The present data demonstrate that the previously observed rise in DHEAS during the MT transition is evident even in the absence of the ovaries in 70% (14 of the 20) BSO women. These data suggest strongly that the menopause transition-associated rise in DHEAS is, in part, an adrenal phenomenon. While the observed increases in DHEAS levels are small on an annual basis, they represent a potentially large contribution of substrate for peripheral conversion to more bioactive sex steroids when the total sex steroid milieu of the menopausal transition is considered 10
. Furthermore, these data suggest that individual differences in adrenal steroid production may be primarily responsible for individual differences in total circulating sex steroid levels during the menopausal transition and therefore contribute to the range of phenotypes that are observed at this time.
The predominant peripheral conversion products of DHEA in women are androgens and not estrogens 11, 12
. Our data therefore also suggests that the androgen-estrogen balance may be determined by adrenal function as well as ovarian function in the years just preceding and at menopause. The decline in ovarian function, which appears to be requisite for inducing an increase in adrenal steroid production, can be either gradual as with natural menopause or abrupt as with surgical menopause as demonstrated here. Furthermore, once initiated, this induction is sustained for several years and continues past the menopause in women with intact ovaries. It would appear therefore that the initial decline of ovarian function provides a trigger for an event that may include years of subsequent increased adrenal steroidogenesis.
While these findings show that the ovaries are not required for the sustained rise of DHEAS through the MT, they do not exclude the ovaries from participating in that event. The source of circulating androgens in mid-aged women has been a contentious issue for decades and the present study provides some clarity to that controversy. Since the circulating levels of DHEAS are maintained after menopause at levels similar to premenopause 13
, comparisons to earlier studies of postmenopausal women may provide useful information regarding the nature of ovarian steroid production. In one of the earliest studies, positive ovarian arterio-venous gradients for testosterone (T), androstenedione (Adione) and DHEA were documented in postmenopausal women and demonstrate the ability of the senescent ovary to continue to produce androgens including DHEA 5
The pre-menopausal ovary contributes approximately half of the circulating T and Adione 14
and continues to produce androgens past the menopause (Longcope et al., 1980
). However, there is controversy regarding the amount of androgens the human ovary produces at different life stages. Couzinet et al 15
found the necessary steroidogenic machinery for androgen production to be missing in post menopausal ovaries of women with adrenal insufficiency. This is in conflict with an earlier study 16
that reported DHEAS levels were more than 2-fold lower in women without ovaries vs. age-matched pre- and postmenopausal women with intact ovaries. In contrast, DHEAS levels were similar in 610 intact and 125 BSO women in the Rancho Bernardo Study and displayed a similar decline with age 17
. These results do not support an ovarian contribution to circulating DHEAS in older women, and are consistent with the observations of an absence of a change in DHEAS levels in 20 postmenopausal women during the 6 weeks following BSO 18
. The bulk of the data to date do not favor an ovarian contribution to the circulating pool of DHEAS.
There is limited but positive evidence to suggest that the human premenopausal ovary can produce significant amounts of DHEAS under specific conditions. Barnes and co-workers 19
treated a woman with isolated follicle stimulating hormone (FSH) deficiency with FSH, followed by human chorionic gondadotropin (hCG) to show that FSH exposure resulted in the ability of the ovary to respond to a luteinizing hormone stimulation by increasing DHEA production. Similarly, Wachs et al.7
demonstrated an increase in circulating DHEA following treatment of women with polycystic ovarian syndrome with recombinant FSH. More recently ovarian arterio-venous samples reveal a DHEA gradient several years after menopause 6
. While all of these studies demonstrate the potential for the ovary to secrete DHEA, none of the study participants were normal, pre-menopausal, mid-aged women. Until there is additional evidence or a better understanding of the mechanism(s) involved, it seems reasonable to conclude that most of the increase in DHEAS observed during the menopausal transition is a result of increased adrenal steroid production.
There are at least two weaknesses in our study. Foremost is that there was no intention or experimental design to investigate adrenal function in the original SWAN design because at that time there was no rationale to do so. In fact, DHEAS was included in SWAN as a measure of somatic aging, with the assumption that circulating levels would continuously decline with chronological age and therefore provide a between-woman, independent reference for ovarian aging which was in line with conventional thinking at that time. Second, is the absence of any measure to determine if either the clearance or sulfation of DHEA changes in middle-age women. Fortunately, there is at least one study that indicates this is not the case 20