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Department of Physiology (B.J.C., I.R.Y.), Monash University, Clayton, Victoria 3168, Australia; and Division of Endocrinology and Metabolism (J.D.V.), Department of Internal Medicine and National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: Dr. B. J. Canny, Department of Physiology, Monash University, Clayton, Victoria, 3168, Australia. E-mail: ben.canny{at}med.monash.edu.au
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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hydroxylase and other
enzymes in the placenta to promote the preferential biosynthesis of
estradiol, rather than progesterone, thus also stimulating the
production of prostaglandins and promoting uterine contractility (3).
The control of the prepartum cortisol surge is complex and, despite
many years of investigation, remains unclear (4). Normal parturition
and fetal maturation will not progress in the absence of a pituitary
gland, though labor and the cortisol surge can be induced in
hypophysectomized fetuses with ACTH treatment (5). It is not clear,
however, whether a prepartum increase in ACTH is a true prerequisite
for the cortisol surge, because not all studies have reported increases
in ACTH concentrations, and in those that have, the increase in ACTH
does not necessarily precede the increase in cortisol and never matches
it in magnitude (reviewed in Ref. 4). Furthermore, in recent studies,
we have shown that a constant infusion of ACTH is sufficient to induce
normal adrenal growth, an appropriate prepartum increase in cortisol
concentrations, and normal labor in hypophysectomized fetuses, without
an associated increase in plasma ACTH concentrations, thereby throwing
into question the precise role of ACTH in adrenal maturation (6, 7). Against this background, the fate of fetuses that have undergone successful hypothalamo-pituitary-disconnection (HPD) poses a number of questions (8, 9, 10). These fetuses fail to generate a normal cortisol surge or initiate labor, a finding consistent with other studies that suggest that an intact hypothalamic drive is necessary for the activation of the fetal pituitary-adrenal axis (11). It has also been recently reported that the HPD operation is associated with a late defect in the expression of steroidogenic enzymes and growth of the fetal adrenal (10, 12). When, however, the concentrations of ACTH in the plasma of HPD fetuses are considered, an extremely complex picture emerges. The HPD operation severely attenuates the ability of the fetal pituitary to secrete ACTH in response to a variety of provocative physiological stimuli (13), but basal ACTH concentrations shortly after surgery seem to be elevated or unchanged, compared with those in sham-lesioned control animals (8, 9, 12, 13, 14, 15). A single study has reported a deficit in ACTH concentrations in HPD fetuses, compared with intact controls (10); this only occurred 7–10 days before the expected time of labor, and after the expected time of the normal emergence of the prepartum cortisol surge. Because the defects in adrenal growth and steroidogenic enzyme expression occurred before the onset of the defects in ACTH secretion, the precise role of ACTH in the development of the adrenal in the HPD ovine fetus is still undetermined.
Because the previous assessments of ACTH secretion in the HPD fetuses have been made using single samples taken on given days of gestation, it remains possible that differences in the pulsatile nature of ACTH secretion could explain the lack of development of the adrenal gland. ACTH, like all anterior pituitary hormones, is secreted in a pulsatile manner (16), and extensive studies have demonstrated a tight nexus between ACTH and cortisol secretion in adults (17, 18, 19). There exist only a few reports where ACTH and cortisol secretion in the ovine fetus have been assessed simultaneously, and these suggest that the degree of concordance between ACTH and cortisol secretory episodes is not so great as that in adults (20, 21). Furthermore, this concordance seems to decrease with advancing GA, suggesting that adrenal cortisol secretion in the ovine fetus may be less tightly controlled by ACTH secretion than it is in adult animals. Accordingly, we have assessed the secretory dynamics of both ACTH and cortisol in HPD and intact fetuses, to examine whether defects in ACTH secretion accompany, and possibly explain, the changes in cortisol secretion seen in HPD animals, and to further investigate the role of the hypothalamus in the activation of the pituitary-adrenal axis in the ovine fetus.
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Materials and Methods |
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Experimental protocol and blood sampling
Pulse bleed experiments. At 126 ± 0.3 and 145 ±
0.4 days GA, fetal blood samples (3 ml) were withdrawn at 5-min
intervals for 2 h. Experiments commenced between 1000 and
1200 h, after daily cleaning of the animal rooms and coincident
with the time of feeding. It has been previously established that ACTH
and cortisol concentrations are maximal in fetuses at this time of day
(23). All the HPD fetuses and 3 of the 10 intact fetuses were studied
at both GAs. Four intact fetuses were studied at the earlier GA only,
because of subsequent cannula failure or, in one case, parturition at
144 days GA before the scheduled time of bleeding. A further 3 fetuses
were studied at the later GA only. The interval between the later pulse
bleed experiments and parturition in intact fetuses ranged from 3–8
days. The mean GA at parturition in the ewes with intact fetuses was
148.3 ± 0.7 days; none of the ewes bearing HPD fetuses underwent
labor, and the ewes were killed electively with an iv injection of
pentobarbitone sodium (80 mg/kg; Lethabarb, Arnolds of Reading Pty
Ltd., Boronia, Australia) at 160 days GA.
Blood sampling. Blood samples (3 ml) were collected into chilled sterile tubes containing 30 IU sodium heparin (CSL, Parkville, Australia) for the measurement of fetal immunoreactive (ir) ACTH and cortisol. All blood tubes were centrifuged immediately for 5 min at 2000 x g at 4 C. The separated plasma for irACTH assay was stored immediately at -20 C in tubes containing 5 x 10-3 trypsin inhibitor units aprotinin. Plasma for cortisol assay was stored in plain plastic tubes. Blood cells were aseptically resuspended in sufficient sterile Hartmann’s solution (Baxter Healthcare, Toongabbie, Australia) to restore the original sample volume and were returned to the fetus within 10 min, to minimize changes in blood volume or hemoglobin concentration during the experiment.
Hormone assays
IrACTH was measured (in duplicate) in unextracted fetal sheep
plasma, by RIA using a commercially available kit (ICN Biomedicals
Australasia, Seven Hills, Australia). The antiserum was raised against
synthetic human ACTH1–24; and it cross-reacts with
peptides containing this sequence, including ACTH1–39 and
its high molecular weight precursors. The antiserum cross-reacts less
than 0.8% with ß-lipotropic hormone and less than 0.1% with
-melanocyte-stimulating hormone, ß-melanocyte-stimulating hormone,
-lipotropic hormone, or ß-endorphin. The sensitivity of the assay
was 10 pg/ml, the intraassay coefficient of variation was 9.0% (n
= 9 replicates of a single sample whose mean concentration was 85.6
pg/ml). For deconvolution analysis, a power function was used to relate
within-sample variance to sample mean for all 25 samples per study
session. All samples from an experiment were analyzed in the same
assay. The interassay coefficient of variation was 18.2% at 45 pg/ml,
based on the 4 assays needed for this study.
Cortisol was measured in triplicate by RIA, in fetal sheep plasma after extraction with dichloromethane using a previously described method (24). Antiserum no. 3368 raised in sheep was supplied by Dr. R. I. Cox (Commonwealth Scientific and Industrial Research Organisation, Division of Animal Production, Prospect, New South Wales, Australia). The sensitivity of this assay was 0.41 ± 0.01 ng/ml, and the intra- and interassay coefficients of variation were 9.9% and 13.8%, respectively.
Statistical analysis
All values are expressed as the mean and SE. Hormone
profiles from each pulse bleed experiment were subjected to
simultaneous multiple-parameter deconvolution analysis (25) to
determine the locations, amplitudes, and durations of irACTH and
cortisol secretory bursts and to estimate the half-lives of the
hormones. Cross-correlation analysis was used to define the lagged and
nonlagged relationship between plasma irACTH and cortisol and their
respective secretory rates. To quantify the regularity of secretory
profiles, we determined approximate entropy (ApEn), using the values m
= 1 and r = 20% for all data sets (26). In endocrine studies,
ApEn has clearly discriminated between normal and tumor-bearing
subjects for GH, ACTH and cortisol, and aldosterone release with those
having tumors secreting markedly more irregularly, which is reflected
in increased values of ApEn (27, 28, 29).
The calculated parameters of pulsatile secretion were grouped by
operation type and GA. Mean results were analyzed by multifactorial
ANOVA, the 2 x 2 variables tested being operative group (HPD or
intact) and GA (126 or 145 days). This analysis is able to determine
whether there are significant effects of each of the main parameters
(i.e. operative group and GA) and whether there is an
interaction between the two parameters (i.e. the effect of
the operation is different at the two GAs). A number of parameters were
square root- or log-transformed before analysis, to achieve homogeneity
of variance. A conservative value of 0.01 was chosen for , because
the values from the deconvolution analysis are necessarily derived and
somewhat interdependent, and a large number of separate ANOVAs were
conducted. Because of the large time difference between the two GAs,
and the fact that data were not available for all individuals at both
GAs, we did not adjust for repeated measures. Where significant effects
of operative group or GA were detected, differences between grouped
means of that parameter were compared; when a significant interaction
occurred, the individual means were compared. All post hoc
analyses were conducted using the least-significant-difference test,
with set at 0.01.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and 2.
For both fetuses, and at both ages, there was pulsatile secretion of
both hormones.
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). Basal irACTH secretion was greater
(P < 0.01) in both groups of fetuses at 145 days GA
than in either group at 126 days GA. There was no significant
difference (P > 0.01) between the two groups of
fetuses in basal cortisol secretion at 126 days GA (Fig. 3B); but at
145 days, GA the basal secretion was six times higher in the intact,
compared with the HPD, fetuses (P < 0.01). The basal
cortisol secretion of the HPD fetuses at 145 days GA was not different
(P > 0.01) from the same group of animals at 126 days
GA.
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). The estimated irACTH half-lives for
the young and old intact fetuses were not different from the HPD
fetuses at either GA. Calculated cortisol half-life did not differ
(P > 0.01) among any of the groups of fetuses (Table 2).
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and 2). Correspondingly, the mean interburst intervals
were similar (P > 0.01) between all experimental
conditions (intact and HPD fetuses, 126 and 145 days, Tables 1 and 2).
There were no significant (P > 0.01) effects of
operative group (intact or HPD fetuses) or GA at the time of the pulse
bleed (126 or 145 days) on the calculated burst half-duration for
irACTH or cortisol (Tables 1 and 2).
There was a significant effect (P < 0.01) of the age
of the fetus on the irACTH burst mass, with burst mass being greater in
the older animals (Fig. 4A). There was no
significant effect of the operation (P > 0.01) on
irACTH burst mass. There was a significant (P < 0.01)
interaction between the age of the fetuses and the operation group,
with respect to cortisol burst mass (Fig. 4B). The cortisol burst mass
of the HPD fetuses at 126 days GA was less (P < 0.01)
than that of the intact fetuses at the same age, with the HPD fetuses
at 145 days GA having a cortisol burst mass that was not different
(P > 0.01) from the 2 groups of fetuses at 126 days.
Intact fetuses at 145 days GA had a cortisol burst mass that was
approximately 15 times greater than their HPD counterparts
(P < 0.01). There was, however, no significant
(P > 0.01) effect of either age or operation on irACTH
burst amplitude (Table 1). On the other hand, there were significant
(P < 0.01) effects of both GA and the operation on
cortisol burst amplitude, with cortisol burst mass being greater in
intact (compared with HPD) fetuses and at 145 days GA (compared with
126 days GA) (Table 2).
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), but there was no significant
(P > 0.01) effect of the operation. Mean cortisol
concentrations were greater (P < 0.01) in the intact
fetuses at 145 days GA than in any other group, which were not
different from one another. IrACTH production rate was greater
(P < 0.01) in both groups of fetuses at 145 days GA
than at 126 days, but there was no significant effect of the operation
(Table 1). The cortisol production rate was greater (P
< 0.01) in the older fetuses, and in intact than in HPD fetuses (Table 2). Integrated irACTH levels were higher (P < 0.01) in
both groups of fetuses at 145 days GA, compared with 126 days GA (Table 1), although there was no significant (P > 0.01)
effect of the operation. There was a significant (P <
0.01) interaction between the age of the fetuses and the operation for
integrated cortisol levels (Table 2), with the values for the intact
fetuses at 145 days GA being significantly (P < 0.01)
greater than all other groups of fetuses, which were not different from
one another.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2-fold). In general, HPD fetuses
demonstrated GA-related increases in irACTH secretion parameters, which
were similar to those observed in the intact fetuses; but there was a
dramatic lack of maturation of cortisol secretion. These findings
suggest that, whereas an intact connection between the hypothalamus and
pituitary is not critical for the normal development of irACTH
secretory parameters in the ovine fetuses, it is essential for normal
adrenal development. IrACTH secretion was found to be pulsatile in intact and HPD fetuses at both 126 and 145 days GA. We estimate that there are approximately 2 bursts of irACTH secretion every hour, in the late gestation ovine fetus, whether the pituitary is disconnected from the hypothalamus or not. This estimate is in close agreement with previous independent assessments of irACTH pulse frequency in the late gestation ovine fetus, and, as has been reported in previous studies, there was no difference between the young and old fetuses in the frequency of irACTH bursts estimated in a 2-h period (20, 21). These observations suggest that an intact hypothalamo-pituitary axis is not an important determinant of pulsatile basal irACTH secretion in the ovine fetus. Of interest, pulsatile irACTH secretion also persists under basal conditions in adult sheep after HPD, at a frequency that is statistically indistinguishable from that seen in intact animals (30). These data are in keeping with studies of the secretion of CRF and arginine vasopressin into the hypophyseal-portal circulation, which have generally revealed a tight relationship between the hypothalamic peptide release and systemic irACTH secretion in response to stress, but not under basal conditions (30, 31). Furthermore, in mice made CRF-deficient by targeted disruption of the expression of the CRF gene, the development of corticotrophs in the anterior pituitary seems unaffected, when compared with wild-type mice, and basal plasma irACTH concentrations are not significantly altered (32, 33). It seems, therefore, that in the basal state of the ovine fetus, and possibly adult animals, there is an endogenous ultradian rhythm of irACTH secretion that is not dependent on the secretion of CRF, arginine vasopressin, or other potential HPD-affected ACTH secretagogues from the hypothalamus.
The primary parameters of irACTH secretion that differed with advancing GA and the state of the hypothalamo-pituitary connection were the rate of basal irACTH secretion and the size or mass of irACTH secretory bursts. For both measures, the values in the HPD animals at 126 days GA tended to be lower than in the intact fetuses. By 145 days, however, there was complete recovery of any defect in basal irACTH secretion or irACTH secretory burst mass, such that the mean values in HPD fetuses were not statistically different from those seen in intact fetuses. These findings suggest that whereas the neurosurgical intervention of HPD may cause some early disruption of irACTH secretion, by the end of gestation, corticotroph secretion in HPD animals is indistinguishable from that seen in intact fetuses.
Previous reports of the effect of HPD on irACTH secretion have varied in their conclusions. Early studies found that after HPD, irACTH secretion was initially increased (8, 13, 15, 34), as has been reported for the effects of HPD on irACTH secretion in the adult sheep (30, 35). These findings have been interpreted as reflecting the role of an endogenous hypothalamic corticotrophin-release inhibitory factor in the fetus, as has been postulated for adult animals by a number of workers (36, 37). Later studies examining the effects of HPD on irACTH secretion have reported either no effect of the operation on basal irACTH secretion (9, 12, 14), or a failure of HPD fetuses to demonstrate the same late gestational increase seen in intact fetuses (10). In the present study, we found no effect of HPD on mean irACTH concentrations at either 126 or 145 days. These various studies on the effect of HPD on fetal irACTH secretion have involved different blood sampling protocols and a variety of GAs at which the surgical procedure was performed (103–135 days GA), but the effect of HPD does not seem to be consistently related to the time of operation. An apparently important variable among the studies is the assay employed to measure ACTH. All studies that have reported increases in irACTH secretion after HPD have employed the same assay (38), whereas those using an immunoradiometric assay (9, 10, 12) or a commercially available RIA (the present study) found no stimulatory effect of the operation. Whether differences in assay technique explain the different conclusions of these studies has not been formally assessed. Taken together, it seems that levels of irACTH are not consistently enhanced after HPD, a conclusion which argues against a significant role for a hypothalamic corticotrophin-release inhibitory factor in regulating ACTH secretion in the ovine fetus, under basal conditions.
The majority of publications (8, 9, 13, 15, and the present study) suggest that basal irACTH concentrations increase with advancing GA in the HPD fetus. An exception to this general observation is the study of Phillips et al., where no increase in basal ACTH1–39 concentrations was found in HPD fetuses between 120 and 140 days GA (10). When GA-related increases in basal irACTH concentrations have been observed in HPD fetuses, they have, in general, been similar to those seen in intact fetuses. These observations further suggest that an intact hypothalamo-pituitary connection is not a prerequisite for the prepartum increase in basal irACTH secretion. Furthermore, the results of the present study, when considered in the light of other reports, suggest that the hypothalamus plays little role in the regulation of a number of aspects of basal irACTH secretion in the ovine fetus, including pulsatile secretion and the prepartum increase.
Cortisol secretion was also found to be pulsatile in both the intact and HPD fetus, exhibiting about two bursts every hour, with no difference observed between intact and HPD animals at either GA. This frequency is similar to both that observed for irACTH in the same animals and previous reports of pulsatile cortisol secretion in the late gestation fetus (20, 21), but unlike Apostolakis et al. (21), we did not find any change in the number of cortisol bursts with advancing gestation. Like irACTH, the parameters of basal cortisol secretion and burst mass varied with advancing GA, though major differences in these parameters existed between the intact and HPD fetuses. The only cortisol deconvolution parameter to differ between intact and HPD fetuses at 126 days was that of cortisol burst mass (3-fold greater in intact fetuses), but the HPD fetuses failed to show the dramatic development of cortisol secretory parameters seen in the intact fetuses by 145 days. All previous reports of the effect of HPD on cortisol secretion in the ovine fetus have found that, whereas deficits in cortisol secretion are not apparent early (<130 days GA), by late gestation, there is a dramatic failure of the prepartum cortisol surge that is often associated with small adrenal glands (8, 9, 10, 12, 14). The present results are consistent with these earlier findings and extend them by identifying that the primary defects lie specifically in a failure of basal secretion and cortisol secretory burst mass. Furthermore, they suggest that the factor(s) that control adrenal development in the late gestation fetus is dependent upon an intact hypothalamo-pituitary unit.
The ApEn of irACTH secretion did not differ between the young and old fetuses or HPD and intact animals, suggesting that there are no changes in the orderliness of irACTH secretion. In contrast, the ApEn of cortisol secretion decreased significantly between 126 and 145 days GA, and this parameter was not affected by the HPD operation. Decreases in ApEn are commonly observed when secretion becomes more ordered (e.g. a tighter feedback system within an organ and/or between trophic and end-organ hormones), whereas increases in ApEn are associated with more disorderly and/or autonomous secretion (e.g. in tumorous states) (27, 28, 29). Accordingly, it can be inferred that cortisol secretion is under greater control as gestation progresses. As cross-ApEn between irACTH and cortisol did not differ with GA or after HPD operation (data not shown), it seems unlikely that ACTH is the primary and sole regulator of cortisol secretion in late gestation. Further evidence for this idea can be derived from the cross-correlation data for irACTH and cortisol profiles. At 126 days GA in intact fetuses, significant correlations between irACTH and cortisol release were observed, with lag times of -5, 0, and 5 min, indicating a tight nexus between the secretion of these two hormones at this stage of gestation. In HPD animals at the same stage, there were no significant correlations between irACTH and cortisol concentrations, suggesting that an intact hypothalamo-pituitary axis is required for ACTH to control cortisol secretion in the 126-day ovine fetus. At 145 days, there was no longer any significant cross-correlation between irACTH and cortisol concentrations in the intact fetus or HPD animals, which suggests that just before parturition (145 days), the usual relationship between ACTH and cortisol secretion may be disrupted in the ovine fetus.
The findings of the present study make it seem unlikely that ACTH has the sole regulatory role in directing cortisol secretion. Alternate explanations of our observations are, however, possible. First, because this study measured total irACTH in ovine fetal plasma and not the presumably bioactive ACTH1–39, it is possible that other forms of irACTH obscured important changes in the secretion of ACTH1–39. This notion is not supported, however, by studies that have examined the concentration of ACTH1–39, as measured by a specific immunoradiometric assay, and found no consistent differences between intact and HPD fetuses (9, 10, 12). Second, it remains formally possible that the modest defects in basal irACTH secretion, mean irACTH concentrations, and irACTH secretory burst mass and amplitude, seen in the HPD fetuses at 126 days GA, are related to the subsequent profound lack of development of cortisol secretion. Although there were no statistically significant differences in the ACTH burst mass or burst amplitude between the intact and HPD fetuses at 126 days, the cross-correlation data demonstrated that, unlike the intact fetus, the bursts of ACTH secretion in the HPD fetus were not sufficient to maintain coordinate bursts of cortisol secretion. Although these parameters of ACTH secretion have apparently recovered in the HPD fetus by 145 days, the adrenal gland may have been denied a critical exposure to robust pulses of ACTH, which sustain adrenal growth and cortisol secretion. This hypothesis is consistent with recent data from our laboratory, which shows that the defect in adrenal growth and cortisol secretion induced by hypophysectomy can be corrected by an infusion of ACTH1–24 that did not elevate irACTH concentrations above those seen in intact animals (7). Finally, as we conducted all our studies at the same time of the day (the time of maternal feeding), it is possible that differences in ACTH secretion exist between intact and HPD fetuses at other times of the day. The time of study was specifically chosen because fetal irACTH and cortisol concentrations are maximal at the time of maternal feeding (23), and we expected, therefore, that any differences between intact and HPD fetuses would also be maximal at this time of the day.
The conclusion that ACTH is not the sole regulator of cortisol secretion does, however, raise a number of paradoxes. First, as indicated in this and other studies, an intact hypothalamo-pituitary axis is necessary for normal adrenal maturation, although pituitary development, as assessed by the nature of irACTH secretion, seems to be normal; and second, the profound adrenal hypoplasia and deficit in cortisol secretion produced by hypophysectomy can be rectified by a modest infusion of ACTH1–24 (6, 7). These observations may indicate that the HPD fetus has an occult defect in ACTH secretion, and that the ACTH1–24 infusion is able to overcome the disruption of pituitary function induced by hypophysectomy and, presumably, HPD. We propose, as a working model, that ACTH has a permissive action, with respect to adrenal maturation, with approximately basal levels necessary to ensure that the adrenal gland is primed to respond to another secretagogue(s), whose identity and source are unclear. A knowledge of the identity of this factor(s) will advance our understanding of the complex regulation of fetal adrenal development and the important late gestational events that are critical for the timing of birth and preparing the fetus for extrauterine life.
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Acknowledgments |
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Footnotes |
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Received November 13, 1997.
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