In an overweight male with type 2 diabetes who is concerned about testosterone, does tirzepatide (Mounjaro) have a direct effect on serum testosterone levels?

Tirzepatide Increases Testosterone Levels in Overweight Men with Type 2 Diabetes

Tirzepatide significantly increases serum testosterone levels in overweight men with type 2 diabetes through weight loss-mediated improvements in metabolic hypogonadism, making it an excellent therapeutic choice for this patient population. 1

Direct Effects on Testosterone

Tirzepatide has demonstrated robust effects on testosterone levels in men with obesity and metabolic hypogonadism:

• After just 2 months of treatment, tirzepatide (starting at 2.5 mg weekly, increased to 5 mg) significantly increased total testosterone, free testosterone, and bioavailable testosterone compared to both placebo and testosterone replacement therapy groups. 1

• Tirzepatide also increased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels while decreasing estradiol, indicating restoration of the hypothalamic-pituitary-gonadal axis rather than direct hormonal supplementation. 1

• The mechanism appears to be reversal of metabolic hypogonadism through dramatic reductions in body weight (5.4-11.7 kg across trials) and fat mass, particularly visceral adipose tissue which suppresses testosterone production. 2, 3

Clinical Significance for Your Patient

This is particularly relevant for an overweight male with type 2 diabetes because:

• Low testosterone levels are extremely common in men with type 2 diabetes, with the relationship being bidirectional and substantially mediated through body fat, especially abdominal visceral adipose tissue. 4

• Tirzepatide produces unprecedented weight loss (20.7-68.4% of patients losing >10% body weight) and glycemic control (HbA1c reductions of 1.24-2.58%), addressing both the diabetes and the obesity driving the hypogonadism. 2, 3

• The improvements in erectile function (measured by IIEF-5 scores) were significantly greater with tirzepatide than with direct testosterone replacement, suggesting functional benefits beyond hormone normalization. 1

Comparison to Testosterone Replacement

A critical finding from the controlled pilot study:

• Tirzepatide was superior to transdermal testosterone replacement in improving lean mass, reducing fat mass, and improving erectile dysfunction scores, while simultaneously normalizing endogenous testosterone production. 1

• Unlike exogenous testosterone which suppresses the hypothalamic-pituitary-gonadal axis, tirzepatide restores natural testosterone production by eliminating the metabolic dysfunction causing secondary hypogonadism. 1

Practical Management Approach

For your patient, the evidence supports:

• Initiate tirzepatide at 2.5 mg weekly, escalating to 5 mg (or higher doses of 10-15 mg as tolerated) for maximal metabolic and hormonal benefits. 1, 2

• Measure morning total testosterone at baseline and at 2-3 months to document improvement; if borderline, calculate free testosterone from total testosterone, SHBG, and albumin. 5

• Obtain LH and FSH levels to confirm this is secondary (metabolic) hypogonadism rather than primary testicular failure, which would not respond to weight loss interventions. 5

• Avoid empiric testosterone replacement therapy in this population, as weight loss through tirzepatide addresses the root cause and avoids the cardiovascular risks associated with exogenous testosterone in men with established metabolic disease. 5, 6

Important Caveats

• The testosterone improvements are mediated through weight loss and metabolic improvement, not through direct hormonal effects of tirzepatide on the testes or hypothalamus. 1, 4

• Gastrointestinal side effects (nausea, vomiting, diarrhea) are dose-dependent and more common at higher doses, though generally manageable with gradual dose escalation. 2, 3

• If the patient has true primary hypogonadism (elevated LH/FSH with low testosterone), tirzepatide will not correct testosterone levels and testosterone replacement would be indicated. 5

• The cardiovascular safety profile of tirzepatide is favorable, with MACE-4 events trending toward reduction and no hazard ratio >1.0 versus comparators, making it safer than testosterone replacement in men with cardiovascular risk factors. 2