During the course of purifying nerve growth factor from the submaxillary gland of the mouse, Cohen (1960) and Levi-Montalcini and Cohen (1960) noticed that daily injections of certain gland extract fractions into newborn mice produced developmental changes that could not be ascribed to nerve growth factor. These changes included precocious opening of the eyelids (7 days compared to the usual 14 days) and a similar early eruption of the incisors. Using these gross anatomical changes as an assay, Cohen (1962) proceeded to isolate the active factor — a polypeptide which he termed epidermal growth factor (EGF).

Epidermal growth factor

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.

MCF-7: A human breast cancer cell line with estrogen, androgen, progesterone, and glucocorticoid receptors

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

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.

The effects of progestins (0.1, 1.0, 6-10 mg/day) alone and in combination with testosterone (0.1 mg/day) on immunoreactive epidermal growth factor (EGF) concentrations in submaxillary glands from normal and androgen-insensitive (tfm/y) mice were studied. Since androgens are known to stimulate increased EGF levels, the responses to progestins were interpreted as androgenic, synandrogenic or antiandrogenic if they simulated, potentiated or inhibited androgen response, respectively. Of the progestins studied, medroxyprogesterone acetate (MPA) caused the greatest androgenic response when given alone; 10 mg produced a greater than 40-fold increase of EGF over control values. Lesser responses were achieved when progesterone or megestrol acetate (Meg Ac) were given alone. Cyproterone acetate (Cyp Ac) had no androgenic activity when administered alone and acted as a potent antiandrogen at all doses used. Progesterone and Meg Ac had weak antiandrogenic activity. The only synandrogenic response elicited was with a high dose (10 mg) of progesterone caproate. Neither MPA nor progesterone alone had any effect on EGF levels in tfm/y mice. These patterns of response differ from those seen in mouse kidney. The data indicate that progestins as a class are capable of androgenic, synandrogenic and antiandrogenic action in the mouse submaxillary gland, but that no single progestin is capable of all three actions. Since tfm/y mice lack a functional androgen receptor, the absence of EGF response in these mice to progestins as well as androgens suggest that the action of progestins may be mediated by the androgen receptor in the submaxillary gland.

The effect of progestins on submaxillary gland epidermal growth factor: demonstration of androgenic, synandrogenic and antiandrogenic actions.

Studies on Leydig Cell Physiology and Pathology: Secretion and Metabolism of Testosterone

Interstitial cell carcinoma of the testis is a singularly rare steroid-producing cancer. Of the seven reported cases (1-7), urinary 17-ketosteroid (17KS) excretion was high in the four cases in which it was measured. Abelson, Bulaschenko, Trommer, and Valdes-Dapena (7) fractionated the urinary 17-ketosteriods and corticoids in one recently reported case. There is, however, no comprehensive study of either the production of androgens or related steroids by this tumor. Wehave had the opportunity to study a patient with metastatic interstitial cell carcinoma, and we have examined the androgens and several related steroids. From these data, we have concluded that interstitial cell carcinoma resembles virilizing adrenal carcinoma in its pattern of biosynthesis of C-19 steroids and 21deoxypregnane analogues. The high testosterone 1

/pdf/metabolism-of-testoterone-and-related-steroids-in-metastatic-3hfob5nn03.pdf

Metabolism of testoterone and related steroids in metastatic interstitial cell carcinoma of the testis.

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.

Bardin Cw

Papers

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

The effect of progestins on submaxillary gland epidermal growth factor: demonstration of androgenic, synandrogenic and antiandrogenic actions.

Studies on Leydig Cell Physiology and Pathology: Secretion and Metabolism of Testosterone

Metabolism of testoterone and related steroids in metastatic interstitial cell carcinoma of the testis.

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