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Departments of Physiology, University of Adelaide, Adelaide, South Australia 5005, Australia; and Academic Division of Child Health, School of Human Development, Queen’s Medical Center (M.E.S.), Nottingham, United Kingdom
Address all correspondence and requests for reprints to: Prof. I. C. McMillen, Department of Physiology, University of Adelaide, Adelaide, South Australia 5005, Australia. E-mail: caroline.mcmillen{at}adelaide.edu.au
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Abstract |
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Introduction |
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Although it is likely that in species such as the rat or mouse the fetus will be exposed to excess glucocorticoids of maternal origin as a consequence of exposure to maternal stressors (4), the fetal adrenal is the major source of circulating glucocorticoids in species such as the sheep or human during late gestation. There are limited data available, however, on the effects of either acute or chronic nutrient restriction or hypoglycemia on the fetal pituitary-adrenal axis in such species.
In the present study we investigated the acute effects of insulin-induced hypoglycemia and the chronic effects of maternal undernutrition on the fetal pituitary-adrenal axis both before and after the normal prepartum activation of this axis at around 135 days gestation in the sheep. We have also determined whether maternal undernutrition has effects on the fetal pituitary-adrenal axis that are independent of those due to the prevailing low fetal glucose concentrations.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Forty-five pregnant Border-Leicester cross Merino ewes were used in this study. Surgery was performed under aseptic conditions between 110 and 116 days gestation, with general anesthesia initially induced by an iv injection of sodium thiopentone (1.25 g; pentothal, Rhone Merieux, Pinkenba, Australia) and maintained with 2.5–4% halothane (Fluothane, ICI Biochemicals, Inc., Melbourne, Australia) in oxygen. At surgery, vascular catheters were implanted in a fetal carotid artery and jugular vein, a maternal jugular vein, and the amniotic cavity, as previously described (6). All catheters were filled with heparinized saline, and the fetal catheters were exteriorized through an incision made in the ewe’s flank. All ewes and fetal sheep received a 2-ml im injection of antibiotics (procaine penicillin, 250 mg/ml; dihydrostreptomycin sulfate, 250 mg/ml; procaine hydrochloride, 20 mg/ml; Penstrip Illium, Troy Laboratories, Smithfield, Australia) at the time of surgery. The ewes were housed in individual pens in animal holding rooms with a 12-h light, 12-h dark cycle and fed once daily at 1100 h with water ad libitum. Animals were allowed to recover from surgery for at least 4 days before collection of fetal blood samples.
Feeding protocol
All ewes were weighed once between 110 and 114 days gestation.
From 115 days gestation ewes were fed either 20 g lucerne/kg and
3 g oats/kg (control group; n = 22) or 10 g lucerne/kg
live wt and 1.5 g oats/kg live wt [undernutrition group (UN);
n = 23]. In both the control and UN groups, the feed allowance
was increased by 15% every 10 days until postmortem.
Gestational study: blood-sampling regimen
Fetal arterial blood samples (3.5 ml) were collected three times
per week, before ewes were fed, for the measurement of glucose,
cortisol, ACTH, and insulin concentrations throughout late gestation.
Fetal arterial blood samples (0.5 ml) were also collected throughout
late gestation from all fetuses (UN, n = 271 samples; control,
n = 376 samples) to measure blood gas status (ABL 520 analyzer,
Radiometer, Copenhagen, Denmark).
Insulin infusion study: experimental protocol
Acute hypoglycemia was induced by intrafetal administration of
insulin (1-IU iv bolus, followed by infusion for 120 min at 0.36
IU/kg/3 ml·60 min; Actrapid, Commonwealth Serum Laboratories,
Edwardstown, Australia) from 125 and 130 days gestation (control,
n = 7 fetal sheep; UN, n = 12 fetal sheep) and from 138 and
141 days gestation (control, n = 6 fetal sheep; UN = 9 fetal
sheep). Saline (0.9%, 3 ml/h) was also administered from 125 and 130
days (control, n = 8; UN, n = 11) and from 138 and 141 days
gestation (control, n = 6; UN, n = 6). Fetal arterial blood
samples (2 ml) were collected at -60, -30, 0, 30, 60, 90, 120, 150,
180, and 240 min relative to the start of the infusion period.
Fetal outcomes and postmortems
In the UN group, 8 fetal sheep died before 144 days (all
singletons; 3 between 130 and 135 days, 3 between 136 and 140 days, and
2 between 141 and 144 days), and in the control group, 3 fetal sheep
died between 140 and 144 days (2 singletons and 1 twin). Within 48
h of fetal death, ewes were killed with an overdose of sodium
pentobarbitone (Virbac, Peakhurst, Australia). All other ewes (control,
n = 19, 13 carrying singletons and 6 carrying twins; UN n =
15, 13 carrying singletons and 2 carrying twins) were killed with an
overdose of sodium pentobarbitone between 144 and 147 days gestation
(term is 147 ± 3 days), and fetal sheep were delivered by
hysterotomy, weighed, and killed by decapitation.
Plasma glucose determination
Fetal plasma glucose concentrations were determined by enzymatic
analysis using hexokinase and glucose-6-phosphate dehydrogenase to
measure the formation of NADH photometrically at 340 nm (COBAS MIRA
automated analysis system, Roche, Basel, Switzerland)
(7). The intra- and interassay coefficients of variation
were less than 5%.
RIAs
Insulin. Insulin concentrations in fetal sheep plasma (UN
group, n = 127 samples; control group, n = 84 samples) were
measured using a RIA kit (Phadaseph RIA kit, Pharmacia & Upjohn, Inc., Uppsala, Sweden). The detection range of the assay was
1.5–240 µU insulin/ml. Guinea pig antiinsulin antisera and
[125I]human insulin (100 µl) were added to
plasma samples, which were incubated before the addition of sheep
antiguinea pig IgG as described by Symonds et al.
(8). The intraassay coefficient of variation was less than
10%, and the interassay coefficient of variation was 4.1%.
ACTH. Immunoreactive ACTH concentrations in fetal sheep
plasma (UN group, n = 588 samples; control group, n = 575)
were measured by RIA using a kit from ICN Biomedicals, Inc. (Seven Hills, Australia), previously validated for fetal
sheep plasma (9). The sensitivity of the assay was 0.9
pg/ml, and the rabbit antihuman ACTH-(1–39) had a cross-reactivity of
less than 0.1% with ß-endorphin, 
MSH, -lipotropin, and
ß-lipotropin. The interassay coefficient of variation was 11.2%, and
the intraassay coefficient of variation was less than 10%.
Cortisol. Cortisol was extracted from fetal plasma using dichloromethane as previously described (10). The efficiency of recovery of [125I]cortisol from fetal plasma using this extraction procedure was always greater than 90%. Fetal cortisol concentrations were then measured (UN, n = 524 samples; control, n = 479 samples) using an Orion Diagnostica RIA kit (Orion Diagnostica, Turku, Finland), validated for extracted fetal sheep plasma. Extracted cortisol from increasing volumes of fetal sheep plasma diluted parallel to the standard curve and cortisol was quantitatively recovered. The sensitivity of the assay was 0.078 nM, and the cross-reactivity of the rabbit anticortisol was less than 1% with pregnenolone, aldosterone, progesterone, and estradiol (as stated by the manufacturer). The interassay coefficient of variation was 11.2%, and the intraassay coefficient of variation was less than 10%.
Statistical analysis
All data are presented as the mean ± SEM.
Hormonal values were log transformed where required to normalize data
variance for parametric analysis.
Fetal outcome, arterial blood gas status, and plasma glucose and
insulin. The number of fetal deaths before 140 days was compared
between the UN and control groups using a 
2
test. For each fetus, the mean arterial blood gas variables
(PaO2, PaCO2, pH,
O2 saturation, and hemoglobin) were calculated as
the average of all values available between 116 and 147 days gestation
for the control singletons (n = 15), the control twin fetuses
(n = 7), and the UN singletons (n = 23). The mean gestation
blood gas variables were compared among the control singleton, control
twin, and UN singleton fetuses using one-way ANOVA. Fetal body weight
and the mean gestational glucose and insulin concentrations were
compared among fetal sheep that survived past 144 days gestation
(control singleton, n = 13; control twin, n = 6; UN
singleton, n = 13) using one-way ANOVA. UN twin fetuses were not
included in the ANOVA due to the small sample size. As plasma glucose
concentrations were significantly reduced in twins compared with
singletons in the control group, twin animals were excluded from the
control group in subsequent analyses of the basal hormonal data.
Insulin infusion experiments. The fetal glucose, ACTH, and cortisol responses to insulin or saline infusion were compared using a multifactorial ANOVA with repeated measures with group (control vs. UN), age (<135 and >136 days), treatment (insulin vs. saline), time (time points before, during, and after the infusion), and animal as the specified factors. When significant interactions were identified between the major factors in the ANOVA, the data were split on the basis of the interaction. Duncan’s new multiple range test was used after the ANOVA to identify significant differences (P < 0.05) between mean values.
Gestational study. Linear regression analysis was used to determine the relationship between plasma glucose and insulin concentrations in the control and UN groups (control, 84 samples from 12 animals; UN, 127 samples from 17 animals) throughout late gestation. The relationship between fetal plasma glucose and log ACTH concentrations and that between fetal plasma glucose and log cortisol concentrations were determined in the control and UN groups using linear regression analysis before (control, 108 samples from 15 animals: UN, 174 samples from 20 animals) and after 135 days gestation (control, 63 samples from 15 animals: UN, 61 samples from 14 animals).
The mean plasma glucose concentrations (1.0 mM) present in twin fetal sheep in the control group was used as a reference value, and we compared fetal ACTH or cortisol concentrations at low fetal glucose values (<1.0 mM) and high fetal glucose values (>1.0 mM) in both control and undernourished ewes using a multifactorial ANOVA with repeated measures. Specified factors included nutrition group (UN vs. control), plasma glucose (low vs. high glucose), and age (<135 vs. >136 days gestation). Duncan’s new multiple range test was used after the ANOVA to identify significant differences (P < 0.05) between mean values.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). There were no differences in
fetal body weight (P = 0.06), crown rump length, or
fetal organ weights at 144–147 days gestation in control twins (n
= 6), control singletons (n = 13), and UN singletons (n = 13;
Table 2).
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].
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). In the control group,
plasma glucose concentrations were lower (P < 0.05)
than baseline values from 60–180 min after the start of the infusion
(minimum values: <135 days, 1.08 ± 0.38 mM
at +90 min: >136 days, 1.01 ± 0.05 mM at
+120 min). In the UN group, plasma glucose concentrations were lower
(P < 0.05) than baseline values at 90–120 min after
the start of the insulin infusion (minimum values; <135 days,
0.89 ± 0.06 mM at +120 min: >136 days,
0.78 ± 0.07 mM at +150 min; Fig. 2).
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). In contrast, in the
UN group before 135 days, fetal plasma ACTH concentrations increased
from baseline values (68 ± 7.2 pg/ml at -60 min and 81.5 ±
12.4 pg/ml at 0 min) by 90 min and remained high until 180 min after
the start of the insulin infusion (Fig. 2).
There was a similar and significant increase in fetal ACTH in both the
control and UN groups after 136 days gestation. In the control group
after 136 days gestation, baseline ACTH concentrations were 97.6
± 8.6 pg/ml (-60 min) and 121.9 ± 11.4 pg/ml (0 min) and
increased significantly (P < 0.001) above basal values
at 90 and 150 min after the start of the insulin (Fig. 2). In the UN
group after 136 days gestation, plasma ACTH concentrations also
increased from baseline values (164.7 ± 38.8 pg/ml at -60 min
and 194.6 ± 51.4 pg/ml at 0 min) at 90 and 150 min after the
start of the insulin infusion (Fig. 2).
Fetal plasma cortisol responses. Plasma cortisol
concentrations were greater (P < 0.001) after insulin
than after saline infusion. Fetal plasma cortisol responses were higher
(P < 0.001) after 136 days than values before 135 days
gestation in both the UN and control groups (Fig. 2). There were no
differences, however, between the UN and control groups in the plasma
cortisol responses to insulin in either gestational age range. Before
135 days gestation, plasma cortisol concentrations were increased above
baseline concentrations (-60 min: control, 3.2 ± 0.4
nM; UN, 3.7 ± 0.6 nM)
between 120–180 min after the start of the insulin infusion in both
groups (Fig. 2). After 136 days gestation, plasma cortisol
concentrations were also increased in both groups above baseline
concentrations (-60 min: control, 17.3 ± 3.2
nM; UN, 43.5 ± 17.4
nM) between 60–180 min after the start of the
insulin infusion (Fig. 2).
Maternal undernutrition
Plasma glucose and ACTH concentrations in late gestation. In
the control group between 115 and 135 days gestation, plasma glucose
concentrations ranged between 1.1–2.4 mM, and there was no
significant correlation between plasma glucose and ACTH concentrations.
After 135 days gestation, plasma glucose concentrations ranged between
1.0–2.0 mM, and there was also no significant relationship
(P = 0.09) between plasma ACTH and glucose
concentrations in the control group.
In the UN group, plasma glucose concentrations ranged between 0.5–2.1
mM, and plasma ACTH and glucose concentrations were
inversely related both before 135 days [log ACTH = -0.31
(glucose) + 2.21; r = -0.37; P < 0.001] and
after 136 days gestation [log ACTH = -0.40 (glucose) + 2.50;
r = -0.54; P < 0.001; Fig. 3].
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Plasma glucose and cortisol concentrations in late gestation. There was no relationship between plasma glucose and cortisol concentrations in the UN or in the control groups before or after 135 days gestation. Independently of the maternal nutritional state, fetal plasma cortisol concentrations were significantly higher (F = 309; P < 0.001) after 136 days than before 135 days. Fetal plasma cortisol concentrations were also significantly greater (F = 18.7; P < 0.05) in fetuses with low plasma glucose concentrations at each gestational age range (115–135 days: low glucose, 9.8 ± 4.6 nM; high glucose, 5.0 ± 1.2 nM; 136–147 days: low glucose, 47.4 ± 12.7 nM; high glucose, 39.6 ± 7.3 nM).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although there have been no other studies that have compared the response of the fetal hypothalamo-pituitary-adrenal axis to acute hypoglycemia both before and after 135 days gestation, it has been demonstrated in the fetal foal that the sensitivity of the hypothalamo-pituitary-adrenal axis to acute hypoglycemia increases toward term (11). Thus, it may be that an increased capacity to sense glucose concentrations develops within the fetal hypothalamic neural network or within afferent pathways to the fetal hypothalamus in late gestation in these species. As has been previously reported in a number of studies (12, 13), there was an increase in fetal ACTH concentrations in both the control and undernourished groups after 135 days gestation. We therefore investigated whether a change in the fetal glucose-ACTH relationship during late gestation might contribute to this prepartum increase in fetal ACTH concentrations.
Fetal ACTH responses to chronic hypoglycemia
Fetal plasma glucose concentrations in the singleton fetuses of
undernourished ewes were similar to those measured in the twin fetuses
of the control group, but were significantly lower than the fetal
glucose concentrations in control singleton pregnancies. Fetuses in the
undernourished group were also hypoinsulinemic, and the expected fetal
glucose-insulin relationship (14) was maintained across
the range of glucose concentrations present in both undernourished and
control groups. In the control group there was no inverse relationship
between the plasma glucose and ACTH concentrations across the range of
fetal glucose concentrations present in this group either before or
after 135 days gestation. It appears, therefore, that in healthy
fetuses of well fed ewes, the variance in fetal plasma ACTH
concentrations before or after 135 days gestation is not explained by
variations in plasma glucose concentrations between 1.0–2.0
mM.
The presence of a glucose-ACTH relationship in the undernourished, but not in the control animals, before 135 days gestation may be explained by the greater range (0.50–2.0 mM) of fetal glucose concentrations with an associated preponderance of low fetal glucose concentrations. Thus, as in the acute hypoglycemia study, fetal ACTH concentrations may be stimulated before 135 days gestation, when plasma glucose concentrations fall below a threshold value of around 1.0 mM as a consequence of maternal undernutrition. Interestingly, although the range of fetal glucose concentrations was the same before and after 135 days gestation in the undernutrition group, more of the variation (30%) in plasma ACTH concentrations in the undernutrition group was explained by the fetal glucose concentrations in the older age group than in the younger fetuses (14%). There was no difference, however, between the fetal ACTH responses to plasma glucose concentrations below 1.0 mM either before or after 135 days gestation.
Fetal glucose and cortisol concentrations
There was a similar and small fetal cortisol response to
insulin-induced hypoglycemia in both the control and undernourished
animals before 135 days gestation. The presence of a fetal cortisol
response in the control ewes in the absence of a robust fetal ACTH
response in this group at this gestational age range is interesting. It
has been demonstrated that ACTH in fetal plasma is present in a range
of mol wt forms (15, 16), and it is possible that acute
hypoglycemia may result in an increase in the secretion of the more
bioactive ACTH-(1–39).
After 135 days gestation, there was an increase in basal fetal plasma concentrations of cortisol in both the control and undernourished groups, and the fetal cortisol response to insulin infusion was significantly greater than that earlier in gestation. The increase in the fetal cortisol responses to insulin-induced hypoglycemia after 135 days gestation presumably reflects the increasing steroidogenic and secretory capacity of the fetal adrenal in later gestation (12). There was no evidence in the present study that exposure of the fetal adrenal to maternal undernutrition and associated low prevailing fetal glucose concentrations increased the sensitivity of the fetal cortisol response to subsequent episodes of acute hypoglycemia. It was also interesting that a fetal ACTH response to acute hypoglycemia was maintained in the face of increased basal and stimulated cortisol concentrations in the older fetal sheep. This suggests that the maturation of the ACTH hypoglycemic response is sufficient to withstand the negative feedback actions of the increase in fetal cortisol concentrations.
In contrast to ACTH, there was no relationship between fetal glucose and cortisol concentrations in the undernourished ewes before or after 135 days gestation. Fetal cortisol concentrations were higher, however, when plasma glucose concentrations were below 1.0 mM. Before 135 days gestation, it is possible that a proportion of the increase in circulating cortisol in fetal sheep with low plasma glucose concentrations is derived from transplacental transfer of maternal cortisol. After 135 days gestation, however, the cortisol present within the fetal circulation is predominantly of fetal origin (17). Independently of the source of cortisol, fetal sheep with low plasma glucose concentrations before or after 135 days gestation have higher plasma cortisol concentrations. It has been proposed that exposure of the developing fetus to excess glucocorticoid concentrations programs permanent changes in the structure or function of the developing cardiovascular, metabolic, and endocrine systems that result in a higher relative risk of adult pathophysiology (18).
A number of recent studies in the sheep have highlighted the suggestion that the timing and degree of exposure of the fetus to undernutrition may be important in determining the subsequent effects on fetal growth and on the development of physiological and metabolic systems in the fetal or newborn lamb (19, 20). A reduction in growth rate that results in body weight significantly below the normal range for fetuses of the same gestational age may be one of the final adaptations of a fetus to a prolonged or significant nutritional challenge. In the present study there was a higher rate of fetal death before 140 days gestation in the UN, and those fetuses that did not survive may have failed to make an appropriate physiological or metabolic adaptation to the nutritional restriction. It is clear, however, that nutritional insults during pregnancy can produce altered postnatal outcomes in the absence of a reduced birth weight (19), which suggests that fetal adaptive responses to nutrient restriction, such as the neuroendocrine responses measured in the present study, may also be important in determining adverse postnatal outcomes.
In summary, therefore, we have found that there is an increased sensitivity of the fetal hypothalamo-pituitary axis to acute falls in glucose concentrations below 1.2 mM after 135 days compared with earlier in gestation. The fetal hypothalamo-pituitary axis can respond, however, when plasma glucose concentrations fall below 1.0 mM before and after 135 days gestation, independently of whether the low glucose concentrations are a consequence of insulin-induced hypoglycemia or maternal nutrient restriction.
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Acknowledgments |
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Footnotes |
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Received October 12, 2000.
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