Testosterone Enanthate Side Effects: Rare but Serious Adverse Events

Does the enanthate label carry a boxed warning?

No. The intramuscular testosterone enanthate label has no boxed warning [1]. In February 2025, FDA told sponsors of all testosterone products to remove the Boxed Warning language about increased cardiovascular risk, add the TRAVERSE results to every label, and add a blood pressure warning where one was missing [2]. The serious events below sit in the Warnings and Precautions and Adverse Reactions sections instead [1].

Erythrocytosis and polycythemia

A 2022 network meta-analysis pooled 29 placebo-controlled randomized trials covering 3,393 men. Intramuscular testosterone enanthate or cypionate raised mean hematocrit by 4.0 percentage points over placebo (95% CI 2.9 to 5.1) [3]. For comparison, gel raised it 3.0 points (95% CI 1.8 to 4.3) and patch 1.4 points (95% CI 0.2 to 2.6) [3]. Intramuscular enanthate or cypionate rose significantly more than patch; the other head-to-head comparisons were not significantly different [3].

A retrospective single-center review of 178 hypogonadal men compared gels, injections and pellets over three years and found erythrocytosis more often among men using injections than among men using gels or pellets; the injection group was younger and started with a higher hematocrit, and the study was not randomized [8].

Two reviews of the same literature agree on the pattern: all formulations raise hemoglobin and hematocrit and short-acting injectables do it most [9][10]. One of them calculated that men on testosterone replacement had a 315% greater risk of erythrocytosis, defined as hematocrit above 0.52, than controls, while the link between erythrocytosis and clotting events remained inconclusive [10]. The other noted the same uncertainty about thromboembolic risk despite the well-established rise in red cell mass [9].

The 2018 Endocrine Society guideline recommends checking hematocrit during the first year of treatment and recommends against starting testosterone in a man who already has an elevated hematocrit [11].

Cardiovascular risk: what TRAVERSE did and did not test

TRAVERSE enrolled 5,246 men aged 45 to 80 with symptoms of hypogonadism, two fasting testosterone levels below 300 ng/dL, and existing or high risk of cardiovascular disease [4]. They were randomized to daily transdermal 1.62% testosterone gel, dose-adjusted to keep levels between 350 and 750 ng/dL, or placebo gel [4]. Mean treatment lasted 21.7 months and mean follow-up 33 months [4].

The primary endpoint was cardiovascular death, nonfatal heart attack or nonfatal stroke. It occurred in 182 men on testosterone (7.0%) and 190 on placebo (7.3%), hazard ratio 0.96 (95% CI 0.78 to 1.17), meeting noninferiority with the upper confidence limit below the prespecified 1.5 [4].

TRAVERSE tested testosterone gel, not injections [4].

The enanthate label has not been rewritten around TRAVERSE. It still states that long-term clinical safety trials have not been conducted, that epidemiologic studies and randomized trials have been inconclusive for major adverse cardiovascular events, and that some studies, but not all, have reported an increased risk of heart attack, stroke and cardiovascular death [1].

On blood pressure, FDA said ambulatory monitoring studies confirmed an increase with all testosterone products [2]. The enanthate label says testosterone can raise blood pressure, which can raise cardiovascular risk over time, that blood pressure should be monitored periodically, and that the product is not recommended in men with uncontrolled hypertension [1].

Venous thromboembolism

The enanthate label reports postmarketing cases of deep vein thrombosis and pulmonary embolism in patients using testosterone products such as testosterone enanthate injection, and instructs that a suspected clot be evaluated and the drug discontinued while workup proceeds [1].

A UK population-based case-control study compared 19,215 men with confirmed venous thromboembolism against 909,530 age-matched controls [5]. Current testosterone use gave a rate ratio of 1.25 (95% CI 0.94 to 1.66); in the first six months of treatment the rate ratio was 1.63 (95% CI 1.12 to 2.37), about 10 additional events per 10,000 person-years above a base rate of 15.8, and after six months it was 1.00 (95% CI 0.68 to 1.47) [5].

Liver effects

The enanthate label states that prolonged use of high doses of androgens has been associated with peliosis hepatis, blood-filled cysts in the liver that can be life-threatening or fatal, and with hepatic neoplasms including hepatocellular carcinoma [1]. It also instructs that if cholestatic hepatitis with jaundice appears or liver function tests become abnormal, the androgen be discontinued and the cause determined, noting that drug-induced jaundice is reversible when the drug is stopped [1]. Cholestatic jaundice and, rarely, hepatocellular neoplasms and peliosis hepatis appear again in the label's adverse reactions list [1].

Sleep apnea

A randomized, double-blind, placebo-controlled crossover study gave 17 healthy men over age 60 three weekly high-dose injections of testosterone esters (500 mg, then 250 mg, then 250 mg) or placebo, with an 8-week washout between periods [12]. Testosterone shortened total sleep by about an hour, lengthened the time spent hypoxemic by about 5 minutes a night, and increased the respiratory disturbance index by about seven events per hour (all P<0.05) [12]. Upper airway dimensions did not change [12].

The 2018 Endocrine Society guideline recommends against starting testosterone therapy in men with untreated severe obstructive sleep apnea [11].

Fertility and sperm production

Exogenous testosterone suppresses pituitary signaling, and with it sperm production; the label lists oligospermia at high dosages [1].

Direct enanthate data come from WHO multicentre contraceptive trials. In the 1990 trial, 271 healthy fertile men received 200 mg testosterone enanthate weekly by intramuscular injection, and 157 became azoospermic on three consecutive semen samples, a cumulative rate of 65% at 6 months [6]. After injections stopped, the estimated median time from azoospermia back to a sperm concentration of at least 20 million/mL was 3.7 months [6].

A pooled analysis of 30 hormonal male contraception studies, 1,549 healthy men in total, found a median of 3.4 months to reach 20 million/mL after stopping; recovery time varied, and was faster with shorter-acting testosterone preparations and shorter treatment courses [13]. These were eugonadal volunteers on experimental contraception, not men being treated for hypogonadism [13].

Recovery is not automatic. In a series of 66 men treated with high-dose hCG plus a selective estrogen receptor modulator after testosterone-associated infertility, 46 (70%) reached a total motile count above 5 million within 12 months; 64.8% of azoospermic men did, against 91.7% of cryptozoospermic men, and older age and longer testosterone use predicted slower recovery [14]. The Endocrine Society guideline recommends against starting testosterone in men who plan fertility in the near term [11].

Prostate effects

Testosterone enanthate is contraindicated in men with known or suspected prostate carcinoma [1]. The label also notes that older men treated with androgens may be at increased risk for prostatic hypertrophy and prostatic carcinoma [1]. In June 2026, FDA asked sponsors to revise prostate cancer and benign prostatic hyperplasia safety information in testosterone labeling [15]. The guideline recommends assessing prostate cancer risk during the first year of treatment [11].

Psychiatric effects and abuse

At therapeutic doses the enanthate label lists anxiety, depression, libido changes, headache and paresthesia among adverse reactions, plus excessive frequency and duration of penile erections [1].

The label's abuse section is where the severe psychiatric picture sits: major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility and aggression have been reported in people abusing anabolic androgenic steroids, alongside cardiac arrest, heart attack, hypertrophic cardiomyopathy, heart failure, stroke and hepatotoxicity [1].

A randomized, placebo-controlled crossover trial gave 56 men aged 20 to 50 testosterone cypionate for 6 weeks at doses rising to 600 mg weekly [16]. Manic symptom scores rose significantly (P=0.002 on the Young Mania Rating Scale) and aggressive responses increased [16]. The reaction was uneven: of 50 men on 600 mg weekly, 42 (84%) had minimal psychiatric effects, 6 (12%) became mildly hypomanic and 2 (4%) markedly hypomanic [16].

Other labeled serious effects

The label warns that sodium and water retention can cause edema with or without congestive heart failure in men with existing heart, kidney or liver disease, and that diuretic therapy may be needed in addition to stopping the drug [1]. It warns that androgen therapy can cause hypercalcemia by stimulating bone breakdown in immobilized patients and in patients with breast cancer, and that hypercalcemia in cancer may signal progression of bone metastasis [1]. Gynecomastia frequently develops and occasionally persists on treatment [1]; estrogens stimulate breast tissue growth while androgens inhibit it, and most gynecomastia comes from deficient androgen action or excess estrogen action [17].

Drug interactions

The enanthate label flags four interactions [1]. Oral anticoagulants: C-17 substituted testosterone derivatives such as methandrostenolone have been reported to decrease the anticoagulant requirement, and patients on oral anticoagulants need close monitoring especially when androgens are started or stopped [1]. Antidiabetic drugs and insulin: androgens may lower blood glucose and insulin requirements [1]. ACTH and corticosteroids: an enhanced tendency toward edema, requiring caution in liver or heart disease [1]. Oxyphenbutazone: serum levels may rise [1].