Editing Disorders of Sexual Differentiation (section)

=== 46,XY Disorder of Sex Development (Under-masculinized Male) ===

* '''Refers to 46,XY individuals with differentiated testes who exhibit varying degrees of feminization phenotypically'''
* '''Impaired male differentiation in these patients is secondary to:'''
*# '''Inadequate secretion of testosterone''' by the testes at the necessary period in development
*# '''Inability of target tissue to respond to androgen appropriately'''
*# '''Impaired production or action of MIS'''

==== Inadequate secretion of testosterone by the testes at the necessary period in development ====
* '''Leydig Cell Aplasia (Luteinizing Hormone Receptor Abnormality)'''
** '''Autosomal recessive trait'''
** '''Expressed only in males'''
** '''Low testosterone level''' is noted in conjunction with an '''elevated LH concentration'''.
*** '''The absence of a rise in serum testosterone level after hCG stimulation is characteristic of this disorder'''
** '''There are no müllerian structures,''' consistent with functioning Sertoli cells, '''and the vagina is short'''
** Clinical diagnosis is typically made as a result of sexual infantilism and the absence of development of secondary sexual characteristics or the discovery of palpable gonads in the inguinal canal or labia on physical examination.
** The differential diagnosis includes androgen insensitivity syndrome or a terminal defect in androgen synthesis.
* '''Disorders of Testosterone Biosynthesis'''
** '''A defect in any of the 5 enzymes required for the conversion of cholesterol to testosterone''' can cause incomplete (or absent) virilization of the male fetus during embryogenesis.
*** '''Autosomal recessive''' for all 5 enzyme deficiencies
*** '''The first 3 enzymes are present in both adrenals and testes. Therefore, their deficiency results in impaired synthesis of glucocorticoids and mineralocorticoids in addition to testosterone'''
*# '''StAR (Cholesterol Side Chain Cleavage Enzyme) Deficiency'''
*#* The steroidogenic acute regulatory protein (StAR) enzyme is involved in cholesterol side chain cleavage
*#* Affected 46,XY individuals have female or ambiguous external genitalia with a blind-ending vaginal pouch; intra-abdominal, inguinal, or labial testes; and absence of müllerian structures, consistent with functioning Sertoli cells; Wolffian duct'''-'''derived structures are present but rudimentary.
*#* '''Infants are often seen in the first few weeks of life with severe adrenal insufficiency and salt wasting''', but delayed presentation has been reported
*#* '''Diagnosis should be considered in any neonate with nonvirilized female external genitalia and evidence of cortisol and aldosterone deficiency with hyponatremia, hyperkalemia, and metabolic acidosis'''.
*#* CT demonstrates large, lipid-laden adrenal glands
*#* Management: similar to 21-hydroxylase deficiency
*# '''3β-Hydroxysteroid Dehydrogenase Deficiency (see above)'''
*# '''17α-Hydroxylase Deficiency'''
*#* 17α-Hydroxylase catalyzes the conversion of pregnenolone and progesterone to 17α- hydroxypregnenolone and 17-hydroxyprogesterone, respectively, in adrenal and gonadal steroidogenesis.
*#* '''A deficiency in 17α-hydroxylase activity impairs cortisol production, causing ACTH hypersecretion and resulting in increased levels of DOC, corticosterone, and 18-hydroxycorticosterone in the adrenals. These compounds with mineralocorticoid activity produce excess salt and water retention, hypertension, and hypokalemia'''
*#* Phenotype varies from female external genitalia with a blind-ending vaginal pouch to perineal hypospadias and chordee.
*#* '''Diagnosis'''
*#** '''Should be considered in a undervirilized male with hypertension'''
*#** Laboratory investigations: elevated serum progesterone, DOC, corticosterone, 18-hydroxycorticosterone, and ACTH
*#* Management
*#** Glucocorticoid replacement brings blood pressure and hypokalemia back to normal by suppressing ACTH and hence adrenal cortical stimulation
*#** Reconstruction of the external genitalia
*#** Appropriate sex steroid replacement at puberty
*# '''17,20-Lyase Deficiency'''
*#* '''Aldosterone, cortisol, and ACTH secretion are normal.'''
*#* '''Hypertension does not result.'''
*#* '''Impaired biosynthesis of testosterone in the 46,XY individual results typically in ambiguous rather than totally female genitalia at birth.'''
*#** The deficient masculinization of the external genitalia can range from severe, resulting in a female gender assignment in the neonate, to mild, resulting only in hypospadias.
*#* At puberty, the secretion of testicular androgen remains low
*#* Diagnosis
*#** May be suspected in undervirilized males with absent müllerian-derived structures and no defect in glucocorticoid or mineralocorticoid synthesis.
*#** At the time of expected pubertal development, patients may have failure to develop secondary sexual characteristics and elevated gonadotropin levels.
*#** May be made prepubertally using hCG and ACTH stimulation
*# '''17β-Hydroxysteroid Oxidoreductase Deficiency'''
*#* Last enzyme in the testosterone biosynthetic pathway
*#* Catalyzes the conversion of androstenedione to testosterone, DHEA to androstanediol, and estrone to estradiol.
*#* '''Clinically similar to 5α-reductase deficiency'''
*#* '''At birth, affected individuals appear to have a normal female phenotype, without significant evidence of virilization. Therefore a female gender assignment is usually made. However, these''' '''individuals have well-differentiated testes located intraabdominally''', inguinally, or in the labia '''and no müllerian structures.'''
*#* In the prepubertal patient, plasma androstenedione and estrone levels may not be increased. '''At puberty, androstenedione, the immediate precursor of testosterone, is increased to 10-15x the normal plasma concentration.''' Earlier precursors are within normal levels. Plasma testosterone is in the low-normal range. Serum levels of LH and FSH are markedly elevated, typically 4-6x normal.
*#* '''At puberty, there is phallic growth and progressive development of male secondary sexual characteristics. The late onset of virilization is related to the pubertal increase in gonadotropin production''', which may partially overcome the block in testosterone biosynthesis.
*#* The diagnosis is rarely made in the neonatal period. '''An hCG stimulation test resulting in an increased testosterone-to-androstenedione ratio would confirm the diagnosis and differentiate this condition from androgen insensitivity.'''
*#* The primary management issue has been gender assignment.
** '''Cytochrome P450 Oxidoreductase Deficiency'''
*** Cytochrome P450 oxidoreductase is a cofactor to all microsomal P450 enzymes, including 17-hydroxylase, 17,20-lyase, 21-hydroxylase, and aromatase
*** Causes of both 46,XY and 46,XX DSDs.

==== 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

==== Impaired production or action of MIS ====

* '''Persistent Müllerian Duct Syndrome'''
** '''Patients with a 46,XY karyotype and normal male external genitalia but internal müllerian duct structures'''
** '''DSD resulting from defective AMH signaling'''
*** '''Aberrant MIS function may be secondary to defects in the gene for MIS or in the gene for the MIS receptor'''
**** Genetically heterogeneous disorder in which some subjects have a defect in the gene for MIS and others have a defect in the gene for its type II receptor. The condition may occur sporadically or may be inherited as an X-linked (or autosomal dominant, sex-limited) trait
** '''Typically, these phenotypic males have unilateral or bilateral undescended testes, bilateral fallopian tubes, a uterus, and an upper vagina draining into a prostatic utricle.'''
*** '''Suggested by the presence of Mullerian structures (uterus, fallopian tube) attached to an undescended testicle (more commonly intra-abdominal)'''
*** '''Usually an intraoperative finding'''
*** Patients should have AMH levels checked and be referred to endocrinology/genetics for investigation
** '''Rarely, can lead to both testicles occupying the same side of the abdomen (transverse testicular ectopia)'''
** '''Management'''
*** '''All patients are phenotypic males who require orchidopexy'''
*** The cases of adult patients with associated testis tumor (most commonly seminoma) probably reflect the increased risk of malignancy in intra-abdominal undescended testes.
*** '''Malignancies have been reported in retained müllerian remnants and at times their attachments can hinder the performance of a tension-free orchidopexy.'''
**** '''When Mullerian remnants are found incidentally during an inguinal orchidopexy, the proximal aspect of the fallopian tube can be transected and removed with the uterus, leaving its distal component attached to the vas deferens, allowing the testis to be brought to a scrotal position''' Such a maneuver avoids separation of the tube from the cord structures, protecting the deferential and testicular blood supply.
***** '''C'''areful surgical excision is required as the vasa deferentia are in close proximity to the uterus and proximal vagina