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Hormonal and Metabolic Features of Complete Androgen Insensitivity Syndrome with and without Gonadectomy
Sanjay Jumani1, Eugenie Lehembre-Shiah2, Harveen Kaur2
1Division of Endocrinology, Diabetes & Metabolism, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; Eunice Kennedy Shriver, National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
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.