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In livestock, the amount of glucose needed by the endometrium and embryo increases during early pregnancy. Yet, how glucose concentrations in the endometrium are regulated remains unclear. The bovine uterine epithelium can store glucose as glycogen, and glycogen content decreases in the luteal phase. Our objective was to elucidate the role of progesterone in glycogen breakdown in immortalized bovine uterine epithelial (BUTE) cells. After 48 hours of treatment, progesterone decreased glycogen abundance in BUTE cells (P<0.001) but did not alter glycogen phosphorylase levels. RU486, a nuclear progesterone receptor (nPR) antagonist, did not block progesterone's effect, suggesting that progesterone acted through membrane progesterone receptors (mPRs). RT-PCR confirmed that BUTE cells express all 5 mPRs, and immunohistochemistry showed that the bovine uterine epithelium expresses mPRs in vivo. A mPRα agonist (Org OD 02-0) reduced glycogen abundance in BUTE cells (P<0.001). Progesterone nor Org OD 02-0 affected cAMP concentrations. Progesterone increased phosphorylated AMP-activated protein kinase (pAMPK) levels (P<0.001), indicating that progesterone increases intracellular AMP concentrations. However, AMPK did not mediate the effect of progesterone. AMP allosterically activates glycogen phosphorylase, and D942 (which increases intracellular AMP concentrations) decreased glycogen abundance in BUTE cells. A glycogen phosphorylase inhibitor partially blocked the effect of progesterone (P<0.05). Progesterone and Org OD 02-0 had similar effects in Ishikawa cells (P<0.01), a human cell line that lacks nPRs. In conclusion, progesterone stimulates glycogen breakdown in the uterine epithelium via mPR/AMP signaling. Glucose released from glycogen could support embryonic development or be metabolized by the uterine epithelium.
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Department of Obstetrics and Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou, China
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In brief
Failure to induce mesenchymal–epithelial transition (MET) during stromal cell decidualization can lead to consequences such as impaired fertility in patients with endometriosis. METTL3-mediated m6A modification plays an important role in attenuating MET and defective decidualization of endometrial stromal cells and contributes to the development of reduced endometrial receptivity in endometriosis.
Abstract
Mesenchymal–epithelial transition (MET)-mediated endometrial decidualization is pivotal for achieving endometrial receptivity and successful pregnancy. We observed blockade of MET in the eutopic secretory endometrium of patients with endometriosis, but the underlying mechanism is unknown. In this study, real-time PCR was used to detect PRL and IGFBP1 expression, whereas western blotting was used to detect the expression of MET markers and METTL3. Phalloidin staining was used to identify changes in cell morphology. M6A levels were quantified using a colorimetric method and m6A dot blots, and functional analysis was performed using spheroid adhesion assays. We first found that increased E-cadherin expression was accompanied by decreased vimentin and Slug expression in the eutopic secretory endometrium of individuals with endometriosis. We also detected a significant increase in both the m6A level and the expression of the related methyltransferase METTL3. Finally, METTL3 expression was negatively correlated with PRL, IGFBP1, and MET markers expression. Collectively, our findings suggest that METTL3 mediates m6A modification, thereby inhibiting MET formation within the eutopic secretory endometrium of patients with endometriosis. Increased METTL3-mediated m6A modification plays a crucial role in attenuating MET formation and decidualization impairment in endometrial stromal cells, ultimately contributing to compromised endometrial receptivity in individuals with endometriosis. These insights could lead to the identification of potential therapeutic targets for improving both endometrial receptivity and pregnancy rate among individuals affected by endometriosis.
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LGBTQ+ patients comprise one of the fastest-growing user demographics in fertility care, yet they remain underrepresented in fertility research, practice, and discourse. Existing studies have revealed significant systemic barriers, including cisheteronormativity, discrimination, and gaps in clinical expertise. In this article, we present a checklist of measures clinics can take to improve LGBTQ+ inclusion in fertility care, co-created with members of the LGBTQ+ community.
This checklist focuses on three key areas: cultural competence, clinical considerations, and online presence. The cultural competence criteria encompass inclusive communication practices, a broad understanding of LGBTQ+ healthcare needs, and knowledge of treatment options suitable for LGBTQ+ individuals. Clinical considerations include awareness of alternative examination and gamete collection techniques for transgender and non-binary patients, the existence of specific clinical pathways for LGBTQ+ patients, and sensitivity to the psychological aspects of fertility care unique to this demographic. The online presence criteria evaluate provider websites for the use of inclusive language and the availability of LGBTQ+-relevant information.
The checklist was used as the foundation for an audit of fertility care providers across the UK in early 2024. Our audit identified a widespread lack of LGBTQ+ inclusion, particularly for transgender and non-binary patients, highlighting deficiencies in clinical knowledge and cultural competence. Our work calls attention to the need for further work to understand the barriers to inclusive and competent LGBTQ+ fertility care from both healthcare provider and patient perspectives.
Search for other papers by Laura Woods in
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Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
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Department of Biochemistry and Molecular Biology, Cumming School of Medicine, Hospital Drive NW, University of Calgary, Calgary, Alberta, Canada
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In Brief
Advanced maternal age is associated with a higher rate of pregnancy complications that are unrelated to karyotypic abnormalities of the oocyte. This study shows that the murine uterine stroma undergoes profound epigenetic changes affecting active and repressive histone modification profiles that are associated with impaired endometrial functionality and underpin the decline in reproductive performance of aged females.
Abstract
Decidualization describes the transformation of the uterine stroma in response to an implanting embryo, a process critical for supporting the development of the early embryo, for ensuring normal placentation and ultimately for a healthy reproductive outcome. Maternal age has been found to impede the progression of decidualization, heightening the risk of reproductive problems. Here, we set out to comprehensively characterize this deficit by pursuing transcriptomic and epigenomic profiling approaches specifically in the uterine stromal cell (UtSC) compartment of young and aged female mice. We find that UtSCs from aged females are globally far less responsive to the decidualization stimulus triggered by exposure to the steroid hormones estrogen and progesterone. Despite an overall transcriptional hyperactivation of genes that are differentially expressed as a function of maternal age, the hormonally regulated genes specifically fail to be activated in aged UtSCs. Moreover, even in their unstimulated ‘ground’ state, UtSCs from aged females are epigenetically distinct, as determined by genomic enrichment profiling for the active and repressive histone marks H3K4me3 and H3K9me3, respectively. We find that many hormone-inducible genes exhibit a profound lack of promoter-associated H3K4me3 in aged UtSCs, implying that a significant enrichment of active histone marks prior to gene stimulation is required to enable the elicitation of a rapid transcriptional response. With this combination of criteria, our data highlight specific deficits in epigenetic marking and gene expression of ion channels and vascular markers. These results point to fundamental defects in muscle-related and perivascular niche functions of the uterine stroma with advanced maternal age.
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Condensins are large protein complexes required for chromosome assembly and segregation during mitosis and meiosis. Mouse or bovine embryos lacking SMC2 (a core component of condensins I and II) do not complete development to term, but it is unknown when they arrest their development. Herein, we have assessed the developmental ability of bovine embryos lacking SMC2 due to a naturally occurring mutation termed HH3 (Holstein Haplotype 3) or by CRISPR-mediated gene ablation. To determine if embryos homozygous for HH3 allele survive to maternal recognition of pregnancy, embryonic day (E)14 embryos were flushed from superovulated carrier cows inseminated with a carrier bull. Mendelian inheritance of HH3 allele was observed at E14 conceptuses but conceptuses homozygous for HH3 failed to achieve elongation and lack embryonic disc. To assess the consequence of the ablation of condensins I and II at earlier developmental stages, SMC2 KO bovine embryos were generated in vitro using CRISPR technology. SMC2 KO embryos were able to form blastocysts but exhibited reduced cell proliferation as evidenced by a significantly lower number of total, trophectoderm (CDX2+) and inner cell mass (SOX2+) cells at Day (D) 8 post-fertilization compared to their WT counterparts and were unable to survive to D12 in vitro. SMC2 ablation did not alter relative telomere length at D8, D12 or E14. In conclusions, condensins I and II are required for blastomere mitosis during early development and embryos lacking those complexes arrest their development shortly after blastocyst hatching.
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In brief
This study reveals that orthotopic transplantation of 3D hUC-MSC spheroids is more effective than monolayer-cultured hUC-MSCs in improving POF and distinctly reducing oxidative stress through the paracrine effect, thereby preventing apoptosis and autophagy of GCs.
Abstract
Premature ovarian failure (POF) is a common reproductive disease in women younger than 40 years old, and studies have demonstrated that the application of human umbilical cord mesenchymal stem cells (hUC-MSCs) is a promising therapy strategy for POF. Given the previously established therapeutic advantages of 3D MSC spheroids, and to evaluate their effectiveness, both 3D hUC-MSC spheroids and monolayer-cultured hUC-MSCs were employed to treat a cyclophosphamide-induced POF rat model through orthotopic transplantation. The effects of these two forms on POF were subsequently assessed by examining apoptosis, autophagy, and oxidative damage in ovarian granulosa cells (GCs). The results indicated that hUC-MSC spheroids exhibited superior treatment effects on resisting autophagy, apoptosis, and oxidative damage in GCs compared to monolayer-cultured hUC-MSCs. To further elucidate the impact of hUC-MSC spheroids in vitro, a H2O2-induced KGN cells model was established and co-cultured with both forms of hUC-MSCs. As expected, the hUC-MSC spheroids also exhibited superior effects in resisting apoptosis and autophagy caused by oxidative damage. Therefore, this study demonstrates that 3D hUC-MSC spheroids have potential advantages in POF therapy; however, the detailed mechanisms need to be further investigated. Furthermore, this study will provide a reference for the clinical treatment strategy of POF.
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Hypospadias is a congenital anomaly of the external genitalia where the urethra does not properly close. In humans, hypospadias is mostly reported in male newborns whereas in females hypospadias is rare, although it is generally considered to be under-reported. Improper urethra closure in the female genitalia can cause recurrent genitourinary tract infections and infertility. In mice, female hypospadias was induced by exposure to exogenous estrogenic compounds. Aside from the link of estrogen exposure to female hypospadias, the process of female urethra closure is largely unstudied, with the precise timing of urethra closure and associated molecular mechanisms remaining poorly understood. To address this gap, we determined when urethra closure occurs and identified gene expression patterns during the process of urethra closure in female neonatal mice from postnatal day (PND) 5 to 10. Using whole mount imaging and histology, we discovered the initiation of urethra closure begins at PND7, and urethra closure is fully completed by PND10. To identify the genes associated with urethra closure, we conducted bulk RNA sequencing on female external genitalia prior to and after urethra closure. Gene ontology analyses revealed an increase of steroidogenic gene expression (Star, Hsd3b6, and Cyp17a1) during urethra closure, suggesting that the female genitalia locally produce steroids which could facilitate steroid signaling within the genitalia. With this study we establish an anatomical timeline of female urethra closure and hypothesize a paracrine steroid signaling mechanism of urethra closure. These observations provide entry points to aid in further understanding external genital abnormalities, like hypospadias, in females.
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Valosin-containing protein (VCP; aka p97), a member of the AAA (ATPases Associated with various cellular Activities) family, has been associated with a wide range of cellular functions. While previous evidence has shown its presence in mammalian sperm, our study unveils its function in mouse sperm. Notably, we found that mouse VCP does not undergo tyrosine phosphorylation during capacitation and exhibits distinct localization patterns. In the sperm head, it resides within the equatorial segment and, following acrosomal exocytosis, it is released and cleaved. In the flagellum, VCP is observed in the principal and midpiece. Furthermore, our research highlights a unique role for VCP in the cAMP/PKA pathway during capacitation. Pharmacological inhibition of sperm VCP led to reduced intracellular cAMP levels that resulted in decreased phosphorylation in PKA substrates and tyrosine residues and diminished fertilization competence. Our results show that in mouse sperm, VCP plays a pivotal role in regulating cAMP production, probably by the modulation of soluble adenylyl cyclase activity.
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Early pregnancy losses cause 25% of pregnancy failures in small ruminants because of an asynchrony between conceptus and uterine signals. In that context, melatonin plays a crucial role in sheep reproductive dynamics, but little is known about its effects in the peri-implantation period. We hypothesized that melatonin supports embryo implantation by modulating the uterine microenvironment. This study aimed to assess the effects of exogenous melatonin on the endometrium and early placenta rearrangement. Ten multiparous ewes either did (MEL, n=5) or did not (CTR, n=5) receive a subcutaneous melatonin implant (18 mg) 50 d before a synchronized mating. On Day 21 of pregnancy, sheep were euthanized. MEL ewes exhibited a higher prolificity rate (2.8 vs. 2.0 embryos/ewe) and plasma progesterone levels (3.84 vs. 2.96 ng/mL, P<0.05) than did CTR ewes. Groups did not differ significantly in embryo crown-rump length. MEL placenta had significantly (P<0.001) more binucleated trophoblast cells in the chorion region and ovine placental lactogen expression was significantly (P<0.05) more strongly upregulated than it was in CTR. Exogenous melatonin increased significantly (P<0.05) gene expression of angiogenic factors (VEGFA, VEGFR1, IGF1R), IFNAR2, and PR in the caruncular endometrium. Expression of the MT2 receptor in the endometrium and placenta was significantly (P<0.05) higher in MEL group. Results indicate that melatonin implants acted differentially on the uterus and placenta rearrangement. Melatonin increases differentiation in the placenta and induces changes that could promote vessel maturation in the endometrium, which suggests that it enhances the uterine microenvironment in the early stage of pregnancy in sheep.
State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, China
Medical Integration and Practice Center, Shandong University, Jinan, Shandong, People’s Republic of China
Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, People’s Republic of China
Reproductive Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China
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State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, China
Medical Integration and Practice Center, Shandong University, Jinan, Shandong, People’s Republic of China
Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, People’s Republic of China
Reproductive Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China
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State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, China
Medical Integration and Practice Center, Shandong University, Jinan, Shandong, People’s Republic of China
Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, People’s Republic of China
Reproductive Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China
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State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, China
Medical Integration and Practice Center, Shandong University, Jinan, Shandong, People’s Republic of China
Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, People’s Republic of China
Reproductive Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China
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State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, China
Medical Integration and Practice Center, Shandong University, Jinan, Shandong, People’s Republic of China
Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, People’s Republic of China
Reproductive Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China
Search for other papers by Xiaotong Dong in
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State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, China
Medical Integration and Practice Center, Shandong University, Jinan, Shandong, People’s Republic of China
Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, People’s Republic of China
Reproductive Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China
Search for other papers by Yanbo Du in
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Shandong Medicine and Health Key Laboratory of Birth Defect Prevention and Genetic Medicine, Jinan, Shandong, China
Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Jinan, Shandong, China
Search for other papers by Zhen Xu in
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State Key Laboratory of Reproductive Medicine and Offspring Health, Shandong University, Jinan, Shandong, China
Medical Integration and Practice Center, Shandong University, Jinan, Shandong, People’s Republic of China
Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, People’s Republic of China
Reproductive Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China
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In brief
Abnormal glucose metabolism may be involved in the pathogenesis of endometriosis. The present study identifies that highly expressed H19 leads to increased aerobic glycolysis and histone lactylation levels in endometriosis.
Abstract
Previous studies from our group and others have shown increased IncRNA H19 expression in both the eutopic endometrium and the ectopic endometriosis tissue during endometriosis. In this study, we use immunofluorescence, immunohistochemistry, and protein quantification to determine that levels of aerobic glycolysis and histone lactylation are increased in endometriosis tissues. In human endometrial stromal cells, we found that high H19 expression resulted in abnormal glucose metabolism by examining the levels of glucose, lactate, and ATP and measuring protein levels of enzymes that participate in glycolysis. At the same time, immunofluorescence and western blotting demonstrated increased histone lactylation in H19 overexpressing cells. Altering aerobic glycolysis and histone lactylation levels through the addition of sodium lactate and 2-deoxy-d-glucose demonstrated that increased aerobic glycolysis and histone lactylation levels resulted in enhanced cell proliferation and cell migration, contributing to endometriosis. To validate these findings in vivo, we constructed an endometriosis mouse model, demonstrating similar changes in endometriosis tissues in vivo. Both aerobic glycolysis and histone lactylation levels were elevated in endometriotic lesions. Taken together, these data demonstrate elevated expression levels of H19 in endometriosis patients promote abnormal glucose metabolism and elevated histone lactylation levels in vivo, enhancing cell proliferation and migration and promoting the progression of endometriosis. Our study provides a functional link between H19 expression and histone lactylation and glucose metabolism in endometriosis, providing new insights into disease mechanisms that could result in novel therapeutic approaches.
