Taylor_Speroff's Clinical Gynecologic Endocrinology and Infe

Chapter 8 • Normal and Abnormal Sexual Development 289

3 β -HSD, and P450 oxidoreductase deficiencies) by the serum levels of ACTH, cortisol, DHEA, and 11-desoxycorti sol, because each has a characteristic serum steroid hormone pattern (described in earlier sections of this chapter). When CAH has been excluded, imaging revealing a uterus or a history of maternal androgen exposure or viriliza tion during pregnancy points clearly toward maternal gesta tional hyperandrogenism (pregnancy luteoma, theca-lutein cysts) or P450 aromatase deficiency. Some of the remaining uncommon causes of XX virilization due to testicular DSD can be differentiated by measuring AMH (or inhibin B) and performing an hCG stimulation test (described below); male levels of AMH and a normal testosterone response to hCG indicate the presence of functional testicular tissue, suggest ing the diagnosis of ovotesticular DSD or a SOX9 duplica tion 127,582 (Figure 8.14) . XY Undervirilization The differential diagnosis of XY undervirilization includes disorders of gonadal (testicular) development, disorders of androgen synthesis or action, LH receptor defects, and disor ders of AMH and its receptor. The diagnostic evaluation for SRY -positive infants is challenging due to the large number of possible causes. In addition to the initial laboratory evalu ation described above, XY undervirilized infants require further evaluation by measuring the serum LH, FSH, AMH, testosterone, androstenedione, and DHT concentrations. Gonadotropin and sex steroid levels should be measured when they normally are detectable, either in the first 24 hours after birth or between 2 and 6 months of age. 583,584 Provocative tests (ACTH stimulation test, hCG stimulation test) and other specialized tests also may be required to establish a diagnosis. The serum concentrations of 17-OHP and 17 α -hydroxy pregnenolone help to narrow the spectrum of diagnostic pos sibilities. Low or absent levels indicate a 17 α -hydroxylase or StAR protein deficiency or partial gonadal dysgenesis ( SF1 mutation, DAX1 duplication), and elevated levels point to a 3 β -HSD or P450 oxidoreductase deficiency; an ACTH stimulation test can better demonstrate the different adrenal enzyme deficiencies 585 and also excludes adrenal insufficiency. The test involves measurements of serum ACTH, cortisol, progesterone, pregnenolone, 17-OHP, 17 α -hydroxypreg nenolone, DHEA, and androstenedione before and 60 min utes after administering cosyntropin (synthetic ACTH 1–24; 1 mg/m 2 or 0.25 mg) 182 ; hormone values must be compared to age-adjusted normal ranges. The absence of any significant steroidogenic response suggests partial gonadal dysgenesis due to a StAR deficiency, an SF1 mutation, or a DAX1 dupli cation. Normal 17-OHP and 17 α -hydroxypregnenolone con centrations require additional evaluation.

to a fully fused normal-appearing male scrotum. The ano genital ratio is defined by the distance from the anus to the posterior fourchette of the vagina, divided by the dis tance from the anus to the base of the clitoris. 579 A ratio greater than 0.5 suggests virilization and some degree of labioscrotal fusion. Once the karyotype is known, the extent of virilization can be further defined by compari son to established gender-specific standards 139,580 to more objectively document the genital phenotype. Imaging Imaging with abdominal and pelvic ultrasonography can help to determine the location of the gonads and the presence or absence of a uterus. However, an infantile uterus can be difficult to image, even with MRI. Imaging is informative when it reveals a uterus but inconclusive when it does not. Although a retro grade urethrogram can be used, cystoscopy/vaginoscopy gen erally is the best method for defining the urethral and vaginal anatomy. 581 Rarely, laparoscopy may be needed to confidently define the reproductive anatomy and to biopsy the gonads. Initial Laboratory Evaluation The initial laboratory evaluation should include the following: ● ● Karyotype, to determine the chromosomal sex ● ● FISH, to determine the presence or absence of SRY ● ● Measures of adrenal and gonadal steroid secretion, including: ● ● 17-OHP—rapidly excludes CAH due to 21-hydroxy lase deficiency, a common cause of ambiguous genita lia that can be life-threatening. ● ● Electrolytes—should be measured immediately and monitored at least daily until salt wasting can be excluded. ● ● ACTH, cortisol, DHEA, 17 α -hydroxypregnenolone, and 11-desoxycortisol—identify less common causes of CAH caused by enzyme deficiencies other than 21-hydroxylase deficiency. Differential Diagnosis Based on the karyotype, the infant can be placed in one of three diagnostic categories: (1) XX virilization, (2) XY undervirilization, or (3) mixed sex chromosome pattern. 115 XX Virilization The differential diagnosis of XX virilization includes disor ders of gonadal (ovarian) development and androgen excess of fetal, fetoplacental, or maternal origin. FISH detection of SRY indicates an SRY translocation. In the absence of SRY , CAH is the most common diagnosis in XX virilized infants. An elevated serum 17-OHP or 17 α -hydroxypregnenolone concentration clearly suggests CAH. The most common cause, 21-hydroxylase deficiency, can be differentiated from other less common causes of CAH (11 β -hydroxylase,

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AMH (or inhibin B) is a marker of Sertoli cell mass and iden tifies patients having functional testicular tissue, even when the testes cannot be imaged. 586 A low serum AMH level suggests a form of partial gonadal dysgenesis, testicular regression syn drome, ovotesticular DSD, or an AMH mutation. Those with Copyright © 2019 Wolters Kluwer, Inc. Unauthorized reproduction of the content is prohibited.