Taylor_Speroff's Clinical Gynecologic Endocrinology and Infe

284 Section II • Clinical Endocrinology

phenotypic men with gynecomastia and perineoscrotal hypospadias. In phenotypic women with incomplete AIS, the family history can be very helpful because others who are affected have a similar appearance, but in undervirilized men, the phenotype of affected family members can vary signifi cantly. At all ages, the differential diagnosis includes steroid 5 α -reductase deficiency, defects in testosterone biosynthesis, and mixed gonadal dysgenesis, which is discussed below. The ratio of testosterone to DHT in serum helps to differentiate incomplete AIS from steroid 5 α -reductase deficiency; the ratio is normal in most with incomplete AIS but increased in patients with steroid 5 α -reductase deficiency. In most cases, androgen receptor defects can be differentiated from defects of testosterone biosynthesis by the serum testosterone con centration, which typically is normal or high in the former and decreased in the latter. Individuals with mixed gonadal dysgenesis (characterized by a unilateral testis, a contralateral streak gonad, and a 46,XY or 45X/46,XY karyotype) often have a single descended gonad or exhibit some of the phe notypic features of Turner syndrome. Androgen insensitivity also should be suspected in undervirilized men with azo ospermia or severe oligospermia. Testosterone or LH concen trations may be elevated but are normal in most 455 ; some have high serum FSH levels and resemble men with microdeletions in the AZF (azoospermia factor) region of the Y chromo some. 468 Although only a few families with the undervirilized fertile male syndrome have been reported, the disorder might be suspected in undervirilized men with a normally formed male urethra and gynecomastia, particularly in those having other family members who are similarly affected. Androgen receptor binding can be evaluated in vitro, using cultured fibroblasts derived from genital skin. However, the method is labor intensive and costly and can not exclude abnormalities of androgen receptor function unrelated to binding. Techniques involving the insertion of an androgen-responsive reporter gene in fibroblasts that can demonstrate impaired androgen receptor function have been described, but their usefulness for diagnosis of mild andro gen insensitivities is unclear. 469 The most reliable method for diagnosis of androgen insensitivity is to sequence the AR gene using DNA derived from blood or tissue, with reference to a database that lists all of the mutations that have been identified in patients with androgen insensitiv ity. Once characterized, the defect can be identified in fetuses at risk using DNA obtained via CVS or amniocentesis or in embryos using preimplantation genetic testing for mono genic disorders (PGT-M, previously called PGD). 470–472 The clinical management of incomplete AIS syndromes is directed toward appropriate gender assignment in infants with ambiguous genitalia, hormone therapy, psychological support, gonadectomy to prevent tumorigenesis in cryptor chid testes, reconstructive surgery where it is needed, and the treatment of gynecomastia in men. In determining gender assignment, the size of the phallus and the feasibility of constructing a penile urethra

are the most important considerations. For phenotypic females and those who are raised as females, estrogen treatment is indicated when gonadectomy is performed after puberty or at the expected time of puberty if gonad ectomy was performed earlier. Whereas adult women can receive normal doses of estrogen therapy immediately, the age and the dose of treatment in children must con sider the growth percentile, growth velocity, bone age, target height, and predicted adult height. In boys with Reifenstein syndrome, treatment with high doses of testos terone or DHT can achieve greater phallic growth 473–475 ; in adult men, high-dose testosterone treatment can, 371,476 but does not always, 442 improve masculinization. As in women with complete AIS, psychological support should be aimed at truthful education after consultation with the family and the development of a support network; early disclo sure may help to limit emotional trauma. 477 Gonadectomy is performed to eliminate the risk of tumors developing in cryptorchid testes (1–2% of undescended testes, more often in abdominal than in inguinal testes), some of which are malignant. 478 Whereas gonadectomy generally is best postponed until after puberty is completed in women with complete AIS, earlier surgery is indicated to prevent the virilization at puberty in those with incomplete AIS. In boys with Reifenstein syndrome, early surgery to correct cryptorchidism both decreases the risk of tumor and helps to maximize testicular function. The gynecomastia observed in men with Reifenstein syndrome and in undervirilized fertile males, which results from both increased estrogen production and androgen resistance, can be treated by mas tectomy when it is disfiguring or otherwise disturbing to the individual. The incidence of breast cancer may be increased in men with Reifenstein syndrome. 479 LH Receptor Defects Leydig cell hypoplasia, describing the absence of mature Leydig cells in the testes, is a rare autosomal recessive 46,XY disorder of sexual development caused by inacti vating mutations in the LH/hCG receptor. 480,481 Testicular Leydig cell testosterone production is stimulated by hCG during fetal life and by LH after birth. In the fetus, the num ber and differentiation of Leydig cells and levels of androgen production parallel the changes in serum hCG concentra tions during pregnancy. Consequently, a decrease in the number or function of Leydig cells results in decreased fetal testosterone production and in the failure of normal male sexual differentiation. Large deletions or nonsense muta tions in the LH/hCG receptor gene ( LHCGR ) yield defective receptors that prevent normal hormone binding; more subtle mutations allow binding but prevent normal signal trans duction or cause misfolding of the receptor that interferes with its normal transport to the cell surface. 481–483 In affected individuals, müllerian duct derivatives are absent (reflecting the normal action of AMH), wolffian

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