Until recently the prevailing dogma was that adrenal weak androgen production in both men and women declined after the third decade of life. In the last ten years, this concept has changed following the analysis of the longitudinal data collected in the Study of Women’s Health Across the Nation (SWAN)1
. Failure to adequately attribute phenotype, symptoms and health trajectories to the observed longitudinal changes in circulating estradiol (E2) and progesterone (P) have led to investigations that focus on adrenal contributions to circulating sex steroids. Emerging data show that there are more ethnic and individual endocrine differences in mid-aged women in circulating adrenal steroids than in either estradiol or cyclic hormone profiles, particularly during the early perimenopause1,2
. Thus, adrenal steroid production may play a larger role in the occurrence of symptoms and the potential for healthier aging than previously recognized.
A distinct rise in circulating dehydroepiandrosterone sulfate (DHEAS) has been detected in most women during the menopausal transition. This rise was detected, however, only
when the annual serum levels of DHEAS were aligned according to ovarian status, defined using the World Health Organization criteria3
(). The expected age-related, gradual decline is observed when the same data are plotted by chronological age in premenopausal women2
. A similar rise in DHEAS had been observed earlier in older female laboratory macaques but has not been reported in any non-primate animal model. In women, it seems clear that most, if not all of the DHEAS rise is attributable to the adrenal and not the ovary, as a similar rise is observed in intact and ovariectomized women4
. Together, these observations not only underscore the importance of longitudinal investigations such as SWAN, but also explain why this specific physiologic trait went unnoticed for decades. It also highlights the value of the nonhuman primate animal model for human reproductive endocrinology, since this steroidogenic pathway is not found in rodent adrenals and therefore would not otherwise have been investigated.
Figure 1 Adjusted mean DHEAS (95% confidence interval) by menopause status from SWAN visits 00 – 09 (15,930 observations from 2,886 women). Reproduced from: Crawford S, Santoro N, Laughlin GA, Sowers MF, et al., Circulating Dehydroepiandrosterone Sulfate (more ...)
While the circulating levels of DHEAS in middle-aged women differ significantly between ethnicities at the beginning of the menopause transition (MT), the subsequent rise in DHEAS during the MT is similar, in both in the percentage of women that express it as well as the similarity in relative increase and trajectory in all five ethnicities studied in SWAN (). The pattern of adrenal weak androgen production that emerges when the DHEAS data are aligned by ovarian status suggests several possibilities regarding control of adrenal androgen secretion in older women. First, the ethnic differences in the circulating concentration of DHEAS in adult women indicate an ethnic-specific predisposition for the regulation of the delta-5 adrenal steroidogenic pathway () in premenopausal women2
. The between-ethnic similarities of the DHEAS trajectories, however, indicate a common physiological controlling mechanism during the MT. The time course of the rise of DHEAS, which is limited to the MT and early post menopause, suggests that changes in ovarian function are part of the controlling mechanism(s). While the finding of an increase in circulating DHEAS demonstrates a gender divergence that seems to be intimately linked to the MT, by itself it does not necessarily indicate a physiologically important event.
Figure 2 Adjusted mean DHEAS (95% confidence interval) by menopause status within ethnicity from SWAN visits 00 – 09 (15,930 observations from 2,886 women). Reproduced from: Crawford S, Santoro N, Laughlin GA, Sowers MF, et al., Circulating Dehydroepiandrosterone (more ...)
Figure 3 The two primary adrenal steroidogenic pathways. The delta four pathway on the left has been considered to be the critical pathway giving rise to the mineralocorticoids and glucocorticoids as well as androstenedione and testosterone which can be aromatized (more ...)
A great deal of attention has been focused on the delta-4 steroidogenic pathway that produces cortisol (F), androstendione (Adione) and testosterone (T; ). There are some relatively weak associations of these circulating steroids to sexual motivation, mood and the development of metabolic syndrome over the course of SWAN5,6
. By comparison, the longitudinal studies of SWAN have suggested that the delta-5 steroidogenic pathway that produces dehydroepiandrosterone (DHEA), its sulfated conjugate DHEAS and androstenediol (Adiol) may play a larger role in women’s healthy aging. Specifically, two reports1,2
show that these two parallel adrenal steroidogenic pathways are controlled separately with gender-specific and ovarian-stage-specific differences in steroid production rates and trajectories for mid-aged women.