AndroGel Side Effects: Rare but Serious Adverse Events

Which label does this page describe?

FDA identifies AndroGel 1.62% as the gel that was tested in TRAVERSE [1]. The detailed warning text below comes from the prescribing information for a generic testosterone gel 1% product (Actavis), which is a different product with its own dosing; that label states that dosing for testosterone gel 1% differs from testosterone gel 1.62% [3].

What does apply to every testosterone product is FDA's February 2025 class-wide labeling action: TRAVERSE results were added to all testosterone labels, language about increased cardiovascular risk was removed from the boxed warnings, and a blood pressure warning was added to products that lacked one [4].

Does the boxed warning concern children?

The testosterone gel 1% label carries a boxed warning titled 'Secondary exposure to testosterone': virilization has been reported in children who were secondarily exposed to testosterone gel [3]. Listed signs include enlargement of the penis or clitoris, development of pubic hair, increased erections and libido, aggressive behavior and advanced bone age [3].

In most reported cases those signs regressed once exposure was removed. In a few, enlarged genitalia did not fully return to age-appropriate size and bone age remained modestly greater than chronological age [3]. The label notes that the risk of transfer was increased in some cases by not following the precautions for appropriate use, and it says children and women should avoid contact with unwashed or unclothed application sites and that the gel should be discontinued until the cause of virilization has been identified [3]. Testosterone gel is contraindicated in pregnant women, because exposure of a female fetus to androgens can cause virilization [3].

Do testosterone gels increase heart attack and stroke risk?

TRAVERSE randomized 5,246 men aged 45 to 80 who had symptoms of hypogonadism, two fasting testosterone levels below 300 ng/dL, and existing cardiovascular disease or high cardiovascular risk to daily 1.62% testosterone gel, dose-adjusted to keep testosterone between 350 and 750 ng/dL, or to placebo gel [2]. Over a mean follow-up of 33 months, the primary composite of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke occurred in 7.0% of the testosterone group and 7.3% of the placebo group, hazard ratio 0.96 (95% CI 0.78 to 1.17), meeting the noninferiority margin [2]. FDA reviewed the results and said they did not demonstrate a new safety signal or trend in adverse cardiovascular outcomes [1].

Other events were more frequent on testosterone: nonfatal arrhythmias requiring intervention in 5.2% versus 3.3%, atrial fibrillation in 3.5% versus 2.4%, acute kidney injury in 2.3% versus 1.5%, and bone fracture in 3.5% versus 2.5% [2].

An older meta-analysis looked at a broader outcome than TRAVERSE's primary one. In 27 placebo-controlled trials (2,994 men, 180 cardiovascular-related events), the odds ratio for a cardiovascular-related event with testosterone therapy was 1.54 (95% CI 1.09 to 2.18), with 2.06 (1.34 to 3.17) in trials not funded by industry and 0.89 (0.50 to 1.60) in industry-funded trials [5].

The Endocrine Society's 2018 guideline recommends against starting testosterone therapy in men who have had a myocardial infarction or stroke within the previous 6 months [6].

How much does testosterone gel raise blood pressure?

In a four-month study of testosterone gel 1% using 24-hour ambulatory monitoring, 169 men with usable recordings at both baseline and week 16 had a mean rise of 1.9 mm Hg systolic and 1.3 mm Hg diastolic; men with hypertension who were taking antihypertensive medicines had a mean rise of 3.0/2.2 mm Hg [3]. In TRAVERSE, mean systolic pressure rose 1.0 mm Hg over 36 months on testosterone gel while falling 0.5 mm Hg on placebo, a between-group difference of 1.5 mm Hg [3]. The gel 1% label says to measure blood pressure periodically and that the product is not recommended for men with uncontrolled hypertension [3]. FDA's class-wide action confirmed blood pressure increases with all testosterone products and added a blood pressure warning where one was missing [4].

Can testosterone gel cause blood clots?

Venous thromboembolism, including deep vein thrombosis and pulmonary embolism, has been reported in patients using testosterone products [3]. TRAVERSE recorded VTE in 1.7% of men on testosterone gel versus 1.2% on placebo, with deep vein thrombosis in 0.6% versus 0.5% and pulmonary embolism in 0.9% versus 0.5% [3]. The label directs evaluation of pain, edema, warmth and erythema in the lower extremity for DVT and of acute shortness of breath for PE, and says treatment should be discontinued and workup started if a VTE is suspected [3].

How often does hematocrit rise?

Increases in hematocrit, reflecting an increase in red blood cell mass, may require lowering the dose or stopping testosterone [3]. The gel 1% label says to check hematocrit before starting, again 3 to 6 months later, and then annually, and to stop therapy if it becomes elevated until hematocrit falls to an acceptable concentration; it adds that increased red blood cell mass may raise the risk of thromboembolic events [3].

Pooled trial data show the size of the effect outside any single product. Across 19 randomized placebo-controlled trials in men aged 45 and older (651 on testosterone, 433 on placebo), the odds of a hematocrit above 50% were higher with testosterone (OR 3.69, 95% CI 1.82 to 7.51) [7]. A 2022 network meta-analysis of 29 placebo-controlled trials (3,393 men) found mean hematocrit increases of 3.0% with gel (95% CI 1.8 to 4.3) and 4.0% with intramuscular enanthate or cypionate (95% CI 2.9 to 5.1) [8]. A retrospective review of 178 men found erythrocytosis, defined there as hematocrit above 50%, in 12.8% of men on gels versus 66.7% on injections; the injection group was younger with a higher baseline hematocrit, and the study was not randomized [9].

Does testosterone gel affect the prostate?

The label warns that men with benign prostatic hyperplasia are at increased risk of worsening signs and symptoms, that men treated with androgens may be at increased risk of prostate cancer, and that patients should be evaluated for prostate cancer before and during treatment [3]. Testosterone gel is contraindicated in men with known or suspected prostate cancer, and in men with breast cancer [3].

In the 180-day controlled trial of the gel 1% product, mean PSA rose by 0.26 ng/mL [3]. Over a 3-year extension, 29 of 162 patients (18%) met a protocol criterion of a PSA more than twice baseline or any single value above 6 ng/mL; most met it by doubling, and in 22 of 25 the highest value stayed below 2 ng/mL [3]. Two prostate cancers were found on biopsy among men whose PSA exceeded 6 ng/mL [3].

Can testosterone gel make a man infertile?

Exogenous androgen administration may lead to azoospermia, and the gel label lists this under warnings and precautions [3]. The Endocrine Society guideline recommends against starting testosterone therapy in men who are planning fertility in the near term [6].

Two case series describe recovery with treatment, but they do not show what typically happens without it. In a series of 49 men with azoospermia or severe oligospermia while taking testosterone, human chorionic gonadotropin 3,000 units subcutaneously every other day combined with clomiphene, tamoxifen, anastrozole or recombinant FSH produced return of spermatogenesis or improved counts in 47 men (95.9%), at an average of 4.6 months [10]. A second series of 66 men given high-dose hCG plus a selective estrogen receptor modulator after stopping testosterone found that 46 (70%) reached a total motile count above 5 million within 12 months; older age and longer testosterone use predicted slower recovery [11].

What about sleep apnea, edema and misuse?

The gel 1% label says sleep apnea may occur in men with risk factors, and that edema, with or without congestive heart failure, may complicate treatment in men with pre-existing cardiac, renal or hepatic disease [3]. It also carries a warning on abuse: testosterone has been abused at doses above those recommended and with other anabolic androgenic steroids, and serious adverse reactions reported with anabolic androgenic steroid abuse include cardiac arrest, myocardial infarction, hypertrophic cardiomyopathy, heart failure, stroke, hepatotoxicity, major depression, mania and psychosis [3].

What monitoring does the label call for?

The testosterone gel 1% label calls for periodic checks of serum testosterone, PSA, hemoglobin, hematocrit, liver function tests and lipids, plus periodic blood pressure checks, with the hematocrit schedule of baseline, 3 to 6 months and then annually [3].