Pharmacology of Androgens and Anabolic Steroids

Introduction/Overview

Androgens represent a critical class of steroid hormones responsible for the development and maintenance of male sexual characteristics and anabolic processes. The pharmacology of these agents encompasses both their endogenous physiological roles and their therapeutic applications, which are often complicated by significant misuse for performance enhancement. The primary endogenous androgen is testosterone, synthesized primarily in the Leydig cells of the testes under the control of luteinizing hormone (LH). Androgens exert their effects by binding to and activating the androgen receptor, a ligand-dependent transcription factor, leading to the modulation of gene expression in target tissues. The clinical relevance of this drug class is broad, extending from legitimate hormone replacement therapy to the controversial and illegal use of anabolic-androgenic steroids (AAS) in sports and bodybuilding.

The importance of understanding this pharmacology lies in the delicate balance between therapeutic benefit and substantial adverse effects. Medical applications are well-established for conditions like male hypogonadism, certain anemias, and hormone-sensitive cancers. However, the non-medical use of AAS, often involving supraphysiological doses and complex polypharmacy regimens, presents a significant public health challenge associated with cardiovascular, psychiatric, and endocrine toxicity.

Learning Objectives

• Describe the classification of androgenic agents based on chemical structure, origin, and pharmacological profile.
• Explain the molecular mechanism of action of androgens, including receptor activation and genomic versus non-genomic effects.
• Analyze the pharmacokinetic properties of major androgen preparations and how they influence clinical dosing and formulation.
• Evaluate the approved therapeutic uses, major adverse effects, and significant drug interactions associated with androgen therapy.
• Identify the special considerations for androgen use in specific populations, including pediatric, geriatric, and those with organ impairment.

Classification

Androgenic agents can be classified according to several criteria, including chemical structure, origin, and the balance between their anabolic and androgenic effects.

Chemical Classification

The foundational structure of all androgens is the sterane (cyclopentanoperhydrophenanthrene) nucleus. Modifications to this core structure at various carbon positions alter the pharmacokinetic and pharmacodynamic properties of the synthetic derivatives.

• Testosterone and Its Esters: These are direct derivatives of the endogenous hormone. Testosterone itself has poor oral bioavailability due to extensive first-pass metabolism. Esterification at the 17β-hydroxyl group (e.g., testosterone enanthate, cypionate, propionate) increases lipid solubility, allowing for depot intramuscular formulations with prolonged release.
• 17α-Alkylated Androgens: Addition of an alkyl group (e.g., methyl, ethyl) at the 17α position (e.g., methyltestosterone, oxandrolone, stanozolol) reduces first-pass hepatic metabolism, conferring oral bioavailability. This modification is also associated with increased risk of hepatotoxicity.
• 19-Nortestosterone Derivatives: These compounds lack the methyl group at the C19 position (e.g., nandrolone, trenbolone). They often exhibit a higher anabolic-to-androgenic ratio, as they are less readily converted to more potent androgens like dihydrotestosterone (DHT) in certain tissues.
• Dihydrotestosterone (DHT) Derivatives: These are based on the 5α-reduced metabolite of testosterone (e.g., stanolone, drostanolone). They cannot be aromatized to estrogens and are potent activators of the androgen receptor in tissues expressing 5α-reductase.

Classification by Origin and Use

• Endogenous Androgens: Testosterone and its active metabolites, dihydrotestosterone (DHT) and estradiol (via aromatization).
• Exogenous Therapeutic Androgens: FDA-approved agents for conditions such as hypogonadism, delayed puberty, and breast cancer. Examples include testosterone gels, patches, and esters; oxandrolone; and danazol.
• Anabolic-Androgenic Steroids (AAS): This term broadly encompasses synthetic testosterone derivatives used, often illicitly, to promote muscle growth and athletic performance. These agents are frequently used in “stacks” (combinations) and “cycles” (periods of use followed by discontinuation).
• Selective Androgen Receptor Modulators (SARMs): A newer class of non-steroidal agents that bind the androgen receptor but demonstrate tissue-selective anabolic activity, potentially offering muscle and bone benefits with reduced androgenic side effects. Their long-term safety and efficacy are still under investigation.

Mechanism of Action

The primary mechanism of action for androgens is mediated through the androgen receptor (AR), a member of the nuclear receptor superfamily. The effects can be broadly categorized as genomic (slow, mediated by changes in gene transcription) and non-genomic (rapid, mediated by membrane-associated or cytoplasmic signaling).

Receptor Interactions and Genomic Signaling

In the classic genomic pathway, lipid-soluble androgens diffuse across the plasma membrane and bind to the cytosolic androgen receptor, which is typically complexed with heat shock proteins (HSPs). Upon ligand binding, the receptor undergoes a conformational change, dissociates from the HSPs, dimerizes, and translocates to the nucleus. The ligand-receptor complex then binds to specific DNA sequences known as androgen response elements (AREs) located in the promoter or enhancer regions of target genes. This recruitment facilitates the assembly of coregulator complexes (coactivators or corepressors) and the general transcription machinery, ultimately modulating the rate of mRNA transcription. The translated proteins then mediate the cellular response, such as increased protein synthesis in muscle or altered gene expression in the prostate.

The differential effects of testosterone and DHT are partly explained by receptor dynamics. DHT binds the AR with approximately 2-3 times greater affinity than testosterone and forms a more stable complex with a slower dissociation rate. Furthermore, the 5α-reductase enzymes that convert testosterone to DHT are expressed in a tissue-specific manner (e.g., high in prostate, skin, liver; low in muscle, bone), creating localized amplification of the androgen signal.

Non-Genomic Mechanisms

Rapid effects of androgens, occurring within seconds to minutes, cannot be explained by gene transcription. These non-genomic actions are thought to be mediated by membrane-associated androgen receptors or through interaction with other signaling pathways. Proposed mechanisms include activation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways, modulation of intracellular calcium, and activation of Src kinase. These pathways can influence cell proliferation, apoptosis, and neuronal excitability independently of genomic effects.

Anabolic vs. Androgenic Effects

The concept of separating anabolic (muscle-building) from androgenic (masculinizing) effects has driven the development of synthetic AAS. While all AR agonists possess both properties to some degree, the anabolic-to-androgenic ratio is influenced by several factors. These include the compound’s susceptibility to 5α-reduction, its affinity for sex hormone-binding globulin (SHBG), its potential for aromatization to estrogens, and its specific interactions with the AR and tissue-specific co-regulators. In practice, a completely selective anabolic agent has not been successfully developed for clinical use, as the receptor mechanisms in muscle and sexual tissues are fundamentally similar.

Pharmacokinetics

The pharmacokinetic profiles of androgens vary dramatically depending on their chemical structure and formulation, directly impacting their route of administration, dosing frequency, and clinical utility.

Absorption

Testosterone is poorly absorbed orally due to extensive first-pass metabolism in the gut wall and liver, where it is rapidly converted to inactive metabolites. Therefore, therapeutic delivery systems are designed to bypass this effect.

• Transdermal: Gels, solutions, and patches provide continuous delivery through the skin, mimicking the normal diurnal rhythm of testosterone secretion more closely than injectable esters. Absorption can be variable and is influenced by skin site, surface area, and washing.
• Intramuscular (IM): Esters of testosterone (enanthate, cypionate) dissolved in oil are administered via deep IM injection. The esterified testosterone is released slowly from the depot site into the circulation, where esterases hydrolyze the ester to release free testosterone. This results in supra-physiological peaks shortly after injection and a gradual decline to trough levels over 1-4 weeks, depending on the ester.
• Oral: 17α-alkylated androgens (e.g., methyltestosterone, oxandrolone) resist first-pass metabolism and are absorbed effectively from the gastrointestinal tract. This convenience is offset by their hepatotoxic potential.
• Buccal: Tablets placed against the gum allow absorption through the oral mucosa directly into the systemic circulation, avoiding first-pass hepatic metabolism.
• Subcutaneous: Pellet implants and newer aqueous subcutaneous injections provide prolonged release over several months or steady delivery over shorter periods, respectively.

Distribution

In the circulation, testosterone is predominantly bound to plasma proteins. Approximately 40-60% is tightly bound to sex hormone-binding globulin (SHBG) with high affinity, and 30-40% is loosely bound to albumin. Only 1-3% circulates as free, biologically active hormone. The binding to SHBG serves as a reservoir and modulates hormone bioavailability. Many synthetic AAS have lower affinity for SHBG, which may increase their free fraction and potency. Androgens distribute widely throughout the body, with lipophilic compounds accumulating in adipose tissue.

Metabolism

Hepatic metabolism is the primary route of inactivation for androgens. The major metabolic pathways include:

• Oxidation/Reduction: The 17β-hydroxyl group is oxidized to a ketone, forming androstenedione. The A-ring is reduced by 5α- and 5β-reductases, producing metabolites like androsterone and etiocholanolone.
• Aromatization: Testosterone and some AAS can be converted by the cytochrome P450 enzyme aromatase (CYP19A1) to estradiol. This is a critical pathway responsible for estrogenic side effects like gynecomastia and epiphyseal closure.
• 5α-Reduction: In target tissues like the prostate and skin, testosterone is irreversibly converted to the more potent DHT by 5α-reductase isoenzymes (types 1 and 2).
• 17α-Alkylated Compounds: These agents undergo slower hepatic degradation, which contributes to their oral activity but also increases their hepatotoxic potential, as they may cause cholestasis and induce hepatic enzyme production.

Metabolites are typically conjugated with glucuronic acid or sulfate to increase water solubility for excretion.

Excretion

Conjugated metabolites are excreted primarily in the urine (≈90%), with a smaller fraction eliminated in the bile and feces. The elimination half-life (t_1/2) varies considerably: free testosterone has a short t_1/2 of about 10-20 minutes, while testosterone esters like enanthate have effective half-lives of 4-8 days following IM injection. Oral 17α-alkylated androgens have half-lives ranging from 6 to 12 hours.

Therapeutic Uses/Clinical Applications

The therapeutic use of androgens is strictly indicated for specific medical conditions where the benefits are judged to outweigh the significant risks.

Approved Indications

• Male Hypogonadism: This is the primary indication for testosterone replacement therapy (TRT). It is used to restore physiological levels in men with documented deficiency due to primary (testicular) or secondary (pituitary-hypothalamic) failure. Goals include improvement in libido, energy, muscle mass, bone mineral density, and mood.
• Delayed Puberty in Boys: Androgens may be used cautiously to induce puberty in boys with constitutional delay. Therapy is typically short-term to stimulate the onset of puberty without compromising final adult height.
• Hormone-Responsive Cancers: Historically, high-dose androgens or estrogens were used for palliative treatment of advanced breast cancer in postmenopausal women. This use has largely been supplanted by newer anti-estrogen therapies. Androgens may also be used to treat anemia associated with bone marrow failure or certain cancers.
• Wasting Syndromes: In conditions associated with catabolism and severe weight loss, such as HIV-associated wasting or severe burns, anabolic steroids like oxandrolone may be used as adjunctive therapy to promote lean body mass accretion and weight gain.
• Angioedema: The attenuated androgen danazol is used for the prophylaxis of hereditary angioedema. It increases the production of C1 esterase inhibitor, thereby preventing attacks.
• Anemias: Androgens stimulate erythropoiesis by increasing renal production of erythropoietin and possibly by a direct effect on bone marrow stem cells. Their use in aplastic anemia and anemia of chronic renal failure has declined with the availability of recombinant erythropoietin.

Off-Label and Investigational Uses

Off-label use may occur in conditions such as osteoporosis in hypogonadal men, although other agents are often first-line. Androgens are sometimes used to increase libido in women with hypoactive sexual desire disorder, though evidence is limited and risks are significant. The use of SARMs is investigational for conditions like sarcopenia, cachexia, and osteoporosis.

Adverse Effects

The adverse effect profile of androgens is extensive and correlates with dosage, duration of use, and the specific compound administered. Effects can be categorized based on the physiological system affected.

Endocrine and Reproductive Effects

• Hypogonadotropic Hypogonadism: Exogenous androgens suppress the hypothalamic-pituitary-gonadal (HPG) axis via negative feedback, reducing secretion of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). This leads to testicular atrophy, reduced spermatogenesis, and infertility, which may be reversible upon discontinuation but can persist for months to years.
• Gynecomastia: Resulting from the aromatization of androgens to estrogens, leading to benign proliferation of glandular breast tissue in males.
• Virilization in Women and Children: In females, androgens can cause hirsutism, male-pattern baldness, clitoromegaly, deepening of the voice, and menstrual irregularities. These effects are often irreversible. In children, androgens cause premature epiphyseal closure, leading to short stature.

Hepatotoxicity

This is a particular risk with 17α-alkylated oral androgens. Effects range from a reversible elevation in liver transaminases and cholestatic jaundice to peliosis hepatis (blood-filled cysts in the liver) and hepatocellular adenomas or carcinomas. The risk with non-alkylated, parenteral testosterone preparations is considered significantly lower.

Cardiovascular Effects

Androgens have complex effects on cardiovascular risk factors. They can induce erythrocytosis (increased hematocrit), which increases blood viscosity and thrombotic risk. They may adversely affect the lipid profile by decreasing high-density lipoprotein (HDL) cholesterol and increasing low-density lipoprotein (LDL) cholesterol. Androgens can also promote hypertension, left ventricular hypertrophy, and direct cardiotoxicity, potentially increasing the risk of myocardial infarction and stroke, particularly with AAS abuse.

Dermatological and Other Effects

• Acne and Oily Skin: Stimulation of sebaceous gland activity.
• Androgenic Alopecia: Acceleration of male-pattern hair loss in genetically predisposed individuals.
• Psychiatric Effects: Mood disturbances are common, including increased aggression (“roid rage”), irritability, euphoria, depression, and dependence. AAS withdrawal can lead to depressive symptoms.
• Musculoskeletal: While promoting muscle growth, AAS abuse may lead to tendon weakening and an increased risk of tendon rupture.

There are no formal FDA black box warnings for testosterone products, but drug labels carry warnings regarding potential increased cardiovascular and prostate cancer risks.

Drug Interactions

Androgens participate in several clinically significant pharmacokinetic and pharmacodynamic drug interactions.

Major Drug-Drug Interactions

• Anticoagulants (Warfarin): Androgens, particularly 17α-alkylated derivatives, can potentiate the effects of coumarin anticoagulants by reducing the synthesis of clotting factors (II, VII, IX, X) and possibly by competitive displacement from plasma protein binding sites. This significantly increases the risk of bleeding, requiring close monitoring of the International Normalized Ratio (INR).
• Insulin and Oral Hypoglycemics: Androgens may enhance the hypoglycemic effect of these agents, potentially necessitating a reduction in their dose.
• Corticosteroids: Concurrent use with androgens may potentiate edema due to synergistic sodium and water retention.
• Hepatotoxic Drugs: Concomitant use of other hepatotoxic agents (e.g., high-dose acetaminophen, certain anticonvulsants, statins) with 17α-alkylated androgens may have additive hepatotoxic effects.
• Drugs Affecting the HPG Axis: GnRH agonists/antagonists, estrogens, progestins, and other androgens will have additive effects on HPG axis suppression.

Contraindications

Absolute contraindications to androgen therapy typically include:

• Men with carcinoma of the breast or known or suspected carcinoma of the prostate.
• Pregnancy and breastfeeding, due to risk of virilization of the fetus or infant.
• Severe hepatic disease (especially for 17α-alkylated compounds).
• Severe cardiac, renal, or hepatic failure due to risk of fluid retention.
• Hypersensitivity to the drug or its components.

Special Considerations

Use in Pregnancy and Lactation

Androgens are classified as Pregnancy Category X (contraindicated). They can cause virilization of the external genitalia in a female fetus. Androgens are contraindicated during breastfeeding, as they can be excreted in milk and cause virilization in the nursing infant.

Pediatric Considerations

Use in children is restricted to clear medical indications like delayed puberty. Careful monitoring of bone age via radiography is essential to prevent premature epiphyseal closure and compromised adult height. Androgen abuse by adolescents is a serious concern, as it can permanently disrupt normal growth and endocrine development.

Geriatric Considerations

Older men may have age-related declines in testosterone. The decision to initiate TRT requires a confirmed diagnosis of hypogonadism, not just aging, and a careful assessment of cardiovascular and prostate cancer risks. The benefits on muscle strength, bone density, and mood must be weighed against potential risks, including exacerbation of subclinical prostate disease and erythrocytosis.

Renal and Hepatic Impairment

In patients with renal impairment, there is an increased risk of edema due to fluid retention. Dose adjustment may not be necessary for testosterone itself, but caution is warranted. In hepatic impairment, the use of androgens, especially 17α-alkylated compounds, is generally contraindicated due to reduced metabolic capacity and heightened risk of hepatotoxicity. Even non-alkylated testosterone may be used with extreme caution, as impaired liver function can alter its metabolism and protein binding.

Summary/Key Points

• Androgens, primarily testosterone, exert effects by activating the intracellular androgen receptor, leading to genomic and non-genomic signaling pathways that mediate both anabolic and androgenic effects.
• Classification is based on chemical structure, with key distinctions between esterified testosterone (for parenteral use), 17α-alkylated compounds (oral, hepatotoxic), and 19-nor derivatives.
• Pharmacokinetics are formulation-dependent. Transdermal and buccal routes mimic physiological secretion, while intramuscular esters produce fluctuating supra-physiological levels. Oral bioavailability requires 17α-alkylation, which carries hepatotoxic risk.
• The primary therapeutic indication is testosterone replacement for documented male hypogonadism. Other uses include delayed puberty, certain wasting conditions, and hereditary angioedema prophylaxis.
• Adverse effects are systemic and significant, including suppression of the HPG axis, virilization, hepatotoxicity (especially with oral agents), adverse lipid changes, erythrocytosis, and psychiatric effects.
• Major drug interactions include potentiation of warfarin and hypoglycemic agents. Androgens are contraindicated in men with prostate or breast cancer and in pregnancy.
• Special caution is required in pediatric patients to avoid premature epiphyseal closure, in geriatric patients due to prostate and cardiovascular risks, and in those with hepatic or renal impairment.

Clinical Pearls

• The diagnosis of hypogonadism requiring therapy should be based on consistent clinical symptoms and unequivocally low serum testosterone levels measured on at least two occasions.
• Monitoring during testosterone replacement therapy should include periodic assessment of hematocrit, lipid profile, prostate-specific antigen (PSA) in appropriate patients, and serum testosterone levels to ensure they are within the therapeutic range.
• Patients presenting with aggressive behavior, severe acne, gynecomastia, or unexplained hepatotoxicity should be questioned confidentially about possible anabolic steroid use.
• The non-medical use of AAS often involves doses 10-100 times higher than therapeutic levels and complex polypharmacy, leading to a unique and severe spectrum of toxicity that requires a high index of suspicion for diagnosis.

References

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