Nonylphenol (NP) is a chemical compound belonging to the class of alkylphenols (APs), known for its widespread environmental distribution and endocrine-disrupting properties. It is commonly used in the production of detergents, pesticides, and plastic materials and, owing to these properties, it can accumulate in both aquatic and terrestrial ecosystems. As a xenoestrogenic compound, NP can bind steroid receptors, including estrogen receptors (ERs), thereby activating ER-dependent pathways. In this work, we investigated the effects of NP alone and in combination with the endogenous hormones 17β-oestradiol (E2) and/or testosterone (T) on a human non-tumoral prostate cell line (PNT1A). Cell viability and migration assays, together with analysis of ER expression and localization, were carried out to assess the xenoestrogenic activity of NP, particularly in the presence of E2 and T. Our results showed that NP retained its endocrine-disrupting features in the mixtures, positively affecting cell viability, except for the NP+E2 mixture, in which cell viability did not significantly differ from control, suggesting an antagonistic interaction between NP and E2. The mixtures also interfered with steroid receptor dynamics, affecting receptor expression and delaying receptor localization and activation kinetics. Moreover, all mixtures negatively affected cell migration compared with treatment with endogenous hormones alone. In conclusion, our results demonstrate that NP retains its xenoestrogenic behavior in mixture, inducing a significant alteration in prostate cell homeostasis.

Background: Shilajit is a complex mineral-organic resin derived from rocks of varied provenance, and it has been assessed here for its antioxidant activity and acute in vivo toxicity. Methods: Despite the increasing interest in shilajit as a dietary supplement, systematic data about its acute toxicity, biochemical safety, and biological effects remain limited. Results: Samples demonstrated moderate free radical scavenging ability, with IC50 values between 1.657 and 3.502 mg/mL for ABTS and 2.042 to 6.011 mg/mL for DPPH. Phenolic profiling identified samples 6 and 7 as the richest in urolithin A and phenolic acids. No fatalities, clinical signs of toxicity, or notable changes in food and water consumption or body weight gain were observed during the 14-day period, suggesting minimal single acute oral toxicity (LD50 > 2000 mg kg-1). Serum analysis revealed changes in lipid and testosterone profiles. In an exploratory follow-up of the two samples with the highest free testosterone values (6 and 7), total and free testosterone were increased approximately 2.5-fold and 3.5-fold, respectively, relative to the control group. Conclusions: The tested shilajit samples were tolerated under the conditions of this study, with no mortality or overt clinical toxicity during the 14-day observation period. Histopathological examination revealed mild to moderate degenerative and necrotic changes in hepatic and renal tissues, without hepatic fibrosis or pronounced renal interstitial lesions. These findings support satisfactory single acute oral tolerability under the study conditions but do not exclude tissue effects or establish their reversibility. Further studies are warranted to assess the long-term safety of standardized shilajit resin.

Background/Objectives: Benign prostatic hyperplasia (BPH) is a common age-related disorder in elderly men and a major cause of lower urinary tract symptoms. Lycopus lucidus Turcz. ex Benth. has been traditionally used in East Asian medicine, but its effects on BPH have not been investigated. This study evaluated the effects of L. lucidus extract (LLE) on testosterone propionate (TP)-induced BPH in rats and explored associated changes in androgen metabolism. Methods: Male Sprague-Dawley rats were orchiectomized except for the sham group and injected with TP (3 mg/kg, s.c.) for 28 days. During TP exposure, rats received oral LLE (100 or 200 mg/kg/day), finasteride (1 mg/kg/day), or vehicle. Prostate weight, prostate index, and histological changes in the ventral prostate were evaluated. Serum testosterone and dihydrotestosterone levels were measured using an enzyme-linked immunosorbent assay. The protein expression of 5α-reductase type 2, aromatase, Bax, and Bcl-2 in the ventral prostate tissue was analyzed by Western blotting. Results: LLE (200 mg/kg) significantly reduced prostate weight and prostate index and improved histological alterations, comparable to finasteride. LLE increased serum testosterone levels and decreased the dihydrotestosterone/testosterone ratio. Expression of 5α-reductase type 2 and aromatase in the ventral prostate tissue was significantly downregulated, while Bax and Bcl-2 expression and the Bax/Bcl-2 ratio remained unchanged. Conclusions: LLE attenuated TP-induced prostatic hyperplasia in rats, suggesting that modulation of androgen metabolism may contribute to its anti-hyperplastic effects. These findings support further investigation of L. lucidus extract in BPH.

Background: Sex hormones play crucial functions in the body via the genomic and non-genomic pathways. 5α- and 5β-dihydrotestosterone (5α- and 5β-DHT) are 5-reduced testosterone metabolites. We aimed to investigate the non-genomic effect of 5α- and 5β-DHT on uterine muscle contractility in vitro and in vivo for non-pregnant and 22-day-pregnant rats. Methods: The rapid in vitro action of 5α-DHT and 5β-DHT (10-9-10-3 M) on KCl (25 mM)-stimulated contractions was examined in an organ bath in the presence of several blockers and after endometrium removal. The actions of DHTs (10-4 M) and nifedipine (10-7 M) were also examined in contractions stimulated by KCl (40 mM) with a cumulative addition of CaCl2 (3-120 mM). Plasma DHT levels were measured by ELISA after a single intraperitoneal (i.p.) administration of DHT (10 mg/kg), and kinetic curves were obtained. The in vivo relaxing action of DHTs was detected by strain-gauge sensors. The animals received 5α- or 5β-DHT alone (3/10/30/100/300 mg/kg i.p.) or with flutamide (100 mg/kg i.p.). Results: DHT showed concentration-dependent relaxation of uterine muscle in vitro, with a higher potency observed for 5β-DHT. Among the blockers used, G15 and L-NAME reduced the potency of 5α-DHT in pregnant rats only. Both DHTs inhibited the contraction-increasing effect of CaCl2, proving their Ca2+ inhibiting effects. DHTs had similar cmax and tmax values in both non-pregnant and pregnant rats. DHT plasma levels before and 30 min after administration were proportional to the administered doses. Their single doses (30/100/300 mg/kg) elicited a flutamide-resistant uterine relaxing effect in vivo. Conclusions: DHTs or their analogs are candidates for further studies in the human uterus to establish their potential to treat conditions associated with uterine hyperactivity.

Porphyromonas gingivalis is a keystone periodontal pathogen strongly associated with periodontitis progression. Although testosterone levels have been associated with periodontal health, its direct effects on P. gingivalis virulence remain poorly understood. The aim of this study was to investigate the impact of testosterone exposure on the key virulence characteristics of P. gingivalis strain W50. We found that testosterone significantly increased the growth and biofilm biomass of P. gingivalis W50 after 48 h. Furthermore, testosterone enhanced the extracellular gingipain activity of both lysine and arginine gingipains from P. gingivalis. We also found that IL-1β release from gingival epithelial cells was significantly lowered following infection with testosterone-primed P. gingivalis compared with unprimed W50. At the mRNA level, no differences in pro-IL-1β, IL-8, or CXCL10 gene expression were detected in gingival epithelial cells infected with testosterone-primed P. gingivalis compared with unprimed W50. Finally, testosterone priming significantly enhanced the ability of P. gingivalis to colonize and invade gingival epithelial cells. Overall, these findings indicate that testosterone exposure modulates several virulence-associated phenotypes of P. gingivalis W50 in vitro. The mechanisms underlying these effects and their relevance to periodontal disease in vivo remain to be determined.

Glucagon-like peptide-1 (GLP-1) receptor agonists and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide are increasingly used to treat obesity and type 2 diabetes in men of reproductive age, but practical guidance for counseling men planning fatherhood remains limited. This structured narrative review distinguishes endocrine, semen, sexual-function, and clinical fertility outcomes. In metabolically impaired men, studies largely involving liraglutide or semaglutide report increases in total testosterone; free-testosterone findings are inconsistent, and the available small short-term studies did not show the marked gonadotropin suppression expected with exogenous testosterone. Some studies report favorable changes in semen parameters, but samples are small, populations heterogeneous, and medication effects cannot be separated reliably from weight loss. The present search identified no adequately powered GLP-1-specific prospective study that prespecified sperm DNA fragmentation, natural conception, assisted-reproduction outcomes, clinical pregnancy, or live birth. Sexual-function findings are mixed and do not establish causality. Evidence on paternal preconception exposure is insufficient, and pregnancy-related label precautions do not by themselves establish risk from paternal exposure. No eligible controlled tirzepatide-specific study assessing semen or clinical fertility outcomes was identified by this search. These therapies should be used for established metabolic indications, not as male infertility treatments. The proposed framework is author-developed, evidence-informed, non-validated, and intended for individualized counseling and prospective evaluation.

Background: Gender-affirming testosterone therapy is an essential component of medical transition for transgender men. Despite its widespread use, the histopathological effects of testosterone exposure on the uterus, ovaries, and fallopian tubes remain incompletely characterized. This study aimed to characterize histopathological findings in the gynecologic organs of transgender men receiving testosterone therapy before gender-affirming hysterectomy with bilateral salpingo-oophorectomy. Methods: This retrospective cohort study included transgender men who underwent laparoscopic hysterectomy with bilateral salpingo-oophorectomy at a tertiary referral center between 2015 and 2019. Demographic characteristics, duration of testosterone therapy, operative findings, and histopathological results were reviewed. Estrogen receptor (ER) and progesterone receptor (PR) expression in uterine tissues was assessed immunohistochemically. Results: Fifty-two transgender men were included. The median age was 25.5 years (range, 19-46 years), the median body mass index was 24.8 kg/m2, and the mean duration of testosterone therapy was 16.1 ± 7.8 months. Proliferative endometrium was the predominant pattern (78.8%), followed by inactive (17.3%) and atrophic (3.8%) endometrium. Endometrial polyps were identified in 13.5% of patients. Multifollicular ovarian morphology was observed in 90.4%, and paratubal cysts in 63.5%. No premalignant or malignant lesions were detected. ER expression was positive in all endometrial samples and in 92% of myometrial specimens, while PR expression was preserved in all evaluated uterine tissues. Conclusions: In this cohort, proliferative endometrium and multifollicular ovarian morphology were common despite testosterone therapy, and uterine ER and PR expression remained detectable. The absence of premalignant or malignant lesions was reassuring within the observed exposure period; however, the retrospective design, modest sample size, absence of a control group, limited characterization of hormone exposure, and lack of longitudinal follow-up preclude conclusions regarding long-term oncologic safety or malignancy risk.

Background: This study aimed to investigate the association between metabolic and atherogenic indices and erectile dysfunction (ED) severity, and to compare their diagnostic performance in predicting severe ED. Methods: This retrospective study included 221 men with ED between January 2025 and January 2026. ED severity was assessed using the International Index of Erectile Function-5 (IIEF-5). The triglyceride-glucose (TyG) index, atherogenic index of plasma (AIP), Castelli Risk Index-1 and -2, and atherogenic coefficient (AC) were calculated from routine laboratory parameters. Correlation, logistic regression, and ROC analyses were performed. Results: Patients with severe ED (n = 57) had significantly higher triglyceride, fasting glucose, TyG, and AIP levels and lower high-density lipoprotein cholesterol (HDL) levels than those with mild-to-moderate ED (all p < 0.05). TyG (ρ = 0.369, p < 0.001) and AIP (ρ = 0.359, p < 0.001) were positively correlated with severe ED. In the multivariable model, the TyG index remained associated with severe ED after adjustment for AIP, age, BMI, total testosterone, and the TyG-by-testosterone interaction (OR: 4.354, 95% CI: 1.668-11.364; p = 0.003). Total testosterone was not independently associated with severe ED (p = 0.510), and the TyG-by-testosterone interaction was not significant (p = 0.281). ROC analysis showed that TyG had the best predictive performance (AUC: 0.743). Conclusions: The TyG index showed discrimination for IIEF-5-defined severe ED and may have value as a complementary metabolic risk-stratification parameter.

Wnt/β-catenin signaling is a key regulator of hair follicle cycle progression, and aberrant activation or suppression of this pathway has been implicated in the pathogenesis of alopecia. Horse oil (HO) and Folium Isatidis (FI) have been traditionally used in East Asian medicine for hair growth, but their combined molecular mechanism remains unclear. We evaluated a topical preparation combining HO and FI (HOFI) in two C57BL/6 mouse models: physiological depilation (telogen-to-anagen transition) and testosterone-induced seborrheic alopecia. Hair growth was assessed by gross appearance, hair length, and histomorphometry (follicle number, size, dermal thickness). Plasma and skin levels of vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1) were measured by ELISA. Protein expression of β-catenin, Bcl-2, and Bax in skin tissue was analyzed by Western blotting. Compared with NC, HO, FI, and HOFI significantly increased hair length, follicle density and size, and dermal thickness (p < 0.05). All three treatments upregulated VEGF and β-catenin, suppressed TGF-β1, elevated Bcl-2, and reduced Bax expression. HOFI exhibited significantly greater effects than either monotherapy across all endpoints (p < 0.05). HOFI promotes hair growth by activating the VEGF/β-catenin signaling axis, inhibiting TGF-β1, and shifting the Bcl-2/Bax balance toward follicular cell survival. These findings provide a molecular rationale for developing HO-FI combinations as topical agents for alopecia.

Background: The demographic crisis observed in industrialized countries has been accompanied by a decline in the reproductive potential of human populations. One of the causes for the global deterioration in men's reproductive health is adiposity and sedentary lifestyle, leading to reduced fertility and a decrease in androgen status. The aim of the study was to assess the association between abdominal obesity and semen parameters, including sperm DNA fragmentation, as well as key indicators of hormonal and metabolic status in young men from the general population. Methods: Our cross-sectional study was conducted among Russian and Belarusian men living in six cities. The examination of men (n = 1283, median age 23 years) included questionnaires, anthropometry, and the collection of peripheral blood and semen samples. Semen analysis was conducted according to WHO guidelines. Sperm DNA fragmentation index (DFI) was evaluated using the SCSA method. The serum and seminal zinc concentration was determined using spectrophotometry and direct calorimetry. Hormonal and metabolic levels were measured using commercial kits. Waist circumference (WC) was used as a surrogate marker of abdominal adiposity. Participants were allocated to three phenotypes: non-obese (control, WC < 94 cm), excess abdominal fat (94 ≤ WC < 102 cm) and abdominal obesity (WC ≥ 102 cm). Results: In our study population, 85.8% of participants were young (under 30 years of age), 8.6% had excess abdominal fat, 5.7% had abdominal obesity (AO), and 65.2% had normozoospermia. Men with AO were characterized by a decrease in semen volume, total sperm count, sperm concentration and progressive motility compared to the non-obese control. DFI was significantly higher in obese compared to non-obese men. Obese participants had significantly lower testosterone and inhibin B levels, but higher FSH and leptin levels compared to non-obese men. Men with AO had elevated serum zinc levels but reduced seminal zinc content. Abdominal obesity was also associated with significant metabolic changes, in particular, with increased levels of triglycerides, total cholesterol, low-density lipoproteins, fasting glucose and uric acid. AO-related testosterone deficiency (serum testosterone level ≤ 12.1 nmol/L) was detected in 38.7% of obese men and was accompanied by elevated DFI, levels of FSH, and zinc, as well as unfavorable changes in metabolic indicators. Physically active AO men (who engaged in recreational sports or physical labor) demonstrated reduced anthropometric indicators of AO and leptin levels, increased LH and testosterone levels, and improved carbohydrate and lipid metabolism compared to sedentary AO men. Conclusions: AO is accompanied by a decrease in the activity of Leydig and Sertoli cells, as well as an imbalance of the hypothalamic-pituitary-testicular axis and metabolic status. AO, associated with testosterone deficiency or a sedentary lifestyle, is a potential risk factor for the weakening of male reproductive health. However, physically active stout men showed more favorable anthropometric, hormonal, and metabolic indicators compared with sedentary stout men. In the long term, obese men who ignore a correction of sedentary lifestyle are not protected from a decline in reproductive health.

Liver cirrhosis is frequently complicated by sarcopenia, a progressive and systemic loss of skeletal muscle mass and function that contributes substantially to increased morbidity, mortality, and healthcare utilisation. The pathogenesis of sarcopenia in cirrhosis is multifactorial, involving hyperammonaemia, altered protein turnover, hormonal and cytokine dysregulation, chronic inflammation, malnutrition, and broader metabolic disturbances. Increasing evidence suggests that these convergent pathological processes are mediated, at least in part, through dysregulation of myokine signalling pathways, particularly those involving myostatin. Myostatin, in concert with downstream effectors such as mechanistic target of rapamycin (mTOR), plays a central role not only in skeletal muscle homeostasis but also in systemic metabolic regulation, highlighting its relevance beyond muscle biology alone. Therapeutic strategies targeting myostatin signalling have been developed, with several myostatin inhibitors advancing into clinical trials. Emerging data indicate that these agents may increase skeletal muscle mass, reduce adiposity, and improve glucose metabolism in patients with sarcopenia and other metabolic disorders, supporting their pleiotropic metabolic effects. However, the mechanistic role and therapeutic implications of myostatin modulation in the specific context of coexisting cirrhosis and sarcopenia remain incompletely understood. This review summarises current knowledge on myokine-mediated regulation of muscle metabolism in cirrhosis, with a focus on the myostatin-mTOR axis. We critically evaluate existing and emerging myostatin-targeting approaches, including pharmacological inhibition and gene-based therapies, as potential strategies to restore muscle mass and function. Finally, we outline future directions for translational research aimed at modulating myostatin signalling in cirrhosis-associated sarcopenia, emphasising the need to elucidate its systemic metabolic effects to identify novel therapeutic targets and improve clinical outcomes in this population.

Iron deficiency (ID) represents one of the most prevalent nutritional disorders worldwide, affecting approximately 1.2 billion individuals. Beyond its well-established hematological consequences, emerging evidence demonstrates that ID profoundly impacts endocrine function across multiple organ systems. Iron serves as an essential cofactor for numerous enzymes involved in hormone synthesis, metabolism, and signaling pathways. This comprehensive review examines the bidirectional relationships between iron deficiency and endocrine pathologies, including thyroid disorders (hypothyroidism, Hashimoto's thyroiditis, thyroid peroxidase impairment), diabetes mellitus (types 1 and 2), obesity, Polyendocrine Metabolic Ovarian Syndrome (PMOS), male hypogonadism, adrenal insufficiency, growth hormone deficiency, pituitary dysfunction, and parathyroid disorders. We systematically analyze the molecular mechanisms linking iron metabolism to endocrine dysfunction, with particular emphasis on thyroid peroxidase activity, insulin secretion and sensitivity, hepcidin regulation, testosterone synthesis, and cortisol production. Furthermore, we critically evaluate the therapeutic potential of liposomal iron supplementation, a novel delivery system that offers superior bioavailability and gastrointestinal tolerability compared to conventional oral iron formulations. Randomized controlled trials demonstrate that liposomal iron achieves comparable efficacy to intravenous iron while significantly reducing adverse events. This review synthesizes current evidence to provide clinicians with a comprehensive understanding of iron-endocrine interactions and evidence-based recommendations for iron supplementation in endocrine disorders. Recognition of these complex relationships is essential for optimizing diagnostic and therapeutic approaches in patients with concurrent iron deficiency and endocrine dysfunction.

T-2 toxin is a typical fusarium mycotoxin that induces reproductive injury. As a male reproductive toxicant, impaired testosterone biosynthesis is the primary reproductive toxic effect induced by T-2 toxin. Therefore, clarifying how T-2 toxin disrupts testosterone synthesis at the molecular level and screening natural plant extracts that can alleviate this reproductive toxicity are of great importance. Lycopene (LYC) is a natural carotenoid known for its reproductive protective properties. Hence, this work assessed the protective efficacy and molecular mechanisms of LYC against T-2 toxin-caused testosterone synthesis disruption. Our results showed that LYC supplementation significantly alleviated testicular structural injury, restored testicular organ coefficients, and rescued serum and intracellular testosterone levels via transcriptional and translational upregulation of key steroidogenic proteins. Mechanistically, LYC suppressed T-2 toxin-triggered reactive oxygen species (ROS) accumulation, inhibited MAPK pathway activation, and prevented ROS/p38/TORC2/CREB axis activation, thereby restoring TORC2/CREB transcriptional activity and steroidogenesis. Pharmacological validation using SB203580 and NAC confirmed the central role of the ROS/p38/TORC2/CREB axis. Taken together, LYC alleviates T-2 toxin-triggered disruption of testosterone synthesis by inhibiting the ROS/p38/TORC2/CREB axis, and we identify LYC as a promising nutritional strategy against mycotoxin-caused reproductive toxicity.

Organoids serve as three-dimensional structures that offer spatial support and mimic cellular niches for experimental studies. The spatial and temporal association of fetal bovine adipose tissue-derived mesenchymal stem/stromal cells (AT-MSCs) with the expression of germ cell (GC) markers was evaluated in testicular organoids (TOs+AT-MSCs) under the effect of retinoic acid and testosterone (0.2, 2 and 20 µM). TOs+AT-MSCs were developed by the co-culture of Leydig, Sertoli, and peritubular myoid cells and PKH26+AT-MSCs and were analyzed for the expression of DAZL, STRA8 and UCHL1. TOs+AT-MSCs treated with 1 µM of retinoic acid and 2 or 20 µM of testosterone maintained their diameter after day 7 of culture. Pearson correlation coefficients (PCCs) of PKH26 and DAZL were higher (p < 0.05) at days 7 and 21 in TOs+AT-MSCs treated with 1 µM retinoic acid and 0.2 or 2 µM of testosterone, respectively. PCCs of PKH26 and STRA8 or UCHL1 were higher (p < 0.05) at days 14 and 21 in TOs+AT-MSCs treated with 1 µM retinoic acid and 0.2 or 2 µM of testosterone. Thus, exposure to 1 µM of retinoic acid and 2 µM of testosterone resulted in a similar diameter with respect to the control and spatial and temporal association of AT-MSCs and DAZL, STRA8 and UCHL1 markers in TOs+AT-MSCs.