I. Introduction IN 1953 lohn Morris, an obstetrician at Yale University, reported a series of 82 individuals (80 cases collated from the literature and two cases of his own) who had a female phenotype despite the presence of bilateral testes (1). Since his initial description, studies of the endocrinology, pathophysiology, biochemistry, and molecular biology of the androgen insensitivity syndrome (AIS) have provided insights into the role of androgens in male sex differentiation, the mechanisms of androgen action, and aspects of the structure/function relationships of the androgen receptor. AIS is an archetypal example of a hormone resistance disorder. Androgens are secreted by the testes of these 46,XY individuals in normal or increased amounts; however, due to defective androgen receptor (AR1) function, there is loss of target organ response to the hormone, and the effects of androgens are reduced or absent. Clinical disorders of the AR are reported far more commonly than resistance disorders of other m...

Androgen receptor defects : Historical, clinical, and molecular perspectives

The androgen receptor (AR) mediates the actions of male sex steroids. Human AR genomic DNA was cloned from a flow-sorted human X chromosome library by using a consensus nucleotide sequence from the DNA-binding domain of the family of nuclear receptors. The AR gene was localized on the human X chromosome between the centromere and q13. Cloned complementary DNA, selected with an AR-specific oligonucleotide probe, was expressed in monkey kidney (COS) cells and yielded a high-affinity androgen-binding protein with steroid-binding specificity corresponding to that of native AR. A predominant messenger RNA species of 9.6 kilobases was identified in human, rat, and mouse tissues known to contain AR and was undetectable in tissues lacking AR androgen-binding activity, including kidney and liver from androgen-insensitive mice. The deduced amino acid sequence of AR within the DNA-binding domain has highest sequence identity with the progesterone receptor.

https://science.sciencemag.org/content/sci/240/4850/327.full.pdf

Cloning of human androgen receptor complementary DNA and localization to the X chromosome.

Publisher Summary This chapter discusses some of the physiological and pathophysiological actions of hormones in controlling the development of the sexual phenotypes of eutherian mammals, the American opossum, and the chicken. The importance of steroid metabolites formed in extraglandular tissues to overall sexual development is also emphasized. Chromosomal sex determines gonadal sex, and gonadal sex determines phenotypic sex. A minimum of 19 genes are implicated in sexual differentiation in man. Some of these are located on sex chromosomes and some on autosomes. Thus, the relatively simple mechanism that imposes male development on the indifferent embryo requires the participation of many genes common to both the male and female embryo. Determinants on the Y chromosome cause the indifferent gonad to develop into a testis. Two hormonal secretions from the fetal testis, mullerian-inhibiting substance and testosterone, then transform the indifferent urogenital tract into one characteristic of the male. Mullerian-inhibiting substance secreted by the Sertoli cells causes regression of the female duct system.

https://science.sciencemag.org/content/sci/211/4488/1278.full.pdf

The hormonal control of sexual development

Sexual dimorphism in selected extragenital tissues is described with emphasis on the molecular basis of the differences. Testosterone rather than 5 alpha-dihydrotestosterone appears to be the major intracellular androgen in organs other than skin and reproductive tract, but other steroid metabolites and their receptors are required to produce the diverse tissue differences observed in males and females. There is also evidence that multiple hormones from several endocrine glands are required to act in concert with androgens to produce and maintain their effects. Although many of the consequences of sexual dimorphism, such as body size and strength, have been evident for centuries, other differences between males and females such as disease incidence, response to drugs and toxins, and the metabolism and assimilation of dietary constituents have only recently been discovered.

Testosterone: a major determinant of extragenital sexual dimorphism

Binding properties of androgen receptors. Evidence for identical receptors in rat testis, epididymis, and prostate.

Publisher Summary This chapter discusses androgen metabolism and the mechanism of action in male pseudohermaphroditism. It has been found that testosterone is the major androgen secreted into the blood of most mammals and that this steroid has biological actions on many tissues. As animals with testicular feminization cannot respond to androgens in utero, tissues, such as prostate, Wolffian duct derivatives, and external genitalia, do not differentiate, and the tfm animal develops as a male pseudohermaphrodite. Male pseudohermaphroditism resembling testicular feminization also develops in animals that are deprived of androgens in utero by one of the several mechanisms, including castration, defective testosterone synthesis, and exposure to pharmacologic agents that either block androgen biosynthesis in the testis or androgen action at the end organ. When the gonaducts and external genitalia fail to undergo androgen-dependent differentiation in utero, they do not develop into a normal reproductive tract when subsequently exposed to large doses of androgens. Thus, certain tissues may acquire insensitivity to androgens during differentiation. The chapter also discusses ultrastructural examination of the interstitial area of vet rat testes that demonstrates increased peritubular connective tissue. The interstitial tissue consisted predominantly of fibroblasts and a few peritubular sheath cells.

Androgen metabolism and mechanism of action in male pseudohermaphroditism: a study of testicular feminization.

Although it has long been known that the lack of androgen dependent differentiation in patients with testicular feminization is secondary to end organ insensitivity, the molecular basis of this genetic disorder has not been elucidated. In the present report a rodent model for testicular feminization is described. The Stanley-Gumbreck pseudohermaphroditic rat has an inherited disorder characterized by a female phenotype, a male genotype and tissue insensitivity to androgens. Even though male differentiation does not occur when these animals are treated with physiologic doses of testosterone, some androgen dependent growth is evident when 100-fold larger doses of testosterone are given. Studies of androgen metabolism in the psuedohermaphroditic animals indicate that testosterone transport and metabolism to dihydrotestosterone are normal. However, intranuclear retention of dihydrotestosterone is defective. These findings suggest that the androgen insensitivity of the pseudohermaphroditic rat is due to an inherited abnormality of a regulatory protein which renders the nucleus of the cell incapable of concentrating androgens at their proposed intracellular site of action. The pseudohermaphroditic rats also have a defect of testicular and adrenal steroid synthesis in addition to the androgen insensitivity. The relation of these two abnormalities in rat and in man are discussed.

Blackburn Wr

Papers

Androgen metabolism and mechanism of action in male pseudohermaphroditism: a study of testicular feminization.

Testosterone metabolism in the androgen-insensitive rat: a model for testicular feminization.