Testosterone Replacement Therapy: Evidence, Risks, and Who Is Actually a Candidate
Dr. RP, MD — Board-Certified, Emergency Medicine & Critical Care Medicine — Founder, Analog Precision Medicine
I was sitting on a couch in Ontario when Ben Johnson broke the world.
September 24, 1988. I was thirteen. Like every other Canadian within range of a television that night, I watched him erupt out of the blocks in Seoul and run a race that didn't look possible — 9.79 seconds, gold medal, world record. The country gave him the kind of celebration it almost never extends to its athletes. Seventy-two hours later, the IOC announced he had tested positive for stanozolol, a synthetic anabolic steroid. The medal was stripped. The record was gone.
The whiplash was total.
Nobody watching that night was thinking about testosterone. That word never came up. What people were thinking — what the headlines said, what got discussed at school the next morning — was steroids. Steroids were cheating. Steroids were what ruined things. And that framing was completely accurate as a description of what Johnson was doing: a systematic doping program using synthetic androgens at doses designed to do things no clean human body can do.
The problem is what happened in the years that followed. As doping scandals accumulated — Barry Bonds, Lance Armstrong, a generation of athletes — steroids and testosterone fused in the public imagination into a single, contaminated concept. The word testosterone inherited the entire stigma of the broader category. Today, mention TRT to someone outside medicine and watch the association land. It's immediate. It's wrong. And it has been quietly costing real patients real health for decades, because men with genuine hormone deficiency don't want to be associated with cheating, and some physicians don't want to be associated with it either.
The distinction that gets lost in all of this: Johnson and his contemporaries were doing supraphysiologic loading — stacking synthetic androgens and exogenous testosterone to levels no healthy endocrine system reaches naturally, to extract performance advantages from elite physiology. His testosterone-to-epitestosterone ratio was reportedly around 15-to-1; the permitted limit was 4-to-1. This wasn't his body's own hormone system running well. It was a pharmacological override.
“TRT in a clinical context is the opposite: restoring a hormone that has fallen below physiologic range back to where it is supposed to be. Not higher than normal. Back to normal.”
TRT in a clinical context is the opposite: restoring a hormone that has fallen below physiologic range back to where it is supposed to be. Not higher than normal. Back to normal. The logic is identical to prescribing thyroid hormone to someone whose thyroid has stopped producing enough. You are filling a deficit, not building an advantage.
That distinction matters. Let me explain why.
Who Actually Has Low Testosterone
Testosterone declines at roughly 1% per year beginning around age 30 to 40. The descent is gradual enough that many men don't recognize what's happening until symptoms have been accumulating for years. The Endocrine Society and AUA guidelines are both explicit: the diagnosis of testosterone deficiency requires both low lab values and consistent symptoms. Neither alone is sufficient.[2,3]
Diagnostically, the threshold is a total testosterone below 300 ng/dL on two separate morning samples — drawn between 7 and 10 a.m. when levels naturally peak. One low value isn't enough. Two confirmatory morning draws are required, along with clinical correlation.
The more specific symptoms of testosterone deficiency include decreased libido, loss of spontaneous erections, reduced ejaculatory volume, and gynecomastia. Less specific but still relevant: persistent fatigue, depressed mood, loss of muscle mass, increased central body fat, reduced bone density, and unexplained anemia. The non-specific symptoms overlap significantly with other conditions — sleep apnea, depression, obesity, hypothyroidism — which is exactly why the biochemical confirmation requirement exists.
LH should also be measured. A low or low-normal LH in the setting of low testosterone suggests secondary (central) hypogonadism — a problem at the pituitary level — which may warrant further workup including pituitary imaging.
What the Evidence Actually Shows
In men with properly confirmed hypogonadism, the benefits of TRT are well-documented across several domains.
Sexual function and libido show the most consistent benefit — a systematic review of 23 randomized trials found the majority demonstrated meaningful improvement. Body composition improves: lean mass increases, fat mass decreases, particularly visceral fat. Bone mineral density benefits are well-established over 12–24 months of treatment. Mood, energy, and cognitive function improve in many patients, though the response is variable. And in men with unexplained anemia, TRT can correct hemoglobin meaningfully through EPO-mediated erythropoiesis.
The TRAVERSE trial — published in the New England Journal of Medicine in June 2023 and representing the largest randomized controlled trial ever conducted on TRT — addressed the biggest clinical question head-on: cardiovascular safety (Lincoff AM et al., N Engl J Med, 2023;389:107–117).[1]
The trial enrolled 5,246 men aged 45 to 80 with confirmed hypogonadism and preexisting or high cardiovascular risk. Patients received daily transdermal testosterone gel or placebo for a mean of nearly 22 months. The primary endpoint — composite of cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke — occurred in 7.0% of the testosterone group versus 7.3% in the placebo group. Testosterone was noninferior to placebo for major cardiovascular events. The FDA warning label that has shadowed TRT prescribing since 2015 was not supported by the best evidence ever produced on the question.
Two caveats from TRAVERSE deserve honest acknowledgment: the testosterone group showed higher rates of nonfatal arrhythmias (including atrial fibrillation), venous thromboembolic events, and acute kidney injury. These signals are real and require clinical consideration, particularly in men with existing arrhythmia history or prior VTE.
Real Risks That Require Real Monitoring
TRT is not a supplement. It is hormone therapy, and it requires ongoing medical oversight.
Polycythemia is the most consistently documented side effect — testosterone stimulates red blood cell production, and over 20% of men on TRT in some series develop hematocrit elevations requiring intervention. Hematocrit above 54% warrants holding therapy. Injectable formulations carry higher risk than transdermal preparations. This alone is reason enough that "subscribe online and receive vials by mail" is not appropriate medical care.[6]
Fertility suppression is underemphasized in clinical conversations. Exogenous testosterone suppresses LH via negative feedback, shutting down endogenous spermatogenesis. Men who haven't completed their families need an explicit discussion of this before initiating TRT.
Prostate: Testosterone does not cause prostate cancer, but it can cause PSA to rise modestly and may accelerate BPH progression. Active prostate cancer is a contraindication. Baseline PSA testing and regular monitoring are standard.
Sleep apnea can worsen on TRT and should be screened for before initiation.
Who Is — and Isn't — a Candidate
The right patient has: (1) symptoms consistent with androgen deficiency, particularly the specific sexual symptoms; (2) two confirmed morning testosterone levels below 300 ng/dL; and (3) no contraindications.
The fatigued, moderately overweight man in his mid-40s who isn't sleeping well and whose testosterone runs 290 ng/dL may or may not be a TRT candidate. If his fatigue is driven by sleep apnea, his mood by undertreated depression, and his body composition by lifestyle factors, treating those first may normalize testosterone without exogenous replacement. The testicular axis is intact — it can recover if given the right conditions.
The man with confirmed libido loss, absent spontaneous erections, declining muscle mass despite effort, and two morning levels of 215 ng/dL is a different situation entirely. That patient deserves treatment.
Absolute contraindications include active or suspected prostate cancer, breast cancer, preexisting polycythemia, desire for fertility, and prior thromboembolic disease. Untreated severe sleep apnea is a relative contraindication requiring management before or concurrent with TRT.
The Ongoing Monitoring Standard
Initiation is not the end of the clinical conversation. Standard monitoring includes testosterone levels at 3 months then annually once stable, complete blood count to track hematocrit, PSA, and symptom reassessment. If symptoms haven't improved meaningfully within 3 months of achieving therapeutic levels, the diagnosis and treatment should be revisited.
This longitudinal oversight is not optional. It is what separates evidence-based testosterone management from the wellness industry's version of it.
Back to the Couch in Ontario
I was thirteen when I watched that race. I didn't have a framework for any of it. I just watched the greatest 100 metres ever run and then watched it taken away. What I thought — what everyone thought — was: steroids. That was the whole story, as far as the public was concerned.
The more nuanced story is that Johnson's doping program included synthetic androgens and exogenous testosterone stacked to levels far beyond anything a healthy endocrine system produces — pharmacological augmentation of elite physiology, not restoration of a deficit. The testosterone-to-epitestosterone ratio in his sample told part of that story. What circulated in his bloodstream that night in Seoul had nothing to do with health and everything to do with performance extraction.
The word testosterone got swept up in the cultural fallout anyway. It has carried that association for thirty-seven years, and real patients have paid a real price for it — men whose hormone systems have declined naturally, whose quality of life has slipped, and who deserve a clinical conversation rather than a reflexive association with cheating.
Properly diagnosed, properly monitored TRT is not what Ben Johnson was doing.
It never was. The evidence is clear on what it actually is.
References
- 1.Lincoff AM et al. TRAVERSE Study Investigators. Cardiovascular safety of testosterone-replacement therapy. N Engl J Med. 2023;389(2):107–117.
- 2.Bhasin S et al. Testosterone therapy in men with hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715–1744.
- 3.Mulhall JP et al. Evaluation and management of testosterone deficiency: AUA Guideline. J Urol. 2018;200(2):423–432.
- 4.Al-Sharefi A, Quinton R. Current guidelines for management of male hypogonadism. Endocrinol Metab. 2020;35(3):526–540.
- 5.Bassil N et al. The benefits and risks of testosterone replacement therapy: a review. Ther Clin Risk Manag. 2009;5:427–448.
- 6.Ohlander SJ et al. Erythrocytosis following testosterone therapy. Sex Med Rev. 2018;6(1):77–85.
- 7.Hackett G, Kirby M. Cardiovascular safety of testosterone replacement therapy (TRAVERSE trial). Trends Urol Mens Health. 2024. doi:10.1002/tre.967.
Dr. RP, MD is dual board-certified in Emergency Medicine and Critical Care Medicine and is the founder of Analog Precision Medicine, a precision medicine practice in Southern California. This article is for educational purposes only and does not constitute medical advice or establish a physician-patient relationship.
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