Ovarian cancer (OC) remains one of the most lethal malignancies among women due to late-stage diagnosis and limited therapeutic options. The discovery of novel, effective treatments is crucial to improving patient outcomes. Flavonoids, a diverse group of polyphenolic compounds found abundantly in fruits, vegetables, and medicinal plants, have garnered significant attention for their anticancer properties, including their potential role in ovarian cancer treatment. This comprehensive review explores the molecular mechanisms underlying the anticancer effects of flavonoids in OC, highlighting their ability to modulate key signaling pathways involved in cell proliferation, apoptosis, invasion, and metastasis. Flavonoids exert their effects through antioxidant activity, inhibition of angiogenesis, and regulation of tumor suppressor genes and growth factors. Additionally, they interact with cellular signaling molecules such as the PI3K/Akt/mTOR, MAPK, and NF-κB pathways, influencing cell survival and death. Notably, flavonoids also enhance the cytotoxicity of chemotherapeutic agents, making them valuable adjuncts in OC therapy. This review further discusses the pharmacokinetics, bioavailability, and potential challenges in the clinical application of flavonoids as therapeutic agents for ovarian cancer. The findings suggest that flavonoids, due to their multifaceted mechanisms of action and relatively low toxicity, hold promise as adjunct or alternative therapies in the treatment of ovarian cancer. Future clinical trials are essential to validate their efficacy and safety in human OC patients.
Estrone (E1), a ubiquitous environmental estrogen, poses a potential threat to the reproductive health of aquatic organisms. To evaluate the inducing effect of E1 exposure on gonadal feminization in male Siniperca chuatsi, male fish were exposed to 0, 0.01, 0.1, and 1 μg/L E1 for 60 days. The effects of E1 exposure on serum sex hormones, gonadal histological sections, vasa in situ hybridization, cell apoptosis, and gene expression in S. chuatsi were systematically examined. The results showed that 0.1 μg/L E1 treatment significantly inhibited testicular germ cell development, while 1 μg/L E1 treatment induced gonad histological feminization in 80% of male fish, with early vitellogenic oocytes appeared. Additionally, E1 exposure caused significant changes in serum sex hormones: 11-ketotestosterone levels significantly decreased, while immunoreactive estradiol levels significantly increased. Vasa gene in situ hybridization showed positive signals and TUNEL cell apoptosis revealed no obvious apoptotic signals in E1-induced histologically feminized gonads. Further molecular analysis revealed that sex regulation and development-related genes were involved in the E1-mediated gonadal feminization process: the expression of key male sex determination genes (dmrt1, amh, gsdf, sox9) and steroidogenic support genes (star, fshr) was significantly down-regulated, while expression of key female differentiation genes (bmp15, foxl2, cyp19a1a, hsd17b1) and germ cell development genes (sox19a, dazl, vasa, ccne2, sox3) was significantly up-regulated. Collectively, these findings demonstrate that E1 exposure induces histological testicular feminization in male S. chuatsi in a dose-dependent manner, concomitant with transcriptional downregulation of male differentiation genes and upregulation of female differentiation genes.
The three major estrogens, estrone (E1), estradiol (E2) and estriol (E3) were identified and characterized in the 1930s; it then took more than 30 years before a new major estrogen, estetrol (15α-hydroxyestriol, E4) was identified. Here we try to highlight the pioneering work of a small group of scientists who made the new discovery possible. The formal identification of E4 was made by a group led by Egon Diczfalusy at the Karolinska Institute, Stockholm in 1967, but was preceded by a series of progressive steps beginning in 1955. Besides isolating the new steroid from maternal and neonatal urine, they were able to determine two unique characteristics of E4: it is present only during pregnancy and in the neonate, and it is produced by the fetal/neonatal liver using E2 as the substrate (phenolic pathway). Following the formal identification of E4 in Stockholm, another group was instrumental in increasing our knowledge of the biosynthesis of the new estrogen. The research group, led by Samuel Solomon at McGill University in Montreal proved that some androgens, and especially dehydroepiandrosterone sulfate (DHEAS), were converted into E4 by the fetoplacental unit (neutral pathway). Today, we know that although the fetal liver plays a key role in E4 production, the placenta is also involved through both the phenolic and neutral pathways. In the early days attempts were made to use conversion of neutral steroids into E4 for clinical purposes. A few investigations seemed to provide positive results, but it was soon realized that its evaluation during pregnancy was controversial due to differing results, making elevated E4 levels in cases of significant pregnancy complications difficult to interpret. However, years later studies on the biochemical and pharmacologic properties of E4, as well as data on its clinical efficacy and safety, led to its current use in hormonal contraception and menopausal hormone therapy (HT), and it is expected to play a major role in future estrogen therapies.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder influenced by genetic and environmental factors, yet the molecular mechanisms linking endocrine-disrupting chemicals (EDCs) to ovarian dysfunction remain unclear. Here, we establish a letrozole-induced PCOS-like rat model and integrate bulk RNA-seq, single-cell RNA-seq of human granulosa cells (GCs), and functional validation to identify CBX2 as a critical epigenetic regulator connecting EDC exposure to PCOS pathogenesis. Transcriptomic profiling revealed dysregulated cell cycle progression, disrupted cholesterol homeostasis, and chronic inflammation in PCOS ovaries. Of these, cholesterol biosynthesis genes (e.g., Ebp, Dhcr7) were broadly suppressed, while efflux (Abca1) and metabolism-related (Cyp27a1) genes showed opposing alterations. Cross-species analysis identified CBX2 as consistently upregulated in both rat and human PCOS GCs, where it strongly correlated with accelerated cell proliferation and impaired cholesterol homeostasis. Mechanistically, exposure to EDCs (BPA and DDT) significantly induced CBX2 expression in human GCs. ChIP-seq analysis demonstrated that CBX2 directly binds to and represses genes from cholesterol-homeostasis-associated transcriptional networks-including CSRNP1, DDIT3, and FOSL1-through H3K27me3-mediated epigenetic silencing. Functional validation showed that CBX2 knockdown suppressed GCs proliferation, reduced lipid droplet accumulation while restoring normal cell cycle distribution. Single-cell RNA-seq confirmed elevated CBX2 activity specifically in PCOS GCs, particularly during G2/M phase, where it exhibited the strongest negative correlation with cholesterol homeostasis signatures (rs = -0.23). These findings reveal a novel EDC-CBX2-H3K27me3 epigenetic axis that decouples GC proliferation from metabolic support functions, establishing CBX2 as both a molecular biomarker and potential therapeutic target for environment-associated PCOS.
Disorders of isolated deficient aldosterone action involve insufficient production of aldosterone caused by aldosterone synthase deficiency (ASD) type I or type II (formerly named corticosterone methyl oxidase (CMO) deficiency type I or type II), as well as pseudohypoaldosteronism (PHA) featuring end-organ hormone resistance. Aldosterone is a key regulator of sodium-potassium homeostasis and blood pressure. Deficient action is characterized by arterial hypotension, hyponatremia, hyperkalemia, and dehydration. We investigated whether gas chromatographic-mass spectrometry (GC-MS) urinary steroid metabolome analysis allows for delineation of these entities.44 urinary steroid metabolites from spot urine (µg/L) were quantified by targeted GC-MS from 124 infants with aldosterone deficient states and 138 matched controls. Relative enzymatic activities were calculated from precursor-to-product metabolite ratios.Decision tree analysis identified tetrahydroaldosterone (TH-aldo), tetrahydro-11-dehydro-corticosterone (6α-OH-THA), and 18-hydroxy-tetrahydro-11-dehydro-corticosterone (18-OH-THA) as sequential biomarkers distinguishing controls, PHA, ASD I and ASD II, with high specificity (94%) and sensitivities (97%, 92%, and 73%), respectively. PHA showed grossly elevated metabolites of aldosterone and its precursors. With respect to precursor-to-product metabolite ratios characterizing relative enzyme activities, the ratio for aldosterone synthase activity discriminated best between PHA and both ASD groups, whereas the ratios for 18-hydroxylase activity and 18-oxidase activity differentiated ASD I from ASD II.Targeted GC-MS urinary steroid metabotyping from spot urine provides a non-invasive and highly reliable new diagnostic tool for delineating aldosterone deficient states in infants. Various metabolites and metabolite ratios effectively discerned controls, patients with ASD subtypes and PHA. The quantitative biomarkers we found allow for a steroid metabolomics based precision medicine approach.
Menopause is a universal physiological transition marked by the permanent cessation of ovarian estrogen secretion, with far-reaching consequences for cardiometabolic health. Among these consequences, lipid dysregulation stands as one of the most clinically significant, substantially elevating the risk of cardiovascular disease and metabolic syndrome in postmenopausal women. Estrogen deficiency disrupts hepatic lipid metabolism, alters lipoprotein particle composition, promotes visceral adiposity, and triggers a chronic low-grade inflammatory state, collectively establishing an atherogenic lipid profile. Although the broad association between menopause and dyslipidemia has long been recognized, the precise cellular and molecular mechanisms underlying this relationship remain incompletely characterized. This review synthesizes current evidence on the pathophysiological mechanisms linking estrogen deficiency to lipid dysregulation in menopause, encompassing alterations in LDL and HDL metabolism, triglyceride accumulation, changes in lipoprotein lipase (LPL) activity, hepatic lipid accumulation, and the roles of estrogen receptor signaling in adipose tissue and liver. Current and emerging therapeutic strategies are also discussed, including hormone replacement therapy (HRT), lifestyle modifications, lipid-lowering pharmacotherapy, and novel molecular targets. Advancing the mechanistic understanding of these processes is essential to developing precision therapeutic approaches that effectively address the heightened cardiometabolic risk in postmenopausal women.
Age-related female infertility is a major reproductive health challenge that accelerates sharply after the age of 34, primarily due to declining oocyte quality, increased chromosomal abnormalities, and impaired embryonic developmental competence. Emerging evidence identifies chronic hyperactivation of the mechanistic target of rapamycin (mTOR) signalling pathway as a central molecular driver of ovarian aging, promoting excessive ribosome biogenesis, impaired proteostasis, suppressed autophagy, mitochondrial dysfunction, and oxidative stress within oocytes and surrounding cumulus cells. Although rapamycin, the prototypical mTOR inhibitor, has demonstrated promising effects in improving ovarian function and in vitro fertilization outcomes, its teratogenic potential, immunosuppressive properties, metabolic side effects, and prolonged pre-conception washout requirements limit its clinical applicability in fertility management. This review synthesises current evidence on the role of mTOR in ovarian aging and is complemented by an original molecular docking analysis performed by the authors to evaluate the interaction between pentadecanoic acid and the mTOR kinase domain, an endogenous odd-chain saturated fatty acid, as a potential fertility-safe mTOR modulator. A comprehensive review of the literature was conducted using PubMed and related databases, encompassing pentadecanoic acid biochemistry, molecular mechanisms, mTOR signalling architecture, ovarian aging biology, rapamycin pharmacology, and molecular docking studies. Available evidence indicates that pentadecanoic acid activates AMP-activated protein kinase (AMPK), modulates PPAR-α/δ signalling, supports cellular antioxidant defence, and collectively attenuates anabolic mTOR activity while promoting autophagic recycling and metabolic homeostasis. Molecular docking analysis against the mTOR kinase domain (PDB ID: 4JSV) demonstrated that pentadecanoic acid binds within the active site with a binding energy of -4.4 kcal/mol through interactions with key hydrophobic residues, including Leu1936, Ile1939, Tyr2144, Val2227, and Gly2142, whereas rapamycin exhibited a stronger affinity (-10.1 kcal/mol). Unlike rapamycin, pentadecanoic acid is endogenously produced, compatible with pregnancy, and requires no washout period. Collectively, these findings position pentadecanoic acid as a promising endogenous mTOR modulator with potential therapeutic relevance for age-related female infertility, warranting further mechanistic investigations and well-designed human clinical trials.
The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor that plays a critical role in regulating cell proliferation, survival, and differentiation. Aberrant activation or overexpression of EGFR has been observed in several cancers, including prostate cancer (PCa), and is associated with aggressive tumor behavior and poor prognosis. The development and progression of PCa largely depend on the involvement of androgen receptor (AR) pathways, which are directly related to EGFR signaling. Research indicates that EGFR can affect AR activity, increasing transcriptional activity or promoting ligand-independent activation, which may lead to castration-resistant prostate cancer (CRPC). Furthermore, emerging evidence suggests that estrogen receptors (ERs) may also interact with EGFR signaling in prostate tissue. These may influence tumor growth, interactions with cellular plasticity, and therapy resistance, but their exact mechanisms require further investigation. Identifying and improving treatment strategies for advanced and treatment-resistant PCa requires understanding the interplay between the EGFR, AR, and ER pathways. However, clinical trials have shown limited success in targeting EGFR alone, possibly through compensatory mechanisms via steroid hormone receptors. Therefore, therapies that simultaneously target EGFR and AR/ER activity may be more effective. Continued research into the molecular interplay between these pathways will broaden our understanding of prostate cancer biology and support the development of more personalized and effective treatments. In this review will focus on EGFR/HER1 and its putative role in prostate cancer. Furthermore, we discuss the potential interaction between EGFR, androgen receptor (AR), and estrogen receptor (ER) signaling pathways.
The prostate is one of the important androgen-dependent organs in the male reproductive system. Although its ability for local steroid hormone synthesis is recognized, the regulatory mechanisms, particularly the role of hormones and the seasonal steroidogenesis expression within the tissue, remain unclear. This study investigated the phenomenon in the seasonal breeder muskrat (Ondatra zibethicus) by comparing breeding (B) and non-breeding (NB) season prostates through histology, immunohistochemistry (IHC), RT-qPCR, and hormone assays. Anatomy shows that the prostate is markedly enlarged during the breeding season. Immunohistochemistry revealed a marked cellular compartmentalization: luteinizing hormone receptor (LHR), steroidogenic acute regulatory protein (StAR), and Steroid 5-alpha-reductase 2 (SRD5A2) were predominant in epithelial cells, whereas cytochrome P450 family 11 subfamily A member 1 (P450scc) and steroid 17 alpha-hydroxylase (P450c17) were primarily localized to stromal cells. The gene expression of the steroidogenesis pathway was coordinately upregulated in the breeding season, and largely downregulated in the non-breeding season, which was further validated at the protein level by Western blot analysis showing significantly higher expression of LHR, P450scc, SRD5A2, and androgen receptor (AR) in the breeding season compared to the non-breeding season. The prostate in the breeding season contained higher levels of intra-tissue testosterone (T) and dihydrotestosterone (DHT). To investigate the underlying mechanism, we performed in vitro experiments using primary cultured muskrat prostate cells. Furthermore, in vitro experiments demonstrated that human chorionic gonadotropin (HCG) treatment promoted the expression of LHR and steroidogenic enzymes and elevated the secretion of T and DHT into the culture media. This induction was inhibited by the Protein Kinase A (PKA) inhibitor H89, which also abolished the HCG-induced increase in T and DHT secretion. H89 pre-treatment abolished the HCG-induced upregulation, confirming the presence of the LH-PKA pathway regulating steroidogenesis in the prostate. Taken together, our results reveal that LH-mediated activation of local steroidogenesis may regulate the seasonal growth of prostates in male muskrats.
Hypermobile Ehlers-Danlos Syndrome (hEDS), characterized by joint hypermobility and multisystem involvement, is the most common type of EDS. Its comorbidities are wide-ranging, reflecting the involvement of connective tissue and its role in a multitude of processes. hEDS has been hypothesized to have hormonal aspects since the disorder is diagnosed more often in women and symptom changes closely correlate with hormonal shifts. To better understand the etiology and biochemical changes in hEDS and its comorbidities, a multiple-omics study was performed in women, controls (n = 45) and those with hEDS (n = 45), alongside the collection of questionnaires related to symptom severity. Metabolomic evaluation was performed on serum samples and RNA isolated from fibroblasts cultured from skin punches was analyzed for transcriptomics. Samples from hEDS patients had statistically significantly lower levels of multiple androgen sulfate metabolites, compared with controls, driven largely by participants aged 30-49. Changes to other classes of steroid hormones (corticosteroids, progestogens, and estrogens) were largely not significant between hEDS and control groups. Transcriptomics of skin fibroblasts from hEDS patients revealed downregulation of multiple enzymes involved in biosynthesis, metabolism, and disposition of androgens, compared with controls. Multiple steroid hormones correlated with symptoms surveyed in 18-29 year old participants with hEDS. Shifts in steroid hormone metabolites in hEDS compared with controls may be due to changes to metabolism and disposition, but more validation is necessary to be conclusive. This data provides insights into the unclear links between steroid hormones and hEDS and its comorbidities.
Estrogen operates as a pleiotropic steroidal, neuroendocrine modulator to combat accelerated brain ageing and neurodegeneration by addressing a convergent inflammatory-metabolic trio. Estrogen receptor-dependent neural cellular signalling reduces TLR4-mediated immune priming and NF-κB activation, preventing NLRP3 inflammasome assembly and pro-inflammatory cytokine release. Concurrently, estrogen increases SIRT1 activity, restoring metabolic and epigenetic equilibrium while inhibiting HMGB1 acetylation, translocation, extracellular release, and activation of the stress-response pathway. Coordinated regulation of the TLR4-NFκB-NLRP3 and SIRT1-HMGB1 molecular triad reduces chronic neuroinflammation, preserves neuronal integrity, metabolic resilience, and slows persistent inflammation-driven brain ageing. This highlights estrogen and estrogen-based steroidal modulators as promising therapeutic candidates for reversing accelerated cognitive ageing and neurodegenerative disorders. However, a crucial research gap persists in the absence of a systems-level assessment of neurosteroids as a multi-target regulator of convergent innate immunological and metabolic signalling networks. The control of the TLR4-NFκB-NLRP3 inflammasome axis and the SIRT1-HMGB1 metabolic-epigenetic checkpoint has not been well studied as an interrelated, steroidal druggable trifecta driving brain homeostasis and neurodegeneration. These pathways are often studied in isolation, despite overwhelming evidence that their bidirectional interplay contributes to persistent neuroinflammation, immunometabolic dysfunction, and cellular senescence. This review synthesises evidence from molecular endocrinology, biochemical, pre-clinical, and clinical models to advance a mechanistically integrated and therapeutically actionable framework that aligns into a unified endocrine, metabolic, and immune target-driven framework relevant to complex, inflammation-driven brain ageing, thereby offering a strong foundation and paving the way for future molecular target validation and disease-modifying, steroid-mimetic interventions against neurodegeneration.
Cytochrome P450 (CYP450) enzymes play critical roles in the pathophysiology of neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), Rett syndrome (RTT), and attention-deficit hyperactivity disorder (ADHD). Although traditionally associated with hepatic and intestinal xenobiotic metabolism, several CYP450 isoforms are expressed in the central nervous system, where they regulate essential pathways involving vitamin D and cholesterol-two molecules fundamental to neural development, synaptogenesis, and membrane homeostasis. The cholesterol-CYP27A1-27-hydroxycholesterol (27-OHC)-liver X receptor (LXR) axis has emerged as a critical regulator of neurodevelopment, influencing INSIG proteins, LXRs, and LDL receptors. Additionally, members of the CYP1A, CYP2B, CYP2C, and CYP3A families contribute to neuroendocrine balance and fetal brain maturation. Dysregulation of these pathways may contribute to synaptic dysfunction, neuronal hyperexcitability, and metabolic imbalance observed in NDDs. This review highlights the interplay between CYP450 enzymes, vitamin D metabolism, and cholesterol homeostasis, emphasizing their mechanistic relevance in ASD and related disorders, and discusses the therapeutic potential of targeting CYP450-mediated pathways to restore metabolic and neurodevelopmental equilibrium.
Polycystic ovary syndrome (PCOS) is the most prevalent endocrine-metabolic disorder in women of reproductive age, and is characterized by hyperandrogenism, anovulation, and polycystic ovarian morphology. Emerging molecular evidence has identified dysregulated ovarian steroidogenesis as a major contributing mechanism linking reproductive and metabolic phenotypes in PCOS, acting in concert with neuroendocrine and metabolic dysfunction. This review synthesizes current knowledge on enzymatic and regulatory perturbations driving androgen excess and estrogen deficiency in PCOS, emphasizing their mechanistic, diagnostic, and therapeutic implications. Dysregulated steroidogenic enzymes and associated signaling pathways contribute to androgen excess, impaired folliculogenesis, and metabolic dysfunction in PCOS. Importantly, these steroidogenic alterations are not uniform across all patients with PCOS but vary according to hyperandrogenic, anovulatory, ovulatory, lean, obese, reproductive, and metabolic phenotypes. Particular focus is placed on how these molecular derangements disrupt theca-granulosa cell communication, impair folliculogenesis, and promote hyperandrogenism, oxidative stress, and insulin resistance in the ovaries. This review also discusses therapeutic strategies according to evidence level, distinguishing established PCOS treatments such as lifestyle intervention, insulin sensitizers, ovulation-induction agents, hormonal regulators, and anti-androgens from investigational enzyme-specific inhibitors and speculative precision approaches such as gene editing and exosome-based delivery systems. Collectively, these insights underscore that the pathophysiology of PCOS extends beyond endocrine imbalance to encompass multi-omic alterations in metabolism and signaling. Understanding enzyme-level dysregulation offers opportunities for mechanism-based interventions that can restore steroidogenic homeostasis, improve fertility outcomes, and mitigate long-term metabolic risk. Future research should prioritize enzyme-signal interdependencies and develop personalized therapeutic strategies targeting the biochemical dysfunctions of PCOS.
Fracture healing is a complex process where osteoblasts appear as central players in restoring bone integrity through proliferation, differentiation, and mineralization. Previous studies have identified several compounds in cortex moutan, which have been testified to significantly expedite osteoblast proliferation and differentiation. In this study, cell experiments were utilized to screen gallic acid, the key active substance in Moutan Cortex that promote osteogenesis. Subsequently, the targets of gallic acid were analyzed through network pharmacology. As a result, HRAS was a potential target of gallic acid. We further verified the regulation of the RAS/ERK pathway by gallic acid through bioinformatics and Western blot (WB) experiments. Finally, through cell and animal experiments, we demonstrated that Moutan Cortex promoted osteoblast differentiation and relieved osteoporosis.
Exemestane (EMT) is a third-generation steroidal aromatase inhibitor extensively used in hormone receptor (HR)-positive breast cancer therapy and has been known to exert cardiovascular effects during prolonged treatment. The current study was planned to investigate the dose-dependent cardiotoxic effects of EMT. Thirty-two Sprague Dawley rats were randomly divided into four groups i.e., control group, EMT (5 mg/kg), EMT (15 mg/kg) and EMT (25 mg/kg) groups. Gene expression analysis showed downregulated expression of ATP2A2 (SERCA2a), CACNA1C, NOS3 (eNOS) and KLF2 coupled with marked upregulation in the expression of RYR2, PLN, CAMK2D, VEGFA, EDN1 and ICAM1, suggesting impaired calcium handling and endothelial dysfunction. The antioxidant enzymes (CAT, SOD, GPx, GST, GSR, HO-1 and GSH) were decreased significantly while the concentrations of ROS and MDA were increased in dose-dependent manner after EMT intoxication. Cardiac function assessment by echocardiography showed that EMT caused dose-dependent cardiac dysfunction as evidenced by reduced heart rate, wall thickness and cardiac chamber volumes of the ventricles thereby suggesting progressive ventricular remodeling, myocardial hypertrophy, and chamber enlargement particularly at 25 mg/kg EMT administration. Furthermore, EMT intoxication caused elevation in the levels of CK-MB, CPK, troponins, LDH, BNP, NT-proBNP and CRP. Significant upregulation observed in the levels of NF-κB, TNF-α, IL-1β, IL-6 and COX-2 after EMT administration. Moreover, EMT exposure promoted the levels of Bax, Caspase-3 and Caspase-9 while suppressing the levels of Bcl-2. Histopathological analysis demonstrated progressive myocardial degeneration, edema, inflammatory infiltration and peripheral necrosis. Overall, chronic EMT exposure leads to severe, dose-dependent cardiotoxicity, characterized by calcium dysregulation, oxidative stress, inflammatory responses, endothelial dysfunction and apoptosis, and thus warrants cardiac monitoring during prolonged EMT therapy.
The human microbiome, a dynamic endocrine organ, exerts profound systemic influence through the production of bioactive metabolites. While the microbiome-gut-brain axis is well-established, the direct conduit between the gut microbiota and the reproductive system, the Microbiome-Gut-Gonad Axis, remains an emerging paradigm. This review explored cutting-edge evidence to construct a comprehensive model of the Microbiome-Gut-Gonad axis, focusing on the mechanistic roles of specific microbial metabolites in both physiological reproductive function and the pathogenesis of endocrine disorders. We move beyond mere correlation to elucidate how gut-derived molecules, such as short-chain fatty acids (SCFAs), secondary bile acids, and indole derivatives, directly and indirectly modulate the hypothalamic-pituitary-gonadal (HPG) axis by modulating the production of neuropeptides and hormones (Gonadotropin-releasing hormone (GnRH)) that regulate reproductive functions and also steroidogenesis and gametogenesis. We examine novel mechanisms including: the epigenetic regulation of steroidogenic enzymes by butyrate; the modulation of enterohepatic circulation of estrogens by β-glucuronidase-producing bacteria; and the role of tryptophan metabolites as ligands for aryl hydrocarbon receptor (AhR) in ovarian and testicular function. Furthermore, we critically appraise the disruptive potential of dysbiosis-driven metabolite shifts in PCOS, endometriosis, and male infertility, highlighting microbial metabolite signatures as promising exploratory biomarkers that require standardized, multi-center clinical validation before diagnostic use. At present, these signatures should be considered candidate biomarkers only, because external validation cohorts, assay reproducibility, and clinically meaningful estimates of sensitivity, specificity, predictive values, and clinical utility have not yet been established. Therapeutically, we evaluate innovative interventions, including precision probiotics, postbiotics, and dietary strategies targeting specific bacterial guilds, but these approaches remain investigational because current human evidence is still limited and heterogeneous. Finally, by integrating microbial endocrinology into reproductive medicine, this review establishes a new framework for understanding the etiology of reproductive endocrine disorders and paves the way for microbiome-targeted therapeutic avenues. Importantly, the evidence base is tiered: mechanistic statements in this review are drawn primarily from in vitro and animal studies, human disease links are described separately as observational evidence, and interventional claims are limited to early clinical studies and randomized trial summaries.
