Arata Moeka, Kou Tamura, Aoki Hidenori, Hiroki Noguchi, Asuka Takeda, Saki Minato, Yamamoto Shota, Riyo Kinouchi, Kanako Yoshida, Yuri Yamamoto, Takashi Kaji and Takeshi Iwasa : The effects of testosterone on hypothalamic and serum oxytocin levels are affected by the estrogen milieu in female rats, Nutrients, Vol.16, No.15, 2533, 2024.
Takashi Kaji, Hiroki Noguchi, Kou Tamura, Hidenori Aoki, Atsuko Yoshida, Yuri Yamamoto, Kanako Yoshida and Takeshi Iwasa : Survey on the incidence of multiple pregnancies and neonatal outcomes by fertility treatment in Tokushima Prefecture, Japan, The Journal of Medical Investigation : JMI, Vol.71, No.3.4, 251-253, 2024.
(Summary)
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.
Rie Masaki, Yuri Yamamoto, Kou Tamura, Hidenori Aoki, Hiroki Noguchi, Asuka Takeda, Saki Minato, Risa Tanano, Erika Yamanaka, Takaaki Maeda, Tatsuo Sugimoto, Hikari Sasada, Hiroaki Inui, Tomohiro Kagawa, Atsuko Yoshida, Ayuka Mineda, Riyo Kinouchi, Kanako Yoshida, Takashi Kaji and Takeshi Iwasa : Comparison of endogenous hypothalamic and serum OT levels between young and middle-aged perimenopausal female rats, The Journal of Medical Investigation : JMI, Vol.71, No.3.4, 246-250, 2024.
(Summary)
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.
Takeshi Iwasa, Hiroki Noguchi and Kou Tamura : 排卵障害 管理のポイントと新規治療薬の使い方, Clinical Gynecology and Obstetrics, Vol.78, No.5, 438-443, 2024.
7.
Yuri Kadota, Takeshi Katou, Kana Kasai, Takako Kawakita, Misaki Murayama, Akari Shinya, Hikari Sasada, Sachiko Katayama, Mari Nii, Shota Yamamoto, Hiroki Noguchi, Kou Tamura, Hidenori Aoki, Miyu Taniguchi, Tomotaka Nakagawa, Takashi Kaji, Masato Nishimura, Riyo Kinouchi, Kanako Yoshida and Takeshi Iwasa : Expression of SMADs in orthotopic human endometrium, ovarian endometriosis, and endometriotic lesions in a murine model, Endocrine Journal, Vol.71, No.4, 395-401, 2024.
(Summary)
Activin A promotes the development of endometriotic lesions in a murine model of endometriosis, and the immunohistochemical localization of phosphorylated suppressor of mothers against decapentaplegic homolog 2/3 (pSMAD2/3) complex in endometriotic lesions has been reported. Activin may therefore be involved in the development and proliferation of endometriotic cells via the SMAD signaling pathway. However, few detailed reports exist on SMAD7 expression in endometriosis. The purpose of this study was to investigate the expression of pSMAD2/3 or pSMAD3 and SMAD7 in the orthotopic human endometrium, ovarian endometriosis, and endometriotic lesions in a murine model and the effect of activin A on pSMAD2/3 and SMAD7 expression. We established an endometriosis murine model via the intraperitoneal administration of endometrial tissue and blood from donor mice. Activin A was intraperitoneally administered to the activin group. We immunohistochemically evaluated orthotopic endometria, ovarian endometriotic tissues, and endometriotic lesions in the murine model followed by western blotting. We found that pSMAD3 and SMAD7 were expressed in ovarian endometriosis and orthotopic endometria from patients with and without endometriosis. In the murine model, endometriotic lesions expressed pSMAD2/3 and SMAD7 in the activin and control groups, and higher SMAD7 expression was found in the activin group. To the best of our knowledge, this study is the first to show that SMAD7 expression is upregulated in endometriosis. In conclusion, these results suggest that activin A activates the SMAD signaling pathway and promotes the development of endometriotic lesions, thus identifying SMAD7 as a potential therapeutic target for endometriosis.
(Keyword)
Endometriosis / Female / Animals / Humans / Endometrium / Mice / Disease Models, Animal / Smad7 Protein / Smad3 Protein / Smad2 Protein / Activins / Ovarian Diseases / Adult / Signal Transduction
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.
Asuka Takeda, Yuri Yamamoto, Kou Tamura, Hidenori Aoki, Hiroki Noguchi, Saki Minato, Shuhei Kamada, Ryosuke Arakaki, Takashi Kaji and Takeshi 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, Vol.50, No.4, 633-638, 2024.
(Summary)
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.
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.
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.
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.
Asuka Takeda, Yuri Yamamoto, Kou Tamura, H. Aoki, Hiroki Noguchi, Saki Minato, Shuhei Kamada, Ryosuke Arakaki, Takashi Kaji and Takeshi Iwasa : 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), The Journal of Obstetrics and Gynaecology Research, Vol.50, No.11, 2164, 2024.
(Summary)
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.
Takeshi Iwasa, Hiroki Noguchi, Risa Tanano, Erika Yamanaka, Asuka Takeda, Kou Tamura, Hidenori Aoki, Tatsuro Sugimoto, Hikari Sasada, Takaaki Maeda, Saki Minato, Shota Yamamoto, Hiroaki Inui, Tomohiro Kagawa, Atsuko Yoshida, Ayuka Mineda, Mari Nii, Riyo Kinouchi, Kanako Yoshida, Yuri Yamamoto and Takashi Kaji : Age-Dependent Changes in the Effects of Androgens on Female Metabolic and Body Weight Regulation Systems in Humans and Laboratory Animals., International Journal of Molecular Sciences, Vol.24, No.23, 16567, 2023.
(Summary)
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.