Androgens in Health and Disease.pdf - E Library

104 McPhaul
on the Y chromosome determines whether the primordial gonad will develop as a testis
or as an ovary (1). This functional differentiation of the gonad determines the subsequent
events in mammalian sexual development (2,3).
In the male embryo, the steroid and polypeptide hormones secreted by the testis
mediate the development of the male phenotype, which requires the combined actions
of testosterone, 5α-dihydrotestosterone, and müllerian-inhibiting substance (MIS). At
approximately the ninth week of development, the Leydig cells of the testes begin to
secrete to steroid hormones. The formation of both testosterone and its 5α-reduced
metabolite, 5α-dihydrotestosterone, are required to induce the virilization of the internal
and external genitalia. In response to these androgens, the external genitalia virilize
with the enlargement of the phallus and fusion of the genital ridges to form the scrotum.
The wolffian ducts grow to form the pelvic portion of the urogenital sinus and
give rise to the seminal vesicles and the epididymis. During this same period, the
Sertoli cells of the testes secrete the polypeptide hormone MIS, which mediates the
regression of the müllerian duct-derived structures, including the uterus and fallopian
tubes (4). In the absence of the actions of these testicular hormones, the uterus and fallopian
tubes develop and the upper vaginal segments and urogenital swellings fail to fuse.
Defects in a number of genes that act to alter normal sexual development have been
identified and it is clear that defects in male development can be caused by any abnormality
that impairs the development of the testes, the normal synthesis of androgen or
MIS, or the capacity of tissues to respond to these hormones (3).
PHENOTYPIC SPECTRUM OF ANDROGEN RESISTANCE CAUSED
BY MUTATIONS OF THE HUMAN ANDROGEN RECEPTOR
Naturally occurring defects of the human androgen receptor have been identified far
more frequently than defects in other members of the nuclear-receptor family. This is
likely due to several unique characteristics of the androgen receptor (AR) and the processes
that it regulates. First, the androgen receptor gene is located on the X chromosome.
As such, normal 46,XY males inherit only a single copy of the gene and
disturbances of AR function will be evident phenotypically. Second, although many
important processes are modulated by the androgen receptor (virilization of the internal
and external male structures, maintenance of bone density, and spermatogenesis), these
functions are not required for life. For this reason, even individuals in whom AR function
is completely defective are viable and available for ascertainment. Finally, the phenotypes
characteristic of androgen insensitivity are often evident at birth (ambiguities of
sexual development) or detected at puberty (complete testicular feminization) and precipitate
endocrine or genetic analyses.
As a result of these characteristics of the androgen receptor, a wide range of individuals
of varying phenotypes are available for study (5,6). In individuals in whom the AR
is nonfunctional or is not expressed, internal and external male structures fail to develop.
This syndrome has been variously termed “complete testicular feminization” (7) or
“complete androgen insensitivity.” Externally, such patients appear as normal females
with developed breasts and normal external female genitalia. Decreased or absent axillary
and pubic hair represents a potential clue to the nature of the underlying disorder.
Careful evaluation of such individuals will identify testes located either intraabdominally
or within the labia majora. Although the tissues of such individuals are incapable of