Diagnostics · Hormone Testing
Caretta N, Facondo P, Mereu S, Delbarba A, Crepaldi MC, Vedovato M, Avogaro A, Ferlin A
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To evaluate in men with type 2 diabetes the association of cardiometabolic indices [Visceral Adiposity Index (VAI), Triglyceride Glucose Index (TyG), and lipid accumulation product (LAP)] with total testosterone (TT) levels, and their predictive cut-off values in identifying hypogonadism.
265 consecutive men aged 40-70 years with type 2 diabetes performed an andrological evaluation; metabolic parameters and TT were determined. Receiver operating characteristic (ROC) curves were used to identify cut-off values of cardiometabolic indices in predicting low testosterone (TT < 12 nmol/l).
VAI, TyG, and LAP were negatively associated with TT levels. The prevalence of hypogonadism in men in the fourth quartiles of VAI, TyG, and LAP was ~ 70.0-75.0% compared to ~ 10.0-17.0% in men in the first quartiles (p < 0.001). The sensitivity and specificity of the three cardiometabolic indices in predicting TT < 12 nmol/l were significantly higher concerning BMI, waist circumference, lipid profile and HbA1c. Cut off values of VAI ≥ 3.985, TyG ≥ 4.925, and LAP ≥ 51.645 predict hypogonadism with good sensitivity and specificity.
This is the first study evaluating the association of VAI, TyG, and LAP with hypogonadism in men with type 2 diabetes. Alterations in these indices should direct the patients to andrological evaluation.
Grande G et al., 2026 · The Journal of clinical endocrinology and metabolism · Free to read
Male factor infertility (MFI) is frequently labelled idiopathic when evaluation relies primarily on semen analysis, potentially overlooking endocrine and pathophysiological mechanisms relevant for targeted management. To phenotypically define MFI and develop a pathophysiology-based classification aimed at reducing idiopathic infertility following comprehensive evaluation. Prospective monocentric cohort study conducted at a tertiary referral academic centre. Eight hundred male partners of infertile couples evaluated between October 2024 and January 2026 after exclusion of isolated female factor infertility. Prevalence of MFI categories, hormonal patterns across phenotypes, and proportion of idiopathic infertility after comprehensive work-up. All patients underwent standardized clinical evaluation, hormonal assessment (total testosterone, FSH, LH), testicular ultrasound, and complete semen analysis. Microbiological testing, transrectal ultrasound, and genetic analyses were performed according to guidelines. Primary spermatogenic failure was the most prevalent category (56.0%), followed by infection/inflammation (22.4%) and hypogonadotropic hypogonadism (8.5%). Idiopathic infertility was identified in only 5.3% of cases. Distinct endocrine profiles were observed, with high-FSH spermatogenic failure representing the dominant phenotype. Comprehensive phenotyping markedly reduces the proportion of patients classified as having idiopathic infertility and identifies clinically relevant subgroups. This prospective study provides validation of a pathophysiology-based classification and supports a shift toward endocrine-integrated diagnostic strategies in male infertility, with potential implications for targeted management.
Rocca MS et al., 2026 · Journal of translational medicine · Free to read
Standard semen analysis has little prognostic value in distinguishing fertile from infertile men. Furthermore, in men with semen parameters within the reference ranges, it cannot distinguish fertile men from infertile men, i.e. partners of couples with idiopathic infertility. Oxidative stress, mitochondrial dysfunction, sperm telomere shortening, and DNA fragmentation have been proposed as contributors to impaired male fertility. However, these biomarkers have not been evaluated as a whole in subjects with normal semen parameters, partners of fertile and infertile couples. To characterise a multidimensional panel of sperm biomarkers-including sperm telomere length (STL), mitochondrial DNA copy number (mtDNAcn), reactive oxygen species (ROS), lipid peroxidation (LP), sperm chromatin dispersion (SCD), and respiratory control ratio (RCR)-and to identify whether these parameters might discriminate, in men with normal semen parameters, infertile men from fertile controls. A total of 150 men with semen parameters within the normal ranges were enrolled: 47 male partners of couples with idiopathic infertility and 103 fertile controls. STL and mtDNAcn were quantified by qPCR; ROS were assessed using OxiSperm®II with semiquantitative imaging; LP was measured spectrophotometrically in seminal plasma; SCD was used to determine DNA fragmentation; and mitochondrial function was evaluated by oxygen consumption and RCR. Correlations between biomarkers and semen parameters were analysed using Pearson or Spearman coefficients, and intergroup comparisons were adjusted for age. Semen parameters did not differ significantly between male partners of fertile and infertile couples. compared to men of fertile couples, men of infertile couples exhibited significantly shorter STL (0.57 ± 0.59 vs 1.21 ± 1.13, p_adj = 0.001) and higher oxidative stress, with both ROS (8300.9 ± 4214.8 vs 6555.3 ± 3394.3, p_adj = 0.027) and LP (88.33 ± 55.50 vs 40.29 ± 46.98, p_adj < 0.001) markedly elevated. mtDNAcn, SCD, and RCR showed no difference between the groups. Across the entire cohort, STL correlated negatively with ROS and LP and positively with RCR. ROS correlated negatively with total sperm count, motility and RCR, and positively with LP. LP displayed the strongest pattern of associations, correlating negatively with concentration, total count, motility, STL and RCR, and positively with age and volume. Among men with normal semen analysis, partners of couples with idiopathic infertility exhibit a distinct sperm molecular profile characterised by telomere shortening and oxidative imbalance. STL, ROS and LP emerged as age-independent biomarkers associated with infertility status and showed promising discriminatory ability in this cohort, supporting their integration as second-level tests to complement routine semen analysis in cases of normozoospermia.
Ponce MR et al., 2026 · Andrology · Free full text on PubMed Central
Transgender individuals assigned male at birth (AMAB) may choose to preserve their fertility prior to starting gender-affirming hormone therapy (GAHT). However, limited data exist regarding the baseline reproductive and hormonal characteristics of this population before and after GAHT. To characterize semen quality and hormonal profiles in transgender AMAB individuals prior to GAHT and compare findings with cisgender men and with transgender individuals who discontinued GAHT for at least 3 months. This retrospective study included transgender AMAB individuals from two tertiary andrology centers who underwent sperm cryopreservation before GAHT initiation (treatment-naïve group). Clinical evaluation included anthropometric measures, testicular volume assessment, varicocele detection, and sex hormone measures. Semen parameters were analyzed according to WHO criteria and compared with those of cisgender men and previously treated transgender individuals. Thirty-two treatment-naïve transgender AMAB individuals were included. Hormonal parameters were generally within reference ranges. Only 46.9% of treatment-naïve individuals met WHO criteria for normozoospermia, compared with 75.5% of cisgender controls. Compared with nine previously treated individuals, estradiol levels were higher and seminal volume lower. A higher frequency of seminal abnormalities was observed, although not statistically significant. A substantial proportion of treatment-naïve transgender AMAB individuals exhibited impaired semen parameters prior to GAHT initiation. Prior GAHT exposure showed a trend toward poorer semen quality. These findings support early fertility counseling and preservation in transgender individuals prior to GAHT initiation.
Delbarba A et al., 2026 · Reviews in endocrine & metabolic disorders · Free full text on PubMed Central
Male hypogonadism is associated with significant alterations in body composition, including reduced lean body mass (LBM), increased fat body mass (FBM), particularly visceral adiposity, and impaired muscle function, contributing to frailty and cardiometabolic risk. These changes reflect the disruption of a complex endocrine crosstalk among bone, muscle, and adipose tissue, mediated by cytokines such as osteokines, myokines, and adipokines. This dysregulation promotes the development of osteosarcopenic obesity, a condition characterized by the coexistence of low bone mass, sarcopenia, and excess adiposity. Testosterone (T) plays a central role in maintaining body composition by stimulating muscle protein synthesis, inhibiting adipogenesis, and preserving bone health. Its deficiency, irrespective of etiology, leads to rapid impairment of anabolic pathways, resulting in decreased lean mass and increased fat accumulation. Evidence from clinical and experimental models demonstrates that these alterations are partially reversible with T replacement therapy (TRT), although variability exists depending on the underlying cause of hypogonadism. Dual-energy X-ray absorptiometry (DXA) represents the gold standard for assessing bone mineral density (BMD) and a key tool for evaluating body composition through a three-compartment model. It allows precise quantification of fat and lean mass, as well as their regional distribution, with minimal radiation exposure. In this review, we provide a comprehensive and clinically oriented overview of body composition alterations in male hypogonadism, focusing on underlying pathophysiological mechanisms and the practical application of DXA across different clinical scenarios. We discuss evidence from conditions such as Klinefelter syndrome, Kallmann syndrome, androgen deprivation therapy, HIV infection, and transgender care, aiming to offer a pragmatic framework for integrating body composition assessment into routine practice and improving patient management.
Caretta N et al., 2024 · The Journal of clinical endocrinology and metabolism
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease, affecting one-fourth of the adult population worldwide. Recent data found an association between MASLD and hypogonadism, but this relation in patients with type 2 diabetes mellitus (T2DM) is still unclear. To evaluate in men with T2DM the association between total testosterone (TT) and noninvasive indices of hepatic steatosis (Fatty Liver Index [FLI], Hepatic Steatosis Index [HSI], Dallas Steatosis Index [DSI]) and fibrosis (AST to Platelet Ratio Index [APRI], Fibrosis-4 Index [FIB-4]), and their predictive cutoff values in identifying hypogonadism. Cross-sectional study on 189 men with T2DM, without history of liver diseases and alcoholism, recruited on an outpatient basis. Interventions were andrological evaluation, metabolic parameters, TT, and liver indices. The main outcome measures were comparison of steatosis and fibrosis indices with testosterone levels and presence of hypogonadism. Receiver operating characteristic curves were used to identify cutoff values of liver indices in predicting low testosterone (<12 nmol/L). FLI, HSI, and DSI were negatively related with TT and were higher in the low-testosterone group than in the normal-testosterone group (FLI: 74.1 [61.4-93.5] vs 56.5 [32.1-78.2], P < .001; 41.5 [39.2-45.9] vs 40.1 [36.6-43.2], P = .005; 0.45 [-0.08-+1.04] vs -0.07 [-1.02-+0.58], P < .001). FLI and DSI also correlated with clinical symptoms of hypogonadism. No differences between groups were observed for APRI and FIB-4. FLI ≥63 was the best parameter as predictive index of low TT (sensitivity 73%, specificity 64%). We found an association between noninvasive indices of steatosis and hypogonadism in patients with T2DM. These indices could be used to direct the patients to andrological evaluation.
Contreras PH et al., 2018 · Front Med (Lausanne) · Free full text on PubMed Central
A cohort of 141 males (18-80 yo, 42.9 ± 12.9) strongly suspected of being Insulin Resistant (IR) was prospectively studied by determining their insulin sensitivity (Pancreatic Suppression Test, PST) and testicular function (total testosterone and SHBG). The subjects were labeled as IR when the Steady State Plasma Glucose (SSPG) was ≥150 mg/dL and Non-Insulin Resistant (NIR) when SSPG was <150 mg/dl; similarly, the subjects were labeled as Hypogonadal (HYPOG) when total testosterone was ≤3.0 ng/mL and Eugonadal (EUG) when total testosterone was >3.0 ng/mL. Two out of three subjects turned out to be IR, while around one in four subjects were HYPOG. Contingency analysis indicated a significant interdependence between insulin resistance and hypogonadism (chi-square was 4.69, p = 0.0303). Age (>43 yo) predicted hypogonadism (AUROC 0.606, p = 0.0308). Twice as many HYPOG subjects were IR as compared with EUG subjects. Also, HYPOG subjects exhibited higher SSPG values as compared with EUG subjects. Statistically, neither Weight nor BMI predicted hypogonadism, while Waist Circumference (>110 cm) was only a mediocre predictor (AUROC 0.640, p = 0.009). SSPG (>224 mg/dL) on the other hand, was the best predictor of hypogonadism (AUROC 0.709, p = 0.002), outperforming Waist Circumference (half of the subjects with an SSPG >224 mg/dL were HYPOG). Age did not predict insulin resistance, while Weight (>99 kg), BMI (>29), and especially, Waist Circumference (>99 cm, AUROC 0.812, p < 0.0001) were all predictors of insulin resistance. Almost 90% of the subjects with a waist circumference >99 cm was IR. As a logical consequence of the selection criteria (various clues suggesting insulin resistance), most subjects with normal weight in this cohort were IR (53.3%) while 20% were HYPOG. On the other hand, 13.6% of the obese subjects were NIR, and 2 out of 3 of them were both NIR and EUG. In conclusion, Waist Circumference predicted both insulin resistance (>99 cm) and hypogonadism (>110 cm), suggesting that the first hit of abdominal obesity is insulin resistance and the second hit is male hypogonadism. Normal weight did not protect from IR, while a relevant proportion of obese subjects were NIR (with 2/3 being also EUG).
Tsai EC et al., 2004 · Diabetes Care
Previous reports of an association between low testosterone levels and diabetes risk were often confounded by covariation of sex hormone-binding globulin (SHBG) and testosterone measurements. Measurements of bioavailable and free testosterone, more reliable indexes of biologically active testosterone, were examined for their associations with markers of insulin resistance and body fat measures in 221 middle-aged nondiabetic men. Bioavailable and free testosterone were calculated from the concentrations of total testosterone, SHBG, and albumin, and they were not significantly correlated with SHBG (r = 0.07-0.1). In contrast, total testosterone correlated significantly with SHBG (r = 0.63). We evaluated the relationship between these measures of circulating testosterone and markers for insulin resistance (i.e., fasting insulin, C-peptide, and homeostasis model assessment for insulin resistance [HOMA-IR]) as well as total body fat (assessed by dual-energy X-ray absorptiometry [DEXA]) and abdominal fat distribution (assessed by single-slice computed tomography [CT]). Bioavailable, free, and total testosterone and SHBG all correlated significantly with fasting insulin (age-adjusted r = -0.15 [P = 0.03], -0.14 [P = 0.03], -0.32 [P < 0.0001], and -0.38 [P < 0.0001], respectively), fasting C-peptide (r = -0.18 [P = 0.009] to -0.41 [P < 0.0001]), HOMA-IR (r = -0.15 [P = 0.03] to - 0.39 [P < 0.0001]), and body fat measures (r = -0.17 [P = 0.008] to -0.44 [P < 0.0001]). Only SHBG and total testosterone were significantly associated with fasting glucose (r = -0.20 [P = 0.003] to -0.21 [P = 0.002]). In multivariate analysis, bioavailable or free testosterone was significantly and inversely associated with insulin, C-peptide, and HOMA-IR, but this was not independent of total body or abdominal fat. SHBG was a significant determinant of insulin, C-peptide, and HOMA-IR, independent of body fat. The associations between total testosterone and insulin resistance were confounded by SHBG. The inverse association between testosterone and insulin resistance, independent of SHBG, was mediated through body fat.
Caretta N et al., 2016 · Endocrine
Diabetes is an established risk factor for erectile dysfunction (ED). The pathophysiology of ED in diabetic men is multifactorial, but it mainly involves a vascular disorder related to a reduction of endothelial function. Recently, several studies have correlated ED risk factors with vitamin D deficiency. In this study, we evaluate the relationship between 25-hydroxyvitamin D [25(OH)D] levels, erectile dysfunction, and vascular disease, in type 2 diabetes mellitus men (T2DM). In this observational study, 92 T2DM males (58.83 ± 9.73 years) underwent medical history collection, International Index of Erectile Function (IIEF-5) questionnaire, that allows the identification and grading of DE, physical examination, biochemical/hormonal blood tests, and penile echo-color Doppler ultrasonography. T2DM patients with lower 25(OH)D levels (<25 nmol/l) showed higher penile IMT (p < 0.05), waist circonference (p < 0.05), glucose concentrations (p < 0.05), and lower IIEF-5 score (p < 0.005), testosterone concentrations (p < 0.05), and cavernous peak systolic velocity (PSV) (p < 0.05), compared to patients with 25(OH)D >50 nmol/l. 25(OH)D levels were directly correlated with IIEF-5 (R = 0.39; p = 0.0001), testosterone (R = 0.24; p = 0.02), and PSV (R = 0.24; p = 0.04) and inversely with waist (R = -0.33; p = 0.002), HbA1c (R = -0.22; p = 0.03), triglyceride (R = -0.21; p = 0.06), and penile IMT (R = -0.30; p = 0.009). At multivariate analysis, 25(OH)D deficiency remained an independent predictor of DE. We demonstrate a significant association between 25(OH)D deficiency and erectile dysfunction in T2DM men. This association may be due to the influence of 25(OH)D deficiency on cardiovascular risk factor (glycaemia, HDL cholesterol, and triglycerides), testosterone plasma levels and endothelial dysfunction.