Androgens and Anabolic Steroids

Introduction / Overview

Androgens comprise a group of steroid hormones that exert diverse physiological effects through the androgen receptor (AR). They are essential for the development and maintenance of male reproductive tissues, but also influence muscle mass, bone density, erythropoiesis, and mood. Anabolic steroids (AS), synthetic derivatives of testosterone, are designed to enhance anabolism and muscle growth while modulating androgenic actions. The clinical relevance of androgens and AS spans endocrinology, oncology, sports medicine, and dermatology, among others. Their therapeutic potential is tempered by a spectrum of adverse effects and a high potential for abuse, necessitating a comprehensive understanding of their pharmacology for safe and effective use.

Learning objectives

• Identify the principal classes of natural and synthetic androgens and understand their chemical diversity.
• Explain the pharmacodynamic mechanisms by which androgens and AS interact with the androgen receptor and downstream signaling pathways.
• Describe the key pharmacokinetic parameters that influence dosing schedules and therapeutic monitoring.
• Recognize approved indications and common off‑label applications, while evaluating the risk–benefit profile of each therapy.
• Identify major adverse effects, drug interactions, and special patient populations that require modified prescribing practices.

Classification

Natural Androgens

Testosterone serves as the prototypical endogenous androgen. It is produced primarily in the Leydig cells of the testes and, to a lesser extent, in the adrenal cortex. Its biosynthetic pathway originates from cholesterol through a series of enzymatic conversions, culminating in 17β‑estradiol and dihydrotestosterone (DHT) as secondary metabolites. DHT, derived from testosterone via 5α‑reductase, exhibits higher affinity for the AR and is implicated in androgenic tissue differentiation.

Other endogenous androgens include:

• Dehydroepiandrosterone (DHEA) and its sulfated form (DHEA‑S), produced by the adrenal cortex and serving as precursors for testosterone and estrone.
• Androstenedione, a direct precursor of testosterone and estrone.
• Progesterone, which can be converted to 17α‑hydroxyprogesterone and subsequently to androstenedione in the adrenal cortex.

Synthetic Anabolic Steroids

AS are chemically modified testosterone analogues designed to enhance anabolic activity while limiting androgenic side effects. Modifications typically involve structural changes at positions 3, 4, 5, 7, 10, and 17, such as esterification, methylation, or addition of alkyl groups. Common pharmacologic classes include:

• Alkylated oral steroids – e.g., methyltestosterone, fluoxymesterone; these possess a 17α‑alkyl group that confers oral bioavailability but increases hepatotoxicity.
• Esterified injectable steroids – e.g., nandrolone decanoate, testosterone enanthate; esterification prolongs release from intramuscular depot formulations.
• 5α‑Reduced steroids – e.g., stanozolol, oxymetholone; these mimic DHT’s high AR affinity.
• Non‑steroidal AR modulators – e.g., selective androgen receptor modulators (SARMs) designed to retain anabolic effects with reduced androgenicity. While not traditional steroids, they are included for completeness.

Chemical Classification

All androgenic compounds share the cyclopentanoperhydrophenanthrene nucleus characteristic of steroids. Variations in functional groups and stereochemistry define subclasses: 17β‑hydroxylated steroids (testosterone, DHT), 17α‑alkylated steroids (methyltestosterone), 17α‑esterified steroids (nandrolone enanthate), and non‑steroidal analogs (SARMs). The presence or absence of the 3‑ketone, 4‑double bond, and 17α‑substituents critically influences metabolic stability, receptor affinity, and androgenic versus anabolic potency.

Mechanism of Action

Receptor Binding and Activation

Androgens exert their primary effects by binding to the cytoplasmic androgen receptor (AR), a member of the nuclear receptor superfamily. Ligand binding induces a conformational change that promotes dissociation of heat shock proteins, receptor dimerization, and translocation into the nucleus. Once bound to androgen response elements (AREs) in promoter regions, the AR complex modulates transcription of target genes. The net effect is a balance between anabolic pathways (e.g., protein synthesis, satellite cell proliferation) and androgenic pathways (e.g., prostate growth, sebaceous gland activity).

Post‑Translational Modulation

AR activity is further regulated by phosphorylation, acetylation, and ubiquitination. Kinases such as MAPK and AKT can phosphorylate the receptor, altering its transcriptional potency. Co‑activators (e.g., SRC‑1, p300) and co‑repressors (e.g., NCoR, SMRT) modulate chromatin remodeling and gene expression. These post‑translational modifications can be influenced by concurrent pharmacologic agents, thereby affecting therapeutic outcomes.

Metabolic Conversion

Testosterone is metabolized to DHT by 5α‑reductase, a process that increases AR affinity by approximately 5‑fold. DHT is further oxidized to 3α‑ and 3β‑hydroxy‑DHT, which act as AR antagonists. In the liver, conjugation reactions (glucuronidation, sulfation) facilitate excretion. Synthetic AS may resist metabolic conversion depending on structural modifications; for instance, 17α‑alkylated steroids are less susceptible to hepatic metabolism, contributing to their oral bioavailability but also to hepatotoxicity.

Non‑Genomic Actions

Emerging evidence indicates that androgens can initiate rapid, non‑genomic signaling via membrane‑associated AR or second‑messenger systems such as PI3K/AKT and ERK pathways. These pathways contribute to acute cellular effects, including vasodilation, ion channel modulation, and cytoskeletal rearrangement. However, the clinical significance of these rapid actions remains under investigation.

Pharmacokinetics

Absorption

Oral and injectable formulations display distinct absorption profiles. Oral AS with a 17α‑alkyl group typically achieve peak plasma concentrations within 1–4 h post‑dose, whereas non‑alkylated steroids require parenteral administration to bypass first‑pass hepatic metabolism. Intramuscular depot formulations demonstrate a slow release, with peak levels occurring weeks after injection; this allows for monthly dosing regimens in many therapeutic indications.

Distribution

Androgens are lipophilic, resulting in extensive tissue distribution. Approximately 90 % of testosterone binds to plasma sex hormone‑binding globulin (SHBG) or albumin, leaving <10 % as free hormone available for receptor interaction. AS with high lipophilicity may accumulate in adipose tissue, potentially prolonging their effects. The volume of distribution for injectable esters often exceeds 10 L/kg due to depot release and tissue sequestration.

Metabolism

Metabolic pathways involve oxidation (e.g., 5α‑reduction to DHT), conjugation (glucuronidation, sulfation), and sulfotransferase activity. 17α‑alkylated steroids are resistant to hepatic oxidation, leading to prolonged systemic exposure but increased hepatocellular stress. Esters are hydrolyzed by plasma esterases, liberating the active androgen for systemic action. Variability in cytochrome P450 enzymes, particularly CYP3A4, influences metabolism of many AS, contributing to drug‑drug interaction potential.

Excretion

The primary route of elimination is biliary excretion of conjugated metabolites, followed by fecal elimination. Renal excretion of the unconjugated parent compound is minimal due to extensive hepatic metabolism. The elimination half‑life varies widely; for example, nandrolone decanoate has a half‑life of 6–8 days, whereas oral 17α‑alkylated steroids may have a half‑life of 1–2 days but maintain activity through sustained release from hepatic stores.

Dosing Considerations

Dosing regimens are tailored to therapeutic objectives and patient characteristics. Injectable esters are typically dosed weekly to monthly, whereas oral AS may require daily dosing. The selection of formulation is influenced by the desired onset of action, duration of effect, and risk of adverse events. Therapeutic drug monitoring is rarely performed but may be considered in patients with hepatic impairment or at risk for supratherapeutic exposure.

Therapeutic Uses / Clinical Applications

Approved Indications

Androgens and AS are approved for several clinical conditions:

• Hypogonadism – exogenous testosterone therapy (oral, transdermal, injectable) is indicated for men with deficient endogenous testosterone leading to symptoms such as fatigue, decreased libido, and loss of muscle mass.
• Delayed puberty in males – testosterone enanthate or cypionate is used to stimulate growth and secondary sexual characteristics.
• Anemia of chronic disease or chemotherapy‑induced anemia – testosterone can stimulate erythropoiesis, improving hemoglobin levels.
• Chronic obstructive pulmonary disease (COPD)‑associated cachexia – testosterone therapy has been shown to enhance lean body mass and functional status.
• Osteoporosis in men – testosterone therapy may reduce fracture risk by increasing bone mineral density.

Off‑Label and Emerging Uses

Off‑label applications are common in clinical practice and include:

• Reconstruction of soft tissues after trauma or surgery, leveraging anabolic effects to promote wound healing.
• Adjunct therapy for certain cancers (e.g., castration‑resistant prostate cancer) in combination with AR antagonists, exploiting a paradoxical “hormonal switch” effect.
• Treatment of androgen insensitivity syndrome (AIS) with high‑dose testosterone to stimulate androgenic tissues.
• Management of hypogonadism in transgender men receiving exogenous testosterone for gender transition.
• Use of 5α‑reduced steroids (e.g., stanozolol) in athletes for performance enhancement, despite legal and ethical concerns.

Non‑Pharmacologic Adjuncts

Co‑therapy with growth hormone, selective estrogen receptor modulators (SERMs), or corticosteroids can modulate the anabolic effects of AS, but such combinations require careful monitoring for compounded adverse effects.

Adverse Effects

Common Side Effects

These effects are dose‑dependent and may resolve with therapy discontinuation:

• Androgenic effects – hirsutism, acne, oily skin, increased sebum production.
• Fluid retention and edema leading to mild hypertension.
• Gynecomastia due to aromatization of testosterone to estradiol, particularly in patients with high aromatase activity.
• Sleep disturbances, including insomnia or sleep apnea.
• Menstrual irregularities or amenorrhea in women receiving AS.

Serious / Rare Adverse Reactions

These events necessitate prompt evaluation and may require discontinuation of therapy:

• Hepatotoxicity – cholestatic jaundice, peliosis hepatis, hepatic adenomas, and hepatocellular carcinoma, especially with 17α‑alkylated oral steroids.
• Cardiovascular events – myocardial infarction, stroke, arrhythmias, and vascular dysfunction due to dyslipidemia (↑LDL, ↓HDL) and endothelial dysfunction.
• Psychiatric manifestations – aggression, mood swings, depression, and in severe cases, psychosis.
• Reproductive effects – infertility owing to suppression of gonadotropin secretion, testicular atrophy, and decreased spermatogenesis.
• Dermatologic reactions – severe acneiform eruptions, seborrheic dermatitis, and potential for folliculitis.

Black Box Warnings

Regulatory agencies have issued black box warnings for several AS, particularly 17α‑alkylated oral steroids, concerning hepatotoxicity, potential for liver tumors, and cardiovascular risk. Patients should be counseled regarding these risks and monitored with periodic liver function tests and lipid panels.

Drug Interactions

Major Drug–Drug Interactions

Androgens and AS interact with various classes of medications through shared metabolic pathways or receptor modulation:

• Cytochrome P450 inhibitors – ketoconazole, erythromycin, and ritonavir can increase serum androgen levels by reducing hepatic metabolism.
• Cytochrome P450 inducers – rifampin, phenytoin, and carbamazepine may decrease androgen concentrations, potentially compromising therapeutic efficacy.
• Hepatotoxic agents – concurrent use of other hepatotoxic drugs (e.g., acetaminophen, methotrexate) may amplify liver injury.
• Anticoagulants – warfarin and direct oral anticoagulants (DOACs) may have altered pharmacodynamics due to steroid‑mediated changes in coagulation factors.
• Estrogens and selective estrogen receptor modulators (SERMs) – can compete for aromatase activity and influence the ratio of testosterone to estradiol.

Contraindications

Androgen therapy should be avoided in the following conditions:

• Active prostate or breast cancer due to risk of tumor progression.
• Untreated sleep apnea or severe cardiovascular disease.
• Pregnancy and lactation because of teratogenic potential.
• Known hypersensitivity to the active ingredient or excipients.
• Severe hepatic or renal impairment where drug metabolism and excretion are compromised.

Special Considerations

Use in Pregnancy and Lactation

Exogenous androgens cross the placenta and can disrupt fetal sexual differentiation, leading to feminization or virilization depending on dose and timing. Consequently, androgen therapy is contraindicated during pregnancy. Breastfeeding mothers should avoid AS due to potential transfer into breast milk and subsequent infant exposure.

Pediatric and Geriatric Considerations

In pediatric populations, dosing must account for developmental stage, ensuring that growth and sexual maturation are not adversely affected. Exogenous testosterone is sometimes prescribed for delayed puberty under strict endocrinologic supervision. In geriatric patients, polypharmacy increases interaction risk; dose adjustments may be necessary due to reduced hepatic and renal function. Monitoring of bone density, cardiovascular status, and androgenic side effects is recommended.

Renal and Hepatic Impairment

Renal elimination of unconjugated testosterone is limited; however, patients with hepatic dysfunction experience impaired metabolism, resulting in elevated plasma concentrations. Caution is advised when prescribing 17α‑alkylated oral steroids to patients with liver disease, as hepatotoxicity risk is amplified. Dosing intervals may need extension, and hepatic function tests should be performed periodically.

Reproductive Health and Fertility

High‑dose androgen therapy suppresses gonadotropin secretion via negative feedback, leading to testicular atrophy and infertility. In men desiring fertility, low‑dose regimens or combined therapy with human chorionic gonadotropin (hCG) may mitigate suppression. Women with androgen excess should be evaluated for ovarian or adrenal pathology prior to initiating therapy.

Summary / Key Points

• Androgens and anabolic steroids share a common cyclopentanoperhydrophenanthrene core but differ in functional groups that dictate pharmacokinetic and pharmacodynamic properties.
• Binding of androgens to the AR initiates genomic transcriptional changes and rapid non‑genomic signaling pathways, driving anabolic and androgenic effects.
• Administration routes and chemical modifications (esterification, alkylation) influence absorption, distribution, metabolism, and elimination, thereby shaping dosing strategies.
• Approved indications include hypogonadism, delayed puberty, anemia, COPD‑related cachexia, and osteoporosis in men; off‑label uses are widespread but warrant caution.
• Adverse effects span androgenic manifestations, hepatotoxicity, cardiovascular risk, psychiatric disturbances, and reproductive suppression; black box warnings apply to certain oral AS.
• Drug interactions, particularly with CYP450 modulators and hepatotoxic agents, necessitate vigilant monitoring and dose adjustments.
• Special populations—pregnancy, lactation, pediatrics, geriatrics, and patients with hepatic or renal impairment—require individual risk–benefit assessment and tailored therapy.
• Clinical pearls: monitor liver enzymes and lipid profiles periodically; counsel patients on potential feminizing or masculinizing effects; consider alternative agents (e.g., SARMs) when appropriate to reduce androgenic side effects.

References

1. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
2. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
3. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
4. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
5. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
6. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
7. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
8. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.