European Journal of Cardiovascular Medicine

Diabetes mellitus is among the foremost contributors to global mortality and disability. According to the Global Burden of Disease Study 2021, an estimated 529 million people were living with diabetes worldwide in 2021, and this number is projected to exceed 1.31 billion by 2050, with type 2 diabetes mellitus (T2DM) accounting for approximately 96% of all cases [1]. The burden is disproportionately concentrated in low- and middle-income countries undergoing rapid nutritional and lifestyle transition. In India, the ICMR-INDIAB national survey reported a weighted diabetes prevalence of 11.4% and a prediabetes prevalence of 15.3%, alongside strikingly high rates of abdominal obesity and dyslipidaemia, underscoring an expanding pool of metabolically vulnerable adults [2].

Beyond its classical micro- and macrovascular complications, T2DM is closely intertwined with male reproductive endocrine dysfunction. Low circulating testosterone is one of the most prevalent yet clinically neglected hormonal abnormalities in diabetic men. Contemporary mechanistic work frames this as a bidirectional relationship: obesity, insulin resistance and chronic low-grade inflammation suppress the hypothalamic–pituitary–gonadal (HPG) axis, while testosterone deficiency in turn aggravates adiposity and impairs insulin signalling in skeletal muscle and adipose tissue [3]. The resulting phenotype is most often functional (hypogonadotropic) hypogonadism, characterised by low testosterone with inappropriately normal gonadotropins, driven principally by visceral adiposity and the associated inflammatory milieu rather than by primary testicular failure [4].

Because adiposity is central to this pathway, cardiometabolic indices reflecting visceral fat predict hypogonadism in diabetic men with greater accuracy than body mass index or HbA1c alone, and the prevalence of low testosterone rises sharply in the most metabolically deranged individuals [5]. Cross-sectional data further indicate that calculated free testosterone correlates inversely with HbA1c, triglycerides and homeostatic model assessment of insulin resistance, with insulin resistance emerging as an independent determinant of hypogonadism in men with T2DM [6]. Therapeutically, meta-analytic evidence suggests that testosterone supplementation in hypogonadal diabetic men can modestly improve insulin resistance and lipid parameters [7], and randomised data from prevention trials show that testosterone treatment can reduce progression to T2DM in high-risk men [8]. However, the cardiovascular safety trial in hypogonadal men demonstrated no meaningful glycaemic benefit over two years [9], and a dedicated substudy found no reduction in progression from prediabetes to diabetes [10], highlighting unresolved questions about causality and clinical utility.

Despite this growing literature, robust population-specific data correlating serum testosterone with the full spectrum of glycaemic control remain limited, particularly from Indian tertiary-care settings, where diabetes frequently presents at younger ages and lower body mass indices, and where sexual and reproductive morbidity is seldom screened [11]. Quantifying how tightly testosterone tracks glycaemia, and whether this association persists after accounting for common confounders, is a necessary step toward identifying men who might benefit from androgen assessment. We therefore conducted a cross-sectional study to estimate serum testosterone in men with T2DM and to assess the impact of glycaemic control on testosterone levels.

Study design and setting

This was a hospital-based, single-centre, cross-sectional observational study conducted in the Department of General Medicine at a tertiary-care teaching hospital. Participants were recruited from the outpatient and inpatient services. The study was designed and reported in keeping with the STROBE recommendations for observational research.

Study population

Men older than 18 years with an established diagnosis of T2DM were eligible for inclusion. Participants were excluded if they had known hypogonadism already receiving testosterone replacement therapy, chronic use of anabolic agents or corticosteroids, Cushing syndrome, chronic liver disease, chronic kidney disease, autoimmune disease, or any malignancy, as these conditions independently influence the hypothalamic–pituitary–gonadal axis or testosterone metabolism and would confound the primary association.

Sample size

The sample size was calculated using the standard formula for estimating a single proportion, n = Z²PQ/d², where Z was 1.96 at the 5% level of significance, P was the anticipated prevalence of hypogonadism (taken as 11%), Q was 1 − P, and d was the absolute precision of 5%. This yielded a minimum required sample of 150 participants, who were enrolled by simple random sampling.

Data collection and laboratory measurements

After written informed consent, each participant underwent a structured clinical evaluation comprising medical history, current medications, and assessment of cardiometabolic risk factors including hypertension and obesity. Anthropometry (body mass index and waist circumference) and blood pressure were recorded using standardised techniques. Fasting venous blood samples were analysed for serum total testosterone, HbA1c and fasting blood glucose. HbA1c was used as the index of long-term glycaemic control and fasting blood glucose as a confirmatory measure. Additional baseline investigations comprising liver function, renal function (serum creatinine and estimated glomerular filtration rate) and a complete lipid profile were obtained to characterise the cohort and to screen for potential confounders.

Statistical analysis

Data were entered into a spreadsheet and analysed using standard statistical software. Continuous variables were summarised as mean ± standard deviation and as median with interquartile range, and categorical variables as frequencies and percentages. The primary association between serum testosterone and HbA1c was examined using Pearson product–moment correlation. Differences in mean testosterone across glycaemic-control categories were tested using one-way analysis of variance (ANOVA), comparisons between hypogonadal and eugonadal men using the independent-samples t test, and the association between hypogonadism and glycaemic category using the chi-square test. A two-sided p value below 0.05 was considered statistically significant.

Ethical considerations

The study was conducted in accordance with the Declaration of Helsinki and institutional ethical guidelines, and was approved by the Institutional Ethics Committee. Participation was voluntary, written informed consent was obtained from all participants, and all data were anonymised before analysis. No investigation beyond standard diabetes care was imposed on participants.

Baseline characteristics of the cohort

A total of 150 men with T2DM were studied. The mean age was 53.1 ± 13.3 years, mean body mass index 26.9 ± 4.0 kg/m², and mean duration of diabetes 5.7 ± 6.0 years. Glycaemic control was suboptimal overall, with a mean HbA1c of 8.31 ± 1.22% and mean fasting blood glucose of 197.6 ± 40.3 mg/dL, while mean serum total testosterone was 421.3 ± 212.1 ng/dL (Table 1). Hypogonadism was present in 71 men (47.3%), 36 men (24.0%) were on insulin therapy, and current smoking and alcohol use were reported by 43.3% and 46.0%, respectively.

Primary outcome: correlation of testosterone with HbA1c and confounders

Serum total testosterone was inversely and strongly correlated with HbA1c (Pearson r = −0.526; 95% CI −0.633 to −0.399; p < 0.0001), indicating that lower testosterone accompanied poorer long-term glycaemic control (Table 2). Among the candidate confounders, only triglycerides showed a significant association, correlating negatively with testosterone (r = −0.170, p = 0.037) and positively with HbA1c (r = 0.302, p = 0.0002). Age, body mass index, diabetes duration and total cholesterol were not significantly correlated with either testosterone or HbA1c, suggesting that the testosterone–glycaemia relationship was not explained by these variables.

Testosterone and hypogonadism across glycaemic-control strata

When the cohort was stratified by glycaemic control, mean serum testosterone declined progressively across worsening categories, from 599.3 ± 223.9 ng/dL in optimally controlled men (HbA1c < 7%) to 285.9 ± 121.2 ng/dL in those with very poor control (HbA1c > 9%); this gradient was highly significant on one-way ANOVA (F = 22.49, p < 0.0001) (Table 3). In parallel, the prevalence of hypogonadism increased more than four-fold, from 18.8% in the optimally controlled group to 78.6% in the very-poorly-controlled group.

Comparison of hypogonadal versus eugonadal men

Men with hypogonadism (n = 71) had significantly worse glycaemic indices than eugonadal men (n = 79), with higher HbA1c (8.83 ± 1.06% vs 7.84 ± 1.17%; mean difference 0.98%, p < 0.0001) and higher fasting blood glucose (213.3 ± 38.6 vs 183.4 ± 36.5 mg/dL; p < 0.0001) (Table 4). In contrast, age, body mass index, diabetes duration and total cholesterol did not differ significantly between the two groups, reinforcing that the testosterone–glycaemia link was independent of these characteristics.

Association between hypogonadism and glycaemic-control category

The relationship was confirmed at the categorical level: hypogonadism status was strongly associated with glycaemic-control category (χ² = 30.67, degrees of freedom = 3, p < 0.0001) (Table 5). Among hypogonadal men, 78.9% fell into the poor or very-poor control categories, compared with only 40.5% of eugonadal men, whereas the optimally controlled stratum was dominated by eugonadal men.

Table 1. Baseline demographic, clinical and biochemical characteristics of the study population (n = 150).

BP = blood pressure; eGFR = estimated glomerular filtration rate; HbA1c = glycated haemoglobin; HDL = high-density lipoprotein; IQR = interquartile range; LDL = low-density lipoprotein; SD = standard deviation; T2DM = type 2 diabetes mellitus.

Table 2. Pearson correlation of serum testosterone and HbA1c with each other and with potential confounders.

r = Pearson product–moment correlation coefficient. The testosterone–HbA1c correlation (95% CI −0.633 to −0.399) is the primary study endpoint. p-values < 0.05 denote statistical significance. HbA1c = glycated haemoglobin; T2DM = type 2 diabetes mellitus.

Table 3. Serum testosterone levels and hypogonadism prevalence stratified by glycaemic-control category.

One-way ANOVA for testosterone across strata: F = 22.49, p < 0.0001. Values are mean ± standard deviation unless otherwise indicated. HbA1c = glycated haemoglobin.

Table 4. Comparison of clinical and biochemical parameters between hypogonadal and eugonadal men.

Independent-samples t test. Mean diff. = absolute difference in group means. p-values < 0.05 denote statistical significance. HbA1c = glycated haemoglobin; T2DM = type 2 diabetes mellitus.

Table 5. Association between hypogonadism status and glycaemic-control category.

Percentages are calculated within each gonadal-status group. Chi-square test: χ² = 30.67, df = 3, p < 0.0001. HbA1c = glycated haemoglobin.

In this cross-sectional study of 150 men with T2DM, serum total testosterone was strongly and inversely associated with glycaemic control. The correlation with HbA1c was moderate-to-strong (r = −0.53), testosterone fell stepwise across worsening glycaemic strata, and hypogonadism—present in nearly half the cohort—clustered markedly among men with poor and very-poor control. Importantly, the relationship was independent of age, body mass index, diabetes duration and cholesterol, with triglycerides being the only confounder linked to both variables.

The secondary objective—assessing the impact of glycaemic control on testosterone—was supported by three convergent analyses: the significant ANOVA gradient across HbA1c categories, the higher HbA1c and fasting glucose in hypogonadal men, and the strong chi-square association between hypogonadism and glycaemic category. These observations echo population data in which lower testosterone tracks adverse glucose homeostasis in men [12], and steroidomic work using tandem mass spectrometry reporting hypogonadism in roughly 70% of diabetic men, with depletion of testosterone precursors indicating genuinely reduced testicular steroidogenesis rather than an assay artefact [13]. The selective correlation of triglycerides with both testosterone and HbA1c in our data is mechanistically coherent: triglyceride-rich visceral fat is the principal driver of the inflammatory suppression of the HPG axis, and adiposity-based indices outperform HbA1c in predicting hypogonadism [5]. Hypovitaminosis D, near-universal in diabetic men, may further modulate this testosterone–glycaemia interface [14].

Our primary finding aligns closely with contemporary cross-sectional evidence. In a study of 353 Indian diabetic men, calculated free testosterone correlated inversely with HbA1c, triglycerides and insulin resistance, and insulin resistance was an independent determinant of hypogonadism [6]. The mechanistic basis for this inverse correlation is now reasonably well delineated. Hyperglycaemia, visceral adiposity and the attendant pro-inflammatory state suppress hypothalamic gonadotropin-releasing hormone secretion, producing the functional hypogonadotropic hypogonadism that predominates in T2DM [4]. At a molecular level, obesity up-regulates hypothalamic micro-RNAs that repress kisspeptin, a key upstream stimulator of the reproductive axis, providing a plausible pathway by which a worsening metabolic state lowers testosterone [15,16]. Reciprocally, testosterone deficiency impairs insulin signalling in muscle and adipose tissue, establishing a self-perpetuating cycle between low androgens and deteriorating glycaemia [3]. The graded decline in testosterone we observed across glycaemic strata, and the four-fold rise in hypogonadism prevalence, are the clinical signature of this vicious cycle.

Whether correcting testosterone improves glycaemia remains contested, and our cross-sectional design cannot resolve causality. Meta-analytic data suggest testosterone supplementation modestly improves insulin resistance and lipids in hypogonadal diabetic men [7], and an Indian interventional study reported reductions in HbA1c, insulin resistance and atherogenic lipids with testosterone undecanoate [15]. Yet the large TRAVERSE cardiovascular safety trial found no clinically meaningful glycaemic benefit [9], its substudy showed no reduction in progression from prediabetes to diabetes [10,17], and HbA1c—being red-cell dependent—may be a suboptimal endpoint for androgen trials [8,18]. The prevention setting tells a different story, with testosterone reducing incident diabetes in men with impaired glucose tolerance, indicating that timing and baseline risk matter [8,19]. Newer antidiabetic agents that reduce visceral adiposity and inflammation, including SGLT2 inhibitors and GLP-1 receptor agonists, may raise testosterone as a secondary benefit and could reshape how hypogonadism in T2DM is managed [20,21]. Current guidance therefore reserves testosterone therapy for men with both biochemical deficiency and symptoms, alongside weight loss and glycaemic optimisation [17].

The clinical implication of our findings is that serum testosterone behaves as a biological barometer of metabolic control in diabetic men, and that androgen screening is warranted in those with persistently poor glycaemia or sexual symptoms, a group frequently overlooked in routine diabetes clinics [11,22]. Several limitations temper our conclusions. The single-centre cross-sectional design precludes causal inference and limits generalisability. Total rather than free testosterone or sex hormone-binding globulin was measured, single morning sampling was used, and gonadotropins were not assayed, so the hypogonadotropic nature of the hypogonadism could not be confirmed directly. Insulin resistance was not formally quantified, and residual confounding from unmeasured factors such as sleep apnoea cannot be excluded. Prospective and interventional studies with free testosterone, gonadotropins and standardised endpoints are needed to define whether restoring testosterone meaningfully improves glycaemic outcomes in this population.

In men with T2DM, lower serum testosterone is robustly and independently associated with poorer glycaemic control, with hypogonadism concentrated among the most poorly controlled patients. These findings support incorporating androgen assessment into the evaluation of diabetic men with suboptimal glycaemia, while prospective trials clarify the therapeutic value of testosterone optimisation.

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