Maternal Plasma ACTH Research Articles

Chronic maternal fluoxetine infusion in pregnant sheep: effects on the maternal and fetal hypothalamic-pituitary-adrenal axes.

Depression during pregnancy is frequently treated with the selective serotonin reuptake inhibitor, fluoxetine (FX). FX increases serotonergic neurotransmission and serotonin plays a role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. We have therefore investigated the effect of chronic administration of FX to the pregnant ewe on the maternal and fetal HPA axes. Nineteen late-gestation sheep were surgically prepared for chronic study of the fetus. FX (n = 7, 98.5 microg/kg/d) or sterile water (control, n = 8) was administered to the ewe for 8 d by constant rate i.v. infusion with an initial FX bolus dose of 70 mg. Maternal and fetal plasma ACTH and cortisol concentrations were determined at 0700 h each day. Maternal plasma ACTH concentrations fell on infusion d 2, but no changes were observed in maternal plasma cortisol concentrations. Fetal plasma ACTH concentrations increased on infusion d 7, and fetal plasma cortisol concentrations increased on infusion d 6, 7, and 8 in the FX group. In addition, the regression coefficient for the relationship between fetal ACTH and cortisol levels was significantly greater in the FX group compared with the control group. Thus, maternal FX treatment increased fetal plasma cortisol concentration. These results are of particular interest in the context that exposure of the fetus to excess glucocorticoids at critical windows during development has been shown to increase the risk of poor health outcomes in later life.

Corticotrophin-releasing hormone and ACTH levels in maternal and fetal blood during spontaneous and oxytocin-induced labour.

The changes in corticotrophin-releasing hormone (CRH), ACTH and dehydroepiandrosterone (DHEA) in maternal and fetal plasma were estimated in women undergoing spontaneous and oxytocin-induced labour to correlate hormone changes with the mode of parturition. Blood was sampled from a maternal peripheral vein 2 days before labour, during the second stage of labour and on the second postnatal day, and also from umbilical vessels just after delivery. Hormone concentrations were measured by RIA and ELSA methods. The maternal plasma CRH concentration before labour was significantly higher in the group of women delivered spontaneously and declined during the labour through to the second postnatal day. Measured in umbilical vessels, CRH as well as ACTH concentrations were higher in the umbilical vein than artery. The mean maternal plasma ACTH was similar in both groups before delivery, then increased significantly in both groups during the labour, decreasing on the second day after delivery. There were no changes in DHEA concentrations among the groups and at all time points of collection. No correlations between CRH and ACTH or DHEA were observed. Our results suggest that the maternal pituitary can respond to stress factors during delivery but peripheral CRH, probably mainly of placental origin, is not a major modulator of pituitary action.

Childbirth as a Biological Model for Stress?

Objective: The aims of this investigation were to measure corticotropin-releasing hormone (CRH), corticotropin (ACTH) and cortisol before, during and after delivery searching for an endocrine intercorrelation of the hypothalamic-pituitary-adrenal (HPA) axis and to correlate these findings with obstetrical variables. Methods: Blood was sampled from 50 women with singleton pregnancies at term without uterine contractions, during delivery (after full cervical dilatation) and on the 4th postnatal day. Hormones were measured by radioimmunoassay (RIA). The correlation between obstetric variables, sociodemographic and endocrine data were evaluated using the Spearman rank coefficient. Group comparisons for continuous variables were calculated using the Mann-Whitney U test and Kruskal-Wallis test. Results: Maternal plasma ACTH and cortisol increased significantly during labor, declining toward the 4th postnatal day (p < 0.001) and showing a significant intercorrelation (p < 0.01). Compared to women without uterine contractions CRH rose during labor (p < 0.05) and decreased rapidly to the 4th postnatal day (p < 0.001). No correlations between CRH and ACTH or cortisol were observed. None of the obstetrical variables (parity, newborn’s weight, duration of delivery) revealed any significant correlation with ACTH. Analgetic medication (pethidine hydrochloride) was not able to influence the endocrine response to labor stress. Conclusions: Stressful experience during childbirth has an impact on endocrine response. However, this is not fully evident along the HPA axis in a simple biological model with monocausal dependencies. This ‘biological stress model’ is not sensitive enough to detect different childbirth conditions and the hormones in the maternal compartment have partially fetal (placental) origin.

Effect of androstenedione administration on the maternal hypothalamo-pituitary-adreno-placental axis in the pregnant rhesus monkey.

To assess the interaction among androgens, placenta, and the hypothalamo-pituitary-adrenal axis we studied effects of androstenedione administered intravascularly to the pregnant monkey on maternal plasma CRH, ACTH, dehydroepiandrosterone sulfate (DHEAS), cortisol, and estradiol concentrations. Ten monkeys (128 +/- 3 days gestation; mean +/- SEM) were instrumented under general halothane anesthesia with maternal femoral artery and venous catheters and uterine electromyogram electrodes. At 137-144 days gestation, baseline maternal femoral artery samples for CRH, ACTH, DHEAS, cortisol, and estradiol measurements were taken at 1.5-h intervals for 7 h starting 2 h before darkness. On the following day, a continuous iv androstenedione infusion (0.3 mg/kg.min at 0.25 ml/h) in 10% intralipid was started at 0930 h in four monkeys; the other six animals received vehicle alone at the same rate starting at the same time. Maternal blood sampling was repeated 1 and 3 days after androstenedione or vehicle administration. Maternal plasma CRH, ACTH, DHEAS, cortisol, and estradiol levels were unaffected by intralipid. In contrast, androstenedione infusion produced a sustained increase in maternal plasma estradiol and a sustained fall in maternal plasma ACTH, but did not affect maternal plasma CRH, DHEAS, or cortisol concentrations. These results provide evidence for negative feedback regulation by androgens at the hypothalamo-pituitary-adrenal axis in the pregnant monkey. Lack of inhibition of maternal plasma CRH after androstenedione administration supports differential regulation of hypothalamic and placental CRH by androgens.

Effect of androstenedione administration on the maternal hypothalamo- pituitary-adreno-placental axis in the pregnant rhesus monkey

To assess the interaction among androgens, placenta, and the hypothalamo-pituitary-adrenal axis we studied effects of androstenedione administered intravascularly to the pregnant monkey on maternal plasma CRH, ACTH, dehydroepiandrosterone sulfate (DHEAS), cortisol, and estradiol concentrations. Ten monkeys (128 +/- 3 days gestation; mean +/- SEM) were instrumented under general halothane anesthesia with maternal femoral artery and venous catheters and uterine electromyogram electrodes. At 137-144 days gestation, baseline maternal femoral artery samples for CRH, ACTH, DHEAS, cortisol, and estradiol measurements were taken at 1.5-h intervals for 7 h starting 2 h before darkness. On the following day, a continuous iv androstenedione infusion (0.3 mg/kg.min at 0.25 ml/h) in 10% intralipid was started at 0930 h in four monkeys; the other six animals received vehicle alone at the same rate starting at the same time. Maternal blood sampling was repeated 1 and 3 days after androstenedione or vehicle administration. Maternal plasma CRH, ACTH, DHEAS, cortisol, and estradiol levels were unaffected by intralipid. In contrast, androstenedione infusion produced a sustained increase in maternal plasma estradiol and a sustained fall in maternal plasma ACTH, but did not affect maternal plasma CRH, DHEAS, or cortisol concentrations. These results provide evidence for negative feedback regulation by androgens at the hypothalamo-pituitary-adrenal axis in the pregnant monkey. Lack of inhibition of maternal plasma CRH after androstenedione administration supports differential regulation of hypothalamic and placental CRH by androgens.

Circadian timekeeping during pregnancy: endogenous phase relationships between maternal plasma hormones and the maternal body temperature rhythm in pregnant rhesus monkeys.

Nine pregnant rhesus monkeys maintained in constant low level lighting (5 Lux) from 56-80 days gestation (dGA) onward were studied to assess the presence or absence of circadian maternal body temperature and maternal plasma hormone variations. Maternal arterial blood samples were taken every 4 h in six monkeys (105-120 dGA) for 48-56 h and every 2 h in three monkeys (108-115 dGA) for 60 h. Maternal intraabdominal temperature was recorded continuously. Cosinor analysis was used to determine circadian rhythmicity. Individual endogenous timekeeping was demonstrated by 1) free-running circadian variations in maternal body temperature in all nine animals, 2) consistent internal acrophase relationships between the maternal body temperature and maternal plasma cortisol rhythm, and 3) idiosyncrasy of the temporal relationship of detectable rhythms to the external environment in individual animals. Only one animal had a significant maternal plasma ACTH rhythm, whereas the presence of 24-h variations in the other hormones varied in individual animals. The mean +/- SD acrophase profiles in hours from the temperature acrophase in those animals who showed significant rhythms were 19.7 +/- 0.6 (n = 8) for cortisol, 19.4 +/- 2.4 (n = 6) for dehydroepiandrosterone sulfate, 8.3 +/- 1.1 (n = 6) for progesterone, and 18.9 +/- 1.6 (n = 3) for estradiol. We conclude that 24-h variations in maternal plasma hormones are truly endogenously generated and not passively dependent on the light-dark cycle. The maternal circadian system regulates the 24 h temporal organization of endogenous plasma hormone variations. We hypothesize that rhythms in cortisol, dehydroepiandrosterone sulfate, progesterone, and estradiol during pregnancy are directly or indirectly governed by the maternal hypothalamus via the circadian oscillatory output of the maternal adrenal.

Human placenta and the hypothalamic-pituitary-adrenal axis.

Maternal plasma bound and free cortisol rises during pregnancy, while maternal plasma IR-ACTH is initially low but soon rises inspite of the further increase of plasma free cortisol. This rise of plasma ACTH during pregnancy, can not be attributed to changes of plasma levels of estrogens or progesterone. It is possible that the human placenta is responsible for the rise in maternal plasma ACTH during pregnancy. There are two possible mechanisms by which this effect could occur: 1) by the placental secretion of CRH into the maternal circulation, which stimulates the maternal pituitary to secrete ACTH, and 2) the secretion of placental POMC-derived peptides. Recent data indicate that the human placenta is capable of both of these actions: A) The POMC and CRH genes are expressed in human placenta; B) the human term placenta is able to secrete both CRH and POMC-derived peptides in vitro; C) the CRH present in the plasma of pregnant women is bioactive and in sufficient levels to be effective on maternal pituitary; D) synthetic hCRH can stimulate the release of placental POMC peptides in vitro. We conclude that the human placenta may be a modulator of the HPA axis during pregnancy in a number of possible ways. Additional experimental work should clarify the intriguing interaction between the HPA axis and the human placenta during pregnancy, labor and delivery.

Adrenocorticotropin and glucocorticoid concentrations in fetal and maternal plasma of rabbit does continuously infused with cortisol from day 21 to day 24 of gestation

Previous studies have suggested that suppression of fetal rabbit adrenocorticotropin (ACTH) secretion results in impaired development of ACTH-specific adenylate cyclase activity. In order to test this hypothesis we measured fetal and maternal plasma ACTH, cortisol, and corticosterone concentrations in control does and does infused with 0.3 mg of cortisol/hour at 21 to 24 days of gestation. This cortisol infusion regimen significantly depressed maternal and fetal plasma ACTH and corticosterone concentrations but did not change fetal serum cortisol concentrations. These findings further support the hypothesis that fetal ACTH plays a role in the normal development of the adenylate cyclase catalytic portion of the ACTH receptor complex and adrenal differentiation during this critical period of fetal life.

THE PITUITARY ADRENAL RESPONSE TO HEMORRHAGIC STRESS OF LAMB FETUSES IN UTERO

29 ewes and their chronically catheterized fetuses(0.46-0.99 gestation)were allowed 48 hr to recover from surgery prior to study. We measured plasma ACTH and Corticosteroid(C)concentration by radioimmunoassay. Maternal plasma ACTH(54±4 pg.ml−1)and C(3.0 ± 0.2 μg.dl−1)did not change. Fetal ACTH(44±4 pg.ml−1)was low. Fetal C increased progressively from 1.5±0.1 μg.dl−1 before 0.85 gestation to maximal concentrations of 9.4±1.2 μg.dl−1 after 0.95 gestation. Lack of parallel increase in fetal ACTH and C suggested increasing fetal adrenal responsiveness to apparently constant fetal ACTH. In 7 of 8 fetuses(0.72-0.89 gestation)hemorrhage of 15% estimated fetal blood volume at 1.5% min−1 caused a decrease(P<0.05) in fetal mean arterial pressure(FMAP)from 43±3 Torr to 26±4 Torr, and increase(P<0.05)in ACTH(Δ ACTH=140±45pgml−1) and a small increase(P<0.05)in C(ΔC=0.9±0.2 μg.dl−1). A much larger increase in plasma C levels(ΔC=7 μg.dl−1)despite comparable FMAP and ACTH responses to hemorrhage occurred in 2 fetuses >0.95 gestation. These findings also suggest increased fetal adrenal responsiveness to endogenous ACTH towards term. Hemorrhage of 15% in 6 younger fetuses(0.55-0.67 gestation)produced no increase in plasma ACTH or C despite a drop in FMAP from 37±1 Torr to 29±2 Torr(P<0.01). This suggests system(s) subserving the plasma ACTH response to mild hemorrhage are either not yet developed or are inactive in fetuses <0.67 gestation. Fetal hemorrhage caused no change in maternal blood pressure, ACTH or C.

DEVELOPMENTAL CHANGES IN THE RESPONSES OF THE ADRENAL GLANDS OF FOETAL SHEEP TO ENDOGENOUS ADRENOCORTICOTROPHIN, AS INDICATED BY HORMONE RESPONSES TO HYPOXAEMIA

The change in plasma ACTH and corticosteroid concentrations in response to a 60 min period of hypoxaemia were studied in foetal and adult sheep during the latter half of pregnancy. Hypoxaemia consistently caused large rises in the concentration of ACTH in foetal plasma, the magnitude of which did not change with gestational age but was related to the physiological state of the foetus. Before 139 days small and slow rises in corticosteroid (predominantly cortisol) concentration in foetal plasma were observed during hypoxaemia, and these may have been of maternal origin. After 139 days, hypoxaemia caused a rapid and large rise in the concentration of cortisol and corticosterone in foetal plasma, which was largely of foetal origin. Hypoxaemia caused no consistent change in maternal plasma ACTH concentration but was associated with progressive increases in plasma cortisol concentrations. The cortisol: corticosterone ratio in foetal plasma was 1-5 before 139 days and increased to 4-1 several days before term which was lower than the value of 9 in maternal plasma. Small concentrations of 11-deoxycortisol and cortisone were detected in maternal and foetal plasma, the changes of which were small during hypoxaemia. The results indicate that a maturational change in the sensitivity of the foetal adrenal to endogenous ACTH occurs several days before term.

CHANGES IN THE CONCENTRATION OF ADRENOCORTICOTROPHIN AND CORTICOSTEROID IN THE PLASMA OF FOETAL SHEEP IN THE LATTER HALF OF PREGNANCY AND DURING LABOUR

The changes in plasma ACTH concentration of pregnant sheep and their foetuses during the latter half of pregnancy and during labour were studied. Before 140 days of gestation the mean concentration in foetal arterial plasma was 117+/-19 (S.E.M.) pg/ml which rose to a mean of 286+/-63 pg/ml. The rise in ACTH occurred at about the same time as, but not before, the rise in corticosteroid concentration in foetal plasma. The maternal plasma ACTH concentration did not change during the latter half of pregnancy and had a mean concentration of 64+/-9 pg/ml. During labour there was a progressive rise in the ACTH concentration in foetal plasma which was not associated with any corticosteroid changes. Ethanol did not suppress labour but reduced the ACTH concentration in foetal plasma.

Changes in plasma ACTH and corticosteroid of the maternal and fetal sheep during hypoxia.

The changes occurring in the plasma concentrations of ACTH and corticosteroids of maternal and fetal sheep, with chronically implanted catheters before, during and after hypoxia have been measured. During hypoxia there was a transient rise in maternal plasma ACTH which was associated with a large rise in plasma corticosteroids. In contrastfetal plasma ACTH showed a large and prolonged rise during hypoxia with little change (except in one case) in plasma corticosteroid levels. In the fetus, therefore, the adrenalappears to be far less sensitive to ACTH stimulation than in the mother. There was no consistent correlation between the pCO2, pH and ACTH changes observed.(Endocrinology 94: 588, 1974)

Maternal-fetal ACTH relationship in man.

ABSTRACT The relationship between maternal and fetal plasma ACTH concentrations were studied at the time of delivery in 9 normal women and their normal offspring, in 1 subject with Nelson's syndrome and her normal neonate and in 2 normal women and their anencephalic babies. The mean plasma ACTH concentration in the normal women was 211 pg/ml (range 93–439 pg/ml) whereas the mean fetal plasma ACTH concentration was 226 pg/ml (range 53–570 pg/ml). The correlation between the maternal and fetal ACTH concentrations was not significant. The maternal plasma ACTH concentration in the woman with Nelson's syndrome was 20 times that of her baby's. The plasma ACTH levels in the anencephalic infants were below the normal range and much lower than their respective mother's plasma ACTH concentration. These data suggest that significant transport of maternally derived ACTH to the fetus does not occur in man.