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Department of Anatomy and Human Biology, The University of Western Australia, Nedlands, Perth, Western Australia 6907, Australia
Address all correspondence and requests for reprints to: Dr. Brendan J. Waddell, Department of Anatomy and Human Biology, University of Western Australia, Nedlands, Perth, Western Australia 6907, Australia. E-mail: bwaddell{at}anhb.uwa.edu.au
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Introduction |
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Several previous studies indicate that estrogen modulation of the HPA axis involves a reduction in feedback sensitivity to corticosterone and an associated increase in pituitary secretion of ACTH, at least under conditions of stress. For example, Burgess and Handa (10) have shown that estrogen replacement increases poststress levels of plasma immunoreactive (I-) ACTH in ovariectomized rats, an effect related to impairment of glucocorticoid receptor-mediated negative feedback. More recently, Carey et al. (11) observed similar effects of estrogen on the response of plasma I-ACTH to stress, although these researchers showed an associated impairment of mineralocorticoid receptor-mediated, rather than glucocorticoid receptor-mediated, feedback. In addition, estrogen has been shown to positively regulate hypothalamic CRH gene expression (15). Regardless of its precise mechanism of action, estrogen clearly has important effects on the response of I-ACTH to stress, but whether basal (unstressed) I-ACTH secretion is similarly affected remains uncertain. Thus, although some evidence suggests plasma I-ACTH is higher in female than in male rats (6) and at proestrus within the female cycle (11), sampling times in these reports were limited, and the absolute level of I-ACTH was either very high (6) or varied only marginally (11). Perhaps more importantly, Viau and Meaney (16) recently suggested that because estrogen enhances the response of the HPA axis to stress, apparent estrous cycle-related variation in I-ACTH may reflect altered responses to sampling rather than differences in resting levels. Although one might expect gender- or cycle-related variation in plasma corticosterone to be a consequence of differences in the pituitary secretion of I-ACTH, this is not necessarily the case. For example, we recently demonstrated that during the second half of rat pregnancy, a marked and progressive rise in the entire plasma corticosterone profile occurs without an associated increase in I-ACTH, suggestive of increased responsiveness of the adrenal cortex at this time of rising estrogen levels (17). Indeed, a direct positive effect of estrogen on basal and ACTH-stimulated adrenal secretion of corticosterone has long been recognized (18) and recently reconfirmed (19). Thus, it is quite feasible that sexual dimorphism and cycle-related variation in resting plasma corticosterone levels reflect altered adrenocortical responsiveness to trophic support and so may occur without parallel changes in plasma I-ACTH. Therefore, the major objective of the present work was to assess the extent of covariation in plasma corticosterone and I-ACTH within male rats and in females at each stage of the estrous cycle. Critical to this analysis was the use of a model that enabled frequent serial blood sampling such that covariation in plasma levels of the two hormones could be assessed across the full circadian range within individual animals. The latter was considered particularly important because it is unclear whether the entire circadian profile of corticosterone is sexually dimorphic and varies with cycle stage or whether only peak levels are subject to variation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Serial blood sampling of chronically cannulated rats
Rats were acclimatized to the experimental environment (housed
singly) and cannulated as previously described (17). Briefly, the
dorsal aorta was cannulated via the left carotid artery under
halothane-nitrous oxide anesthesia, and the free end of the cannula was
exteriorized to allow subsequent blood sampling without disturbing the
rat. Cannula patency was maintained by flushing every second day with
20 IU/ml heparinized sterile saline. All cannulations in female rats
were performed at diestrus of the cycle to minimize the effects of
surgery (20). Estrous cycles were perturbed in approximately half the
rats after surgery (for one or two cycles) before resuming their
typical 4-day pattern. In all cases a minimum of 7 days elapsed between
the cannulation procedure and blood sampling.
Blood samples were obtained at 2- to 3-h intervals (0800, 1100, 1400, 1700, 2000, 2200, 0030, 0300, and 0600 h) over a single 24-h period from a group of male rats (n = 6) and separate groups of female rats (n = 5–9/group) at each day of the 4-day estrous cycle. Rats were assigned to a specific cycle stage based on the expected vaginal cytology at the time of the first sample (0800 h). Blood samples (0.3–0.4 ml) were collected on ice in plastic microcentrifuge tubes containing 400 µg EDTA, centrifuged at 1800 x g for 15 min at 4 C, and stored at -20 C until analysis. To maintain blood volume, heparinized whole blood from a diestrous rat, equivalent in volume to that removed by three blood samples, was administered via the cannula after every third sample.
Decapitation
Female rats were housed six per cage and handled daily by the
same investigator for at least 2 weeks, then transferred to separate
cages 1 day before sampling. Rats were decapitated within 30 sec of
initially touching each cage, at either 0800 or 2000 h on
diestrus. Trunk blood was collected into ice-cold tubes containing 6 mg
EDTA and centrifuged at 1800 x g for 15 min at 4 C.
Plasma was removed and stored at -20 C until analysis.
Hormone analyses
Corticosterone was measured in unextracted, thermally denatured
plasma as previously described (17, 21) using
[1,2,6,7-3H]corticosterone (SA, 81 Ci/mmol; Amersham
Australia, Sydney, Australia) and a corticosterone antiserum (B3–163,
Endocrine Sciences Products, Calabasas, CA) that exhibits minimal
cross-reactivity with other corticosteroids and sex steroids. All
samples from a given rat were included in a single assay, and the
intraassay coefficient of variation was 9.7%. Plasma I-ACTH was
measured in unextracted plasma using a double antibody 125I
kit supplied by Diagnostic Products Corp. (Los Angeles, CA) as
previously described and validated for rat plasma (17). The ACTH
antibody used exhibits low cross-reactivity with 
MSH and
ß-endorphin, and all samples from a given rat were included in a
single assay; the intraassay coefficient of variation was 5.7%.
Statistical analyses
Circadian variation in plasma corticosterone and I-ACTH was
assessed by fitting a single cosine function to profiles within each
rat by the method of least squares using a Sigmaplot nonlinear curve
fitter (Jandel Scientific, San Rafael, CA) (17). The cosine function
used was: y = M + Acos(x + 
), where
y is the measured variable (corticosterone or I-ACTH
concentration), M is the mesor (mean value of the rhythmic profile), A
is the amplitude of the rhythm, x is the time of day
(expressed in radians, where 24 h = 2
radians), and is the
phase angle. A coefficient of determination (r2) for
nonlinear functions was used as an index of cosinor rhythmicity.
Comparisons among group means were made using one-way ANOVA, and where the F test was significant, differences between specific group means were assessed by a least significant difference (LSD) test. For comparisons among cosinor r2 values, the ANOVA was carried out on arcsine-transformed data to adjust for nonnormality. Within groups, paired t tests were used to determine whether the derived amplitude of the circadian variation was significantly different from zero.
The interrelationship between plasma I-ACTH and corticosterone within rats was assessed separately for each of the five groups using analysis of covariance (ANCOVA), with common correlation coefficients and common slopes determined as previously described (22). Differences among groups for the derived slopes were also compared by one-way ANOVA.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and Fig. 1), with the amplitude always
significantly greater than zero (P < 0.05). The degree
of rhythmicity (as reflected in the cosinor r2 value) was
similar in male rats and females at all stages of the cycle (Table 1).
Moreover, there were no differences in the timing of the corticosterone
rhythm among all groups, with the average peak time (acrophase) ranging
from 21 min before to 70 min after lights off. There were, however,
marked differences in the absolute value of corticosterone between male
and female rats and within females across the estrous cycle.
Specifically, the average daily concentration of corticosterone (mesor)
varied with cycle stage (P < 0.001), being lowest at
estrus (129 ± 11 ng/ml) and rising progressively over the next 3
days to a maximum at proestrus (246 ± 14 ng/ml) that was almost
double the value at estrus (Fig. 2). The
mesor corticosterone value in male rats (102 ± 21 ng/ml) was not
different from that in estrous females, but was significantly lower
than values in females at all other stages of the cycle
(P < 0.001). Cycle-related changes in the
corticosterone mesor were primarily due to increases in peak values
(P < 0.001), with trough values remaining unchanged;
therefore, the amplitude of the rhythm also appeared to vary with cycle
stage, although this just failed to reach statistical significance
(P = 0.07). Thus, peak corticosterone levels in females
rose progressively from 293 ± 17 ng/ml at estrus to 472 ±
49 ng/ml at proestrus; the lowest peak corticosterone was observed in
male rats (206 ± 39 ng/ml), but this did not differ significantly
from corresponding values in females at either estrus or
postestrus.
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).
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). Unlike the corticosterone profiles, however,
there were no detectable gender- or cycle-related differences in
absolute levels of the derived I-ACTH parameters (i.e.
mesor, amplitude, trough, or peak; Table 1).
Interrelationship of plasma I-ACTH and corticosterone
There was a strong positive relationship between plasma
corticosterone and I-ACTH in male rats and in females at all stages of
the estrous cycle. The common correlation coefficient derived by ANCOVA
was highly significant for each group (P < 0.001;
Table 3), and the associated common slope
appeared to be higher at proestrus than those in all other groups (see
Fig. 3). Accordingly, the slope of the
within-rat regression lines for the association between plasma
corticosterone and I-ACTH varied significantly among the groups
(P < 0.01, by one-way ANOVA), being higher in
proestrous females than in male rats or females at estrus or diestrus
(Table 3). Thus, for each unit of circulating I-ACTH, the greatest
amount of circulating corticosterone was evident at proestrus.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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During the estrous cycle, the absolute concentration of corticosterone varied considerably with cycle stage, but the degree of circadian rhythmicity was maintained. Thus, the corticosterone mesor (average daily concentration) rose progressively from the day of estrus to the following proestrus, effectively doubling over this period. This change was primarily due to increased corticosterone levels at the peak of the daily rhythm, consistent with previous studies employing serially independent sampling models (11, 12, 13). Although we detected no cycle-related differences in corticosterone trough levels derived by cosinor analysis, there was a small, but transitory, increase in plasma corticosterone in the morning of proestrus. A similar rise in plasma corticosterone has been observed in previous studies in which more than one morning blood sample was collected at proestrus (12, 13). The proximity of this rise to the onset of the light phase suggests that it involves a neuroendocrine response to the light-dark cycle, but interestingly, this effect did not appear to be mediated via I-ACTH.
In addition to these cycle-related changes, the present study also provides an important clarification of gender-related differences in plasma corticosterone. Our data show for the first time that there was no difference in the plasma corticosterone profiles between males and estrous females, but a minor difference became evident at postestrus, and this progressed to a more than 2-fold difference in mesors by proestrus. The similarity in corticosterone profiles of male rats and estrous females has not been reported in previous gender studies, possibly because females in these reports were considered as a single group with apparently no account taken of stage, length, or regularity of estrous cycles. The sexual dimorphism in plasma corticosterone observed at other cycle stages is presumably due to increased adrenal secretion in females, as the MCR of corticosterone is similar between the sexes (23, 24, 25) despite the considerably higher plasma level of corticosteroid-binding globulin (CBG) in females (26). Although the latter would be expected to result in a reduced MCR of corticosterone, this appears to be negated by the higher expression of catabolic enzymes for corticosterone in the female liver (25). Changes in plasma corticosterone during the estrous cycle are also unlikely to reflect shifts in CBG levels, as the proportion of total plasma corticosterone that is unbound appears stable across the cycle (11). This is consistent with the observation that sexual dimorphism in CBG levels of the rat primarily reflects the masculinizing effect of androgens during development in males, rather than any sensitivity of CBG to estrogen in adult females (27). Indeed, even ovariectomy in the adult female rat has no demonstrable effect on the level of plasma CBG (27).
A distinct circadian pattern of plasma I-ACTH, synchronous with that of corticosterone, was also clearly evident across the estrous cycle and in male rats. Unlike plasma corticosterone, however, there were no differences in absolute values of I-ACTH with regard to either sexual dimorphism or estrous cycle stage. This contrasts with previous reports suggesting that gender- and cycle-related differences in corticosterone are associated with changes in plasma I-ACTH (6, 8, 11). This disparity is most likely due to the different approaches to blood sampling, as in these previous studies blood was obtained after decapitation. On the basis of observations made using a chronically cannulated rat model, Viau and Meaney (16) proposed that cycle-related differences in I-ACTH levels may reflect variable responses to the stress of sampling rather than differences in resting levels. Indeed, we show in the present study that morning levels of I-ACTH in plasma obtained after decapitation at diestrus are higher than corresponding levels in chronically cannulated rats, a sampling effect that precluded detection of any diurnal variation in I-ACTH. Importantly, this effect on I-ACTH was not reflected in plasma corticosterone levels, which were similar in the two groups. Because changes in plasma corticosterone in response to acute stress are known to occur relatively slowly (over a period of minutes) (9, 28, 29) compared with more immediate I-ACTH changes, these results indicate that differences observed between the chronically cannulated and the decapitated rats reflect the stress associated with sampling. A similar effect of sampling stress may also explain why Allen-Rowlands et al. (5) were able to show clear diurnal variation in plasma corticosterone, but not in plasma I-ACTH, in decapitated male and female rats.
Although cycle-related variation in plasma corticosterone was not due to corresponding variation in plasma I-ACTH, levels of both hormones remained strongly and positively correlated at all stages of the cycle, indicative of continued regulatory control of the adrenal by the pituitary. These observations show that the nature of the relationship between plasma corticosterone and I-ACTH is sexually dimorphic and changes across the estrous cycle. Indeed, the slope of this relationship within rats varied significantly with cycle stage and was higher (i.e. more corticosterone per unit I-ACTH) in proestrous females than in males. This effect is most likely due to increased adrenal responsiveness to a given trophic stimulus, as the strong correlation between plasma corticosterone and I-ACTH was always maintained. In addition to changes in adrenal responsiveness, the nature of the corticosterone/I-ACTH relationship could be affected by shifts in the bioactive (B)/I-ACTH ratio, which is known to vary in other species (30, 31). Buckingham et al. (13) reported elevated levels of ACTH measured by a cytochemical bioassay at proestrus, although plasma samples in this previous study were obtained after decapitation, so this may simply reflect the heightened response to sampling at this stage of the cycle (see above). Potentially, any changes in the B/I-ACTH ratio could involve a shift in the posttranslational processing of the POMC molecule from which ACTH is derived. Indeed, different products of the POMC molecule can either suppress (32) or enhance (33) ACTH stimulation of adrenocortical steroidogenesis. Clearly, therefore, direct assessment of gender- and cycle-related variation in the plasma B/I-ACTH ratio is warranted.
It is also noteworthy that changes in the relationship between plasma corticosterone and I-ACTH imply that feedback sensitivity to corticosterone must also change across the cycle, as I-ACTH levels consistently exhibited the same daily increase despite higher plasma corticosterone. This contention is supported by recent observations of impaired negative feedback of glucocorticoids after stress at times of high estrogen exposure (10, 11) and thus suggests that this feedback impairment is also operable in the basal unstressed state.
Sex differences in the HPA axis have previously been attributed to the stimulatory effect of estradiol. In the present study the pattern of mesor corticosterone variation across the estrous cycle closely paralleled that of the normal pattern of ovarian estradiol secretion (14), and given that this variation in plasma corticosterone is not driven by changes in I-ACTH secretion, any effect of estrogen would probably be at the level of the adrenal. This contention is consistent with evidence from both in vitro and in vivo studies showing a direct, positive effect of estrogen on adrenal corticosteroid secretion (18, 19) and the presence of the estrogen receptor within the adrenal cortex of the rat (34, 35, 36) and other species (37, 38). It is also noteworthy that there was no difference between the respective corticosterone or I-ACTH profiles of male rats and estrous females. This absence of sexual dimorphism in females at estrus suggests that the low levels of estradiol present at this stage of the cycle are insufficient to stimulate the HPA axis. Moreover, although androgens have been shown to suppress the stress response of the HPA axis (39), the present work shows that no such effect is apparent with respect to basal activity.
Despite the clear variation in absolute levels of corticosterone across the estrous cycle, circadian rhythms of both corticosterone and I-ACTH always remained synchronous, and the timing of each was unaffected by gender or cycle stage. This contrasts with previous observations of marked sexual dimorphism in the circadian pattern of rat hypothalamic CRH content (2) and the loss of diurnal variation in hypothalamic CRH content at diestrus of the cycle (40). The reasons for these discrepancies are not clear, but may relate to changes in the relationship between secreted and stored hypothalamic CRH, with the implication that this relationship varies with gender and cycle stage.
The rise in mesor corticosterone observed at proestrus may be physiologically important in relation to the mobilization of fuel supplies, as normally at this stage of the cycle, or after estradiol supplementation, rats become more active but decrease their food and water intake (41, 42, 43). In this setting, increased plasma corticosterone may be required to promote mobilization of fuel supplies and thus facilitate the greater energy expenditure associated with increased activity. It has also been proposed that because stress can be detrimental to the hypothalamic-pituitary-ovarian axis (44), estrogen-induced impairment of negative feedback at proestrus (10, 11) ensures that female fertility is maximally sensitive to environmental stresses at this time (16). As part of the stress-induced inhibition of the hypothalamic-pituitary-ovarian axis relates directly to elevated glucocorticoid levels (45), the results of the present study suggest that the heightened response of the HPA axis to stress at proestrus may be amplified through greater adrenocortical responsiveness at this time.
In conclusion, this study shows that the extent of sexual dimorphism in resting plasma corticosterone levels is clearly dependent on estrous cycle stage, being absent at estrus and maximal at proestrus. Moreover, although plasma corticosterone is always positively associated with plasma I-ACTH within rats, the nature of this association changes across the estrous cycle. Thus, the gender- and cycle-related variations in absolute levels of plasma corticosterone are not accompanied by corresponding shifts in plasma I-ACTH, suggesting increased responsiveness of the adrenal cortex to trophic stimulation at times of high estrogen secretion.
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Footnotes |
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2 Supported by an Australian Postgraduate Research Award.
Received April 4, 1997.
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4-steroid hydrogenase activity on adrenal cortical
function. Endocrinology 68:747–758
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