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Acute myocardial infarction (AMI) is associated with a stimulation of cortisol which lasts 24 hours in patients treated by thrombolysis. Percutaneous transluminal coronary angioplasty (PTCA) is an alternative treatment for AMI which reduces the length of myocardial ischemia. Our objective was the determination of the amplitude and duration of cortisol and other hormones of the hypothalamo-pituitary-adrenal (HPA) axis release in patients undergoing PTCA. These responses were also analyzed in relation with the time of onset of AMI. The effect of coronarography with or without angioplasty in patients without AMI was also studied. Plasma ACTH, cortisol, corticotropin-releasing hormone and arginine vasopressin levels were determined during the first 48 hours in 20 patients with first AMI, treated by PTCA and in 10 patients without AMI undergoing coronarography (and angioplasty in five of them). A strong stimulation of the HPA axis was observed in AMI patients, but the duration of cortisol secretion was significantly reduced (less than 8 hours) as compared with previous studies in patients treated with thrombolysis. A clear-cut ACTH-cortisol dissociation was also observed after the third hour. ACTH and cortisol stimulation was higher in patients admitted between 04:00 h and 16:00 h than in patients admitted between 16:00 h and 04:00 h In patients without AMI, coronarography induced a moderate, but significant short-lasting ACTH and cortisol stimulation. In conclusion, our data suggest that the degree of stimulation of the HPA axis may depend upon the type of treatment and the circadian rhythm of this axis.

As fetal overexposure to glucocorticoids has been postulated to induce intrauterine growth retardation (IUGR) in humans, we investigated the effects of maternal 50% food restriction (FR50) in rats during the last week of gestation on the hypothalamo-pituitary adrenal (HPA) axis activity in both mothers and their fetuses. In mothers, FR50 increased both the plasma corticosterone (B) level from embryonic days 19-21 and the relative adrenal weight at term. FR50 decreased at term both the maternal plasma corticosteroid-binding globulin level and placental 11beta-hydroxysteroid dehydrogenase type 2 expression. In newborns, maternal FR50 reduced body and adrenal weights, glucocorticoid and mineralocorticoid receptor expressions in the hippocampus, corticoliberin expression in the hypothalamic paraventricular nucleus, and plasma ACTH. In FR50 newborns, the plasma B level was increased at birth and decreased 2 h later. When maternal circulating B was maintained at the basal level by adrenalectomy and B supply, FR50 induced IUGR in pups and decreased placental 11beta- hydroxysteroid dehydrogenase type 2 expression at term, but did not disturb the offspring's HPA axis. These results suggest that maternal undernutrition during late gestation induces both IUGR and an overexposure of fetuses to maternal B, which disturb the development of the HPA axis.

Hypothyroid pups were obtained by adding methimazole in the mother's drinking water from day 15 of gestation and sacrificed at 4, 8 or 15 days. Circulating corticosterone decreased at all ages, while CBG concentrations diminished at day 4, increased at day 8 and did not change at day 15 in hypothyroid rats. As opposed to controls, plasma ACTH concentrations decreased steadily with age while there was an accumulation of ACTH in the anterior pituitary of hypothyroid 15-day-old rats. Anterior pituitary POMC contents were unaffected by the treatment. In the hypothalamic PVN, CRF mRNA levels in the total population of CRF-synthesizing cells and in the CRF+/AVP+ subpopulation were below those of controls whatever the age considered while AVP mRNA in the CRF+/AVP+ subpopulation did not change at day 4 and decreased at day 8 and 15 in hypothyroid animals. Both the number of cell bodies expressing detectable levels of CRF mRNA and the percentage of CRF and AVP colocalization decreased at day 4 and were unchanged thereafter. CRF and AVP immunoreactivity in the zona externa of the median eminence increased with age but was not affected by methimazole treatment. The concentration of AVP mRNA in the magnocellular cell bodies of the PVN and the SON as well as AVP immunoreactivity in the zona interna of the median eminence were not changed by the treatment at days 4 and 8. In hypothyroid 15-day-old rats, SON AVP mRNA increased, AVP immunoreactivity decreased while plasma osmolality was enhanced. In conclusion, our data demonstrate that experimental hypothyroidism impairs specifically the maturation of hypothalamic parvocellular CRF and AVP gene expression during the stress hyporesponsive period. These observations suggest that the physiological peak in plasma thyroxine concentrations that occur between day 8-12 may participate in the maturation of hypothalamic CRF- and AVP-synthesizing cells.

To analyse further the ACTH(1-24) low-dose test, which is of clinical interest, we have examined the dose-response relationship between plasma ACTH(1-24) and cortisol concentrations after i.v. administration of increasing doses (1, 5 or 250 microg) of ACTH(1-24) as a bolus. In addition, we have measured plasma ACTH(1-39) and cortisol levels after an insulin tolerance test (ITT). Although there was a dose response relationship between plasma ACTH(1-24) immunoreactivity and the dose injected, cortisol peaks were comparable, but lower than those reached after an ITT. Under these experimental conditions, an increase in plasma ACTH as low as 13 pmol/l (i.e. the increase obtained with the 1 microg dose) induced a near maximal cortisol response. Following injection of 1 microg ACTH(1-24), peak ACTH values were short lasting, similar to physiological daily bursts. After injection of 5 microg ACTH(1-24), plasma ACTH concentrations were higher than those reached during an ITT, but clearly shorter lasting. Injection of 250 microg ACTH(1-24) induced strikingly supraphysiological levels of plasma ACTH. We conclude that neither regular nor low-dose ACTH tests can fully reproduce the ITT. Our observations strongly suggest that the low-dose ACTH(1-24) test (1 microg) can be useful to estimate the adrenal sensitivity under basal, physiological conditions.

The hypothalamo-pituitary-adrenal axis is already functional in rat fetuses in late gestation. We have reported previously that prenatal morphine exposure induced a severe atrophy of the adrenals and a decrease of corticosterone release in newborn rats at birth and during the early postnatal period. The first aim of the present study was to determine the effects of prenatal morphine exposure (1) on corticotrophin releasing factor (CRF) content of the hypothalamus, CRF immunofluorescence in the median eminence, CRF mRNA in the paraventricular nucleus (PVN) and pro-opiomelanocortin (POMC) mRNA in the anterior pituitary gland; (2) on CRF-induced ACTH release from the anterior pituitary gland in vitro; and (3) on ACTH-induced corticosterone release by the adrenals in vitro. Moreover, as morphine is a hepatotoxic factor, we determined the effects of prenatal morphine on liver weight and plasma corticosteroid binding globulin (CBG) binding capacity in newborn rats. Since acute administration of morphine stimulates corticosterone secretion in adult rats and since maternal corticosterone can cross the placental barrier, we also measured both adrenal weight and glucocorticoid activity in newborns from adrenalectomized mothers treated with morphine. The present results show that prenatal morphine given to intact mothers induced adrenal atrophy and hypoactivity in newborns but did not affect the responsiveness of the anterior pituitary gland to CRF or that of the adrenal gland to ACTH. Prenatal morphine reduced both CRF content in the newborn hypothalamus and CRF immunofluorescence in the median eminence without a significant effect on CRF mRNA expression in the PVN. Moreover, morphine induced a significant decrease of POMC mRNA in the anterior pituitary gland. However, morphine did not significantly affect the weight of the liver, or the plasma CBG binding capacity for corticosterone, in rat pups. In contrast, morphine treatment of the adrenalectomized mothers did not induce adrenal atrophy in newborns and did not impair adrenal activation during the early postnatal period. Maternal adrenalectomy also prevented the effects of prenatal morphine on hypothalamic content of CRF, CRF immunofluorescence in the median eminence, and POMC mRNA in the anterior pituitary gland. However, adrenal atrophy was observed at term in newborns of adrenalectomized mothers treated with both morphine and corticosterone or only corticosterone. In conclusion, morphine given to pregnant rats induced inhibition of the hypothalamo-pituitary-adrenal axis in pups at term. As maternal adrenalectomy prevented these effects, we speculate that an adrenal factor of maternal origin, probably corticosterone, mediated these drug effects on newborns.

The hypersecretion of glucocorticoids during exposure to various stressors may induce or worsen pathological states in predisposed subjects. Therefore it is of interest to evaluate drugs able to reduce glucocorticoid secretion. It has recently been shown that chronic administration of a Ginkgo biloba extract (EGb 761) inhibits stress-induced corticosterone hypersecretion through a reduction in the number of adrenal peripheral benzodiazepine receptors. The present study was designed to analyze the effect of EGb 761 and one of its components, Ginkgolide B on the biosynthesis and secretion of CRH and AVP, the hypothalamic neurohormones that regulate the pituitary-adrenal axis. Chronic administration of EGb 761 (50 or 100 mg/kg p.o. daily for 14 days) reduced basal corticosterone secretion and the subsequent increase in CRH and AVP gene expression. Under the same conditions, surgically-induced increase in CRH secretion was attenuated while the activation of CRH gene expression, ACTH and corticosterone secretion following insulin-induced hypoglycemia remained unchanged. Chronic i.p. injection of Ginkgolide B reduced basal corticosterone secretion without alteration in the subsequent CRH and AVP increase. However, the stimulation of CRH gene expression by insulin-induced hypoglycemia was attenuated by Ginkgolide B. These data confirm that the administration of EGb 761 and Ginkgolide B reduces corticosterone secretion. In addition, these substances act also at the hypothalamic level and are able to reduce CRH expression and secretion. However the latter effect appears to be complex and may depend upon both the nature of stress and substance (Ginkgolide B or other compounds of EGb 761).

The effects of acute and chronic administration of tianeptine, a novel antidepressant agent, on the hypothalamo-pituitary-adrenal axis were studied in the adult male rat. A single injection of tianeptine did not alter the activity of the hypothalamo-pituitary-adrenal axis. In contrast, chronic administration of tianeptine (10 mg/kg twice a day for 15 days) induced a significant decrease in the concentration of corticotropin-releasing factor (CRF) in the hypothalamus and adrenocorticotropin (ACTH) in the anterior lobe of the pituitary. Chronic tianeptine treatment did not modify CRF levels in the cerebral cortex and hippocampus, and did not alter alpha-melanocyte-stimulating hormone and beta-endorphin levels in the neurointermediate lobe of the pituitary. Using the in situ hybridization technique, we observed that chronic administration of tianeptine did not modify CRF mRNA levels in the paraventricular nucleus of the hypothalamus. The effect of chronic tianeptine treatment on the neuroendocrine response to stress was also investigated. Tube restraint stress for 30 min induced a significant depletion of hypothalamic CRF and a substantial increase of plasma ACTH and corticosterone. Tianeptine abolished the stress-induced reduction of hypothalamic CRF concentration and markedly reduced the stress-induced increase in plasma ACTH and corticosterone levels. Taken together, these results suggest that tianeptine acts primarily at the level of the hypothalamus: (1) in unstressed rats, tianeptine reduces hypothalamic CRF and pituitary ACTH contents; (2) in stressed animals, tianeptine attenuates the activation of the hypothalamo-pituitary-adrenal axis.

ACTH and cortisol diurnal variations and responses to two types of stress (insulin-induced hypoglycemia and isolation-restraint stress) and to an acute injection of CRF were determined in intact as well as in actively antiarginine vasopressin (AVP)-immunized rams. All immunized sheep developed antibodies to AVP, displayed diabetes insipidus, and looked healthy in spite of their lower gain weight. Basal secretion and diurnal variations of ACTH and cortisol were unaltered in the group of anti-AVP-immunized animals. In contrast, ACTH and cortisol responses to both types of stress and CRF injection were significantly reduced compared to those in controls. These results suggest that endogenous AVP plays a physiological role in the corticotropic response to stress. However, endogenous AVP does not appear to affect basal secretion and diurnal variations of ACTH and cortisol.

ACTH and cortisol diurnal variations and responses to two types of stress (insulin-induced hypoglycemia and isolation-restraint stress) or to an acute injection of lysine-vasopressin were studied in intact and anti-corticotropin-releasing factor (CRF) actively immunized rams. Immunization was obtained by the injection of synthetic ovine CRF coupled to BSA with carbodiimide. All animals developed antibodies anti-CRF and displayed an alteration of their general condition and a body weight reduction. The mean basal ACTH and cortisol secretion as well as the number and mean amplitude of diurnal pulses of these hormones was significantly reduced in the group of anti-CRF immunized rams. However, the reduction in all three parameters was much more pronounced for cortisol than for ACTH. No ACTH and cortisol response to insulin-induced hypoglycemia and isolation-restraint stress was observed. The stimulating action of lysine-vasopressin on ACTH release was significantly reduced as compared to controls. These results indicate that CRF is a major physiological component of the ovine hypothalamo-hypophysial-adrenal axis and participates in the events that regulate ACTH and cortisol diurnal variations and response to stress.

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.

Plasma adrenocorticotropic hormone (ACTH) and corticosterone were detectable in fetal plasma on day 16 of pregnancy. Thereafter, the levels of both hormones increased steadily in a parallel manner and reached a peak on day 19 of pregnancy. Administration of an antiserum anti-rat corticotropin-releasing factor (CRF) to pregnant rats was followed by a significant decrease in fetal plasma corticosterone as early as day 17. Plasma ACTH measured under the same experimental conditions on day 19 of gestation was also significantly decreased. Similar results have been obtained with fetal plasma collected from adrenalectomized pregnant rats, indicating that the plasma corticosterone decrease in fetuses after immunoneutralization of CRF reflects changes in fetal adrenal secretion and not a diminution of corticosterone transfer from the maternal to the fetal circulation. These results show that endogenous CRF begins to play a physiological role in the regulation of ACTH and corticosterone secretion as early as in 17-day-old fetuses. This effect may occur before the connections between the neurosecretory CRF axons and the hypophysial portal capillaries have been established. Therefore, endogenous CRF may enter the hypophysial portal circulation after intercellular diffusion in hypothalamic tissue.