Androgens

1. Sources and Classification

Adrenal androgens are peripheral prohormones - Basic Medical Biochemistry, 6e

2. Biosynthesis

Adrenal Androgens

• Most 17-hydroxypregnenolone enters the glucocorticoid pathway.
• A fraction undergoes oxidative side-chain cleavage by 17,20-lyase (part of P450c17, a dual-function enzyme).
• This yields DHEA, which is converted to androstenedione by 3β-OHSD and Δ5,4-isomerase.
• Reduction of androstenedione at C-17 forms testosterone.
• In adrenogenital syndrome (CAH), impaired glucocorticoid synthesis shunts precursors into androgen synthesis, causing androgen excess.

Testicular Androgens (Leydig Cells)

• LH from the anterior pituitary is the primary stimulus.
• Rate-limiting step: cholesterol → pregnenolone via side-chain cleavage enzyme (P450scc), delivered by the transport protein StAR.
• The predominant pathway in human testes is the Δ5 pathway: pregnenolone → 17α-hydroxypregnenolone → DHEA → androstenedione → testosterone.
• Five enzyme activities in three proteins carry out the conversion:
  1. 3β-hydroxysteroid dehydrogenase + Δ5,4-isomerase
  2. 17α-hydroxylase + 17,20-lyase (both in P450c17)
  3. 17β-hydroxysteroid dehydrogenase
• Harper's Illustrated Biochemistry, 32e, p. block4

Formation of DHT

• In target tissues (prostate, external genitalia, skin, epididymis), testosterone is converted to DHT by 5α-reductase.
• DHT is more potent than testosterone because of its higher affinity for the androgen receptor.
• The other metabolic pathway (oxidation at C-17) yields inactive or less-active 17-ketosteroids - primarily hepatic.

3. Mechanism of Action

1. Testosterone enters target cells and either acts directly or is converted to DHT by 5α-reductase (in skin, prostate, seminal vesicles, epididymis).
2. Testosterone or DHT binds the intracellular androgen receptor (AR).
3. The hormone-receptor complex undergoes conformational change, translocates to the nucleus, and binds androgen response elements (ARE) on DNA.
4. This drives transcription of genes regulating growth, differentiation, and protein synthesis.

• Katzung's Basic and Clinical Pharmacology, 16e

4. Physiological Effects

Male

• In utero: differentiation of Wolffian ducts into epididymis, vas deferens, seminal vesicles (testosterone); external genitalia masculinization (DHT).
• Puberty: growth of testes, penis, and accessory glands; appearance of pubic, axillary, and facial hair; deepening of voice; acne; growth spurt followed by epiphyseal closure; enlargement of larynx; skeletal muscle growth.
• Adult: maintenance of secondary sex characteristics, spermatogenesis, libido.
• Erythropoiesis: natural androgens stimulate erythrocyte production.
• Protein anabolism: reduce urinary nitrogen excretion (increase protein synthesis or reduce catabolism) - more pronounced in women and children than in eugonadal men.

Female (when elevated)

• Facial and body hair growth (hirsutism)
• Deepening of voice
• Clitoral enlargement
• Frontal baldness
• Prominent musculature
• Menstrual irregularity

5. Feedback Regulation

• Androgens exert negative feedback on the hypothalamus (reducing GnRH) and anterior pituitary (reducing LH and FSH secretion).
• Inhibin, produced by Sertoli cells, also contributes to feedback suppression of FSH.
• Large doses are needed to suppress gonadotropins, suggesting inhibin + androgens together mediate physiological feedback.

6. Pharmacological Preparations

Androgenic:Anabolic Ratios (Animal Models)

Replacement Therapy Preparations

• Katzung's Basic and Clinical Pharmacology, 16e, Table 40-6

7. Clinical Uses

1. Hypogonadism - primary indication for replacement therapy in males with primary or secondary hypogonadal states. Long-acting IM esters (enanthate, cypionate) are preferred.
2. Delayed puberty - gradually escalating doses in hypopituitary boys at expected pubertal age.
3. Gynecologic uses - postpartum breast engorgement (with estrogens); endometriosis (danazol, a weak androgen); postmenopausal replacement (combined with estrogen); breast carcinoma in premenopausal women.
4. Protein anabolic uses - catabolic states (burns, surgery, chronic illness); osteoporosis; aplastic anemia (though erythropoietin is now preferred).
5. Male pattern baldness - finasteride 1 mg/d (via 5α-reductase inhibition).

8. Adverse Effects

• Virilization in women and children (irreversible deepening of voice)
• Premature epiphyseal closure in children (reduced final height)
• Hepatotoxicity - especially oral 17α-alkylated androgens (methyltestosterone); risk of cholestatic jaundice and hepatocellular carcinoma with prolonged use
• Polycythemia - from erythropoietic stimulation
• Sodium and water retention - edema, hypertension (caution in renal/cardiac disease)
• Suppression of spermatogenesis - testicular atrophy with large doses
• Gynecomastia - from peripheral aromatization to estrogens
• Dyslipidemia - decrease HDL, increase LDL

9. Androgen Suppression and Antiandrogens

Sites of Intervention (numbered in diagram above)

1. GnRH receptor antagonists - competitive block (e.g., degarelix)
2. GnRH agonists - continuous (not pulsatile) administration desensitizes receptors, suppresses LH/FSH (e.g., leuprolide, goserelin, nafarelin, buserelin)
3. Testicular synthesis inhibitors - ketoconazole, spironolactone
4. 5α-Reductase inhibitors - block testosterone → DHT conversion
   • Finasteride (5 mg/d for BPH; 1 mg/d for baldness) - onset within 8 hours, ~24h duration
   • Dutasteride (0.5 mg/d) - slower onset, much longer half-life
5. Androgen receptor antagonists (competitive)
   • Flutamide - substituted anilide; used in prostate carcinoma; causes gynecomastia
   • Bicalutamide, enzalutamide - newer, higher-affinity AR antagonists
   • Cyproterone acetate - steroidal antiandrogen
   • Spironolactone - weak AR antagonist in addition to aldosterone antagonism

Synthesis Pathway Inhibitors

• Ketoconazole - inhibits adrenal and gonadal steroidogenesis; increases estradiol:testosterone ratio (gynecomastia); toxicity limits use
• Abiraterone - 17α-hydroxylase/17,20-lyase inhibitor; approved for metastatic castration-resistant prostate cancer

10. Clinical Disorders

• Katzung's Basic and Clinical Pharmacology, 16e, Chapter 40
• Basic Medical Biochemistry: A Clinical Approach, 6e, Chapter 32
• Harper's Illustrated Biochemistry, 32e, Chapter 41
• Goodman & Gilman's Pharmacological Basis of Therapeutics