Molecular human reproduction最新文献

{"title":"From organoids to assembloids: modeling tissue crosstalk in female reproductive biology and disease.","authors":"Qinyi Zhang, Sihui Yu, Qingying Wang, Jiawen Zhang","doi":"10.1093/molehr/gaag060","DOIUrl":"https://doi.org/10.1093/molehr/gaag060","url":null,"abstract":"<p><p>The female reproductive tract is a multi-tissue system in which epithelial, stromal, immune, and vascular cells coordinate responses to hormonal signals. Single-tissue organoids have advanced epithelial modeling in vitro but cannot capture the inter-tissue communication underlying key reproductive processes. Assembloids, which recombine cells from distinct tissue compartments in three-dimensional space, offer a means to restore these missing interactions. This review examines reproductive assembloid research across three biology-driven contexts. In menstrual cycle modeling, organoid-based systems have recapitulated epithelial breakdown and regeneration, yet stromal, immune, and vascular integration remain incomplete. In implantation modeling, embryo-endometrial co-cultures and receptive assembloids have begun to capture maternal-fetal crosstalk, though immune and vascular dimensions are largely missing. In endometriosis and adenomyosis modeling, assembloids have started to reconstruct pathogenic microenvironments that single organoids cannot replicate. Three issues are examined in depth. The first is the gap between what current models can and cannot reveal about reproductive biology. The second is the risk that added complexity may only confirm findings already established in vivo. The third is the point at which an additional tissue component stops contributing new information. Progress in this field is likely to depend not on greater structural complexity but on questions that only multi-tissue models can address.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hippo signaling regulates spontaneous human trophoblast syncytialization in three-dimensional cultures.","authors":"Michael Zheng, Lin Zhao, Richard Xi, Jahdiel DeNobrega, Mary Tammo, Stephen J Renaud, Peeyush K Lala","doi":"10.1093/molehr/gaag054","DOIUrl":"10.1093/molehr/gaag054","url":null,"abstract":"<p><p>Proper trophoblast development is essential for placental function and is a key determinant of pregnancy outcomes. Three-dimensional spheroid and organoid cultures using cells from placental tissues or trophoblast stem cells have emerged as models that recapitulate cell-cell interactions and aspects of the physiological environment. Trophoblast organoids typically contain self-renewing cytotrophoblasts located toward the periphery in contact with basement membrane, whereas cells within the core fuse into hormone-producing syncytiotrophoblasts. Removing cells from matrix and/or culturing them in suspension can reverse this organization. In both cases, spontaneous syncytialization occurs, but the underlying mechanisms remain poorly understood. To identify signaling pathways associated with spontaneous trophoblast differentiation in three-dimensional conditions, human trophoblast stem cells were either maintained in the stem state as two-dimensional (2D) monolayers or aggregated in suspension without an exogenous matrix to form three-dimensional cultures. Expression and localization of trophoblast subpopulation markers were compared between two- and three-dimensional cultures. Three-dimensional cultures displayed increased spontaneous differentiation into the syncytiotrophoblast lineage along the periphery, accompanied by reduced proliferation of cytotrophoblasts. Consistent with this observation, BeWo choriocarcinoma cells exhibited increased chorionic gonadotropin levels in three-dimensional culture, whereas this response was not observed in HTR8/SVneo immortalized trophoblasts. Gene expression and pathway enrichment analyses identified Hippo signaling as altered in three-dimensional trophoblast stem cell cultures, with reduced expression of several genes associated with YAP1/TAZ-TEAD transcriptional activity. Inhibition of LATS1/2, which activates YAP1/TAZ-TEAD signaling, reduced spontaneous syncytiotrophoblast formation. These findings suggest that reduced YAP1/TAZ-TEAD activity may facilitate self-organized syncytialization in three-dimensional trophoblast cultures.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactobacillus johnsonii attenuates chronic stress-induced ovarian dysfunction by modulating ovarian clock-related steroidogenic signaling.","authors":"Jiarui Liang, Yuying Chen, Shanshui Zeng, Ziwei Zhou, Shulei Chen, Xuyu Li, Siqi Yan, Dongxin Zhang, Hongwei Zhou, Bingyu Li","doi":"10.1093/molehr/gaag058","DOIUrl":"10.1093/molehr/gaag058","url":null,"abstract":"<p><p>Chronic psychological stress is increasingly implicated in female reproductive disorders, yet the mechanistic link between stress and ovarian dysfunction remains incompletely understood. Using a chronic restraint stress (CRS) mouse model, we demonstrated that CRS induced anxiety-like behaviors and ovarian dysfunction, evidenced by elevated serum FSH levels, reduced estradiol (E2) and anti-Müllerian hormone levels, and impaired folliculogenesis. These phenotypes were accompanied by pronounced gut microbiota dysbiosis and disturbed metabolic profiles. Moreover, transplantation of stress-altered microbiota further exacerbated ovarian impairment in recipient mice. Stress-related gut microbiota alterations were associated with changes in ovarian clock gene expression and steroidogenic pathways. Notably, preventive oral supplementation with Lactobacillus johnsonii modulated gut microbial composition, mitigated stress-related behavioral and endocrine abnormalities, and attenuated CRS-induced alterations in ovarian clock protein expression, improved estrogen biosynthesis and follicular development. In conclusion, these findings support a proposed regulatory framework involving stress-associated gut microbiota alterations, ovarian clock gene expression, and steroidogenic dysfunction, and suggest L. johnsonii as a potential preventive microbiota-based intervention for stress-associated ovarian dysfunction.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endometriosis pain: genes linked to inflammation distinguish symptomatic from asymptomatic disease.","authors":"Ramanaiah Mamillapalli, Howard J Li, Shant Apelian, Monish Kumar, Sarah F Wang, Nishita Pondugula, Gabriela de Queiroz Campos, Sumaiya Sayeed, Yonghee Cho, Hugh S Taylor","doi":"10.1093/molehr/gaag055","DOIUrl":"10.1093/molehr/gaag055","url":null,"abstract":"<p><p>Endometriosis is a multifaceted disease, causing debilitating pelvic pain in some patients, while being completely asymptomatic in others. The pathophysiology of endometriosis pain is not well understood and poorly correlated to stage. We hypothesized that this clinical heterogeneity may be explained by examining differences in gene expression. We performed RNA sequencing of 27 formalin-fixed, paraffin-embedded peritoneal biopsies from 9 symptomatic (Sx) and 10 asymptomatic (ASx) subjects. Eight hundred and ninety genes were differentially expressed between Sx and ASx samples. Of these, the most significant including genes involved inflammatory signaling (IL16, IL17RA, JAK3, SMPD3, RELT), cell adhesion (OLFML1, CDON, VCAN), and neuromodulation (SEMA6D, ADRA2C, SLC7A5). Gene set enrichment analysis identified functional enrichment in 22 gene ontology pathways, of which 7 represented immunologic pathways. Weighted gene correlation network analysis identified 11 co-expression modules significantly correlated with symptomaticity, including one module strongly enriched for immunologic/inflammatory functions. Of all molecules identified as associated with pain, IL16 expression also correlated with symptom severity when cases were stratified into mild versus severe pain based on clinical criteria. These findings suggest that endometriotic lesions of symptomatic subjects are characterized by distinct molecular signatures, including altered expression of inflammatory pathways, highlighting potential mechanisms underlying symptom variability and identifying candidate pathways for future therapeutic interventions.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia and estrogen cooperatively enhance angiogenesis through the GPER/ESR1-HIF-1α/VEGF axis in adenomyosis.","authors":"Lin Gan, Wenjuan Zhou, Jiali Sun, Huixian Chen, Bei Wang, Meihua Huang, Zhenli Li, Tao Gui","doi":"10.1093/molehr/gaag057","DOIUrl":"10.1093/molehr/gaag057","url":null,"abstract":"<p><p>Adenomyosis (AM) is a benign gynecological disorder characterized by the presence of endometrial tissue within the myometrium and is commonly associated with dysmenorrhea and menorrhagia. Although angiogenesis is considered a key process in its pathogenesis, the underlying molecular mechanisms remain incompletely understood. In this study, we investigated the role of the hypoxia-inducible factor 1-alpha (HIF-1α)/vascular endothelial growth factor (VEGF) axis in AM. Immunohistochemical analysis revealed that the expression levels of HIF-1α and VEGF, as well as microvessel density (MVD), were significantly increased in the eutopic endometrium of patients with AM, with significant positive correlations among these parameters. Paired analysis further showed that adenomyotic lesion tissues exhibited stronger HIF-1α and VEGF expression and higher MVD than matched eutopic endometrium. In vitro, using adenomyosis-derived eutopic endometrial stromal cells under cobalt chloride-induced hypoxic conditions, we found that estrogen further enhanced HIF-1α and VEGF expression. Mechanistically, estrogen promoted angiogenesis through two distinct pathways: G protein-coupled estrogen receptor (GPER)-dependent activation of the PI3K/AKT and ERK pathways, which enhanced HIF-1α accumulation, and estrogen receptor alpha (ESR1)-mediated transcriptional upregulation of HIF-1α. These two pathways converged to increase VEGF secretion and ultimately promoted tube formation, migration, and invasion of human umbilical vein endothelial cells. Collectively, these findings demonstrate that under hypoxic conditions, estrogen drives angiogenesis in AM through dual regulation of the HIF-1α/VEGF pathway by GPER and ESR1. This study provides new mechanistic insight into the pathogenesis of AM and supports the GPER/ESR1-HIF-1α-VEGF axis as a potential mechanistic target for further investigation.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterologous cell-cell junctions support transepithelial endometrial trophoblast invasion in human.","authors":"Liubov Izmaylova, Eva Miriam Buhl, Irmgard Classen-Linke, Benjamin Rösing, Rudolf E Leube","doi":"10.1093/molehr/gaag053","DOIUrl":"10.1093/molehr/gaag053","url":null,"abstract":"<p><p>The first step of embryonic trophoblast invasion involves penetration of the endometrial epithelium, which is a unique biological process involving the junction-free apical surfaces of two distinct epithelia. Although cell-cell junctions have been shown to play a role in the establishment of endometrial receptivity, data on their role in the invasion process are lacking. To examine whether human transepithelial trophoblast invasion is linked to heterologous junction formation between trophoblast and endometrial epithelial cells, we used a three-dimensional in vitro implantation model. Hybridoma-derived AC-1M88 extravillous trophoblast spheroids of defined size (∼300 µm) were placed either on endometrial adenocarcinoma-derived Ishikawa monolayers or on biopsy-derived primary endometrial epithelial cell monolayers. Labeling trophoblast and endometrial cells with different fluorescent dyes allowed differentiation of the two cell populations and monitoring of the invasion process for up to 2 days after attachment. Trophoblast invasion was tracked by fluorescence microscopy and quantified with the help of image analysis tools. We observed collective transepithelial invasion of the trophoblast into the endometrial monolayers. Junction formation was then assessed by transmission electron microscopy and immunofluorescence microscopy. We observed that transepithelial trophoblast invasion was accompanied by de novo formation of tight junctions, adherens junctions, and desmosomes between trophoblast and endometrial cells. The relevance of desmosomal adhesion for invasion was furthermore examined by using blocking antibodies against the desmosomal cadherin desmoglein 2. We could demonstrate that the blocking antibodies stalled the invasion process. Together, we conclude that formation of heterologous cell-cell junctions between trophoblast and endometrial epithelial cells is a robust and important mechanism that facilitates implantation. These findings extend previous studies and offer completely new insights into the functional contribution of cell-cell junction rearrangement to embryo implantation.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prepubertal exposure to SARS-CoV-2 single-stranded RNA disrupts spermatogenesis and causes intergenerational effects in mice.","authors":"Yu-Xuan Wu, Chiao-Hsin Chang, Chia-Ying Wu, Shuoh-Wen Chen, Ting-An Lin, Min-Hui Chen, Eric Chang-Yi Lin, I-Shen Huang, Yuan-I Chang","doi":"10.1093/molehr/gaag059","DOIUrl":"https://doi.org/10.1093/molehr/gaag059","url":null,"abstract":"<p><p>The COVID-19 pandemic has caused widespread morbidity and mortality worldwide, with emerging evidence documenting transient reproductive impairment in adult males following SARS-CoV-2 infection. However, prepubertal males appear especially vulnerable to infection-related testicular injury, yet the underlying mechanisms and long-term consequences remain poorly understood. We investigated the impact of systemic exposure to synthetic SARS-CoV-2 guanine-uracil (GU)-rich single-stranded RNA (ssRNA), a viral pathogen-associated molecular pattern (PAMP), on testicular integrity and reproductive outcomes in a juvenile mouse model. 4-week-old C57BL/6J males received systemic administration of GU-rich ssRNA, and we comprehensively assessed testicular architecture, molecular signatures, and offspring outcomes extending into adulthood. Exposure induced robust systemic and local inflammation that disrupted blood-testis barrier (BTB) integrity, disorganized seminiferous tubule architecture, and coordinately suppressed transcripts essential for spermatogonial maintenance (Kit, Csf1), germ cell survival (Bcl2, Bcl6), and meiotic progression (Spo11, Mlh1, Atm, Msh5). Paradoxically, despite significant upregulation of steroidogenic enzymes (Star, Hsd3b2, Cyp17a1, Hsd17b3), serum testosterone levels were markedly reduced, coinciding with profound downregulation of genes critical for ganglioside biosynthesis (B3galt4, St3gal5, St8sia1, B4galnt1), which are essential for maintaining lipid-raft-dependent junctional integrity and hormone transport. Paternal CoV2 GU-rich ssRNA exposure did not alter litter size or offspring sex distribution but was associated with reduced early postnatal offspring body weight, impaired glucose handling, and selective changes in metabolic tissue weights. Our findings reveal a critical developmental vulnerability window and provide mechanistic insights that support the need to monitor testicular function following systemic inflammation triggered by viral PAMPs in prepubertal males.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mass spectrometry-based quantitation of cervicovaginal progesterone and steroids in women at high risk of preterm birth.","authors":"Katia Capuccini, Gonçalo D S Correia, Lucia Olmo Garcia, Charis Uhlson, Ada H Y Yuen, Belen Gimeno-Molina, Lynne Sykes, Zoltan Takats, Robert Murphy, Phillip R Bennett, David A MacIntyre","doi":"10.1093/molehr/gaag045","DOIUrl":"https://doi.org/10.1093/molehr/gaag045","url":null,"abstract":"<p><p>Placental production of steroids, like progesterone, drives increasing circulating concentrations during pregnancy. It is postulated that reduced cervicovaginal progesterone contributes to cervical shortening and increased preterm birth (PTB) risk. Although vaginal progesterone is recommended for PTB prevention, its effectiveness remains uncertain. While serum and urinary progesterone are routinely measured in pregnancy, little is known about cervicovaginal fluid (CVF) progesterone concentrations. To address this, we adapted existing mass spectrometry-based assays to quantify 13 steroid hormones in CVF collected between 12-24 weeks gestation from uncomplicated term pregnancies (n = 14) and those with adverse outcomes (n = 11). Only progesterone, androstenedione, and cortisol were detected above detection limits. In uncomplicated term pregnancies, mean concentrations of these steroids were 6.61 ± 8.13, 4.16 ± 2.98 and 0.34 ± 0.21 ng/g of CVF, respectively. Cervicovaginal progesterone was weakly, positively associated with gestational age (r2= 0.15, p-value= 0.02) which was also observed in paired samples collected at 12 and 22 weeks (n = 5, paired Wilcoxon, p-value = 0.03). No differences in CVF steroid levels were observed between women who subsequently delivered preterm (n = 9) or at term (n = 15). Our study provides a robust method for quantifying CVF steroids and suggests that second-trimester PTB risk is not associated with cervicovaginal progesterone concentrations.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148706710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel circular RNA hsa_circ_0079474 facilitates intrauterine adhesion by targeting miR-630/YAP1 axis to stimulate epithelial-mesenchymal transition.","authors":"Yan Zhou, Jiwen Wang, Zhenzhen Song, Danxuan Zhu, Ying Sun, Yue Zhao, Xiaohong Sun, Tonghui Ji, Huihua Dai, Wei Ding, Xing Chen","doi":"10.1093/molehr/gaag051","DOIUrl":"10.1093/molehr/gaag051","url":null,"abstract":"<p><p>Emerging evidence highlights the critical role of circular RNAs (circRNAs) in regulating pathological processes in various diseases, including organ fibrosis. Endometrial fibrosis, commonly referred to as intrauterine adhesion (IUA), is a major cause of uterine infertility. However, the involvement of circRNAs in the pathogenesis of IUA remains largely unexplored, necessitating further research. This study aimed to identify a specific circRNA that may serve as a diagnostic biomarker and therapeutic target for IUA. CircRNA microarray analysis was performed to compare circRNA expression profiles between paired fibrotic and normal endometrial samples from patients with IUA. The expression of hsa_circ_0079474 was significantly upregulated in fibrotic tissues compared with normal tissues. Functional analyses demonstrated that hsa_circ_0079474 enhanced cell proliferation, promoted cell cycle progression, and facilitated epithelial-mesenchymal transition (EMT) in vitro, as assessed by qRT-PCR, CCK-8 assays, EdU assays, flow cytometry, and Masson staining. Mechanistically, dual-luciferase reporter assays and RNA immunoprecipitation confirmed that hsa_circ_0079474 acted as a molecular sponge for miR-630, leading to the upregulation of YAP1. In an IUA rat model, hsa_circ_0079474 was found to drive EMT, whereas miR-630 administration reversed this process and ameliorated endometrial fibrosis. Consequently, these findings indicate that hsa_circ_0079474 contributes to the progression of IUA by modulating the miR-630/YAP1 axis, providing new insights into circRNA-mediated mechanisms in IUA and highlighting hsa_circ_0079474 as a potential therapeutic target.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Androgen signaling is dispensable for fetal testis formation: decoupling testis organogenesis from fetal masculinization programming.","authors":"Caroline Despicht, Anna O Bindel, Anna K Rosenmai, Terje Svingen","doi":"10.1093/molehr/gaag044","DOIUrl":"10.1093/molehr/gaag044","url":null,"abstract":"<p><p>Androgen receptor (AR) signaling is central to male sexual differentiation. Notably, however, fetal testis formation and androgen-dependent masculinization are temporally and mechanistically distinct processes that are not always clearly differentiated in developmental and toxicological interpretations. Evidence from human androgen insensitivity syndromes (AIS) and rodent genetic models demonstrates fetal testis formation proceeds independently of AR, whereas downstream masculinization is AR-dependent. Across mammals, early testis differentiation is driven by intrinsic programs that establish Sertoli cells, organize testis cords, and specify fetal Leydig cells in the absence of AR activity. Consistently, mouse Ar-knockout models show persistent fetal testis formation, and individuals with complete androgen insensitivity syndrome (CAIS) develop structurally intact testes that produce normal or elevated testosterone despite absent virilization. These conserved outcomes reflect shared developmental timing, as key morphogenetic events occur before AR is expressed in Sertoli or fetal Leydig lineages in both rodents and humans. By contrast, AR-mediated androgen signaling becomes essential once androgens from the fetal testes begin to act on peripheral target tissues, governing masculinization of external genitalia, testis descent, and postnatal maturation of somatic testis compartments, as demonstrated by graded AIS phenotypes and cell-specific Ar ablation in mice. This developmental uncoupling explains why disruption of androgen signaling still allows establishment of early testis architecture yet predictably impairs downstream male reproductive development. Recognizing this distinction is crucial for interpreting human genetic disorders, aligning rodent models with human biology, but also to refine toxicological frameworks to target androgen-dependent windows of vulnerability.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13421082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}