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.[1]
- 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 addresses the main cardiovascular safety question for appropriately selected patients.[3]
- 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 steadily thereafter; in the Baltimore Longitudinal Study of Aging, about 20% of men over 60, 30% over 70 and 50% over 80 had total testosterone in the hypogonadal range.[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 mean 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.[3] This addresses 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]
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 is real but modest: lean mass rises and fat mass falls over the first year of treatment.[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. Protocols vary, and dosing should be set by a specialist.[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 monitoring. The American Urological Association guideline recommends checking hemoglobin and hematocrit before starting, because testosterone can raise red blood cell counts (polycythemia), and measuring PSA before treatment in men over 40 to exclude prostate cancer. Estradiol is measured before treatment only in men with breast symptoms or breast enlargement. Once on therapy, the dose is adjusted to bring total testosterone into the middle of the normal range, about 450 to 600 ng/dL, with an initial follow-up level to confirm the target is reached and testosterone checked every 6 to 12 months after that. The guideline also advises telling patients that there is no evidence linking testosterone therapy to the development of prostate cancer.[11] AUA reviewed the guideline and confirmed it remains valid in 2024 (AUA).
Put this research into practice: Biomarker Reference Tool · What Should I Test Next?
References
- 1Harman SM, et al. "Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging." J Clin Endocrinol Metab. 2001;86(2):724-31. PubMed · DOI
- 2Basaria S, et al. "Adverse events associated with testosterone administration." N Engl J Med. 2010;363(2):109-22. PubMed · DOI
- 3Lincoff AM, et al. "Cardiovascular Safety of Testosterone-Replacement Therapy." N Engl J Med. 2023;389(2):107-117. PubMed · DOI
- 4Bhasin S, et al. "Cardiovascular Safety of Testosterone-Replacement Therapy. Reply." N Engl J Med. 2023;389(12):1150-1151. PubMed · DOI
- 5Bhasin S, et al. "Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline." J Clin Endocrinol Metab. 2018;103(5):1715-1744. PubMed · DOI
- 6Corona G, et al. "Meta-analysis of Results of Testosterone Therapy on Sexual Function Based on International Index of Erectile Function Scores." Eur Urol. 2017;72(6):1000-1011. PubMed · DOI
- 7Snyder PJ, et al. "Effect of testosterone treatment on bone mineral density in men over 65 years of age." J Clin Endocrinol Metab. 1999;84(6):1966-72. PubMed · DOI
- 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 · DOI
- 9Wenker EP, et al. "The Use of HCG-Based Combination Therapy for Recovery of Spermatogenesis after Testosterone Use." J Sex Med. 2015;12(6):1334-7. PubMed · DOI
- 10Krzastek SC, et al. "Long-Term Safety and Efficacy of Clomiphene Citrate for the Treatment of Hypogonadism." J Urol. 2019;202(5):1029-1035. PubMed · DOI
- 11Mulhall JP, et al. "Evaluation and Management of Testosterone Deficiency: AUA Guideline." J Urol. 2018;200(2):423-432. PubMed · DOI