What are the uses and dosing of Gonadotropin-Releasing Hormone (GnRH) analogs?

GnRH Analog Uses and Dosing

Primary Clinical Applications

GnRH analogs are indicated for hormone-dependent conditions requiring gonadal suppression, including prostate cancer, breast cancer, endometriosis, precocious puberty, and as adjunctive therapy in specific gynecologic conditions. 1

Oncologic Indications

Prostate Cancer

• Goserelin 3.6 mg subcutaneously every 28 days for palliative treatment of advanced prostate cancer or in combination with flutamide for locally confined disease 1
• GnRH agonists work through continuous stimulation causing gonadotroph desensitization, resulting in profound suppression of testosterone (biochemical castration) 2, 3
• Monitor for tumor flare during first few weeks - transient worsening may include ureteral obstruction and spinal cord compression 1

Breast Cancer

• Indicated for premenopausal and perimenopausal women with advanced breast cancer 1
• Produces objective tumor regression in approximately 44% of premenopausal patients with progressive disease, with median duration of 9 months 3
• All women develop amenorrhea after at least 10 weeks of treatment with profound suppression of estradiol and progesterone 3
• For hormone receptor-positive early breast cancer in premenopausal women, GnRH agonists combined with adjuvant therapy reduce recurrence risk 4

Gynecologic Indications

Endometriosis

• Recommended duration is 6 months for women 18 years and older 1
• Goserelin 3.6 mg subcutaneously every 28 days 1
• Common adverse effects include hot flushes (>20%), headache, sweating, emotional lability, and decreased libido 1

Menstrual-Related Conditions

• For cyclic attacks in acute hepatic porphyrias: Initiate GnRH treatment during days 1-3 of menstrual cycle to prevent initial agonistic ovulation effect 4
• With prolonged use, gonadotropin receptors downregulate, preventing ovulation and corpus luteum formation 4
• Add low-dose estradiol skin patch after 3 months to prevent menopausal symptoms and bone loss if GnRH analog is preventing attacks 4
• Treatment beyond 6 months requires low-dose estrogen supplementation 4

Dysfunctional Uterine Bleeding

• Used as endometrial-thinning agent prior to endometrial ablation 1
• Caution: May increase cervical resistance when dilating cervix 1

Fertility-Preserving Therapy for Endometrial Cancer

• LNG-IUD with or without GnRH analogs can be considered as alternative to oral progestins 4
• Demonstrates similar remission and recurrence rates as medroxyprogesterone acetate or megestrol acetate 4

Pediatric Indication

Central Precocious Puberty

• Indicated for Tanner stage 2 breast development before age 8 years 4
• GnRH analogs desensitize gonadotrophs through continuous stimulation, reducing LH release and halting ovarian stimulation 4
• Treatment continues until normal age of puberty to preserve final adult height and delay menarche 4

Critical Dosing Considerations

Route of Administration

• Subcutaneous injection is essential - intranasal therapy produces incomplete ovarian suppression (only ~2% absorption) and should not be used 3
• Goserelin 3.6 mg implant administered subcutaneously every 28 days 1

Timing Considerations

• Complete ovarian suppression not achieved for several weeks after initiation 5
• For menstrual-related conditions, must initiate during days 1-3 of cycle to avoid initial agonistic effect 4

Major Warnings and Precautions

Cardiovascular and Metabolic

• Increased risk of myocardial infarction, sudden cardiac death, and stroke in men receiving GnRH analogs 1
• Hyperglycemia and increased diabetes risk - monitor blood glucose according to current clinical practice 1
• May prolong QT/QTc interval - consider risks and benefits of androgen deprivation therapy 1

Bone Health

• Accelerated bone loss with prolonged use, particularly concerning in premenopausal women 4
• Mandatory calcium (1000 mg daily) and vitamin D (800-2000 IU) supplementation 4
• For treatment beyond 6 months, low-dose estrogen supplementation required to prevent bone loss 4

Hypersensitivity and Injection Site

• Systemic hypersensitivity reactions reported 1
• Injection site injury and vascular injury can occur during administration 1

Psychiatric

• Depression may occur or worsen in women receiving GnRH agonists - monitor and manage appropriately 1

Contraindications

• Hypersensitivity to goserelin or any component 1
• Pregnancy (except for advanced breast cancer treatment) 1
• Should not be used in premenopausal women not receiving ovarian suppression for breast cancer disease modification 4

Important Clinical Pitfalls

NOT Effective for Fertility Preservation

GnRH analogs should NOT be used as a reliable method for fertility preservation during chemotherapy 4, 5. Despite widespread anecdotal use, evidence shows:

• Conflicting results across multiple phase III trials 4
• Studies show higher menses recovery rates but no increase in pregnancy rates 4
• Embryo or oocyte cryopreservation remains the established method for female fertility preservation 4
• Patients interested in ovarian suppression for fertility preservation should only participate in clinical trials 4

Tumor Flare Management

• Transient worsening occurs during first few weeks in both men and women treated for cancer 1
• Monitor patients at risk for ureteral obstruction and spinal cord compression 1

Special Populations

• No dose adjustment necessary for renal or hepatic impairment 1
• Discontinue nursing or drug when used in lactating women 1
• No pediatric dosing information available beyond precocious puberty indication 1