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Original Studies |
Department of Family and Preventive Medicine, Division of Epidemiology, University of California–San Diego, School of Medicine, La Jolla, California 92093-0607
Address correspondence to: Dr. Elizabeth Barrett-Connor, Professor, Department of Family and Preventive Medicine, Division of Epidemiology, School of Medicine, University of California–San Diego, La Jolla, California 92093-0607.
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Abstract |
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Overall, age and BMI-adjusted DHEA and DHEAS [collectively DHEA(S)] levels were 40% lower and cortisol levels 10% higher in women than men, resulting in a 1.7-fold higher cortisol/DHEAS molar ratio for women (both, P < 0.001). Cortisol levels increased progressively (20% overall) with age in both men and women (both, P < 0.01). Although DHEA(S) levels declined 60% and the cortisol/DHEAS ratio increased 3-fold across the 40-yr age range for both men and women (all P < 0.001), the pattern of the change differed (all P < 0.01 for interaction). For men, DHEA(S) fell in a curvilinear fashion, with the degree of change decreasing with each decade. In contrast, DHEA(S) levels in women fell 40% from the 50s to 60s, were unvarying from 60–80 yr of age, and declined an additional 18% in the 80s. The cortisol/DHEAS ratio increased in a linear fashion for men, but was flat during the 60–80-yr age range for women. Despite these differences in the effect of aging, levels of DHEA(S) remained lower and cortisol and the cortisol/DHEAS ratio higher, in women than men throughout the 50–89-yr age range. These results were independent of adiposity, smoking, and alcohol consumption.
In summary, among older, healthy adults DHEA(S) levels are lower and cortisol levels higher in women than men. The age-related decline in adrenal androgens persists into advanced age for both men and women, but exhibits a sexually dimorphic pattern. In contrast, cortisol levels in men and women show a parallel, linear increase with aging. These findings may have important implications for a host of age-related processes that exhibit gender differences, including brain function, bone metabolism, and cardiovascular disease.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although the physiologic role of adrenal androgens remains to be clearly defined, their importance as sex hormone precursors in older individuals is established. In older men, 50% of androgens are derived from peripheral conversion of DHEA(S), whereas adrenal androgen precursors provide close to 100% of active estrogens in postmenopausal women (26). DHEA(S) is also thought to act directly as a neurosteroid and may have immunoenhancing, cardioprotective, antidiabetic, and antiobesity properties (25). Cortisol is an integral part of the hypothalamic-pituitary-adrenal (HPA) axis response to stress; growing evidence supports the view that chronic cortisol excess may lead to hippocampal atrophy (8, 11) and cognitive impairments (7, 8, 9, 10, 11) during aging. Cortisol also has diverse metabolic actions, including playing a role in the regulation of lipolysis and visceral fat accumulation (27, 28). Clearly, changes in adrenal endocrine function with aging may have far-reaching physiologic significance.
To our knowledge, no population-based studies have simultaneously assessed endogenous levels of adrenal steroid hormones in both men and women, using older community-dwelling subjects and adjusting for the influence of major life-style variables. This cross-sectional study examines age and gender differences in plasma levels of cortisol, DHEA, DHEAS, and the molar ratios of cortisol/DHEAS and DHEAS/DHEA in 1592 community-dwelling men and women 50–89 yr of age.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Blood samples for hormone assay were obtained by venipuncture between 0730 h and 1100 h after a requested 12-h fast; plasma was separated and frozen at -70 C. Steroid hormone levels were measured on first-thawed samples 6–9 yr later, between 1992 and 1994, in the endocrinology research laboratory of the Department of Reproductive Medicine, University of California (San Diego, CA). DHEA levels were determined by RIA after solvent extraction and celite column chromotography; DHEAS and cortisol were determined by direct RIA. The assay sensitivities and intra- and interassay coefficients of determination, respectively, were 0.14 nmol/L, 6.1% and 7.1% for DHEA; 0.22 µmol/L, 3.1% and 7.3% for DHEAS; and 17 nmol/L, 5.4% and 10.5% for cortisol.
This study was intended to evaluate adrenal hormone levels in unselected community-dwelling adults. Among the men and the postmenopausal women who were not using estrogen, 885 men and 757 women had adrenal hormone levels measured. Five of these women were excluded from the present analysis because their estrogen levels suggested unreported estrogen use; seventeen women and 28 men were excluded because of the use of diabetes medications. The remaining 735 women and 857 men are the focus of this report. Adrenal hormone levels for all subjects were above the assay sensitivity.
Statistical analyses
Data were analyzed using SPSS (SPSS Inc., Chicago,
IL). For statistical analysis, hormone levels and the molar ratios of
cortisol/DHEAS and DHEAS/DHEA were log-transformed to correct for
skewed distributions; values in figures and tables are antilogs. Gender
differences in demographic characteristics were tested by Student’s t
tests for continuous variables and 
tests for categorical variables.
The significance of potential covariates were determined by Pearson
correlations for continuous variables and ANOVA for categorical
variables. Hormone levels and molar ratios were stratified by decade of
age (50–59, 60–69, 70–79, and 80–89) for each gender and compared
by two-factor (age and gender) ANOVA adjusted for covariates, followed
by one-factor (age) ANOVA for each gender. DHEA(S) levels were also
compared for men and women 65–84 yr of age stratified by 5-yr age
groups. Results are presented as the mean (±SE)
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mean age for the 735 women (74 ± 8 yr; median, 75 yr) was greater (P < 0.001) than that for the 857 men (71 ± 10 yr; median, 73 yr); eighty-nine percent of women and 72% of men were 65 yr of age or older. The women had a lower mean BMI and smaller waists and WHRs than the men (all, P < 0.003). Fewer (P = 0.003) women than men participated in regular exercise (three or more times per week), and women consumed less (P < 0.001) alcohol than men.
The relation of three measures of adiposity and fat distribution, BMI, waist girth, and WHR with adrenal hormone levels was assessed. Cortisol levels for both men and women were inversely related to BMI and waist girth, but not WHR. The strongest associations were with BMI, with no additional variance explained by waist girth in partial correlations controlling for age and BMI (data not shown). In this population, BMI declined with increasing age in men, but not women, and was inversely correlated with cortisol levels in both men (r = -0.16) and women (r = -0.12) (P < 0.01). Among all women and men, levels of DHEA and DHEAS were inversely related and cortisol and the cortisol/DHEAS molar ratio were positively related to age (all P < 0.001).
Influence of ovarian status
Because the ovary has been reported to influence adrenal androgen levels (29), adrenal hormone levels for a subset of 123 women who reported bilateral oophorectomy were compared with those for a subset of 438 women who reported the presence of both ovaries. The mean age for both groups was 74 yr; the intact women were a mean of 25 yr postmenopausal, and the oophorectomized women were a mean of 24 yr postsurgery. Overall, age- and BMI-adjusted adrenal hormone levels did not differ between the intact and oophorectomized women (cortisol, 272 ± 4 and 266 ± 8 nmol/L; DHEA, 3.36 ± 0.09 and 3.23 ± 0.19 nmol/L; DHEAS, 1.28 ± 0.05 and 1.24 ± 0.08 µmol/L, respectively), and the effect of age on adrenal hormone levels was similar for the two groups (data not shown). Hormone levels for the women were not stratified on the basis of ovarian status for subsequent analyses.
Gender differences
Figure 1
shows individual values for
plasma levels of DHEA, DHEAS, cortisol, and the molar ratio of
cortisol/DHEAS for men and for women. Thirty-six percent of women, as
compared with 13% of men, had plasma DHEAS levels less than an
arbitrary cutpoint of 1 µmol/L, whereas more than twice as many women
as men had cortisol levels higher than 350 nmol/L (24% vs.
9%), the cortisol level associated with hippocampal atrophy and
cognitive impairment in the study of Lupien et al (8).
These two cutpoints result in a molar ratio of cortisol/DHEAS of 0.350,
a value seen in four times as many women as men (27% vs.
7%).
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). The molar ratio of
DHEAS/DHEA was 10% higher (P < 0.001) among women
(384 ± 5) than men (351 ± 6). In age- and BMI-adjusted
partial correlations, levels of DHEA, but not DHEAS, were positively
related to cortisol levels for both genders (r = 0.23,
P < 0.001 for both); DHEA and DHEAS concentrations
were strongly associated with each other in men (r = 0.68,
P < 0.001) and in women (r = 0.82,
P < 0.001).
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. A
progressive and parallel elevation of cortisol levels was observed in
both men and women, with an overall increase of 20% from the 50s to
the 80s in both genders (both, P < 0.01). Although,
DHEA(S) levels declined 60% and the cortisol/DHEAS ratio increased
3-fold across the 40-yr age range for both genders (all
P < 0.001), the pattern of the change differed (both
P < 0.01) for interaction). For men, DHEA(S) fell in a
curvilinear fashion with the degree of change decreasing with each
decade. In contrast, DHEA(S) levels in women fell 40% from the 50s to
60s, were unvarying from 60–80 yrs of age, and declined an additional
18% in the 80s. The cortisol/DHEAS ratio increased in a linear fashion
for men, but was flat for women during the 60–80-yr age range. The
absence of a change in DHEA(S) levels in women 60–80 yrs of age was
confirmed by stratifying levels by 5-yr spans from 60–84 yr of age
(Fig. 4). (The number of women was too
small for similar 5-yr stratification analyses in subjects <60 and
>85 yr of age). Despite the gender differences in the effect of aging,
levels of DHEA(S) remained lower, and cortisol and the cortisol/DHEAS
ratio higher, in women than men throughout the age range. The molar
ratio of DHEAS/DHEA did not vary with age in either gender (data not
shown).
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In age- and BMI-adjusted partial correlations, alcohol consumption was directly related to cortisol and DHEAS levels and the DHEAS/DHEA molar ratio in both men (r = 0.12, r = 0.12, and r = 0.09, respectively) and women (r = 0.14, r = 0.11, and r = 0.09, respectively), and to DHEA levels in women only (r = 0.11) (all, P < 0.01). For both genders, current smokers had significantly higher levels of DHEA(S) and lower molar ratios of cortisol/DHEAS than nonsmokers (all, P < 0.01). Physical activity, waist girth, and WHR were not related to adrenal hormone levels in men or women in age- and BMI-adjusted partial correlations. Adjusting for alcohol consumption and current smoking did not significantly alter gender or age differences in adrenal hormone levels (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Until recently, human corticotropic function under basal conditions was thought to be unaffected by aging (19, 20, 21). Several studies with frequent sampling have now demonstrated a 20–50% increase in 24-h mean cortisol levels between 20 and 80 yr of age (22, 23, 24, 25); only two compared genders (22, 24). One with a small number of subjects found no interaction between age and gender for any cortisol parameter (24). In the other study, Van Cauter et al. (22) analyzed 24-h cortisol patterns for 90 men and 87 women, 18–83 yr of age, collected from seven laboratories. Overall, cortisol levels and the morning maxima were lower in young women than in young men. These gender differences disappeared with aging due to an age-related increase in the morning acrophase in women, but not men. Samples for the present study were drawn between 0730 h and 1100 h, around or soon after the time of the cortisol acrophase (30). In contrast to Van Cauter et al. (22), we found a modest, but consistent, elevation of early morning cortisol levels in older women compared with older men. The difference in these two studies may be due to our larger sample size or to the selection of subjects. Frequent sampling studies have shown that the most pronounced elevation of cortisol with aging occurs during the evening nadir (22, 23, 24), thus random morning sampling may have underestimated the association of age with cortisol, but is unlikely to have produced it.
To our knowledge, this is the first population-based study to report a parallel, progressive elevation of morning cortisol levels in older, healthy individuals of both genders, independent of adiposity. Previous population-based studies have had contradictory results. Morning cortisol levels increased 30% between the ages of 40 and 80 in a cross-sectional study of more than 2000 randomly selected Canadian men (31), concordant with the 20% elevation from age 50–89 yr observed in this study. However, cortisol levels did not vary with age in 415 healthy, 40–70-yr-old men from the Massachusetts Male Aging Study (32) or in the Rotterdam Study of 216 healthy men and women aged 55–80 yr (33). Other than the smaller sample sizes, the reason for these discrepant results is not apparent.
Our cortisol findings are compatible with recently reported gender-specific, age-related alterations of the HPA axis. Cortisol secretion in response to ovine CRH administration was increased in older compared with younger adults (34) and was higher and more prolonged in older women than older men (35, 36). Although ACTH levels are unaltered (23) or only moderately elevated with aging (24), cortisol responses to a bolus of ACTH are higher in older as compared with younger women (37). The sensitivity of the hypothalamic-pituitary axis to the negative feedback effects of glucocorticoids decreases with aging (35, 36, 37), and this decline is more profound in older women than older men (38, 39). Thus, healthy aging is associated with an increase in cortisol responses to challenge and diminished hypothalamic-pituitary sensitivity to glucocorticoid feedback inhibition, more so in women than men.
Cortisol circulates, in large part, bound to corticosteroid binding globulin (CBG). In most cases, only free cortisol elicits glucocorticoid responses (40), thus the potential biological impact of the increase in circulating cortisol with age depends on whether CBG levels change as well. In fact, an increase in CBG levels with aging might account for the increase in total cortisol. CBG levels were not measured in this study, and limited data is available from other studies. Levels of CBG did not vary with age in healthy men, age 21–86 yr (34), and were similar in a small group of postmenopausal women as compared with younger women (41). In a longitudinal study of elderly men and women, changes in free cortisol levels paralleled those of total cortisol (42). All suggest that CBG levels are not altered in older adults.
In men, the gonad provides 10–20% of adrenal androgens (43). Although the ovary does not synthesize DHEAS directly, it has been suggested that ovarian factors influence DHEAS levels independent of age. In an early study (29), DHEAS levels were more than 2-fold lower in castrate vs. age-matched intact pre- and postmenopausal women. In a subset of 123 bilaterally oophorectomized women in this study, adrenal androgen levels were the same as those of the intact women and displayed a similar decline with age. These results are consistent with the absence of a change in DHEAS levels in 20 postmenopausal women during the 6 weeks following bilateral oophorectomy (44) and do not support an ovarian contribution to adrenal androgen regulation in older women.
The gender difference in DHEAS levels seen in young adults, with higher levels in men than women, was maintained in older age, in agreement with some (14, 45, 46), but not all (47, 48, 49), previous studies. Few studies have examined gender differences in levels of the unconjugated hormone, DHEA, and results have been conflicting. Zumoff et al. (50) found higher DHEA levels in women than men less than age 50, with no difference among older individuals, whereas Carlstrom et al. (51) found no gender difference in DHEA levels for individuals 20–87 yr of age. In the present study, levels of DHEA and DHEAS were highly correlated in both men and women, were consistently higher in men than women, and were similarly influenced by age. Unlike DHEAS, which is relatively stable, DHEA is released episodically and displays a marked circadian rhythm parallel to that of cortisol (30). Thus, the relatively small numbers of subjects in the earlier studies, together with the high degree of interindividual DHEA variability, may account for the inconsistent results. Based on our results, it seems that DHEAS measurements may be substituted for DHEA measurements and vice versa in studies involving older adults.
The mechanism underlying gender differences in adrenal androgen levels is not known; some studies suggest sex steroids may be involved. Early cross-sectional studies with small subject numbers observed either higher, lower, or unchanged adrenal androgen levels in postmenopausal and ovariectomized women receiving exogenous estrogen [reviewed in Ref. 52 ]. In a previous Rancho Bernardo study (52), DHEAS levels were 25% lower for 301 postmenopausal women using unopposed oral estrogen compared with 676 postmenopausal women not using estrogen. Others report a 23% decrease in DHEAS levels in 28 postmenopausal women given oral micronized estradiol for 3 months (53) and a marked decline in DHEAS in estrogen-treated prostatic cancer patients (43). During long-term, high-dose sex steroid administration to transsexual patients, DHEAS levels decreased by 48% in men treated with ethinyl-estradiol and increased 23% in women treated with testosterone (54). Based on these studies, testosterone seems to have a stimulatory effect and estradiol an inhibitory effect on adrenal androgen levels, consistent with higher levels in men than in women. However, all of these studies involved oral steroids. Physiologic replacement of estrogen by the transdermal route for 3 months in postmenopausal women did not alter baseline levels of DHEA(S) nor responses to ACTH (55). Effects of oral steroids may involve first pass hepatic factors, rather than normal physiology. In vitro studies demonstrating an inhibitory effect of estrogen on 3-ß hydroxysteroid dehydrogenase activity in human adrenal cells (56, 57), resulting, presumably, in higher DHEAS levels, add further to the confusion.
The age-related decline of the adrenal androgen, DHEAS, the most abundant steroid in the human, has been extensively characterized (for review see Refs. 19, 20, 21). In both men and women DHEAS levels reach a peak at about 20 yr of age, decrease progressively after age 30, and are about one third young adult levels by age 60 (47, 58). Most of the decline in DHEAS has been thought to occur before the age of 60 with only small changes in older adults (46, 59, 60). In this study, DHEA(S) levels declined 60% from 50–89 yr of age in both men and women. Thus, a substantial decline in adrenal androgen levels continues in older, healthy adults. The gender-specific pattern of the decline in adrenal androgens, with a continuous, curvilinear decline for men and a plateau for women 60–80 yr of age is in general agreement with previous studies reporting no change for women after age 50–60 (46, 47, 48, 51). The significance of the lower DHEAS levels observed here in 147 women more than 80 yr old is uncertain. If high DHEAS levels are a risk factor for mortality in women, continuous selection of individuals with low DHEAS values would result in lower DHEAS in the oldest women. A 19-yr follow-up of women in this cohort failed to identify a significant increased risk of fatal CVD, although higher DHEAS levels were associated with increased cardiovascular risk factors (1). These issues can only be resolved by longitudinal studies.
The metabolic clearance of DHEA(S) is not altered with aging (61), and, in contrast to cortisol, there is no feedback action of DHEA(S) on the pituitary or hypothalamus (21), thus the mechanism responsible for the decay in adrenal androgen production with aging is likely to be related to changes at the adrenal level. DHEA responses to ACTH (37) and CRH challenge (30, 34) are blunted in older adults. Loss of adrenal androgen sensitivity is thought to be related to either diminished 17,20 lyase activity of the P450c17 enzyme (30) or a reduction in the relative size of the adrenal zona reticularis (62), the site of adrenal androgen synthesis. We have recently reported (63) a decline in androstenedione levels with age among the intact, but not the bilaterally oophorectomized, women in this cohort. Unlike intact women for whom androstenedione is derived from both the ovary and the adrenal, circulating androstenedione levels in oophorectomized women reflect only adrenal secretion. The absence of a decline in androstenedione levels in these women suggests that the adrenal defect in aging involves the zona reticularis, not adrenal androgen synthesis in general.
This investigation has a number of limitations, foremost being the cross-sectional design. Variability in the timing of the samples and the fact that they were obtained during the morning hours when levels of cortisol and DHEA are falling are also limiting. These shortcomings may be outweighed by the large number of observations. Although hormone levels were based on only one sample, single measurements of DHEA(S) have been shown to reliably characterize average levels in older individuals over a 1–3-yr period (64, 65), and cortisol levels show stability over 2.5 yr (33). Changes in hormone levels during long-term storage are unlikely to explain the observed associations. Hormone levels were measured in never previously thawed plasma and levels did not vary by season of sampling or duration of storage. In addition, others have shown that levels of steroid hormones are relatively stable in frozen plasma stored for 3–10 yr (58, 66, 67).
The changes in adrenal hormone levels with aging reported here and their gender differences may have widespread clinical significance. A number of studies suggest a gender-specific link between adrenal hormones and cardiovascular disease (CVD). DHEAS levels seem to be inversely related to CVD in men (1, 3, 4) but not in women (1, 2) and are, in fact, positively associated with some CVD risk factors in women (1, 2, 5). High cortisol levels are associated with increasing HDL cholesterol for both men and women (68, 69), but with elevated blood pressure in men only (6) and higher fasting serum triglycerides in women only (6). Aging-related changes in adrenal hormones are also thought to effect brain function. Lupien et al. (8) recently reported hippocampal atrophy and deficits in hippocampus-dependent memory in older individuals with persistently elevated cortisol levels. The MacArthur study (10) found that increasing cortisol levels over a 3-yr period predicted declines in memory performance in women, but not in men. In contrast, in the Rotterdam Study (9) basal cortisol levels and the cortisol/DHEAS ratio were positively related to cognitive impairment in elderly adults, independent of gender. Both the Rancho Bernardo Study (12, 13) and a French Community-based study (14) have found an association of endogenous DHEAS levels with depressed mood in older women and not in older men. Gender specificity extends to bone metabolism as well. DHEA(S) levels are positively associated with bone mineral density at three sites in women, but not in men (16). In healthy elderly men, cortisol levels are inversely related to bone mineral density (17) and the rate of bone loss (18) and are more strongly associated with the risk of clinical fractures than in women (15).
The significance of the higher molar ratio of cortisol/DHEAS in women and its increase with age in both genders, is not clear. An antiglucocorticoid effect of DHEAS has been proposed, based primarily on animal studies [for review, see Ref. 70 ], and is thought to mediate the putative neuroprotective effects of DHEA (71). The increase in cortisol relative to DHEA(S) may also play a role in the metabolic shift to a catabolic state during aging (72) and has been speculated to be causally linked to several physical diseases and psychiatric disorders (73, 74).
In summary, healthy aging is associated with marked sexual dimorphism in adrenal hormone regulation. DHEA(S) levels are lower and cortisol levels higher in older women than older men, independent of adiposity and other lifestyle covariates. The age-related decline in adrenal androgens persists into advanced age for both men and women, but exhibits a gender-specific pattern. In contrast, cortisol levels in men and women show a progressive, parallel increase with aging. These findings may have important implications for a host of age-related processes including cardiovascular disease, brain function, and bone metabolism.
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Footnotes |
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Received April 26, 2000.
Revised June 22, 2000.
Accepted July 7, 2000.
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References |
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) and 735 women (
),
50–89 yr of age. ***, P < 0.001. Values are
antilogs.
) 50–89 yr of age (n = 141, 209,
322 and 154 for men; n = 49, 127, 355, and 147 for women). Values
are antilogs.