Testosterone Cypionate Side Effects: Rare but Serious Adverse Events

What counts as rare but serious with this drug?

The cypionate label's own adverse reactions section lists myocardial infarction, stroke, venous thromboembolism, polycythemia, cholestatic jaundice and anaphylactoid reactions alongside acne and injection site pain, and introduces the list as reactions that have occurred with some androgens [1]. The label gives no frequencies for them [1].

Testosterone is a Schedule III controlled substance [1]. The label warns that abuse, typically at doses above those recommended and combined with other anabolic steroids, can cause serious cardiovascular and psychiatric reactions, and that testosterone levels may be normal or low in men abusing synthetic derivatives [1].

Does testosterone cypionate cause heart attacks and strokes?

The Depo-Testosterone label calls the evidence unsettled. It states that long-term clinical safety trials have not been conducted to assess cardiovascular outcomes, that epidemiologic studies and randomized controlled trials have been inconclusive for major adverse cardiovascular events (MACE), and that some studies, but not all, have reported an increased risk of MACE [1]. In February 2025, FDA recommended adding TRAVERSE results to testosterone labels. The current Depo-Testosterone label still describes cardiovascular study findings as inconclusive [2][1].

TRAVERSE enrolled 5,246 men aged 45 to 80 with hypogonadism and existing or high risk of cardiovascular disease and assigned them daily 1.62% testosterone gel or placebo gel [3]. The primary composite of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke occurred in 7.0% (182 men) on testosterone and 7.3% (190 men) on placebo, hazard ratio 0.96 (95% CI 0.78 to 1.17), which met noninferiority; mean treatment lasted 21.7 months and mean follow-up 33 months [3]. No outcome trial of this size has tested an injectable testosterone product [3].

In TRAVERSE, some adverse events occurred more often with testosterone gel than with placebo: nonfatal arrhythmias needing intervention 5.2% vs 3.3%, atrial fibrillation 3.5% vs 2.4%, acute kidney injury 2.3% vs 1.5% and bone fracture 3.5% vs 2.5% [3].

Blood pressure: the warning that applies to every product

FDA says its ambulatory blood pressure studies confirmed an increase in blood pressure with all testosterone products, class-wide [2]. The cypionate label warns that testosterone can increase blood pressure, which can increase cardiovascular risk over time; it advises measuring blood pressure periodically, especially in men with hypertension, and states the products are not recommended in patients with uncontrolled hypertension [1].

Erythrocytosis and polycythemia

Erythrocytosis is well established with testosterone therapy, and short-acting injectable formulations have the highest incidence [6]. The label explains that androgens stimulate red blood cell production by enhancing production of erythropoietic stimulation factor, and lists polycythemia among adverse reactions [1].

A 2022 network meta-analysis of 29 placebo-controlled randomized trials (3,393 men) found intramuscular testosterone enanthate or cypionate raised mean hematocrit by 4.0 percentage points versus placebo (95% CI 2.9 to 5.1), compared with 3.0 for gel and 1.4 for patch [4]. A retrospective comparison found more erythrocytosis among men using injectable testosterone than among men using gels or pellets. The groups differed in age and starting hematocrit, so the comparison cannot establish that formulation alone caused the difference [7].

One review put the risk of hematocrit above 0.52 at 315% higher than controls across formulations, with injectables highest, and concluded that the link between erythrocytosis and thromboembolic events is inconclusive [8].

For monitoring, the Depo-Testosterone label calls for periodic hemoglobin and hematocrit checks during long-term use [1].

Venous thromboembolism

The label describes postmarketing reports of deep vein thrombosis and pulmonary embolism in patients using testosterone products such as testosterone cypionate, and says to evaluate leg pain, swelling, warmth or redness for DVT and acute shortness of breath for PE, and to discontinue treatment if an event is suspected [1].

A UK population-based case-control study looked at timing: 19,215 men with confirmed venous thromboembolism and 909,530 age-matched controls drawn from 370 general practices between 2001 and 2013 [5]. The adjusted rate ratio was 1.25 (95% CI 0.94 to 1.66) for current versus no testosterone treatment; within the first six months of treatment it was 1.63 (1.12 to 2.37), and after six months it was 1.00 (0.68 to 1.47) [5]. The first-six-month ratio corresponded to 10.0 additional venous thromboembolisms (95% CI 1.9 to 21.6) above a base rate of 15.8 per 10,000 person-years [5].

In TRAVERSE, venous thromboembolism occurred in 1.7% of men on testosterone gel versus 1.2% on placebo, with deep vein thrombosis 0.6% vs 0.5% and pulmonary embolism 0.9% vs 0.5% [3].

The label's adverse reaction list also notes suppression of clotting factors II, V, VII and X, and bleeding in patients on concomitant anticoagulant therapy [1].

Liver

The label says prolonged use of high doses of androgens, principally the 17-alpha-alkylated drugs, has been associated with hepatic adenomas, hepatocellular carcinoma and peliosis hepatis, all potentially life-threatening [1]. The cypionate label's adverse reactions list includes nausea, cholestatic jaundice, alterations in liver function tests, and rarely hepatocellular neoplasms and peliosis hepatis [1]. Serious hepatic disease is a contraindication to Depo-Testosterone [1].

Mood, aggression and sleep apnea

In a 6-week randomized, placebo-controlled crossover trial of 56 men aged 20 to 50, testosterone cypionate in doses rising to 600 mg per week increased manic scores and aggressive responses; manic scores on the Young Mania Rating Scale rose significantly (P=.002) and aggressive responses on a computer provocation test increased (P=.03) [9]. Of the 50 men who received 600 mg per week, 42 (84%) had minimal psychiatric effects, 6 (12%) became mildly hypomanic and 2 (4%) markedly hypomanic [9].

The label lists anxiety, depression and increased or decreased libido among adverse reactions, and its abuse section describes mania, paranoia, psychosis, hostility and aggression in people taking anabolic androgenic steroids at doses above those prescribed [1].

Sleep apnea is a separate concern. The Endocrine Society guideline recommends against starting testosterone in men with untreated severe sleep apnea [10]. In a randomized, double-blind crossover trial of 17 healthy men over 60, three weekly high-dose intramuscular injections of testosterone esters (500 mg, then 250 mg, then 250 mg) increased the total and non-REM respiratory disturbance indices by about seven events per hour and shortened total sleep time by about an hour (P<0.05) [11].

Prostate effects

Two prostate statements appear on the cypionate label: geriatric patients treated with androgens may be at increased risk of prostatic hypertrophy and prostatic carcinoma, although the label says conclusive evidence is lacking; and known or suspected prostate carcinoma is a contraindication [1]. FDA said in June 2026 that it had requested revisions to prostate cancer and benign prostatic hyperplasia safety information on testosterone labels [12].

A 2026 phase 2 trial randomized 136 men with undetectable PSA for at least two years after radical prostatectomy for low-grade cancer to testosterone cypionate 100 mg intramuscularly weekly or placebo for 12 weeks; no participant in either group had a biochemical recurrence, defined as PSA of 0.2 ng/mL or higher [13]. That is a 12-week window in carefully selected men, not a long-term answer. The Endocrine Society guideline recommends against starting testosterone in men with breast or prostate cancer [10].

Suppressed sperm production and fertility

Exogenous testosterone shuts off the pituitary signals that drive sperm production: it inhibits luteinizing hormone and, at large doses, follicle stimulating hormone [1]. The Depo-Testosterone label lists oligospermia as an adverse reaction at high dosages [1].

Recovery data come mostly from healthy men on hormonal contraception rather than from men on replacement. An integrated analysis of 30 studies in 1,549 healthy men using hormonal contraception found the median time for sperm concentration to return to 20 million/mL was 3.4 months. Those men were healthy volunteers, not men on replacement therapy [14]. Among 66 men treated for infertility after testosterone use, 70% reached a total motile count above 5 million within 12 months of stopping testosterone and starting high-dose hCG plus a selective estrogen receptor modulator; 64.8% of the azoospermic men did versus 91.7% of the cryptozoospermic men, and older age and longer testosterone use predicted slower recovery [15]. A case series of 49 men with azoospermia or severe oligospermia on testosterone reported return of spermatogenesis or improved counts in 47 (95.9%) on hCG-based combination therapy, after an average of 4.6 months [16].

The Endocrine Society guideline recommends against starting testosterone therapy in men planning fertility in the near term [10].

Allergic reactions and injection sites

The label lists hypersensitivity including skin manifestations and anaphylactoid reactions, plus pain and inflammation at the intramuscular injection site [1]. Known hypersensitivity to the drug is a contraindication [1]. Depo-Testosterone contains cottonseed oil, benzyl benzoate and benzyl alcohol as a preservative [1].

Interactions

The label notes that androgens may increase sensitivity to oral anticoagulants, so the anticoagulant dose may need to be reduced to maintain therapeutic hypoprothrombinemia [1]. In diabetes, the metabolic effects of androgens may lower blood glucose and insulin requirements [1]. With corticosteroids or ACTH, androgens may increase fluid retention, which is a particular concern in people with heart, kidney or liver disease [1].