To study the effects of physical conditioning on the hypothalamic-pituitary-adrenal axis, we examined the plasma ACTH, cortisol, and lactate responses in sedentary subjects, moderately trained runners, and highly trained runners to graded levels of treadmill exercise (50, 70, and 90 percent of maximal oxygen uptake) and to intravenous ovine corticotropin-releasing hormone (1 microgram per kilogram of body weight). Basal evening concentrations of ACTH and cortisol, but not of lactate, were elevated in highly trained runners as compared with sedentary subjects and moderately trained runners. Exercise-stimulated ACTH, cortisol, and lactate responses were similar in all groups and were proportional to the exercise intensity employed. These responses, however, were attenuated in the trained subjects when plotted against applied absolute workload. Only the highly trained group had diminished responses of ACTH and cortisol to ovine corticotropin-releasing hormone, consistent with sustained hypercortisolism. We conclude that physical conditioning is associated with a reduction in pituitary-adrenal activation in response to a given workload. Alterations of the hypothalamic-pituitary-adrenal axis consistent with mild hypercortisolism and similar to findings in depression and anorexia nervosa were found only in highly trained runners. Whether these alterations represent an adaptive change to the daily stress of strenuous exercise or a marker of a specific personality profile in highly trained athletes is unknown.

Primary depression can be associated with substantial hypercortisolism, thus prompting some researchers to suggest that depression shares pathophysiologic features with Cushing's disease. Clinically, depression can be difficult or impossible to distinguish from mild or early Cushing's disease that is associated with depressive features. The purpose of this study was to evaluate whether the pituitary-adrenal responses to ovine corticotropin-releasing hormone could help to clarify the mechanism of hypercortisolism in depression and in Cushing's disease and to assist in the differential diagnosis of these disorders. As compared with controls (n = 34), depressed patients (n = 30) had basal hypercortisolism (P less than 0.001) that was associated with attenuated plasma ACTH responses to ovine corticotropin-releasing hormone (P less than 0.001). This indicates that in patients with depression, the corticotroph cell in the pituitary responds appropriately to the negative feedback of high cortisol levels. In contrast, patients with Cushing's disease (n = 29) had plasma ACTH hyperresponsiveness to ovine corticotropin-releasing hormone (P less than 0.001), despite basal hypercortisolism (P less than 0.001), which indicates a gross impairment of the mechanism by which cortisol exerts negative feedback on the pituitary. Less than 25 percent of the patients with depression or Cushing's disease had peak ACTH responses that overlapped. We conclude that the pathophysiologic features of hypercortisolism in depression and Cushing's disease are distinct in each of the disorders and that the ovine corticotropin-releasing hormone stimulation test can be helpful in their differential diagnosis.

Growth retardation as well as the development of Cushingoid features in adrenally insufficient patients treated with the currently accepted replacement dose of cortisol (33-41 mumol/day.m2; 12-15 mg/m2.day) prompted us to reevaluate the cortisol production rate (FPR) in normal subjects and patients with Cushing's syndrome, using a recently developed thermospray liquid chromatography-mass spectrometry method. The stable isotope [9,12,12-2H3]cortisol was infused continuously for 31 h at about 5% of the anticipated FPR. Blood samples were obtained at 20-min intervals for 24 h, spun, and pooled in 4-h groups. Tracer dilution in plasma was determined by liquid chromatography/mass spectrometry. The method was validated with controlled infusions in 6 patients with adrenal insufficiency. Results from 12 normal volunteers revealed a FPR of 27.3 +/- 7.5 mumol/day (9.9 +/- 2.7 mg/day) or 15.7 mumol/day.m2; 5.7 mg/m2. day). A previously unreported circadian variation in FPR was observed. Patients with Cushing's syndrome demonstrated unequivocal elevation of FPR and cortisol concentration correlated during each sample period in normal volunteers, indicating that cortisol secretion, rather than metabolism, is mainly responsible for changes in plasma cortisol. Our data suggest that the FPR in normal subjects may be lower than previously believed.

ObjectiveThe authors review the historical basis for the provision of perioperative glucocorticoid coverage, and detail the evolution in the understanding of the role of the hypothalamic-pituitary-adrenal cortical (HPA) axis in response to physical stressors. New recommendations are proposed for glucocorticoid-dependent patients who require anesthesia and surgery. Summary Background DataIn 1952, a patient developed surgery-associated adrenal insufficiency as a result of preoperative withdrawal from glucocorticoid therapy. That case report, and one other in the ensuing 12 months, prompted the publication of recommendations for perioperative glucocorticoid coverage, which became the standard of care. The understanding of the role of the HPA axis in the stress response has been subsequently refined; however, recommendations for perioperative glucocorticoid coverage have not been altered in parallel. MethodsStudies were identified beginning with the first reports of the physiologic actions of the adrenal glands (1855) and the description and clinical use of cortisone . Studies were selected for review if they were related to or evaluated the provision of stress-related glucocorticoid administration. All clinical studies were evaluated to determine the basis for the provision of perioperative glucocorticoid coverage and the validity of the data used to justify these conclusions. ConclusionsClinical and experimental evidence support the concept that the current amount of perioperative glucocorticoid coverage is excessive and has been based on anecdotal information. New recommendations are proposed which suggest that the amount and duration of glucocorticoid coverage should be determined by: a) the preoperative dose of glucocorticoid taken by the 416

ABSTRACT. The concentrations of the adrenal steroids dehydroepiandrosterone (DHA), dehydroepiandrosterone sulfate (DHAS), and A 4 -androstenedione (A 4 -A) have been measured by RIA before and after sexual maturation in plasma of rodents, domestic animals, and primates to determine whether these species exhibit an adrenarchal process comparable to man. The average concentrations of DHA and DHAS were less than 60 ng/dl and 5 fig/dl, respectively, in plasma of sexually mature rodents and domestic animals, and a significant increase in the plasma DHA level after sexual maturation was seen only in the rabbit and dog. The concentrations of DHA, DHAS, and A 4 -A in 21 rhesus monkeys from 0-3 yr of age were 2021 ± 235 ng/dl (mean ± SE), 357 ± 60 jug/dl, and 107 ± 9 ng/dl, respectively, and did not increase during sexual maturation. By contrast, DHA, DHAS, and A 4 -A levels in plasma of chimpanzees were 5.9-fold, 3.3-fold, and 4.8-fold greater, respectively, in 7-to 22-compared to 0-to 3-yr-old animals. Temporally, the increase in DHA levels in the chimpanzee is apparent at 5 yr and this precedes the increase in gonadal steroids, as is characteristic of human adrenarche. It is apparent that adrenal androgen levels and their developmental patterns differ markedly among species, and that among the species examined, only the chimpanzee exhibits an adrenarche comparable to that of man. (Endocrinology 103: 2112(Endocrinology 103: , 1978