GLP-1 AGONISTS IN MEN: EFFECTS ON TESTOSTERONE, SPERM, AND SEXUAL FUNCTION

Introduction

Glucagon-like peptide-1 (GLP-1) receptor agonists have revolutionized the management of type 2 diabetes and obesity in recent years. Agents such as Ozempic and Wegovy (semaglutide), Mounjaro and Zepbound (tirzepatide), and earlier drugs like liraglutide and exenatide have gained prominence for their potent glucose-lowering and weight-loss effects. As their use expands, clinicians and patients alike are examining not only their metabolic benefits but also broader physiological effects – including male reproductive and sexual health. This evidence-based review provides a comprehensive overview of the GLP-1 receptor agonist class, comparing their mechanisms, indications, pharmacokinetics, and efficacy, and summarizes safety data and guideline recommendations. Special emphasis is placed on emerging data about how these agents may influence sperm production, testosterone levels, and sexual function in men.

GLP-1 Receptor Agonists: Mechanisms of Action and Class Overview

Mechanism of Action: GLP-1 receptor agonists (“incretin mimetics”) work by mimicking the action of endogenous GLP-1, a gut hormone (incretin) that is released in response to nutrient intake. By activating GLP-1 receptors, these drugs enhance glucose-dependent insulin secretion from pancreatic β-cells and suppress inappropriate glucagon release from α-cells, thereby lowering blood glucose only when levels are elevated (reducing hypoglycemia risk). They also delay gastric emptying and act on the brain’s appetite centers to increase satiety and reduce appetite, resulting in decreased caloric intake and weight. Through these mechanisms, GLP-1 agonists improve glycemic control and promote weight reduction – two key factors that can indirectly influence hormonal and reproductive health. Notably, GLP-1 receptors are not confined to the pancreas; they are also expressed in diverse tissues, including the gastrointestinal tract, heart, and even male reproductive organs like the testes. This widespread receptor distribution underlies both the therapeutic benefits and some off-target effects of the class.

Key Agents and Pharmacological Profiles: Since the first GLP-1 analog was approved in 2005, multiple agents have been developed, varying in structure, receptor selectivity, dosing frequency, and clinical applications. Table 1 - summarizes the prominent GLP-1 receptor agonists and related dual agonists:

• Exenatide (Byetta®, Bydureon®): A synthetic exendin-4 peptide (from Gila monster venom) and the first GLP-1 RA (approved 2005). Exenatide IR (immediate-release) is given twice daily, while exenatide ER is a once-weekly microsphere formulation. It has a shorter half-life (~2–4 hours for IR) requiring frequent dosing. Exenatide primarily targets postprandial glucose; it lowers HbA1c ~0.5–1.0% and causes modest weight loss (~2–3 kg). Indication: type 2 diabetes (T2D).
• Liraglutide (Victoza®, Saxenda®): A human GLP-1 analog (97% homology) with fatty-acid modification allowing albumin binding and a 24-hour duration. It is injected once dailymdpi.com. Victoza (liraglutide 1.2–1.8 mg) is for T2D, whereas Saxenda is a higher dose (3.0 mg) approved for obesity in 2014mdpi.com. Liraglutide reduces HbA1c by ~1.0–1.5% and, at 3 mg, can produce ~8% body weight loss in obesity trials. Notably, liraglutide has demonstrated cardiovascular benefit in high-risk diabetes patients (LEADER trial) and is now regarded as cardioprotective.
• Dulaglutide (Trulicity®): A long-acting GLP-1 RA consisting of two GLP-1 analog sequences covalently linked to an Fc fragment, which extends its half-life to ~5 days. It is a once-weekly subcutaneous injection for T2D. Dulaglutide lowers HbA1c ~1.0% or more and typically leads to ~3–5 kg weight loss. Importantly, dulaglutide showed reduced major adverse cardiovascular events (MACE) in the REWIND trial, making it another GLP-1 RA with proven cardiovascular benefit.
• Semaglutide (Ozempic®, Wegovy®, Rybelsus®): A potent GLP-1 analog with a large side chain for albumin binding, giving it a ~7-day half-lifemdpi.com. Ozempic (injectable semaglutide up to 2.0 mg weekly) is for T2D, while Wegovy (2.4 mg weekly) is for chronic weight management (approved 2021). Additionally, Rybelsus is an oral semaglutide tablet (3–14 mg daily) for T2D – the first oral GLP-1 RA. Semaglutide has among the largest effects in its class: HbA1c reductions up to ~1.5–2.0% and robust weight loss. In the STEP1 trial, weekly semaglutide 2.4 mg caused an average ~15% body weight reduction over 68 weeks, vs ~2.5% with placebonews.cornell.edunews.cornell.edu. This translated to ~15 kg weight loss in treated patients – a magnitude approaching bariatric surgery in some cases. Semaglutide (at 0.5–1 mg doses) also improved cardiovascular outcomes (SUSTAIN-6 and SOUL trials).
• Tirzepatide (Mounjaro®, Zepbound®): A first-in-class dual GLP-1 and GIP receptor agonist (often termed a “twincretin”). Tirzepatide combines GLP-1 RA activity with agonism of glucose-dependent insulinotropic polypeptide (GIP) receptors, potentially harnessing synergistic effects on insulin secretion and appetite regulation. It is given once weekly. Mounjaro (approved 2022) is indicated for T2D, while Zepbound(approved late 2024) is indicated for chronic weight management in obese adults, including those with weight-related conditions like obstructive sleep apnea. Tirzepatide has demonstrated unprecedented efficacy: in T2D trials (SURPASS program), the highest dose (15 mg) lowered HbA1c by ~2.0–2.5% on average and produced weight loss of 10–12 kgpmc.ncbi.nlm.nih.gov. In obesity trials (SURMOUNT), tirzepatide 10–15 mg achieved 20% or more body weight reduction on average. For example, a head-to-head trial (SURMOUNT-5) reported 20.2% weight loss with tirzepatide vs 13.7% with semaglutide 2.4 mg over ~72 week. Such outcomes position tirzepatide as one of the most powerful anti-obesity medications available. Like other GLP-1 RAs, tirzepatide’s glucose-lowering is glucose-dependent, with low hypoglycemia risk unless combined with insulin or sulfonylureas.

Table 1. Key GLP-1 Receptor Agonists and Dual Agonists

SC = subcutaneous; BID = twice daily; QD = once daily; OSA = obstructive sleep apnea; BMI = body mass index; CV = cardiovascular; A1c = hemoglobin A1c.

Pharmacokinetic Notes: Short-acting GLP-1 RAs (exenatide BID, lixisenatide) primarily affect postprandial glucose and tend to cause more gastrointestinal side effects initially due to rapid high peaks. Long-acting agents (weekly formulations, liraglutide daily) provide sustained GLP-1 activity day-long, improving fasting and postprandial glucose with less fluctuation. Tolerance to the gastric slowing effect often develops over time with long-acting agents, which may reduce GI side effects after initial weeks. The dual agent tirzepatide has pharmacokinetics similar to weekly GLP-1 RAs and exhibits dose-dependent effects on both glucose and appetite regulation. All GLP-1 RAs are eliminated mainly via proteolytic degradation (not renal clearance, except exenatide which has some renal excretion). Because they are peptide drugs, none (except oral semaglutide) are given orally.

Clinical Indications and Efficacy Comparison

Type 2 Diabetes: GLP-1 receptor agonists are established as effective glucose-lowering therapies in T2D. They are typically used after first-line metformin, or even as initial therapy in some cases of metformin intolerance or when weight loss is a priority. According to the American Diabetes Association (ADA) Standards of Care, a GLP-1 RA should be considered in T2D patients who have not met glycemic goals on metformin, especially if additional factors are present such as atherosclerotic cardiovascular disease (ASCVD), heart failure, or chronic kidney disease. In fact, ADA’s 2023 guidelines emphasize using a GLP-1 RA (or SGLT2 inhibitor) in patients with established ASCVD to reduce cardiovascular risk, independent of baseline A1c. Several GLP-1 RAs (liraglutide, injectable semaglutide, dulaglutide) have demonstrated reductions in heart attack, stroke, or cardiovascular death in large trials. Thus beyond lowering glucose (where they can drop A1c roughly 1–2% as monotherapy or add-on), GLP-1 RAs confer weight loss and cardioprotective benefits – a combination particularly advantageous in the many patients with T2D who are overweight or have cardiovascular risk factorsdiabetesonthenet.com. In head-to-head comparisons, semaglutide and tirzepatide achieve the greatest glycemic efficacy, often normalizing blood sugar in a substantial fraction of patients, whereas older agents like exenatide and lixisenatide have somewhat lesser potency. Notably, tirzepatide 15 mg was superior to semaglutide 1 mg in lowering A1c in a trial (SURPASS-2), reflecting the added GIP action.

Obesity and Weight Management: Many GLP-1 RAs are now also approved explicitly for obesity management in non-diabetics. Wegovy (semaglutide 2.4) and Zepbound (tirzepatide) are recent breakthroughs, enabling average weight losses of 15–20% in clinical trials. For perspective, older weight-loss medications typically produced 5–10% weight reduction. The weight loss from GLP-1 agonism derives from appetite suppression and possibly enhanced satiety signals; some agents also promote a preference for lower-calorie foods. Guidelines from bodies such as the Endocrine Society and AACE (American Association of Clinical Endocrinology) recommend considering GLP-1 RAs (or other anti-obesity medications) in patients with BMI ≥30, or ≥27 with weight-related comorbidities, when lifestyle measures alone are insufficient. These drugs are particularly valuable for patients with obesity-related conditions like metabolic syndrome, prediabetes, or as recently approved, obstructive sleep apnea (OSA) – the FDA approved tirzepatide in OSA because weight loss led to significant improvement in apnea-hypopnea index and symptom resolutionfda.govfda.gov. It’s important to counsel patients that medication-induced weight loss requires sustained treatment; if the drug is stopped, appetite typically increases again and weight regain can occur in absence of continued lifestyle efforts.

Other Emerging Uses: Beyond diabetes and obesity, GLP-1 RAs are being explored in other conditions. There is interest in their use in non-alcoholic fatty liver disease (NASH), as they have shown improvements in liver enzymes and histology in trials (e.g., semaglutide in NASH). Some data suggest GLP-1 agonists may modestly lower blood pressure and LDL cholesterol, improving overall cardiometabolic profilediabetesonthenet.com. Research is ongoing in polycystic ovary syndrome (PCOS) and even neurodegenerative diseases (due to GLP-1’s actions in the brain). However, a particularly intriguing area, and the focus of our later discussion, is their potential impact on male reproductive function – a topic of growing interest as more men of reproductive age use these agents for weight or diabetes control.

Safety Profile and Contraindications

General Side Effects: As a class, GLP-1 RAs are generally well-tolerated, with the most common adverse effects being gastrointestinal symptoms due to slowed gastric emptying and central appetite effects. Nausea affects a significant portion of patients (up to 20–50% early on), along with possible vomiting, diarrhea, or constipation. These GI effects are typically dose-dependent and tend to improve over time or with dose titration. Patient education on eating smaller meals and avoiding rich, fatty foods at initiation can help mitigate nausea. Some individuals also report early satiety or altered taste preferences. Because of the GI effects, caution is advised in patients with severe gastroparesis (e.g., long-standing diabetic gastroparesis) – GLP-1 RAs can worsen gastric emptying delays and are generally not recommended in that scenario.

Rare but Serious Risks: Serious adverse events are uncommon, but the class has a few important considerations:

• Pancreatitis: Post-marketing reports linked GLP-1 RAs to cases of acute pancreatitis. While a causal relationship remains inconclusive (patients with T2D and obesity have other pancreatitis risk factors), prudence dictates avoiding these drugs in patients with a history of pancreatitis or at least using with caution. Patients should be counseled on symptoms of pancreatitis (persistent severe abdominal pain) and advised to seek evaluation if these occur. Large outcomes trials have not shown a significantly higher pancreatitis incidence with GLP-1 RAs versus placebo, but the labeling still lists it as a warning.
• Gallbladder disease: Rapid weight loss can predispose to gallstones, and some trials (particularly with high-dose semaglutide and liraglutide for obesity) noted a slight increase in gallstone-related events. Patients should be aware of possible gallbladder symptoms. Maintaining hydration and a moderate rate of weight loss might help reduce risk.
• Thyroid C-cell Tumors: All GLP-1 RAs carry a boxed warning for risk of medullary thyroid carcinoma (MTC). This stems from rodent studies in which chronic high-dose exposure caused C-cell tumors in rats. Importantly, no cases of MTC have been causally linked to GLP-1 RA use in humans to date, and rodent C-cells are known to be more sensitive to GLP-1 stimulation than human C-cells. Nonetheless, the class is contraindicated in patients with a personal or family history of MTC or multiple endocrine neoplasia type 2 (MEN2) as a precaution. Routine calcitonin monitoring is not recommended in the general population, but any patient with neck mass or compressive symptoms while on therapy should be evaluated.
• Hypoglycemia: GLP-1 RAs by themselves do not usually cause hypoglycemia because they augment insulin only in the presence of elevated glucose. However, when combined with other medications that can induce hypoglycemia (especially insulin or sulfonylureas), the risk of low blood sugar increases. In such combinations, a reduction in the dose of the secretagogue or insulin is often necessary.
• Renal effects: There is no direct nephrotoxicity, but profound nausea/vomiting can lead to dehydration and transient increases in creatinine. Caution is advised in patients with severe renal impairment mainly due to risk of volume depletion; exenatide is specifically not recommended in patients with end-stage renal disease (it is cleared renally). Overall, GLP-1 RAs may actually benefit the kidney via improved glycemic control and blood pressure; some have shown slowed progression of diabetic kidney disease.

Contraindications: As noted, history of MTC or MEN2 is a contraindication. Pregnancy is another important contraindication – weight-loss medications including GLP-1 RAs are not used in pregnancy (intentional weight loss is not recommended for pregnant women, and animal studies with GLP-1 RAs have shown some fetal growth effects). Women of childbearing potential on these drugs should use effective contraception and discontinue the medication if planning to conceive. There is no contraindication for men trying to conceive; however, due to the theoretical reproductive effects (discussed below), some guidelines suggest discontinuing GLP-1 RAs in men actively attempting fertility until more safety data are available. Finally, hypersensitivity to any component (e.g. anaphylaxis to exenatide or semaglutide, which is exceedingly rare) would preclude use.

Guideline Recommendations: Leading diabetes organizations highlight GLP-1 RAs as a preferred tool in multiple scenarios. The ADA and the European Association for the Study of Diabetes (EASD) recommend GLP-1 RAs (or SGLT2 inhibitors) with proven cardiovascular benefit for T2D patients with cardiovascular disease. They also prioritize GLP-1 RAs for patients in whom weight loss is desired or hypoglycemia avoidance is a concern. ADA/EASD consensus reports have even proposed GLP-1 RAs as first-line injectable therapy before insulin for most T2D patients who need an injection, given the superior weight and hypoglycemia profile. For obesity, AACE and Obesity Society guidelines endorse using GLP-1 RAs when BMI criteria are met and lifestyle measures need augmentation, especially if there are weight-related comorbidities. From a urology standpoint, the American Urological Association (AUA) in its male infertility guidance acknowledges that obesity and metabolic syndrome can impair male fertility and recommends weight reduction as part of holistic managementncbi.nlm.nih.gov. While AUA does not yet explicitly mention GLP-1 agonists, the emerging evidence (below) suggests these agents could play a role in improving metabolic hypogonadism and should be considered in consultation with endocrinologists for obese men with fertility issues. Similarly, in men with erectile dysfunction (ED), AUA guidelines stress lifestyle optimization (including weight loss) as a foundational step, which in the modern era may include medical weight loss therapy.

Effects of GLP-1 Agonists on Male Reproductive and Sexual Health

One of the most intriguing and evolving aspects of GLP-1 pharmacotherapy is its intersection with male reproductive physiology. Historically, little was known about how these drugs might affect male fertility or sexual function. However, the rapid rise in use of GLP-1 RAs among men (for diabetes or obesity) has spurred research into outcomes like testosterone levels, sperm parameters, and erectile function. This section reviews current evidence from animal studies, clinical trials, case reports, and patient observations regarding GLP-1 agonists and male reproductive health. Table 2 (below) provides a summary of key studies and findings in this domain.

GLP-1, Metabolic Health, and Hormonal Interplay

It is well established that obesity and diabetes can adversely affect male reproductive function. Men with obesity or metabolic syndrome often exhibit functional hypogonadism (low testosterone levels due to excess adiposity) and impaired sperm parameters, as well as higher rates of erectile dysfunctionfrontiersin.orgmdpi.com. Adipose tissue aromatizes testosterone to estrogen and contributes to systemic inflammation and insulin resistance, all of which can disrupt the hypothalamic–pituitary–gonadal (HPG) axis and spermatogenesis. Weight loss and improved glycemic control are therefore generally beneficial for reproductive health – for example, weight reduction can raise testosterone levels and improve semen quality in obese menmdpi.compubmed.ncbi.nlm.nih.gov. GLP-1 RAs, by virtue of inducing significant weight loss and metabolic improvements, could indirectly enhance male reproductive function simply by reversing these deleterious effects of obesity/diabetes.

Beyond indirect effects, researchers have discovered that GLP-1 receptors are present on male reproductive tissuesincluding the testes (particularly on Leydig cells, which produce testosterone)frontiersin.org. Animal models and in vitro studies suggest that GLP-1 signaling can influence testicular function. GLP-1 receptors on Leydig cells might modulate steroidogenesis, and receptors on Sertoli cells could affect sperm support and development. This raises a critical question: do GLP-1 agonists have any direct effects (positive or negative) on hormone production or sperm parameters independent of weight loss? The answer appears to be nuanced, with some conflicting data, but a few themes have emerged:

• Insulin and hormonal cross-talk: GLP-1 RAs improve insulin sensitivity and lower insulin levels (especially in obese insulin-resistant men). Hyperinsulinemia in obesity can suppress SHBG and reduce gonadotropin release; thus improving insulin dynamics might help normalize the HPG axis. Indeed, studies have documented increases in sex hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in men treated with GLP-1 RAs, suggesting a relief of metabolic inhibition on the pituitary-gonadal axis.
• GLP-1 and the hypothalamus: GLP-1 acts in the brain to reduce appetite, and animal research hints it might also influence GnRH neurons or other neuroendocrine pathways. Any central effect is not well-characterized yet, but it is a subject of ongoing research.
• Direct testicular effects: Preclinical evidence indicates mixed effects. One early study (Jeibmann et al. 2005) found that activating GLP-1 receptors decreased testosterone production in an experimental model, raising concern that GLP-1 agonism could theoretically impair Leydig cell function. On the other hand, some recent rodent studies show improvements in sperm function with GLP-1 RA treatment despite little change in testosterone. For instance, Zhang et al. 2015 examined obese male mice on a high-fat diet and reported that while the HFD mice had lower serum testosterone (which exenatide treatment did not fully restore), the GLP-1 RA–treated mice did show improved sperm motility, enhanced sperm mitochondrial activity, and reduced sperm DNA fragmentation compared to untreated obese controls. The exenatide appeared to attenuate some detrimental effects of obesity on the sperm, even though circulating testosterone remained low. Similarly, other animal experiments have noted reductions in testicular inflammatory cytokines and improved sperm parameters with GLP-1 RA therapy, hinting at direct beneficial effects on the testis microenvironment. For example, exenatide-treated obese mice had lower intratesticular TNF-α levels and better sperm motility than controls. However, those same models confirm that GLP-1 RA did not significantly raise testosterone in the obese animalsmdpi.com, indicating that weight loss or additional interventions might be needed to normalize androgens.

In summary, the mechanistic picture suggests GLP-1 RAs could improve the “fertile milieu” by aiding weight loss and reducing metabolic inhibitors of fertility, and they may even directly improve certain sperm functions, but they are not magic bullets for restoring testosterone in severely obese or diabetic states (at least in isolation). We now turn to human studies for clinical evidence.

Effects on Testosterone and Hormonal Profile in Men

Several clinical studies – both observational and interventional – have measured testosterone and other hormone changes in men on GLP-1 RAs:

• Improvements in Hypogonadism: An important randomized trial by La Vignera et al. (2023) focused on obese men with “functional” hypogonadism (low testosterone due to obesity). In this 4-month study, 110 young obese men were divided into three treatment groups: Group A received gonadotropin injections (hCG and FSH) to stimulate testis, Group B received liraglutide 3.0 mg daily, and Group C received transdermal testosterone replacement. Notably, only Group A was actively trying to conceive (hence given gonadotropins), while Group B did not desire immediate fertility (so weight loss with liraglutide was tried), and Group C had completed fertility (hence got testosterone which, while treating hypogonadism symptoms, can suppress spermatogenesis)mdpi.com. The outcomes were striking: the liraglutide group (Group B) achieved significantly greater benefits than either gonadotropins or testosterone therapy. After 4 months, men on liraglutide had a +46% increase in total testosterone, along with significant increases in LH and FSH (indicating improved endogenous gonadotropin output)mdpi.com. By contrast, those on external testosterone (Group C) saw testosterone levels go up (as expected) but their LH/FSH were suppressed, and those on gonadotropins (Group A) saw some improvement in T but not as robust as liraglutide’s effect. More importantly, sperm parameters improved markedly with liraglutide: sperm concentration roughly tripled (from ~6 million/mL to 16 million/mL, p<0.05), progressive motility more than doubled (14% to 34%, p<0.01), and normal morphology increasedacademic.oup.com. Essentially, liraglutide turned many severe oligospermic men into men with near-normal sperm counts. Gonadotropin therapy also improved sperm counts but not to the same degree, and exogenous testosterone tended to worsen sperm output (as expected). Liraglutide patients even reported better sexual function – the study measured erectile function via the IIEF-5 questionnaire, and only Group B (liraglutide) showed a significant improvement in erectile function scoresmdpi.com. By the study’s end, liraglutide had elevated testosterone and SHBG to higher levels than achieved in the other groups and led to higher sperm counts and motility, earning the authors’ conclusion that “liraglutide is a useful drug for the treatment of obese males with metabolic hypogonadism,” outperforming traditional hormonal approaches This pioneering trial suggests that tackling the root cause (obesity/insulin resistance) with a GLP-1 RA can reverse obesity-related hypogonadism and improve fertility potential in men.
• Weight Loss Maintenance and Sperm Counts: Another randomized controlled trial by Andersen et al. (2022)in Denmark investigated weight loss and semen parameters. In this study, obese men underwent an initial 8-week low-calorie diet (very low calorie, ~800 kcal/day), losing on average 16.5 kg (about 15% of body weight) pubmed.ncbi.nlm.nih.gov. This induced substantial improvements in sperm counts – sperm concentration increased ~1.5-fold and total sperm count ~1.4-fold after the diet. The men were then randomized to 1 year of different maintenance strategies: placebo, exercise, liraglutide 3.0 mg, or liraglutide + exercise (this was the S-LITE trial). After one year, those who maintained the weight loss (notably, the groups on liraglutide and/or exercise) largely maintained the improved sperm counts, whereas men who regained weight saw their semen improvements disappear. The authors concluded that maintaining weight loss – either via lifestyle or pharmacotherapy – is key to preserving the fertility benefits of initial weight reduction. This trial highlights that GLP-1 RA therapy can be an effective tool to sustain weight loss and associated sperm count improvements. In the liraglutide-treated maintenance group, not only was weight regain prevented, but the higher sperm concentration/count achieved after the diet was sustained at 52 weekspubmed.ncbi.nlm.nih.gov. Thus, in obese men, weight loss (with diet) improves semen quality, and ongoing GLP-1 treatment helps maintain those gains if lifestyle alone is insufficient to keep the weight off.
• General Testosterone Increases: In men with type 2 diabetes or obesity, treatment with GLP-1 RAs has been linked to higher testosterone levels in several reports. For example, an observational study noted that diabetic men on liraglutide had significantly higher total testosterone after 6 months of therapy compared to baseline, along with improved glycemic control and weight loss. Another small trial in obese hypogonadal men compared liraglutide vs testosterone gel over 16 weeks: the liraglutide group lost ~6% body weight and showed rising LH/FSH and SHBG (as mentioned earlier), whereas the testosterone therapy group gained lean mass but lost some endogenous gonadal function. These data suggest GLP-1 RAs can reverse the obesity-driven suppression of the HPG axis, effectively “rebooting” the system to produce more testosterone on its own. It is noteworthy that these improvements may take a few months to manifest and correlate with the degree of weight loss and metabolic improvement.

On balance, current evidence indicates that GLP-1 agonists do not harm testosterone levels – if anything, they tend to raise testosterone in overweight men by aiding weight loss and possibly through direct pituitary stimulation (higher LH). In men with normal baseline gonadal function, short-term GLP-1 RA use has not caused any drop in testosterone or semen measures. A recent study in healthy, normal-weight men treated with dulaglutide for 4 weeks found no negative effect on testosterone, libido, or sperm parameters compared to placebofrontiersin.org. This is reassuring for eugonadal men: GLP-1 RAs did not perturb their reproductive hormones in the short term.

Effects on Sperm Parameters and Fertility

The ultimate concern for men desiring fertility is whether GLP-1 RAs could impair or improve their ability to father children. While we’ve seen that improving obesity can increase sperm counts, there have been isolated case reports and conflicting findings that warrant caution:

• Case Report of Sperm Impairment: The first report to raise alarm was by Fontoura et al. (2014). They described a 35-year-old diabetic man with a year of infertility whose semen analysis worsened dramatically after starting liraglutide (0.6 mg daily, uptitrated). Initially, he had normal volume and mild oligozoospermia, but two months into liraglutide therapy, his sperm concentration fell to near-zero (0.01 million/mL) with complete absence of motile sperm. This raised the possibility that liraglutide “interrupted spermatogenesis” in this individualsciencedirect.com. Liraglutide was discontinued, and over the next 4–5 months his sperm parameters gradually recovered: concentration rose to 8.7 million/mL with restored motility by month 4, and by month 5 post-discontinuation his semen analysis was back to normal ranges. The patient subsequently achieved a successful pregnancy via IVF with intracytoplasmic sperm injection (ICSI) using his sperm. This single-case report suggests a possible idiosyncratic adverse effect of GLP-1 RA on spermatogenesis in some men. However, it’s important to interpret it in context – this was one patient, and he was also a diabetic which can itself affect fertility. No underlying genetic fertility issue was reported, and given the temporal relationship, liraglutide was deemed the likely culprit. To date, this remains an isolated report of severe sperm suppression linked to a GLP-1 drug. It underscores the need for further research and caution in men actively trying to conceive, but it has not been replicated in larger studies.
• No Detriment in Clinical Study: Contrasting with the above, a recent analysis of diabetic men at a fertility clinic found no evidence that GLP-1 RA use harms sperm. In an abstract presented by Gago et al. (AUA, 2024), investigators compared semen parameters in diabetic men who had been exposed to GLP-1 RAs vs those who had not. They concluded that “GLP-1 RA use is not associated with impaired semen parameters among diabetic men undergoing fertility evaluation.”auajournals.org In other words, the men on GLP-1 therapy had similar sperm counts, motility, etc., as those not on the therapy, after controlling for other factors. This real-world data is reassuring and suggests that any negative effect, if present, is not common.
• Improvement in Sperm Morphology: Beyond count and motility, there is interest in whether GLP-1 RAs affect sperm morphology and DNA integrity. A small pilot study of men with type 2 diabetes on semaglutide noted an improvement in the percentage of morphologically normal sperm after 24 weeks, along with rises in total testosterone and improved symptoms of hypogonadism. Sperm DNA fragmentation is another metric of fertility; as mentioned, the animal study by Zhang 2015 found reduced DNA fragmentation in sperm of GLP-1-treated mice, hinting at a protective effect on sperm DNA perhaps via less oxidative stress or inflammation.

Overall, the preponderance of evidence so far indicates neutral to beneficial effects of GLP-1 RAs on sperm quantity and quality, especially when used to treat obesity-related subfertility. Weight loss and metabolic health improvements are clearly associated with better semen parameters. Direct drug effects, if any, seem to favor improved motility and possibly morphology. The concerning case report of sperm suppression remains an outlier but has prompted calls for vigilance. Until more data are available, a pragmatic approach for men actively attempting conception might be to use the lowest effective dose and ensure periodic semen analysis, or temporarily hold the GLP-1 RA if fertility is an immediate priority (balancing against the risk of weight regain). Importantly, fertility is a long-term consideration – spermatogenesis takes ~74 days, so any intervention or insult could take 2–3 months to manifest in semen changes. Clinicians should keep this timeline in mind when assessing any reproductive effects of medication.

Effects on Erectile Function and Libido

Sexual health, particularly erectile function, is another facet of male well-being that might be influenced by GLP-1 agonists. Erectile dysfunction (ED) often coexists with T2D and obesity; improvements in weight and glycemic control typically correlate with better erectile function. There are a few angles to consider:

• Improved Vascular Function: ED is largely a vascular issue. GLP-1 RAs have been found to have vasodilatory and anti-atherosclerotic effects in animal models and some human studies. In patients with T2D, GLP-1 RAs may improve endothelial function and blood pressure, which can translate to better penile blood flow. A retrospective cohort study in 2024 suggested that men with T2D on GLP-1 RAs had improved erectile function compared to those not on GLP-1, potentially due to positive effects on vascular health and weight loss. Additionally, GLP-1 RAs often reduce inflammation and oxidative stress, which are contributors to ED in diabetes.
• Weight Loss and ED: Weight reduction by any means is known to alleviate ED. Studies have shown that losing even 5–10% of body weight in obese men can significantly improve erectile function scores and raise testosterone (which can enhance libido and erectile mechanism). Therefore, the substantial weight loss induced by agents like semaglutide or tirzepatide could indirectly improve ED. In fact, a genetic Mendelian randomization study in 2024 found that having a genetic profile akin to being on GLP-1 RA therapy was associated with ~50% lower odds of ED, partly mediated by lower obesity, diabetes, and blood pressure. This supports the idea that GLP-1 RAs as a class are likely “friends” rather than foes to erectile function, insofar as they ameliorate the underlying causes of ED.
• Clinical Observations: The previously mentioned liraglutide trial by La Vignera not only improved sperm counts but also showed better erectile function scores on liraglutide than either fertility hormones or testosterone therapymdpi.com. This suggests that beyond fertility, the overall sexual quality of life (libido, erections) improved when metabolic health was targeted. Some patients on GLP-1 RAs have anecdotally reported increased energy and sexual desire as they lose weight and their diabetes is controlled – likely a byproduct of feeling healthier.

On the other hand, there have been isolated reports and rumors of ED as a side effect of GLP-1 drugs, particularly semaglutide. Because these medications can cause fatigue, mild dehydration, or GI discomfort, a few men have subjectively noted reduced sexual drive or performance. This has been picked up in social media and even one or two small studies. Notably, one analysis of the FDA Adverse Event Reporting System (FAERS) looked at reports of sexual dysfunction (including ED, decreased libido, and orgasmic disorders) in men on GLP-1 RAs. Among millions of users, only 182 cases were found from 2003–2024, mostly with exenatide or semaglutide, typically in men around 40–60nature.com. When analyzed statistically, the reporting odds ratio for ED with GLP-1 RAs was actually below 1 (approximately 0.41), meaning no disproportionate signal of ED – if anything, ED was reported less frequently than expected on these. The authors concluded that while vigilance is warranted as usage grows, the overall risk of medication-induced ED appears lownature.com. In plainer terms, the vast majority of men do not experience new ED attributable to the drug itself; underlying conditions remain the main driver.

A separate meta-analysis of trials in diabetic men found that those treated with GLP-1 RAs had significantly better erectile function scores than those on placebo or even other diabetes meds like metforminpmc.ncbi.nlm.nih.gov. This aligns with a mechanistic view that GLP-1 RAs might improve endothelial nitric oxide and penile blood flow. Another retrospective study (2023) focusing on dulaglutide in T2D reported lower incidence of new-onset moderate-to-severe ED in the group on dulaglutide over 1–2 years compared to those not on it.

Taken together, the evidence suggests GLP-1 agonists may actually help sexual function by treating risk factors, rather than harm it. Any direct pharmacologic negative effect on erections is not substantiated strongly. That said, clinicians should be aware of and inquire about sexual side effects. If a patient reports new ED after starting a GLP-1 RA, it is worth evaluating other factors (changes in weight, blood pressure, medication interactions, psychological factors, etc.). In rare cases, adjusting the dose or switching classes might be tried, but such reports are uncommon. On the flip side, improvements in ED might be a motivating benefit to mention when prescribing these agents to men – for example, better erections and sexual satisfaction often accompany the improved testosterone and fitness that result from significant weight loss.

Table 2. Key Studies of GLP-1 RAs on Male Reproductive and Sexual Outcomes

T = testosterone; HFD = high-fat diet; IIEF = International Index of Erectile Function; RCT = randomized controlled trial; MR = Mendelian randomization; OR = odds ratio; ROR = reporting odds ratio; N/A = not applicable.

As shown above, the balance of evidence tilts toward a beneficial or neutral impact of GLP-1 receptor agonists on male reproductive and sexual health. The drugs’ ability to induce weight loss, improve glycemic control, and reduce cardiovascular risk factors likely contributes to better fertility outcomes (higher testosterone, better sperm quality) and improved erectile function in men who have metabolic dysfunction. For an overweight man with borderline fertility or ED, starting a GLP-1 RA and losing significant weight might be one of the best things he can do – it addresses the root causes (obesity, insulin resistance) that underlie many cases of male subfertility and ED.

However, given the few conflicting findings (like the 2014 case report), it is prudent to approach each patient individually. Guidance for clinicians: if you have a male patient of reproductive age on a GLP-1 agonist, monitor their weight, glycemic status, and inquire about any changes in sexual function. If the patient is actively trying to conceive and experiencing difficulty, consider a semen analysis. It may be reasonable to hold the GLP-1 RA if no other cause for infertility is found, although evidence does not strongly implicate the drug in most cases. On the contrary, if the patient’s obesity is a main barrier to conception, continuing the GLP-1 RA to achieve weight loss might substantially improve chances of natural conception. Current reviews emphasize that more research is needed on long-term effects of GLP-1 RAs on spermatogenesis and male fertility outcomes. Ongoing trials and post-marketing studies will further clarify this in the coming years.

Conclusion

GLP-1 receptor agonists have emerged as powerful agents that improve metabolic health – lowering blood sugar, inducing weight loss, and reducing cardiovascular risk in patients with diabetes or obesity. Key drugs like semaglutide (Ozempic®/Wegovy®) and the dual agonist tirzepatide (Mounjaro®/Zepbound®) are at the forefront of a paradigm shift in treating metabolic disease. Their mechanisms of action (stimulating insulin, curbing appetite, slowing gastric emptying) translate into meaningful clinical benefits, supported by robust evidence from trials and reflected in guideline recommendations by ADA/EASD and others.

For physicians, it is important to understand the comparative profiles of these agents – differences in dosing, efficacy, and safety – to individualize therapy. For instance, a patient with established heart disease might particularly benefit from liraglutide or semaglutide given their cardiovascular outcome datancbi.nlm.nih.gov, whereas a patient with severe obesity might be a candidate for high-dose semaglutide or tirzepatide to achieve maximum weight loss. Safety considerations (like GI tolerability, thyroid cancer precautions, and pancreatitis risk) should be discussed openly with patients. In the context of male patients, clinicians should also be aware of the encouraging data that metabolic improvements via GLP-1 RAs can favorably influence male reproductive hormones and function.

From the available evidence, GLP-1 RAs do not cause male infertility or sexual dysfunction in any common or systematic way. On the contrary, by helping men lose weight and improve their diabetes, these drugs often lead to higher testosterone levels, better sperm parameters, and improved erectile performance as secondary benefits. Cutting-edge research even posits that GLP-1 agonists might someday be intentionally used in managing male infertility related to obesity – a concept under investigation. The story is still unfolding, and physicians should stay updated on new findings.

For now, the take-home messages for an informed patient or provider are:

• GLP-1 RAs (Ozempic, Wegovy, Mounjaro, etc.) are highly effective for T2D and obesity, offering glycemic control and substantial weight loss along with protective effects on the heart and possibly kidneys. They should be used in appropriate patients as per guidelines, with careful titration and monitoring of side effects.
• In men, these medications tend to improve hormonal profiles – alleviating obesity-related low testosterone and supporting better sperm production in those who lose weight. Men have even seen normalized sperm counts and improved erectile function when using GLP-1 RAs as part of a weight-loss or diabetes treatment planmdpi.commdpi.com.
• While rare instances of adverse reproductive effects have been noted, current data do not indicate any widespread detrimental impact on male fertility. In fact, initial concerns (like the single case of liraglutide-related azoospermia) have not been borne out in larger studiesauajournals.org. Pharmacovigilance data show no significant signal of drug-induced sexual dysfunctionnature.com.
• Men trying to conceive can generally continue GLP-1 RA therapy if needed for their health, but it’s reasonable to have a discussion about the limited data and perhaps perform baseline and follow-up semen analyses. If any negative changes occur, a trial off the medication could be considered to see if semen parameters improve. Given that fertility involves both partners, the man’s weight loss and health improvement on a GLP-1 RA may actually increase the couple’s chance of conception (and certainly will improve his overall health).
• As always, a multidisciplinary approach is valuable. Endocrinologists, primary care physicians, and urologists should collaborate when managing a patient who is on a GLP-1 agonist and has reproductive goals. Lifestyle modifications – diet, exercise, quitting smoking – remain foundational and synergistic with GLP-1 therapy, benefitting both metabolic and reproductive outcomesncbi.nlm.nih.gov.

In conclusion, GLP-1 receptor agonists represent a major advance in metabolic medicine and, based on current evidence, offer collateral benefits for male reproductive and sexual health rather than harm. Ongoing research will further elucidate their role in this realm, but the data so far are reassuring. By treating the whole patient – addressing blood sugar, body weight, and hormonal balance – these agents contribute to improved vitality that encompasses not just longer life, but better living, potentially including a healthier reproductive life for men.

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