Androgen Insensitivity Syndrome
- Cedars Sinai
- Nov 24, 2024
- 12 min read
Updated: May 4
Androgen insensitivity syndrome (AIS) is a condition characterized by the inability to respond to androgens, usually due to androgen receptor dysfunction.
It occurs in 1 in 20,000 to 64,000 XY (karyotypically male) births. This condition leads to a partial or complete inability of cells to respond to androgens. This lack of response can hinder or prevent the development of male genitals, as well as affect or inhibit the development of male secondary sexual characteristics during puberty. It does not significantly affect female genital or sexual development. Androgen insensitivity is clinically relevant only in genetic males, (i.e., individuals with a Y-chromosome, or more specifically, an SRY gene). Clinical phenotypes in these individuals can range from a typical male habitus with mild spermatogenic issues or reduced secondary terminal hair, to a complete female habitus, despite having a Y-chromosome.
AIS is classified into three categories based on the degree of genital masculinization:
Mild androgen insensitivity syndrome (MAIS) is indicated when the external genitalia are typically male (a penis and a scrotum).
Partial androgen insensitivity syndrome (PAIS) is indicated when the external genitalia are partially, but not fully, masculinized.
Complete androgen insensitivity syndrome (CAIS) is indicated when the external genitalia resemble those of a typical female (a vulva)
Androgen insensitivity syndrome is the most common cause of 46,XY undermasculinized genitalia.
Management of AIS is currently focused on symptomatic management; there is no available method to correct the defective androgen receptor proteins caused by AR gene mutations. Management areas include sex assignment, genitoplasty, gonadectomy to lower tumor risk, hormone replacement therapy, genetic counseling, and psychological counseling.
Genetics
The human androgen receptor (AR) is a protein encoded by a gene located on the proximal long arm of the X chromosome (locus Xq11-Xq12). The protein coding region consists of about 2,757 nucleotides (919 codons) spanning eight exons, labeled 1-8 or A-H. Introns vary in size from 0.7 to 26 kb. Like other nuclear receptors, the AR protein consists of several functional domains: the transactivation domain (also known as the transcription-regulation domain or the amino / NH2-terminal domain), the DNA-binding domain, the hinge region, and the steroid-binding domain (also referred to as the carboxyl-terminal ligand-binding domain). The transactivation domain is encoded by exon 1, constituting more than half of the AR protein. Exons 2 and 3 encode the DNA-binding domain, while the 5' part of exon 4 encodes the hinge region. The remaining portions of exons 4 through 8 encode the ligand binding domain.
Trinucleotide Satellite Lengths and AR Transcriptional Activity
The AR gene features two polymorphic trinucleotide microsatellites in exon 1. The first microsatellite, located nearest the 5' end, consists of 8 to 60 repetitions of the glutamine codon "CAG" and is referred to as the polyglutamine tract. The second microsatellite includes 4 to 31 repetitions of the glycine codon "GGC" and is known as the polyglycine tract. The average number of repetitions varies among ethnic groups, with Caucasians having an average of 21 CAG repeats and Blacks 18. In men, extreme lengths of the polyglutamine tract are linked to various diseases; fewer repetitions are associated with prostate cancer, hepatocellular carcinoma, and intellectual disability, while spinal and bulbar muscular atrophy (SBMA) is linked to 40 or more CAG repeats. Some research suggests an inverse relationship between the length of the polyglutamine tract and transcriptional activity in the AR protein, with longer tracts potentially linked to male infertility and undermasculinized genitalia. However, other studies have found no such correlation. A 2007 meta-analysis supports the correlation's existence, suggesting discrepancies can be resolved by considering sample size and study design. Some research also indicates that longer polyglycine tract lengths may be associated with genital masculinization defects in men, though other studies dispute this association.
AR Mutations
As of 2010, the AR mutation database has reported over 400 mutations, with the number continuing to rise. Inheritance is typically maternal and follows an X-linked recessive pattern; individuals with a 46,XY karyotype always express the mutant gene due to having only one X chromosome, while 46,XX carriers are minimally affected. Approximately 30% of AR mutations occur spontaneously and are not inherited. These de novo mutations result from a germ cell mutation or germ cell mosaicism in one of the parent's gonads, or a mutation in the fertilized egg itself. In one study, three out of eight de novo mutations occurred postzygotically, suggesting up to one-third result in somatic mosaicism. Not all AR gene mutations lead to androgen insensitivity; one specific mutation appears in 8 to 14% of genetic males but only affects a small number of individuals when other genetic factors are present.
Other Causes
Some individuals with CAIS or PAIS lack AR mutations despite having clinical, hormonal, and histological features that justify an AIS diagnosis; up to 5% of women with CAIS and 27 to 72% of individuals with PAIS do not have an AR mutation. In one patient, PAIS was attributed to a mutant steroidogenic factor-1 (SF-1) protein. In another case, CAIS resulted from a defect in transmitting a transactivating signal from the N-terminal region of the androgen receptor to the cell's basal transcription machinery. A coactivator protein interacting with the activation function 1 (AF-1) transactivation domain of the androgen receptor might have been deficient. The signal disruption could not be corrected by any known coactivators at the time, nor was the absent coactivator protein identified, leaving some experts skeptical that a mutant coactivator explains androgen resistance in CAIS or PAIS patients with a typical AR gene.
XY karyotype
Depending on the mutation, an individual with a 46,XY karyotype and AIS can exhibit a male (MAIS) or female (CAIS) phenotype, or may possess genitalia that are partially masculinized (PAIS). The gonads are testes regardless of phenotype due to the Y chromosome's influence. Therefore, a 46,XY female does not have ovaries and cannot contribute an egg for conception. In certain cases, 46,XY females develop a vestigial uterus and have been able to gestate children. Such instances are rare and have necessitated the use of an egg donor, hormone therapy, and IVF.
Several case studies of fertile 46,XY males with AIS have been documented, although they are considered a minority. In some cases, infertile males with MAIS have managed to conceive children by increasing their sperm count through supplementary testosterone.
A genetic male conceived by a man with AIS would not inherit his father's X chromosome, thus would neither inherit nor carry the gene for the syndrome. A genetic female conceived in this manner would receive her father's X chromosome and thus become a carrier.
XX karyotype
Genetic females (46,XX karyotype) possess two X chromosomes and thus have two AR genes. A mutation in one (but not both) results in a minimally affected, fertile female carrier. Some carriers have been observed to have slightly reduced body hair, delayed puberty, and/or tall stature, likely due to skewed X-inactivation. A female carrier will pass the affected AR gene to her children 50% of the time. If the affected child is a genetic female, she will also be a carrier. An affected 46,XY child will have AIS.
A genetic female with mutations in both AR genes could theoretically arise from the union of a fertile man with AIS and a female carrier of the gene, or from a de novo mutation. However, given the rarity of fertile AIS men and the low incidence of AR mutation, the likelihood of this is small. The phenotype of such an individual remains speculative; as of 2010, no such documented case has been reported.
Correlation of Genotype and Phenotype
Individuals with partial AIS, as opposed to those with complete or mild forms, are born with ambiguous genitalia, making the decision to raise the child as male or female not straightforward. Unfortunately, precise knowledge of the AR mutation offers little insight into the phenotype; the same AR mutation can lead to significant variation in masculinization levels among different individuals, even within the same family. The exact reasons for this variation are not fully understood, but potential factors include the lengths of polyglutamine and polyglycine tracts, sensitivity to and variations in the intrauterine endocrine environment, the impact of coregulatory proteins active in Sertoli cells, somatic mosaicism, expression of the 5RD2 gene in genital skin fibroblasts, and reduced AR transcription and translation from factors other than AR coding region mutations, an unidentified coactivator protein, enzyme deficiencies such as 21-hydroxylase deficiency, or other genetic variations like a mutant steroidogenic factor-1 protein. The extent of this variation is not uniform across all AR mutations and is more pronounced in some cases. Missense mutations that lead to a single amino acid change are known to produce the greatest phenotypic diversity.
Pathophysiology
Androgens and the Androgen Receptor
The effects of androgens on the human body (virilization, masculinization, anabolism, etc.) are not directly caused by androgens themselves but occur when androgens bind to androgen receptors; the androgen receptor mediates these effects in the human body. Similarly, the androgen receptor is generally inactive in the cell until it binds with androgens.
The following steps illustrate how androgens and the androgen receptor collaborate to produce androgenic effects:
Androgen enters the cell.
Only specific organs in the body, like the gonads and the adrenal glands, produce the androgen testosterone.
Testosterone is transformed into dihydrotestosterone, a chemically similar androgen, in cells that contain the enzyme 5-alpha reductase.
Both androgens exert their effects by binding with the androgen receptor.
Androgen binds with the androgen receptor.
The androgen receptor is present throughout the tissues of the human body.
Before binding with an androgen, the androgen receptor is attached to heat shock proteins.
These heat shock proteins are released when androgen binds.
Androgen binding prompts a stabilizing, conformational change in the androgen receptor.
The two zinc fingers of the DNA-binding domain become exposed due to this new conformation.
AR stability is believed to be supported by type II coregulators, which influence protein folding and androgen binding, or aid NH2/carboxyl-terminal interaction.
The hormone-activated androgen receptor is phosphorylated.
Receptor phosphorylation can occur prior to androgen binding, though the presence of androgen encourages hyperphosphorylation.
The biological implications of receptor phosphorylation remain unknown.
The hormone-activated androgen receptor translocates to the nucleus.
Nucleocytoplasmic transport is partly facilitated by an amino acid sequence on the AR known as the nuclear localization signal.
The AR's nuclear localization signal is mainly encoded in the hinge region of the AR gene.
Homodimerization occurs.
Dimerization is mediated by the second (nearest the 3' end) zinc finger.
DNA binding to regulatory androgen response elements occurs.
Target genes contain (or are flanked by) transcriptional enhancer nucleotide sequences that interact with the first zinc finger.
These regions are referred to as androgen response elements.
Coactivators are recruited by the AR.
Type I coactivators (i.e., coregulators) are believed to affect AR transcriptional activity by facilitating DNA occupancy, chromatin remodeling, or the recruitment of general transcription factors associated with RNA polymerase II holocomplex.
Target gene transcription follows.
Thus, androgens bound to androgen receptors regulate the expression of target genes, thereby producing androgenic effects.
In theory, some mutant androgen receptors can operate without androgens; in vitro research has shown that a mutant androgen receptor protein can trigger transcription without androgen if its steroid binding domain is removed. On the other hand, the steroid-binding domain might suppress the AR transactivation domain, possibly due to the AR's unliganded conformation.
Androgens in fetal development
Human embryos develop in a similar manner for the first six weeks, irrespective of genetic sex (46,XX or 46,XY karyotype); the only way to distinguish between 46,XX or 46,XY embryos during this period is to identify Barr bodies or a Y chromosome. The gonads start as tissue bulges known as 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 termed indifferent gonads. By the sixth week, the indifferent gonads begin to differentiate based on genetic sex. If the karyotype is 46,XY, testes form due to the influence of the Y chromosome's SRY gene. This process does not require androgen presence or a functional androgen receptor.
Until about the seventh week of development, the embryo has indifferent sex accessory ducts, which include two pairs of ducts: the Müllerian ducts and the Wolffian ducts. Sertoli cells within the testes release anti-Müllerian hormone at this stage to inhibit the development of the Müllerian ducts, causing 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 do not develop by default. In the presence of testosterone and functional androgen receptors, the Wolffian ducts transform into the epididymides, vasa deferentia, and seminal vesicles. If the testes do not secrete testosterone, or if the androgen receptors are not functional, the Wolffian ducts degenerate.
Masculinization of the male external genitalia (the penis, penile urethra, and scrotum), as well as the prostate, relies on the androgen dihydrotestosterone. Testosterone is converted into dihydrotestosterone by the 5-alpha reductase enzyme. If this enzyme is missing or deficient, dihydrotestosterone is not produced, and the external male genitalia do not develop properly. As is the case with the internal male genitalia, a functional androgen receptor is required for dihydrotestosterone to regulate the transcription of target genes involved in development.
Pathogenesis of AIS
Mutations in the androgen receptor gene can disrupt any stage of androgenization, from the synthesis of the androgen receptor protein to the transcriptional capability of the dimerized androgen-AR complex. AIS can occur if any of these steps are significantly impaired, as each is crucial for androgens to activate the AR and regulate gene expression. The specific steps affected by a mutation can often be predicted by identifying the mutation's location within the AR. This predictive ability is mainly retrospective, as the various functional domains of the AR gene have been understood through the analysis of specific mutations in different AR regions. For instance, mutations in the steroid binding domain have been shown to affect androgen binding affinity or retention, mutations in the hinge region affect nuclear translocation, mutations in the DNA-binding domain impact dimerization and DNA binding, and mutations in the transactivation domain affect target gene transcription regulation. However, even knowing the affected functional domain doesn't make predicting the phenotypical outcomes of a mutation straightforward.
Some mutations can negatively impact multiple functional domains. For example, a mutation in one domain might adversely affect another by altering domain interactions. A single mutation can influence all downstream functional domains if it results in a premature stop codon or framing error, leading to a completely unusable (or unsynthesizable) androgen receptor protein. The steroid binding domain is especially susceptible to premature stop codons or framing errors, as it is located at the gene's end, making its information more prone to truncation or misinterpretation compared to other domains.
More complex relationships have been observed due to mutated AR; some mutations linked to male phenotypes have been associated with male breast cancer, prostate cancer, or in cases of spinal and bulbar muscular atrophy, diseases of the central nervous system. The male breast cancer seen in some PAIS cases is caused by a mutation in the AR's DNA-binding domain. This mutation is believed to disrupt AR's interaction with target genes, enabling it to act on additional targets, possibly in collaboration with the estrogen receptor protein, leading to cancerous growth. The pathogenesis of spinal and bulbar muscular atrophy (SBMA) shows that even the mutant AR protein itself can cause pathology. The trinucleotide repeat expansion of the polyglutamine tract in the AR gene associated with SBMA leads to the production of a misfolded AR protein that the cell cannot proteolyze and properly disperse. These misfolded AR proteins accumulate in the cell's cytoplasm and nucleus. Over 30 to 50 years, these aggregates build up and have a cytotoxic effect, eventually leading to the neurodegenerative symptoms associated with SBMA.
Diagnosis
The phenotypes associated with androgen insensitivity are not exclusive to AIS, so diagnosing AIS requires careful exclusion of other possibilities. Clinical signs suggestive of AIS include a short vagina or underdeveloped genitalia, partial or complete regression of Müllerian structures, bilateral nondysplastic testes, and impaired spermatogenesis and/or virilization. Laboratory results show a 46,XY karyotype and normal or elevated postpubertal testosterone, luteinizing hormone, and estradiol levels. The androgen binding activity of genital skin fibroblasts is generally reduced, though exceptions exist. The conversion of testosterone to dihydrotestosterone might be impaired. AIS is confirmed if androgen receptor gene sequencing identifies a mutation, although not all AIS cases (especially PAIS) will show an AR mutation (see Other Causes).
Each AIS type (complete, partial, and mild) has its own set of differential diagnoses to consider. There are reports of individuals with both AIS and certain conditions listed here, such as Klinefelter syndrome or Turner syndrome with mosaicism. The differential list varies depending on the suspected form of AIS:
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
Management
The management of AIS is currently restricted to symptomatic treatment; there is no available method to rectify the defective androgen receptor proteins caused by AR gene mutations. Management areas include sex assignment, genitoplasty, gonadectomy concerning tumor risk, hormone replacement therapy, genetic counseling, and psychological counseling.
