Nelson Vergel
Founder, ExcelMale.com
TRT and GLP-1 Medications: What Men Need to Know About Combining Testosterone Therapy with Semaglutide and Tirzepatide
The convergence of two major therapeutic developments—testosterone replacement therapy (TRT) and GLP-1 receptor agonists—has created both unprecedented opportunities and important clinical questions for men managing hypogonadism alongside obesity or type 2 diabetes. As prescriptions for semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound) have increased by over 500% in the past five years, understanding how these medications interact with testosterone optimization has become essential for informed patient decision-making.
This comprehensive guide examines the current evidence on combining TRT with GLP-1 therapies, addressing the synergistic benefits, potential concerns, and practical protocols that clinicians and patients should consider.
GLP-1 receptor agonists address several of these underlying mechanisms. By promoting significant weight loss (typically 15-25% of body weight with semaglutide 2.4mg weekly), these medications can reduce aromatase activity, improve insulin sensitivity, and decrease inflammation—all factors that support endogenous testosterone production and may enhance the effectiveness of exogenous testosterone therapy.
A randomized controlled trial published in Diabetes, Obesity and Metabolism compared semaglutide directly to testosterone replacement therapy in men with type 2 diabetes and obesity-related functional hypogonadism. Both groups experienced significant increases in total testosterone and improvements in aging male symptoms (AMS) scores. However, the semaglutide group achieved superior outcomes in body composition and weight loss, while TRT showed greater improvements in sexual function (IIEF-15 scores).
These findings suggest that for men with obesity-related ("pseudo") hypogonadism—where low testosterone is secondary to metabolic dysfunction rather than primary testicular failure—GLP-1 medications may help restore natural testosterone production through weight loss and metabolic improvement.
Testosterone's anabolic effects on muscle tissue may help counteract this lean mass loss. TRT enhances protein synthesis and promotes muscle retention even during caloric restriction, potentially improving the "quality" of weight loss by shifting the ratio toward greater fat loss and muscle preservation. For men already on TRT, adding GLP-1 therapy allows them to achieve significant fat loss while maintaining the muscle-building benefits of optimized testosterone levels.
The combination of testosterone's effects on cholesterol profiles and vascular function with the established cardioprotection of GLP-1 therapy represents a compelling strategy for men with both hypogonadism and elevated cardiovascular risk.
However, these findings require careful interpretation. The absolute risk increase was small (approximately 1%), and the study design could not establish causation. The researchers speculated that GLP-1 receptor expression in testicular Leydig cells might influence pulsatile testosterone secretion, but this mechanism remains hypothetical. Importantly, studies in men with diabetes have shown the opposite effect—GLP-1 agonists improving erectile function, likely through weight loss and metabolic improvement.
For men on TRT, these concerns may be less relevant, as exogenous testosterone maintains hormone levels independent of any effects on endogenous production. Nevertheless, clinicians should monitor for sexual side effects when initiating GLP-1 therapy, particularly in men not receiving testosterone replacement.
For men who want both weight loss and fertility preservation, GLP-1 therapy may represent a superior choice compared to TRT alone. Those requiring both testosterone optimization and fertility maintenance should discuss hCG or FSH co-therapy options with their clinician, or consider whether GLP-1-induced weight loss might be sufficient to restore endogenous testosterone production.
For men with more severe hypogonadism, significant symptoms, or evidence of primary testicular failure, initiating TRT first—or simultaneously with GLP-1 therapy—may be more appropriate. Starting both medications at once, however, complicates side effect attribution if problems arise.
For men on TRT, protein requirements may be even higher to maximize the anabolic stimulus of testosterone. Prioritizing protein at each meal and tracking intake can help ensure muscle preservation during the weight loss phase.
Men should aim for 2-4 resistance training sessions weekly, focusing on compound movements that stimulate major muscle groups. Those experiencing GLP-1-related fatigue may need to adjust training volume initially, but most patients report improved energy and exercise tolerance as weight loss progresses.
Sexual function should be assessed using validated questionnaires (such as IIEF-5), and any changes in libido or erectile function should prompt evaluation. For men on TRT who experience new-onset erectile dysfunction after starting GLP-1 therapy, transient dose reduction of the GLP-1 medication or addition of PDE5 inhibitors may be considered.
For men on TRT, these emerging therapies may provide even more effective tools for optimizing body composition. The combination of testosterone's anabolic effects with next-generation weight loss medications targeting multiple pathways represents an exciting frontier in metabolic and hormonal health.
Key principles for success include adequate protein intake, consistent resistance training, regular monitoring of both hormonal and metabolic parameters, and open communication with healthcare providers about any changes in symptoms or side effects. For many men, this combination represents the most comprehensive approach to restoring metabolic health, optimizing body composition, and maintaining quality of life.
As with any medical decision, the choice to combine TRT with GLP-1 therapy should be individualized based on clinical presentation, goals, and risk factors. Consultation with providers experienced in both hormone optimization and metabolic medicine ensures the best outcomes.
• Looking for Retatrutide Experiences – User experiences with the emerging triple-agonist GLP-1
• Clean Nutrition for Health, Muscle Gain and Fat Loss – Optimizing nutrition while on TRT and weight loss medications
• Treatments for Low Libido in Men – Addressing sexual side effects and libido concerns
• Fertility Maintenance Before, During, and After TRT – Preserving fertility while on testosterone therapy
• HCG Dose Frequency for Men – Fertility & Testicular Atrophy – Optimizing hCG protocols alongside TRT
• The Science of Testosterone and Atherosclerosis – Understanding cardiovascular implications of TRT
• Low Testosterone: Recommendations on Diagnosis, Treatment and Monitoring – Evidence-based clinical guidelines
2. Gregorič N, et al. Semaglutide improved sperm morphology in obese men with type 2 diabetes mellitus and functional hypogonadism. Diabetes Obes Metab. 2024. [Full Text]
3. Neeland IJ, et al. Changes in lean body mass with glucagon-like peptide-1-based therapies and mitigation strategies. Diabetes Obes Metab. 2024;26:16-27. [PubMed]
4. Able C, et al. Prescribing semaglutide for weight loss in non-diabetic, obese patients is associated with an increased risk of erectile dysfunction. Int J Impot Res. 2024. [PubMed]
5. Jensterle M, et al. Effects of liraglutide on obesity-associated functional hypogonadism in men. Endocr Connect. 2019;8:195-202. [Full Text]
6. Gregorič N, et al. The effects of semaglutide vs testosterone replacement therapy on functional hypogonadism and sperm quality. Endocrine Abstracts. 2024 (ECE 2024). [Abstract]
7. Varnum AA, et al. Impact of GLP-1 agonists on male reproductive health—a narrative review. Medicina. 2024. [PMC Full Text]
8. Neeland IJ, et al. Muscle Mass and Glucagon-Like Peptide-1 Receptor Agonists: Adaptive or Maladaptive Response to Weight Loss? Circulation. 2024. [AHA Journals]
9. American Diabetes Association. New GLP-1 Therapies Enhance Quality of Weight Loss by Improving Muscle Preservation. ADA Press Release. 2025. [ADA Newsroom]
10. Idris I. Potential new therapies to preserve lean muscle mass loss when used in combination with GLP-1 receptor agonists. Diabetes Obes Metab Now. 2024. [Wiley]
11. Liao B, et al. Prescribing Ozempic and Wegovy for Weight Loss is Associated with Increased Risk of ED and Hypogonadism. J Sex Med. 2024. [Oxford Academic]
12. Semaglutide in Obesity: Unmet Needs in Men. PMC Review. 2023. [PMC Full Text]
Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always consult with a qualified healthcare provider before starting, stopping, or modifying any medication regimen. Individual responses to therapy vary, and what works for one person may not be appropriate for another.
About ExcelMale.com: ExcelMale is a men's health forum with over 24,000 members and 20+ years of archived discussions on testosterone replacement therapy, hormone optimization, and sexual health. Founded by Nelson Vergel, author of Built to Survive, Testosterone: A Man's Guide and Beyond Testosterone, ExcelMale provides evidence-based information and peer support for men navigating hormone health decisions.
By Nelson Vergel | ExcelMale.com | Updated December 2025
The convergence of two major therapeutic developments—testosterone replacement therapy (TRT) and GLP-1 receptor agonists—has created both unprecedented opportunities and important clinical questions for men managing hypogonadism alongside obesity or type 2 diabetes. As prescriptions for semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound) have increased by over 500% in the past five years, understanding how these medications interact with testosterone optimization has become essential for informed patient decision-making.
This comprehensive guide examines the current evidence on combining TRT with GLP-1 therapies, addressing the synergistic benefits, potential concerns, and practical protocols that clinicians and patients should consider.
Understanding the TRT-GLP-1 Connection
The relationship between testosterone, body composition, and metabolic health creates a physiological rationale for combining these therapies. Approximately 40% of men over 45 have clinically low testosterone, with obesity being a significant contributing factor. Excess adipose tissue increases aromatase activity—the enzyme that converts testosterone to estrogen—while also promoting insulin resistance and chronic inflammation, both of which further suppress the hypothalamic-pituitary-gonadal (HPG) axis.GLP-1 receptor agonists address several of these underlying mechanisms. By promoting significant weight loss (typically 15-25% of body weight with semaglutide 2.4mg weekly), these medications can reduce aromatase activity, improve insulin sensitivity, and decrease inflammation—all factors that support endogenous testosterone production and may enhance the effectiveness of exogenous testosterone therapy.
The Evidence: Can GLP-1 Medications Improve Testosterone Levels?
Recent research has provided encouraging data on the testosterone-boosting potential of GLP-1 therapy. A 2025 study presented at the Endocrine Society's annual meeting tracked 110 men with obesity or type 2 diabetes using GLP-1 medications over 18 months. The findings were notable: participants experienced an average 10% reduction in body weight accompanied by a 53-77% increase in total testosterone levels.A randomized controlled trial published in Diabetes, Obesity and Metabolism compared semaglutide directly to testosterone replacement therapy in men with type 2 diabetes and obesity-related functional hypogonadism. Both groups experienced significant increases in total testosterone and improvements in aging male symptoms (AMS) scores. However, the semaglutide group achieved superior outcomes in body composition and weight loss, while TRT showed greater improvements in sexual function (IIEF-15 scores).
These findings suggest that for men with obesity-related ("pseudo") hypogonadism—where low testosterone is secondary to metabolic dysfunction rather than primary testicular failure—GLP-1 medications may help restore natural testosterone production through weight loss and metabolic improvement.
Synergistic Benefits of Combined TRT and GLP-1 Therapy
Muscle Preservation During Weight Loss
One of the most significant advantages of adding TRT to GLP-1 therapy relates to body composition optimization. Current evidence indicates that 15-40% of weight lost with GLP-1 medications may come from lean body mass rather than fat. This muscle loss is particularly concerning for men, as it can accelerate age-related sarcopenia and negatively impact metabolic health long-term.Testosterone's anabolic effects on muscle tissue may help counteract this lean mass loss. TRT enhances protein synthesis and promotes muscle retention even during caloric restriction, potentially improving the "quality" of weight loss by shifting the ratio toward greater fat loss and muscle preservation. For men already on TRT, adding GLP-1 therapy allows them to achieve significant fat loss while maintaining the muscle-building benefits of optimized testosterone levels.
Enhanced Metabolic Health
Both TRT and GLP-1 medications independently improve insulin sensitivity, and their combination may provide additive benefits. Testosterone replacement has been shown to reduce the progression from prediabetes to diabetes in hypogonadal men (TRAVERSE trial substudy), while GLP-1 agonists are established first-line treatments for glycemic control. Together, these therapies address metabolic dysfunction from complementary angles—TRT through improvements in body composition and muscle glucose uptake, and GLP-1s through direct effects on insulin secretion, glucagon suppression, and gastric emptying.Cardiovascular Risk Reduction
The cardiovascular implications of combined therapy are particularly relevant given historical concerns about testosterone and heart health. The TRAVERSE trial demonstrated that TRT does not increase cardiovascular events in hypogonadal men with or at risk for cardiovascular disease. Meanwhile, GLP-1 agonists have shown significant reductions in major adverse cardiovascular events (MACE) in large outcomes trials. Semaglutide reduced cardiovascular death, heart attack, and stroke by 20% in the SELECT trial, with benefits extending to patients without diabetes.The combination of testosterone's effects on cholesterol profiles and vascular function with the established cardioprotection of GLP-1 therapy represents a compelling strategy for men with both hypogonadism and elevated cardiovascular risk.
Potential Concerns and Considerations
GLP-1 Effects on Erectile Function and Libido
A 2024 study published in the International Journal of Impotence Research raised concerns about sexual side effects of semaglutide. In a database analysis of non-diabetic men using semaglutide for weight loss, researchers found a higher rate of erectile dysfunction diagnoses (1.47% vs. 0.32%) and testosterone deficiency diagnoses (1.53% vs. 0.80%) compared to controls.However, these findings require careful interpretation. The absolute risk increase was small (approximately 1%), and the study design could not establish causation. The researchers speculated that GLP-1 receptor expression in testicular Leydig cells might influence pulsatile testosterone secretion, but this mechanism remains hypothetical. Importantly, studies in men with diabetes have shown the opposite effect—GLP-1 agonists improving erectile function, likely through weight loss and metabolic improvement.
For men on TRT, these concerns may be less relevant, as exogenous testosterone maintains hormone levels independent of any effects on endogenous production. Nevertheless, clinicians should monitor for sexual side effects when initiating GLP-1 therapy, particularly in men not receiving testosterone replacement.
Impact on Fertility
A notable finding from the semaglutide vs. TRT comparison study was the differential effect on sperm parameters. While TRT predictably suppressed spermatogenesis (reducing sperm concentration by approximately 60%), semaglutide actually improved sperm morphology and maintained or enhanced sperm parameters. This has significant implications for men desiring fertility preservation.For men who want both weight loss and fertility preservation, GLP-1 therapy may represent a superior choice compared to TRT alone. Those requiring both testosterone optimization and fertility maintenance should discuss hCG or FSH co-therapy options with their clinician, or consider whether GLP-1-induced weight loss might be sufficient to restore endogenous testosterone production.
Practical Protocols for Combining TRT and GLP-1 Therapy
Sequencing Considerations
When a man presents with both low testosterone and obesity, the question of which therapy to initiate first requires individualized assessment. Some clinicians prefer to start GLP-1 therapy and assess whether weight loss improves testosterone levels naturally before committing to lifelong TRT. This approach may be appropriate for men with milder hypogonadism (testosterone 250-350 ng/dL) where obesity is a clear contributing factor.For men with more severe hypogonadism, significant symptoms, or evidence of primary testicular failure, initiating TRT first—or simultaneously with GLP-1 therapy—may be more appropriate. Starting both medications at once, however, complicates side effect attribution if problems arise.
Optimizing Protein Intake
Given the muscle preservation concerns with GLP-1 therapy, adequate protein intake becomes even more critical. Current recommendations suggest 1.6-2.2 grams of protein per kilogram of fat-free mass daily for men on GLP-1 medications. The appetite-suppressing effects of these drugs can make achieving protein targets challenging, requiring deliberate meal planning and potentially protein supplementation.For men on TRT, protein requirements may be even higher to maximize the anabolic stimulus of testosterone. Prioritizing protein at each meal and tracking intake can help ensure muscle preservation during the weight loss phase.
Resistance Training Integration
Resistance exercise is perhaps the most important adjunctive intervention for men combining TRT and GLP-1 therapy. Studies consistently show that combining exercise with GLP-1 treatment preserves significantly more lean mass compared to medication alone. The enhanced protein synthesis from TRT further amplifies the muscle-building response to resistance training.Men should aim for 2-4 resistance training sessions weekly, focusing on compound movements that stimulate major muscle groups. Those experiencing GLP-1-related fatigue may need to adjust training volume initially, but most patients report improved energy and exercise tolerance as weight loss progresses.
Monitoring and Follow-Up
Men on combined TRT and GLP-1 therapy require comprehensive monitoring that addresses both hormonal and metabolic parameters. Recommended assessments include regular testosterone levels (total and free), complete metabolic panel including HbA1c and fasting glucose, lipid profile, PSA, hematocrit, and periodic body composition analysis (DEXA scan) to track changes in lean mass versus fat mass.Sexual function should be assessed using validated questionnaires (such as IIEF-5), and any changes in libido or erectile function should prompt evaluation. For men on TRT who experience new-onset erectile dysfunction after starting GLP-1 therapy, transient dose reduction of the GLP-1 medication or addition of PDE5 inhibitors may be considered.
The Future: Emerging Therapies and Research Directions
The landscape of obesity pharmacotherapy continues to evolve rapidly. Retatrutide, a triple agonist targeting GLP-1, GIP, and glucagon receptors, has shown even greater weight loss efficacy in trials and may offer advantages for body composition. The BELIEVE study combining bimagrumab (a myostatin inhibitor) with semaglutide demonstrated the potential to enhance fat loss while actually increasing lean mass—a "holy grail" outcome that could transform obesity treatment.For men on TRT, these emerging therapies may provide even more effective tools for optimizing body composition. The combination of testosterone's anabolic effects with next-generation weight loss medications targeting multiple pathways represents an exciting frontier in metabolic and hormonal health.
Conclusion: A Rational Approach to Combined Therapy
For men managing both hypogonadism and obesity, the combination of TRT and GLP-1 therapy offers synergistic benefits that address the metabolic and hormonal dimensions of these interconnected conditions. While individual responses vary, the available evidence supports the safety and potential efficacy of combined therapy when appropriately monitored.Key principles for success include adequate protein intake, consistent resistance training, regular monitoring of both hormonal and metabolic parameters, and open communication with healthcare providers about any changes in symptoms or side effects. For many men, this combination represents the most comprehensive approach to restoring metabolic health, optimizing body composition, and maintaining quality of life.
As with any medical decision, the choice to combine TRT with GLP-1 therapy should be individualized based on clinical presentation, goals, and risk factors. Consultation with providers experienced in both hormone optimization and metabolic medicine ensures the best outcomes.
Related ExcelMale Forum Discussions
Continue the conversation and share your experiences with our community:• Looking for Retatrutide Experiences – User experiences with the emerging triple-agonist GLP-1
• Clean Nutrition for Health, Muscle Gain and Fat Loss – Optimizing nutrition while on TRT and weight loss medications
• Treatments for Low Libido in Men – Addressing sexual side effects and libido concerns
• Fertility Maintenance Before, During, and After TRT – Preserving fertility while on testosterone therapy
• HCG Dose Frequency for Men – Fertility & Testicular Atrophy – Optimizing hCG protocols alongside TRT
• The Science of Testosterone and Atherosclerosis – Understanding cardiovascular implications of TRT
• Low Testosterone: Recommendations on Diagnosis, Treatment and Monitoring – Evidence-based clinical guidelines
Key References
1. Portillo Canales S, et al. Effect of Incretin-Based Weight Loss Drugs on Testosterone Concentrations in Men. Presented at ENDO 2025. [Healthline Coverage]2. Gregorič N, et al. Semaglutide improved sperm morphology in obese men with type 2 diabetes mellitus and functional hypogonadism. Diabetes Obes Metab. 2024. [Full Text]
3. Neeland IJ, et al. Changes in lean body mass with glucagon-like peptide-1-based therapies and mitigation strategies. Diabetes Obes Metab. 2024;26:16-27. [PubMed]
4. Able C, et al. Prescribing semaglutide for weight loss in non-diabetic, obese patients is associated with an increased risk of erectile dysfunction. Int J Impot Res. 2024. [PubMed]
5. Jensterle M, et al. Effects of liraglutide on obesity-associated functional hypogonadism in men. Endocr Connect. 2019;8:195-202. [Full Text]
6. Gregorič N, et al. The effects of semaglutide vs testosterone replacement therapy on functional hypogonadism and sperm quality. Endocrine Abstracts. 2024 (ECE 2024). [Abstract]
7. Varnum AA, et al. Impact of GLP-1 agonists on male reproductive health—a narrative review. Medicina. 2024. [PMC Full Text]
8. Neeland IJ, et al. Muscle Mass and Glucagon-Like Peptide-1 Receptor Agonists: Adaptive or Maladaptive Response to Weight Loss? Circulation. 2024. [AHA Journals]
9. American Diabetes Association. New GLP-1 Therapies Enhance Quality of Weight Loss by Improving Muscle Preservation. ADA Press Release. 2025. [ADA Newsroom]
10. Idris I. Potential new therapies to preserve lean muscle mass loss when used in combination with GLP-1 receptor agonists. Diabetes Obes Metab Now. 2024. [Wiley]
11. Liao B, et al. Prescribing Ozempic and Wegovy for Weight Loss is Associated with Increased Risk of ED and Hypogonadism. J Sex Med. 2024. [Oxford Academic]
12. Semaglutide in Obesity: Unmet Needs in Men. PMC Review. 2023. [PMC Full Text]
Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always consult with a qualified healthcare provider before starting, stopping, or modifying any medication regimen. Individual responses to therapy vary, and what works for one person may not be appropriate for another.
About ExcelMale.com: ExcelMale is a men's health forum with over 24,000 members and 20+ years of archived discussions on testosterone replacement therapy, hormone optimization, and sexual health. Founded by Nelson Vergel, author of Built to Survive, Testosterone: A Man's Guide and Beyond Testosterone, ExcelMale provides evidence-based information and peer support for men navigating hormone health decisions.
