Testosterone Cypionate
Depo-Testosterone · Azmiro · Generics
Indications for Testosterone Cypionate
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Primary hypogonadism (congenital or acquired) | Males with testicular failure (cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter syndrome, toxic damage) | Replacement therapy | FDA Approved |
| Hypogonadotropic hypogonadism (congenital or acquired) | Males with gonadotropin or LHRH deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation | Replacement therapy | FDA Approved |
Testosterone cypionate is one of the most widely prescribed injectable testosterone preparations in the United States for male hypogonadism. The diagnosis must be confirmed by measuring serum testosterone on at least two separate mornings with levels below the normal range (generally <300 ng/dL per the Endocrine Society 2018 guideline). Testosterone cypionate is specifically indicated for conditions with documented deficiency or absence of endogenous testosterone, not for age-related declines in testosterone (“late-onset hypogonadism”), for which safety and efficacy have not been established in the FDA labeling.
Gender-affirming hormone therapy (female-to-male transition): Testosterone cypionate is widely used for masculinizing hormone therapy per Endocrine Society 2017 guidelines. Typical starting doses are 50–100 mg IM every week or 100–200 mg every 2 weeks, titrated to male-range testosterone levels. Evidence quality: High (guideline-supported).
Delayed puberty in males: Used at lower doses (50–200 mg IM every 2–4 weeks) for limited courses to initiate puberty in adolescent boys with constitutional delay. Evidence quality: Moderate (longstanding clinical practice).
Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Male hypogonadism — initial replacement | 100 mg IM every 2 weeks | 50–400 mg IM every 2–4 weeks | 400 mg every 2 weeks | Individualize based on clinical response and testosterone levels; the Endocrine Society recommends 75–100 mg/week or 150–200 mg every 2 weeks Administer deep into gluteal muscle; rotate injection sites |
| Male hypogonadism — dose titration | Measure serum testosterone midway between injections (trough) at 3–6 months; target 400–700 ng/dL | If trough level is low, shorten interval or increase dose; if supraphysiologic, reduce dose Check hematocrit at 3–6 months and then annually (Endocrine Society 2018) | ||
| Delayed puberty — male (off-label) | 50–100 mg IM every 2–4 weeks | 50–200 mg IM every 2–4 weeks | 200 mg every 2 weeks | Short courses (4–6 months); monitor bone age every 6 months to avoid premature epiphyseal closure Use lowest effective dose for shortest duration |
| Gender-affirming therapy (FTM, off-label) | 50–100 mg IM weekly | 50–100 mg IM weekly or 100–200 mg every 2 weeks | 100 mg/week | Titrate to male-range testosterone (320–1000 ng/dL); monitor hematocrit, lipids, liver function Per Endocrine Society 2017 transgender guideline |
The FDA label and the Endocrine Society both require that hypogonadism be confirmed by at least two morning serum testosterone measurements below the normal range before initiating therapy. Morning levels are preferred because testosterone follows a circadian rhythm, peaking in the early morning. The Endocrine Society 2018 guideline uses a threshold of 264–300 ng/dL (depending on assay) and recommends measuring total testosterone using a reliable assay (LC-MS/MS preferred). Confirming the diagnosis prevents inappropriate prescribing for non-hypogonadal men with age-related symptoms.
Pharmacology
Mechanism of Action
Testosterone cypionate is a long-acting ester of the endogenous androgen testosterone, formulated in cottonseed oil for intramuscular depot injection. After IM injection, the ester is slowly released from the oil depot and hydrolyzed to free testosterone, which then enters the systemic circulation. Testosterone and its principal active metabolite, dihydrotestosterone (DHT, formed via 5-alpha reductase), bind to the intracellular androgen receptor. The steroid-receptor complex translocates to the nucleus, where it initiates gene transcription responsible for the development and maintenance of male sex characteristics, skeletal muscle mass, bone density, erythropoiesis, and libido. Testosterone also undergoes aromatization to estradiol via the aromatase enzyme, which mediates some of its effects on bone metabolism and contributes to feedback regulation of gonadotropins (LH and FSH) at the hypothalamic-pituitary level.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Slow IM depot release from cottonseed oil; Cmax ~758 ng/dL (SD 288.7) after single 200 mg dose; median Tmax ~72 hours (range 24–191 hours) | Peak-trough variation is inherent; levels peak within 2–5 days and decline over 2–4 weeks; weekly dosing produces more stable levels than biweekly dosing |
| Distribution | 98% bound in plasma: ~40% to SHBG, ~58% to albumin, ~2% free; MW 412.61 Da | Free testosterone concentration determines biological activity; SHBG levels (affected by age, obesity, thyroid status, liver disease) alter the free/bound ratio |
| Metabolism | Primarily hepatic; converted to DHT (5-alpha reductase) and estradiol (aromatase); inactivated to 17-keto steroids; not a 17-alpha-alkylated androgen | Lower hepatotoxicity risk than oral 17-alpha-alkyl androgens (methyltestosterone); aromatization to estradiol can cause gynecomastia; DHT mediates prostate and hair follicle effects |
| Elimination | t½ ~8 days (IM); ~90% excreted in urine as glucuronic and sulfuric acid conjugates; ~6% in feces (unconjugated) | The 8-day half-life supports dosing every 1–4 weeks depending on desired trough level; longer intervals produce larger peak-trough swings |
Side Effects
Adverse reaction data below come from the Azmiro (testosterone cypionate) clinical trial (Study 1, N = 27 hypogonadal men, single-dose), class-effect data from the FDA PI, and the TRAVERSE cardiovascular safety trial (N = 5246, NEJM 2023). Testosterone cypionate shares the adverse effect profile common to all exogenous testosterone formulations.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Injection site erythema | 26% | All cases categorized as mild; typically transient; rotate injection sites |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Injection site reaction (other) | 4% | Mild; includes pain, swelling at site |
| Polycythemia (Hct elevation) | Common (class effect) | Most clinically important AE of TRT; monitor hematocrit; discontinue if persistently elevated (>54%) |
| Acne / Seborrhea | Common (class effect) | DHT-mediated; dose-dependent; manage with topical treatments; reduce dose if severe |
| Gynecomastia | Common (class effect) | Due to aromatization of testosterone to estradiol; may be dose-related; occasionally persistent |
| Edema (fluid retention) | Common (class effect) | Sodium and water retention; monitor in patients with cardiac, renal, or hepatic disease |
| Mood changes (irritability, anxiety, depression) | Common (class effect) | Can worsen with supraphysiologic levels or during trough periods; dose adjustment may help |
| Headache | Common (class effect) | Usually transient |
| Male pattern alopecia | Common (class effect) | DHT-mediated; genetic predisposition determines susceptibility |
| Increased libido | Common (class effect) | Expected pharmacologic effect; may require dose adjustment if excessive |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Polycythemia / Erythrocytosis (Hct >54%) | Up to 20% develop elevated Hct; clinically significant in ~5–10% | Months; cumulative effect | Monitor hematocrit at baseline, 3–6 months, then annually; withhold if Hct >54%; resume at lower dose if normalized; increased VTE risk |
| Major adverse cardiovascular events (MACE) | TRAVERSE trial: noninferior to placebo (7.0% vs 7.3%; HR 0.96) | Variable; studied over mean 33 months | Inform patients of possible CV risk; epidemiologic data remain inconclusive; the TRAVERSE trial showed no increase in MACE but found more atrial fibrillation and PE in the testosterone group |
| Venous thromboembolism (DVT/PE) | Postmarketing reports; TRAVERSE: PE higher in testosterone group | Any time during therapy | Evaluate leg pain/swelling or acute dyspnea; discontinue and investigate if VTE suspected; use with caution in patients with thromboembolic history |
| Spermatogenesis suppression / Infertility | Expected at therapeutic doses; may be irreversible | Weeks to months | Counsel about fertility impact BEFORE initiating; exogenous testosterone suppresses FSH/LH; consider alternatives (e.g., clomiphene, hCG) if fertility desired |
| Sleep apnea (new or worsened) | Uncommon; higher risk with obesity or chronic lung disease | Weeks to months | Screen for OSA symptoms; consider sleep study if symptoms develop; may require dose reduction or discontinuation |
| Hepatic adverse effects (peliosis hepatis, neoplasms) | Rare with injectable esters; primarily associated with oral 17-alpha-alkyl androgens | Months to years of continuous use | Testosterone cypionate is NOT a 17-alpha-alkyl androgen and carries lower hepatotoxicity risk; nonetheless, report jaundice or hepatic dysfunction; monitor LFTs |
| Prostate cancer risk | Uncertain; TRAVERSE found no increase in prostate events | N/A | Contraindicated in known/suspected prostate carcinoma; monitor PSA at baseline, 3–6 months, then annually; evaluate if PSA rises >1.4 ng/mL within 12 months or >4 ng/mL |
Testosterone stimulates erythropoiesis via erythropoietin and direct effects on bone marrow stem cells. Hematocrit elevation is dose-dependent and the most common reason for dose reduction or withholding. The Endocrine Society recommends withholding testosterone if hematocrit exceeds 54% and resuming at a lower dose once it normalizes. Strategies to reduce polycythemia risk include using lower doses, switching to shorter-acting preparations (e.g., weekly injections to reduce peaks), and considering therapeutic phlebotomy in refractory cases. Polycythemia increases VTE risk, which is why hematocrit monitoring is mandatory throughout therapy.
Drug Interactions
Testosterone cypionate is metabolized by hepatic cytochrome P450 enzymes (primarily CYP3A4 for hydroxylation) and undergoes 5-alpha reduction and aromatization. Clinically relevant interactions are primarily pharmacodynamic.
Monitoring
- Serum Testosterone3–6 months after initiation; then annually
RoutineMeasure midway between injections (trough level) for injections Q2W, or at any point for weekly injections. Target: 400–700 ng/dL (Endocrine Society). If supraphysiologic (>1000 ng/dL at peak), reduce dose or lengthen interval. If sub-therapeutic at trough, increase dose or shorten interval. - Hematocrit / HemoglobinBaseline; 3–6 months; then annually
RoutineMost important safety parameter. Withhold testosterone if hematocrit exceeds 54%. Restart at lower dose after normalization. Persistently elevated Hct requires permanent discontinuation or consideration of phlebotomy. - PSABaseline; 3–6 months; then per age-appropriate screening
RoutineEvaluate for prostate cancer if PSA >4.0 ng/mL or rises >1.4 ng/mL within 12 months of starting TRT (Endocrine Society). Digital rectal exam at baseline if clinically indicated. Refer to urology for PSA elevation. - Lipid PanelBaseline; 6–12 months
RoutineTestosterone may decrease HDL and increase LDL. Monitor and adjust lipid-lowering therapy if needed. Clinical significance debated; TRAVERSE showed no excess MACE despite lipid changes. - Liver Function TestsBaseline; periodically
Trigger-basedTestosterone cypionate is not a 17-alpha-alkyl androgen and carries low hepatotoxicity risk. Monitor LFTs if symptoms of hepatic dysfunction arise (jaundice, dark urine, abdominal pain). - Bone Density (DXA)Baseline (if osteoporosis risk); then 1–2 years
Trigger-basedTestosterone improves BMD in hypogonadal men. Monitor in patients treated for osteoporosis to assess response. - Bone Age (pediatric)Every 6 months during treatment
RoutineTestosterone accelerates skeletal maturation and may cause premature epiphyseal closure, compromising adult height. Wrist and hand X-ray every 6 months in pediatric patients. - Serum ProlactinBaseline; 3–4 months
RoutineTestosterone may increase serum prolactin. If prolactin remains elevated at 3–4 months, consider discontinuation and pituitary evaluation (per Azmiro PI).
Contraindications & Cautions
Absolute Contraindications
- Known or suspected prostate carcinoma: Exogenous testosterone may stimulate growth of androgen-sensitive prostate tumors.
- Male breast carcinoma: Testosterone is contraindicated in men with breast cancer.
- Pregnancy: Testosterone causes virilization of the female fetus. Contraindicated in pregnant women.
- Known hypersensitivity: To testosterone cypionate or any excipient (cottonseed oil, benzyl benzoate, benzyl alcohol). Anaphylactoid reactions have been reported.
Relative Contraindications (Specialist Input Recommended)
- Severe untreated sleep apnea: Testosterone may worsen obstructive sleep apnea. Screen and treat OSA before initiating TRT.
- Uncontrolled heart failure: Fluid retention from androgens may exacerbate CHF.
- Baseline hematocrit >50%: High pre-treatment hematocrit increases the risk of clinically significant polycythemia during TRT.
- Desire for current fertility: Exogenous testosterone suppresses spermatogenesis and may cause irreversible infertility. Alternatives (clomiphene, hCG) should be considered in men planning conception.
Use with Caution
- BPH: May worsen urinary symptoms; monitor for LUTS progression.
- Pre-existing cardiac, renal, or hepatic disease: Risk of edema from sodium and water retention.
- Patients on anticoagulants: Increased anticoagulant sensitivity; monitor INR closely.
- History of thromboembolic events: Use with caution; TRAVERSE found higher PE incidence in the testosterone group.
- Cancer patients at risk of hypercalcemia: Androgens may exacerbate hypercalcemia; monitor serum calcium.
In 2015, the FDA required all testosterone product labels to include a warning about the possible increased risk of MACE (MI, stroke, CV death) based on inconclusive epidemiologic data. The landmark TRAVERSE trial (NEJM 2023, N = 5246) subsequently demonstrated that TRT was noninferior to placebo for MACE in men with hypogonadism and pre-existing or high CV risk (HR 0.96; noninferiority margin met). However, the testosterone group had more nonfatal arrhythmias (including atrial fibrillation) and pulmonary embolism. Testosterone is also a Schedule III controlled substance with potential for abuse and dependence, particularly at supratherapeutic doses combined with other AAS.
Patient Counselling
Purpose of Therapy
Testosterone cypionate replaces the testosterone your body is not producing in adequate amounts. Treatment aims to restore testosterone levels to the normal male range, which can improve energy, mood, sexual function, muscle strength, and bone density. This medication is given as an injection into the buttock muscle, typically every 1 to 4 weeks, depending on your prescribed dose and schedule.
How to Take
Injections are administered deep into the gluteal (buttock) muscle by a healthcare provider. Some patients may be trained to self-inject at home. The medication should be stored at room temperature and protected from light. Do not inject intravenously. Keep all laboratory monitoring appointments, as regular blood tests are essential to ensure the medication is working safely.
Sources
- Azmiro (testosterone cypionate) injection prescribing information. Slayback Pharma LLC. Revised February 2024. FDA LabelModern-format PI with comprehensive dosing, PK data (Table 1), adverse reactions, and updated warnings including CV risk, polycythemia, VTE, and prolactin increases.
- Depo-Testosterone (testosterone cypionate injection) prescribing information. Pharmacia & Upjohn/Pfizer. Revised 2018. FDA LabelOriginal brand label for Depo-Testosterone; provides legacy PK data, class-effect adverse reactions, and original dosing guidance.
- Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular safety of testosterone-replacement therapy. N Engl J Med. 2023;389(2):107-117. DOI: 10.1056/NEJMoa2215025The landmark TRAVERSE trial (N = 5246): TRT noninferior to placebo for MACE in men with hypogonadism and CV risk; found more atrial fibrillation and PE in the testosterone group.
- Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment in older men. N Engl J Med. 2016;374(7):611-624. DOI: 10.1056/NEJMoa1506119The Testosterone Trials (TTrials): showed modest improvements in sexual function, physical function, and vitality in older men with low testosterone; informed the design of TRAVERSE.
- Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559. DOI: 10.1210/jc.2009-2354Prior version of the Endocrine Society guideline; established testosterone cypionate dosing standards and monitoring parameters widely adopted in clinical practice.
- Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744. DOI: 10.1210/jc.2018-00229Current gold-standard guideline for TRT: defines diagnostic criteria (2 morning T levels <300 ng/dL), recommends cypionate 75–100 mg/week or 150–200 mg Q2W, and details monitoring schedule.
- Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine treatment of gender-dysphoric/gender-incongruent persons: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(11):3869-3903. DOI: 10.1210/jc.2017-01658Provides testosterone cypionate dosing recommendations for gender-affirming masculinizing hormone therapy (off-label use).
- Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and management of testosterone deficiency: AUA guideline. J Urol. 2018;200(2):423-432. DOI: 10.1016/j.juro.2018.03.115AUA guideline addressing diagnosis, treatment, and monitoring of hypogonadism; complements the Endocrine Society guideline with a urology-focused perspective.
- Nieschlag E, Behre HM, Bouchard P, et al. Testosterone replacement therapy: current trends and future directions. Hum Reprod Update. 2004;10(5):409-419. DOI: 10.1093/humupd/dmh035Comprehensive review of testosterone ester pharmacokinetics, including cypionate depot kinetics and peak-trough profiles.
- Morgentaler A, Zitzmann M, Traish AM, et al. Fundamental concepts regarding testosterone deficiency and treatment. Mayo Clin Proc. 2016;91(7):881-896. DOI: 10.1016/j.mayocp.2016.04.007Reviews the clinical pharmacology of testosterone replacement, including metabolism to DHT and estradiol, and the polycythemia dose-response.
- Basaria S. Male hypogonadism. Lancet. 2014;383(9924):1250-1263. DOI: 10.1016/S0140-6736(13)61126-5Authoritative review of hypogonadism pathophysiology, testosterone mechanisms of action, and clinical management considerations.