Expanding the therapeutic potential of GLP-1 receptor agonists: implications for male reproductive and perioperative urologic health

Deameh et al. conducted a systematic review evaluating the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on male reproductive hormones, semen parameters, and metabolic outcomes (1). Ten studies involving a total of 639 men were included. The included studies consisted of randomized controlled and cross-over trials, and prospective and retrospective studies that evaluated GLP-1 RAs such as semaglutide, liraglutide, dulaglutide, and exenatide. Overall, GLP-1 RA use was consistently associated with increased total testosterone, particularly in men with obesity, type 2 diabetes, or functional hypogonadism, with hormonal recovery often paralleling improvements in weight loss and glycemic control.

Several studies, including trials by Gregorič et al. and La Vignera et al., have demonstrated improvements in semen concentration, morphology, and motility with GLP-1 RA use in metabolically compromised men, while a study by Lengsfeld et al. found no significant changes in reproductive parameters in healthy eugonadal men (2-4). However, interpretation of the Gregorič et al. findings warrants caution, as testosterone replacement therapy (TRT) served as the comparator. Given the suppressive effects of exogenous testosterone on the hypothalamic-pituitary-gonadal axis and spermatogenesis, some between-group differences in semen parameters may have been driven by TRT-induced suppression rather than a direct effect of semaglutide (5). In addition, this review highlights the potential role of GLP-1 RAs as fertility-sparing therapeutic option in men with obesity-related functional hypogonadism. The authors noted several limitations including short follow-up durations, inconsistent reporting of testosterone measurements, and substantial heterogeneity across study designs, populations, comparator arms, and hormonal assays. In addition, only three studies included semen parameter assessments, making it unclear whether benefits were driven by metabolic improvements or by direct effects on spermatogenesis. Due to the trial heterogeneity, a quantitative meta-analysis was not performed.

This systematic review represents an important and comprehensive contribution to the rapidly evolving field of obesity-related functional hypogonadism, arriving at a pivotal time when the therapeutic landscape is shifting toward metabolic restoration beyond TRT alone. This emerging paradigm recognizes obesity-related functional hypogonadism as a reversible metabolic condition, positioning GLP-1 RAs as therapies to address the underlying pathophysiology rather than simply correcting circulating testosterone levels. This perspective aligns with Jensterle and Janez, who describe this approach as “therapeutic recalibration” (6). The findings of Deameh et al. further reinforce this concept by demonstrating improvements in testosterone and semen parameters across men with obesity, type 2 diabetes, or functional hypogonadism, in contrast to healthy eugonadal men, who derived little to no benefit from GLP-1 RA therapy. This pattern suggests these agents primarily restore endocrine function in metabolically compromised individuals rather than enhancing normal physiology (1). Furthermore, unlike TRT alone, GLP-1 RAs preserve gonadotropin function while simultaneously benefiting metabolic health, supporting their potential role in fertility preservation (2,6,7).

Within urologic patient care, these GLP-1 RAs may have important implications for perioperative optimization in genitourinary (GU) surgery, where obesity, diabetes, and metabolic conditions are well-established risk factors for postoperative complications. GLP-1 RAs have transformed the management of these metabolic conditions through sustained weight loss, improved glycemic control, and cardiovascular risk reduction, making them attractive candidates for metabolic optimization prior to GU surgeries in selected patients (8,9). For men with erectile dysfunction undergoing penile prosthesis surgery, evidence indicates that poor preoperative glycemic control is associated with a significantly increased risk of infection, with infection rates more than doubling in diabetic patients with hemoglobin A1c (HbA1c) ≥8%, underscoring the importance of metabolic optimization before implantation (10). These GLP-1 RAs may also decrease perioperative risks in hypogonadal men, who have been shown to have worse surgical outcomes when undergoing major GU surgery (11). While GU surgical perioperative evidence remains limited, a recent TriNetX national database study found that obese patients with recent GLP-1 RA use had improved renal outcomes after nephrectomy when compared to obese patients who were not on GLP-1 RAs (12). However, these potential perioperative benefits must be balanced against concerns regarding delayed gastric emptying, which may result in retained gastric contents and increase the risk of regurgitation and pulmonary aspiration during anesthesia (13). More recent evidence has prompted a shift toward individualized perioperative risk assessment rather than universal discontinuation, particularly based on gastrointestinal symptoms, dose escalation, and aspiration risk (13). Given the growing prescribing and usage of these medications, it is imperative to have prospective clinical trials investigating their perioperative safety and efficacy in reducing perioperative complications. Overall, these findings position GLP-1 RAs as a promising tool for optimizing both reproductive and perioperative outcomes in metabolically vulnerable urologic patients.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0618/prf

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