Hormonal and Metabolic Features of Complete Androgen Insensitivity Syndrome with and without Gonadectomy.

Context

Complete Androgen Insensitivity Syndrome (CAIS) is a variation of sex characteristics caused by androgen receptor gene mutations. As clinical practice increasingly supports deferring gonadectomy when appropriate, understanding hormonal and metabolic profiles is critical to inform longitudinal health.

Objective

To characterize hormonal, metabolic, and anthropometric features in CAIS, including those with intact gonads.

Design

Cross-sectional analysis of participants enrolled in an ongoing natural history study. (NCT04708431).

Setting

Tertiary referral center.

Participants

Twenty-two individuals with a 46-XY Karyotype and CAIS; 14 retained gonads and 8 with gonadectomy. OUTCOMES Fasting hormonal and cardiometabolic assays, anthropometrics, and dual-energy X-ray absorptiometry (DXA) for bone mineral density (BMD) and body composition.

Results

Participants were tall and lean; median height was at the 86th percentile and 70% had body and truncal fat below female norms. 80% demonstrated insulin resistance (HOMA-IR >2). Estradiol levels below 30 pg/mL were seen in one-third of individuals. Testosterone was elevated (>871ng/dL) in 43% of those with intact gonads. Those with gonadectomy were significantly older, had lower androgens, higher FSH, total cholesterol and LDL, and Android/Gynoid body fat ratios than those with intact gonads. Approximately one-third of individuals with intact gonads had elevated FSH and LH, suggesting early gonadal insufficiency with lower estradiol and DHEAS. There were no significant differences in BMD in any subcohort.

Conclusions

Our cohort had a high frequency of low estrogen exposure and evidence of early insulin resistance despite normal body composition. These findings highlight the need for longitudinal endo-metabolic monitoring and may inform the timing of gonadectomy.