general transcription factors associated with rna polymerase ii holocomplex.target gene transcription ensues. in this way, androgens bound to androgen receptors regulate the expression of target genes, thus produce androgenic effects. theoretically, certain mutant androgen receptors can function without androgens; in vitro studies have demonstrated that a mutant androgen receptor protein can induce transcription in the absence of androgen if its steroid binding domain is deleted. conversely, the steroid-binding domain may act to repress the ar transactivation domain, perhaps due to the ar's unliganded conformation. sexual differentiation: the human embryo has indifferent sex accessory ducts until the seventh week of development. androgens in fetal development human embryos develop similarly for the first six weeks, regardless of genetic sex (46,xx or 46,xy karyotype); the only way to tell the difference between 46,xx or 46,xy embryos during this time period is to look for barr bodies or a y chromosome. the gonads begin as bulges of tissue called the genital ridges at the back of the abdominal cavity, near the midline. by the fifth week, the genital ridges differentiate into an outer cortex and an inner medulla, and are called indifferent gonads. by the sixth week, the indifferent gonads begin to differentiate according to genetic sex. if the karyotype is 46,xy, testes develop due to the influence of the y chromosome’s sry gene. this process does not require the presence of androgen, nor a functional androgen receptor. until around the seventh week of development, the embryo has indifferent sex accessory ducts, which consist of two pairs of ducts: the müllerian ducts and the wolffian ducts. sertoli cells within the testes secrete anti-müllerian hormone around this time to suppress the development of the müllerian ducts, and cause their degeneration. without this anti-müllerian hormone, the müllerian ducts develop into the female internal genitalia (uterus, cervix, fallopian tubes, and upper vaginal barrel). unlike the müllerian ducts, the wolffian ducts will not continue to develop by default. in the presence of testosterone and functional androgen receptors, the wolffian ducts develop into the epididymides, vasa deferentia, and seminal vesicles. if the testes fail to secrete testosterone, or the androgen receptors do not function properly, the wolffian ducts degenerate. masculinization of the male genitalia is dependent on both testosterone and dihydrotestosterone. masculinization of the male external genitalia (the penis, penile urethra, and scrotum), as well as the prostate, are dependent on the androgen dihydrotestosterone. testosterone is converted into dihydrotestosterone by the 5-alpha reductase enzyme. if this enzyme is absent or deficient, then dihydrotestosterone is not created, and the external male genitalia do not develop properly. as is the case with the internal male genitalia, a functional androgen receptor is needed for dihydrotestosterone to regulate the transcription of target genes involved in development. pathogenesis of ais mutations in the androgen receptor gene can cause problems with any of the steps involved in androgenization, from the synthesis of the androgen receptor protein itself, through the transcriptional ability of the dimerized, androgen-ar complex. ais can result if even one of these steps is significantly disrupted, as each step is required for androgens to activate the ar successfully and regulate gene expression. exactly which steps a particular mutation will impair can be predicted, to some extent, by identifying the area of the ar in which the mutation resides. this predictive ability is primarily retrospective in origin; the different functional domains of the ar gene have been elucidated by analyzing the effects of specific mutations in different regions of the ar. for example, mutations in the steroid binding domain have been known to affect androgen binding affinity or retention, mutations in the hinge region have been known to affect nuclear translocation, mutations in the dna-binding domain have been known to affect dimerization and binding to target dna, and mutations in the transactivation domain have been known to affect target gene transcription regulation. unfortunately, even when the affected functional domain is known, predicting the phenotypical consequences of a particular mutation (see correlation of genotype and phenotype) is difficult. some mutations can adversely impact more than one functional domain. for example, a mutation in one functional domain can have deleterious effects on another by altering the way in which the domains interact. a single mutation can affect all downstream functional domains if a premature stop codon or framing error results; such a mutation can result in a completely unusable (or unsynthesizable) androgen receptor protein. the steroid binding domain is particularly vulnerable to the effects of a premature stop codon or framing error, since it occurs at the end of the gene, and its information is thus more likely to be truncated or misinterpreted than other functional domains. other, more complex relationships have been observed as a consequence of mutated ar; some mutations associated with male phenotypes have been linked to male breast cancer, prostate cancer, or in the case of spinal and bulbar muscular atrophy, disease of the central nervous system. the form of breast cancer seen in some men with pais is caused by a mutation in the ar's dna-binding domain. this mutation is thought to cause a disturbance of the ar's target gene interaction that allows it to act at certain additional targets, possibly in conjunction with the estrogen receptor protein, to cause cancerous growth. the pathogenesis of spinal and bulbar muscular atrophy (sbma) demonstrates that even the mutant ar protein itself can result in pathology. the trinucleotide repeat expansion of the polyglutamine tract of the ar gene that is associated with sbma results in the synthesis of a misfolded ar protein that the cell fails to proteolyze and disperse properly. these misfolded ar proteins form aggregates in the cell cytoplasm and nucleus. over the course of 30 to 50 years, these aggregates accumulate and have a cytotoxic effect, eventually resulting in the neurodegenerative symptoms associated with sbma. diagnosis the phenotypes that result from the insensitivity to androgens are not unique to ais, thus the diagnosis of ais requires thorough exclusion of other causes. clinical findings indicative of ais include the presence of a short vagina or undermasculinized genitalia, partial or complete regression of müllerian structures, bilateral nondysplastic testes, and impaired spermatogenesis and/or virilization. laboratory findings include a 46,xy karyotype and typical or elevated postpubertal testosterone, luteinizing hormone, and estradiol levels. the androgen binding activity of genital skin fibroblasts is typically diminished, although exceptions have been reported. conversion of testosterone to dihydrotestosterone may be impaired. the diagnosis of ais is confirmed if androgen receptor gene sequencing reveals a mutation, although not all individuals with ais (particularly pais) will have an ar mutation (see other causes). each of the three types of ais (complete, partial, and mild) has a different list of differential diagnoses to consider. depending on the form of ais suspected, the list of differentials can include: chromosomal anomalies: klinefelter syndrome (47,xxy karyotype) turner syndrome (45,xo karyotype) mixed gonadal dysgenesis (45,xo/46,xy karyotype) tetragametic chimerism (46,xx/46,xy karyotype) androgen biosynthetic dysfunction in 46,xy individuals: luteinizing hormone (lh) receptor mutations smith–lemli–opitz syndrome (associated with intellectual disability) lipoid congenital adrenal hyperplasia 3β-hydroxysteroid dehydrogenase 2 deficiency 17α-hydroxylase deficiency 17,20 lyase deficiency 17β-hydroxysteroid dehydrogenase deficiency 5α-reductase deficiency androgen excess in 46,xx individuals: 21-hydroxylase deficiency 3β-hydroxysteroid dehydrogenase 2 deficiency cytochrome p450 oxidoreductase deficiency (disorder in mother causes 46,xx fetal virilization) 11β-hydroxylase deficiency aromatase deficiency glucocorticoid receptor mutations maternal virilizing tumor (e.g. luteoma) increased androgen exposure in utero, not otherwise specified (e.g. androgenic drugs) developmental mayer–rokitansky–küster–hauser syndrome (46,xx karyotype) swyer syndrome (46,xy karyotype) xx gonadal dysgenesis (46,xx karyotype) leydig cell agenesis or hypoplasia, not otherwise specified (46,xy karyotype) absent (vanishing) testes syndrome ovotesticular dsd testicular dsd (i.e. 46,xx sex reversal) teratogenic causes (e.g. estrogens, antiestrogens) other causes: frasier syndrome (associated with progressive glomerulopathy) denys–drash syndrome (associated with nephropathy and wilms tumor) wagr syndrome (associated with wilms tumor and aniridia) mckusick–kaufman syndrome (associated with postaxial polydactyly) robinow syndrome (associated with dwarfism) aarskog–scott syndrome (associated with facial anomalies) hand-foot-genital syndrome (associated with limb malformations) popliteal pterygium syndrome (associated with extensive webbing behind knees) kallmann syndrome (often associated with anosmia) hypospadias not otherwise specified cryptorchidism not otherwise specified vaginal atresia not otherwise specified classification women with ais and related dsd/intersex conditions ais is broken down into three classes based on phenotype: complete androgen insensitivity syndrome (cais), partial androgen insensitivity syndrome (pais), and mild androgen insensitivity syndrome (mais). a supplemental system of phenotypic grading that uses seven classes instead of the traditional three was proposed by pediatric endocrinologist charmian a. quigley et al. in 1995. the first six grades of the scale, grades 1 through 6, are differentiated by the degree of genital masculinization; grade 1 is indicated when the external genitalia is fully masculinized, grade 6 is indicated when the external genitalia is fully feminized, and grades 2 through 5 quantify four degrees of decreasingly masculinized genitalia that lie in the interim. grade 7 is indistinguishable from grade 6 until puberty, and is thereafter differentiated by the presence of secondary terminal hair; grade 6 is indicated when secondary terminal hair is present, whereas grade 7 is indicated when it is absent. the quigley scale can be used in conjunction with the traditional three classes of ais to provide additional information regarding the degree of genital masculinization, and is particularly useful when the diagnosis is pais. complete ais main article: complete androgen insensitivity syndrome partial ais main article: partial androgen insensitivity syndrome mild ais main article: mild androgen insensitivity syndrome management management of ais is currently limited to symptomatic management; no method is currently available to correct the malfunctioning androgen receptor proteins produced by ar gene mutations. areas of management include sex assignment, genitoplasty, gonadectomy in relation to tumor risk, hormone replacement therapy, genetic counseling, and psychological counseling. cais main article: management of complete androgen insensitivity syndrome pais main article: management of partial androgen insensitivity syndrome mais main article: management of mild androgen insensitivity syndrome epidemiology ais represents about 15% to 20% of dsds and affects 1 in 20,000 to 1 in 64,000 males. estimates for the incidence of androgen insensitivity syndrome are based on a relatively small population size, thus are known to be imprecise. cais is estimated to occur in one of every 20,400 46,xy births. a nationwide survey in the netherlands based on patients with genetic confirmation of the diagnosis estimates that the minimal incidence of cais is one in 99,000. the incidence of pais is estimated to be one in 130,000. due to its subtle presentation, mais is not typically investigated except in the case of male infertility, thus its true prevalence is unknown. controversy preimplantation genetic diagnosis preimplantation genetic diagnosis (pgd or pigd) refers to genetic profiling of embryos prior to implantation (as a form of embryo profiling), and sometimes even of oocytes prior to fertilization. when used to screen for a specific genetic sequence, its main advantage is that it avoids selective pregnancy termination, as the method makes it highly likely that a selected embryo will be free of the condition under consideration. in the uk, ais appears on a list of serious genetic diseases that may be screened for via pgd. some ethicists, clinicians, and intersex advocates have argued that screening embryos to specifically exclude intersex traits is based on social and cultural norms as opposed to medical necessity. history recorded descriptions of the effects of ais date back hundreds of years, although significant understanding of its underlying histopathology did not occur until the 1950s. the taxonomy and nomenclature associated with androgen insensitivity went through a significant evolution that paralleled this understanding. timeline of major milestones 1950: lawson wilkins administers daily methyltestosterone to a karyotype|46,xy female patient, who shows no signs of virilization. his experiment is the first documented demonstration of the pathophysiology of ais. 1970: mary f. lyon and susan hawkes reported that a gene on the x chromosome caused complete insensitivity to androgens in mice. 1981: barbara migeon et al. narrowed down the locus of the human androgen receptor gene (or a factor controlling the androgen receptor gene) to somewhere between xq11 and xq13. 1988: the human androgen receptor gene is first cloned and partially analyzed by multiple parties. terry brown et al. reported the first mutations proven to cause ais. 1989: terry brown et al. reported the exact locus of the ar gene (xq11-xq12), and dennis lubahn et al. published its intron-exon boundaries. 1994: the androgen receptor gene mutations database was created to