3136 natural cycles and 792 letrozole-induced cycles associated with fresh, single-embryo transfer and resulting in a clinical pregnancy were included in the analysis. The main pregnancy outcomes were miscarriage, ectopic pregnancy and still birth, and the neonatal outcomes were preterm delivery, low birth weight, small/large for gestational age and major congenital anomalies. Terminated pregnancies were included in the analysis of major congenital anomalies. Odds ratios (ORs) and 95% CIs were calculated using multivariate logistic regression analysis adjusted for maternal age and calendar year. The risk of miscarriage was significantly lower in women administered letrozole (adjusted OR [aOR], 0.37, 95% CI, 0.30-0.47, P < 0.001). There was no significant difference in the overall risk of major congenital anomalies between the two groups (natural cycle 1.5% vs letrozole 1.9%, aOR, 1.24, 95% CI, 0.64-2.40, P = 0.52), and no increased risk for any specific organ system. Subgroup analysis demonstrated that the risk of major congenital anomalies was not increased in patients who underwent either in vitro fertilization or ICSI, or in those who received early cleavage stage or blastocyst embryo transfer. All other pregnancy and neonatal outcomes were comparable between the two groups. Despite the large sample size, we were only able to rule out the possibility that letrozole might cause large increases in birth-defect risks in ART patients. The results suggest that letrozole stimulation reduces the risk of miscarriage, with no increase in the risk of major congenital anomalies or adverse pregnancy or neonatal outcomes compared with natural cycles in women undergoing ART. Letrozole may thus be a safe option for mild ovarian stimulation. None. Not applicable.
Toshiya Matsuzaki, Altankhuu Tungalagsuvd, Takeshi Iwasa, Munkhsaikhan Munkhzaya, Rie Yanagihara, Takako Tokui, Kiyohito Yano, Yiliyasi Mayila, Takeshi Katou, Akira Kuwahara, Sumika Matsui and Minoru Irahara : Kisspeptin mRNA expression is increased in the posterior hypothalamus in the rat model of polycystic ovary syndrome., Endocrine Journal, Vol.64, No.1, 7-14, 2016.
(Summary)
Hypersecretion of luteinizing hormone (LH) is a common endocrinological finding of polycystic ovary syndrome (PCOS). This derangement might have a close relationship with hypothalamic kisspeptin expression that is thought to be a key regulator of gonadotropin-releasing hormone (GnRH). We evaluated the relationship between the hypothalamic-pituitary-gonadal axis (HPG axis) and kisspeptin using a rat model of PCOS induced by letrozole. Letrozole pellets (0.4 mg/day) and control pellets were placed subcutaneously onto the backs of 3-week-old female Wistar rats. Body weight, vaginal opening and vaginal smear were checked daily. Blood and tissues of ovary, uterus and brain were collected at 12-weeks of age. An hypothalamic block was cut into anterior and posterior blocks, which included the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC), respectively, in order to estimate hypothalamic kisspeptin expression in each area. The letrozole group showed a similar phenotype to human PCOS such as heavier body weight, heavier ovary, persistent anovulatory state, multiple enlarged follicles with no corpus luteum and higher LH and testosterone (T) levels compared to the control group. Kisspeptin mRNA expression in the posterior hypothalamic block including ARC was higher in the letrozole group than in the control group although its expression in the anterior hypothalamic block was similar between groups. These results suggest that enhanced KNDy neuron activity in ARC contributes to hypersecretion of LH in PCOS and might be a therapeutic target to rescue ovulatory disorder of PCOS in the future.
Junpei Yamamoto, Midori Omura, Koichiro Tuchiya, Mayumi Hidaka, Akira Kuwahara, Minoru Irahara, Tamotsu Tanaka and Akira Tokumura : Preferable existence of polyunsaturated lysophosphatidic acids in human follicular fluid from patients programmed with in vitro fertilization., Prostaglandins & Other Lipid Mediators, Vol.126, 16-23, 2016.
(Summary)
Lysophosphatidic acid (LPA) exerts diverse physiological effects on various types of animal cells, including reproductive cells, through its binding to six LPA receptors. We previously found that LPA promoted maturation of the nucleus and cytoplasm of mouse and hamster oocytes surrounded by cumulus cells in vitro. Using gas-liquid chromatography, we previously reported detection of several species of LPA by analyzing the fatty acid methyl esters derived from thin layer chromatography-purified LPA in lipid extract from incubated follicular fluids programmed with in vitro fertilization. In this study using liquid chromatography- tandem mass spectrometry, we directly detected high levels of linoleoyl, arachidonoyl, and docosahexaenoyl LPAs in human follicular fluid. This unique molecular species composition of LPA was suggested to be due to a balance between the low LPA-degrading activity and high LPA-producing activity of autotaxin in human follicular fluid. Our results suggest that polyunsaturated LPAs produced by autotaxin in human follicular fluid exert unknown physiological effects on cumulus cells.
Takeshi Iwasa, Toshiya Matsuzaki, Altankhuu Tungalagsuvd, Munkhsaikhan Munkhzaya, Maira Yiliyasi, Takeshi Katou, Akira Kuwahara and Minoru Irahara : Developmental changes in the hypothalamic mRNA expression levels of PACAP and its receptor PAC1 and their sensitivity to fasting in male and female rats., International Journal of Developmental Neuroscience, Vol.52, 33-37, 2016.
(Summary)
The actions and responses of hypothalamic appetite regulatory and factors change markedly during the neonatal to pre-pubertal period. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been found to play pivotal roles in the regulation of metabolic and nutritional status through its specific receptor PAC1. PACAP/PAC1 have anorectic roles, and their functions are regulated by leptin in adulthood. In the present study, we showed that hypothalamic PACAP mRNA expression decreases during the neonatal to pre-pubertal period (from postnatal day 10-30) in both male and female rats. During this period, hypothalamic PACAP mRNA expression was not affected by 24h fasting in either sex, while the serum leptin levels (leptin is a positive regulator of hypothalamic PACAP expression in adulthood) of both sexes were decreased by fasting. On the other hand, hypothalamic PAC1 mRNA expression did not change during the neonatal to pre-pubertal period in either sex; however, its levels were consistently higher in males than in females. Hypothalamic PAC1 mRNA expression was decreased by 24h fasting in males, but no such changes were observed in females. These results indicate while hypothalamic PACAP expression is sensitive to a negative energy state and the serum leptin level in adulthood, no such relationships are seen in the pre-pubertal period. In addition, we speculate that differences in the gonadal steroidal milieu might induce sexual dimorphism in the basal hypothalamic PAC1 mRNA level and its response to fasting. The mechanisms responsible for and the physiological effects of such changes in hypothalamic PACAP and PAC1 expression during the developmental period remain to be clarified.
(Keyword)
Age Factors / Analysis of Variance / Animals / Animals, Newborn / Fasting / Female / Gene Expression Regulation, Developmental / Hypothalamus / Leptin / Male / Pituitary Adenylate Cyclase-Activating Polypeptide / Pregnancy / RNA, Messenger / Rats / Rats, Sprague-Dawley / Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Sex Characteristics
Sumika Matsui, Toshiyuki Yasui, Kana Kasai, Kaoru Keyama, Takeshi Katou, Hirokazu Uemura, Akira Kuwahara, Toshiya Matsuzaki and Minoru Irahara : Changes of liver enzymes and triglyceride during the menopausal transition in Japanese women., Journal of Obstetrics and Gynaecology, Vol.36, No.6, 806-811, 2016.
(Summary)
We examined detailed changes in liver enzymes as surrogate markers for metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) during the menopausal transition and the associations of liver enzymes with lipid profiles related to risk of metabolic syndrome and endocrinological hormones. We divided 393 women into seven stages by menstrual regularity, follicle-stimulating hormone level and years since menopause. Serum levels of alanine aminotranferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase, lipid parameters, glucose, and endocrinological hormones were measured. Both levels of AST and ALT increased towards early post-menopause. AST remained high in late post-menopause but ALT decreased. The AST/ALT ratio decreased towards late menopausal transition and very early post-menopause and increased thereafter. This ratio was negatively correlated with triglyceride. Significant changes in ALT and AST/ALT ratio during the menopausal transition, which were associated with triglyceride, might be involved in the occurrence of metabolic syndrome and NAFLD in Japanese women.
Takashi Kaji, Kazuhisa Maeda, A Hichijo, Y Takahashi, S Nakayama and Minoru Irahara : Three-dimensional HDlive rendering of fetal perineum in anorectal atresia., Ultrasound in Obstetrics & Gynecology, Vol.47, No.6, 784-785, 2016.
Altankhuu Tungalagsuvd, Toshiya Matsuzaki, Takeshi Iwasa, Munkhsaikhan Munkhzaya, Mayila Yiliyasi, Takako Kawami, Takeshi Katou, Akira Kuwahara and Minoru Irahara : The expression of orexigenic and anorexigenic factors in middle-aged female rats that had been subjected to prenatal undernutrition., International Journal of Developmental Neuroscience, Vol.49, 1-5, 2016.
(Summary)
Fetal growth retardation, which affects short- and long-term fetal brain development, is associated with metabolic, hematological, and thermal disturbances, which can increase the risk of metabolic syndrome later in life. Orexigenic and anorexigenic factors regulate food intake and energy expenditure. We studied how the expression of these factors was affected by food deprivation (FD) in middle-aged female rats that had been subjected to prenatal undernutrition. Eight pregnant rats were divided into two groups, the normal nutrition (NN) (n=4) group and the undernutrition (UN) (n=4) group, which received 50% (approximately 11g) of the daily food intake of the normal nutrition rats from day 13 of pregnancy to delivery. The pups from these dams were defined as the maternal NN (mNN) and maternal UN (mUN) groups, respectively. After weaning, all of the pups were housed and allowed ad libitum access to food and water. At the age of 6 months, both groups of pups were sub-divided into three groups. One group was allowed to consume normal amounts of food (Fed), and the other two groups were subjected to 24h or 48h FD (n=7-8 per group). The rats' serum leptin levels and hypothalamic mRNA expression levels of various orexigenic or anorexigenic factors were measured. In both the mNN and mUN rats, the serum leptin levels of the 24h and 48h FD groups tended to be lower than those of the Fed group, and the serum leptin levels of the 24h FD mUN rats and the Fed mUN rats differed significantly. The hypothalamic neuropeptide Y (NPY) mRNA expression levels of the 24h and 48h FD groups were significantly higher in the mUN rats than in the mNN rats. In addition, among the mUN rats the hypothalamic NPY mRNA expression levels of the 48h FD group were significantly higher than those of the Fed group. In both the mNN and mUN rats, prepro-orexin mRNA expression was lower in the 48h FD group than in the corresponding Fed group. Among the mUN rats, the 48h FD group exhibited significantly lower hypothalamic proopiomelanocortin (POMC) mRNA expression than the Fed group, and a similar tendency was seen among the mNN rats. Among the mNN rats, the 24h FD group displayed significantly higher hypothalamic leptin receptor (OBRb) mRNA levels than the Fed group. However, no such differences were seen among the mUN rats. As a result, the hypothalamic OBRb mRNA expression levels of the mUN rats in the 24h and 48h FD groups were lower than those of the corresponding mNN rat groups. These findings indicate that rats that are subjected to prenatal undernutrition exhibit upregulated expression of orexigenic factors and are more sensitive to FD in middle age, which might increase their risk of developing metabolic disorders in later life.
Kazuki Saito, Toshiya Matsuzaki, Takeshi Iwasa, Mami Miyado, Hidekazu Saito, Tomonobu Hasegawa, Keiko Homma, Eisuke Inoue, Yoshimichi Miyashiro, Toshiro Kubota, Minoru Irahara, Tsutomu Ogata and Maki Fukami : Steroidogenic pathways involved in androgen biosynthesis in eumenorrheic women and patients with polycystic ovary syndrome., The Journal of Steroid Biochemistry and Molecular Biology, Vol.158, 31-37, 2016.
(Summary)
The conventional Δ5 and Δ4 steroidogenic pathways mediate androgen production in females. While multiple non-conventional pathways to dihydrotestosterone (DHT) have recently been postulated in humans, the functional significance of these pathways remains to be elucidated. The aim of this study was to clarify the origin of androgens in healthy women and in patients with polycystic ovary syndrome (PCOS), a multifactorial disorder characterized by androgen overproduction. We measured 13 steroids in blood samples of 31 eumenorrheic females and 28 PCOS patients using liquid chromatography-tandem mass spectrometry and chemiluminescent enzyme immunoassay. We found that 17-hydroxy (17-OH) progesterone (17-OHP), androstenedione (Δ4A), testosterone, androstanedione, androsterone, and androstanediol levels were higher in the patient group than in the eumenorrheic group, while levels of other steroids were comparable between the two groups. In the eumenorrheic group, DHT levels were correlated with testosterone, androstanedione, and androstanediol. Quantitative correlations were also observed among 17-OH allopregnanolone, androsterone, androstanediol, and DHT, and among Δ4A, androstanedione, androsterone, and androstanediol. In the patient group, DHT levels were correlated with testosterone levels, but not with androstanedione or androstanediol levels. Δ4A and testosterone paralleled 17-OHP. Androstanedione, androsterone, androstanediol, and 17-OH allopregnanolone were quantitatively correlated. In both groups, multivariable linear regression analyses suggested relationships between androsterone and androstanedione, as well as between androsterone and 17-OH allopregnanolone. These results indicate that multiple androgen biosynthesis pathways are operating in eumenorrheic females and PCOS patients. In PCOS patients, excessive androgens are produced primarily via the conventional pathways, while two alternative pathways; i.e., an androstanedione-mediated pathway and a so-called backdoor pathway, likely serve as sources of a weak androgen and potential precursors of DHT.
(Keyword)
Adult / Androgens / Chromatography, High Pressure Liquid / Female / Hormones / Humans / Polycystic Ovary Syndrome / Spectrometry, Mass, Electrospray Ionization / Tandem Mass Spectrometry / Young Adult
Takeshi Iwasa, Toshiya Matsuzaki, Altankhuu Tungalagsuvd, Munkhsaikhan Munkhzaya, Mayila Yiliyasi, Takeshi Katou, Akira Kuwahara and Minoru Irahara : Prenatal undernutrition results in greater lipopolysaccharide-induced changes in hypothalamic TNF- expression, but does not affect the equivalent changes in the serum levels of luteinizing hormone and testosterone, in adult male rats., International Journal of Developmental Neuroscience, Vol.48, 80-83, 2016.
(Summary)
Immune stress can cause reproductive dysfunction. Some hypothalamic factors such as pro-inflammatory cytokines play pivotal roles in reproductive disorders under immune stress conditions. Recently, it has been reported that prenatal undernutrition affects not only metabolic functions, but also the responses of physiological functions to immune stress in adulthood. In this study, the long-term effects of prenatal undernutrition on the responses of hypothalamic pro-inflammatory cytokine (interleukin (IL)-1, tumor necrosis factor (TNF)-, and IL-6) expression; reproductive endocrine factors; i.e., the serum levels of gonadotropins and testosterone; and hypothalamic kisspeptin expression to lipopolysaccharide (LPS) were examined in male rats. Pregnant rats were divided into two groups; i.e., the normally nourished group and the undernourished (50% food restricted) group. The offspring of the normally nourished mothers (control) and undernourished mothers (the intrauterine growth restriction [IUGR] group) were sub-divided into saline-injected and LPS (500g, i.p.)-injected groups at 10 weeks of age. The rats' hypothalamic pro-inflammatory cytokine levels and serum luteinizing hormone (LH) and testosterone levels were measured and compared between the control and IUGR groups. The hypothalamic pro-inflammatory cytokine mRNA levels of the LPS-injected rats were significantly higher than those of the saline-injected rats in both the control and IUGR groups. The changes in the hypothalamic expression level of TNF-, but not those of the other cytokines, induced in response to LPS were more marked in the IUGR group than in the control group. On the other hand, although the serum LH and testosterone levels of the LPS-injected rats were significantly lower than those of the saline-injected rats in both the control and IUGR groups, their levels did not differ between the control and IUGR groups under the LPS-injected conditions. These results suggest that prenatal undernutrition results in more marked LPS-induced changes in hypothalamic TNF- expression, but does not alter the effects of LPS on the serum levels of LH or testosterone, in adult male rats.
Kazumi Takeshima, Seung Chik Jwa, Hidekazu Saito, Aritoshi Nakaza, Akira Kuwahara, Osamu Ishihara, Minoru Irahara, Fumiki Hirahara, Yasunori Yoshimura and Tetsuro Sakumoto : Impact of single embryo transfer policy on perinatal outcomes in fresh and frozen cycles-analysis of the Japanese Assisted Reproduction Technology registry between 2007 and 2012., Fertility and Sterility, Vol.105, No.2, 337-46.e3, 2015.
(Summary)
To investigate whether the introduction of single embryo transfer (SET) policy in Japan has improved perinatal outcomes. A retrospective cohort study. Not applicable. A total of 140,718 live births and 510 stillbirths (after 22 weeks of gestation) conceived by assisted reproductive technology in Japan between 2007 and 2012 were reviewed. None. Preterm birth (PTB), low birth weight (LBW), very low birth weight (VLBW), small for gestational age (SGA), large for gestational age (LGA), perinatal mortality, and other pregnancy complications. The rate of SET increased significantly from 52.2% in 2007 to 82.6% in 2012, while the rate of multiple pregnancy decreased significantly from 10.7% to 4.1% over the same period. The rates of PTB, LBW, and SGA decreased significantly, while that of LGA increased. Perinatal mortality decreased from 0.70% to 0.40% in fresh cycles, while that of frozen cycles did not change. Double ET or more was associated with a significantly increased risk for multiple pregnancy, placenta accreta, preterm premature rupture of membrane, cesarean section (CS), PTB, LBW, SGA, and early neonatal death compared with SET. Compared with before the SET policy was launched, the risks of multiple pregnancy, CS, early PTB before 32 weeks, LBW, VLBW, and SGA were significantly decreased after the policy was launched, with significant interactions of fresh/frozen status. The results suggest that the SET policy improved perinatal outcomes in Japan. The impact of SET policy was different in fresh and frozen cycles for several perinatal outcomes.
(Keyword)
Adult / Cryopreservation / Embryo Culture Techniques / Female / Fertility / Fertilization in Vitro / Humans / Infant, Newborn / Infertility / Japan / Live Birth / Male / Perinatal Mortality / Policy Making / Pregnancy / Pregnancy Complications / Pregnancy Rate / Program Evaluation / Registries / Retrospective Studies / Risk Assessment / Risk Factors / Single Embryo Transfer / Time Factors / Treatment Outcome
Takeshi Katou, Kaoru Keyama, Sumika Matsui, Mikio Yamasaki, Kanako Yoshida and Minoru Irahara : Step Up from Salpingo-Oophorectomy to Total Laparoscopic Hysterectomy Incorporating Incision Dissectiong Procedures., Journal of Minimally Invasive Gynecology, Vol.22, No.6S, S217, 2015.
Anna Tani, S Yamamoto, Masahiko Maegawa, Koutaro Kunimi, Sumika Matsui, Kaoru Keyama, Takeshi Katou, Hirokazu Uemura, Akira Kuwahara, Toshiya Matsuzaki, Toshiyuki Yasui, M Kamada, Takeshi Soeki, Masataka Sata and Minoru Irahara : Arterial stiffness is increased in young women with endometriosis., Journal of Obstetrics and Gynaecology, Vol.35, No.7, 711-715, 2015.
(Summary)
Endometriosis is a chronic gynaecological disorder that is accompanied by inflammation and oxidative stress. Atherosclerosis has a long subclinical progression in arteries of children and young adults decades before overt clinical manifestations of the disease. In this study, we determined arterial stiffness by measuring brachial-ankle pulse wave velocity (baPWV) in women with endometriosis to assess the presence of subclinical atherosclerosis. We also measured markers of inflammation and oxidative stress in women with endometriosis. baPWV in women with endometriosis aged over 30 years was significantly higher than that in women without endometriosis aged over 30 years (p < 0.05), but not in women aged less than 30. Serum high-sensitivity C-reactive protein level in women with endometriosis was significantly higher than that in controls (p < 0.05). Young women with endometriosis show significantly increased arterial stiffness, suggesting that women with endometriosis need to be cautious of the future onset of atherosclerosis.
(Keyword)
arterial stiffness / endometriosis / hs CRP / subclinical inflammation / young women
Yuko Yasuhara, Hirokazu Ito, Yumi Kuwamura, 梅田 弥生, 浦西 由美, Tetsuya Tanioka, Kazuya Kondo, Sachi Kishida and Minoru Irahara : Nurse administrators and hospital directors' perspectives about nurses' abilities in performing specific medical practices in hospitals within Tokushima Prefecture, Shikoku Acta Medica, Vol.71, No.3,4, 59-70, 2015.
(Summary)
The purpose of this survey was to determine nurse administrators and hospital directors' perspectives about nurses' abilities in performing specific medical practices in hospitals in Tokushima Prefecture. The nurse administrators and hospital directors of all hospitals (113 hospitals) in Tokushima Prefecture were invited to respond to a survey questionnaire by mail posted during the period between February and March of 2015. Responses were received from 46 nurse administrators (response rate, 41%) and 38 hospital directors (response rate, 34%). The obtained data were analyzed using descriptive statistics and the narrative descriptions summarized. Majority of responses from nurse administrators and hospital directors were accepting that nurses have responsibilities for administering medicines such as tranquilizers, anti-anxiety and anticonvulsant drugs. This result was not affected by the size of the hospital, in which fifty four percent (54%) of respondents were from hospitals with less than 100 beds. In Japan, only hospitals with 100 beds or more may have procedures involving highly invasive treatments. Because of this, many of the respondents answered ``not applicable'' to statements in the questionnaire which were related to invasive treatments. Recruitment of nurses, strategies to cope with accidents and education curriculum were important concerns of nurse administrators and hospital directors which remain to be answered in future investigations.
(Keyword)
nurses' abilities in performing specific medical practices / Tokushima prefecture / nurse administrators / hospital directors
Yasuyo Saijo, Hiroyuki Furumoto, Kanako Yoshida, Masato Nishimura and Minoru Irahara : Clinical Significance of Vascular Endothelial Growth Factor Expression and Microvessel Density in Invasive Cervical Cancer., The Journal of Medical Investigation : JMI, Vol.62, No.3-4, 154-160, 2015.
(Summary)
To determine whether vascular endothelial growth factor (VEGF) expression and microvessel density are predictive of prognosis in cases of invasive cervical cancer, correlations among VEGF expression, microvessel density, and clinicopathological parameters were identified. VEGF expression was evaluated in 50 cervical cancer samples by immunohistochemical staining. Microvessel density was assessed by immunostaining for CD31-positive endothelial cells in the most vascularized areas of tumors. VEGF expression and microvessel density were significantly higher in adenocarcinomas than in squamous cell carcinomas. However, in cases of adenocarcinoma, no significant correlations were found among VEGF expression, microvessel density, and clinicopathological parameters. In contrast, for squamous cell carcinomas, microvessel density was significantly higher in cases at an advanced stage and in those with several other poor prognostic factors. The finding that cervical adenocarcinomas exhibited greater VEGF expression and microvessel density than squamous cell carcinomas may explain the poorer prognosis of adenocarcinoma compared with squamous cell carcinoma. Moreover, microvessel density in squamous cell carcinomas was significantly correlated with poor prognostic factors. Therefore, there is possibility that bevacizumab, a humanized monoclonal antibody against VEGF-A, may be useful in the initial treatment targeting angiogenesis for early-stage cervical cancer.
Kazuhisa Maeda, Issei Imoto, Takashi Kaji, Yukiko Yoshida, Souichiro Nakayama and Minoru Irahara : Case of non-mosaic trisomy 20 in amniotic fluid cultures without anomalies in the fetus: Cytogenetic discrepancy between amniocytes and fetal blood., The Journal of Obstetrics and Gynaecology Research, Vol.41, No.1, 141-144, 2014.
(Summary)
We report a case of non-mosaic trisomy 20 detected prenatally by amniocentesis during the 16th week of pregnancy. Fetal blood sampling showed a normal karyotype and no fetal, neonatal or infant abnormalities were observed. Amniotic fluid cell karyotyping revealed a trisomy 20 (47,XY,+20) with 100% trisomic cells (38/38); however, a subsequent cordocentesis revealed a normal male karyotype. Moreover, a follow-up ultrasonographic examination did not reveal any major congenital malformations, and a healthy male infant was delivered subsequently at an appropriate gestational age without obvious anomalies. Cytogenetic analysis of blood lymphocytes from the infant revealed a normal karyotype, but cultured cells from the term placenta showed a mosaic karyotype 47,XY,+20/46,XY with 88% trisomic cells (44 of 50). Furthermore, no anomalies or developmental delays were observed in the neonatal period, thus suggesting two possibilities: confined placental mosaicism with the presence of normal and abnormal cell lineages, or generalized mosaicism affecting a limited number of tissues in both the placenta and fetus.
Takeshi Iwasa, Toshiya Matsuzaki, Sumika Matsui, Munkhsaikhan Munkhzaya, Altankhuu Tungalagsuvd, Takako Kawami, Masahiro Murakami, Takeshi Katou, Akira Kuwahara, Toshiyuki Yasui and Minoru Irahara : The effects of LPS-induced endotoxemia on the expression of adiponectin and its receptors in female rats., Endocrine Journal, Vol.61, No.9, 891-900, 2014.
(Summary)
Adiponectin (APN), secreted by white adipose tissue (WAT), acts as a protective factor against inflammatory conditions. However, the changes in the expression levels of endogenous APN and the two types of APN receptor (AdipoR1 and AdipoR2) induced by acute inflammatory conditions have not been fully elucidated. In this study, the changes in peripheral and/or central APN and AdipoR expression caused by lipopolysaccharide (LPS)-induced sepsis were examined in gonadal-intact (Sham) and ovariectomized (OVX) female rats. As it has been reported that APN and AdipoR suppress the production of inflammatory cytokines to prevent excessive inflammation, the mRNAs of these molecules were also examined. LPS injection induced increases in visceral WAT APN mRNA without affecting the serum APN level in both the Sham and OVX rats. OVX rats exhibited higher serum APN levels than Sham rats. LPS injection increased the subcutaneous WAT APN mRNA in OVX rats. In both Sham and OVX rats, LPS injection led to a decrease in hepatic AdipoR2 mRNA and an increase in hypothalamic AdipoR2 mRNA. Hypothalamic AdipoR2 mRNA was upregulated 24 h after LPS injection in OVX but not Sham rats. Serum TNF- level at 6 h after LPS injection and hypothalamic and hepatic IL-6 and TNF- mRNA at 24 h after LPS injection were significantly higher in Sham than OVX rats. These results suggest that APN and AdipoR play roles in modulating inflammation under septic conditions in female rats.
Takeshi Iwasa, Toshiya Matsuzaki, Altankhuu Tungalagsuvd, Munkhsaikhan Munkhzaya, Takako Kawami, Hirobumi Niki, Takeshi Kato, Akira Kuwahara, Hirokazu Uemura, Toshiyuki Yasui and Minoru Irahara : Hypothalamic Kiss1 and RFRP gene expressions are changed by a high dose of lipopolysaccharide in female rats., Hormones and Behavior, Vol.66, No.2, 309-316, 2014.
(Summary)
Reproductive function is suppressed by several types of stress. Hypothalamic kisspeptin, which is a product of the Kiss1 gene, and GnIH/RFRP have pivotal roles in the regulation of GnRH and gonadotropins through their receptors Kiss1r and GPR147 in many species. However, alterations of these factors under stress conditions have not been fully evaluated. This study investigated the mechanisms of immune stress-induced reproductive dysfunction, especially focusing on the changes of Kiss1 and RFRP gene expression. Serum LH levels and hypothalamic Kiss1 and GnRH mRNA levels were decreased, while hypothalamic RFRP and GPR147 mRNA levels were increased by administration of a high dose of LPS (5mg/kg) in both ovariectomized and gonadal intact female rats. In this condition, Kiss1 and/or RFRP mRNA levels were positively and negatively correlated with GnRH expression, respectively. In contrast, hypothalamic Kiss1, RFRP, and GPR147 mRNA levels were not changed by administration of a moderate dose of LPS (500g/kg) in ovariectomized rats. Rats with high-dose LPS injection showed more prolonged fever responses and severe anorexia compared with rats with moderate-dose LPS injection, indicating that more energy was used for the immune response in the former. These results suggest that the underlying mechanisms of dysfunction of gonadotropin secretion are changed according to the severity of immune stress, and that changes of some reserved factors, such as kisspeptin and RFRP, begin to participate in the suppression of GnRH and gonadotropin in severe conditions. As reproduction needs a large amount of energy, dysfunction of gonadotropin secretion under immune stress may be a biophylatic mechanism by which more energy is saved for the immune response.
Sumika Matsui, Toshiyuki Yasui, Kaoru Keyama, Anna Tani, Takeshi Katou, Hirokazu Uemura, Akira Kuwahara, Toshiya Matsuzaki and Minoru Irahara : High adiponectin level in late postmenopausal women with normal renal function., Clinica Chimica Acta, Vol.430, 104-108, 2014.
(Summary)
We examined whether high circulating adiponectin level is associated with renal function and is favorable for lipid and glucose metabolism in late postmenopausal women with normal renal function. We conducted a cross-sectional study in 115 postmenopausal women and divided the subjects into 2 groups (early postmenopausal women and late postmenopausal women). Serum levels of adiponectin, blood urea nitrogen, creatinine (Cr), glucose, insulin and lipid profiles were measured. Glomerular filtration rate (GFR) was estimated by age and Cr. Serum adiponectin level in late postmenopausal women was significantly higher than that in early postmenopausal women, and eGFR in late postmenopausal women was significantly lower than that in early postmenopausal women. Adiponectin level showed a negative correlation with eGFR and tended to have a negative correlation with eGFR after adjustments for age, BMI and bioavailable testosterone in all subjects, but adiponectin level did not show a significant correlation with eGFR in late postmenopausal women. Adiponectin level in late postmenopausal women showed a significant negative correlation with triglyceride (TG) and a positive correlation with high-density lipoprotein cholesterol (HDL-C) after adjustments for age and BMI. In late postmenopausal women with normal renal function, high adiponectin level is associated with favorable lipid profiles. High adiponectin level may be involved in not only eGFR but also other factors in late postmenopausal women.
Katsuyoshi Kume, Yasuo Tsutsumi M, Tomohiro Soga, Yoko Sakai, Noriko Kambe, Ryosuke Kawanishi, Eisuke Hamaguchi, Tomiya Kawahara, Asuka Kasai, Yoshimi Nakaji, Yousuke Horikawa T, Souichiro Nakayama, Takashi Kaji, Minoru Irahara and Katsuya Tanaka : A case of placenta percreta with massive hemorrhage during cesarean section., The Journal of Medical Investigation : JMI, Vol.61, No.1-2, 208-212, 2014.
(Summary)
We describe a case of a 39-year-old woman diagnosed with placenta percreta complicated by massive hemorrhage during a cesarean section. At 27 weeks of gestation, she underwent an emergency cesarean section under general anesthesia for vaginal bleeding and an intrauterine infection. Soon after delivery, a massive hemorrhage was encountered while attempting to separate the placenta percreta from the bladder wall. Although total abdominal hysterectomy and partial cystectomy were performed, massive hemorrhaging persisted. Bleeding was finally controlled following bilateral internal iliac artery embolization. We used a cell salvage device and a rapid infuser for hemodynamics stabilization. Total blood loss was 47,000 mL, and anesthesia time was 12 h and 47 min. The patient was discharged on the 32(nd) postoperative day without major complications. Placenta accreta can be associated with life-threatening hemorrhage and it is vital to plan accordingly preoperatively.
Hirobumi Niki, Toshiya Matsuzaki, Riyo Kinouchi, Takeshi Iwasa, Takako Kawami, Takeshi Katou, Akira Kuwahara and Minoru Irahara : Improvement in diagnostic performance of the revised total testosterone measuring system in Japanese women with polycystic ovary syndrome., The Journal of Medical Investigation : JMI, Vol.61, No.1-2, 65-71, 2014.
(Summary)
Hyperandrogenemia has become an important factor in the diagnosis of polycystic ovary syndrome (PCOS), in Japan as well as Western countries, since the Japanese PCOS diagnostic criteria were revised in 2007. The revised electrochemiluminescence immunoassay (ECLIA) reagent for total testosterone (T) (ECLusys TESTO II; New T assay), which has lower cross-reactivity with DHEA-S than the previous reagent (ECLusys TESTO I; Old T assay), has recently been developed. We studied the improvement between New and Old T assays in regards to the diagnostic performance of serum T for patients with PCOS. Serum T levels were measured in both normal women (Control, n=92) and PCOS patients (n=86). The rate of elevated T using each kit was significantly higher in the PCOS group than in the Control group, and significantly higher using New T assay (38/86, 44.2%) compared with Old T assay (26/86, 30.2%). A significant correlation was found between T level and body mass index, but not LH level. Furthermore, higher detection rates of hormonal abnormalities were seen in PCOS patients using combined measurement of both T and LH (63/80) compared with single measurement of either T (37/80) or LH (36/80). Therefore, the serum T assay is essential for the diagnosis of PCOS, and New T assay combined with the LH assay may improve the diagnostic process for PCOS. J. Med. Invest. 61: 65-71, February, 2014.
(Keyword)
Adult / Asian Continental Ancestry Group / Biological Markers / Body Mass Index / Case-Control Studies / Diagnostic Tests, Routine / Electrochemical Techniques / Female / Humans / Japan / Luminescent Measurements / Outcome Assessment (Health Care) / Polycystic Ovary Syndrome / Sensitivity and Specificity / Testosterone
Sumika Matsui, Toshiyuki Yasui, A Tani, Takeshi Katou, Hirokazu Uemura, Akira Kuwahara, Toshiya Matsuzaki, Kokichi Arisawa and Minoru Irahara : Effect of ultra-low-dose estradiol and dydrogesterone on arterial stiffness in postmenopausal women., Climacteric, Vol.17, No.2, 191-196, 2013.
(Summary)
Abstract Background Ultra-low-dose estradiol is known to improve menopausal symptoms and increase bone mineral density. However, the effect of ultra-low-dose estradiol on vascular function has not been clarified. Objectives We examined the effects of ultra-low-dose estradiol on brachial-ankle pulse wave velocity (baPWV) and circulating markers of cardiovascular risk. Patients and methods Twenty-eight postmenopausal women were enrolled in this study. Fourteen women received oral estradiol (0.5 mg) and dydrogesterone (5 mg) every day for 12 months (ultra-low-dose group) as hormone replacement therapy (HRT) and 14 women as a control group did not receive HRT. The baPWV, lipid profiles, homeostasis model assessment of insulin resistance (HOMA-IR) and vascular inflammatory markers were measured. Results The baPWV level significantly decreased in the ultra-low-dose group (p = 0.037), while the baPWV level did not significantly change in the control group. HOMA-IR tended to decrease in the ultra-low-dose group (p = 0.076). Systolic blood pressure and diastolic blood pressure did not change significantly in either group. Conclusion An HRT regimen using oral ultra-low-dose estradiol and dydrogesterone has an effect on arterial stiffness and insulin resistance.
Sumika Matsui, Toshiyuki Yasui, Anna Tani, Takeshi Katou, Kotaro Kunimi, Hirokazu Uemura, Akira Kuwahara, Toshiya Matsuzaki and Minoru Irahara : Difference in the Ratio of High-Molecular Weight (HMW) to Total Adiponectin and HMW Adiponectin in Late Postmenopausal Women., Journal of Endocrinological Investigation, 2013.
(Summary)
Objective: High-molecular weight (HMW) isoform level and HMW ratio have been shown to be better predictors of insulin sensitivity and metabolic syndrome than total adiponectin level. We examined the changes in circulating levels of HMW adiponectin and ratios of HMW to total adiponectin in women during the menopausal transition. Methods: We conducted a cross-sectional study in 217 healthy women and divided them into 4 stages: 58 women in premenopausal, 69 women in perimenpausal, 62 women in early postmenopausal and 28 women in late postmenopausal women. Serum levels of total adiponectin and HMW adiponectin were measured by an enzyme-linked immunosorbent assay. Results: In late postmenopausal women, HMW adiponectin level was significantly higher than that in perimenopausal women and the HMW to total adiponectin ratio was significantly lower than that in early postmenopausal women. In perimenopausal women, HMW adiponectin level was significantly lower than that in premenopausal women and HMW to total adiponectin ratio was significantly lower than the ratios in premenopausal and early postmenopausal women. Conclusion: The ratio of HMW to total adiponectin is low in late postmenopausal women, though both levels of total and HMW adiponectin were high after menopause in our cross-sectional study.
Sumika Matsui, Toshiyuki Yasui, Anna Tani, Kotaro Kunimi, Hirokazu Uemura, Satoshi Yamamoto, Akira Kuwahara, Toshiya Matsuzaki and Minoru Irahara : Associations of estrogen and testosterone with insulin resistance in pre- and postmenopausal women with and without hormone therapy., International Journal of Endocrinology and Metabolism, Vol.11, No.2, 65-70, 2013.
(Summary)
Estrogen deficiency due to natural menopause or surgical menopause has been suggested to have an adverse effect on insulin resistance. Testosterone and sex hormone-binding globulin (SHBG) as well as estrogen are also associated with insulin resistance in women. However, to date, the associations of estradiol, testosterone and SHBG with insulin resistance according to estrogen level have not been clarified. We examined the associations of estradiol, testosterone and SHBG with insulin resistance in pre- and in postmenopausal women and postmenopausal women who had received hormone therapy to clarify whether the associations differ depending on the estrogen status. Twenty premenopausal women and thirty-two postmenopausal women were enrolled in this study. Fifteen postmenopausal women received oral conjugated equine estrogen (CEE) (0.625 mg) everyday for 12 months. Serum levels of estradiol, testosterone, SHBG and insulin and plasma levels of glucose were measured. Serum estradiol levels tended to have a negative correlation with homeostasis model assessment of insulin resistance (HOMA-IR) in premenopausal women but not in postmenopausal women. On the other hand, free testosterone levels tended to have a positive correlation with HOMA-IR in postmenopausal women but not in premenopausal women. Serum SHBG levels showed significant negative correlations with HOMA-IR in both pre- and postmenopausal women. SHBG level was significantly increased, free testosterone level was significantly decreased and HOMA-IR was significantly decreased at 12 months after CEE administration. However, there were no significant correlations of changes between estradiol, SHBG or free testosterone and HOMA-IR. The associations of sex steroid hormones with insulin resistance are different depending on the estrogen status.
河見 貴子, Hiroyuki Furumoto, Kanako Yoshida, Takeshi Katou, Masato Nishimura and Minoru Irahara : Effectiveness and tolerability of hysterectomy for the local recurrence of cervical cancer after radiation therapy, Modern Trends in Obstetrics & Gynecology, Vol.61, No.2, 321-324, 2013.
(Keyword)
recurrent uterine cervical cancer / concurrent chemoradiation (CCRT) / hysterectomy
Takeshi Iwasa, Toshiya Matsuzaki, Riyo Kinouchi, Ganbat Gereltsetseg, Masahiro Murakami, Akira Kuwahara, Toshiyuki Yasui and Minoru Irahara : Developmental changes in the responsiveness of hypothalamic ER alpha mRNA levels to food deprivation., Neuroendocrinology Letters, Vol.34, No.6, 543-548, 2013.
(Summary)
Estrogen plays an important role in feeding and energy balance, and the critical role of estrogen in the control of appetite and energy balance is mediated by hypothalamic estrogen receptor (ER) alpha. In undernourished rodents, hypothalamic ER alpha mRNA expression are decreased. Responses of some hypothalamic factors to negative energy balance develop during the early neonatal period. In this study, we examined the developmental changes of fasting-induced alterations in hypothalamic ER alpha mRNA expression in female rats. ER alpha mRNA expression was reduced after a 12-h or 24-h fast at postnatal days 15 and 25, but not at day 5. Serum estradiol levels in postnatal day 25 rats were not changed by fasting. Although serum leptin levels were suppressed by fasting at all ages, hypothalamic ER alpha mRNA expression at postnatal day 25 was not changed by leptin administration after a 24-h fast. These data show that the sensitivity of hypothalamic ER alpha to negative energy balance may not be established in the early neonatal period, and that it develops by postnatal day 15. Decreased leptin levels might not be involved in the alterations of hypothalamic ER alpha mRNA expression in the undernourished condition.
Satoru Yoshie, Masanori Nishinaga, Shohei Kawagoe, Satoshi Hirahara, Shinsuke Fujita, Minoru Irahara, Yoriko Anzai, Shigeru Onozawa, Yoshiya Oishi, Hiroshi Suzuki, Miyuki Numata, Fumie Katayama, Hiroshi Murayama, Rumiko Tsuchiya, Mari Kimata, Kouji Shibasaki, Katsuya Iijima and Tetsuo Tsuji : [Development of a home care educational program for community physicians and other professionals-a trial in Kashiwa City]., Japanese Journal of Cancer and Chemotherapy, Vol.39 Suppl 1, 80-85, 2012.
(Summary)
From May to October 2011, we conducted an 8-day homecare educational program for physicians, dentists, pharmacists, visiting nurses, long-term care managers, and hospital staff in Kashiwa city, Chiba, which was primarily intended to increase home visits by physicians. The characteristics of the program were as follows: 1) active and busy community physician participation, 2) attendance of practical training by physicians, 3) interprofessional discussion, 4) recruitment of participants from the same city, 5) recommendation of participant recruitment by a community-level professional association such as Kashiwa City Medical Association. By comparison of the pre- and post-program questionnaires completed by participants, the motivation for homecare practice, knowledge about homecare, and interactions with other professionals have increased. We will further standardize and generalize this program in order to contribute to homecare promotion in Japan.
(Keyword)
Community Networks / Education, Medical, Continuing / Home Care Services / Japan
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23268908
Riyo Kinouchi, Toshiya Matsuzaki, Takeshi Iwasa, Ganbat Gereltsetseg, Hiroshi Nakazawa, Kotaro Kunimi, Akira Kuwahara, Toshiyuki Yasui and Minoru Irahara : Prepubertal exposure to glucocorticoid delays puberty independent of the hypothalamic Kiss1-GnRH system in female rats., International Journal of Developmental Neuroscience, Vol.30, No.7, 596-601, 2012.
(Summary)
Secretion of glucocorticoids is widely known as a key endocrine response to stresses. Prenatal dexamethasone administration induces intrauterine growth retardation and delayed onset of puberty in female rats independent of the hypothalamic Kiss1-gonadotropin-releasing hormone (GnRH) system. The aim of this study was to evaluate the influence of chronic intracerebroventricular (central, CD) or subcutaneous (peripheral, PD) dexamethasone administration to prepubertal female rats on the onset of puberty and body weight change. Rats administered dexamethasone from day 25 to day 34 (CD and PD) showed significantly reduced body weight gain throughout the experimental period and delayed onset of vaginal opening compared with rats administered saline centrally (CS) or peripherally (PS). At 34 days old, hypothalamic Kiss1r mRNA levels were significantly lower with CD than with CS. No significant differences were seen between rats administered saline and rats administered dexamethasone with regard to hypothalamic Kiss1, GnRH and NPY mRNA levels or serum LH levels. Serum leptin concentrations were higher in CD and PD than in the controls (CS and PS). These results suggest that the delayed onset of puberty induced by prepubertal dexamethasone administration occurs independent of the hypothalamic Kiss1-GnRH system.
Sumika Matsui, Toshiyuki Yasui, Anna Tani, Takeshi Katou, Kotaro Kunimi, Hirokazu Uemura, Akira Kuwahara, Toshiya Matsuzaki and Minoru Irahara : Association of circulating adiponectin with testosterone in women during the menopausal transition., Maturitas, Vol.73, No.3, 255-260, 2012.
(Summary)
We examined (1) the change in circulating adiponectin in women during the menopausal transition and (2) the associations of adiponectin levels with estrogen, androgen and sex hormone-binding globulin (SHBG) in women during the menopausal transition. We conducted a cross-sectional study in 235 healthy women and divided them into 7 stages by menstrual regularity and follicle-stimulating hormone (FSH) level. Serum levels of adiponectin, estradiol, total testosterone, dehydroepiandrosterone-sulfate (DHEA-S) and SHBG were measured. Levels of free and bioavailable testosterone were calculated by using total testosterone, albumin and SHBG. Serum adiponectin levels showed a U-curve, levels being low in early and late menopausal transition and gradually becoming higher after menopause. Adiponectin levels were negatively correlated with levels of free testosterone, bioavailable testosterone and DHEA-S and were positively correlated with SHBG in postmenopausal women for whom more than 1 year had passed since menopause. Adiponectin level was not correlated with estradiol level. Circulating adiponectin level shows a U-curve during the menopausal transition and adiponectin level is associated with levels of free and bioavailable testosterone and DHEA-S in postmenopause.
Takashi Kaji, K Maeda, M Suto, M Sato and Minoru Irahara : Simultaneous recordings of pulsed wave Doppler signals in hepatic vein and descending aorta using dual Doppler: a novel method for evaluating fetal arrhythmias., Ultrasound in Obstetrics & Gynecology, Vol.39, No.3, 357-359, 2012.
Sumika Matsui, Toshiyuki Yasui, Anna Tani, Kotaro Kunimi, Hirokazu Uemura, Satoshi Yamamoto, Akira Kuwahara, Toshiya Matsuzaki, Naoko Tsuchiya, Mitsutoshi Yuzurihara, Yoshio Kase and Minoru Irahara : Changes in insulin sensitivity during GnRH agonist treatment in premenopausal women with leiomyoma., Clinica Chimica Acta, Vol.413, No.11-12, 960-965, 2012.
(Summary)
The purpose of this study was to determine (1) the influence of estrogen deficiency induced by gonadotropin-releasing hormone (GnRH) agonist administration on insulin sensitivity as well as hormones and factors related to insulin resistance and (2) the differences in the influence for these parameters by the degree of basal insulin sensitivity. Thirty-five women diagnosed with leiomyoma were enrolled in this study. Serum levels of fasting glucose, insulin, sex steroid hormones, sex hormone-binding globulin (SHBG), vascular inflammatory markers and cytokines before and at 6months after commencement of GnRH agonist administration were examined. In all women, levels of insulin, glucose and homeostasis model assessment of insulin resistance (HOMA-IR) were not significantly changed. However, in women who had a low HOMA-IR before treatment, levels of insulin, glucose and HOMA-IR showed significant increases and total testosterone level showed a significant decrease. In women who had a high HOMA-IR, levels of insulin, HOMA-IR and SHBG were significantly decreased and levels of highly sensitive C-reactive protein, soluble intercellular adhesion molecule-1, E-selectin and monocyte chemoattractant protein-1 were significantly increased. Change in insulin sensitivity caused by GnRH agonist administration for premenopausal women with leiomyoma differs depending on baseline insulin sensitivity before treatment.
Takeshi Iwasa, Toshiya Matsuzaki, Masahiro Murakami, Riyo Kinouchi, Tomohiro Osugi, Ganbat Gereltsetseg, Shinobu Yoshida, Minoru Irahara and Kazuyoshi Tsutsui : Developmental changes in the mammalian gonadotropin-inhibitory hormone (GnIH) ortholog RFamide-related peptide (RFRP) and its cognate receptor GPR147 in the rat hypothalamus., International Journal of Developmental Neuroscience, Vol.30, No.1, 31-37, 2012.
(Summary)
The mammalian gonadotropin-inhibitory hormone (GnIH) ortholog RFamide-related peptide (RFRP) is considered to act on gonadotropin-releasing hormone (GnRH) neurons and on the pituitary to inhibit gonadotropin release and synthesis. To understand the functional significance of this neuropeptide, we investigated the physiological changes in RFRP at mRNA and peptide levels, as well as at the mRNA level of its cognate receptor, G protein-coupled receptor 147 (GPR147), in the rat hypothalamus during development. We also investigated the effects of gonadal steroids on mRNA expression levels of these molecules. In male rats, mRNA expressions of both RFRP and GPR147 increased from postnatal days 12 and 16, peaking at postnatal days 35 and 42, respectively. However, their expressions fell at postnatal day 49. In female rats, mRNA expression of RFRP continued to increase throughout development; mRNA expression of GPR147 in female rats increased from postnatal day 16, peaking at postnatal day 28, but decreased from postnatal day 35. The hypothalamic contents of RFRP on postnatal days 28 and 42 were significantly higher than on postnatal day 4 in male rats, and those on postnatal day 42 were significantly higher than those on postnatal days 4 and 28 in females. Neither orchidectomy nor ovariectomy influenced mRNA expression levels of RFRP or GPR147 in the prepubertal period when endogenous sex steroid levels were low in males and females. Administration of estradiol-17β (E2) increased mRNA expression of RFRP in prepubertal females. These results suggest that the hypothalamic RFRP system changes during development. An ovarian sex steroid, E2, may stimulate mRNA expression of RFRP in the prepubertal period when the basal E2 concentration is low.
Yoshio Kasahara, Masaaki Kawai, Ichiro Tsuji, Eriko Tohno, Takao Yokoe, Minoru Irahara, Akira Tangoku and Noriaki Ohuchi : Harms of screening mammography for breast cancer in Japanese women., Breast Cancer, 2012.
(Summary)
BACKGROUND: The US Preventative Services Task Force assesses the efficacy of breast cancer screening by the sum of its benefits and harms, and recommends against routine screening mammography because of its relatively great harms for women aged 40-49 years. Assessment of the efficacy of screening mammography should take into consideration not only its benefits but also its harms, but data regarding those harms are lacking for Japanese women. METHODS: In 2008 we collected screening mammography data from 144,848 participants from five Japanese prefectures by age bracket to assess the harms [false-positive results, performance of unnecessary additional imaging, fine-needle aspiration cytology (FNA), and biopsy and its procedures]. RESULTS: The rate of cancer detected in women aged 40-49 years was 0.28%. The false-positive rate (9.6%) and rates of additional imaging by mammography (5.8%) and ultrasound (7.3%) were higher in women aged 40-49 years than in the other age brackets. The rates of FNA (1.6%) and biopsy (0.7%) were also highest in women aged 40-49 years. However, they seemed to be lower than the rates reported by the Breast Cancer Surveillance Consortium (BCSC) and other studies in the US. CONCLUSIONS: The results, although preliminary, indicate the possibility that the harms of screening mammography for Japanese women are less than those for American women.
Tomomi Iba, Yuya Yano, Mayumi Umeno, Kenji Hinokio, Akira Kuwahara, Minoru Irahara, Shuji Yamano and Toshiyuki Yasui : Roscovitine in combination with calcium ionophore induces oocyte activation through reduction of M-phase promoting factor activity in mice., Zygote, Vol.20, No.4, 321-325, 2011.
(Summary)
SummaryThe aim of the present study was to determine oocyte activation and change in M-phase promoting factor (MPF) activity induced by treatment with calcium ionophore and roscovitine in comparison with those induced by treatment with roscovitine alone and treatment with calcium ionophore and puromycin in mice. Freshly ovulated oocytes obtained from 6-8-week-old mice were divided into five groups (no activation treatment; 5 μM calcium ionophore A23187; 50 μM roscovitine; 5 μM calcium ionophore and 10 μg/ml puromycin; and 5 μM calcium ionophore and 50 μM roscovitine) and were incubated for 6 h. Oocyte activation, assessed by morphological changes, and changes in MPF activity in the five groups at 0, 2, 4 and 6 h of incubation were examined. Activated oocytes were defined as oocytes with at least one pronucleus. Oocytes treated with roscovitine alone were not activated during the 6-h incubation period. All of the oocytes in the calcium ionophore with puromycin group and in the calcium ionophore with roscovitine group were activated. The percentage activity of MPF in oocytes treated with roscovitine alone was decreased after 2 h and increased after 4 h of incubation. The percentage activity of MPF in oocytes treated with calcium ionophore and roscovitine was significantly decreased with suppression of MPF activity being maintained for 6 h, and this change was similar to that in oocytes treated with calcium ionophore and puromycin. Roscovitine with calcium ionophore is effective for induction of oocyte activation through suppression of MPF activity in mice.
Toshiya Matsuzaki, Takeshi Iwasa, Riyo Kinouchi, Shinobu Yoshida, Masahiro Murakami, Ganbat Gereltsetseg, Satoshi Yamamoto, Akira Kuwahara, Toshiyuki Yasui and Minoru Irahara : Fasting reduces the kiss1 mRNA levels in the caudal hypothalamus of gonadally intact adult female rats., Endocrine Journal, Vol.58, No.11, 1003-1012, 2011.
(Summary)
Kisspeptin, which is the product of the kiss1 gene and its receptor kiss1r, have emerged as the essential gatekeepers of reproduction. The present study used gonadally intact female rats to evaluate fasting-induced suppression of the KiSS-1 system of anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC) under normal physiological conditions. Starting on the day of estrous, one group of rats was subjected to 72 h of food deprivation, while the other group of rats was able to continue feeding ad libitum. The length of the estrous cycle was significantly longer in the food-deprived rats as compared to the feeding rats. At the end of the 72-h food deprivation period, all of the food-deprived rats were at the diestrous phase, with their serum concentrations of LH and leptin significantly lower than that observed in the feeding rats. In addition, as compared to the feeding rats, the expression levels of kiss1 mRNA were significantly lower in the food-deprived rats in the posterior hypothalamic block, which contained the ARC, but not in the anterior hypothalamic block, which contain the AVPV. However, both the kiss1r mRNA expression levels in the anterior and posterior hypothalamic blocks and the neurokinin B and neurokinin 3 receptor mRNA expression levels in the posterior hypothalamic block were not significantly different between the feeding and food-deprived rats. Thus, lower kiss1 mRNA levels in the ARC appear to be responsible for the fasting-induced inhibition of gonadotrophin secretion and subsequent prolongation of the estrous cycle.
Takeshi Iwasa, Toshiya Matsuzaki, Riyo Kinouchi, Ganbat Gereltsetseg, Masahiro Murakami, Hiroshi Nakazawa, Shinobu Fujisawa, Satoshi Yamamoto, Akira Kuwahara, Toshiyuki Yasui and Minoru Irahara : Effect of immune stress on body weight regulation is altered by ovariectomy in female rats., Journal of Reproductive Immunology, Vol.91, No.1-2, 41-47, 2011.
(Summary)
It has been suggested that obesity and loss of ovarian function alter the inflammatory response to immune stress. Ovariectomized (OVX) rats, which are used as a model of human menopause, exhibit both hyperphagia-induced obesity and gonadal steroid deficiency. To evaluate the effects of ovariectomy on inflammatory responses, we compared the anorectic response to LPS in OVX rats and gonad intact female rats. As leptin and hypothalamic interleukin-1β (IL1β) play pivotal roles in the anorectic response to immune stress, these factors were also measured. It was found that the OVX rats exhibited an increased anorectic response to LPS compared with the sham-operated rats. The OVX rats showed higher serum leptin concentrations and a greater increase in hypothalamic IL1β mRNA expression after LPS injection. In addition, in order to determine whether gonadal steroid deficiency contributes to the changes in the inflammatory responses of OVX rats, we compared responses between OVX rats treated with gonadal steroids and untreated OVX rats. There were no differences in appetite, the serum leptin level, and hypothalamic IL1β mRNA expression between the two groups after LPS injection. These findings suggest that the loss of ovarian function increases the induction of leptin and hypothalamic IL1β synthesis and consequently increases the anorectic response under immune stress conditions. It is possible that these alterations are caused by OVX-induced obesity rather than the direct effects of gonadal steroid deficiency.
Kanako Yoshida, Hiroyuki Furumoto, Akiko Abe, Takeshi Katou, Masato Nishimura and Minoru Irahara : The possibility of vertical transmission of human papillomavirus through maternal milk, Journal of Obstetrics and Gynaecology, Vol.31, No.6, 503-506, 2011.
(Summary)
Human papillomavirus (HPV) DNA has been detected in the oral cavity of infants and breast cancer tissue, suggesting its vertical transmission through maternal milk. We determined whether HPV is detected in maternal milk and is vertically transmitted by breast-feeding. Informed consent was obtained, and maternal milk samples (n=80) were analysed for high-risk HPV DNA. In 43 women, this DNA was measured in the uterine cervix. In women with positive samples, this DNA was measured in the oral cavities of their children. The domain including HPV E6 and E7 was amplified by polymerase chain reaction using consensus primers, and HPV serotype determined by electrophoresis after restriction enzyme digestion. High-risk HPV-16 was detected in two of 80 samples (2.5%), and in these two cases, high-risk HPV was not detected in the uterine cervix or oral cavity of the child. It was concluded that the infection of HPV in maternal milk is rare (2/80); vertical transmission through maternal milk was not detected in this study (0/80). HPV infection through maternal milk may occur, but its likelihood is low.
Sumika Matsui, Toshiyuki Yasui, Hirokazu Uemura, Satoshi Yamamoto, Toshiya Matsuzaki, Naoko Tsuchiya, Mitsutoshi Yuzurihara, Yoshio Kase and Minoru Irahara : Induction of circulating monocyte chemoattractant protein-1 in women with gonadotropin-releasing hormone agonist., Journal of Reproductive Immunology, Vol.90, No.2, 227-234, 2011.
(Summary)
The aim of the present study was to determine the influence of acute estrogen deficiency induced by administration of a gonadotropin-releasing hormone (GnRH) agonist on circulating levels of cytokines and chemokines. Eighty-three women with uterine leiomyoma were assigned in open, parallel-group fashion to a no-treatment (control) group and a GnRH-agonist group. Serum levels of nine cytokines and chemokines as well as vascular inflammatory markers were measured. Serum levels of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor-α (TNFα) in the GnRH-agonist group were increased significantly at 6 months. There were also significant differences in percentage changes in interleukin (IL)-6, IL8, MCP1, and macrophage inflammatory protein-1β (MIP1β) between the control and GnRH agonist groups. Soluble intercellular adhesion molecule-1 (sICAM1) and E-selectin levels showed significant increases in the GnRH agonist group at 6 months. Serum MCP1 concentrations showed weak correlations with levels of sICAM and E-selectin. We conclude that a hypo-estrogenic state due to administration of a GnRH agonist increases circulating levels of cytokines and chemokines, especially MCP1.
Takeshi Iwasa, Toshiya Matsuzaki, Masahiro Murakami, Riyo Kinouchi, Ganbat Gereltsetseg, Hiroshi Nakazawa, Satoshi Yamamoto, Akira Kuwahara, Toshiyuki Yasui and Minoru Irahara : Changes in responsiveness of appetite, leptin and hypothalamic IL-1β and TNF-α to lipopolysaccharide in developing rats., Journal of Neuroimmunology, Vol.236, No.1-2, 10-16, 2011.
(Summary)
In addition to its role as a regulator of energy homeostasis, leptin plays a pivotal role in some immune/inflammatory responses. Synthesis and secretion of leptin are increased under immune stress conditions, and increased leptin may participate in the development of anorexia and fever. These actions are partially mediated by up-regulation of hypothalamic IL-1β. Leptin also protects against immune stress-induced lethality. On the other hand, the response and roles of leptin to immune stress conditions in the neonatal period have scarcely been examined. We hypothesized that 1. the response of leptin to immune stress would be suppressed in the early neonatal period, 2. hyporesponse of leptin in the early neonatal period would attenuate the anorectic response and increase the lethal rate under immune stress conditions and 3. supplementation of leptin in the early neonatal period would increase the anorectic response, whereas it would decrease the lethal rate under immune stress conditions. To test these hypotheses, we first examined the developmental changes in the responses of leptin and hypothalamic proinflammatory cytokines, i.e., IL-1β and TNF-α, to LPS-induced immune stress in female rats. We also examined the developmental changes in the anorectic response and lethality rate under LPS-induced immune stress conditions. Five- and 15-day-old rats showed no leptin response and a weak hypothalamic IL-1β response to LPS when compared with 25- and 42-day-old rats. Fifteen-day-old rats showed low anorectic responses and high lethality rates when compared with 25- and 42-day-old rats under LPS-induced immune stress conditions. We then examined whether administration of leptin affected the response to the anorectic and lethal effects of LPS in 15-day-old rats. Administration of leptin further attenuated body weight after LPS injection, but not after saline injection. On the other hand, administration of leptin did not affect survival rate. In addition, hypothalamic IL-1β mRNA levels were not affected by leptin administration. In conclusion, the absence of a leptin response may act to prevent immune stress-induced anorexia during the early neonatal period.
Souichiro Nakayama, Toshiyuki Yasui, Masanori Suto, Miki Sato, Takashi Kaji, Hirokazu Uemura, Kazuhisa Maeda and Minoru Irahara : Differences in bone metabolism between singleton pregnancy and twin pregnancy., Bone, Vol.49, No.3, 513-519, 2011.
(Summary)
The objective of this study was to examine the influence of twin pregnancy on calcium metabolism, including bone turnover markers and calcium-regulating factors, by comparison between singleton pregnancy and twin pregnancy in women during pregnancy and puerperium in cross-sectional and longitudinal studies. Women with singleton and twin pregnancies were recruited from the outpatient clinic of Tokushima University Hospital. In both cross-sectional and longitudinal studies, bone formation and resorption markers, mineral metabolism and calcium-regulating factors were measured at 10, 25, 30 and 36 weeks of pregnancy and at 4 days and 1 month postpartum in women with singleton and twin pregnancies. Urinary levels of cross-linked type I collagen N-telopeptides and C-terminal telopeptides of type I collagen in women with twin pregnancy were significantly higher than those in women with singleton pregnancy and those high levels were observed earlier than those in women with singleton pregnancy. In the cross-sectional study, serum levels of bone-specific alkaline phosphatase, calcium and phosphate in women with twin pregnancy were higher and the levels of 1,25-(OH)2 vitamin D and 25-(OH) vitamin D in women with twin pregnancy were lower than those in women with singleton pregnancy. Changes in bone metabolism in women with twin pregnancy are different from those in women with singleton pregnancy. Early and large increases in bone turnover markers allow women with twin pregnancy to meet high fetal demand for calcium during pregnancy.
(Keyword)
Adult / Alkaline Phosphatase / Biological Markers / Bone Remodeling / Bone and Bones / calcium / Collagen Type I / Cross-Sectional Studies / Female / Gestational Age / Humans / Longitudinal Studies / Parathyroid Hormone / Peptide Fragments / Phosphates / Postpartum Period / Pregnancy / Pregnancy, Twin
Ayako Kobayashi, Masahiko Maegawa, Satoshi Yamamoto, Natsuyo Ugumori, Yuka Kasai, Anna Tani, Hirokazu Uemura, Akira Kuwahara, Toshiya Matsuzaki, Toshiyuki Yasui, Hiroyuki Furumoto, Masaharu Kamada and Minoru Irahara : The role of blood in early endometrial-peritoneal interactions in a syngeneic mouse model of endometriosis, Reproductive Medicine and Biology, Vol.10, No.1, 15-20, 2011.
(Keyword)
Blood / Coagulation / Endometriosis / Fibrinolysis / Murine model
Akiko Abe, Hiroyuki Furumoto, Kanako Yoshida, Takeshi Katou, Yasuyo Saijo and Minoru Irahara : Gene gun-mediated skin transfection with FL gene suppresses the growth of murine fibrosarcoma., The Journal of Medical Investigation : JMI, Vol.58, No.1-2, 39-45, 2011.
(Summary)
Particle-mediated transfection is known as an efficient method of non-viral gene transfer. Flt3 ligand (FL) is a growth factor for hematopoietic progenitors; it promotes the growth of dendritic cells (DC). DCs are powerful antigen-presenting cells (APCs) and show a remarkable capacity to stimulate antigen-specific T-cell responses. In this study, we intended to investigate the suppressive effect on tumor growth by gene gun-mediated transfer of FL in a murine model. C57BL/6J mice were injected intradermally with MCA205 cells. DNA (pNGVL-hFLex)-coated gold particles were delivered to the mouse skin surrounding the target tumor. The expression of FL was determined by RT-PCR. Analyses by immunohistochemistry and fluorescence-activated cell sorter (FACS) revealed an increase in the number of DC after treatment with FL. Gene gun-mediated pNGVL-hFLex transfer significantly inhibited the growth of the MCA205 tumor. FL transfer markedly increased the number of CD11c(+) DCs in the tumor tissue. Further, the FL-transfected mice exhibited a significantly higher number of CD80(+) MHC-II cells. We successfully performed FL therapy using an in vivo gene gun in order to effectively mobilize DCs in situ and induce suppressive immunity.
Hiroaki Yanagawa, Minoru Irahara, Hitoshi Houchi, Yoshiyuki Kakehi, Takashi Moritoyo, Masahiro Nomoto, Mitsuhiko Miyamura and Taro Shuin : View and present status of personnel involved in clinical trials: a survey of participants from the First Symposium of the Shikoku Collaborative Group for Promotion of Clinical Trials., The Journal of Medical Investigation : JMI, Vol.58, No.1-2, 81-85, 2011.
(Summary)
Clinical trials leading to drug approval (registration trials) play a central role in the drug development process. Since the introduction of the Good Clinical Practice (GCP) standard in 1997, the Japanese infrastructure for registration trials has improved. The contribution of support staff, including clinical research coordinators (CRCs), to clinical trials is now widely recognized in Japan. Quality issues and career development for these support staff are being increasingly emphasized. The Shikoku Collaborative Group for Promotion of Clinical Trials was organized in 2008 to address these issues through communication with the personnel involved in clinical trials in regional areas of Japan. To understand the views and present status of personnel involved in clinical trials, we used questionnaires to survey the participants of the First Symposium of the Shikoku Collaborative Group for Promotion of Clinical Trials held in August 2009. Group discussions and special lectures occurred at the symposium. The questionnaire began with questions about basic patient characteristics, followed by practical questions. Of 110 participants, there were 68 respondents (62%), including clinical trial support staff (clinical research coordinators [n=36, 53%], administrative officers [n=9, 13%]), and medical staff [n=23, 34%]). Among the support staff, 36 (80%) had more than 5 years of experience. The most common questionnaire answer selected for participation in the symposium was "willing to contact staff from other medical institutions or organizations" for support staff and "to obtain further knowledge concerning clinical trials" for medical staff. The overall view of the discussion ("Was the discussion satisfactory?") was favorable for 36 (53%) respondents. This survey revealed that the group discussion in the present symposium appears to be valuable for participants, using overall satisfaction as a surrogate. Based on the information obtained in the present study, further development of the clinical trial infrastructure, including training opportunities and career development for support staff, is required. Due to the limitations of this study, further analysis is warranted to determine the optimal strategy for training support staff.
(Keyword)
Clinical Protocols / Clinical Trials as Topic / Cooperative Behavior / Drug Approval / Drug Discovery / Health Personnel / Humans / Japan / Questionnaires
Yuka Kasai, Masahiko Maegawa, Satoshi Yamamoto, Masaharu Kamada, Toshiyuki Yasui, Hirokazu Uemura, Ayako Kobayashi, Masayo Kaneyama, Anna Tani, Sumika Matsui, Akira Kuwahara, Toshiya Matsuzaki, Hiroyuki Furumoto and Minoru Irahara : Effects of raloxifene on the production of cytokines in stimulated whole blood in ex vivo and in vitro studies., The Journal of Medical Investigation : JMI, Vol.58, No.1-2, 110-117, 2011.
(Summary)
The aims of this study were to determine the effects of raloxifene therapy on production of cytokines and in vitro effects of raloxifene on production of cytokines by whole blood cultures. We obtained samples of peripheral blood from 6 postmenopausal women with osteopenia at baseline and after 3 and 6 months of raloxifene therapy and 10 postmenopausal women who did not receive raloxifene therapy. Whole blood from raloxifene-treated women was stimulated with lipopolysaccharide (LPS) or phytohemeagglutinin (PHA). Whole blood from postmenopausal women who were not treated with raloxifene was preincubated with raloxifene at concentrations of 10(-10)-10(-7) M and then stimulated with LPS or PHA. Concentrations of IL-1β, IL-4, IL-6, IL-12p40, IL-12p70, TNF-α and IFN-γ in the supernatant were measured by respective ELISAs. In ex vivo cultures, raloxifene therapy inhibited LPS-stimulated production of IL-1β, IL-6, IL-12p40, IL-12p70 and TNF-α, but not PHA-stimulated production of IL-4 and IFN-γ. In in vitro cultures, raloxifene at a concentration (10(-9) M) inhibited LPS-stimulated production of IL-1β, IL-6 and IL-12p40 and PHA-stimulated production of IFN-γ. Raloxifene therapy decreases the production of IL-1β, IL-6, IL-12 and TNF-α but not that of IL-4 and IFN-γ, suggesting that modulation of cytokines could play a role in the mechanisms of the osteoprotective effect of raloxifene.
(Keyword)
Aged / Bone Density Conservation Agents / Bone Diseases, Metabolic / Cell Survival / Cytokines / Female / Humans / Leukocytes, Mononuclear / Menopause / Middle Aged / Raloxifene / Selective Estrogen Receptor Modulators / Time Factors
Toshiyuki Yasui, Sumika Matsui, S Yamamoto, Hirokazu Uemura, N Tsuchiya, M Noguchi, M Yuzurihara, Y Kase and Minoru Irahara : Effects of Japanese traditional medicines on circulating cytokine levels in women with hot flashes., Menopause, Vol.18, No.1, 85-92, 2011.
(Summary)
The effects of the Japanese traditional medicines keishibukuryogan and kamishoyosan on circulating cytokines were examined to clarify the difference in the actions of Japanese traditional medicines in women with hot flashes. Seven premenopausal, 51 perimenopausal, 45 spontaneously postmenopausal and 17 surgically postmenopausal women who had complained of hot flashes were enrolled in this study. Eighty women who hoped to receive Japanese traditional medicines were randomly assigned in open, parallel-group fashion to a keishibukuryogan group or kamishoyosan group. Forty women who did not want any treatment for hot flashes were followed up for 6 months as a control group. Serum levels of cytokines were measured using a multiplexed human cytokine assay. The proportions of responders in women treated with keishibukuryogan and kamishoyosan were 73.7% and 69.2%, respectively. Serum monocyte chemotactic protein-1 level in women treated with keishibukuryogan decreased significantly (P = 0.0037). On the other hand, concentrations of interleukin (IL)-6 and macrophage inflammatory protein-1β in women treated with kamishoyosan decreased significantly (P = 0.019 and P = 0.039, respectively). In both keishibukuryogan and kamishoyosan responder groups, serum IL-8 concentrations were reduced significantly (P = 0.021 and P = 0.014, respectively). Both treatments with keishibukuryogan and kamishoyosan reduce the circulating IL-8 level, which is involved in thermoregulation in perimenopausal women with hot flashes. In addition, keishibukuryogan decreases circulating monocyte chemotactic protein-1 level in postmenopausal women.
菊地 久美子, Masahito Tomotake, Junichi Iga, Shu-ichi Ueno, Minoru Irahara and Tetsuro Ohmori : Psychological features of pregnant women predisposing to depressive state during the perinatal period, Rinsho Seishin Igaku, Vol.39, No.11, 1459-1468, 2010.
(Keyword)
周産期 / perinatal period / 抑うつ / depressive state / 心理特性 / psychological features / EPDS / Edinburgh Postnatal Depression Scale
Akiko Abe, Hiroyuki Furumoto, Minoru Irahara, Hiroyasu Ino, Masaharu Kamada, Osamu Naka, Masaru Sasaki, Toshiaki Kagawa, Osamu Okitsu and Norio Kushiki : The impact of systematic para-aortic and pelvic lymphadenectomy on survival in patients with optimally debulked ovarian cancer., The Journal of Obstetrics and Gynaecology Research, Vol.36, No.5, 1023-1030, 2010.
(Summary)
The objective of this study was to verify the impact of systematic retroperitoneal lymphadenectomy on survival in patients with ovarian cancer.
Yuji Taketani, Kelly Eduardo, Yoshimura Yasunori, Hoshiai Hiroshi, Minoru Irahara, Mizunuma Hideki, Saito Hidekazu, Andoh Kazumichi, Bebia Zourab and Yanaihara Takumi : Recombinant follicle-stimulating hormone (follitropin alfa) for ovulation induction in Japanese patients with anti-estrogen-ineffective oligo- or anovulatory infertility: results of a phase II dose response study, Reproductive Medicine and Biology, Vol.9, No.2, 91-97, 2010.
木内 理世, Toshiya Matsuzaki, Takeshi Iwasa, 三室 卓久 and Minoru Irahara : エクルーシス試薬テストステロンⅡ,LH,FSHの基準値の検討, Japanese Journal of Medicine and Pharmaceutical Science, Vol.64, No.1, 87-93, 2010.
115.
Hiroaki Yanagawa, Masatoshi Kishuku, Masashi Akaike, Hiroyuki Azuma and Minoru Irahara : View of physicians on and barriers to patient enrollment in a multicenter clinical trial: experience in a Japanese rural area, International Archives of Medicine, Vol.3, No.1, 7, 2010.
(Summary)
Clinical trials in the general practice setting are important for providing evidence on the effectiveness and safety of different agents under various conditions. In conducting these trials, the participation of physicians and patient recruitment are important issues. Various investigations in the literature have reported views and attitudes of physicians on various types of clinical trials. Nevertheless, there is still little information concerning physicians participating in a clinical trial and among them, those who could not recruit any patients (unsuccessful physician recruiters). In 2003, we collaborated in a large-scale multicenter study of Japanese hypertensive patients (COPE Trial). In Tokushima University Hospital and 18 other medical institutions, we investigated the views and attitudes of unsuccessful physician recruiters in comparison with successful physician recruiters, using a questionnaire. The questionnaire was provided by mail to 47 physicians and 27 (57%) responded. The response rate was 79% for successful physician recruiters compared to 43% (P = 0.014) for unsuccessful physician recruiters. More successful physician recruiters (73%) than unsuccessful physician recruiters (42%) stated they had participated and enrolled patients in previous multicenter clinical trials. A significantly higher number of successful physician recruiters than unsuccessful physician recruiters (42%; P = 0.040) considered the presence of a support system with clinical research coordinators (CRC) as the reason for participation (80%). A large number of unsuccessful physician recruiters experienced difficulty in obtaining informed consent (67%), whereas a significantly smaller number of successful physician recruiters experienced such difficulty (20%; P = 0.014). The difficulties experienced by unsuccessful physician recruiters in the trial were as follows: inability to find possible participants (100%), difficulty in obtaining informed consent (58%), cumbersome procedures (58%), difficulty in long-term follow up (33%), and insufficient tools for explanation and obtaining informed consent (8%). This survey showed that successful physician recruiters consider a support system with CRC of value, and that they are skillful in obtaining informed consent. These views and attitudes may have originated from past experience involving clinical trials. In this regard, we need to develop an infrastructure to enlighten physicians on this support system for the promotion of clinical trials.
Hiroaki Yanagawa, Junji Terao, Eiji Takeda, Yoshihisa Takaishi, Yoshiki Kashiwada, Kazuyoshi Kawazoe, Fushitani Shuji, Koichiro Tsuchiya, Aiko Yamauchi, Sato Chiho and Minoru Irahara : Consultation clinics for complementary and alternative medicine at Japanese university hospitals: An analysis at Tokushima University Hospital, Experimental and Therapeutic Medicine, Vol.1, No.3, 481-483, 2010.
(Summary)
Here, we report on a Consultation Clinic for Complementary and Alternative Medicine (CAM) which we established at Tokushima University Hospital in July of 2007 with the aim of providing person-to-person information on CAM, though not CAM therapy itself. In December of 2008, we received 55 applications for consultation, 37% concerning health foods, 37% Japanese herbal medicine (Kampo), and 26% various other topics. The consultants (nutritionists and pharmacists) communicated individually with 38 applicants; malignancies (26%) and cardiovascular disease (24%) were the main underlying concerns. To promote the quality of consultation, data was collected by means of focus group interviews concerning the perspective of the consultants. Safe and effective use of CAM requires a network of communication linking individuals, consultation teams, physicians, primary care institutions and university hospitals. To advance this goal, we plan to broaden the efforts described herein. Our findings indicate that the specific role of the consultation clinic in promoting the scientific use of CAM merits further study.
Takeshi Iwasa, Toshiya Matsuzaki, Riyo Kinouchi, Shinobu Fujisawa, Masahiro Murakami, Machiko Kiyokawa, Akira Kuwahara, Toshiyuki Yasui and Minoru Irahara : Neonatal LPS injection alters the body weight regulation systems of rats under non-stress and immune stress conditions., International Journal of Developmental Neuroscience, Vol.28, No.1, 119-124, 2010.
(Summary)
It has been reported that prenatal immune stress induced by lipopolysaccharides or cytokines increases food intake and leads to obesity and other features of metabolic syndrome in adulthood. Using Sprague-Dawley rats, we evaluated whether neonatal LPS injection altered their body weight regulation systems under non-stress and immune stress conditions. On Day 10 after birth, all pups were injected with LPS (100 microg/kg, i.p.) (PND(10)LPS) or saline (PND(10)Saline). After weaning, body weight was significantly elevated in PND(10)LPS compared with PND(10)Saline. Thereafter, the rats were injected with LPS (100 microg/kg, i.p.) or saline (used as a basal condition) from 7 to 8 weeks of age. Under basal conditions, cumulative food intake were significantly higher, serum leptin concentration was significantly increased, and hypothalamic NPY mRNA expression was significantly decreased in PND(10)LPS compared with PND(10)Saline. Under adult LPS injected conditions, body weight gain and cumulative food intake were suppressed in both the PND(10)LPS and PND(10)Saline groups compared with those observed under basal adult saline-injected conditions. The suppressive effects induced by adult LPS injection were less evident in the PND(10)LPS group than in the PND(10)Saline group. Adult LPS injection increased the serum leptin concentration in the PND(10)Saline rats, but not in the PND(10)LPS rats. In addition, adult LPS injection increased the mRNA expression of anorexinergic factors (IL-1beta, and TNF-alpha), and decreased that of the orexinergic factor NPY in both groups. However, the influence of adult LPS injection upon these factors was less evident in the PND(10)LPS group than in the PND(10)Saline group. These results suggest that neonatal LPS injection alters body weight regulation under both non-stress and immune stress conditions in male rats. Changes in the endocrine, neuropeptide, and cytokine regulation systems might be involved in these alterations.
Toshiyuki Yasui, Sumika Matsui, Ayako Saijo, Takashi Kaji, Satoshi Yamamoto, Hirokazu Uemura, Toshiya Matsuzaki and Minoru Irahara : Association of N-terminal pro B-type natriuretic peptide and sex hormone-binding globulin in non-obese peri- and postmenopausal women., Clinica Chimica Acta, Vol.411, No.3-4, 280-284, 2010.
(Summary)
BACKGROUND: The relationships between N-terminal fragment proBNP (B-type natriuretic peptide) (NT-proBNP) and sex steroid hormones have not been fully elucidated. We examined these associations in pre-, peri- and postmenopausal women without known cardiovascular disease. We also examined the change in circulating NT-proBNP caused by a gonadotrophin-releasing hormone (GnRH) agonist in order to clarify the effect of acute hormone deficiency on NT-proBNP. METHODS: Forty-nine premenopausal women, 101 perimenopausal women and 108 postmenopausal women were enrolled in one study. Forty-four premenopausal women with leiomyoma were recruited for another study, and 22 of those women were treated with a GnRH agonist. Serum levels of NT-proBNP, estradiol, testosterone and sex hormone-binding globulin (SHBG) were measured. RESULTS: NT-proBNP concentrations showed significant inverse correlations with body mass index (BMI) in peri- and postmenopausal women. Serum NTproBNP concentrations showed significant positive correlations with SHBG in peri- and postmenopausal women. These significant correlations remained after adjustment for age and BMI. Serum NT-proBNP concentration was significantly decreased after GnRH agonist administration, while NT-proBNP concentration in the control group did not change significantly. Serum SHBG level was also significantly decreased after GnRH agonist administration. CONCLUSION: Circulating NT-proBNP levels are positively associated with SHBG levels in non-obese peri- and postmenopausal women, and this relationship was found under the condition of acute hormone deficiency induced by GnRH agonist treatment.
Takeshi Iwasa, Toshiya Matsuzaki, Masahiro Murakami, Shinobu Fujisawa, Riyo Kinouchi, Ganbat Gereltsetseg, Akira Kuwahara, Toshiyuki Yasui and Minoru Irahara : Effects of intrauterine undernutrition on hypothalamic Kiss1 expression and the timing of puberty in female rats., The Journal of Physiology, Vol.588, No.Pt 5, 821-829, 2010.
(Summary)
Recent studies have suggested that intrauterine undernutrition is closely associated with the pathogenesis of diseases after birth. Perinatal undernutrition is known to disturb the development of reproductive function and delay the onset of puberty in some species. Using a rat model, we determined the effects of prenatal undernutrition on the development of the hypothalamic kisspeptin system and evaluated whether the alteration of the kisspeptin system contributes to the delayed onset of puberty induced by prenatal undernutrition. We also evaluated the effects of prenatal undernutrition on the developmental changes in serum leptin levels because leptin was a putative positive regulator of the hypothalamic kisspeptin system. We compared the timing of vaginal opening (VO) and the developmental changes in body weight, hypothalamic Kiss1 mRNA levels, and serum leptin concentrations between offspring with prenatal undernutrition (UN offspring) and normal nutrition (NN offspring). After birth, the UN offspring showed rapid growth and had caught up to body weight of the NN offspring by postnatal day 12. After postnatal day 16, the UN offspring showed significantly lower Kiss1 mRNA levels than the NN offspring, despite their significantly higher serum leptin levels (at days 20 and 28). The timing of VO in the UN offspring was delayed compared with that in the NN offspring, and chronic central injection of kisspeptin normalized the timing of VO in the UN offspring. These results suggest that decreased hypothalamic kisspeptin action contributes to the delayed onset of puberty in prenatally undernourished female rats. Increased leptin resistance in the kisspeptin system might be involved in these alterations.
Rie Ogata, Toshiya Matsuzaki, Takeshi Iwasa, Machiko Kiyokawa, Naoko Tanaka, Akira Kuwahara, Toshiyuki Yasui and Minoru Irahara : Hypothalamic Ghrelin suppresses pulsatile secretion of luteinizing hormone via beta-endorphin in ovariectomized rats., Neuroendocrinology, Vol.90, No.4, 364-370, 2009.
(Summary)
OBJECTIVES: Ghrelin, an endogenous growth hormone secretagogue, is a known accelerator of feeding behavior and suppresses pulsatile secretion of luteinizing hormone (LH) in ovariectomized rats. However, the mechanisms underlying this action remain unclear. We examined the effects of naloxone (NAL), a specific opioid antagonist, on the suppression of pulsatile LH secretion by ghrelin to determine whether beta-endorphin (beta-END) is involved in this suppressive effect. METHODS: Ghrelin was administered intracerebroventricularly, and NAL was injected intravenously in ovariectomized rats; then, serum LH concentrations were measured by radioimmunoassay in blood samples drawn every 6 min for 2 h to analyze pulsatile secretion. RESULTS: Administration of ghrelin significantly reduced mean LH concentration and pulse frequency. Coadministration of NAL with ghrelin significantly restored mean LH concentration and pulse frequency. CONCLUSION: Suppressive effect of intracerebroventricular injection of ghrelin on pulsatile LH secretion was mediated by beta-END, suggesting that hypothalamic ghrelin suppressed pulsatile gonadotropin-releasing hormone secretion via beta-END in female rats.
Toshiyuki Yasui, Ayako Saijo, Hirokazu Uemura, Naoko Tsuchiya, Mitsutoshi Yuzurihara, Yoshio Kase and Minoru Irahara : Interleukin-7 is associated with monocyte chemoattractant protein-1 and soluble E-selectin levels in peripheral blood of newly post-menopausal women., Journal of Reproductive Immunology, Vol.81, No.1, 97-102, 2009.
(Summary)
Interleukin (IL-7), which is a regulator of development and homeostatic maintenance of T and B cells, is implicated in the induction of leukocyte-endothelial cell adhesion during inflammatory events. We hypothesized that circulating IL-7 is associated with cytokines and chemokines, vascular inflammatory markers and lipid profiles involved in regulating cell adhesion in post-menopausal women. Serum levels of 8 cytokines and chemokines were simultaneously measured in 200 post-menopausal women using a multiplexed human cytokine assay. C-reactive protein, soluble vascular cell adhesion molecule, soluble intercellular adhesion molecule and soluble E-selectin were measured as inflammatory markers. Serum IL-7 concentration was significantly correlated with serum MCP-1 concentration and the correlation remained after adjustment for age and body mass index (BMI). Serum IL-7 levels also showed significant positive correlations with serum levels of IL-10 and IL-6. In addition, the serum IL-7 concentration showed significant positive correlations with levels of soluble E-selectin and triglyceride after adjustment for age and BMI. We conclude that there is a relationship between circulating IL-7, MCP-1 and soluble E-selectin, and that IL-7 may be involved in regulating inflammatory cell adhesion together with MCP-1 and E-selectin in post-menopausal women.
(Keyword)
Age Factors / Body Mass Index / C-Reactive Protein / Cell Adhesion / Chemokine CCL2 / E-Selectin / Female / Humans / Inflammation / Intercellular Adhesion Molecule-1 / Interleukin-10 / Interleukin-6 / Interleukin-7 / Middle Aged / Postmenopause / Triglycerides / Vascular Cell Adhesion Molecule-1 / Vascular Diseases
Takeshi Iwasa, Toshiya Matsuzaki, Masahiro Murakami, Fumi Shimizu, Akira Kuwahara, Toshiyuki Yasui and Minoru Irahara : Reproducibility of luteinizing hormone hypersecretion in different phases of the menstrual cycle in polycystic ovary syndrome., The Journal of Obstetrics and Gynaecology Research, Vol.35, No.3, 514-519, 2009.
(Summary)
AIM: We evaluated the reproducibility of an elevated luteinizing hormone (LH) level or elevated LH/follicle-stimulating hormone (FSH) ratio in different phases of the menstrual cycle in patients with polycystic ovary syndrome (PCOS). Furthermore, we evaluated the influence of cycle days and body mass index on LH levels using different days from menses or withdrawal bleeding. METHODS: Forty-three patients with PCOS and 37 controls were enrolled. All patients with PCOS had elevated LH levels and LH/FSH ratio, polycystic ovarian morphology and chronic anovulation at diagnosis. After their diagnoses, we measured serum LH and FSH in the early period and/or late period of the follicular phase. RESULTS: The rate of patients with elevated LH levels and LH/FSH ratio were significantly higher in the late phase than in the early phase in PCOS. In the early phase, only 52% of patients had elevated LH levels and LH/FSH ratio. We failed to demonstrate an inverse relationship between the LH level and BMI. Conclusions: LH levels of patients with PCOS were strongly influenced by the days from menses or withdrawal bleeding. In the early period, the reproducibility of elevated LH levels or LH/FSH ratio was poor even in patients previously diagnosed with them.
(Keyword)
Adult / Body Mass Index / Female / Follicle Stimulating Hormone / Humans / Luteinizing Hormone / Menstrual Cycle / Polycystic Ovary Syndrome
Toshiyuki Yasui, Ayako Saijo, Hirokazu Uemura, Toshiya Matsuzaki, Naoko Tsuchiya, Mitsutoshi Yuzurihara, Yoshio Kase and Minoru Irahara : Effects of oral and transdermal estrogen therapies on circulating cytokines and chemokines in postmenopausal women with hysterectomy., European Journal of Endocrinology, Vol.161, No.2, 267-273, 2009.
(Summary)
OBJECTIVE: The aim of the present study was to determine the different effects of oral estrogen therapy (ET) and transdermal ET on changes in circulating levels of cytokines and chemokines in relationship to changes in markers of inflammation in postmenopausal women with hysterectomy. METHODS: Fifty-five postmenopausal women with hysterectomy were randomly assigned in open, parallel-group fashion to an oral ET group and a transdermal ET group. Serum levels of cytokines and chemokines were simultaneously measured using a multiplexed human cytokine assay. Serum concentrations of high-sensitive C-reactive protein, soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1, and E-selectin were measured as vascular inflammation markers. RESULTS: Both oral ET and transdermal ET significantly decreased serum interleukin (IL)-7 concentrations at 12 months (P=0.020 and P=0.015 respectively). Transdermal ET decreased serum concentrations of IL-8, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-1beta (P=0.05, P=0.019, and P=0.029), but oral ET increased IL-8 level (P=0.025). There were significant differences in percentage changes in IL-8 and MIP-1beta between the oral and transdermal ET groups. Oral ET significantly decreased E-selectin level after 12 months. CONCLUSION: Transdermal ET reduces circulating levels of IL-8, MCP-1, and MIP-1beta, while both oral ET and transdermal ET reduce circulating level of IL-7.
Takeshi Iwasa, Toshiya Matsuzaki, Masahiro Murakami, Riyo Kinouchi, Rie Ogata, Akira Kuwahara, Toshiyuki Yasui and Minoru Irahara : Neonatal lipopolysaccharide exposure attenuates the homotypic stress-induced suppression of LH secretion in adulthood in male rat., International Journal of Developmental Neuroscience, Vol.27, No.4, 345-349, 2009.
(Summary)
Neonatal immune challenges have a long-lasting influence on immune response. Using male Sprague-Dawley rats, we examined whether neonatal lipopolysaccharide (LPS) challenge alters the sensitivity of male reproductive function to adult LPS challenge and at which level (central or testes) the alteration occurs. We also examined the mRNA expression of proinflammatory cytokines in the hypothalamus and testes because they have a pivotal role in immune stress-induced suppression of gonadotropin secretion and testosterone synthesis. On day 10 after birth, all the pups were injected with LPS (100 microg/kg, i.p.) or saline. Thereafter, LPS (100 microg/kg, i.p.) or saline was injected in adulthood at 8 weeks of age. The serum LH concentration was decreased by LPS injection during adulthood in the neonatal saline-injected rats. This suppressive effect was not seen in the neonatal LPS-injected rats. The serum testosterone concentration was decreased by adult LPS injection in both the neonatal LPS-injected and neonatal saline-injected rats. The expression levels of KiSS-1, which encodes kisspeptin, known to have a crucial role in the regulation of gonadotropin secretion, and GnRH mRNA in the hypothalamus and LHbeta mRNA in the pituitary were not influenced by neonatal or adult LPS injection. On the other hand, the expression levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) mRNA in the hypothalamus and testes were increased by adult LPS injection in both the neonatal LPS-injected and neonatal saline-injected rats. Furthermore, the expression levels of these factors in the hypothalamus after adult LPS injection were significantly lower in the neonatal LPS-injected rats than in the neonatal saline-injected rats. These findings indicate that neonatal LPS challenge reduces the sensitivity of male reproductive function to the suppressive effects of LPS, mainly at the central level. Attenuation of proinflammatory cytokine synthesis in the hypothalamus might be involved in this alteration.
Toshiyuki Yasui, Masayo Yamada, Hirokazu Uemura, Shu-Ichi Ueno, Shusuke Numata, Tetsuro Ohmori, Naoko Tsuchiya, Masamichi Noguchi, Mitsutoshi Yuzurihara, Yoshio Kase and Minoru Irahara : Changes in circulating cytokine levels in midlife women with psychological symptoms with selective serotonin reuptake inhibitor and Japanese traditional medicine., Maturitas, Vol.62, No.2, 146-152, 2009.
(Summary)
OBJECTIVE: The aim of the present study was to compare the effects on serum cytokine concentrations of paroxetine, a selective serotonin re-uptake inhibitor, and kamishoyosan, a Japanese traditional medicine, in midlife women with psychological symptoms. METHODS: Seventy-six women with psychological symptoms such as anxiety and mild depression as menopausal symptoms were enrolled in this study. Thirty-eight women received oral administration of 10mg paroxetine every day, and 38 women received oral administration of kamshoyosan every day for 6 months. Overall climacteric symptoms were assessed using Greene's climacteric scale. Serum levels of cytokines were measured using a multiplexed human cytokine assay. RESULTS: Greene's total scores in both women treated with paroxetine and in women treated with kamishoyosan decreased significantly. Percentage decreases in Greene's total, psychological and vasomotor scores during the 6-month period in the paroxetine group were significantly greater than those in the kamishoyosan group. Serum IL-6 concentration in women treated with paroxetine decreased significantly. Serum concentrations of IL-8, IL-10, macrophage inflammatory protein (MIP)-1beta and monocyte chemoattractant protein-1 in women treated with paroxetine decreased significantly. On the other hand, serum IL-6 concentration in women treated with kamishoyosan decreased significantly, but other serum concentrations did not change significantly. CONCLUSION: Decrease in IL-6 concentration may be involved in the mechanism of the actions of both paroxetine and kamishoyosan in women with psychological symptoms, and IL-6 may therefore be useful as a marker of treatment. The action of paroxetine may also be associated with decreases in IL-8, IL-10, MIP-1beta.
(Keyword)
Administration, Oral / Angiosperms / Climacteric / Cytokines / Depression / Drugs, Chinese Herbal / Hot Flashes / Humans / Medicine, East Asian Traditional / Middle Aged / Paroxetine / Phytotherapy / Plant Extracts / Serotonin Uptake Inhibitors
Toshiyuki Yasui, Hirokazu Uemura, S Hyodo, M Yamada, Satoshi Yamamoto, M Maegawa, N Tsuchiya, M Noguchi, M Yuzurihara, Y Kase and Minoru Irahara : Raloxifene reduces circulating levels of interleukin-7 and monocyte chemoattractant protein-1 in postmenopausal women., Atherosclerosis, 2009.
(Summary)
OBJECTIVE: The aim of the present study was to determine the effects of raloxifene on changes in circulating levels of cytokines and chemokines in relation to changes in lipid profiles and markers of inflammation in postmenopausal women. METHODS: Fifty-three postmenopausal women aged 45-65 years old were randomly assigned in open, parallel-group fashion to a control group or raloxifene group. Twenty-six women received oral administration of 60mg raloxifene every day and 27 women did not receive any drugs for 12 months. Serum cytokines levels were simultaneously measured using a multiplexed human cytokine assay. RESULTS: Serum IL-7 concentrations in women who received raloxifene were decreased significantly (p=0.014), and serum monocyte chemoattractant protein (MCP)-1 concentrations in women who received raloxifene were decreased significantly (p=0.0003) at 12 months. In the control group, serum levels of MCP-1 and IL-7 did not show significant changes. There were significant differences (p=0.032 and p=0.0024, respectively) in percentage changes in IL-7 and MCP-1 in the control group and in the raloxifene group. Levels of low-density lipoprotein cholesterol (LDL-C) and E-selectin were decreased significantly in women who received raloxifene, but the percentage changes in LDL-C and E-selectin over a period of 12 months were not significantly correlated with percentage changes in IL-7 and MCP-1 over the same period. CONCLUSION: Circulating levels of IL-7 and MCP-1 decrease in postmenopausal women who received raloxifene.
Takeshi Iwasa, Toshiya Matsuzaki, Masahiro Murakami, Riyo Kinouchi, Fumi Shimizu, Akira Kuwahara, Toshiyuki Yasui and Minoru Irahara : Neonatal immune challenge affects the regulation of estrus cyclicity and feeding behavior in female rats., International Journal of Developmental Neuroscience, Vol.27, No.1, 111-114, 2008.
(Summary)
A single immune challenge with lipopolysaccharide (LPS) in the neonatal period has a long-lasting influence on immune response. Using female Sprague-Dawley rats, we examined whether neonatal LPS challenge influences the life-long neuroendocrine sensitivity of reproductive function and feeding behavior to LPS, and whether stress-related neuropeptides and their receptors are involved in neonatal LPS-induced physiological change. On day 10 after birth, all pups were injected with LPS (100 microg/kg, i.p.) or saline. Then, in Experiment 1, LPS (100 microg/kg, i.p.) or saline was injected at diestrous in adulthood, and the length of the estrous cycle, 24h food intake and body weight change were recorded. In Experiment 2, the mRNA expression levels of corticotropin-releasing hormone (CRH), urocortin (UCN), urocortin 2 (UCN2), CRH receptor type 1 (CRH-R1) and CRH receptor type 2 (CRH-R2) in the hypothalamus were measured using real-time PCR. LPS injection in adulthood prolonged the estrous cycle in neonatal LPS-injected rats. LPS injection in adulthood decreased food intake and body weight in both neonatal LPS- and saline-injected rats, more so in the latter. Basal expressions of UCN2 and CRH-R2 mRNA were higher in neonatal LPS-injected rats than in saline-injected rats. These findings indicate that neonatal immune challenge influences the anti-stress regulation of the estrous cycle and feeding behavior in adulthood. Increased expression of UCN2 and CRH-R2 might enhance the sensitivity of the estrous cycle in suppressing the effects of LPS.
Toshiyuki Yasui, Hirokazu Uemura, Minoru Irahara, Makoto Arai, Noriko Kojimahara, Ryugo Okabe, Yasutomo Ishii, Shin-Ichi Tashiro and Hiroshi Sato : Associations of endogenous sex hormones and sex hormone-binding globulin with lipid profiles in aged Japanese men and women., Clinica Chimica Acta, Vol.398, No.1-2, 43-47, 2008.
(Summary)
BACKGROUND: The associations of endogenous estrogen with lipid profiles and insulin resistance were conflicting in both men and women. We determined the associations of serum estradiol level and free estradiol index (FEI) with lipid profiles and insulin resistance in aged Japanese men and women. METHODS: One hundred seventy-four men and 208 postmenopausal women aged from 50 to 85 y were included in this study. Lipid profiles, fasting glucose and insulin as well as estradiol, testosterone, dehydroepiandrosterone-sulfate (DHEA-S) and sex hormone-binding globulin (SHBG) in serum were measured. RESULTS: Serum estradiol concentration in men showed a significant and negative correlation with high density lipoprotein-cholesterol (HDL-C) concentration and a significant and positive correlation with triglyceride (TG) after adjustment for age and body mass index (BMI). In addition, estradiol level was positively correlated with insulin and HOMA index. In women, serum levels of estradiol and testosterone were not correlated with lipid profiles and insulin resistance. SHBG concentration was negatively correlated with TG after adjustment for age and BMI in women. CONCLUSION: Endogenous estradiol level is associated with unfavorable lipid profiles and insulin resistance in aged men. In aged women, SHBG level is associated with favorable lipid profiles.
(Keyword)
Aged / Aged, 80 and over / Androgens / Body Mass Index / Cholesterol, HDL / Dehydroepiandrosterone Sulfate / Estradiol / Female / Gonadal Steroid Hormones / Homeostasis / Humans / Insulin / Insulin Resistance / Japan / Lipids / Male / Middle Aged / Sex Hormone-Binding Globulin / Testosterone / Triglycerides
Masahiro Murakami, Toshiya Matsuzaki, Takeshi Iwasa, Toshiyuki Yasui, Minoru Irahara, Tomohiro Osugi and Kazuyoshi Tsutsui : Hypophysiotropic role of RFamide-related peptide-3 in the inhibition of LH secretion in female rats., The Journal of Endocrinology, Vol.199, No.1, 105-112, 2008.
(Summary)
Gonadotropin-inhibitory hormone (GnIH), a newly discovered hypothalamic RFamide peptide, inhibits reproductive activity by decreasing gonadotropin synthesis and release in birds. The gene of the mammalian RFamide-related peptides (RFRP) is orthologous to the GnIH gene. This Rfrp gene gives rise to the two biologically active peptides RFRP-1 (NPSF) and RFRP-3 (NPVF), and i.c.v. injections of RFRP-3 suppress LH secretion in several mammalian species. In this study, we show whether RFRP-3 affects LH secretion at the pituitary level and/or via the release of GnRH at the hypothalamus in mammals. To investigate the suppressive effects of RFRP-3 on the mean level of LH secretion and the frequency of pulsatile LH secretion in vivo, ovariectomized (OVX) mature rats were administered RFRP-3 using either i.c.v. or i.v. injections. Furthermore, the effect of RFRP-3 on LH secretion was also investigated using cultured female rat pituitary cells. With i.v. administrations, RFRP-3 significantly reduced plasma LH concentrations when compared with the physiological saline group. However, after i.c.v. RFRP-3 injections, neither the mean level of LH concentrations nor the frequency of the pulsatile LH secretion was affected. When using cultured pituitary cells, in the absence of GnRH, the suppressive effect of RFRP-3 on LH secretion was not clear, but when GnRH was present, RFRP-3 significantly suppressed LH secretion. These results suggest that RFRP-3 does not affect LH secretion via the release of GnRH, and that RFRP-3 directly acts upon the pituitary to suppress GnRH-stimulated LH secretion in female rats.
Yuka Miyatani, Toshiyuki Yasui, Hirokazu Uemura, Masayo Yamada, Toshiya Matsuzaki, Akira Kuwahara, Naoko Tsuchiya, Mitsutoshi Yuzurihara, Yoshio Kase and Minoru Irahara : Associations of circulating adiponectin with estradiol and monocyte chemotactic protein-1 in postmenopausal women., Menopause, Vol.15, No.3, 536-541, 2008.
(Summary)
OBJECTIVE: The aim of the present study was to clarify the association of serum adiponectin concentrations with serum 17beta-estradiol concentrations in pre-, peri-, and postmenopausal women. In addition, the associations of serum adiponectin with serum concentrations of proinflammatory and anti-inflammatory cytokines were examined in women during the menopausal transition. DESIGN: A total of 197 women were enrolled in this study: 33 premenopausal women, 80 perimenopausal women, and 84 postmenopausal women. Serum adiponectin concentration was measured by an enzyme-linked immunosorbent assay. Serum concentrations of the proinflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha, anti-inflammatory cytokine IL-10, and the chemokines IL-8, macrophage inflammatory protein-1beta and monocyte chemotactic protein-1 were measured by using a multiplexed human cytokine assay. RESULTS: Serum adiponectin concentration showed a significant negative correlation with serum estradiol concentration (r= -0.400, P=0.001) in postmenopausal women but not in pre- and perimenopausal women, and this correlation was significant after adjustment for age and body mass index. Serum adiponectin concentration also showed a significant negative correlation with serum monocyte chemotactic protein-1 concentration (r= -0.244, P=0.05) in postmenopausal women. CONCLUSION: An increase in adiponectin level due to a decrease in estradiol results in a reduction in monocyte chemotactic protein-1 level in postmenopausal women, suggesting that adiponectin may be associated with a protective role against insulin resistance and atherosclerosis, which occur in the postmenopausal stage.
Fumi Shimizu, Toshiya Matsuzaki, Takeshi Iwasa, Naoko Tanaka, Masahiro Minakuchi, Akira Kuwahara, Toshiyuki Yasui, Hiroyuki Furumoto and Minoru Irahara : Transition of leptin receptor expression during pubertal development in female rat pituitary., Endocrine Journal, Vol.55, No.1, 191-198, 2008.
(Summary)
Leptin is thought to play important roles in pubertal development and reproductive function in the female. Leptin receptor is expressed in various tissues including the pituitary and hypothalamus. We investigated the transition of leptin receptor (Ob-R) expression in female rat pituitary during pubertal development. Real-time RT-PCR was performed for long-form leptin receptor (Ob-Rb) and short-form leptin receptor (Ob-Ra) in the pituitary and cerebrum of the rats aged 4 (juvenile), 6 (pubertal), and 8 weeks (adult). Double immunohistochemical colocalization of Ob-R and luteinizing hormone (LH) was performed in pituitaries from 4-week-old female rats. Serum leptin concentrations of 4-, 6-, and 8-week-old rats were measured by radioimmunoassay. In the pituitary, expression of Ob-Rb mRNA in 4-week-old rats (1.00 +/- 0.16) was significantly higher than in 8-week-old rats (0.61 +/- 0.07, p<0.05), although expression of Ob-Ra mRNA did not differ among 4-, 6-, and 8-week-old rats. In cerebrum, Ob-Ra and Ob-Rb mRNA expressions did not differ significantly among 4-, 6-, and 8-week-old rats. Intense staining of Ob-R and colocalization of Ob-R and LH were seen in 4-week-old rat pituitary. On the other hand, serum concentrations of leptin in 6- and 8-week-old rats were significantly higher than those in 4-week-old rats (p<0.05, p<0.01, respectively). In conclusion, since the pituitary gonadotroph is a potential target of leptin, the juvenile rat pituitary might prepare for a subsequent increase of serum leptin concentration by expressing Ob-Rb.
Hirokazu Uemura, Toshiyuki Yasui, Y Miyatani, M Yamada, Mineyoshi Hiyoshi, Kokichi Arisawa and Minoru Irahara : Circulating profiles of osteoprotegerin and soluble receptor activator of nuclear factor kappaB ligand in post-menopausal women., Journal of Endocrinological Investigation, Vol.31, No.2, 163-168, 2008.
(Summary)
OBJECTIVE: The aim of this study was to elucidate the detail profiles of circulating osteoprotegerin (OPG) and soluble receptor activator of nuclear factor kappaB ligand (sRANKL) in post-menopausal women. METHODS: Eighty Japanese post-menopausal women were enrolled in this cross-sectional study. Circulating OPG and free fraction of sRANKL (free sRANKL), PTH, calcium and phosphorus, age, years since menopause, body mass index, bone mineral density of the vertebral bodies (LBMD) and bone turnover markers were determined in each subject. RESULTS: In rank order correlation analysis, serum OPG concentrations had a significant positive correlation with age (r=0.291, p=0.024) and a marginal significant negative correlation with LBMD (r=-0.247, p=0.062). However they did not have correlations with LBMD or other parameters after adjustment for age. Serum free sRANKL concentrations had a significant positive correlation with age (r=0.332, p=0.010) and a significant negative correlation with LBMD (r=-0.608, p<0.001). This correlation with LBMD persisted after adjustment for age. In a multiple regression analysis with a stepwise model, the main determinants of LBMD were age and serum free sRANKL (p=0.015 and p=0.006, respectively). CONCLUSIONS: We found the increase in circulating OPG and sRANKL with age and a robust negative correlation between circulating free sRANKL and LBMD after adjustment for age. The increase in circulating free sRANKL may reflect directly or indirectly the conditions coexistent with bone loss in post-menopausal women.
(Keyword)
Alkaline Phosphatase / Bone Density / Calcium / Collagen Type I / Female / Humans / Middle Aged / Osteoporosis, Postmenopausal / Osteoprotegerin / Parathyroid Hormone / Peptides / Phosphorus / Postmenopause / RANK Ligand / Solubility
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Toshiyuki Yasui, Hirokazu Uemura, Masayo Yamada, Toshiya Matsuzaki, Naoko Tsuchiya, Masamichi Noguchi, Mitsutoshi Yuzurihara, Yoshio Kase and Minoru Irahara : Associations of interleukin-6 with interleukin-1beta, interleukin-8 and macrophage inflammatory protein-1beta in midlife women., Cytokine, Vol.41, No.3, 302-306, 2008.
(Summary)
OBJECTIVE: The aim of the present study was to determine the associations of interleukin (IL)-6 with other cytokines and chemokines and to compare these associations in peri- and postmenopausal women. METHODS: Ninety-nine perimenopausal and 92 postmenopausal women were enrolled in this study. Serum concentrations of IL-6, IL-1beta, IL-2, IL-4, IL-5, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, tumor necrosis factor (TNF)-alpha, interferon gamma, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage (GM)-CSF, macrophage inflammatory protein (MIP)-1beta and monocyte chemotactic protein (MCP)-1 were measured simultaneously using a multiplexed cytokine assay. RESULTS: Among the 17 cytokines, IL-6, IL-1beta, IL-5, IL-7, IL-8, IL-10, MCP-1 and MIP-1beta were detected in serum in more than 50% of the women. Serum levels of IL-4 and MCP-1 in postmenopausal women were significantly higher than those in perimenopausal women. Serum IL-6 concentrations showed significant and positive correlations with serum concentrations of IL-1beta, IL-8, MIP-1beta, IL-7 and MCP-1 in women regardless of menopausal status, and these correlations were still significant after adjustment for age and body mass index. CONCLUSION: Serum IL-6 concentration was found to be closely associated with serum concentrations of IL-1beta, IL-8, MIP-1beta, IL-7 and MCP-1 in women regardless of menopausal status, suggesting that these cytokines act in concert with the progression of several symptoms and various diseases.
Sawako Kinouchi, Junichi Iga, Shu-ichi Ueno, Ken Yamauchi, Shusuke Numata, Hongwei Song, Satsuki Sumitani, Sumiko Shibuya-Tayoshi, Mari Haku, Toshiyuki Yasui, Minoru Irahara, Kyoko Morita, Kazuhito Rokutan and Tetsuro Ohmori : FKBP5, SERT and COMT mRNA expressions in the peripheral leukocytes during menstruation cycle in healthy reproductive females., Neuroscience Letters, Vol.434, No.1, 124-128, 2008.
(Summary)
There have been several evidences that the mRNA expressions in the peripheral leukocytes may indicate not only physical but also psychological states. The purpose of this study is whether the mRNA expressional changes in the leukocytes are related to the mental states across the menstrual cycle in reproductive healthy female subjects. Thirty-eight female subjects (22.4+/-1.4 year-old) were participated in this study at three menstruation cycle periods (menstrual, follicular and luteal phase). The FKBP5 (FK506-binding protein gene), SERT (serotonin transporter gene) and COMT (catechol-o-methyltransferase gene) mRNA expressions in the leukocytes were determined with hormonal data. The psychological changes were assessed with self-rating hospital anxiety and depression scale (HADS). Only one thirds of subjects (n=12) had regular menstrual cycles during the experiment. So we analyzed the data from these 12 subjects. The anxiety score of each subject was changed across the menstrual cycle (Friedman test: P<0.05). The FKBP5 mRNA expression was significantly lower in the follicular phase than in the other phases but no changes were seen in either SERT or COMT mRNA expressions among the phases. In conclusion, there are differences of HADS anxiety score and FKBP5 mRNA expression in the leukocytes across the menstrual cycle but there is no correlation between anxiety scores and FKBP5 mRNA.
Hirokazu Uemura, Toshiyuki Yasui, Yuka Miyatani, Masayo Yamada, Mineyoshi Hiyoshi, Kokichi Arisawa and Minoru Irahara : Circulating osteoprotegerin is associated with age and systolic blood pressure, but not with lipid profile or fasting glucose, in postmenopausal women., Menopause, Vol.15, No.1, 180-184, 2008.
(Summary)
OBJECTIVE: Osteoprotegerin (OPG), an inhibitor of osteoclastogenesis and osteoclast activation, has been reported to be linked to vascular biology. The aim of this study was to clarify the relationships between circulating OPG and the risk factors for vascular disorders in postmenopausal women. DESIGN: Eighty Japanese postmenopausal women were enrolled in this cross-sectional study. Clinical parameters (age, number of years since menopause, body mass index, systolic and diastolic blood pressure); serum concentrations of OPG, creatinine, calcium, and phosphorus; serum lipid profile; plasma glucose; and bone mineral density of the L2-4 vertebral bodies were determined for each woman. RESULTS: In rank-order correlation analysis, serum OPG concentrations had significant positive correlations with age (r = 0.29, P = 0.03), systolic blood pressure (r = 0.45, P < 0.01), diastolic blood pressure (r = 0.34, P < 0.01), and serum creatinine (r = 0.29, P = 0.04). Serum OPG concentration also had a marginally significant negative correlation with bone mineral density of the L2-4 vertebral bodies (r = -0.25, P = 0.06). However, serum OPG did not correlate with body mass index, serum lipid profile, or plasma glucose. The correlation of serum OPG with systolic blood pressure persisted after adjustment for both age and serum creatinine. CONCLUSIONS: These results suggest that increased circulating OPG in postmenopausal women is closely related to higher systolic blood pressure, which could cause atherosclerosis.
(Keyword)
Age Factors / Atherosclerosis / Blood Glucose / Blood Pressure / Body Mass Index / Bone Density / Calcium / Creatinine / Cross-Sectional Studies / Female / Humans / Japan / Lipids / Middle Aged / Osteoprotegerin / Phosphorus / Postmenopause / Risk Factors
Takeshi Iwasa, Toshiya Matsuzaki, Masahiro Murakami, Fumi Shimizu, Akira Kuwahara, Toshiyuki Yasui and Minoru Irahara : Decreased expression of kisspeptin mediates acute immune/inflammatory stress-induced suppression of gonadotropin secretion in female rat., Journal of Endocrinological Investigation, Vol.31, No.7, 656-659, 2008.
(Summary)
Kisspeptin and its corresponding receptor, the G protein-coupled receptor 54, play an important role in reproductive systems. It has been suggested that reproductive disorders in metabolically disrupted animals are caused by the alteration of hypothalamic KiSS-1 systems. Immune/inflammatory challenge is also known to disrupt reproductive function. However, the effects of immune/inflammatory challenge on KiSS-1 systems have not been investigated. In this study, we showed that lipopolysaccharide (LPS) injection decreased hypothalamic KiSS-1 mRNA expression as well as plasma LH levels in ovariectomized rats. Indomethacin completely blocked the suppressive effects of LPS on LH secretion and KiSS-1 mRNA level. Furthermore, we showed that i.v. injection of kisspeptin increased plasma LH levels in LPS-administrated rats to the same degree as in saline-injected rats. These results suggest that KiSS-1 systems are sensitive to immune/inflammatory challenge conditions and transmit these signals into the central reproductive system.
Toshiyuki Yasui, Hirokazu Uemura, Minoru Irahara, Makoto Arai, Noriko Kojimahara, Ryugo Okabe, Ishii Yasutomo, Shin-ichi Tashiro and Hiroshi Sato : Differences in sensitivity to cold in Japanese men and postmenopausal women aged > or =50 years., Gender Medicine, Vol.4, No.4, 359-366, 2007.
(Summary)
Sensitivity to cold is associated with several factors, such as aging, sex, and body composition. However, no previous studies have examined the differences in sensitivity to cold in men and women or the association of hormonal levels with sensitivity to cold. The aim of the present study was to clarify both the change in sensitivity to cold with aging and the difference in sensitivity to cold between men and women. Associations were also examined between circulating hormonal concentrations and the changes with aging and differences in sensitivity. This population-based cohort study enrolled healthy Japanese men and women aged > or = 50 years. A standardized 210-item health questionnaire was used to obtain information on symptoms of sensitivity to cold. Serum concentrations of luteinizing hormone, follicle-stimulating hormone (FSH), estradiol, testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin (SHBG) were measured. Of the 154 men and 180 women enrolled in this study, more women than men had sensitivity to cold. Whereas the percentage of men who had sensitivity to cold significantly increased with aging (P < 0.05), the percentage of women who had sensitivity to cold was already high (23.7%) at 50 to 60 years of age and did not change with aging. In men, advancing age and low body mass index (BMI) were significantly associated with sensitivity to cold (P < 0.05); however, age and BMI in women were not similarly associated. In addition, the effect of sex after adjustment for age was significant (P < 0.05), and there was also a numeric but nonsignificant effect of sex after adjustment for BMI. In men, low serum levels of the gonadal hormone FSH were significantly associated with sensitivity to cold in logistic analysis, but this association was nonsignificant after multivariate analysis. Serum concentrations of gonadal hormones and SHBG in women were not associated with sensitivity to col. The association of age with sensitivity to cold was different in men and women; the association of BMI with sensitivity to cold might be different in men and women. In addition, these changes in sensitivity to cold were not associated with circulating hormonal concentrations.
(Keyword)
Age Factors / Aged / Aged, 80 and over / Aging / Asian Continental Ancestry Group / Body Mass Index / Cohort Studies / Cold Temperature / Female / Gonadal Steroid Hormones / Gonadotropins, Pituitary / Health Surveys / Humans / Male / Middle Aged / Sex Factors / Sex Hormone-Binding Globulin / Thermosensing
Fumi Shimizu, Toshiya Matsuzaki, Takeshi Iwasa, Masahiro Minakuchi, Akira Kuwahara, Toshiyuki Yasui and Minoru Irahara : Estradiol suppresses NMU mRNA expression during sexual maturation in the female rat pituitary., International Journal of Developmental Neuroscience, Vol.26, No.3-4, 381-384, 2007.
(Summary)
Neuromedin U (NMU) suppresses food intake and gonadotropin secretion. However, the developmental transition of NMU expression in the pituitary gland and the regulation of NMU expression are unclear. The objective of this study was to examine the transition of the expression of NMU mRNA in the pituitary glands of female rats from the juvenile period to the mature period of development. Furthermore, factors such as estradiol, insulin, leptin, and inhibin A, whose expressions change throughout puberty and which affect gonadotropin secretion in pituitary cell culture, were examined. In the pituitary gland, the expression of NMU mRNA was significantly lower in 8-week-old rats than in 4- and 6-week-old rats. In the pituitary cell culture, the expressions of NMU mRNA in the estradiol- and insulin-treated groups were significantly lower than in the control group. These results suggest that the expression of NMU mRNA in the female rat pituitary is reduced as the rats develop from the pubertal to the mature period. Additionally, the reduction of NMU expression in the pituitary may be related to the increases in serum estradiol and insulin levels that occur during the pubertal period, which may negate NMU suppression of gonadotropin secretion.
Toshiyuki Yasui, Junko Tomita, Yuka Miyatani, Masayo Yamada, Hirokazu Uemura, Minoru Irahara, Makoto Arai, Noriko Kojimahara, Ryugo Okabe, Yasutomo Ishii, Shin-ichi Tashiro and Hiroshi Sato : Associations of adiponectin with sex hormone-binding globulin levels in aging male and female populations., Clinica Chimica Acta, Vol.386, No.1-2, 69-75, 2007.
(Summary)
Changes with aging in serum gonadal hormones, sex hormone-binding globulin (SHBG) and adiponectin, which are involved in insulin resistance and metabolic syndrome, are different in men and women. We examined the relationships of serum adiponectin concentrations with serum concentrations of hormones and SHBG in men and women. One hundred fifty-four men and 180 women aged from 50 to 85 years were included in the cross-sectional study. Serum concentrations of testosterone, estradiol, dehydroepiandrosterone-sulfate, SHBG and adiponectin were measured in men and women. Serum adiponectin concentration showed a significant positive correlation with serum SHBG concentration in men and women (r=0.404, p<0.0001 and r=0.348, p<0.0001, respectively). Multiple regression analysis also showed that SHBG was the significant predictor for adiponectin in men and women. Serum adiponectin concentration in men showed a significant positive correlation with total testosterone concentration, but that in women was not significantly correlated with total testosterone concentration. Both adiponectin and SHBG concentrations in men (r=-0.222, p=0.0051 and r=-0.334, p<0.0001, respectively) and women (r=-0.281, p=0.0014 and r=-0.251, p=0.0048, respectively) showed significant negative correlations with the homeostasis model assessment (HOMA) index. Correlations between adiponectin and SHBG were significantly positive in both men and women, and both adiponectin and SHBG might be involved in insulin resistance in both sexes.
(Keyword)
Adiponectin / Aged / Aged, 80 and over / Aging / Body Mass Index / Female / homeostasis / Humans / insulin resistance / Male / Metabolic Syndrome X / Middle Aged / Models, Biological / Regression Analysis / Risk Assessment / Sex Factors / Sex Hormone-Binding Globulin / Testosterone
Kumiko Sakamoto, Yuki Hibino, Masaru Kihara, Shuji Yamano, Kazuhisa Maeda, Minoru Irahara and Aiko Yamauchi : Prescribing patterns during pregnancy at Tokushima University Hospital, Japanese Journal of Pharmaceutical Health Care and Sciences, Vol.33, No.4, 377-385, 2007.
(Summary)
The purpose of this study was to investigate the drugs prescribed for pregnant women at Tokushima University Hospital in Japan, and to evaluate the risks associated with the use of these drugs during pregnancy according to the pregnancy risk classification systems of the PDA, ADEC and that used in manufacturers' package inserts. Of 496 female outpatients who gave birth at Tokushima University Hospital, 81% had been prescribed at least one drug, and the mean was 4.0 drugs per patient. Analysis of the prescriptions revealed a pattern of drug use very different from that in other countries, in that Kampo (Japanese herbal) medicines were also prescribed. For more than half of the oral drugs prescribed, risks were not given in the PDA and/or ADEC pregnancy risk systems. In addition, there was no listing of pregnancy risks in the package inserts of 20 drugs. We therefore consider it to be very important to develop a globally harmonized system for evaluating the risks associated with prescription drugs taken during pregnancy.
Toshiyuki Yasui, Masahiko Maegawa, Junko Tomita, Yuka Miyatani, Masayo Yamada, Hirokazu Uemura, Shu-ichi Ueno, Shusuke Numata, Tetsuro Ohmori, Naoko Tsuchiya, Mitsutoshi Yuzurihara, Shuichi Takeda and Minoru Irahara : Association of serum cytokine concentrations with psychological symptoms in midlife women., Journal of Reproductive Immunology, Vol.75, No.1, 56-62, 2007.
(Summary)
The purpose of the present study was to clarify the association of serum cytokine concentrations, determined using a multiplexed cytokine assay, with psychological symptoms in midlife women. Fifty-three peri- and post-menopausal women with and without psychological symptoms in Greene's climacteric scale were enrolled in this study. Levels of 17 cytokines in serum samples were measured simultaneously using a multiplexed human cytokine assay. Serum interleukin (IL)-6 concentration in women with psychological symptoms (2.71+/-047 pg/ml) was significantly (p=0.009) higher than that in women without psychological symptoms (0.98+/-0.18 pg/ml). Serum IL-8 concentration in women with psychological symptoms (33.4+/-8.17 pg/ml) was also significantly (p=0.022) higher than that in women without psychological symptoms (7.87+/-1.64 pg/ml). In addition, serum IL-10 concentration in women with psychological symptoms (0.74+/-0.26 pg/ml) was significantly (p=0.048) higher than that in women without psychological symptoms (0.07+/-0.04 pg/ml). Tumor necrosis factor (TNF)-alpha in serum was detected only in women with psychological symptoms. Serum IL-2 concentration in women with psychological symptoms tended (p=0.066) to be higher than that in women without psychological symptoms. No significant differences were found between levels of other cytokines in women with and without psychological symptoms. Psychological stress manifested as climacteric symptoms in midlife women may be associated with increases in serum concentrations of IL-6, IL-8, IL-10, and TNF-alpha.
Takeshi Iwasa, Toshiya Matsuzaki, Masahiro Minakuchi, Naoko Tanaka, Fumi Shimizu, Yohko Hirata, Akira Kuwahara, Toshiyuki Yasui, Masahiko Maegawa and Minoru Irahara : Diagnostic performance of serum total testosterone for Japanese patients with polycystic ovary syndrome., Endocrine Journal, Vol.54, No.2, 233-238, 2007.
(Summary)
It is reported that the incidence of clinical and biochemical hyperandrogenism may be lower in Japanese patients with PCOS. Hyperandrogenism is included as a referential but not as an essential factor in the diagnostic criteria of the Japanese Society of Obstetrics and Gynecology (JSOG 1993). However, some patients with the typical clinical features of PCOS are not diagnosed with PCOS using JSOG 1993 criteria because they do not have a high LH level, which is defined as essential for diagnosis. In this study, we compared total testosterone (T) levels between Japanese patients with PCOS diagnosed using the JSOG 1993 criteria and normal menstrual women (controls). Fifty controls and 46 patients with PCOS were enrolled in this study. Furthermore, we evaluated the sensitivity and specificity of each cut-off value of T. The mean T level of patients with PCOS was significantly higher than that of the control (86 +/- 48 vs 68 +/- 46, P<0.01), and the prevalence rates of hyperandrogenism (T >114 ng/dL; defined as the mean +2SD of the control) were 10.2% in patients with PCOS and 4% in controls. The area under the ROC curve of T was 0.72, and there was no decision threshold to diagnose PCOS by T alone with both high sensitivity and high specificity. If the threshold is set as 110 ng/dL in order to gain high specificity, 94% of women whose serum level passed the threshold will be patients with PCOS. Although T should not be used as an independent essential factor of Japanese PCOS, it might be useful as a complementary factor in order to diagnose patients who have typical clinical features of PCOS but does not fulfill the JSOG 1993 criteria for PCOS.
(Keyword)
Asian Continental Ancestry Group / Chemiluminescent Measurements / Female / Humans / Hyperandrogenism / Immunoassay / Polycystic Ovary Syndrome / Prevalence / ROC Curve / Sensitivity and Specificity / Testosterone
Takashi Kaji, Toshiyuki Yasui, Masanori Suto, Ryuji Mitani, Mikio Morine, Hirokazu Uemura, Kazuhisa Maeda and Minoru Irahara : Effect of bed rest during pregnancy on bone turnover markers in pregnant and postpartum women., Bone, Vol.40, No.4, 1088-1094, 2007.
(Summary)
The aims of our study were to evaluate the changes in bone turnover markers during pregnancy and puerperium as a longitudinal study and to elucidate the effect of bed rest during pregnancy on bone turnover markers in pregnant and postpartum women. The study population comprised 27 Japanese pregnant women aged 23-40 years. All women were recruited for the longitudinal study from the outpatients clinic of the Department of Obstetrics and Gynecology, Tokushima University Hospital. Concentrations of serum bone-specific alkaline phosphatase (BAP), urinary cross-linked type I collagen N-telopeptides (NTx), serum NTx and urinary C-terminal telopeptide of type I collagen (CTx) were measured at 10, 26, 30 and 36 weeks of pregnancy and at 4 days and 1 month postpartum. In addition, we recruited 15 pregnant women (aged 25-35 years) who were treated by bed rest before 30 weeks of pregnancy for threatened premature delivery and compared bone turnover markers in these women with those in 22 normal pregnant women (aged 22-39 years). Concentrations of serum BAP, serum NTx, urinary NTx and urinary CTx were measured at 30 and 34 weeks of pregnancy and at 4 days and 1 month postpartum. In the longitudinal study, serum BAP concentration at 1 month postpartum was significantly higher than that at any stage of pregnancy and that at 4 days postpartum. Urinary concentration of NTx increased gradually during pregnancy and showed a peak at 36 weeks of pregnancy, followed by a decrease in the postpartum period. Serum NTx concentration and urinary CTx concentration showed the same patterns of change as that of urinary NTx concentration. In the comparison study, urinary concentrations of NTx and CTx at 30 and 34 weeks of pregnancy in women with bed rest were significantly (p<0.0001 and p<0.001, respectively) higher than those in normal pregnant women. Serum NTx concentration at 34 weeks of pregnancy in women with bed rest was also significantly (p=0.0029) higher than that in normal pregnant women. Serum BAP concentration at 34 weeks of pregnancy in women with bed rest was significantly (p=0.0038) higher than that in normal pregnant women, and these high levels were maintained during puerperium. Serum BAP concentration at 34 weeks of pregnancy was significantly correlated with duration of bed rest (r=0.767, p=0.0041). Immobilization due to bed rest during pregnancy is associated with increases in bone turnover markers in pregnant and postpartum women. Concentrations of bone resorption markers increased rapidly at the start of bed rest, while the concentration of a bone formation marker gradually increased toward puerperium.
(Keyword)
Adult / Alkaline Phosphatase / Bed Rest / Biological Markers / Bone Remodeling / Calcium / Case-Control Studies / Collagen Type I / Female / Humans / Longitudinal Studies / Peptides / Postpartum Period / Pregnancy / Pregnancy Complications / Prospective Studies
Takeshi Iwasa, Toshiya Matsuzaki, Machiko Kiyokawa, Fumi Shimizu, Masahiro Minakuchi, Akira Kuwahara, Masahiko Maegawa, Toshiyuki Yasui and Minoru Irahara : The type 2 corticotrophin-releasing hormone receptor mediates orexin A-induced luteinising hormone suppression in ovariectomised rats., Journal of Neuroendocrinology, Vol.19, No.9, 732-738, 2007.
(Summary)
Orexins are thought to be regulatory factors of the arousal and sleep patterns. They also affect immune, feeding, autonomic and neuroendocrine systems. We have previously shown that intracerebroventricular (i.c.v.) injection of orexin decreases pulsatile luteinising hormone (LH) secretion in ovariectomised (OVX) rats. However, the details of this mechanism have not been fully examined. Intracerebroventricular injection of orexin A also stimulates corticotrophin-releasing hormone (CRH) systems, which have been implicated in the stress-induced suppression of reproductive function. In the present study, we investigated the role of CRH systems in orexin-induced LH suppression. OVX rats were implanted with i.c.v. and intravenous (i.v.) cannulae. After i.c.v. injection of orexin and/or CRH receptor antagonists, blood samples were collected through the i.v. cannula at 6-min intervals for 120 min for LH measurement. Intracerebroventricular injection of orexin A or B (3 nmol/2.5 microl) suppressed pulsatile LH secretion. Coadministration of orexin A and alpha-helical corticotrophic-releasing factor (CRF), a nonselective CRH receptor antagonist (13 nmol/2.5 microl), or astressin(2)B, a selective type2 (CRH-R2) CRH receptor antagonist (28 nmol/2.5 microl), partly restored pulsatile LH secretion. Orexin B-induced LH suppression was not restored by alpha-helical CRF. In addition, i.c.v. injection of orexin A increased CRH and urocortin II (UcnII), but not Ucn mRNA levels, in the hypothalamus. These findings suggest that CRH-R2 mediates orexin A-induced LH suppression and it is possible that CRH and UcnII in the hypothalamus are involved in this pathway.
The purpose of the present study was to clarify the changes in serum concentrations of 17 cytokines in healthy women during the menopausal transition by using a multiplexed cytokine assay and to clarify the associations of these cytokines with serum estradiol concentration. Sixteen premenopausal, 54 perimenopausal and 52 postmenopausal women were enrolled in this study. Seventeen cytokines in serum samples were measured simultaneously using a Bio-Plex human cytokine 17-Plex assay. Serum IL-6 concentration showed a weak positive correlation with age (r=0.196, p<0.05). Postmenopausal women for whom less than 5 years had passed since menopause showed significant (p<0.05) increase in serum concentrations of IL-2, GM-CSF and G-CSF, while serum IL-4 concentration was significantly (p<0.05) increased in postmenopausal women for whom more than 5 years had passed since menopause. Serum estradiol concentration showed a significant negative correlation with serum IL-6 concentration and weak negative correlations with serum concentrations of IL-2, IL-8 and GM-CSF. We were able to simultaneously measure the levels of 17 cytokines using a highly sensitive cytokine assay, and we found that the changes in serum cytokine concentrations during the menopausal transition differed. We also found that serum IL-6 concentration during the menopausal transition was negatively correlated with serum estradiol concentration.
Toshiyuki Yasui, Hirokazu Uemura, J Tomita, Y Miyatani, M Yamada, M Miura and Minoru Irahara : Association of serum undercarboxylated osteocalcin with serum estradiol in pre-, peri- and early post-menopausal women., Journal of Endocrinological Investigation, Vol.29, No.10, 913-918, 2006.
(Summary)
We investigated changes in serum concentration of undercarboxylated osteocalcin (ucOC), which is a sensitive marker of vitamin K status, and association of ucOC concentration with estradiol concentration in pre-, peri- and early post-menopausal women. The study population consisted of 193 pre-, peri- and post-menopausal Japanese women aged 39-66 yr. Serum ucOC concentration was measured to assess vitamin K status; serum concentrations of intact osteocalcin (OC) and bone-specific alkaline phosphatase (BAP) were measured as bone formation markers; and urine concentration of N-telopeptide was measured as a bone resorption marker. Serum estradiol and estrone concentrations were measured by a highly sensitive radioimmunoassay. Bone mineral density (BMD) was measured at the lumbar spine. Serum concentration of ucOC in peri-menopausal women was significantly (p=0.0005) higher than that in pre-menopausal women, while serum OC concentration in post-menopausal women for whom 1 yr had passed since menopause was significantly (p=0.0003, p=0.024, respectively) higher than the concentrations in pre-menopausal and peri-menopausal women. Serum ucOC concentration showed a significant negative correlation with estradiol concentration (r=-0.372, p<0.0001) and a significant positive correlation with serum FSH concentration (r=0.324, p<0.0001). Serum OC concentration was positively correlated with serum FSH concentration (r=0.317, p<0.001). The results showed that the change in ucOC concentration during the menopausal transition is different from that in OC concentration. In addition, serum ucOC concentration is closely associated not only with FSH concentration but also estradiol concentration.
(Keyword)
Adult / Aged / Aging / Alkaline Phosphatase / Bone Density / Collagen Type I / Cross-Sectional Studies / Estradiol / Female / Follicle Stimulating Hormone / Humans / Lumbar Vertebrae / Middle Aged / Osteocalcin / Peptides / Perimenopause / Postmenopause / Premenopause / Vitamin K
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 17185901
We investigated changes in serum undercarboxylated osteocalcin (ucOC) concentrations, bone turnover markers and spine bone mineral density (BMD) in women who had undergone bilateral oophorectomy during the premenopausal period. The study population comprised 141 bilaterally oophorectomized and 32 premenopausal women for a cross-sectional study. The longitudinal study consisted of 21 bilaterally oophorectomized women. Serum ucOC concentration, serum concentrations of intact osteocalcin (OC) and bone-specific alkaline phosphatase (BAP) as bone formation markers, urine N-telopeptide (NTx) concentration as a bone resorption marker and serum parathyroid hormone (PTH) concentration were measured. Serum concentration of ucOC in women at 1 month after bilateral oophorectomy was significantly (p<0.05) higher than that in premenopausal women and the high level was sustained after surgical menopause. On the other hand, serum OC concentration at 1 month after surgical menopause was not different from that in premenopausal women. In the longitudinal study, serum ucOC concentration at 1 month after surgical menopause was significantly (p<0.05) increased compared to that before bilateral oophorectomy, while serum OC concentrations before and at 1 month after surgical menopause were not significantly different. The results of this study showed that serum ucOC concentration rapidly increases in women after bilateral oophorectomy and that change in serum ucOC concentration after surgical menopause is different from change in serum OC concentration.
Toshiyuki Yasui, Hirokazu Uemura, Junko Tomita, Yuka Miyatani, Masayo Yamada, Akira Kuwahara, Toshiya Matsuzaki, Masahiko Maegawa, Naoko Tsuchiya, Mitsutoshi Yuzurihara, Shuichi Takeda and Minoru Irahara : Association of interleukin-8 with hot flashes in premenopausal, perimenopausal, and postmenopausal women and bilateral oophorectomized women., The Journal of Clinical Endocrinology and Metabolism, Vol.91, No.12, 4805-4808, 2006.
(Summary)
The purpose of this study was to identify serum cytokine concentrations in premenopausal, perimenopausal, and postmenopausal women and bilateral oophorectomized women with hot flashes. Serum concentrations of 17 cytokines were simultaneously measured using a multiplexed human cytokine assay in 129 premenopausal, perimenopausal, and postmenopausal women and 50 bilateral oophorectomized women. Serum IL-8 concentrations in midlife women and bilateral oophorectomized women with severe hot flashes were significantly higher than the concentrations in women without hot flashes and women with mild and moderate hot flashes. Serum macrophage inflammatory protein-1beta concentration in women with severe hot flashes was significantly higher than those in women without hot flashes and women with mild and moderate hot flashes. Serum IL-8 concentrations in premenopausal, perimenopausal, and postmenopausal women and bilateral oophorectomized women with hot flashes were significantly higher than those in women without hot flashes. IL-8 may be associated with peripheral vasodilation in women with hot flashes.
Junko Komatsu, Shuji Yamano, Akira Kuwahara, Akira Tokumura and Minoru Irahara : The signalling pathways linking to lysophosphatidic acid-promoted meiotic maturation, Life Sciences, Vol.79, No.5, 506-511, 2006.
(Summary)
The signaling pathways linking to lysophosphatidic acid-promoted meiotic maturation in mice were studied. When mouse oocyte-cumulus cells complexes were cultured with 10(-5) M lysophosphatidic acid (the LPA group), the rate of oocyte nuclear maturation was significantly increased. Additions of pertussis toxin, genistein, U73122, Ro320432, PD98059 or SB203580 significantly suppressed the increase in lysophosphatidic acid-stimulated nuclear maturation rate. These results suggested that Gi/o-coupled lysophosphatidic acid receptors activate phosphatidylinositol-specific phospholipase C, and result in ERK and MAP kinase activation, which is triggered by diacylglycerol-dependent protein kinase C. When intracellular cAMP concentrations of oocytes in the LPA and control groups were measured using the acetylation assay, the intracellular cAMP concentration of an oocyte in the LPA group was significantly lower than the control oocyte (0.117+/-0.04 fmol/oocyte vs. 0.176+/-0.036 fmol/oocyte, p<0.05). In conclusion, our results suggested that lysophosphatidic acid stimulates phospholipase C through a Gi-protein linked receptor on the surface of mouse cumulus cells and stimulates both extracellular signal-regulated kinase and p38 mitogen-activated kinase, resulting in the closure or loose of gap junctions between cumulus cells and the oocyte. The resultant early decrease of oocyte cAMP levels may promote nuclear maturation of mouse oocytes in vitro.
Toshiyuki Yasui, Yuka Miyatani, Junko Tomita, Masayo Yamada, Hirokazu Uemura, Masakazu Miura and Minoru Irahara : Effect of vitamin K2 treatment on carboxylation of osteocalcin in early postmenopausal women., Gynecological Endocrinology, Vol.22, No.8, 455-459, 2006.
(Summary)
We examined the serum level of undercarboxylated osteocalcin (uc OC), which is a sensitive marker of vitamin K status, and levels of bone turnover markers in early postmenopausal women receiving vitamin K2 treatment with or without vitamin D3. Thirty-four postmenopausal women with a mean age of 53 years whose bone mineral density (BMD) was less than 0.809 g/cm2 (osteopenia and osteoporosis) were treated with vitamin K2 or with a combination of vitamin K2 and vitamin D3. Seventeen women received daily oral administration of 45 mg vitamin K2 and 17 women received daily oral administration of 45 mg vitamin K2 plus 0.75 microg 1alpha-hydroxyvitamin D3. Serum levels of uc OC, intact osteocalcin (OC) and bone alkaline phosphatase (BAP), urinary deoxypyridinoline (DPD) levels and BMD at the lumbar spine were measured before and at 1 and 2 years after the start of treatment. Serum uc OC levels in women treated with vitamin K2 alone and with both vitamin K2 and vitamin D3 decreased significantly (p < 0.05). Serum levels of intact OC and BAP in women treated with vitamin K2 did not show significant changes, while those in women who received the combined treatment decreased significantly (p < 0.05). On the other hand, urinary DPD level in women treated with vitamin K2 did not change, while that in women who received the combined treatment tended to decrease (p < 0.1). Serum uc OC levels in early postmenopausal women who received vitamin K2 decreased due to carboxylation of uc OC. Combined treatment with vitamin K2 and vitamin D3 may be effective for sustaining BMD in early postmenopausal women whose bone turnovers are highly activated.
(Keyword)
Alkaline Phosphatase / Amino Acids / Bone Density / Bone Density Conservation Agents / Bone Diseases, Metabolic / Cholecalciferol / Drug Therapy, Combination / Female / Humans / Middle Aged / Osteocalcin / Osteoporosis, Postmenopausal / Postmenopause / Vitamin K 2
Kumiko Sakamoto, Yuki Hibino, Shuji Yamano, Kazuhisa Maeda, Minoru Irahara and Aiko Yamauchi : Prescription drug use during pregnancy in Japan, Reproductive Toxicology, Vol.22, No.2, 283, 2006.
154.
Toshiyuki Yasui, Hirokazu Uemura, Junko Tomita, Yuka Umino, Masayo Yamada, Akira Kuwahara, Toshiya Matsuzaki, Masahiko Maegawa, Masakazu Miura and Minoru Irahara : Different effects of oral conjugated equine estrogens and transdermal estrogen on undercarboxylated osteocalcin concentration in postmenopausal women., Menopause, Vol.13, No.4, 651-659, 2006.
(Summary)
Undercarboxylated osteocalcin (ucOC) is a sensitive marker of vitamin K status, and triglyceride (TG) has been shown to be the main transporter of vitamin K. In the present study, we examined the difference between ucOC concentrations in postmenopausal women receiving hormone therapy (HT) with oral conjugated equine estrogens (CEE) and transdermal estradiol (TE2). We also examined the associations of ucOC concentration with estradiol concentration and TG. Ninety-two postmenopausal women were recruited for this study. Serum concentrations of ucOC, intact osteocalcin, estradiol, and TG were measured before and after 12 months of HT. Forty-six women received oral administration of 0.625 mg of CEE and 2.5 mg of medroxyprogesterone acetate daily, and 46 women received transdermal administration of 50 mug of 17beta-estradiol twice weekly and 2.5 mg of medroxyprogesterone acetate daily. The ucOC concentration in women during HT with oral CEE was significantly (P < 0.01) lower than that in women during HT with TE2. Serum estradiol concentrations during HT with CEE showed a significant inverse correlation with ucOC concentrations and the ratio of ucOC/OC during HT (P < 0.05 and P < 0.01, respectively). In addition, the serum ucOC concentration in women with an increased percentage of change in TG was significantly (P < 0.01) lower than that in women with a decreased percentage of change in TG during HT with oral CEE. The effect of HT with TE2 on ucOC concentration in women is weaker than the effect of HT with oral CEE. Suppression of ucOC concentration in postmenopausal women during HT with oral CEE might be associated with the effect of vitamin K through increased TG induced by oral CEE.
Aiko Yamauchi, 坂本 久美子, 日比野 有紀, Hiroshi Chuman and Minoru Irahara : Pharmacotherapy During Pregnancy-Influence on both the Mother and the Fetus-, 性差と医療, Vol.3, No.5, 27(521)-32(526), 2006.
157.
Dan Kinoshita, Fumiko Hirota, Tsuneyasu Kaisho, Michiyuki Kasai, Keisuke Izumi, Yoshimi Bando, Yasuhiro Mouri, Akemi Matsushima, Shino Niki, Hongwei Han, Kiyotaka Oshikawa, Noriyuki Kuroda, Masahiko Maegawa, Minoru Irahara, Kiyoshi Takeda, Shizuo Akira and Mitsuru Matsumoto : Essential role of IkappaB kinase alpha in thymic organogenesis required for the establishment of self-tolerance., The Journal of Immunology, Vol.176, No.7, 3995-4002, 2006.
(Summary)
IkappaB kinase (IKK) alpha exhibits diverse biological activities through protein kinase-dependent and -independent functions, the former mediated predominantly through a noncanonical NF-kappaB activation pathway. The in vivo function of IKKalpha, however, still remains elusive. Because a natural strain of mice with mutant NF-kappaB-inducing kinase (NIK) manifests autoimmunity as a result of disorganized thymic structure with abnormal expression of Rel proteins in the thymic stroma, we speculated that the NIK-IKKalpha axis might constitute an essential step in the thymic organogenesis that is required for the establishment of self-tolerance. An autoimmune disease phenotype was induced in athymic nude mice by grafting embryonic thymus from IKKalpha-deficient mice. The thymic microenvironment that caused autoimmunity in an IKKalpha-dependent manner was associated with defective processing of NF-kappaB2, resulting in the impaired development of thymic epithelial cells. Thus, our results demonstrate a novel function for IKKalpha in thymic organogenesis for the establishment of central tolerance that depends on its protein kinase activity in cooperation with NIK.
Toshiyuki Yasui, Hirokazu Uemura, Yuka Umino, Masayo Yamada, Akira Kuwahara, Toshiya Matsuzaki, Masahiko Maegawa, Hiroyuki Furumoto, Masakazu Miura and Minoru Irahara : Undercarboxylated osteocalcin concentration in postmenopausal women receiving hormone therapy daily and on alternate days., Menopause, Vol.13, No.2, 314-322, 2006.
(Summary)
Undercarboxylated osteocalcin (ucOC) is a sensitive marker of vitamin K status. The authors examined the difference in serum ucOC concentrations in postmenopausal women receiving hormone therapy (HT) daily and on alternate days, and assessed the association between ucOC and triglyceride concentrations, which are related to the transport of vitamin K. Seventy-three postmenopausal women were recruited for this study. Thirty-seven women received 0.625 mg of conjugated equine estrogens (CEE) and 2.5 mg of medroxyprogesterone acetate (MPA) daily, and 36 women received 0.625 mg of CEE and 2.5 mg of MPA on alternate days. The concentrations of serum ucOC, bone turnover markers, lipid profiles, and hormones were measured before and after 12 months of HT. The ucOC concentration in women taking HT daily was significantly (P < 0.01) lower than that in women taking HT on alternate days. Serum ucOC concentrations during HT showed a significant (P < 0.01) inverse correlation with estradiol concentrations during HT. Serum estradiol concentrations during HT showed a significant (P < 0.01) positive correlation with triglyceride concentrations during HT. Furthermore, ucOC concentrations during HT showed a significant (P < 0.05) inverse correlation with triglyceride concentrations in women receiving HT. The effect of HT on alternate days on ucOC concentration was weaker than the effect of HT daily. In addition, ucOC concentration after 12 months of HT daily might be decreased due to the conversion of ucOC to carboxylated OC by the effect of vitamin K through increased triglyceride levels induced by oral CEE.
Takeshi Iwasa, Toshiya Matsuzaki, Naoko Tanaka, Masahiro Minakuchi, Fumi Shimizu, Rie Ogata, Machiko Kiyokawa, Masahiko Maegawa, Toshiyuki Yasui, Akira Kuwahara and Minoru Irahara : Comparison and problems of measured values of LH, FSH, and PRL among measurement systems., Endocrine Journal, Vol.53, No.1, 101-109, 2006.
(Summary)
Several measurement systems are used for LH, FSH, and PRL in Japan, but the comparison of the measured values is difficult in some cases. In this study, we compared the measured values of 3 types of measurement systems widely used in Japan, SPAC-S, ARCHITECT, and Centaur, in females with a normal menstrual cycle and with various ovulatory disorders. Variant LH was discriminated by the criterion, SPAC-S LH/ARCHITECT LH ratio <0.5. Excluding the variant LH, the correlation of the measured LH values among the measurement systems was high, 0.94-0.99, and the value measured by ARCHITECT LH and Centaur LH was slightly higher than that measured by SPAC-S LH. As for FSH, the correlation was also high, 0.94-1.00, and the value measured by ARCHITECT FSH and Centaur FSH was slightly lower than that measured by SPAC-S FSH. The important judgment criterion of polycystic ovary syndrome (PCOS), a high level of LH relative to FSH, has been set to 1.0 or higher LH/FSH using SPAC-S. When the regression line of the LH/FSH ratio among the measurement systems was investigated, it can be said that 1.25 or higher by ARCHITECT and 1.40 or higher by Centaur are appropriate for the judgment criteria of a high level of LH relative to FSH. As for PRL, the correlation was high, 0.96-0.99, but the value showed large differences among the systems. For the diagnosis of hyperprolactinemia, the higher limit of the normal range may be 15 ng/mL for SPAC-S, 30 ng/mL for ARCHITECT, and 24 ng/mL for Centaur.
Hirokazu Uemura, Toshiyuki Yasui, Y Umino, M Yamada, Akira Kuwahara, Toshiya Matsuzaki, M Maegawa and Minoru Irahara : Regulatory factors on parathyroid hormone-related peptide production by primary culture of lactating rat mammary gland., Hormone and Metabolic Research, Vol.37, No.8, 463-467, 2005.
(Summary)
Parathyroid hormone-related protein (PTHrP) is a major cause of humoral hypercalcemia of malignancy, but has also been widely found in fetal and adult non-neoplastic tissues. Lactating mammary gland has been shown to produce large amounts of PTHrP, and high levels of PTHrP have been measured in milk. We have examined the influences of several substances on the secretion of two different forms of PTHrP by primary cultures of mammary cells isolated from lactating rats to examine the regulatory mechanisms of PTHrP production by mammary cells. Primary cultures of mammary cells seeded at a density of 10(5) cells per 35 mm culture dish were grown on collagen gels. First, after cells were left 24 hours for attachment and incubated in 2 % FCS containing medium with for 12 hours, PTHrP (1 - 87) secretions were measured in conditioned medium with hormone supplementation for 1, 24 and 48 hours. Progesterone (10(-7) - 10(-5) mol/l) significantly suppressed PTHrP (1 - 87) secretion in a dose-dependent manner (p < 0.01), while 17beta-estradiol had no influence on PTHrP (1 - 87) secretion. Prolactin, a known stimulator of PTHrP expression in vivo, had no effect in this in vitro model. Second, PTHrP (1 - 34) secretion levels from confluent lactating mammary cells for 24 hours were evaluated. The same results were obtained in the case of PTHrP (1 - 87) secretion from non-confluent cells. Furthermore, dexamethasone (10(-6) mol/l) significantly suppressed PTHrP (1 - 34) secretion (p < 0.01). These results suggest that PTHrP production from the lactating mammary gland is suppressed by progesterone as well as dexamethasone. Progesterone dramatically falls after delivery, thus possibly accelerating PTHrP production by lactating mammary glands and resulting in considerable amounts of PTHrP secreted into the milk.
Hirokazu Uemura, M Kamada, M Maegawa, Y Ohmoto, K Murata, Akira Kuwahara, Toshiya Matsuzaki, Toshiyuki Yasui, T Takeji and Minoru Irahara : Effect of hormone replacement therapy on the production of bone-resorbing cytokines by peripheral blood cells in postmenopausal women., Hormone and Metabolic Research, Vol.37, No.4, 226-230, 2005.
(Summary)
We studied the effects of hormone replacement therapy (HRT) with estrogen on postmenopausal changes in the production of bone-resorbing cytokines interleukin 1 beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha). Both cytokines were measured in the supernatants of lipopolysaccharide (LPS)-stimulated whole-blood cells from 72 untreated and 44 HRT-treated women by ELISA. The levels of IL-1beta were significantly higher in women in their 40s and 50s and in postmenopausal women than in women in their teens, 20s and 30s, while the levels of TNFalpha did not show any changes related to age. Both levels in HRT-treated women were significantly lower than those in untreated women at almost every postmenopausal stage. In a prospective study, HRT induced significant declines in both levels. These results show that estrogen decreases the accelerated production of IL-1beta and reduces the production of TNFalpha in postmenopausal women at each postmenopausal stage, even in late-postmenopausal women.
Kazuyo Ariuchi, Hiroaki Yanagawa, Toshiko Miyamoto, Mitstuko Imura, Masako Nishiya, Rika Nakanishi and Minoru Irahara : Development of a checklist to ensure protocol details in clinical trials, JNI : The Journal of Nursing Investigation, Vol.3, No.2, 99-105, 2005.
(Summary)
治験は医薬品の開発において必須であり，その過程では逸脱を防ぎ，データの質を確保することが必要である．CRC(clinical research coordinator)の立場から，治験依頼者と医療機関の意思疎通のためのミーティングをより効率的に活用し，治験の品質の向上を行うためのチェックリストを作成した． T大学病院臨床試験管理センターのCRCがこれまでのミーティングにおいて経験した問題点を抽出し，それらを統合してミーティングチェックリストの原案を作成した．原案を平成16年5月∼6月に治験が開始された6件において主担当CRCが使用し，必要時には修正，補充を行い，それらを追記内容として直接チェックリストに記載した．治験開始後にこれらのチェックリストを回収し，追記内容等について検討した． 詳細な追記は，除外基準や費用の負担(特定療養費の期間に関する規定，入院時の取り扱いなど)などの項目で見られた．画像の取り扱い，同種同効薬と併用禁止薬，条件付き可能薬の一般名表記等においても指摘があった．追加項目として受託事例数が，修正項目として表記方法やレイアウトについての意見があった．これらを総合的に評価し，またあまりに詳細なリストは実用的ではないという意見なども取り入れ，除外基準は疾患名を列記しチェックする形に，また検査，投薬に関しては詳しい内容とするなどの変更を加え，最終的なチェックリストとした． 治験における逸脱の原因として，治験依頼者，治験責任医師の間での記載内容の解釈の微妙な不一致の関与の可能性が指摘されている．その克服にはCRCが中心となった品質保証のシステム化が必要であり，今回作成したチェックリストの活用などが有用と考えられる．今後は逸脱防止を目的とし，チェックリストの改良や活用法の検討を重ね対応するとともに，チェックリスト使用の有用性に関する評価を行う予定である．
Toshiyuki Yasui, Yuka Umino, Masaya Takikawa, Hirokazu Uemura, Akira Kuwahara, Toshiya Matsuzaki, Masahiko Maegawa, Hiroyuki Furumoto, Masakazu Miura and Minoru Irahara : Effects of postmenopausal hormone therapy every day and every other day on lipid levels according to difference in body mass index, Menopause, Vol.12, No.2, 223-231, 2005.
(Summary)
The objective of this study was to determine the effects of postmenopausal estrogen and progestogen therapy (EPT) every day and every other day on lipid levels, particularly triglyceride (TG) levels, according to difference in body mass index (BMI). Ninety-nine postmenopausal women (mean age, 53.9 +/- 5.6 years; mean BMI, 22.8 +/- 2.8 kg/m) were randomly treated with EPT every other day or every day for 1 year. Fifty women received oral administration of 0.625 mg of conjugated equine estrogen (CEE) and 2.5 mg of medroxyprogesterone acetate (MPA) every other day, and 49 women received oral administration of 0.625 mg of CEE and 2.5 mg of MPA every day. Blood samples were collected at baseline and after 1 year of therapy for measurement of fasting TG, total cholesterol, high-density lipoprotein-cholesterol (HDL-C), and apolipoproteins. Data from 88 of the 99 postmenopausal women were used for analysis. In women whose BMI was 25 kg/m or higher, TG levels during EPT every day increased by 26.8%, while TG levels during EPT every other day decreased by 12.3%. There was a significant (P < 0.05) difference between percentage changes in TG during EPT every day and every other day. In women whose BMI was less than 25 kg/m, TG levels during EPT every day increased by 21.7%, while during EPT every other day TG levels did not change. The mean levels of estradiol during EPT every day in women whose BMI was less than 25 kg/m and in women whose BMI was 25 kg/m or higher were 28.5 and 38.7 pg/mL, respectively, the difference between these levels was significant (P < 0.01). On the other hand, there was no significant difference between levels of estradiol during EPT every other day in these two BMI groups. Triglyceride levels during EPT every day with conventional doses of CEE and MPA increased more in overweight and obese postmenopausal women in association with increased estrogen levels.
Toshiyuki Yasui, Hirokazu Uemura, Yuka Umino, Masaya Takikawa, Seiichiro Saito, Akira Kuwahara, Toshiya Matsuzaki, Masahiko Maegawa, Hiroyuki Furumoto, Masakazu Miura and Minoru Irahara : Serum estrogen level after hormone replacement therapy and body mass index in postmenopausal and bilaterally ovariectomized women, Maturitas, Vol.50, No.1, 19-29, 2005.
(Summary)
The objective of this study was to determine the relationships of serum estrogen levels after hormone replacement therapy (HRT) every other day and every day with body mass index (BMI) in postmenopausal and bilaterally ovariectomized women. Eighty-six postmenopausal and 51 bilaterally ovariectomized women who had been suffering from vasomotor symptoms such as hot flush or atrophy of the vagina were randomly treated with HRT every other day or every day. Seventy-four patients received oral administration of 0.625 mg conjugated equine estrogen (CEE) and 2.5 mg medroxyprogesterone acetate (MPA) every other day, and 63 patients received oral administration of 0.625 mg CEE and 2.5 mg MPA every day as conventional HRT. Eighty-four postmenopausal and 50 bilaterally ovariectomized women completed this study. Serum estradiol levels after HRT every day in postmenopausal and bilaterally ovariectomized women were significantly (P <0.05 and <0.01, respectively) correlated with BMI, while those after HRT every other day were not correlated with BMI. The differences between estradiol levels after 12 months of treatment and initial estradiol levels were also significantly (P <0.01) correlated with BMI in both postmenopausal and bilaterally ovariectomized women who received HRT every day but not in women who received HRT every other day. Serum estrone level after HRT every day and the difference between estrone level after 12 months of treatment and initial estrone level were significantly (P <0.05 and <0.01, respectively) correlated with BMI only in bilaterally ovariectomized women. Serum estradiol levels after HRT every day increase more in overweight women than in non-overweight postmenopausal and bilaterally ovariectomized women. The results of the present study regarding the relationship between serum estradiol levels after HRT and BMI should be useful for selecting dosages of drugs to be used in HRT.
(Keyword)
Serum estrogen level / Hormone replacement therapy / Ovariectomized women
Koji Nakagawa, Shuji Yamano, Masaharu Kamada, Masahiko Maegawa, Akira Tokumura, Minoru Irahara and Hidekazu Saito : Sperm-immobilizing antibodies suppress an increase in the plasma membrane fluidity of human spermatozoa, Fertility and Sterility, Vol.82, No.Supplement 3, 1054-1058, 2004.
(Summary)
To clarify the mechanism by which capacitation is blocked by sperm-immobilizing antibodies, changes in the plasma membrane fluidity of human spermatozoa exposed to sperm-immobilizing antibodies were evaluated. In vitro cell culture study using human spermatozoa. Department of Obstetrics and Gynecology, School of Medicine, The University of Tokushima. Semen samples were obtained from four healthy, fertile volunteers. The internalization of [3H]lyso-platelet activating factor (lyso-PAF) across the plasma membranes of human spermatozoa, which were exposed to sperm-immobilizing antibodies (antisperm group) or not exposed (control group), was measured at 20 and 60 minutes after the addition of a phospholipid probe using the modified albumin-back extraction method. The percentage of internalization of [3H]lyso-PAF across the plasma membrane of human spermatozoa. Although the percentages of internalization of [3H]lyso-PAF (mean +/- SE) in the antisperm and control groups 20 minutes after addition of [3H]lyso-PAF were not significantly different (6.6% +/- 1.5% and 9.2% +/- 2.1%, respectively), at 60 minutes after the addition, the percentage in the antisperm group (9.0% +/- 1.3%) was significantly lower than that in the control group (13.4% +/- 1.3%). This inhibitory effect was diminished when spermatozoa exposed to sperm-immobilizing antibodies were incubated in an antibody-free medium. Sperm-immobilizing antibodies suppress the increase in internalization of an alkyl ester lysophospholipid probe in plasma membranes of human spermatozoa, and this inhibitory effect is reversible. Therefore, sperm-immobilizing antibodies suppress the fluidity of the plasma membranes of human spermatozoa, thus blocking capacitation.
Masahiko Maegawa and Minoru Irahara : (11)Treatments of infertile women of advanced reproductive age, Obstetrical and Gynecological Therapy, Vol.88, No.5, 1141-1147, 2004.
Mitsuko Imura, Hiroaki Yanagawa, Toshiko Miyamoto, Kayoko Inui, Rika Nakanishi, Masako Nishiya and Minoru Irahara : Analysis of nurse speciality in functions as clinical research coordinator for clinical trials, JNI : The Journal of Nursing Investigation, Vol.2, No.1, 21-26, 2004.
Shuji Yamano, Jun Yamazaki, Minoru Irahara, Akira Tokumura, Koji Nakagawa and Hidekazu Saito : Human spermatozoa capacitated with progesterone or a long incubation show accelerated internalization by an alkyl ether lysophospholipid, Fertility and Sterility, Vol.81, No.3, 605-610, 2004.
(Summary)
To evaluate changes that occur in sperm plasma membranes during capacitation, the internalization of [(3)H]lyso-platelet activating factor ([(3)H]lyso-PAF) across the plasma membrane of human spermatozoa was measured as a function of incubation time or exposure to progesterone (P). In vitro cell culture study using human spermatozoa. Department of Obstetrics and Gynecology, School of Medicine, the University of Tokushima, Japan. Semen were obtained from three fertile healthy volunteers. The internalization of [(3)H]lyso-PAF across the plasma membranes of human spermatozoa that were incubated for an extended period or exposed to P was measured at 5, 20, 60, and 120 minutes after the addition of the phospholipid probe using the modified albumin back-exchange method. The percentage of capacitated and acrosome-reacted sperm and the proportion of internalization of lyso-PAF across the plasma membrane. A 6-hour incubation period significantly increased the percentage of capacitated spermatozoa and the proportion of internalization of [(3)H]lyso-PAF across the plasma membrane of human spermatozoa compared with controls (capacitated spermatozoa, 20.3 +/- 10.6% vs. 8.5 +/- 1.8%; internalization 120 minutes after the addition of the phospholipid probe, 25.6 +/- 2.5% vs. 11.6 +/- 3.0%) (mean +/- SEM). Exposure to P significantly increased the percentage of capacitated spermatozoa compared with controls (19.6 +/- 6.8% vs. 11.0 +/- 2.4%) and also significantly accelerated the internalization of [(3)H]lyso-PAF compared with controls (internalization 120 minutes after the addition of the phospholipid probe, 26.2 +/- 1.8% vs. 21.4 +/- 1.1%). The administration of P or a long incubation increased the proportion of internalization and consequently induced capacitation in human spermatozoa.
Toshiyuki Yasui, Hirokazu Uemura, Yuka Umino, Masaya Takikawa, Akira Kuwahara, Seiichiro Saito, Toshiya Matsuzaki, Masahiko Maegawa, Hiroyuki Furumoto, Masakazu Miura and Minoru Irahara : Serum estradiol concentration as measured by HPLC-RIA and bone mineral density in postmenopausal women during hormone replacement therapy, Hormone Research, Vol.61, No.3, 117-125, 2004.
(Summary)
To determine the relationship between the serum estradiol concentration and bone mineral density (BMD) of the lumbar spine in postmenopausal women treated with conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) every other day and every day. Eighty-four postmenopausal women were randomly treated with hormone replacement therapy (HRT) every other day and every day. Forty-seven women received oral administration of 0.625 mg CEE and 2.5 mg MPA every other day, and 37 women received oral administration of 0.625 mg CEE and 2.5 mg MPA every day. BMD of the lumbar spine at 12 months and serum concentrations of estradiol and estrone at 6 and 12 months after treatment were examined. The estradiol concentration in subjects treated every other day showed a significant (p < 0.001) positive correlation with the percentage change in lumbar BMD, while that in subjects treated every day was not correlated with the percentage change in BMD. The differences between serum estradiol concentrations after 12 months of treatment and initial serum estradiol values in women treated every other day and every day also showed a significant (p < 0.01 and 0.05, respectively) positive correlation with percentage changes in BMD. In women treated every other day, body mass index (BMI) in the subjects in whom BMD did not increase was significantly (p < 0.01) lower than that in the subjects in whom BMD did increase. The serum estradiol concentration in women treated every other day has a strong positive correlation with the percentage change in lumbar BMD, but a higher estradiol concentration may be needed for women in whom BMD did not increase with HRT every other day after due consideration of individual characteristics such as BMI.
Masahiko Maegawa and Minoru Irahara : EBMからみた不妊治療の実際, Obstetrical and Gynecological Therapy, Vol.87, No.5, 602-607, 2003.
(Keyword)
不育症 / 習慣流産 / 抗リン脂質抗体症候群 / 免疫療法
176.
Hirokazu Uemura, Toshiyuki Yasui, Yuka Umino, Hirobumi Niki, Masaya Takikawa, Seiichiro Saito, Hiroyuki Furumoto and Minoru Irahara : Circulating osteoprotegerin in women during GnRH-agonist treatment and their relationships with mineral components and biomarkers of bone turnover, Bone, Vol.33, No.5, 860-866, 2003.
(Summary)
A novel cytokine termed osteoprotegerin (OPG) that is also called osteoclastogenesis-inhibitory factor, which inhibits osteoclast maturation and activity, was recently isolated. In order to determine the influence of estrogen deficiency on the levels of circulating OPG in women, we studied the changes in the levels of circulating OPG in 10 Japanese women ages 25-49 (mean +/- SD, 34.0 +/- 6.9) years with endometriosis receiving gonadotropin-releasing hormone agonists (GnRH-a) therapy. We further analyzed whether the levels of circulating OPG have relations with the levels of the biomarkers of bone turnover or those of circulating mineral components in these patients during GnRH-a treatment. The patients were treated with a monthly injection of 3.75 mg leuprolide acetate depot for 6 months. In all patients, the concentrations of serum estradiol decreased after 6 months of GnRH-a treatment. The bone mineral density of the lumber spines in these patients significantly (P < 0.01) decreased (percentage change: mean +/- SD, -5.4 +/- 2.1%), while circulating OPG levels significantly (P < 0.01) increased after 6 months of treatment. The values of circulating OPG had significant correlations with those of urinary pyridinoline (r = 0.59, P < 0.01), urinary deoxypylridinoline (Dpd) (r = 0.46, P < 0.05), and serum alkaline phosphatase (r = 0.66, P < 0.01) but not with those of serum carboxy-terminal propeptide of type I procollagen during GnRH-a treatment. The values of circulating OPG also correlated significantly with those of serum calcium (Ca) and phosphorus (P) (r = 0.65 and 0.72, P < 0.01). Further analyses revealed that the percentage change in the value of circulating OPG had a significant correlation with that of urinary Dpd (r = 0.84, P < 0.01). These results suggest that circulating OPG levels rise against the increase in osteoblastic bone resorption and circulating Ca levels in the case of estrogen deficiency, possibly as a compensatory mechanism serving to limit circulating Ca levels and bone density.
(Keyword)
Adult / Bone Density / Bone Remodeling / Endometriosis / Female / Glycoproteins / Gonadotropin-Releasing Hormone / Humans / Leuprolide / Middle Aged / Osteoprotegerin / Receptors, Cytoplasmic and Nuclear / Receptors, Tumor Necrosis Factor / Statistics, Nonparametric
Toshiyuki Yasui, Hirokazu Uemura, Masaya Takikawa and Minoru Irahara : Hormone replacement therapy in postmenopausal women., The Journal of Medical Investigation : JMI, Vol.50, No.3-4, 136-145, 2003.
(Summary)
Hormone replacement therapy (HRT) is effective for relieving vasomotor symptoms such as hot flash and vaginal atrophy and for preventing bone loss in postmenopausal and bilaterally ovariectomized women. However, compliance with HRT was reported to be low despite the benefits of HRT. In addition, results of several recent large-scale randomized clinical trials have demonstrated that protection from cardiovascular disease is not an indication for treatment with estrogen and progestin in postmenopausal women. Recent studies have demonstrated that low-dose HRT is safe and effective for prevention of postmenopausal bone loss. Low-dose HRT has also been shown to be effective for reducing the number and severity of hot flashes, improving vaginal atrophy, and inducing favorable changes in lipids, lipoproteins and hemostatic factors. Moreover, low-dose regimens of CEE (conjugated equine estrogen) and MPA (medroxyprogesterone acetate) result in higher rates of amenorrhea and endometrial protection compared with the conventional dose of HRT. Low-dose HRT may improve the compliance rate and may be more effective than conventional-dose HRT for reducing the risk of breast cancer. On the other hand, it has been shown that transdermal estrogen treatment reduces the incidence and severity of hot flashes and that long-term treatment with transdermally administered estrogen is effective for protection against osteoporosis. Transdermal administration of estrogen is recommended in postmenopausal women with hypertriglycemia because this treatment has little effect on lipid metabolism. The serum estradiol level was reported to be closely related to estrogenic effects on various tissues. An HRT regimen should be based on the needs of each patient. Serum estradiol levels in women should be maintained at appropriate levels for benefits and not be excessively high in order to prevent side effects. Selection of the most appropriate regimen of HRT (dose, route of administration and schedule) for the needs of the individual are important factors to increase the rate of continuation with HRT.
Toshiyuki Yasui, Toshiya Matsuzaki, Kenjiro Ushigoe, Akira Kuwahara, Masahiko Maegawa, Hiroyuki Furumoto, Toshihiro Aono and Minoru Irahara : Stimulatory Effect of the Herbal Medicine Keishi-bukuryo-gan on a Cytokine-induced Neutrophil Chemoattractant,in Rat Ovarian Cell Culture, American Journal of Reproductive Immunology, Vol.50, No.1, 90-97, 2003.
(Summary)
We investigated the effects of Keishi-bukuryo-gan, a Japanese herbal medicine, and its crude ingredients in relation to the production of cytokine-induced neutrophil chemoattractant (CINC/gro), interleukin 1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha), which are known to stimulate the secretion of CINC/gro in the ovulatory process, and the effects of Keishi-bukuryo-gan with those of Toki-shakuyaku-san, which has been shown to have an effect on the ovary. We cultured whole ovarian dispersates from immature (3-week-old) female rats with Keishi-bukuryo-gan, Toki-shakuyaku-san and crude ingredients of Keishi-bukuryo-gan. The contents of CINC/gro, IL-1beta and TNFalpha in the cultured media were determined by enzyme-linked immunosorbent assay (ELISA). Keishi-bukuryo-gan stimulated the secretion of CINC/gro in a dose-dependent manner, and the secretion of CINC/gro into the culture medium increased significantly at concentrations of Keishi-bukuryo-gan of 10 and 100 microg/mL (P < 0.001). The stimulatory effect of Keishi-bukuryo-gan on the production of CINC/gro is significantly (P < 0.001) stronger than that of Toki-shakuyaku-san at the same concentrations of 100 microg/mL. In addition, Keishi-bukuryo-gan stimulated the secretion of IL-1beta in a dose-dependent manner, while it did not stimulate the secretion of TNFalpha even at a concentration of 100 microg/mL. Moutan Cortex, Paeoniae Radix and Persicae Semen, which are crude ingredients of Keishi-bukuryo-gan, enhanced the secretion of CINC/gro significantly (P < 0.01) in cultured whole ovarian dispersates. These results show that Keishi-bukuryo-gan can stimulate the secretion of CINC/gro as well as the production of IL-1beta and that this stimulatory effect of Keishi-bukuryo-gan was significantly stronger than that of Toki-shakuyaku-san in immature rat ovarian cell culture.
Toshiyuki Yasui, Toshiya Matsuzaki, Rie Ogata, Machiko Kiyokawa, Kenjiro Ushigoe, Hirokazu Uemura, Akira Kuwahara, Hiroshi Ikawa, Masahiko Maegawa, Hiroyuki Furumoto, Toshihiro Aono and Minoru Irahara : The herbal medicine Unkei-to stimulates the secretion of a cytokine-induced neutrophil chemoattractant, CINC/gro, in the rat ovarian cell culture, American Journal of Reproductive Immunology, Vol.49, No.1, 14-20, 2003.
(Summary)
We investigated the ovulation-inducing effects of Unkei-to, a Japanese herbal medicine, in relation to the production of sex steroid hormones (17beta-estradiol and progesterone), cytokine-induced neutrophil chemoattractant (CINC/gro), interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) in the rat ovarian cell culture. Unkei-to at a concentration of 100 microg/mL significantly stimulated the secretions of 17beta-estradiol and progesterone (P < 0.01) in cultured whole ovarian dispersates. Unkei-to also enhanced the secretion of CINC/gro in a dose-dependent manner, and the secretions of CINC/gro increased significantly at concentrations of 10 and 100 microg/mL (P < 0.01). These stimulatory effects of Unkei-to on steroidgenesis and CINC/gro production are very similar to those of another Japanese herbal medicine, Toki-Shakuyaku-san. In addition, Unkei-to significantly (P < 0.01) enhanced the secretions of both IL-1beta and TNF-alpha, which are known to stimulate the secretion of CINC/gro in the ovulatory process, at concentrations of 10 and 100 microg/mL. The stimulatory effect of Unkei-to at a concentration of 100 microg/mL on IL-1beta/was significantly (P < 0.01) lower than that of Toki-Shakuyaku-san, while the stimulatory effects of these two herbal medicines at a concentration of 100 microg/mL on TNF-alpha were similar. These results show that Unkei-to can stimulate ovarian steroidgenesis and the ovulatory process by inducing the secretion of CINC/gro with IL-1beta and TNF-alpha in vitro. Unkei-to has stimulatory effects on both steroidgenesis and the ovulatory process in the ovary as well as a stimulatory effect on the hypothalamus-pituitary axis, and it may be useful for treating patients with ovulatory disorders.
Masayo Yamada, Toshiya Matsuzaki, Takeshi Iwasa, Fumi Shimizu, Naoko Tanaka, Rie Ogawa, Machiko Kiyokawa, Toshiyuki Yasui, Minoru Irahara and Toshihiro Aono : Serum Leptin Levels in Women throughout Life;Relationship to Body Mass Index and Serum Estradiol Levels, Japanese Journal of Reproductive Endocrinology, Vol.8, 55-60, 2003.
(Keyword)
Leptin / Estradiol / Body mass index
187.
Koji Nakagawa, Shuji Yamano, Yukari Tsutsumi, M Matsumoto, Kenji Hinokio, Minoru Irahara and Toshihiro Aono : The scheduled ovarian hyperstimulation method makes it easy to perform ICSI with fresh testicular sperm (ICSI/TESE), Archives of Andrology, Vol.48, No.5, 329-336, 2002.
(Summary)
The authors evaluated whether scheduled ovarian stimulation makes it easy to perform ICSI with fresh testicular sperm. Scheduled ovarian hyperstimulation was applied for testicular sperm extraction and ICSI with fresh testicular spermatozoa. Fifteen cycles in 10 couples were included in the present study; all couples were azoospermic, 5 were obstructive, and the remaining 5 were nonobstructive. No cycles were canceled, and all oocyte retrievals were performed on the scheduled day. Testicular sperm were obtained in 14 treatment cycles (93%). The mean numbers of retrieved and injected oocytes were 9.4 and 6.4, respectively. The fertilization and cleavage rates were 47 and 91%, respectively. Embryo transfers were performed in 12 cycles except 2 cycles that had no embryos. The number of transferred embryos was 2.3. Two clinical pregnancies were obtained. This scheduled ovarian hyperstimulation was applicable for ICSI with fresh testicular sperm.
Hirokazu Uemura, Toshiyuki Yasui, Machiko Kiyokawa, Akira Kuwahara, Hiroshi Ikawa, Toshiya Matsuzaki, Masahiko Maegawa, Hiroyuki Furumoto and Minoru Irahara : Serum osteoprotegerin/osteoclastogenesis-Inhibitory factor during pregnancy and lactation and their relationships with calcium regulating hormones and bone turnover markers, The Journal of Endocrinology, Vol.174, No.2, 353-359, 2002.
(Summary)
Pregnancy and lactation induce dynamic changes in maternal bone and calcium metabolism. A novel cytokine termed osteoprotegerin (OPG)/osteoclastogenesis-inhibitory factor (OCIF) was recently isolated; this cytokine inhibits osteoclast maturation. To define the effects of pregnancy and lactation on circulating OPG/OCIF in mothers, we studied the changes in the levels of OPG/ OCIF as well as those of calcium-regulating hormones and biochemical markers of bone turnover in the maternal circulation during pregnancy (at 8-11 weeks, at 22-30 weeks, at 35-36 weeks and immediately before delivery) and lactation (at 4 days and at 1 month postpartum). Serum intact parathyroid hormone levels did not change and were almost within the normal range in this period. In contrast, serum 1,25-dihydroxyvitamin D levels increased with gestational age and were above the normal range during pregnancy. After delivery, they fell rapidly and significantly (P<0.01) to the normal range. The levels of serum bone-specific alkaline phosphatase, one of the markers of bone formation, increased with gestational age. After delivery, these levels were further increased at 1 month postpartum. The levels at 1 month postpartum were significantly higher than those at 8-11 and 22-30 weeks of pregnancy (P<0.01 and P<0.05 respectively). The levels of serum C-terminal telopeptides of type I collagen, one of the markers of bone resorption, did not change during pregnancy. After delivery, they rapidly and significantly (P<0.01) rose at 4 days postpartum, and had then fallen by 1 month postpartum. Circulating OPG/OCIF levels gradually increased with gestational age and significantly (P<0.01) increased immediately before delivery to 1.40+/-0.53 ng/ml (means+/-S.D.) compared with those in the non-pregnant, non-lactating controls (0.58+/-0.11 ng/ml). After delivery, they fell rapidly to 0.87+/-0.27 ng/ml at 4 days postpartum and had fallen further by 1 month postpartum. These results suggest that the fall in OPG/OCIF levels may be partially connected with the marked acceleration of bone resorption after delivery.
Masahiko Maegawa, Masaharu Kamada, Minoru Irahara, Satoshi Yamamoto, Shuji Yoshikawa, Yuka Kasai, Yasukazu Ohmoto, Hironori Gima, Christian J Thaler and Toshihiro Aono : A repertoire of cytokines in human seminal plasma, Journal of Reproductive Immunology, Vol.54, No.1-2, 33-42, 2002.
(Summary)
The pathophysiological significance of seminal cytokines in sperm function is still controversial. We determined the repertoire of cytokines in seminal plasma obtained from men with or without abnormalities in semen and assessed the pathophysiological significance of seminal cytokines. After conventional analysis of semen samples obtained from 86 men, levels of seminal cytokines (interleukin [IL]-1alpha, IL-2, IL-4, IL-6, IL-8, tumor necrosis factor-alpha [TNF-alpha], interferon-gamma, granulocyte colony-stimulating factor [G-CSF], macrophage CFS [M-CSF]) and granulocyte elastase were measured by an enzyme-linked immunosorbent assay. Leukocytospermia was defined as seminal plasma, which has > or =1000 ng/ml granulocyte elastase. Leukocytospermia was found in nine of 62 of the subjects in the normozoospermic group but in none of the 24 subjects showing abnormal sperm parameters (azoospermia, n=5; oligozoospermia, n=4; asthenozoospermia, n=15). The IL-8 level in the leukocytospermic group was significantly higher than those in the normal and oligozoospermic groups. IL-1alpha and TNF-alpha levels in the leukocytospermic group were significantly higher than those in the normal and asthenozoospermic groups. Although the G-CSF level in the leukocytospermic group was significantly higher than that in the normal group, high levels of M-CSF were detected in all groups. The IL-8 level was strongly correlated with IL-1alpha (r=0.935, P<0.0001) and G-CSF (r=0.916, P<0.0001) levels. Cytokines detected in seminal plasma are associated with the pathogenesis of leukocytospermia but not with the pathogenesis of asthenozoospermia and oligozoospermia.
Mitsuhiro Kimura, Minoru Irahara, Toshiyuki Yasui, Seiichiro Saito, Michiko Tezuka, Shuji Yamano, Masaharu Kamada and Toshihiro Aono : The Obesity in Bilateral Ovariectomized Rats is Related to a Decrease in the Expression of Leptin Receptors in the Brain, Biochemical and Biophysical Research Communications, Vol.290, No.4, 1349-1353, 2002.
(Summary)
We investigated the expression levels of leptin receptors in the brain of ovariectomized (OVX) rats. The mean expression level of ob mRNA in adipose tissues of OVX rats was significantly (P < 0.01) lower than that in the SHAM operation group rats, and the mean body weight of OVX rats was significantly (P < 0.01) greater than that in the SHAM group rats. However, there were no differences between serum leptin concentrations in these two groups. The mean level of leptin receptor (OB-R) mRNA expression in the brain tissue and the mean level of long form type OB-R (OB-RL) mRNA expression in the hypothalamus of the OVX rats were significantly (P < 0.05) lower than those in the SHAM group rats. These changes were cancelled by supplementation with 17 beta-estradiol in OVX rats. These results suggested that not only changes in the expression level of ob mRNA in adipose tissue and the serum leptin concentration but also changes in the OB-R mRNA in the brain are involved in the body weight increase in OVX rats and that a decrease in OB-R makes transmission of signals to suppress the amount of food intake difficult, thus leading to an increase in body weight.
(Keyword)
leptin receptor / long form / short form / estrogen
Michiko Tezuka, Minoru Irahara, Koji Ogura, Machiko Kiyokawa, Takao Tamura, Toshiya Matsuzaki, Toshiyuki Yasui and Toshihiro Aono : Effects of leptin on gonadotropin secretion in juvenile female rat pituitary cells, European Journal of Endocrinology, Vol.146, No.2, 261-266, 2002.
Kenji Hinokio, Shuji Yamano, Koji Nakagawa, Minoru Irahara, Masaharu Kamada, Akira Tokumura and Toshihiro Aono : Lysophosphatidic acid stimulates nuclear and cytoplasmic maturation of golden hamster immature oocytes in vitro via cumulus cells, Life Sciences, Vol.70, No.7, 759-767, 2002.
(Summary)
Lysophosphatidic acid (LPA), a member of the phospholipid autacoid family, is induced in incubated human follicular fluid by lysophospholipase D. It is well known that LPA functions as a growth factor and the hypothesis that LPA in human follicular fluid takes a part in meiosis of oocytes is quite plausible. We studied the effects of LPA on the maturation of golden hamster immature oocytes in vitro. Hamster oocytes with a germinal vesicle were cultured in Tyrode's albumin lactate pyruvate (TALP) medium with 10(-5) M LPA, 10 ng/ml epidermal growth factor (EGF), 30 ng/ml insulin-like growth factor-1, 1 ng/ml tumor growth factor-alpha or 1 ng/ml basic fibroblast growth factor. The nuclear maturation rates in the LPA and EGF groups were significantly higher than in the control group and the other growth factors did not show any stimulatory effect (LPA group; 74.3% [75/101], EGF group; 82.4% [89/108] vs. control group; 60.2% [59/98], p < 0.05, p < 0.01, respectively). When the cells of cumulus were removed, EGF and LPA did not increase the nuclear maturation rates. Cotreatment EGF and LPA did not significantly enhance the stimulatory effect observed with LPA alone on maturation in vitro. The penetration rate determined by the zona-free hamster oocyte test was significantly higher in the LPA group than in the control group (26.7% vs. 13.2%, p < 0.05) and was comparable with that of oocytes matured in vivo. In conclusion, LPA stimulates the nuclear and cytoplasmic maturation of hamster immature oocytes via cumulus cells.
Masahiko Maegawa, Masaharu Kamada, Satoshi Yamamoto, Shuji Yamano, Minoru Irahara, Hiroshi Kido and Toshihiro Aono : Involvement of carbohydrate molecules on zona pellucida in human fertilization, Journal of Reproductive Immunology, Vol.53, No.1-2, 79-89, 2002.
(Summary)
Although the involvement of several receptors and ligand molecules in sperm-zona interaction in many species have been proposed, there has been a little analysis of the kinetics between these molecules during the interaction. In the present study, we applied the detection method using surface plasmon resonance (SPR) by a BIAcore apparatus for the analysis of the putative receptor-ligand interaction of sperm-egg binding. Mannose-BSA or [man](5)-[GlcNAc](2)-Asp was immobilized on the surface of a sensor chip. When concanavalin A (Con A) was delivered to each of two different sensor chips to evaluate their usefulness, the resonance signal after sample injection onto a [man](5)-[GlcNAc](2)-Asp-fixed chip decreased rapidly than the mannose-BSA-fixed chip. However, the amount of binding for Con A during the injection onto the [man](5)-[GlcNAc](2)-Asp-fixed chip was high. When acid sperm extracts (acid extracts) and fractions through a CM column, containing protease activity (protease fractions), were delivered to the mannose-BSA-fixed chip, the SPR signal during the injection was not obviously changed compared with that of the control. However, when sperm samples were delivered to the [man](5)-[GlcNAc](2)-Asp-fixed chip, the SPR response during the injection was enormous. These results suggest that the [man](5)-[GlcNAc](2)-Asp-fixed chip is more useful than the mannose-BSA-fixed chip for investigating the interactions with sperm extracts and that the sensitive method using SPR by a BIAcore apparatus is applicable for the analysis of the putative receptor-ligand interaction of sperm-egg binding.
Song Quan, Shuji Yamano, Koji Nakagawa, Minoru Irahara, Masaharu Kamada and Toshihiro Aono : Penetrating capacity of human spermatozoa cool preserved in electrolyte-free solution, The Journal of Reproductive Medicine, Vol.46, No.11, 957-961, 2001.
(Summary)
To evaluate whether human spermatozoa preserved in electrolyte-free (EF) solution at 4 degrees C possess normal penetrating capacity. The acrosomal status of human spermatozoa cool preserved in EF solution was evaluated before preservation and before and after reinitiation by using chlortetracycline staining. The zona-free hamster egg sperm penetration test was performed using spermatozoa cool preserved in EF solution. The percentages of capacitated and acrosome-reacted spermatozoa cool preserved in EF solution before reinitiation were similar to those of fresh spermatozoa, but they significantly increased after reinitiation. The penetration rate and fertility index of spermatozoa cool preserved in EF solution were comparable to those of fresh spermatozoa (48.3% vs. 50.8% and 1.37 +/- 0.15 vs. 1.29 +/- 0.10, respectively). Human spermatozoa cool preserved in EF solution for one week can possess as much penetrating capacity as fresh spermatozoa.
(Keyword)
Acrosome / Adult / Animals / Cell Survival / Cold Temperature / Cricetinae / Electrolytes / Female / Fertilization / Humans / Male / Organ Preservation Solutions / Refrigeration / Semen Preservation / Sperm-Ovum Interactions / Spermatozoa / Time Factors
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11762151
Minoru Irahara, Hirokazu Uemura, Toshiyuki Yasui, Hiromi Kinoshita, Masayo Yamada, Michiko Tezuka, Machiko Kiyokawa, Masaharu Kamada and Toshihiro Aono : Efficacy of every-other-day administration of conjugated equine estrogen and medroxyprogesterone acetate on gonadotropin-releasing hormone agonists treatment in women with endometriosis, Gynecologic and Obstetric Investigation, Vol.52, No.4, 217-222, 2001.
(Summary)
We performed a randomized controlled study to determine the efficacy of add-backed therapy by every-other-day administration of 0.625 mg conjugated equine estrogen (CEE) and 2.5 mg medroxyprogesterone acetate (MPA) on GnRH agonists (GnRH-a) treatment in Japanese women with symptomatic endometriosis. At the end of treatment, serum estrone and estradiol levels in the add-back group (n = 11) were significantly higher than those in the control group (n = 10). The assessment of Beecham classification by bimanual examination, serum CA-125 levels, and the frequency of genital bleeding revealed no significant differences between the two groups. The add-back group showed reduced Kupperman indices relative to those of the control group, and could prevent the loss of bone density. These findings led to a conclusion that GnRH-a therapy added back by every-other-day administration of 0.625 mg CEE and 2.5 mg MPA was a safe and effective treatment for Japanese women with endometriosis.
Masahiko Maegawa, Masaharu Kamada, Minoru Irahara, Satoshi Yamamoto, Shuji Yamano, Y Ohmoto, H Gima, C J Thaler and Toshihiro Aono : Concentration of Granulocyte Elastase in Seminal Plasma is not Associated with Sperm Motility, Archives of Andrology, Vol.47, No.1, 31-36, 2001.
(Summary)
Although elastase could affect sperm motility in vitro, secretory leukocytes protease inhibitor (SLPI) prevents sperm from being attacked by elastase. The authors investigated the correlations of elastase level with sperm motility and SLPI level in vivo. Semen samples (n = 116) were collected and centrifuged after semen analysis. Elastase and SLPI levels were determined by an enzyme immunosorbent assay. Samples were classified by elastase levels into low (<250 ng/mL), moderate (250-1,000 ng/mL), and high elastase groups (> or =1,000 ng/mL). Elastase levels (range, 2.8-23,974.4 ng/mL) were not associated with sperm motility. The median SLPI level in the high elastase group was 15,900 ng/mL (range, 2.860-46,900 ng/mL). However, there was no significant correlation between elastase and SLPI levels in seminal plasma. Since SLPI forms a 1:1 complex with elastase, these results suggest that seminal plasma has a sufficient amount of SLPI to protect spermatozoa from elastase.
Keizo Deguchi, Masaharu Kamada, Minoru Irahara, Masahiko Maegawa, Satoshi Yamamoto, Yasukazu Ohmoto, Kaoru Murata, Toshiyuki Yasui, Shuji Yamano and Toshihiro Aono : Postmenopausal changes in production of type 1 and type 2 cytokines and the effects of hormone replacement therapy, Menopause, Vol.8, No.4, 266-273, 2001.
(Summary)
An appropriate defense against infective agents or malignant cells is attributed to the exquisitely balanced T helper 1 type (cellular) and T helper 2 type (humoral) immune reactions. We investigated the effect of hormone replacement therapy (HRT) on postmenopausal changes in the production of interferon (IFN)-gamma and interleukin (IL)-10, a type 1 and a type 2 cytokine, respectively. Both cytokines were measured by ELISA in the supernatant of lipopolysaccharide-stimulated whole blood cells from 72 untreated and 44 HRT-treated women. Thirteen women were examined before and during HRT. The production of IFN-gamma in women in their 40s and in postmenopausal women was significantly higher compared with that of younger women. However, IFN-gamma fell to the lowest level in the late postmenopausal stage, whereas the production of IL-10 increased gradually with age and in parallel with the postmenopausal period. Thus, in women in the mid-and late postmenopausal period, excessive production of type 2 cytokine (IL-10) compared with type 1 cytokine (IFN-gamma) occurred. The IFN-gamma levels of women on HRT were significantly lower than those of untreated women in the early and mid-postmenopausal stages, and IL-10 levels of women on HRT were significantly lower than those of untreated women in the mid-and late postmenopausal stages. HRT induced a significant decrease in the production of IL-10 and tended to lower the level of IFN-gamma. Production of IL-10 is augmented in postmenopausal women. HRT probably prevents postmenopausal women from an aberration of the immune system by improving the balance of type 1 and type 2 immune reactions.
Koji Ogura, Minoru Irahara, Machiko Kiyokawa, Michiko Tezuka, Toshiya Matsuzaki, Toshiyuki Yasui, Masaharu Kamada and Toshihiro Aono : Effects of leptin on secretion of LH and FSH from primary cultured female rat pituitary cells, European Journal of Endocrinology, Vol.144, No.6, 653-658, 2001.
(Summary)
Leptin, which is the product of the obese gene, is believed to play important roles in pubertal development and reproductive function in females. In a study using adult male rats, it was found that leptin stimulated secretion of gonadotropin from the pituitary in a dose-related manner. However, there has been no such study in female rats. To investigate the effects of leptin on the production of LH and FSH from the pituitary in female rats, using primary cultured pituitary cells. In this study, we determined body weight, serum leptin concentration and serum estradiol (E(2)) concentration in female Wistar rats at 3, 5, 6, 7, 9 and 11 weeks of age, and cultured pituitary cells from 6-week-old female Wistar rats with leptin (0--10(-7) mol/l) and GnRH (0 or 10(-8) mol/l). Then basal and GnRH-stimulated extra- and intracellular LH and FSH were assayed by RIA. Serum leptin concentration increased with increases in body weight and E(2) concentration. The pubertal serum leptin concentration was about 10(-10) mol/l. At a lower or moderate concentration, leptin produced dose-related increases in both basal and GnRH-stimulated extra- and intracellular LH and FSH in pituitary cells. At a concentration of 10 mol/l, leptin significantly (P<0.05) stimulated both basal and GnRH-stimulated extra- and intracellular LH and FSH. However, at greater concentrations, these effects diminished. These results indicated that leptin induced pituitary cells to produce and secrete both LH and FSH, with or without GnRH. The concentration of leptin that induced the greatest production of gonadotropins by pituitary cells was 10(-10) mol/l, which was the same as the physiological pubertal concentration. Leptin may be involved in the onset of puberty. It is also conceivable that leptin may be a cause of ovulatory failure, not only in weight loss but also in weight gain.
Masaya Takikawa, Masaharu Kamada, Masahiko Maegawa, Shuji Yamano, Minoru Irahara, Toshihiro Aono, Siroh Futaki, Yasukazu Ohmoto and Samuel S Koide : Evaluation of two sperm antigens,rSMP-B and YWK-||,as targets for immunocontraception, Zygote, Vol.9, No.2, 145-151, 2001.
(Summary)
To determine whether sperm membrane components, rSMP-B and YWK-II, are suitable candidates as immunocontraceptives in humans, antifertility activities of the antibodies to the peptide fragments, rSMP-229 and rSMP-230 of rSMP-B and YAL-198 of YWK-II, were examined. In a previous report, anti-rSMP-230 antibody was shown to immobilise human sperm and to block human fertilisation, and the antigen (rSMP-230) to interact with antisperm antibodies found in sera of infertile women. Antibody to the second synthetic peptide, rSMP-229, corresponding to a different segment of rSMP-B, mimicked the biological activities of the anti-rSMP-230 antibody. Anti-YAL-198 antibody significantly, although weakly, inhibited human fertilisation. In the murine model, the anti-rSMP-B antibodies blocked in vitro fertilisation of mouse eggs but had no influence on embryo growth. Anti-YAL-198 antibody, however, arrested the growth of zygotes. In conclusion, rSMP-B, a human sperm protein, is a promising candidate in the development of an immunocontraceptive for human application. A second sperm protein, YWK-II, is effective as an antifertility immunogen in experimental animals.
(Keyword)
Antisperm antibody / Contraception / embryonic growth / Fertilisation / Human sperm protein
Takeshi Katou, Hiroyuki Furumoto, Tomoko Ogura, Yasuyo Onishi, Minoru Irahara, Shuji Yamano, Masaharu Kamada and Toshihiro Aono : Expression of IL-17 mRNA in Ovarian Cancer, Biochemical and Biophysical Research Communications, Vol.282, No.3, 735-738, 2001.
(Summary)
IL-17 is considered as a proinflammatory cytokine. We have demonstrated IL-17 is an angiogenic factor and promotes tumor growth in murine tumor models. In this report, we investigated the expression of IL-17 mRNA by RT-PCR and the relationship between IL-17 expression and microvascular density in ovarian cancer. IL-17 mRNA was expressed in 11 (64.7%) of 17 ovarian cancer. And the average number of blood vessels observed in IL-17 positive tumors (173.4 +/- 55.1/mm(2)) was significantly higher than that in negative tumors (107.7 +/- 57.8/mm(2)). These results indicated IL-17 is expressed in a considerable proportion of ovarian cancer and promotes tumor angiogenesis. There was no significant relationship between IL-17 expression and clinicopathologic parameters.
Miho Senuma, Shuji Yamano, Koji Nakagawa, Minoru Irahara, Masaharu Kamada and Toshihiro Aono : Progesterone accelerates the onset of capacitation in mouse sperm via T-type calcium channels, Archives of Andrology, Vol.47, No.2, 127-134, 2001.
(Summary)
This study was undertaken to evaluate whether progesterone induces capacitation of mouse spermatozoa. When sperm were evaluated by chlortetracycline staining, addition of progesterone significantly increased the proportion of spermatozoa exhibiting the B pattern at 60 minutes of incubation, compared with that before incubation (23 +/- 6.2% vs. 13 +/- 2.9%, p < 0.01) and that in hTF medium without progesterone (23 +/- 6.2% vs. 13 +/- 4.2%, p < 0.01). If the redistribution of proteins in sperm plasma membrane such as protein binding calcium ion were defined as capacitation, it could be said that progesterone promoted capacitation of mouse sperm. This progesterone-induced capacitation was prevented by depletion of extracellular calcium ion and addition of NiCl2, a T-type calcium channel blocker, although thapsigargin, an inhibitor of Ca2+-ATPase, did not increase the number of capacitated sperm (B pattern; progesterone vs. progesterone + depletion of calcium ion, 18 +/- 3.5% vs. 8 +/- 2.5%, p < 0.05, progesterone vs. progesterone + NiCl2, 20 +/- 3.8% vs. 6 +/- 5.2%, p < 01). Furthermore, genistein, a protein tyrosine phosphorylation inhibitor, inhibited progesterone-induced capacitation (B pattern; progesterone vs. progesterone + genistein, 20 +/- 3.8% vs. 11 +/- 2.4%, p < 01). In conclusion, progesterone induces capacitation in mouse sperm and this capacitation may be associated with calcium influx and tyrosine phosphorylation.
Masaharu Kamada, M Takikawa, Masahiko Maegawa, Satoshi Yamamoto, Shuji Yamano, Minoru Irahara and Toshihiro Aono : Specific Cytotoxicity of Antibody to YAL-198, a Sperm Antigen Peptide, to Murine Zygote, Archives of Andrology, Vol.47, No.2, 89-96, 2001.
(Summary)
Active immunization with the peptide segments rSMP-230 and YAL-198, corresponding to the hydrophilic extracellular domain of two human sperm antigens (rSMP-B and YWK-II, respectively), reduced fertility in female rats by different mechanisms. The anti-rSMP-230 antibody interferes with human and murine fertilization, and the anti-YAL-198 antibody blocks the development of mouse embryos. The authors examined in vitro at which stage the antibodies to rSMP-230 and YAL-198 were cytotoxic to murine embryos up to morula/blastocyst stage. Anti-rSMP-230 antibody was not cytotoxic to any stages. On the other hand, the anti-YAL-198 antibody arrested the growth of embryos at the 2-cell stage but not at more advanced developmental stages. When the anti-YAL-198 antibody was used, spotty staining was observed only on the surfaces of embryos that had arrested at the 2-cell stage. Unstained embryos, however, continued to develop normally. In contrast, the anti-rSMP-230 antibody stained murine sperm but failed to stain murine ova and embryos. The present results suggest that the human sperm components rSMP-B and YWK-II play important roles in sperm-egg interaction and early development of the embryo, respectively.
K Myogo, Shuji Yamano, Koji Nakagawa, Masaharu Kamada, Masahiko Maegawa, Minoru Irahara and Toshihiro Aono : Sperm-Immobilizing Antibodies Block Capacitation in Human Spermatozoa, Archives of Andrology, Vol.47, No.2, 135-142, 2001.
(Summary)
Sperm-immobilizing antibodies block human fertilization by interfering with the acrosome reaction (AR). To clarify the mechanism of blockage of AR by sperm-immobilizing antibodies, the authors examined their effects on the increase of intracellular free Ca2+ concentration induced by follicular fluids (Ca2+ influx) in spermatozoa and on their capacitation. Sperm-immobilizing antibodies did not suppress Ca2+ influx induced by follicular fluid, but they inhibited capacitation of human spermatozoa. Namely delta%AR (%AR after addition of an AR inducer--%AR before treatment) induced by progesterone was significantly (p < .0001) lower when spermatozoa were incubated in human tubal fluid medium cotaining antibody-positive serum (1.2%), compared to that when incubated in control medium (19.2%). Furthermore, the proportion of both spermatozoa that became capacitated and ones that had become capacitated decreased significantly (p < .0001) after 2, 4, and 6 h of incubation in medium containing antisperm antibody-positive serum, compared to those of spermatozoa incubated in control medium. In conclusion, sperm-immobilizing antibodies may be closely related to their blockage of capacitation.
Minoru Irahara, Takao Tamura, Toshiya Matsuzaki, Seiichiro Saito, Toshiyuki Yasui, Shuji Yamano, Masaharu Kamada and Toshihiro Aono : Orexin-A Suppresses the Pulsatile Secretion of Luteinizing Hormone via β-Endorphin, Biochemical and Biophysical Research Communications, Vol.281, No.1, 232-236, 2001.
(Summary)
Orexins, the novel hypothalamic neuropeptides that stimulate feeding behavior, have been shown to suppress the pulsatile secretion of LH in ovariectomized rats. However, the mechanism of this action is still not clear. We examined the effect of naloxone, a specific opioid antagonist, on the suppression of the pulsatile secretion of LH by orexins to determine whether beta-endorphin is involved in this suppressive effect. We administered orexins intracerebroventricularly and injected naloxone intravenously in ovariectomized rats, and we measured the serum LH concentration to analyze the pulsatile secretion. Administration of orexin-A significantly reduced the mean LH concentration and the pulse frequency, but coadministration of naloxone significantly restored the mean LH concentration and the pulse frequency. Administration of orexin-B also significantly reduced the mean LH concentration and the pulse frequency, and coadministration of naloxone did not restore them. These results indicate that orexin-A, but not orexin-B, suppresses GnRH secretion via beta-endorphin.
Masaharu Kamada, Minoru Irahara, Masahiko Maegawa, Yasukazu Ohmoto, Takashi Takeji, Toshiyuki Yasui and Toshihiro Aono : Postmenopausal changes in serum cytokine levels and hormone replacement therapy, American Journal of Obstetrics and Gynecology, Vol.184, No.3, 309-314, 2001.
(Summary)
Our purpose was to investigate the effect of hormone replacement therapy on the postmenopausal changes in serum cytokine levels. Fifteen cytokines were measured by an enzyme-linked immunosorbent assay in 97 untreated and hormone replacement-treated women. Thirteen women were examined before and during hormone replacement therapy. Serum concentrations of macrophage colony-stimulating factor were significantly (P < .05) lower during the early postmenopausal period (< or = 10 years) than the values in premenopause and the elevated levels in the late postmenopausal period (< or = 30 years). A significant increase in tumor necrosis factor alpha and a decline in transforming growth factor beta1 were found in late postmenopausal women. Serum levels of macrophage colony-stimulating factor in women receiving hormone replacement therapy were significantly higher than those in untreated postmenopausal women. Furthermore, hormone replacement therapy induced a significant (P < .01) increase in serum levels of macrophage colony-stimulating factor, whereas serum levels of other cytokines were not affected. It is well documented that macrophage colony-stimulating factor lowers serum cholesterol concentrations and prevents atherosclerosis. Inducing the production of macrophage colony-stimulating factor is a possible additional mechanism of hormone replacement therapy in mediating the antiatherogenic effect.
Masaharu Kamada, Minoru Irahara, Masahiko Maegawa, Toshiyuki Yasui, Shuji Yamano, Masayo Yamada, Mitiko Tezuka, Yuka Kasai, Keiichi Deguchi, Yasukazu Ohmoto and Toshihiro Aono : B cell subsets in postmenopausal women and the effect of hormone replacement therapy, Maturitas, Vol.37, No.3, 173-180, 2001.
(Summary)
In elderly subjects the capacity for antibody production is depressed. This immunosenescence state of humoral immunity is associated with the occurrence of autoimmune disorders involving CD5+ B (B-1) cells. Since estrogen is capable of stimulating the production of autoantibodies, this sex steroid hormone may be a contributing cause of the higher incidence of autoimmune diseases in women. In the present study, B cell subsets in women during the postmenopausal period was determined. The effect of hormone replacement therapy (HRT) on B cell subsets was examined to establish whether the administration of gonadal hormones influence humoral immunity in postmenopausal women. Forty six untreated pre- and postmenopausal women and 39 women on HRT were studied. The proportion of B-1 (CD5+) and conventional CD5- B (B-2) lymphocytes was determined by two-color flow cytometry. Serum autoantibodies to a nuclear antigen and to interleukin (IL)-1alpha were measured by immunofluorescence and by radioimmunoassay, respectively. Thirteen women were examined prospectively before and during HRT. In late postmenopausal women (> or = 30 years postmenopausal period), the proportion of B-2 cells was significantly reduced (p<0.01) compared to those of premenopausal and perimenopausal women. HRT induced a significant (p<0.01) increase in the percentage of B-2 cells, while that of B-1 cells remained unchanged. HRT did not affect autoantibody production. HRT may retard the progress of immunosenescence by increasing the production of B-2 cells. Moreover, HRT appears not to increase the risk of autoimmune diseases developing in postmenopausal women.
Hiromi Kinoshita, Toshiyuki Yasui, Kenjiro Ushigoe, Minoru Irahara, Minoru Tanaka, Kunio Nakashima and Toshihiro Aono : Expression of Ovarian Prolactin Receptor in Relation to Hormonal Changes during Induction of Ovulation in the Rat, Gynecologic and Obstetric Investigation, Vol.52, No.2, 132-138, 2001.
(Summary)
We examined the relationships between the expression of the short and long forms of the prolactin (PRL) receptor (PRLR) mRNA in the ovary and changes in the levels of serum hormones such as sex steroid hormones and PRL during induction of ovulation in the rat. The expression of both forms of PRLR mRNA in the ovary was examined by Northern blot analysis in immature female rats treated with pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG). Ovarian tissues and blood samples were obtained before treatment, 24 and 48 h after PMSG injection and 4, 6, 8, 12, 24 and 48 h after hCG treatment. Serum levels of 17beta-estradiol, progesterone and PRL were determined by radioimmunoassay. Serum levels of 17beta-estradiol rapidly increased to a maximal level 48 h after PMSG injection and then rapidly declined until 4 h after hCG injection. Serum levels of progesterone gradually increased after PMSG treatment, markedly increased to 114.2 nmol/l 8 h after hCG treatment and remained high until 48 h after hCG treatment. The serum level of PRL peaked at 66.2 microg/l (p < 0.01) 48 h after PMSG injection, and a temporary decrease after hCG treatment was followed by a continuously high level from 8 to 48 h. The expression of the long form of PRLR mRNA increased significantly (p < 0.01) to 688% of the control level after PMSG treatment, while that of the short form increased to only 184% of the control level. The expression of the long form of PRLR-mRNA rapidly declined until 6 h and then gradually increased until 48 h after hCG treatment. On the other hand, the expression of the short form of PRLR mRNA decreased to a nadir 12 h after hCG injection and then increased significantly (p < 0.01) to 142% of the control level. Our results showed that the changes in the short and long forms of PRLR mRNA differed in a time-specific manner and that these two forms are involved in different functions in the rat ovary during induction of ovulation. It is thought that the long form of PRLR mRNA is involved in folliculogenesis, while the short form of PRLR mRNA may play an important role in the formation and maintenance of the corpus luteum in the rat ovulatory cycle.
(Keyword)
Prolactin / Prolactin receptor / Overy / Induction of ovulation
Masaharu Kamada, Minoru Irahara, Masahiko Maegawa, Yasukazu Ohmoto, Kaoru Murata, Toshiyuki Yasui, Shuji Yamano and Toshihiro Aono : Transient Increase in the Levels of T-Helper 1 Cytokines in Postmenopausal Women and the Effects of Hormone Replacement Therapy, Gynecologic and Obstetric Investigation, Vol.52, No.2, 82-88, 2001.
(Summary)
The aim of this study was to determine, at least in part, T-cell function in postmenopausal women and the effects of hormone replacement therapy (HRT). Levels of T-helper 1 (Th1) cytokines (IL-2 and IFN-gamma) and T-helper 2 (Th2) cytokines (IL-4 and IL-10) produced by phytohemagglutinin-stimulated whole blood cells from 72 untreated and 44 HRT-treated women were measured by ELISA. Thirteen of the 44 HRT-treated women were examined before and during HRT. The production of IL-2 increased gradually with advance of the postmenopausal period. The levels of IL-2 in women in the early (< or =10 years) and mid (>10 and <30 years) postmenopausal stages were significantly higher than those in women in their second, third and fourth decades. The level in women in the late (> or =30 years) postmenopausal stage, however, was significantly lower than those in women in the early and mid postmenopausal stages. The level of IFN-gamma was highest in women in the mid postmenopausal stage. On the other hand, the levels of Th2 cytokines did not change with age or after menopause until the mid postmenopausal period but were significantly lower in women in the late postmenopausal stage. IFN-gamma levels in women on HRT were significantly lower than those in untreated postmenopausal women at all postmenopausal stages. HRT induced a significant decrease in the production of IL-2 and IL-4. In conclusion, production of Th1 cytokines is augmented in women after menopause. HRT prevents this increase, thereby improving the aberration of Th1/Th2 balance that is implicated in an inadequate immune response and pathological conditions.
Toshiyuki Yasui, Hirokazu Uemura, Michiko Tezuka, Masayo Yamada, Minoru Irahara, Masakazu Miura and Toshihiro Aono : Biological Effects of Hormone Replacement Therapy in Relation to Serum Estradiol Levels, Hormone Research, Vol.56, No.1-2, 38-44, 2001.
(Summary)
Tissues in various parts of the body have different sensitivities to estradiol. However, it is very difficult to measure the serum estradiol levels precisely in women receiving oral conjugated equine estrogen, which is a mixture of estrogens. In the present study, we precisely measured the serum levels of estradiol in postmenopausal women undergoing hormone replacement therapy (HRT), and we clarified the relationships between serum estradiol levels and the effects of HRT on the Kupperman index, bone mineral density (BMD), serum gonadotropin, lipid metabolism and unscheduled bleeding as the clinical endpoints. Sixty-eight postmenopausal or bilaterally ovariectomized women, aged 30-64 years, who had been suffering from vasomotor symptoms such as hot flush or atrophy of the vagina were randomly assigned to two groups: one group of 34 patients who received oral administration of 0.625 mg conjugated equine estrogen (CEE, Premarin, Wyeth) and 2.5 mg medroxyprogesterone acetate (MPA, Provera, Upjohn) every other day, and another group of 34 patients who received oral administration of 0.625 mg CEE and 2.5 mg MPA every day. All subjects were re-classified into three groups according to the serum estradiol level after 12 months of treatment: (1) low estradiol group (<15 pg/ml, n = 25); (2) middle estradiol group (> or =15 and <25 pg/ml, n = 27), and (3) high estradiol group (> or =25 pg/ml, n = 16). We examined the relationships between serum estradiol level and the effects of estradiol on the Kupperman index, BMD, serum gonadotropin levels, lipid profile and unscheduled bleeding in these three groups. RESULTS obtained by using our newly developed high-performance liquid chromatography (HPLC)-radioimmunoassay (RIA) system clearly showed that the effects on each tissue in postmenopausal women receiving oral CEE and MPA is closely related to estradiol level. The effects of HRT on BMD, serum gonadotropin levels and lipid profile were shown to be clearly dependent on the serum estradiol levels, while the effect of HRT on the Kupperman index was independent of the serum estradiol level. Furthermore, it was also found that a very low concentration of estradiol (<15 pg/ml) was sufficient to suppress the serum LH and FSH levels and to relieve vasomotor symptoms, and that the minimum concentration of estradiol required to increase BMD was 15 pg/ml. On the other hand, the level of estradiol required to reduce total cholesterol, low density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (Apo B) was found to be more than 25 pg/ml, while the level required to increase high density lipoprotein-cholesterol (HDL-C) and apolipoprotein A1 (Apo A1) was at least 15 pg/ml. The incidence of unscheduled bleeding was also lower in the low estradiol group than in the other estradiol level groups. These results suggest that the different clinical endpoints have different response thresholds and thus reflect tissue sensitivity to estradiol levels achieved by HRT.
Shuji Yoshikawa, Masaharu Kamada, Masahiko Maegawa, Satoshi Yamamoto, Minoru Irahara, Shuji Yamano, Toshihiro Aono, Hiroshi Kido and Samuel S Koide : Hormonal Control of mRNA Expression of Immunoglobulin Binding Factor in Uterine Cervix, Biochemical and Biophysical Research Communications, Vol.279, No.3, 898-903, 2000.
(Summary)
Uterine cervical mucus contains an immunoglobulin binding factor (IgBF). It may play a role in preventing antibody production against sperm in the female reproductive tract. To elucidate the mechanism involved in the production of activated IgBF, we determined the effects of hormones on the expression of mRNAs of IgBF and of protein disulfide isomerase (PDI), activating enzyme, in uterine cervix by quantitative RT-PCR. The uterine cervices of female rats were excised at preovulatory, ovulatory, and postovulatory phases. The human uterine cervical adenocarcinoma cells (TCO-2) were cultured for 24 h in serum-free medium containing 17beta-estradiol or progesterone. Expression of IgBF and PDI mRNAs was significantly highest during the ovulatory phase. 17beta-estradiol stimulated the expression of both mRNAs in TCO-2; whereas progesterone was ineffective. In conclusion, estrogen regulates the production of IgBF by the endocervix and PDI in vivo, thereby increasing the level of activated IgBF in the female reproductive tract during the ovulatory phase, allowing sperm to enter the uterine cavity.
Minoru Irahara, Toshiyuki Yasui, Michiko Tezuka, Kenjiro Ushigoe, Shuji Yamano, Masahiko Kamada and Toshihiro Aono : Evidence that Toki-shakuyaku-san and its Ingredients Enhance the Secretion of a Cytokine-Induced Neutrophil Chemoattractant (CINC/gro) in the Ovulatory Process, Methods and Findings in Experimental and Clinical Pharmacology, Vol.22, No.10, 725-730, 2000.
(Summary)
We investigated the effects of Toki-shakuyaku-san and its crude ingredients in relation to the secretion of a cytokine-induced neutrophil chemoattractant, CINC/gro, interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF alpha) in the ovulatory process. Toki-shakuyaku-san significantly (p < 0.01) stimulated the secretion of 17 beta-estradiol but did not stimulate the secretion of progesterone in cultured whole ovarian dispersates. Toki-shakuyaku-san enhanced the secretion of CINC/gro in a dose-dependent manner and the production of CINC/gro at concentrations of 10 and 100 micrograms/ml of Toki-shakuyaku-san increased significantly (p < 0.01). Toki-shakuyaku-san also enhanced secretions of both IL-1 beta and TNF alpha, which are known to stimulate the secretion of CINC/gro in the ovulatory process. The production of TNF alpha increased significantly (p < 0.05) with 10 and 100 micrograms/ml of Toki-shakuyaku-san. Atractylodis Lanceae Rhizoma, Cnidii Rhizoma, Angelicae Radix, Paeoniae Radix and Alismatis Rhizoma, which are crude ingredients of Toki-shakuyaku-san, significantly (p < 0.01) enhanced the secretion of CINC/gro at concentrations of 100 micrograms/ml. The results of this study show that Toki-shakuyaku-san can stimulate the secretion of 17 beta-estradiol and stimulate the ovulatory process by stimulating the production of CINC/gro, IL-1 beta and TNF alpha in vitro. As a treatment for ovulatory disorders, Toki-shakuyaku-san may have stimulatory effects on both steroidogenesis and the ovulatory process.
Masaharu Kamada, Minoru Irahara, Masahiko Maegawa, Toshiyuki Yasui, Takashi Takeji, Masayo Yamada, Mitiko Tezuka, Yuka Kasai and Toshihiro Aono : Effect of hormone replacement therapy on post-menopausal changes of lymphocytes and T cell subests, Journal of Endocrinological Investigation, Vol.23, No.6, 376-382, 2000.
(Summary)
Immunosenescence is associated with the occurrence of lethal diseases, such as infection and malignancy. Since endocrinosenescence occurs simultaneously with immunosenescence, we determined whether or not lymphocytes and T cell subsets were altered in post-menopausal women. The ability of hormone replacement therapy (HRT) to reverse or modify the aberrations of the cell populations observed in elderly women was also examined. Thirty-nine untreated post-menopausal women and 39 women on HRT were studied. The proportions of lymphocytes and T cell subsets (helper, cytotoxic and immature T cells, and naive and memory/activated T cells) were determined by two color flow cytometry. Thirteen women were examined before and during HRT. At late post-menopause (> or = 30 years post-menopausal period), the proportion of peripheral blood lymphocytes showed a tendency to decline (p=0.06) compared with that at early (< or = 10 years) post-menopause. Significant (p<0.05) decrease in naive T cells and an increase in memory/activated T cells occurred at late post-menopause compared to those at early post-menopause. The percentage of lymphocytes in women on HRT was significantly (p<0.05) higher than that in untreated women at late post-menopausal stage. Furthermore, in a prospective study, HRT induced a significant (p<0.02) increase in the percentage of lymphocytes but showed no effect on the aberrations of naive and memory/activated T cells. HRT prevents the decline in the lymphocytes observed in post-menopausal women. However, HRT appears not to influence the observed alteration in T cell subsets.
(Keyword)
Menopause / immunosenescence / naive T cell / memory T cell / estrogen deficiency / aging
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Noriko Tamura, Minoru Irahara, Akira Kuwahara, Kenjiro Ushigoe, Hiromu Sugino and Toshihiro Aono : Effect of activin on production and secretion of prolactin and growth hormone in cultured rat GH3 cells, European Journal of Endocrinology, Vol.142, No.5, 506-511, 2000.
(Summary)
To evaluate the effect of the growth factor activin A on the secretion of prolactin (PRL) and GH in cultured GH3 cells. The concentrations of PRL and GH secreted from GH3 cells cultured in media with and without activin A were measured by RIA, and the expression of PRL mRNA and GH mRNA were analyzed using the Northern blot method. Activin A significantly inhibited PRL release from GH3 cells cultured for 48h in a dose-dependent manner (activin: 0.3-3nM). The inhibitory effects of 3nM activin A were observed in the culture from 12h to 48h (53.2% of control). Activin A (3nM) also significantly inhibited the expression of PRL mRNA at 24h (33.8% of control). In contrast, activin A significantly stimulated GH release from GH3 cells cultured for 48h in a dose-dependent manner (activin: 0.3-3nM). The stimulatory effect of 3nM activin A was observed in the culture for 48h (157.6% of control). Activin A (3nM) also significantly stimulated the expression of GH mRNA at 24h (183.6% of control). In spite of these significant changes in PRL and GH secretion, pit-1 mRNA levels were not significantly changed by activin A. These findings indicated that activin A modulates PRL and GH secretion through the regulation of PRL and GH gene transcription in GH3 cells, but that these effects are unrelated to pit-1 gene expression.
Hirokazu Uemura, Minoru Irahara, Naoto Yoneda, Toshiyuki Yasui, Kaori Genjida, Ken-ichi Miyamoto, Toshihiro Aono and Eiji Takeda : Close correlation between estrogen treatment and renal phosphate reabsorption capacity, The Journal of Clinical Endocrinology and Metabolism, Vol.85, No.3, 1215-1219, 2000.
(Summary)
To determine the influence of estrogen on the activity of renal proximal tubular reabsorption of inorganic phosphate (Pi) in women, we examined the changes of the renal threshold phosphate concentration (also denoted as TmP/GFR), as well as the changes in the concentrations of mineral components in the circulation in two groups of women--one receiving hormone replacement therapy (HRT) and one receiving gonadotropin-releasing hormone agonists (GnRH-a) therapy. We also examined the changes in the concentrations of serum PTH in the GnRH-a group. The patients in the HRT group were continuously treated with 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate per day. The patients in the GnRH-a group were treated with a monthly injection of 3.75 mg leuprolide acetate depot for 6 months. The values of TmP/GFR decreased in all of the patients who received HRT. The mean percentage change in TmP/GFR was -14.5% (range, -24.3% to -9.6%). In contrast, in all of the patients treated with GnRH-a, the values of TmP/GFR increased after 6 months of treatment (the mean percentage change was 28.5%; range, 18.2-78.3%) and returned to the preadministration level at 12 weeks after stopping therapy. In these patients, both the values of TmP/GFR and the concentrations of serum Pi correlated significantly with circulating estradiol levels (r = -0.767, P < 0.01 and r = -0.797, P < 0.01, respectively), but the concentrations of serum corrected calcium did not correlate. Moreover, in the same patients, the levels of serum intact PTH decreased significantly (P < 0.05) after 6 months of treatment, but at 12 weeks after stopping therapy the trends of these levels varied among individual patients. These results suggest that estrogen could act directly to suppress sodium-dependent Pi reabsorption in the renal proximal tubules.
Takao Tamura, Minoru Irahara, Michiko Tezuka, Machiko Kiyokawa and Toshihiro Aono : Orexins, Orexigenic Hypothalamic Neuropeptides, Suppress the Pulsatile Secretion of Luteinizing Hormone in Ovariectomized Female Rats, Biochemical and Biophysical Research Communications, Vol.264, No.3, 759-762, 1999.
(Summary)
It is well known that feeding disorders are deeply related to reproductive dysfunction, and some feeding regulatory factors may modulate the reproductive function. We examined the effect of orexins, the newly discovered orexigenic hypothalamic neuropeptides, on the pulsatile secretion of LH to clarify their influence on the reproductive function. We administered orexins or saline into the third ventricle of bilaterally ovariectomized (OVX) rats, and measured the serum LH concentration by RIA in blood samples drawn every 6 min for 2 hours to analyze the pulsatile secretion. In the orexin-treated groups, the mean LH concentration and the pulse frequency were significantly reduced (p < 0.01), but the pulse amplitude did not differ significantly. These data indicate that orexins suppress the pulsatile secretion of LH by influencing GnRH neurons at the hypothalamic level.
Seiichiro Miyamoto, Minoru Irahara, Kenjiro Ushigoe, Akira Kuwahara, Hiromu Sugino and Toshihiro Aono : Effects of activin on hormone secretion by signal female rat pituitary cells: Analysis by cell immunoblot assay, The Journal of Endocrinology, Vol.161, No.3, 375-382, 1999.
(Summary)
We investigated the effect of activin A on secretion of LH, FSH, and prolactin (PRL) by female cultured rat pituitary cells at the single-cell level by means of the cell immunoblot assay. Anterior pituitary cells from 8-week-old female rats were preincubated with or without activin A for 24 h, after which they were monodispersed and immediately used for cell immunoblot assay. The percentages of LH-, FSH- and PRL-immunoreactive cell blots detected were 5.5, 5.3 and 43.1%, respectively, of all pituitary cells applied to the transfer membrane. The percentage of LH-secreting cells and mean LH secretion per cell did not change after treatment with activin. In contrast, activin significantly increased the percentage of FSH-secreting cells and mean FSH secretion per cell to 136.0 and 114. 5% respectively. In addition, activin significantly decreased the percentage of PRL-secreting cells and mean PRL secretion per cell to 52.2 and 72.0% respectively. These results suggest that (1) activin A has effects on female rat pituitary cells that increase not only the amount of FSH secretion per cell but also the number of FSH-secreting cells, and (2) activin A decreases both the amount of PRL secretion per cell and the number of PRL-secreting cells.
Toshiyuki Yasui, M Yamada, H Kinoshita, Hirokazu Uemura, N Yoneda, Minoru Irahara, Toshihiro Aono, S Unahara, Y Mito, F Kuritoto and K Hata : Combination of automatic HPLC-RIA method for determination of estrone and estradiol in serum, Journal of Clinical Laboratory Analysis, Vol.13, No.6, 266-272, 1999.
(Summary)
We developed a highly sensitive assay for estrone and 17 beta-estradiol in serum. Estrone and 17 beta-estradiol, obtained by solid-phase extraction using a Sep pak tC18 cartridge, were purified by high-performance liquid chromatography (HPLC). Quantitation of estrone and 17 beta-estradiol were carried out by radioimmunoassay. Not insignificantly, this automatic system of extraction and HPLC succeeded in analyzing 80 samples a week. Intra-assay coefficients of variation (CV) for estrone and 17 beta-estradiol ranged from 19.5 to 28.7%, and from 8.5 to 13.7%, respectively. The minimum detectable dose for estrone and 17 beta-estradiol were 1.04 pg/ml and 0.64 pg/ml, respectively. The serum levels of 17 beta-estradiol using our method strongly correlated with those by Gas chromatography mass spectrometry (GC-MS). The serum levels of estrone and 17 beta-estradiol in 154 peri- and postmenopausal women were estimated to be between 15 and 27 pg/ml and between 3.5 and 24.0 pg/ml, respectively, while the serum level of 17 beta-estradiol in postmenopausal women, in particular, was estimated to be from 3.5 to 6.3 pg/ml. For postmenopausal women who suffered from vasomotor symptoms, the mean levels of estrone and 17 beta-estradiol at 12 to 18 hours after treatment with daily 0.625 mg conjugated equine estrogen (CEE) and 2.5 mg medroxyprogesterone acetate (MPA) were 135.0 and 21.3 pg/ml at 12 months, respectively. On the other hand, levels of estrone and 17 beta-estradiol at 12 to 18 hours after treatment with CEE and MPA every other day, were 73.4 and 15.3 pg/ml, respectively. These highly sensitive assays for estrone and 17 beta-estradiol are useful in measuring low levels of estrogen in postmenopausal women, and monitoring estrogen levels in women receiving CEE as hormone replacement therapy.
Hirokazu Uemura, Toshiyuki Yasui, N Yoneda, Minoru Irahara and T Aono : Measurement of N- and C-terminal-region fragments of parathyroid hormone-related peptide in milk from lactating women and investigation of the relationship of their concentrations to calcium in milk., The Journal of Endocrinology, Vol.153, No.3, 445-451, 1997.
(Summary)
Parathyroid hormone-related peptide (PTHrP) is found in very high concentrations in the milk of various mammals. However, little is known about its physiological role in this fluid. To obtain detailed profiles of PTHrP in milk, we measured the concentrations of PTHrP in human milk by two different region-specific assays, PTHrP(1-87) (N-PTHrP) and PTHrP(109-141) (C-PTHrP). We also examined the correlations between PTHrP and Ca concentrations in milk as well as the correlations between PTHrP and secreted milk volume. The levels of N-PTHrP and C-PTHrP were relatively low after delivery and gradually increased to 13.87 +/- 2.40 nmol/l (mean +/- S.E.M.) and 56.39 +/- 11.31 nmol/l respectively on the 10th day postpartum. N-PTHrP concentration remained steady until the 6th month postpartum when weaning starts, at which point it decreased slightly. C-PTHrP levels changed in a similar way to N-PTHrP levels but were 2- to 5-fold higher. Milk Ca concentration, and content, correlated with C-PTHrP concentration, and content (r = 0.422 and r = 0.769 respectively; P < 0.0001) but not with N-PTHrP. N-PTHrP concentration in the milk samples on the 4th day postpartum correlated with the volume of milk secreted during the 24 h before the samples were taken (r = 0.524, P < 0.01), but C-PTHrP concentration did not. These results suggest that PTHrP in human milk may play some role in the maintenance of lactation through the N-terminal region and in promoting Ca transfer into milk via the C-terminal region.
Toshiyuki Yasui, Hirokazu Uemura, Minoru Irahara and Toshihiro Aono : Effects of transforming growth factor-β on the production of parathyroid hormone-related peptide in a human ovarian cancer cell line in vitro, Journal of Obstetrics and Gynaecology Research, Vol.23, No.3, 231-238, 1997.
228.
Haruhiko Saito, Eiji Hosoi, Ryuichi Yamasaki, Kazuhito Kameyama, Minoru Irahara, Yoshio Ohno and Shiro Saito : Immunoreactive growth hormone-releasing hormone(IR-GHRH) in the feto-placental circulation and differential effects of L-Dopa, L-Arginine and Somatostatin-14 on the plasma levels of IR-GHRH in normal adults, Hormone and Metabolic Research, Vol.29, No.4, 184-189, 1997.
(Summary)
The relation of the physiological releases of growth hormone-releasing hormone (GHRH) and growth hormone (GH) into the circulation in various conditions was investigated using a sensitive and specific radioimmunoassay for plasma GHRH. The mean fasting plasma level of immunoreactive (IR)-GHRH in 72 normal adults was 10.3 +/- 0.5 (mean +/- SEM) pg/ml and there was no significant sex difference in the level. The concentrations of IR-GHRH in plasma from the umbilical artery and umbilical vein were 107.3 +/- 20.5 pg/ml and 33.6 +/- 3.8 pg/ml, respectively, and a marked arterio-venous gradient was observed in all 12 individuals examined. The plasma level of IR-GHRH in the maternal vein was significantly lower than that in the cord blood, but was similar to that in non-pregnant women. In normal adults, although there was no apparent fluctuation in the level of plasma IR-GHRH or of plasma GH during bed rest, a significant increase of plasma IR-GHRH was detected followed by, or synchronized with the surge of plasma GH after oral administration of L-dopa. In contrast, on L-arginine infusion, no proportional elevation of plasma IR-GHRH with increase in plasma GH was observed. During and after intravenous infusion of somatostatin, the circulating IR-GHRH level did not increase, but on stopping the infusion there was an immediate and marked rebound surge of GH. We conclude that 1) the elevated IR-GHRH in the cord blood plasma originates from the fetus and may have a primary role in enhancing secretion of GH which promotes growth in early human life, and 2) the participations of GHRH in the mechanisms of GH secretion seen after administrations of L-dopa, L-arginine and somatostatin are different.
Seiichiro Miyamoto, Kenjiro Ushigoe, Noriko Tamura, Akira Kuwahara, Keiji Shitsukawa, Keijiro Azuma, Minoru Irahara, Toshihiro Aono and Hiromu Sugino : The effects of activin on prolactin secretion from individual GH3 cells: Analysis by the cell immunoblot assay. The Interaction of activin, activin receptors and gonadal steroids in rat pituitary, 3rd Ares-Serono Symposium on Inhibin, Activin, Follistatin - Recent Advances and Future Views, 1996.
230.
N Yoneda, Minoru Irahara, S Saito, Hirokazu Uemura and T Aono : Usefulness of recombinant human prolactin for treatment of poor puerperal lactation in a rat model., European Journal of Endocrinology, Vol.133, No.5, 613-617, 1995.
(Summary)
Recombinant human prolactin (r-hPRL) was produced by a line of murine C127 cells transfected with human PRL gene. To assess the biological efficacy of r-hPRL in vivo, we studied its influence on milk secretion using a rat model in which lactation was reduced by bromocriptine treatment. Puerperal rats were injected daily for 9 days after delivery with bromocriptine or bromocriptine plus r-hPRL, and lactational performance was assessed by weighing the pups. The concentrations of rat and human PRL in rat serum were measured by specific radioimmunoassays and the mammary glands were examined on postpartum day 10. Daily injection of bromocriptine (0.1 mg/rat) significantly reduced the endogenous level of rat PRL and impaired the weight gain of the pups. Administration of r-hPRL increased the serum level of human PRL. Daily injections of r-hPRL (50 micrograms/rat, twice a day) restored lactational performance and significantly increased the weight of the pups. The detrimental effect of bromocriptine on the mammary glands, assessed by both weight and histological appearance, was reversed by administration of r-hPRL. These results demonstrate that r-hPRL is biologically active in vivo and replacement therapy of r-hPRL is effective in improving the lactational performance in bromocriptine-treated rats, and also that r-hPRL may be useful for the treatment of women with poor lactation.
Toshiyuki Yasui, Hirokazu Uemura, N Yoneda, Minoru Irahara, T Aono, S Sunahara and K Hata : [Assessment of serum estrogen levels by RIA with HPLC during hormone replacement therapy]., Acta Obstetrica et Gynaecologica Japonica, Vol.47, No.7, 655-661, 1995.
(Summary)
We studied the serum estradiol and estrone levels in 146 peri and postmenopausal women, and in 38 women who had complained of various climacteric disturbance symptoms during daily hormone replacement therapy (HRT) with conjugated equine estrogen (CEE) 0.625 mg and medroxyprogesterone acetate (MPA) 2.5 mg. Serum estradiol and estrone were measured before treatment, and at 6 months, and after one year of the HRT therapy by HPLC-radioimmunoassay. In 146 peri and postmenopausal women, the serum level of estradiol was from 3 to 6pg/ml. The serum level of estradiol in 38 women after HRT significantly increased (p < 0.01) from 3.34 to 23.6 pg/ml at 6 months, and 21.5 pg/ml at 12 months. The serum level of estrone significantly increased (p < 0.01) from 26.6pg/ml to 156.7pg/ml at 6 months, and 137.2pg/ml at 12 month. These results are very useful for deciding on the doses of hormones and the expected serum estradiol level in HRT for Japanese women.
Yuji Yokoyama, Takanori Nakamura, Rikiya Nakamura, Minoru Irahara, Toshihiro Aono and Hiromu Sugino : Identificaiton of activins and follistatin proteins in human follicular fluid and placenta, The Journal of Clinical Endocrinology and Metabolism, Vol.80, No.3, 915-921, 1995.
234.
Toshiyuki Yasui, Minoru Irahara, Toshihiro Aono, Hisatoshi Takahashi, Hiroyasu Ino, Osamu Naka, Teruhiko Matsushita, Akira Sakaguchi, Tadahiro Yoshimoto, Kyouya Kishi, Akemi Yamashita, Mikihiko Takemoto, Yoshio Ohno, Makoto Takayanagi, Norio Nagamachi, Satoru Takeuchi and Toshikazu Miyake : Studies on the Combination Treatment with Clomiphene Citrate and Toki-shakuyaku-san, 日本不妊学会雑誌, Vol.40, No.1, 82-91, 1995.
235.
Toshiya Matsuzaki, Toshiyuki Yasui, Keijiro Azuma, Toshihiro Aono and Minoru Irahara : Mechanism of anovulation in hyperprolactinemic amenorrhea determined by pulsatile gonadotropin-releasing hormone injection combined with human chorionic gonadotropin, Fertility and sterility, Vol.62, No.6, 1143-1149, 1994.
Toshiyuki Yasui, Naoto Yoneda, Hirokazu Uemura, Hiroyuki Kaji, Akira Kuwahara, Yuji Yokoyama, Seiichiro Saito, Keiji Shitsukawa, Keiichiro Azuma, Minoru Irahara and Toshihiro Aono : The effect of continuous combined regimen of estrogen progestin on the postmenopausal woman, The Journal of the Japan Menopause Society, Vol.2, No.1, 130-138, 1994.
Toshiyuki Yasui, Minoru Irahara, Masaharu Kamada and Toshihiro Aono : Inhibitory effect of Sho-saiko-to on the growth of gynecological cancer cell lines by autocrine mechanism of transforming growth factor-β, Journal of Traditional Medicinen, Vol.11, No.3, 161-167, 1994.
(Keyword)
Sho-saiko-to / gynecological cancer / TGF-β / MTT / assay
239.
Toshikazu Miyake, Minoru Irahara, Keiji Shitukawa, Toshiyuki Yasui and Toshihiro Aono : Interaction of Activin A and Gonadal Steroids on FSH Secretion from Primary Cultured Rat Anterior Pituitary Cells, Biochemical and Biophysical Research Communications, Vol.194, No.1, 413-419, 1993.
240.
Toshiyuki Yasui, Minoru Irahara, K Shisukawa, K Azuma and Toshihiro Aono : The mechanism of the effect of combination treatment with clomiphene and bromocriptine in patients with normoprolactinemic anovulation, Journal of Endocrinological Investigation, Vol.13, No.7, 549-554, 1990.
Takeshi Iwasa, Toshiya Matsuzaki, Kiyohito Yano, Yiliyasi Mayila, Rie Yanagihara, Yuri Yamamoto, Akira Kuwahara and Minoru Irahara : Effects of Low Energy Availability on Reproductive Functions and Their Underlying Neuroendocrine Mechanisms., Journal of Clinical Medicine, Vol.7, No.7, Jul. 2018.
(Summary)
It is known that metabolic disturbances suppress reproductive functions in females. The mechanisms underlying metabolic and nutritional effects on reproductive functions have been established based on a large body of clinical and experimental data. From the 1980s to 1990s, it was revealed that disrupted gonadotropin-releasing hormone (GnRH) secretion is the main cause of reproductive impairments in metabolic and nutritional disorders. From the late 1990s to early 2000s, it was demonstrated that, in addition to their primary functions, some appetite- or metabolism-regulating factors affect GnRH secretion. Furthermore, in the early 2000s, kisspeptin, which is a potent positive regulator of GnRH secretion, was newly discovered, and it has been revealed that kisspeptin integrates the effects of metabolic status on GnRH neurons. Recent studies have shown that kisspeptin mediates at least some of the effects of appetite- and metabolism-regulating factors on GnRH neurons. Thus, kisspeptin might be a useful clinical target for treatments aimed at restoring reproductive functions in individuals with metabolic or nutritional disturbances, such as those who exercise excessively, experience marked weight loss, or suffer from eating disorders. This paper presents a review of what is currently known about the effects of metabolic status on reproductive functions and their underlying mechanisms by summarizing the available evidence.
Akiko Abe, Masato Nishimura, 炬口 恵理, Takako Kawakita and Minoru Irahara : Endometrial cancer in a 28-year-old woman with Peutz Jeghers syndrome, Japanese Journal of Gynecological Oncology, Vol.34, No.4, 640-647, Oct. 2016.
(Keyword)
uterine body / Peutz-Jeghers syndrome / young endometrial cancer
Toshiya Matsuzaki, Takeshi Iwasa and Minoru Irahara : 新たに開発されたアーキテクト・テストステロンⅡの性能評価と多囊胞性卵巣症候群(PCOS)の診断における有用性の検討, Japanese Journal of Medicine and Pharmaceutical Science, Vol.70, No.20, 331-339, Aug. 2013.
木内 理世, Toshiya Matsuzaki, Sumika Matsui, 中澤 浩志 and Minoru Irahara : エクルーシス試薬エストラジオールⅢの基礎的および臨床的有用性についての検討, Japanese Journal of Medicine and Pharmaceutical Science, Vol.68, No.2, 319-326, Aug. 2012.
Sumika Matsui, Toshiyuki Yasui, Takashi Kaji, 山本 哲史, Hirokazu Uemura and Minoru Irahara : NT-proBNP in perimenopausal women, The Journal of Japan Society for Menopause and Women's Health, Vol.19, No.1, 37-41, Apr. 2011.
Minoru Irahara, Akira Kuwahara, 後藤田 浩司 and Tomiaki Morikawa : 国立大学におけるDPC対応の実際, 病院新時代, Aug. 2005.
50.
Toshiyuki Yasui, 海野 友香, 山田 正代, Hirokazu Uemura and Minoru Irahara : Effects of hormone replacement therapy, Obstetrical and Gynecological Therapy, Vol.90, No.5, 860-867, May 2005.
(Keyword)
ホルモン補充療法 / 効用 / テーラーメイド
51.
桑原 章, Kenji Hinokio, Shuji Yamano and Minoru Irahara : Blastocyst transfer, its risk of Ectopic Pregnancy in Assisted Reproduction, Journal of Mammalian Ova Research, Vol.22, No.2, 59-63, Apr. 2005.
Hiroaki Yanagawa and Minoru Irahara : Supporting system for promotion of clinical trials at Tokushima University Hospital, Shikoku Acta Medica, Vol.59, No.6, 299-303, Dec. 2003.
(Keyword)
clinical trial / supporting system / health promotion / clinical research coordinator
Toshiyuki Yasui and Minoru Irahara : Herbal medicine in women with infertility, Obstetrical and Gynecological Therapy, Vol.86, No.5, 960-967, May 2003.
(Keyword)
不妊症 / 漢方薬 / エビデンス
61.
Toshiyuki Yasui and Minoru Irahara : Improvement of long-term comliance with hormone replacement therapy by modulating dose and route of administration, The Journal of the Japan Menopause Society, Vol.11, No.1, 125-132, Apr. 2003.
Toshiyuki Yasui, Minoru Irahara and Toshihiro Aono : Chinese herbal medicine in gynecology, Obstetrical and Gynecological Therapy, Vol.82, No.3, 284-292, Mar. 2001.
(Tokushima University Institutional Repository: 112159)
79.
Toshiyuki Yasui, Minoru Irahara and Toshihiro Aono : プロラクチン受容体の発現機構, HORMONE FRONTIER IN GYNECOLOGY, Vol.5, No.4, 35(343)-42(350), Dec. 1998.
(Keyword)
プロラクチン受容体 / long form / short form / JAK/STAT / ノックアウトマウス
Proceeding of International Conference:
1.
Takashi Kaji, Eishi Sogawa, Atsuko Yoshida, 米谷 直人, 前田 和寿 and Minoru Irahara : Visualization of the sagittal view of the anal canal and sphincters using the high-frequency linear transducer in normal fetuses: a feasibility study., 30th World Congress on Ultrasound in Obstetrics and Gynecology, WEB, Oct. 2020.
2.
Takashi Kaji, Kazuhisa Maeda, Atsuko Hichijyo, Naoto Yonetani and Minoru Irahara : Fetal hypospadias: association of its severity and prenatal diagnosis, 29th World Congress on Ultrasound in Obstetrics and Gynecology Berlin, Berlin, Oct. 2019.
Chisato Tonoiso, Hitoshi Ikushima, Akihiro Haga, Shunsuke Furutani, Takashi Kawanaka, Akiko Kubo, Masato Nishimura, Akiko Abe, Minoru Irahara and Masafumi Harada : Investigation of prognostic factors of cervical cancer using pre-treatment MRI images, The 2018 International Gynecologic Cancer Society Meeting, Sep. 2018.
4.
Sachi Kishida, Yumi Kuwamura, Toshiyuki Yasui, M Tuji, Issei Imoto and Minoru Irahara : Characteristics of Japanese Pregnant Women Who Had Hereditary Counseling About Noninvasive Prenatal Genetic Testing (NIPT) In Tokushima, 2nd Technological Competency as Caring in the Health Sciences 2018, 80, Aug. 2018.
(Keyword)
NIPT / Pregnant women / Hereditary counseling
5.
Minoru Irahara : New concept of diagnosis of PCOS, The 103rd Annual Congress of KSOG, Seoul, Sep. 2017.
6.
Minoru Irahara : Sympodium : PCOS and androgen excess, The 22nd Seoul International Symposium, Seoul, Sep. 2017.
7.
Minoru Irahara : Symposium:Androgen Excess in Women-Polycystic Ovary Syndrome, The 8th Congress of the International Society for Gender Medicine, Sendai, Sep. 2017.
8.
Takashi Kaji, Yasunobu Hayabuchi, Kazuhisa Maeda, Atsuko Hichijyo, Naoto Yonetani, Takahashi Yohei, Nakayama Soichiro and Minoru Irahara : Prenatal assessment of coronary artery anatomy using color Doppler in cases of D-transposition of the great arteries: case reports., Prenatal assessment of coronary artery anatomy using color Doppler in cases of D-transposition of the great arteries: case reports., Rome, Sep. 2016.
9.
Akira Kuwahara, Saito Hidekazu, Ishihara Osamu, Kugu Koji and Minoru Irahara : Assisted Reproductive Technology (ART) in Japan, Annual reports of Japan ART registry., IFFS2016, India, Sep. 2016.
10.
YAMASAKI Mikio, Akira Kuwahara, TANIGUCHI Yuka, Yuri Yamamoto, Takeshi Iwasa, HINOKIO Kenji, Toshiya Matsuzaki and Minoru Irahara : Comparison of AMH and FSH an indicator of ovarian reserve in ART., IFFS/JSRM International Meeting,2015, Yokohama, Apr. 2015.
11.
Yuri Yamamoto, Akira Kuwahara, YANO Yuya, TANIGUCHI Yuka, YAMASAKI MIkio, HINOKIO Kenji and Minoru Irahara : Clinical significance of serum hCG in early pregnancy periods in ART., IFFS/JSRM International Meeting,2015, Yokohama, Apr. 2015.
12.
Akira Kuwahara, HINOKIO Kenji, TANIGUCHI Yuka, Yuri Yamamoto, YAMASAKI Mikio, Takeshi Iwasa and Minoru Irahara : Clinical significance of estradiol and transvaginal ultrasonography for pregnancy outcomes in natural frozen-thawed blastcyst transfer cycles., IFFS/JSRM International Meeting,2015, Yokohama, Apr. 2015.
13.
TAKAHASHI Yohei, Takashi Kaji, NAKAYAMA Soichiro, HICHIJO Atsuko, Kazuhisa Maeda and Minoru Irahara : Intrauterine death by cord entanglement in monoamniotic twin reversed arterial perfusion sequence after infertility treatment: a case report., IFFS/JSRM International Meeting 2015, Yokohama, Apr. 2015.
14.
HICHIJO Atsuko, TAKAHASHI Yohei, NAKAYAMA Soichiro, Takashi Kaji, NAKAOKU Daichi, MURAKAMI Masahiro, KONDO Akane, MORINE Mikio, Kazuhisa Maeda, Issei Imoto and Minoru Irahara : Case of placental mesenchymal dysplasia associated with cytogenetic discrepancy between amniotic fluid cells and fetal blood., IFFS/JSRM International Meeting,2015, Yokohama, Apr. 2015.
15.
NAKAYAMA Soichiro, Takashi Kaji, Toshiyuki Yasui, HICHIJO Atsuko, TAKAHASHI Yohei and Minoru Irahara : Serum 25(OH)D3 concentrations and season-specific correlates in Japanese pregnancy women., IFFS/JSRM International Meeting,2015, Yokohama, Apr. 2015.
16.
Takashi Kaji, Toshiyuki Yasui, HICHIJO Atsuko, TAKAHASHI Yohei, NAKAYAMA Soichiro, Hirokazu Uemura, Kazuhisa Maeda and Minoru Irahara : Effect of bed rest during pregnancy on bone turnover markers in pregnant and postpartum women., IFFS/JSRM International Meeting,2015, Yokohama, Apr. 2015.
17.
Takeshi Iwasa, Toshiya Matsuzaki, KAWAMI Takako, MUNKHZAYA Mukhsaikhan, TUNGALAGSUVD Altankhuu and Minoru Irahara : Hypothalamic Kiss1 and RFRP gene expressions are changed by a high dose of lipopolysaccharide in female rats., IFFS/JSRM International Meeting 2015, Yokohama, Apr. 2015.
18.
TUNGALAGSUVD Altankhuu, Toshiya Matsuzaki, Takeshi Iwasa, MUNKHZAYA Munkhsaikhan, KAWAMI Takako and Minoru Irahara : Senktide does not recover suppression of HPG axis induced by acute fasting in male rats., IFFS/JSRM International Meeting,2015, Yokohama, Apr. 2015.
19.
MUNKHZAYA Munkhsaikhan, Toshiya Matsuzaki, Takeshi Iwasa, TUNGALAGSUVD Altankhuu, KAWAMI Takako and Minoru Irahara : Suppressive effect of immune stress on LH secretion is absent in early neonatal period in rats., IFFS/JSRM International Meeting,2015, Yokohama, Apr. 2015.
20.
Sumika Matsui, Toshiyuki Yasui, Kaoru Keyama, Takeshi Katou, Hirokazu Uemura and Minoru Irahara : Ultra-low-dose estradiol improves arterial stiffness in postmenopausal women., IFFS/JSRM International Meeting,2015, Yokohama, Apr. 2015.
21.
Takeshi Katou, KASAI Kana, Kaoru Keyama, Sumika Matsui, TANI Anna and Minoru Irahara : Accidental findings of minimal endometriosis during laparoscopic surgery : a retrospective study., IFFS/JSRM International Meeting 2015, Yokohama, Apr. 2015.
22.
MAEGAWA Masahiko, TANI Anna, YAMAMOTO Satoshi, KUNIMI Kotaro, Takeshi Katou, Sumika Matsui, Kaoru Keyama, Hirokazu Uemura, Toshiyuki Yasui, KAMADA Masaharu, MITANI Ryuji, MIYATANI Yuka and Minoru Irahara : Arterial stiffness is increased in young women with endometriosis., IFFS/JSRM International Meeting 2015, Yokohama, Apr. 2015.
23.
Kaoru Keyama, TANI Anna, Sumika Matsui, Takeshi Katou and Minoru Irahara : LPS progress the development of endometriosis in murine model., IFFS/JSRM International Meeting 2015, Yokohama, Apr. 2015.
24.
Akiko Abe, Masato Nishimura, Eri Takiguchi, Takako Kawakita, TANIGUCHI Yuka, Yuri Yamamoto, YAMASAKI Mikio, Takeshi Iwasa, Akira Kuwahara, Toshiya Matsuzaki and Minoru Irahara : Survey on oncologist and gynecologist concerned with fertility for cancer survivors in reproductive age., IFFS/JSRM International Meeting,2015, Yokohama, Apr. 2015.
25.
Masato Nishimura, Eri Takiguchi, Takako Kawakita, Akiko Abe, TANIGUCHI Yuka, Yuri Yamamoto, YAMASAKI Mikio, Takeshi Iwasa, Akira Kuwahara, Toshiya Matsuzaki and Minoru Irahara : Efficacy and pregnant outcomes of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical endometrial hyperplasia in young women., IFFS/JSRM International Meeting,2015, Yokohama, Apr. 2015.
26.
SATO Kenji, SUEOKA Kou, SENBA Hitoshi, IINO Kotaro, SUZUKI Mariko, MIZUGUCHI Yuki, IZUMI Yoko, Minoru Irahara, YOSHIMURA Yasunori and TANAKA Mamoru : Current status of preimplantation genetic dagonosis in Japan., IFFS/JSRM International Meeting,2015, Yokohama, Apr. 2015.
27.
Akira Kuwahara, Mikio Yamasaki, Fukushima Chiemi and Minoru Irahara : Effect of elective cryopreservation of all embryo, Recent analysis of Japan ART registry., FFS Regional Meeting, Recent Progress and New Trends of ART in Japan, Boston, Oct. 2013.
28.
Nakazawa Hiroshi, Toshiya Matsuzaki, Takeshi Iwasa, Kinouchi Riyo, Gereltsetseg Ganbat and Minoru Irahara : Early Postnatal Lipopolysaccharide Exposure : Effects on Adult Male Rat LH Response to Homotypic Stress., The Endocrine Society's 94th Annual Meeting & Expo, Houston, Jun. 2012.
29.
Gereltsetseg Ganbat, Toshiya Matsuzaki, Takeshi Iwasa, Kinouchi Riyo, Nakazawa Hiroshi and Minoru Irahara : Delay in the Onset of Puberty of Intrauterine Growth Retarded Female Rats Cannot Be Rescued with Hypernutrition after Birth., The Endocrine Society's 94th Annual Meeting & Expo, Houston, Jun. 2012.
30.
Toshiya Matsuzaki, Gereltsetseg Ganbat, Takeshi Iwasa, Kinouchi Riyo, Nakazawa Hiroshi and Minoru Irahara : Delay in the onset of puberty of intrauterine growth retarded female rats cannot be rescued by hypernutrition after birth., 15th International & 14th European Congress of Endocrinology(ICE/ECE 2012), Florence, May 2012.
31.
Kazuhisa Maeda, Suto Masanori, Sato Miki, Takashi Kaji and Minoru Irahara : What is the predictive factor of onset of labor pain after long term tocolysis treated with intravenous ritodorine for preterm labor?, ISUOG, Los Angels, Sep. 2011.
32.
Takashi Kaji, Kazuhisa Maeda, Masanori Sutoh, Miki Sato and Minoru Irahara : Assessment of fetal atrioventricular time intervals by dual Doppler in hepatic vein and descending aorta., 21th World Congress on Ultrasound in Obstetrics and Gynecology, Los Angeles , USA, Aug. 2011.
33.
Toshiya Matsuzaki, Iwasa Takeshi, Kinouchi Riyo, Gereltsetseg Ganbat and Minoru Irahara : Sensitivities of messenger ribonucleic acid expression levels of Kiss1 and its receptor, Kiss1r, to nutritional status are changed during the developmental period in female rats, The Endocrine Society's 93rd Annual Meeting, Boston, Jun. 2011.
34.
Takashi Kaji, Kenji Mori, Souichirou Nakayama, Ryuuji Mitani, Kazuhisa Maeda, Shoji Kagami and Minoru Irahara : Prenatal diagnosis of total anomalous pulmonary venous connection to the portal vein with absence of ductus venosus : A case report, 20th World Congress on Ultrasound in Obstetrics and Gynecology, Prague, Czech, Oct. 2010.
35.
Kazuhisa Maeda, Masanori Sutoh, Miki Satou, Takashi Kaji and Minoru Irahara : Ultrasonographic and magnetic resonance imaging (MRI) detection of placenta accrete., 20th World Congress on Ultrasound in Obstetrics and Gynecology, Prague, Czech, Oct. 2010.
36.
Takeshi Iwasa, Toshiya Matsuzaki, Shinobu Fujisawa, Riyo Kinouchi, Gereltsetseg Ganbat and Minoru Irahara : Effects of Intra-Uterine Undernutrition on Hypothalamic Kiss1 Expression and the Timing of Puberty in Female Rats., The Endocrine Society's 92nd Annual Meeting, San Diego,CA,USA., Jun. 2010.
37.
K Tsutsui, VS Chowdhury, T Osugi, T Ubuka, Toshiya Matsuzaki, Takeshi Iwasa, Minoru Irahara, LJ Kriegsfeld and G Bentley : Discovery of GnIH: first in birds and then in mammals Symposium: Gonadotropin inhibitory hormone (GnIH) functions in mammals., The Endocrine Society's 92nd Annual Meeting, San Diego,CA,USA., Jun. 2010.
38.
Toshiya Matsuzaki, Takeshi Iwasa, Shinobu Fujisawa, Riyo Kinouchi and Minoru Irahara : Neonatal LPS Injection Alters the Body Weight Regulation Systems of Rats under Non-Stress and Immune Stress Conditions., The Endocrine Society's 92nd Annual Meeting, San Diego, CA ,USA., Jun. 2010.
39.
Toshiyuki Yasui, Hirokazu Uemura, Y Miyatani, M Yamada, N Tsuchiya, M Yuzurihara, S Takeda and Minoru Irahara : Interleukin-8 and hot flushes in pre-, peri- and postmenopausal women and bilateral oophorectomized women., The 3rd Scientific Meeting of the Asian Pacific Menopause Federation (APMF), Taipei, Mar. 2007.
40.
Hirokazu Uemura, Toshiyuki Yasui, Y Miyatani, M Yamada, Mineyoshi Hiyoshi, Hideo Takeda, Kokichi Arisawa and Minoru Irahara : Relationships between circulating osteoprotegerin and the risk factors of vascular disorders in postmenopausal women., The 3rd Scientific Meeting of the Asian Pacific Menopause Federation (APMF), Taipei, Mar. 2007.
41.
Kumiko Sakamoto, Yuki Hibino, Shuji Yamano, Kazuhisa Maeda, Minoru Irahara and Aiko Yamauchi : Prescription drug use during pregnancy in Japan, 34th Annual Conference of the European Teratology Society, Abano Terme, Sep. 2006.
42.
Masahiko Maegawa, A Nakajima, Satoshi Yamamoto, Y Kasai, A Tani, D Kinoshita and Minoru Irahara : Effects of ovarian hormones on adhesion and early development of autotransplanted endometrium in an immunocompetent murine model, IX World Congress on Endometriosis, Maastricht(The Netherlands), Sep. 2005.
43.
A Nakajima, Masahiko Maegawa, Satoshi Yamamoto, A Tani, D Kinoshita, Y Kasai and Minoru Irahara : The process of blood coagulation enhances early endometrial-peritrial interaction in a murine model of endometriosis, IX World Congress on Endometriosis, Maastricht(The Netherlands), Sep. 2005.
44.
Masahiko Maegawa, Anna Tani, Ayako Nakajima, Dan Kinoshita, Yuka Sakai, Satoshi Yamamoto, Kazuhisa Maeda, Masahiko Maegawa, Masaharu Kamada and Minoru Irahara : Changes on Pro-Inflammatory Cytokine Responses in Peripheral Blood During Normal Human Pregnancy, IX International Congress of Reproductive Immunology, Vol.52, No.Supplement 1, 26, Kanagawa, Oct. 2004.
45.
Satoshi Yamamoto, Anna Tani, Ayako Nakajima, Dan Kinoshita, Yuka Kasai, Masahiko Maegawa, Masaharu Kamada, Yuji Okumura, Hiroshi Kido and Minoru Irahara : Development of an Expression Vector Encoding Sperm Protein,Designated RSMP-B,as an Immunocontrraceptive Vaccine, IX International Congress of Reproductive Immunology, Vol.52, No.Supplement 1, 55, Kanagawa, Oct. 2004.
46.
Kotaro Kunimi, Ayako Nakajima, Dan Kinoshita, Satoshi Yamamoto, Masahiko Maegawa, Masaharu Kamada and Minoru Irahara : The Expression of Myeloid-Related Protein-8(MRP8: S100A8) and MRP14(S100A9) in the Human Uterine Cervix, IX International Congress of Reproductive Immunology, Vol.52, No.Supplement 1, 58, Kanagawa, Oct. 2004.
47.
Ayako Nakajima, Anna Tani, Dan Kinoshita, Yuka Kasai, Satoshi Yamamoto, Masahiko Maegawa and Minoru Irahara : A Repertoire of Cytokines in Human Cervical Mucus of Infertile Women, IX International Congress of Reproductive Immunology, Vol.52, No.Supplement 1, 58, Kanagawa, Oct. 2004.
48.
Yuka Kasai, Anna Tani, Ayako Nakajima, Dan Kinoshita, hirokazu Uemura, Masahiko Maegawa, Toshiyuki Yasui, Masaharu Kamada and Minoru Irahara : Pro-Inflammatory Cytokine Changes in Postmenopausal Women Treated with Hormone Replacement Therapy, IX International Congress of Reproductive Immunology, Vol.52, No.Supplement 1, 57, Kanagawa, Oct. 2004.
49.
Junko Komatsu, Akira Kuwahara, Shuji Yamano and Minoru Irahara : Lysophosphatidic acid promotes oocyte maturation in mice via MAP kinase of cumulus oocyte complex, The 4th Conference of the Pacific Rim Society for Fertility and Sterility, Okinawa, Mar. 2004.
50.
Akira Kuwahara, Yu Tanaka, Yukari Tsutsumi, Kenji Hinokio, Toshiya Matsuzaki, Masahiko Maegawa, Toshiyuki Yasui, Shuji Yamano and Minoru Irahara : Clinical outcomes of "true" unexplainedinfertility after laparoscopy, The 4th Conference of the Pacific Rim Society for Fertility and Sterility, Okinawa, Mar. 2004.
51.
Naoko Moride, Yu Tanaka, Yukari Tsutsumi, Kenji Hinokio, Akira Kuwahara, Shuji Yamano and Minoru Irahara : Cdc25C is related pronuclear formation fertilization of mouuse eggs, The 4th Conference of the Pacific Rim Society for Fertility and Sterility, okinawa, Mar. 2004.
52.
Dan Kinoshita, Ayako Nakajima, Toshiko Kinoshita, Satoshi Yamamoto, Kazuhisa Maeda, Masahiko Maegawa, Minoru Irahara, Toshifumi Daitoh and Masaharu Kamada : Changes in type 1 and type 2 cytokine production profile stimulated with mitogen during normal pregnancy, The 4th Conference of the Pacific Rim Society for Fertility and Sterility, Okinawa, Mar. 2004.
53.
Masahiko Maegawa, Satoshi Yamamoto, Ayako Nakajima, Dan Kinoshita, Masayo Kanayama, Minoru Irahara, Masaharu Kamada, Yuji Okumura and Hiroshi Kido : Development of an Expression Vector Encoding Sperm Protein,Designated rSMP-B,as an Immunocontrraceptive, The 4th Conference of the Pacific Rim Society for Fertility and Sterility, Okinawa, Mar. 2004.
54.
R Ogata, Toshiyuki Yasui, Hirokazu Uemura, Machiko Kiyokawa, Masakazu Miura, Toshihiro Aono and Minoru Irahara : Serum estradiol level that is required to achieve a sufficient increase in bone mineral density during hormone replacement therapy, 9th International Menopause Society World Congress on the Menopause, Berlin, Jun. 2002.
55.
Minoru Irahara, Masaharu Kamada, Hirokazu Uemura, Toshiyuki Yasui, Machiko Kiyokawa, Akira Kuwahara, Hiroshi Ikawa, Toshiya Matsuzaki and Toshihiro Aono : Postmenopausal changes in production of type 1 and type 2 cytokines and the effects of hormone replacement therapy, 9th International Menopause Society World Congress on the Menopause, Berlin, Jun. 2002.
56.
Hirokazu Uemura, Toshiyuki Yasui, Machiko Kiyokawa, Akira Kuwahara, Hiroshi Ikawa, Toshiya Matsuzaki, Toshihiro Aono and Minoru Irahara : Changes in the levels of circulating osteoprotegerin in case of estrogen deficiency, 9th International Menopause Society World Congress on the Menopause, Berlin, Jun. 2002.
57.
Minoru Irahara, Seiichiro Miyamoto, Kenjiro Ushigoe, Akira Kuwahara and Hiromu Sugino : The effect of activin on hormone secretion from female rat pituitary cells: Analysis by cell immunoblot assay, 16th World Congress on Fertility and Sterility, San Francisco, Oct. 1998.
58.
Kenjiro Ushigoe, Akira Kuwahara, Seiichiro Miyamoto, Minoru Irahara, Hiromu Sugino and Toshihiro Aono : Expression of activin receptors in rat pituitary cells, 16th World Congress on Fertiligy and Sterility, San Francisco, Oct. 1998.
59.
Minoru Irahara, Noriko Tamura, Akira Kuwahara, Kenjiro Ushigoe and Hiromu Sugino : Effect of activin on production and secretion of prolactin in cultured rat GH3 cells, 15th World Congress of Gynecology and Obstetrics, Copenhagen, Aug. 1997.
60.
Seiichiro Miyamoto, Minoru Irahara, Kenjiro Ushigoe, Akira Kuwahara, Hiromu Sugino and Toshihiro Aono : The effect of activin on hormone secretion from female rat pituitary cells: Analysis by cell immunoblot assay, 15th World Congress of Gynecology and Obstetrics, Copenhagen, Aug. 1997.
61.
Noriko Tamura, Kenjiro Ushigoe, Seiichiro Miyamoto, Akira Kuwahara, Keiji Shitsukawa, Keijiro Azuma, Minoru Irahara, Toshihiro Aono and Hiromu Sugino : Effects of activin on production and secretion of prolactin in GH3 cells. The interaction of activin, activin receptors and gonadal steroids in rat pituitary, 3rd Ares-Serono Symposium on Inhibin, Activin, Follistatin - Recent Advances and Future Views, Tokushima, Nov. 1996.
62.
Akira Kuwahara, Noriko Tamura, Kenjiro Ushigoe, Seiichiro Miyamoto, Keiji Shitsukawa, Keijiro Azuma, Minoru Irahara, Toshihiro Aono and Hiromu Sugino : Expression of activin receptors in rat pituitary cells. The Interaction of activin, activin receptors and gonadal steroids in rat pituitary, 3rd Ares-Serono Symposium on Inhibin, Activin, Follistatin - Recent Advances and Future Views, Tokushima, Nov. 1996.
63.
Toshihiro Aono, Akira Kuwahara, Noriko Tamura, Kenjiro Ushigoe, Seiichiro Miyamoto, Keiji Shitsukawa, M. Miyake, Keijiro Azuma, Minoru Irahara and Hiromu Sugino : The interaction of activin, activin receptors and gonadal steroids in rat pituitary, 3rd Ares-Serono Symposium on Inhibin, Activin, Follistatin - Recent Advances and Future Views, Tokushima, Nov. 1996.
64.
Hiromu Sugino, Yuji Yokoyama, Takanori Nakamura, Kishiko Sugino, Rikiya Nakamura, Minoru Irahara and Toshihiro Aono : Identification of activins and follistatin in human follicular fluid and placenta, 76th Annual Meeting of the American Endocrine Society, Anaheim, Jun. 1994.
65.
Yuji Yokoyama, Takanori Nakamura, Kishiko Sugino, Minoru Irahara, Hiromu Sugino and Toshihiro Aono : Isolation of three isoforms of activins (A, AB and B) and follistatin in human follicular fluid, 8th Worlid Congress on in Vitro Fertilization and Alternate Assisted Reproduction, Kyoto, Sep. 1993.
Kanako Yoshida, Takeshi Katou, Yuri Kadota, Kana Kasai, Takako Kawakita, 桑原 章 and Minoru Irahara : 当科における腹腔鏡下仙骨腟固定術(LSC)導入の現状, 第72回日本産科婦人科学会学術講演会, Apr. 2020.
11.
Takashi Kaji, Eishi Sogawa, Atsuko Yoshida, Naoto Yonetani and Minoru Irahara : Visualization of the sagittal view of the anal canal and sphincters using the high-frequency linear transducer in normal fetuses: a feasibility study., 第72回日本産科婦人科学会学術集会, Apr. 2020.
Kanako Yoshida, 門田 友里, Kana Kasai, Takako Kawakita, Takeshi Katou and Minoru Irahara : 妊娠中の腹腔鏡下卵巣腫瘍手術におけるアプローチ法の工夫, The Journal of Japan Society for Menopause and Women's Health, Vol.26, Oct. 2018.
Kanako Yoshida, Kadota Yuri, Kasai Kana, Kawakita Takako, Takeshi Katou and Minoru Irahara : Healthcare for young gynecologic malignant tumor patients at our hospital, Acta Obstetrica et Gynaecologica Japonica, Vol.70, No.2, 637, Feb. 2018.
32.
Kanako Yoshida, 門田 友里, Kana Kasai, Takako Kawakita, Takeshi Katou and Minoru Irahara : 妊娠中の腹腔鏡下卵巣腫瘍手術におけるアプローチ法の工夫, Japanese Journal of Gynecologic and Obstetric Endoscopy, Vol.34, 2018.
Mayumi Takeuchi, Kenji Matsuzaki, Masato Nishimura, Masafumi Harada and Minoru Irahara : 付属器腫瘤の鑑別における''preserved follicle sign''の臨床的有用性について, JSAWI (The Japanese Society for the Advancement of Women's Imaging) 第15回シンポジウム, Sep. 2017.
Mayumi Takeuchi, Kenji Matsuzaki, Masafumi Harada and Minoru Irahara : 婦人科領域におけるreduced FOV DWIの有用性について, JSAWI (The Japanese Society for the Advancement of Women's Imaging) 第16回シンポジウム, Sep. 2015.
68.
Minoru Irahara : 特別講演:女性ヘルスケアの観点からみた少子晩産化時代の乳がん検診, 第23回日本がん検診・診断学会総会，第24回日本婦人科がん検診学会総会・学術講演会, Aug. 2015.
Mayumi Takeuchi, Kenji Matsuzaki, Masafumi Harada and Minoru Irahara : 女性骨盤部領域における磁化率強調像の有用性について, JSAWI (The Japanese Society for the Advancement of Women's Imaging) 第15回シンポジウム, Sep. 2014.
75.
Minoru Irahara : 特別講演: 子宮内膜症の疼痛管理と不妊治療, 第6回新潟子宮内膜症研究会, May 2014.
Mayumi Takeuchi, Kenji Matsuzaki, Masafumi Harada, Masato Nishimura and Minoru Irahara : 子宮膿瘍のMR Spectroscopy, JSAWI (The Japanese Society for the Advancement of Women's Imaging) 第14回シンポジウム, Sep. 2013.
88.
Minoru Irahara : 特別講演:子宮内膜症における疼痛対策と不妊治療, 第24回近畿エンドメトリオーシス研究会, Aug. 2013.
89.
Minoru Irahara : 指定講演:日本生殖医学会の現状と未来・専門医制度のあり方について, 第49回中国四国生殖医学会学術講演会, Aug. 2013.
90.
Minoru Irahara : ランチョンセミナー:ART難治症例における卵巣刺激法を含めた総合戦略, 第31回日本受精着床学会総会, Aug. 2013.
91.
Minoru Irahara : 特別講演: 我が国の生殖補助医療の発展とこれからの課題, 札幌東豊セミナー, Aug. 2013.
E Takagi, R Ota, Toshiyuki Niki, M Kadota, Y Kawabata, T Hara, A Takashima, Mika Bando, S Bando, T Matsuura, Takayuki Ise, J Hotchi, Yuka Ueda, Koji Yamaguchi, Shusuke Yagi, Takashi Iwase, Yoshio Taketani, N Tomita, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Masataka Sata, Souichiro Nakayama, Kazuhisa Maeda and Minoru Irahara : 妊娠を契機にATⅢ欠損症と診断され，血栓管理の後に出産に至った一例, 第246回徳島医学会学術集会(平成24年度冬期), Feb. 2013.
Mayumi Takeuchi, Kenji Matsuzaki, Masafumi Harada, Hiroyuki Furumoto and Minoru Irahara : 卵巣腺線維腫・嚢胞腺線維腫のMRI診断, JSAWI (The Japanese Society for the Advancement of Women's Imaging) 第13回シンポジウム, Sep. 2012.
Takako Kawakita, Takeshi Katou, Yuri Kadota, 笠井 可菜, Kanako Yoshida and Minoru Irahara : International Session Workshop : New mouse model of uterine adenomyosis., 第72回日本産科婦人科学会学術講演会, Apr. 2021.
Atsuko Hichijyo, Takashi Kaji, Naoto Yonetani, Ryuji Nakagawa and Minoru Irahara : 当院における精神疾患合併妊娠の検討, 徳島産婦人科医報, No.51, 34, Aug. 2018.
8.
Atsuko Yoshida, Takashi Kaji, Junki Imaizumi, Naoto Yonetani, Ryuji Nakagawa and Minoru Irahara : 男性ホルモン投与中に自然妊娠し，女児を出産したFemale to Maleの一例, Journal of Japan Society of Perinatal and Neonatal Medicine, Vol.54, No.2, 611, Jun. 2018.
Improvement of diagnostic performance of polycystic ovary syndrome using serum reproductive hormones and anti-Mullerian hormone (Project/Area Number: 18K09293 )
Effects of prenatal and postnatal nutritional status on reproductive function (Project/Area Number: 18K09292 )
Long-term influence of the stress exposure in early life on the sexual function in adulthood (Project/Area Number: 18K09264 )
Study of timing regulation in the network among the pituitary, the ovary and the adrenal gland in women during the menopausal transition (Project/Area Number: 16K11143 )
Basic study for ovulation induction using novel hypothalamic peptide analogues in suppressed hypothalamic GnRH secretion (Project/Area Number: 15K10673 )
Significance of serum anti-Mullerian hormone and insulin resistance in the diagnosis of polycystic ovary syndrome (Project/Area Number: 15K10672 )
The effects of ovariotomy on the central and peripheral stress responses (Project/Area Number: 26462526 )
Role of androgen for metabolism in women during the menopausal transition (Project/Area Number: 25462596 )
Basic study for new ovulation induction using hypothalamic neuropeptide (Project/Area Number: 24592473 )
Endocrinological study for individual treatment of polycystic ovary syndrome (Project/Area Number: 24592472 )
Effects of endocrinological and immunological factors on metabolism in women during the menopausal transition (Project/Area Number: 22591857 )
regulation of gonadotropin secretion by novel brain peptides and stresses (Project/Area Number: 21592100 )
Study for improving the diagnosis of polycystic ovary syndrome (Project/Area Number: 20591951 )
Development of safe and convenient ovulation induction (Project/Area Number: 17591744 )
Crosstalk from energy regulating system to female reproductive system (Project/Area Number: 14571566 )
The Lole of Local Regulator in the Rat Ovary during Ovulatory Process (Project/Area Number: 13671722 )
Development of an immunocontraceptive DNA vaccine using sperm (Project/Area Number: 12557137 )
Study on the significance and control mechanism of apoptosis in follicle atresia system (Project/Area Number: 10671548 )
Study on the assesment of effective and safe protocols in ovulation induction by gonadotropin therapy (Project/Area Number: 10557148 )
Physiological function of parathyroid hormone related peptide (Project/Area Number: 07671789 )
Study on mechanisms of single folliculugenesis in human women and multiple pregnancy by ovulation induction. (Project/Area Number: 07457389 )
The study on the improvements in diagnosis and treatment of patients with polycystic ovarian syndrome (Project/Area Number: 04454421 )
The study on the etiological meaning of oligosaccharide residures in immunological infertility and development of treatment for that infertility. (Project/Area Number: 62570759 )
Molecular mechanism of gonadotropin and prolactin release from pituitary cells (Project/Area Number: 60480367 )