Konstantine T. Kalogeras

Effects of the glucocorticoid antagonist RU 486 on pituitary-adrenal function in patients with anorexia nervosa and healthy volunteers : enhancement of plasma ACTH and cortisol secretion in underweight patients

To further explore whether the hypercortisolism of anorexia nervosa reflects an alteration in the set point for corticotropin-releasing hormone (CRH) secretion or is a manifestation of glucocorticoid resistance, we examined plasma ACTH and cortisol responses to the competitive glucocorticoid antagonist RU 486 (10 mg/kg, p.o. at 8.00 h) versus placebo (PBO) in 7 healthy female volunteers and 8 patients with DSM-III-R anorexia nervosa, all of whom were studied while underweight [64.3 +/- 2.1% average body weight (ABW), mean +/- SE] and 5 of whom were restudied longitudinally following refeeding (> or = 85% ABW, mean 87.4 +/- 0.4% ABW). Blood samples were obtained from 16.00 to 16.30 h and from 4.00 to 8.00 h following dosing. Underweight anorexics were significantly hypercortisolemic by 24 h urinary free cortisol excretion compared with controls (239 +/- 37 vs. 119 +/- 12 nmol/day, p < 0.01). Both controls and underweight anorexics had robust early morning (4.00-8.00 h) plasma cortisol responses to RU 486 (465 +/- 61 and 719 +/- 49 nmol/l) compared with PBO (370 +/- 52 and 451 +/- 31 nmol/l; p < 0.02 and p < 0.01, respectively). The underweight anorexics showed a significant mean early morning plasma ACTH response to RU compared with placebo (3.28 +/- 0.63 vs. 2.01 +/- 0.24 pmol/l, p < 0.05), while the controls showed a trend toward an increase in mean plasma ACTH after RU (3.11 +/- 0.36 pmol/l) compared with PBO (2.31 +/- 0.41 pmol/l, p < 0.13); plasma ACTH means were greater on the RU day than the placebo day at 20 of 25 sampling points (p < 0.001). However, the increment in ACTH on the RU day compared to the placebo day was greater in the underweight anorexics at the first 20 of 25 consecutive time points of the early morning sampling period (p < 0.001). Moreover, underweight anorexics showed a significant plasma ACTH and cortisol response to RU 486 at 16.00-16.30 h (8-8.5 h following administration), while the controls showed no significant response of plasma ACTH or cortisol at this time. When restudied following weight recovery, anorexic patients showed reductions in 24-hour urinary free cortisol excretion (to 191 +/- 40 nmol/day) which were no longer significantly elevated compared with control values.(ABSTRACT TRUNCATED AT 400 WORDS)

Neuroendocrine Responses to Emotional Stress: Possible Interactions Between Circulating Factors and Anterior Pituitary Hormone Release

We have shown that a psychological stressor can elicit increases in plasma AVP levels in normal human subjects. Since AVP can enhance the release of ACTH, and the pituitary gland is outside the blood-brain barrier, AVP present in the general circulation might extend the time course of stress-induced, CRF-mediated release of ACTH from the anterior lobe. Since PRA is involved in the synthesis of angiotensin I, the precursor of AII, and AII is known to enhance CRF-mediated release of ACTH from pituitary cells and to stimulate release of AVP, it is possible that the increase in PRA also contributed to the release of AVP and ACTH in this study. Reports differ as to whether circulating catecholamines can release ACTH in vivo by direct action on the pituitary. Finally, it has been reported that beta-EP enhances the release of PRL, and inhibits release of AVP. Since the increase in beta-EP in the present study was quite robust, it might have extended the PRL release, and truncated the AVP response.

Peripheral measures of arginine vasopressin, atrial natriuretic peptide and adrenocorticotropic hormone in premenstrual syndrome

Because of the unique combination of physical (e.g. bloating, water retention) and psychological (e.g. mood, memory) symptoms associated with premenstrual syndrome (PMS), various hypothalamic and pituitary hormones have been implicated in the pathophysiology of PMS. We measured plasma adrenocorticotropic hormone (ACTH), arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) across the menstrual cycle in 19 women with PMS and 12 normal women. AVP concentrations were lower throughout the menstrual cycle in symptomatic PMS patients compared with PMS patients during asymptomatic cycles and normal women. No differences in ACTH and ANP were observed between patients and controls. However, ACTH and ANP were positively and significantly correlated with each other in women with PMS but not in controls. These findings contribute to a growing list of menstrual cycle-independent findings in women with PMS and suggest that there may be an underlying neurobiological vulnerability that predisposes some women to experience somatic and mood dysregulation in the luteal phase of the menstrual cycle.

The Clinical Implications of Corticotropin-Releasing Hormone

We now appreciate that the brain is the most prolific of all endocrine organs producing scores of neurohormones within and beyond the boundaries of the endocrine hypothalamus. The idea that the brain functions as a gland, however, is not new. Indeed, the evolution of thought leading to the identification of corticotropin releasing hormone (CRH) began around 400 B.C. (1,2). At this time, Hippocrates, in his work entitled De Glandulis, states explicitly, “The flesh of the glands is different from the rest of the body, being spongy and full of veins; they are found in the moist part of the body where they receive humidity... and the brain is a gland as well as the mammae.”

Clinical Studies with Corticotropin Releasing Hormone: Implications for Hypothalamic-Pituitary-Adrenal Dysfunction in Depression and Related Disorders

We now appreciate that the brain is the most prolific of all endocrine organs, producing scores of neurohormones within and beyond the boundaries of the endocrine hypothalamus. The idea that the brain functions as a gland, however, is not new. Indeed, the evolution of thought leading to the identification of corticotropin releasing hormone (CRH) began around 400 B.C. (Zuingerus 1669; Iason 1946). At that time, Hippocrates, in his work entitled De Glandulus, stated explicitly “The flesh of the glands is different from the rest of the body, being spongy and full of veins; they are found in the moist part of the body where they receive humidity ′ and the brain is a gland as well as the mammae.”

Effects of inhibition of norepinephrine synthesis on spontaneous and growth hormone-releasing hormone-induced GH secretion in cynomolgus macaques: evidence for increased hypothalamic somatostatin tone.

To define the role of noradrenergic regulation of growth hormone (GH) secretion in a primate species, spontaneous and GH-releasing hormone (GHRH) stimulated GH secretion was studied in 6 chronically catheterized adult male cynomolgus monkeys before and after inhibition of norepinephrine synthesis. Blood samples were obtained at 15-min intervals during an 8-hour period to characterize the pattern of GH secretion, and the GH response to GHRH, 10 micrograms/kg i.v., was determined. These measurements were repeated 2 weeks later, 2 h after the intravenous administration of 12.5 mg/kg of the dopamine-beta-hydroxylase inhibitor diethyldithiocarbamate (DDTC), which has been shown to be an effective norepinephrine synthesis inhibitor in the rat. Spontaneous and stimulated GH secretory patterns before and after DDTC administration were compared. Both the frequency and the amplitude of spontaneous GH pulses were markedly reduced by DDTC [3.8 +/- 0.4 before vs. 1.8 +/- 0.4 peaks/8 h after DDTC (p less than 0.005) and 5.5 +/- 0.7 vs. 2.0 +/- 0.6 ng/ml (p less than 0.01)]. Areas under the curve were also reduced by DDTC treatment [10.8 +/- 1.0 vs. 5.7 +/- 1.1 ng.h/ml (p less than 0.01)], and DDTC administration diminished the peak GH responses to GHRH [12 +/- 6 vs. 4 +/- 2 ng/ml (p less than 0.05)]. These results are consistent with the belief that DDTC is a potent inhibitor of spontaneous and GHRH-induced GH secretion. The action of DDTC could be mediated by a reduction in GHRH due to reduced norepinephrine synthesis, by an increase in somatostatin release through a dopaminergic stimulus, or by a direct dopaminergic effect on somatotrophs.