Taylor_Speroff's Clinical Gynecologic Endocrinology and Infe

282 Section II • Clinical Endocrinology

Approximately 40% of patients with complete AIS have no family history of the disorder, 434 presumably representing de novo mutations. The pathophysiology, and the phenotype, of complete AIS are logical and predictable. The receptor defect results in insensitivity to androgen. Consequently, androgen-induced wolffian duct development cannot proceed normally; the presence or absence of wolffian duct derivatives (epididy mides, vasa deferentia) varies with the type of mutation. Whereas remnants can be observed (adjacent to the testes) in those having point mutations in the ligand-binding domain of otherwise normally expressed receptors, which may per mit a very limited response to high local androgen concen trations in utero, wolffian structures are completely absent in those having mutations that yield premature stop codons or frameshift mutations that prevent androgen receptor expression. 435 The normal testes produce normal amounts of AMH, which effectively suppress müllerian duct develop ment. Therefore, the uterus and fallopian tubes typically are absent, although vestiges also have been observed. 436 The tes tes may be found in the abdomen but, more commonly, are located in the inguinal canals or in the labia majora, probably because AMH normally mediates their descent; their histol ogy resembles that of undescended testes, with a normal or increased number of Leydig cells and absent spermatogene sis. The external genitalia are clearly female, due to androgen insensitivity, although the labia and clitoris may be slightly underdeveloped. The vagina is either blind and short or alto gether absent, reflecting only the developmental contribu tion of the urogenital sinus. Axillary and pubic hair is scant or absent, again due to androgen insensitivity. Breast devel opment is female and may be enhanced, probably due to the action of estrogen unopposed by the actions of androgens. The overall body habitus also is female, although the average height and weight of women with complete AIS is greater than that of normal women. 437,438 Women with complete AIS also exhibit normal female sexual orientation and maternal instincts. 439,440 In women with complete AIS, serum testosterone con centrations are normal or moderately increased, LH levels are increased, and the serum FSH usually is in the normal range. The increase in LH levels results from resistance to the negative feedback effects of androgens at the hypotha lamic-pituitary level; both the frequency and amplitude

of pulsatile LH secretion are increased in patients with complete AIS. 441,442 Whereas estrogen production (estrone and estradiol) also is increased by approximately 70% over that in normal men, DHT production is decreased due to the absence of male urogenital tissues, which are the primary site of DHT production. 367 The diagnosis of complete AIS should be suspected in girls with inguinal hernias or labial masses 443 and in women with primary amenorrhea. In the adolescent or adult, diag nosis usually is not difficult. Most patients with complete AIS present with primary amenorrhea, normal breast development, absent or scant pubic and axillary hair, a short vagina, and an absent cervix and uterus; a serum tes tosterone in the normal male range and a 46,XY karyotype establish the diagnosis. Whereas males with defects in tes tosterone biosynthesis can have a female phenotype, breast development does not occur. Patients with complete AIS generally are easily differentiated from those with mül lerian agenesis who have normal amounts of pubic and axillary hair, normal female serum testosterone concen trations, and a 46,XX karyotype. The location of the testes usually can be defined by ultrasonography or MRI. 444 The clinical management of complete AIS includes appro priate hormone therapy, creation of a functional vagina, gonadectomy to prevent tumorigenesis in cryptorchid testes, and psychological support, all discussed in detail in Chapter 10 (Amenorrhea) and summarized here. Estrogen treatment is indicated when gonadectomy is performed after puberty is completed, or at the time of expected puberty if the gonads were removed before puberty. Options for creation of a functional vagina include progressive vaginal dilation and vaginoplasty. The short but distinct vagina observed in most patients with complete AIS facilitates efforts with vaginal dilation, 323,324,369 but surgical treatment also produces good results, when necessary. 370 In patients with complete AIS, gonadectomy generally is best delayed until after puberty is completed (approximately age 16–18) because puber tal development generally proceeds more smoothly in response to endogenous hormone production and because the overall risk for tumor development is quite low (5–10%), particularly before puberty. 431,445–447 Psychological support should be directed toward reinforcement of their female gender identity and include truthful education for both patient and parents (Figure 8.12) .

Androgen Insensitivity Syndromes

Complete androgen insensitivity

Incomplete androgen insensitivity

Reifenstein syndrome

Infertile male

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Female

Male

Phenotypic Spectrum

FIGURE 8.12