Vol. 274, Issue 1, R81-R87, January 1998
ACTH responses to hypotension and feedback inhibition of ACTH
increased by chronic progesterone treatment
Maureen
Keller-Wood
Department of Pharmacodynamics, University of Florida, Gainesville,
Florida 32610
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ABSTRACT |
During pregnancy, arterial pressure,
baroreceptor sensitivity, and adrenocorticotropic hormone (ACTH)
responses to hypotension are decreased. Basal ACTH and cortisol are
increased in pregnancy, suggesting a reduction in cortisol feedback
inhibition of ACTH. Acute treatment with progesterone decreases
arterial pressure, baroreflex-mediated responses, and corticosteroid
feedback effects on ACTH. These experiments test the hypothesis that
chronic increases in progesterone produce changes in arterial pressure,
ACTH responses to stress, and feedback inhibition of ACTH similar to
pregnancy. Ewes were treated with progesterone for 60-80 days.
This increase in plasma progesterone (to 7.6 ± 0.4 ng/ml) did not
alter basal ACTH, cortisol, arterial pressure, or heart rate. However,
ACTH and AVP responses to hypotension were augmented in
progesterone-treated ewes compared with untreated ewes. Chronic
progesterone treatment resulted in greater inhibition of ACTH by
cortisol. Because chronic progesterone treatment did not decrease the
ACTH response to hypotension or attenuate the feedback control of ACTH
secretion, these results suggest that the changes in pituitary-adrenal
control during pregnancy do not reflect a simple effect of progesterone
alone.
adrenocorticotropic hormone; glucocorticoid; corticotropin; maternal
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INTRODUCTION |
PREGNANCY APPEARS TO ALTER the regulation of both
adrenocorticotropic hormone (ACTH) secretion and blood pressure. During pregnancy, mean arterial pressure (MAP) and baroreflex responsiveness are decreased, and ACTH and AVP responses to hypotension are also attenuated (9, 12, 19). ACTH responses to hypoglycemia, on the other
hand, are augmented, suggesting that the alteration of hormonal
responses to hypotension is specific to this stimulus pathway. It has
been suggested (9, 12, 24) that progesterone plays a role in the
altered baroreflex responses during pregnancy. Acute treatment of sheep
with progesterone results in a rapid decrease in MAP within minutes
(24); a decrease in arterial pressure has also been demonstrated after
administration of neurosteroid metabolites of progesterone which bind
at 
-aminobutyric acidA receptors (9). Treatment of ewes with progesterone for 10-14 days
decreased MAP and shifted the midportion of the baroreflex response
curve to the left, consistent with reset of the regulated resting
pressure to a lower value (18). However, this progesterone treatment
does not decrease heart rate, ACTH, or AVP responses to hypotension.
Other experiments in rabbits have also suggested that progesterone may
not cause all of the changes in cardiovascular control that occur in
pregnancy. In that species, the change in pressure and baroreflex
responses occurs relatively late in pregnancy, whereas progesterone and
estrogen are increased early in gestation (19).
Pregnancy results in an increase in plasma cortisol and plasma ACTH
concentrations (2, 5, 16, 23). In women, the elevated plasma cortisol
is not completely suppressed by standard doses of glucocorticoids,
suggesting that negative feedback efficacy is reduced (16). It has been
suggested that estrogens or progesterone may alter glucocorticoid
feedback inhibition of ACTH or alter stimulus-induced ACTH secretion
(16). Consistent with this hypothesis, acute infusion of progesterone
with cortisol decreases the feedback effectiveness of cortisol on ACTH
secretion (14). However, we have also found that suppression of ACTH by
increases in cortisol is normal or increased in ovine pregnancy (13),
suggesting that chronic increases in progesterone might not exert an
inhibitory effect on glucocorticoid-mediated actions. On the other
hand, we also observed an apparent increase in the set-point for basal plasma cortisol in the pregnant state, suggesting that the altered steroid environment of pregnancy may alter feedback control at low
basal levels of cortisol.
Because acute treatment with progesterone produced changes in blood
pressure, baroreceptor responsiveness, and control of ACTH similar to
those observed in studies of pregnant subjects, we have proposed that
progesterone may be responsible for these changes. The purpose of this
study is to directly test the hypothesis that a sustained increase in
plasma progesterone would produce changes similar to pregnancy: reduced
MAP, a reduced ACTH response to hypotension, and an increase in basal
ACTH and the ACTH response to hypoglycemia, but normal suppression of
stimulated ACTH by cortisol.
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MATERIALS AND METHODS |
Experimental protocols.
Twelve adult ewes were studied. Six ewes were studied 60-80 days
after subcutaneous placement of implants containing progesterone. The
other six ewes were studied without implants. All ewes were studied
between February and April, a time when the ewes would normally be
entering the anestrus period. However, five of the six untreated ewes
showed patterns of progesterone consistent with normal estrous
cyclicity. Six experiments were performed in each ewe: infusion of
saline, infusion of nitroprusside at 5 and 10 µg · kg
1 · min1,
injection of insulin at a dose of 0.10 and 0.25 U/kg, and infusion of
cortisol for 2 h followed by infusion of nitroprusside at 10 µg · kg1 · min1.
The ewes were studied in groups of four ewes: two treated and two
untreated. The order of the saline, insulin, and nitroprusside experiments was varied among the study groups. The feedback experiment was usually performed as the final experiment.
Progesterone was administered to the six treated ewes via subcutaneous
implants. These implants were prepared as previously described (18)
using sterilized sheets of silicone polymer (PharmElast; SF Medical,
Hudson, MA) folded into packets (50 × 75 mm), which were filled
with crystalline progesterone (Steraloids, Wilton, NH). These packets
were incubated at 37°C and then were aseptically placed between the
scapulae of the ewes. Four implants were inserted into each ewe. During
implantation, the ewes were sedated with ketamine (Ketaset, ~5 mg/kg
iv; Fort Dodge Laboratories, Fort Dodge, ID) and locally anesthetized
with lidocaine (200-400 mg sc; Abbott Laboratories, North Chicago,
IL). Ewes were treated with 500 mg of ampicillin intramuscularly at the
time of placement of the implants and one time per day for 5 days after
placement of the implants. Experiments were performed at least 60 days
after placement of the implants.
All ewes were prepared with indwelling femoral arterial and venous
catheters using aseptic techniques, as previously described (2). In the
treated ewes, catheters were placed ~2 mo after placement of the
progesterone implants. Ewes were studied over a 2- to 3-wk period
beginning 5-7 days after surgery.
Ewes were housed in pens with controlled lighting and temperature in
the Health Center Animal Resources Department. The ewes were allowed
access to food, water, and a salt block ad libitum. At least 16 h
before the experiments, catheters were threaded through a vinyl duct
and were swivel suspended above the pen. This method allows access to
the catheters without disturbing the sheep (2).
Body temperatures were monitored in all ewes after catheter placement
and throughout this study; all ewes had normal body temperatures
(102-104°F) before study. Experiments in which body temperature was elevated at the end of the experiment, presumably due
to catheter clotting or contamination, were repeated. Ewes were treated
with antibiotics (Polyflex, 500-750 mg) two times daily for 5 days
after surgery and then after the end of each experiment.
In each experiment, samples were collected for measurement of hormones,
electrolytes, and/or glucose. The volume of blood sampled in
each experiment was <100 ml (3 ml/kg), which does not stimulate
hormonal or blood pressure responses (12, 13). During the experiments
in which nitroprusside was infused, samples for hormone measurements
were collected before the start of the infusion and at 5, 10, 20, 30, 40, 50, and 60 min. Samples for plasma electrolytes were collected at
10, 30, and 60 min. Nitroprusside (Elkin-Sinn, Cherry Hill, NJ) was
delivered at 5 µg · kg1 · min1
and 10 µg · kg1 · min1
in 5% dextrose infused for 10 min at 1.67 ml/min. During experiments in which saline was infused or insulin was injected, samples for hormones and glucose were collected at 10, 20, 30, 40, 50, 60, 70, 80, and 90 min; samples for plasma electrolyte concentrations were
collected at 30, 60, and 90 min. Saline infusions were delivered at a
rate of 1.67 ml/min. All blood samples for hormone analysis were
collected into tubes containing EDTA (0.15 M tetrasodium EDTA; Sigma,
St. Louis, MO). Samples collected for electrolyte analysis were placed
in heparinized plastic microcentrifuge tubes. All sample tubes were
kept on ice until the end of the experiment; they then were centrifuged
at 3,000 g for 20 min in a
refrigerated centrifuge (Sorvall RT6000B, DuPont, Newtown, CT). The
plasma for hormone analysis was aliquoted and frozen at
20°C.
In the experiment to test the feedback effectiveness of increased
plasma cortisol, infusion of nitroprusside was preceded by the infusion
of cortisol (cortisol hemisuccinate, Solucortef; Upjohn, Kalamazoo, MI)
at 1 µg · kg1 · min1
for 1 h, beginning 2 h before the start of the nitroprusside infusion
(120 to 60 min). This infusion was delivered at a rate of
0.5 ml/min.
In all experiments, direct arterial pressure was measured using a
Statham P23Db transducer (Gould, Oxnard, CA) and a Gould recorder
(Gould, Cleveland, OH). Arterial pressure was sampled from the analog
output of the recorder at 10 Hz using a Keithley system 570 analog-to-digital converter (Keithley Instruments, Cleveland, OH),
Asystant+ software (Asyst Software Technologies, Rochester, NY), and an
AST 286 microcomputer. MAP was averaged for each minute of study. Heart
rate was calculated over 30-s intervals at 2, 3, 5, and 10 min
after the start of the infusion of nitroprusside.
Analyses.
Plasma sodium and potassium concentrations were measured using a Nova 1 analyzer (Nova, Waltham, MA). Plasma ACTH and arginine vasopressin
(AVP) concentrations were measured using antibodies raised in
collaboration with Dr. Charles Wood. The antibody against ACTH has
100% cross-reactivity with ACTH-(11
24), ACTH-(124), or
hACTH-(139) but does not cross-react with ACTH-(410),
Met-enkephalin, vasopressin, oxytocin, or CRF (2). The antibody against
AVP is specific for AVP and does not cross-react against oxytocin, vasotocin, or lysine-vasopressin (20). For both assays, the samples
were extracted before assay as described (2, 20). Human ACTH-(139)
was used as the standard in the ACTH assay, and the lower limit of
detection was 20 pg/ml. The lower limit of detection in the vasopressin
assay was 1.56 pg/ml. Plasma cortisol was measured using antibody
raised in our laboratory, as previously described (32); this antibody
does not significantly cross-react with progesterone and has a lower
limit of detection of 1 ng/ml using 20 µl of plasma. Plasma
progesterone was measured using kits (Diagnostic Products, Los Angeles,
CA); the limit of detection of this assay is 0.3 ng/ml.
The data were analyzed by two-way analysis of variance corrected for
repeated measures to test for interactions between treatment and time
on hormone concentrations during hypoglycemia or during hypotension
(30). The data were analyzed by three-way analysis of variance to test
for interaction among cortisol, treatment, and time on the response to
hypotension. Differences among means were compared by Duncan's
multiple-range test. The analysis of hormone data was performed after
logarithmic transformation because the raw data were not normally
distributed.
The total ACTH response to hypotension was also compared between the
groups by Mann-Whitney's rank sum test. The total ACTH response was
calculated by triangulation (calculation of the area under the curve)
of the ACTH values from 0 to 60 min. The degree of suppression of ACTH
after the cortisol feedback signal was compared between the groups by
calculating the percent suppression of the total response; this
comparison was also performed using Mann-Whitney's rank sum test. The
relationship between stimulus intensity and ACTH response was also
analyzed for each stimulus. The relationship between the logarithm of
the nadir in plasma glucose concentration and the logarithm of the peak
ACTH concentration after insulin injection and saline infusion were
analyzed in each group by linear regression analysis. The relationship
between the integrated change in MAP, calculated by triangulation of
the 1-min mean values from 0 to 10 min and the ACTH concentration after
10 min of infusion of nitroprusside were also analyzed in each group by
linear regression analysis. The slopes of the stimulus-response relationships were compared between the two groups of ewes by t-test. The criterion for significance
in all tests was P < 0.05.
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RESULTS |
Basal values.
Plasma progesterone was increased to 7.6 ± 0.4 ng/ml in the
progesterone-treated ewes. This value was significantly greater than
the average plasma progesterone concentration of 2.3 ± 1.0 ng/ml in
the untreated ewes. The values were also greater than those measured in
our lab in previous studies of cycling nonpregnant ewes (mean values of
2.5 ng/ml) or anestrous or ovariectomized ewes (0.3 ng/ml) (2). The
values were less than those measured in previous studies in pregnant
ewes [mean values of 14.5 ng/ml overall, including both singleton
and twin pregnancies (2)]. There were no statistically
significant differences in the progesterone values among the six
experiments in the untreated ewes.
Progesterone treatment did not significantly alter the basal values of
MAP, heart rate, plasma glucose, or cortisol concentrations measured
during the infusion of saline (Table 1).
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Table 1.
Basal values of plasma glucose concentration, MAP, plasma ACTH
concentration, and plasma cortisol concentration
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Responses to hypotension.
Infusion of nitroprusside at 5 or 10 µg · kg1 · min1
significantly decreased MAP in both groups of ewes. The progesterone
treatment did not alter the change in MAP during the infusion of 5 µg · kg1 · min1
nitroprusside but resulted in a smaller decrease in MAP after the
infusion of 10 µg · kg1 · min1
nitroprusside (Fig. 1). The progesterone
treatment did not significantly alter the heart rate response to the
infusion of nitroprusside (Table 2).
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Fig. 1.
Mean arterial pressure (MAP), plasma adrenocorticotropic hormone
(ACTH), and plasma arginine vasopressin (AVP) concentrations in
progesterone-treated ( ) or untreated ( ) ewes during and after
infusion of nitroprusside at 5 (A)
or 10 µg · kg1 · min1
(B) from 0 to 10 min. Data are means ± SE. * Values in progesterone-treated ewes significantly
different from those of untreated ewes by Duncan's multiple-range
test.
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Although there was no significant main effect of treatment on plasma
ACTH concentrations during nitroprusside, ACTH concentrations were
significantly greater at 10-30 min after 5 µg · kg1 · min1
nitroprusside and at 5 and 20-40 min after 10 µg · kg1 · min1
nitroprusside in the progesterone-treated ewes (Fig. 1). These differences in the ACTH response resulted in a significantly smaller total ACTH response in the progesterone-treated ewes (Table
3). The ACTH response was significantly
related to the degree of hypotension in both groups of ewes. The slope
of the relationship between MAP and ACTH was significantly increased by
progesterone treatment [for untreated ewes, log
ACTH(10 min) = 2.396
MAP(0-10 min) + 1.675, r = 0.75; for
progesterone-treated ewes, log
ACTH(10 min) = 4.455
MAP(0-10 min) + 1.729, r = 0.81]. This change in
slope reflects the greater ACTH response relative to the degree of
hypotension in the progesterone-treated ewes.
Plasma AVP concentrations were also measured to determine if the AVP
response to hypotension was similarly increased by progesterone treatment. The AVP response to hypotension produced by the infusion of
10 µg · kg1 · min1
of nitroprusside was also significantly increased (Fig. 1).
Responses to hypoglycemia.
The doses of insulin used in this study produced moderate to severe
acute hypoglycemia without causing hypotension (Fig.
2). The progesterone treatment did not
alter MAP after injection of insulin; this is consistent with the lack
of progesterone effect on MAP values measured during saline infusion.
Progesterone treatment significantly altered the glucose and ACTH
responses over time after insulin injection. Both the glucose and ACTH
responses were delayed in the progesterone-treated ewes (Fig. 2),
although there was no difference in the total ACTH response after
insulin injection (Table 3). This difference in timing of the response
can also be taken into account by analyzing the relationship between
the nadir in plasma glucose and the resulting peak in plasma ACTH; there was no difference in this relationship between the treated and
untreated ewes [for untreated ewes, log ACTH = 1.537(log glucose) + 4.455, r = 0.64; for
progesterone-treated ewes, log ACTH = 1.642(log glucose) + 4.572, r = 0.56].
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Fig. 2.
MAP, plasma glucose, and ACTH concentrations in progesterone-treated
() or untreated () ewes after injection of 0.1 (A) or 0.25 U/kg
(B) of insulin at 0 min. Data are
means ± SE. * Values in progesterone-treated ewes
significantly different from those of untreated ewes by Duncan's
multiple-range test.
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Feedback effect of cortisol.
Infusion of cortisol increased plasma cortisol to similar levels in the
progesterone-treated and untreated ewes (Table
4). Infusion of cortisol before the
induction of hypotension significantly reduced the ACTH response in
both groups of ewes (Fig. 3); ACTH concentrations at all time points were significantly reduced after prior infusion of cortisol in both groups of ewes.
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Fig. 3.
MAP (A) and plasma ACTH
(B) concentrations in
progesterone-treated () or untreated () ewes in response to
infusion of nitroprusside (10 µg · kg1 · min1)
after prior infusion of cortisol from 120 to 60 min. Data
are means ± SE. * Values in progesterone-treated ewes
significantly different from those of untreated ewes by Duncan's
multiple-range test.
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Chronic treatment with progesterone did not decrease the feedback
effectiveness of cortisol and in fact appeared to increase the degree
of suppression of the ACTH response to hypotension. The ACTH
concentrations at 10 min were lower in the progesterone-treated ewes
after cortisol than in the untreated ewes after cortisol. The total
ACTH response over the 60 min was also lower in the progesterone-treated ewes (Table 3). Therefore, the degree of inhibition was significantly greater in the progesterone-treated ewes
than in the untreated ewes; ACTH was suppressed by 90.7 ± 2.8% in
the progesterone-treated ewes and 72.8 ± 5.5% in the untreated ewes. The greater suppression of ACTH in the progesterone-treated ewes
is also reflected in the reduced cortisol response to hypotension in
this group; the cortisol response to hypotension was only reduced in
the progesterone-treated ewes (Fig. 4).
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DISCUSSION |
On the basis of the effects of acute treatment with progesterone, it
was predicted that chronic progesterone treatment would reduce blood
pressure and ACTH responses to hypotension but augment ACTH responses
to hypoglycemia. It was also predicted that chronic progesterone treatment would decrease feedback effectiveness of cortisol, which might increase basal ACTH and cortisol levels. However,
the results show a dramatically different pattern of effects with
chronic progesterone treatment than had been found with acute
progesterone treatment. Chronic treatment with progesterone increased
the ACTH and AVP responses to hypotension without altering the ACTH
response to hypoglycemia; the degree of suppression of ACTH produced by
infusion of cortisol was also increased. Chronic treatment with
progesterone did not change basal concentrations of ACTH or cortisol or
change MAP.
Chronic progesterone treatment also did not significantly decrease
resting MAP, as occurs during pregnancy, and did not appear to alter
the heart rate response to hypotension. Therefore, these results
suggest that baroreflex responsiveness is not dramatically altered by
chronic exposure to increased levels of progesterone. In previous
experiments in our lab, we had also failed to find an effect of
10-14 days of progesterone treatment on the heart rate and ACTH
response to hypotension; however, we had found a decrease in MAP and a
shift in the baroreflex response curve at resting MAPs
(18). The results therefore suggest that despite the acute
effects of progesterone on regulation of arterial pressure, which are
observed rapidly (9, 24) or over days to weeks (18), chronic exposure
to elevated plasma progesterone is not the major or sole factor causing
alteration of resting pressure or reflex regulation of pressure in
pregnancy. However, the results do not exclude the possibility that
progesterone may act in concert with changes in other factors or
hormones in pregnancy to effect these changes.
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Fig. 4.
Plasma cortisol concentrations in progesterone-treated () or
untreated () ewes in response to infusion of nitroprusside (10 µg · kg1 · min1)
after no prior infusion of cortisol
(A) or after prior infusion of
cortisol (B) from 120 to
60 min. Data are means ± SE. * Values in
progesterone-treated ewes significantly different from those of
untreated ewes by Duncan's multiple-range test.
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Plasma ACTH and cortisol also were not increased in the
progesterone-treated ewes. The increase in plasma ACTH during pregnancy is not easily demonstrated and requires careful control of
environmental stressors or within subject comparison (2, 5, 23).
However, the increase in plasma cortisol with pregnancy is a consistent finding in pregnant ewes and in women (2, 13). The finding that
progesterone treatment did not result in an increase in cortisol concentrations suggests that other factors, such as stimulation of the
hypothalamic-pituitary axis and adrenal sensitivity by estrogens (3, 4,
26, 28) are more important in the regulation of basal ACTH in
pregnancy.
The increase in the ACTH and AVP responses to hypotension with
progesterone treatment in these experiments was not expected based on
the results of previous studies. A possible explanation of the
increased ACTH response could be a reduced effect of cortisol negative
feedback inhibition of ACTH by endogenous circulating cortisol.
Progesterone is a weak glucocorticoid receptor (GR) agonist and
therefore can act as an antagonist to glucocorticoid action (25).
However, in these ewes, the degree of suppression of ACTH was increased
in the group chronically exposed to increased circulating progesterone.
This result suggests that chronic exposure to progesterone does not
reduce glucocorticoid action. However, we cannot exclude the
possibility that chronic progesterone exposure reduces the
effectiveness of the hypotension-induced increase in cortisol in
limiting the ACTH response by a fast-feedback mechanism. The results of
studies in the rat (22) suggest that estrogens may be necessary for
fast feedback but that progesterone may reduce the effectiveness of
endogenous corticosteroids as a fast-feedback inhibitor of ACTH. The
effect of chronic progesterone on the ACTH response to hypotension in
the ewes is most marked from 20 to 40 min, suggesting that progesterone
primarily acts to increase the duration of the response. This could
occur if the rapid effect of cortisol was impaired. A difficulty in
this interpretation of the data is that although fast feedback has been
demonstrated in humans, rats, and dogs, cortisol does not appear to
rapidly inhibit ACTH responses in ewes (31). However, it is possible that endogenous progesterone may have been a confounding variable because it was not measured in that study.
The increased ACTH response to hypotension with chronic progesterone
treatment is interesting in view of our previous finding that long-term
removal of ovarian steroids causes a decrease in the ACTH response to
hypotension without altering the ACTH response to hypoglycemia or
corticotropin-releasing factor (CRF) infusion, or basal ACTH or blood
pressure (17). This effect was observed 4-7 mo
postovariectomy but not 2-4 wk after ovariectomy. Similarly, we
have found that the ACTH response to hypotension occurs in ewes after
2-3 mo of increased circulating progesterone but not after
10-14 days of treatment (18). This suggests that the decreased response to hypotension in chronically ovariectomized ewes may be the
result of a long-term absence of progesterone. The effect of
progesterone is therefore likely to be a neurotrophic effect rather
than a neurostimulatory effect, which one would expect to be expressed
more acutely.
The failure to find decreased effectiveness of delayed glucocorticoid
feedback is surprising in view of our previous experiments in which an
acute increase in plasma progesterone concentration at the time of the
increase in cortisol led to reduced suppression of the ACTH response to
hypotension (14). In vitro experiments have also found that
progesterone decreases the inhibition of endorphin secretion from the
anterior pituitary by cortisol and reduces corticosterone-induced
inhibition of stimulated ACTH and CRF secretion by the pituitary and
hypothalamus, respectively (1, 8, 10, 11). The fact that a chronic
increase in progesterone did not reduce glucocorticoid feedback
inhibition of ACTH is not completely surprising; pregnancy also does
not result in a decrease in feedback effectiveness of cortisol. In these studies, as in our studies of pregnant ewes (13), we found a
slightly increased suppression of ACTH by a delayed cortisol feedback
signal. This suggests that despite the long-term exposure of GR to
increased progesterone in both cases and the fact that GR has an
affinity for progesterone consistent with progesterone binding to GR at
physiological concentrations, there is no decrease in GR availability
to cortisol. Because other experiments have shown decreased GR
availability with more acute progesterone treatment (6), our results
suggest that either this change is not sufficient to change
glucocorticoid function as a feedback signal or that during chronic
treatment GR production might be increased to match the reduction in GR
availability.
In summary, chronic treatment with progesterone does not mimic the
cardiovascular or endocrine changes of pregnancy. Chronic progesterone
treatment does increase the AVP and ACTH responses to hypotension; this
effect does not appear to be mediated by a change in baroreflex
responsiveness because the heart rate response is not altered. Chronic
progesterone treatment also does not alter basal ACTH or cortisol or
the response to hypoglycemia, suggesting that the effect of
progesterone is not a generalized increase in ACTH secretion. Because
both the AVP and ACTH responses are increased and peripheral plasma AVP
is known to be a component of the ACTH response to hypotension (21), it
is possible that the increased AVP response is a factor in increasing
the ACTH response. In our previous studies, less-chronic increases in
progesterone increased basal AVP without altering AVP responses to
stimuli (18). The site and mechanism of progesterone effects on AVP are
not known; however, there are both GR and progesterone receptors in
several areas of the hypothalamus responsible for control of AVP (27).
Therefore, it is possible that the effect of progesterone on
hypotension-stimulated ACTH secretion is the result of progesterone effects on AVP production and/or secretion from the
paraventricular nucleus. Progesterone may also alter CRF
production and/or secretion.
Perspectives
This study demonstrates the difficulty of explaining the complex
changes in ACTH, AVP, and cardiovascular control in pregnancy by
extrapolation from known acute effects of treatment with progesterone or other hormones. Progesterone has been shown to have both
antimineralocorticoid and antiglucocorticoid effects in various animal
models and in vitro systems (1, 7, 10, 11, 25, 29), which could reasonably explain the changes in both blood pressure and ACTH levels
in pregnancy. However, chronic treatment with progesterone alone did
not produce either of these changes, suggesting that chronic
progesterone exposure does not result in production of a new steady
state in which these effects of progesterone predominate. This suggests
either that progesterone is unimportant as a regulator of these changes
in pregnancy or that progesterone requires changes in other factors,
stimulated by other mechanisms, for these effects of progesterone to be
chronically expressed. There are many other factors that have been
implicated in the control of blood pressure in pregnancy, including
estrogens (15), prostaglandins, and nitric oxide (7). Estrogens have
also been shown to modulate ACTH responses to some stimuli (3, 4, 26,
28). Understanding the mechanisms of changes in ACTH will require a
more thorough understanding of the altered control of blood pressure by
these agents as well as a more complete understanding of the
interactions between progesterone, cortisol, and estrogens and of
regulation of corticosteroid receptors by these hormones and in
pregnancy.
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ACKNOWLEDGEMENTS |
I thank Sara Caldwell for technical assistance.
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FOOTNOTES |
This work was supported by National Institute of Diabetes and Digestive
and Kidney Diseases Research Grant DK-38114 and Research Career
Development Award DK-01898.
Address for reprint requests: M. Keller-Wood, Dept. of
Pharmacodynamics, Box 100487, College of Pharmacy, Univ. of Florida,
Gainesville, FL 32610-0487.
Received 19 May 1997; accepted in final form 23 September
1997.
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REFERENCES |
1.
Abou-Samra, A. B.,
B. Loras,
M. Pugeat,
J. Tourniaire,
and
J. Bertrand.
Demonstration of an antiglucocorticoid action of progesterone on the corticosterone inhibition of 
-endorphin release by rat anterior pituitary in primary culture.
Endocrinology
115:
1471-1475,
1984[Abstract].
2.
Bell, M. E.,
C. E. Wood,
and
M. Keller-Wood.
Influence of reproductive state on pituitary-adrenal activity in the ewe.
Domest. Anim. Endocrinol.
8:
245-254,
1991[Medline].
3.
Burgess, L. H.,
and
R. J. Handa.
Chronic estrogen-induced alterations in adrenocorticotropin and corticosterone secretion, and glucocorticoid receptor mediated functions in female rats.
Endocrinology
131:
1261-1269,
1992[Abstract].
4.
Carey, M. P.,
C. H. Deterd,
J. de Koning,
F. Helmerhorst,
and
E. R. de Kloet.
The influence of ovarian steroids on hypothalamic-pituitary-adrenal regulation in the rat.
J. Endocrinol.
144:
311-321,
1995[Abstract].
5.
Carr, B. R.,
C. R. Parker,
J. D. Madden,
P. C. MacDonald,
and
J. C. Porter.
Maternal adrenocorticotropin and cortisol relationships throughout human pregnancy.
Am. J. Obstet. Gynecol.
139:
416-422,
1981[Medline].
6.
Chou, Y.-C.,
and
W. G. Luttge.
Activated type II receptors in brain cannot rebind steroids: relationship to progesterone's antiglucocorticoid actions.
Brain Res.
440:
67-78,
1988[Medline].
7.
Chu, Z. M.,
and
L. J. Beilin.
Mechanisms of vasodilation in pregnancy: studies of the role of prostaglandins and nitric oxide in changes in vascular reactivity in the in situ blood perfused mesentery of pregnant rats.
Br. J. Pharmacol.
109:
322-329,
1993[Medline].
8.
Duncan, M. R.,
and
G. R. Duncan.
An in vivo study of the action of antiglucocorticoids on thymus weight ratio, antibody titre and the adrenal-pituitary-hypothalamus axis.
J. Steroid Biochem.
10:
245-259,
1979[Medline].
9.
Heesch, C. M.,
and
R. C. Rogers.
Effects of pregnancy and progesterone metabolites on regulation of sympathetic outflow.
Clin. Exp. Pharmacol. Physiol.
22:
136-142,
1995[Medline].
10.
Jones, M. T.,
and
E. W. Hillhouse.
Structure-activity relationship and the mode of action of corticosteroid feedback on the secretion of corticotropin-releasing factor (corticolieberin).
J. Steroid Biochem.
7:
1189-1202,
1976[Medline].
11.
Jones, M. T.,
E. W. Hillhouse,
and
J. L. Burden.
Structure-activity relationships of corticosteroid feedback at the hypothalamic level.
J. Endocrinol.
74:
415-424,
1977[Abstract].
12.
Keller-Wood, M.
Reflex regulation of hormonal responses during pregnancy.
Clin. Exp. Pharmacol. Physiol.
22:
143-151,
1995[Medline].
13.
Keller-Wood, M.
Inhibition of stimulated and basal ACTH by cortisol during ovine pregnancy.
Am. J. Physiol.
271 (Regulatory Integrative Comp. Physiol. 40):
R130-R136,
1996[Abstract/Free Full Text].
14.
Keller-Wood, M.,
J. Silbiger,
and
C. E. Wood.
Progesterone attenuates the inhibition of adrenocorticotropin responses by cortisol in nonpregnant ewes.
Endocrinology
123:
647-651,
1988[Abstract].
15.
Magness, R. R.,
C. R. Parker, Jr.,
and
C. R. Rosenfeld.
Systemic and uterine responses to chronic infusion of estradiol 17b.
Am. J. Physiol.
265 (Endocrinol. Metab. 28):
E690-E698,
1993[Abstract/Free Full Text].
16.
Nolten, W. E.,
and
P. A. Ruekert.
Elevated free cortisol index in pregnancy: possible regulatory mechanisms.
Am. J. Obstet. Gynecol.
139:
492-498,
1981[Medline].
17.
Pecins-Thompson, M.,
and
M. Keller-Wood.
Prolonged absence of ovarian hormones in the ewe reduces the adrenocorticotropin response to hypotension, but not to hypoglycemia or corticotropin-releasing factors.
Endocrinology
134:
678-684,
1994[Abstract].
18.
Pecins-Thompson, M.,
and
M. Keller-Wood.
Effects of progesterone on blood pressure, plasma volume and responses to hypotension.
Am. J. Physiol.
272 (Regulatory Integrative Comp. Physiol. 41):
R377-R385,
1997[Abstract/Free Full Text].
19.
Quesnell, R. R.,
and
V. L. Brooks.
Alterations in the baroreflex occur late in pregnancy in conscious rabbits.
Am. J. Obstet. Gynecol.
176:
692-694,
1997[Medline].
20.
Raff, H. R.,
C. W. Kane,
and
C. E. Wood.
Arginine vasopressin responses to hypoxia and hypercapnia in late-gestation fetal sheep.
Am. J. Physiol.
260 (Regulatory Integrative Comp. Physiol. 29):
R1077-R1081,
1991[Abstract/Free Full Text].
21.
Raff, H.,
D. C. Merrill,
M. M. Skelton,
M. S. Brownfield,
and
A. W. Cowley.
Control of adrenocorticotropin secretion and adrenocortical sensitivity in neurohypophysectomized conscious dogs: effects of acute and chronic vasopressin replacement.
Endocrinology
122:
1410-1418,
1988[Abstract].
22.
Redei, E.,
L. Li,
I. Halcsz,
R. F. McGivern,
and
F. Aird.
Fast glucocorticoid feedback inhibition of ACTH secretion in the ovariectomized rat: effect of chronic estrogen and progesterone.
Neuroendocrinology
60:
113-123,
1994[Medline].
23.
Rees, L. H.,
C. W. Burke,
T. Chard,
S. W. Evans,
and
A. T. Letchworth.
Possible placental origin of ACTH in normal pregnancy.
Nature
254:
620-622,
1975[Medline].
24.
Roesch, D. M.,
and
M. Keller-Wood.
Progesterone rapidly reduces arterial pressure in ewes.
Am. J. Physiol.
272 (Heart Circ. Physiol. 41):
H386-H391,
1997[Abstract/Free Full Text].
25.
Rupprecht, R.,
J. M. H. Reul,
B. van Steensel,
D. Spengler,
M. Soder,
B. Berning,
F. Holsboer,
and
K. Damm.
Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands.
Eur. J. Pharmacol. Mol. Pharmacol. Sect.
247:
145-154,
1993[Medline].
26.
Saoud, C.,
and
C. E. Wood.
Modulation of ovine fetal adrenocorticotropin secretion by androstenedione and 17-estradiol.
Am. J. Physiol.
272 (Regulatory Integrative Comp. Physiol. 41):
R1128-R1134,
1997[Abstract/Free Full Text].
27.
Stumpf, W. E.
Steroid hormones and the cardiovascular system: direct actions of estradiol, progesterone, testosterone, gluco- and mineralocorticoids and cortisol (vitamin D) on central nervous regulatory and peripheral tissues.
Experientia
46:
13-25,
1990[Medline].
28.
Viau, V.,
and
M. J. Meaney.
Variations in the hypothalamo-pituitary-adrenal response to stress during the estrous cycle in the rat.
Endocrinology
129:
2503-2511,
1991[Abstract].
29.
Wambach, G.,
and
J. R. Higgins.
Antimineralocorticoid action of progesterone in the rat: correlation with renal mineralocorticoid receptors.
Endocrinology
102:
1686-1693,
1978[Medline].
30.
Winer, B. J.,
D. R. Brown,
and
K. M. Michels.
Statistical Principles in Experimental Design (3rd ed.). New York: McGraw-Hill, 1991.
31.
Wood, C. E.
Absence of fast negative feedback control of ACTH and renin in fetal and adult sheep.
Am. J. Physiol.
250 (Regulatory Integrative Comp. Physiol. 19):
R403-R410,
1986.
32.
Wood, C. E.,
T. A. Cudd,
C. Kane,
and
K. Engelke.
Fetal ACTH and blood pressure responses to thromboxane mimetic U-46619.
Am. J. Physiol.
265 (Regulatory Integrative Comp. Physiol. 34):
R858-R862,
1993[Abstract/Free Full Text].
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Abstract
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