Taylor_Speroff's Clinical Gynecologic Endocrinology and Infe

Chapter 8 • Normal and Abnormal Sexual Development 273

estriol, respectively) and is encoded by the CYP19A1 gene, located on chromosome 15 (15p21.1). The enzyme is active in the gonads, the placenta, the brain, and in adipose; tis sue-specific regulation is controlled, in part, by alternative tissue-specific promoters. Aromatase deficiency is a rare autosomal recessive disorder caused by mutations in the CYP19A1 gene. As a consequence, fetal androgens are not converted to estrogens in the placenta, resulting in female fetal virilization (due to the accumulation of fetal andro gens), low maternal serum estrogen levels, and maternal hirsutism, which typically develops during the second half of pregnancy and regresses after delivery. Affected females classically present with ambiguous genitalia at birth and, at puberty, exhibit signs of hyperandrogenism, absent breast development, primary amenorrhea associated with hypergonadotropic hypogonadism, and multicystic ova ries. 270–273 Aromatase mutations also can produce variable or nonclassic phenotypes characterized by varying degrees of breast development. 274 P450 Oxidoreductase Deficiency The classical forms of CAH all are caused by mutations in genes encoding steroidogenic enzymes, resulting in reduced or absent enzyme activity, and in clinical signs and symp toms caused by the accumulation of steroid precursors and/ or decreased production of the principal steroid end prod uct. Another newly described form of CAH results from a deficiency in the P450 oxidoreductase (POR) enzyme. Although not a steroidogenic enzyme per se, POR nonethe less affects several steroidogenic pathways and now is rec ognized as a cause of both 46,XX DSD (female virilization) and 46,XY DSD (incomplete male virilization), which is dis cussed below. 275

adulthood, generally involving clitoroplasty and vaginoplasty. Approximately half of procedures performed during infancy will require later revision. 139,266 Psychological counseling, ideally beginning soon after the diagnosis is established, is an important part of the treatment of classical CAH. Although data are limited and conflicting, the incidence of adult psychiatric disorders may be increased in women with classical CAH. 267,268 Sexual relationships may develop somewhat later than usual and sexual function may not be completely normal, even in those having had recon structive surgery. 5 Treatment During Pregnancy Although normal reproduction is possible with effective treatment, fertility generally is decreased in women with classical CAH, particularly in those with the salt-wasting variety of the disorder, due to chronic anovulation and, in some cases, due to poor surgical results. 3 In those who do conceive, serum concentrations of androstenedione, tes tosterone, and 17-OHP should be carefully monitored and the dosage of glucocorticoids increased as needed to maintain normal levels for gestational age. Treatment with long-acting glucocorticoids should be discontin ued in favor of treatment with hydrocortisone, which is metabolized by the placenta and thereby avoids the risk of suppressing the fetal hypothalamic-pituitary-adrenal axis. In general, term pregnancies, delivery of healthy female infants with normal external genitalia, and normal growth and development in both girls and boys can be achieved. 180,269 Even when maternal androgen levels cannot be suppressed to normal, the high capacity of placental aromatase activity effectively protects the fetal female genitalia. 180 The incidence of cesarean delivery is increased, primar ily because of concerns that vaginal delivery may disrupt a previous surgical reconstruction of perineal anatomy. An android pelvis is no more common than usual, because the form and size of the adult pelvis are determined during the pubertal growth spurt. However, a small pelvis might result if bone age is advanced to age 13–14 before treatment started. The need for stress doses of glucocorticoids during labor and delivery is obvious and does not increase the risk for infection or poor wound healing. Androgen Excess—Fetoplacental Origin Two rare enzyme deficiencies associated with androgen excess—aromatase deficiency and P450 oxidoreductase deficiency—are distinct from those causing classical forms of CAH because they involve both the fetal adrenal and the placenta. Aromatase (P450arom) Deficiency The enzyme aromatase (also designated P450arom and CYP19A1) catalyzes the conversion of 19-carbon andro gens (androstenedione, testosterone, 16 α -hydroxy DHEA) to aromatic 18-carbon estrogens (estrone, estradiol, and

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First described in 2004, 276 POR deficiency is perhaps the most complex form of CAH because it affects the activity of all of the P450 enzymes involved in steroidogenesis, to vary ing degrees, resulting in varying patterns of abnormal steroid hormone production and a spectrum of clinical manifes tations, and has other “nonendocrine” effects on skeletal development and drug metabolism. POR is a flavoprotein associated with the endoplasmic reticulum and is encoded by the POR gene, located on chromosome 7 (7q11.2). POR serves as the electron donor in the activation of all microsomal P450 enzymes, including P450c21 (the adrenal 21-hydroxy lase, CYP21A2), P450c17 (CYP17A1, which catalyzes both 17 α -hydroxylase and 17,20-lyase activities), and P450arom (aromatase, CYP19A1, which mediates the conversion of androgens to estrogens). POR deficiency is an autosomal recessive disorder and more than 25 different POR mutations already have been identified, most being missense mutations in the central electron transfer domain of the protein. 275,277 Patients with the same mutation, even siblings, can exhibit phenotypic differences, but the hormonal profile of all patients with POR mutations reflects partial deficiencies of 21-hydroxylase and 17 α -hydroxylase/17,20-lyase. Because Copyright © 2019 Wolters Kluwer, Inc. Unauthorized reproduction of the content is prohibited.