Antigonadotropic agents

Introduction

Antigonadotropic agents are a class of drugs that inhibit the secretion or action of gonadotropins—luteinizing hormone (LH) and follicle-stimulating hormone (FSH)—or interfere with the downstream effects of these hormones on gonadal steroidogenesis. By reducing gonadotropin signaling, these drugs lower the synthesis of sex steroids (testosterone, estrogen, and progesterone), thereby suppressing reproductive function and modulating hormone-dependent conditions.

They have clinical application in contraception, hormone-dependent cancers, endometriosis, precocious puberty, benign prostatic hyperplasia, and gender-affirming therapy. Their action may be central (hypothalamic–pituitary level) or peripheral (gonadal steroid antagonism).

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Mechanisms of Action

Antigonadotropic activity can be achieved through several pharmacological mechanisms:

1. Gonadotropin-Releasing Hormone (GnRH) Agonists (leuprolide, goserelin, triptorelin, nafarelin)

   • Continuous stimulation of GnRH receptors causes receptor desensitization and downregulation, leading to reduced LH/FSH release (medical castration).

2. GnRH Antagonists (degarelix, cetrorelix, ganirelix, relugolix)

   • Directly block pituitary GnRH receptors, leading to immediate suppression of LH and FSH.

3. Progestins (medroxyprogesterone acetate, norethisterone, megestrol acetate, levonorgestrel)

   • Inhibit LH/FSH secretion via negative feedback on the hypothalamus and pituitary.

4. Androgen Receptor Antagonists (cyproterone acetate, spironolactone, flutamide, bicalutamide)

   • Block the effects of testosterone and dihydrotestosterone (DHT); cyproterone acetate also has progestational antigonadotropic activity.

5. Estrogens (ethinylestradiol, estradiol valerate)

   • Provide negative feedback on the hypothalamus and pituitary, reducing gonadotropin secretion.

6. Other Antigonadotropic Steroids

   • Danazol (a synthetic androgen with weak antigonadotropic activity used in endometriosis).

   • Gestrinone (anti-estrogenic and anti-progestogenic steroid with antigonadotropic activity).

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Representative Generic Agents

GnRH Agonists

• Leuprolide

• Goserelin

• Triptorelin

• Nafarelin

GnRH Antagonists

• Degarelix

• Cetrorelix

• Ganirelix

• Relugolix

Progestins with Antigonadotropic Action

• Medroxyprogesterone acetate

• Norethisterone

• Megestrol acetate

• Levonorgestrel

Androgen Receptor Antagonists (with antigonadotropic effect)

• Cyproterone acetate

• Spironolactone

• Flutamide

• Bicalutamide

Other Steroidal Antigonadotropins

• Danazol

• Gestrinone

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Therapeutic Uses

1. Hormone-Dependent Cancers

   • Prostate cancer: GnRH agonists (leuprolide, goserelin) and antagonists (degarelix, relugolix).

   • Breast cancer: Progestins (megestrol acetate, medroxyprogesterone) and GnRH modulators.

2. Gynecological Disorders

   • Endometriosis: GnRH agonists, danazol, gestrinone, progestins.

   • Uterine fibroids: GnRH agonists/antagonists.

   • Polycystic ovary syndrome (PCOS): Cyproterone acetate for hyperandrogenism.

3. Contraception

   • Progestins (oral contraceptives, depot medroxyprogesterone acetate, levonorgestrel implants).

   • Estrogen-progestin combinations (suppress LH surge).

4. Reproductive Medicine

   • Controlled ovarian hyperstimulation: GnRH antagonists (cetrorelix, ganirelix) to prevent premature LH surge.

   • Precocious puberty: GnRH agonists for pubertal suppression.

5. Androgen-Related Disorders

   • Hirsutism, acne: Cyproterone acetate, spironolactone.

   • Gender-affirming hormone therapy: Antiandrogens (cyproterone acetate, spironolactone) to suppress testosterone.

6. Other Uses

   • Benign prostatic hyperplasia (BPH).

   • Appetite stimulation in cachexia (megestrol acetate).

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Contraindications

• Pregnancy and lactation (GnRH modulators, androgen receptor antagonists, progestins in high doses).

• Severe hepatic impairment (cyproterone acetate, flutamide, danazol).

• Thromboembolic disorders (estrogens, high-dose progestins).

• Undiagnosed vaginal bleeding (progestins, estrogens).

• Hypersensitivity reactions to specific agents.

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Adverse Effects

GnRH Agonists/Antagonists

• Hot flashes, decreased libido, erectile dysfunction

• Osteoporosis with long-term use (hypogonadism)

• Mood changes, headache, injection site reactions

Progestins

• Weight gain, bloating

• Mood changes, depression

• Menstrual irregularities

• Decreased bone mineral density (with depot medroxyprogesterone acetate)

Antiandrogens

• Gynecomastia, breast tenderness

• Reduced libido, erectile dysfunction

• Hepatotoxicity (flutamide, cyproterone)

• Hyperkalemia (spironolactone)

Estrogens

• Nausea, breast tenderness

• Thromboembolic events

• Increased risk of stroke and myocardial infarction in predisposed patients

Danazol / Gestrinone

• Androgenic effects: acne, hirsutism, weight gain, voice deepening

• Hepatotoxicity, adverse lipid profile

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Precautions

• Bone health monitoring in patients on long-term GnRH analogues.

• Liver function monitoring in patients on cyproterone, flutamide, or danazol.

• Electrolyte monitoring with spironolactone.

• Cardiovascular risk assessment in patients on estrogens or high-dose progestins.

• Psychological monitoring as hormonal suppression may lead to mood changes.

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Drug Interactions

• Cyproterone acetate: Potentiates hepatotoxicity with alcohol; may interact with anticoagulants.

• Flutamide/Bicalutamide: CYP450 metabolism interactions with warfarin, phenytoin.

• Spironolactone: Risk of hyperkalemia with ACE inhibitors, ARBs, potassium-sparing diuretics.

• GnRH analogues: Additive bone loss with corticosteroids.

• Danazol: Increases plasma concentration of cyclosporine, warfarin, and carbamazepine.

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Clinical Considerations

• Choice of agent depends on indication:

  • Prostate cancer: GnRH agonist/antagonist ± antiandrogen.

  • Endometriosis/fibroids: GnRH agonist/antagonist, danazol, progestin.

  • Contraception: Progestin or estrogen–progestin combinations.

  • PCOS with hyperandrogenism: Cyproterone acetate, spironolactone.

• Monitoring: Bone mineral density (long-term hypogonadism), liver enzymes, electrolytes, cardiovascular status.

• Duration of therapy: GnRH analogues typically limited to 6 months without add-back therapy due to osteoporosis risk; longer if combined with low-dose estrogen/progestin.