View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by University of East Anglia digital repository Seminar Androgen insensitivity syndrome Ieuan A Hughes, John D Davies, Trevor I Bunch, Vickie Pasterski, Kiki Mastroyannopoulou, Jane MacDougall Androgen insensitivity syndrome in its complete form is a disorder of hormone resistance characterised by a female Lancet 2012; 380: 1419–28 phenotype in an individual with an XY karyotype and testes producing age-appropriate normal concen trations of Published Online androgens. Pathogenesis is the result of mutations in the X-linked androgen receptor gene, which encodes for the June 13, 2012 ligand-activated androgen receptor—a transcription factor and member of the nuclear receptor superfamily. This http://dx.doi.org/10.1016/ S0140-6736(12)60071-3 Seminar describes the clinical manifestations of androgen insensitivity syndrome from infancy to adulthood, reviews Department of Paediatrics, the mechanism of androgen action, and shows examples of how mutations of the androgen receptor gene cause the University of Cambridge, syndrome. Management of androgen insensitivity syndrome should be undertaken by a multidisciplinary team and Cambridge, UK include gonadectomy to avoid gonad tumours in later life, appropriate sex-hormone replacement at puberty and (Prof I A Hughes MD, beyond, and an emphasis on openness in disclosure. J D Davies PhD, T I Bunch, V Pasterski PhD, K Mastroyannopoulou BSc); Introduction menses. Development of oestrogen-dependent secondary and Section of Reproductive Several clinical disorders arise because of complete sexual characteristics occurs as the result of excess Medicine, Department of Obstetrics and Gynaecology, or partial resistance to the action of hormones.1 aromatisation of androgens. Pubic and axillary hair is Addenbrooke’s Hospital, 2 Examples include diabetes due to insulin resistance usually absent or can be present in sparse amounts. No Cambridge, UK and reproductive disorders caused by resistance to precise fi gures are available for the prevalence of (J MacDougall MD) 3 gonadotropin and steroid hormones. Male development complete androgen insensitivity syn drome, but estimates Correspondence to: during fetal life occurs only when an XY zygote directs range from one in 20 400 to one in 99 100 genetic males Prof Ieuan A Hughes, the bipotential gonad to become a testis (sex deter- on the basis of a proven molecular diagnosis.7 Department of Paediatrics, University of Cambridge, mination), which in turn secretes suffi cient amounts of In infancy, complete androgen insensitivity syndrome Addenbrooke’s Hospital, Hills active androgen to produce the male phenotype (sex presents as an inguinal hernia or labial swelling containing Road, Cambridge CB2 0QQ, UK diff erentiation).4 Figure 1 shows the pathway of healthy a testis in an apparently female infant. Bilateral inguinal [email protected] male and female fetal sex development, modifi ed to herniae are rare in female infants—the incidence of include complete resistance to the action of androgens complete androgen insensitivity syndrome in such resulting in a female phenotype—ie, a hormone- patients is 1–2% during infancy.8,9 Clinicians recommend resistance syndrome. that karyotyping or a biopsy of a gonad within the hernial Hormone-resistance syndrome was fully characterised sac is done after the parents give consent.10 Alternatively, by John Morris, who reviewed the clinical features of vaginal length can be measured in prepubertal girls 82 patients.5 Because the patients were women and girls undergoing inguinal hernia repair to screen for complete with bilateral testes that seemed to produce oestrogen-like androgen in sensitivity syndrome;9 a shortened vagina and hormones, Morris coined the term testicular feminisation the absence of ovaries or fallopian tubes suggests the need syndrome. This contradictory label was renamed as for karyotyping. The uterus, cervix, and proximal vagina complete androgen insensitivity syndrome, which is now are absent in complete androgen insensitivity syndrome the accepted terminology.6 Partial androgen insensitivity because of the action of antimüllerian hormone produced syndrome refers to a phenotype of varying degrees of by Sertoli cells of the testis.4 The vagina varies from a masculinisation of the external genitalia due to partial dimple in the perineum to normal length, but is always androgen responsiveness. Mild androgen insensitivity blind-ending. Occasionally, older sisters of people with syndrome is reported in healthy men and boys who can complete androgen insensitivity syndrome have also had present with adolescent gynaecomastia or infertility in later life. Thus, androgen insensitivity syndrome can be defi ned as a disorder resulting from complete or partial Search strategy and selection criteria resistance to the biological actions of androgens in an XY We searched PubMed mainly with the search terms man or boy with normal testis determination and “androgen insensitivity syndrome” in combination with the production of age-appropriate androgen concentrations. additional terms “complete” and “partial”. For the molecular The pathophysi ology of this syndrome is based on the section, we searched for the terms “androgen receptor”, mechanism of action of androgens (appendix). “androgen receptor mutation”, “nuclear receptor”, and See Online for appendix “nuclear receptor co-regulators”. For the management Complete androgen insensitivity syndrome section, we used the terms “germ cell tumours”, “hormone Clinical presentation replacement therapy”, “vaginal dilators”, and “gender The typical presentation for complete androgen insensi- identity”. We selected publications from the past 10 years, but tivity syndrome is either primary amenorrhoea in older papers related to fi rst descriptions of the syndrome are adolescence, or inguinal swellings in an infant. A female cited, as are relevant review articles from monographs and adolescent with the disorder has breast development and book chapters. a pubertal growth spurt at the appropriate age, but no www.thelancet.com Vol 380 October 20, 2012 1419 Seminar Zygote at fertilisation for men and boys and luteinising hormone (LH) concen trations are inappropriately increased.19 Con cen- Bipotential gonad trations of follicle-stimulating hormone and inhibin are gener ally normal. Excess testosterone is produced and peripherally aromatised to oestrogen which, together with LH-induced direct secretion of testicular oestrogen, XY XX results in serum oestradiol concentrations higher than Testis Ovary those noted in men and boys but lower than those reported in women without complete androgen insensi- tivity syndrome.20 Serum gonadotropin concentrations AMH No AMH No müllerian ducts Müllerian ducts increase further after gonadectomy, but are only CAIS partly suppressed with oestrogen substitution. These Wolffian ducts; Androgens/AR No androgens No wolffian ducts; male genitalia female genitalia fi ndings suggest resistance to the negative-feedback No AR eff ect of androgens on hypothalamic–pituitary control Male phenotype Female phenotype of gonadotropin secretion in complete androgen in- Figure 1: Simplifi ed pathway of fetal sex development sensitivity syndrome, but maintenance of a partial AR=androgen receptor. CAIS=complete androgen insensitivity syndrome. AMH=antimüllerian hormone. negative feedback by oestrogens. Concentrations of sex- hormone-binding globulin are sexually dimorphic; androgens decrease and oestrogens increase hepatic an inguinal hernia repair in infancy, and can have a 46,XY production, respectively. Concentrations of this protein karyotype (unpublished). in patients with complete androgen insensitivity Diagnosis of complete androgen insensitivity syn- syndrome are similar to those in women without drome can happen by chance. The sex of a fetus is now the syndrome and do not decrease after androgen increasingly known before birth through analysis of administration.21 karyotypes, chorionic villi, amniotic fl uid samples, or The pattern of gonadotropin and testosterone con- maternal circulating free fetal DNA,11 and use of three- centrations is less suggestive of hormone resistance dimensional ultrasonography. Complete androgen when complete androgen insensitivity syndrome pre- insen sitivity syndrome can therefore some times be diag- sents in infancy.22,23 Usually, LH-induced serum testos- nosed as a result of mismatch between the prenatal sex terone concentrations surge during the fi rst few months prediction and the phenotype at birth.12 Other modes of of life—a so-called mini-puberty.24,25 This profi le, however, presentation include a known family history of X-linked cannot be used to diagnose complete androgen in- complete androgen insensitivity syndrome and, sensitivity syndrome in many infants, although serum occasion ally, the discovery of a pelvic mass arising from testosterone concentrations do increase appropriately a gonadal tumour.13 after stimulation with human chorionic gonadotropin.22 Adult women with complete androgen insensitivity Infants with partial androgen insensitivity syndrome syndrome are generally taller than women without have a more responsive pattern of LH and testosterone, the syndrome, but are on average shorter than the male both basally and after stimulation with human chorionic population.14 Patients in whom gonadectomy is delayed gonadotropin. The human chorionic gonadotropin are even taller, suggesting a relative oestrogen defi ciency stimulation test is