• Patients with ambiguous genitalia have disorders of sexual development (DSD).
  • Previously termed intersex conditions
• The nomenclature used to describe atypical sexual differentiation has changed.
  • Patient advocacy groups were concerned that the terminology was pejorative
• Historically, the term male pseudohermaphrodite was used to describe the patient with incompletely masculinized external genitalia possessing XY chromosomes and a typical number of autosomes (also known as 46, XY karyotype).
  • These conditions are now denoted as 46, XY DSD.
• The term female pseudohermaphrodite was used to describe the patient with 46, XX karyotype and with masculinized external genitalia.
  • Currently, these disorders are denoted as 46, XX DSD.
• In some rare cases, a patient has both ovarian and testicular tissue.
  • These patients had been called true hermaphrodites in the past.
  • They are now considered to have ovotesticular DSD.

• 46, XX disorders of sexual development
  • Occurs in 1 in 14,000 white infant births
  • Late-onset, or nonclassical, 21-hydroxylase deficiency usually occurs in childhood or the teenage years.
  • Defects in 11β-hydroxylation are rarer than defects in 21-hydroxylation, occurring in roughly 1 in 100,000 white infant births.
    • Occurs more frequently in children of Middle Eastern descent

• Disorders of gonadal differentiation (sex chromosome disorders of sexual development)
  • Klinefelter syndrome
    • Most common form of primary hypogonadism in males
    • Incidence of 1 in 1000 males
  • Turner syndrome (syndrome of gonadal dysgenesis)
    • Occurs in 1 in 2500 live-born female infants
    • Occurs in a greater percentage of conceived pregnancies
      • ~ 15% of first-trimester spontaneous abortions have an XO karyotype.
    • Cardiac involvement is common.
      • ~ 10% of patients have coarctation of the aorta leading to hypertension in the upper extremities.
      • An even greater percentage of patients have bicuspid aortic valves, which increases their risk for subacute bacterial endocarditis.
    • In some cases, short stature may be the sole phenotypic manifestation of the syndrome.
• 90% of infants with ambiguous genitalia have congenital adrenal hyperplasia.
  • >50% of these patients experience significant sodium loss.
• Rarely, disorders of either testicular or ovarian differentiation may lead to gonadal dysgenesis and thus anomalous sexual development.

• Disorders of sexual development arise from chromosomal, gonadal, or anatomic abnormalities in the pathway of sexual differentiation.
• Incomplete masculinization of a fetus with testes may result from
  • Decreased synthesis or secretion of testosterone or dihydrotestosterone (DHT)
  • Peripheral tissue resistance to androgen action
  • Defective production or action of antimüllerian hormone (AMH)
• 46, XX DSD may result from abnormally high levels of androgen from either a fetal or exogenous source.

46, XX disorders of sexual development

• ~ 90% of cases of congenital adrenal hyperplasia (CAH) are caused by 21-hydroxylase deficiency.
• Virilization of a female fetus results from excess androgen exposure from either a fetal or maternal source.
• Timing is important.
  • If the female fetus is exposed to elevated androgen levels after the 8th week of gestation but before the 13th week, the vaginal opening may fuse posteriorly and appear slitlike.
  • Females with CAH will have posterior fusion of the labia and not clitoromegaly, given their high circulating androgen levels between weeks 8 and 12.
  • Exposure to androgen after the 12th week of gestation (e.g., exogenous administration to the mother) will result in clitoromegaly without fusion of the labioscrotal folds.
• Fetal sources of androgen excess
  • CAH
    • Overproduction of adrenal androgens by the female fetus may occur in virilizing CAH.
    • Group of disorders in which a biochemical defect in cortisol synthesis leads to hyperplasia of the adrenal gland resulting from compensatory elevation in adrenocorticotropic hormone (ACTH)
    • These disorders are inherited in an autosomal-recessive manner.
    • The degree and timing of virilization, as well as the presence or absence of salt wasting, depend on the specific genetic lesion (Table 286-1).
  • P450c21 hydroxylase converts 17-hydroxyprogesterone (17-OHP) to II-deoxycortisol.
    • Deficiency in this enzyme leads to extreme elevation in 17-OHP levels.
    • Defects in 21-hydroxylase will lead to low aldosterone and cause renal salt wasting and potassium retention in approximately 50% of patients.
  • P450c11 hydroxylase deficiency typically results in:
    • Hypertension in either gender as a result of elevated levels of 11-deoxycorticosterone
    • Virilization of the female fetus as a result of increased adrenal androgen production
  • 3β-Hydroxysteroid-dehydrogenase deficiency causes mineralocorticoid, glucocorticoid, and sex-steroid deficiency.
    • Genetic females may be phenotypically normal or have varying levels of clitoromegaly or labial fusion.
    • Virilization occurs in genetic females because of increased levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S).
    • Peripheral conversion of DHEA to testosterone may cause virilization in females.
    • May be a common cause of late-onset CAH
    • Salt loss, as a result of aldosterone deficiency, occurs to varying degrees.
  • Aromatase deficiency
    • In rare cases, deficiency in the enzyme aromatase caused by mutations in the CYP19 gene may lead to virilization of the female fetus and often of the mother during pregnancy.
    • Aromatase catalyzes the conversion of androgen to estradiol.
    • Deficiency leads to elevated levels of androstenedione and testosterone and low levels of estrogens.
• Maternal or exogenous sources of elevated androgen levels
  • Maternal use of androgenic steroids, such as danazol or certain progesterone compounds, during pregnancy may lead to virilization of the female fetus.
  • Exposure to these compounds during weeks 8–12 of gestation may lead to significant ambiguity.
    • Later exposure may result only in an enlarged clitoris.
  • In rare instances, maternal CAH or a virilizing maternal tumor of ovarian or adrenal origin may lead to masculinization of the fetus.
  • Luteomas of pregnancy have been reported to cause genital ambiguity in the newborn.
    • More commonly, result only in maternal virilization

46, XY disorders of sexual development

• Luteinizing hormone (LH) receptor defects
  • Testosterone secretion is controlled by human chorionic gonadotropin (hCG) early in gestation and LH from the fetal pituitary later in gestation.
  • Failure of hCG or LH to stimulate testosterone production at the critical times is due to mutations in the LH/hCG receptor. This will result in incomplete masculinization of a male fetus.
  • This failure may occur in the situation of Leydig cell agenesis or hypoplasia.
  • Stimulation testing with hCG will result in little or no increase in androgen levels.
  • Basal and stimulated LH levels are typically elevated.
• Androgen biosynthesis defects
  • Enzyme defects in the pathways of testosterone biosynthesis may result in incomplete virilization of the male fetus.
    • Some of the defects affect synthesis of corticosteroids and are thus forms of CAH.
  • The initial conversion of cholesterol to delta-5-pregnenolone requires the enzyme P450scc (side chain cleavage), as well as the steroidogenic acute regulatory protein, which transports cholesterol to the inner mitochondrial membrane where P450scc is located.
    • Owing to low testosterone levels, patients with steroidogenic acute regulatory protein or P450scc enzyme deficiencies have:
      • Lipid-laden adrenal glands
      • Adrenal insufficiency
      • Sexual infantilism in males
  • 3β-Hydroxysteroid dehydrogenase deficiency may result in:
    • Mineralocorticoid
    • Glucocorticoid
    • Sex-steroid deficiencies
  • 17-Hydroxylase deficiency caused by a defect in the CPY17 gene results in deficiencies in cortisol and testosterone and thus can result in an incompletely masculinized 46, XY fetus.
    • Excess of the mineralocorticoid deoxycorticosterone leads to:
      • Hypertension in both sexes (caused by increased salt and water resorption)
      • Hypokalemia
      • Suppression of aldosterone production
  • Enzyme defects affecting testosterone biosynthesis without affecting corticosteroid production are described.
    • In a male fetus, 17,20 lyase (also called 17,20 desmolase) deficiency and 17β-hydroxysteroid dehydrogenase-3 deficiency will lead to an incompletely masculinized phenotype without any abnormalities related to mineralocorticoid or glucocorticoid effects.
    • Virilization may occur at puberty in either condition.
    • Gynecomastia may occur at puberty in those with 17,20 lyase deficiency.

Defects in androgen action

• Syndrome of complete androgen resistance (androgen insensitivity syndrome or testicular feminization) results from a defect in the androgen receptor.
• Affected individuals are phenotypic females with a 46, XY karyotype and bilateral testes that secrete elevated levels of testosterone.
• At puberty, LH increases and leads to elevations in testosterone, some of which is converted peripherally to estrogens.
• Incomplete forms of androgen resistance are caused by mutations in the androgen receptor.

5α-reductase-2 deficiency

• Mutations in the SRD5A2 gene coding for 5α-reductase-2, an enzyme that converts testosterone to dihydrotestosterone, lead to deficiency of DHT.
  • At birth, affected males may have ambiguous genitalia or be phenotypically female as a result of decreased conversion of testosterone to DHT in the sexual skin during the critical times of male genital development.
  • These patients have well-developed wolffian ducts (given that these structures are testosterone and not DHT responsive) and absent müllerian structures (given that AMH is produced from the normal testes).
  • During puberty, virilization occurs with growth of the phallus and testes, probably secondary to expression of a different form of the 5α-reductase enzyme (type 1) in the liver and other tissues at that time, with subsequent increases in circulating DHT levels.

Disorders of gonadal differentiation (sex chromosome disorders of sexual development)

• Turner syndrome (syndrome of gonadal dysgenesis)
  • Classic manifestations of Turner syndrome are linked to the absence of the SHOX gene on the X chromosome.
• Other disorders of gonadal development
  • Additional disorders of testicular development may be caused by:
    • Complete XY gonadal dysgenesis (Swyer syndrome)
    • Partial gonadal dysgenesis
    • Gonadal regression
  • Gonadal dysgenesis is descriptive and bears no etiologic relationship to the syndrome of gonadal dysgenesis or Turner syndrome.
  • 15–20% of these cases are caused by mutations in the SRY gene.
  • Partial gonadal dysgenesis in 46, XY individuals leads to variable amount of testosterone and AMH production.
  • Anorchia must be considered in all phenotypic male patients with bilaterally nonpalpable testes.
  • Gonadal dysgenesis may occur in patients with a 46, XX karyotype who may have streak gonads and sexual infantilism, but none of the other characteristics of Turner syndrome.
  • Genetic abnormalities, such as translocation of the SRY gene, can result in a 46, XX genotypic patient developing testicular instead of ovarian tissue.