Departments of Physiology and Pharmacology, Obstetrics and Gynecology, and Perinatal Research Laboratories, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27157-1066
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ABSTRACT |
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We examined the effects of exogenous cortisol on
plasma immunoreactive adrenocorticotropic hormone (iACTH), bioactive
ACTH (bACTH), and ACTH-(139) in nine adrenalectomized fetuses at
126-130 and 136-140 days of gestation. Fetuses received 4 h
of cortisol (2 µg · kg
1 · min
1)
or saline infusions on consecutive days. Blood was obtained before and
at intervals during infusions. Arterial blood gases and hematocrits
were normal and did not change with age. Plasma cortisol did not change
during saline infusions but increased significantly (range 30-70
ng/ml) during cortisol infusions. Basal plasma iACTH, bACTH,
ACTH-(1
39), and bACTH-to-iACTH and ACTH-(1
39)-to-iACTH ratios were
significantly higher in the older fetuses. Cortisol infusions decreased
plasma iACTH, bACTH, and ACTH-(1
39) in both groups, and the
suppression as a percent of the baseline was similar. The
bACTH-to-iACTH ratio declined to the same level at 126-130 (0.201 ± 0.040 to 0.051 ± 0.002) and 136-140 (0.389 ± 0.088 to 0.046 ± 0.002) days of gestation. These data
suggest that physiological concentrations of cortisol selectively
inhibit bACTH secretion, and the ACTH response to cortisol inhibition
is not different between 126 and 140 days of gestation in
adrenalectomized sheep fetuses.
ovine; adrenocorticotropin; adrenalectomy; pituitary; adrenocorticotropic hormone; bioactive adrenocorticotropic hormone; immunoreactive adrenocorticotropic hormone
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INTRODUCTION |
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IN THE SHEEP FETUS, maturation of the hypothalamic-pituitary-adrenal axis is necessary for organ maturation, the response to stress, and the onset of parturition (6). Adrenocorticotropic hormone (ACTH), secreted by anterior pituitary corticotrophs, plays an integral role in this axis by inducing the synthesis and release of cortisol from the adrenal cortex. Plasma concentrations of ACTH are regulated positively by the hypothalamic hormones corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) and negatively by cortisol.
ACTH-(139) is synthesized as part of larger precursor molecules (7).
Two posttranslational processing steps of pro-opiomelanocortin are
necessary for the production of ACTH-(1
39). ACTH-(1
39) and its
precursors [the latter have been reported to have weak
steroidogenic activity (8)] represent immunoreactive ACTH (iACTH)
secretory products of the anterior pituitary. Because ACTH antibodies
bind to specific amino acid sequences of the ACTH-(1
39) molecule, radioimmunoassays (RIAs) for ACTH can react with both ACTH-(1
39) and
its higher molecular weight precursors. Given the differences in
bioactivity of ACTH and its precursors, changes in iACTH may or may not
reflect identical changes in bioactivity.
There is increasing evidence of differential regulation of the
secretion of bioactive ACTH (bACTH), iACTH, ACTH-(139), and ACTH
precursors during basal and stimulated conditions. ACTH-(1
39) is the
most potent known activator of adrenal steroidogenesis, whereas the
ACTH precursors have been shown to block this effect at the fetal
adrenal (21). Experiments in humans (10), dogs (8), and sheep (3, 28)
have shown that the basal secretion of iACTH consists predominantly of
ACTH precursors that contain relatively little ACTH bioactivity. In
contrast, various stressors not only increase plasma iACTH but also
increase the bACTH-to-iACTH (8, 10, 28) and ACTH-(1
39)-to-ACTH
precursor ratios [bACTH/iACTH and ACTH-(1
39)/ACTH
precursors] (3, 28). In the developing sheep fetus it is also
particularly interesting that the ACTH-(1
39)/ACTH precursors under
basal conditions increases as a function of age over the last third of
gestation (3).
Recent findings have shown that the secretion of bACTH and ACTH-(139)
appears to be relatively more sensitive to negative steroid feedback
than is secretion of iACTH and ACTH precursors. We have observed that a
chronic elevation of plasma cortisol attenuated the iACTH and abolished
the bACTH responses to hemorrhage in 0.70 gestation sheep fetuses (28).
We have also observed that in fetuses with higher concentrations of
plasma cortisol, the bACTH and ACTH-(1
39) responses to both CRF and
AVP were reduced, whereas the iACTH and ACTH precursor responses were
unchanged (29). These results were consistent with the finding that
dexamethasone, a potent synthetic corticosteroid, inhibited the CRF-
and AVP-induced pituitary secretion of ACTH-(1
39) but had little or
no effect on the secretory responses of ACTH precursors in vitro (20).
The primary goal of this investigation was to test the hypothesis that
an acute elevation of plasma cortisol would have a greater negative
feedback effect on plasma bACTH than plasma iACTH, thereby causing a
reduction in the plasma bACTH/iACTH. We tested this hypothesis in
adrenalectomized sheep fetuses to begin with a situation in which
plasma iACTH and bACTH would be elevated. We also measured ACTH-(139)
to better characterize the nature of the plasma peptides constituting
iACTH. Furthermore, because there are some data that suggest the
sensitivity of ACTH secretion to steroid feedback is reduced near term,
we studied the same fetuses at 128-131 (0.70) and 136-140
(0.95) days of gestation to determine whether the inhibitory effects of
cortisol are diminished close to term (15, 26, 27).
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METHODS |
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Animal preparation. In a longitudinal study, fetuses of nine time-dated sheep of mixed breeds were all studied twice at 126-130 and at 136-140 days of gestation (term is about 145 days). The ewes were kept in portable carts and given food and water ad libitum. One day before surgery (120 ± 0.5 days of gestation) food and water were removed. The surgery included bilateral adrenalectomy of the fetus and the placement of catheters in the femoral arteries and veins of the fetus and ewe. Details of the surgical procedures have been described (17). Because the dose of cortisol was relative to weight, fetal weight was estimated at the time of each infusion and was based on previous data (11). All procedures were approved by our Institutional Animal Care and Use Committee.
Infusion.
Each study was performed at the two ages. On two consecutive days the
fetus received either a 4-h infusion of 2 µg · kg1 · min
1
cortisol (11
,17
,21-trihydroxy-4-pregnene-3,20-dione) or isotonic saline (room temperature) in random order at an infusion rate of 1.0 ml/h. Based on previous work this dose of cortisol has been shown to
increase plasma cortisol within a physiological range.
Blood collection.
Arterial blood (6-8 ml) was obtained before (0) and 30, 60, 120, 180, and 240 min after the infusions began to measure blood gases,
hematocrit, and hormone concentrations. After each sample an equivalent
volume of saline was given as volume replacement, and at the end of the
experiment 40 ml of maternal blood were infused into the fetus. Blood
was collected in sterile syringes with 0.70 ml used for the measurement
of blood gases and pH, whereas the remainder was transferred to chilled
polystyrene test tubes with EDTA (1.4 mg EDTA/ml blood) and centrifuged
(3,000 revolutions/min) for 10 min at 4°C for the measurement of
plasma hormones. Plasma was then collected and stored at
20°C.
RIAs.
Cortisol in plasma and incubation medium was measured by RIA as
previously described (19). The tracer
([1,2,6,7-3H]cortisol)
was supplied by Amersham, and the antibody [antigen: cortisol-3-O-carboxymethyl-ether-bovine serum
albumin] was supplied by ICN (Costa Mesa, CA). Total iACTH was
measured by RIA as previously described (18). We define iACTH as that
material obtained from plasma that displaces the binding of tracer
quantities of 125I-labeled ACTH
from antisera directed toward the 624 portion of the ACTH molecule
(4, 5). Our antisera show 100% cross-reactivity with human
ACTH-(1
24), human ACTH-(1
39), and rat ACTH-(1
39), <20%
cross-reactivity with NH2-terminal
ACTH-(1
17) or ACTH-(18
39), and no cross-reactivity with
ACTH-(1
10), ACTH-(1
10) amide, ACTH-(4
11), ACTH-(11
19),
ACTH-(11
24), or ACTH-(25
39). The same standard preparation
[human ACTH-(1
39)] was used for the RIA,
immunoradiometric assay (IRMA), and bioassay. It was
obtained from Peninsula Laboratories, and the amino acid composition
was confirmed by the Protein Core Laboratory at the Bowman Gray School
of Medicine.
Extraction for bioassay. Fetal plasma unknowns and ACTH standards added to ACTH-free plasma were extracted by adsorption onto 70-mg 100-mesh glass (Corning Glass Works, Corning, NY) and then washed in 0.05 M phosphate buffer. ACTH-like bioactivity was eluted from the glass by treatment with 0.25 N hydrochloride-acetone. The recovery of 125I-ACTH extracted from plasma with each assay was 65 ± 3%. Details of these extraction procedures have been recorded (4, 5).
Bioassay.
We define bACTH as that material obtained from plasma extracts that
stimulates the secretion of cortisol from dispersed, cultured adult
sheep adrenocortical cells. Bioactivity is compared with known
concentrations of synthetic ACTH-(139) in the same assay. Adrenocortical cells were cultured and equilibrated to serum-free conditions for 3 days and then replicate wells were exposed to either
standard ACTH or various concentrations or a sample of plasma extract
(same volume). After 2 h the media were recovered, and cortisol
secreted into the media was measured by RIA. The minimum effective
concentration of bACTH was 2 pg/ml, and all data were corrected for
recovery. Details of the bioassay procedures have been described (4, 5,
21).
IRMA.
Because saline had no inhibitory effects on plasma iACTH and bACTH,
ACTH-(139) was measured by a two-site IRMA only in the cortisol-infused groups. The IRMA for ACTH-(1
39) uses two
radiolabeled monoclonal antibodies: one is directed at the sequence
ACTH-(10
18) and the other is directed at the sequence ACTH-(25
39).
The IRMA is specific for ACTH-(1
39). At concentrations present in
fetal sheep plasma, cross-reactivity with ACTH precursors is
negligible. Details of the IRMA procedures and validation for use in
sheep plasma have been given (2, 23).
Statistical analysis. Changes in hormone concentrations, blood gases, and hematocrits were analyzed by the analysis of variance. Newman-Keuls test was used for post hoc analyses. Regression analysis was used to compute the slope of the lines describing the relationship between the change in cortisol and the percent change in ACTH between 0 and 120 min for animals at both gestational age ranges. Student's t-test was then used to compare the slopes at the two age ranges. Differences were significant when P < 0.05. Data are presented as means ± SE.
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RESULTS |
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Blood gases, pH, and hematocrit. Arterial blood gases, pH, and hematocrit were not significantly different between the age groups. The means for both groups were pH 7.32 ± 0.01, PO2 22.0 ± 2.0 mmHg, PCO2 53.0 ± 4.0 mmHg, and hematocrit 37.0 ± 2.0%. In each age group there were small, yet significant, increases (37.4 ± 2.0 to 38.6 ± 2.0%) in hematocrit in the cortisol-infused groups and decreases in PO2 (21.3 ± 2 to 20.5 ± 2 mmHg) in the saline-infused group.
Plasma cortisol. Basal plasma concentrations of cortisol were not significantly different between the age groups and did not significantly change during the saline infusions (Table 1). Plasma cortisol concentrations significantly increased during the cortisol infusions at all time points in each age group and were not significantly different between the age groups at 0, 30, 60, or 120 min, but were higher at 180 and 240 min in the older animals.
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Plasma iACTH by RIA. Plasma concentrations of iACTH were significantly greater in the older than younger group (F = 8.4, P < 0.02) at 0 (i.e., basal) and 60 min (Fig. 1, top). In both age ranges, plasma concentrations of iACTH significantly decreased during the cortisol infusion (F = 16, P < 0.01). In contrast, plasma concentrations of iACTH did not significantly change at either age during the saline infusion with the exception of an increase observed at 240 min (not shown).
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Plasma bACTH by bioassay. Basal plasma bACTH concentrations were significantly higher in the older than younger group (F = 7.1; P < 0.04; Fig. 1, middle). Plasma concentrations of bACTH significantly decreased (F = 15.1, P < 0.01) during the cortisol infusion but did not significantly change in either age group during the saline infusion.
Plasma ACTH-(1Percent suppression of iACTH, bACTH, and ACTH-(139).
Relative to basal concentrations, plasma iACTH, bACTH, and ACTH-(1
39)
were significantly reduced in each age group
(F = 58.7, P < 0.01). Furthermore, there were
no significant differences between the age groups in the percent
reductions in iACTH, bACTH, and ACTH-(1
39).
Correlations among iACTH, bACTH, and ACTH-(139).
The correlations for iACTH-ACTH-(1
39) and bACTH-ACTH-(1
39) were
0.79. The correlation for iACTH-bACTH was 0.69.
Plasma bACTH/iACTH and ACTH-(139)/iACTH.
Basal plasma bACTH/iACTH was significantly higher in the older than
younger group (F = 7.7;
P < 0.02; Fig.
2). Plasma bACTH/iACTH and
ACTH-(1
39)/iACTH significantly decreased during the cortisol infusion
at each age (F = 9.8, P < 0.01).
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DISCUSSION |
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To our knowledge this is the first study that measures the bioactivity
of ACTH in fetal plasma after adrenalectomy and tests the hypothesis
that an acute elevation of plasma cortisol has a greater negative
feedback effect on plasma bACTH than plasma iACTH, thereby causing a
reduction in plasma bACTH/iACTH. We tested this hypothesis in
bilaterally adrenalectomized sheep fetuses because we anticipated
marked elevations in both resting plasma iACTH and bACTH. The results
of this study supported our hypothesis as well as our expectations
regarding resting plasma iACTH and bACTH. Thus the present study
suggests that secretion of the different molecular weight forms of ACTH
may be subject to differential influence by exogenous cortisol in
adrenalectomized sheep fetuses, thereby resulting in alterations of the
ratios of bioactive to immunoreactive ACTH and total immunoreactive to
ACTH-(139) in the plasma.
Several studies have shown that the secretion of bACTH appears to be
more sensitive to negative steroid feedback than the secretion of
iACTH. In intact fetuses at 0.70 gestation, a 6-day infusion of
cortisol that increased basal plasma cortisol concentrations from about
3 to 21 ng/ml attenuated the iACTH but abolished the bACTH responses to
hemorrhage (28). Other experiments have compared responses at two
gestational ages with different background levels of cortisol. In older
(0.92 gestation) intact fetuses with basal plasma concentrations of
cortisol ranging from about 30 to 40 ng/ml, the bACTH and ACTH-(139)
responses to CRF and AVP were reduced, whereas the iACTH and ACTH
precursor responses were unchanged compared with responses in younger
(0.70 gestation) intact fetuses with basal plasma cortisol
concentrations ranging from 3 to 7 ng/ml (29). In another study, the
percentage of low molecular weight ACTH in plasma was found to be
higher (48%) in adrenalectomized than intact fetuses (27%) between
126 and 139 days of gestation (16), again suggesting a selective
inhibition of ACTH-(1
39) by adrenal steroids. In the present study a
4-h infusion of cortisol that increased plasma cortisol from about 4 to
60 ng/ml led to greater and more rapid reductions in bACTH than iACTH.
Taken together these studies suggest that the secretion of bACTH is
more sensitive to physiological increments in cortisol than iACTH in
both intact and adrenalectomized sheep fetuses.
In this study adrenalectomized sheep were used to test the effects of cortisol against a background of elevated ACTH. In intact term fetal sheep plasma ACTH concentrations are low relative to the magnitude of ongoing pulsatile fluctuations (1, 12). After adrenalectomy, ACTH levels are higher and the effects of cortisol more likely to be pronounced and measurable.
The quicker decrease in plasma bACTH than iACTH may be due to the
relative activity of cortisol on different cells. In rat pituitaries
there are reports of heterogeneity among individual corticotrophs with
respect to the presence of unprocessed pro-opiomelanocortin relative to
fully processed ACTH in secretory granules (22). In adult
sheep pituitary cells dexamethasone inhibits the ACTH-(139) secretory
response to vasopressin in some but not all classes of corticotrophs
(20). A preferential action of glucocorticoids on cells that contain
relatively more ACTH-(1
39) would thus be expected to decrease bACTH
concentration more than iACTH. In this regard, a decrease in the
ACTH-(1
39)/ACTH precursors secreted in response to glucocorticoids
has been demonstrated in vitro using slices of fetal sheep pituitary
(14). Another possible explanation for the more rapid decrease in bACTH
involves clearance from the plasma rather than, or in addition to,
effects on secretion. If bACTH [probably mostly
ACTH-(1
39)] is degraded or excreted faster than other
immunoactive forms of ACTH in fetal sheep, as in rats (2), then
cortisol could produce the results reported here.
It is important to note that several investigators have reported that
at increasing gestational ages there are increases in the percentage of
low molecular weight ACTH and ACTH-(139) in fetal sheep plasma during
both unstimulated and stimulated conditions (3-5, 12, 13). In
light of the finding that ACTH-(1
39)/ACTH precursors secreted by
fetal sheep pituitary slices increase with age, the changes in plasma
ACTH-(1
39) and ACTH precursors likely reflect the physiological
maturation of the pituitary. In a recent study we did not observe
age-related increments in the basal bACTH/iACTH in intact fetal sheep
(29). However, we noticed an interesting difference between the earlier
study (intact fetuses) and the present study (adrenalectomized
fetuses). Compared with intact fetuses, the basal bACTH/iACTH and
ACTH-(1
39)/iACTH were significantly greater at both ages in the
adrenalectomized fetuses. This suggests that the rising concentrations
of plasma cortisol during the last third of gestation are necessary for
maintaining the low bACTH/iACTH in fetal plasma under basal conditions.
Another aim of this investigation was to determine if the degree of suppression of plasma bACTH and iACTH by cortisol changes between 126-130 and 136-140 days of gestation in adrenalectomized fetuses. Based on previous work in adrenalectomized fetuses, we anticipated that basal concentrations of iACTH and bACTH would increase with age (24). As expected, the basal concentrations of bACTH and iACTH were higher in the older group. Therefore, we expressed the negative effects of cortisol on bACTH and iACTH by measuring the suppression of bACTH and iACTH relative to their basal concentrations. Although significantly higher concentrations of plasma cortisol were measured in the older fetuses at 180 and 240 min (probably because of an overestimate of growth), the suppression (as a percent of basal value) of bACTH and iACTH was very similar in both groups when plasma cortisol concentrations were not significantly different (i.e., at 30, 60, and 120 min) between groups. Furthermore, when comparing the percent suppression of bACTH or iACTH vs. the absolute changes in cortisol, the two age groups were not significantly different (P > 0.8). Thus the ability of increase in plasma cortisol to suppress bACTH and iACTH levels does not appear to change between 126 and 140 days of gestation in adrenalectomized sheep fetuses.
However, there are data suggesting that the sensitivity of ACTH secretion to steroid feedback is reduced in intact sheep fetuses late in gestation. For example, cortisol infusions did not inhibit basal or stress-induced increments in ACTH levels between 132 and 142 days of gestation (26, 27), whereas between 117 and 131 days of gestation the fetal ACTH responses to stress were blocked (25). Also, plasma iACTH concentrations do not decline despite exponential increments in endogenous plasma cortisol in late gestation (6). Furthermore, the negative effects of dexamethasone implants adjacent to the paraventricular nucleus on steady-state concentrations of corticotropin-releasing hormone and pro-opiomelanocortin mRNA appear to be attenuated in late-term fetuses (15). Thus some data suggest that both the hypothalamus and pituitary may exhibit reduced sensitivity to glucocorticoids in late gestation, but the specific mechanisms are unknown. If there is, in fact, a reduced sensitivity to cortisol feedback in late gestation, then the results of this present study indicate that the reduced sensitivity is dependent on the presence of the fetal adrenal glands.
Finally, this is the first study that measured the correlations among
bACTH, iACTH, and ACTH-(139). The correlations suggest that although
ACTH measurements by RIA, bioassay, and IRMA are not quantitatively
identical, they do reflect similar qualitative changes.
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ACKNOWLEDGEMENTS |
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We are grateful for the supply of reagents for the ACTH-(139)
IRMA from Dr. Anne White, University of Manchester, and for the support
and encouragement of Dr. Eberhard Mueller-Heubach.
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FOOTNOTES |
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This work was supported by the National Institute of Child Health and Human Development Grant HD-11210.
Address for reprint requests: J. C. Rose, Dept. of Physiology, Bowman Gray School of Medicine of Wake Forest Univ., Winston-Salem, NC 27157-1066.
Received 30 July 1997; accepted in final form 14 November 1997.
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