Reproduction

Gu, Yan; Chen, Ling-Han; Yang, Long; Shi, Yan; Xu, Hao-Lan; Xin, Ya-Wei; Song, Ning; Gu, Wen-Wen; Wang, Jian

doi: 10.1530/rep-23-0502pmid: 39475824

In briefInsufficiency of extravillous trophoblast (EVT) cell invasion is implicated in pregnancy complications. This study reveals the roles of the miR-486-5p/Smad2 pathway in lipopolysaccharide (LPS)-induced EVT dysfunctions and in the pathogenesis of early pregnancy loss (EPL).AbstractPlacenta-associated pathologies, including EPL and preeclampsia, are characterized by insufficient EVT invasion. Previously, downregulated miR-486-5p expression was shown to inhibit the invasion of EVTs, and decreased peripheral miR-486-5p expression was associated with EPL. However, the exact roles of miR-486-5p in the pathogenesis of EPL, as well as the molecular pathway underlying the role of miR-486-5p in EVT invasion, remain poorly understood. In this study, decreased miR-486-5p expression in the uterine embryo implantation site on gestational day 8.5 and increased uterine expression of Smad2, a target of miR-486-5p, were observed in an LPS-induced EPL model. The invasion and viability of the immortalized human EVT line, HTR-8/SVneo, were inhibited by LPS, accompanied by reduced miR-486-5p expression. LPS promoted Smad2 expression, which was attenuated by the miR-486-5p mimics. The downregulation of Smad2 effectively restored the impaired invasion and viability of HTR-8/SVneo cells caused by LPS or the miR-486-5p inhibitor. Furthermore, LPS promoted TNFα production in HTR-8/SVneo cells, whereas both siSMAD2 and miR-486-5p mimics reversed this effect. An analysis of human decidua single-cell RNA sequencing and transcriptome datasets derived from Gene Expression Omnibus revealed that, compared with that in control early pregnant women, SMAD2 expression was significantly increased in recurrent miscarriage patients. Collectively, these data suggest that decreased miR-486-5p expression might lead to EPL, at least partially by inhibiting invasion and/or promoting TNFα production in EVTs by targeting SMAD2.

Luderer, Ulrike

doi: 10.1530/rep-24-0194pmid: 39441766

In briefParticulate matter (PM) air pollution contains many chemicals that are individually known to have adverse effects on reproduction, as well as numerous others that have not been investigated for effects on reproduction. This review discusses the scientific literature investigating the effects of ambient and experimentally generated PM mixtures on reproduction.AbstractPM air pollution consists of liquid and solid particles, which are categorized by size as less than 10 (PM10) μm, 2.5 (PM2.5) μm, or 0.1 μm (PM0.1 or ultrafine) in aerodynamic diameter and which vary in composition depending on the sources. PM exposure is ubiquitous and has been associated with many adverse health effects. This narrative review focuses on epidemiological and experimental studies that investigated the effects of PM exposure on female and male reproduction and on pregnancy.

Peiris, Mario T; Chen, Yu; Shaw, Geoff; Renfree, Marilyn B

doi: 10.1530/rep-24-0259pmid: 39569971

In briefOvarian differentiation in tammar wallabies begins after birth, allowing direct experimental manipulation during the period of differentiation. Using this unique model, we demonstrate that the environmental endocrine-disrupting chemical bisphenol A (BPA) interferes with normal morphological development and gene expression in the developing ovary.AbstractBPA, an environmental endocrine disruptor, is used widely in the manufacturing of various plastics. While BPA can have detrimental effects on fertility and reproductive health, the effects of BPA on early ovarian differentiation in mammals remain unclear. Marsupials have undifferentiated gonads at birth, so this study investigated the gross morphology, protein localisation of FOXL2 and FST and the expression profile of key ovarian differentiating genes FOXL2, WNT4, FST, ESR1 and ESR2 every 2 days from the day of birth to day 10 postpartum (pp) in the marsupial tammar wallaby. A second group of newborn female pouch young were treated with 50 μg/kg of BPA daily from day 0 to day 10 pp, and the morphology and gene expression were examined at day 10 pp. Ovigerous cords in tammar ovaries were first formed between day 2 and day 4 pp. FOXL2 localisation became nuclear by day 4 in pre-granulosa cells. FST was initially in the cytoplasm of pre-granulosa cells at day 2 pp but was then secreted into the extracellular matrix in ovaries by day 10 pp. FOXL2, FST, ESR1 and ESR2 mRNA were upregulated in ovaries around day 2–4 pp, indicating that ovarian differentiation in the tammar begins from day 2 to day 4 pp. Interestingly, BPA treatment from day 0 to day 10 pp blocked the morphological differentiation of the cortex and medulla and ovigerous cord formation and downregulated the expression of FST and FOXL2 at day 10 pp.

Singh, Isha; Parte, Priyanka

doi: 10.1530/rep-24-0035pmid: 39447008

In briefThis study investigates the role of TH2B in pre-implantation embryos and found that TH2B deposition varies between gametes but rapidly redistributes in two-cell embryos after fertilization. Our ultra-low-input native chromatin immunoprecipitation and sequencing (ULI-NChIP-seq) revealed that TH2B is enriched in early chromatin but decreases after the two-cell stage, with strong correlations to key regulatory regions, histone modifications and transposable elements (TEs), indicating its critical role in zygotic genome activation and early developmental processes.AbstractThe histone variant TH2B, enriched in oocytes, sperm and early embryos, decreases as embryos differentiate into pre-gastrula stages. Despite its presence, the role of TH2B in epigenetic reprogramming during early embryonic development remains largely under-researched. Our study employed ULI-NChIP-seq to analyze the genome-wide distribution of TH2B in metaphase II (MII) oocytes and early embryos. We found that TH2B is enriched in the chromatin of oocytes and two-cell stage embryos but becomes less prevalent after the two-cell stage. Correlation analysis revealed that the TH2B chromatin patterns in sperm and pre-implantation embryos are more similar to each other than to those in MII oocytes. Gene ontology (GO) analysis of TH2B-occupied loci linked them to various developmental processes including oogenesis, fertilization, chromatin modification and transcription regulation. The study also identified a strong association of TH2B with specific TEs, particularly long terminal repeats, which are known to regulate pre-implantation development. Additionally, early embryos showed H3K9me3 marks at TH2B-bound loci. TH2B exhibited strong correlations with H2A.Z and H3.3 in the two-cell and eight-cell stages, a positive association with H3K27Ac and H3K4me3 and a negative correlation with H3K27me3. Allelic reprogramming analysis of TH2B in embryos from C57BL/6J and DBA/2J crosses revealed differential dynamics between maternal and paternal alleles, with a notable paternal bias at the promoter in two-cell embryos. Thus, TH2B’s enrichment in early embryonic stages and its association with key regulatory regions and histone modifications underscore its importance in zygotic genome activation and subsequent developmental processes.

Das, Kirsten; Gomez Lobo, Veronica

doi: 10.1530/rep-24-0080pmid: 39418097

In briefTransmasculine and gender diverse adolescents and young adults can often have nuanced considerations when utilizing contraception. This narrative review discusses contraception utilization patterns and specific considerations in this population and proposes a patient-oriented comparison of contraceptive options.AbstractContraception care is an important aspect of comprehensive gender-affirming care in transgender and gender diverse (TGD) adolescents and young adults (AYAs). TGD AYAs seek contraception care for a variety of reasons, and several important considerations are unique to this population. In addition to pregnancy prevention, transmasculine and gender nonbinary persons may seek contraception to achieve amenorrhea and reduce gender dysphoria, or as part of their gender-affirming journey. While patients on testosterone therapy often experience amenorrhea, pregnancy has been reported and testosterone is not a form of contraception. Visits for contraceptive counseling provide an opportunity to discuss fertility goals and preservation planning as well as the possibility that some methods may provide endometrial protection. In this narrative review, we analyze the current literature and discuss specific considerations for contraceptive use in this population. We also propose a contraception overview for shared decision making for patients and their clinicians.

Takahashi, Takayuki; Ogiwara, Katsueki

doi: 10.1530/rep-24-0184pmid: 39441770

In briefOvulation, the female reproductive process whereby fertilizable oocytes are released from a mature ovarian follicle, is widely seen in all animals that sexually reproduce. This paper reveals that, despite the remarkably diverse styles of ovulation among animal taxa, most ovulate via follicle rupture and suggests that the rupture process may operate via similar cellular mechanisms across animals.AbstractOvulation is the process by which a fertilizable oocyte is extruded from the interior of the follicle. Herein, we conducted a literature survey to explore the ovulation patterns of 11 sexually reproducing species belonging to 10 animal phyla. These results indicate a large variety of ovulation patterns. Further comparative biological and evolutionary considerations of these results led us to conclude that most female animals ovulate via follicle rupture. We propose that in all animals that ovulate by follicle rupture, two cellular events may be critically involved in the process: i) the disintegration of cell junctional systems leading to intracellular cytoskeleton rearrangement in the follicle cells and ii) the degradation of extracellular matrix (ECM) proteins filled between follicle cells. These events may result in follicular cell deformation and increased motility, both of which are necessary for the formation of a path through which an oocyte escapes from the follicle. In addition to the requirement of ECM degradation for disintegrating cell junctions, intensive ECM protein degradation at the apical region of the follicle probably became increasingly important in late-evolving animals, such as vertebrates, in which a thick follicle wall containing a large abundance of ECM proteins is formed. We also considered hypothetical scenarios for the evolution of ovulation in these animals. Furthermore, this article discusses future problems that need to be solved for a more comprehensive understanding of ovulation in the animal kingdom.

De Cesaro, Matheus P; de Macedo, Mariana P; da Rosa, Paulo R A; dos Santos, Joabel T; Mea, Ricardo D; da Nóbrega, Janduí E; Duggavathi, Raj; Gasperin, Bernardo G; Gonçalves, Paulo Bayard D; Bordignon, Vilceu

doi: 10.1530/rep-24-0187pmid:

Rubin, Elizabeth; Palmor, Marissa; Amato, Paula

doi: 10.1530/rep-24-0120pmid: 39441758

In briefMany transgender and gender diverse (TGD) people want to have biologically related children. This review summarizes and discusses the options for fertility treatment and preservation in TGD adults and adolescents, with an emphasis on gender-affirming hormone therapy in the context of fertility treatment, clinical management strategies to minimize gender dysphoria during treatment and major factors in future use of cryopreserved gametes.AbstractYears of growing research demonstrate that TGD people desire fertility counseling and family building; however, social and medical factors can impact future fertility options. Fortunately, TGD individuals have many viable options for family building using their own gametes and/or reproductive organs. However, the nuanced ways in which different gender-affirming treatments affect reproduction, the interplay with nontreatment-related infertility factors and mitigation of likely dysphoria triggers are all critical to actual utilization. This review focuses on fertility treatment and preservation options for TGD patients and highlights these influential social and medical factors. Fertility treatments may be associated with worsening gender dysphoria in TGD people, and an affirming clinical environment and conscientious provider approach is paramount to treatment success. However, reducing gender dysphoria can also require specific changes to medically assisted reproduction and sperm collection protocols, some of which carry the potential for diminished outcomes or unknown effects. Adolescents undergoing fertility preservation treatments may need more support or additional protocol modifications, and outcomes may be poorer in this age group compared with adults. Testicular and ovarian tissue cryopreservation may present a fertility preservation option for prepubertal TGD children; however, in vitro gamete maturation remains experimental in this situation.

Matsushige, Cassandra; Kitazumi, Kaelyn; Beaman, Amanda; Miyagi, Marissa; Tallquist, Michelle D; Yamazaki, Yukiko

doi: 10.1530/rep-24-0151pmid: 39441765

In briefThree-dimensional ovarian tissue culture is a unique model to define the effects of molecules on folliculogenesis. Using this model, we determined that RGD–integrin interaction plays a role in antrum formation and theca cell differentiation.AbstractWe recently developed a three-dimensional (3D) ovarian tissue culture system supported by bacterial-derived dextran hydrogel. Arg-Gly-Asp (RGD) is an extracellular matrix-derived triple peptide. Immature ovarian tissues cultured in RGD-modified dextran hydrogel significantly promoted antral follicle growth and oocyte quality compared with those cultured in dextran hydrogel alone. In this study, we examined the mechanism of follicle growth stimulated by RGD treatment in the 3D system. First, we detected that direct contact between RGD-modified dextran hydrogel and ovarian interstitial cells is necessary to promote antral follicle growth. Therefore, we hypothesized that RGD stimulates antral follicle growth through RGD-binding integrin receptors expressed in the interstitial cell mass. Using quantitative PCR (qPCR) and immunochemical staining, we identified that integrins ⍺vβ3 and ⍺v5 are predominantly expressed in the ovarian interstitial compartment. To assess the effect of RGD–integrin interaction on follicle growth, ovarian tissues were cultured with cilengitide (Ci), an inhibitor specific for ⍺vβ3 and ⍺vβ5. Ci treatment suppressed RGD-induced follicle growth and oocyte quality in a dose-dependent manner. When the interstitial cell aggregates were cultured with RGD, cell migration and theca-related gene expression were significantly upregulated. Ci treatment dramatically suppressed these RGD-induced activities. In coculturing the interstitial aggregate and secondary follicles with RGD, migrating cells formed the outermost cell layers around the follicles, like theca layers, which were totally blocked by Ci treatment. In conclusion, our results suggest that RGD stimulates theca cell differentiation in the ovarian interstitial cells through integrins ⍺vβ3 and ⍺v5 to promote antral follicle growth in our 3D system.

Moldovan, Genna E; Massri, Noura; Vegter, Erin L; Pauneto-Delgado, Ivonne N; Burns, Gregory W; Joshi, Niraj; Gu, Bin; Arora, Ripla; Fazleabas, Asgerally T

doi: 10.1530/rep-24-0355pmid: 39503541

In briefThe HIPPO signaling effectors YAP1 and WWTR1 are required for murine pregnancy initiation, and mutation of these factors compromises the decidualization response and overall pregnancy success.AbstractEndometrial stromal cell decidualization is required for pregnancy success. Although this process is integral to fertility, many of the intricate molecular mechanisms contributing to decidualization remain undefined. One pathway that has been implicated in endometrial stromal cell decidualization in humans in vitro is the HIPPO signaling pathway. Two previously conducted studies showed that the effectors of the HIPPO signaling pathway YAP1 and WWTR1 are required for decidualization of primary endometrial stromal cells in vitro. To investigate the in vivo role of YAP1 and WWTR1 in decidualization and pregnancy initiation, we generated progesterone receptor Cre-mediated mutation of a combination of Yap1 and Wwtr1 alleles. Female Yap1 and Wwtr1 triple allele mutants exhibited subfertility, a compromised decidualization response, decreased endometrial receptivity, delayed embryonic development and a unique transcriptional profile at 7.5 days post-coitus (dpc). Bulk mRNA sequencing revealed aberrant maternal remodeling evidenced by significant alterations in extracellular matrix-encoding genes at 7.5 dpc in mutant dams and enrichment for terms associated with fertility-compromising diseases such as pre-eclampsia and endometriosis. In addition, differentially expressed genes overlapped directionally with estrogen receptor- and epidermal growth factor receptor-regulated genes as identified by microarray. Our results indicate that Yap1 and Wwtr1 are necessary for successful mammalian pregnancy initiation.