Mechanism of action
Testosterone is a steroid hormone derived from cholesterol. It exerts its effects by binding to intracellular androgen receptors (AR) located in target tissues including muscle, bone, prostate, and central nervous system. Upon binding, the testosterone-receptor complex translocates to the nucleus where it acts as a transcription factor, binding to androgen response elements (ARE) on DNA and modulating gene expression.
In certain tissues, testosterone is converted by 5α-reductase to dihydrotestosterone (DHT), a more potent androgen with higher affinity for the androgen receptor. DHT is responsible for development of external male genitalia, prostate growth, male pattern baldness, and sebaceous gland activity. In other tissues, testosterone is aromatized by the enzyme aromatase to estradiol, which contributes to bone maturation, epiphyseal closure, and regulation of lipid metabolism.
Testosterone also exerts negative feedback on the hypothalamic-pituitary-gonadal (HPG) axis. It suppresses secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary. This feedback mechanism is clinically significant because exogenous testosterone administration suppresses endogenous production and can lead to testicular atrophy and infertility.
The anabolic effects of testosterone include increased protein synthesis, muscle mass, bone density, and red blood cell production via stimulation of erythropoietin. Androgenic effects include development and maintenance of male secondary sexual characteristics such as deepening of the voice, facial and body hair growth, and increased libido.
- Testosterone suppresses LH and FSH via negative feedback, causing testicular atrophy and infertility — a key reason it cannot be used alone for male infertility treatment
- 5α-reductase converts testosterone to DHT (more potent); aromatase converts it to estradiol (important for bone closure)
- Erythrocytosis occurs in 10-20% of patients on testosterone therapy due to increased erythropoietin; hematocrit >54% requires dose reduction or discontinuation
- Exogenous testosterone does not cause prostate cancer but can accelerate growth of existing androgen-sensitive cancer; monitor PSA and perform DRE
- Schedule III controlled substance in the US due to abuse potential by athletes and bodybuilders
- Transdermal testosterone gels can transfer to others through skin contact, causing virilization in women and children
- Testosterone potentiates warfarin effect; monitor INR closely when initiating or adjusting testosterone therapy
- Two separate morning measurements of low testosterone plus clinical symptoms are required to diagnose hypogonadism before starting therapy
Indications
Testosterone replacement therapy is indicated for male hypogonadism with both clinical symptoms and consistently low serum testosterone levels. Hypogonadism may be primary (testicular failure, Klinefelter syndrome) or secondary (hypothalamic or pituitary dysfunction).
Approved indications
- Primary hypogonadism: congenital (anorchia, Klinefelter syndrome) or acquired (trauma, orchitis, chemotherapy)
- Hypogonadotropic hypogonadism: Kallmann syndrome, pituitary tumors, hyperprolactinemia
- Delayed puberty in males: when constitutional delay is confirmed and intervention is warranted
- Gender-affirming hormone therapy: for transgender men and non-binary individuals assigned female at birth
- Certain breast cancers: palliative treatment of advanced inoperable metastatic breast cancer in women (rarely used today)
Off-label uses
Testosterone is sometimes used off-label for female hypoactive sexual desire disorder, though evidence is limited and it is not FDA-approved for this indication in the United States. It should not be used for age-related decline in testosterone in older men without true hypogonadism ("low T" marketing claims), as risks may outweigh benefits.
Diagnosis of hypogonadism requires documentation of low serum testosterone on at least two separate morning measurements, along with clinical symptoms such as decreased libido, erectile dysfunction, fatigue, reduced muscle mass, or infertility.
Pharmacokinetics
Testosterone is available in multiple formulations including intramuscular injections, transdermal gels and patches, subcutaneous pellets, oral preparations, buccal tablets, and nasal gels. Pharmacokinetics vary significantly by route of administration.
Oral testosterone undergoes extensive first-pass hepatic metabolism, resulting in poor bioavailability and potential hepatotoxicity with alkylated formulations. Newer oral testosterone undecanoate is absorbed via the lymphatic system, bypassing first-pass metabolism.
Intramuscular testosterone esters (testosterone enanthate, cypionate, undecanoate) are lipophilic and slowly released from the injection depot. Testosterone enanthate and cypionate have half-lives of approximately 4-5 days, typically requiring administration every 1-2 weeks. Testosterone undecanoate has a much longer half-life, allowing for dosing every 10-12 weeks after a loading phase.
Transdermal formulations (gels, patches) provide steady-state levels that more closely mimic physiologic diurnal variation. Gels are applied daily to the shoulders, upper arms, or abdomen; patches to the back, abdomen, thighs, or upper arms. Transdermal absorption is approximately 10% for gels.
Metabolism: Testosterone is metabolized in the liver to various 17-keto steroids and conjugated metabolites. It is also converted peripherally to DHT by 5α-reductase and to estradiol by aromatase. Approximately 90% of testosterone is excreted in urine as metabolites; 6% is excreted in feces.
Protein binding: Approximately 98% of circulating testosterone is bound to sex hormone-binding globulin (SHBG, 40-50%) and albumin (50%). Only 2% circulates as free, biologically active hormone. Conditions that alter SHBG levels (obesity decreases SHBG; hyperthyroidism increases SHBG) affect total but not necessarily free testosterone concentrations.
Adverse effects
Testosterone therapy carries multiple risks that require monitoring and patient counseling.
Cardiovascular effects
Increased cardiovascular risk remains controversial but is a significant concern. Observational studies and some trials have shown increased risk of myocardial infarction, stroke, and cardiovascular mortality, particularly in older men and those with pre-existing cardiovascular disease. The FDA requires a warning about possible increased cardiovascular risk.
Erythrocytosis (polycythemia) occurs in 10-20% of patients, particularly with intramuscular formulations. Elevated hematocrit (>54%) increases blood viscosity and thrombotic risk. Periodic monitoring of hemoglobin and hematocrit is required; dose reduction or temporary discontinuation may be necessary.
Reproductive effects
- Suppression of spermatogenesis and infertility: Exogenous testosterone suppresses LH and FSH, reducing intratesticular testosterone and impairing sperm production. This effect is dose-dependent and may take months to reverse after discontinuation. Men desiring fertility should consider alternatives such as human chorionic gonadotropin (hCG) or clomiphene.
- Testicular atrophy: Results from suppression of gonadotropins
- Gynecomastia: Due to aromatization of testosterone to estradiol
Prostate effects
Prostate enlargement and lower urinary tract symptoms can worsen with testosterone therapy. While testosterone does not cause prostate cancer, it can accelerate growth of existing hormone-sensitive prostate cancer. Baseline prostate-specific antigen (PSA) and digital rectal examination are recommended before initiation, with periodic monitoring during therapy.
Hepatotoxicity
Oral 17α-alkylated androgens (not commonly used testosterone preparations) can cause cholestatic jaundice, hepatic adenomas, and hepatocellular carcinoma. Modern testosterone preparations have much lower hepatotoxicity.
Other adverse effects
- Acne and oily skin: Due to increased sebaceous gland activity
- Male pattern baldness: In genetically predisposed individuals
- Sleep apnea: Testosterone may worsen obstructive sleep apnea
- Mood changes: Aggression, irritability, mood swings (dose-dependent)
- Edema and weight gain: Due to sodium and water retention
- Lipid effects: Decreased HDL cholesterol, variable effects on LDL and triglycerides
- Venous thromboembolism: Rare but reported
Formulation-specific effects
Transdermal gels carry a risk of transfer to others (especially women and children) through skin contact. Patients must wash hands after application and cover application sites.
Intramuscular injections can cause pain, swelling at injection site, and rare pulmonary oil microembolism (especially with testosterone undecanoate).
Contraindications and warnings
Absolute contraindications
- Prostate cancer or male breast cancer: Testosterone can stimulate androgen-sensitive tumors
- Pregnancy: Testosterone is FDA pregnancy category X. It causes virilization of female fetuses
- Lactation: Excreted in breast milk and may suppress lactation
- Hypersensitivity to testosterone or formulation components
Relative contraindications and warnings
Cardiovascular disease: Use with caution in men with history of myocardial infarction, stroke, or heart failure. Consider baseline cardiovascular risk assessment.
Polycythemia: Pre-existing erythrocytosis (hematocrit >50%) is a relative contraindication. Monitoring is required during therapy.
Severe liver or kidney disease: Testosterone may worsen hepatic or renal function and cause fluid retention.
Obstructive sleep apnea: Testosterone may exacerbate symptoms. Screen patients with obesity, snoring, or daytime somnolence.
Benign prostatic hyperplasia with severe urinary symptoms: Testosterone may worsen lower urinary tract symptoms.
Black box warnings
The FDA has issued warnings regarding:
- Serious pulmonary oil microembolism reactions and anaphylaxis with testosterone undecanoate injection (requires administration in healthcare settings with monitoring)
- Potential for abuse: Testosterone is a Schedule III controlled substance in the United States due to potential for non-medical use and abuse by athletes and bodybuilders
- Increased cardiovascular risk: Including myocardial infarction and stroke, especially in older men
Monitoring requirements
- Baseline: testosterone levels (morning), PSA, digital rectal exam, hemoglobin/hematocrit, lipid profile, liver function tests
- During therapy: testosterone levels at 3-6 months then annually; PSA and prostate exam at 3-6 months, 12 months, then annually in men >40 years; hematocrit at 3-6 months then annually
- Monitor for signs of virilization in women and children exposed to transdermal formulations
Drug interactions
Anticoagulants
Testosterone enhances the effects of warfarin and other oral anticoagulants by increasing sensitivity of clotting factors to anticoagulation and potentially decreasing synthesis of clotting factors. INR should be monitored more frequently when initiating or changing testosterone therapy, and warfarin dose adjustment may be necessary.
Insulin and oral hypoglycemic agents
Testosterone may enhance insulin sensitivity and decrease blood glucose levels, potentially requiring reduction in insulin or oral hypoglycemic agent doses in diabetic patients. Monitor glucose more frequently when initiating testosterone therapy.
Corticosteroids
Concurrent use of testosterone with corticosteroids may increase the risk of edema, particularly in patients with cardiac, renal, or hepatic disease, due to additive sodium and water retention.
Hepatic enzyme inducers and inhibitors
Drugs that induce CYP3A4 (rifampin, phenytoin, carbamazepine, barbiturates) may increase testosterone metabolism and reduce serum levels. CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir) may decrease metabolism and increase testosterone levels, though clinical significance varies by formulation.
Other interactions
- ACTH and corticotropin: May enhance edema formation
- Oxyphenbutazone: Elevated serum levels of oxyphenbutazone may result
- Propranolol: Testosterone may increase clearance of propranolol
Anabolic steroids and androgens are frequently used concurrently in non-medical settings, but polypharmacy with multiple androgens or performance-enhancing drugs significantly increases risks and is not recommended in therapeutic contexts.
Clinical pearls
Diagnosis before treatment: Always confirm true hypogonadism with at least two morning testosterone measurements and corresponding clinical symptoms. Do not treat age-related decline alone without documented hypogonadism.
Fertility counseling: Counsel all men of reproductive age that testosterone therapy will suppress spermatogenesis and may cause infertility. Sperm banking should be considered. For men desiring fertility, consider alternatives such as hCG, clomiphene, or selective estrogen receptor modulators that preserve HPG axis function.
Peak and trough levels matter: With intramuscular testosterone esters, patients may experience supraphysiologic peaks shortly after injection and subtherapeutic troughs before the next dose, causing mood and energy fluctuations. More frequent dosing with smaller amounts or switching to transdermal formulations may improve symptom control.
PSA velocity: An increase in PSA >1.4 ng/mL over 12 months or a PSA >4.0 ng/mL warrants urologic evaluation, even if still within "normal" range. Testosterone therapy typically causes a modest PSA increase in the first 6-12 months that then stabilizes.
Hematocrit monitoring: If hematocrit exceeds 54%, hold therapy until it decreases to safe levels. Consider therapeutic phlebotomy for persistent elevations. Do not simply continue therapy assuming the polycythemia is benign.
Transdermal transfer risk: Educate patients using gels about the risk of transfer to intimate partners and children. Application sites should be covered with clothing, and patients should wash hands immediately after application. Women and children exposed to gels may develop signs of virilization.
Not for athletic enhancement: Emphasize that testosterone is a controlled substance and use for athletic or cosmetic enhancement carries medical and legal risks.
Aromatase inhibitors are not routine: Some clinicians add aromatase inhibitors to prevent estradiol-related side effects (gynecomastia, water retention), but this is not standard practice and may have adverse effects on bone health and lipid profiles.
Consider SHBG: In obese men with metabolic syndrome, SHBG is often low, leading to low total testosterone but potentially normal free testosterone. Measure free or bioavailable testosterone when total testosterone is borderline low.
Practice questions
1. A 62-year-old man with type 2 diabetes and coronary artery disease is started on testosterone cypionate injections for confirmed hypogonadism. Three months later, he presents with fatigue and headaches. Laboratory studies show hemoglobin 18.5 g/dL (normal 13.5-17.5) and hematocrit 56% (normal 38-50%). What is the most appropriate next step in management?
2. A 28-year-old man and his wife present to the fertility clinic after 18 months of unsuccessful attempts at conception. He reports receiving testosterone injections from his primary care physician for the past 2 years for 'low energy.' Physical examination reveals bilateral testicular atrophy. Semen analysis shows azoospermia. Which of the following best explains his infertility?
3. A 55-year-old man on chronic warfarin therapy for atrial fibrillation starts testosterone gel for hypogonadism. Two weeks later, he presents to the emergency department with epistaxis and gingival bleeding. His INR is 5.8 (therapeutic range 2-3). His warfarin dose has not changed. What is the mechanism of this drug interaction?
Frequently asked questions
How does testosterone work in the body?
Testosterone binds to intracellular androgen receptors, forming a complex that enters the nucleus and regulates gene transcription. It is converted to dihydrotestosterone (DHT) by 5α-reductase in some tissues, which has higher androgen receptor affinity, and to estradiol by aromatase in others. Testosterone promotes protein synthesis, increases muscle and bone mass, stimulates erythropoietin production, and maintains male secondary sexual characteristics. It also suppresses gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) through negative feedback on the hypothalamic-pituitary axis.
What are the side effects of testosterone therapy?
Common side effects include erythrocytosis (elevated red blood cell count), acne, oily skin, testicular atrophy, and infertility due to suppression of sperm production. Testosterone therapy increases cardiovascular risk, including myocardial infarction and stroke, particularly in older men. It can worsen sleep apnea, cause gynecomastia from aromatization to estradiol, and accelerate male pattern baldness. Prostate enlargement and worsening urinary symptoms may occur. Transdermal formulations risk transfer to others, causing virilization in women and children. Mood changes and aggression can occur at high doses.
Is testosterone a controlled substance?
Yes, testosterone is a Schedule III controlled substance in the United States under the Controlled Substances Act due to its potential for abuse and non-medical use, particularly by athletes and bodybuilders seeking performance enhancement. Prescribing testosterone requires DEA registration, and prescriptions are subject to specific regulations including limits on refills and requirements for written or electronic prescriptions in most states. Illegal possession or distribution of testosterone without a valid prescription carries criminal penalties.
Can testosterone cause infertility?
Yes, exogenous testosterone causes infertility by suppressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion through negative feedback on the pituitary gland. This suppression reduces intratesticular testosterone production and impairs spermatogenesis, often leading to severe oligospermia or azoospermia. Testicular atrophy commonly occurs. The effect is dose-dependent and generally reversible, but recovery of spermatogenesis may take 6-12 months or longer after discontinuation. Men desiring fertility should not use testosterone therapy; alternatives include human chorionic gonadotropin (hCG) or clomiphene citrate.
Testosterone vs DHT — what is the difference?
Dihydrotestosterone (DHT) is a metabolite of testosterone formed by the enzyme 5α-reductase. DHT has 2-3 times greater affinity for the androgen receptor compared to testosterone, making it more potent. DHT is responsible for development of male external genitalia in utero, prostate growth, male pattern baldness, facial and body hair growth, and sebaceous gland activity. Testosterone itself is responsible for muscle mass, bone density, libido, and spermatogenesis. DHT cannot be aromatized to estrogen, unlike testosterone, which is converted to estradiol by aromatase.
Conditions it is used for
Related drugs
Sources and further reading
DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: G03BA03
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.