Overview

Epidemiology

• Incidence: 1 in 20,000 live births in genetic male individuals (46,XY) 
• Androgen insensitivity syndrome (AIS) is the 3rd most common cause of primary amenorrhea Primary Amenorrhea Primary amenorrhea is defined as the absence of menstruation in a girl by age 13 years in the absence of secondary sex characteristics or by the age of 15 years with the presence of secondary sex characteristics. Etiologies can originate in the hypothalamic-pituitary-ovarian (HPO) axis or from anatomic abnormalities in the uterus or vagina. Primary Amenorrhea in phenotypic female individuals.

Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics

• Karyotype: 46,XY
• Inheritance: X-linked recessive
• Etiology:
  • Mutation in the coding region of the gene for androgen receptor ( AR AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation) protein 
  • Mutations often lead to amino-acid substitutions and varying levels of loss of androgen function, and are responsible for the wide range of clinical phenotypes.
  • In 30%–40% of cases, AIS is owing to the spontaneous de novo mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of a germ cell.

Pathophysiology

• ARs are required for cells to respond appropriately to androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens, including testosterone.
• Androgens (and their receptors) are required for normal sexual development in both men and women.
• Testosterone synthesis is normal in AIS, but typical post-receptor events mediating hormonal effects in tissues are altered or absent.
• Any of the steps involved in androgenization, from the synthesis of the AR AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation protein through the transcriptional ability of the androgen- AR AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation complex, may be affected.
• Alterations in any of the above steps result in varying levels of resistance to androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens either through impairment in androgen binding or impaired ability to respond to androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens.

Classification

Sexual characteristics of affected individuals can vary and lead to 1 of the 3 classification types:

1. Complete AIS (CAIS): characterized by feminization (phenotypic female) in an individual with a male genotype
2. Partial AIS (PAIS): characterized by undervirilization of a phenotypic male or virilization of a phenotypic female in an individual with a male genotype
3. Mild AIS (MAIS): characterized by a phenotypic and genotypic male individual with infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility

Clinical Presentation

Complete androgen insensitivity syndrome

• Infancy:
  • Phenotypic female at birth with male genotype
  • Female external genitalia appear normal.
  • Short, blind-ended vagina Vagina The vagina is the female genital canal, extending from the vulva externally to the cervix uteri internally. The structures have sexual, reproductive, and urinary functions and a rich blood supply, mainly arising from the internal iliac artery. Vagina, Vulva, and Pelvic Floor
  • Female internal genitalia ( ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries, uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Posterior Abdominal Wall, and fallopian tubes Fallopian tubes The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The fallopian tubes receive an ovum after ovulation and help move it and/or a fertilized embryo toward the uterus via ciliated cells lining the tubes and peristaltic movements of its smooth muscle. Posterior Abdominal Wall) are absent.
  • Male internal genitalia are absent, with the exception of testes.
• Adolescence:
  • Primary amenorrhea 
  • Sparse or absent pubic- and axillary-hair development
  • Breast development occurs
  • Pubertal growth spurt occurs 
• Adulthood:
  • Normal-appearing female body habitus
  • Infertility

Partial androgen insensitivity syndrome

• Presentation may vary depending on the response of external genitalia to androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens.
• Male phenotype:
  • Hypospadias (urethral opening on the underside of the penis Penis The penis is the male organ of copulation and micturition. The organ is composed of a root, body, and glans. The root is attached to the pubic bone by the crura penis. The body consists of the 2 parallel corpora cavernosa and the corpus spongiosum. The glans is ensheathed by the prepuce or foreskin. Penis)
  • Micropenis or macroclitoris
  • Bifid scrotum (deep midline cleft dividing the scrotum), which may contain testes
  • May have complete failure of fusion of scrotum with a pseudovagina 
  • Gynecomastia Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia begins at puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty and persists.
  • Facial- and body-hair development decreased or absent
  • Infertility (impaired spermatogenesis)
• Virilized female phenotype:
  • Complete or incomplete (partial) fusion of labioscrotal folds
  • Clitoromegaly
  • Short, blind-ended vagina Vagina The vagina is the female genital canal, extending from the vulva externally to the cervix uteri internally. The structures have sexual, reproductive, and urinary functions and a rich blood supply, mainly arising from the internal iliac artery. Vagina, Vulva, and Pelvic Floor
  • May have incompletely developed male urogenital structures internally 
  • Sparse axillary and pubic hair
  • Infertility

Mild androgen insensitivity syndrome

• Male external genitalia appear normal.
• Normal internal urogenital structures
• Gynecomastia Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia
• Infertility

Diagnosis

• History and physical examination
• Lab tests:
  • Testosterone levels: 
    • Infancy: basal levels possibly low, but ↑ with administration of hCG
    • Prepubertal: ↑ testosterone concentration 
    • Post puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty: normal or ↑ slightly
    • If low, rule out other abnormalities in the steroidogenesis pathway.
  • Luteinizing hormone (LH) levels:
    • Infancy: may be low but ↑ with stimulation of gonadotropin-releasing hormone (GnRH)
    • Puberty: ↑ concentration (due to impaired feedback secondary to androgen resistance)
  • Normal follicle-stimulating hormone (FSH) levels
  • Androstenedione, dihydrotestosterone (DHT), anti-Müllerian hormone (AMH), and inhibin B levels may be determined to help exclude other diagnoses.
• Imaging: abdominal or pelvic ultrasound
  • To determine the presence of reproductive organs
  • If female reproductive organs are identified, the diagnosis should be reconsidered.
• Genetic testing: 
  • Confirms diagnosis 
  • Karyotype analysis to determine genotypic sex: FISH to confirm presence of Y chromosome
• Histopathology of testes: normal architecture of testes with markedly reduced spermatogonia and/or sperm in post-pubertal individuals
• May be diagnosed incidentally in utero during antenatal ultrasonography. Diagnosis is confirmed by subsequent karyotype analysis, chorionic villus sampling, or amniotic fluid sampling.

Management

• Management depends on receptor status, phenotype, and gender identity of the affected individual. 
• All individuals: 
  • Offer psychological counseling.
  • Calcium and vitamin D supplementation for optimal bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones health
• Hormone-replacement therapy: 
  • Female phenotype: estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries replacement after gonadectomy
  • Male phenotype (PAIS): high-dose androgen therapy 
• Tamoxifen therapy may be considered for phenotypic males with gynecomastia.
• Surgery:
  • Reconstructive and/or reassignment surgery of genitalia if necessary, after expert evaluation
  • Orchiopexy (moving and permanently fixing the position of testes) or orchiectomy (removal of testes) in cases of abnormally located testes (intra-abdominal or intra-labial locations)
  • Vaginal dilatation and/or vaginoplasty to prevent dyspareunia
  • Mastectomy may be indicated for gynecomastia.
  • Hypospadias repair

Clinical Relevance

Differential diagnosis

All disorders affecting sexual development must be considered. The following are select conditions that are part of the differential diagnoses for AIS:

• Müllerian agenesis: also known as Mayer-Rokitansky-Küster-Hauser syndrome or vaginal agenesis. Müllerian agenesis is a congenital condition of uncertain etiology, in which the Müllerian ducts fail to develop properly in genotypic female individuals (46,XX). Normal female external genitalia and functioning ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries are present, but the vagina Vagina The vagina is the female genital canal, extending from the vulva externally to the cervix uteri internally. The structures have sexual, reproductive, and urinary functions and a rich blood supply, mainly arising from the internal iliac artery. Vagina, Vulva, and Pelvic Floor and uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Posterior Abdominal Wall may be absent or underdeveloped. Women present with primary amenorrhea Primary Amenorrhea Primary amenorrhea is defined as the absence of menstruation in a girl by age 13 years in the absence of secondary sex characteristics or by the age of 15 years with the presence of secondary sex characteristics. Etiologies can originate in the hypothalamic-pituitary-ovarian (HPO) axis or from anatomic abnormalities in the uterus or vagina. Primary Amenorrhea, but the remainder of secondary sexual characteristics develop normally. Hormone levels are typically normal. Management involves surgery for anatomical abnormalities.
• 46,XY complete gonadal dysgenesis: a rare genetic disorder of sexual development with varying inheritance patterns, also known as Swyer’s syndrome. Infants present with female external genitalia and streak gonads ( ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries or testes). Women experience primary amenorrhea Primary Amenorrhea Primary amenorrhea is defined as the absence of menstruation in a girl by age 13 years in the absence of secondary sex characteristics or by the age of 15 years with the presence of secondary sex characteristics. Etiologies can originate in the hypothalamic-pituitary-ovarian (HPO) axis or from anatomic abnormalities in the uterus or vagina. Primary Amenorrhea and infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility. Diagnosis is made based on imaging studies and genetic testing. Management includes hormone-replacement therapy and removal of the streak gonads. 
• Mixed gonadal dysgenesis: a condition with asymmetric gonadal development involving both male and female gonads and respective internal and external reproductive anatomy. Mixed gonadal dysgenesis is associated with Turner syndrome Turner syndrome Turner syndrome is a genetic condition affecting women, in which 1 X chromosome is partly or completely missing. The classic result is the karyotype 45,XO with a female phenotype. Turner syndrome is associated with decreased sex hormone levels and is the most common cause of primary amenorrhea. Turner Syndrome mosaicism with a 45,X0/46,XY karyotype. Additional features of Turner syndrome Turner syndrome Turner syndrome is a genetic condition affecting women, in which 1 X chromosome is partly or completely missing. The classic result is the karyotype 45,XO with a female phenotype. Turner syndrome is associated with decreased sex hormone levels and is the most common cause of primary amenorrhea. Turner Syndrome may be present. Karyotyping and biopsy of gonadal tissue help in the diagnosis. 
• Steroid 5-alpha-reductase deficiency 5-alpha-reductase deficiency 5-alpha-reductase deficiency is an autosomal recessive intersex or "disorder of sex development" (DSD) condition caused by a loss-of-function mutation in a gene on chromosome 2. The affected subjects have a 46,XY karyotype, bilateral testes, and normal testosterone production but have impaired virilization during embryogenesis. 5-alpha-reductase Deficiency: an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancegenetic condition affecting individuals with the 46,XY karyotype. External genitalia most often appears female but may appear male or ambiguous. Affected individuals have testes and normal testosterone production; however, there is impaired conversion of testosterone to DHT, causing undervirilization. Hormonal and genetic testing help make the diagnosis. Management depends on phenotype and gender identity, and may involve hormone replacement and/or surgery.

Related conditions

The following condition is related to AIS in that it involves the AR AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation gene and impairs androgen receptivity:

Spinobulbar muscular atrophy: an X-linked genetic condition, also known as Kennedy disease. Spinobulbar muscular atrophy is caused by abnormal expansion repeat in the AR AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation gene, resulting in AR AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation impairment. Spinobulbar muscular atrophy is characterized by a progressive deterioration of anterior motor neurons and is associated with the development of gynecomastia, infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility, and hormonal profiles, similar to that seen in AIS.