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Wednesday, August 20, 2025

Antiandrogens


Introduction

Antiandrogens are a class of drugs that block or suppress the effects of androgens (male sex hormones such as testosterone and dihydrotestosterone [DHT]). They achieve this by interfering with androgen production, blocking androgen receptors, or inhibiting enzymes responsible for androgen metabolism.

These agents have diverse applications in medicine, ranging from prostate cancer, androgen-dependent conditions (acne, hirsutism, alopecia), precocious puberty, to gender-affirming hormone therapy in transgender women. Antiandrogens are broadly divided into:

  1. Androgen receptor antagonists (ARAs)

  2. Androgen synthesis inhibitors

  3. 5-alpha reductase inhibitors (5-ARIs)

  4. Other drugs with antiandrogenic activity

This review provides a comprehensive professional overview of antiandrogens, including their classification, mechanisms of action, therapeutic uses, generic drug names, recommended doses, adverse effects, contraindications, precautions, and drug interactions.

Classification of Antiandrogens

1. Androgen Receptor Antagonists (ARAs)

  • Non-steroidal ARAs: Flutamide, Bicalutamide, Nilutamide, Enzalutamide, Apalutamide, Darolutamide.

  • Steroidal ARAs: Cyproterone acetate (also has progestational activity).

2. Androgen Synthesis Inhibitors

  • CYP17 (17α-hydroxylase/17,20-lyase) inhibitors: Abiraterone acetate, Ketoconazole (at high doses).

3. 5-Alpha Reductase Inhibitors (5-ARIs)

  • Finasteride (type II isoenzyme selective).

  • Dutasteride (nonselective, inhibits type I and II).

4. Other Antiandrogenic Agents

  • GnRH analogs (indirect antiandrogens): Leuprolide, Goserelin (suppress testicular androgen production).

  • Spironolactone: Primarily a potassium-sparing diuretic, but also blocks androgen receptors and inhibits testosterone synthesis.

Mechanisms of Action

  1. Androgen Receptor Antagonists (ARAs):

    • Competitively block binding of androgens (testosterone/DHT) to the androgen receptor.

    • Prevent androgen-driven transcription and cellular proliferation.

  2. Androgen Synthesis Inhibitors (Abiraterone):

    • Inhibit CYP17 enzyme in adrenal and testicular tissue, blocking androgen biosynthesis.

  3. 5-Alpha Reductase Inhibitors:

    • Prevent conversion of testosterone to DHT, the more potent androgen, particularly in the prostate and hair follicles.

  4. Others:

    • GnRH analogs suppress LH secretion, leading to decreased testicular testosterone production.

    • Spironolactone blocks androgen receptors and inhibits testosterone biosynthesis at the enzymatic level.

Clinical Uses of Antiandrogens

  1. Prostate Cancer

    • First-line or adjunct therapy (ARAs, CYP17 inhibitors, GnRH analogs).

  2. Benign Prostatic Hyperplasia (BPH)

    • 5-alpha reductase inhibitors reduce prostate volume.

  3. Androgenic Alopecia (Male-pattern hair loss)

    • Finasteride, Dutasteride.

  4. Hirsutism and Acne in Women

    • Spironolactone, Cyproterone acetate, Flutamide.

  5. Gender-Affirming Hormone Therapy

    • Spironolactone, Cyproterone acetate, GnRH analogs in transgender women.

  6. Precocious Puberty (boys)

    • GnRH analogs, cyproterone acetate.

  7. Other Off-Label Uses

    • Endometriosis (cyproterone acetate).

    • Polycystic ovary syndrome (hirsutism management).

Generic Drugs, Doses, and Profiles

Androgen Receptor Antagonists (ARAs)

  • Flutamide

    • Dose: 250 mg orally every 8 hours.

    • Uses: Prostate cancer (often with GnRH analogs).

    • Adverse effects: Hepatotoxicity, gynecomastia, hot flashes.

  • Bicalutamide

    • Dose: 50 mg once daily (with GnRH analog) or 150 mg daily (monotherapy).

    • Uses: Prostate cancer, off-label hirsutism.

    • Adverse effects: Gynecomastia, breast tenderness, mild hepatotoxicity.

  • Nilutamide

    • Dose: 150 mg once daily.

    • Unique adverse effects: Visual disturbances, interstitial pneumonitis.

  • Enzalutamide / Apalutamide / Darolutamide

    • Dose: Enzalutamide 160 mg daily; Apalutamide 240 mg daily; Darolutamide 600 mg twice daily.

    • Uses: Metastatic castration-resistant prostate cancer (mCRPC).

    • Adverse effects: Fatigue, seizures (Enzalutamide, Apalutamide), less CNS penetration with Darolutamide.

  • Cyproterone Acetate

    • Dose: 50–100 mg twice daily (cancer), 2 mg daily with ethinylestradiol (contraception).

    • Uses: Prostate cancer, hirsutism, androgen suppression in women.

    • Adverse effects: Hepatotoxicity, depression, weight gain, venous thromboembolism.

Androgen Synthesis Inhibitors

  • Abiraterone Acetate

    • Dose: 1000 mg PO once daily (empty stomach) + prednisone 5–10 mg/day.

    • Uses: Metastatic castration-resistant prostate cancer.

    • Adverse effects: Hypertension, hypokalemia, edema, hepatotoxicity.

  • Ketoconazole (high dose)

    • Dose: 200–400 mg PO three times daily.

    • Uses: Prostate cancer (off-label, less common).

    • Adverse effects: Hepatotoxicity, adrenal insufficiency.

5-Alpha Reductase Inhibitors (5-ARIs)

  • Finasteride

    • Dose: 5 mg once daily (BPH), 1 mg once daily (alopecia).

    • Uses: BPH, male-pattern baldness.

    • Adverse effects: Sexual dysfunction, gynecomastia, depression.

  • Dutasteride

    • Dose: 0.5 mg once daily.

    • Uses: BPH, alopecia (off-label).

    • Adverse effects: Similar to finasteride.

Other Antiandrogenic Drugs

  • Spironolactone

    • Dose: 25–200 mg/day orally.

    • Uses: Hirsutism, acne in women, adjunct in transgender hormone therapy.

    • Adverse effects: Hyperkalemia, gynecomastia, menstrual irregularities.

  • GnRH Analogs (Leuprolide, Goserelin, Triptorelin)

    • Leuprolide: 7.5 mg IM monthly or depot formulations.

    • Uses: Prostate cancer, precocious puberty, endometriosis.

    • Adverse effects: Hot flashes, osteoporosis, sexual dysfunction.

Adverse Effects of Antiandrogens

  • Endocrine: Gynecomastia, hot flashes, decreased libido, impotence.

  • Metabolic: Weight gain, insulin resistance (cyproterone, spironolactone).

  • Hepatic: Hepatotoxicity (flutamide, cyproterone, abiraterone).

  • Neurological: Fatigue, seizures (enzalutamide).

  • Cardiovascular: Hypertension, edema, thromboembolism.

Contraindications

  • Severe liver disease (flutamide, cyproterone, abiraterone).

  • Pregnancy (category X, teratogenic).

  • Breastfeeding.

  • Hypersensitivity to the drug.

  • Severe untreated adrenal insufficiency (abiraterone).

Precautions

  • Monitor liver function tests for flutamide, cyproterone, abiraterone.

  • Monitor potassium levels with spironolactone.

  • Use contraception in women of childbearing potential.

  • Adjust dosing in renal/hepatic impairment.

Drug Interactions

  • Abiraterone: CYP3A4 substrate; interactions with ketoconazole, rifampin, phenytoin.

  • Flutamide/Bicalutamide: Warfarin metabolism interference (↑ INR).

  • Spironolactone: Additive hyperkalemia with ACE inhibitors, ARBs, potassium supplements.

  • Finasteride/Dutasteride: Interfere with PSA levels (monitor carefully in prostate cancer screening).

Clinical Efficacy and Limitations

  • Prostate Cancer: Antiandrogens (especially enzalutamide, abiraterone, apalutamide) significantly improve survival in metastatic disease.

  • BPH: Finasteride and dutasteride reduce prostate volume and improve urinary symptoms.

  • Dermatology: Spironolactone, cyproterone, and finasteride are effective for acne, hirsutism, and alopecia.

  • Endocrinology: Essential in managing precocious puberty and transgender care.

Limitations include side effect burden, hepatotoxicity risks, cardiovascular effects, and long-term endocrine complications.




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