Peripheral resistance to androgens occurs with 2 basic defects: (1) a deficiency of androgen production through the absence of 5α-reductase or (2) a deficiency in the androgen receptor. In general, these conditions are a consequence of single gene deletions.

Figure 42-13 shows the algorithm of normal male development. Androgen insensitivity syndromes stem from aberrations in this pathway.

A. 5α-Reductase Deficiency
5α-Reductase deficiency results in normal development of the testes and wolffian duct structures (internal genitalia) but ambiguous external genitalia. The ambiguity results from an inborn deficiency of the 5α-reductase enzyme that converts testosterone to DHT in androgen-sensitive tissues like the prostate, seminal vesicle, and external genitalia. Thus far, 29 mutations have been described in the culprit enzyme. The diagnosis is made by measuring the ratio of testosterone metabolites in urine and confirmed by finding decreased 5α-reductase in genital skin fibroblasts. Spermatogenesis has been described in descended testes; however, fertility has not been reported in these patients. The lack of fertility may be due largely to functional abnormalities of the external genitalia.

B. Androgen Receptor Deficiency
Androgen receptor deficiency is an X-linked genetic condition marked by resistance to androgens. The androgen receptor, a nuclear protein, is absent or functionally altered such that testosterone or DHT cannot bind to it and activate target cell genes. Since androgens have no effect on tissues, both internal and external genitalia are affected. Fertility effects depend on the specific receptor abnormality. Some patients are 46,XY males with complete end-organ resistance to androgens. They have female external genitalia with intra-abdominal testes. Testes show immature tubules and the risk of testis cancer is elevated: Tumors will develop in 10-30% of patients without orchiectomy. Fertility is absent. Patients with mild receptor defects may present as normal-appearing infertile men. Spermatogenesis may be present, although impaired. It is unclear exactly how common this occurs in infertile men.