Taylor_Speroff's Clinical Gynecologic Endocrinology and Infe

280 Section II • Clinical Endocrinology

before puberty and followed with gonadectomy and estrogen therapy in those with female genitalia. In those born with ambiguous genitalia, early diagnosis may allow male sex assignment because androgen treatment can promote devel opment of a nearly normal adult male phenotype. 412,413 When suspected, an elevated basal serum androstenedi one level and low serum testosterone/androstenedione ratio (<0.8–0.9) after exogenous hCG stimulation suggest the diagnosis of 17 β -HSD deficiency, but the method lacks spec ificity, because normal values have not been firmly estab lished in age-matched controls and because similar results can be observed in individuals with other defects in testos terone biosynthesis or Leydig cell hypoplasia. Genotyping permits definitive diagnosis. A variety of different mutations has been described, most yielding an enzyme having little or no significant activity. 405 P450 Oxidoreductase Deficiency The genetics and pathophysiology of P450 oxidoreductase (POR) deficiency are discussed in detail in the earlier section of this chapter devoted to causes of 46,XX DSD (female vir ilization). The disorder is included again here because, like 3 β -HSD deficiency, P450 oxidoreductase deficiency also is among the causes of 46,XY DSD (incomplete masculiniza tion in males). As described earlier, POR is not a steroidogenic enzyme but a flavoprotein that serves as the electron donor in the activation of all microsomal P450 enzymes, includ ing P450c21 (the adrenal 21-hydroxylase, CYP21A2), P450c17 (CYP17A1, which catalyzes both 17,20-lyase and 17 α -hydroxylase activities), and P450arom (aromatase, CYP19A1, which mediates the conversion of androgens to estrogens). 275 The developmental consequences of POR defi ciency in males result primarily from partial deficiencies of 21-hydroxylase and 17,20-lyase, and to a lesser extent, 17 α -hydroxylase activity. Serum concentrations of 17-OHP are elevated and androgen levels are low. Not surprisingly, affected boys often are undervirilized, because decreased 17,20-lyase activity prevents generation of 19-carbon andro gens, including testosterone. Steroid Acute Regulatory (StAR) Protein Deficiency The rarest and most severe form of CAH is known as con genital lipoid adrenal hyperplasia. The disorder is charac terized by a deficiency of all adrenal and gonadal steroid hormones, increased ACTH secretion, and marked adrenal hyperplasia associated with progressive accumulation of cholesterol esters.

of ACTH and mineralocorticoids while avoiding glucocor ticoid excess. Because almost all affected patients are raised as females, estrogen therapy also should be provided, at the time of diagnosis at puberty or the expected time of puberty. In genetic females having a uterus, progestational treatment also must be provided. 3 β -Hydroxysteroid Dehydrogenase Deficiency Defects in the enzyme 3 β -hydroxysteroid dehydrogenase/ D 5 -D 4 isomerase (3 β -HSD) and its endocrine and develop mental consequences in genetic females are discussed in detail in the earlier section of this chapter devoted to causes of female virilization (46,XX DSD). The enzyme defect is con sidered here again, briefly, because it can cause incomplete masculinization of males as well as virilization in females. Type II 3 β -HSD catalyzes the oxidation and isomerization of D 5 -3 β -hydroxysteroid precursors into D 4 -ketosteroids in the adrenals and gonads. A 3 β -HSD deficiency results in the accumulation of excessive amounts of D 5 -3 β -hydroxysteroids, including pregnenolone, 17 α -hydroxypregnenolone, DHEA, and DHEA-S, and in low levels of D 4 -ketosteroids such as androstenedione and testosterone and, subsequently, DHT. Consequently, affected males exhibit varying degrees of incomplete masculinization, ranging from hypospadias to nearly normal female external genitalia. 219,402,403 17 β -Hydroxysteroid Dehydrogenase Deficiency The 17 β -hydroxysteroid dehydrogenase (17 β -HSD) fam ily of enzymes includes the type 3 isoenzyme, which cata lyzes the conversion of androstenedione into the biologically active androgen, testosterone, in the Leydig cells of the testis. Mutations in the HSD17B3 gene, located on chromosome 9 (9q22), can result in 17 β -HSD deficiency, an autosomal recessive disorder caused by impaired testicular testosterone production. 404,405 Although rare, 17 β -HSD deficiency is the most common hereditary defect in testosterone synthesis. Males with homozygous or compound heterozygous mutations have testes and normally developed internal genitalia but have severely undervirilized external geni talia, which typically appear female and include a short, blind vagina, much like patients with incomplete androgen insensitivity. 405,406 Consequently, most are assigned a female gender at birth and are raised as females. Alternatively, they can exhibit genital ambiguity, with varying degrees of cli toromegaly and labial fusion, or have male genitalia with micropenis or hypospadias. 404,407 The testes may be located in the abdomen, in the inguinal canals, or in the labia majora. Virilization occurs at puberty, probably due to extrates ticular conversion of androstenedione to testosterone by unaffected 17 β -HSD isoenzymes in peripheral tissues (e.g., liver, skin, adipose). 405,408–410 The phallus enlarges, muscle mass increases, a male body habitus and hair pattern develop, and the voice may deepen. Gender role reversal has been observed in one- to two-thirds of those affected and raised as girls. 411 Ideally, therefore, the diagnosis is best made

Congenital lipoid adrenal hyperplasia is an autosomal recessive disorder that results from mutations in the gene encoding the steroidogenic acute regulatory (StAR) pro tein. 414,415 StAR mediates the acute response to steroidogenic stimuli by facilitating transport of cholesterol from the outer to the inner mitochondrial membrane, the rate-limiting step in steroidogenesis, 415,416 and is expressed in the adrenal cortex Copyright © 2019 Wolters Kluwer, Inc. Unauthorized reproduction of the content is prohibited.