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Androgen insensitivity syndrome

Androgen insensitivity syndrome in its complete form is a disorder of hormone resistance characterised by a female phenotype in an individual with an XY karyotype and testes producing age-appropriate normal concentrations of androgens. Pathogenesis is the result of mutations in the X-linked androgen receptor gene, which encodes for the ligand-activated androgen receptor—a transcription factor and member of the nuclear receptor superfamily. This Seminar describes the clinical manifestations of androgen insensitivity syndrome from infancy to adulthood, reviews the mechanism of androgen action, and shows examples of how mutations of the androgen receptor gene cause the syndrome. Management of androgen insensitivity syndrome should be undertaken by a multidisciplinary team and include gonadectomy to avoid gonad tumours in later life, appropriate sex-hormone replacement at puberty and beyond, and an emphasis on openness in disclosure.

Gonadectomy in Complete Androgen Insensitivity Syndrome: Why and When?

Prophylactic gonadectomy has been recommended in complete androgen insensitivity syndrome (CAIS) because of an increased risk for the development of malignant germ cell tumors in the intra-abdominal gonads. No reliable screening parameters are available to detect early (pre-)malignant changes. Because the tumor risk before puberty is very low, the timing of gonadectomy has been postponed to allow spontaneous puberty and involvement of the patients in important decisions affecting their body and health. Gonadectomy after puberty is still discussed controversially. There are difficulties in determining the absolute malignancy risk for individuals with CAIS, difficulties with hormone therapy, and lack of studies supporting different protocols. In contrast, endogenous hormone profiles show very specific features that influence bone health, psychosocial well-being, and many other aspects which still have to be investigated. For women with CAIS who wish to keep their gonads, we propose a biannual screening program which has to be evaluated in a prospective multi-center trial.

Bone Mineral Density in Women Living with Complete Androgen Insensitivity Syndrome and Intact Testes or Removed Gonads

Complete androgen insensitivity syndrome (CAIS) is due to complete androgen resistance in androgen-dependent tissues. Since androgens are involved in growth, development, and mass maintenance of the skeleton, bone health may be a relevant clinical issue for improving quality of life of women living with CAIS. Bone mineral density (BMD) in women with CAIS and intact gonads has been reported in a normal range, although exceptions are known showing a low BMD mainly at the lumbar level. In women with CAIS and removed gonads, BMD is usually reduced at both the lumbar spine and femoral neck. However, the fracture risk remains largely unknown. In women with CAIS, hormonal replacement therapy may improve BMD, but it does not normalize it. Several factors may be operative (e.g., loss of AR signaling at the bone level, gonadal removal, and age at surgery [before or after attainment of the peak bone mass], inadequate sex steroid replacement therapy, poor compliance with hormonal treatment, high serum FSH levels, lack of testicular protein hormones after gonadal removal), but they are poorly evaluated. In conclusion, the maintenance of testes may represent a strategy to improve bone health in women with CAIS, but a strict follow-up to monitor the cancer risk is mandatory mainly from their 20s onwards. Optimal sex steroid substitutive therapy in adolescence and adulthood is a key factor to improve BMD status in women with CAIS and removed gonads, but conclusive data on optimal management are lacking.

Normalization of the vagina by dilator treatment alone in Complete Androgen Insensitivity Syndrome and Mayer-Rokitansky-Kuster-Hauser Syndrome

Background: Various surgical and non-surgical treatment options are available for women with congenital vaginal agenesis. We report results of vaginal dilation therapy delivered by a multi-disciplinary team as first line treatment for vaginal agenesis.

Methods: Twenty-six women were recruited into a prospective observational study: 18 had Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH) and 8 had Complete Androgen Insensitivity Syndrome (CAIS). All women underwent a vaginal dilation programme co-ordinated by a clinical nurse specialist with input from a clinical psychologist. Vaginal length was compared to a normal reference range, and psycho-sexual questionnaires were completed before and after therapy.

Results: Twenty-one (81%) patients completed the programme. Seventeen of these 21 (81%) were sexually active without any reported difficulties, whereas 4 were on a maintenance regime. In those who completed the programme the mean vaginal length increased from 4.0 to 8.5 cm and 86% achieved a vaginal length within the normal range. Subjective appraisal of vaginal size recorded that the number of women who reported that their vaginal size was 'more or less normal' increased from 1 to 12 following treatment. Questionnaire scores for sexual satisfaction and sexual depression improved in the CAIS group but did not alter significantly in the MRKH group.

Conclusion: Non-surgical dilation delivered by a multi-disciplinary team is an effective alternative to vaginal surgery and usually normalizes vaginal length.