What are the uses and dosages of Gonadotropin-Releasing Hormone (GnRH) agonists, such as leuprolide (Lupron), and antagonists, such as cetrorelix (Cetrotide), in patients with conditions like endometriosis, uterine fibroids, hormone-sensitive cancers, including prostate cancer, and a history of fertility issues?

GnRH Agonists and Antagonists: Clinical Applications and Dosing

GnRH Agonists (Leuprolide, Goserelin)

Established Indications and Dosing

For hormone-sensitive cancers and reproductive conditions, GnRH agonists achieve therapeutic hypogonadism through initial receptor stimulation followed by pituitary desensitization. 1, 2

Prostate Cancer

• Leuprolide: 3.75-7.5 mg IM every 4 weeks OR 11.25-22.5 mg IM every 12 weeks 1
• Goserelin: 3.6 mg SC every 4 weeks OR 10.8 mg SC every 12 weeks 1, 3
• Monitor testosterone suppression to castrate levels (<50 ng/dL) 3

Breast Cancer (Premenopausal, Hormone Receptor-Positive)

• Leuprolide: 3.75 mg IM monthly for 5 years (optimal duration based on SOFT/TEXT trials) 1
• Minimum 2-year duration acceptable, achieving 85.4% 8-year disease-free survival with ovarian suppression plus tamoxifen versus 80.2% with tamoxifen alone 1
• Critical: Monitor estradiol and FSH/LH levels in women <45 years to confirm adequate ovarian suppression 1
• Premenopausal estradiol levels indicate treatment failure requiring dose adjustment 1

Endometriosis

• Leuprolide depot: 3.75 mg IM monthly for maximum 6 months 2, 4
• Goserelin: 3.6 mg SC monthly 3
• Efficacy comparable to danazol 800 mg/day or buserelin 900 mcg/day intranasal 2
• Duration strictly limited to 6 months due to bone mineral density loss 2

Uterine Fibroids

• Leuprolide: 3.75 mg IM monthly for 6 months maximum 2
• Reduces uterine volume and fibroid symptoms, but effects dissipate after discontinuation 2
• Primarily used preoperatively to reduce fibroid size and treat anemia 5

Central Precocious Puberty

• Leuprolide depot: 3.75-15 mg IM/SC monthly, dose titrated to weight and response 2
• Decreases growth velocity, halts sexual maturation, increases predicted adult height 2

Fertility Preservation During Chemotherapy

GnRH agonists should NOT be used as a primary fertility preservation method and must never replace embryo or oocyte cryopreservation. 6, 7

When to Consider (Secondary Option Only)

• Breast cancer patients only: GnRH agonists during chemotherapy reduce premature ovarian insufficiency (POI) from 30.9% to 14.1% (OR 0.38,95% CI 0.26-0.57) and increase post-treatment pregnancies (IRR 1.83,95% CI 1.06-3.15) 6
• Benefit applies to both hormone receptor-positive and -negative breast cancer, regardless of age or chemotherapy type 6
• Hematologic malignancies: No protective effect demonstrated (RR 0.70,95% CI 0.20-2.47 for POI; RR 1.13,95% CI 0.66-1.93 for pregnancies) 6

When GnRH Agonists May Be Discussed

• Only after embryo/oocyte cryopreservation completed OR when cryopreservation not accessible due to timing, cost, or ethical concerns 6
• May provide secondary benefit of menstrual cycle control and prevention of menometrorrhagia in patients with chemotherapy-induced thrombocytopenia 6
• Start concurrently with chemotherapy, not after 1

Critical Limitation

• Complete ovarian suppression requires several weeks after first injection, making timing crucial 1, 7, 8

Mandatory Monitoring and Testing

Baseline Assessment

• Bone mineral density (BMD) in patients >65 years, with family history of osteoporosis, or chronic steroid use 1, 8
• Baseline estradiol and FSH/LH levels 1

Ongoing Monitoring

• Estradiol and FSH/LH levels in women <60 years, amenorrheic ≤12 months, post-chemotherapy, when switching from tamoxifen to aromatase inhibitor, or if discontinuing ovarian suppression 1
• BMD at 3-6 month intervals during prolonged therapy 1, 8
• Cardiovascular risk assessment in patients with pre-existing cardiac disease 8

Side Effects and Management

Hypoestrogenic Symptoms (Majority of Patients)

• Hot flashes, sweating, vaginal dryness, diminished libido, sexual dysfunction 6, 8
• Typically low severity grade and reversible 6, 8
• Management: Discuss contrasting adverse effect profiles when choosing between tamoxifen and aromatase inhibitor with ovarian suppression 1
• Low threshold for re-evaluating benefits versus trade-offs in women with marked symptoms 1
• Discontinue ovarian suppression if symptoms intolerable and untreatable 1

Bone Health (Critical Long-Term Risk)

• Standard 6-month regimens cause significant trabecular and cortical bone loss 1, 8
• Recovery slow after discontinuation and may be incomplete 1, 8
• Prevention: Calcium and vitamin D supplementation mandatory; bisphosphonates when appropriate 1
• Monitor BMD according to postmenopausal guidelines 1

Metabolic and Cardiovascular

• Risk of metabolic syndrome with prolonged use 1, 8
• Potential cardiovascular effects in at-risk patients 8

Tumor Flare Phenomenon

• Initial testosterone/estrogen surge in first 1-2 weeks can worsen cancer symptoms 3
• Consider anti-androgen co-administration in prostate cancer 3

Critical Contraindications

• Pregnancy (Category X) 3
• Hypersensitivity to GnRH agonists or any component 3
• Undiagnosed vaginal bleeding 3

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GnRH Antagonists (Cetrorelix, Relugolix)

Mechanism Advantage

GnRH antagonists provide immediate gonadotropin suppression through competitive receptor blockade, avoiding the initial flare effect of agonists. 9, 5, 4

Clinical Applications

Assisted Reproductive Technology (Primary Use)

• Cetrorelix: Prevents premature LH surge during controlled ovarian stimulation for IVF 9, 4
• Reduces cycle cancellation rates and severe ovarian hyperstimulation syndrome 4
• First GnRH antagonist approved for clinical use (IVF indication) 9

Uterine Fibroids

• Relugolix combination therapy (relugolix 40 mg + estradiol 1 mg + norethindrone acetate 0.5 mg): Once-daily oral tablet 5
• FDA-approved (MYFEMBREE) for heavy menstrual bleeding associated with uterine fibroids 5
• EU/UK-approved (RYEQO) for symptom management in uterine fibroids 5
• Advantage over agonists: Add-back estrogen/progestin maintains therapeutic estradiol range while mitigating bone loss and vasomotor symptoms, enabling longer-term treatment 5

Endometriosis

• Relugolix combination therapy: FDA-approved for moderate to severe pain (dysmenorrhea, nonmenstrual pelvic pain, dyspareunia) 5
• Same formulation as uterine fibroid indication 5

Prostate Cancer

• Relugolix 120 mg (ORGOVYX): First oral androgen-deprivation therapy for advanced prostate cancer 5
• Approved in US, EU, and UK 5

Advantages Over Agonists

• Immediate suppression without initial hormone surge 9, 4
• Rapid but reversible gonadotropin suppression 4
• Reduced risk of tumor flare in hormone-sensitive cancers 9
• With add-back therapy (relugolix-CT), enables longer treatment duration for benign conditions 5

Side Effects

• Similar hypoestrogenic profile to agonists when used without add-back therapy 8
• Relugolix combination therapy mitigates bone loss and vasomotor symptoms through estrogen/progestin component 5
• Cardiovascular monitoring recommended in at-risk patients 8

Key Clinical Pearls

• Cetrorelix remains primarily an IVF medication, not for long-term disease management 9
• Relugolix combination therapy represents paradigm shift for chronic management of uterine fibroids and endometriosis, potentially delaying or preventing surgery 5
• Concept that complete sex-steroid suppression unnecessary for benign conditions (fibroids, endometriosis, BPH) drives antagonist development with add-back therapy 9