AndroGel Safety Signals and FDA Actions

How AndroGel Works: Mechanism Before Safety Context

Testosterone gel delivers exogenous testosterone through the skin into the dermal vasculature, restoring serum concentrations in men whose hypothalamic-pituitary-gonadal axis fails to maintain adequate production. Understanding the pharmacology matters because several safety signals trace directly to supratherapeutic levels or off-label dosing.

After application to intact, clean, dry skin on the shoulders or upper arms, testosterone partitions into the stratum corneum and forms a depot. Absorption into the bloodstream occurs over roughly 24 hours, producing relatively stable serum testosterone when applied at the same time each day 1. The T-Trials confirmed that daily application of 1% testosterone gel raised serum testosterone into the mid-normal range (400 to 700 ng/dL) in men aged 65 and older with levels below 275 ng/dL at baseline.

Once in circulation, testosterone acts on androgen receptors throughout the body. It also undergoes 5-alpha reduction to dihydrotestosterone (DHT) in peripheral tissues and aromatization to estradiol via the aromatase enzyme. This aromatization pathway is relevant to the cardiovascular safety debate: estradiol influences vascular endothelial function, lipid metabolism, and erythropoiesis. Testosterone also stimulates erythropoietin production, which increases red blood cell mass. A hematocrit above 54% raises blood viscosity and thromboembolic risk, and this effect became one of the earliest safety signals flagged in clinical practice 2.

The 2010 TOM Trial: The First Major Red Flag

The Testosterone in Older Men with Mobility Limitations (TOM) trial was the first randomized controlled study to trigger widespread concern about testosterone therapy and cardiovascular events. The trial enrolled 209 men aged 65 and older with mobility limitations and low testosterone.

The Data Safety Monitoring Board stopped the TOM trial early. Among 106 men randomized to testosterone gel, 23 experienced cardiovascular adverse events compared with 5 of 103 men in the placebo group 3. The event rate was striking, though the absolute numbers were small and the population was uniquely frail. Many participants had pre-existing hypertension, diabetes, obesity, or prior cardiovascular disease.

Critics noted the trial was not designed or powered to assess cardiovascular safety. Testosterone doses were titrated aggressively, with some men reaching supratherapeutic levels above 1,000 ng/dL. The Endocrine Society's 2018 clinical practice guideline acknowledged the TOM signal but stated it could not be generalized to younger or healthier hypogonadal men 4. Still, the TOM findings set the stage for the FDA's subsequent review.

2013 to 2014: Observational Studies and the FDA Safety Review

Two large observational studies published in 2013 and 2014 amplified the cardiovascular concern. Vigen et al. analyzed VA medical records of 8,709 men who underwent coronary angiography and had low testosterone. Among those who filled a testosterone prescription, the composite rate of death, myocardial infarction, and stroke was 25.7% compared with 19.9% in the untreated group (adjusted HR 1.29, 95% CI 1.04 to 1.58) 5. That study drew criticism for methodological problems. JAMA published two corrections after independent analysts identified coding errors that, when fixed, attenuated the hazard ratio. The original finding remained directionally concerning but less definitive.

Finkle et al. used an insurance claims database of 55,593 men prescribed testosterone and found a twofold increase in myocardial infarction rates in the 90 days after the first prescription among men aged 65 and older 6. Younger men with pre-existing heart disease also showed elevated risk.

In January 2014, the FDA announced a formal safety review of testosterone products, including AndroGel 7. The agency stated: "We are investigating the risk of stroke, heart attack, and death in men taking FDA-approved testosterone products."

The 2015 FDA Label Overhaul

On March 3, 2015, the FDA issued a safety communication requiring all testosterone product manufacturers to update their labeling. This was the single most consequential regulatory action affecting AndroGel.

Three changes defined the 2015 overhaul. First, the FDA restricted the approved indication. Testosterone products had previously been indicated broadly for "conditions associated with a deficiency or absence of endogenous testosterone." The 2015 revision narrowed this to men with documented low testosterone caused by specific medical conditions: disorders of the testes, pituitary, or hypothalamus 8. Age-related testosterone decline alone no longer qualified.

Second, the FDA mandated a new warning about possible increased cardiovascular risk. The label language reads: "Long-term clinical safety trials have not been conducted to assess the cardiovascular outcomes of testosterone replacement therapy in men. To date, epidemiologic studies and randomized controlled trials have been inconclusive for determining the risk of major adverse cardiovascular events."

Third, the FDA added a warning for venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, based on postmarketing reports. The Endocrine Society's guideline recommended checking hematocrit at baseline, at 3 to 6 months, and then annually, with dose reduction or phlebotomy if hematocrit exceeds 54% 4.

The 2018 Abuse and Dependence Warning

In October 2016 and finalized by 2018, the FDA required another label update for all testosterone products: a warning about abuse and dependence potential. The agency reviewed 19 years of adverse event reports and published literature documenting testosterone misuse at doses far exceeding therapeutic ranges 9.

The warning noted that testosterone abuse can cause serious heart and liver problems, including heart attacks and strokes. Reported misuse included bodybuilders and athletes using supratherapeutic doses, sometimes combining testosterone with other anabolic steroids. Withdrawal symptoms after discontinuation of high-dose use included depression, fatigue, irritability, and loss of appetite.

This action reinforced testosterone's Schedule III status under the Controlled Substances Act. Prescribers must now use DEA-compliant prescribing procedures, and pharmacies track testosterone dispensing like other controlled substances. For clinically hypogonadal men prescribed appropriate doses, the abuse warning is less directly relevant but does affect how insurance companies handle prior authorizations and refill policies.

The TRAVERSE Trial: A Decade of Uncertainty Addressed

The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial, published in June 2023 in the New England Journal of Medicine, was the first adequately powered randomized controlled trial designed specifically to evaluate cardiovascular safety of testosterone replacement 10.

TRAVERSE enrolled 5,246 men aged 45 to 80 with hypogonadism (two fasting testosterone levels below 300 ng/dL) and either pre-existing cardiovascular disease or high cardiovascular risk. Participants were randomized to daily transdermal testosterone gel (1.62%) or placebo and followed for a mean of 33 months. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE).

The results: MACE occurred in 7.0% of the testosterone group and 7.3% of the placebo group (HR 0.96, 95% CI 0.78 to 1.17), meeting the pre-specified non-inferiority margin of 1.5 10. Testosterone did not increase the rate of major cardiovascular events compared with placebo in this high-risk population.

Dr. Steven Nissen, the trial's lead investigator and chair of cardiovascular medicine at the Cleveland Clinic, stated: "These results should be reassuring. The data show that in men with hypogonadism who have or are at high risk for cardiovascular disease, testosterone replacement therapy can be administered without increasing the risk of major adverse cardiovascular events."

TRAVERSE did identify two secondary safety signals. Atrial fibrillation occurred more frequently in the testosterone group (3.5% vs. 2.4%). Acute kidney injury was also more common (2.3% vs. 1.5%). Both findings require further investigation, and neither was part of the pre-specified primary analysis.

The Endocrine Society responded to TRAVERSE by noting it provides "the first large-scale evidence that testosterone therapy does not increase short-to-intermediate-term cardiovascular risk in hypogonadal men with or at high risk for cardiovascular disease" 4.

Polycythemia and Hematocrit: The Persistent Monitoring Requirement

Among all safety signals associated with AndroGel, erythrocytosis (hematocrit above 54%) is the most consistently observed in clinical practice and the most actionable. Testosterone stimulates erythropoietin release from the kidneys and acts directly on bone marrow erythroid progenitors.

In the T-Trials, hematocrit increases were dose-dependent. Men receiving testosterone gel experienced a mean hematocrit increase of approximately 3 percentage points over 12 months 1. Among men who started with a hematocrit of 48% or higher, the risk of exceeding 54% was clinically meaningful.

The Endocrine Society guideline is explicit: "We recommend measuring hematocrit at baseline, at 3 to 6 months after starting treatment, and then annually. If hematocrit rises above 54%, stop testosterone therapy until hematocrit decreases to a safe level, evaluate the patient for hypoxia and sleep apnea, and reinitiate therapy at a reduced dose" 4.

This threshold is not arbitrary. A hematocrit above 54% increases whole-blood viscosity and raises the risk of stroke and venous thromboembolism. Transdermal testosterone produces smaller hematocrit increases than intramuscular injections because it avoids the supraphysiologic peaks that follow each injection. This pharmacokinetic advantage is one reason guidelines and the FDA label recommend stable delivery methods.

Secondary Transfer Risk: A Unique Topical Concern

AndroGel carries a risk that injectable testosterone does not: secondary exposure through skin-to-skin contact. The FDA mandated a boxed warning (the most serious type) on all topical testosterone products after reports of virilization in children exposed to testosterone gel from contact with treated adults 11.

Reported cases included prepubertal children who developed enlarged genitalia, premature pubic hair, increased libido, and aggressive behavior after repeated contact with the application site. Some cases involved women who developed acne, hirsutism, or voice deepening.

The boxed warning instructs patients to wash hands thoroughly after application, cover the treated area with clothing after the gel dries, and wash the application site before anticipated skin-to-skin contact with another person. These precautions are effective when followed but require consistent adherence.

Prostate Safety: What Monitoring Is Required

The relationship between testosterone and prostate cancer has been debated for decades. The FDA label for AndroGel states that testosterone is contraindicated in men with known or suspected prostate cancer. Current evidence, however, does not support the older theory that testosterone replacement causes de novo prostate malignancy.

TRAVERSE included prostate safety as a secondary endpoint. Over the mean 33-month follow-up, prostate cancer was diagnosed in 0.19% of men in the testosterone group and 0.12% in the placebo group, a difference that was not statistically significant 10. PSA levels rose modestly with testosterone therapy (mean increase approximately 0.4 ng/mL), consistent with prior studies.

The Endocrine Society guideline recommends measuring PSA at baseline, at 3 to 6 months, and then per age-appropriate screening guidelines. A PSA increase greater than 1.4 ng/mL within 12 months of starting testosterone, or an absolute value above 4.0 ng/mL, should prompt urological referral 4.

Current FDA Labeling Status and Clinical Implications

As of 2026, AndroGel labeling reflects the cumulative weight of all prior regulatory actions. The label includes a boxed warning for secondary transfer, warnings for cardiovascular risk, VTE, polycythemia, abuse and dependence, and liver toxicity (primarily relevant to oral methyltestosterone, retained as a class warning).

Prescribers must confirm hypogonadism with two morning serum testosterone levels below the laboratory's lower limit of normal, along with signs and symptoms consistent with deficiency. The FDA does not require a specific threshold, but the Endocrine Society uses 264 ng/dL (measured by liquid chromatography-tandem mass spectrometry) as its diagnostic cutoff 4.

The standard monitoring protocol requires hematocrit and testosterone levels at 3 to 6 months, PSA per guidelines, and a clinical assessment for edema, sleep apnea symptoms, and mood changes. Men with hematocrit above 50% at baseline deserve closer surveillance. Those with untreated severe sleep apnea, uncontrolled heart failure, or a recent (within 6 months) cardiovascular event should not start testosterone therapy until these conditions are stabilized.