Endocrine Abstracts

Background: In people with gender incongruence, the assigned sex at birth and their own gender identity do not align. Some individuals decide to undergo gender-affirming hormone therapy (GAHT). In transgender individuals assigned-male-at-birth (t-AMAB) GAHT often consists of a combination of anti-androgens and a feminizing estrogen treatment. However, feminizing hormone therapy target ranges are ill-defined. The Endocrine Society 2017 guideline [1] recommends not exceeding peak physiological estradiol (E2) levels of 100-200 ng/l. However, these hormonal targets are often misquoted. Most notably, the SOC8 [2] guideline erroneously recommends optimal E2 levels between 100 and 200 ng/l. Simultaneously, the pharmacokinetic (Pk) properties of estradiol valerate (EV) remain largely uninvestigated in t-AMAB individuals. Sexual dimorphism related to body composition, hepatic metabolism, circulating blood volume and renal function could alter the Pk profile of EV in t-AMAB individuals compared to cisgender women.

Objective: To describe Pk characteristics of EV in a cohort of t-AMAB-individuals using GAHT.

Methods: Participants were part of the European Network for the Investigation of Gender Incongruence (ENIGI) study. Self-reported time of drug administration and time of blood draw were recorded. All participants used Progynova (oral EV) 2 mg twice daily. The E2 levels were measured using liquid chromatography followed by tandem mass spectrometry (LC-MS/MS). Extreme outliers as defined by Tukey’s rule were removed prior to data analysis. B-spline regression using RStudio ver. 2024.04.01 was performed to model E2 level evolution after 2 mg EV ingestion. Missing data was handled using spline interpolation. The model was then reinforced by adding data from individuals in which E2 levels were calculated using immunoassay (IA). Finally, the results were compared to historic Pk data retrieved after a scoping review of the literature in the Medline database [3].

Results: A total of 46 unique individuals with LC-MS/MS data, and 15 individuals with IA data were selected. Median age at start of GAHT was 23.7 years (range: 17.7-58.8 years). Median GAHT duration was 17 months (range: 2-40 months). A crude 24h Pk profile was generated. The 24h area under the curve (AUC) was 1684.1 ng/l*h. The median E2 level was 62.7 ng/l (range: 13.4-153.0 ng/l). A nearly horizontal trend line was observed, indicating minimal variation in E2 levels during the first 12 hours after drug administration. However, significant inter-individual variance was noted. The Pk profile of 2 mg oral EV in this cohort of t-AMAB individuals was comparable to historic Pk data of cisgender women.

Conclusion: The Pk model currently lacks robustness to formulate dosing recommendations. The preliminary data seem harmonious with the 2017 Endocrine Society guidelines, although standardized Pk studies in gender-diverse cohorts are needed to optimize endocrine care.

References: 1. Hembree, et al. (2017). The Journal of clinical endocrinology and metabolism. https://doi.org/10.1210/jc.2017-01658.

2. Coleman, et al. (2022). International journal of transgender health, 23. https://doi.org/10.1080/26895269.2022.2100644.

3. Zimmerman, H. et al. (2000). Clinical drug investigation, 20(2), 123–134. https://doi.org/10.2165/00044011-200020020-00007.