Testosterone Formulations Class Overview Monograph

What Is the Testosterone Formulations Drug Class?

Testosterone formulations are exogenous androgens used to restore physiological testosterone levels in men with documented hypogonadism and to support gender-affirming therapy in transgender men. All agents in this class act as full agonists at the androgen receptor (AR), driving transcriptional changes that regulate muscle protein synthesis, erythropoiesis, bone mineral density, libido, and secondary sex characteristics. The class prototype is testosterone cypionate, an oil-soluble esterified form given by deep intramuscular or subcutaneous injection.

Hypogonadism affects approximately 2.1% of men aged 40-79 years when both low testosterone and symptoms are required for diagnosis, rising to roughly 5.6% by symptom criteria alone, according to the European Male Ageing Study (N=3,369) published in the European Journal of Endocrinology. [1] The FDA defines biochemical hypogonadism as a total serum testosterone consistently below 300 ng/dL on two separate morning measurements. [2]

Class Mechanism of Action

Testosterone diffuses across the cell membrane and binds cytoplasmic AR. The hormone-receptor complex translocates to the nucleus, dimerizes, and binds androgen-response elements (AREs) to activate or repress gene transcription. In prostate and skin, 5-alpha reductase converts testosterone to dihydrotestosterone (DHT), a more potent AR agonist. Peripheral aromatase (CYP19A1) converts a fraction of testosterone to estradiol, which is necessary for bone health, libido, and cardiovascular function in men.

Exogenous testosterone suppresses pituitary LH and FSH through negative feedback on the hypothalamic-pituitary-gonadal (HPG) axis. This suppression reduces intratesticular testosterone and impairs spermatogenesis, a consideration in men wishing to preserve fertility.

Diagnostic Threshold and Patient Selection

The Endocrine Society's 2018 Clinical Practice Guideline states: "We recommend making a diagnosis of androgen deficiency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels." [3] Symptoms warranting testing include decreased libido, erectile dysfunction, reduced morning erections, decreased energy, hot flushes, and loss of body or facial hair. Two confirmatory morning total testosterone measurements below 300 ng/dL, taken on separate days, are required before initiating therapy.

FDA-Approved Testosterone Formulations: A Comparative Overview

Six delivery routes carry FDA approval for male hypogonadism. Each trades off peak-to-trough variability, patient convenience, transfer risk, and cost differently.

Intramuscular and Subcutaneous Esters

Testosterone cypionate (Depo-Testosterone) and testosterone enanthate (Delatestryl) are the most commonly prescribed formulations in the United States. Both are esterified at the 17-beta hydroxyl group, dissolved in cottonseed or sesame oil, and depot-released after IM injection. Cypionate has a reported half-life of approximately 8 days; enanthate is slightly shorter at 4.5 days. [4]

Standard dosing is 100-200 mg IM every 1-2 weeks, though many clinicians divide to 50-100 mg weekly to reduce peak-to-trough swings. Subcutaneous administration at 50-100 mg weekly is increasingly used for self-injection programs; a 2017 study in the Journal of Urology (N=400) demonstrated non-inferior serum levels and lower injection-site discomfort with the subcutaneous route. [5]

Testosterone undecanoate (Aveed) is a long-acting IM formulation dosed 750 mg at weeks 0 and 4, then every 10 weeks. It carries an FDA-mandated REMS program because of risk of serious pulmonary oil microembolism and anaphylaxis, requiring a 30-minute post-injection observation period in a certified healthcare setting. [6]

Transdermal Gels and Solutions

Testosterone gel formulations (AndroGel 1% and 1.62%, Testim 1%, Vogelxo 1%, Fortesta 2%) are applied daily to shoulders, upper arms, or thighs. They achieve stable serum concentrations within 3-5 days. The AUA 2023 guideline recommends checking testosterone 2-8 hours after gel application to assess peak levels. [7]

Transfer to women and children through skin contact is a documented risk. The FDA issued a black-box warning for all transdermal testosterone products after cases of virilization in children exposed secondhand. [8] Patients must wash hands after application, cover the site, and avoid skin-to-skin contact for at least 2 hours.

Axillary solutions (Axiron) are applied with a metered pump to the axilla. They carry the same transfer precautions and produce comparable steady-state concentrations to gel products.

Buccal and Nasal Delivery

Testosterone buccal system (Striant) is a bioadhesive mucoadhesive tablet, 30 mg, applied to the gum above an incisor every 12 hours. It avoids first-pass hepatic metabolism and produces stable serum levels. Patients report gum irritation in roughly 16% of cases in clinical trials. [9] This route is largely supplanted by gel and injection options in clinical practice.

Testosterone nasal gel (Natesto) 5.5 mg per actuation is dosed three times daily (one actuation per nostril per dose). It is the only formulation that may have less suppressive effect on LH and FSH; a 2019 study published in the Journal of Urology (N=60) found that 22% of Natesto-treated men maintained sperm concentrations above 15 million/mL, compared with 0% in the testosterone cypionate group, making it an option for men with hypogonadism who wish to preserve fertility. [10]

Subcutaneous Testosterone Pellets

Testopel pellets (75 mg each) are implanted subcutaneously in the hip or buttock under local anesthesia, typically 3-6 pellets (225-450 mg) per procedure, repeated every 3-6 months depending on symptom recurrence and serum levels. Pellets provide the most stable serum concentrations of all routes. Extrusion occurs in approximately 5-10% of insertions. [11] Dose adjustment requires waiting until the next insertion cycle, making over- or under-dosing harder to correct quickly compared to injections or gels.

Pharmacokinetics Across Formulations

Understanding half-life and serum variability directly informs monitoring schedules and symptom interpretation.

Half-Life and Serum Profiles

| Formulation | Half-life (approx.) | Dosing Frequency | Peak-to-Trough Ratio | |---|---|---|---| | Testosterone cypionate | 8 days | Weekly to biweekly | High (biweekly dosing) | | Testosterone enanthate | 4.5 days | Weekly to biweekly | Moderate-high | | Testosterone undecanoate (IM) | 20-21 days | Every 10 weeks | Low | | Testosterone gel 1.62% | 70 min (transdermal, steady-state maintained by daily application) | Daily | Very low | | Testosterone nasal gel | ~10 min (rapid absorption/clearance) | Three times daily | Very low | | Testosterone pellets | Weeks (slow diffusion) | Every 3-6 months | Very low |

Cypionate and enanthate administered biweekly produce the most pronounced trough symptoms, including fatigue, mood changes, and reduced libido in the days before the next injection. Dividing the dose to weekly injections substantially attenuates this variability, a recommendation endorsed by the Endocrine Society. [3]

Hepatic Metabolism and First-Pass Effects

Oral 17-alpha-alkylated testosterone (methyltestosterone) is no longer FDA-indicated for hypogonadism due to hepatotoxicity and is not covered in this monograph. All currently FDA-approved formulations avoid first-pass hepatic metabolism by using parenteral, transdermal, buccal, or nasal delivery. Testosterone undergoes hepatic conjugation (glucuronidation and sulfation) after absorption; conjugates are excreted primarily in urine.

Dosing and Administration Reference

Injection-Based Protocols

Testosterone cypionate and enanthate dosing for hypogonadism:

• Standard biweekly: 150-200 mg IM every 2 weeks (trough often subtherapeutic by day 10-14)
• Weekly divided: 75-100 mg IM or SC every 7 days (preferred for serum stability)
• Target: trough total testosterone 400-700 ng/dL; peak (24-48 h post-injection) should not exceed 1,100 ng/dL

Testosterone undecanoate (Aveed) protocol:

• 750 mg (3 mL) IM gluteal injection at day 0, week 4, then every 10 weeks. Observe 30 minutes post-injection per REMS requirements. [6]

Transdermal Gel Protocols

AndroGel 1.62% starting dose: two pump actuations (40.5 mg testosterone) daily. Titrate after 14 days based on serum levels checked 2-8 hours post-application. Maximum 4 actuations (81 mg) daily.

Fortesta 2%: starting dose 40 mg (4 actuations) to thigh daily; titrate based on levels at 14 and 35 days.

Monitoring Schedule

Check total testosterone after 3-6 months of stable dosing, then annually. Monitor hematocrit at baseline, 3-6 months, then annually. PSA should be checked at baseline, 6 months, and then per age-appropriate prostate cancer screening guidelines. Bone mineral density should be measured at baseline in men with osteoporosis risk or prior fragility fracture, repeated after 1-2 years of therapy. [3]

Adverse Effects and Safety Profile

Erythrocytosis

The most common serious adverse effect is secondary erythrocytosis. Testosterone stimulates renal erythropoietin production and direct erythroid progenitor proliferation. The Endocrine Society guideline recommends withholding or dose-reducing testosterone when hematocrit exceeds 54%, as this level increases viscosity and venous thromboembolism risk. [3] A 2017 meta-analysis in JAMA Internal Medicine (N=11 trials, 2,351 participants) found hematocrit elevation was the most consistently dose-dependent adverse effect across all formulations, with injectable routes producing the highest rates. [12]

Phlebotomy may be required in refractory cases. Switching from biweekly IM to weekly divided dosing or to a lower-variability route (gel, pellet) often reduces erythrocytosis without abandoning therapy.

Cardiovascular Considerations

The cardiovascular safety of testosterone therapy has been studied extensively and remains an area of active clinical debate. The TRAVERSE trial (N=5,246), published in the New England Journal of Medicine in 2023, randomized men aged 45-80 with hypogonadism and elevated cardiovascular risk to testosterone gel 1.62% or placebo. The primary MACE endpoint (cardiovascular death, nonfatal MI, nonfatal stroke) showed non-inferiority of testosterone vs. Placebo at 33 months of follow-up (HR 0.96, 95% CI 0.78-1.17). [13] Atrial fibrillation (3.5% vs. 2.4%) and acute kidney injury (2.3% vs. 1.5%) were numerically higher in the testosterone arm.

The AUA 2023 guideline notes that testosterone therapy should be used with caution in men with a recent (within 6 months) MI or stroke, uncontrolled heart failure, or hematocrit above 54%. [7]

Prostate Safety

Testosterone does not appear to cause de novo prostate cancer, but it may accelerate growth of undiagnosed subclinical disease. PSA should be measured at 3-6 months after initiation. A confirmed rise of more than 1.4 ng/mL above baseline within the first year, or any PSA above 4 ng/mL, warrants urology referral before continuing therapy. [3] Absolute contraindications include metastatic prostate cancer and locally advanced (T3/T4) prostate cancer.

Transfer, Fertility, and Other Effects

Skin-to-skin transfer from gel users to female partners and children can cause virilization. Men who wish to father children should be counseled that exogenous testosterone suppresses spermatogenesis in most cases. FSH and LH suppression begins within weeks of initiation; spermatogenesis may not recover for 12-24 months after discontinuation, and recovery is not guaranteed. Natesto (nasal gel) represents the best-studied alternative for men seeking to maintain fertility while treating symptomatic hypogonadism. [10]

Sleep apnea may worsen with testosterone therapy due to increased upper-airway muscle bulk and altered ventilatory drive. Screen for sleep apnea at baseline and reassess if new snoring or daytime sleepiness develops.

Contraindications and Precautions

Absolute Contraindications

• Metastatic or locally advanced prostate cancer (T3/T4)
• Male breast cancer
• Desire for near-term fertility (relative, not absolute, in select cases using Natesto)
• Hematocrit >54% at baseline before any dose titration
• Uncontrolled or decompensated heart failure (New York Heart Association class IV)
• Pregnancy (teratogenic; testosterone is Category X)

Relative Contraindications and Cautions

• Benign prostatic hyperplasia with severe lower urinary tract symptoms (AUA symptom score >19)
• Obstructive sleep apnea (untreated)
• Active venous thromboembolism
• Recent cardiovascular event (within 6 months)
• Polycythemia vera or secondary erythrocytosis not related to hypogonadism

Selecting the Right Formulation for Your Patient

The choice of formulation should match the patient's lifestyle, comorbidities, monitoring access, and goals. The following decision framework reflects current guideline recommendations and prescribing patterns at HealthRX:

Step 1. Establish diagnosis. Two morning total testosterone measurements below 300 ng/dL plus consistent symptoms. Measure LH/FSH to distinguish primary (hypergonadotropic) from secondary (hypogonadotropic) hypogonadism. Secondary hypogonadism warrants evaluation for pituitary pathology and may indicate gonadotropin therapy rather than testosterone replacement.

Step 2. Screen for contraindications. PSA, digital rectal exam (or referral), hematocrit, lipids, CBC, CMP, sleep apnea screening.

Step 3. Match formulation to patient profile.

• Weekly self-injection preferred, low cost: testosterone cypionate 50-100 mg SC weekly
• Needle aversion, stable lifestyle (no children at home): testosterone gel 1.62% or 1% daily
• Long dosing interval, healthcare-setting injection tolerated: testosterone undecanoate 750 mg IM every 10 weeks
• Fertility preservation desired: testosterone nasal gel (Natesto) 11 mg (2 actuations) three times daily
• Maximum serum stability, office-based procedure every 3-6 months: Testopel pellets 225-450 mg SC

Step 4. Titrate and monitor. Recheck total testosterone at 6-8 weeks after any dose change. Target 400-700 ng/dL. Recheck hematocrit at 3 months. Adjust dose or route if adverse effects arise.

Step 5. Assess symptom response at 3-6 months. If total testosterone is in range but symptoms persist, evaluate for comorbid conditions (depression, sleep apnea, hypothyroidism, low vitamin D) before escalating testosterone dose.

Drug Interactions

Testosterone can potentiate the effects of anticoagulants, particularly warfarin. The INR should be monitored closely when testosterone is initiated or dose-adjusted in patients on warfarin therapy. Corticosteroids taken concurrently may increase fluid retention. Testosterone may suppress insulin requirements in diabetic patients by improving insulin sensitivity, necessitating blood glucose monitoring. Concurrent use of 5-alpha reductase inhibitors (finasteride, dutasteride) reduces conversion to DHT and may blunt androgenic effects on hair follicles and prostate tissue.

Special Populations

Older Men (Age >65)

The Testosterone Trials (TTrials, N=790), published across multiple NEJM papers in 2016, enrolled men 65 and older with total testosterone below 275 ng/dL. Testosterone gel improved sexual function, mood, and volumetric bone mineral density, but effects on physical function and cognition were modest at 12 months. [14] Cardiovascular plaque volume increased in the testosterone arm (a secondary finding from the TTrials Cardiovascular Trial), and a higher proportion of men in the testosterone group had an increase in non-calcified plaque. Prescribers should weigh these findings carefully in older men with pre-existing cardiovascular disease.

Transgender Men

Testosterone therapy for gender affirmation typically uses the same formulations and dosing as male hypogonadism treatment. The Endocrine Society 2017 guideline for gender-dysphoric individuals recommends initiating testosterone at low doses and titrating to male reference ranges (400-700 ng/dL). [15] Ongoing surveillance for polycythemia, dyslipidemia, and uterine atrophy is recommended.

Men with Obesity

Obesity lowers sex-hormone-binding globulin (SHBG), causing total testosterone to underestimate free androgen activity. In men with BMI >30, measuring free testosterone or calculated free testosterone is advisable. The Endocrine Society recommends against diagnosing hypogonadism solely on the basis of low total testosterone when SHBG is also low; symptoms must accompany biochemical findings. [3]