Testosterone Therapy in Middle-Aged and Older Men with Hypogonadism: Balancing Clinical Benefits and Risks

Highlights

• Testosterone therapy modestly improves sexual function, corrects anemia, and increases bone density in older men with hypogonadism.
• Risks include increased venous thromboembolism, clinical fractures, and atrial fibrillation; no significant increase in major cardiovascular events or prostate cancer observed in trials to date.
• Therapy should be reserved for men with unequivocally low testosterone levels and persistent symptoms after careful diagnostic workup.

Study Background and Disease Burden

Age-associated hypogonadism, characterized by reduced serum testosterone and symptoms such as decreased libido, anemia, fatigue, and loss of muscle mass, is increasingly diagnosed in aging men. Although testosterone replacement therapy (TRT) is FDA-approved for classical hypogonadism (pituitary or testicular disease), the majority of men currently receiving TRT are older, with only mild-to-moderate testosterone reductions and non-specific symptoms overlapping with normal aging or chronic illness. This has fueled debate over the true benefit-risk balance of TRT in this population, especially given concerns about cardiovascular, thrombotic, and prostate-related adverse events.

Study Design

The evidence base for TRT comprises a series of randomized, placebo-controlled trials (RCTs), most notably the Testosterone Trials (TTrials), the TRAVERSE cardiovascular outcomes trial, and the T4DM diabetes prevention study.

• TTrials: Seven coordinated double-blind RCTs involving 790 men (mean age 72, mean baseline testosterone 234 ng/dL) with symptoms of hypogonadism, randomized to daily transdermal testosterone gel or placebo for 12 months. Endpoints included sexual function, anemia correction, bone density, vitality, mood, and cognition.
• TRAVERSE: The largest safety trial to date, enrolling 5,204 men (mean age 63, baseline testosterone 227 ng/dL) at high cardiovascular risk, randomized to daily transdermal testosterone or placebo gel, with a mean follow-up of 33 months. The primary endpoint was major adverse cardiovascular events (MACE: nonfatal MI, nonfatal stroke, cardiovascular death).
• T4DM: An Australian trial in 1,007 men (mean age 60, mean baseline testosterone 395 ng/dL) with impaired glucose tolerance or newly diagnosed T2DM, randomized to intramuscular testosterone undecanoate or placebo every 3 months for 2 years, combined with intensive lifestyle intervention. Endpoints included diabetes incidence and metabolic control.

Key Findings

Benefits:

• Sexual Function: TRT consistently increased sexual activity (up to 40% more weekly events), libido (25% improvement), and, to a lesser extent, erectile function (mean IIEF-EF increase 2.6 points). However, benefit for erectile dysfunction was less than that of phosphodiesterase inhibitors (e.g., sildenafil).
• Anemia: TRT corrected anemia in about one-third of men, with hemoglobin rises ≥1 g/dL comparable to erythropoiesis-stimulating agents.
• Bone Health: TRT increased vertebral trabecular bone density (up to 7%) and improved bone strength (quantitative CT) after 1-2 years, though clinical fracture prevention was not demonstrated.
• Mood and Vitality: Modest improvements in mood (3–4% increase), reduced depressive symptoms (up to 10% reduction), and minor gains in self-reported energy were observed, but no significant effect on major depression or objective fatigue scales.

Risks:

• Venous Thromboembolism (VTE): Slightly increased risk in TRT group, especially within first 6 months (TRAVERSE: 0.9% vs 0.5% for pulmonary embolism). Events clustered in men with underlying thrombophilia.
• Atrial Fibrillation: Higher rates of nonfatal arrhythmia and atrial fibrillation in TRT group (TRAVERSE: AF 3.5% vs 2.4%), though meta-analyses do not show a consistent signal.
• Clinical Fractures: Contrary to expectations, TRT increased all-site clinical fracture risk by 43% in TRAVERSE, despite gains in bone density. Most fractures were typical of osteoporotic sites (ankle, wrist, ribs). The mechanism is unclear but may relate to increased physical activity without corresponding muscle strength gain.
• Polycythemia: Dose-dependent risk, more frequent with injectable formulations (22% in T4DM), but rare with well-titrated transdermal regimens (≤2%).
• Prostate Events: No significant increase in prostate cancer or progression of lower urinary tract symptoms in trials excluding high-risk men, but TRT raises PSA and may increase detection of indolent prostate cancers.
• Other: Higher rates of acute kidney injury in TRT group (2.3% vs 1.5%), but no signal for hepatotoxicity.

Neutral Findings:

• No improvement in glycemic control or diabetes progression in most RCTs (TTrials, TRAVERSE), except in T4DM, where intensive lifestyle intervention may have confounded results.
• No benefit for cognitive function in men without baseline impairment.

Expert Commentary

Expert consensus and current guidelines emphasize that TRT should be reserved for men with unequivocally low morning testosterone on repeated measurement, accompanied by consistent symptoms and after ruling out reversible causes (e.g., obesity, acute illness, medications). The greatest likelihood of benefit is seen with levels below 200 ng/dL (6.9 nmol/L). Risks should be minimized by appropriate patient selection, baseline prostate and cardiovascular risk assessment, and ongoing monitoring of hematocrit, PSA, and adverse symptoms. Men with prior VTE or high fracture risk should be counseled on alternative strategies or additional prophylaxis.

Conclusion

Testosterone therapy in older men with moderate hypogonadism offers modest gains in sexual function, anemia correction, and bone density, but is offset by increased risks of VTE, arrhythmia, and fractures. Decisions must be individualized, grounded in robust diagnostic criteria, and supported by shared decision-making that incorporates patient values and preferences. Ongoing surveillance for adverse events is essential, and clinical practice should evolve as longer-term outcomes become available.

References

Bhasin S, Snyder PJ. Testosterone Treatment in Middle-Aged and Older Men with Hypogonadism. N Engl J Med. 2025;393:581-91.
Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374:611-24.
Snyder PJ, Ellenberg SS, Cunningham GR, et al. The Testosterone Trials: Seven Coordinated Trials. J Clin Endocrinol Metab. 2018;103(8):3013-3024.
Nehra A, et al. Testosterone Replacement Therapy and Cardiovascular Risk: A Scientific Statement From the American Heart Association. Circulation. 2022;146:e1-e12.