Testosterone Cypionate Side Effects: Severity Distribution by Patient Phenotype

Does testosterone cypionate carry a boxed warning?

No. The Depo-Testosterone label for intramuscular testosterone cypionate has no boxed warning [4].

FDA's history explains why the warning sections read the way they do. A January 2014 Drug Safety Communication warned of reported risks of stroke, heart attack and death in men taking FDA-approved testosterone products, and a March 2015 communication urged caution in men using testosterone for low testosterone due to aging [3]. In February 2025, FDA called for removal of boxed-warning language about adverse cardiovascular outcomes and for blood pressure warnings on products that lacked them [3].

The cypionate label remains more cautious than that headline suggests. It states that long-term clinical safety trials have not been conducted to assess cardiovascular outcomes, 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 [4].

What the cypionate label lists, without rates

The Depo-Testosterone label gives its adverse reactions as a plain list with no frequencies [4]. It names gynecomastia and excessive frequency and duration of penile erections, low sperm output at high doses, hirsutism, male-pattern baldness, seborrhea and acne, myocardial infarction and stroke, fluid retention, nausea, cholestatic jaundice and liver test changes, polycythemia, anxiety, depression, changes in libido, headache, venous thromboembolism, injection site pain and inflammation, and rare central serous chorioretinopathy [4].

The contraindications are written as patient types rather than reactions: known hypersensitivity, breast cancer in men, known or suspected prostate cancer, pregnancy, and serious cardiac, hepatic or renal disease [4]. The warnings add that edema, with or without congestive heart failure, can be a serious complication in men who already have heart, kidney or liver disease, and that geriatric patients may be at increased risk of prostatic hypertrophy and prostatic carcinoma, although conclusive evidence for that is lacking [4].

How much does hematocrit rise?

A 2022 network meta-analysis of 29 placebo-controlled randomized trials in 3,393 men found mean hematocrit rose 4.0 percentage points (95% CI 2.9 to 5.1) with intramuscular enanthate or cypionate, 4.3 points with oral testosterone undecanoate, 3.0 with gel, 1.6 with intramuscular undecanoate and 1.4 with patch. Intramuscular enanthate or cypionate rose significantly more than patch; the other pairings did not differ significantly [2].

A retrospective single-center review followed 178 hypogonadal men for three years: erythrocytosis, defined as a hematocrit above 50%, occurred in 66.7% of the men on injectable testosterone [5]. That study was not randomized, the injection group was younger (mean 42.5 years versus about 54 in the gel and pellet groups), and the injection group started with higher baseline free testosterone, hemoglobin and hematocrit [5].

Reviews point the same direction. Erythrocytosis risk with testosterone therapy is well established, and short-acting injectable formulations have the highest incidence [7]. Men on testosterone replacement had a 315% greater risk of a hematocrit above 0.52 than controls [8]. In a meta-analysis of 19 randomized placebo-controlled trials in men 45 and older, hematocrit above 50% was nearly four times as likely on testosterone as on placebo (odds ratio 3.69, 95% CI 1.82 to 7.51; 651 men on testosterone, 433 on placebo), and hematocrit increase was the most frequent adverse event [6].

What the label and guideline say about monitoring

The Depo-Testosterone label says to check hemoglobin and hematocrit periodically during long-term use, and notes that increased red blood cell mass may raise the risk of thromboembolic events [4]. The Endocrine Society guideline recommends monitoring symptoms, serum testosterone, hematocrit and prostate cancer risk during the first year of therapy, and recommends against starting testosterone in a man whose hematocrit is already elevated [1].

Blood pressure and cardiovascular events

FDA's postmarket ambulatory blood pressure studies confirmed a rise in blood pressure with all testosterone products, class-wide [3].

The Depo-Testosterone label warns that testosterone can increase blood pressure, which can increase cardiovascular risk over time, that blood pressure should be measured periodically in men using testosterone products, especially men with hypertension, and that the products are not recommended in men with uncontrolled hypertension [4].

The largest cardiovascular outcome trial in this field tested a different product and route. TRAVERSE randomized 5,246 men aged 45 to 80 with hypogonadism and existing or high risk of cardiovascular disease to daily 1.62% testosterone gel or placebo gel, with mean treatment of 21.7 months and mean follow-up of 33 months. The primary cardiovascular endpoint 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 noninferiority [9]. No outcome trial of that size exists for injectable testosterone [9].

Sleep apnea, prostate and older men

The Endocrine Society guideline recommends against starting testosterone in men with untreated severe sleep apnea [1]. In the meta-analysis of 19 placebo-controlled trials in men 45 and older, sleep apnea was not significantly more frequent with testosterone than with placebo [6].

In the meta-analysis of 19 trials in men 45 and older, the combined rate of prostate events was significantly higher on testosterone (odds ratio 1.78, 95% CI 1.07 to 2.95); prostate cancer, PSA above 4 ng/mL and prostate biopsies were each numerically higher but not individually significant [6]. Known or suspected prostate cancer is a contraindication on the Depo-Testosterone label [4]. In June 2026 FDA asked sponsors to revise prostate cancer and benign prostatic hyperplasia safety information [10].

The label says safety and efficacy in men with age-related, or late-onset, hypogonadism have not been established, and FDA says none of the approved products is approved for low testosterone without an associated medical condition [4][10]. FDA asked in June 2026 for that limitation to be removed, so the wording is in transition [10]. Depo-Testosterone is labeled for males only [4].

Younger men and fertility

Exogenous testosterone inhibits pituitary luteinizing hormone and, at large doses, follicle stimulating hormone, which suppresses sperm production, and the label lists low sperm output at high doses [4]. The Endocrine Society guideline recommends against starting testosterone therapy in men who plan to have children in the near term [1].

Recovery data come mostly from men who were not hypogonadal. An integrated analysis of 30 hormonal male contraception studies in 1,549 healthy men found the median time for sperm concentration to return to 20 million/mL was 3.4 months, with 67% recovered by 6 months and 90% by 12 [11]. Among 49 men with azoospermia or severe oligospermia while on testosterone, hCG-based combination therapy restored or improved spermatogenesis in 47 (95.9%), at an average of 4.6 months [12]. In a second series of 66 men with infertility after testosterone use, 46 (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, and older age and longer prior testosterone use predicted slower recovery [13].

Injection-site, skin and breast-tissue reactions

The label lists inflammation and pain at the injection site, plus acne, seborrhea, hirsutism and male-pattern baldness [4]. It also directs that the injection be given deep in the gluteal muscle and never intravenously [4].

In a retrospective cohort of 63 transgender men given testosterone cypionate or enanthate weekly under the skin at doses of 50 to 150 mg, minor and transient local reactions were reported in 9 [14].

The label says gynecomastia may develop and occasionally persists [4]. Estrogens stimulate breast-tissue growth while androgens inhibit it [15], and aromatase converts androgens to estrogens [16].

Drug interactions

Androgens may increase sensitivity to oral anticoagulants, so the anticoagulant dose may need to be reduced, with INR and prothrombin time monitored more often when testosterone is started or stopped [4]. In diabetes, androgens may lower blood glucose and insulin requirements [4]. The Depo-Testosterone label warns that fluid retention can be a serious complication in people with pre-existing heart, kidney or liver disease [4]. Oxyphenbutazone levels may rise when it is taken with androgens [4].