ESPE Yearbook of Paediatric Endocrinology

Endocrine. 2022 Jun;76(3):722-732. PMID: 35258786, doi: 10.1007/s12020-022-03017-8.

Brief Summary: In this multicentre, randomized, double-dummy, double-blind crossover trial the authors investigated differences in metabolic parameters between the individuals with complete androgen insensitivity syndrome (CAIS) receiving testosterone versus estradiol replacement therapy. This is the first study investigating these different treatment options in CAIS. It finds no major differences in metabolic and safety parameters between the treatments.

CAIS is the most common 46, XY DSD, and is characterized by complete loss of androgen receptor function due to X-linked recessive mutations within the androgen receptor gene. The testosterone concentrations are in the normal-to-upper male reference range, while estradiol concentrations are normal to slightly increased relative to male references originating primarily from testicular secretion and peripheral aromatization of androstenedione and testosterone. However, despite aromatization, estradiol concentrations are usually below the usual female reference range.

The researchers analyzed data from 17 females with CAIS who undertook a two-month run-in phase with estradiol, then either received transdermal estradiol followed by crossover to transdermal testosterone or vice versa. After six months, differences in lipids, fasting glucose, insulin, hematocrit, liver parameters, and blood pressure between the treatment phases were investigated. Although it may seem unlikely that testosterone should exert any distinct effect from that of estradiol in females with CAIS, the authors could show that testosterone replacement is non-inferior to estradiol in terms of quality of life and results in comparable levels of estrogens. Both treatments resulted in a less favorable lipid profile, as there was a significant increase in total and LDL-cholesterol and a significant decrease in HDL-cholesterol. In addition, there was a slight but significant increase in BMI in both groups.

The results did not reveal major differences according to treatment for the investigated outcomes. Furthermore, this study provides a different point of view in that testosterone treatment may have beneficial effects on wellbeing and sexual functioning in these individuals. The underlying hypothesis is that testosterone is not only metabolized to estradiol but also to neurosteroids that exert their activity neither via estrogen - nor androgen receptors. Further studies may address the potential differences of both treatments assuming that there is a difference between a systemic increase in estradiol in comparison to a local increase of estradiol via aromatization of testosterone depending on the distribution of aromatase expression in the corresponding target tissues such as bone.