Testosterone, Aging, and TRT: What the 2023 TRAVERSE Trial Finally Settled — and What It Didn't
Testosterone replacement therapy has been one of the most debated interventions in men's health for three decades. Advocates cite dramatic improvements in energy, body composition, libido, mood, and cognitive function. Critics have long worried about cardiovascular risk. In 2023, the landmark TRAVERSE trial published the largest and most rigorous safety data on TRT ever collected. Here is what it means for the longevity-focused man.
- Testosterone declines approximately 1–2% per year after age 30, with a more pronounced decline after 50. Hypogonadism (clinically low testosterone) affects an estimated 20% of men over 60 and 30% over 70, though definitions and diagnostic thresholds vary.
- The TRAVERSE trial (2023, NEJM) — a 5,246-patient RCT in men with hypogonadism and elevated cardiovascular risk — found that TRT did not increase the risk of major cardiovascular events (MACE). This largely resolves the longstanding cardiovascular safety debate for appropriately selected patients.
- TRAVERSE did find a higher rate of atrial fibrillation, acute kidney injury, and pulmonary embolism in the TRT group — requiring individualized risk assessment rather than blanket reassurance.
- The primary benefits of TRT in truly hypogonadal men are well-established: improved body composition, sexual function, energy, and bone density. Evidence for cognitive benefits is more mixed. Benefits in eugonadal men (normal testosterone) are less clear and risks are less studied.
- Men wishing to preserve fertility on TRT should discuss concurrent hCG (human chorionic gonadotropin) or clomiphene therapy, which maintain intratesticular testosterone and spermatogenesis while achieving systemic testosterone goals.
Testosterone is a 19-carbon steroid hormone produced primarily in the Leydig cells of the testes (in men), with smaller amounts from the adrenal cortex and, in women, from the ovaries and adrenal glands. In men, it is the primary anabolic sex hormone: it drives muscle protein synthesis, bone density, erythropoiesis (red blood cell production), libido, and exerts complex effects on mood, cognitive function, and metabolic health. Peak levels occur in early adulthood and decline thereafter at approximately 1–2% per year — a trajectory that, by age 70, leaves many men with total testosterone levels 30–40% below their young-adult peak.[1]
Whether this decline is pathological and should be treated has been debated since the widespread introduction of TRT in the 1990s. The cardiovascular safety concerns crystallized in 2010 when a small trial (the Testosterone in Older Men with Mobility Limitations trial) was halted early due to an apparent excess of cardiovascular events in the TRT arm. That result was disputed, but it intensified scrutiny and delayed a definitive resolution for over a decade.[2] The TRAVERSE trial was designed specifically to provide that resolution.
TRAVERSE: What the Trial Found
The TRAVERSE trial enrolled 5,246 men aged 45–80 with symptomatic hypogonadism (total testosterone under 300 ng/dL on two measurements) and pre-existing cardiovascular disease or elevated cardiovascular risk. They were randomized to transdermal testosterone gel (titrated to maintain levels between 350–750 ng/dL) or placebo gel for a median follow-up of 33 months.[3]
The primary finding: TRT did not increase the risk of the primary composite endpoint (major adverse cardiovascular events — cardiovascular death, nonfatal MI, nonfatal stroke). The hazard ratio was 0.96 (95% CI 0.78–1.17), establishing non-inferiority. This largely resolves the primary cardiovascular safety concern for TRT in appropriately selected hypogonadal men with cardiovascular risk.
The secondary findings requiring attention: TRAVERSE found statistically significant higher rates of three adverse events in the TRT group: atrial fibrillation (3.5% vs 2.4%), acute kidney injury (2.3% vs 1.5%), and pulmonary embolism (0.9% vs 0.5%). These were not catastrophic findings — absolute risk differences were modest — but they represent real considerations that individualize the risk-benefit calculation rather than rendering TRT uniformly safe for all comers.[4]
"TRAVERSE gave us the data we needed on cardiovascular events — which is genuinely reassuring. But the atrial fibrillation signal is real and clinically meaningful. Men with pre-existing AF or risk factors for it need specific counseling."— Dr. Shalender Bhasin, Harvard Medical School, principal investigator of multiple testosterone trials
Established Benefits in Hypogonadal Men
Body composition: Meta-analyses of TRT trials in hypogonadal men consistently demonstrate significant reduction in fat mass (particularly visceral fat) and increase in lean mass. The effect size is clinically meaningful — typically 2–5 kg lean mass gain and 1.5–3 kg fat mass reduction over 12 months.[5]
Sexual function and libido: Among the most consistently and robustly demonstrated benefits. TRT improves erectile function, libido, and sexual satisfaction in hypogonadal men, with effect sizes that are clinically meaningful in the IIEF-5 questionnaire. This is perhaps the most established efficacy signal in the TRT literature.[6]
Bone density: TRT has well-established effects on bone mineral density in hypogonadal men, reducing fracture risk — particularly relevant given sarcopenia-osteoporosis co-occurrence in aging men.[7]
Energy and mood: Consistently reported in clinical trials and observational series, though more variable in magnitude and harder to quantify objectively. Men with the lowest pre-treatment testosterone and most severe symptoms tend to report the most dramatic improvements.
Cognitive function: Evidence is more mixed. Some trials show improvements in verbal memory and spatial cognition; others show no significant effect. The cognitive benefit may be concentrated in men with the lowest baseline testosterone and most significant symptoms of hypogonadism.[8]
TRT Delivery Methods: Comparison
| Delivery Method | Dosing | Pros | Cons |
|---|---|---|---|
| Transdermal gel/cream | Daily application | Steady levels; easy titration; most studied | Transfer risk; skin irritation |
| Intramuscular injection (cypionate) | Weekly or biweekly | Cost-effective; no transfer risk | Peak-trough fluctuations; self-injection |
| Subcutaneous injection | Twice weekly | Smoother levels than IM; easy self-injection | Less established long-term data |
| Pellet implants | Every 3–6 months | Highly convenient; steady levels | Surgical procedure; cannot titrate quickly |
| Oral (undecanoate) | Twice daily with meals | Non-invasive | Variable absorption; liver metabolism |
Fertility Preservation: hCG and Clomiphene
TRT suppresses the HPG (hypothalamic-pituitary-gonadal) axis through negative feedback — reducing LH and FSH, which in turn shuts down intratesticular testosterone production and spermatogenesis. Men who wish to preserve fertility while on TRT should discuss concurrent hCG (human chorionic gonadotropin) therapy, which mimics LH action at the Leydig cells to maintain intratesticular testosterone and sperm production. Typical protocols use 500–1,000 IU of hCG two to three times weekly alongside TRT.[9]
Clomiphene citrate (an estrogen receptor modulator that increases LH and FSH via HPG axis stimulation) is an alternative that raises endogenous testosterone without suppressing the axis, making it a fertility-preserving option particularly suited to younger men or those with mild hypogonadism who wish to maintain natural testosterone production and fertility.[10]
Essential Monitoring Parameters
Appropriate TRT requires regular monitoring: total testosterone (target 400–700 ng/dL for most men), estradiol (testosterone aromatizes to estrogen; elevated E2 can cause gynecomastia, fluid retention, and mood effects), hematocrit (TRT stimulates erythropoiesis; elevated hematocrit increases thrombosis risk and requires dose reduction or therapeutic phlebotomy), PSA (prostate-specific antigen; TRT does not cause prostate cancer but may accelerate occult disease), and lipid panel. Annual monitoring is minimum standard of care; every 3–6 months in the first year of therapy.[11]
References
- 1Harman SM, et al. "Longitudinal effects of aging on serum total and free testosterone levels in healthy men." Journal of Clinical Endocrinology & Metabolism. 2001;86(2):724-731. [PubMed]
- 2Basaria S, et al. "Adverse events associated with testosterone administration." NEJM. 2010;363(2):109-122. [PubMed]
- 3Lincoff AM, et al. "Cardiovascular safety of testosterone-replacement therapy." NEJM. 2023;389(2):107-117. [PubMed]
- 4Bhasin S. "Testosterone-replacement therapy — a clarifying perspective on the TRAVERSE trial." NEJM. 2023;389(2):168-170. [PubMed]
- 5Bhasin S, et al. "Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline." Journal of Clinical Endocrinology & Metabolism. 2018;103(5):1715-1744. [PubMed]
- 6Corona G, et al. "Meta-analysis of results of testosterone therapy on sexual function based on international index of erectile function scores." European Urology. 2017;72(6):1000-1011. [PubMed]
- 7Snyder PJ, et al. "Effect of testosterone treatment on bone mineral density in men over 65 years of age." Journal of Clinical Endocrinology & Metabolism. 1999;84(6):1966-1972. [PubMed]
- 8Resnick SM, et al. "Testosterone treatment and cognitive function in older men with low testosterone and age-associated memory impairment." JAMA. 2017;317(7):717-727. [PubMed]
- 9Wenker EP, et al. "The use of HCG-based combination therapy for recovery of spermatogenesis after testosterone use." Journal of Sexual Medicine. 2015. [PubMed]
- 10Krzastek SC, et al. "Long-term safety and efficacy of clomiphene citrate for the treatment of hypogonadism." Journal of Urology. 2019;202(5):1029-1035. [PubMed]
- 11Mulhall JP, et al. "Evaluation and management of testosterone deficiency." Journal of Urology. 2018;200(2):423-432. [PubMed]