In the early 2010s, testosterone therapy was one of the fastest growing prescriptions in American medicine, driven in part by advertising that framed tiredness and low libido as a treatable condition. Then a handful of observational studies suggested the drug might raise the risk of heart attacks and strokes. Prescriptions fell. Regulators added warnings. For years, the honest answer to the question "is testosterone safe for my heart" was that nobody knew.
TRAVERSE was designed to find out.
What the trial did
The study, published in the New England Journal of Medicine1 in 2023, enrolled 5,246 men between 45 and 80 years old. All had symptoms of hypogonadism and two fasting morning testosterone levels below 300 nanograms per deciliter. All had either existing cardiovascular disease or a high risk of it. That was deliberate. If testosterone harmed the heart, this was the group where the harm would show up.
The men were randomly assigned to a daily testosterone gel or a placebo gel and followed for an average of about 33 months. The main measure was major adverse cardiac events, a composite of cardiovascular death, nonfatal heart attack and nonfatal stroke.
The result was clear. Those events occurred in 7.0 percent of the testosterone group and 7.3 percent of the placebo group. Testosterone met the trial's standard for being no worse than placebo on heart attacks and strokes.
If testosterone harmed the heart, this was the group where the harm would show up. It did not, at least not in the way people feared.
View the data
| Group | Major cardiac events |
|---|---|
| Placebo gel | 7.3% |
| Testosterone gel | 7.0% |
Source: Lincoff et al., New England Journal of Medicine, 2023
What it did not settle
TRAVERSE is reassuring, but it is not a blank check. A few findings deserve as much attention as the headline.
The testosterone group had a higher incidence of atrial fibrillation, acute kidney injury and pulmonary embolism. The absolute numbers were small, but they were real signals, and they matter for men with a history of clots or heart rhythm problems.
Adherence was a challenge. A large share of participants stopped their assigned treatment before the trial ended, which is common in long studies but makes it harder to know exactly what consistent use over many years looks like.
The trial tested a transdermal gel at doses adjusted to keep levels in the normal range. It does not tell us much about injections, pellets, or the supraphysiologic doses some men pursue for performance. It also did not test men with normal testosterone, who have no clear medical reason to take it.
Getting the diagnosis right
The diagnostic bar has not moved. Both the American Urological Association2 and the Endocrine Society3 call for consistent symptoms plus low testosterone confirmed on at least two separate early-morning blood draws. The AUA uses 300 nanograms per deciliter as a reasonable cutoff for total testosterone.
Testosterone levels swing during the day, drop after a bad night of sleep, and fall during acute illness. A single afternoon lab drawn during a stressful week is not a diagnosis. Neither is fatigue alone, which has a long list of causes including sleep apnea, depression, thyroid disease, anemia and plain overwork. A good workup looks for those first.
A diagnosis also means asking why testosterone is low. Obesity, opioid use, high prolactin and pituitary problems can all suppress it, and some are reversible. Guidelines recommend measuring luteinizing hormone and, in some cases, prolactin, to separate a problem in the testes from a signaling problem upstream.
The fertility problem, and where enclomiphene fits
Here is the part many men do not hear until it is too late. External testosterone tells the brain that the body has plenty, so the brain reduces the signals that drive sperm production. The AUA guideline states plainly that men who want to preserve fertility should not be started on testosterone therapy.
That is one reason clinicians sometimes turn to medications that raise the body's own production instead. Clomiphene citrate, approved for female infertility and used off label in men, blocks estrogen's feedback at the brain, which increases the hormones that tell the testes to make both testosterone and sperm. Enclomiphene is one of the two isomers that make up clomiphene. It is not approved by the FDA for any indication and is generally available in the United States through compounding pharmacies. Evidence for it is promising but much smaller than for testosterone itself, so it belongs in a careful conversation rather than a default prescription.
Monitoring is part of the treatment
Any man on testosterone therapy needs follow-up. Guidelines recommend checking testosterone levels to make sure they land in the target range, monitoring hematocrit because testosterone can thicken the blood, and following prostate-specific antigen in age-appropriate men. Blood pressure deserves attention too, especially with some oral formulations.
What TRAVERSE did not answer is just as important as what it did. The trial enrolled men with low testosterone and symptoms, and the average man stayed on treatment for under two years. It says little about younger men without a clear deficiency, about doses pushed above the normal range, or about decades of use. Men in those groups are outside the evidence, and an honest prescriber will say so.
