GnRH Modulators (Agonists and Antagonists)

Mechanism

Mechanism of Action

Gonadotropin-releasing hormone receptor (GnRH-R) modulators act by directly regulating the synthesis and secretion of gonadotropins by the gonadotroph cells of the adenohypophysis.

GnRH agonists (Leuprolide/Goserelin)

Synthetic pituitary receptor superagonist peptides:

• Initial stimulus phase ("Flare-up"): Acute administration causes an initial massive release of FSH and LH by the pituitary in the first 24-48 hours.
• Suppression phase (Down-regulation): Continuous and uninterrupted exposure completely desensitizes and deregulates GnRH receptors, inducing a deep pharmacological castration in 2 weeks (estradiol levels to postmenopausal range).

GnRH antagonists (Cetrorelix/Elagolix)

Compounds with immediate competitive binding to the GnRH receptor:

• Immediate competitive blockade: They competitively inhibit the binding of endogenous GnRH without inducing initial activation (avoid the "flare-up" effect).
• Immediate suppression: Plasma levels of FSH, LH and estradiol decrease exponentially in a matter of hours.
• Elagolix: It is the first orally active non-peptide GnRH antagonist that allows dosable and modulable estrogen suppression.

Pharmacokinetics

Pharmacokinetics

• Leuprolide: Ineffective orally. It is administered by monthly or quarterly intramuscular or subcutaneous depot injections in biodegradable polymer microspheres. Steady extended release. Short plasma half-life after release, but sustained biological duration during the deposition period of 30 to 90 days.
• Cetrorelix: Administration by daily subcutaneous injection in the late follicular phase of ovarian stimulation. High bioavailability. Elimination half-life of approx. 30 hours.
• Elagolix: Oral administration once or twice a day. Rapid oral absorption that reaches peak serum in 1.5 hours. It is metabolized in the liver by CYP3A4. Elimination half-life of 4 to 6 hours.

Indicators and dose

Indications

• Agonists (Leuprolide/Goserelin): Symptomatic treatment of moderate to severe endometriosis, reduction in the size of uterine fibroids before elective surgery (myomectomy or hysterectomy) and treatment of central precocious puberty.
• Peptide Antagonists (Cetrorelix/Ganirelix): Prevention of premature ovulation (premature LH surge) in controlled ovarian stimulation (COS) cycles as part of in vitro fertilization (IVF) protocols.
• Oral Antagonists (Elagolix): Treatment of moderate to severe pelvic pain associated with endometriosis in adult women.

Dosage and Schemes

• Leuprolide (Endometriosis/Fibroids): 3.75 mg IM once a month, or 11.25 mg IM once every 3 months for a maximum recommended cumulative period of 6 months (unless strictly add-back regimen is given).
• Cetrorelix (IVF Protocols): 0.25 mg subcutaneously once a day in the late follicular phase (starting on day 5 or 6 of the gonadotropin stimulation cycle) until the day of induction of follicular maturation with hCG.
• Elagolix (Endometriosis Pain): 150 mg orally once daily for up to 24 months; or 200 mg orally twice daily for up to 6 months for severe pain with active dyspareunia.

Pregnancy and Breastfeeding

FDA Category X for everyone. Absolutely contraindicated. Exclude pregnancy before starting any dose of these treatments and strictly prescribe non-hormonal strict barrier contraceptive methods throughout the treatment.

Security

Contraindications

• Confirmed pregnancy and active breastfeeding (high risk of spontaneous abortion and serious fetal malformations).
• Base undiagnosed abnormal vaginal bleeding.
• Pre-existing severe osteoporosis confirmed by densitometry (especially for long-term treatment with GnRH agonists or Elagolix without add-on therapy).

Adverse Effects (ADR)

• Severe Estrogen Deprivation Syndrome (castration range): Intense hot flashes (80% of patients), profuse night sweats, dryness of the vaginal mucosa with severe dyspareunia, drastic decrease in libido, emotional instability and migraine headache.
• Loss of bone mineral density (BMD): The state of severe hypoestrogenism prolonged for more than 6 months induces accelerated osteoporosis. It is mandatory to prescribe "Add-back therapy" (low doses of an estrogen and progestin, such as norethisterone + estradiol) to counteract bone resorption without reactivating the source of endometrial pain.
• Transient functional ovarian cysts: They can develop during the initial "flare-up" phase of GnRH agonists.