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Purpose: Decidualization is an important event for embryo implantation and successful pregnancy. Impaired decidualization leads to implantation failure and miscarriage. However, it is unclear how often decidualization failure occurs in infertile women. By analyzing the endometrium at late-secretory phase, we investigated the incidence and pathogenesis of decidualization failure among infertile women., Methods: Endometrial dating was performed on the endometria obtained in the late-secretory phase from 33 infertile women. Endometrial dating of more than 2 days delay was taken as an indication of decidualization failure. The expression of essential transcription factors for decidualization (FOXO1, WT1, and C/EBPβ) was examined by immunohistochemistry., Results: Among 32 cases, 20 cases (62.5%) showed decidualization failure. These patients tended to have a history of more frequent miscarriages than those without decidualization failure. The percentage of cells that immunostained positive for the expression of three transcription factors was significantly lower in the patients with decidualization failure than in those without decidualization failure. Serum progesterone levels measured in the mid- and late-secretory phase were not significantly different between the cases with and without decidualization failure., Conclusions: The incidence of decidualization failure is high in infertile women., Competing Interests: The authors declare no conflict of interest. Isao Tamura and Norihiro Sugino are Editorial Board members of Reproductive Medicine and Biology and co‐authors of this article. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication., (© 2024 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Purpose: To investigate whether long noncoding RNAs (lncRNAs) are involved in the development or malignant behavior of ovarian high-grade serous carcinoma (HGSC), we attempted to identify lncRNAs specific to HGSC., Methods: Total RNAs were isolated from HGSC, normal ovarian, and fallopian tube tissue samples and were subjected to a PCR array that can analyze 84 cancer-associated lncRNAs. The lncRNAs that were upregulated and downregulated in HGSC in comparison to multiple samples of normal ovary and fallopian tube were validated by real-time RT-PCR. To infer the function, ovarian cancer cell lines that overexpress the identified lncRNAs were established, and the activation of cell proliferation, migration, and invasion was analyzed., Results: Eleven lncRNAs (ACTA2-AS1, ADAMTS9-AS2, CBR3-AS1, HAND2-AS1, IPW, LINC00312, LINC00887, MEG3, NBR2, TSIX, and XIST) were downregulated in HGSC samples. We established the cell lines that overexpress ADAMTS9-AS2, CBR3-AS1, or NBR2. In cell lines overexpressing ADAMTS9-AS2, cell proliferation was suppressed, but migration and invasion were promoted. In cell lines overexpressing CBR3-AS1 or NBR2, cell migration tended to be promoted, although cell proliferation and invasion were unchanged., Conclusion: We identified eleven lncRNAs that were specifically downregulated in HGSC. Of these, CBR3-AS1, NBR2, and ADAMTS9-AS2 had unique functions in the malignant behaviors of HGSC., Competing Interests: The authors declare that there are no conflicts of interest. Norihiro Sugino is an Editorial Board member of Reproductive Medicine and Biology and a co‐author of this article. To minimize bias, he was excluded from all editorial decision‐making related to the acceptance of this article for publication., (© 2024 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Purpose: We investigated the interactions between mural granulosa cells (MGCs) and cumulus granulosa cells (CGCs) during ovulation after the LH surge., Methods: We performed clustering, pseudotime, and interactome analyses utilizing reported single-cell RNA sequencing data of mouse ovary at 6 h after eCG-hCG injection., Results: Clustering analysis classified granulosa cells into two distinct populations, MGCs and CGCs. Pseudotime analysis divided granulosa cells into before and after the LH surge, and further divided them into two branches, the ovulatory MGCs and the ovulatory CGCs. Interactome analysis was performed to identify the interactions between MGCs and CGCs. Twenty-six interactions were acting from CGCs toward MGCs, involving ovulation and steroidogenesis. Thirty-six interactions were acting from MGCs toward CGCs, involving hyaluronan synthesis. There were 25 bidirectional interactions, involving the EGFR pathway. In addition, we found three novel interactions: Ephrins-Ephs pathway and Wnt-Lrp6 pathway from CGCs to MGCs, associated with steroidogenesis and lipid transport, respectively, and TGF-β-TGFBR1 pathway from MGCs to CGCs, associated with hyaluronan synthesis., Conclusions: MGCs and CGCs interact with each other in the preovulatory follicle after the LH surge, and their interactions have roles in corpus luteum formation, oocyte maturation, and follicle rupture., Competing Interests: Norihiro Sugino is Editor‐in‐Chief of the Reproductive Medicine and Biology and co‐author of this article. He was excluded from the peer‐review process and all editorial decisions related to the acceptance and publication of this article. Peer review was handled independently by Editors‐in‐Associate Chief Tasuku Harada to minimize bias., (© 2024 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Purpose: To test the theory that invaginated ovarian surface epithelium and endometrial implants on the ovary form ovarian endometriomas., Methods: Adhesion sites of ovarian endometrioma on the peritoneum and consecutive ovarian endometrioma cyst wall, called non-adhesion sites, were histologically examined. DNA methylomes of the adhesion sites, non-adhesion sites, and blueberry spots were compared with those of ovary, endometrium, and peritoneum., Results: The non-adhesion sites showed an ovarian surface epithelium-like structure near the adhesion site, which continued to a columnar epithelium-like structure. Calretinin staining was strong in the ovarian surface epithelium-like structure but weak in the columnar epithelium-like structure. Estrogen receptors were absent in the ovarian surface epithelium-like structure, but present in the columnar epithelium-like structure. The adhesion sites had endometrial gland-like structures that expressed estrogen receptors. Analyses of DNA methylomes classified the non-adhesion sites and ovaries into the same group, suggesting that ovarian endometriomas originate from the ovarian surface epithelium. The adhesion sites, blueberry spots and peritoneum were classified in the same group, suggesting that the adhesion sites and blueberry spots originate from the peritoneum., Conclusions: The present results support the invagination theory. Ovarian endometriomas consist of invaginated ovarian surface epithelium with celomic metaplasia and endometrium implants on the peritoneum., Competing Interests: Norihiro Sugino and Isao Tamura are Editorial Board members of Reproductive Medicine and Biology and co‐authors of this article. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication., (© 2023 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Purpose: We investigate the relationships between oocyte developmental capacity and follicular size of its origin in Japanese women: those undergoing conventional IVF (cIVF) and ICSI, respectively., Methods: A total of 3377 follicles were punctured separately and were classified into three groups (large, medium, and small) by their diameters. A total of 1482 retrieved oocytes were individually cultured and received cIVF or ICSI. The oocytes receiving ICSI were denuded and the number of mature (MII) oocytes was counted., Results: The oocyte retrieval rates and the proportion of MII oocytes were significantly lower in small follicles than in large follicles. Under cIVF, the fertilization rate was significantly lower in oocytes from small follicles than large follicles. Under ICSI, the fertilization rate for MII oocytes was not significantly related to follicular size. Follicular size was not significantly related to the development potential to blastocyst and pregnancy rate for either the cIVF oocytes or the ICSI oocytes., Conclusions: Although the fertilization rate by cIVF is low in oocytes from small follicles due to the lower proportion of mature oocytes, their development potential is comparable to that of oocytes from larger follicles if they could be fertilized. Under ICSI using mature oocytes, their development potential is not related to follicular size., Competing Interests: Conflict of interest: All authors have no conflict of interest. Ethics Statement: Informed consent was obtained from all the patients in this study. The study design was reviewed and approved by the institutional review board of Yamaguchi University Hospital., (© 2021 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Purpose: To identify the aberrantly expressed long non-coding RNAs (lncRNAs) in ovarian high-grade serous carcinoma (HGSC)., Methods: Total RNA was isolated in HGSC cell lines, ovarian surface epithelial cells, and normal ovaries. Aberrantly expressed lncRNAs in HGSC were identified by PCR array, which analyzes 84 kinds of lncRNAs. To infer their functions, HGSC cell lines with different levels of expression of the identified lncRNAs were established, and then, activities of proliferation, migration, and apoptosis were examined. Expression levels of the identified lncRNAs were also examined in multiple ovarian HGSC tissues., Results: Ten aberrantly expressed lncRNAs, six upregulated and four downregulated, were identified in the HGSC cell lines. The authors established four HGSC cell lines: in two of the cell lines, one of the upregulated lncRNAs was knocked down, and in two other cell lines, one of the downregulated lncRNAs (MEG3 and POU5F1P5) was overexpressed. Migration activities were inhibited in the HGSC cell lines overexpressing MEG3 or POU5F1P5 while there were no differences in proliferation and apoptosis between the established and control cell lines. The four lncRNAs downregulated in the HGSC cell lines were also observed to be downregulated in ovarian HGSC tissues., Conclusion: The authors identified four downregulated lncRNAs in ovarian HGSC., Competing Interests: The authors declare that there are no conflicts of interest., (© 2020 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Purpose: Carbonyl reductase 1 (CBR1) is involved in cancer progression. Recently, the authors reported that the loss of CBR1 expression is associated with a poor prognosis in uterine cervical cancer. Here, we investigated whether the decreased CBR1 expression promotes cancer progression by inducing the epithelial mesenchymal transition (EMT)., Methods: Antisense constructs of CBR1 complementary DNA (antisense clones) and the empty vectors (control clones) were transfected into human uterine cervical squamous cell carcinoma cell lines (SKG II and SiHa) and the proliferation and EMT marker expression of these clones were analyzed in vitro. In an in vivo study, 10 7 cells of the antisense and control clones were subcutaneously injected into nude mice and the tumorigenesis was observed for 8 weeks., Results: With the decreased CBR1 expression, the proliferation of the antisense clones increased, accompanied by a decrease in epithelial markers (E-cadherin and cytokeratin) and an increase in mesenchymal markers (fibronectin, alpha-smooth muscle actin, and N-cadherin), which suggests EMT induction. In the in vivo study, the tumor volume in the antisense group was significantly larger than that in the control group., Conclusion: Decreased CBR1 expression promotes tumor growth by inducing EMT in uterine cervical squamous cell carcinomas.

Purpose: To investigate the impact of adenomyosis on the complications and outcomes of pregnancy in Japan., Methods: We carried out a multicenter retrospective questionnaire survey. A questionnaire regarding pregnancy complications and the outcomes of pregnancy was sent to 725 facilities., Results: Data were obtained on the cases of 272 pregnant women with adenomyosis from 65 facilities. The complications of pregnancy included miscarriage before 12 weeks of pregnancy (14.8%), miscarriage after 12 weeks of pregnancy (9.9%), preterm delivery (24.4%), fetal growth restriction (11.8%), pregnancy-induced hypertension (9.9%), intrauterine infection (7.3%), and cervical incompetency (5.3%). The rates of pregnancy complications in the three groups classified according to pretreatment for adenomyosis (no pretreatment, medication, surgery) did not differ to a statistically significant extent. The rates of miscarriage (>12 weeks) and cervical incompetency increased according to the size of the adenomyosis. The rates of pregnancy-induced hypertension and uterine infection in patients with diffuse-type adenomyosis were higher than that in patients with focal-type adenomyosis., Conclusions: Our results show that the increased size and diffuse type of adenomyosis are associated with adverse pregnancy outcome. We should be aware of the higher incidence of pregnancy-induced hypertension and uterine infection in patients with diffuse-type adenomyosis.

Purpose: Prenatal exposure to environmental chemicals is a growing concern, because such exposures have been shown to be associated with various diseases. The levels of chemicals and heavy metals in maternal blood, cord blood, maternal urine and amniotic fluid in Japanese pregnant women were investigated., Methods: A total of 145 women, including 14 fetal growth restriction cases, were included in the present study. The levels of phthalates (di[2-ethylhexyl]phthalate and mono[2-ethylhexyl]phthalate), perfluorinated compounds (perfluorooctane sulfonate, perfluorohexanoic acid, perfluorooctanoic acid, and perfluorononanoic acid), pesticides (dimethylphosphate, dimethylthiophosphate, diethylphosphate, diethylthiophosphate, 3-phenoxybenzoic acid, and octachlorodipropyl ether), bisphenol A, nicotine (nicotine, nornicotine, cotinine, norcotinine, and trans-3'-hydroxycotinine), polybrominated diphenyl ethers, and heavy metals were measured. The relationship between fetal growth and the levels of chemicals and heavy metals were investigated., Results: Phthalates, perfluorinated compounds, pesticides, polybrominated diphenyl ethers, and heavy metals were detected in high frequency, whereas nicotine and bisphenol A were almost negative. Phthalates, perfluorinated compounds, and several heavy metals were transferred to the fetus. High perfluorononanoic acid levels in the maternal blood and cord blood, and low perfluorooctanoic acid level in the cord blood were significantly and negatively associated with fetal growth., Conclusions: The present study showed that pregnant women in Japan and their fetuses are exposed to a variety of chemicals and heavy metals.

Aim: A multicenter, retrospective survey was conducted in order to investigate the current clinical status of adenomyosis in Japan., Methods: The questionnaires covered the management of infertile women with adenomyosis and the outcomes of infertility treatment in women with adenomyosis. The questionnaires were sent to 1149 facilities in Japan., Results: The data were obtained on 535 infertile women with adenomyosis from 190 facilities. Regarding management, infertility treatment was performed without pretreatment for adenomyosis in 37 facilities, after medication in eight facilities, and after an operation in four facilities. Management policies were not established in 106 facilities. Regarding outcomes, the pregnancy rate was 41.7% and the abortion rate was 29.8%. Eighty-five patients received medication and 89 patients underwent surgery as a pretreatment before infertility treatment, while 361 patients had no pretreatment. In relation to the type of adenomyosis, 162 patients had the focal type and 336 patients had the diffuse type. The pregnancy rate and abortion rate were not affected by pretreatment or the type of adenomyosis., Conclusion: The management policy for infertile women with adenomyosis has not been established. The pregnancy rate of infertility treatment is about 40%. There were no data to suggest that medication or surgery as a pretreatment for adenomyosis increased the pregnancy rate in infertile women.

Aim: Although a thin endometrium has been well recognized as a critical factor in implantation failure, little information is available regarding the molecular mechanisms. The present study investigated these mechanisms by using genome-wide mRNA expression analysis., Methods: Thin and normal endometrial tissue was obtained from a total of six women during the mid-luteal phase of the menstrual cycle. The transcriptomes were analyzed with a microarray. Differentially expressed genes were classified according to Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways., Results: The study identified 318 up-regulated genes and 322 down-regulated genes in the thin endometrium, compared to the control endometrium. The GO and KEGG pathway analyses indicated that the thin endometrium possessed aberrantly activated immunity and natural killer cell cytotoxicity that was accompanied by an increased number of inflammatory cytokines, such as IFN- γ. Various genes that were related to metabolism and anti-oxidative stress were down-regulated in the thin endometrium., Conclusion: Implantation failure in the thin endometrium appears to be associated with an aberrantly activated inflammatory environment and aberrantly decreased response to oxidative stress.

Angiogenesis is important for the formation and development of the corpus luteum and for maintenance of luteal function. Blood vessel regression is an important physiological phenomenon in the corpus luteum, which is associated with tissue involution during structural luteolysis. Angiogenesis actively occurs during the early luteal phase and is completed by the mid-luteal phase. Perivascular cells (pericytes) increase in number from the early luteal phase to the mid-luteal phase, suggesting that blood vessels are gradually stabilized until the mid-luteal phase. In the corpus luteum undergoing luteolysis, blood vessels and pericytes decrease in number, which is related to structural involution. In the corpus luteum of early pregnancy, the number of blood vessels with pericytes increases, suggesting that angiogenesis occurs again, accompanied by blood vessel stabilization. These changes in vasculature of the corpus luteum are regulated by the collaboration with vascular endothelial growth factor, which is involved in proliferation of vascular endothelial cells, and angiopoietins, which are involved in stabilization of blood vessels. This review focuses on angiogenesis, blood vessel stabilization and blood vessel regression during the divergent phases of luteal formation, luteal regression and luteal rescue by pregnancy. (Reprod Med Biol 2008; 7 : 91-103).

Cells living under aerobic conditions always face oxygen paradox. Oxygen is necessary for cells to maintain their lives. However, reactive oxygen species such as superoxide radical ( ), hydroxyl radical (OH - ) and hydrogen peroxide (H 2 O 2 ) are generated from oxygen and damage cells. Oxidative stress occurs as a consequence of excessive production of reactive oxygen species and impaired antioxidant defense systems. Antioxidant enzymes include: superoxide dismutase (SOD), which is a specific enzyme to scavenge superoxide radicals; copper-zinc SOD, located in the cytosol; and manganese SOD, located in the mitochondria. Both types of SOD belong to the first enzymatic step to scavenge superoxide radicals. It has been reported that a number of local factors such as cytokines, growth factors and eicosanoids are involved in the regulation of ovarian function, in addition to gonadotropins and ovarian steroid hormones. Since reactive oxygen species are generated and SOD is expressed in the ovary, there is a possibility that reactive oxygen species and SOD work as local regulators of ovarian function. The present review reports that reactive oxygen species and their scavenging systems play important roles in several processes of reproductive physiology, including follicular development, oocyte maturation, ovulation, corpus luteum function and follicular atresia. (Reprod Med Biol 2005; 4 : 31- 45).

Background:  Patients with polycystic ovarian syndrome (PCOS) are often resistant to clomiphene citrate, which causes the need for subsequent gonadotropin treatment. However, careful administration is required because of the potential side-effects, that is, ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy. Methods:  Forty-three cycles in 22 patients with PCOS were enrolled in this study. Ovarian stimulation was initiated on day 7 of the menstrual cycle with 150 IU/day of follicle stimulating hormone (FSH; 150 IU course), 100 IU/day (100 IU course), and 75 IU/day (75 IU course), successively. If follicles over 12 mm in diameter did not develop after 1 week, the dose was increased. In each treatment course, the number of developed follicles, the serum estradiol level before ovulation, total FSH dosage and duration of administration, the incidence of OHSS, and pregnancy rate were examined. Results and Conclusion:  The largest number of developed follicles and the highest serum estradiol level were found in the 150 IU course. In contrast, the total FSH dosage and duration of administration were highest and longest in the 75 IU course. The incidence of OHSS and pregnancy rate were highest in the 150 IU course and in the 75 IU course, respectively. The present study indicates that 100 IU or 75 IU of FSH is recommended as an initial injection dose for PCOS patients. (Reprod Med Biol 2003; 2 : 63-67).

Background: Serum prolactin (PRL) concentration is known to transiently increase in rats; however, its change is obscure and the role of it is also unclear in women. We studied the relationship between estradiol (E 2 ) and PRL production and the role of transient hyperprolactinemia in the late follicular phase of the gonadotropin-stimulated cycle. Methods: (1) Serum E 2 and PRL concentrations were measured on an early follicular day and immediately before a human chorionic gonadotropin (hCG) injection in 60 patients with normoprolactinemia. Twelve of the 60 patients also received a gonadotropin injection with bromocriptine, and serum hormone levels were compared with those without bromocriptine. (2) Preovulatory serum E 2 and PRL concentrations were compared between the natural and clomiphene treatment cycles in 14 hormonally normal women. (3) Changes of serum PRL concentrations were measured before and after E 2 loading in five premature ovarian failure (POF) patients. (4) The E 2 production by granulosa cells in the presence of PRL was measured. Results and Conclusion: Serum E 2 and PRL concentrations were significantly increased by the gonadotropin injection. Bromocriptine treatment completely inhibited the PRL increase, but further increased serum E 2 concentration on the late follicular day. The E 2 loading increased serum PRL levels in POF patients. The clomiphene treatment increased serum E 2 but decreased PRL concentrations. Prolactin significantly decreased E 2 production by granulosa cells. A feedback loop may exist between E 2 and PRL to control the excess E 2 production induced by gonadotropin injection. (Reprod Med Biol 2002; 1 : 69-74).