Taylor_Speroff's Clinical Gynecologic Endocrinology and Infe

Chapter 8 • Normal and Abnormal Sexual Development 283

normally descended but exhibit either an absent germi nal epithelium or spermatogenic arrest. They have normal amounts of body hair and some have gynecomastia. The prevalence of partial androgen insensitivity in men with azoospermia or severe oligospermia is unknown but may be as high as 10%. 455,456 Still other men with partial androgen insensitivity are undervirilized but fertile 457,458 (Table 8.4) . Serum hormone levels in phenotypic women with incom plete AIS, in men with Reifenstein syndrome, and in infertile men with partial androgen insensitivity are similar to those in individuals with complete AIS. 450,454,459 In undervirilized fertile men with partial androgen insensitivity, testosterone concentrations are elevated but LH levels are in the normal range. 457 Whereas major AR gene deletions and premature ter mination codons have been identified only in patients with complete AIS, point mutations resulting in amino acid sub stitutions in the androgen receptor can cause the entire spec trum of phenotypes associated with androgen insensitivity. Approximately 80% of amino acid substitutions are located in the hormone-binding domain of the receptor. Most of the remainder is in the DNA-binding domain, permitting nor mal androgen binding but preventing activation of andro gen-responsive genes. 460 How or why different mutations or even the same mutation can result in varying degrees of androgen insensitivity is poorly understood but may relate to differences in the timing of receptor expression, differ ences in testosterone synthesis or metabolism, differences in transcription factors, or polymorphisms that influence the effect of a given mutation. 460–463 In some, androgen resis tance results not from a mutation in the androgen receptor but from a defective coactivator protein required for normal function of the androgen-androgen receptor complex. 464,465 In others with somatic mosaicism, the androgen receptor is normal in some, but not all, tissues. 466,467 Incomplete AIS often presents in newborns, as ambigu ous genitalia. In adults, the diagnosis generally is not dif ficult. Affected individuals present as phenotypic women with mild virilization of the external genitalia (otherwise appearing the same as women with complete AIS) or as

Incomplete Androgen Insensitivity Syndromes (Table 8.4) Incomplete AIS describes a variety of disorders that result from defects in androgen action less severe than those asso ciated with complete AIS. The spectrum of clinical pre sentations can vary from phenotypic females with mild virilization to undervirilized males who may be fertile or infertile, even within one affected family. 448,449 Phenotypic women with mild virilization are at one end of the clinical spectrum of incomplete or partial AIS. They resemble women with complete AIS but have normal body hair, external genitalia exhibiting partial fusion of the labio scrotal folds, with or without clitoromegaly, and they both virilize and feminize at puberty. They have no müllerian structures (due to the actions of AMH), underdeveloped male internal genitalia (epididymides, vasa deferentia, semi nal vesicles, ejaculatory ducts), and testes similar to those with complete AIS. Axillary and pubic hair is normal. Breast development, the overall body habitus, and gender identity are distinctly female. The phenotype is approximately one tenth as common as that of complete AIS. 431 Reifenstein syndrome describes individuals having a predominantly male phenotype who are undervirilized. 450 The most common clinical presentation is an infertile man with a bifid scrotum and perineoscrotal hypospadias. However, the appearance of the external genitalia can vary widely, from a microphallus with a normal penile urethra to complete failure of scrotal fusion. The internal genitalia are male but not completely developed; müllerian structures are absent and, usually, so too is the prostate. The testes can be cryptorchid or normally descended and small and exhibit a maturation arrest in spermatogenesis. Men with Reifenstein syndrome have normal axillary and pubic hair but, typically, little or no chest or facial hair. They have a male body habi tus but usually develop gynecomastia at the time of puberty. Gender identity corresponds with the sex of rearing, and sexual dysfunction is common in those raised as males. 451–453 Some men with partial androgen insensitivity are only mildly undermasculinized and infertile. 454 Their inter nal and external genitalia are normal and their testes are

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TABLE 8.4 Androgen Insensitivity Syndromes Complete Incomplete

Reifenstein

Infertile

Inheritance

X-linked recessive

X-linked recessive

X-linked recessive

X-linked recessive

Spermatogenesis

Absent

Absent

Absent

Decreased

Müllerian Copyright © 2019 Wolters Kluwer, Inc. Unauthorized reproduction of the content is prohibited. Absent Absent Absent Absent

Wolffian

Absent

Underdeveloped

Male

Male

External

Female

Female (clitoromegaly)

Male (hypospadias)

Male

Breasts

Female

Female

Gynecomastia

Male (gynecomastia)