AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 89:210–217 (1999) ARTICLE Androgen Insensitivity BRUCE GOTTLIEB,* LEONARD PINSKY, LENORE K. BEITEL, AND MARK TRIFIRO The androgen receptor (AR) protein regulates transcription of certain genes. Usually, this activity depends upon a central DNA-binding domain that permits the binding of androgen–AR complexes to regulatory DNA sequences near or in a target gene. The AR also has a C-terminal androgen-binding domain (ABD) and an N-terminal modulatory domain. These domains interact among themselves and with coregulatory, nonreceptor proteins to determine vector control over a gene’s transcription rate. The precise roles of these proteins are active research areas. Severe X-linked androgen receptor gene (AR) mutations cause complete androgen insensitivity, mild ones impair virilization with or without infertility, and moderate ones some- times yield a wide phenotypic spectrum among sibs. Different expressivity may reflect variability of AR- interactive proteins. The family history must identify heterozygous XX females with sparse, delayed, or asymmetric pubic/axillary hair or delayed menarche and infertile XY maternal aunts or uncles. Mutation type and density vary along the length of the AR. N-terminal polyglutamine tract expansion limits AR transactivation, causing a form of mild androgen insensitivity. Analysis of ABD mutations that do not impair androgen binding or impair it selectively will illuminate its intradomain properties. For partial androgen insensitivity and mild androgen insensitivity, pharmacotherapy with certain androgens or other steroids may overcome some dysfunction of certain mutant ARs. Experience with this approach is limited; outcomes have been generally disappointing. Am. J. Med. Genet. (Semin. Med. Genet.) 89:210–217, 1999. ᮊ 2000 Wiley-Liss, Inc. KEY WORDS: androgen insensitivity; androgen receptor; gene mutations; pharmacotherapy mosomal locus Xq11-q12) is currently Bruce Gottlieb, Ph.D., is a geneticist/ INTRODUCTION molecular biologist who is the curator of available on a research basis only. AIS the Androgen Receptor Gene Mutations can be subdivided into three pheno- database and is particularly interested in The X-linked intracellular androgen types: complete androgen insensitivity the development of gene mutation da- receptor (AR) is essential for androgen tabases. He is a senior scientist at the syndrome (CAIS), partial androgen in- action, whether of testosterone (T) or Lady Davis Institute for Medical Re- sensitivity syndrome (PAIS), and mild search, Sir Mortimer B. Davis–Jewish of its 5␣-reduced derivative, 5␣-dihy- androgen insensitivity syndrome General Hospital, and professor of biol- drotestosterone (DHT). Hence, the ogy at John Abbott College, Montreal. (MAIS). The diagnosis of CAIS usually Leonard Pinsky, M.D., was a staff in- AR is essential for normal primary male is made on clinical findings and labora- vestigator 1969–1999 and director of the sexual development before birth (mas- androgen receptor lab 1974–1999 at the tory evaluations alone. The diagnosis of culinization) and for normal secondary Lady Davis Institute for Medical Re- PAIS and MAIS may require, in addi- search. At McGill University, Montreal, male sexual development around pu- he was director of the Center for Human tion, a family history consistent with X- berty (virilization). AR dysfunctions in Genetics 1979–1999 and professor of linked inheritance. medicine and pediatrics and chairman, XY individuals result in androgen in- Department of Human Genetics, from sensitivity syndromes (AIS). Androgens 1994. He is now retired. Lenore K. Beitel, Ph.D., is a bio- also participate in female sexual devel- chemist/molecular biologist who is inter- opment around puberty and in adult fe- ested in many aspects of the structure/ Mutation analysis of the function relationship of the androgen male sexual function. Therefore, an- receptor and, in particular, androgen re- drogens are involved in male and AR gene (chromosomal ceptor–interacting proteins. She is a re- search scientist at the Lady Davis Insti- female reproduction, and AR muta- locus Xq11-q12) is tute for Medical Research. tions may interfere with reproduction currently available on a Mark Trifiro, M.D., is a clinical and in either sex, albeit much more subtly research molecular endocrinologist and heads the Molecular Endocrinology in females. research basis only. Laboratory at the Lady Davis Institute for Medical Research. He is an associate pro- fessor of medicine at McGill University. Contract grant sponsor: Medical Re- BASIC DIAGNOSIS OF search Council, Canada; Contract grant The clinical findings that permit a sponsor: Fonds de la Recherche en Sante´, ANDROGEN presumptive diagnosis of AIS include Que´ bec; Contract grant sponsor: Fonds INSENSITIVITY the following: absence of extragenital pour la Formation de Chercheurs et SYNDROMES l’Aide a` la Recherche, Que´ bec. abnormalities, two nondysplastic testes, *Correspondence to: Lady Davis In- absent or rudimentary mu¨llerian struc- stitute for Medical Research, Sir Mor- timer B. Davis–Jewish General Hospital, The diagnosis of AIS is based on clinical tures (i.e., no fallopian tubes, uterus, or 3755 Cote Ste. Catherine Road, Montre- findings, endocrine evaluation, and, cervix) and presence of a short vagina, al, Que´ bec, Canada H3T 2E1. E-mail: [email protected] whenever possible, family history. Mu- undermasculinization of the external tation analysis of the AR gene (chro- genitalia at birth, and impaired sper- © 2000 Wiley-Liss, Inc. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 211 matogenesis and/or somatic virilization their mutant alleles should represent be normal male in morphologically but at puberty. The laboratory findings re- new mutations. A recent report on small, or there may be simple coronal quired for the diagnosis of AIS include single-case families with CAI or partial hypospadias or a prominent midline ra- the following: 46,XY karyotype, nor- androgen insensitivity (PAI) gene mu- phe of the scrotum. Between these ex- mal or increased synthesis of T by the tations [Hiort et al., 1998a] found a de tremes are all grades of frank external testes, normal conversion of T to DHT, novo AR mutation rate of close to 30% genital ambiguity that require delicate normal or increased luteinizing hor- (eight of 30), thereby affirming the decision making in order to choose a mone production by the pituitary theoretical expectation of 33% for an sex of rearing that is compatible with gland, and deficient or defective andro- X-linked recessive genetic lethal [Hal- surgical, anatomical constraints and gen-binding activity of genital skin dane, 1935]. Thus, two-thirds of moth- with some predictive information con- fibroblasts. ers of CAI subjects are heterozygous cerning the probable balance between carriers of the mutant allele. Further- virilization and feminization at puberty. more, because of random X-chromo- MAI takes two phenotypic forms SPECIAL DIAGNOSTIC some inactivation, such carriers may at puberty: in one, spermatogenesis and CHARACTERISTICS OF express their heterozygosity clinically fertility are impaired [Migeon et al., ANDROGEN by delayed, diminished, or asymmetric 1984; Cundy et al., 1986]; in the other, INSENSITIVITY pubic and/or axillary hair and by de- spermatogenesis is normal or sufficient SYNDROMES layed menarche [Kaufman et al., 1976]. to preserve fertility [Pinsky et al., 1989; The reason for delayed menarche is not Tsukada et al., 1994; Grino et al., AR mutations that severely impair the entirely clear, but it has been recog- 1988]. In both, gynecomastia, high- amount, structure, or function of the nized that females homozygous for 5␣- AR cause the phenotype of complete reductase type 2 deficiency also have androgen insensitivity (CAI). Standard delayed menarche [Katz et al., 1995]. Mild androgen insensitivity references quote rates of two to five per Since 5␣-reductase type 2 is responsible takes two phenotypic forms 100,000 for CAI. These estimates are for an important fraction of T→DHT derived from the number of otherwise conversion in some parts of the body, it at puberty: in one, normal girls whose inguinal hernias are follows that DHT deficiency or T ex- spermatogenesis and discovered to contain normal testes. cess or both contribute to delayed men- Subjects are born appearing unambigu- arche. However, the effect of DHT de- fertility are impaired; in the ously female because DHT-dependent ficiency can be mimicked by DHT other, spermatogenesis is masculinization of the external genital resistance. Furthermore, by aromatiza- normal or sufficient to primordia is totally absent. They are tion, T excess can generate estrogen ex- typically not suspected of being abnor- cess. The latter mimics an androgen- preserve fertility. mal until the onset of puberty, when resistant state. Thus, pubertal resetting breast development is normal, but pu- of the gonadostat in heterozygous fe- bic and axillary hair development is not. males may be delayed directly by DHT pitched voice, sparse sex hair, and im- Menarche, initially considered late, resistance or indirectly by an increased potence may be noted. In the form never occurs. Mu¨llerian duct regres- ratio of estrogen/androgen action. where fertility is preserved, one pre- sion, being androgen independent, is sumes that the dysfunction of the mu- normal. Hence, these patients usually tant AR is sufficiently mild that it can lack a uterus, oviducts, and the cervix. Because