Perimenopausal Stage

Fig. 4. Estradiol and testosterone parameters during the menopausal transition. The concentrations of estradiol and testosterone, their blood production rates, and their metabolic clearance rates are shown for women at various indicated phases of perimenopause. FSH, follicle-stimulating hormone. (Data from ref. 32.)

Burger and associates (35) also conducted longitudinal studies of women through the menopausal transition. As found by others, they noted little, if any, change in total testosterone levels leading up to, during, and for several years after menopause. However, reductions in SHBG levels were observed in concert with the reduction in estradiol observed leading up to the menopause and thereafter. The net effect of declining SHBG levels in the face of unwavering levels of testosterone is to increase the free testosterone fraction by 80% over the interval beginning 4 years prior to menopause and ending 2 years after the menopause. If free testosterone levels are actually increased during the perimenopausal period, this could have physiological impacts on androgen-dependent systems, such as libido, in these women.

Although the utilization of hormone replacement therapy (estrogen with or without a progestin) in postmenopausal women is in a period of flux because of concerns relating to potential adverse side effects, the impact of such agents is still of academic if not practical importance to our understanding of the regulation of androgen production and metabolism in women. Several investigators have compared women treated with various hormone replacement regimens to those who were not treated. Abraham and Maroulis (36) observed increased levels of DHEA and DHEAS among postmenopausal women treated with estrogen compared to untreated women; no impact on testosterone, DHT, or A4 was noted in this study. In contrast, Casson and associates (37) found that DHEAS and testosterone levels declined significantly in women during 12 weeks of treatment with an oral micron-ized estradiol. Just as SHBG levels have been found to increase in premenopausal women being treated with estrogen (e.g., oral contraceptives) or experiencing natural significant increases in estro-genicity (e.g., pregnancy), treatment of postmenopausal women with estrogens (±progestogen) also leads to significantly increased levels of SHBG. Among such women, Gower and Nyman (38) found no changes in total testosterone, albeit a 50% reduction in calculated free testosterone. When the group of subjects was considered as a whole, there was a positive correlation between free testosterone levels and total lean and leg lean mass; such findings could indicate that there is a risk that oral estrogen use could accelerate muscle loss already occurring during aging in women.

2.5. Androgens in Aging Women

The role of the ovary in androgen production in postmenopausal women has been the topic of many studies, often with conflicting results. Sluijhmer et al. (39) found that treatment of postmeno-pausal women with a gonadotropin-releasing hormone (GnRH) agonist reduced peripheral levels of testosterone, which declined further after ovariectomy, whereas neither A4 nor DHEAS levels were affected by either maneuver. Nevertheless, significant ovarian/peripheral venous gradients for A4 and testosterone were noted in GnRH agonist-treated and control subjects in this study. Others have also noted ovarian/peripheral gradients for A4 and testosterone. Vermeulen (15) reported that testosterone levels were lower in perimenopausal ovariectomized women compared to similarly aged women with intact ovaries; there were no differences in circulating levels of A4, DHEA, or DHEAS. In a more comprehensive study, Laughlin and associates (40) reported that among postmenopausal women 50-89 years of age, total testosterone and bioavailable testosterone levels were significantly lower among those with bilateral oophorectomy compared to intact women; A4 levels were unaffected by oophorectomy. These relationships were consistent, regardless of age or years postmenopause or postoophorectomy.

Davidson and colleagues (41) also observed a reduction in testosterone but not A4 levels in ova-riectomized women. They reported in their cross-sectional study of women ages 18-75 years that testosterone, DHEAS, and A4 decline with age and that the decline is greatest among younger women. Couzinet and colleagues (42), however, concluded that the postmenopausal ovary played a very minor role in contributing to the circulating androgenic milieu. They based their conclusions on the findings that testosterone, bioavailable testosterone, and A4 were similar among intact and ova-riectomized women, whereas the levels of all of these were extremely low or undetectable among postmenopausal women with adrenal insufficiency (with or without their ovaries). They also noted

  1. 5. Effect of aging on androgen levels in women. The concentrations in peripheral plasma of dehydroepiandrosterone (DHEA), androstenedione, and DHEA sulfate (DHEAS) in healthy postmenopausal women, none of whom were being treated with hormone replacement therapy, are compared to those in healthy, normally ovulating young women. (Data from ref. 43.)
  2. 5. Effect of aging on androgen levels in women. The concentrations in peripheral plasma of dehydroepiandrosterone (DHEA), androstenedione, and DHEA sulfate (DHEAS) in healthy postmenopausal women, none of whom were being treated with hormone replacement therapy, are compared to those in healthy, normally ovulating young women. (Data from ref. 43.)

that the levels of testosterone, A4, and DHEAS all declined 80% or more after thorough adrenal suppression (1 mg dexamethasone twice daily for 4 days) among normal postmenopausal women, but did not respond to human chorionic gonadotropin (hCG) stimulation. Finally, they found immu-noreactivity for steroidogenic enzymes in only 1 of 7 frozen ovarian specimens and only 3 of 10 paraffin-embedded ovarian samples tested from postmenopausal women. We recently studied the responses of androgens to overnight adrenal suppression in premenopausal and postmenopausal women and found that the extent of the reduction in A4 levels was greatest in postmenopausal women; no differences in suppression of DHEA or cortisol were noted as a function of age or menopausal status (43). These findings suggest that the adrenal may contribute more to the circulating pool of A4 in postmenopausal women than in young ovulatory women.

Age-associated reductions in circulating levels of androgens primarily considered to be of adrenal origin, such as DHEA and DHEAS, as well as A4 have been noted in several cross-sectional studies. As shown in Fig. 5, plasma levels of DHEA, DHEAS, and A4 in young ovulatory women are higher than those in postmenopausal women not exposed to any hormone replacement regimens. In general, cross-sectional studies have concluded that the highest levels of these steroids are found in women (and men) during their 20s and that a decrease in circulating levels occurs fairly steadily thereafter through the sixth or seventh decade of life, at which time the decline begins to plateau. Some evidence for racial differences in the endocrine milieu of women during aging has been noted, although this topic of inquiry has not been thoroughly addressed as yet. Manson et al. (44) found significantly lower levels of DHEAS, but not testosterone, among African American women approaching menopause compared to Caucasian women, and this relationship persisted over several months of observation.

Based on studies that employed dynamic adrenal testing strategies, it appears that the A4 steroid pathway in the adrenal is not altered substantially with aging, whereas the A5 pathway and 17,20-lyase activity in the adrenal are impaired to varying degrees (16,43,45). For example, Liu and col leagues (16) found that there was a striking decrease in the pulse amplitude of DHEA secretion in postmenopausal women compared to that of young women; no alteration was noted for cortisol secretory patterns. They also found evidence for reduced adrenal secretion of DHEA and DHEAS, but not cortisol, in response to corticotropin-releasing hormone infusions. Vermeulen and associates (45) tested the adrenal responses to an acute bolus injection of ACTH and found that the responses of A5 steroids, such as DHEA and 17-hydroxypregnenolone, were reduced in postmenopausal women compared to those in young women; A4 steroids, such as A4 and cortisol, were not impaired with aging. Similar findings were observed when comparing young and old men, suggesting that the age-associated defect in adrenal androgen production in women is not a gender-specific phenomenon (45).

We sought to determine if the impairment in adrenal DHEA/DHEAS production during aging in women was a consequence of reduced sensitivity of the adrenal to ACTH and/or because of a reduction in total secretory capacity in response to ACTH (43). We found, using graded infusions of varying doses of ACTH followed by a standard 250 |J,g bolus in women who had undergone an overnight dexamethasone suppression prior to the infusion, that the minimal required ACTH dose to elicit a statistically significant rise in DHEA levels was similar in young and postmenopausal women, as were the minimal doses of ACTH required to activate A4 and cortisol in both age groups. On the other hand, we found that the maximal increment in DHEA levels over baseline in the postmeno-pausal women was significantly reduced compared to that of young women; however, no impairments in the maximal output of A4 or cortisol were noted.

Based on the above-mentioned studies, and in view of the functional zonation of the adrenal cortex, the steroidogenic defect that occurs in aging appears to be localized primarily to the zona reticularis. The potential changes in the zona reticularis that could lead to reduced C19 steroid production in aging are numerous. For example, the reductions noted during in vivo studies could result from a selective decrease in zona reticularis cells (but not cells of other cortical zones) in the expression of one or many of the genes that encode steroidogenic enzymes, factors involved with cholesterol production and import/transport, the ACTH receptor, or various elements of signal transduction. To date, there is no evidence to support any of the above-mentioned possibilities.

Another possibility is that there could be a selective loss of zona reticularis cells with age through a variety of mechanisms. We have obtained some evidence for such a phenomenon in aging humans. Based on image analysis studies of adrenals obtained from adults who died suddenly after traumatic injury, we found that the width of the zona reticularis was significantly reduced in elderly adults than in young adult men and women (46,47); the thickness of the zona fasciculata/zona glomerulosa was not subnormal in aging adults. We also have recently reported that the width of the cell population that contains cytochrome b5 (presumably synonymous with the zona reticularis) is also significantly reduced in the adrenal cortex of aging humans (47). Our additional evaluations have suggested that a decrease in the thickness of the zona reticularis during aging is not because of cell shrinkage, but rather to a reduction in the number of zona reticularis cells (48). The potential mechanisms for such cell loss are numerous, including increased rates of apoptosis, among others. Confirmation of these morphological findings should provide important directions to future studies of adrenal androgen deficiency in aging.

From PMS To PPD

From PMS To PPD

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