ANDROGEN PRODUCTION AND ANDROGEN ACTION
In women, androgens are produced in the adrenal glands, the ovaries, and adipose tissue, where there is extraglan-dular production of testosterone from androstenedione. The following three androgens may be measured when evaluating a woman with hirsutism and virilization.
· Dehydroepiandrosterone (DHEA): a weak androgensecreted principally by the adrenal glands. (This is gen-erally measured as dehydroepiandrosterone sulfate [DHEA-S] because of its longer half-life, making it a more reliable measure.)
· Androstenedione: a weak androgen secreted in equalamounts by the adrenal glands and ovaries.
· Testosterone: a potent androgen secreted by theadrenal glands and ovaries and produced in adipose tis-sue from the conversion of androstenedione.
The sites of androgen production and proportions pro-duced are presented in Table 36.1. In addition, testosterone is also converted within hair follicles and within genital skin to dihydrotestosterone (DHT), which is an androgen even more potent than testosterone. This metabolic con-version is the result of the local action of 5α-reductase on testosterone at these sites. This is the basis for constitu-tional hirsutism, which is discussed later.
Adrenal androgen production is controlled by recip-rocal feedback regulation through pituitary secretion of adrenocorticotropic hormone (ACTH). ACTH stimulates the adrenal cortical production of cortisol. In the metabolic sequence of cortisol production, DHEA is one precursor hormone.
In enzymatic deficiencies of adrenal steroidoge-nesis (21-hydroxylase deficiency and 11β-hydroxylase defi-ciency), DHEA accumulates and is further metabolized to androstenedione and testosterone. The flow of adrenal hormone production is shown in Figure 36.2.
Ovarian androgen production is regulated by luteiniz-ing hormone (LH) secretion from the pituitary gland. LH stimulates theca-lutein cells surrounding the ovarian fol-licles to secrete androstenedione and, to a lesser extent, testosterone. These androgens are precursors for estrogen production by granulosa cells of the ovarian follicles. In conditions of sustained or increased LH secretion, andro-stenedione and testosterone increase.
Extraglandular testosterone production occurs in adi-pocytes (fat cells) and depends on the magnitude of adrenal and ovarian androstenedione production. When andro-stenedione production increases, there is a dependent increase in extraglandular testosterone production. When a woman becomes obese, the conversion of androstene-dione to testosterone is increased.
Testosterone is the primary androgen that causes increased hair growth, acne, and the physical changes associated with viril-ization. After testosterone is secreted, it is bound to a carrierprotein—sex hormone-binding globulin (SHBG)—and primarily circulates in plasma as a bound steroid hormone. Bound testosterone is unable to attach to testosterone receptors and is, therefore, metabolically inactive. Only a small fraction (1% to 3%) of testosterone is unbound (free). This small fraction of free hormones exerts the effects. The liver produces SHBG. Estrogens stimulate hepatic produc-tion of SHBG. Greater estrogen production is associated with less free testosterone, whereas decreased estrogen pro-duction is associated with increased free testosterone. Therefore, measurement of total testosterone alone may not reflect the amount of biologically active testosterone.
Testosterone receptors are scattered throughoutthe body. For the purpose of this discussion, testosterone receptors are considered only in hair follicles, sebaceous glands, and genital skin. Free testosterone enters the cytosol of testosterone-dependent cells. There it is bound to a testosterone receptor and carried into the nucleus of the cell to initiate its metabolic action. When testosterone is exces-sive, increased hair growth, acne, and rugation of the genital skin is seen. Some individuals have increased 5α-reductasewithin hair follicles, resulting in excessive local production of DHT.
Excess androgen production has several causes, includ-ing polycystic ovarian syndrome, testosterone-secreting tumors, adrenal disorders, and iatrogenic and idiopathic causes. Figure 36.3 presents a scheme for the evaluation of hirsutism that encompasses the various conditions that lead to this condition.