Androgen Insensitivity Syndrome

Overview

Epidemiology

• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 1 in 20,000 live births in genetic male individuals (46,XY) 
• Androgen insensitivity syndrome ( AIS AIS Scoliosis) is the 3rd most common cause of primary amenorrhea Amenorrhea Absence of menstruation. Congenital Malformations of the Female Reproductive System in phenotypic female individuals.

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

• Karyotype Karyotype The full set of chromosomes presented as a systematized array of metaphase chromosomes from a photomicrograph of a single cell nucleus arranged in pairs in descending order of size and according to the position of the centromere. Congenital Malformations of the Female Reproductive System: 46,XY
• Inheritance: X-linked recessive X-Linked Recessive Duchenne Muscular Dystrophy
• Etiology:
  • 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 in the coding region of the gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics for androgen receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors ( 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 AIS Scoliosis 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 Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens.
• 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 (and their receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors) are required for normal sexual development in both men and women.
• Testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens synthesis Synthesis Polymerase Chain Reaction (PCR) is normal in AIS AIS Scoliosis, but typical post-receptor events mediating hormonal effects in tissues are altered or absent.
• Any of the steps involved in androgenization, from the synthesis Synthesis Polymerase Chain Reaction (PCR) 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 complex, may be affected.
• Alterations in any of the above steps result in varying levels of resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing 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 AIS Scoliosis ( CAIS CAIs Carbonic anhydrase inhibitors (CAIS) block the carbonic anhydrase enzymes in the proximal convoluted tubule, inhibiting the reabsorption of sodium bicarbonate (NaHCO3), which results in diuresis and metabolic acidosis. Carbonic Anhydrase Inhibitors): characterized by feminization (phenotypic female) in an individual with a male genotype Genotype The genetic constitution of the individual, comprising the alleles present at each genetic locus. Basic Terms of Genetics
2. Partial AIS AIS Scoliosis (PAIS): characterized by undervirilization of a phenotypic male or virilization of a phenotypic female in an individual with a male genotype Genotype The genetic constitution of the individual, comprising the alleles present at each genetic locus. Basic Terms of Genetics
3. Mild AIS AIS Scoliosis (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 Genotype The genetic constitution of the individual, comprising the alleles present at each genetic locus. Basic Terms of Genetics
  • 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: Anatomy
  • 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: Anatomy, 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. Uterus, Cervix, and Fallopian Tubes: Anatomy, 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. Uterus, Cervix, and Fallopian Tubes: Anatomy) are absent.
  • Male internal genitalia are absent, with the exception of testes Testes Gonadal Hormones.
• Adolescence:
  • Primary amenorrhea Amenorrhea Absence of menstruation. Congenital Malformations of the Female Reproductive System 
  • Sparse or absent pubic- and axillary-hair development
  • Breast development occurs
  • Pubertal growth spurt Growth spurt Puberty occurs 
• Adulthood:
  • Normal-appearing female body habitus
  • 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

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 Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics:
  • Hypospadias Hypospadias A birth defect due to malformation of the urethra in which the urethral opening is below its normal location. In the male, the malformed urethra generally opens on the ventral surface of the penis or on the perineum. In the female, the malformed urethral opening is in the vagina. Penile Anomalies and Conditions (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: Anatomy)
  • Micropenis or macroclitoris
  • Bifid scrotum Scrotum A cutaneous pouch of skin containing the testicles and spermatic cords. Testicles: Anatomy (deep midline cleft dividing the scrotum Scrotum A cutaneous pouch of skin containing the testicles and spermatic cords. Testicles: Anatomy), which may contain testes Testes Gonadal Hormones
  • May have complete failure of fusion of scrotum Scrotum A cutaneous pouch of skin containing the testicles and spermatic cords. Testicles: Anatomy 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 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 (impaired spermatogenesis Spermatogenesis The process of germ cell development in the male from the primordial germ cells, through spermatogonia; spermatocytes; spermatids; to the mature haploid spermatozoa. Gametogenesis)
• Virilized female phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics:
  • 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: Anatomy
  • May have incompletely developed male urogenital structures internally 
  • Sparse axillary and pubic hair
  • 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

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 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

• History and physical examination
• Lab tests:
  • Testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens levels:
    • Infancy: basal levels possibly low, but ↑ with administration of hCG
    • Prepubertal: ↑ testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens 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 LH A major gonadotropin secreted by the adenohypophysis. Luteinizing hormone regulates steroid production by the interstitial cells of the testis and the ovary. The preovulatory luteinizing hormone surge in females induces ovulation, and subsequent luteinization of the follicle. Luteinizing hormone consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle) levels:
    • Infancy: may be low but ↑ with stimulation of gonadotropin-releasing hormone Gonadotropin-releasing hormone A decapeptide that stimulates the synthesis and secretion of both pituitary gonadotropins, luteinizing hormone and follicle stimulating hormone. Gnrh is produced by neurons in the septum preoptic area of the hypothalamus and released into the pituitary portal blood, leading to stimulation of gonadotrophs in the anterior pituitary gland. Puberty (GnRH)
    • 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: ↑ concentration (due to impaired feedback secondary to androgen resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing)
  • Normal follicle-stimulating hormone ( FSH FSH A major gonadotropin secreted by the adenohypophysis. Follicle-stimulating hormone stimulates gametogenesis and the supporting cells such as the ovarian granulosa cells, the testicular sertoli cells, and leydig cells. Fsh consists of two noncovalently linked subunits, alpha and beta. Within a species, the alpha subunit is common in the three pituitary glycoprotein hormones (TSH, LH, and FSH), but the beta subunit is unique and confers its biological specificity. Menstrual Cycle) levels
  • Androstenedione Androstenedione A delta-4 C19 steroid that is produced not only in the testis, but also in the ovary and the adrenal cortex. Depending on the tissue type, androstenedione can serve as a precursor to testosterone as well as estrone and estradiol. Androgens and Antiandrogens, dihydrotestosterone Dihydrotestosterone A potent androgenic metabolite of testosterone. It is produced by the action of the enzyme 3-oxo-5-alpha-steroid 4-dehydrogenase. Gonadal Hormones ( DHT DHT A potent androgenic metabolite of testosterone. It is produced by the action of the enzyme 3-oxo-5-alpha-steroid 4-dehydrogenase. Gonadal Hormones), anti-Müllerian hormone ( AMH AMH A glycoprotein that causes regression of mullerian ducts. It is produced by sertoli cells of the testes. In the absence of this hormone, the mullerian ducts develop into structures of the female reproductive tract. In males, defects of this hormone result in persistent mullerian duct, a form of male pseudohermaphroditism. Primary Amenorrhea), 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 Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies: 
  • Confirms diagnosis 
  • Karyotype Karyotype The full set of chromosomes presented as a systematized array of metaphase chromosomes from a photomicrograph of a single cell nucleus arranged in pairs in descending order of size and according to the position of the centromere. Congenital Malformations of the Female Reproductive System analysis to determine genotypic sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria: FISH FISH A type of in situ hybridization in which target sequences are stained with fluorescent dye so their location and size can be determined using fluorescence microscopy. This staining is sufficiently distinct that the hybridization signal can be seen both in metaphase spreads and in interphase nuclei. Chromosome Testing to confirm presence of Y chromosome Y chromosome The male sex chromosome, being the differential sex chromosome carried by half the male gametes and none of the female gametes in humans and in some other male-heterogametic species in which the homologue of the X chromosome has been retained. Basic Terms of Genetics
• Histopathology of testes Testes Gonadal Hormones: normal architecture of testes Testes Gonadal Hormones 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 Karyotype The full set of chromosomes presented as a systematized array of metaphase chromosomes from a photomicrograph of a single cell nucleus arranged in pairs in descending order of size and according to the position of the centromere. Congenital Malformations of the Female Reproductive System analysis, chorionic villus sampling, or amniotic fluid Amniotic fluid A clear, yellowish liquid that envelopes the fetus inside the sac of amnion. In the first trimester, it is likely a transudate of maternal or fetal plasma. In the second trimester, amniotic fluid derives primarily from fetal lung and kidney. Cells or substances in this fluid can be removed for prenatal diagnostic tests (amniocentesis). Placenta, Umbilical Cord, and Amniotic Cavity sampling.

Management

• Management depends on receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors status, phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics, and gender Gender Gender Dysphoria identity of the affected individual. 
• All individuals:
  • Offer psychological counseling.
  • Calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes and vitamin D Vitamin D A vitamin that includes both cholecalciferols and ergocalciferols, which have the common effect of preventing or curing rickets in animals. It can also be viewed as a hormone since it can be formed in skin by action of ultraviolet rays upon the precursors, 7-dehydrocholesterol and ergosterol, and acts on vitamin D receptors to regulate calcium in opposition to parathyroid hormone. Fat-soluble Vitamins and their Deficiencies 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. Bones: Structure and Types health
• Hormone-replacement therapy:
  • Female phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics: 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: Anatomy replacement after gonadectomy
  • Male phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics (PAIS): high-dose androgen therapy 
• Tamoxifen Tamoxifen One of the selective estrogen receptor modulators with tissue-specific activities. Tamoxifen acts as an anti-estrogen (inhibiting agent) in the mammary tissue, but as an estrogen (stimulating agent) in cholesterol metabolism, bone density, and cell proliferation in the endometrium. Antiestrogens therapy may be considered for phenotypic males with 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.
• Surgery:
  • Reconstructive and/or reassignment surgery of genitalia if necessary, after expert evaluation
  • Orchiopexy Orchiopexy A surgical procedure in which an undescended testicle is sutured inside the scrotum in male infants or children to correct cryptorchidism. Orchiopexy is also performed to treat testicular torsion in adults and adolescents. Cryptorchidism (moving and permanently fixing the position of testes Testes Gonadal Hormones) or orchiectomy (removal of testes Testes Gonadal Hormones) in cases of abnormally located testes Testes Gonadal Hormones (intra-abdominal or intra-labial locations)
  • Vaginal dilatation and/or vaginoplasty to prevent dyspareunia Dyspareunia Recurrent genital pain occurring during, before, or after sexual intercourse in either the male or the female. Primary Ovarian Insufficiency
  • Mastectomy Mastectomy Surgical procedure to remove one or both breasts. Fat Necrosis of the Breast may be indicated for 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.
  • Hypospadias Hypospadias A birth defect due to malformation of the urethra in which the urethral opening is below its normal location. In the male, the malformed urethra generally opens on the ventral surface of the penis or on the perineum. In the female, the malformed urethral opening is in the vagina. Penile Anomalies and Conditions 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 AIS Scoliosis:

• Müllerian agenesis Agenesis Teratogenic Birth Defects: also known as Mayer-Rokitansky-Küster-Hauser syndrome or vaginal agenesis Agenesis Teratogenic Birth Defects. Müllerian agenesis Agenesis Teratogenic Birth Defects 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: Anatomy 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: Anatomy 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. Uterus, Cervix, and Fallopian Tubes: Anatomy may be absent or underdeveloped. Women present with primary amenorrhea Amenorrhea Absence of menstruation. Congenital Malformations of the Female Reproductive System, but the remainder of secondary sexual characteristics Secondary Sexual Characteristics Precocious Puberty develop normally. Hormone levels are typically normal. Management involves surgery for anatomical abnormalities.
• 46,XY complete gonadal dysgenesis Gonadal dysgenesis A number of syndromes with defective gonadal developments such as streak gonads and dysgenetic testes or ovaries. The spectrum of gonadal and sexual abnormalities is reflected in their varied sex chromosome (sex chromosomes) constitution as shown by the karyotypes of 45, X monosomy (Turner syndrome); 46, XX (gonadal dysgenesis, 46xx); 46, XY (gonadal dysgenesis, 46, xy); and sex chromosome mosaicism. Their phenotypes range from female, through ambiguous, to male. This concept includes gonadal agenesis. Wilms Tumor: 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 Gonads The gamete-producing glands, ovary or testis. Hormones: Overview and Types ( 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: Anatomy or testes Testes Gonadal Hormones). Women experience primary amenorrhea Amenorrhea Absence of menstruation. Congenital Malformations of the Female Reproductive System 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 Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies. Management includes hormone-replacement therapy and removal of the streak gonads Gonads The gamete-producing glands, ovary or testis. Hormones: Overview and Types. 
• Mixed gonadal dysgenesis Gonadal dysgenesis A number of syndromes with defective gonadal developments such as streak gonads and dysgenetic testes or ovaries. The spectrum of gonadal and sexual abnormalities is reflected in their varied sex chromosome (sex chromosomes) constitution as shown by the karyotypes of 45, X monosomy (Turner syndrome); 46, XX (gonadal dysgenesis, 46xx); 46, XY (gonadal dysgenesis, 46, xy); and sex chromosome mosaicism. Their phenotypes range from female, through ambiguous, to male. This concept includes gonadal agenesis. Wilms Tumor: a condition with asymmetric gonadal development involving both male and female gonads Gonads The gamete-producing glands, ovary or testis. Hormones: Overview and Types and respective internal and external reproductive anatomy. Mixed gonadal dysgenesis Gonadal dysgenesis A number of syndromes with defective gonadal developments such as streak gonads and dysgenetic testes or ovaries. The spectrum of gonadal and sexual abnormalities is reflected in their varied sex chromosome (sex chromosomes) constitution as shown by the karyotypes of 45, X monosomy (Turner syndrome); 46, XX (gonadal dysgenesis, 46xx); 46, XY (gonadal dysgenesis, 46, xy); and sex chromosome mosaicism. Their phenotypes range from female, through ambiguous, to male. This concept includes gonadal agenesis. Wilms Tumor 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 Mosaicism The occurrence in an individual of two or more cell populations of different chromosomal constitutions, derived from a single zygote, as opposed to chimerism in which the different cell populations are derived from more than one zygote. Chromosome Testing with a 45,X0/46,XY karyotype Karyotype The full set of chromosomes presented as a systematized array of metaphase chromosomes from a photomicrograph of a single cell nucleus arranged in pairs in descending order of size and according to the position of the centromere. Congenital Malformations of the Female Reproductive System. 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 Karyotyping Mapping of the karyotype of a cell. Chromosome Testing and biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma 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 Inheritance genetic condition affecting individuals with the 46,XY karyotype Karyotype The full set of chromosomes presented as a systematized array of metaphase chromosomes from a photomicrograph of a single cell nucleus arranged in pairs in descending order of size and according to the position of the centromere. Congenital Malformations of the Female Reproductive System. External genitalia most often appears female but may appear male or ambiguous. Affected individuals have testes Testes Gonadal Hormones and normal testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens production; however, there is impaired conversion of testosterone Testosterone A potent androgenic steroid and major product secreted by the leydig cells of the testis. Its production is stimulated by luteinizing hormone from the pituitary gland. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to dihydrotestosterone or estradiol. Androgens and Antiandrogens to DHT DHT A potent androgenic metabolite of testosterone. It is produced by the action of the enzyme 3-oxo-5-alpha-steroid 4-dehydrogenase. Gonadal Hormones, causing undervirilization. Hormonal and genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies help make the diagnosis. Management depends on phenotype Phenotype The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics and gender Gender Gender Dysphoria identity, and may involve hormone replacement and/or surgery.

Related conditions

The following condition is related to AIS AIS Scoliosis 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 Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics and impairs androgen receptivity:

Spinobulbar muscular atrophy Spinobulbar Muscular Atrophy Motor Neuron Lesions: an X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) genetic condition, also known as Kennedy disease. Spinobulbar muscular atrophy Spinobulbar Muscular Atrophy Motor Neuron Lesions 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 Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics, 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 Spinobulbar Muscular Atrophy Motor Neuron Lesions is characterized by a progressive deterioration of anterior motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology and is associated with the development of 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 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 AIS Scoliosis.