Leuprolide Acetate: Mechanism and Side Effects
What is Leuprolide Acetate?
Leuprolide acetate is a synthetic gonadotropin-releasing hormone (GnRH) agonist that suppresses sex hormone production by initially stimulating, then desensitizing the pituitary gland, leading to medical castration in adults and pubertal suppression in children. 1
Mechanism of Action
Leuprolide acts as a potent GnRH receptor agonist that initially causes a transient surge in luteinizing hormone (LH) and follicle-stimulating hormone (FSH), followed by receptor desensitization and down-regulation with continuous use 1, 2
Within 2-4 weeks of continuous administration, testosterone levels in males drop to castrate levels (below 50 ng/dL), and estrogen levels in premenopausal females fall to postmenopausal ranges 1, 2
The drug is administered as subcutaneous or intramuscular injections because it is not orally bioavailable (it's a peptide that would be degraded in the GI tract) 1
Common formulations include daily subcutaneous injections (5 mg/mL) or depot preparations given monthly (3.75 mg or 7.5 mg) or every 3-6 months 3, 2
Clinical Applications
Primary indication: Advanced prostate cancer - used as androgen deprivation therapy (ADT), either alone or in combination with antiandrogens like bicalutamide or flutamide 3
Endometriosis treatment - monthly depot injections of 3.75 mg show comparable efficacy to danazol 800 mg/day or buserelin 900 mcg/day, but use is limited to 6 months due to bone density loss 2
Central precocious puberty - doses of 3.75-15 mg monthly suppress sexual maturation and improve predicted adult height 2, 4, 5, 6
Fertility preservation - used as gonadotropin-releasing hormone agonist co-therapy with cyclophosphamide to prevent ovarian insufficiency in women with rheumatic diseases 3
Side Effects
Cardiovascular Effects
Atrial fibrillation occurs in approximately 0.73% of patients treated with leuprolide 3
Leuprolide combined with newer agents (abiraterone, enzalutamide) may increase cardiovascular risk, though leuprolide alone shows fewer cardiovascular effects than older hormonal therapies like diethylstilbestrol 3, 2
In patients with prostate cancer receiving GnRH analogues (including leuprolide), atrial fibrillation was reported in 16% of cases 3
Hormonal and Metabolic Effects
Tumor flare phenomenon: During the first 1-2 weeks of treatment, the initial surge in testosterone can temporarily worsen prostate cancer symptoms (bone pain, urinary obstruction, spinal cord compression) - this is why short-term antiandrogen coverage is planned for approximately 93% of patients starting leuprolide 3
Hot flashes and vasomotor symptoms are nearly universal in adults due to sex hormone suppression 2
Bone mineral density loss occurs with prolonged use, which is why endometriosis treatment is limited to 6 months 2
Sexual dysfunction and loss of libido are expected consequences of medical castration 2
Reproductive Effects
In men: Leuprolide causes infertility during treatment - sperm cryopreservation should be offered before starting therapy, as the drug causes maximum damage to post-meiosis spermatids 3
In women: Ovarian suppression and potential for premature ovarian insufficiency, though co-therapy with GnRH agonists may provide some ovarian protection during chemotherapy 3
Pediatric-Specific Effects
In children with central precocious puberty, leuprolide decreases growth velocity initially but ultimately improves predicted adult height by slowing premature bone age advancement 2, 4, 6
Side effects in children are generally minimal, though long-term safety data beyond 24.9 months of treatment are limited 4
Other Notable Effects
Injection site reactions with subcutaneous administration 1
The depot formulation contains benzyl alcohol (9 mg/mL) as a preservative 1
Minimal drug-drug interactions expected because leuprolide is degraded by peptidases rather than cytochrome P-450 enzymes, and only 43-49% protein-bound 1