記述言語：英語   出版者・発行元：Journal of Obstetrics and Gynaecology Research  

Aim: Both morbidity and mortality rates of cervical cancer are increasing, especially in reproductive-aged women. Radical trachelectomy (RT) is an effective fertility-preserving surgery for early-stage cervical cancer. This study aimed to determine the influence of RT on endometrial thickness during in vitro fertilization-embryo transfer (IVF-ET). Methods: Forty-four patients had undergone RT, and 23 women undergoing IVF-ET treatment (105 ET cycles) were included. Endometrial thickness during hormone replacement therapy (HRT) was retrospectively evaluated and compared between patients with and without RT. Results: Eleven patients (50 ET cycles) in the RT group and 12 (52 ET cycles) in the control group were investigated. Compared with the control group, higher ET cancellation rates were observed in patients in the RT group (1 of 52 cycles [control group] vs. 8 of 50 cycles [RT group], p < 0.01). Endometrial thinning was not affected by patient age at first IVF-ET treatment, history of artificial abortion, preservation of uterine arteries during RT, or postoperative chemotherapy (p = 0.27, 1, 1, and 1, respectively). Conclusions: Our data revealed that RT influenced endometrial thickness in IVF-ET. This was not affected by the background of the patients or perioperative management in this study. We could not reveal the underlying mechanism, but it is postulated that the transient postoperative uterine blood flow status and postoperative infections may have some effect on the endometrium. To resolve these issues, accumulation of evidences are required. We recommend informing patients about the impact of RT on IVF-ET before starting assisted reproductive technology (ART).

DOI： 10.1111/jog.15841

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記述言語：英語   出版者・発行元：Frontiers in Endocrinology  

Background: Polycystic ovary syndrome (PCOS) is a common disorder resulting in irregular menstruation and infertility due to improper follicular development and ovulation. PCOS pathogenesis is mediated by downregulated follicle-stimulating hormone receptor (FSHR) expression in granulosa cells (GCs); however, the underlying mechanism remains elusive. Unkeito (UKT) is a traditional Japanese medicine used to treat irregular menstruation in patients with PCOS. In this study, we aimed to confirm the effectiveness of UKT in PCOS by focusing on follicle-stimulating hormone (FSH) responsiveness. Methods: A rat model of PCOS was generated by prenatal treatment with 5α-dihydrotestosterone. Female offspring (3-week-old) rats were fed a UKT mixed diet or a normal diet daily. To compare the PCOS phenotype in rats, the estrous cycle, hormone profiles, and ovarian morphology were evaluated. To further examine the role of FSH, molecular, genetic, and immunohistological analyses were performed using ovarian tissues and primary cultured GCs from normal and PCOS model rats. Results: UKT increased the number of antral and preovulatory follicles and restored the irregular estrous cycle in PCOS rats. The gene expression levels of FSHR and bone morphogenetic protein (BMP)-2 and BMP-6 were significantly decreased in the ovarian GCs of PCOS rats compared to those in normal rats. UKT treatment increased FSHR staining in the small antral follicles and upregulated Fshr and Bmps expression in the ovary and GCs of PCOS rats. There was no change in serum gonadotropin levels. In primary cultured GCs stimulated by FSH, UKT enhanced estradiol production, accompanied by increased intracellular cyclic adenosine monophosphate levels, and upregulated the expression of genes encoding the enzymes involved in local estradiol synthesis, namely Cyp19a1 and Hsd17b. Furthermore, UKT elevated the expression of Star and Cyp11a1, involved in progesterone production in cultured GCs in the presence of FSH. Conclusions: UKT stimulates ovarian follicle development by potentiating FSH responsiveness by upregulating BMP-2 and BMP-6 expression, resulting in the recovery of estrous cycle abnormalities in PCOS rats. Restoring the FSHR dysfunction in the small antral follicles may alleviate the PCOS phenotype.

DOI： 10.3389/fendo.2023.1228088

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出版者・発行元：医歯薬出版  

DOI： 10.32118/ayu28611887

CiNii Research

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記述言語：日本語   出版者・発行元：日本小児血液・がん学会  

<p>2020年8月に東海北陸若手がん・生殖ネットワークが発足し，がん・生殖医療に関する情報共有や啓発活動を行っている．今回，小児・思春期血液がん患者の生殖機能に関する医療連携の現状を調査し，課題の抽出や今後の展望を見出した．</p><p>2013年1月1日～2021年6月30日までに，当ネットワーク参加9施設のがん・生殖医療外来を受診した小児・思春期の血液がん患者（年齢18歳まで）について，後方視的に検討した．</p><p>全症例115例（男性71例，女性44例）で，年齢別では9歳以下が4例，10–12歳が9例，13–15歳が42例，16–18歳が60例であった．精子凍結は希望した66例中13例が完遂できなかったが，その原因は無精子症が大半を占めていた．卵巣組織凍結は希望した17例中16例が完遂でき，がん治療中で造血細胞移植前処置前のタイミングで行われている症例が多かった．また，7例に周術期の輸血を要した．未受精卵子凍結は希望した11例中8例が完遂でき，思春期前（14歳以下）の女児でも完遂例が4例みられた．</p><p>小児・思春期の血液がん患者におけるがん・生殖医療は，若年になるにつれ情報提供・紹介は少なく，妊孕性温存療法を行うにあたっても骨髄抑制などリスクを伴い，その実施には注意を要する．しかし，妊孕性温存療法のニーズやその完遂率は比較的高いため，今後も特に思春期前の小児を中心に患者・医療関係者含め啓発を続けていきたい．</p>

DOI： 10.11412/jspho.60.20

CiNii Research

記述言語：英語   出版者・発行元：Scientific Reports  

Familial neurohypophyseal diabetes insipidus (FNDI) is a degenerative disease of vasopressin (AVP) neurons. Studies in mouse in vivo models indicate that accumulation of mutant AVP prehormone is associated with FNDI pathology. However, studying human FNDI pathology in vivo is technically challenging. Therefore, an in vitro human model needs to be developed. When exogenous signals are minimized in the early phase of differentiation in vitro, mouse embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) differentiate into AVP neurons, whereas human ESCs/iPSCs die. Human ESCs/iPSCs are generally more similar to mouse epiblast stem cells (mEpiSCs) compared to mouse ESCs. In this study, we converted human FNDI-specific iPSCs by the naive conversion kit. Although the conversion was partial, we found improved cell survival under minimal exogenous signals and differentiation into rostral hypothalamic organoids. Overall, this method provides a simple and straightforward differentiation direction, which may improve the efficiency of hypothalamic differentiation.

DOI： 10.1038/s41598-022-22405-8

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記述言語：英語   出版者・発行元：Reproductive Sciences  

Polycystic ovary syndrome (PCOS), a common endocrine disorder, is associated with impaired oocyte development, leading to infertility. However, the pathogenesis of PCOS has not been completely elucidated. This study aimed to determine the differentially expressed genes (DEGs) and epigenetic changes in the oocytes from a PCOS mouse model to identify the etiological factors. RNA-sequencing analysis revealed that 90 DEGs were upregulated and 27 DEGs were downregulated in mice with PCOS compared with control mice. DNA methylation analysis revealed 30 hypomethylated and 10 hypermethylated regions in the PCOS group. However, the DNA methylation status did not correlate with differential gene expression. The pathway enrichment analysis revealed that five DEGs (Rps21, Rpl36, Rpl36a, Rpl37a, and Rpl22l1) were enriched in ribosome-related pathways in the oocytes of mice with PCOS, and the immunohistochemical analysis revealed significantly upregulated expression levels of Rps21 and Rpl36. These results suggest that differential gene expression in the oocytes of mice in PCOS is related to impaired folliculogenesis. These findings improve our understanding of PCOS pathogenesis.

DOI： 10.1007/s43032-022-01095-7

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記述言語：英語   出版者・発行元：Scientific Reports  

Retained products of conception (RPOC) is a common cause of postpartum bleeding, which may be life-threatening; however, no evidence-based guidelines exist to assist in evaluating the risk of massive hemorrhage in women with RPOC. In this prospective study, we aimed to evaluate the predictive factors for massive hemorrhage in women with RPOC. The primary and secondary endpoints were to validate the usefulness of power Doppler color scoring (PDCS) in evaluating hypervascularity and to identify other predictive factors (such as maximum RPOC diameter and serum βhCG and Hb level at first visit), respectively. Among the 51 women with RPOC included in this study, 16 (31.5%) experienced massive hemorrhage during follow-up. None of the women with PDCS 1 or 2 (18) experienced massive hemorrhage, whereas 16 (48.5%) women with PDCS 3 or 4 (33) did. Multiple logistic regression analysis showed that the odds ratio [95% confidence interval] (P value) for PDCS, assisted reproductive technology (ART), and low serum hemoglobin (Hb) levels were 22.39 [2.25 − 3087.92] (P = 0.004), 5.72 [1.28 − 33.29] (P = 0.022), and 4.24 [0.97 − 22.99] (P = 0.056), respectively. Further, the decision tree method identified PDCS, ART, and low serum Hb levels as potential predictive factors for massive hemorrhage. This study identified PDCS as useful predictor of massive hemorrhage in women with RPOC. With additional inclusion of factors such as ART and low serum Hb levels, the risk of massive hemorrhage may be effectively evaluated, leading to better management of women of reproductive age.

DOI： 10.1038/s41598-022-15564-1

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記述言語：英語   出版者・発行元：Reproductive Biology and Endocrinology  

Background: Endometriosis is a complex syndrome characterized by an estrogen-dependent chronic inflammatory process that affects 10% of women of reproductive age. Ovarian endometriosis (OE) is the most common lesion in endometriosis and may cause infertility, in addition to dysmenorrhea. Hormonal treatments, which are the conventional treatment methods for endometriosis, suppress ovulation and hence are not compatible with fertility. The inflammasome is a complex that includes Nod-like receptor (NLR) family proteins, which sense pathogen-associated molecular patterns and homeostasis-altering molecular processes. It has been reported that the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing (NLRP) 3 inflammasome, which contributes to the activation of interleukin-1 beta (IL-1β), might be related to the progression of endometriosis. Therefore, the aim of the present study was to evaluate non-hormonal therapies for OE, such as inhibitors of the NLRP3 inflammasome. Methods: The expression of NLRP3 was measured in the eutopic endometrium (EM) of patients with and without endometriosis and OE samples, as well as stromal cells derived from the endometrium of patients with and without endometriosis and OE samples (endometrial stromal cells with endometriosis [ESCs] and cyst-derived stromal cells [CSCs]). The effects of an NLRP3 inhibitor (MCC950) on ESCs and CSCs survival and IL-1β production were evaluated. We then administered MCC950 to a murine model of OE to evaluate its effects on OE lesions and ovarian function. Results: NLRP3 gene and protein expression levels were higher in OE and CSCs than in EM and ESCs, respectively. MCC950 treatment significantly reduced the survival of CSCs, but not that of ESCs. Moreover, MCC950 treatment reduced the co-localization of NLRP3 and IL-1β in CSCs, as well as IL-1β concentrations in CSCs supernatants. In the murine model, MCC950 treatment reduced OE lesion size compared to phosphate-buffered saline treatment (89 ± 15 vs. 49 ± 9.3 mm3 per ovary; P < 0.05). In the MCC950-treated group, IL-1β and Ki67 levels in the OE-associated epithelia were reduced along with the oxidative stress markers of granulosa cells. Conclusions: These results indicated that NLRP3/IL-1β is involved in the pathogenesis of endometriosis and that NLRP3 inhibitors may be useful for suppressing OE and improving the function of ovaries with endometriosis.

DOI： 10.1186/s12958-022-00924-3

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：Endocrinology (United States)  

Prolactin (PRL), a hormone involved in lactation, is mainly produced and secreted by the lactotrophs of the anterior pituitary (AP) gland. We previously reported a method to generate functional adrenocorticotropic hormone-producing cells by differentiating the AP and hypothalamus simultaneously from human induced pluripotent stem cells (iPSCs). However, PRL-producing cells in the induced AP have not been investigated. Here, we confirmed the presence of PRL-producing cells and evaluated their endocrine functions. We differentiated pituitary cells from human iPSCs using serum-free floating culture of embryoid-like aggregates with quick reaggregation (SFEB-q) method and evaluated the appearance and function of PRL-producing cells. Secretion of PRL from the differentiated aggregates was confirmed, which increased with further culture. Fluorescence immunostaining and immunoelectron microscopy revealed PRL-producing cells and PRL-positive secretory granules, respectively. PRL secretion was promoted by various prolactin secretagogues such as thyrotropin-releasing hormone, vasoactive intestinal peptide, and prolactin-releasing peptide, and inhibited by bromocriptine. Moreover, the presence of tyrosine hydroxylase-positive dopaminergic nerves in the hypothalamic tissue area around the center of the aggregates connecting to PRL-producing cells indicated the possibility of recapitulating PRL regulatory mechanisms through the hypothalamus. In conclusion, we generated pituitary lactotrophs from human iPSCs; these displayed similar secretory responsiveness as human pituitary cells in vivo. In the future, this is expected to be used as a model of human PRL-producing cells for various studies, such as drug discovery, prediction of side effects, and elucidation of tumorigenic mechanisms using disease-specific iPSCs. Furthermore, it may help to develop regenerative medicine for the pituitary gland.

DOI： 10.1210/endocr/bqac004

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開催年月日： 2023年6月

記述言語：日本語   会議種別：ポスター発表  

開催地：名古屋国際会議場   国名：日本国  

開催年月日： 2023年5月

記述言語：英語   会議種別：口頭発表（一般）  

国名：日本国  

開催年月日： 2023年3月

記述言語：英語   会議種別：ポスター発表  

開催地：the Brisbane Convention & Exhibition Centre   国名：オーストラリア連邦  

開催年月日： 2022年8月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）