Testosterone Formulations: How to Select the Right Agent Within the Class

What are the products approved for?

Depo-Testosterone is labeled for replacement therapy in men with primary or hypogonadotropic hypogonadism [5]. The testosterone enanthate label also includes delayed puberty in carefully selected boys and metastatic breast cancer in postmenopausal women [6]. Depo-Testosterone is labeled for males only [5]. FDA states that none of the approved products is approved for low testosterone in men who lack an associated medical condition [1]. The labels still say safety and efficacy in age-related hypogonadism have not been established, although FDA asked sponsors in June 2026 to remove that limitation [1].

In a 24-week randomized study of 66 hypogonadal men, intramuscular testosterone enanthate 200 mg every two weeks produced supraphysiologic total and bioavailable testosterone and estradiol for several days after each injection, while a nightly testosterone patch produced circadian variation that stayed within normal ranges [7].

Intramuscular cypionate and enanthate

Depo-Testosterone (cypionate) and generic enanthate are injected deep in the gluteal muscle, never intravenously, at 50 to 400 mg every 2 to 4 weeks [5][6]. The cypionate label gives a half-life of about eight days after intramuscular injection [5]. The enanthate label adds that total doses above 400 mg per month are not required and that injections more often than every two weeks are rarely indicated [6]. Neither the Depo-Testosterone label nor the generic enanthate label carries a boxed warning [5][6].

Subcutaneous, oral and nasal options

Xyosted is an FDA-approved weekly subcutaneous testosterone enanthate autoinjector with its own label, separate from the generic intramuscular enanthate label [6]. The Xyosted label says to start at 75 mg once weekly, check trough total testosterone 7 days after the last dose after 6 weeks, and adjust in 25 mg steps, with a usual trough target of 350 to 650 ng/dL; in its ambulatory study, weekly Xyosted raised average blood pressure by 3.9/1.5 mm Hg at week 12. An older small pilot, not the autoinjector, had 22 hypogonadal men self-inject a weekly low dose of testosterone enanthate with an insulin syringe; peak and trough levels stayed within the normal range in all 22, with no local reactions reported [9].

Oral testosterone undecanoate was tested in a randomized, open-label phase 3 trial: 166 men took oral undecanoate and 56 took a topical product for 3 to 4 months, and 87% of each group reached a mean testosterone concentration in the eugonadal range [10]. Oral undecanoate was associated with a mean systolic blood pressure increase of 3 to 5 mm Hg [10].

Nasal testosterone gel was studied in a 90-day randomized, open-label, dose-ranging trial of 306 men; 73% of the intent-to-treat group had an average testosterone within the eugonadal range at day 90, and the trial report lists no risk of secondary transference among the formulation's advantages [11].

Patches, gels and pellets

Patch tolerability is the weak point. In the 24-week comparison with intramuscular enanthate, transient skin irritation was reported by 60% of patch users and led 9% to stop, while intramuscular injections caused local reactions in 33% [7].

Pellets are the lowest-frequency option covered here. In a pooled series of 380 men and 702 insertions, six to ten or more pellets (450 to 750 mg or more) brought testosterone into the therapeutic range at one month and held levels above 300 ng/dL for 4 to 6 months, with eight or more pellets giving the best results; four extrusions and three hematomas were reported, mostly early in the experience [12].

Gels are the formulation used in the largest cardiovascular trial, described below.

Hematocrit: where the routes separate most clearly

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

In a six-month randomized trial in older men with mobility limitation, testosterone gel raised hemoglobin and hematocrit by roughly 7% to 10%, associated with higher erythropoietin and lower ferritin and hepcidin [13]. The Depo-Testosterone label likewise states that androgens stimulate red blood cell production by enhancing production of erythropoietic stimulating factor [5].

Observational data point the same way. A retrospective review of 178 men followed for three years found erythrocytosis (hematocrit above 50%) in 66.7% of men on injectable testosterone, 35.1% on pellets and 12.8% on gels; the injection group was younger (mean 42.5 versus 54.1 years) with higher baseline hematocrit, and the study was not randomized [14]. Reviews describe short-acting injectable formulations as having the highest incidence of erythrocytosis, with the link to thromboembolic events still unclear [15], and one review reported a 315% greater risk of erythrocytosis (hematocrit above 0.52) than controls across formulations, with injectables raising hemoglobin and hematocrit the most [16]. In the randomized patch-versus-injection study, abnormal hematocrit elevations occurred in 43.8% of injection users versus 15.4% of patch users [7].

Blood pressure and cardiovascular data

In February 2025, FDA called for TRAVERSE results to be added to testosterone labels. The Depo-Testosterone and generic enanthate labels checked still do not include those results; both warn that testosterone can increase blood pressure [4][5][6].

TRAVERSE itself tested a gel, not an injection. The trial randomized 5,246 men aged 45 to 80 with hypogonadism and existing or high cardiovascular risk to daily 1.62% testosterone gel or placebo gel, with a mean treatment duration of 21.7 months and mean follow-up of 33 months. A primary cardiovascular event occurred in 7.0% of men on testosterone and 7.3% on placebo (hazard ratio 0.96, 95% CI 0.78 to 1.17) [17]. Mean systolic blood pressure rose 1.0 mm Hg on gel against a 0.5 mm Hg fall on placebo at 36 months [17].

Labels have not converged. The Depo-Testosterone and generic enanthate labels state 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; both also state that testosterone can increase blood pressure and that testosterone products are not recommended in men with uncontrolled hypertension [5][6].

Fertility and the choice of route

Exogenous testosterone inhibits pituitary luteinizing hormone and, at large doses, follicle stimulating hormone, which suppresses sperm production [5]. The 2018 Endocrine Society guideline recommends against starting testosterone therapy in men planning fertility in the near term, and also in men with breast or prostate cancer, an elevated hematocrit, untreated severe sleep apnea, uncontrolled heart failure, or a myocardial infarction or stroke within the past six months [3].

Recovery is common but variable. An integrated analysis of 30 studies of 1,549 healthy men who used hormonal contraception found a median of 3.4 months for sperm concentration to recover to 20 million/mL, with faster recovery after shorter treatment and with shorter-acting testosterone preparations [18]. Among 66 men treated for 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 testosterone use predicted slower recovery [19].

In a single-center, open-label, single-arm trial, 60 men with symptomatic hypogonadism used nasal testosterone three times daily for six months; total motile sperm count remained above 5 million in 88.4% of men assessed at three months and 93.9% at six months, and luteinizing hormone and follicle stimulating hormone stayed within the normal range in most men at six months [20]. The authors concluded that studies beyond six months are needed before nasal testosterone can be prescribed for men interested in fertility [20].

Monitoring

The Depo-Testosterone and generic enanthate injection labels require two separate low morning testosterone measurements before treatment, both below the normal range [5][6]. The Endocrine Society guideline recommends monitoring symptoms, serum testosterone, hematocrit and prostate cancer risk during the first year [3].