Taylor_Speroff's Clinical Gynecologic Endocrinology and Infe

274 Section II • Clinical Endocrinology

TABLE 8.2 Hormone Profile Associated with P450 Oxidoreductase Deficiency

17-Hydroxy progesterone

ACTH-stimulated Response

Hormone

Basal Level

5 α -reductase 3 α -hydroxysteroid dehydrogenase (reductive)

17-OHP

High

Exaggerated

DHEA/DHEA-S

Low

Low

5 α− pregnane 3 α ,17 α -diol-20-one

Androstenedione

Low

Low

Cortisol

Normal

Low

17,20 lyase (desmolase) (P450c17)

21-hydroxylase and 17,20-lyase activities are impaired to a greater degree than 17 α -hydroxylase activity, basal serum 17-OHP concentrations are elevated and exhibit an exag gerated response to ACTH stimulation (due to impaired 21-hydroxylase activity), and levels of DHEA/DHEA-S and androstenedione are low (due to impaired 17,20-lyase activ ity). Basal cortisol levels usually are normal or near normal, but do not rise normally with ACTH stimulation, revealing a chronically compensated adrenal insufficiency 275 (Table 8.2) . Surprisingly, females with POR deficiency frequently become virilized in utero, something not expected, given that fetal adrenal androgen production should be decreased, not increased. There are two hypotheses concerning the source of androgen excess that might explain the apparent dichotomy, but neither has been established conclusively. 278–280 The first envisions that even the modest amount of androgens pro duced could accumulate due to the deficiency of placental P450arom in patients with POR deficiency. The second invokes an alternative “backdoor pathway” to androgen production in which elevated levels of 17-OHP, which cannot be efficiently metabolized via P450c21 or P450c17 activities, seek alterna tive metabolism via 5 α -reduction and ultimately are converted to DHT, circumventing the usual pathway via androstene dione and testosterone (“Backdoor pathway” of androgen production is shown in Figure 8.10 ). 279–281 Although the backdoor pathway still involves P450c17, the enzyme’s affinity for its substrate in the alternative pathway (5 α -pregnane-3 α , 17 α -diol-20-one) is much higher than for 17-OHP. Therefore, the backdoor pathway likely functions better than the conven tional metabolic pathway in patients with POR deficiency. 281 The phenotype of POR deficiency varies widely. Whereas some exhibit a characteristic spectrum of skeletal abnor malities known as the Antley-Bixler syndrome (cranio synostosis, midface hypoplasia, choanal atresia or stenosis, radiohumeral and/or radioulnar synostosis, femoral bow ing and fractures, and joint contractures), indistinguishable from that observed in patients with mutations in the fibro blast growth factor receptor-2 gene ( FGFR2 ), bony abnor malities are subtle or altogether absent in others. 275 The phenotypic spectrum in patients with proven POR deficiency has included asymptomatic patients identified by neona tal screening for 21-hydroxylase deficiency, asymptomatic

5 α− DHT

Androsterone

17 β -hydroxysteroid dehydrogenase 3 α -hydroxysteroid dehydrogenase (oxidative)

FIGURE 8.10

patients whose mothers virilized during pregnancy, virilized female infants, and an adult female with primary amenor rhea and multicystic ovaries. 276,278,281,282 The widely varying phenotype has led to speculation that POR deficiency may be relatively common and frequently goes unrecognized or is misdiagnosed. Diagnosis of POR deficiency is not straightforward. The diagnosis should be considered in the evaluation of chil dren with sexual ambiguity and when prenatal screening for trisomy 21 reveals low maternal estriol levels. Mutation anal ysis is indicated for patients who exhibit compatible steroid hormone profiles. Androgen Excess—Maternal Origin (Gestational Hyperandrogenism) Maternal gestational hyperandrogenism is another, albeit very uncommon, cause of fetal virilization and may result from maternal ingestion of androgens or drugs having androgenic actions or from excess maternal androgen pro duction. The possibility should be considered when a preg nant woman exhibits a rapid onset of masculinizing signs, including hirsutism, temporal balding, clitoromegaly, and deepening of the voice. It also should be considered after delivery of a virilized female infant, remembering that luteo mas and theca-lutein cysts regress after delivery. The possible or probable extent of fetal virilization relates to the time of exposure to maternal androgens. Whereas exposure during early pregnancy can cause labio scrotal fusion and clitoromegaly, exposure after 12 weeks of gestation causes only clitoral hypertrophy.

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