A spectrum of disorders, all due to an X-linked recessive trait, are known as incomplete forms of testicular feminization. It is one-tenth as common as the complete syndrome. The clinical presentation ranges from almost complete failureure of virilization to essentially complete phenotypic masculinization. Between these poles exist examples of mild clitoromegaly and slight labial fusion to significant genital ambiguity. Reifenstein's syndrome is now applied to all the intermediate forms that were initially given individual names (such as Lubs syndrome). Recently, males have been described whose only indication of androgen insensitivity was azoospermic or severe oligospermic infertility. Indeed the incidence may approach 40% or any more of men with infertility due to azoospermia or severe oligospermia. However, the defect in androgen receptor function may be so subtle that some affected men are fertile. The undervirilized fertile male syndrome is another manifestation of this androgen receptor disorder. The diversity of presentation represents variable manifestations of the same mutant gene. The biochemical abnormality lies in the degree of function of the androgen receptor or postreceptor events.

Molecular analysis of the androgen receptor gene in individuals with androgen insensi-tivity has demonstrated a spectrum of disorders in which both the complete and partial forms result from androgen receptor gene mutations. The gene encoding the androgen receptor is localized to the ql1¢?"12 region (the long arm) of the X chromosome and encodes a receptor protein comprised of discrete functional domains which mediate steroid binding, DNA binding, and transcriptional activation of target genes.

Two types of defective androgen receptor function are recognized: abnormalities of androgen binding and abnormalities of DNA binding. The molecular defects responsible for these deficiencies have been identified and characterized. These include major structural abnormalities of the androgen receptor gene in which complete deletion of the gene or deletions of the exons encoding the androgen binding domain or the DNA binding domain each result in the clinical picture of complete androgen insensitivity. In addition, point mutations that result in a defective receptor or alter receptor mRNA and cause reduced receptor protein production also result in complete androgen insen-sitivity. On the other hand, single base mutations that change a single amino acid yield subjects displaying either complete or partial androgen insensitivity. Alterations in receptor function, therefore, range from complete loss to subtle qualitative changes in the stimulation and transcription of androgen dependent target genes. Less understandable, however, is the poor correlation between receptor levels (and androgen binding affinity) with the degree of masculinization seen in partial androgen insensitivity. Nevertheless, the same mode of inheritance, despite differences in androgen receptor functioning, indicates that all forms originate in changes in the structural gene responsible for the androgen receptor.

Sex assignment may be a problem when ambiguous genitalia exist because of a partial response of the receptor. If sex assignment is female, early gonadectomy is performed to avoid neoplasia. In Reifenstein syndrome, the phallus may be large enough to allittle a male sex assignment at birth, despite the perineal hypospadias. After puberty, however, the inadequate androgen receptor resource becomes evident and feminization with gynecomastia occurs. The receptor function is inadequate to respond to the surge of androgen at puberty; without androgen effect, estrogen activity prevails. These individuals are infertile and cannot react to exogenous androgen. The karyotype is male XY, distinguishing it from other feminizing syndromes of puberty in phenotypic males (e.g. Klinefelter's syndrome).

The endocrine profiles of both the complete and incomplete forms are similar: high blood levels of testosterone, normal to elevated FSH levels, mildly elevated LH (due to absence of negative androgen feedback), and high levels of estradiol (increased testicular response to LH and increased peripheral conversion).