Androgen dynamics in women

In women, androgens have been both celebrated and cursed as the hormones of "aggression and anger" and as "fuel for passion". In reality, while the effects of testosterone in men have been widely studied and a clear testosterone deficiency state identified, investigation into the role of testosterone in women is a far more recent venture that is only now yielding fruit. Until recently, circulating androgens in women have simply been considered either by-products of adrenal cortical or ovarian estrogen production, with little inherent clinical relevance. As a result androgen dynamics in women, both in their reproductive and post-reproductive years, are poorly understood. Surprisingly, if one considers the contribution of the adrenal cortex, androgens circulate in levels far exceeding any other steroid hormone in women, as seen in Table 17.1; testosterone itself circulates in levels usually

Table 17.1 Androgens in women: levels, potencies, and bioconversion

Androgen

Serum Level

Potency (rel. to testosterone)

DHEAS

200 ^g/dl

0.001

DHEA

500 ng/dl

0.01

A4A

100 ng/dl

0.1

Testosterone

50 ng/dl

1.0

DHT

5 ng/dl

5

exceeding those seen with serum estradiol (E2), a hormone of undisputed significance in females. The intriguing possibility is thus raised that perhaps androgens serve a fundamental physiologic purpose in women; by extension, a deficiency of these hormones may result in adverse consequences, possibly rectified by testosterone replacement.

The three sources from which androgens in women arise from are the adrenal cortex, the ovarian theca (and to a lesser degree, ovarian stromal cells), and by peripheral bioconversion of circulating androgenic prohormones. The adrenal gland produces about 95% of circulating serum dehydroepiandrosterone (DHEAS, the production rate of which is 19 mg/day in young women) and 50% of dehydroepiandrosterone (DHEA, the production rate of which is 16 mg/day). The rest of circulating DHEA is produced by peripheral conversion of DHEAS (30%) in addition to a small ovarian contribution (20%) (Burger 2002). DHEAS circulates unbound to protein, has virtually no androgenic action, and has a half-life of 10 hours; it serves as a circulating prohormone for production of DHEA and the more potent downstream androgens both in the circulation and in peripheral tissues. Twenty-eight percent of DHEA comes from hydrolysis of DHEAS, and about 31% of DHEA is sulfated to DHEAS (Haning etal. 1989; Bird etal. 1978). The production of both DHEAS and DHEA is controlled by adrenocortical reticularis cell stimulation by adrenocorticotropin (ACTH) and negative feedback by circulating cortisol, as well as most probably by other as of yet unidentified adrenal androgen stimulating factors.

Androstenedione [ A4A] is produced in about equal portions by both the adrenocortical cells and by the thecal cells of the ovary. Additionally, about 40% of A4A is produced by peripheral bioconversion of DHEA (Burger 2002). The ovary produces both A4A and testosterone under tropic stimulation by leutinizing hormone (LH) with negative feedback by serum E2, with lesser contributions from testosterone and progesterone. The circulating level of A4A is subject to significant short-term variation secondary to the diurnal nature of its adrenal contribution as well as the variation in ovarian contribution over the menstrual cycle.

Fig. 17.1 Androgen dynamics in premenopausal women.

Testosterone, the most clinically relevant circulating androgen, has both an adrenal contribution (about 25%) and an ovarian contribution (about 25%), but is mostly produced by peripheral bioconversion from circulating A4A (Burger 2002). By virtue of its relatively large ovarian contribution, serum testosterone is probably the best measure of ovarian androgen production. Dihydrotestosterone (DHT) is produced almost exclusively in target tissues by 5a-reductase action on circulating testosterone; circulating levels are negligible and felt to be largely a reflection of spillover from the primarily intracrine action of this hormone. The circulatory androgen dynamics in premenopausal women are illustrated in Fig. 17.1.

Androgen dynamics in women are subject to three temporal phenomena: ovarian cyclicity, the decline of the adrenal androgens with age (adrenopause), and ovarian follicular depletion with resultant menopausal transition. Throughout the course of the normal ovulatory cycle, changing patterns of LH secretion includingamid-cycle LH surge result in varying ovarian follicular thecal cell stimulation of testosterone and A4A production. In turn, the thecal A4A acts as a substrate for granulosa cell estrogen production. These changes result in a mid-cycle peak in circulating A4A and testosterone production (which parenthetically has been related to a mid-cycle increase in female-initiated sexual activity).

With follicular depletion and the onset of the menopausal transition, ovarian E2 production declines precipitously, leading to loss of negative feedback at the pituitary and the hypothalamus. In response, circulating serum LH and follicle stimulating hormone (FSH) levels increase dramatically and the circulating LH drives the ovarian theca/stroma to produce increasing amounts of testosterone (Adashi 1994). Thus, the concept that the ovary undergoes endocrine senescence at

to 2

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2024

25- 3029 34

3539

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5054

5559

60- 6564 69

1519

2024

25- 3029 34

3539

40- 4544 49

5054

5559

60- 6564 69

Age Group (Years)

Fig. 17.2 Adrenopause: the senescent, cortisol-independent decline of adrenocortical secretion of androgens (Orientech 1984). Dehydroepiandrosterone sulfate (DHEAS), circulates in amounts far exceeding any other steroid, and after peripheral bioconversion, represents the source of a significant portion of circulating testosterone in women.

the time of menopause is a misperception. Indeed, the ovary actually produces more testosterone after the menopausal transition because of this increased LH-driven androgen secretion. This effect appears to continue well into the postmenopausal years, without attenuation (Meldrum etal. 1981).

Superimposed on this androgen tableau is the phenomenon of diminishing adrenocortical androgen production. The adrenal androgens DHEA and DHEAS are produced by the reticularis cells of the adrenal cortex, and in concert with a diminuition of these cells, there is a decline in circulating steroids as well as their responses to ACTH stimulation. Adrenopause is the term coined for this senescent, cortisol-independent decline of adrenocortical secretion of androgens and is illustrated in Fig. 17.2; it occurs in a linear fashion from about the age of 20 or 25 onward, to the point where a woman in her 80s would have about 10% of circulating DHEAS of that of a woman in early reproductive age (Orentreich et al. 1984). Because the adrenal androgens circulate in such high quantities and provide a substantial proportion of circulating A4A and testosterone by virtue of peripheral conversion, adrenopause represents a significant substrate loss for circulating testosterone and thus creates an age-related gradual decline in testosterone levels, independent of menopause.

The cumulative effect of adrenopause and the concurrent increase in ovarian testosterone production over the menopausal transition injects some variability in serum testosterone levels in aging women. Several large cross-sectional studies addressing this issue have demonstrated that circulating testosterone levels do not reproducibly change in relation to the menopausal transition. This is best illustrated by the Melbourne Women's Midlife Health Project, as seen in Fig. 17.2 (Burger 2000). Indeed, because of diminuition of E2 and a subsequent decline in hepatic production of sex hormone binding globulin (SHBG), the free androgen index, a marker of free testosterone, increases over the menopausal transition. Subsequent testosterone effect may therefore actually increase over the menopausal transition, an explanation for the widely observed clinical phenomenon of menopausal hir-sutism. However, there does appear to be a small but significant decline in serum testosterone levels in older reproductive age women probably due to decreased availability of adrenal androgen precursors. A schematic of changes in female androgen dynamics with age is presented in Fig. 17.3.

From PMS To PPD

From PMS To PPD

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