Purpose: We aimed to evaluate whether and to what extent an association exists between male aging and worsening of semen parameters and to determine whether a threshold age can be identified above which the decline in semen quality becomes statistically significant. Methods: 2612 men (age: 16–56 years) attending an andrology outpatient clinic for semen analysis and clinical evaluation were studied. Semen analyses were performed according to the ongoing WHO-recommended procedures. Total motile count (TMC) and total progressive motile count (TPMC) were calculated by multiplying total sperm number by total motility and progressive motility, respectively. Results: Significant negative correlations were found between age and total motility (r = − 0.131, p < 0.0001), progressive motility (r = − 0.112, p < 0.0001), TPMC (r = − 0.042, p = 0.037), and normal sperm morphology (r = − 0.053, p = 0.007). All these associations persisted in multivariate regression models adjusted for abstinence time, smoking, history of male accessory gland infections, varicocele and the year in which semen analysis was performed. When comparisons were performed among quartiles of increasing age, the fourth quartile, corresponding to the age group > 40 years, was associated with a significant decrease in total and progressive motility. An earlier decline in the TPMC and percentage of normal forms was also observed. Conclusion: Advancing male age exhibits an independent association with a decrease in the percentage of motile and morphologically normal spermatozoa, with greater evidence from the age of > 40 years. Further studies are warranted to elucidate the mechanisms and clinical reflections of these associations.

Hormone replacement therapy is associated with an increased thromboembolic risk. The effects of testosterone (T) on coagulation markers in people assigned female at birth (AFAB) under gender affirming hormone therapy (GAHT) are not well described. Systematic review and meta-analysis on English-language articles retrieved from PubMed, Scopus and Cochrane Library up to April 2023 investigating T therapy in AFAB people. Coagulation parameters included international normalized ratio (INR), fibrinogen, activated partial thromboplastin clotting time (aPTT), plasminogen activator inhibitor-1 (PAI-1); hematological variables included hemoglobin (Hb) and hematocrit (HCT). We also reported the rate of thromboembolic events. Data were combined as mean differences (MD) with a 95 % confidence interval (CI) of pre- vs post-follow-up values, using random-effects models. We included 7 studies (6 prospective and 1 retrospective) providing information on 312 subjects (mean age: 23 to 30 years) who underwent GAHT with variable T preparation. T therapy was associated with a significant increase in INR values [MD: 0.02, 95 % confidence interval (CI): 0.01-0.03; p = 0.0001], with negligible heterogeneity (I² = 4 %). T therapy was associated with increased Hb (MD: 1.48 g/dL, 95%CI: 1.17 to 1.78; I² = 9 %) and HCT (4.39 %, 95%CI: 3.52 to 5.26; I² = 23 %) values. No effect on fibrinogen, aPTT and PAI-1 was found. None of the study reported thromboembolic events during the follow-up. Therapy with T increased blood viscosity in AFAB men. A slight increase in INR values was also found, but the clinical relevance and mechanism(s) of this finding needs to be clarified.

Purpose: There is a paucity of data on the safety and efficacy of long-term testosterone (T)-based gender-affirming hormone therapy (GAHT) on anthropometric parameters, body composition, and glycolipid metabolism in assigned female at birth (AFAB) persons. The purpose of this study was to provide an updated meta-analysis on this topic. Methods: We searched PubMed, Scopus, and Cochrane Library for relevant studies. Pre-/post-therapy changes in body mass index (BMI), waist-to-hip ratio (WHR), body composition, lipid glycemic/insulinemic profiles were combined as mean differences (MD) with 95% confidence interval (CI), using random-effect models. Results: Thirty-nine studies ( N =1949) were analyzed. At pooled estimates, GAHT was associated with significant decrease in fat mass (MD: −1.29 kg; 95% CI: −2.52 to −0.05; p =0.04) and increase in lean mass (4.12 kg; 95% CI: 3.07–5.16; p <0.00001), BMI (0.78 kg/m ² ; 95% CI: 0.50–1.07; p <0.00001), and WHR (0.02; 95%CI: 0.01–0.03; p =0.003) in the absence of heterogeneity ( I ² =0%). T therapy was also accompanied by unfavorable effects on lipid profile, including increases in total cholesterol (4.95 mg/dL; 95% CI: 1.53–8.37; p =0.005), LDL (11.15 mg/dL; 95% CI: 7.57–14.74; p <0.00001), and triglycerides (9.49 mg/dL; 95% CI: 4.39–14.58; p =0.0003) and decrease in HDL concentration (−7.52 mg/dL; 95% CI: −9.38 to −5.67; p <0.00001). Finally, T therapy resulted in a significant decrease in blood glucose concentration (−2.06 mg/dL; 95% CI: −3.37 to −0.74; p =0.002), with no significant effects on homeostatic model assessment index of insulin resistance. Conclusion: T-based GAHT in AFAB people is associated with androgenic changes in body composition and body fat distribution, accompanied by the acquisition of a more unfavorable cardiovascular lipid profile.

Purpose: To assess the effects of testosterone (T)-based gender affirming hormone therapy (GAHT) on liver blood tests (LBTs) in assigned female at birth adults, using a meta-analytic approach. Methods: Prospective and retrospective studies were selected that reported the prevalence of biochemical liver damage (BLD) and LBTs changes during T therapy. Data collected included pre-and-during therapy alanine-aminotransferase (ALT), aspartate-aminotransferase (AST), gamma-glutamyl-transferase (GGT), and alkaline phosphatase (ALP) mean concentration values. Results: The prevalence of BLD in 14 studies on 1698 subjects was 1% (95% CI 0.00–3.00; I² = 14.1%; p = 0.82). In 17 studies on 2758 subjects, GAHT was associated with a statistically (but not clinically) significant increase in AST, GGT and ALP at 12 months and ALT at 3–7 (MD: 1.19 IU/l; 95% CI 0.31, 2.08; I²: 0%), at 12 (MD: 2.31 IU/l; 95% CI 1.41, 3.21; I²: 29%), but with no more significant increase at 24 months (MD: 1.71 IU/l; 95% CI −0.02, 3.44; I²: 0%). Conclusions: Analysis of aggregate estimates confirms a low risk of BLD and abnormalities in LBTs, transient in most cases, during T-based GAHT, thus suggesting a limited need for careful liver monitoring in AFAB people.

Objective: The impact of testosterone-based gender affirming hormone therapy (T-GAHT) on kidney function in transgender individuals assigned female at birth (AFAB) remains a matter of clinical uncertainty and debate. This study aimed to quantify through a meta-analytical approach the changes in estimated glomerular filtration rate (eGFR), a widely used clinical parameter that reflects how efficiently the kidneys filter waste products from the blood, and in secondary markers of kidney functions in this population during 24 months of GAHT. The eGFR was calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation, which estimates kidney filtration based on serum creatinine, age, and sex.Methods: A thorough search of MEDLINE, COCHRANE LIBRARY, SCOPUS and WEB OF SCIENCE databases was carried out to identify suitable studies. Quality of the articles was scored using the Effective Public Health Practice Project. Data were combined using random effects models and the between-study heterogeneity was assessed using Cochrane’s Q and I².Results: Twenty included studies provided information about an overall sample of 2380 individuals. The pooled estimates documented a significant decrease in eGFR (CKD-EPI equation) at 6 and 12 months with respect to baseline, using the attributed (female) gender. When the CKD-EPI equation was referred to the perceived (male) gender, eGFR significantly decreased after 12 months but not after 6 months of T-GAHT. The trend of eGFR values showed a transient decline during the first year of therapy, followed by stabilization at 18 and 24 months. This pattern is likely attributable to increased creatinine production due to testosterone-induced gains in muscle mass, rather than to a true decline in kidney function. Among the secondary outcomes, pooled estimates revealed significant increases of creatinine and uric acid levels at all follow-up times. On the contrary, blood urea nitrogen (BUN), a waste product filtered by the kidneys and commonly used to assess renal function, did not change significantly after either 6 months or 12 months of T-GAHT.Conclusions: The influence of T-GAHT on eGFR in the first two years in healthy, young AFAB transgender individuals appears to be statistically significant, but is likely not clinically relevant. This interpretation is supported by the stability of BUN levels and the absence of adverse renal events in the included studies, suggesting preserved kidney function despite changes in creatinine-based estimates. Further research is warranted to identify more accurate tools for evaluating kidney function in this population, particularly during the early months of treatment or in individuals with pre-existing renal conditions.Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024596106.

Transgender and gender diverse individuals experience a gender identity that differs from the sex assigned at birth. Some transgender men may request testosterone to induce virilization; however, its impact on bone health remains to be fully elucidated. The objective of this systematic review and meta-analysis was to evaluate the modifications in bone metabolism over a short-term period among transgender men initiating testosterone therapy. A systematic search was conducted in PubMed, Scopus, Web of Science, and Cochrane Library. The articles of interest had to report longitudinal evaluation conducted among transgender men, before starting testosterone and after 12 and 24 months of therapy. The analyzed parameters were BMD, calcium, phosphate, 25OHD, PTH, P1NP, BAP, osteocalcin and CTx. Mean differences with 95% coefficient intervals were combined using random effects models. Funnel plot, Egger’s test, and trim-and-fill analysis were used to assess publication bias. Fourteen studies met the inclusion criteria, including 1484 subjects. In absence of heterogeneity, BMD did not significantly change at lumbar spine, hip, femoral neck, and whole-body evaluations. Calcium, phosphate, 25OHD and PTH remained stable over time. Regarding bone turnover markers, only P1NP showed a statistically significant increase after 12 months of T therapy, in absence of heterogeneity (SMD 0.61 mcg/l; 95% CI: 0.40–0.83; p < 0.0001; I² = 0%, Pforheterogeneity = 0.48). Testosterone therapy among transgender men seems not to disrupt bone health after 12 and 24 months. A statistically significant elevation in P1NP levels after 12 months of therapy may indicate a positive anabolic effect of testosterone in the short-term.