Androgens and Pharmacology

Overview of Androgens and Related Pharmacology

• Androgens, synthetic androgens, actions, uses, adverse effects and antiandrogens.

Testosterone

• Synthesis occurs in the Leydig cells when stimulated by LH.
• It is metabolized into 5a-dihydrotestosterone by 5a-reductase
• 5a-reductase has two types: Type I is expressed in skin and liver, Type II in prostate, seminal vesicles and hair follicles.
• Administration can be done transdermally and intramuscularly.

Synthetic Androgens

• 17-substituted testosterone esters can be Testosterone propionate, testosterone enanthate, or testosterone cypionate.
• 17-alkyl testosterone derivates include Methyltestosterone, fluoxymesterone, oxymetholone, and can be administered sublingually.
• Nandrolone has a higher anabolic to androgenic ratio and is administered parentally.
• Oxandrolone is administered orally.

Androgen Actions

• Signal through intracellular receptors to control specific gene transcription.
• Control cell differentiation, development, and growth.
• Androgenic effects lead to differentiation and development of wolffian structures (epididymis, seminal vesicles, prostate, penis).
• Also have androgenic effects development and maintenance of male secondary sexual characteristics.
• Anabolic effects include acceleration of epiphyseal closure, linear growth at puberty, increase in muscle mass, and a positive nitrogen balance.
• Can cause aggressiveness and increased libido.

Androgen Uses

• Used for prepubertal and postpubertal hypogonadism, addressing linear growth, sexual maturation, male secondary sexual characteristics, libido, and potency.
• Addresses anemia by stimulating erythropoietin secretion, now largely replaced by recombinant erythropoietin.
• Can manage estrogen-dependent breast cancers.
• Can be used for wasting disorders.
• Treats severe burns.
• Addresses hereditary angioedema through androgen-dependent increases in C1 complement inhibitor.
• Part of menopausal hormone therapy, especially when estrogens are not effective.

Illicit Androgen Use

• Anabolic androgens are used by athletes.
• They are used to enhance the extent and rate of muscle formation.
• They are used to increase training intensity.
• Their adverse effects make their use inadvisable.

Androgen Adverse Effects

• Decrease testicular function.
• Can cause edema.
• Cause altered plasma lipids (increased LDL, decreased HDL).
• Cause masculinization in women.
• Increases plasma fibrinolytic activity which can cause severe bleeding with concomitant anticoagulant therapy.
• 17-alkyl substituted androgens can cause increased hepatic enzymes, hyperbilirubinemia, cholestatic hepatitis, and liver tumors.
• They are contraindicated in pregnant women, patients with hepatic or prostate cancer, and renal or cardiovascular disease.

Anti-Androgens

• Block the action or synthesis of endogenous androgens.

Anti-Androgens – Receptor Inhibitors

• Flutamide is a steroidal oral antiandrogen and a competitive androgen receptor antagonist.
• Nilutamide and bicalutamide are nonsteroidal androgen receptor antagonists.
• These are used as treatment for prostate cancer.
• They can be combined with GnRH agonist therapy.

Antiandrogens – Receptor Inhibitors Adverse Effects

• They can cause gynecomastia, elevation in liver enzymes, chest pain, GI disturbances, and can act as teratogenic agents.

Finasteride

• Inhibits type II 5a-reductase.
• Reduces 5a-dihydrotestosterone production.
• Treats benign prostatic hypertrophy and male pattern baldness.
• Decreases prostate volume and increases urine flow.

Dutasteride

• Inhibits both Type I and II 5a-reductase, making it more potent than finasteride.
• Treats benign prostatic hyperthrophy and baldness.

Ketoconazole

• Antifungal agent, this blocks multiple p450 dependent steps in the steroidogenesis cascade, including desmolase.
• Treats precocious puberty and hirsutism.

Spironolactone

• Prevents androgens and aldosterone from binding to their receptors.
• Decreases 17-hydroxylase activity.
• Treats hirsutism in women.