What is the role of Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH) in hormone therapy for male-to-female gender transition, particularly in relation to testosterone suppression?

Role of FSH and LH in Hormone Therapy for Male-to-Female Gender Transition

For male-to-female gender transition, suppression of FSH and LH is a key mechanism for reducing testosterone production, which is achieved through estradiol therapy combined with anti-androgens to effectively feminize physical characteristics and improve quality of life. 1, 2

Hormonal Regulation in Gender-Affirming Hormone Therapy

• Estradiol, the cornerstone of feminizing hormone therapy, acts through binding to nuclear receptors in estrogen-responsive tissues and modulates pituitary secretion of gonadotropins (LH and FSH) through a negative feedback mechanism 3
• This negative feedback suppression of FSH and LH is essential for reducing endogenous testosterone production in transgender women 1, 4
• The goal of feminizing hormone therapy is to suppress testosterone levels to <50 ng/dL while maintaining estradiol levels in the cisgender female reference range 1

Anti-Androgen Options and Their Effects on FSH/LH

Several anti-androgen options are available to enhance testosterone suppression:

• GnRH analogues (puberty blockers): Most directly suppress FSH and LH production by acting on the hypothalamic-pituitary axis, effectively halting testosterone production at its source 2
• Cyproterone acetate: Commonly used in Europe, acts as both an anti-androgen and has progestational effects that further suppress gonadotropins 5, 4
• Spironolactone: Most commonly used anti-androgen in many countries, primarily blocks androgen receptors but has less effect on FSH/LH levels 1
• Bicalutamide and finasteride: Act peripherally as androgen receptor antagonists without necessarily lowering testosterone concentrations 2

Mechanism of Action

• Estradiol therapy reduces FSH and LH through negative feedback on the hypothalamic-pituitary axis, similar to how endogenous estrogens function in cisgender women 3, 4
• Different testosterone formulations have varying degrees of FSH/LH suppression - longer-acting formulations (like injectables) can decrease FSH by up to 86.3% and LH by 71.8%, while shorter-acting preparations have less suppressive effects 6
• Complete suppression of the pituitary-gonadal axis often requires both estradiol and an anti-androgen, especially before orchiectomy 4

Clinical Effects and Timeline

• Feminizing hormone therapy induces physical changes including decreased muscle mass (5% decrease in thigh muscle volume and 4% decrease in quadriceps cross-sectional area) 1, 2
• Breast development is a key outcome for many transgender women, with variable results in cup size development 1
• Changes in body composition include 3.0-5.5% reduction in lean body mass and increases in total body fat 2, 1
• Hemoglobin levels decrease significantly, approaching female reference ranges 1

Monitoring Recommendations

• Baseline assessment should include complete blood count, liver function, lipid profile, glucose, and baseline hormone levels 1
• Initial follow-up at 3 months to check estradiol and testosterone levels, with ongoing monitoring every 3-6 months during the first year, then annually if stable 1
• Target testosterone levels should be <50 ng/dL with estradiol levels in the cisgender female reference range 1

Cardiovascular Risk Considerations

• Transgender women have an increased risk of venous thromboembolism compared to cisgender individuals 1, 2
• The thrombosis risk persists despite changes in estradiol dosing and preparations over time, requiring individualized risk assessment 1
• Ethinyl estradiol may increase VTE risk more than other estrogen formulations and should be avoided 2

Clinical Pitfalls to Avoid

• Inadequate testosterone suppression may result in suboptimal feminization - monitoring both FSH/LH and testosterone levels is crucial 4, 7
• Excessive estrogen dosing to achieve testosterone suppression increases cardiovascular risks - adding an appropriate anti-androgen is preferable to high-dose estrogen monotherapy 1, 2
• After orchiectomy, anti-androgen therapy can be discontinued as the primary source of testosterone production is removed, but estrogen therapy should be continued to maintain feminization and bone health 4