Porcine Placental Extract Improves the Lipid Profile and Body Weight in a Post-Menopausal Rat Model Without Affecting Reproductive Tissues


多囊胞性卵巣症候群の診断におけるアクセス試薬を用いた血中LH基礎値及びLH/FSH比のカットオフ値の設定と内分泌異常の発現率に関する検討

Japanese Journal of Medicine and Pharmaceutical Science


生殖補助医療におけるLH濃度低値の症例に対するFSH単剤使用の臨床成績

生殖補助医療におけるLH濃度低値の症例に対するFSH単剤使用の臨床成績


多囊胞性卵巣症候群に対するクロミフェン・レトロゾール・FSHなど排卵誘発薬の使い分けと効果


The effects of testosterone on hypothalamic and serum oxytocin levels are affected by the estrogen milieu in female rats


Survey on the incidence of multiple pregnancies and neonatal outcomes by fertility treatment in Tokushima Prefecture, Japan

A survey on the incidence of multiple pregnancies and neonatal outcomes by assisted reproductive technology (ART) and non-ART fertility treatments was performed in 2011 and 2021. Questionnaires were sent to all institutions with obstetrics and gynecology departments in Tokushima Prefecture, Japan, to collect data on fertility treatments and neonatal outcomes in 2011 and 2021. Non-ART fertility treatments were classified into ovarian stimulation (treatments for cases without ovulation disorder) and ovulation induction (treatments for cases with ovulation disorder). Among all pregnancies, the multiple pregnancy rates in 2011 were 7.7% for ovarian stimulation, 5.5% for ovulation induction, and 8.4% for ART, whereas those in 2021 were 3.8%, 2.3%, and 1.9%, respectively. The rates of triplet pregnancies in 2011 were 0.85% for ovulation induction, 2.4% for ovulation induction, and 1.4% for ART, whereas those in 2021 were 0% for all treatments. The rates of low birth weight, admission to a neonatal intensive care unit, and neonatal death in 2011 were 53.8%, 9.61%, and 9.61%, respectively, whereas those in 2021 were 40.9%, 22.7%, and 0%, respectively. These findings indicate that rates of multiple pregnancies, including higher-order multiple pregnancies, by fertility treatment have decreased over the last 10 years in Tokushima Prefecture. However, some adverse neonatal outcomes have still occurred. J. Med. Invest. 71 : 251-253, August, 2024.

The Journal of Medical Investigation : JMI


Comparison of endogenous hypothalamic and serum OT levels between young and middle-aged perimenopausal female rats

Oxytocin (OT) regulates food intake and body weight, particularly in obese individuals. Decreases in the effects of OT have recently been implicated in metabolic disturbances, and the administration of estradiol (E2) increased serum OT levels. Although weight gain is frequently observed in perimenopausal women, endogenous OT levels remain unclear. Therefore, we herein compared endogenous levels of hypothalamic and serum OT between young and middle-aged perimenopausal female rats and examined the relationship between serum estrogen and leptin levels. Body weight and visceral and subcutaneous fat weights were higher in middle-aged rats. Although no significant differences were observed in serum OT and E2 levels, serum leptin levels and hypothalamic mRNA levels of OT and the OT receptor (OTR) were significantly higher in middle-aged rats than in young rats. Serum OT levels did not correlate with hypothalamic OT mRNA levels or serum E2 levels. E2 maintains serum OT levels in perimenopausal rats, and other factors may elevate hypothalamic OT/OTR mRNA levels. Increases in body and fat weights in perimenopausal rats may be attributed to factors other than OT. Therefore, the administration of OT alone may not be sufficient to prevent metabolic disorders induced by the perimenopausal status. J. Med. Invest. 71 : 246-250, August, 2024.


Kisspeptin administration may promote precopulatory behavior in male rats independently or supplementally to testosterone and contribute to proceptive behavior in female partners, reducing mating failure

Kisspeptin is a peptide that plays an important role through its effects on the hypothalamus-pituitary-gonadal (HPG) axis. It has also been implicated in sexual behavior. The present study investigated whether the relationship between kisspeptin and sexual behavior is independent of the HPG axis, i.e., testosterone. Sexual behavior was examined after the administration of kisspeptin to gonadally intact male rats and gonadectomized male rats that received testosterone supplementation. Other male rats were also observed for sexual behavior once a week from 2 to 5 weeks after gonadectomy and receiving kisspeptin for the sixth postoperative week. Sexual behavior in female rats serving as the partner for each male was also observed. Female rats were not administered kisspeptin in the present study. The results obtained showed that the administration of kisspeptin increased precopulatory behavior in gonadally intact male rats and gonadectomized male rats that received testosterone supplementation and proceptive behavior in their female partners. Precopulatory behavior in males and receptive behavior in females increased, while copulatory behavior in males and receptive behavior in females remained unchanged. Furthermore, the administration of kisspeptin increased precopulatory behavior in gonadectomized males, but did not affect receptive behavior in females. These results suggest that kisspeptin affected males independently and/or supplementally to testosterone, and also that changes in the presence of testosterone in males had an impact on proceptive behavior in their female partners. In conclusion, kisspeptin may involve an as-yet-unidentified neural pathway in sexual desire independently of the HPG axis.


Stress responses to bacterial and viral mimetics in polycystic ovary syndrome model rats

Polycystic ovary syndrome (PCOS) is associated with an increased risk of psychological distress as well as enhanced responses to psychosocial stress. Recently, it was hypothesized that PCOS patients may be at high risk of novel COVID-19 infections and worse clinical presentations during such infections. Here, we evaluated the effects of PCOS on stress responses to bacterial and viral mimetics using dihydrotestosterone-induced PCOS model rats. Lipopolysaccharide (LPS; a bacterial mimetic) or polyinosinic-polycytidylic acid (Poly-IC; a viral mimetic) was injected into PCOS model rats (PCOS) and non-PCOS rats (control), and the rats' stress responses were evaluated. In the PCOS group, the rats' anorectic and febrile responses to LPS injection were enhanced, whereas their anorectic and febrile responses to Poly-IC injection were unaltered. The PCOS group also exhibited greater changes in peripheral cytokine levels in response to LPS, but not Poly-IC. On the contrary, after the injection of Poly-IC depressed locomotor activity was more evident in the PCOS group, whereas no such changes were observed after LPS injection. These findings indicate that although the stress responses of PCOS model rats to infection may be enhanced, the patterns of change in stress responses and their underlying mechanisms may differ between bacterial and viral infections.


Oncologic, fertility, and obstetric outcomes with MPA therapy in women with endometrial cancer and atypical endometrial hyperplasia

Medroxyprogesterone acetate (MPA) is one of the treatments of atypical endometrial hyperplasia (AEH) and endometrial cancer (EC) to preserve the fertility. Efficacy of MPA therapy and fertility and obstetric outcomes after remission were evaluated in EC or AEH patients. Among patients diagnosed with EC or AEH at Tokushima University Hospital between January 2002 and October 2020, we retrospectively analyzed patients, ages range from 26 to 40, who underwent conservative management using MPA (400-600 mg/day). In total, 19 patients underwent MPA therapy. The 18 (94%) patients achieved complete response (CR), and 1 (5%) patient achieved partial response (PR). Relapse occurred in 6 (32%) patients who had achieved CR. Of the patients who relapsed, 4 patients resumed MPA therapy and were in remission. Among 19 patients, 13 patients attempted pregnancy after CR. All of them underwent ovulation induction or assisted reproductive technology. As a result, 20 pregnancies in 10 (77%) patients and 12 live births in 9 (69%) patients were achieved. Rate of spontaneous abortion was 35% (7/20). MPA therapy can produce a high remission rate, and be considered an effective treatment for patients who wish fertility preservation. Around 70% patients who attempt to pregnancy can have at least one baby by infertility treatments. Because recurrence rate after MPA therapy is high, it may be desirable to aim for early pregnancy by active intervention.

The Journal of Obstetrics and Gynaecology Research


New treatment strategies for uterine sarcoma using secreted frizzledrelated proteins

Secreted frizzled-related proteins (SFRPs) are involved in the development of various types of cancer and function by suppressing the Wnt signaling pathway. To elucidate the clinical implications of SFRPs in uterine sarcoma, SFRP expression levels and their effects on uterine leiomyosarcoma cells were examined. Immunostaining for SFRP4 was performed on uterine smooth muscle, uterine fibroid and uterine leiomyosarcoma tissues. Additionally, the effects of SFRP4 administration on cell viability, migration and adhesion were evaluated in uterine leiomyosarcoma SKN cells using the WST-1 assay (Roche Diagnostics) and the CytoSelect™ 24-well Cell Migration Assay Kit and the CytoSelect™ 48-well Cell Adhesion Assay Kit. The expression levels of SFRP4 in uterine leiomyosarcoma tissues were lower than those in normal smooth muscle and uterine fibroid tissues. In addition, SFRP4 suppressed the viability and migration, and increased the adhesion ability of uterine leiomyosarcoma cells compared with in the control group. In conclusion, SFRP4 may suppress the viability and migration, and enhance the adhesion of sarcoma cells. These results suggested that SFRP4 could be considered as a novel therapeutic target for uterine sarcoma.


Progesterone treatment reduces food intake and body weight in ovariectomized female rats

While the effects of progesterone on body weight and appetite in pre-menopausal conditions have been well elucidated, its effects in post-menopausal conditions have not been clarified. On the contrary, the effects of estrogen on body weight and appetite in post-menopausal conditions have been well established. In this study, the effects of progesterone treatment on body weight, appetite, and fat mass in ovariectomized rats were evaluated. In addition, the central and/or peripheral levels of oxytocin (OT), leptin, and their receptors, which are potent anorectic factors, were examined. Female rats were ovariectomized and divided into control, progesterone-treated, and estrogen-treated groups. Body weight, food intake, and subcutaneous fat mass were lower in both the progesterone and estrogen groups than in the control group. The estrogen group exhibited higher serum OT levels than the control group, whereas the OT levels of the progesterone and control groups did not differ. The serum leptin levels of both the progesterone and estrogen groups were lower than those of the control group. Gene expression analysis of OT, leptin, and their receptors in the hypothalamus and adipose tissue found few significant differences among the groups. Hypothalamic neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) mRNA levels involved in appetite regulation were slightly altered in the progesterone and estrogen groups. These findings suggest that progesterone treatment may have favorable effects on body weight, appetite, and fat mass regulation in post-menopausal conditions and that the mechanisms underlying these effects of progesterone differ from those underlying the effects of estrogen.


当院におけるAYA世代の妊孕性温存症例の治療背景とその転帰

当院におけるAYA世代の妊孕性温存症例の治療背景とその転帰

Modern Trends in Obstetrics & Gynecology


当院におけるART妊娠者でのNIPT受検率について

当院におけるART妊娠者でのNIPT受検率について


Effects of activation with a Ca ionophore and roscovitine on the development of human oocytes that failed to fertilize after ICSI.

Sequential treatment with an Ca ionophore and roscovitine activates oocytes that remain unfertilized after ICSI. In TESE-ICSI, the activation rate tended to be increased by the co-administration of roscovitine with a Ca ionophore. J. Med. Invest. 70 : 321-324, August, 2023.

The Journal of Medical Investigation : JMI


当院における精巣内精子採取術・顕微授精(testicular sperm extraction-intracytoplasmic sperm injection: TESE-ICSI)の治療成績と周産期予後の検討


A novel PCOS rat model and an evaluation of its reproductive, metabolic, and behavioral phenotypes.

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.


Oxytocin treatment reduced food intake and body fat and ameliorated obesity in ovariectomized female rats.

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.


Current status of chromosomal analysis in couples with recurrent miscarriage at Tokushima University Hospital

徳島大学病院産科婦人科における不育症患者に対する染色体検査の実施状況


Intra-follicular kisspeptin levels are related to oocyte maturation and gonadal hormones in patients who are undergoing assisted reproductive technology.

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.


Development-related changes in the expression of the ovarian Kiss1 and Kiss1r genes and their sensitivity to human chorionic gonadotropin in prepubertal female rats.

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.

The Journal of Reproduction and Development


Expression of cytokine-induced neutrophil chemoattractant suppresses tumor necrosis factor alpha expression and thereby prevents the follicles from undergoing atresia and apoptosis.

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.


骨盤内膿瘍に対する腹腔鏡手術の有用性

骨盤内膿瘍に対する腹腔鏡手術の有用性

骨盤内膿瘍に対する治療は，抗生剤による薬物療法が主体であるが，抗生剤無効例や，消化管から発生した膿瘍との鑑別を要する症例では外科的アプローチが必要となる．骨盤内膿瘍の場合，炎症による癒着が強いことが多く，手術は比較的難易度が高い．しかし，高度の炎症で疲弊した患者の負担を軽減するために，近年では腹腔鏡手術が積極的に導入されており，当院でも可能な限り腹腔鏡手術で対応している．抗生剤による治療が無効であった付属器膿瘍に対して腹腔鏡下手術を施行した4症例について報告する．4例とも輸血を要するような出血はなく，また他臓器損傷もなかった．術後は，速やかに炎症所見が改善し特に問題なく経過した． 骨盤内膿瘍に対する腹腔鏡手術は，ドレナージによりすみやかな炎症軽減が可能であり，かつ低侵襲であることから有用性は高い．一方で，(汎発性腹膜炎などで，)腸管麻痺を伴う症例では，腸管の膨隆のため腹腔鏡下の視野確保が困難であり，腹腔鏡手術の適応は慎重であるべきであると考える．

Modern Trends in Obstetrics & Gynecology


Retraction: Self-assembling anticaries mucosal vaccine containing ferritin cage nanostructure and glucan-binding region of S. mutans glucosyltransferase effectively prevents caries formation in rodents (Human Vaccines & Immunotherapeutics, (2017), 13, 10, (2332-2340), 10.1111/jog.16113)

A. Takeda , Y. Yamamoto , K. Tamura , H. Aoki , H. Noguchi , S. Minato , S. Kamada , R. Arakaki , T. Kaji , and T. Iwasa , "Oncologic, Fertility, and Obstetric Outcomes With MPA Therapy in Women with Endometrial Cancer and Atypical Endometrial Hyperplasia," The Journal of Obstetrics and Gynaecology Research 50, no. 4 (2024): 633-638, https://doi.org/10.1111/jog.15872. The above article, published online on 28 December 2023 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors; the journal Editor-in-Chief, Hiroaki Kajiyama; and John Wiley & Sons, Australia, Ltd. The retraction has been agreed upon following an investigation into concerns raised by a third party, which revealed major conceptual overlap and significant primary data redundancy with a previously published article by an overlapping group of authors. Such publishing practice is against the journal's policy and Wiley's Best Practice Guidelines on Research Integrity and Publishing Ethics.


Age-Dependent Changes in the Effects of Androgens on Female Metabolic and Body Weight Regulation Systems in Humans and Laboratory Animals.

In recent years, the effects of androgens on metabolic and body weight regulation systems and their underlying mechanisms have been gradually revealed in females. In women and experimental animals of reproductive age, androgen excess can adversely affect metabolic functioning, appetite, and body weight regulation. In addition, excess androgens can increase the risk of metabolic disorders, such as obesity, insulin resistance, and diabetes. These unfavorable effects of androgens are induced by alterations in the actions of hypothalamic appetite-regulatory factors, reductions in energy expenditure, insulin resistance in skeletal muscle, and β-cell dysfunction. Interestingly, these unfavorable effects of androgens on metabolic and body-weight regulation systems are neither observed nor evident in ovariectomized animals and post-menopausal women, indicating that the adverse effects of androgens might be dependent on the estrogen milieu. Recent findings may provide novel sex- and age-specific strategies for treating metabolic diseases.

International Journal of Molecular Sciences


子宮内膜癌・子宮内膜異型増殖症に対する妊孕性温存治療の治療効果と妊娠成績，周産期予後