Blunted corticotropin and normal cortisol response to human corticotropin-releasing factor in depression.

Cushing's disease

This chapter discusses the accumulated data. A broad concept of the role of corticotropin-releasing hormone (CRH) as a mediator of adaptive response to all forms of stress has now emerged. The evidence presented in the chapter proposes that: (1) CRH integrates not only the hormonal but also the physiological and behavioral pattern in response to environmental and endogenous challenges perceived as stress and (2) continuous alterations in the fine-tuned neuro-endocrine pathways result in overt psychopathology, perpetuate clinical symptoms, and may lower the threshold for the development of full-blown clinical syndromes in individuals carrying a genetic risk for psychiatric disorders. The neuroendocrine and behavioral systems are inextricably intertwined. Given this bidirectional loop, distinctions between cause and effect are clearly only useful within a limited experimental context. Keeping this in mind, the ambitious goal of understanding how neural and endocrine systems regulate behavior and how psychopathology develops may yet be achieved.

The role of corticotropin-releasing hormone in the pathogenesis of Cushing`s disease, anorexia nervosa, alcoholism, affective disorders and dementia

The effects of ovine CRF, lysine vasopressin (LVP), and their interrelationships, and rat hypothalamic extract (HME), on ACTH and β-endorphin release by human pituitary tumor cells from two patients with Nelson's syndrome and one with Cushing's disease and on ACTH and cortisol secretion in vivo were studied. In cultured pituitary tumor cells, both LVP and CRF greatly stimulated ACTH and β-endorphin release at maximally active concentrations of 0.1 μM and 10 nM, respectively. At these concentrations, the combination of the two substances had an additive or synergistic effect on hormone release. Low concentrations of HME potentiated and/or were synergistic with CRF-mediated ACTH release. In vivo, the combination of CRF (1 μg/kg) and LVP (10 pressor units) induced greater ACTH release than the sum of the responses to CRF and LVP alone. This synergistic effect of CRF plus LVP concerned only ACTH release, while cortisol release after CRF plus LVP was equivalent to the sum of the maximal increments in this horm...

Corticotropin-Releasing Factor (Ovine) and Vasopressin Exert a Synergistic Effect on Adrenocorticotropin Release in Man

Synthetic CRF-41 has been given to 43 patients with hypothalamic, pituitary or adrenal diseases and contrasted with the responses in 20 normal subjects. In the normal subjects the mean increment in serum cortisol (+/- SE) was 276 +/- 38 nmol/l; the increments showed a significant negative correlation with the basal serum cortisol levels (r = -0.56; P less than 0.02). The mean peak serum cortisol was 662 +/- 34 nmol/l and the mean peak corticosterone was 28.6 +/- 3.8 nmol/l. There was a significant positive correlation between the peak serum corticosterone and cortisol concentrations (r = 0.84; P less than 0.0001). Dexamethasone pretreatment abolished the rise in cortisol in response to CRF-41. The peak serum cortisol following CRF-41 was not significantly different between the normal subjects and those patients with pituitary disease who had normal cortisol responses to insulin-induced hypoglycaemia. However, in individual patients the peak cortisol levels induced by hypoglycaemia were greater than, but significantly correlated with, those induced by 100 micrograms of CRF-41. Seven patients were ACTH deficient in response to hypoglycaemia, and of these six responded normally to CRF-41. Only one of these patients had a lesion clearly originating in the hypothalamus; four had pituitary tumours with suprasellar extensions and the remaining patient had idiopathic GH and ACTH deficiency. Our data suggest that these patients have a functional defect of ACTH secretion due to the failure of CRF to reach the corticotroph. Of the four patients with pituitary-dependent Cushing's disease who were on no treatment at the time of testing, three showed an exaggerated and one a normal response to CRF-41. These normal or enhanced responses of hypercortisolaemic patients with Cushing's syndrome contrast with the complete inhibition of the responses to CRF-41 in normal subjects given dexamethasone. In the treated patients with Cushing's syndrome and normal serum cortisol levels, those with pituitary-dependent disease showed an enhanced ACTH response to CRF-41 as compared with the ectopic ACTH group, but there was some overlap between the two groups. Acromegalic patients did not show a GH response to CRF-41. We conclude that administration of CRF-41 is a safe new method for investigating disorders of the hypothalamo-pituitary axis.

Corticotrophin releasing factor: responses in normal subjects and patients with disorders of the hypothalamus and pituitary

Intravenous application of 100 µg synthetic ovine corticotropin releasing factor (CRF) led to stimulation of ACTH-secretion in nine normal controls, with a maximum 30 min after CRF. Cortisol, corticosterone, cortisone and 11-deoxycortisol increased with a maximum at 60 min after CRF, whereas no rise was seen in aldosterone, 11-deoxycorticosterone, 17-α-hydroxyprogesterone, progesterone, DHEA-S and testosterone. The specificity of CRF-stimulation was also shown by unchanged TSH, LH, FSH, hGH, prolactin and thyroid hormone levels, als well as unchanged insulin and gastrin levels. No serious side-effects were observed during the test period and afterwards.

B. Hagen

Papers

Corticotropin releasing factor (CRF)-stimulation test in normal controls and patients with disturbances of the hypothalamo-pituitary-adrenal axis