Pharmacology of Androgens and Anabolic Steroids

1. Introduction/Overview

Androgens and anabolic steroids represent a class of steroid hormones and their synthetic analogs that exert profound effects on the development and maintenance of male sexual characteristics, as well as on protein anabolism and tissue growth. The primary endogenous androgen is testosterone, synthesized primarily in the Leydig cells of the testes, with smaller amounts produced in the adrenal cortex and ovaries. The clinical relevance of these agents extends beyond the treatment of androgen deficiency to include a range of conditions from certain anemias to palliative care in wasting syndromes. However, their non-medical use for performance and physique enhancement presents significant public health challenges due to a well-documented profile of serious adverse effects.

The importance of understanding the pharmacology of these compounds lies in their dual nature as essential therapeutic agents and as substances with high abuse potential. A nuanced grasp of their mechanisms, pharmacokinetics, and toxicology is required for appropriate clinical management and for addressing the complications arising from illicit use.

Learning Objectives

• Describe the physiological synthesis and regulation of endogenous androgens and differentiate between various classes of exogenous androgen and anabolic steroid agents.
• Explain the molecular mechanism of action of androgens via the androgen receptor, including genomic and non-genomic pathways, and the concept of the anabolic-androgenic ratio.
• Outline the pharmacokinetic properties of key androgen preparations, including absorption, metabolism, and routes of elimination, and how these properties influence clinical dosing regimens.
• Identify the approved therapeutic indications for androgen therapy, such as male hypogonadism and specific types of anemia, and recognize common off-label uses.
• Analyze the spectrum of adverse effects associated with androgen and anabolic steroid use, including cardiovascular, hepatic, endocrine, and psychiatric risks, particularly in the context of supraphysiological dosing and abuse.

2. Classification

Androgens and anabolic steroids can be classified based on their origin, chemical structure, and predominant pharmacological activity. The fundamental classification distinguishes between endogenous compounds and exogenous synthetic derivatives.

Endogenous Androgens

• Testosterone: The principal circulating androgen in males, serving as a prohormone for more potent metabolites.
• Dihydrotestosterone (DHT): A 5α-reduced metabolite of testosterone with significantly higher affinity for the androgen receptor; it is the primary androgen in tissues like the prostate and skin.
• Androstenedione: A weak androgen that serves as a direct precursor for testosterone and estrone synthesis.
• Dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S): Weak adrenal androgens that function as precursors for more potent sex steroids.

Exogenous Androgens and Anabolic Steroids

Synthetic derivatives are engineered to alter oral bioavailability, duration of action, and the balance between anabolic (muscle-building) and androgenic (masculinizing) effects. The anabolic-androgenic ratio (A:A ratio) is a theoretical construct comparing the myotrophic (anabolic) potency to the virilizing (androgenic) potency, with testosterone assigned a reference value of 1:1.

Chemical Classification

1. 17α-Alkylated Derivatives:
   • These compounds have an alkyl group (e.g., methyl, ethyl) at the 17α position of the steroid ring, which reduces first-pass hepatic metabolism and confers oral bioavailability.
   • Examples include methyltestosterone, oxandrolone, oxymetholone, and stanozolol.
   • This modification is strongly associated with hepatotoxicity.
2. Esters of Testosterone:
   • Testosterone is esterified at the 17β-hydroxyl group with fatty acid chains (e.g., enanthate, cypionate, propionate, undecanoate).
   • Esterification increases lipid solubility, allowing for formulation in oil for intramuscular injection. The ester side chain slows release from the injection site, prolonging the duration of action. Longer chains (e.g., undecanoate) provide longer half-lives.
   • These esters are hydrolyzed in vivo to release free testosterone.
3. 19-Nortestosterone Derivatives (Nandrolone Analogs):
   • Characterized by the absence of the 19-methyl group, these compounds, such as nandrolone decanoate, are often described as having a more favorable A:A ratio, with purportedly greater anabolic and lesser androgenic effects, though this distinction is not absolute.
4. Other Structural Modifications:
   • Various other modifications exist, such as the introduction of double bonds (e.g., boldenone), heterocyclic rings (e.g., stanozolol with a pyrazole ring fused to the A-ring), or alterations to the A-ring (e.g., oxandrolone, which contains an oxygen atom in place of carbon-2).

3. Mechanism of Action

The pharmacological effects of androgens are mediated predominantly through the androgen receptor (AR), a member of the nuclear receptor superfamily. The mechanism involves both classical genomic pathways and faster, non-genomic signaling.

Androgen Receptor Structure and Function

The AR is an intracellular protein with several functional domains: an N-terminal transactivation domain, a central DNA-binding domain (DBD), a hinge region, and a C-terminal ligand-binding domain (LBD). In the absence of ligand, the AR is sequestered in the cytoplasm in a complex with heat shock proteins (HSPs). Upon binding of an agonist like testosterone or DHT, a conformational change occurs, leading to dissociation of HSPs, receptor dimerization, and translocation into the nucleus.

Genomic (Slow) Signaling Pathway

This is the primary mechanism for most androgenic and anabolic effects. The ligand-bound AR dimer binds to specific DNA sequences known as androgen response elements (AREs) located in the promoter or enhancer regions of target genes. The DNA-bound AR recruits coactivator proteins and components of the general transcription machinery, leading to upregulation or, in some cases, repression of gene transcription. The resulting changes in mRNA and subsequent protein synthesis underlie effects such as increased production of muscle contractile proteins, erythropoietin, and proteins involved in male sexual development.

Non-Genomic (Rapid) Signaling Pathway

Androgens can also elicit rapid cellular responses within seconds to minutes, which are independent of gene transcription. These effects are mediated by membrane-associated or cytoplasmic ARs, or potentially through other receptors. Non-genomic signaling can activate second messenger systems such as mitogen-activated protein kinase (MAPK), protein kinase C (PKC), and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. These pathways can influence cell proliferation, apoptosis, and ion channel function, and may also modulate the classical genomic pathway through cross-talk.

Metabolic Activation and Tissue Selectivity

The activity of testosterone is modulated by tissue-specific metabolism. In tissues like the prostate, scalp, and skin, the enzyme 5α-reductase converts testosterone to the more potent DHT, which drives androgenic effects. In contrast, in skeletal muscle, testosterone acts largely without conversion to DHT. The enzyme aromatase, present in adipose tissue, liver, and brain, converts testosterone to estradiol. This conversion is responsible for estrogenic side effects (e.g., gynecomastia) and may contribute to some anabolic and central nervous system effects. The concept of selective androgen receptor modulators (SARMs) is based on designing ligands that induce conformational changes in the AR favoring interactions with coactivators prevalent in muscle over those in prostate, though no true SARM is yet approved for clinical use.

4. Pharmacokinetics

The pharmacokinetic profiles of androgens vary widely depending on their chemical structure and formulation, critically influencing their route of administration, dosing frequency, and side effect profile.

Absorption

• Oral Administration: Unmodified testosterone undergoes extensive first-pass hepatic metabolism, resulting in very low oral bioavailability. 17α-alkylated compounds resist this metabolism and are effective orally. Testosterone undecanoate, when formulated in oil with a lipophilic carrier, is absorbed via the intestinal lymphatics, partially bypassing the portal circulation, and is also available as an oral preparation.
• Parenteral Administration: Intramuscular injection of testosterone esters in oil is the traditional route for achieving sustained systemic levels. Absorption rate depends on the ester; propionate is short-acting (injected every 2-3 days), while enanthate, cypionate, and decanoate are longer-acting (injected every 1-4 weeks). Testosterone undecanoate injection has an extended duration of up to 12 weeks.
• Transdermal Administration: Gels, patches, and solutions deliver testosterone through the skin, providing steady-state physiological levels and mimicking the normal diurnal rhythm more closely than injections. Absorption can be variable and is influenced by skin site, surface area, and washing.
• Buccal and Subcutaneous Administration: Buccal tablets and subcutaneous pellet implants offer alternative delivery methods for sustained release.

Distribution

Androgens are highly bound to plasma proteins. Testosterone is bound approximately 98% to sex hormone-binding globulin (SHBG) and albumin. Only the free fraction (about 2%) is considered biologically active. Synthetic steroids often have different binding affinities for SHBG, which can influence their bioavailability and activity. Androgens distribute widely throughout the body, crossing the blood-brain barrier.

Metabolism

Hepatic metabolism is the primary route of biotransformation. Key metabolic pathways include:

1. Oxidation/Reduction: The A-ring is reduced by 5α- and 5β-reductases. 5α-reduction to DHT is critical in certain tissues.
2. Hydroxylation: Occurs at various positions on the steroid nucleus.
3. Conjugation: Metabolites are conjugated with glucuronic acid or sulfate to form water-soluble compounds for renal excretion.
4. Aromatization: Testosterone and some precursors are converted to estradiol and estrone, respectively, by the aromatase enzyme complex.

The 17α-alkylated compounds are metabolized more slowly due to their structural resistance to hepatic breakdown, which contributes to their hepatotoxicity.

Excretion

Conjugated metabolites are excreted predominantly in urine, with a smaller fraction eliminated in bile. The elimination half-life (t_1/2) varies considerably: testosterone propionate has a t_1/2 of approximately 0.8 days, testosterone enanthate about 4.5 days, and testosterone undecanoate injection up to 34 days. Oral 17α-alkylated steroids have half-lives ranging from several hours (e.g., oxandrolone, ~9 hours) to a day or more.

5. Therapeutic Uses/Clinical Applications

The use of androgens and anabolic steroids in clinical medicine is reserved for specific, well-defined indications where the benefits are judged to outweigh the risks.

Approved Indications

• Male Hypogonadism: This is the primary indication for testosterone therapy. It includes conditions characterized by low serum testosterone levels accompanied by symptoms such as fatigue, reduced libido, erectile dysfunction, loss of muscle mass, and osteoporosis. Causes can be primary (testicular failure, e.g., Klinefelter syndrome) or secondary (hypothalamic-pituitary dysfunction).
• Delayed Puberty in Males: Androgens may be used cautiously to stimulate the onset of puberty in boys with documented constitutional delay.
• Metastatic Breast Cancer in Women: Androgens like fluoxymesterone have historical use as palliative therapy in estrogen receptor-positive breast cancer, though their use has largely been superseded by other endocrine therapies.
• Anemia Associated with Bone Marrow Failure: Anabolic steroids (e.g., oxymetholone, nandrolone) can stimulate erythropoiesis in certain refractory anemias, such as aplastic anemia or anemia related to myelofibrosis or chronic renal failure, primarily by increasing erythropoietin production and possibly through a direct effect on erythroid precursors.
• Angioedema (Hereditary): The attenuated androgen stanozolol is used prophylactically to reduce the frequency and severity of attacks in patients with hereditary angioedema, likely by increasing the synthesis of C1 esterase inhibitor.
• Wasting/Catabolic States: Oxandrolone is approved for promoting weight gain following extensive surgery, chronic infection, or severe trauma, and for offsetting protein catabolism associated with prolonged corticosteroid therapy.

Common Off-Label Uses

• Androgen Replacement in Postmenopausal Women: Testosterone may be used in combination with estrogen for the treatment of hypoactive sexual desire disorder in postmenopausal women, though formulations are not universally approved for this indication.
• Wasting in HIV/AIDS: Prior to the advent of effective antiretroviral therapy, anabolic steroids were used to counteract cachexia and muscle wasting.
• Osteoporosis in Men: Testosterone therapy is considered in hypogonadal men with osteoporosis to improve bone mineral density.
• Gender-Affirming Hormone Therapy: Testosterone is a cornerstone of masculinizing hormone therapy for transgender men and non-binary individuals assigned female at birth.

The non-medical use of anabolic steroids for athletic performance enhancement or cosmetic physique alteration represents a significant public health issue but is not a therapeutic application.

6. Adverse Effects

The adverse effect profile of androgens is extensive and correlates with dosage, duration of use, the specific compound, and individual patient factors. Effects can be categorized as androgenic, estrogenic, metabolic, organ-specific, and psychological.

Common Side Effects

• Androgenic Effects: Acne, seborrhea, male-pattern baldness (in genetically predisposed individuals), increased body and facial hair (hirsutism in women), and increased libido.
• Estrogenic Effects: Result from aromatization of androgens to estrogens. Gynecomastia is a common and often troublesome effect in men. Fluid retention (edema) can also occur.
• Endocrine Effects: Suppression of the hypothalamic-pituitary-gonadal (HPG) axis via negative feedback, leading to reduced endogenous testosterone production, testicular atrophy, and oligospermia or azoospermia. This suppression can be prolonged and may not fully reverse after discontinuation.
• Dermatological: Acne vulgaris, oily skin, and injection site reactions.

Serious/Rare Adverse Reactions

• Cardiovascular: Androgens can adversely affect the lipid profile, typically decreasing high-density lipoprotein (HDL) cholesterol and increasing low-density lipoprotein (LDL) cholesterol, particularly the 17α-alkylated compounds. They may also promote hypertension, left ventricular hypertrophy, and a prothrombotic state, potentially increasing the risk of myocardial infarction, stroke, and venous thromboembolism.
• Hepatic: 17α-alkylated steroids are associated with a dose-dependent risk of hepatotoxicity. This can manifest as elevated liver transaminases, cholestatic jaundice, peliosis hepatis (blood-filled cysts in the liver), hepatic tumors (both benign adenomas and hepatocellular carcinoma), and rarely, hepatic failure.
• Psychiatric and Behavioral: Mood disturbances are common, including increased aggression (“roid rage”), irritability, euphoria, depression, and dependence. Psychotic symptoms can occur, particularly with high doses.
• Musculoskeletal: Premature epiphyseal closure in adolescents, leading to stunted growth. Tendons may become more brittle and prone to rupture.
• Reproductive: In women, virilization is a major concern, presenting as deepening of the voice, clitoromegaly, menstrual irregularities, and irreversible changes in body hair distribution. In men, besides testicular atrophy, chronic use can lead to infertility.
• Other: Sleep apnea may be induced or exacerbated. There is concern about a potential increased risk of prostate hyperplasia and carcinoma, although a direct causal link remains controversial.

Black Box Warnings

Testosterone products carry a black box warning regarding the risk of venous thromboembolism. Furthermore, they are contraindicated in men with breast cancer or known or suspected prostate cancer. All androgens are contraindicated in pregnancy due to the risk of virilization of a female fetus.

7. Drug Interactions

Androgens and anabolic steroids can interact with several classes of medications, altering the effects of either the androgen or the co-administered drug.

Major Drug-Drug Interactions

• Anticoagulants (Warfarin): Androgens can potentiate the anticoagulant effect of warfarin by reducing the synthesis of vitamin K-dependent clotting factors and possibly by direct competition for protein binding sites. This significantly increases the risk of bleeding, necessitating close monitoring of the International Normalized Ratio (INR).
• Oral Hypoglycemic Agents and Insulin: Androgens may enhance the hypoglycemic effect of these agents, potentially necessitating a dose reduction, as androgens can improve insulin sensitivity.
• Corticosteroids: Concurrent use with anabolic steroids may potentiate the edema associated with corticosteroids. Conversely, anabolic steroids may be used to counteract the catabolic effects of long-term corticosteroid therapy.
• Cyclosporine and Tacrolimus: Androgens may inhibit the metabolism of these calcineurin inhibitors, potentially leading to increased blood levels and toxicity (nephrotoxicity, neurotoxicity).
• Hepatotoxic Agents: Concomitant use of 17α-alkylated androgens with other hepatotoxic drugs (e.g., certain anticonvulsants, antitubercular drugs, high-dose acetaminophen) can have additive hepatotoxic effects.
• Oxyphenbutazone: May increase serum levels of oxymetholone.

Contraindications

• Men with carcinoma of the breast or known or suspected carcinoma of the prostate.
• Pregnancy and breastfeeding.
• Severe cardiac, hepatic, or renal disease.
• Hypercalcemia (in patients with breast cancer).
• Known hypersensitivity to the drug or its components.

8. Special Considerations

Use in Pregnancy and Lactation

Androgens are classified as Pregnancy Category X (contraindicated). They can cause virilization of an external female fetus, leading to ambiguous genitalia (clitoromegaly, labial fusion). Use during lactation is also contraindicated as androgens can be excreted in breast milk and cause virilization in the nursing infant.

Pediatric Considerations

Use in children is restricted to very specific indications, such as constitutional delay of puberty. Extreme caution is required due to the risk of premature epiphyseal closure, which results in permanent short stature. Androgen therapy can also accelerate bone age disproportionately to chronological age. Use for performance enhancement in adolescent athletes is a form of abuse with serious long-term consequences.

Geriatric Considerations

Older men may have age-related declines in testosterone. Treatment should only be initiated after confirmed diagnosis of hypogonadism with consistent symptoms. The risk-benefit ratio must be carefully evaluated, with particular attention to pre-existing prostate conditions (benign prostatic hyperplasia, risk of carcinoma) and cardiovascular risk factors. Monitoring of prostate-specific antigen (PSA), hematocrit, and lipid profile is essential.

Renal Impairment

Androgens can promote sodium and water retention, which may exacerbate edema and hypertension in patients with renal impairment. Dose adjustments may be necessary, and 17α-alkylated compounds should be avoided due to their hepatotoxic potential, as renal and hepatic dysfunction often coexist. Anabolic steroids have been used to treat anemia of chronic kidney disease, but this requires careful monitoring.

Hepatic Impairment

Androgens, especially the 17α-alkylated oral agents, are contraindicated in patients with significant hepatic impairment due to their hepatotoxic potential and reliance on hepatic metabolism. Transdermal or injectable testosterone esters, which bypass first-pass metabolism, may be considered with caution in stable liver disease, but close monitoring of liver function is mandatory.

9. Summary/Key Points

• Androgens, primarily testosterone, are essential steroid hormones for male sexual development and function, with significant anabolic effects on muscle and bone. Synthetic anabolic steroids are designed to amplify these anabolic properties.
• The primary mechanism of action is via binding to the intracellular androgen receptor, leading to genomic regulation of target gene expression. Non-genomic signaling pathways also contribute to their effects.
• Pharmacokinetics are highly formulation-dependent. Oral bioavailability requires 17α-alkylation (linked to hepatotoxicity) or specialized delivery (testosterone undecanoate). Transdermal and intramuscular ester formulations provide sustained release.
• The cornerstone therapeutic indication is the treatment of male hypogonadism. Other approved uses include certain anemias, hereditary angioedema prophylaxis, and catabolic/wasting states.
• Adverse effects are widespread and potentially serious, including cardiovascular risks (dyslipidemia, thromboembolism), hepatotoxicity (with 17α-alkylated compounds), suppression of the HPG axis, psychiatric effects, and virilization in women and children.
• Significant drug interactions exist, most notably potentiation of warfarin anticoagulation and additive hepatotoxicity with other agents.
• These agents are contraindicated in pregnancy, prostate or male breast cancer, and severe hepatic disease. Use requires careful consideration in pediatric, geriatric, and renally/hepatically impaired populations.

Clinical Pearls

• Before initiating testosterone therapy for suspected hypogonadism, the diagnosis must be biochemically confirmed with consistently low morning serum testosterone levels on at least two occasions, in conjunction with clinical symptoms.
• Monitoring during testosterone replacement therapy should include periodic assessment of hematocrit (for polycythemia), PSA and digital rectal exam (for prostate monitoring), lipid profile, and liver function tests (particularly with oral alkylated agents).
• The non-medical use of anabolic steroids for performance enhancement is associated with a high risk of adverse effects due to the use of supraphysiological doses, polypharmacy (“stacking”), and the use of unregulated, potentially adulterated products.
• Patient education is crucial, particularly regarding the expected benefits, realistic timelines for symptom improvement, the importance of adherence to monitoring schedules, and the serious risks of sharing or abusing these medications.
• When discontinuing anabolic steroid abuse, a supervised taper may be considered to mitigate withdrawal symptoms, and post-cycle therapy to restore endogenous HPG axis function is a complex area often managed by specialists.

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