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As in many vertebrates, hormonal responses to stress vary seasonally in red-sided garter snakes (Thamnophis sirtalis parietalis). For example, males generally exhibit reduced glucocorticoid responses to a standard stressor during the spring mating season. We asked whether variation in adrenal sensitivity to adrenocorticotropic hormone (ACTH) explains why glucocorticoid responses to capture stress vary with sex, season and body condition in red-sided garter snakes. We measured glucocorticoids at 0, 1 and 4 h after injection with ACTH (0.1 IU g(-1)body mass) or vehicle in males and females during the spring mating season and autumn pre-hibernation period. Because elevated glucocorticoids can influence sex steroids, we also examined androgen and estradiol responses to ACTH. ACTH treatment increased glucocorticoids in both sexes and seasons. Spring-collected males had a smaller integrated glucocorticoid response to ACTH than autumn-collected males. The integrated glucocorticoid response to ACTH differed with sex during the spring, with males having a smaller glucocorticoid response than females. Although integrated glucocorticoid responses to ACTH did not vary with body condition, we observed an interaction among season, sex and body condition. In males, ACTH treatment did not alter androgen levels in either season, but androgen levels decreased during the sampling period. Similar to previous studies, plasma estradiol was low or undetectable during the spring and autumn, and therefore any effect of ACTH treatment on estradiol could not be determined. These data provide support for a mechanism that partly explains how the hypothalamus-pituitary-adrenal (HPA) axis integrates information about season, sex and body condition: namely, variation in adrenal responsiveness to ACTH., (© 2016. Published by The Company of Biologists Ltd.)

Glucocorticoids (GCs) and adrenocorticotropic hormone (ACTH) are major components of the classic endocrine stress response. Free-living vertebrates are characterized by circannual changes in the baseline and/or stress-induced secretion of GCs and ACTH. In mammalian species, GC and ACTH levels vary seasonally but there is no consensus to the season in which animals have elevated GC and ACTH levels. The aim of our study was to determine, for the first time, the type and amount of glucocorticoids produced in free-living beaver (Castor fiber L.)--the largest rodent in Eurasia, and to find out whether stress-induced plasma GC and ACTH levels show seasonal variations. Blood samples were obtained from animals under general anesthesia in April (pregnancy in females), July (offspring rearing) and November (preparing for the winter). The adrenals of beavers produce both cortisol and corticosterone, and plasma cortisol levels were higher than corticosterone. In the current experiment, plasma cortisol concentrations in beavers were affected by the season. The highest stress-associated cortisol levels were noted in males in July during offspring rearing. Corticosterone and ACTH concentrations in beavers remained generally constant, regardless of the season and sex. In conclusion, seasonal changes were observed only in relation to stress-induced plasma cortisol levels in the beaver.

ACTH1-24(1 mg/kg) administered to 5-7-day-old rats reduced their locomotor activity and did not alter blood levels of corticosterone. ACTH administration on postnatal days 12-14 increased corticosterone levels, but had no effect on locomotor activity. Thus, the behavioral effect of ACTH is not due to corticotropic action of the hormone and is not associated with blood levels of glucocorticoids.

A dog with an unexpected presentation of primary hypoadrenocorticism was evaluated for clinical signs and electrolyte abnormalities characteristic of Addison's disease. Although the initial adrenocorticotropic hormone (ACTH) stimulation test documented serum cortisol concentrations within the reference range, subsequent assessments confirmed hypoaldosteronism. Mineralocorticoid replacement promptly normalized electrolytes and transiently improved clinical illness. Six weeks after initial ACTH stimulation testing, the dog became glucocorticoid deficient. Concurrent primary hypothyroidism was also documented. Hypoaldosteronism preceding hypocortisolemia is a unique presentation of canine Addison's disease.

Since high expression of farnesoid X receptor (FXR) has been detected in glucocorticoid-producing adrenocortical cells, we evaluated the potential role of FXR in adrenal glucocorticoid production. FXR agonist GW4064 increased fasting plasma corticosterone levels (+45%; P<0.01) in C57BL/6 mice, indicative of enhanced adrenal steroidogenesis. GW4064 treatment did not affect plasma ACTH levels, adrenal weight, or adrenal expression of steroidogenic genes. Scavenger receptor BI (SR-BI) mRNA and protein expression, respectively, increased 1.9-fold (P<0.01) and 1.5-fold, which suggests a stimulated lipoprotein-associated cholesterol uptake into the adrenals upon GW4064 treatment. In line with an enhanced flux of cellular cholesterol into the steroidogenic pathway, adrenal unesterified and esterified cholesterol stores were 21-41% decreased (P<0.01) upon GW4064 treatment. In conclusion, we have shown that the FXR agonist GW4064 stimulates plasma corticosterone levels in C57BL/6 mice. Our findings suggest a novel role for FXR in the modulation of adrenal cholesterol metabolism and glucocorticoid synthesis in mice., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Myasthenia gravis (MG) is an autoimmune disorder generally mediated by antibodies against the acetylcholine receptors of the skeletal muscles. Depending on the disease burden, MG patients may experience chronic dysregulation of both the hormonal stress axis and the immune system, consequently, aggravating the disease itself but also leading to secondary psychopathological abnormalities. A long-term clinical course requires long-term glucocorticoid (GC) therapy, which may change the psychological state by affecting the pituitary-adrenocortical system in MG patients. In this study, we investigated the function of the pituitary-adrenocortical system in MG patients who were treated with prednisolone (PSL) and evaluated their quality of life by using the Medical Outcomes Study 36-item Short-Form Health Survey and the 28-item general health questionnaire (GHQ-28). ACTH and cortisol levels in the plasma of patients who were treated with PSL (PSL[+] group, n = 18) were lower than those in the plasma of patients who were treated without PSL (PSL[-] group, n = 29; P < 0.05 and P < 0.01, respectively). In the PSL(+) group, we confirmed that cortisol levels negatively correlated with daily PSL dosages (P < 0.05). The anxiety and depression scores from the GHQ-28 in the PSL(+) group were lower than those in the PSL(-) group (P < 0.05, respectively). There was no significant correlation between cortisol levels and corticotropin levels in plasma of the PSL(-) group. However, we confirmed that corticotropin levels positively correlated with cortisol levels in plasma (P < 0.01) and negatively correlated with anxiety/insomnia scores from the GHQ-28 (P < 0.05) in the PSL(+) group. In conclusion, low-dose GC treatment complemented the pituitary-adrenocortical system and improved the psychological state in MG patients.

A wide range of individual differences exist in the total number of functional and structural units in each organ, such as β cells in pancreatic islands, and these units are the basis of the organ's overall function, including its functional reserve. The endocrine environment may influence organ histogenesis, during which functional and structural units are formed and increase in number. We analyzed the effects of a continuous high level of adrenocorticotropic hormone (ACTH) and/or secondarily induced glucocorticoid on histogenesis of the pancreas in mouse embryos. Pituitary tumor-derived AtT20 cells, which secrete ACTH continuously, were injected subcutaneously into mouse embryos at embryonic day (E) 12.5, and the embryos were allowed to develop exo utero until E18.5 (AtT20 group). E18.5 AtT20 group embryos with high ACTH levels (23.74 ± 6.19 ng/mL vs control group, 0.48 ± 0.40 ng/mL, P < 0.05) were examined for the effects on histogenesis of the pancreas. Using serial sections of the E18.5 pancreas, we stereologically measured the volumes, and counted total cell numbers and numbers of mitotic or pyknotic cells of the whole pancreas, endocrine and exocrine cells, and glucagon-immunopositive α cells and insulin-immunopositive β cells in the endocrine part. Although the volumes of the whole pancreas and exocrine part did not change significantly, in the AtT20 group the endocrine part was significantly larger, with fewer pyknotic cells and lower ratios of α and β cells than in the control group. These results suggest that the high level of ACTH and/or glucocorticoid affects histogenesis of the pancreas., (© 2011 The Authors. Congenital Anomalies © 2011 Japanese Teratology Society.)

Our aim was to investigate the usefulness of circulating levels of adrenocorticotropic hormone (ACTH) and also salivary cortisol to monitor cortisone substitution in patients with Addison's disease. 13 patients with primary adrenal insufficiency (8 women and 5 men, age 44 ± 11 years) received 12.5 mg cortisone acetate orally at 16:00 h and 25 mg at 07:00 h. Blood samples for cortisol and ACTH analysis were drawn every hour for 24 h, and also every half hour between 07:00 and 12:00 h. Samples for salivary cortisol were collected in parallel. Total ACTH levels showed large inter-individual variations and a diurnal rhythm with a nadir in the early evening at 19:00 (median 19 ng/l, range 2-434 ng/l) and high levels in the early morning, with a peak around 07:30 (median 844 ng/l, range 45-2,249 ng/l). Plasma cortisol concentrations showed 2 peaks distinct in time, but variable in height, 1-2 h after intake of cortisone. Plasma cortisol correlated significantly with ln(ACTH) at 17:00 h (r=-0.56), at 10:00 h (r=-0.51), and at 10.30 h (r=-0.57). When tested at different time points, ln(ACTH) at 10:00 to 12:00 h was negatively correlated with plasma cortisol between 08:30 and 12:00 h. Plasma cortisol was highly correlated to ln(salivary cortisol) most of the time points measured, but 30-60 min after intake of cortisone acetate the correlation disappeared. In conclusion, the large interindividual variation in ACTH levels most likely indicates varying sensitivity to cortisol with a need for individualized dosing schemes. Furthermore ACTH-determinations may be useful for dose titration of cortisol., (© Georg Thieme Verlag KG Stuttgart · New York.)

The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system that regulates the circulating levels of vital glucocorticoid hormones. The activity of the HPA axis is characterized not only by a classic circadian rhythm, but also by an ultradian pattern of discrete pulsatile release of glucocorticoids. A number of psychiatric and metabolic diseases are associated with changes in glucocorticoid pulsatility, and it is now clear that glucocorticoid responsive genes respond to these rapid fluctuations in a biologically meaningful way. Theoretical modelling has enabled us to identify and explore potential mechanisms underlying the ultradian activity in this axis, which to date have not been identified successfully. We demonstrate that the combination of delay with feed-forward and feedback loops in the pituitary-adrenal system is sufficient to give rise to ultradian pulsatility in the absence of an ultradian source from a supra-pituitary site. Moreover, our model enables us to predict the different patterns of glucocorticoid release mediated by changes in hypophysial-portal corticotrophin-releasing hormone levels, with results that parallel our experimental in vivo data.

Because no single test is definitive for Cushing's disease (CD), establishing the diagnosis has remained a challenge that relies on building a critical mass of evidence. The differential diagnosis of corticotropin (ACTH)-dependent Cushing's syndrome (CS) traditionally has rested on noninvasive biochemical and radiologic testing. Bilateral inferior petrosal sinus sampling (BIPSS) is an invasive procedure that has become part of the diagnostic armamentarium surrounding CD. When used appropriately-that is, for patients who have biochemically confirmed ACTH-dependent CS but discordant biochemical or radiologic studies-BIPSS is the reference standard confirmatory test for CD.

Although exercise is a common and potent activator of the hypothalamic-pituitary adrenal (HPA) axis, the effects of exercise on the acute stress response are not well understood. Here, we investigated the effects of short- (2 wk) and long-term (8 wk) voluntary wheel running on adrenal sensitivity to ACTH stimulation and the acute stress response to restraint in male rats. Diurnal glucocorticoid patterns were measured on days 7 (all groups) and 35 (8-wk groups). Rats were subjected to 20 min of restraint stress on either week 1 or on week 7 of treatment to assess HPA activation. One week later, exogenous ACTH (75 ng/kg) was administered to assess adrenal sensitivity to ACTH. Following this, adrenals were collected and analyzed for key proteins involved in corticosterone (CORT) synthesis. By the end of week 1, exercising (E) animals had twofold higher peak diurnal CORT levels compared with sedentary (S) animals (P < 0.01). CORT values were not different between groups at week 8. In response to restraint stress at week 2, CORT values in E were approximately threefold greater than in S (P < 0.05). No difference was found between E and S rats in the response to, or recovery from, restraint at week 8. During the ACTH challenge at week 2, E demonstrated a approximately 2.5-fold increase in adrenal sensitivity compared with S, while no difference was found between E and S at week 8. The expression of steroidogenic acute regulatory protein was found to be approximately 50% higher in the adrenals in E compared with S at week 2 (P < 0.05), but no difference existed between groups at week 8. These results show that volitional wheel running initially causes hyperactivation of the HPA axis, due to enhanced adrenal sensitivity to ACTH, but that these alterations in HPA activity are completely restored by 8 wk of training.

Background: ACTH secretion is under hypothalamic stimulatory (feedforward) and adrenal inhibitory (feedback) control., Hypothesis: Assessment of overnight ACTH secretion during a hypocortisolemic clamp will permit the estimation of changing feedforward and feedback., Subjects: Seven healthy men., Interventions: An oral dose of placebo (PLAC), metyrapone (METY, 3 g), or ketoconazole (KTCZ, 1.2 g) was given at midnight (MN) to block glucocorticoid synthesis. Plasma ACTH was sampled every 10 min (MN to 0800 h)., Analysis: Variable-waveform deconvolution analysis of ACTH secretion and approximate entropy (ApEn) analysis of pattern regularity., Results: Compared with PLAC, administration of METY and KTCZ reduced morning cortisol concentrations by >or=77 and 54% respectively (P<0.001). Hypocortisolemia elevated pulsatile ACTH secretion by 8.2- (METY) and 5.3-fold (KTCZ; both P<0.001). Basal ACTH secretion rose by 3.4-fold under METY-induced cortisol depletion (P=0.020). ACTH secretory-burst shape and half-life were stable. ApEn of ACTH release declined overnight (P=0.021) and with the drug (P=0.001), denoting enhanced feedforward coordination., Conclusion: The combined data predict overnight amplification and coordination of hypothalamic feedforward drive onto ACTH release. Therefore, disruption of either mechanism might contribute to clinical pathophysiology, such as late-day elevations of cortisol output in fasting, alcoholism, depression, or aging.

There is anecdotal evidence that athletes use the banned substance Synacthen because of its perceived benefit with its associated rise in cortisol. To test the performance-enhancing effects of Synacthen, eight trained cyclists completed two, 2-day exercise sessions separated by 7-10 days. On the first day of each 2-day exercise session, subjects received either Synacthen (0.25 mg, TX) or placebo (PLA) injection. Performance was assessed by a 20-km time trial (TT) after a 90-min fatigue period on day 1 and without the fatiguing protocol on day 2. Plasma androgens and ACTH concentrations were measured during the exercise bouts as well as the rate of perceived exertion (RPE). Spot urines were analyzed for androgens and glucocorticoids quantification. Basal plasma hormones did not differ significantly between PLA and TX groups before and 24 h after the IM injection (P > 0.05). After TX injection, ACTH peaked at 30 min and hormone profiles were significantly different compared to the PLA trial (P < 0.001). RPE increased significantly in both groups as the exercise sessions progressed (P < 0.001) but was not influenced by treatment. The time to completion of the TT was not affected on both days by Synacthen treatment. In the present study, a single IM injection of synthetic ACTH did not improve either acute or subsequent cycling performance and did not influence perceived exertion. The investigated urinary hormones did not vary after treatment, reinforcing the difficulty for ACTH abuse detection.

Little is known about baseline concentrations of adrenal hormones and hormonal responses to stress in sea ducks, although significant population declines documented in several species suggest that sea ducks are exposed to increased levels of environmental stress. Such declines have been observed in geographically distinct harlequin duck populations. We performed an adrenocorticotropic hormone (ACTH) challenge to evaluate adrenal function and characterize corticosterone concentrations in captive harlequin ducks and investigated the effects of capture, surgery, and short term confinement on corticosterone concentrations in wild harlequin ducks. Harlequin ducks responded to the ACTH challenge with an average three-fold increase in serum corticosterone concentration approximately 90 min post injection, and a four- to five-fold increase in fecal glucocorticoid concentration 2 to 4 h post injection. Serum corticosterone concentrations in wild harlequin ducks increased within min of capture and elevated levels were found for several hours post capture, indicating that surgery and confinement maintain elevated corticosterone concentrations in this species. Mean corticosterone concentrations in wild harlequin ducks held in temporary captivity were similar to the maximum response levels during the ACTH challenge in captive birds. However, large variation among individuals was observed in responses of wild birds, and we found additional evidence suggesting that corticosterone responses varied between hatch year and after hatch year birds.

We present a case of a 61-year-old female patient with ectopic corticotropin (ACTH) syndrome, hypopituitarism, and catecholamine excess due to a paraganglioma at the inferior pole of the left kidney. In this article we discuss the hormonal findings in the patient and its consequences, the pitfalls of the endocrine workup, and the results of our immunohistological and molecular studies in more detail.

Background: Glucocorticoid therapy is associated with potentially serious side-effects, but there is no information available regarding glucocorticoid requirement in adult hypopituitary patients with partial ACTH deficiency., Subjects: Ten male adult hypopituitary patients with partial ACTH deficiency, baseline plasma cortisol > 200 nmol/l but a peak stimulated cortisol < 500 nmol/l and 10 matched healthy male control volunteers participated., Design: Patients were assigned, in a random order, to a cross-over protocol of treatment for 1 week with full dose hydrocortisone (10 mg twice daily), half-dose hydrocortisone (5 mg twice daily), or no treatment. All patients completed all three of the treatment limbs., Measurements: Following each treatment schedule, patients underwent an 11-h cortisol day curve (CDC), and the results were compared with those from the 10 control volunteers on no glucocorticoid treatment., Results: The integrated CDC values were significantly higher in patients taking a full dose of hydrocortisone compared to controls (P < 0.001). There was no significant difference in the integrated CDC between patients on half-dose (P = 0.37) or no hydrocortisone treatment (P = 0.13), compared to control subjects. Peak postabsorption cortisol values were higher in patients receiving full-dose hydrocortisone treatment compared to controls (P < 0.001). There was no significant difference in plasma sodium concentration, blood pressure or corticosteroid-binding globulin between patients on any treatment schedule and controls., Conclusion: Adult patients with pituitary disease and partial ACTH deficiency have a cortisol secretory pattern comparable to that of healthy controls. Conventional full-dose replacement with 10 mg twice daily of hydrocortisone produces hypercortisolaemia, whereas half-dose produces a CDC that is not statistically different from that of healthy controls. The results suggest that current conventional glucocorticoid replacement overtreats patients with partial ACTH deficiency under normal unstressed physiological conditions.

The effect of adrenocorticotropic hormone (ACTH) administration on plasma cortisol concentrations was determined in pregnant gilts and their fetuses. In a first experiment, 100 IU ACTH (Synacthen Depot) was administered intramuscularly to the gilts every second day from Days 49 to 75 of gestation. ACTH injections were carried out at 08:00 h and, thereafter, 10 blood samples were taken within the following 8h via jugular catheters. Blood samples were analysed for plasma cortisol concentrations, and results were compared with values from animals which were treated with physiological saline and untreated animals (blood sampling only). The values for plasma cortisol concentrations increased until 3h after ACTH applications to a mean maximum level of 276.5+/-17.2 nmol/l in the whole 4-week stimulation period. Plasma cortisol levels did not return to pre-treatment values within the 8 h post-injection. No differences in cortisol levels were found between the physiological saline and untreated control, and no habituation of the adrenocortical response to ACTH was found during the 4-week stimulation period. In a second experiment, 100 IU ACTH were administered to pregnant gilts at gestation Day 65. After 3 h, fetuses were recovered under general anaesthesia and blood samples were taken from the umbilical vein, artery, and, after decapitation, from periphery. Application of ACTH to the sows significantly increased their plasma cortisol concentrations (P<0.001), and also increased plasma cortisol concentrations in peripheral blood samples from the fetuses (P=0.09) and in the umbilical vein (P<0.001) and artery (P<0.01), respectively. Plasma ACTH concentrations did not differ in fetuses from ACTH-treated or control sows. The results show that in gilts the adrenocortical response to an exogenous application of Synacthen Depot is consistent over time during mid-gestation. Furthermore, cortisol but not ACTH levels were increased in fetuses from ACTH-treated sows, indicating that maternal cortisol can cross the placenta during mid-gestation. The stimulation of maternal cortisol release through exogenous ACTH with subsequent elevation of fetal cortisol levels is, therefore, a useful approach for studying effects of elevated maternal glucocorticoids in prenatal stress studies in pigs.

Dysfunction of the hypothalamic-pituitary-adrenal axis might contribute to metabolic disturbances frequently encountered in myotonic dystrophy. We hypothesized that abnormal adrenocortical sensitivity to ACTH and/or glucocorticoid metabolism could be important in myotonic dystrophy. We assessed diurnal rhythmicity of saliva cortisol, adrenocortical reactivity by a low-dose (1 microg) Synacthen test, and glucocorticoid metabolism in blood and urine in 42 myotonic dystrophy patients (22 males) and 50 controls (27 males). CTG triplet repeat expansions were quantified by Southern blot. Diurnal rhythmicity of saliva cortisol was flattened in both men and women with myotonic dystrophy, with significantly increased afternoon/evening levels (P < 0.013). The cortisol response to ACTH was associated with increased (CTG)(n) expansions in myotonic dystrophy men and women (P < 0.01). Male myotonic dystrophy patients also had increased activation of cortisol from cortisone by 11beta-hydroxysteroid dehydrogenase type 1. Both men and women with myotonic dystrophy had an increased 5alpha/5beta-reductase ratio (P < 0.05 and P < 0.01, respectively). Cortisol metabolites were related to the genetic defect in myotonic dystrophy men (P < 0.05), whereas ratios reflecting 11beta-hydroxysteroid dehydrogenase type 1 activity in myotonic dystrophy women were positively associated with obesity (P < 0.05). Increased 11beta-hydroxysteroid dehydrogenase type 1 activity and adrenocortical reactivity to ACTH are related to the genetic defect in myotonic dystrophy men, whereas abnormal glucocorticoid metabolism is associated with alterations in body composition in female myotonic dystrophy patients. These disturbances may explain altered circulating cortisol levels and contribute to features of the metabolic syndrome in myotonic dystrophy.

Conventionally, the assessment of adrenal responses to stress relies on blood sample collection. However, blood collection from animals is impossible without restraint or immobilisation that influences results. This study was undertaken to validate recently established enzyme immunoassays that measure faecal glucocorticoid metabolites in elephants, and to perform a preliminary investigation into the biological relevance of this non-invasive method for use in assessing the degree of stress in this species. Four juvenile African elephants were injected i.m. with 2.15 mg synthetic adrenocorticotrophic hormone (Synacthen, Novartis, Switzerland). Blood and faecal samples were collected over 4 h and 7 d respectively. Concentrations of serum cortisol and faecal cortisol metabolites were determined using immunoassay. Variability of basal and peak values in blood and faeces was observed among the elephants. After ACTH injection, serum cortisol concentrations increased by 400-700%. An 11-oxoaetiocholanolone enzyme immunoassay (EIA) proved best suited to measure cortisol metabolites (11,17-dioxoandrostanes) when compared to a cortisol and corticosterone EIA in faecal samples. Concentrations of faecal 11,17-dioxoandrostanes increased by 570-1070%, reaching peak levels after 20.0-25.5 h. Greater levels of glucocorticoid metabolites were measured in faecal samples from elephants kept in small enclosures compared to levels in the faeces of animals ranging over a larger area. The results of this preliminary study suggest that non-invasive faecal monitoring of glucocorticoid metabolites is useful in investigating adrenal activity in African elephants.

The effects on the pituitary-adrenocortical functions of the prolonged (7-day) blockade of endogenous bradykinin (BK) synthesis, obtained by the administration of the kallikrein inhibitor (K-I) cyclohexylacetyl-Phe-Arg-Ser-Val-Gln amide, were investigated in the rat. K-I treatment did not cause significant changes in the (i) body and adrenal weights; (ii) basal plasma levels of ACTH, aldosterone and corticosterone; and (iii) average volume of adrenocortical cells and their basal secretory capacity. Conversely, K-I administration induced a significant magnification of the in vivo mineralo- and glucocorticoid responses to the intraperitoneal (i.p.) bolus injection of ACTH. Moreover, K-I-treated rats, but not control ones, displayed a moderate and short-term adrenal secretory response to the mild stress evoked by the placebo i.p. injection. Collectively, these findings rule out the possibility that endogenous BK plays a relevant role in the control of adrenocortical function under basal conditions. However, they suggest that endogenous BK may be involved in quenching exceedingly high adrenocortical responses to ACTH and stresses.

Transient global ischemia results in delayed selective neuronal death of hippocampal CA1 pyramidal cells. Glucocorticoids increase and adrenalectomy decreases the rate of neuronal death; however, they also produce changes in brain temperature, serum glucose and adrenocorticotropic hormone levels. In order to understand the role of glucocorticoids in regulating ischemic cell death, we studied RU 38486, a glucocorticoid receptor blocker, and Org 2766, a non-steroidogenic adrenocorticotropic hormone 4-9 analog. Male Mongolian gerbils were subjected to 5 min of bilateral carotid artery occlusion under a controlled temperature environment (37.0-38.0 degrees C). Animals were injected with either physiological saline, Org 2766 (10 microg/kg/24 h) or RU 38486 (50 mg/kg/8 h), beginning just prior to the occlusion until killing at either day 4 or 7. Blood was collected for serum glucose and cortisol analysis. Damage was evaluated by blinded counts of CAI neurons. Both RU 38486 and Org 2766 treatment significantly (P<0.004) reduced hippocampal CA1 damage at day 4, but not on day 7. While RU 38486 raised serum cortisol and adrenocorticotropic hormone levels, neither treatment affected temperature or serum glucose. The fact that RU 38486 mimicked adrenalectomy without changing temperature suggests that the decreased rate of cell death resulted from either removal of glucocorticoids or increases in adrenocorticotropic hormone. The ability of Org 2766 to affect this rate strongly suggests that adrenocorticotropic hormone is the active regulatory hormone rather than glucocorticoids. While both RU 38486 and Org 2766 prolong the survival of CA1 neurons after transient global ischemia, only RU 38486, which is available and tested in both animals and humans, can block the detrimental effects of post-ischemia glucocorticoid elevations. Thus, the administration of RU 38486 may be a practical adjunct to other neuroprotective agents for victims of cardiac arrest, anesthetic accidents or drowning.

A 48-year-old with bilateral adrenal incidentalomas was studied. Although the serum cortisol level was normal, autonomous cortisol secretion was shown by the loss of diurnal rhythm, no suppressibility by dexamethasone, and complete suppression of plasma adrenocorticotropin levels. Imaging analyses revealed bilateral adrenal masses, showing isotope uptake. He was diagnosed as preclinical Cushing's syndrome due to adrenocorticotropin-independent bilateral adrenocortical macronodular hyperplasia, confirmed histologically. Despite the undetectable plasma adrenocorticotropin level and renin activity, serum mineralocorticoids levels were not suppressed, which were decreased after subtotal adrenalectomy. It was suggested that hyperplastic adrenal glands could produce both gluco- and mineralocorticoids concomitantly.

High concentrations of unbound cortisol in late pregnancy have been explained by the antiglucocorticoid activity of high progesterone levels. To further test this hypothesis we studied the effect of high-dose progesterone on baseline and corticotrophin-releasing hormone (CRH)-induced hormone secretion in humans. In a double-blind crossover study eight healthy male volunteers received either progesterone (0.714 mg.kg-1.h-1 for 60 min followed by a dose of 0.45 mg.kg-1.h-1 over a total infusion time of 315 min) or vehicle as a continuous intravenous infusion. At 210 min a CRH test (0.1 microgram/kg body weight as bolus iv) was performed. Within 30 min after the start of progesterone administration the serum progesterone level increased to 454 +/- 31 nmol/l and remained in the range of third trimester pregnancy concentrations throughout the infusion period. During vehicle infusion the progesterone level remained in the normal range for healthy males and demonstrated a small but significant increase after CRH (1.52 +/- 0.23 vs 0.74 +/- 0.14 mmol/l; p < 0.01). However, baseline and CRH-stimulated serum cortisol and plasma adrenocorticotrophic hormone remained unaffected by high-dose progesterone. Moreover, unbound salivary cortisol also was not affected by progesterone, suggesting that there is no significant competition for transcortin binding sites. In conclusion, no antiglucorticoid activity was found after short-term administration of progesterone in males. These findings cast doubts on the concept that the alterations of the pituitary-adrenal axis in late pregnancy are induced by the antiglucocorticoid activity of high progesterone concentrations.

Aging, as well as some frequently associated pathological conditions (depression, dementia, Alzheimer's disease, etc.), has been shown to have a profound impact on the normal functioning of the hippocampus-hypothalamo-pituitary-adrenocortical axis system. The hypothalamo-pituitary-adrenocortical axis in the aged rat is characterized by an increase in the basal level of circulating corticosterone, an impaired ability to recover from the adrenocortical stress response, and a reduced sensitivity to the dexamethasone suppression test. All these alterations may arise from a reduced hippocampal negative feedback control of the axis, as suggested by the age-dependent loss of hippocampal adrenocorticoid receptors. Among the hypothalamic corticotropin secretagogues, corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP) are considered the main physiological mediators of hypothalamic control of ACTH release. Thus, we have investigated the dynamic and the temporal course of the adrenocortical response to CRH and AVP in the aged rat. Freely moving jugular-catheterized male Sprague-Dawley rats (3- and 24-month-old) were injected with CRH (0.5, 0.05 and 0.01 microgram/kg i.v.), or AVP (1.0, 0.1 and 0.05 microgram/kg i.v.), or CRH and AVP in combination. In addition, adrenocortical sensitivity to corticotropin has been studied by injecting ACTH (10 ng/kg i.v.). Our study has (1) indicated that the response to ACTH secretagogues is dampened with aging, and (2) shown in the aged rat a slower recovery. Moreover, the results had confirmed the age-dependent increase in the basal level of corticosterone in the rat, and shown no age-related differences in the glucocorticoid response to ACTH.

Angiotensin II (ANG II) and vasopressin participate in baroreflex regulation of adrenocorticotropic hormone (ACTH), glucocorticoid, and renin secretion. The purpose of this study was to determine whether this participation is enhanced in water-deprived dogs, with chronically elevated plasma ANG II and vasopressin levels, compared with water-replete dogs. The baroreflex was assessed by infusing increasing doses of nitroprusside (0.3, 0.6, 1.5, and 3.0 micrograms.kg-1.min-1) in both groups of animals. To quantitate the participation of ANG II and vasopressin, the dogs were untreated or pretreated with the competitive ANG II antagonist saralasin, a V1-vasopressin antagonist, or combined V1/V2-vasopressin antagonist, either alone or in combination. The findings were as follows. 1) Larger reflex increases in ANG II, vasopressin, and glucocorticoids, but not ACTH, were produced in water-deprived dogs compared with water-replete dogs. 2) ANG II blockade blunted the glucocorticoid and ACTH responses to hypotension in water-deprived dogs, but not water-replete dogs. In contrast, vasopressin blockade reduced the ACTH response only in water-replete dogs. 3) Vasopressin or combined vasopressin and ANG II blockade reduced the plasma level of glucocorticoids related either to the fall in arterial pressure or to the increase in plasma ACTH concentration in water-replete dogs, and this effect was enhanced in water-deprived dogs. 4) In both water-deprived and water-replete animals, saralasin and/or a V1-antagonist increased the renin response to hypotension, but a combined V1/V2-antagonist did not. These results reemphasize the importance of endogenous ANG II and vasopressin in the regulation of ACTH, glucocorticoid, and renin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

The pattern of adrenal steroid secretion under basal and stress conditions and the response to tetracosactid (20.0 micrograms/kg body weight) were studied in adult male rabbits. In animals repeatedly stressed by artery puncture, plasma glucocorticosteroid levels were slightly higher than those found in unstressed control animals. The combined stress of repeated exposure to ether vapor for 60 sec, followed by artery puncture, significantly stimulated glucocorticosteroid release, concentrations progressively increasing with the number of ether exposures applied. A much faster and more pronounced stimulation of glucocorticosteroid release was seen in animals treated with 20.0 micrograms/kg body weight tetracosactid. Plasma aldosterone levels in animals stressed by artery puncture were higher, although not significantly, than those of unstressed control animals. Repeated exposure to ether vapor for 60 sec, followed by artery puncture, on the other hand slightly decreased plasma aldosterone concentrations. A strong stimulation of aldosterone release at 20--60 min after injection could be elicited only by intravenous administration of 20.0 micrograms/kg body weight tetracosactid. Because of the insensitivity of the zona glomerulosa cells to increased ACTH levels under stress conditions, it is concluded that ACTH is only of minor importance both under basal and stress conditions in the regulation of aldosterone secretion in the rabbit.

Glucocorticoid response to exogenous adrenocorticotropin was used as an indicator of stress in cows fed different diets ad libitum during the dry period and throughout lactation. Twenty-three Holstein cows were administered adrenocorticotropin at 2 d after initiation of the dry period and at 2 d and 35 d postpartum, and plasma glucocorticoid response was evaluated. Cows were fed diets using only corn silage as forage or mixed forage with or without supplemental concentrate. Mean basal plasma glucocorticoid concentrations were 6.1 ng/ml on d 2 after dry off, 4.7 ng/ml on d 2 postpartum, and 6.7 ng/ml on d 35. Cows on the 32.5:32.5:35 corn silage:grass-legume silage:concentrate diet had the lowest basal glucocorticoid concentrations on d 2 postpartum but highest concentrations on d 35 of lactation. Mean glucocorticoid response was 33.2 ng/ml on d 2 of lactation compared with 50.6 ng/ml on d 35 and 48.5 ng/ml plasma on d 2 following drying off. Diet interactions suggest that feed components may be involved with ability to tolerate stresses that occur during lactation and the dry period and thus may lead to altered adrenal function.

An injection of several doses of ovine corticotropin-releasing factor (oCRF) was made into an allantoic blood vessel of 18-day-old chick embryos. All doses used (0.5, 1, 2, and 5 micrograms) induce a quick increase of plasma corticosterone concentrations after 15 and 30 min and 1 and 2 hr and this in a dose-dependent manner with the high doses having a prolonged effect lasting up to 2 hr. An increase in plasma levels of thyroxine (T4) and triiodothyronine (T3) was observed after 1 and 2 hr. After the oCRF injection, no stimulation of the hepatic 5'-monodeiodination activity was observed and there was no increase, but even a small decrease in the T3 to T4 ratio could be calculated. It was therefore concluded that oCRF in the chick embryo has a thyrotropic effect presumably by stimulating the release of thyrotropin from the pituitary.

The disappearance of 125-I-ACTH from the circulation of 4 pregnant and fetal sheep has been followed after a single injection to the ewe or fetus. The mean metabolic clearance rate for the fetus and the ewe was 55 and 34 ml/min/kg respectively, giving a half-life in each case of about 1 min. The higher fetal than maternal arterial plasma ACTH concentration has been ascribed to a higher rate of secretion rather than a reduced rate of clearance compared with the ewe. There was no evidence of placental transfer of immunologically reactive ACTH.

Ten Holstein cows, in second to fifth lactation, received 200 IU adrenocorticotrophin at approximately 4, 8, 16, 24, 32, and 40 wk of lactation. Blood samples were collected from indwelling jugular catheters at -60 and 0 min pre-injection and at 2, 6, 10, 15, 20, 30, 45, 60, 120, 180, 240, 360, 540, and 720 min postinjection. Post-injection concentrations of glucocorticoids were influenced by milk yield, stage of lactation, age, and mean environmental temperature but not by pre-injection concentration of glucocorticoids or days pregnant. As milk yield, cow age, and daily temperature (range 6.4 to 26.9 C) increased, glucocorticoid response decreased whereas it increased with advancing stage of lactation. Curves of adrenal response for the six injection times during lactation were not parallel, and average response adjusted for significant independent variables increased roughly in linear fashion from 15 to 53 ng/ml between 4 and 40 wk of lactation. Adrenal responsiveness was less in cows injected on days when temperatures were above 21.1 C than in those injected below this temperature. There was no evidence that adrenal function or milk production was altered in high producing cows at higher environmental temperatures differently from in low producing cows. The change in adrenal function during advancing lactation was not associated with pre-treatment peripheral plasma glucocorticoid concentrations which did not change. There appears to be a well mainained adrenal potential and sustained adrenocortical activity throughout lactation.

During the nycthemeral cycle, ACTH modulated the aldosterone production and increases plasmatic level at the end of night. The chronic stimulant effect of angiotensin II is a permissive factor of ACTH influence on aldosterone formation.

Adrenal responsiveness was evaluated by injecting 10 multiparous dairy cows with 200 IU adrenocorticotropin between -13 and -2 days prepartum (I) and postpartum between 24 and 40 h (II) and 21 and 24 days (III). Concentrations of glucocorticoids following injection were influenced by day of injection, temperature, and minimum percent relative humidity but not by breed, breed X injection day interaction, or age of cow. Likewise differences in regressions for adrenal response and mean response (ng/ml) for the three injections were nil. Mean concentrations at peak (45, 60, and 120 min postinjection samples) adjusted for preinjection concentrations also did not differ for the three periods of injection. Mean concentrations of glucocorticoids in plasma for daily samples between -13 and -2 days prepartum were 5.3 +/- .4 (n = 61), reached a peak of 14.8 +/- .3 ng/ml the day of calving, and remained high for 2 days postpartum. Estradiol increased through prepartum sampling from 23.3 to 339.6 +/- 94.1 pg/ml the day of calving, then declined abruptly. Progestins began to decline about -5 days prepartum from mean concentration of 4.09 +/- .62 (n = 25) and attained low concentrations (.30 +/- .06 ng/ml) 2 days postpartum. Although there was a surge of glucocorticoids at parturition, this was not associated with a modification in adrenal responsiveness or with prepartum concentrations of other steroid hormones of plasma. Adrenal potential in prepartum and postpartum dairy cows appears well maintained.

The adrenocortical secretory activity under basal conditions and after treatment with tetracosactid (1-24ACTH) has been investigated in chronically cannulated male rabbits. Basal plasma concentrations of glucocorticosteroids (0.74 micrograms/100 ml) and aldosterone (78 pg/ml) have been determined in a greater number of animals. No significant positive correlation between basal glucocorticosteroid and aldosterone plasma levels could be found. After intravenous injection of 2.5, 5.0, 10.0 and 20.0 micrograms/kg body weight tetracosactid glucocorticosteroid concentrations were significantly elevated between 40--100 min after administration; aldosterone release, on the other hand, was significantly increased only after injection of 10.0 or 20.0 micrograms/kg body weight tetracosactid between 20--60 min after injection. After administration of high tetracosactid doses glucocorticosteroid and aldosterone plasma concentrations were significantly correlated (10.0 micrograms/kg: r = 0.62; 20.0 micrograms/kg: r = 0.26). Because of the relative insensitivity of the zona glomerulosa cells to tetracosactid administered intravenously, it is concluded that ACTH is only of minor importance in the regulation of aldosterone secretion in the rabbit.

Tne Holstein heifers acclimated to either -2.7 or 19.1 C were used to determine glucocorticoid concentrations in plasma following injection of adrenocorticotropin (200 IU). Environmental treatments did not change glucocorticoids following adrenococorticotropin. Adrenocorticotropin injection elevated mean glucocorticoids to 41.6 ng/ml plasma at -2.7 C and 42.8 ng/ml at 19.1 C. Adrenal response to adrenocorticotropin in Holstein heifers was not altered by low environmental temperature.

Four open, dry Holstein cows in the University of Missouri Climatic Laboratory were used to study the effect of adrenocorticotropic hormone administration on glucocorticoids and antidiuretic hormone of plasma in two reversal trials at thermoneutral (20 C, 50% relative humidity) and heat (33 C, 50% relative humidity) conditions. Average glucocorticoids (saline versus adrenocorticotropic hormone) at thermoneutral were 8.3 and 41.2 ng/ml while values for heat were 6.2 and 40.4 ng/ml. The effect of heat on glucocorticoids of plasma was not significant. Injection of adrenocorticotropic hormone under thermoneutrality and heat caused a marked increase in antidiuretic hormone within 5 min which lasted to 120 min. At thermoneutral average antidiuretic hormone levels (saline versus adrenocorticotropic hormone) were .5 and 1.9 pg/ml while values for heat were 1.8 and 3.6 pg/ml. Antidiuretic hormone concentrations under heat were higher than thermoneutral in cows injected with saline and andrenocorticotropic hormone. The fast response of antidiuretic hormone of plasma to exogenous adrenocorticotropic hormone suggests that adrenocorticotropic hormone might act directly at higher levels of the central nervous system causing release of antidiuretic hormone.

Plasma cortisol, progesterone, testosterone and aldosterone levels were measured on serial blood samples drawn in 10 healthy adult human males up to 6h after single administration at about 07 of increasing amounts of the short-chain analogue ACTH-agonist alsactide (Synchrodyn 1-17). The following doses were employed: 2, 4, 8, 10 and 20 micrograms subcutaneously (s.c.), as well as 2, 4 and 8 micrograms intravenously (i.v.). Data were compared with those obtained by placebo (isotonic saline) injections. The s.c. injections of 2 and 4 micrograms resulted to be ineffective in changing the hormonal pattern. A significant rise of cortisol and progesterone, but not of aldosterone and testosterone, followed the s.c. injections of 8 and 10 micrograms. The differential pattern of the glucocorticoid vs. the mineralocorticoid response was also apparent after the s.c. injection of 20 micrograms alsactide; when compared with placebo, this dose was able to elicit a significant increase of all examined hormones except testosterone. All i.v. injections of 2, 4 and 8 micrograms alsactide were effective; the highest dose did cause a sustained rise of plasma cortisol, progesterone and aldosterone, but also the other doses were able to change significantly the mineralocorticoid levels. These results provide evidence that circadian-stage-specified s.c. or i.v. administration of the analogue can be employed in the clinical practice for enhancing selectively and transiently the morning glucocorticoid secretion.

The objective was to determine if semen quality and output could be affected by pharmacological doses of adrenocorticotropin. Three Holstein bulls, one 7 yr old and two yearlings, were treated with 200 IU adrenocorticotropic hormone every 8 h for 6 days. Effects of treatment on semen traits and peripheral concentrations of glucocorticoids, testosterone, and androstenedione were measured. Viability of spermatozoa (percentage motility and percentage intact acrosomes), ejaculate volume, sperm concentration, and weekly sperm output were unaffected by adrenocorticotropin treatment up to 8 wk posttreatment. The proportion of spermatozoa with cytoplasmic droplets and head abnormalities was elevated slightly from .8 +/- .1 and 4.2 +/- .3% to 1.3 +/- .2 and 5.8 +/- .4% during treatment. Total glucocorticoids increased from 11.9 +/- 2.7 ng/ml before treatment to 73.5 +/- 4.1 ng/ml during treatment. Testosterone decreased in the yearling bulls from 5.5 +/- .9 ng/ml plasma before treatment to .5 +/- .5 ng/ml afterward; the decrease began 8 h following the initial adrenocorticotropin injection and persisted until 24 h following last injection. The mature bull had normal testosterone concentrations for the first 4 days of injection, and decreased concentrations for the last 2 days of injection. Semen viability, concentration, and sperm output are unaffected by a pharmocological administration of adrenocorticotropin and subsequent marked increase of glucocorticoids and decrease of testosterone. Only a small increase of semen content of immature sperm or sperm with abnormal heads may be associated with these marked endocrine changes.

Plasma adrenocorticotrophin (ACTH) and glucocorticoid concentrations were measured during and for 3 hours after exchange transfusion in four groups of infants. Transfusion with ACD blood via the umbilical artery were performed on 10 infants of 35--40 weeks gestation and 11 infants of 27 to 33 weeks gestation. Ten transfusions via the umbilical vein were performed with ACD blood and 9 with heparin blood on infants of 32 to 41 weeks gestation. In all four types of transfusion there was a significant washing out of ACTH and glucocorticoids from the baby. An associated rise of plasma ACTH and glucocorticoid levels indicated increased secretion in the larger infants transfused with ACD blood via the umbilical artery. Equivocal results were obtained in the other groups. After all types of transfusion plasma glucocorticoid levels remained relatively constant for one hour and then doubled and then doubled in the second and third hour. The results suggest that (a) exchange transfusion via the umbilical artery is more stressful than that via the umbilical vein, (b) the glucocorticoid response of premature infants to exchange transfusion is similar to that of mature ifants, (c) an unspecified stimulus, which is not solely hypoglycaemia nor the metabolic reaction to a citrate load, results in a rise in plasma glucocorticoid levels 2-3 hours after all types of transfusion.

Nine Holstein-Friesian cows in the same stage of lactation were randomly given IM injections of saline solution, 100 IU of ACTH, or 200 IU of ACTH for a period of 3 days at 0800 and 1600 hours on one day and at 0100 hours the next day. A dose of 100 IU of ACTH represented the amount of ACTH released during physiologic stress and 200 IU of ACTH represented a therapeutic dose. Blood samples were obtained from indwelling jugular catheters for total circulating leukocyte and total plasma corticosteroid determinations at -1, 0, 0.25, 0.50, 1, 1.50, 2, 4, 6, and 8 hours after the 0800-hour ACTH injections. Concentrations of blood leukocytes and total plasma corticosteroids were affected significantly (P < 0.05) by treatment, cow within treatment, day of injection, treatment by day interaction, time, treatment by time interaction, and day by time interaction. Total plasma corticosteroids were 5.6 ng/ml (saline), 38.9 ng/ml (100 IU of ACTH), and 59.8 ng/ml (200 IU of ACTH). Mean corticosteroid concentrations from 0.5 to 8 hours were 29.2 ng/ml on day 1, 42.5 ng/ml on day 2, and 32.7 ng/ml on day 3. Blood leukocytes were 8,545 cells/mm3 (saline, 11,241 cells/mm3 (100 IU of ACTH) and 9,777 cells/mm3 (200 IU of ACTH). When compared with basal circulating leukocyte concentrations (within cow), this represented increases of 20.7% for 100 IU of ACTH and 24.5% for 200 IU. Mean circulating leukocyte concentrations from 0.5 to 8 hours were 8,900 cells/mm3 on day 1, 10,500 cells/mm3 on day 2, and 10,000 cells/mm3 on day 3. These data indicate that the adrenal gland responded less on day 3 and that continuous stimulation of bovine adrenal glands by ACTH at physiologic and therapeutic concentration could lead to reduced synthesis or release of adrenal corticosteroids (or both) with concomitant reduction in the concentration of total circulating leukocytes.

Superphysiological doses of ACTH were administered for 3 consecutive days to nine patients with CAH, five with the classical simple virilizing (CSV) type and four with nonclassical simple virilizing type (NCSV; late onset), receiving a sodium-restricted diet. In the CSV patients, cortisol levels were lower [4.9 +/- 2.2 (+/- SEM) micrograms/dl] than in the NCSV patients (10.9 +/- 3.8; P less than 0.005) and normal subjects (10.7 +/- 4.0; P less than 0.05). ACTH produced a subnormal increase to only 14.5 micrograms/dl by day 3. In the NCSV patients, cortisol rose slowly during the first 24 h, but reached normal response levels by 48 h (42.5 +/- 11.5 micrograms/dl). In all patients, basal plasma corticosterone and 18-hydroxydeoxycorticosterone (18-OHDOC) levels were normal, but deoxycorticosterone (DOC) was elevated at 25.3 +/- 5.0 ng/dl (P less than 0.05). ACTH failed to increase plasma levels of DOC, corticosterone, and 18-OHDOC. Aldosterone and 18-hydroxycortisol were elevated in both groups [29.1 +/- 5.8 (P less than 0.02) and 83.8 +/- 15.3 (P less than 0.01) ng/dl, respectively] and increased briskly after the first 24 h of ACTH. However, neither steroid returned to normal levels in the CSV group, but both did in the NCSV group. Paired values of stimulated cortisol and aldosterone in normal subjects and CSV and NCSV patients (n = 76) were significantly negatively correlated (r = -0.63; P less than 0.001), suggesting that cortisol inhibits aldosterone biosynthesis. Prolonged ACTH administration after initial increases returned aldosterone and 18-hydroxycortisol levels from the zona glomerulosa to baseline values in the NCSV type, but not in the CSV type. The capacity to increase cortisol levels, which occurred only in NCSV patients, is linked to the reduction of aldosterone in the zona glomerulosa. In contrast, in both types of 21-hydroxylase deficiency, sustained impairment of both the 17-hydroxy pathway (cortisol) and the 17-deoxy pathway of the zona fasciculata (DOC, corticosterone, and 18-OHDOC) was demonstrated.

We studied the fetal pituitrary-adrenal axis in 9 growth retarded fetal lambs by serially measuring plasma glucocorticoids and ACTH concentrations from 115 to 140 days of gestation and adrenal blood flow at 138 days of gestation. At each gestational age period studied, plasma glucocorticoid and ACTH concentrations were similar in both growth retarded and control fetuses (Figs. 1, 2). However, ACTH concentration tended to be higher in the last 20 days of gestation in the growth retarded fetuses. This resulted in a significantly lower glucocorticoid/ACTH ratio between 121 to 130 days of gestation in the growth retarded fetal lambs as compared to the control fetuses (212 +/- 111 vs. 1042 +/- 257). The glucocorticoid/ACTH ratio in the growth retarded fetuses became similar to the ratio of the control fetuses at 131 to 140 days (445 +/- 145 vs. 554 +/- 182). Adrenal blood flow was significantly increased at term in the the growth retarded fetuses (535 +/- 87 vs. 302 +/- 40 ml/min/100g). These data indicate that the pattern of maturation of the fetal adrenal gland in the growth retarded fetal lamb is similar to that of the normal sized fetus. Because of the increased adrenal blood flow observed at 138 days of gestation, there is a suggestion of a decreased sensitivity to ACTH in these animals.