| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
Yerkes Regional Primate Research Center (D.A.G., M.E.W., T.S., S.C., T.P.G.) and Department of Psychiatry and Behavioral Sciences (P.M.P.), Emory University, Atlanta, Georgia 30322
Address all correspondence and requests for reprints to: Dr. D. A. Gust, Yerkes Primate Research Center, Emory University, Field Station, 2409 Taylor Lane, Lawrenceville, Georgia 30043. E-mail: deb{at}rmy.emory.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The suppression of serum cortisol was not different between the two doses of dexamethasone. Before dexamethasone administration (2100 h), serum cortisol was significantly higher in old control females than in either young or old separated females, who were not different from one another. The young control females had baseline cortisol concentrations significantly lower than all other groups. Serum cortisol was suppressed approximately 75% below baseline values in all groups by 10 h after dexamethasone administration. Age significantly affected serum cortisol after dexamethasone, as the old control group showed a release from suppression 19 h posttreatment compared to the young control group and compared to the separated groups.
Social condition had a significant effect on the responses of serum cortisol and plasma ACTH to CRF administration. At baseline (0930 h), serum cortisol was significantly higher in young controls compared with older controls, with both separated groups having intermediate values. Similarly, plasma ACTH at baseline was significantly higher in young controls compared to all other groups. Social separation significantly diminished the elevation of both serum cortisol and ACTH after stimulation with either dose of CRF. Control females showed a prolonged increase in plasma ACTH through 60 min and an increase in serum cortisol through 120 min after CRF. In contrast, these hormones either declined by 60 min or did not increase in socially separated females after CRF administration.
These data suggest that the circadian rhythm in serum cortisol may be affected by aging, as levels were higher in the evening and lower in the morning in old control compared to young control females. The effect of age on the response to dexamethasone treatment among the control groups lends support to the hypothesis that the sensitivity of glucocorticoid negative feedback diminishes with aging. Although age did not affect the response to CRF, social separation diminished the elevation in both serum cortisol and plasma ACTH. Whether this effect was due to stress-induced down-regulation of pituitary CRF receptors remains to be determined.
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Experimental challenges to the HPA axis highlight age-related differences. Circulating concentrations of ACTH and corticosterone after dexamethasone administration are higher in aged compared to younger rats, suggesting an escape from glucocorticoid negative feedback (8, 9). Furthermore, the administration of CRF after dexamethasone results in a larger increase in ACTH in aged animals (10). Although some studies report increased adrenocortical sensitivity to ACTH stimulation in older animals (11), other data indicate a negative relationship between age and ACTH-induced glucocorticoid release in vivo under normal conditions (12) and in response to an acute stressor (13, 14, 15).
Data on the effect of aging on activity within the HPA axis in humans is equivocal. Some studies suggest that HPA sensitivity decreases with age (16, 17, 18, 19), expressed as an impairment of glucocorticoid negative feedback (20) and a flattening of the circadian cortisol rhythm (21, 22, 23). However, other studies indicate that age has little effect on the HPA axis (24, 25). Systematic studies of the relationship between aging and the HPA axis in humans are relatively few due in part to the difficulty in recruiting a group of comparable elderly subjects with similar backgrounds, health status, diet, and drug and alcohol use. This difficulty can be overcome by using socially housed, nonhuman primates as a model. Consequently, the present study tested the hypothesis that the HPA axis is altered in older compared with younger female rhesus monkeys. Age-related differences were assessed in response to dexamethasone suppression and CRF stimulation during socially undisturbed conditions and in response to a social stressor.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Forty female rhesus macaques, 20 old (15–27 yr) and 20 young adult (7–8 yr), served as subjects. Subjects were housed in 1 of 7 social groups as described previously (26). Group sizes ranged from 80–100, comprised of 2–4 adult males, other females, juveniles, and infants. One subject lived in a smaller outdoor enclosure with 1 adult male, 2 adult females, and 1 juvenile. Animals had continuous access to water and were fed standard monkey chow twice daily and fresh fruit once each day. This protocol was approved by the Emory University animal care and use committee in accordance with NIH and USDA standards.
Procedures
The studies were performed during the spring and summer months in 2 successive yr. At this time of year, all females were seasonally anovulatory (27), and none was lactating. Estradiol concentrations in seasonally anovulatory rhesus monkeys are acyclic and average less than 15 pg/mL (27). Ten subjects in each age class were randomly assigned to either a control condition or a stressor condition. The stressor consisted of moving a subject from her social group for 1 week to an individual cage in a remote building separated from other monkeys. This manipulation produces significant activation of the HPA axis in monkeys within 24 h of removal, which persists for approximately 7 days (28, 29, 30). In contrast, control subjects were moved to the indoor quarters attached to their outdoor compound, enabling them to have continual visual, auditory, and tactile contact with others members of their social group. To verify the effectiveness of the removal as a stressor and to demonstrate that a second removal 3 months later produced a similar activation, serum samples were obtained at 0930 h the day before the removal and at 0930 h the next day, 24 h after the removal. The percent change in serum cortisol was significantly greater in separated compared to control females at both the first (+30 ± 8% vs. -4 ± 6%) and the second removal (+65 ± 10% vs. +3 ± 6%).
The HPA axis was assessed as a function of age and social condition
using the dexamethasone suppression test (DST) and stimulation with
CRF. The design as well as the body weights for each of the groups are
illustrated in Table 1
. Body weights did
not differ significantly as a function of age
(F1,36 = 0.46; P = 0.50), social
condition (F1,36 = 0.22; P =
0.63), or age by condition interaction (F1,36 =
0.04; P = 0.84). The effects of two doses of
dexamethasone and two doses of CRF were evaluated, with the order of
drug dose between each group counterbalanced. A 3-month washout period
separated each dose-response assessment. One cohort of animals (n
= 20) within each age and social condition category (n = 5/group)
received the DST, and a second cohort of animals (n = 20) received
the CRF challenge (n = 5/group). Twenty subjects (10 young and 10
old) were studied in yr 1, and the remaining 20 were studied in yr 2
(10 young and 10 old). The first year, the old subjects (control and
separated, n = 5 each) received both doses of dexamethasone and
the young subjects (control and separated, n = 5 each) received
both doses of CRF. In yr 2, the old subjects (control and separated,
n = 5 each) received both doses of CRF, and the young subjects
(control and separated, n = 5 each) received both doses of the
dexamethasone. The control subjects received the DST and CRF challenges
while housed in the indoor quarters attached to their home compound,
whereas the separated subjects received these assessments while removed
to a remote, nonsocial environment. All subjects were fully habituated
to the handling procedures, so blood samples (3 mL) could be collected
without anesthesia, as described previously (26, 31). Plasma for ACTH
analysis was collected in chilled tubes containing ethylenediamine
tetraacetate, and serum was collected for cortisol analysis.
|
For the CRF challenge, CRF was administered iv (in the saphenous vein) at a low (0.25 µg/kg) and a high (1.0 µg/kg) dose. Forty-eight hours after the separated subjects had been removed from the group to the remote location, a baseline blood sample was obtained at 0930 h (time zero), followed immediately by the CRF injection. Subsequent samples were obtained at 30, 60, and 120 min after the injection. Control subjects were moved from the group to the attached indoor quarters 10 min before initiation of the CRF challenge. Sampling was begun at 0930 h and followed the same time sequence as the separated subjects. After the final sample (+120 min), control females were returned to their group.
Analyses
Serum cortisol concentrations were determined using commercially available reagents (Diagnostic Products, Los Angeles, CA). The sensitivity of the assay using 10 µL serum was 0.40 µg/dL. Between- and within-assay coefficients of variation (CVs) were 10% (n = 15 assays) and less than 3%, respectively. Plasma concentrations of ACTH were determined using commercially available reagents (DPC). Sensitivity of the assay using 100 µl of plasma was 7.5 pg/mL. Between- and within assay coefficients of variation were 12% (n = 15 assays) and less than 3%, respectively. All samples from an individual female for a given challenge were analyzed in the same assay. All assays were performed in the Assay Services Laboratory at Yerkes. The Yerkes Regional Primate Research Center is fully accredited by the American Association for Accreditation of Laboratory Animal Care.
Data for each age-social condition group were expressed as the
mean ± SEM. Differences between groups were evaluated
with an ANOVA for repeated measures (GB-Stat, version 6.5.4, Dynamic
Microsystems, Inc., Silver Springs, MD), with age (young vs.
old) and social manipulation (control vs. separated) as
between-group effects, and dose (low vs. high) and time from
challenge (hours for DST and minutes for CRF) as within-group or
repeated effects. Comparisons of groups at specific time points were
evaluated with Fisher’s least significant diffference (LSD)
post-hoc tests. These post-hoc analyses were
carried out if significant interactions between the main effects were
observed. Furthermore, the area under the response curve for cortisol
and ACTH after CRF was calculated using the trapezoid rule. Statistical
tests with a P 
0.05 were considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Social condition differentially affected baseline cortisol
concentrations in young compared to older females (Fig. 1). As the dose of dexamethasone did not
differentially affect serum cortisol as a function of age or social
condition (F1,16 = 1.51; P =
0.22), data were combined for illustration. All groups showed a
significant decline in serum cortisol after dexamethasone
administration (F3,48 = 127.12; P
< 0.0001). Serum cortisol varied significantly over time as a function
of age (F3,48 = 3.11; P = 0.03),
but not social condition (F3,48 = 0.52;
P = 0.67). The effect of age was due to a significant
difference in baseline cortisol concentrations among the groups and
differences in the cortisol response to dexamethasone between the old
control group and each of the other groups. At baseline (2100 h),
cortisol levels in old controls were significantly higher than those in
all other groups, whereas concentrations in the young controls were
significantly lower than those in both the young and old separated
females (Fisher’s LSD tests). Although groups did not differ
significantly from one another at 10 or 15 h after dexamethasone
administration (Fisher’s least significant difference tests), the
cortisol levels had risen by +19 h in old control females and were now
significantly higher than those in the old separated and both younger
groups (Fisher’s LSD tests). Serum cortisol was suppressed no further
after 10 h, as the percent change from baseline at 10, 15, and
19 h from dexamethasone for all of the groups was not
significantly different (F2,32 = 0.29;
P = 0.75). Thus, serum cortisol remained suppressed
relative to baseline from 10–19 h for each of the groups, but had
begun to increase by +19 h in old control females. The average percent
change from baseline was 74.0 ± 2.4% for the young controls,
76.3 ± 2.7% for young separated females, 73.5 ± 5.9% for
old controls, and 75.5 ± 2.5% for old separated females.
|
The social condition in which the female was tested
(F1,16 = 14.04; P = 0.002),
but not her age (F1,16 = 0.93; P
= 0.35), had a significant effect on serum cortisol during acute
stimulation with CRF (Fig. 2). As the
dose of CRF did not differentially affect the response of serum
cortisol (F1,16 = 1.31; P =
0.27), data were collapsed across doses for illustration. The response
of serum cortisol to CRF varied significantly as a function of social
condition (F3,48 = 100.89; P
0.0001). At baseline (0930 h), serum cortisol was significantly higher
in the young controls compared with the old controls and young
separated females, but was not different from that observed in the old
separated females (Fisher’s LSD tests). The old control females had
baseline cortisol values significantly less than the old separated
females, but not different from those of the young separated females
(Fisher’s LSD tests). After the administration of CRF, serum cortisol
was significantly elevated from baseline in all groups 30 min after the
administration of CRF (Fisher’s LSD tests), with values significantly
higher in young controls compared to those in the other groups
(Fisher’s LSD tests). However, by 60 min after CRF, the groups began
to diverge, with levels continuing to rise significantly in the young
and old control groups, but returning to baseline in young and old
separated females (Fisher’s LSD tests). This pattern continued through
120 min from CRF (see Fig. 2). These effects of social separation were
also seen in the area (nanograms per mL/min) under the cortisol
response curve to CRF, with effects in young (7.07 ± 0.4) and old
(6.4 ± 0.3) controls significantly greater than those in young
(5.2 ± 0.5) and old (5.2 ± 0.3) separated females
(F1,16 = 17.74; P = 0.0009;
Fisher’s LSD tests).
|
). As can be seen, social condition
(F1,16 = 34.69; P < 0.0001), but
not age (F1,16 = 0.67; P = 0.43)
significantly affected the change from baseline in serum cortisol after
CRF administration (F2,32 = 113.45;
P < 0.001). At 30 min after CRF treatment, the percent
increase in serum cortisol was significantly greater in old control
females compared with the other groups (Fisher’s LSD tests). However,
at 60 and 120 min, both control groups were significantly greater than
either separated group (Fisher’s LSD tests). During these times, the
young and old controls did not differ significantly from one another
(Fisher’s LSD tests).
|
). As the dose of CRF did not
differentially affect the response of plasma ACTH
(F1,16 = 0.23; P = 0.61), data
were collapsed across doses for illustration. At baseline, plasma ACTH
concentrations were significantly higher in young controls than in the
other groups (Fisher’s LSD tests). Thirty minutes after the CRF
injection, ACTH levels had increased significantly in old controls
compared to baseline values, but were still similar to baseline in the
other three groups (Fisher’s LSD tests). However, at this time,
concentrations were still significantly higher in young controls, with
values in old controls higher than those in either separated group
(Fisher’s LSD tests). At 60 min after CRF, plasma ACTH was still
similar to baseline values in both separated groups, but had increased
significantly from baseline in both control groups (Fisher’s LSD
tests). Consequently, levels were similar between the control groups,
yet were significantly higher than those in the separated groups
(Fisher’s LSD tests). Finally, at 120 min, plasma ACTH was again not
significantly different compared with baseline values for the separated
groups, had returned to baseline for the young controls, and was still
higher than baseline in the old controls (Fisher’s LSD tests). Thus,
at 120 after CRF, plasma ACTH was significantly higher in the two
control groups compared with the two separated groups (Fisher’s LSD
tests). This overall effect of social condition on plasma ACTH in
response to CRF is also illustrated in the area (micrograms per mL/min)
under the cortisol response curve to CRF, with values in young
(7.16 ± 2.4) and old (4.6 ± 0.7) controls significantly
greater than those in young (1.0 ± 0.1) and old (2.4 ± 0.6)
separated females (F1,16 = 9.80;
P = 0.007; Fisher’s LSD tests).
As baseline values of plasma ACTH differed significantly among the
groups, the data were analyzed as a percent change from baseline. As
illustrated in Fig. 3, the change in plasma ACTH from baseline was
significantly affected by social condition (F1,16
= 16.19; P = 0.001) and varied significantly with time
from CRF (F2,32 = 12.88; P <
0.0001). At 30 and 120 min from CRF administration, the percent change
in plasma ACTH from baseline was significantly higher in old controls
compared to the other groups (Fisher’s LSD tests). However, at 60 min
after CRF, the percent increase was significantly higher in both the
young and old controls compared with the two separated groups
(Fisher’s LSD tests).
Diurnal differences in serum cortisol
As baseline cortisol measurements for the dexamethasone and CRF
challenge tests were performed in the evening (2100 h) and morning
(0930 h), respectively, data were analyzed to examine diurnal
differences. As illustrated in Fig. 4, morning values were significantly higher than evening values in each of
the four groups (F1,31 = 94.21; P
< 0.0001). As stated above in the discussion of the morning baseline
values before CRF administration, cortisol levels were significantly
higher in the young controls compared with the old controls and young
separated females, but were not different from those in the old
separated females (Fisher’s LSD tests). The old control females had
baseline cortisol values significantly less than those in the old
separated females, but not different from those in the young separated
females (Fisher’s LSD tests). As stated above in the discussion of the
evening baseline values before dexamethasone administration, cortisol
levels in old controls were significantly higher than those in all
other groups, whereas concentrations in the young controls were
significantly lower than those in both the young and old separated
females (Fisher’s LSD tests).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
These diurnal differences in serum cortisol as a function of female age could be attributed to age-dependent differences in glucocorticoid negative feedback, with older females being less sensitive in the evening and more sensitive in the morning. The initial similarity in the degree of suppression of cortisol (calculated as percent change from baseline values) between old and young females is supported by other data suggesting that there is no change in sensitivity to glucocorticoid suppression with advancing age in humans (36, 37). However, other data suggest that the glucocorticoid-mediated negative feedback mechanism becomes increasingly dysfunctional with age (10, 16, 38). Although dexamethasone did not differentially affect the subsequent suppression of serum cortisol throughout the night and into the morning hours, an age-related difference in suppression was apparent 19 h after dexamethasone treatment. Using the criteria from humans that serum cortisol concentrations after dexamethasone that exceed 5 µg/dL represent resistance to glucocorticoid-mediated negative feedback (39), old control females would be the only group considered to be dexamethasone resistant, as they show an escape from dexamethasone suppression by +19 h. Because the old separated group remained suppressed, as did both young control and separated groups, the earlier escape from dexamethasone suppression with aging may be compromised by exposure to a stressful situation.
The effect of social separation was also evident in the response to CRF administration. Accounting for the differences in baseline cortisol concentrations, age also affected the magnitude of the response to CRF, but this was not modified by social separation. Although all groups responded with an abrupt increase in serum cortisol 30 min after CRF, by 60 min levels had fallen to baseline in the separated females, but continued to rise in the control females. The old and young controls showed a similar pattern in plasma ACTH in response to CRF. However, plasma ACTH did not change from baseline within the periods sampled for the separated females. Given the rise at 30 min in serum cortisol for both separated groups, it seems likely that ACTH was also elevated before the 30 min sample. Although younger controls had higher absolute levels of cortisol and ACTH, given the differences in baseline values, older control females actually responded to CRF to a greater degree. These data from separated females do not support the idea that the response to stress is less in older individuals in terms of ACTH secretion (40) and stress-sensitive neurotransmitters (41). Some studies suggest that responsivity to CRF and/or ACTH does not change with age (12, 42), whereas others indicate that the responses of ACTH and cortisol to CRF are higher in elderly humans, an effect attributed to reduced glucocorticoid negative feedback suppression in older individuals (22, 43, 44). On the other hand, the reduced response to CRF in old rats (45) is associated with reduced CRF messenger ribonucleic acid in specific brain regions (46), elevated portal concentrations of CRF (35), and down-regulation of pituitary CRF receptor number. Thus, in aged rats, deficits in the ACTH response to CRF are attributed to a down-regulation of pituitary CRF receptors secondary to the hypersecretion of CRF resulting from a decrease in hippocampal glucocorticoid receptors in the hippocampus (35, 46). These differences in response to CRF challenge between humans and rats are not easily reconcilable. The present data indicate that the differences between young and old females are due to diminished endogenous CRF stimulation resulting in lower baseline morning ACTH and cortisol levels in older females. The response to CRF suggests that pituitary CRF receptors are not irrevocably compromised. Although the present study found no age-related differences in the response to social separation, the results do suggest that aging differentially affects mechanisms regulating the trough set-point of the axis without altering mechanisms responsible for stress-induced activation and shut-off.
Social separation blunted the increase in serum cortisol and plasma ACTH in response to CRF administration. Other studies in humans (47) and rats (48) also report blunting of the response in ACTH to CRF during a stressful compared to a nonstressful situation. The inability of individuals in a stressful situation to respond to an ACTH challenge has been documented previously (14). The current results support the hypothesis that stress-induced hypersecretion of CRF results in a down-regulation of CRF pituitary receptors and diminished responses of ACTH and, consequently, cortisol (35).
The impact of aging on the HPA axis is attributed to a loss of glucocorticoid receptors in the hippocampus, resulting in a diminution of glucocorticoid negative feedback of CRF and other neuropeptides that influence ACTH secretion (9, 49, 50). It is hypothesized that the loss of glucocorticoid receptors is the result of chronic exposure to glucocorticoids and, in extreme cases, subsequent neuronal toxicity (51). A number of studies indicate that chronic exposure to either a stressor or glucocorticoids produce a decrease in hippocampal neurons (51, 52, 53, 54, 55, 56), although other data do not agree (57). Stress-induced increases in glucocorticoids produce atrophy of both dendritic branching and neuronal morphology in the hippocampus (58). Prolonged exposure of hippocampal neurons to glucocorticoids in older individuals may further reduce glucocorticoid receptor number and negative feedback inhibition of HPA axis regulatory peptides, and thus alter the response to stressors (2, 5). The present data suggest that advancing age may affect the circadian rhythm of serum cortisol levels as well as negative feedback sensitivity of the hypothalamic-pituitary axis to glucocorticoids.
We cannot at this time say whether these effects are specific to the female or also apply to the male. We have previously shown the increase in serum cortisol in male monkeys separated from their group is not as extensive or as sustained as that in females (30). Data from humans indicate that the circadian rhythm of serum cortisol is lower in women than men before, but not after, menopause (33). However, other studies suggest that the responses of circulating cortisol and ACTH to CRF are lower in men than in women, and this difference is exacerbated with aging (44). Further studies are needed to define how gender may differentially affect the response to social stress during aging and how these differences are modified by circadian activity within the HPA axis.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received August 2, 1999.
Revised March 2, 2000.
Accepted March 23, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  R. Zhou, I. M. Bird, D. A. Dumesic, and D. H. Abbott Adrenal Hyperandrogenism Is Induced by Fetal Androgen Excess in a Rhesus Monkey Model of Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6630 - 6637. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Kasckow, T. M. Segar, C. Xiao, A. R. Furay, N. K. Evanson, M. M. Ostrander, and J. P. Herman Stability of Neuroendocrine and Behavioral Responsiveness in Aging Fischer 344/Brown-Norway Hybrid Rats Endocrinology, July 1, 2005; 146(7): 3105 - 3112. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. R. Ayala, J. Pushkas, J. D. Higley, D. Ronsaville, P. W. Gold, G. P. Chrousos, K. Pacak, K. A. Calis, M. Gerald, S. Lindell, et al. Behavioral, Adrenal, and Sympathetic Responses to Long-Term Administration of an Oral Corticotropin-Releasing Hormone Receptor Antagonist in a Primate Stress Paradigm J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5729 - 5737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Vicentic, G. Dominguez, R. G. Hunter, K. Philpot, M. Wilson, and M. J. Kuhar Cocaine- and Amphetamine-Regulated Transcript Peptide Levels in Blood Exhibit a Diurnal Rhythm: Regulation by Glucocorticoids Endocrinology, September 1, 2004; 145(9): 4119 - 4124. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Erwin, X. T. Tigno, G. Gerzanich, and B. C. Hansen Age-Related Changes in Fasting Plasma Cortisol in Rhesus Monkeys: Implications of Individual Differences for Pathological Consequences J. Gerontol. A Biol. Sci. Med. Sci., May 1, 2004; 59(5): B424 - B432. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Lyons, C. Yang, S. Eliez, A. L. Reiss, and A. F. Schatzberg Cognitive Correlates of White Matter Growth and Stress Hormones in Female Squirrel Monkey Adults J. Neurosci., April 7, 2004; 24(14): 3655 - 3662. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Umezaki, D. L. Hess, G. J. Valenzuela, and C. A. Ducsay Fetectomy Alters Maternal Pituitary-Adrenal Function in Pregnant Rhesus Macaques Biol Reprod, November 1, 2001; 65(5): 1616 - 1621. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. Tausk and H. Nousari Stress and the Skin Arch Dermatol, January 1, 2001; 137(1): 78 - 82. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
