Obesity‐Related Functional Hypogonadism Requires Therapeutic Recalibration: Implications for GLP‐1–Based Therapies

1.

The 2025 Lancet Diabetes & Endocrinology Commission included hypogonadism among the 18 diagnostic criteria for the newly proposed entity of “clinical obesity” [1]. As “clinical obesity” is defined as a disease state that requires active medical treatment, this classification provides a strong rationale for intervention with second‐generation glucagon‐like peptide‐1 (GLP‐1)–based therapies in men with obesity‐related hypogonadism [1]. When positioned as an entry point for GLP‐1–based strategies, this gains major public health relevance [2], enabling durable improvements in metabolic profile and long‐term reductions in cardiometabolic risk in a large population of middle‐aged men living with obesity [3].

Current clinical practice continues to rely predominantly on lifestyle counseling and testosterone replacement strategies developed for primary gonadal failure [4]. Although testosterone therapy remains justified for symptomatic men [4], prioritizing testosterone normalization as the principal therapeutic endpoint risks decoupling treatment from the underlying disease biology and its high multisystem burden, whereas GLP‐1–based therapies offer more biologically aligned, multisystem intervention with an increasingly broad range of clinically relevant outcomes [3]. A recent meta‐analysis of seven studies involving 680 men reported that GLP‐1 RAs are associated with increases in total and free testosterone, gonadotropins, and erectile function, alongside consistent improvements in body weight, waist circumference, and glycated hemoglobin [5]. Meta‐regression analyses link improvements in testosterone to the magnitude of weight loss [5]. However, these findings are tempered by substantial heterogeneity and reliance on observational data [5].

Notably, the reproductive consequences of obesity‐related hypogonadism remain markedly underrepresented. Multiple observational studies and meta‐analyses demonstrate that men with obesity, particularly those with type 2 diabetes, exhibit reduced sperm concentration, impaired motility, a lower proportion of morphologically normal sperm, and increased sperm DNA fragmentation [6, 7]. Notably, these abnormalities frequently occur even when circulating testosterone concentrations remain within or near reference ranges, underscoring a dissociation between gonadal hormone levels and spermatogenic integrity. The 2026 systematic review encompassing 10 studies and 639 men confirmed that baseline semen impairment is common in metabolically compromised men and is not proportional to the degree of testosterone reduction [8]. This dissociation indicates that testosterone‐centered frameworks fail to capture the primary reproductive pathology of obesity‐related hypogonadism, justifying focused attention on spermatogenesis as a distinct and clinically relevant endpoint.

Mechanistically, spermatogenesis depends on intact metabolic support from Sertoli cells, which rely on insulin‐sensitive glucose uptake and glycolysis to generate lactate for developing germ cells. Insulin resistance related to obesity and type 2 diabetes disrupts this process. Experimental and clinical studies show that obesity and diabetes are also associated with mitochondrial dysfunction, increased oxidative stress, and elevated inflammatory cytokine levels within testicular tissue, all of which impair germ‐cell maturation and DNA integrity [9]. Increased visceral adiposity further contributes to scrotal hyperthermia and altered testicular microcirculation. Importantly, these mechanisms operate largely independently of circulating androgen concentrations.

Incretin signaling has emerged as a plausible regulator of testicular energy metabolism, linking systemic metabolic control to spermatogenic function. The direct role of incretin biology in spermatogenesis is supported by experimental data. GLP‐1 receptors are expressed along the hypothalamic–pituitary–gonadal axis and within testicular tissue, including Leydig cells, Sertoli cells, and mature spermatozoa. Preclinical studies demonstrate that GLP‐1 receptor activation improves mitochondrial efficiency, reduces oxidative stress, and modulates cellular energy metabolism in reproductive tissues. In vitro studies show altered sperm metabolic activity and motility following GLP‐1 receptor stimulation, supporting a mechanistic link between incretin signaling and spermatogenic processes  [10].

In the clinical setting, evidence supporting this concept remains limited. Our group has conducted a randomized open‐label trial that compared treatment with the GLP‐1 receptor agonist semaglutide 1.0 mg versus testosterone undecanoate in men with obesity, type 2 diabetes, and functional hypogonadism [11]. At baseline, semen quality was markedly impaired in both groups, with sperm concentration, morphology, and total sperm number below the fifth percentile of WHO reference values. Over 24 weeks, semaglutide treatment was associated with a significant within‐group improvement in sperm morphology, whereas testosterone therapy was,  as expected, accompanied by further deterioration of spermatogenic parameters. Importantly, improvements observed with semaglutide were not correlated with changes in body weight or circulating testosterone concentrations, suggesting a mechanism distinct from weight loss or androgen normalization [11]. However, several limitations warrant cautious interpretation. The study was open‐label, small, and of short duration, limiting internal validity and generalizability [11]. The improvement in sperm morphology represents a within‐group, hypothesis‐generating signal, and the absence of a placebo control limits causal inference, particularly given the reliance on single semen samples and inherent biological variability. Furthermore, although gonadotropins remained stable, the relative contributions of metabolic, weight‐dependent, and potential direct testicular effects cannot be clearly distinguished [11]. Accordingly, these findings are preliminary and require confirmation in larger, blinded, placebo‐controlled trials with appropriate fertility‐preserving comparators. Consistent with this, a recent systematic review reports modest but directionally favorable effects of GLP‐1 receptor agonists on sperm parameters, while highlighting substantial heterogeneity and the need for standardized reproductive endpoints [8].

Taken together, obesity‐related functional hypogonadism is best understood as a disorder of metabolic–reproductive integration rather than isolated androgen deficiency. Incretin biology provides a mechanistic framework linking metabolic regulation with spermatogenesis and testicular function. While evidence directly guiding clinical management remains very limited, a pragmatic clinical approach may be cautiously informed by emerging data and by analogy to female infertility in women with obesity, where metabolic optimization is prioritized before or alongside fertility treatment.

In men with obesity‐related functional hypogonadism who seek fertility, testosterone replacement therapy (TRT) should be avoided due to its suppressive effects on spermatogenesis. We propose that first‐line care should focus on metabolic intervention, including structured lifestyle therapy and GLP‐1–based pharmacotherapy, with reassessment of semen parameters and symptoms after achieving clinically meaningful weight loss, typically ≥5–10%. This emphasis on metabolic optimization is supported by evidence that weight reduction improves endogenous testosterone and the metabolic milieu relevant for spermatogenesis. However, the effects of GLP‐1‐based therapies on semen parameters remain uncertain, with currently very limited data. Accordingly, a flexible clinical approach is warranted: metabolic optimization followed by reassessment, with timely integration of fertility‐preserving endocrine therapies as needed, either after metabolic improvement or in parallel, particularly in men with persistent impairment or when delay is not appropriate.

In men not actively pursuing fertility, management should remain anchored in a GLP‐1–driven, etiology‐based approach. TRT may be introduced selectively in persistently symptomatic individuals, preferably after initial weight reduction, particularly where restoration of the hypothalamic–pituitary–gonadal axis is not achieved. As an adjunct to GLP‐1–based therapy, TRT may enhance sexual function, attenuate loss of lean mass, and further improve body composition during obesity treatment.

In summary, consideration may be given to a cautious shift in the treatment sequencing of obesity‐related functional hypogonadism: GLP‐1–based therapies as first‐line, reassessment after clinically meaningful weight loss, integration of fertility‐preserving endocrine strategies when conception is desired, either sequentially or in parallel, and selective addition of TRT for residual symptoms and lean mass preservation after initial weight reduction in men without immediate reproductive goals.

In future perspective, the potential of GLP‐1–based therapies in male reproductive medicine needs further investigation. Whether these drugs can improve sperm function and reproductive capacity via and beyond the effects of weight reduction remains to be determined. It is also unclear whether GLP‐1–based therapies exert direct effects within the seminiferous tubules or whether their beneficial effects on spermatogenesis are mediated indirectly through anti‐inflammatory and immunomodulatory pathways [11]. In parallel, evidence linking improvements in testosterone to the magnitude of weight loss [5] suggests that higher‐dose regimens and more potent antiobesity therapies capable of inducing ≥20% weight loss, including subcutaneous semaglutide up to 7.2 mg per week, tirzepatide, and emerging triple incretin agonists such as retatrutide, may confer proportionally greater reproductive benefits, although evidence remains lacking. In addition, rare causes of syndromic obesity accompanied by hypogonadism, such as Bardet–Biedl syndrome, which have distinct therapeutic implications, including treatment with setmelanotide, merit further exploration.

In conclusion, emerging clinical evidence, including recent systematic reviews, suggests that GLP‐1‐based therapies may represent fertility‐preserving and disease‐modifying therapies in men with obesity‐related functional hypogonadism [5, 8, 11]. Beyond reproductive outcomes, these therapies substantially reduce long‐term cardiovascular risk, which remains the leading determinant of morbidity and mortality in this population [3]. Therapeutic success should, therefore, be redefined beyond testosterone normalization, with management strategies recalibrated toward metabolic restoration using high‐efficacy, GLP‐1‐based antiobesity pharmacotherapies, including semaglutide, tirzepatide, and retatruide.