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

Non-neoplastic diseases of the testis

A 46,XY infant with perineoscrotal hypospadias and microphallus was identified in a family in which seven individuals have severe hypospadias that is inherited in a pattern compatible with an X-linked defect. The infant had small testes that were palpable in the labioscrotal folds, the proximal urethra was male in character, and there was no vagina. Serum testosterone rose from 0.5 to 5.1 nmol/L in response to hCG, and there was a negligible clinical response to a short term course of testosterone enanthate. A clinical diagnosis of male pseudohermaphroditism due to androgen resistance was made. Studies in cultured genital skin fibroblasts disclosed normal 5α-reductase activity, a normal amount of high affinity dihydrotestosterone binding, and normal up-regulation of androgen receptors when monolayers were incubated with dihydrotestosterone or mibolerone. Fibroblast cytosol preparations contained a normal 7–8S sedimenting peak of androgen binding. However, androgen binding in monolayers decreased 60% when ...

Androgen Resistance Associated With a Qualitative Abnormality of the Androgen Receptor and Responsive to High Dose Androgen Therapy

Publisher Summary The undifferentiated gonad is formed from three sources—(1) coelomic epithelium, (2) underlying mesenchyme, and (3) primordial germ cells. The primordial germ cells develop into spermatogonia in the male and ova in the female; the sex cords become either seminiferous tubules or primary ovarian follicles; and the mesenchymal cells form either the Leydig cells or the theca and stromal cells in the female. Ovarian development from the undifferentiated gonad does not begin until approximately 50 days of gestation. The external genitalia, like the gonad, develop from common primordia: urogenital tubercle, urogenital swellings, and urogenital folds. Testicular differentiation occurs between the seventh and eighth week of intrauterine life. This chapter describes incomplete forms of androgen insensitivity. The known etiologic causes for male pseudohermaphroditism or incomplete masculinization can be divided into three basic categories—(1) the disorders of testicular differentiation and development, (2) the disorders of testicular function, and (3) the disorders of function at the androgen-dependent target areas.

Sexual Differentiation: Normal and Abnormal

A family is described in which gynecomastia and undervirilization in five men (four of whom have fathered children) were inherited in a manner compatible with an X-linked defect. Three members from whom blood could be obtained had supranormal serum testosterone and normal LH and FSH levels. One man had severe oligospermia with decreased motility, and one had normal sperm density and motility. In fibroblasts cultured from genital skin biopsies from two of the men, the levels of androgen receptor and affinity of binding of receptor to dihydrotestosterone were normal. However, androgen binding i n fibroblast monolayers was thermolabile, up-regulation of receptor levels did not occur after prolonged incubation of mono-layers with dihydrotestosterone or methyltrienolone, and dissociation rates at 37 C were increased with the synthetic androgen mibolerone. In addition, in cytosol preparations the androgen receptor protein was unstable. This disorder probably represents the most subtle functional abnormality of ...

A mutation of the androgen receptor associated with partial androgen resistance, familial gynecomastia, and fertility.

Four postpubertal 46 XY male patients with an inherited form of bilateral gynecomastia were studied to delineate the nature of the disease. Normal serum FSH and moderately elevated serum LH with concomitantly increased circulating levels of testosterone (T) and estradiol (E2) were found persistently in all cases in blood samples drawn at frequent intervals. LRH pituitary stimulation resulted in an exaggerated LH response and a normal FSH response. Chronic administration of T-cyclopentylate failed to decrease serum LH levels. The peripheral conversion rate of androstenedione to estrone was within normal limits. All patients had low ejaculate volumes with relatively normal spermatozoa counts. Testicular biopsies revealed normal Leydig cells and complete spermatogenesis. Urological examination disclosed that the prostate gland was extremely small. The breast tissue demonstrated the presence of tubular structures as well as the specific binding of [3H]T and [3H]dihydrotestosterone (DHT), which was inhibited by nonlabeled T, DHT, E2, and progesterone, but not by cortisol. The pedigree suggested a recessive X-linked inherited trait. A patient with a nonfamilial form of gynecomastia served as a control in all studies. These data were interpreted as demonstrating that this inherited type of gynecomastia represents the mildest expression of the androgen resistance syndromes and, therefore, belongs to the type 1 form of familial incomplete male pseudohermaphroditism.

Gynecomastia as a familial incomplete male pseudohermaphroditism type 1: a limited androgen resistance syndrome.

Estrogenic effects of the synthetic aminoestrogen 17β-(5-hydroxy-1-pentylamino)-1,3,5(10)-estratrien-3-ol (pentolame)

A 20-yr-old phenotypical male with a 46, XY chromosome complement, a hernia uteri inguinale, and bilateral anorchia was studied. Eunochoidal body proportions, infantile type of male external genitalia with empty scrotum, underdeveloped sexual characteristics, and delayed bone age suggested the existence of inadequate testicular function. Extremely low levels of circulating testosterone and a lack of response to hCG stimulation was found. Persistently elevated blood levels of LH and FSH with an adequate pituitary response to an iv bolus of synthetic LRH was demonstrated, thus indicating inadequate endocrine gonadal function as well as functional integrity of the hypothalamic-pituitary unit. At the time of an inguinal hernioplasty, a small but well developed uterus was removed. No gonads were found within the true pelvis, inguinal canals, or along the anatomical pathways of testicular descent. A cord-like structure found in the left inguinal canal contained only fibrous tissue without gonadal elements. It i...

Fernando Larrea

Papers

Gynecomastia as a familial incomplete male pseudohermaphroditism type 1: a limited androgen resistance syndrome.

Estrogenic effects of the synthetic aminoestrogen 17β-(5-hydroxy-1-pentylamino)-1,3,5(10)-estratrien-3-ol (pentolame)

Anorchia and Persistent Müllerian Duct: A Variant of the Embryonic Testicular Regression Syndrome*