Testosterone Formulations Class Overview Monograph

What are testosterone formulations approved to treat?

These products are approved for replacement therapy in men with conditions associated with deficiency or absence of endogenous testosterone. The labels name two groups: primary hypogonadism (testicular failure from cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome or orchiectomy) and hypogonadotropic hypogonadism (gonadotropin or LHRH deficiency, or pituitary-hypothalamic injury from tumor, trauma or radiation) [1]. FDA states that none of the approved testosterone products are approved for men with low testosterone who lack an associated medical condition [2].

FDA lists the approved formulations as oral, topical gel, transdermal patch, buccal system and injection [6].

The Depo-Testosterone and generic enanthate labels each still state that safety and efficacy in men with age-related (late-onset) hypogonadism have not been established [1][3]. That position is moving at FDA but has not yet moved onto those labels: in June 2026 FDA requested removal of the limitation of use and revision of prostate cancer and benign prostatic hyperplasia safety information [2].

Depo-Testosterone is labeled for males only, and its label states the drug has not been shown to be safe and effective for enhancing athletic performance and should not be used for that purpose [1]. The generic enanthate label also lists delayed puberty in carefully selected boys and, secondarily, metastatic breast cancer in postmenopausal women [3].

How the esters behave

Cypionate and enanthate are oil-soluble esters of testosterone. Given by injection in oil, they are absorbed slowly from the oil depot and split to free testosterone; the Depo-Testosterone label gives a half-life of about 8 days after intramuscular injection [1]. Exogenous testosterone inhibits pituitary LH and, at large doses, also FSH, which suppresses sperm production [1]. Aromatase converts androgens to estrogens, and estrogens stimulate breast tissue growth while androgens inhibit it; gynecomastia is listed as a side effect that may persist [1][9][10].

What changed in the labels after TRAVERSE?

In February 2025, FDA recommended adding TRAVERSE results across testosterone labels, keeping the Limitation of Use for age-related hypogonadism, removing language from the Boxed Warning about increased risk of adverse cardiovascular outcomes, and adding a blood pressure warning, with product-specific ambulatory blood pressure data where those studies were done. FDA said the ambulatory studies confirmed a blood pressure increase with all testosterone products, class-wide [6]. The Depo-Testosterone and generic enanthate labels discussed here still retain the older cardiovascular-risk wording [1][3].

TRAVERSE was a randomized, double-blind, placebo-controlled noninferiority trial of 5,246 men aged 45 to 80 with hypogonadism and existing or high cardiovascular risk. It compared daily 1.62% testosterone gel with placebo gel over a mean treatment of 21.7 months and follow-up of 33 months. The primary cardiovascular endpoint 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), meeting noninferiority [11]. FDA concluded the trial did not demonstrate a new safety signal or trend in adverse cardiovascular outcomes [2].

TRAVERSE tested a topical gel, not an injection, and no cardiovascular outcome trial of that size has tested injectable testosterone [11]. The labeling updates are also not uniform: the Depo-Testosterone and generic enanthate labels still contain the older paragraph stating that long-term safety trials have not been conducted, that studies have been inconclusive for major adverse cardiovascular events, and that some, but not all, studies reported an increased risk [1][3].

How are the injectable esters dosed?

Both labels require confirming the diagnosis first: serum testosterone measured in the morning on at least two separate days, both below the normal range [1][3]. The Depo-Testosterone label specifies deep gluteal intramuscular injection only, not intravenous administration, and gives a replacement dose of 50 to 400 mg every 2 to 4 weeks [1]. The generic enanthate label uses the same 50 to 400 mg every 2 to 4 weeks range, notes that total doses above 400 mg per month are not required, and that injections more often than every 2 weeks are rarely indicated [3].

Subcutaneous testosterone enanthate given weekly with a single-use autoinjector was tested in a phase II study of 39 hypogonadal men: 50 mg and 100 mg weekly both produced normal average testosterone concentrations across a 168-hour dosing interval, with mean steady-state levels at week 6 of 422.4 and 895.5 ng/dL [4].

What do the labels warn about?

Blood pressure. Both injectable labels state that testosterone can increase blood pressure, which can increase cardiovascular risk over time, that blood pressure should be measured periodically, especially in men with hypertension, and that testosterone products are not recommended in uncontrolled hypertension [1][3].

Venous thromboembolism. Deep vein thrombosis and pulmonary embolism have been reported with testosterone products such as cypionate and enanthate. The labels direct clinicians to evaluate leg pain, edema, warmth and erythema for DVT and acute shortness of breath for PE, and stopping the drug if an event is suspected [1][3].

Red blood cell mass. Testosterone stimulates red blood cell production [1]. A network meta-analysis of 29 placebo-controlled trials in 3,393 men found mean hematocrit rose with every formulation: intramuscular enanthate or cypionate 4.0% (95% CI 2.9 to 5.1), oral testosterone undecanoate 4.3%, gel 3.0%, patch 1.4%, and intramuscular undecanoate 1.6% [12]. A retrospective review of hypogonadal men on gels, injections or pellets and followed for 3 years found erythrocytosis more often with injections than with gels or pellets; the injection group was younger (mean 42.5 versus about 54 years), started with higher hematocrit, and the study was not randomized [13]. Another review put the risk of erythrocytosis (hematocrit above 0.52) at 315% higher than in controls, highest with short-acting injectables, with the link to thromboembolic events still inconclusive [14][15].

Prostate. Testosterone is contraindicated in men with known or suspected prostate carcinoma [1]. The Depo-Testosterone label notes that older men treated with androgens may be at increased risk of prostatic hypertrophy and prostatic carcinoma, while stating that conclusive evidence for this is lacking [1].

Other label warnings. Gynecomastia may develop and occasionally persists [1]. Edema, with or without congestive heart failure, may be a serious complication in men with existing cardiac, renal or hepatic disease [1]. Hypercalcemia can occur in immobilized patients [1]. Prolonged high doses of androgens, principally the 17-alpha-alkyl androgens, have been associated with hepatic adenomas, hepatocellular carcinoma and peliosis hepatis [1]. Testosterone has been subject to abuse, typically at doses above those recommended and combined with other anabolic steroids, and abuse can cause serious cardiovascular and psychiatric reactions [1].

What monitoring does the class require?

The 2018 Endocrine Society guideline recommends diagnosing hypogonadism only in men with symptoms and consistently low testosterone, confirming with a repeat morning fasting total testosterone, and monitoring symptoms, serum testosterone, hematocrit and prostate cancer risk during the first year of treatment [7]. For hematocrit, every formulation in the analysis increased mean hematocrit versus placebo. A separate review found the highest incidence of erythrocytosis with short-acting injections [12][14].

Does testosterone affect fertility?

The labels state that with large doses of exogenous androgens, sperm production may be suppressed through FSH feedback inhibition, possibly lowering sperm count, and that oligospermia may occur at high dosages [1]. Recovery is common but variable. In an integrated analysis of 30 hormonal male contraception studies (1,549 healthy eugonadal men, not men with hypogonadism), median time for sperm concentration to return to 20 million/mL was 3.4 months [16]. In 66 men treated for infertility after testosterone use, stopping testosterone and starting high-dose hCG plus a selective estrogen receptor modulator brought 46 men (70%) above a total motile count of 5 million within 12 months; 64.8% of azoospermic men reached that threshold versus 91.7% of cryptozoospermic men, and older age and longer testosterone use predicted slower recovery [17]. In a separate retrospective series of 49 men with azoospermia or severe oligospermia while on testosterone, hCG-based combination therapy restored or improved spermatogenesis in 47 (95.9%), with a mean time of 4.6 months [18]. The Endocrine Society recommends against starting testosterone therapy in men planning fertility in the near term [7].

Which drugs interact with testosterone?

The Depo-Testosterone label says androgens may increase sensitivity to oral anticoagulants such as warfarin, that the anticoagulant dose may need to be reduced, and that INR and prothrombin time should be monitored more often when testosterone is started or stopped [1]. The labels say androgens may lower blood glucose and insulin requirements in diabetic patients [1][3], that corticosteroids and ACTH taken with testosterone may increase fluid retention, especially in hepatic or cardiac disease [3], and that concurrent oxyphenbutazone may reach elevated serum levels [1].

Who should not use testosterone?

Depo-Testosterone lists known hypersensitivity, men with breast carcinoma, men with known or suspected prostate carcinoma, women who are pregnant, and patients with serious cardiac, hepatic or renal disease [1]. The generic enanthate label lists carcinomas of the breast or known or suspected prostate carcinoma, women who are or may become pregnant, and hypersensitivity to any component [3]. The Endocrine Society also recommends against starting therapy in men with elevated hematocrit, untreated severe sleep apnea, uncontrolled heart failure, or a heart attack or stroke within the previous 6 months [7].

Is testosterone a controlled substance?

Yes. Testosterone is a Schedule III anabolic steroid under the US Controlled Substances Act, and the Depo-Testosterone and generic enanthate labels each state Schedule III [1][5][3]. It is not Schedule II.

In WADA-governed sport, testosterone is an S1 anabolic agent prohibited at all times, in and out of competition, and a prescription does not make it permitted; an athlete needs a Therapeutic Use Exemption [8].

What about older men?

The Testosterone Trials assigned 790 men aged 65 or older with testosterone below 275 ng/dL to testosterone gel or placebo gel for 1 year. Testosterone increased sexual activity, sexual desire and erectile function, and men on testosterone reported slightly better mood and lower severity of depressive symptoms. There was no significant benefit in vitality. The share of men whose 6-minute walking distance rose by at least 50 m was higher with testosterone only when all three trials were pooled (20.5% versus 12.6%, P=0.003), not in the physical function trial alone. Adverse event rates were similar, and the trial was too small to draw conclusions about risks [19].

What about the non-injection routes?

FDA lists topical gel, transdermal patch, buccal system and oral formulations alongside injections [6]. The buccal system was studied at 30 mg applied twice daily in 82 hypogonadal men over 3 months; serum testosterone stayed above the lower limit of the adult male range 80.1% of a 24-hour period, and gum-related adverse events occurred in 16.3% [20]. The large cardiovascular outcome data for this class come from a 1.62% gel, which is what TRAVERSE tested [11].