Takako Kawakita, Takeshi Iwasa, Shuhei Kamada, Kanako Yoshida and Takeshi Katou : Effects of gonadal status and the estrogen milieu on hypothalamic oxytocin gene expression and serum oxytocin levels in female rats., Hormones and Behavior, Vol.133, No.8, 105005, 2021.
(要約)
Oxytocin (OT) and its receptor (OTR) play various roles in the central and peripheral regulation of appetite and body weight. Previously, we have shown that the administration of OT markedly decreased appetite and body weight gain in ovariectomized (OVX) obese rats. In addition, recent studies have shown that the endogenous OT system is also affected by endogenous or exogenous estrogen. In this study, we showed that ovariectomy decreased rats' hypothalamic OT/OTR mRNA and serum OT levels, but did not affect their visceral fat OTR mRNA levels. The chronic administration of estradiol (E2) abrogated these ovariectomy-induced changes; i.e., it increased the rats' hypothalamic OT/OTR mRNA and serum OT levels, and may be associated with reductions in food intake and body weight gain. In addition, acute E2 administration increased the rats' hypothalamic OTR mRNA and serum OT levels, but did not affect their hypothalamic OT mRNA levels. Taken together, these results suggest that endogenous OT and/or OTR expression might be positively regulated by E2 and that the suppressive effects of E2 on appetite and body weight gain might be mediated, at least in part, by the OT system. Thus, we consider that OT might be a target hormone to pursue subsequent interventions of menopause for menopause-induced metabolic disorders.
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.
(要約)
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.
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.
(要約)
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.
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.
(要約)
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.
(要約)
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.
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.
(要約)
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.
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.
(要約)
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.
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.
(要約)
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.
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.
(要約)
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.
(キーワード)
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.
(要約)
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.
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.
(要約)
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.
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.
(要約)
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.
(キーワード)
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.
(要約)
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.
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.
(要約)
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.
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.
(要約)
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.
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.
(要約)
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.
(キーワード)
arterial stiffness / endometriosis / hs CRP / subclinical inflammation / young women
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.
(要約)
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.
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.
(要約)
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.
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.
(要約)
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.
(キーワード)
Adult / Asian Continental Ancestry Group / Biological Markers / Body Mass Index / Case-Control Studies / Diagnostic Tests, Routine / Electrochemical Techniques / Female / Humans / 日本 (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.
(要約)
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.
(要約)
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, 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.
(要約)
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.
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.
(要約)
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.
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.
(要約)
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.
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.
(要約)
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.
Takeshi Katou : Examination about the influence that hormone replacement therapy gives to breast density of mammography, North american menopause society 2019 annual meeting, Chicago, Sep. 2019.
2.
Takeshi Katou : THE DYSMENORRHEA IMPROVEMENT EFFECT OF RESECTION OF DEEP INFILTRATING ENDOMETRIOSIS AFTER CONTINUOUS HORMONAL THERAPY, 11th Congress of the European pain federation, Sep. 2019.
3.
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.
4.
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.
5.
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.
6.
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.