Editing Disorders of Sexual Differentiation (section)

==== 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.