Tirzepatide Tops TRT for Men With Hypogonadism and Obesity
In a study of 83 men with obesity, functional hypogonadism, and insulin resistance, those treated with the dual glucose-dependent insulinotropic peptide and glucagon-like peptide 1 (GLP-1) receptor agonist tirzepatide for 2 months had greater weight loss, increased endogenous testosterone production, and improved erectile dysfunction compared to those treated with transdermal testosterone replacement therapy (TRT) or who received no treatment.
'Tirzepatide offers a dual benefit, substantial weight loss and restoration of gonadal function in obese men. This may change first-line management strategies for metabolic hypogonadism, encouraging a shift away from immediate testosterone supplementation in select patients,' lead study author Rossella Cannarella, MD, research fellow in the Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy, told Medscape Medical News .
She added, 'Unlike TRT, which suppresses gonadotropins, tirzepatide appears to restore axis function. This offers an alternative for functional hypogonadism that addresses root metabolic causes rather than symptomatically replacing testosterone.'
Cannarella presented the findings at ENDO 2025: The Endocrine Society Annual Meeting. The data were also published recently in Reproductive Biology and Endocrinology .
Asked to comment, session co-moderator Olena Klindukhova, MD, assistant professor at the Medical College of Wisconsin, Milwaukee, told Medscape Medical News , 'there are a number of good publications in the past on bariatric surgery patients who were able to achieve improvement in fertility, in testosterone level, and all aspects of sexual function. So, we were waiting the GLP-1 data to come in, and it's great to hear. It will definitely empower my clinical practice. Having patients achieve weight loss will improve their physiologic, natural production of testosterone. This gives us more validation.'
Tirzepatide Tops Testosterone in Metabolic, Hormonal Improvements
The study participants were allocated to three groups, based on their preferences, health status, and overall circumstances: 28 to tirzepatide (2.5 mg for the first month, increased to 5 mg in the second month), 30 to no pharmacological treatment, and 25 to transdermal testosterone. All were instructed to follow a low-calorie diet and to engage in 20 minutes per day of brisk walking.
At baseline, all patients had ED, with International Index of Erectile Function (IIEF-5) scores ranging from 5 to 12. At least half in each group were classified as having severe ED. Baseline waist circumference was significantly higher in the no-treatment group, while baseline scores on the Binge Eating Scale (BES), percentage lean mass, and luteinizing hormone (LH) levels were all significantly higher in the tirzepatide-treated group.
After 2 months, the tirzepatide group showed significantly greater improvements from baseline than the other two groups in body weight (-8.1%, vs -2.4% and -3.0% for lifestyle only and testosterone, respectively, P = .0007), BMI, waist circumference, fat mass, and BES score. The tirzepatide group also had a greater increase in lean mass than the lifestyle-alone group but not the testosterone group.
All groups showed reductions in insulin resistance, with those in the two pharmacologic treatment groups showing greater reductions than the lifestyle-only group. The increase in IIEF-5 was higher in the tirzepatide group than the lifestyle-only group, and also higher than the testosterone group although not significantly.
With tirzepatide, levels of LH, follicle-stimulating hormone (FSH), and total testosterone were significantly higher than in the other two groups, while 17β-estradiol (E 2 ) was lower (all P < .00001). The testosterone-treated group showed smaller changes in most parameters, including a slight increase in E 2 levels.
Also asked to comment, session co-moderator Maja Stefanovic-Racic, MD, PhD, associate professor of medicine and director of the endocrinology, diabetes, and metabolism fellowship training program at the University of Pittsburgh School of Medicine, Pennsylvania, told Medscape Medical News , 'I was very impressed is that the GLP-1 improved erectile dysfunction, because we know that especially in obese men, adding testosterone often does not improve ED at all. This may relate to endothelial function outside of weight.'
Indeed, Cannarella also pointed out that weight loss might not be the only mechanism contributing to all the observed improvements. 'While weight loss undoubtedly plays a major role, the magnitude and speed of hormonal recovery — along with increases in gonadotropins (LH, FSH) and SHBG [sex hormone-binding globulin] — suggest that tirzepatide may exert additional regulatory effects on the hypothalamic-pituitary-gonadal axis.'
Klindukhova commented, 'from an endocrinologist standpoint, if there's a patient who is open to it, I would personally go for GLP-1 over testosterone.'
Cannarella, Klindukhova, and Stefanovic-Racic had no disclosures.
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