What is the role of Lupron (leuprolide) in gender-affirming healthcare?

Lupron (Leuprolide) in Gender-Affirming Healthcare

Lupron (leuprolide acetate) serves as a puberty suppressor in transgender and gender-diverse adolescents who have entered Tanner Stage G2/B2, acting as a GnRH agonist to suppress gonadotropin secretion and subsequently suppress endogenous sex hormone production, allowing time for continued gender identity exploration before initiating partially irreversible gender-affirming hormones. 1

Mechanism and Clinical Application

• Leuprolide functions as a gonadotropin-releasing hormone (GnRH) agonist that initially stimulates then suppresses pituitary secretion of LH and FSH, resulting in decreased production of testosterone and estrogen within 2-4 weeks of continuous administration. 2, 1

• The Endocrine Society Clinical Practice Guideline (2017) recommends treating gender-dysphoric/gender-incongruent adolescents at Tanner Stage G2/B2 with GnRH agonist suppression, with leuprolide being the most commonly used agent in this population. 1

• Puberty suppression with leuprolide is fully reversible—discontinuation allows endogenous puberty to resume—making it distinct from subsequent gender-affirming hormone therapy which produces partially irreversible changes. 1

Dosing and Formulations

• Two formulations are available and effective: intramuscular Lupron and subcutaneous Eligard, both typically dosed at 22.5 mg every 3 months for adolescents. 3

• Clinical puberty suppression occurs in essentially all patients (100% in recent studies), though biochemical suppression rates differ slightly between formulations (90% for Eligard vs 69% for Lupron, though this difference was not statistically significant). 3

• For younger children with central precocious puberty, doses range from 3.75 to 15 mg monthly, demonstrating the dose flexibility based on age and clinical indication. 4

Prerequisites and Multidisciplinary Requirements

• Before initiating leuprolide, adolescents require assessment by appropriately trained diagnosing clinicians (required) and a mental health provider (required for adolescents, recommended for adults) who confirm persistent gender dysphoria/gender incongruence. 1

• The treating endocrinologist must be knowledgeable about diagnostic criteria for gender dysphoria, have sufficient training in assessing psychopathology, and commit to ongoing care throughout the endocrine transition. 1

• An expert multidisciplinary team should manage treatment of peripubertal youth and older adolescents, comprised of medical professionals and mental health professionals working collaboratively. 1

Timing of Gender-Affirming Hormones

• Gender-affirming hormones (estradiol for transgender females, testosterone for transgender males) may be added after the multidisciplinary team confirms persistence of gender dysphoria/incongruence and the patient demonstrates sufficient mental capacity for informed consent to partially irreversible treatment. 1

• Most adolescents have capacity for informed consent by age 16 years, though compelling reasons may exist to initiate earlier, with minimal published experience treating prior to 13.5-14 years of age. 1

• In clinical practice, 50% of transgender youth receiving leuprolide for puberty suppression are concurrently receiving gender-affirming hormones, demonstrating the common overlap of these treatments. 3

Role in Adult Transgender Care

• For transgender women who retain their gonads, leuprolide may serve dual purposes: as part of feminizing gender-affirming therapy to suppress testosterone production, and potentially as treatment for prostate cancer if diagnosed. 5

• Transgender women who undergo orchiectomy as gender-affirming surgery would not require leuprolide for testosterone suppression, as the primary source of testosterone production has been removed. 5

• Some transgender women may prefer orchiectomy over continuous GnRH agonist therapy because residual testes may exacerbate gender dysphoria, making surgical gonadectomy both medically effective and psychologically affirming. 5

Quality of Life Considerations

• Gender-affirming treatment including leuprolide remains life-saving for many transgender individuals, as it may improve gender dysphoria, quality of life, and lessen depression, anxiety, and suicidality. 5

• The decision to use leuprolide must balance medical efficacy with each individual's gender-embodiment goals and experiences of gender dysphoria, requiring patient-centric risk-benefit discussions. 5

Pharmacokinetics and Safety Profile

• Leuprolide is not orally active and must be administered parenterally (intramuscular or subcutaneous), with bioavailability comparable between routes. 2

• The drug is primarily degraded by peptidases rather than cytochrome P-450 enzymes and is only 43-49% protein-bound, making clinically significant drug-drug interactions unlikely. 2

• Terminal elimination half-life is approximately 3 hours following intravenous administration, with less than 5% recovered as parent drug and metabolite in urine. 2

Critical Pitfall to Avoid

• Never assume all transgender individuals require or desire leuprolide—treatment decisions must account for individual anatomy (whether gonads are present), surgical history, personal goals regarding gender expression, and whether the individual experiences gender dysphoria requiring medical intervention. 5, 1