Chapter 32 · Module 2 Visual Summary
GnRH Analogs in Clinical Practice
Agonists, antagonists, oral agents, and clinical applications
LH = luteinizing hormone  ·  FSH = follicle-stimulating hormone  ·  PLGA = poly(lactic-co-glycolic acid)  ·  BCRP = breast cancer resistance protein  ·  MACE = major adverse cardiovascular events  ·  PSA = prostate-specific antigen  ·  ADT = androgen deprivation therapy
Agonist vs. Antagonist — Mechanism and Key Differences
Feature GnRH Agonist Depot Injectable Antagonist (Degarelix) Oral Antagonist (Relugolix)
Mechanism Continuous receptor activation → downregulation Competitive receptor blockade — no activation Competitive receptor blockade — no activation
Testosterone flare YES — covers with anti-androgen x 4 weeks NO NO
Onset of castration 3–4 weeks Within 3 days Within days
Dosing Monthly to quarterly IM or SC depot Monthly SC injection Once daily oral
Cardiovascular QTc prolongation; metabolic syndrome risk Injection site reactions common (35–40%) 54% lower MACE vs. leuprolide (HERO trial)
Testosterone recovery Slow (months to >1 year after depot) Moderate (weeks to months) Fast (t½ ~25 h; weeks after stopping)
GnRH Agonist Depot Formulations
Leuprolide
PLGA Microsphere (IM) or Atrigel (SC)
  • 1-month: 7.5 mg IM / SC
  • 3-month: 22.5 mg IM / SC
  • 4-month: 30 mg IM
  • 6-month: 45 mg IM / SC
  • Lupron Depot (IM); Eligard (SC atrigel)
  • Pediatric: 0.3 mg/kg IM q4 weeks (min 7.5 mg)
Goserelin
Biodegradable SC Rod Implant
  • 1-month: 3.6 mg SC implant
  • 3-month: 10.8 mg SC implant
  • Placed with trocar in anterior abdominal wall
  • Must be SC — IM placement prevents controlled release
  • Eliminated renally (~90%); no renal dose adjustment needed
Triptorelin
Microsphere Depot (IM)
  • 1-month: 3.75 mg IM
  • 3-month: 11.25 mg IM
  • 6-month: 22.5 mg IM
  • Hepatic peptidase metabolism; renal elimination
  • Histrelin implant (Supprelin LA): annual SC replacement for central precocious puberty
Oral GnRH Antagonists — Drug Interaction Profiles
Elagolix (Orilissa)
CYP3A4 Substrate — Dose-Dependent Suppression
  • Oral bioavailability ~57%
  • 150 mg once daily: partial suppression (endometriosis, up to 24 months)
  • 200 mg twice daily: near-complete suppression (max 6 months without add-back)
  • CYP3A4 substrate: strong inhibitors (ketoconazole, ritonavir) increase exposure
  • 200 mg twice-daily dose contraindicated with strong CYP3A4 inhibitors
  • CYP3A4 inducers (rifampin) reduce efficacy
  • OATP1B1 substrate: cyclosporine increases levels
  • P-gp inhibitor: may increase digoxin exposure
Relugolix (Orgovyx / Myfembree)
P-gp Substrate — Immediate Suppression
  • Oral bioavailability ~12%; t½ ~25 h; once-daily dosing
  • Prostate cancer: 120 mg once daily (360 mg loading dose)
  • Fibroids/endometriosis: 40 mg + estradiol 1 mg + norethindrone 0.5 mg (Myfembree)
  • P-gp and BCRP substrate: strong P-gp inhibitors (amiodarone, clarithromycin, verapamil) increase exposure up to 4x — contraindicated
  • P-gp inducers (rifampin, carbamazepine) reduce efficacy
  • NOT a major CYP3A4 substrate — differentiates from elagolix
  • HERO trial: 54% lower MACE vs. leuprolide
Clinical Applications by Indication
Indication First-Line Agent(s) Key Considerations Monitoring
Prostate cancer (ADT) Leuprolide depot or relugolix (preferred if high CV risk) Cover agonist flare with bicalutamide x 4 weeks; target testosterone <50 ng/dL (ideally <20) PSA, testosterone, fasting glucose, lipids, DEXA q12 months
Endometriosis Leuprolide or goserelin depot; elagolix oral Add-back therapy if >6 months; estradiol target 20–40 pg/mL Bone mineral density at 6–12 months; symptom reassessment
Uterine fibroids Myfembree (relugolix combination) or leuprolide depot preoperatively Fibroid regrowth occurs within 3–6 months of stopping agonist monotherapy Bone mineral density with prolonged use; symptom assessment
Central precocious puberty Leuprolide depot-Ped or histrelin implant Confirm suppression: stimulated LH <2 IU/L; bone age X-ray annually Growth velocity, bone age, stimulated LH q3–6 months
Androgen Deprivation Therapy Adverse Effects — High-Yield Monitoring
QTc prolongation: baseline ECG if on QT-prolonging drugs; avoid if QTc >500 ms.  •  Bone loss: calcium + vitamin D for all; DEXA at baseline and 12 months; zoledronic acid or denosumab if high fracture risk.  •  Metabolic syndrome: screen for diabetes and cardiovascular risk factors every 3–6 months; prescribe exercise; statin per guidelines.  •  Hot flashes (50–80% of men on ADT): venlafaxine, gabapentin, or medroxyprogesterone acetate.