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Gonadotropin-Releasing Hormone Antagonist

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Gonadotropin-Releasing Hormone Antagonist, Gonadotropin Releasing Hormone Antagonist, GnRH Antagonist, LHRH Antagonist, Degarelix, Firmagon, Relugolix, Orgovyx, Elagolix, Orilissa, Abarelix, Plenaxis, Ganirelix, Fyremadel, Antagon, Cetrorelix, Cetrotide

  • Indications
  1. Fertility Treatment - Inhibits premature LH surge in controlled Ovarian Hyperstimulation (women)
    1. Ganirelix (Fyremadel, Antagon)
    2. Cetrorelix (Cetrotide)
  2. Endometriosis (moderate to severe pain in women)
    1. Elagolix (Orilissa)
  3. Advanced Prostate Cancer (Men)
    1. Degarelix (Firmagon)
    2. Relugolix (Orgovyx)
    3. Abarelix (Plenaxis)
  • Contraindications
  1. Pregnancy
  2. Osteoporosis
  3. Severe liver disease (Elagolix)
  • Mechanism
  1. Gonadotropin-Releasing Hormone (GnRH)
    1. GnRH is generated within hypothalamic Neurons (infundibular nucleus, arcuate nucleus)
    2. GnRH is released typically in pulses in men and women
      1. GnRH is also released in a surge before Ovulation
    3. GnRH binds receptors on the Pituitary Gland triggering release of gonadotropins
      1. Luteinizing Hormone (LH)
      2. Follicle Stimulating Hormone (FSH)
    4. Gonadotropins (LH, FSH) stimulate release of sex Hormones (e.g. Estrogen, Testosterone)
  2. GnRH Antagonist
    1. GnRH Antagonists are synthetic peptides that block GnRH receptors on the surface of Gonadotroph cells in the anterior pituitary
    2. Decrease LH and FSH release from the anterior Pituitary Gland's Gonadotroph cells
    3. Results in decreased Estrogen synthesis (ovaries) and Testosterone synthesis (Testes)
  3. Images
    1. hypothalamusPituitaryHormones.png
  • Medications
  • Women
  1. Elagolix (Orilissa)
    1. Endometriosis: 150 mg orally once daily (<=24 months, <=6 months in liver disease) or 200 mg orally twice daily (<=6 months)
  2. Ganirelix (Fyremadel, Antagon)
    1. Infertility: Start day 5-6 of cycle (after FSH therapy on Day 2-3), giving 250 mcg SQ daily during the mid-late Follicular Phase
  3. Cetrorelix (Cetrotide)
    1. Infertility: Start day 5-6 of cycle (after FSH therapy on Day 2-3), giving 0.25 mcg SQ daily during the mid-late Follicular Phase
  1. Degarelix (Firmagon)
    1. Prostate Cancer: Start with 240 mg SQ, then 80 mg SQ every 28 days
  2. Relugolix (Orgovyx)
    1. Prostate Cancer: Start with 360 mg orally day 1, then 120 mg orally daily at same time each day
  3. Abarelix (Plenaxis)
    1. Older agent, replaced by newer agents (e.g. Degarelix)
  • Adverse Effects
  • Women
  1. Menopausal symptoms
    1. Hot Flashes
    2. Insomnia
    3. Emotional changes (includes Major Depression)
  2. Liver Function Test abnormalities (Elagolix)
    1. Increased transaminases
  3. Bone density loss with prolonged use
  4. Other adverse effects
    1. Headache
    2. Nausea
    3. Arthralgias
  1. Hypersensitivity including Anaphylaxis (Degarelix, Relugolix)
  2. QTc Prolongation (Degarelix, Relugolix)
  3. Bone density loss with prolonged use
  4. Liver Function Test abnormalities (Degarelix, Relugolix)
    1. Increased transaminases
  5. Other adverse effects
    1. Injection site reactions (Degarelix)
    2. Hot Flashes
    3. Altered bowel habits (Relugolix)
    4. Musculoskeletal pain (Relugolix)
  • Safety
  1. Avoid in Pregnancy
  2. Avoid in Lactation
  • Drug Interactions
  1. Strong P-gp Inhibitors (esp. combined with strong CYP3A Inducers)
    1. Avoid with Relugolix (or separate doses by at least 6 hours)
  2. OATP 1B1 Inhibitors
    1. Avoid with Elagolix (significantly increases drug levels)
  • Resources
  1. Degarelix (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ab11dd8a-0fd9-4013-89ab-e114557c7e4b
  2. Relugolix (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=077a92f6-9f1b-479a-87c7-c92b5db6aa9c
  3. Elagolix (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a86757b3-09c5-fd3b-1223-244e94f50a66
  4. Ganirelix (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=32fb74ff-993a-49fe-8943-e029372b863e
  5. Cetrorelix (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=aca7768e-28a7-4027-b1d8-e66247665f79
  • References
  1. (2022) Presc Lett, Medications to treat Prostate Cancer, Resource #380108
  2. Fairchild (2015) AJR Am J Roentgenol 204(6):W620-30 +PMID: 26001251 [PubMed]