The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)

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How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

We have examined factors concerned with the maintenance of uterine quiescence during pregnancy and the onset of uterine activity at term in an animal model, the sheep, and in primate species. We suggest that in both species the fetus exerts a critical role in the processes leading to birth, and that activation of the fetal hypothalamic-pituitary-adrenal axis is a central mechanism by which the fetal influence on gestation length is exerted. Increased cortisol output from the fetal adrenal gland is a common characteristic across animal species. In primates, there is, in addition, increased output of estrogen precursor from the adrenal in late gestation. The end result, however, in primates and in sheep is similar: an increase in estrogen production from the placenta and intrauterine tissues. We have revised the pathway by which endocrine events associated with parturition in the sheep come about and suggest that fetal cortisol directly affects placental PGHS expression. In human pregnancy we suggest that cortisol increases PGHS expression, activity, and PG output in human fetal membranes in a similar manner. Simultaneously, cortisol contributes to decreases in PG metabolism and to a feed-forward loop involving elevation of CRH production from intrauterine tissues. In human pregnancy, there is no systemic withdrawal of progesterone in late gestation. We have argued that high circulating progesterone concentrations are required to effect regionalization of uterine activity, with predominantly relaxation in the lower uterine segment, allowing contractions in the fundal region to precipitate delivery. This new information, arising from basic and clinical studies, should further the development of new methods of diagnosing the patient at risk of preterm labor, and the use of scientifically based strategies specifically for the management of this condition, which will improve the health of the newborn.

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Endocrine and paracrine regulation of birth at term and preterm

Neuroendocrine pharmacology of stress

I. Introduction II. Definitions and Etiology III. Diagnostic Overview IV. Clinical Features V. Biochemical Diagnosis of Cushing’s Syndrome A. Cardinal features B. Urinary free cortisol (UFC) C. Low-dose dexamethasone testing D. Circadian rhythm assessment E. Cyclical Cushing’s syndrome VI. ACTH-Dependent vs. ACTH-Independent Cushing’s Syndrome VII. Differential Diagnosis of ACTH-Dependent Cushing’s Syndrome A. Overview B. Basal testing C. Dynamic noninvasive testing D. Invasive testing VIII. Other Causes of Cushing’s Syndrome IX. Imaging A. Pituitary B. Adrenal C. Ectopic secretion X. Differentiation from Pseudo-Cushing’s States XI. Conclusions

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The Diagnosis and Differential Diagnosis of Cushing’s Syndrome and Pseudo-Cushing’s States

Central nervous system mechanisms of pain modulation

Hormonal and metabolic responses to an enkephalin analogue in normal man

SUMMARY
Studies were performed to define the responses of plasma met-enkephalin to various endocrine and pathological stimuli and to determine the relationship between plasma β-endorphin and met-enkephalin. During insulin-induced hypoglycaemia ACTH, β-LPH and β-endorphin immunoreactivity rose in parallel, but plasma met-enkephalin did not change significantly. Sephadex G75 chromatography of samples taken at the time of the peak response (45 min) confirmed the rise in both β-LPH and β-endorphin. During administration of dexamethasone, 0·5mg 6 hourly for 48 h, plasma cortisol and ACTH became undetectable at 24 h, and β-LPH and β-endorphin fell significantly by 24 h and were undetectable by 48 h; plasma met-enkephalin, however, showed no significant change. Nine adrenalectomized patients with Cushing's disease and four patients with Addison's disease had elevated plasma ACTH, β-LPH and β-endorphin but normal plasma met-enkephalin levels. Each of ten patients with renal failure had markedly elevated plasma met-enkephalin immunoreactivity which co-eluted with synthetic met-enkephalin on BioGel P4 chromatography. Trypsin and carboxypeptidase-B digestion of the P4 chromatography fractions generated met-enkephalin immunoreactivity in earlier fractions, indicating the presence of a potential high molecular weight met-enkephalin precursor.

The results imply that different control mechanisms govern β-endorphin and met-enkephalin plasma levels and that the adrenal is not the only source of plasma met-enkephalin. The elevated levels of met-enkephalin in renal failure may be due to impaired clearance of met-enkephalin or of its precursor or to increased met-enkephalin production.

Studies on circulating met-enkephalin and beta-endorphin: normal subjects and patients with renal and adrenal disease.

SUMMARY
Basal and stimulated secretion of N-terminal pro-opiocortin (Pro-γ-MSH), ACTH and LPH from seven pituitary and three ectopic ACTH secreting tumours have been studied in vitro using a perfused isolated cell system. The peptides were shown to be released concomitantly and in equimolar amounts. The pituitary tumours responded to stimulation with rat stalk median eminence extracts (SME) and synthetic AVP. However, peptide release from the ectopic tumours, although pulsatile, remained autonomous. Prior to surgery, gel-chro-matographic profiles of plasma immunoreactive ACTH showed only one peak, which eluted in the position of 1–39 ACTH, in patients with the pituitary tumours, but there was a second peak of large molecular weight ACTH present in the plasma from those with the ectopic ACTH syndrome. This second form of ACTH could not be detected in any of the tumour cell column effluents. An eighth pituitary tumour was atypical, in its unusually large size, clinically aggressive nature and spectrum of peptide release. Although peptide release in response to stimulation with SME was similar to that observed with the other pituitary tumours, the chromatography of the plasma ACTH resembled the ectopic plasma pattern, showing two peaks of immunoreactivity.

Pro‐opiocortin related peptides in human pituitary and ectopic acth secreting tumours

A chromatographic procedure has been developed for the characterization of ACTH- and lipotrophin- (LPH) related peptides in human plasma under acid-dissociating conditions to minimize artifacts of protein binding. The recovery and sensitivity of this method permits identification of ACTH at normal physiological levels in the circulation. Plasma profiles obtained from normal subjects and patients with pituitary dependent Cushing's disease, Addison's disease and Nelson's syndsrome showed only one significant peak of ACTH activity eluting in the position of purified native human 1--39 ACTH. However, the plasma profiles obtained from all the patients with the ectopic ACTH syndrome demonstrated a second peak of immunoreactive larger-molecular-weight ACTH and in some plasma samples this was the only form of ACTH observed. This larger-molecular-weight ACTH eluted midway between the void volume and 1--39 ACTH and co-eluted with a protein marker of molecular weight 22 000.

Chromatographic characterization of adsrenocorticotrophin in human plasma.

Twenty-three patients with adrenocorticotrophic hormone-(ACTH)-dependent Cushing's syndrome were subjected to selective venous catheterisation and sampling for ACTH on a total of 26 occasions. Out of 10 patients with pituitary-dependent disease, nine had raised ACTH concentrations in one or both high internal jugular vein samples. Eight patients had 11 proved sites of ectopic hormone production: of these, six were correctly identified by the sampling technique, and in four of them this was the only accurate method of localisation. The results of one catheterisation were misleading, and on 10 occasions they were inconclusive; five patients remained undiagnosed by any method. Overall, 15 of the 26 catheterisations provided diagnostically valuable information. Selective venous catheterisation and sampling for ACTH is effective in confirming a pituitary source of the hormone and may be valuable in locating the source of ectopic ACTH production in some cases.

Sally J. Ratter

Papers

Hormonal and metabolic responses to an enkephalin analogue in normal man

Studies on circulating met-enkephalin and beta-endorphin: normal subjects and patients with renal and adrenal disease.

Pro‐opiocortin related peptides in human pituitary and ectopic acth secreting tumours

Chromatographic characterization of adsrenocorticotrophin in human plasma.

Experience with selective venous sampling in diagnosis of ACTH-dependent Cushing's syndrome.