The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 1 48-54
Copyright © 2000 by The Endocrine Society
From The Clinical Research Centers |
Effects of Aging on Adrenal Function in the Human: Responsiveness and Sensitivity of Adrenal Androgens and Cortisol to Adrenocorticotropin in Premenopausal and Postmenopausal Women1
C. Richard Parker, Jr.,
Scott M. Slayden,
Ricardo Azziz,
S. Lolita Crabbe,
Gene A. Hines,
Larry R. Boots and
Sejong Bae
Departments of Obstetrics and Gynecology, Medicine, and
Biostatistics and Biomathematics, University of Alabama, Birmingham,
Alabama 35233
Address all correspondence and requests for reprints to: C. Richard Parker, Jr., Ph.D., Department of Obstetrics and Gynecology, University of Alabama, Birmingham, Alabama 35233-7333.
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Abstract
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We sought to determine the effects of aging on several aspects of
adrenal steroidogenesis in the hopes of characterizing the possible
causes of adrenal androgen deficiency in elderly women. To this end, we
quantified basal morning concentrations of cortisol (F),
dehydroepiandrosterone (DHEA), dehydroepiandrosterone
sulfate (DS), and androstenedione (A4) and then evaluated the effects
of overnight dexamethasone (DEX) suppression followed by adrenal
responses to graded hourly infusions of ACTH, ranging from 20–1280
ng/1.5 m2·h. Finally, we performed a standard 0.25-mg
ACTH bolus stimulation test, with sampling at 1 h thereafter.
Basal serum levels of DHEA, DS, and A4 were significantly
reduced (
50% each) in a group of 35 healthy postmenopausal women,
55–68 yr old, compared to those in 30 healthy, regularly menstruating
women, 20–25 yr old. Post-DEX levels of these C19 steroids
also were significantly lower in the older women than in the younger
women; the percent decrease after DEX for A4 was greater in the older
women, whereas those in DHEA and DS were not age related.
Basal and post-DEX levels of F were similar in both groups. Secretory
responses of DS to ACTH were not informative due to its large plasma
pool and slow clearance rate. The maximally stimulated levels of
DHEA after ACTH bolus were significantly lower in the
older women than in younger women; those of A4 were similar in both age
groups, and the maximally achieved levels of F were higher in the older
women than in the younger women. The sensitivity of adrenal
DHEA, A4, and F to ACTH (defined as the minimal dose of
ACTH required to significantly increase the steroid levels above basal
post-DEX values) was similar in older and younger women. The
responsiveness of the steroids of interest to ACTH (defined as the
slope of the dose-response curve over the linear portion of the
dose-response curve) also was similar among younger and older women.
These data demonstrate that the deficiency in adrenal androgen
production in women is restricted to the 
5-pathway
steroid products (DHEA and DS), whereas there is no
reduction in the capacity of the adrenal to produce A4 or cortisol. As
DHEA and DS are likely to be produced mainly in the zona
reticularis of the adrenal cortex, we propose that these data point to
an alteration in that cortical zone as the cause of adrenal androgen
deficiency in aging. The reductions in A4 in aging are probably due to
reduced ovarian secretion after menopause.
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Introduction
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CROSS-SECTIONAL analyses revealed decreased
circulating levels of several C19 steroids such
as testosterone, androstenedione (A4), dehydroepiandrosterone
(DHEA), and DHEA sulfate (DS) in
postmenopausal women compared to those in younger women (1, 2, 3, 4, 5, 6).
Deficiencies in such hormones may have an adverse impact on the health
and well-being of women during aging, as is suggested by the results of
several studies (6, 7, 8, 9, 10). Although it is likely that ovulatory failure
and the resultant loss of ovarian follicular steroidogenesis play a
direct role in the decreased production of some androgens, reductions
in adrenal C19 steroid production also occurs for
unknown reasons. The issue is complicated due to the fact that there
appears to be no deficiency of adrenal production of corticosteroids in
aging. A deficiency of pituitary ACTH secretion is not likely to be a
cause of the reductions in adrenal androgen production in aging.
Indeed, as there may, in fact, be a loss of sensitivity of the
hypothalamic-pituitary axis to negative feedback effects of cortisol
(F), the adrenal may actually be exposed to higher amounts of ACTH on a
daily basis in aging (11, 12).
In studies designed to address certain dynamics of adrenal
steroidogenesis in response to ACTH, Liu et al. proposed
that aging in women is associated with a defect in 17,20-lyase activity
of cytochrome P450–17
(CYP450–17) in the adrenal (13). No
evidence for age-associated alterations in 17-hydroxylase activity or
3ß-hydroxysteroid dehydrogenase (3ßHSD) activity were inferred in
their study. Reduced production of DHEA, but not
androstenedione (A4) or F, was noted in response to bolus injections of
ACTH in men and women in the study by Vermeulen and associates (14). As
17,20-lyase activity also is required for adrenal production of A4,
perhaps the results from the above studies are suggestive of a
zone-specific defect in the steroidogenic pathway. In the present study
we sought to compare the responses of F to those of DHEA
and A4 to ACTH stimulation to determine whether there were alterations
in either the sensitivity or the responsiveness of the
5 C19 steroid pathway
compared to those of the 4
C19 pathway and also the pathway leading to F
synthesis in women during aging. Our goal was to better characterize
the pattern of adrenal androgen production during aging in healthy
women and to attempt to provide insights in such individuals to the
likely cause for deficient adrenal androgen production that has been
noted by many investigators to occur in a cross-section of aging
adults.
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Materials and Methods
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Our protocol included careful screening of subjects to exclude
those with chronic illnesses such as hypertension and diabetes and also
those with any history of ovulatory disorders. To ensure as much
homogeneity as possible in ovarian contribution to the steroidal
milieu, we scheduled studies in the younger women (20–35 yr old) to
occur during the early to midfollicular phase of their ovarian cycle.
Only women with regular, spontaneous menstrual cycles and not currently
or within the past 3 months being exposed to contraceptive steroids
were included in the study due to the observed impact of oral
contraceptive steroids on certain aspects of adrenal steroidogenesis.
Among the older women (55 yr of age and older), we only included those
who had undergone spontaneous menopause (still had at least one ovary)
a minimum of 6 months previously, who had random FSH levels over 40
ng/mL, and who had not been exposed to any sex steroid hormone
replacement for at least 3 months before the study. Basic
characteristics of the women in the two age groups are shown in Table 1
. The body mass indexes and waist/hip
ratios for both groups were similar, whereas the younger women were
taller and heavier than the older women. All subjects were studied at
the General Clinical Research Center after giving informed written
consent to participate in this protocol, which was approved by the
institutional review board of the University of Alabama at
Birmingham.
The in vivo adrenal testing was conducted as follows. An
early morning fasting blood sample was obtained to provide normal
hormone values. Subsequently, the volunteers ingested 1 mg
dexamethasone (DEX) at 2300 h and again on the following morning
before an ACTH infusion protocol. DEX was administered to inhibit
endogenous ACTH secretion and thus ensure a stable baseline of steroid
levels for subsequent testing of responses to exogenous ACTH. A
secondary rationale for adrenal suppression in this manner was to
provide information about the relative adrenal and gonadal
contributions to circulating levels of steroids; the difference between
normal control levels of steroids and that after adrenal suppression
was considered representative of adrenal contribution to total plasma
concentrations, and the level achieved after adrenal suppression was
considered to approximate gonadal contribution to plasma steroid
levels. Blood was obtained in the morning after the second DEX dose to
provide data for steroid levels achieved after adrenal suppression. The
volunteers were then infused ACTH [ACTH-(1–24), Cortrosyn] in
graded, increasing doses that included 20, 40, 80, 160, 320, 640, and
1280 ng/1.5 m2·h for 1 h at each dose
level, with blood sampling at the end of each infused dose. Finally,
the subjects were administered a standard bolus 0.25-mg ACTH
stimulation test, with blood sampling 1 h thereafter. In this
latter instance, the difference between the concentration achieved
after the 0.25-mg ACTH bolus and that noted at the baseline after
overnight adrenal suppression was considered to be representative of
maximal adrenal steroid output. The subtle aspects of adrenal responses
to graded, stepwise increases in doses of infused ACTH that we sought
to determine were 1) the sensitivity of the various adrenal steroids to
ACTH (i.e. the minimal dose of ACTH required to
significantly increase a given steroid hormone’s concentration above
its steady state, suppressed level after dexamethasone ingestion), and
2) the responsiveness of the steroids to ACTH (i.e. the
slope of the dose-response curve for each steroid), which would
indicate whether there was any blunting of the androgen biosynthetic
pathway responses to ACTH stimulation during aging.
All steroids were quantified by RIA as indicated below.
DHEA, A4, and DS were quantified by the use of
commercially available RIA kits provided by Diagnostics Systems Laboratories, Inc. (Webster, TX). Cortisol was quantified by use
of a direct in-house assay in methanol-treated diluted serum (1:10).
The assay employs a highly specific antiserum (gift from Dr. C. E.
Gomez-Sanchez, Columbia, MO), [3H]cortisol as
assay tracer, and dextran-coated charcoal for separation of bound and
free hormone. The assay sensitivity is 7.8 pg/tube, and the intraassay
coefficients of variation for low and high values are 7.1% and
4.9%.
The methodology used for mathematical determination of the data
pertaining to adrenal sensitivity and responsiveness to ACTH was
adapted from that originally described by Komindr et al.
(15) and is presented in great detail in our recent publication (16).
Briefly described, these mathematical manipulations were performed to
establish the dose of ACTH at which a given steroid’s concentration
rose above baseline, which defined the sensitivity of that steroid to
ACTH in both age groups, and also to establish the rate of rise during
the linear portion of the dose-response curve, which defined the
responsiveness to ACTH in each study group. The statistical analyses
were conducted by use of SAS (Statistical Analysis Systems, Inc., Cary,
NC).
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Results
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Morning serum levels of DHEA, DS, and A4 were
significantly reduced in the older, postmenopausal women compared to
those in the younger, ovulatory women (Table 2). The reduction in concentration of
each of these C19 steroids was approximately 50%
in the older group of women. Serum levels of F, however, were similar
in both groups. The post-DEX baseline concentrations of
DHEA, DS, and A4 also were significantly lower in the
older women, whereas those of F were not age dependent. The extent of
reduction in serum levels of DHEA and cortisol after
overnight DEX suppression of the hypothalamic-pituitary axis
(percentage of control levels) was similar in younger and older women
(Fig. 1). On the other hand, the percent
reduction in circulating levels of A4 after overnight DEX suppression
was greater in the older women than in the younger women
(P < 0.001), suggesting that more of the circulating
A4 in the premenopausal women was of nonadrenal origin (presumably
ovarian), than that in postmenopausal women. That the percent reduction
in DHEA levels was not as great as that in F is probably
due to the continuing systemic conversion of the large circulating DS
pool to DHEA after adrenal secretion was suppressed.
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Table 2. Effects of aging on morning steroid concentrations
before and after overnight dexamethasone suppression in women
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Figure 1. Effects of aging on the suppressability of
adrenal steroids by dexamethasone in women. The data are presented as
the mean ± SE for each of the indicated steroids (the
SE for cortisol in the younger women was too small to be
visible as plotted). *, P < 0.001 compared to A4
suppression in younger women.
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The increments in DHEA and A4 above the post-DEX
suppressed baseline seen after the final bolus of 0.25 mg ACTH are
shown in Fig. 2. Whereas there was an
age-related deficiency in the total response of DHEA to
ACTH (P = 0.016), the maximal output of A4 in response
to ACTH was similar in younger and older women. The increment in DS
also was reduced (P = 0.03) in the older women
(295 ± 37 ng/mL) compared to that in the younger women (451
± 57 ng/mL). Short term changes in DS levels are, however, difficult
to interpret due to its long plasma half-life (7–10 h) (6). On the
other hand, the maximal F output in response to the bolus ACTH
injection was slightly, albeit significantly, increased
(P = 0.04) in the older women (27.6 ± 1.3
µg/dL) than in the younger women (24.4 ± 0.74 µg/dL).
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Figure 2. Effects of aging on maximal output of
DHEA and A4 in women in response to ACTH after overnight
DEX suppression. The data are presented as the mean ±
SE and represent the increment in hormone concentration
between the post-DEX baseline concentration and that achieved 1 h
after a 0.25-mg bolus of ACTH. *, P < 0.02
compared to DHEA output in younger women.
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The dose-response curves for DHEA, A4, and F to the graded
infusions of ACTH are presented in Figs. 3-5.
The responses of DS to these relatively low doses of ACTH were small
(<50% increase over DEX-suppressed levels) in younger and older women
as a consequence of its large plasma pool size and low MCR and are
therefore not presented. There were no obvious differences in the
characteristics of the dose-response curves for any of these steroids
according to age. The sensitivity of each steroid to ACTH, defined as
the minimal dose of ACTH required to elicit a significant rise in each
steroid’s level above the baseline, did not change significantly with
age (Fig. 6). In each group, F secretion was
approximately 2 times more sensitive to ACTH than was
DHEA. The sensitivity of A4 to ACTH was enhanced, but not
significantly, among the older women compared to that in younger women.
The responsiveness of F to ACTH was considerably greater than that of
either DHEA or A4 in both age groups (Table 3). However, there was no change in the
responsiveness of any steroid to ACTH (defined as the slope of the
linear portion of the dose-response curve) as a function of aging
(Table 3). Nevertheless, as pointed out earlier, there was a
significant reduction in overall output of DHEA in
response to ACTH in the postmenopausal women compared to the younger
women.
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Figure 3. Dose-response plot of DHEA in
younger and older women during graded 1-h infusions of increasing doses
of ACTH. ACTH doses are in nanograms per 1.5 m2/h.
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Figure 6. Effects of aging on the sensitivity of
cortisol, DHEA, and A4 to ACTH in women. The data, which
are plotted as the mean, represent the dose of infused ACTH (nanograms
per 1.5 m2/h) required to significantly increase serum
levels of each steroid above the post-DEX suppressed baseline values.
The reduction in the sensitivity of A4 secretion to ACTH in the older
women was not statistically significant.
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Discussion
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Although many investigators have noted dramatically lower levels
of DHEA and DS in elderly humans compared to young adults
(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 14), a satisfactory explanation for the cause of this
adrenal androgen-deficient state has not been forthcoming. The current
study demonstrates that although the total adrenal output of
DHEA and DS is reduced in response to ACTH in
postmenopausal women, the adrenal output of A4 seems to be stable as a
function of age. Our data also suggest that the strikingly reduced
levels of A4 in the postmenopausal women compared to those in the
younger women are probably a consequence of reductions in ovarian
production in aging and also partially due to reductions in circulating
levels of DHEA that could be converted to A4 in peripheral
tissues. In premenopausal women, the ovary contributes significantly to
the plasma A4 pool (17, 18, 19). Consequently, our data are consistent with
the view that most of the A4 in plasma of postmenopausal women is
ultimately of adrenal origin, which supports the findings of Whorl
et al., who reported that A4 levels were reduced over 90%
after adrenalectomy in postmenopausal women (19). A similarly high
contribution of the adrenal to plasma DHEA was apparent
among women in that study (19). We found that F secretion by the
adrenal in response to ACTH infusion followed by a bolus of ACTH was
increased somewhat in the older women compared to that in younger
ovulatory women. Clearly, then, there would seem to be no evidence for
a deficiency in the 4 3-ketosteroid pathway in
the adrenal leading to either glucocorticosteroid production (F) or to
that of the C19 steroid, A4. In two other
studies, there also appeared to be no reductions in the ability of the
adrenal to secrete A4 in response to ACTH in postmenopausal women (13, 14).
Both F and A4 are dependant upon the combined actions of 3ßHSD
and of CYP450–17. These components of the steroidogenic pathway are
coexistent in the zona fasciculata (20, 21, 22). One could therefore
speculate that if there is any adrenal deficiency of 17,20-lyase
activity of CYP450–17, as suggested by Liu et al. (13),
such a deficiency probably is not manifested in the zona fasciculata.
Formation of DHEA and DS is dependant upon the absence of
3ßHSD but the presence of CYP450–17 and, at least in the case of
DS, the added availability of DHEA-sulfotransferase. The
zona reticularis of the adrenal cortex clearly has the appropriate set
of enzymes to serve as the site of formation of DS and is likely to be
a major site of DHEA formation as well (20, 21, 22, 23, 24, 25).
Therefore, our current data coupled with the functional zonation of the
steroidogenic pathway suggest that adrenal androgen deficiency in aging
is probably due to a defect in the zona reticularis, specifically the
5 C19 steroidogenic
pathway.
In support of such a view, we recently found that there are
morphological alterations in the adrenal in men during aging, such that
the zona reticularis is reduced in size compared to the rest of the
cortex (26). Subsequently, we also noted that the distribution of
DHEA sulfotransferase in the adrenals of aging men and
women is reduced compared to that in young adults (25). As there is no
evidence for reductions in the 4 3-ketosteroid
steroidogenic pathway for C21 or
C19 steroids from the results of our current
study [or from those of others (13, 14)], we propose that most if not
all of the age-associated deficiency in adrenal androgen production is
due to changes in the maintenance of the functional and morphological
integrity of the zona reticularis. The nature of the problem could
involve a deleterious shift in the relative rates of formation of
reticularis cells compared to the rates of cell death in that zone.
Another possibility might be that there is morphological and functional
conversion of some reticularis cells into a population of cells that no
longer have the capability of forming DHEA/DS.
Unfortunately, very little is currently known about the origin or
maintenance of cells of the human zona reticularis.
Insofar as the steroidogenic pathway of the zona reticularis is
concerned, it seems to be strikingly similar to that of the fetal zone
of the human fetal adrenal gland, which also has a paucity of 3ßHSD
(27, 28), but has abundant DHEA sulfotransferase (29, 30)
and CYP450–17 (28). DHEA sulfotransferase in cultured
human adrenal cells is modulated by the protein kinase A and C pathways
(31, 32, 33). Transforming growth factor-ß inhibits basal and
ACTH-stimulated DS production in human adrenal cells (34, 35), and we
have found that this cytokine inhibits basal and ACTH-stimulated levels
of DHEA sulfotransferase messenger ribonucleic acid and
enzyme in such cells (33, 36). Beyond these observations, knowledge of
the regulation of DHEA sulfotransferase in the human
adrenal is very incomplete. Studies to address the maintenance of this
enzymatic activity and other characteristics of the zona reticularis
functional phenotype may provide clues to the mechanisms for the
age-associated deficiency in secretion of DHEA/DS.
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Figure 4. Dose-response plot of A4 in younger and
older women during graded 1-h infusions of increasing doses of ACTH.
ACTH doses are in nanograms per 1.5 m2/h.
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Figure 5. Dose-response plot of cortisol in younger
and older women during graded 1-h infusions of increasing doses of
ACTH. ACTH doses are in nanograms per 1.5 m2/h.
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Acknowledgments
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We thank Vanessa Black, B.S., for assistance with patient
recruitment, H. Downing Potter for technical assistance, and the staff
of the General Clinical Research Center for their invaluable help with
this project.
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Footnotes
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1 This work was supported by Grant AG-12142 (to C.R.P.) and
NIH/National Center for Research Resources Grant MO1-RR-00032,
which supported the General Clinical Research Center at the University
of Alabama-Birmingham. 
Received October 28, 1998.
Revised September 15, 1999.
Accepted September 22, 1999.
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Top
Abstract
Introduction
