Ovarian follicle steroidogenesis associated with embryo quality results in a successful pregnancy. Each follicle consists of an oocyte surrounded by granulosa cells, which secrete several steroid and peptide hormones. Follicles harvested from women who conceived after assisted reproductive therapy (ART) had significantly higher estradiol levels in follicular fluids than the follicles from women who failed to conceive after ART. The higher follicular estradiol levels correlate well with successful fertilization following ART. Mitochondria are the central sites for steroid hormone biosynthesis. The first and rate-limiting step in the biosynthesis of steroid hormones occurs in the mitochondria of granulosa cells. In the present study, we hypothesized that the mitochondria in granulosa cells are critical for maintaining oocyte quality and fertility capacity. This study aims to clarify the relationship between mitochondrial function and granulosa cell steroidogenesis, and the relationship between hormone levels and fertility capacity. Sera, follicular fluids and granulosa cells were obtained from individuals undergoing IVF-ET treatment. The oocyte numbers, oocyte quality, fertilization rate, and pregnancy rate were also recorded. The patients who provided the granulosa cells were further classified into four groups: endometriosis, ovarian endometrioma, endometriosis without ovarian endometrioma, and polycystic ovary syndrome (PCOS); patients with other female factor infertility and male factor infertility were used as controls. We measured the levels of estradiol (E2) by radioimmunoassay. Concurrently, we analyzed the mitochondrial mass and membrane potential, and apoptosis by flow cytometry using nonyl acridine orange, TMRE, Annexin V-FITC and PI. Mitochondrial morphology was visualized by transfection with pLV-mitoDsRed. In addition, we assessed the protein levels of steroidogenic enzymes, steroidogenic acute regulatory protein (StAR) and 3β-hydroxysteroid dehydrogenase (3β-HSD) by Western blot. The results showed significantly decreased serum E2 and follicular E2 levels, and decreased IVF outcomes, in the patients with endometriosis. Reduced mitochondrial mass and decreased mitochondrial membrane potential were correlated with lower E2. Furthermore, a significant decrease in StAR and 3β-HSD was found in patients with ovarian endometrioma. The enzyme levels of StAR and 3β-HSD were highly correlated with E2 levels. Finally, elevated cumulus cell apoptosis was found in the patient group with ovarian endometrioma and PCOS. In conclusion, mitochondrial dysfunction of human granulosa cells may contribute to the decline of steroidogenesis, decreased fertilization rate, oocyte maturation rate, and oocyte quality, and it can ultimately jeopardize fertility.

Endometriosis is an estrogen-dependent inflammatory disease that affects up to 10% of women of reproductive age and accounts for up to 50% of female infertility cases. It has been highly associated with poorer outcomes of assisted reproductive technology (ART), including decreased oocyte retrieval, lower implantation, and pregnancy rates. A better understanding of the pathogenesis of endometriosis-associated infertility is crucial for improving infertility treatment outcomes. Current theories regarding how endometriosis reduces fertility include anatomical distortion, ovulatory dysfunction, and niche inflammation-associated peritoneal or implantation defects. This review will survey the latest evidence on the role of inflammatory niche in the peritoneal cavity, ovaries, and uterus of endometriosis patients. Nonhormone treatment strategies that target these inflammation processes are also included. Furthermore, mesenchymal stem cell-based therapies are highlighted for potential endometriosis treatment because of their immunomodulatory effects and tropism toward inflamed lesion foci. Potential applications of stem cell therapy in treatment of endometriosis-associated infertility in particular for safety and efficacy are discussed.

Background: While screening on thyroid peroxidase antibody (TPO-Ab) has been recommended in women with primary ovarian insufficiency, the relationship between thyroid autoimmunity (TAI) and ovarian reserve remains undetermined. Because the TAI prevalence was reported to be different between races, we aimed to investigate the TAI prevalence in Chinese women with different ovarian reserve. Methods: This is a cross-sectional study conducted in a university infertility clinic between October 2013 and March 2016. Among patients at their first entry to the infertility clinic, a total of 1044 patients with available results of anti-Müllerian hormone (AMH), thyroid-stimulating hormone (TSH), TPO-Ab, and thyroglobulin antibody (TG-Ab) were enrolled. The TSH levels and the prevalence of positive TPO-Ab and positive TG-Ab were compared between patients with low, normal, and high ovarian reserve categorized with age-specific AMH levels. Results: For the whole study population, the TSH levels, TPO-Ab positivity and TG-Ab positivity were comparable between patients with different ovarian reserve. However, after patients with known causes compromising ovarian reserve (iatrogenic or genetic) were excluded, only TPO-Ab positivity became significantly different between patients with low (22.7%), normal (14.0%), and high ovarian reserve (10.3%), P=0.012. The TPO-Ab levels were not significantly correlated to AMH levels (Spearman’s rho= -0.027, P=0.413). For the infertile subgroup, TPO-Ab positivity was significantly associated with idiopathic low ovarian reserve in unexplained infertility (low ovarian reserve: 28.6%, normal: 15.7%, and high: 9.5%, P=0.020). Conclusions: Idiopathic low ovarian reserve was associated with more frequent positive TPO-Ab rather than thyroid function or TG-Ab positivity in Chinese women.

Objective: To investigate changes in utero‐ovarian blood flow during the peri‐implantation period and their significance in successful embryo implantation.Methods: A prospective longitudinal study was conducted in 317 women undergoing in‐vitro fertilization–embryo transfer (IVF–ET) treatment. All of them had at least one good‐quality embryo for transfer on the second or third day after oocyte retrieval. Measurement of endometrial thickness and color flow imaging with pulsed waveform analysis of uterine and ovarian arteries were performed before ET and 5–6 days after ET.Results: There were no significant differences in the age of patients, duration of infertility or number of embryos transferred between women who became pregnant (n = 91) and those who did not (n = 226). There was no difference in mean endometrial thickness between the two groups before ET, while a thicker endometrium was found in women who had conceived compared with those who had not 5–6 days after ET (P = 0.02). Mean uterine arterial resistance index (RI) and pulsatility index (PI) values were significantly lower in the pregnant than in the non‐pregnant group before ET (P = 0.04 and P = 0.003, respectively), but no significant differences were found between the two groups 5–6 days after ET. In contrast, the mean ovarian arterial RI and PI values were similar between the two groups before ET, yet the pregnant group showed significantly lower RI and PI values compared with the non‐pregnant group 5–6 days after ET (P = 0.002 and P = 0.01, respectively). A significantly higher peak systolic velocity (PSV) of intraovarian vessels was also noted in the pregnant group 5–6 days after ET.Conclusion: Different utero‐ovarian blood flow changes during the peri‐implantation period occur in conception and non‐conception cycles in women following IVF. Doppler assessment of uterine arterial resistance can help to determine a time interval within the menstrual cycle that is of optimal endometrial status for embryo implantation in assisted conception programs. Delay in achieving adequate uterine perfusion during the temporal window of embryo implantation may have an impact on endometrial receptivity. Copyright © 2004 ISUOG. Published by John Wiley & Sons, Ltd.

Introduction: Estrogen is involved in several physiological and pathological processes through estrogen receptor (ER)-mediated transcriptional gene regulation. miRNAs (miRs), which are noncoding RNA genes, may respond to estrogen and serve as posttranscriptional regulators in tumorigenic progression, especially in breast cancer; however, only limited information about this possibility is available. In the present study, we identified the estrogen-regulated miR-34b and investigated its functional role in breast cancer progression. Methods: Estrogen-regulated miRNAs were identified by using a TaqMan low density array. Our in vivo Tet-On system orthotopic model revealed the tumor-suppressive ability of miR-34b. Luciferase reporter assays and chromatin immunoprecipitation assay demonstrated miR-34b were regulated by p53-ER interaction. Results: In this study, we identified one such estrogen downregulated miRNA, miR-34b, as an oncosuppressor that targets cyclin D1 and Jagged-1 (JAG1) in an ER+/wild-type p53 breast cancer cell line (MCF-7), as well as in ovarian and endometrial cells, but not in ER-negative or mutant p53 breast cancer cell lines (T47D, MBA-MB-361 and MDA-MB-435). There is a negative association between ERα and miR-34b expression levels in ER+ breast cancer patients. Tet-On induction of miR-34b can cause inhibition of tumor growth and cell proliferation. Also, the overexpression of miR-34b inhibited ER+ breast tumor growth in an orthotopic mammary fat pad xenograft mouse model. Further validation indicated that estrogen's inhibition of miR-34b expression was mediated by interactions between ERα and p53, not by DNA methylation regulation. The xenoestrogens diethylstilbestrol and zeranol also showed similar estrogenic effects by inhibiting miR-34b expression and by restoring the protein levels of the miR-34b targets cyclin D1 and JAG1 in MCF-7 cells. Conclusions: These findings reveal that miR-34b is an oncosuppressor miRNA requiring both ER+ and wild-type p53 phenotypes in breast cancer cells. These results improve our ability to develop new therapeutic strategies to target the complex estrogenic pathway in human breast cancer progression through miRNA regulation.

BACKGROUND: The occurrence of fluid accumulation within the uterine cavity was examined in women undergoing IVF to investigate its correlation with tubal disease and impact on the pregnancy outcome. METHODS: A registry of ultrasound procedures spanning 5 years was retrospectively studied. RESULTS: Thirty five out of 746 (4.7%) IVF cycles were identified as having uterine fluid accumulation, and 15 (2.0%) persisted until the day of embryo transfer. Two of the 20 cycles of women with transient fluid accumulation were pregnant, and none of those with fluid retention on the day of embryo transfer conceived. The pregnancy rate was only 5.7% (2/35) in women with uterine fluid accumulation detected during IVF cycles. In contrast, the pregnancy rate was 27.1% (193/711) among women in whose cycles no fluid accumulation was detected (P = 0.0048). Uterine fluid accumulation during IVF cycles was found in 8% (18/225) of women documented with tubal factor compared with 3.3% (17/521) with non-tubal factor (P = 0.005). CONCLUSIONS: Fluid accumulation within the uterine cavity during the IVF transfer treatment could be observed in patients with both tubal and non-tubal factors; however, it mainly occurred in women with tubal infertility. Although it is not a common complication of IVF cycles, excessive uterine fluid is detrimental to embryo implantation.