Biology of Reproduction最新文献

Ovulation failure accounts for over 25% of infertility cases in reproductive-age women in the U.S., with obese women three times more likely to experience anovulatory infertility. The mechanisms by which obesity impairs ovulation remain unclear. The preovulatory luteinizing hormone (LH) surge induces changes in ovarian vasculature crucial for ovulation. We hypothesized that obesity disrupts ovarian vascular function, contributing to impaired ovulation. Using Doppler ultrasonography, we assessed ovarian hemodynamics in adult normal-weight mice and two obese groups: high-fat diet (HFD) and Agouti viable Yellow (AvY) mice. Both obese groups had reduced ovulation rates following superovulation. In normal-weight mice, flow velocity in the ovarian vessels increases within the first hour following ovulation induction by human chorionic gonadotropin, whereas this increase was absent in obese mice. This change in velocity correlated with ovulation rates, suggesting its importance for ovulation success. Ovarian hemodynamics were disturbed in naturally cycling obese mice compared to normal-weight controls during diestrus. Immediately before ovulation induction, ovarian vasculature analysis through lectin labeling revealed an increased abundance of capillaries in HFD ovaries compared to AvY; transcriptomic analysis of granulosa cells and ovarian stroma identified differentially expressed genes involved in vascular development, extracellular matrix organization, and inflammation, all crucial for vascular function and ovulation. This study characterizes for the first time in vivo ovarian hemodynamics in normal-weight adult mice, and demonstrates disrupted ovarian hemodynamics in obese mice during the preovulatory and luteal phases. These findings pinpoint that improving ovarian vascular function could be a therapeutic target for enhancing ovulation in obese women.

Hormonal contraceptives modulate the hypothalamic-pituitary-ovarian (HPO) axis; however, underlying mechanisms and differences between contraceptives are underexplored. The Women's Health Injectable Contraception and HIV trial randomised 521 women to intramuscular depot medroxyprogesterone acetate (DMPA-IM) or norethisterone enanthate (NET-EN) and showed similar decreased estradiol levels, but more amenorrhea for DMPA-IM users. This secondary study excluded for misreporting contraceptive use for 128 participants (DMPA-IM n = 65; NET-EN n = 63). Peripheral blood serum collected at initiation and one week after the 24-week injection (25W), at peak progestin levels, was analysed for gonadal steroids, progestins and peptide hormones. While no changes were detected in peripheral gonadotropin-releasing hormone levels, DMPA-IM decreased luteinising hormone (LH) less than NET-EN. DMPA-IM increased, while NET-EN decreased follicle-stimulating hormone (FSH). Both contraceptives substantially decreased gonadal steroid levels, more so in NET-EN users for testosterone and estradiol. Post-menopausal-like hypoestrogenic effects were greater than previously reported, consistent with the substantial reduction in LH levels. Whether reduced LH levels are due to direct pituitary, hypothalamic, or supra-hypothalamic effects by progestins, is unclear. MPA, unlike NET, increased fsh expression in LβT2 cells, likely via the glucocorticoid receptor, consistent with direct effects on the pituitary by MPA in women. Amenorrhea associated in a time-varying manner with MPA and HPO hormone levels and LH/FSH, for DMPA-IM but not NET-EN users. HPO hormone profiles differ between DMPA-IM and NET-EN users and compared to pre- and post-menopausal women. Mechanisms affecting amenorrhea likely differ between contraceptives, with lower 25W LH/FSH being consistent with more amenorrhea for DMPA-IM.

Ovarian aging reduces oocyte quality and is a major limiting factor in assisted reproductive technologies (ART) such as IVF and ICSI. This review highlights the role of follicular fluid (FF) as a mirror of the oocyte microenvironment and summarizes molecular alterations linked to aging and ovarian dysfunction. We focus on metabolites, proteins, microRNAs, and exosomes within FF that influence oocyte quality and reproductive outcomes, aiming to identify novel clinical biomarkers. Follicular fluid contains diverse biomolecules-including hormones, growth factors, cytokines, oxidative stress markers, and exosomes-that shape oocyte maturation, fertilization capacity, and embryonic competence. Recent multi-omics studies suggest that metabolic and redox-related molecules, amino acid and lipid profiles, and exosomal microRNAs are associated with ART outcomes. Mitochondrial DNA (mtDNA) and cell-free mtDNA (cf-mtDNA) also emerge as promising indicators of mitochondrial function and oocyte developmental potential. However, variations in patient background, sample handling, and analytical methods limit reproducibility. Overall, FF provides a valuable, minimally invasive source for assessing the oocyte environment and understanding ovarian aging. Future studies should integrate metabolomic, proteomic, transcriptomic, and exosomal data through multi-omics and functional analyses to establish reliable clinical biomarkers. Such advances may enable precise assessment of oocyte quality, prediction of ART success, and early diagnosis of ovarian aging.

Male infertility is a significant concern in both human medicine and livestock. As it is mainly impacted by sperm quality, understanding the intrinsic characteristics of sperm that contribute to infertility is crucial. Male fertility relies on the sperm's ability to reach the site of fertilization, fertilize the oocyte, and support early embryonic development. Thus, classical sperm parameters such as motility, morphology, and the integrity of the plasma membrane, acrosome, and DNA are critical indicators of sperm quality. Recently, molecular sperm features have also been recognized as key components of sperm quality. Although sperm are transcriptionally inert and rely on external factors to shape their molecular cargo, "sperm-borne" RNAs and proteins impact embryo development. Sperm-borne molecules are acquired as sperm transit through the male and, potentially, female reproductive tracts, where they interact with components, including extracellular vesicles (EVs) from fluids within both systems. EVs play a key role in intercellular communication and carry regulatory molecules, such as proteins and miRNAs, that modulate sperm function. These interactions are vital for spermatogenesis, maturation, capacitation, and influence the sperm-borne molecular cargo. Since sperm remain interacting with the female tract, it is evident that sperm's fertility potential is also outlined in the post-ejaculatory environment. This review provides an overview of these interactions, particularly within the female reproductive system where EVs participate in sperm-borne modulation, sperm capacitation and might also be involved in sperm selection. Herein, we provide insights for further research into the mechanisms involved and their effects on sperm fertilizing potential across mammalian species.

Maternal-effect genes (MEGs) play a crucial role in early mammalian development, and their dysfunction can lead to severe embryonic and extra-embryonic abnormalities. NLRP2, a MEG that encodes a subcortical maternal complex (SCMC) protein, has been implicated in preimplantation development, but its role after implantation remains underexplored. In this study, we investigated the developmental consequences of maternal Nlrp2 loss-of-function in a maternal knockout (KO) mouse model at embryonic day 11.5. Embryos derived from Nlrp2-KO females have abnormal yolk sac vasculature, increased embryonic resorption, craniofacial abnormalities, neural tube defects, and congenital heart defects. Placental architecture is disrupted with an altered junctional zone and labyrinth structure. Transcriptome profiling of maternal decidua and placenta demonstrated dysregulation of genes involved in trophoblast differentiation and extra-embryonic development. Bisulfite sequencing of these tissues revealed persistence at E11.5 of previously observed locus-specific disruption in DNA methylation at four imprinted loci following maternal Nlrp2 loss. We further describe pregnancy outcomes and offspring phenotypes for two unrelated women with bi-allelic maternal NLRP2 variants. The first carried homozygous NLRP2 nonsense variants and experienced recurrent pregnancy loss and fetuses with multiple structural anomalies, including omphalocele, craniofacial dysmorphism, and cardiac defects. The second carried compound heterozygous frameshift and missense NLRP2 variants and had a child with neurodevelopmental impairment of uncertain etiology. These findings indicate a conserved role for maternal NLRP2 in embryonic viability and placental development, and support further studies in humans into the contribution of NLRP2 and other similar MEGs to offspring congenital anomalies and adverse pregnancy outcomes.

Embryonic implantation is a crucial developmental phase characterised by intricate molecular crosstalk between the embryo and endometrium, with emerging evidence implicating circular RNAs (circRNAs) as important regulators. This study elucidated the role of hsa_circ_0001550 in impairing embryo adhesion and evaluated recombinant human granulocyte colony-stimulating factor (rhG-CSF) as a therapeutic strategy. Overexpression of hsa_circ_0001550 in an in vitro adhesion model using Ishikawa cells reduced the adhesion capacity of BeWo or JAR spheroids and diminished the murine blastocyst implantation rate. Knocking down hsa_circ_0001550 increased the adhesive ability of BeWo spheroids. Crucially, administration of rhG-CSF downregulated hsa_circ_0001550 expression and upregulated homeobox A10 (HOXA10) and leukaemia inhibitory factor (LIF), thereby restoring the adhesive capacity. In an endometrial injury model, administration of rhG-CSF enhanced epithelial proliferation (as measured by Ki67), suppressed apoptosis (based on the TUNEL assay), and activated mesenchymal-to-epithelial transition pathways, ultimately improving the embryo implantation rate. Collectively, this study reveals that recombinant human granulocyte colony-stimulating factor (rhG-CSF) improves implantation partly by downregulating hsa_circ_0001550. These findings provide new perspectives for understanding implantation mechanisms and developing therapeutic strategies.

Obstructive sleep apnea (OSA), common in pregnancy, is linked to preeclampsia and long-term maternal hypertension, but the underlying mechanisms remain unclear. We hypothesized that intermittent hypoxia (IH), a core feature of OSA, primes the maternal vasculature for heightened responses to hypertensive stressors postpartum. Pregnant Sprague-Dawley rats were exposed to either room air or gestational IH from gestational days 10-21. Two months after delivery, all dams were subjected to a high-salt challenge (2% NaCl in drinking water). Blood pressure and heart rate were measured during gestation and before and following salt loading. Vascular function and protein expression were analyzed in mesenteric arteries at study completion. A parallel group of nonpregnant rats underwent identical IH and salt exposure to delineate pregnancy-specific effects. IH exposure in pregnancy led to gestational hypertension that resolved postpartum, whereas nonpregnant rats showed no blood pressure changes. However, following high-salt challenge, postpartum IH-exposed dams displayed significantly greater increases in blood pressure and heart rate, abnormalities not seen in nonpregnant counterparts. Ex vivo, arteries from IH-exposed dams showed enhanced vasocontraction to phenylephrine and impaired vasodilation to both acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent). Molecular analysis revealed increased endothelial nitric oxide synthase activation and decreased protein kinase G (PKG) in the IH group, with no change in α1-adrenergic receptor expression, indicating disrupted vascular smooth muscle signaling. Virgin rats showed no such alterations. Gestational IH induces a pregnancy-specific predisposition to postpartum salt-sensitive hypertension and vascular dysfunction, driven by disrupted PKG signaling. Early OSA detection and intervention in pregnancy may reduce cardiovascular risk.

Follicle-stimulating hormone (FSH) and its receptor (FSHR) constitute one of the cores signaling axes that regulate the reproductive process of mammals. Studies have shown that the glycosylation pattern of FSH and the polymorphism of receptor genes can affect the ligand-receptor binding efficiency and downstream signal intensity, and are related to the susceptibility and phenotype of diseases such as polycystic ovary syndrome (PCOS) and primary ovarian insufficiency (POI). FSH/FSHR not only regulates normal reproductive function by activating multiple pathways such as cAMP/PKA, PI3K/Akt, β-arrestin, and MEK/ERK, but also promotes the progression of malignant tumors such as ovarian cancer (OC) and prostate cancer through mechanisms like activation of cancer stem cells, metabolic reprogramming, and angiogenesis. Therefore, targeting the FSH/FSHR axis has become a highly promising therapeutic strategy. This review summarizes the latest research advances of FSH/FSHR axis in reproductive system diseases and tumors, especially the therapeutic value of FSH/FSHR signaling axis.