Effects of GLP-1 analogs on metabolic alterations including male sexual function, hypogonadism and erectile dysfunction: a narrative review

Introduction

In chronic metabolic diseases such as obesity, dyslipidemia, and type 2 diabetes mellitus (T2DM), subacute chronic inflammation occurs, characterized by cytokine release. These cytokines induce insulin resistance (IR), hypertriglyceridemia, and lower high-density lipoprotein (HDL) cholesterol. Inflammation also alters glucagon-like peptide-1 (GLP-1) fractions (1,2). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are now used to manage T2DM and obesity and to improve patient outcomes, with their medium- and long-term effects still under investigation. Metabolic changes associated with diseases such as diabetes and obesity alter hormonal mechanisms, leading to chronic inflammation, oxidative stress, and microvascular dysfunction. These contribute to male fertility disorders like hypogonadism, erectile dysfunction (ED), and altered sperm parameters. The expanded use of GLP-1RAs for weight-loss treatments encourages further exploration into their benefits for treating male infertility in patients with obesity.

One recent area of study is their possible benefit in functional hypogonadism, often linked to male infertility, as they have been shown to improve sperm parameters, restore testosterone levels, and enhance microvascular function in ED (3,4). In this scenario, meta-analyses provide growing evidence that improving metabolism, along with weight loss, could also be effective in reducing the progression of infertility (5,6).

This review aimed to analyze scientific evidence on the mechanisms by which obesity or metabolic issues cause male sexual dysfunction; assess the potential of GLP-1RAs to improve fertility in this context; and examine hormonal changes associated with obesity or diabetes that contribute to hypogonadism, thereby evaluating GLP-1RAs effects in affected men. We present this article in accordance with the Narrative Review reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0285/rc).

Methods

A comprehensive literature search was conducted across online databases, including PubMed, Web of Science, and ScienceDirect, using the keywords: GLP-1, GLP-1RA, metabolic syndrome, obesity, endothelial dysfunction, erectile dysfunction, hypogonadism, male sexual dysfunction, body mass index (BMI), and male infertility. Only studies that delved into the molecular mechanisms underlying GLP-1 regulation and the clinical applications of GLP-1RAs were selected for inclusion; therefore, the references included in this review were obtained. The search strategy is summarized in Table 1, and the keyword combination example for searching each item appears in Appendix 1.

GLP-1: physiological functions and metabolic pathologies such as obesity and diabetes

The intestinal enteroendocrine system regulates energy homeostasis by releasing gastrointestinal hormones, including GLP-1, which was the second incretin identified in 1983. The human glucagon gene is located on chromosome 2. It encodes a preproprotein that is cleaved into four mature peptides (Figure 1A,1B). Among these peptides, GLP-1 is released by PCSK1 (8,9). GLP-1 is a peptide hormone of 30 or 31 amino acids, part of a family of hormones known as incretins (Figure 1A). It is released from intestinal L-cells, whose secretion depends on the presence of nutrients in the small intestinal lumen. After food intake, it increases insulin secretion and regulates glycemia (10,11) (Figure 1A-1C).

Figure 1 GLP-1/ GLP-1R structure, interaction and functions. (A) Primary sequence of the incretin peptide GLP-1. (B) GLP-1 bound to its receptor (Created in https://BioRender.com). (C) Dynamic structural model of the GLP-1R, showing the ECD and the transition of the TMD toward the active state after GLP-1 binding. The ECD is shown in green. The inactive and active TMDs are shown in blue and yellow, respectively; the G protein from the active structure is shown in brown. Cell membranes are represented as grey lipid bilayers. Modified from: Wu et al. 2020 (7). cAMP, cyclic adenosine monophosphate; ECD, extracellular domain; Epac-2, exchange protein directly activated by cAMP 2; GLP-1, glucagon-like peptide-1; GLP-1R, GLP-1 receptor; PKA, protein kinase A; TMD, transmembrane domain.

Besides, Mojsov et al. identified the glucagon gene, which is expressed in the pancreas and produces pancreatic glucagon. Intestinal endocrinocytes called L-cells in the terminal portion of the small intestine also express the proglucagon peptide and, through proteolysis, generate other glucagon-like peptides, such as GLP-1 and GLP-2, glicentin, and oxyntomodulin (7,12,13). Once GLP-1 enters circulation, the enzyme dipeptidyl peptidase-4 (DPP-4) rapidly degrades it, resulting in a half-life of only a few minutes (14,15).

GLP-1’s main physiological function is to control blood glucose, but it also contributes to metabolic homeostasis after nutrient absorption by suppressing glucose-dependent glucagon secretion, inhibiting gastric emptying, and promoting satiety (11,15) (Figure 2).

Figure 2 GLP-1 functions in various organs and tissues of the body (created in https://BioRender.com). GLP-1, glucagon-like peptide-1; IL, interleukin; TNF-α, tumor necrosis factor-alpha.

GLP-1 binds to a receptor known as GLP-1R, a vital member of the G protein-coupled receptor (GPCR) family, primarily found on the surface of various cell types (Figure 1C) (16). GLP-1 specifically interacts with this receptor, a heterodimeric protein with three domains: a prodomain, a catalytic domain (which contains the catalytic triad functioning only in autocatalytic excision), and a C-terminal domain (Figure 1C). The body predominantly expresses this receptor in the liver and is also widely distributed in various tissues of the body, including the lungs, kidneys, central nervous system (CNS), cardiovascular system, gastrointestinal tract, skin, and vagus nerve. In the case of GLP-1RAs, weight loss is thought to be achieved by several mechanisms, including delayed gastric emptying, increased satiety, increased resting energy expenditure, and direct effects on the brain’s appetite center (7,13,17) (Figure 1).

Chronic non-transmissible metabolic diseases such as overweight, obesity, and especially type 2 diabetes, pose a growing global public health challenge. These comorbidities have negative health consequences, reducing quality of life and life expectancy (4,18). Their global surge can be attributed, in part, to hypercaloric diets, which lead to a metabolic imbalance between energy intake and expenditure. Scientific evidence links overconsumption of simple carbohydrates to increased lipogenesis and inflammatory processes, elevating cardiovascular risk and upregulating leptin, a hormone that regulates body weight, intake, and expenditure (1,19) (Figure 2).

Hypercaloric diets also disrupt intestinal microbiota, compromising the gut barrier and altering neurotransmitter metabolism of the gut-brain axis. This results in elevated lipid and glucose levels, elevated blood pressure, and increased body fat. Diets rich in saturated fats and simple carbohydrates decrease short-chain fatty acid (SCFA) production—important protective metabolites from gut microbes—and impair GLP-1 production (20) (Figure 2). In parallel, under obesity, adipocytes secrete substances related to immune response [tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6], vascular function [vascular endothelial growth factor (VEGF), angiotensin, plasminogen activator inhibitor-1 (PAI-1)], and IR (resistin). Thus, obesity and T2DM trigger inflammation that further activates mechanisms, including the production of reactive oxygen species (ROS) (2,21). Also, abnormal immunological responses, including the production of autoantibodies, defective immune tolerance, and chronic systemic inflammation, have been associated with infertility, in combination with oxidative stress that produces inflammation and hormonal imbalance in metabolic disease. Thus, oxidative stress is associated with the production and inactivation of oxidative mechanisms, both of which are involved in obesity and metabolic diseases. These conditions are characterized by lower levels of antioxidant molecules, such as vitamin C, superoxide dismutase (SOD), and tocopherol, along with decreased activity of antioxidant enzymes. In addition, adipose tissue is capable to aromatize androgens to estrogens, leading to lower levels of circulating testosterone due to its increased aromatization to estradiol in obese men, and hyperestrogenism further inhibits testosterone production by negative feedback on the hypothalamus-pituitary-testicular (HPT) axis (17,21). Recently, in the case of men and women, as in experimental model rodents female and males lose weight and eat less in response to GLP-1 and its analogs. However, a growing body of literature highlights quantitative sex differences in how males and females respond to GLP-1 and its analogs.

GLP-1RAs in the treatment of T2DM and obesity

The management of T2DM has evolved over the last decade with the incorporation of new therapies and the optimization of insulin therapy, requiring an individualized approach that prioritizes weight loss, minimizes hypoglycemia, and considers cardiovascular and renal benefits. Drugs that support these aspects are GLP-1RAs, which are generally administered orally or subcutaneously. GLP-1RA acts on the incretin system by activating the GLP-1 receptor (GLP-1R), increasing glucose-dependent insulin secretion, reducing glucagon release, delaying gastric emptying, and promoting satiety, among other mechanisms (Table 2). GLP-1RAs were approved a decade ago for the treatment of obesity, highlighting how these medications help to reduce body weight by decreasing appetite and energy intake. In the case of males of reproductive age, obesity is also an important risk factor for male factor infertility and has been found to be associated with worsened assisted reproductive technology outcomes (5).

But treatment can be associated with micronutrient deficiencies and muscle loss, highlighting the need for professional nutritional support, especially in individuals with obesity (22). Synthetic GLP-1R agonists regulate hunger centrally (23), inhibit glucagon secretion (24), and reduce intestinal motility (25), resulting in a significant reduction in food intake and notable weight loss. Treatment with liraglutide and semaglutide has demonstrated weight loss of 5% and 12%, respectively, in patients compared with those receiving placebo (26,27). Given limited evidence, it is recommended to consider multivitamin and mineral supplementation at physiological doses and to regularly monitor nutrient status in patients using GLP-1RAs to prevent potential micronutrient deficiencies. Some meta-analyses have also concluded that higher BMIs in males are associated with decreased fertility (5,6).

Classification of GLP-1RAs

GLP-1RAs classification goes according to their chemical structure into exendin-4 derivatives (lixisenatide, exenatide, and extended-release exenatide) and human GLP-1 analogues (liraglutide, dulaglutide, and semaglutide) (Table 3). In current clinical practice, dulaglutide and semaglutide are the most widely used GLP-1RAs due to their efficacy, safety, weekly administration, and ease of device use, with typical doses of 0.75–1.5 mg and 0.25–1 mg per week, respectively, in higher doses than those used for diabetes treatment (28,29). Semaglutide is available for diabetes as subcutaneous administration and oral presentation, and orfoglipron oral pills are approved for obesity at higher doses (Table 3). The recent appearance of multiple-agonist includes the glucose-dependent insulinotropic peptide (GIP) in the dual GLP-1-GIP agonist tirzepatide in patients with diabetes and obesity with good results, and the recent announcement of the finalization of phase 3 clinical trial (TRIUMPH-1) exclusive for obesity, with the highest efficacy results of the triple GIP/GLP-1/glucagon agonists, Retatrutide, but without formal approval by Food and Drug Administration (FDA) (Table 3) (29,30).

Clinical effects of GLP-1RA drugs

Drugs used in T2DM are biguanides, sulfonylureas, DPP-4 inhibitors, sodium-glucose cotransporter type 2 inhibitors (SGLT2 inhibitors), thiazolidinediones, meglitinides, alpha-glucosidase inhibitors, insulin, and GLP-1RAs.

Many patients with weight problems find GLP-1RAs highly effective, leading to an exponential increase in demand in the USA. Clinicians should recommend using GLP-1RAs in conjunction with behavioral therapy and calorie restriction. These medications have reduced body weight by approximately 8% to 21% in adults (31). Practitioners currently use GLP-1RAs in areas such as neuroprotection, anti-infective therapy, reduction of various types of inflammation, and improvement of cardiovascular function. This agent provides a comprehensive assessment of the efficacy of GLP-1RAs across multiple body systems, including the nervous, cardiovascular, musculoskeletal, and digestive systems (Figure 2). Particularly interesting and little known are the effects of GLP-1RA (like semaglutide and tirzepatide) on urological health, which have been found to improve pelvic floor mechanical pressure and stress urinary control in non-diabetic patients with an overactive bladder receiving onabotulinumtoxin A (BTX-A) (32). The use of GLP-1RAs has also been associated with a reduction in urological infections (Table 2), but further studies in this area are needed.

One of the main concerns is that individuals with eating disorders, particularly those with anorexia nervosa (AN) or bulimia nervosa (BN), might misuse these drugs, as these conditions are characterized by a pathological pursuit of weight loss (33).

Researchers need to perform more large-scale studies to evaluate the impact of GLP-1RA drugs, carefully assessing changes in depression, suicidal tendencies, and substance use. Some research suggests that GLP-1RA drugs may increase these symptoms. Investigators must further examine how these drugs intervene in the CNS to control these pathological behaviors.

Mechanism of action of GLP-1RAs in the CNS

GLP-1R also appears in CNS regions that regulate feeding behavior, including the hypothalamus (which controls food intake) and the brainstem. In these areas, they provide neuroprotective and anti-inflammatory effects, improving cognitive function (34,35). GLP-1RAs also participate in autonomic functions, such as regulating heart rate and thermogenesis, and modulating the sympathetic nervous system (36).

GLP-1RAs act specifically on the arcuate nucleus (ARH) by stimulating pro-opiomelanocortin (POMC)/amphetamine-regulated transcript (CART) neurons. In turn, they inhibit orexigenic NPY/Agouti-related peptide (AgRP) neurons, leading to rapid satiety and reduced food intake (34-36). GLP-1RAs also act on brain regions, such as the nucleus accumbens and the ventral tegmental area (VTA), that associate food rewards with highly palatable foods, cravings, and flavor enhancers. This leads to a loss of interest in these types of foods, but sometimes quiets the reward centers responsible for sexual desire (36).

In addition to controlling hunger and satiety, GLP-1RAs also act on the hypothalamic-pituitary-adrenal (HPA) axis, which releases glucocorticoid hormones in response to stress and supports the fight-or-flight response. GLP-1 can activate corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus, promoting cortisol production and modulating the endocrine response to stress and anxiety (37). GLP-1 modulates elements of the hypothalamic-pituitary-gonadal (HPG) axis, and GLP-1R expression is abundant in the hypothalamic-pituitary region. In neurons stimulated with GLP-1 in vitro, the release of gonadotropin-releasing hormone (GnRH) has been observed, preceded by cAMP accumulation and the regulation of the Kiss1 gene, which also increases GnRH in hypothalamic cell lines. In vivo evidence suggests that GLP-1RAs act by increasing the levels of nitric oxide and 2-arachidonoylglycerol, thereby causing non-pulsatile GnRH secretion. This means that luteinizing hormone (LH) and follicle-stimulating hormone (FSH) production is dysregulated in the hypophysis, and LH then affects testosterone production in Leydig cells, which is necessary for adequate spermatogenesis and libido. Thus, reproductive hormonal control can be modulated by GLP-1 and its analogs (38). GLP-1RAs modulate the central and endocrine nervous systems through direct receptor actions in both systems, thereby regulating hormone secretion (Table 2).

GLP-1 agonists and endothelial dysfunction

Endothelial dysfunction is predisposed by metabolic alterations, such as high blood pressure, hyperglycemia, dyslipidemia, a sedentary lifestyle, and estrogen deficiency, which increase vascular oxidative stress and contribute to its development (39).

In this context, several studies of GLP-1RAs suggest vascular effects that go beyond glycemic control and, at least in part, explain the consistent reduction in major adverse cardiovascular events (MACE) observed in large clinical trials (40,41). Given the short half-life of endogenous GLP-1, these drugs were developed, as GLP-1R is abundantly expressed in endothelial cells (41).

However, GLP-1RAs have been shown to improve endothelial function through an integrated action that includes restoration of endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) signaling, reduction of oxidative stress, preservation of mitochondrial function, anti-inflammatory modulation, decreased leukocyte recruitment, and promotion of endothelial repair and angiogenesis (Table 2).

Taking the above into account, one of the main mechanisms by which GLP-1RAs improve endothelial function is the direct activation of the GLP-1R expressed in endothelial cells. The binding of GLP-1RA to GLP-1R sequentially activates the intracellular signaling pathways cAMP/protein kinase A (PKA) and PI3K/Akt/ERK1/2, leading to the activating phosphorylation of eNOS and a sustained increase in NO production (42-44).

NO is a key mediator of endothelium-dependent vasodilation, with anti-aggregatory, anti-inflammatory, and antiproliferative effects, so its restoration is a fundamental pillar in reversing endothelial dysfunction. This pathway is clinically reflected by improved flow-mediated dilation (FMD) after GLP-1RA treatment, even in experimental ischemia-reperfusion models, where no bioavailability is typically markedly reduced (44).

Excess ROS are key determinants of endothelial dysfunction, as they reduce NO bioavailability and promote mitochondrial damage and endothelial apoptosis. Preclinical and clinical evidence indicate that GLP-1RAs significantly attenuate vascular oxidative stress by inhibiting NADPH oxidase (NOX), particularly NOX4, and activating AMPK, thereby reducing ROS production and preserving mitochondrial function in endothelial cells (42,44).

These effects restore mitochondrial membrane potential, improve oxygen consumption, and reduce endothelial apoptosis induced by chronic hyperglycemia. Additionally, suppression of the NLRP3 inflammasome and pro-inflammatory pathways, such as TRIB3/NF-κB, contributes to a less oxidative and inflammatory vascular microenvironment, promoting the recovery of endothelial integrity beyond mere glucose reduction (42).

Chronic endothelial activation is characterized by the overexpression of proinflammatory cytokines and adhesion molecules that facilitate leukocyte recruitment and atherosclerotic progression. GLP-1RAs exert a potent anti-inflammatory effect by reducing circulating levels of TNF-α, IL-6, and IL-1β, and by suppressing endothelial expression of VCAM-1, ICAM-1, and E-selectin through inhibition of the NF-κB pathway and activation of the cAMP/PKA axis (42,44).

Importantly, the concomitant reduction of CD11b in monocytes suggests that GLP-1RAs modulate both the endothelium and circulating myeloid cells, thereby reducing cell-cell interactions that perpetuate vascular inflammation. This endothelial deactivation contributes to the stabilization of atherosclerotic plaque and reduces the risk of cardiovascular events, as observed in large clinical trials (41).

Similarly, evidence indicates that these drugs promote vascular repair. Endothelial progenitor cells (EPCs), essential for endothelial regeneration and post-ischemic angiogenesis, are quantitatively and functionally increased after treatment with GLP-1Rs, thereby enhancing EPC proliferation, migration, adhesion, and tube-forming ability by activating the GLP-1R and the cAMP, Akt, and ERK1/2 pathways (42,44).

Additionally, GLP-1RAs increase VEGF expression and activate its receptor, VEGFR-2, triggering angiogenic cascades that restore tissue perfusion and capillary density, as demonstrated in both healthy volunteers and animal models of peripheral ischemia (44).

In addition to their effects on endothelial function in the cardiovascular system, GLP-1R agonists modulate GLP-1 actions by the same mechanism in the smooth muscle of the penile corpus cavernosum, improving erectile function. From a mechanistic point of view, it has been proposed that GLP-1RA ameliorates ED through the improvement of metabolic conditions and a reduction of the oxidative stress state, which, in turn, acts positively on vascular and endothelial function, key mechanisms in the improvement of this genital condition that exerts an important role in male sexual and reproductive aspects (3,4).

GLP-1RA and ED

From a pathophysiological perspective, metabolic ED is characterized by endothelial dysfunction in the cavernous tissue, reduced nitric oxide bioavailability, and impaired penile smooth muscle function, processes that are promoted by chronic hyperglycemia, IR, oxidative stress, and low-grade inflammation. Concurrently, obesity is associated with functional hypogonadism and worsening vascular function, establishing a common pathophysiological substrate in the presence of arterial hypertension, dyslipidemia, and cardiovascular disease (4,45).

The erection-relief process involves interaction between the Ras homolog family member A (RhoA) and the Rho-associated kinase (ROCK). However, the homeostasis of this relationship is mainly affected by the increased levels of advanced glycation end products (AGE), which increase ROS.

This contributes to the upregulation of this relaxation mechanism and impairs smooth muscle function in the corpus cavernosum, leading to ED. It has been observed that GLP-1R expression decreases in the corpus cavernosum of diabetic rats with ED, and that liraglutide administration restores GLP-1R expression, reduces ROS production and NOX levels, and downregulates RhoA and ROCK2 independently of glucose or weight reduction (4,46).

In this context, GLP-1RAs have attracted interest for their pleiotropic effects beyond glycemic control, particularly for their potential impact on ED. Various clinical trials have demonstrated the beneficial effects of these GLP-1R agonists on ED. For instance, two prospective studies, in which the GLP-1RA liraglutide was administered, have shown that men with obesity related hypogonadism and receiving 3 mg/day of this drug had higher testosterone levels as well as increased libido, better sperm quality, and erectile performance. Moreover, the aforementioned studies demonstrated that liraglutide renders better outcomes in the improvement of male sexual and reproductive functions than the administration of gonadotropins or testosterone replacement therapy (4,47,48). On the other hand, a retrospective study reported that combined administration of liraglutide and metformin in patients with T2DM results in higher levels of total and free testosterone than those observed with metformin only; moreover, men with a higher baseline score of the 5-item International Index of Erectile Function (IIEF-5), carotid artery stenosis, and weight loss reported greater benefits after treatment (4,49). A couple of years ago, Bajaj et al. (2021) made an analysis of the ED outcome of men enrolled in the Researching Cardiovascular Events with a weekly incretin in diabetes (REWIND) study, finding that 3,725 men out of 53,112, who underwent baseline and follow-up IIEF-5 assessments under dulaglutide treatment, presented an important reduction in cases of moderate to severe ED (4,50). On the contrary, other studies have reported negative secondary effects upon GLP-1RAs administration. For instance, a retrospective study based on the TriNetX Research database showed that the administration of semaglutide for weight loss purposes, in non-diabetic obese men without ED, was associated with a higher incidence of developing this condition or with a greater probability of starting therapy for PDE5 inhibition. Also, these patients presented lower testosterone levels (4,51). GLP-1RAs treatments have been reported to have a positive effect on male sexual function and an increase in libido. Although murine models indicate that GLP-1RA treatments decrease sexual behaviors. Likewise, results from the cross-sectional FDA Adverse Event Reporting System database (2023–2024) revealed 182 adverse events reported among GLP-1RAs such as exenatide, semaglutide and liraglutide which have shown that some users experience a decrease in libido and sexual desire due to stimulation of the reward and satisfaction centres of the nervous system, where ED accounts for 71.4% of negative sexual outcomes (4,52).

Weight loss induced by these drugs has been associated with increases in testosterone levels and improvements in inflammatory status, providing a plausible pathophysiological framework for a beneficial effect on ED, especially in men with obesity and type 2 diabetes (3). GLP-1RAs have a greater effect on improving ED in patients with diabetes than metformin, and this effect is even greater if the patient is obese (BMI < 30). Studies have also shown improvements with other antidiabetic agents such as acarbose, insulin and SGLT-2 inhibitors (53).

Most of these studies report beneficial, neutral or adverse effects with respect to ED and libido (38).

Obesity, diabetes, and male infertility

Male infertility accounts for 20–50% of infertility problems in couples. Among the environmental factors that can contribute to its development are overweight and obesity, as well as other chronic conditions such as metabolic syndrome and diabetes mellitus (54). Metabolic syndrome, characterized by hypertension, IR, dyslipidemia, and obesity, leads to a pathological state characterized by elevated oxidative stress, which increases lipid peroxidation, ROS, DNA fragmentation, and apoptosis in sperm (55). There is a negative association between BMI and sperm parameters, including progressive motility and concentration (5,6).

Furthermore, men with morbid obesity have twice the risk of developing oligozoospermia. The accumulation of adipose tissue alters estradiol production by aromatizing testosterone and decreasing its concentration. Other hormones, such as LH, sex hormone-binding globulin (SHBG), inhibin, and anti-Müllerian hormone (AMH), also decrease as BMI increases. Excess estradiol suppresses gonadotropin synthesis, altering some sperm parameters and producing hypogonadism and ED (54). Bariatric surgery reverses morbid obesity and improves sexual function in patients; a meta-analysis shows that domains such as erectile function, orgasmic function, libido and satisfaction show improved scores after surgery. The same increase in total testosterone as the weight decrease suggests that the improvement in sexual function is due to the reduction in BMI (56). However, sperm parameters without significant changes after bariatric surgery were analyzed in the meta-analysis and data on conception and assisted reproduction are not sufficient to support conclusions (57).

Treatments for hypertension, dyslipidemia, and diabetes also have positive or negative effects on sperm production, since these cells are insulin-sensitive and insulin-secreting, thereby sharing metabolic targets. Just as a positive effect has been observed with metformin in infertile patients, improving their sperm parameters, it is expected that new treatments such as GLP-1 agonists will also produce a similar result (55). The meta-analysis by Salvio et al. (2025) of seven studies found that patients treated with GLP-1RAs had higher total serum testosterone. Similarly, FSH, LH, SHBG, and free testosterone increased as weight, BMI, and waist circumference decreased (58).

Disruption of the Glp1r gene results in mice with delayed puberty, reduced adrenal gland volume, and decreased testicular and seminal vesicle volumes, yet they retain fertility. Although their testosterone and thyroid-stimulating hormone (TSH) levels remain normal, only cortisone levels increase in male mice (59). In humans and mice, GLP-1Rs have been identified in Leydig and Sertoli cells, as well as in the midpiece of the flagellum and acrosome of spermatozoa, suggesting that GLP-1 and its agonists signal these receptors in spermatozoa. GLP-1 and its agonists may cross the blood-testis barrier and signal GLP-1R in Leydig and Sertoli cells and in spermatozoa, decreasing oxidative damage and increasing lactate dehydrogenase (LDH) (60). In sperm, GLP-1R increases cAMP and activates PKA, which in turn phosphorylates Akt in the absence of insulin. This alters glucose metabolism, increasing LDH, glucose-6-phosphate dehydrogenase (G6PD), and insulin secretion (61,62). Similarly, GLP-1R activation in Leydig cells has been shown to promote Leydig stem cell development and the expression of genes involved in testosterone production (38). Studies of the effect of GLP-1RA on diabetes and weight that tracked serum testosterone levels, included in a meta-analysis, show an increase in free testosterone levels compared with control groups and other antidiabetic treatments (58).

Furthermore, GLP-1R promotes the expression of genes related to spermatogenesis in Sertoli cells. It has also been shown in vitro that insulin-independent sperm motility is enhanced by the interaction of GLP-1 and its receptor in sperm (62). It is also known that chronic inflammation and oxidative stress caused by obesity negatively impact male fertility, which is mitigated by the effect of GLP-1, thus contributing to improved conception rates in male-factor infertility (60). Interestingly, GLP-1R levels were decreased in samples from infertile patients with oligoasthenozoospermia and varicocele (62). In various clinical studies of GLP-1RA administration, participants showed improvements in positive erectile function, sperm parameters, including concentration, morphology, and motility (58,63).

However, further clinical studies evaluating fertility with GLP-1RA administration are still needed (38). Prescribing GLP-1RA for obesity may activate different cellular mechanisms that restore spermatogenesis and improve seminal parameters, thus promoting male fertility in obese patients.

Hypogonadism and GLP-1R agonists

Male hypogonadism results from the metabolic alterations of obesity and IR, which disrupt the normal production and secretion of testosterone. Male hypogonadism is defined as low testosterone (below 9.2 nmol/L) and is present in approximately 44% of patients with diabetes mellitus and obesity (diabesity) (60).

In a study in which the authors aim was to assess the association among tirzepatide, a dual agonist of GIP and GLP-1, administered to patients under obesity treatment, and metabolic hypogonadism, patients presented weight loss (8%) and waist circumference reduction, as well as significant changes in LH, FSH, testosterone levels, as well as a reduction of 17β-estradiol concentration, therefore improving the score given by the IEF-5, a questionnaire that evaluates ED (64). Clinical and preclinical studies report improvements in sperm concentration, motility, and morphology after the use of GLP-1RAs in obese or hypogonadic men (38).

Most studies in obese individuals treated with GLP-1RA indicate an improvement in their hormone levels. In contrast, intravenous administration of GLP-1 in healthy men showed no change in LH levels; however, fewer testosterone pulses and longer pulse durations were observed compared with oral glucose ingestion, demonstrating that GLP-1 administration decreases testosterone (65). Meta-analysis studies comparing GLP-1RAs, testosterone, and sodium-glucose cotransporter type 2 inhibitors (SGLT2i) treatments examined the effects on hormones and sexual function. GLP-1RAs identified improvements in total testosterone, SHBG, LH, and FSH levels, the latter two not observed with tirzepatide treatment. The improvement in total testosterone led to improvements in hypogonadism and an improvement in ED and sexual desire, without improvement in orgasm or sexual satisfaction. This analysis found a reversal of obesity-related secondary hypogonadism due to the increase in total testosterone (5.3 nmol/L), likely due to the influence of GLP-1RAs on the HPT axis (58,63).

The observed improvement in male fertility may be largely attributable to reduced obesity and the beneficial effects of this reduction on hormone production that obesity previously impaired (38).

Conclusions

In summary, each advance built on previous discoveries and led to new therapeutic possibilities. Thus, GLP-1 analogs represent significant advances in the treatment of metabolic diseases and have demonstrated benefits in cardiovascular health, skeletal muscle-related diseases, obesity management, and neurodegenerative conditions. Moreover, in reproductive health, GLP-1RAs now offer new possibilities for restoring male fertility for those seeking offspring. The safety of GLP-1RAs use is established as it does not affect or improve male reproductive functions in individuals without obesity/diabetes; however, it emerges as a therapeutic alternative in obese/diabetic patients with ED or hypogonadism. However, there have been reports of adverse effects on sexual function in some users of semaglutide, which suggests that the negative effects on sexual function of new GLP-1 agonists due to obesity are still being studied. Weight management with GLP-1RA should include appropriate counseling regarding the possible improvement of male infertility as a side effect and in the prevention of unwanted pregnancies.

Acknowledgments

The authors acknowledge the support of the Instituto Mexicano del Seguro Social (IMSS) and the SNII-SECIHTI for the realization of this work.

Footnote

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