Reproduction最新文献

The Hippo signaling pathway, so named for its massive overgrowth mutant phenotypes, has become one of the most exciting signaling pathways to emerge in the field of reproductive biology. While disruption of Hippo is associated with tumorigenesis in many organs and tissues, relatively less is understood about the normal roles of Hippo signaling in the reproductive organs. Here, we highlight the recent literature illuminating the roles of Hippo pathway members in mouse and human reproduction. We place special emphasis on the inputs and outputs of Hippo signaling during preimplantation development, where Hippo signaling has been extensively studied in both mouse and human. We note a common emerging theme is the critical and highly conserved role of Hippo signaling in epithelia of the reproductive organs. We also discuss human reproductive disorders, whose etiology may be related to dysregulation of Hippo signaling, and possible therapies that have been proposed to correct this dysregulation. Finally, we describe the edge of our knowledge, which currently limits our understanding of Hippo signaling in reproductive health and disease.

In brief: The adrenal glands are an additional source of hyperandrogenemia in a significant proportion of women with polycystic ovary syndrome (PCOS). This review presents the evidence for the role of adrenal hyperandrogenism in the development and clinical manifestations of the syndrome across the lifetime.

Abstract: Functional adrenal hyperandrogenism is a common feature of PCOS, observed in roughly 20-30% of affected women. The mechanisms of adrenal hyperandrogenism in PCOS require additional clarification but seem to be related to increased adrenal sensitivity to ACTH at the level of the adrenal gland. Studies in animal models and in girls at risk for PCOS suggest a potential role for early adrenal androgen exposure in the development of PCOS during reproductive maturity. Importantly, adrenal androgens may be elevated in at-risk girls from childhood through menopause, suggesting these androgens are clinically relevant over the lifetime. The presence or absence of adrenal hyperandrogenism is just one of a number of clinical phenotypes, which vary among women with PCOS. Recent exciting work has focused on defining distinct subtypes of PCOS based on these distinct phenotypes. This will be an important first step toward the development of more individualized treatment approaches in affected women.

In brief: During uterine receptivity, exocytosis from uterine epithelial cells (UECs) contributes to uterine fluid composition, playing a role in communication with an implanting blastocyst. SNAREs, a family of proteins involved in exocytosis, are increased in the receptive uterine epithelium of the rat.

Abstract: Uterine luminal fluid is composed of secretions from the uterine luminal and glandular epithelial cells. The fluid composition plays a role in cell-to-cell communication between the receptive endometrium and an invading blastocyst. Part of this fluid is released from the epithelial cells via exocytosis, mechanisms regulating this are not yet understood. Using transmission electron microscopy, this study identified extracellular vesicles in the uterine lumen at the time of fertilisation and uterine receptivity. Immunofluorescence microscopy showed SNARE proteins syntaxin 2 and SNAP23 in the apical area of UECs at the time of receptivity. SNAP23 was also found in the uterine fluid on day 5.5 of early pregnancy. Western blotting of isolated UECs demonstrated a significant increase in syntaxin 2 and SNAP23 at the time of uterine receptivity compared to the time of fertilisation. The morphological evidence of extracellular vesicles in the uterine lumen and the presence of SNARE proteins syntaxin 2 and SNAP23 in the apical part of the luminal epithelium at the time of uterine receptivity suggests that exocytosis contributes to the composition of the uterine luminal fluid, a potential component of maternal-foetal communication during early pregnancy.

In brief: Ethnic disparities in hypertensive disorders of pregnancy (HDP) are well-described but poorly understood, with complex interplays between biological, environmental, socio-cultural and healthcare factors potentially contributing. This article provides a contemporary review of this topic and makes recommendations for research and clinical care to improve outcomes for minoritised women.

Abstract: HDP affect approximately one in ten pregnancies and are associated with increased risk of adverse maternal and perinatal outcomes. Despite advances in prevention of pre-eclampsia and improved management of blood pressure in pregnancy, stark disparities in HDP incidence and outcomes persist across maternal ethnic groups. This article provides a contemporaneous review of the epidemiology of ethnic disparities in HDP, potential contributors to ethnic disparities, and how maternal ethnicity is currently conceptualised and utilised as a risk factor in clinical practice. We present the challenges of utilising ethnicity as a risk factor and suggest actions needed to tackle ethnic disparities in pregnancy hypertension. Women of Black ethnic backgrounds consistently experience a higher risk of pre-eclampsia, HDP and associated adverse outcomes compared to women of other ethnicities across diverse healthcare settings. While traditional cardiovascular risk factors and socioeconomic status contribute to these disparities, they do not fully explain the observed differences. Understanding these disparities requires research examining complex interactions across biological, behavioural, environmental, socio-cultural, and healthcare system factors. Ensuring appropriate diversity in HDP research is crucial for equitable application of incoming genomic and personalised medicine advances. While the fundamental drivers of ethnic disparities in HDP remain to be fully understood, healthcare systems should prioritise optimising blood pressure control during pregnancy and postpartum for women from minoritised ethnic backgrounds. Ensuring minoritised women with lived experience are equal partners in designing and implementing research and initiatives to address these disparities will be critical to their success.

In brief: Superovulation is widely used in reproductive technologies, but its impact on ovarian vascular development and oocyte quality remains poorly understood. This study provides the first 3D quantitative analysis of perifollicular vasculature in superovulated mice, revealing dose-dependent vascular changes and offering a novel imaging approach for reproductive research.

Abstract: Superovulation is widely used to maximise oocyte/embryo yield in animal models. However, it has been implicated in disrupting normal follicular development, potentially affecting perifollicular angiogenesis. This study investigated the impact of superovulation on ovarian perifollicular neoangiogenesis using light sheet fluorescence microscopy (LSFM), and by quantitatively profiling the three-dimensional (3D) perifollicular capillary bed in murine antral follicles. Dioestrus CD1 mice received 2.5, 5.0 or 7.5 IU pregnant mare serum gonadotrophin (PMSG) intraperitoneally, and ovaries were collected 24 and 48 h later, with those from normal cycling females (dioestrus, proestrus or oestrus) as controls. Ovaries were fixed and labelled with fluorescently tagged wheat germ agglutinin lectin and anti-CD34 to visualise the oocyte zona pellucida and thecal vasculature, respectively. Optically cleared samples were imaged using LSFM, and 3D volume rendering, vessel segmentation and image analysis were performed using Arivis Vision 4D and Fiji. Quantitative metrics including vessel volume, length, branching, density, spatial arrangement and oocyte characteristics were profiled. Statistical analysis was based on Kruskal-Wallis tests. PMSG-induced superovulation showed dose-dependent effects on perifollicular vasculature, causing premature (24 h) neoangiogenesis at 7.5 IU (increase in total vessel volume, length and number of branches, and decrease in average branch length; P < 0.05 for all), and reduced final (48 h) vessel density at 2.5 IU compared to naturally cycling animals (P < 0.05). The early angiogenesis observed at 7.5 IU may reflect a compensatory mechanism, while the reduced density at 2.5 IU suggests an insufficient angiogenic response. By contrast, intrafollicular metrics were largely unaffected. This study provides the first comprehensive quantitative 3D analysis of thecal vasculature and oocytes in murine ovaries, and highlights its potential applications in other areas of reproductive biology.

In brief: Phosphate plays a critical role in conceptus development, yet the mechanisms regulating utero-placental availability remain underinvestigated. This research characterized the spatiotemporal expression and endocrine regulation of XPR1, a phosphate exporter, in ovine utero-placental tissues, suggesting a potential role of XPR1 in the regulation of utero-placental phosphate availability.

Abstract: Phosphate is an essential regulator of conceptus development, but there is limited understanding of mechanisms regulating phosphate availability in utero-placental tissues. These experiments characterized the expression of xenotropic and polytropic retrovirus receptor 1 (XPR1), a phosphate exporter, in ovine utero-placental tissues. In Experiment 1, ewes were hysterectomized on day 1, 9, or 14 of the estrous cycle or day 30, 50, 70, 110, or 125 of pregnancy. Day of the estrous cycle did not affect XPR1 mRNA expression or protein localization. Expression of XPR1 mRNA decreased with day of gestation in placentomes, while XPR1 protein was detectable in uterine epithelia, blood vessels, endometrial stromal cells, myometrium, caruncular stroma, and syncytium of the placentome. In Experiment 2, ewes received daily injections of either corn oil vehicle (CO) or 25 mg progesterone (P4) in vehicle for the first 8 days of pregnancy and were hysterectomized on either day 9, 12, or 125. Endometrial stroma from P4-treated ewes had greater XPR1 immunoreactivity than CO-treated ewes on day 9. On day 125, endometria from P4-treated ewes had decreased expression of XPR1 mRNA compared to CO-treated ewes. Greater XPR1 protein immunoreactivity was present in uterine epithelia and stratum compactum stroma of P4-treated than CO-treated ewes. P4-treated ewes with a singleton fetus tended to have greater expression of XPR1 mRNA in placentomes than CO-treated ewes with a singleton fetus. Collectively, these results suggest a potential role of XPR1 in the regulation of phosphate availability in utero-placental tissues in ruminants.

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. The condition can have an enduring negative effect on women's reproductive health from menarche to menopause, although its impact can vary significantly. PCOS is associated with premature pubarche and a wider age range of menarche. Diagnosis of PCOS in adolescents remains challenging. Oligo/anovulation is the most common feature of PCOS, and leads to subfertility. This may require induction of ovulation with medical therapies, such as oestrogen receptor antagonists, aromatase inhibitors or by giving exogenous follicle-stimulating hormone, which are effective for most women with PCOS. Pregnancy in women with PCOS is associated with a higher risk of complications including gestational diabetes, particularly in those with obesity. Optimisation of pre-conception health, including weight management, is recommended in order to maximise fertility potential and improve pregnancy outcomes. The other key feature of PCOS is hyperandrogenism, which may contribute to ovulatory dysfunction and results in hirsutism and persistent acne, and also negatively impacts mental health, quality of life and psychosexual function. Women with PCOS may also have a later age of menopause, although longitudinal studies are lacking. This narrative review explores the impact of PCOS on women's reproductive health throughout their reproductive lifespan.

In brief: Induction of DNA double-strand breaks results in oocyte death caused by the activation of TAp63α. This study investigates which chemotherapeutic drugs activate p63 and which cause oocyte death without p63 activation.

Abstract: Primary ovarian insufficiency is a severe side effect of classical chemotherapy and radiotherapy in treatment of female cancer patients of reproductive age. The p53-homolog TAp63α emerged as the key protein regulating apoptosis following DNA damage in oocytes of primordial follicles. In this study, we monitored the toxicity of widely used chemotherapeutic agents on oocytes of primordial follicles utilizing a GFP-c-kit transgenic mouse model, the involvement of active TAp63α and the mechanism of action leading to its activation. Our studies show that alkylating agents and topoisomerase II poisons are potent activators of TAp63α by directly inducing DNA damage. Oxidative stress and DNA intercalation were not sufficient to trigger TAp63α activation despite showing a strong general toxicity. These results are in agreement with several previous investigations that have demonstrated that DNA double-strand breaks are the most effective way to initiate apoptosis in oocytes of primordial follicles. The widely used catalytic topoisomerase II inhibitor ICRF-187 was able to prevent activation of TAp63α by the topoisomerase II poison doxorubicin but did not prevent oocyte death, suggesting an alternative mechanism of cell death induction.

In brief: Emerging viral infections pose a significant risk to pregnant women and their offspring. This review summarizes what is known about maternal and fetal outcomes following infection with emerging viruses and discusses how we can prepare for the next outbreak.

Abstract: Viral infections during pregnancy pose significant risks to both maternal and fetal health. While several viruses are well known to cause adverse pregnancy outcomes, often little is known about emerging viruses. This review summarizes the known maternal and fetal consequences of infection during pregnancy with novel and re-emerging viruses. Focus is placed on viruses such as Zika and SARS-CoV-2, among others, discussing the mechanisms by which these viruses may disrupt fetal development at the maternal-fetal interface. The review also addresses the challenges that need to be overcome, such as the need for ongoing disease surveillance, prioritization of pregnant women for clinical trials and the importance of pre-clinical models of placenta infection, to adequately prepare for the next virus outbreak.

In brief: NAD+ levels were reduced in streptozotocin (STZ)-induced diabetic mice, but nicotinamide riboside (NR) supplementation improved these levels in diabetic ovaries and oocytes, enhancing oocyte quality and early embryo development by improving mitochondrial function and lowering reactive oxygen species (ROS) levels.

Abstract: Diabetes mellitus is strongly correlated with a decline in oocyte quality; however, noninvasive and effective methods to improve this issue have yet to be fully development. Here, we demonstrate that in vivo supplementation with NR 400 mg/kg/day for 14 days effectively enhances the quality of oocytes from diabetic mice induced by streptozocin 190 mg/kg by restoring nicotinamide adenine dinucleotide (NAD+) levels. NR supplementation not only improved superovulation function of diabetic mice but also improved their oocyte quality and embryonic development potential after fertilization by maintaining normal spindle structure and alleviating mitochondrial dysfunction. In addition, NR supplementation reduced ROS levels in oocytes from diabetic mice. Overall, our findings suggest that dietary NR supplementation is a viable strategy to protect oocytes from diabetes-related deterioration, thereby enhancing reproductive outcomes in maternal diabetes and improving the efficacy of assisted reproductive technology.