Effect of maternal nutrient restriction in early gestation on responses of the hypothalamic-pituitary-adrenal axis to acute isocapnic hypoxaemia in late gestation fetal sheep

Epidemiological and experimental evidence suggests that maternal undernutrition during pregnancy may alter development of fetal organ systems. We have demonstrated previously that fetal hypothalamic-pituitary-adrenal (HPA) axis responses to exogenous corticotropin-releasing hormone (CRH) + arginine vasopressin (AVP), or adrenocorticotrophin hormone (ACTH), are reduced in fetuses of mildly undernourished ewes. To examine these effects further we tested HPA axis responses to acute isocapnic hypoxaemia in fetal sheep at 114-129 days gestation (dGA), following 15% reduction in maternal nutritional intake between 0 and 70 dGA. Fetuses from control (C) and nutrient-restricted (R) ewes were chronically catheterised and plasma ACTH and cortisol responses were determined at 114-115, 120-123 and 126-129 dGA during hypoxaemia (1 h) induced by lowering the maternal inspired O2 fraction (FI,O2). Basal plasma cortisol concentrations and HPA axis responses at 114-115 and 120-123 dGA did not differ between C and R fetuses. At 126-129 dGA, both plasma ACTH (P < 0.01) and cortisol (P < 0.05) responses were smaller in R fetuses compared to C fetuses. Fetal blood gas status, fetal body weight, body proportions and organ weights did not differ between the groups. We conclude that mild maternal undernutrition alters development of the fetal HPA axis producing a reduction in pituitary and adrenal responsiveness to endogenous stimuli.     

Effects of sex, litter size and periconceptional ewe nutrition on offspring behavioural and physiological response to isolation

Maternal periconceptional undernutrition alters fetal hypothalamic-pituitary-adrenal (HPA) axis development. However, the effects of this early nutritional insult on postnatal HPA axis function and stress-related behaviours are unknown. We investigated in sheep the effects of different periods of undernutrition, and of sex and litter size, on offspring behavioural and cortisol responses to isolation stress. We studied four nutritional groups: controls well nourished throughout pregnancy (n = 39), or ewes undernourished (UN, 10-15% body weight reduction) before mating (−60 to 0 d, n = 26), after mating (−2 to + 30 d, n = 20) or both (−60 to + 30 d, n = 36). At 4 and 18 months of age, offspring were isolated for 5 min, their behaviour video recorded, and plasma cortisol concentrations measured.Offspring of all undernourished groups demonstrated 50% fewer escape attempts than controls at 4 months of age, and offspring of UN−60 + 30 ewes had 20% lower plasma cortisol area under the curve in response to isolation at 18 months. Females had higher cortisol concentrations and vocalised more than males at 4 and 18 months, and were more active at 18 months. After isolation, UN−2 + 30 males had higher cortisol concentrations than UN−2 + 30 females whereas in all other groups males had lower concentrations than females. Singleton males made more escape attempts than females, whereas in twins females made more escape attempts than males.These findings suggest that maternal periconceptional undernutrition in sheep can suppress behavioural reactions and cortisol secretion in response to isolation stress in the offspring into adulthood, and that these effects differ between males and females.     

Effect of feeding on the diurnal rhythm of plasma cortisol and adrenocorticotrophic hormone concentrations in the pregnant ewe and sheep fetus.

The effects of two different feeding regimes on the 24 h profiles of maternal and fetal plasma cortisol and adrenocorticotrophic hormone (ACTH) concentrations were studied in eight pregnant ewes between 123 and 144 days of gestation. Once daily-fed ewes (n = 4) received 1 kg of lucerne-chaff at 11.00 h, and multi-fed ewes (n = 4) received 100-200 g of lucerne-chaff at 09.00, 11.00 and 13.00 h and then 150 g until 09.00 h the following day. There were significant differences between the two feeding groups in the 24 h profile of maternal plasma osmolality; once daily feeding at 11.00 h was associated with a peak in maternal plasma osmolality at 15.00 h whereas maternal plasma osmolality reached plateau levels at around 17.00 h in the multi-fed group. There were also differences between the two feeding groups in the 24 h profiles of maternal and fetal plasma glucose. Maternal and fetal plasma glucose reached peak concentrations at 19.00 h in the once daily-fed ewes in contrast to the multi-fed group, where a plateau in maternal and fetal plasma glucose was reached between 19.00 h and 09.00 h the following day. A significant diurnal variation in the plasma concentrations of cortisol was present in the once daily-fed ewes from 123 days gestation and in their fetuses after, but not before, 135 days gestation. Plasma cortisol peaked at 11.00 h in the ewes and at 13.00 h in the fetuses of this group. In the once daily-fed group there was also a significant diurnal variation in maternal and fetal plasma ACTH; plasma ACTH concentrations were highest at 11.00 h in the ewes aged between 123 and 144 days and in fetuses after 135 days gestation. In the multi-fed group, whilst ACTH was highest at 09.00 h in the ewes and at 13.00 h in the fetuses, there was no significant diurnal variation in the plasma concentrations of cortisol in the ewes or fetuses of this group at any stage between 123 and 144 days gestation.     

Increased uncoupling protein-2 mRNA abundance and glucocorticoid action in adipose tissue in the sheep fetus during late gestation is dependent on plasma cortisol and triiodothyronine

The endocrine regulation of uncoupling protein-2 (UCP2), an inner mitochondrial protein, in fetal adipose tissue remains unclear. The present study aimed to determine if fetal plasma cortisol and triiodothyronine (T₃) influenced the mRNA abundance of UCP2, glucocorticoid receptor (GR) and 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and 2 (11βHSD2) in fetal adipose tissue in the sheep during late gestation. Perirenal–abdominal adipose tissue was sampled from ovine fetuses to which either cortisol (2–3 mg kg⁻¹ day⁻¹) or saline was infused for 5 days up to 127–130 days gestation, or near term fetuses (i.e. 142–145 days gestation) that were either adrenalectomised (AX) or remained intact. Fetal plasma cortisol and T₃ concentrations were higher in the cortisol infused animals and lower in AX fetuses compared with their corresponding control group, and increased with gestational age. UCP2 and GR mRNA abundance were significantly lower in AX fetuses compared with age-matched controls, and increased with gestational age and by cortisol infusion. Glucocorticoid action in fetal adipose tissue was augmented by AX and suppressed by cortisol infusion, the latter also preventing the gestational increase in 11βHSD1 mRNA and decrease in 11βHSD2 mRNA. When all treatment groups were combined, both fetal plasma cortisol and T₃ concentrations were positively correlated with UCP2, GR and 11βHSD2 mRNA abundance, but negatively correlated with 11βHSD1 mRNA abundance. In conclusion, plasma cortisol and T₃ are both required for the late gestation rise in UCP2 mRNA and differentially regulate glucocorticoid action in fetal adipose tissue in the sheep during late gestation.     

Adrenocortical Response Profiles to Corticotrophin-Releasing Hormone and Adrenocorticotrophin Challenge in the Chronically Catheterized Adult Guinea-Pig

The guinea-pig has been used extensively to investigate adrenal steroidogenesis. However, very little is known about adrenocortical responses to corticotrophin-releasing hormone (CRH) and adrenocorticotrophin (ACTH) in this species, in vivo. In the present study, we have developed a stress-free sampling system, in the chronically catheterized adult guinea-pig, that has allowed us to investigate basal and activated adrenocortical activity. Indwelling carotid artery and jugular vein catheters were surgically implanted into female guinea-pigs (n = 5). Each animal was treated with vehicle, human CRH (0.2 or 2 microg kg-1) and ACTH1-24 (0.2 or 2 microg kg-1), and serial plasma samples removed for analysis of ACTH and cortisol concentrations by radioimmunoassay. There was no effect of serial sampling on pituitary-adrenocortical activity, indicating that the animals remain in an unstressed state. Basal plasma ACTH and cortisol concentrations were 703.9 +/- 24.5 pg ml-1 and 117.9 +/- 5.2 ng ml-1, respectively. Both CRH and ACTH significantly increased adrenocortical activity in a dose-dependent manner. ACTH (2 microg kg-1) was the most potent activator leading to plasma cortisol concentrations of 647 +/- 116 ng ml-1. In conclusion, we have shown that basal plasma cortisol concentrations in the guinea-pig are low compared to those obtained in previous studies by cardiac puncture or following decapitation. However, plasma ACTH concentrations are high compared to other species. We have also shown that human CRH and ACTH1-24 act as potent activators of the guinea-pig pituitary-adrenocortical axis, leading to response profiles consistent with mild cortisol resistance.     

Maternal melatonin selectively inhibits cortisol production in the primate fetal adrenal gland

We tested the hypothesis that in primates, maternal melatonin restrains fetal and newborn adrenal cortisol production. A functional G-protein-coupled MT1 membrane-bound melatonin receptor was detected in 90% gestation capuchin monkey fetal adrenals by (a) 2-[¹²⁵I] iodomelatonin binding ( K _d, 75.7 ± 6.9 p m ; B _max, 2.6 ± 0.4 fmol (mg protein)⁻¹), (b) cDNA identification, and (c) melatonin inhibition of adrenocorticotrophic hormone (ACTH)- and corticotrophin-releasing hormone (CRH)-stimulated cortisol but not of dehydroepiandrosterone sulphate (DHAS) production in vitro . Melatonin also inhibited ACTH-induced 3β-hydroxysteroid dehydrogenase mRNA expression. To assess the physiological relevance of these findings, we next studied the effect of chronic maternal melatonin suppression (induced by exposure to constant light during the last third of gestation) on maternal plasma oestradiol during gestation and on plasma cortisol concentration in the 4- to 6-day-old newborn. Constant light suppressed maternal melatonin without affecting maternal plasma oestradiol concentration, consistent with no effect on fetal DHAS, the precursor of maternal oestradiol. However, newborns from mothers under constant light condition had twice as much plasma cortisol as newborns from mothers maintained under a normal light–dark schedule. Newborns from mothers exposed to chronic constant light and daily melatonin replacement had normal plasma cortisol concentration. Our results support a role of maternal melatonin in fetal and neonatal primate cortisol regulation.     

Timing of fetal exposure to stress hormones: effects on newborn physical and neuromuscular maturation

The purpose of the study was to determine the specific periods during pregnancy in which human fetal exposure to stress hormones affects newborn physical and neuromuscular maturation. Blood was collected from 158 women at 15, 19, 25, and 31 weeks' gestation. Levels of placental corticotropin-releasing hormone (CRH) and maternal cortisol were determined from plasma. Newborns were evaluated with the New Ballard Maturation Score. Results indicated that increases in maternal cortisol at 15, 19, and 25 weeks and increases in placental CRH at 31 weeks were significantly associated with decreases in infant maturation among males (even after controlling for length of gestation). Results also suggested that increases in maternal cortisol at 31 weeks were associated with increases in infant maturation among females, although these results were not significant after controlling for length of gestation. Findings suggest that stress hormones have effects on human fetal neurodevelopment that are independent of birth outcome.     

Ontogeny and nutritional programming of uncoupling protein-2 and glucocorticoid receptor mRNA in the ovine lung

This study investigated the developmental and nutritional programming of uncoupling protein-2 (UCP2), glucocorticoid receptor (GR) and 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) mRNA in the sheep lung from the time of uterine attachment to 6 months of age. The effect of maternal nutrient restriction on lung development was determined in early to mid gestation (i.e. 28–80 days gestation, period of maximal placental growth, and embryonic and pseudoglandular stages of fetal lung development) and late gestation (i.e. 110–147 days gestation, period of maximal fetal growth, and canalicular and saccular stages of fetal lung development). Fetal lungs were sampled at 80 and 140 days (term ∼148 days) gestation, and sheep lungs at 1, 7, 30 days and 6 months. GR and 11βHSD1 mRNA were maximal at 140 days gestation, whereas UCP2 mRNA peaked at 1 day of age and then declined with postnatal age. Maternal nutrient restriction in both early-to-mid and late gestation had no effect on lung weight, but increased UCP2, GR and 11βHSD1 mRNA abundance at every sampling age. These findings suggest that the developmental ontogeny of UCP2 mRNA in the ovine lung is under local glucocorticoid hormone action and that maternal nutrient restriction has long-term consequences for UCP2 and GR mRNA abundance in the lung irrespective of its timing.     

Different therapeutic efficacy of ketoconazole in patients with Cushing's syndrome

Summary The property of ketoconazole to inhibit adrenal biosynthesis of cortisol was used in a clinical study of 14 patients with Cushing's syndrome (pituitary-dependent Cushing's disease,n=10; adrenocortical adenoma,n=2; adrenocortical carcinoma,n=1; ectopic ACTH syndrome,n=1). Five patients were treated in a short-term manner (1000 mg over 24 h) and nine patients for a longer period (600 mg/die from 1 week up to 12 months). After short-term administration of ketoconazole, serum cortisol levels fell distinctly only in the patient with adrenocortical adenoma, but not at all or only slightly in the other patients, whereas serum levels of progesterone and 11-deoxy-compounds increased markedly in all patients, with the exception of the patient with adrenocortical carcinoma. Plasma ACTH levels increased in the patients with Cushing's disease but not in the patients with tumor. After long-term treatment of three patients with Cushing's disease over 3, 10, and 12 months, the clinical signs of hypercortisolism persisted or were only slightly ameliorated. In these three patients as well as in three other patients with Cushing's disease treated for a shorter period of 1 to 4 weeks, serum and urinary cortisol levels decreased, but were not normalized, whereas plasma ACTH levels increased variably. Only in one patient with Cushing's disease, in the second patient with adrenocortical adenoma, and in the patient with ectopic ACTH syndrome, serum and urinary cortisol levels returned to normal. We concluded from our data, that the antimycotic drug inhibits biosynthesis of cortisol by blocking adrenal 11- and 17-hydroxylase activity. This effect was compensated in part by a rebound increase of pituitary ACTH secretion in most patients with Cushing's disease. Therefore, ketoconazole treatment is above all effective in patients with Cushing's syndrome due to an adrenal tumor or in patients with ectopic ACTH syndrome, who cannot respond with an increased pituitary ACTH secretion.Abbreviations ACTH Adrenocorticotropic hormone - AA Adrenocortical adenoma - AC Adrenocortical carcinoma - B Corticosterone - CRH Corticotropin-releasing hormone - EAS Ectopic ACTH syndrome - PDCD Pituitary-dependent Cushing's disease - P Progesterone - 17OH-P 17-hydroxyprogesterone - RIA Radioimmunoassay - S 11-deoxycortisol - DOC 11-deoxycorticosterone     

Corticotropin releasing hormone increases apparent potency of adrenocorticotropic hormone stimulation of cortisol secretion.

HYPOTHESIS: Corticotropin releasing hormone (CRH) has a regulatory effect on cortisol secretion in addition to its classic effect of stimulating adrenocorticotropic hormone (ACTH) secretion. REVIEW: There is growing evidence of "long-loop" and paracrine adrenal stimulation by CRH. Data from a study of the ovine-corticotropin releasing hormone (oCRH) stimulation test in 13 sexually abused girls and 13 normal controls was used in Montecarlo simulations of the hypothalamic-pituitary-adrenal axis, to get estimates of adrenal sensitivity to ACTH and cortisol elimination kinetics before and after oCRH administration. In both controls and sexually abused girls, ACTH had an apparent greater effect on cortisol secretion after administration of oCRH compared to its effect during the baseline period. This lends support to the hypothesis and suggests that it should be tested experimentally.     

Functions of corticotropin-releasing hormone in anthropoid primates: from brain to placenta.

Corticotropin-releasing hormone (CRH) is an ancient regulatory molecule. The CRH hormone family has at least four ligands, two receptors, and a binding protein. Its well-known role in the hypothalamic-pituitary-adrenal (HPA) axis is only one of many. The expression of CRH and its related peptides is widespread in peripheral tissue, with important functions in the immune system, energy metabolism, and female reproduction. For example, CRH is involved in the implantation of fertilized ova and in maternal tolerance to the fetus. An apparently unique adaptation has evolved in anthropoid primates: placental expression of CRH. Placental CRH stimulates the fetal adrenal zone, an adrenal structure unique to primates, to produce dehydroepiandrosterone sulfate (DHEAS), which is converted to estrogen by the placenta. Cortisol induced from the fetal and maternal adrenal glands by placental CRH induces further placental CRH expression, forming a positive feedback system that results in increasing placental production of estrogen. In humans, abnormally high placental expression of CRH is associated with pregnancy complications (e.g., preterm labor, intrauterine growth restriction (IUGR), and preeclampsia). Within anthropoid primates, there are at least two patterns of placental CRH expression over gestation: monkeys differ from great apes (and humans) by having a midgestational peak in CRH expression. The functional significance of these differences between monkeys and apes is not yet understood, but it supports the hypothesis that placental CRH performs multiple roles during gestation. A clearer understanding of the diversity of patterns of placental CRH expression among anthropoid primates would aid our understanding of its role in human pregnancy.     

Carcinoid tumors of the thymus and Cushing's syndrome: Clinicopathologic features and current best evidence regarding the cell of origin of these unusual neoplasms

It is uncertain whether thymic neuroendocrine tumors (NET) associated with Cushing's syndrome (CS) produce corticotropin-releasing hormone (CRH) and adrenocorticotropin hormone (ACTH) and whether the thymus contains ACTH and/or CRH cells that could originate NET.The clinicopathologic features of 5 typical (TC) and 6 atypical carcinoids (ATC), 10 additional non-neoplastic thymi, 6 adrenal glands with bilateral nodular hyperplasia and 8 adrenal cortical adenomas were reviewed. Representative slides were immunostained for ACTH and CRH. Four (36.4%) of the 11 patients had CS. The incidence of Masaoka stage IV was higher (p < 0.0001) in patients with ATC than TC. Only 2 (18.1%) of the 11 patients were alive at follow-up. Ten NET were CRH immunoreactive and 6 were ACTH immunoreactive. Thymic NET with CS exhibited stronger immunoreactivity for ACTH and CRH than those without CS. Non-neoplastic thymi exhibited scattered ACTH and CRH immunoreactive cells. Normal adrenal cortex and glands with bilateral nodular hyperplasia showed diffuse CRH immunoreactivity while adrenal adenomas showed no or only focal CRH immunoreactivity. Literature review showed no association between thymic NET and adrenal adenomas.The thymus contains CRH and ACTH immunoreactive cells that are probably the origin of thymic NET. Neoplasms associated with CS exhibit strong immunoreactivity for both hormones, suggesting that CRH probably plays a role in the pathogenesis of CS. As adrenals with bilateral nodular hyperplasia exhibit diffuse CRH immunoreactivity and adrenal cortical adenomas either lack this finding or show few immunoreactive cells, this marker may be useful to distinguish these lesions.     

The effect of confinement during lactation on the hypothalamic-pituitary-adrenal axis and behaviour of primiparous sows

Commercial sows are typically confined in crates before and during parturition and remain there throughout lactation. In various animal species including non-lactating pigs, confinement over similar periods leads to adaptive changes in the HPA axis, consistent with chronic stress. To investigate evidence for chronic stress in lactating sows, primiparous sows (gilts) were kept in behaviourally confining crates with straw bedding (CS, n = 8) or without bedding (C, n = 8) or in larger strawed pens (PS, n = 16) between 5 days before parturition until 29 days postpartum (piglets were weaned on day 28). Behavioural and physiological recordings (Plasma ACTH and cortisol) were taken at intervals (baseline), and CRH injections were given on five occasions (days 2, 8, 15, 22 and 29 postpartum). The PS gilts spent more time in substrate-directed behaviour and lying ventrally, and less time lying laterally and sitting than the two crated treatments (C and CS) throughout lactation. Baseline plasma ACTH and cortisol levels showed no treatment differences, although we confirmed that a diurnal pattern exists, with morning (1000 h) cortisol being higher than later in the day. CRH challenge tests suggested changes in the HPA axis, consistent with chronic stress, by the end of the lactation period. Cortisol response to CRH tended to be higher in CS than PS across all days, and by day 29 cortisol response to CRH was significantly higher in CS compared to PS and tended to be higher in C than PS. Cortisol/ACTH ratio following CRH challenge also tended to be higher in the crate treatments (C and CS) by day 29. These data suggest that prolonged confinement in farrowing crates may have a negative impact on sow welfare.     

The role of vasopressin in the nicotine-induced stimulation of ACTH and cortisol in men

Summary Experimental evidence indicates that arginine vasopressin (AVP) contributes to the release of ACTH under certain conditions. The present study investigates the role of vasopressin as a secretagogue of ACTH during cigarette smoking or nicotine infusion with additional injection of corticotropin releasing hormone (CRH) and using the specific AVP antagonist d(CH₂)₅Tyr(Me)-AVP. We first tested the effect of the AVP antagonist (10 g/kg body weight i.v.) on ACTH and cortisol release following cigarette smoking in 15 healthy young male smokers. Smoking led to marked increments in plasma nicotine and to a small rise in plasma ACTH and cortisol. Mean plasma ACTH and cortisol levels were at no time significantly altered by the antagonist. This might be due to a slight agonistic effect of the AVP antagonist, to high interindividual variability of the ACTH and cortisol responses after smoking or to a neglegible role of AVP in smoking-induced ACTH release. In a second study we performed the following tests in six healthy male non-smokers: (1) nicotine infusion (1.0 g/kg body weight per min); (2) CRH i.v. (100 g); (3) AVP antagonist i.v. (5 g/ kg); (4) nicotine infusion plus CRH i.v.; (5) nicotine infusion plus AVP antagonist i.v. ; (6) nicotine infusion plus CRH and AVP antagonist i.v.; and (7) sham infusion. Nicotine infusion led to greater increments of AVP, ACTH and cortisol than smoking without causing nausea. Peak nicotine levels after nicotine infusion were lower than after smoking. The AVP antagonist in the reduced dosage given alone had no effect on hormone levels. However, it slightly attenuated the effect of nico tite on ACTH and cortisol (P<0.05, ANOVA). Nicotine and CRH given together stimulated AACH and cortisol in a less than additive manner. The combined effect of nicotine and CRH was not inhibited by the antagonist. Our results indicate that the effect of nicotine on ACTH and cortisol may be partly mediated by hypothalamic AVP. Nicotine may also enhance CRH release by stimulating acetylcholine receptors of hypothalamic CRH neurons.Abbreviations ACTH adrenocorticotropic hormone - ANOVA analysis of variance - AVP arginin vasopressin - CRH corticotropin releasing hormone - K⁺a potassium; d (CH₂)₅ Tyr(Me)- - AVP vasopressin (V₁)-antagonist Supported by a grant from Forschungsrat Rauchen und Gesundheit     

Fetal undernutrition induces overexpression of CRH mRNA and CRH protein in hypothalamus and increases CRH and corticosterone in plasma during postnatal life in the rat

Prenatal undernutrition induces a variety of cardiovascular alterations in mammals when adults, including hypertension and hypercortisolism, which are thought to be caused by decreased glucocorticoid feedback control of the hypothalamus–pituitary–adrenal (HPA) axis programmed during fetal life. Hypothalamic CRH seems to be involved in blood pressure elevation of spontaneously hypertensive rats and in primary hypertension of humans, but the influence of prenatal undernutrition on CRH expression has deserved little attention. Here, we studied the expression of both CRH mRNA and CRH protein in the hypothalamus of neonatal and juvenile offspring of rats undernourished during fetal life, as well as the plasma levels of CRH and corticosterone. Prenatal undernutrition of pups was induced by submitting pregnant rats to diet restriction (10 g daily of 21% protein standard laboratory diet). Pups born from dams with free access to the standard laboratory diet served as controls. At day 2 of postnatal age, undernourished pups showed lower body and brain weights, but higher plasma CRH and corticosterone than normal pups. At day 40 of age, brain weight was significantly decreased in the undernourished rats, while plasma corticosterone, plasma CRH and systolic pressure were significantly increased in these animals. At days 2 and 40 of postnatal age, increased CRH mRNA expression and CRH concentration were found in the hypothalamus of undernourished rats. Results indicate that, in the rat, prenatal undernutrition led to fetal programming of CRH overexpression, a neuropeptide serving as activating signal to the HPA axis and/or to extrahypothalamic brain regions concerned with cardiovascular regulation.     

Pituitary–adrenal responses to arm versus leg exercise in untrained man

The purpose of this study was to examine pituitary–adrenal (PA) hormone responses [beta-endorphin (β-END), adrenocorticotropic hormone (ACTH) and cortisol] to arm exercise (AE) and leg exercise (LE) at 60 and 80% of the muscle-group specific VO₂ peak. Eight healthy untrained men (AE VO₂ peak=32.4±3.0 ml kg⁻¹ min⁻¹, LE VO₂ peak=46.9±5.3 ml kg⁻¹ min⁻¹) performed two sub-maximal AE and LE tests in random order. Plasma β-END, ACTH and cortisol were not different (P>0.05) between AE and LE at either exercise intensity; the 60% testing elicited no changes from pre-exercise (PRE) values. For 80% testing, plasma β-END, ACTH and cortisol were consistently, but not significantly, greater during LE than AE. In general, plasma β-END and ACTH were higher (P<0.05) during 80% exercise, than PRE, for both AE and LE. Plasma cortisol was elevated (P<0.05) above PRE during 80% LE, and following 80% for both AE and LE. Plasma ACTH was higher (P<0.05) during 80% LE and AE versus 60% LE and AE, respectively. Plasma β-END and cortisol were significantly higher during and immediately after 80% LE than 60% LE. Thus, plasma β-END, ACTH and cortisol responses were similar for AE and LE at the two relative exercise intensities, with the intensity threshold occurring somewhere between 60 and 80% of VO₂ peak. It appears that the smaller muscle mass associated with AE was sufficient to stimulate these PA axis hormones in a manner similar to LE, despite the higher metabolic stress (i.e., plasma La^-) associated with LE.     

Enhanced corticotropin response to corticotropin-releasing hormone as a predictor of mania in euthymic bipolar patients.

BACKGROUND: Dysregulation of corticotropin (ACTH) and cortisol response after corticotropin-releasing hormone (CRH) stimulation has been reported in bipolar patients. Most findings involve the pathophysiology of the depressive phase of the illness and its prediction. However, the possible predictive value of the CRH challenge test with respect to manic episodes remains unknown. METHODS: The ACTH and free cortisol response to the injection of 100 microg of synthetic human CRH and plasma cortisol-binding globulin levels were measured in 42 lithium-treated patients suffering from Research Diagnostic Criteria bipolar I disorder in remission, and 21 age- and sex-matched normal controls. A 1-year follow-up was conducted to assess any possible relationship between outcome and the hormonal response. RESULTS: Bipolar patients showed higher baseline and peak ACTH concentrations than control subjects. A higher area under ACTH concentration curve after CRH stimulation predicted manic/hypomanic relapse within 6 months by multiple regression analysis. CONCLUSION: Bipolar patients in remission show mild abnormalities in ACTH levels before and after CRH stimulation. CRH challenge may be a potentially good predictor of manic or hypomanic relapse in remitted bipolar patients.     

Effects of aging on hypothalamic-pituitary-adrenal system function in non-human primates

The study was aimed at characterizing the changes in hypothalamic-pituitary-adrenal (HPA) axis function during aging in monkey models (Papio hamadryas and Macaca mulatta). It has been established by specific radioimmunoassay and enzyme immunoassay that basal plasma levels of adrenal androgenes (dehydroepiandrosterone-DHEA, dehydroepiandrosterone sulfate-DHEAS) and the early precursors of steroid hormones (pregnenolone and 17-hydroxypregnenolone) progressively decrease with age in baboons and macaques, while cortisol and 11-desoxycortisol concentrations do not change. The old female rhesus monkeys exhibited a higher cortisol and corticosterone response, but a lower DHEAS response to corticotropin-releasing hormone (CRH) administration then the young monkeys. The aged rhesus monkeys also exhibited a decrease of the adrenal cortex resiliency, that was manifested in the deceleration of the decrease of cortisol concentrations after the peak values had been reached in response to ACTH 1-39 administration. At the same time the ACTH 1-24 depot test revealed no age-related changes in the maximum capacity of monkey adrenals to synthesize and secrete cortisol. The aged monkeys also developed less sensitivity of the HPA axis to dexametasone suppression test. The age-related hormonal changes may play an important role in the age-related involutive processes and in the disorders of the adaptive ability of old organisms.     

Maternal and environmental factors influence the hypothalamic-pituitary-adrenal axis response to corticotropin-releasing hormone infusion in offspring of mothers with or without mood disorders

Individuals with melancholic major depression exhibit basal hypercortisolism and an attenuated ACTH response to exogenous corticotropin-releasing hormone (CRH) infusion. Given the greater incidence of depression in children of depressed parents, we examined the ACTH and cortisol responses to ovine CRH (oCRH) infusion in 63 adolescent offspring of mothers with major depression, bipolar illness, or no psychiatric illness. Psychiatric and observational assessments of these families had been conducted over the course of 10 years preceding this study. We examined the children's responses to CRH in relation to maternal characteristics and family environment and found the following: (a) cortisol responses were negatively related to chronic family stress and (b) offspring of depressed mothers with an avoidant personality disorder showed an exaggerated ACTH response. In addition, adolescents in late puberty (Tanner 4 and 5) had lower ACTH and cortisol responses to oCRH infusion than those in early puberty. Further, offspring with early histories of mood problems, and those who developed major depressive disorder as young adults, did not exhibit basal hypercortisolism but did show an attenuated ACTH response to CRH. Our results add to the growing body of literature showing the influence of maternal characteristics and environmental factors on hypothalamic-pituitary-adrenal axis patterns in children.     

Etomidate: A selective adrenocortical 11β-hydroxylase inhibitor

Summary To investigate the adrenocortical suppression caused by the anesthetic etomidate, plasma levels of progesterone (P), 17-hydroxyprogesterone (17-OHP), 11-deoxycorticosterone (DOC), corticosterone (B), aldosterone (Aldo), 11-deoxycortisol (S), cortisol (F), and cortisone (E) were measured simultaneously before and after a short-term ACTH stimulation test in a 6.5-year-old boy whose convulsions could be kept under control only with constant etomidate infusions. During etomidate therapy, plasma levels of DOC and S were extremely elevated, the progestins P and 17-OHP were slightly elevated, whereas B and Aldo were in the lower normal range, and F and E were markedly decreased. A short-term ACTH stimulation test during etomidate infusion gave a blunted response of B, Aldo, F and E, whereas the level of DOC remained high and S even further increased. P and 17-OHP showed a positive response to ACTH. The ratios of B/DOC and F/S, which reflect adrenocortical 11-hydroxylase activity, were extremely decreased during etomidate and did not change after ACTH stimulation. In contrast, the ratios of DOC/P and S/17-OHP, which relect 21-hydroxylase activity, were elevated and remained elevated after ACTH stimulation. After discontinuation of etomidate therapy, all the baseline steroid levels were somewhat elevated, but responded normally to ACTH. These results demonstrate that etomidate causes a specific and reversible blockade of the 11-hydroxylation of adrenal steroid synthesis.Abbreviations P progesterone - DOC 11-deoxycorticosterone - B corticosterone - Aldo aldosterone - 170HP 17-hydroxyprogesterone - S 11-deoxycortisol - F cortisol - E cortisone - ACTH adrenocorticotrophic hormone Supported by a grant from the Deutsche Forschungsgemeinschaft