Editing Disorders of Sexual Differentiation (section)

==== Inability of target tissue to respond to androgen appropriately ====
* '''Disorders of androgen receptor function represent the most common definable cause of 46,XY DSD or the undervirilized male'''
* '''These patients characteristically have a 46,XY karyotype and testes and a spectrum of phenotypic abnormalities that vary from'''
** '''Complete external feminization: complete androgen insensitivity''' '''syndrome'''
** '''Ambiguous genitalia: partial androgen insensitivity'''
** '''Phenotypically infertile male'''
* '''In disorders of the androgen receptor, such as androgen insensitivity syndrome, testosterone production is normal but the hormone is unable to reach the nucleus and interact with DNA.'''

===== Complete (Severe) Androgen Insensitivity Syndrome (CAIS) =====
* Incidence of 1 in 20,000 to 1 in 60,000 males
* '''X-linked trait'''
** '''The androgen receptor has been mapped to the X chromosome'''
** Males have only one copy of this gene
** Point mutations of the gene account for > 90% of cases of androgen insensitivity
* '''Characterized by 46,XY karyotype, bilateral testes, female-appearing external genitalia, and absence of müllerian-derived structures,''' consistent with functioning Sertoli cells
** Patients have a normal female phenotype with the exception of diminished axillary and pubic hair.
*** Breast development and body habitus are feminine in character
**** '''At puberty, gonadotropin levels rise, leading to increased levels of plasma estradiol, which results in feminization, including breast development.'''
*** '''≈80% will have "normal" appearing, although the vagina is short and blind ending.'''
** Wolffian-derived structures may be present
*** Screening of the paratesticular area revealed well-developed epididymis and/or vasa deferentia in 42% of patients
** The testes may be found in the labia, inguinal canal, or abdomen
* '''Rarely diagnosed in the neonatal period; patients typically present by one of 5 different means:'''
*# Fetal karyotype (46 XY) incongruent with newborn infant's phenotype (5% of patients)
*# Relative or family member with CAIS, with patient diagnosed due to recommendation for genetic screening (15% of patients)
*# Ambiguous genitalia at birth, i.e., female phenotype with palpable gonads or mild to moderate clitorimegaly (20% of patients)
*# '''Primary amenorrhea (30% of patients)'''
*# '''Testicle found within a inguinal hernia at the time of surgical repair (30% of patients)'''
*#* Vaginoscopy to confirm the presence of a cervix or endoscopy through a hernia sac to identify an intra-abdominal testis at the time of inguinal herniorrhaphy in female patients is a prudent maneuver.
* '''Diagnosis and Evaluation'''
** '''History and Physical Exam'''
*** '''May readily be made in the postpubertal patient on the basis of clinical and hormonal findings of amenorrhea, absence of pubic hair, or inguinal hernias containing testes'''
*** '''Vaginal examination confirms a blind-ending vagina without a cervix'''
** '''Labs'''
*** '''Karyotype: 46,XY'''
*** '''Endocrine evaluation'''
**** '''Neonatal period: normal male levels of testosterone, DHT, and gonadotropins'''
**** '''Puberty:'''
***** '''Testosterone production and secretion by the Leydig cells is normal'''
***** '''LH is increased because of the apparent lack of testosterone by the target organs including the pituitary gland that not recognize the testosterone due to faulty receptors.'''
***** '''FSH is normal since it is controlled by inhibin'''
**** '''In the prepubertal child, diagnosis is more difficult and requires an hCG stimulation test.'''
***** [Unlike 17β-Hydroxysteroid Oxidoreductase Deficiency, hCG stimulation test in androgen insensitivity would not result in an increased testosterone-to-androstenedione ratio]
*** PCR can be used characterize the androgen receptor gene
** '''Imaging'''
*** '''Pelvic US confirms the absence of müllerian-derived structures'''
* '''Management'''
** '''Relates primarily to the optimal timing of gonadectomy'''
*** '''Patients with CAIS will have a substantial increased risk of developing a testicular seminoma'''
**** If the testis is left in situ, ≈20% of the patients will have developed a testicular malignancy by the age of 30.
**** '''Removal of the testicles are, therefore, strongly recommended either prior to or immediately following pubescence'''
***** '''Because the testes produce estradiol, which results in the appropriate changes for the female phenotype, it is considered by many preferable to leave the testes in situ until puberty is complete. In general, delayed gonadectomy after puberty is believed to be safe'''
***** '''Gonadoblastoma is a tumor that is associated with disorders of sex development. Specifically, it is found in infants noted to have partial or pure gonadal dysgenesis (46 XY or 46 XY/XO genotypes) and is not associated with complete androgen insensitivity syndrome'''
*** '''After orchiectomy, cyclic estrogen-progestin therapy is begun.'''
** '''All studies CAIS have been in patients with an unequivocal female gender identity''', consistent with androgen resistance of brain tissue as well.

===== Syndrome of Partial Androgen Insensitivity Syndrome (PAIS) =====
* Also known as Reifenstein syndrome
* '''X-linked disorder'''
* '''A disorder of androgen receptor quantity or function'''
* '''Ambiguious external genitalia to varying degrees,''' from hypospadias and a pseudovagina to gynecomastia and '''azoospermia'''
** Classic phenotype is that of a male with perineoscrotal hypospadias, cryptorchidism, rudimentary wolffian-derived structures, gynecomastia, and infertility.
* Diagnosis
** Can be difficult; a family history consistent with X-linked inheritance of ambiguous genitalia is suggestive of the disorder
** In the neonatal period, it may be made in the setting of a 46,XY karyotype, ambiguous external genitalia, and absent müllerian-mullerian structures on pelvic ultrasound.
** '''Endocrine evaluation demonstrates normal male levels of testosterone''' and gonadotropins, and a normal testosterone/DHT ratio.
** An hCG stimulation test and characterization of the androgen receptor gene in serum DNA by PCR should confirm the diagnosis.
* Management
** Must be individualized depending on the degree of genital ambiguity
** A course of androgen injections in early infancy is often used to assess androgen responsiveness, which can aid in gender assignment.

===== Mild Androgen Insensitivity Syndrome =====
* '''Variety of mutations, usually quite discrete within the androgen receptor gene, that accounts for the infertility in these patients'''
** This suggests that infertility in otherwise normal males may be the clinical manifestation of mild androgen insensitivity, representing the far end of a variable phenotypic spectrum.
* May have normal phenotypically or have a history of mild hypospadias repair but are azoospermic or severely oligospermic.
* '''Endocrine evaluation demonstrates normal to elevated serum testosterone levels with normal to elevated LH levels.'''

===== 5α-Reductase Deficiency =====
* '''Autosomal recessive''', only homozygous males are affected
* '''The type 2 isoenzyme is affected in patients with 5α-reductase deficiency, resulting in an increased testosterone/DHT ratio owing to a reduced testosterone-to-DHT conversion rate'''
* '''Phenotype that may vary from normal female to markedly ambiguous genitalia (more common) to penoscrotal hypospadias to the rare, isolated microphallus'''
** Typically the phallus is quite small, appearing as a normal or enlarged clitoris
** Presence of labioscrotal fusion; vaginal pouch is short and blind ending.
** Testes and epididymides are located in the labia, inguinal canals, or abdomen; and the vasa terminate in the blind-ending vaginal pouch.
** '''At puberty,''' partial masculinization occurs with an increase in muscle mass, development of male body habitus, increase in phallic size, and onset of erections, '''virilization is presumed to occur because the androgen receptor binds markedly higher levels of testosterone at low affinity or because of the normal increase at puberty in the activity of the 5α-reductase type 1 isoform, resulting in sufficient DHT for virilization'''
** '''Other secondary sexual characteristics, including enlargement of the prostate and hairline recession, do not develop.'''
** '''Although DHT appears to be critical for the development of normal external genitalia in utero, testosterone alone appears sufficient for wolffian duct development.'''
* '''Endocrine evaluaiton: elevated mean plasma testosterone but low DHT levels.''' After hCG stimulation, the testosterone-to-DHT ratio increases to > 20:1.
* Strong tendency toward reversal of gender identity in 5α-reductase deficiency