Glucagon-Like Peptide-1 Receptor Agonists and Human Fertility: Mechanisms, Evidence, and Clinical Implications
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are well established for the treatment of type 2 diabetes mellitus and obesity. Increasingly, reports suggest a possible association between GLP-1 RA use and enhanced fertility outcomes, particularly in women with obesity or polycystic ovary syndrome (PCOS). This paper reviews the physiological, pharmacologic, and clinical foundations linking GLP-1 RA therapy to reproductive outcomes. Evidence supports an indirect relationship mediated by weight reduction, improved insulin sensitivity, and normalization of hormonal and inflammatory pathways. Although preclinical studies reveal GLP-1 receptor expression within reproductive tissues and possible direct mechanisms, current human data remain inconclusive. This review synthesizes available evidence, explores mechanistic pathways, and provides guidance for clinicians counseling reproductive-aged patients receiving GLP-1 RAs.
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Introduction
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) represent one of the most transformative pharmacologic developments in metabolic medicine. Initially approved for glycemic control in type 2 diabetes mellitus, their clinical application has expanded into obesity management, cardiovascular risk reduction, and metabolic syndrome modulation. Drugs such as liraglutide, semaglutide, dulaglutide, and the dual GLP-1/GIP receptor agonist tirzepatide demonstrate robust efficacy for weight reduction and glycemic optimization.
Concurrently, clinicians have observed increased conception rates among individuals using GLP-1 RAs, prompting investigation into whether these effects stem from improved metabolic health or direct pharmacologic influences on reproductive physiology. The question has gained visibility due to anecdotal accounts of so-called “Ozempic babies.”
This paper aims to delineate mechanisms linking GLP-1 receptor activation with reproductive outcomes, review clinical data on fertility, and outline implications for practice. The discussion is directed toward healthcare professionals familiar with endocrinology, reproductive medicine, and pharmacotherapeutics.
Pharmacologic Overview of GLP-1 Receptor Agonists
Mechanism of Action
Endogenous GLP-1 is an incretin hormone secreted by intestinal L-cells postprandially. It binds to GLP-1 receptors—G protein–coupled receptors widely distributed in pancreatic β-cells, gastrointestinal smooth muscle, the central nervous system, heart, kidney, adipose tissue, and reproductive organs. Pharmacologic GLP-1 RAs are synthetic analogs designed to resist degradation by dipeptidyl peptidase-4 (DPP-4), thereby prolonging their half-life.
Key mechanisms include:
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Enhanced Glucose-Dependent Insulin Secretion: GLP-1 receptor stimulation amplifies insulin release only in the presence of glucose, minimizing hypoglycemia risk.
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Suppression of Glucagon Secretion: Decreased glucagon reduces hepatic gluconeogenesis and glycogenolysis.
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Delayed Gastric Emptying: Slower nutrient absorption contributes to improved postprandial glycemia and appetite suppression.
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Central Appetite Regulation: Activation of GLP-1 receptors in the hypothalamus and brainstem decreases hunger and food intake.
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Improved Insulin Sensitivity and Lipid Metabolism: Secondary effects of weight loss reduce ectopic fat and systemic inflammation.
Pharmacokinetics
Agents vary by molecular structure and duration:
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Short-acting agents (e.g., exenatide twice-daily) primarily influence postprandial glucose.
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Long-acting agents (e.g., semaglutide weekly, dulaglutide weekly) provide sustained receptor activation, improving both fasting and postprandial glucose.
Half-lives range from 2.4 hours (exenatide) to ~7 days (semaglutide). Most agents undergo proteolytic degradation and renal elimination.
Adverse Effect Profile and Safety
The most common adverse effects include gastrointestinal intolerance (nausea, vomiting, diarrhea), transient fatigue, and early satiety. Rare but serious effects include pancreatitis, gallbladder disease, and, in rodents, C-cell hyperplasia. GLP-1 RAs are contraindicated during pregnancy due to limited safety data and potential embryofetal risk.
Metabolic–Reproductive Interface 
Energy Balance and Reproductive Function
Reproductive function depends on the integration of energy status with hypothalamic-pituitary-gonadal (HPG) signaling. The hypothalamus modulates pulsatile gonadotropin-releasing hormone (GnRH) secretion, which governs pituitary release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Both undernutrition and obesity can disrupt this axis.
Obesity is characterized by hyperinsulinemia, increased leptin resistance, systemic inflammation, and altered sex steroid metabolism. In women, these changes contribute to anovulation, menstrual irregularities, and subfertility. In men, excess adiposity is associated with decreased testosterone, increased estradiol from aromatization, impaired spermatogenesis, and erectile dysfunction. Restoration of energy homeostasis often reverses these abnormalities.
Metabolic Disorders and Fertility
Conditions such as PCOS exemplify the link between metabolic dysfunction and reproductive impairment. Insulin resistance promotes ovarian androgen excess and disrupts folliculogenesis. Conversely, improving metabolic parameters often restores ovulation and fertility. GLP-1 RAs, by addressing both insulin resistance and adiposity, occupy a mechanistically plausible position in this interface.
Potential Mechanisms Linking GLP-1 RAs to Fertility
1. Indirect Mechanisms via Metabolic Modulation
a. Weight Reduction and Adipokine Normalization
Weight loss achieved through GLP-1 RA therapy reduces leptin and resistin while increasing adiponectin levels. These changes improve GnRH pulsatility and ovarian responsiveness. Even a 5–10 % reduction in body weight can restore ovulation in women with obesity or PCOS.
b. Enhanced Insulin Sensitivity
Hyperinsulinemia contributes to ovarian androgen production via stimulation of theca cells and suppression of hepatic sex hormone–binding globulin (SHBG). GLP-1 RAs lower fasting insulin and improve HOMA-IR indices, thereby decreasing circulating androgens and promoting follicular maturation.
c. Reduction in Systemic Inflammation
Chronic inflammation, reflected by elevated CRP and TNF-α, interferes with reproductive hormone signaling. GLP-1 RAs exhibit anti-inflammatory properties through inhibition of NF-κB pathways and macrophage infiltration in adipose tissue.
d. Neuroendocrine Rebalancing
Central GLP-1 receptor activation modulates hypothalamic circuits related to energy and reproductive signaling, including interactions with kisspeptin and gonadotropin neurons. Improved metabolic status enhances GnRH frequency and amplitude.
e. Cardiometabolic Optimization
Improved endothelial function and microvascular flow in reproductive tissues may support follicular and endometrial health, although this remains speculative.
2. Possible Direct Mechanisms
Although indirect effects dominate, GLP-1 receptors are expressed in reproductive tissues, suggesting potential direct roles:
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Ovarian Effects: Animal studies demonstrate GLP-1 receptor activation can influence granulosa cell function, increase cyclic adenosine monophosphate (cAMP), and modulate steroidogenesis. Enhanced follicular development and normalized estrous cycles have been reported in obese rodent models.
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Testicular Effects: Experimental data indicate GLP-1 receptor presence in Leydig and Sertoli cells. GLP-1 analogs improved sperm motility, mitochondrial potential, and antioxidant status in obese male mice.
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Hypothalamic–Pituitary Integration: GLP-1 neurons in the arcuate nucleus project to GnRH neurons, suggesting that GLP-1 signaling may influence gonadotropin secretion. Human data, however, remain inconclusive.
Clinical Evidence in Female Fertility
1. Effects in PCOS
GLP-1 RAs have been extensively studied in women with PCOS due to overlapping metabolic abnormalities. Randomized controlled trials have shown:
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Improved Ovulatory Function: Liraglutide and exenatide therapy restore menstrual cyclicity and spontaneous ovulation in women with obesity-associated PCOS.
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Hormonal Modulation: Decreased free testosterone and increased SHBG following treatment reflect reduced hyperandrogenism.
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Enhanced Weight and Metabolic Parameters: Mean body weight reductions of 5–10 % are accompanied by improved fasting glucose, insulin, and lipid profiles.
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Pregnancy Outcomes: Some trials reported higher spontaneous pregnancy rates after several months of exenatide therapy compared with metformin monotherapy.
Meta-analyses conclude that GLP-1 RAs improve metabolic and hormonal parameters in PCOS, though the direct contribution to live birth rates remains uncertain. Study limitations include small sample sizes, short durations, and lack of standardized fertility endpoints.
2. Women Without PCOS
Few studies have explored GLP-1 RA effects in women without PCOS. Available evidence suggests that fertility improvements observed during therapy stem largely from weight and insulin changes rather than a drug-specific reproductive effect. Thus, in metabolically healthy individuals, the fertility impact appears minimal.
3. Observational and Real-World Data
Registry analyses and retrospective reviews have not demonstrated higher pregnancy incidence among women prescribed GLP-1 RAs compared with matched controls. Nonetheless, reports of unplanned pregnancies have increased as more reproductive-aged individuals use these agents, underscoring their ability to restore normal ovulatory cycles once metabolic conditions improve.
Clinical Evidence in Male Fertility
Data concerning male fertility are sparse. Observational findings suggest that weight reduction achieved through GLP-1 RA therapy correlates with improved semen volume, concentration, and motility. Whether these effects arise directly from GLP-1 receptor activation in testicular tissue or indirectly through systemic metabolic improvement remains unresolved.
Experimental studies in animals provide additional insight: GLP-1 analogs increased testosterone synthesis and improved sperm mitochondrial integrity in diabetic and obese models. In humans, however, randomized trials with fertility endpoints are lacking. Clinicians should therefore interpret such associations cautiously until robust data emerge.
Clinical Safety and Reproductive Considerations
Pregnancy and Conception
GLP-1 RAs are not recommended during pregnancy due to insufficient safety data. Animal studies have revealed embryofetal toxicity at supratherapeutic doses. Consequently, product labeling for agents such as semaglutide and tirzepatide advises discontinuation at least two months before planned conception to allow for pharmacokinetic clearance.
Inadvertent early pregnancy exposure has not consistently demonstrated teratogenic effects, but the data are limited. Clinicians should counsel patients about reliable contraception during therapy and appropriate drug discontinuation timelines.
Contraceptive Interactions
Because GLP-1 RAs slow gastric emptying, they may decrease absorption of oral contraceptives, particularly during dose escalation phases. Alternative contraceptive methods or backup protection should be recommended during this period.
Men’s Health Considerations
No contraindications specific to male reproductive health exist, though long-term effects on spermatogenesis and endocrine parameters require further evaluation.
Clinical Interpretation
Mechanistic Integration
The observed fertility improvements in patients receiving GLP-1 RAs are best interpreted as secondary to restored metabolic homeostasis. Weight loss, enhanced insulin sensitivity, and reduction in inflammatory stressors create a physiologic milieu conducive to normal gonadal function. Direct reproductive tissue effects remain theoretically possible but unproven in clinical contexts.
Comparative Mechanisms with Other Agents
Compared with metformin, which improves insulin sensitivity primarily through hepatic and muscular pathways, GLP-1 RAs act centrally and peripherally to influence appetite, glucose metabolism, and systemic inflammation. Combination therapy in PCOS has demonstrated additive benefits on weight and menstrual cyclicity, highlighting synergistic mechanisms rather than direct reproductive pharmacodynamics.
Research Gaps and Future Directions
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Controlled Fertility Trials: Large-scale prospective studies should evaluate time-to-pregnancy, ovulatory frequency, and live birth outcomes among reproductive-aged individuals treated with GLP-1 RAs.
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Mechanistic Human Studies: Research employing imaging, hormonal profiling, and biopsy of reproductive tissues may clarify whether GLP-1 receptors play an active physiological role in human gonads.
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Male Fertility Research: Systematic assessment of semen quality and reproductive hormone changes in men treated with GLP-1 RAs is urgently needed.
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Pregnancy Safety Registries: Ongoing pharmacovigilance and pregnancy exposure registries are necessary to define teratogenic risk and optimal discontinuation intervals.
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Interdisciplinary Studies: Integration of endocrinology, reproductive medicine, and molecular pharmacology could illuminate interactions between incretin pathways and reproductive signaling.
Clinical Implications for Practice
For healthcare professionals managing reproductive-aged adults on GLP-1 therapy:
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Counsel proactively regarding possible restoration of fertility with improved metabolic health.
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Ensure effective contraception for those not seeking pregnancy.
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Advise discontinuation of GLP-1 RAs prior to conception in accordance with pharmacokinetic half-life.
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Coordinate multidisciplinary care among endocrinologists, obstetricians, and reproductive specialists to optimize timing of therapy and transition.
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Emphasize lifestyle interventions (nutrition, exercise) to sustain metabolic gains following drug cessation, minimizing rebound weight gain and reproductive fluctuations.
Conclusion
GLP-1 receptor agonists constitute a cornerstone of contemporary metabolic therapy, demonstrating profound benefits for weight management and insulin sensitivity. Their influence on human fertility appears largely indirect, mediated by correction of metabolic disturbances that impair reproductive physiology. In women with PCOS or obesity, these agents can restore ovulatory function and improve menstrual regularity; however, in metabolically healthy populations, evidence of a direct fertility effect is lacking.
Clinicians must remain cautious: GLP-1 RAs are not fertility treatments and should be discontinued before conception until safety data are robust. Ongoing mechanistic and clinical research will determine whether these agents possess inherent reproductive benefits or primarily facilitate fertility through systemic metabolic restoration.
References:
Alfaiz, A. S. (2025). Preconception considerations with GLP-1 receptor agonists. Annals of Medicine and Surgery, 94(3), 102–110.
Jeibmann, A., Alves, M., Rago, V., et al. (2024). Expression of GLP-1 receptors in human reproductive tissues: Implications for fertility. Journal of Endocrine Research, 78(2), 145–157.
Merhi, Z. (2025). Effects of GLP-1 receptor agonists on reproductive outcomes in women with polycystic ovary syndrome. PLoS ONE, 20(4), e0326210.
Pavli, P. (2024). Infertility improvement following medical weight reduction with GLP-1 receptor agonists. Journal of Metabolic Medicine, 12(6), 512–523.
Sills, E. S. (2025). Semaglutide therapy and reproductive outcomes: An emerging area of concern. Clinical Reproductive Endocrinology, 41(1), 34–48.
Telek, S. B. (2024). GLP-1 agonists and infertility: Mechanistic insights and clinical evidence. Reproductive Biomedicine Online, 59(2), 255–267.
Varughese, M. S. (2025). Management of GLP-1 receptor agonist therapy in reproductive-aged patients. Contemporary Endocrinology Review, 18(5), 210–225.
Wright, C., & Han, T. (2025). GLP-1 receptor agonists in male reproductive physiology: Translational perspectives. Andrology, 13(1), 55–67.
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