Testosterone Enanthate FAERS Safety Signals: What Post-Market Surveillance Reveals

What Is FAERS and How Does It Apply to Testosterone Enanthate?

The FDA Adverse Event Reporting System (FAERS) is a database that collects voluntary reports of adverse drug reactions from healthcare professionals, patients, and manufacturers. It serves as the primary post-market surveillance tool the FDA uses to detect safety signals once a drug reaches the general population 1.

Testosterone enanthate has been on the U.S. market since 1953. That long exposure window means FAERS contains decades of accumulated reports. The system cannot prove causation. It identifies disproportionality signals, cases where a drug-event pair appears more often than expected against the background reporting rate for similar medications 2.

For testosterone enanthate specifically, the highest-volume FAERS categories include cardiovascular events (myocardial infarction, stroke, sudden cardiac death), hematologic abnormalities (polycythemia, erythrocytosis), venous thromboembolic events (deep vein thrombosis, pulmonary embolism), and psychiatric effects. These signals drove two separate FDA regulatory actions: a 2014 addition of venous thromboembolism to the label and a 2015 cardiovascular risk warning applied to the entire testosterone product class 3.

FDA Approval Timeline and Label Evolution

Testosterone enanthate received FDA approval in 1953 under the brand name Delatestryl, manufactured by Endo Pharmaceuticals. The original indication was replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone: primary hypogonadism and hypogonadotropic hypogonadism 4.

The label remained relatively stable for decades. That changed after 2010. Three events forced the FDA to act.

First, the Testosterone in Older Men with Mobility Limitations (TOM) trial was stopped early in 2010 after an excess of cardiovascular adverse events in the testosterone gel arm (23 events in 106 testosterone-treated men vs. 5 in 103 placebo-treated men) 5. Second, a 2013 retrospective cohort study by Vigen et al. published in JAMA reported a 29% increased absolute risk of all-cause mortality, myocardial infarction, or stroke among male veterans prescribed testosterone who had pre-existing coronary artery disease (event rate 25.7% in the testosterone group vs. 19.9% in the non-prescribed group) 6. Third, Finkle et al. published a 2014 analysis of insurance claims data showing a twofold increase in myocardial infarction rates in the 90 days following a testosterone prescription among men aged 65 and older 7.

These three data points, combined with FAERS signal detection, prompted the FDA's 2015 Safety Communication requiring all testosterone product labels to include warnings about possible increased cardiovascular risk.

Cardiovascular Safety Signals: What FAERS Data Show

Cardiovascular adverse events represent the most scrutinized category in testosterone FAERS reporting. The signal includes myocardial infarction, cerebrovascular accident, and sudden cardiac death. The FDA's own analysis of FAERS, disclosed in its 2015 advisory committee briefing document, identified a disproportionality signal for these events across all testosterone formulations.

The concern triggered the largest cardiovascular outcomes trial (CVOT) ever conducted for testosterone therapy. The TRAVERSE trial enrolled 5,246 men aged 45 to 80 with hypogonadism and pre-existing cardiovascular disease or high cardiovascular risk. Over a mean follow-up of 33 months, the primary composite endpoint of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) occurred in 7.0% of the testosterone group versus 7.3% of the placebo group (hazard ratio 0.96; 95% CI 0.78 to 1.17) 8. This met the pre-specified non-inferiority margin.

Dr. Shalender Bhasin, principal investigator of the TRAVERSE trial and professor at Harvard Medical School, stated: "These findings provide reassurance that testosterone replacement therapy in men with hypogonadism who have cardiovascular risk factors does not increase the incidence of major adverse cardiovascular events over the near to intermediate term" 8.

The TRAVERSE data did not lead the FDA to remove the cardiovascular warning from testosterone labels. The label language remains as of 2026. The reasoning: TRAVERSE followed patients for approximately 3 years, and longer-term cardiovascular effects remain uncharacterized.

Polycythemia and Erythrocytosis: The Most Pharmacologically Predictable Signal

Testosterone stimulates erythropoiesis through direct effects on erythroid progenitor cells and by suppressing hepcidin. This is not an unexpected adverse event. It is a dose-dependent pharmacologic effect. But when hematocrit exceeds 54%, the risk of hyperviscosity-related events (stroke, venous thromboembolism, myocardial infarction) rises.

FAERS reports for testosterone-associated polycythemia span all formulations, but injectable esters like testosterone enanthate generate higher peak serum levels than gels or patches. That pharmacokinetic profile produces a higher rate of erythrocytosis. Published clinical data show hematocrit exceeding 54% in roughly 5 to 14% of men receiving intramuscular testosterone, depending on dose and injection frequency 9.

The Endocrine Society's 2018 Clinical Practice Guideline recommends measuring hematocrit at baseline, at 3 months, at 6 months, and then annually after initiating testosterone therapy. The guideline specifies: "If hematocrit rises above 54%, stop testosterone therapy until hematocrit decreases to a safe level; evaluate the patient for hypoxia and sleep apnea; reinitiate therapy with a reduced dose" 2.

Subcutaneous administration and lower, more frequent dosing (e.g., 50 to 80 mg every 3.5 days rather than 200 mg every 14 days) can blunt the supraphysiologic peaks that drive erythrocytosis. This dosing strategy is not yet reflected in the FDA-approved label but has gained wide adoption in clinical practice based on pharmacokinetic modeling 10.

Venous Thromboembolism: The 2014 Label Addition

In June 2014, the FDA required all testosterone product labels to include venous thromboembolism (VTE), specifically deep vein thrombosis and pulmonary embolism, in the Warnings and Precautions section. This change preceded the broader 2015 cardiovascular warning by roughly one year 3.

The VTE signal emerged from both FAERS case reports and published epidemiologic data. A nested case-control study by Martinez et al. using a UK primary care database found that current testosterone use was associated with a 63% increase in VTE risk (adjusted odds ratio 1.63; 95% CI 1.12 to 2.37) 11. Risk was highest in the first 6 months of therapy.

Polycythemia likely mediates part of this risk. Elevated hematocrit increases blood viscosity, predisposing to venous stasis and thrombosis. Some patients also carry undiagnosed thrombophilia (Factor V Leiden, prothrombin G20210A mutation) that becomes clinically apparent only after the added hematologic stress of exogenous testosterone.

Current label language instructs prescribers to consider VTE risk before initiating testosterone and to evaluate patients who develop signs or symptoms of DVT or PE during therapy. Routine thrombophilia screening before starting testosterone is not recommended by the Endocrine Society, though some clinicians order it in patients with a personal or family history of clotting events.

The T-Trials: Efficacy Context for the Safety Discussion

The Testosterone Trials (TTrials), published in the New England Journal of Medicine in 2016, enrolled 790 men aged 65 and older with serum testosterone below 275 ng/dL and symptoms of hypogonadism. Men were randomized to testosterone gel or placebo for 12 months 12.

The TTrials demonstrated modest improvements in sexual function, walking distance, and mood. Effect sizes were small. For sexual activity, the mean change from baseline was 0.58 (on a 12-point scale) greater with testosterone than with placebo. These results framed the regulatory question: are the benefits of testosterone therapy in older men with age-related decline sufficient to justify the safety signals seen in FAERS?

Dr. Peter Snyder, lead investigator of the TTrials and professor of medicine at the University of Pennsylvania, noted: "The effects of testosterone treatment on most outcomes were moderate and their clinical significance uncertain, supporting the need for larger, longer trials to determine whether benefits outweigh risks" 12.

This question remains open. The FDA has not expanded the approved indication for testosterone to include age-related decline alone, and the label continues to restrict the indication to documented hypogonadism caused by specific medical conditions.

Hepatic Adverse Event Reports

Oral 17-alpha-alkylated androgens (methyltestosterone, fluoxymesterone) carry well-documented hepatotoxicity risk, including peliosis hepatis and hepatocellular carcinoma. Injectable testosterone enanthate is not 17-alpha-alkylated and does not undergo first-pass hepatic metabolism in the same way. Its hepatotoxicity profile in FAERS is correspondingly much smaller.

A small number of FAERS reports describe elevated transaminases, cholestatic jaundice, or hepatic neoplasms in patients receiving injectable testosterone. Causality assessment in these cases is confounded by concurrent use of other medications (statins, NSAIDs, supplements) and pre-existing liver conditions (non-alcoholic fatty liver disease, alcohol use) 13.

The current testosterone enanthate label includes hepatic adverse reactions under the Warnings section, largely based on class labeling derived from the oral androgen experience rather than injectable-specific data.

Psychiatric and Behavioral Adverse Event Reports

FAERS contains reports of aggression, mood swings, depression, mania, and psychosis associated with testosterone products. Quantifying the true incidence is difficult because these reports rarely control for baseline psychiatric history, concurrent substance use, or supraphysiologic dosing.

The TRAVERSE trial included mood and depression assessments as secondary endpoints. Over 33 months, there was no significant difference in PHQ-9 depression scores between the testosterone and placebo groups 8. This provides prospective, controlled reassurance for physiologic-dose testosterone therapy but does not address misuse at supraphysiologic levels.

FAERS psychiatric reports likely over-represent cases involving supratherapeutic doses, bodybuilding use, or concurrent anabolic steroid stacking. These patterns of use are outside the approved indication and are not reflected in clinical trial safety data.

How Clinicians Should Interpret FAERS Data for Testosterone Enanthate

FAERS data are hypothesis-generating. They cannot establish causation, calculate incidence rates, or replace randomized controlled trials. The reporting rate for any adverse event is influenced by media coverage (cardiovascular reports spiked after the 2014 JAMA publication), litigation trends, and shifts in prescribing volume.

Between 2000 and 2013, testosterone prescribing in the United States increased more than threefold, from approximately 1.3 million prescriptions to over 4.4 million per year 14. A raw increase in FAERS reports over that period reflects expanded exposure, not necessarily increased per-patient risk.

The most responsible clinical approach integrates FAERS signals with prospective trial data (TTrials, TRAVERSE, TOM), guideline recommendations (Endocrine Society 2018), and individual patient risk factors. For testosterone enanthate specifically:

• Confirm the diagnosis of hypogonadism with two morning total testosterone levels below 300 ng/dL before initiating therapy 2.
• Assess baseline cardiovascular risk, hematocrit, and personal or family history of VTE.
• Monitor hematocrit at 3, 6, and 12 months, then annually. Withhold therapy if hematocrit exceeds 54%.
• Use the lowest effective dose. Consider more frequent, lower-volume injections to minimize peak-to-trough fluctuation.
• Re-evaluate the indication annually. Document ongoing symptomatic benefit and laboratory confirmation of therapeutic testosterone levels (400 to 700 ng/dL trough).

Current Label Warnings: A Summary of Required Language

The FDA-approved label for testosterone enanthate, as of 2026, includes the following boxed and bolded warnings in the Warnings and Precautions section:

Cardiovascular risk. Testosterone products may increase the risk of heart attack, stroke, and cardiovascular death. This warning was added in 2015 and applies to all testosterone products regardless of formulation.

Venous thromboembolism. Cases of DVT and PE have been reported in men using testosterone. This warning was added in 2014.

Polycythemia. Testosterone can increase red blood cell mass. Periodic hematocrit monitoring is recommended.

Secondary exposure. For topical products only (not applicable to injectable testosterone enanthate, but included in class labeling).

Abuse potential. Testosterone enanthate is a Schedule III controlled substance under the Controlled Substances Act.

The complete prescribing information is available through the Drugs@FDA database 4. Clinicians should review the full label, including contraindications (breast cancer, prostate cancer, pregnancy), before prescribing.

Prescribers treating men with confirmed hypogonadism should document hematocrit at baseline and at standardized intervals per the Endocrine Society protocol: 3 months, 6 months, 12 months, and annually thereafter 2.