Search Results (487)

Background/Objectives: Preeclampsia is associated with placental, vascular, and endocrine alterations. We compared peripartum maternal androgen-related hormone measures and anogenital distance (AGD) between women with preeclampsia and normotensive controls and assessed whether observed differences persisted after clinical and sampling-related adjustment. Methods: In this prospectively recruited cross-sectional case-control study, 129 women were assessed for eligibility during delivery admission, and 87 women with singleton pregnancies were included: 41 with preeclampsia and 46 normotensive controls. Serum total testosterone, estradiol, androstenedione, dehydroepiandrosterone sulfate, and sex hormone-binding globulin were measured, and the free androgen index (FAI) was calculated. AGD was assessed as anus-to-clitoris distance (AGDac) and anus-to-fourchette distance (AGDaf). Adjusted linear models used heteroscedasticity-consistent robust standard errors; hormone outcomes were log-transformed. Sensitivity analyses excluded at-delivery samples. Results: Women with preeclampsia had higher total testosterone (3.22 vs. 2.31 nmol/L; p = 0.032), higher FAI (0.95% vs. 0.64%; p = 0.007), lower mean AGDac (10.41 vs. 11.35 cm; p = 0.032), and lower mean AGDaf (3.20 vs. 3.72 cm; p = 0.008). In adjusted models, preeclampsia remained associated with higher total testosterone (+78.3%), higher FAI (+99.9%), shorter AGDac (−1.56 cm), and shorter AGDaf (−0.60 cm). After excluding at-delivery samples (n = 69), only the AGDac association remained statistically significant (−1.39 cm; 95% confidence interval, −2.62 to −0.16; p = 0.026). Conclusions: Peripartum endocrine and AGD differences were observed in preeclampsia. After exclusion of at-delivery samples, AGDac remained statistically significant, whereas the endocrine associations and AGDaf did not. These cross-sectional findings do not establish causality or predictive utility and warrant longitudinal confirmation. Full article

Sinanodonta woodiana is one of the most widely distributed freshwater bivalves in the world. However, the sexual dimorphism of this species remains poorly understood. In this study, gonads of clearly sexed S. woodiana were used to analyze steroid hormones, including estrone (E1), estradiol-17β (E2), estriol (E3), and testosterone (T), by liquid chromatography-mass spectrometry, followed by comparative transcriptome analysis. Compared with males, females showed no significant differences in E1 (p = 0.251), E3 (p = 0.136), or T (p = 0.917), whereas E2 concentration in females (15.2 ± 1.4 ng/g wet weight) was significantly higher than that in males (3.2 ± 1.7 ng/g wet weight) (p = 0.009). In addition, a total of 6716 differentially expressed genes (DEGs) were identified, including several sex-related genes such as forkhead box L2 (FOXL2), upregulated in females, and splicing factor 1 (SF1), upregulated in males. All DEGs were mainly enriched in biological processes such as metabolic process, cellular process, and single-organism process, as well as signaling pathways including neuroactive ligand–receptor interaction, glycosphingolipid biosynthesis—lacto and neolacto series, and oocyte meiosis. Our findings provide valuable information for sex identification of adult S. woodiana and offer candidate markers for future testing in juveniles, while also enhancing our understanding of its sex-specific gene-expression diversity. Full article

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. Full article

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. Full article

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. Full article

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. Full article

Testicular germ cell tumors (TGCTs) are the most common solid malignancy in young men and are highly curable, making reproductive and endocrine survivorship central concerns. Gonadal dysfunction is often attributed to orchiectomy and gonadotoxic therapy, yet semen and hormonal abnormalities may already be present at diagnosis. This narrative review synthesizes evidence obtained before orchiectomy and, where explicitly identified, broader pretreatment or pre-gonadotoxic evidence. Pre-orchiectomy studies generally report reduced sperm concentration, total sperm count, and progressive motility, together with impaired Sertoli and Leydig cell function. Tumor-derived human chorionic gonadotropin (hCG) can mask reduced Leydig reserve; in hCG-negative men, research-derived testosterone-to-luteinizing hormone and calculated free testosterone-to-luteinizing hormone ratios may aid risk stratification but lack standardized diagnostic cutoffs. Proposed contributors include testicular dysgenesis, contralateral impairment, germ cell neoplasia in situ, local tumor effects, and oxidative or proteomic alterations, although evidential support varies. These findings support fertility counseling at diagnosis, sperm cryopreservation before orchiectomy when feasible without delaying treatment, selected use of onco-microTESE when no usable ejaculate is available, and hCG-aware endocrine follow-up. Full article

Introduction: Male infertility is a complex global health challenge, with emerging evidence suggesting that vitamin D plays a pivotal role in testicular function and spermatogenesis. This systematic review and meta-analysis aimed to evaluate the impact of vitamin D supplementation on semen parameters and reproductive hormones in infertile men. Methods: A comprehensive search of electronic databases (PubMed, Cochrane Library, and Web of Science) was conducted to identify randomized controlled trials (RCTs) investigating vitamin D supplementation in infertile males. Primary outcomes included Follicle-Stimulating Hormone (FSH), total testosterone, and Sex Hormone-Binding Globulin (SHBG). Secondary outcomes focused on semen quality, specifically volume, concentration, and motility. Data were pooled using fixed-effects or random-effects models based on heterogeneity (I²). Results: Analysis of six trials (n = 696) revealed that vitamin D supplementation significantly increased total testosterone levels compared to controls (SMD: 0.38; 95% CI: 0.13, 0.62; p = 0.002), with no statistical heterogeneity (I² = 0%). In contrast, no significant differences were observed for FSH (SMD: 0.01; 95% CI: −0.28, 0.29; p = 0.96) or SHBG (SMD: 0.95; 95% CI: −0.12, 2.02; p = 0.08). For semen parameters, supplementation was associated with notable improvements in sperm concentration and progressive motility, whereas semen volume remained largely unchanged across the included studies. High heterogeneity in SHBG results (I² = 91%) suggests that individual study characteristics, such as baseline vitamin D deficiency, may influence hormonal responses. Conclusions: Vitamin D supplementation selectively enhances endocrine function by increasing testosterone levels and improves functional semen parameters in infertile men. These findings support the use of vitamin D as a cost-effective adjuvant therapy, though its impact on definitive fertility outcomes, such as live birth rates, requires further large-scale clinical investigation. Full article

Objectives: This study aims to compare the effects of three interventions, namely hyperbaric oxygen (HBO) therapy, HBO combined with lycopene (LYC) supplementation, and natural recovery, on oxidative stress and inflammatory responses following high-intensity exercise. The goal is to provide a theoretical foundation and methodological reference for strategies that help reduce fatigue after intense physical activity. Methods: Collegiate badminton players (n = 45) were randomly assigned to control, HBO, and HBO+LYC groups. Each group completed a 4-week intervention in accordance with its assigned protocol. The levels of oxidative stress, inflammation-related markers, and exercise-induced fatigue indicators were assessed before and after the intervention. Changes in these markers following high-intensity exercise were analyzed using repeated-measures ANOVA to evaluate the effects of HBO and HBO+LYC. Results: Following the intervention, the control group showed significant increases in malondialdehyde (MDA), interleukin-6 (IL-6), tumor necrosis factor (TNF), C-reactive protein (CRP), creatine kinase (CK), blood urea (BU), and heart rate (HR), along with a significant decrease in testosterone (T) (all p < 0.05). Compared with the control group, both intervention groups had significantly lower MDA, IL-6, TNF, CRP, CK, BU, and HR and higher superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (T-AOC) (all p < 0.05). Compared with the HBO group, the HBO+LYC group showed significantly higher CAT and lower IL-6 and CK levels (all p < 0.05). Conclusions: Both HBO alone and HBO+LYC effectively reduced oxidative stress, inflammation, and exercise-induced fatigue, as evidenced by decreased MDA, IL-6, TNF, CRP, CK, BU, and HR, along with increased SOD and CAT, T-AOC, and T. Moreover, HBO+LYC demonstrated superior efficacy over HBO alone for selected outcomes, particularly by further enhancing glutathione peroxidase 3 activity. These findings suggest that HBO, especially when combined with LYC, may be an effective strategy to attenuate oxidative stress and inflammation and promote recovery following high-intensity exercise. Full article

Background/Objectives: Polycystic ovary syndrome (PCOS) is closely associated with insulin resistance, metabolic syndrome (MetS), and non-alcoholic fatty liver disease (NAFLD); however, whether fatty pancreas disorder is also more common in PCOS remains insufficiently clarified. This study aimed to compare the frequency of hepatic and fatty pancreas disorder and tissue stiffness between women with PCOS and a healthy control group and to determine the relationship of these findings with metabolic and biochemical parameters. Methods: In this retrospective case–control study, 40 women diagnosed with PCOS according to the 2003 Rotterdam criteria and 40 age- and body mass index (BMI)-matched healthy women were evaluated by abdominal ultrasonography and two-dimensional shear wave elastography (2D-SWE) of the liver and pancreas. Four validated non-invasive indices of hepatic steatosis (NAFLD liver fat score, lipid accumulation product [LAP], hepatic steatosis index [HSI], FIB-4, APRI) were calculated and correlated with clinical, anthropometric, and biochemical data. MetS was defined according to International Diabetes Federation (IDF) criteria. Results: Fatty pancreas disorder was detected in 47.5% of PCOS patients versus 17.5% of controls (p = 0.008); hepatic steatosis was found in 37.5% and 15%, respectively (p = 0.04); these differences were observed despite similar age and BMI between groups. LAP and HSI scores were higher in the PCOS group (p = 0.02 and p = 0.005, respectively), as were serum triglyceride and total testosterone levels (p = 0.001 and p = 0.005, respectively). Overall MetS frequency did not differ between the PCOS and control groups (p = 0.61) but was significantly higher among participants with fatty pancreas disorder (p = 0.009) and hepatic steatosis (p = 0.05). Hepatic and pancreatic 2D-SWE values were significantly higher in participants with steatosis than in those without (p = 0.02 and p = 0.04, respectively), and both correlated positively with BMI (p < 0.001 and p = 0.003, respectively). Conclusions: The frequency of fatty pancreas disorder and hepatic steatosis is increased in women with PCOS independent of obesity, and both are associated with a higher frequency of MetS; the association between fatty pancreas disorder and PCOS remained significant in a multivariable analysis adjusted for BMI. Fatty pancreas disorder showed a stronger association with MetS, suggesting that it may serve as an early, low-cost, ultrasound-detectable marker of metabolic risk in PCOS and warrants systematic evaluation alongside hepatic steatosis. Full article

Background/Objectives: Women with polyendocrine metabolic ovarian syndrome (PMOS) are known to be at higher risk of developing metabolic-related disorders. Here, we conducted a retrospective observational study to compare physical and laboratory findings associated with PMOS across different generations. Methods: We analyzed 470 medical records from 155 patients with PMOS from December 2002 to March 2023. Demographic, metabolic, and hormonal data were extracted and compared among age groups: <30, 30s, and ≥40 years. Results: The 30s group had significantly higher total cholesterol and glycated hemoglobin levels than the <30 group, while the ≥40 group had significantly higher diastolic blood pressure than both the <30 and 30s groups. The ≥40 group had significantly higher follicle-stimulating hormone and lower testosterone levels than both the <30 and 30s groups. Dehydroepiandrosterone sulfate levels and ovarian volume also differed significantly among the three groups, with both parameters decreasing with age. No significant differences in fasting glucose, fasting insulin, or homeostatic model assessment for insulin resistance were observed among the three groups. In multivariable linear mixed-effects models including age, BMI, and PMOS diagnostic criteria, BMI was independently associated with a broader range of metabolic parameters than age, whereas age was independently associated with follicle-stimulating hormone, testosterone, dehydroepiandrosterone sulfate, and ovarian volume. Conclusions: The present findings suggest that metabolic risk factors may emerge from a relatively young age in women with PMOS, with BMI showing broader associations with metabolic parameters than age. These observations support current recommendations for long-term metabolic monitoring and lifestyle management in women with PMOS. Full article

Background: Exercise-induced fatigue (EIF) and exercise-induced muscle damage (EIMD) impair neuromuscular performance and delay post-exercise recovery. However, human evidence regarding the structural and functional recovery kinetics following Lactiplantibacillus plantarum GKK1 supplementation remains limited. Objective: This randomized, double-blind, placebo-controlled trial investigated whether 4 weeks of L. plantarum GKK1 supplementation improves functional recovery and modulates biochemical responses after an EIMD protocol in healthy men. Methods: Forty-eight healthy men with no regular exercise habits were randomly assigned to receive either placebo (n = 24) or L. plantarum GKK1 (two capsules daily, totaling 1.0 × 10¹¹ CFU; n = 24) for 28 consecutive days. The trial was registered at ClinicalTrials.gov (NCT06893549). After supplementation, participants completed 100 maximal plyometric jumps. Countermovement jump (CMJ), isometric mid-thigh pull (IMTP), and Wingate anaerobic performance were assessed before EIMD and at 3, 24, and 48 h post-EIMD. Blood biomarkers of muscle damage, inflammation, oxidative stress, endocrine response, and sympathoadrenal activity were analyzed, and urinary 3-methylhistidine and creatinine were measured. Results: Compared with placebo, GKK1 supplementation was associated with smaller post-exercise decrements in the CMJ rate of force development, relative peak force, jump height, IMTP relative peak force and peak RFD, and Wingate anaerobic performance (p < 0.05). GKK1 also attenuated post-exercise increases in CK, myoglobin, hs-CRP, and TBARS, and was associated with more favorable testosterone, HGH, catecholamine, and dopamine responses. At 24 h post-EIMD, urinary 3-methylhistidine and the 3-methylhistidine/urinary creatinine ratio were lower in the GKK1 group than in the placebo group. No adverse changes were observed in clinical safety biomarkers. Conclusion: These findings suggest that GKK1 may be a safe nutritional strategy to facilitate functional recovery, attenuate secondary inflammatory responses and modulate urinary markers associated with muscle breakdown following muscle-damaging exercise in healthy young men. Full article

Objective: Polycystic ovary syndrome (PCOS) and nonclassic congenital adrenal hyperplasia (NCAH) overlap clinically, but direct comparative data specifically addressing non-National Institutes of Health (non-NIH) Rotterdam phenotypes of polycystic ovary syndrome are limited. We compared women with polycystic ovary syndrome, of whom 66.7% were classified as having non-NIH Rotterdam phenotypes, with women with nonclassic congenital adrenal hyperplasia and healthy controls to characterize the extent of phenotypic overlap and evaluate the discriminatory performance of individual androgen measures. Methods: This single-center, prospective, exploratory cross-sectional study evaluated 58 women divided into three groups: PCOS (n = 24, Rotterdam criteria), NCAH due to 21-hydroxylase deficiency (n = 16, previously confirmed by adrenocorticotropic hormone (ACTH)-stimulated 17-hydroxyprogesterone (17-OHP)), and healthy controls (n = 18). Demographic, clinical, metabolic, and hormonal parameters were compared using analysis of variance (ANOVA), Kruskal–Wallis with Dunn’s post hoc test (Bonferroni-adjusted), and chi-square or Fisher’s exact tests. A sensitivity analysis was performed after excluding 12 participants receiving oral contraceptives (n = 8) or glucocorticoids (n = 4). Results: Within the PCOS group, 66.7% had non-NIH Rotterdam phenotypes. Hirsutism, defined as a modified Ferriman–Gallwey (mFG) score ≥ 8, was more frequent in both patient groups than in controls (p = 0.003) but did not differ between PCOS and NCAH. Total testosterone levels were 0.40 [0.20–0.60], 0.59 [0.45–0.94], and 0.20 [0.15–0.20] ng/mL in the PCOS, NCAH, and control groups, respectively, and androstenedione levels were 1.40 [1.20–2.20], 2.55 [1.64–4.07], and 0.87 [0.56–1.00] ng/mL, respectively; both were higher in the patient groups than in controls (both p < 0.001), without differing between PCOS and NCAH. Basal 17-OHP was the only parameter distinguishing NCAH from both PCOS and controls (p < 0.001). Dehydroepiandrosterone sulfate (DHEAS) levels were 356.5 [217–422], 292 [156–448], and 219 [146–240] µg/dL, respectively (p = 0.020), with a significant difference only between PCOS and controls. Anti-Müllerian hormone (AMH) levels were 3.27 [3.02–4.13], 3.13 [2.87–3.54], and 3.34 [2.93–5.37] ng/mL, respectively, with no between-group difference (p = 0.600). Other metabolic parameters, gonadotropins, estradiol, and prolactin showed no between-group differences. The principal hormonal findings remained unchanged after excluding women receiving oral contraceptives or glucocorticoids. Conclusions: In this PCOS cohort, in which 66.7% of women were classified as having non-NIH Rotterdam phenotypes, PCOS and NCAH showed substantial clinical, metabolic, and hormonal overlap, whereas basal early-follicular 17-OHP was the only parameter that consistently distinguished NCAH from both PCOS and healthy controls. These findings support the inclusion of basal 17-OHP in the evaluation of women presenting with hyperandrogenism. Full article

Objectives: This study aimed to evaluate the hormonal, hematologic, and biochemical outcomes of a conservative protocol for androgen therapy for transgender males. Methods: This was an observational, prospective, and comparative study conducted in the gender identity clinic of a tertiary university hospital. Testosterone therapy consisted of testosterone cypionate administered intramuscularly every month at an initial dosage of 25 mg/month, which was increased to 50 mg/month at month 3, 100 mg/month at month 6, and 250 mg/month at month 9. Assessments consisted of a complete blood count, biochemical tests, urine analysis, and hormonal tests. We also administered the Transgender Congruence Scale (TCS) post hoc. Results: We recruited 40 transgender males with a mean (SD) age of 22.5 (8.4) years. Only changes in the hematocrit were statistically significant as early as month 9. There were no significant changes in the biochemical parameters related to cardiovascular risk, including serum lipids, over time. There was a significant increase in total, free, and bioavailable testosterone, while SHBG levels significantly decreased; the free androgen index, urine androstanediol glucuronide, androstenedione, and prostate-specific antigen as a marker of androgenization also significantly increased over time. Among the 20 evaluable individuals, 14 (70%) scored ≥4 on the appearance congruence subscale, and 16 (80%) scored ≥4 on the gender identity subscale of the TCS. Conclusions: Our results suggest that this conservative treatment paradigm with testosterone is associated with a reduced adverse impact on hematocrit and lipids but is sufficient to achieve the gender congruence and identity acceptance desired by transgender males. Full article

Background/Objectives: Male hypogonadism affects 35–50% of men with type 2 diabetes mellitus (T2DM) and obesity. The relationship between testosterone deficiency and response to incretin-based therapies (GLP-1 and GIP receptor agonists) remains incompletely understood. This systematic literature review, conducted following PRISMA 2020 guidelines, examines whether male hypogonadism represents a risk factor for poor response to incretin therapy or, conversely, whether these agents offer therapeutic benefits for this population. Methods: A comprehensive systematic literature search was conducted on 31 December 2024, across PubMed/MEDLINE, Scopus, and Web of Science using three search domains: (1) hypogonadism and incretin therapy response; (2) testosterone deficiency and GLP-1/GIP receptor agonists; (3) incretin response and testosterone. Eligibility criteria included human studies (randomized controlled trials [RCTs], observational studies, cohort studies, cross-sectional studies, systematic reviews, and meta-analyses) in adult men reporting testosterone levels and/or incretin response. Animal studies, pediatric populations, case reports with n < 5, editorials, and letters without data were excluded. Study selection followed PRISMA 2020 guidelines with independent dual screening. Risk of bias was assessed using the Cochrane Risk-of-Bias 2.0 tool (ROB2) for RCTs, the Newcastle–Ottawa Scale (NOS) for observational studies, and AMSTAR-2 for systematic reviews and meta-analyses. Due to substantial heterogeneity in study designs, populations, interventions, and outcome measures, a meta-analysis was not feasible; therefore, a narrative synthesis was performed. Results: From 326 records identified, 29 studies were included after deduplication and screening (primary studies: 14; systematic reviews/meta-analyses: five; narrative reviews/expert opinion: 10). Risk-of-bias assessment revealed moderate-to-high overall risk: RCTs had small sample sizes (n = 12–42) and short follow-up (12–24 weeks), raising concerns about statistical power; observational studies were of fair-to-good quality (NOS 4–7 stars) but subject to confounding; and systematic reviews were of low-to-moderate confidence (AMSTAR-2). Primary evidence from RCTs and observational studies demonstrates that GLP-1 receptor agonists (GLP-1RAs)—particularly semaglutide and liraglutide—and the dual GIP/GLP-1 receptor agonist tirzepatide significantly increase total testosterone levels in men with obesity-related functional hypogonadism (mean increase 2.5–5.2 nmol/L). This effect is largely mediated by weight loss and improvement of insulin resistance rather than direct androgenic action. Evidence regarding whether baseline hypogonadism impairs glycemic or weight-loss response to incretin therapy is limited and indirect; no adequately powered comparative trials stratified by baseline testosterone status were identified. Conclusions: Incretin-based therapies, particularly GLP-1 receptor agonists and the dual GIP/GLP-1 receptor agonist tirzepatide, appear to improve testosterone levels in men with obesity-related functional hypogonadism, an effect that is largely mediated by weight loss and improvement of insulin resistance rather than a direct androgenic action. However, direct comparative evidence between hypogonadal and eugonadal men regarding glycemic or weight-loss response to incretin therapy remains insufficient to draw firm conclusions. The hypothesis that male hypogonadism does not impair incretin therapy response is biologically plausible but is currently supported only by indirect evidence. Prospective, adequately powered trials stratified by baseline testosterone status are needed to resolve this question. Full article