Therapeutic intervention based on gene sequencing analysis of microbial 16S ribosomal RNA of the intrauterine microbiome improves pregnancy outcomes in IVF patients: a prospective cohort study.

PURPOSE: A Lactobacillus-dominated microbiota in the endometrium was reported to be associated with favorable reproductive outcomes. We investigated in this study whether 16S ribosomal RNA (rRNA) gene sequencing analysis of the uterine microbiome improves pregnancy outcomes. METHODS: This prospective cohort study recruited a total of 195 women with recurrent implantation failure (RIF) between March 2019 and April 2021 in our fertility center. Analysis of the endometrial microbiota by 16S rRNA gene sequencing was suggested for all patients who had three or more failed embryo transfers (ETs). One hundred and thirty-one patients underwent microbial 16S rRNA gene sequencing (study group) before additional transfers, while 64 patients proceeded to ET without that analysis (control group). The primary outcome was to compare the cumulative clinical pregnancy rate of two additional ETs. MAIN RESULTS: An endometrial microbiota considered abnormal was detected in 30 patients (22.9%). All but one of these 30 patients received antibiotics according to the bacterial genus detected in their sample, followed by treatment with probiotics. As a result, the cumulative clinical pregnancy rate (study group: 64.5% vs. control group: 33.3%, p = 0.005) and the ongoing pregnancy rate (study group: 48.9% vs. control group: 32.8%, p = 0.028) were significantly increased in the study group compared to the control group. CONCLUSION: Personalized treatment recommendations based on the microbial 16S rRNA gene sequencing of the uterine microbiota can improve IVF outcomes of patients with RIF. TRIAL REGISTRATION: The University Hospital Medical Information Network (UMIN) Clinical Trial Registry: UMIN000036050 (date of registration: March 1, 2019).

New treatment strategy for endometriosis using progestin-primed ovarian stimulation with dienogest: A prospective cohort study, comparison of dienogest versus dydrogesterone.

Dienogest (DNG) is an oral progestin effective for the treatment of symptomatic endometriosis, such as reduction of endometrial lesion and control of pain intensity. Progestin-primed ovarian stimulation (PPOS) is a new controlled ovarian hyperstimulation (COH) regimen, and several reports have shown that dydrogesterone (DYG) is an appropriate progestin for PPOS. The purpose of this study was to evaluate the efficacy of DNG in patients undergoing PPOS during COH in comparison with DYG. This was a prospective, cohort, parallel-group, non-inferiority trial of 150 women with endometriosis undergoing assisted reproductive technology between February 2018 and May 2020 at the single fertility center. The assignment to each protocol was based on the optimal treatment for each patient. Patients taking DNG 2 mg continuously were assigned in the DNG group(n = 73). The other patients were allocated in DYG group(n = 77). All viable embryos were cryopreserved for subsequent transfer. The main outcome measures were the mature oocyte and fertilization rates. During this study, no premature LH surge was detected. A smaller number of oocytes were retrieved in the DNG group than in the DYG group (6.18 ± 3.60 vs. 9.85 ± 5.77); however, the rate of mature oocytes was significantly higher in the DNG group than in the DYG group (89.1 % vs. 78.9 %). The fertilization rate was comparable between two groups. Therefore, patients taking DNG for PPOS can continue endometriosis treatment and obtain good-quality embryos during COH. Further prospective randomized-controlled trial should be performed to confirm of this novel strategy of DNG.

New trial of progestin-primed ovarian stimulation using dydrogesterone versus a typical GnRH antagonist regimen in assisted reproductive technology.

PURPOSE: To compare the clinical and ongoing pregnancy rates between a protocol using oral dydrogesterone with human menopausal gonadotropin (HMG) for progestin-primed ovarian stimulation (PPOS) and the typical gonadotropin-releasing hormone (GnRH) antagonist regimen in women undergoing controlled ovarian hyperstimulation (COH). METHODS: This was a prospective, controlled study of 251 women who underwent COH for in vitro fertilization between October 2016 and July 2017. The patients were allocated alternately into two groups: a dydrogesterone protocol (study group) and a GnRH antagonist protocol (control group). In study group, dydrogesterone (20 mg/day) plus HMG (150 or 225 IU) were administered simultaneously beginning on days 2 or 3 of the menstrual cycle. In both groups, all high-quality embryos were cryopreserved for later transfer. The primary outcome was the ongoing pregnancy rate at 12 weeks per frozen-thawed embryo transfer (FET) and the secondary outcome was the clinical pregnancy rate. RESULTS: None of the patients experienced a premature luteinizing hormone surge. During the follow-up period, 397 FET cycles were completed. The ongoing pregnancy rates at 12 weeks were 40.0% in study group versus 38.1% in control group (absolute difference 1.9%; 95% CI - 6.83 to 17.2%). The clinical pregnancy rate in study group (52.8%) was also not inferior to that in control group (49.5%; absolute difference 3.3%; 95% CI - 4.02 to 20.2%). CONCLUSIONS: The clinical and ongoing pregnancy rates in study group were comparable to those in control group. Therefore, PPOS with dydrogesterone is a reasonable option to provide COH.

The contributions of resistin and adiponectin gene single nucleotide polymorphisms to the genetic risk for polycystic ovary syndrome in a Japanese population.

Polycystic ovary syndrome (PCOS) is a heterogeneous group of disorders that occur fairly commonly in women of reproductive age and are characterized by a variety of clinical manifestations, including insulin resistance that is independent of obesity. Recent studies suggest that altered adipocytokine gene expression is closely associated with insulin resistance and that single nucleotide polymorphisms (SNPs) modulate the expression and/or function of these genes, thereby affecting insulin sensitivity. With that in mind, we investigated whether SNPs at position -420 of the resistin gene (RETN) and/or -11377 of the adiponectin gene (ADIPOQ) modulate the susceptibility to PCOS. We evaluated the genotypes of 117 women with PCOS and 380 healthy fertile controls and measured the index of insulin resistance and hormonal profiles in the PCOS women. The RETN-420G/G homozygous variant genotype occurred significantly more frequently among the PCOS group than among the control group (15.4% vs. 8.4%, p = 0.035). PCOS women with the RETN-420G/G genotype also showed significantly higher BMIs and greater insulin resistance than those with RETN-420 C/C or C/G genotypes. The ADIPOQ SNP at -11377 showed no association with PCOS. We conclude that the RETN G/G at -420 genotype is associated with PCOS in Japanese women.

Spontaneous ovarian hyperstimulation syndrome and pituitary adenoma: incidental pregnancy triggers a catastrophic event.

OBJECTIVE: To report a rare case of spontaneous ovarian hyperstimulation syndrome (OHSS) associated with spontaneous pregnancy and a FSH-secreting pituitary adenoma. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 32-year-old woman with spontaneous OHSS. INTERVENTION(S): Transsphenoidal resection of the tumor. MAIN OUTCOME MEASURE(S): Regression of the symptoms of OHSS and hyperestrogenemia. RESULT(S): At presentation, the patient's ovaries were markedly enlarged and massive ascites was seen. Her serum E(2) level was markedly elevated, but her LH level was low, and FSH was within the normal range. In addition, her TSH level was normal, and hCG was appropriate for the date of pregnancy. Subsequently, the patient developed massive thrombophlebitis in her right internal jugular and subclavian veins. Termination of the pregnancy ameliorated the accumulation of ascites, but ovarian enlargement and hyperestrogenemia persisted. No mutations of the FSH receptor, LH receptor, or aromatase genes were detected, but magnetic resonance imaging (MRI) of the head revealed a pituitary adenoma. After transsphenoidal resection of the tumor, the patient got better. CONCLUSION(S): A gonadotropin-secreting adenoma caused ovarian hyperstimulation (ovarian enlargement and hyperestrogenemia). In addition, spontaneous pregnancy and intrinsic hCG increased vascular permeability, which complicated the patient's disease.

Association between polycystic ovary syndrome and female-to-male transsexuality.

BACKGROUND: The aim of this study is to understand the relationship between polycystic ovary syndrome (PCOS), altered hormonal characteristics and insulin resistance in female-to-male (FTM) transsexual patients. METHODS: We studied 69 Japanese FTM cases, aged 17-47 years, who were seen in the Gender Identity Disorder Clinic of Sapporo Medical University Hospital between December 2003 and May 2006. The subjects had never received hormonal treatment or sex re-assignment surgery. Prior to treatment, they received physical examinations entailing measurement of anthropometric, metabolic and endocrine parameters, after which we compared the values obtained according to the presence or absence of PCOS and/or obesity. Insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Of the 69 participating FTM cases, 40 (58.0%) were found to have PCOS. Of the 49 for whom HOMA-IR was calculated, 15 (30.6%) also showed insulin resistance, whereas of the 59 for whom adiponectin was measured, 18 (30.5%) showed hypoadiponectinaemia. Of 69 for whom androgens were measured, 29 (39.1%) showed hyperandrogenaemia. Insulin resistance was associated with obesity but not with PCOS. In contrast, hyperandrogenaemia was associated with both PCOS and obesity. CONCLUSION: FTM transsexual patients have a high prevalence of PCOS and hyperandrogenaemia.

Significance of matrix metalloproteinases in the pathophysiology of the ovary and uterus.

Matrix metalloproteinases (MMP) are capable of degrading a variety of extracellular matrix (ECM) proteins and are also involved in the processing of a number of bioactive molecules. Our findings indicate that the functions of MMP in the ovary and uterus are organ-specific and time-dependently vary during the reproductive cycle. Prolactin induces structural luteolysis indicated by loss of luteal weight, protein and DNA within 36 h after pretreatment with ergot alkaloid. MMP activation appears crucial for the selective depletion of protein during luteal involution, which entails loss of ECM accompanied by apoptosis. During GnRHagonist-induced luteolysis, this response was also associated with marked increases in MMP-2, which degraded collagen type IV, and MT1-MMP, which in addition to activating MMP-2 also degrades collagen type I, III and V. We also found that the level of MT1-MMP and MMP-2 expression in the human CL is greater during the late luteal phase than during either the early mid luteal phases or during gestation, respectively. That dehydroepiandrosterone (DHEA) treatment caused the formation of cysts from antral follicles in the ovaries of immature rats while depressing MMP-2 collagenolytic activity and enhancing lysyl oxidase expression highlights the importance of collagen degradation in the process of ovulation and suggests that changes in the activities of these enzymes play a key role in ovarian cystogenesis in polycystic ovary syndrome patients. Furthermore, immunohistochemical analyses showed that MT1-MMP and FasL co-localize with TdT-mediated dUTP-biotin nick end-labeling (TUNEL)-positive apoptotic granulosa cells in rats treated with DHEA, that the Fas/FasL/Caspase-8 (death receptor-dependent) pathway is pivotal for follicular atresia and that increased levels of MT1-MMP likely play an important role in tissue remodeling during follicular atresia. After parturition, the uterus undergoes involution, a conspicuous feature characterized by a rapid reduction in the collagen content mediated by degradation of extracellular collagen bundles. Our findings strongly suggest that MT1-MMP, MMP-2 and MMP-9 are each time-dependently regulated and play important roles in tissue remodeling during postpartum uterine involution. (Reprod Med Biol 2006; 5: 235-243).