Testosterone Cypionate in Year One: What the Evidence Shows

What does the evidence show for year one?

Testosterone cypionate is given by intramuscular injection, typically every 2 to 4 weeks according to the Depo-Testosterone label [3]. The picture below comes from that label, from meta-analyses of randomized trials, from clinic cohorts and from Endocrine Society monitoring guidance. Most of the figures are pooled or come from other populations, so they are not cypionate-only measurements at exactly 12 months.

Hematocrit

The Depo-Testosterone label says androgens have been reported to stimulate production of red blood cells [3]. A network meta-analysis of 29 placebo-controlled randomized trials in 3,393 men found every formulation raised mean hematocrit; intramuscular testosterone enanthate or cypionate raised it by 4.0% (95% CI 2.9 to 5.1) versus placebo, second only to oral testosterone undecanoate at 4.3% [1].

A retrospective single-center review of 178 hypogonadal men followed for three years found erythrocytosis (hematocrit above 50%) in 66.7% of men on injectable testosterone, 12.8% on gels and 35.1% on pellets. The injectable group was younger (mean 42.5 years versus about 54) and started with a higher hematocrit, and the study was not randomized [5]. One review concluded that short-acting injectable formulations carry the highest incidence of erythrocytosis [6], and another reported a 315% greater risk of erythrocytosis (hematocrit above 0.52) in men on testosterone replacement than in controls [7].

The Depo-Testosterone label lists polycythemia as an adverse reaction and says to check hemoglobin and hematocrit periodically during long-term use [3].

Blood pressure and cardiovascular outcomes

FDA's February 2025 class-wide review found that ambulatory blood pressure studies confirmed a blood pressure increase with all testosterone products, and the agency required a blood pressure warning on products that lacked one [2]. The Depo-Testosterone label says testosterone can increase blood pressure, which can increase cardiovascular risk over time. It says to monitor blood pressure periodically and that testosterone products are not recommended in patients with uncontrolled hypertension [3].

The largest outcome trial, TRAVERSE, enrolled 5,246 men aged 45 to 80 with hypogonadism and existing or high cardiovascular risk and gave them daily 1.62% testosterone gel or placebo gel, not injections. Major adverse cardiovascular events 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, over a mean treatment of 21.7 months and mean follow-up of 33 months [8]. No outcome trial of that size exists for injectable testosterone [8]. The Depo-Testosterone label still carries older language saying long-term cardiovascular safety trials have not been conducted, that studies have been inconclusive, and that some, but not all, studies reported an increased risk of major adverse cardiovascular events [3].

Body composition

A meta-analysis of 59 randomized trials (3,029 men on testosterone, 2,049 controls) found testosterone was associated with reduced fat mass and increased lean mass, with no significant change in body weight, waist circumference or BMI [9]. In a 20-week dose-response trial of 61 healthy young men whose own testosterone was suppressed with a GnRH agonist, fat-free mass rose by 3.4, 5.2 and 7.9 kg at weekly testosterone enanthate doses of 125, 300 and 600 mg respectively [10].

Fertility

Exogenous testosterone inhibits pituitary luteinizing hormone and, at large doses, follicle stimulating hormone, which suppresses sperm production; the label lists oligospermia at high doses [3].

In an integrated analysis of 30 studies of 1,549 healthy men using androgen or androgen-progestin contraception regimens, median time for sperm concentration to return to 20 million/mL was 3.4 months, with 90% recovered by 12 months and 100% by 24 [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 separate series of 66 men, 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; older age and longer testosterone use predicted slower recovery [13]. The Endocrine Society recommends against starting testosterone therapy in men planning fertility in the near term [4].

What the label says to watch for

The Depo-Testosterone label lists venous thromboembolism, including deep vein thrombosis and pulmonary embolism, and says that if one is suspected, treatment should be discontinued and appropriate workup started [3]. It warns that edema with or without heart failure can be a serious complication in men with heart, kidney or liver disease, and that gynecomastia may develop and occasionally persists [3]. Listed reactions include acne, hirsutism, male pattern baldness, increased or decreased libido, headache, anxiety, depression, and pain and inflammation at the injection site [3].

The label says androgens may increase sensitivity to oral anticoagulants, so the anticoagulant dose may require reduction; that they may decrease blood glucose and insulin requirements; and that concurrent use with oxyphenbutazone may elevate oxyphenbutazone levels [3]. Contraindications include pregnancy, breast carcinoma, known or suspected prostate carcinoma, serious cardiac, hepatic or renal disease, and hypersensitivity [3]. The label states the drug has not been shown safe and effective for enhancing athletic performance and should not be used for that purpose [3].

What monitoring in year one involves

The Endocrine Society recommends monitoring symptoms, serum testosterone, hematocrit and prostate cancer risk during the first year of treatment [4]. The label says that before treatment starts, the diagnosis should be confirmed with morning serum testosterone measured on at least two separate days, both below the normal range [3].