Cerebrospinal Fluid Immunoreactive Cortieotropin-Releasing Hormone and Adrenocorticotropin Secretion in Cushing's Disease and Major Depression: Potential Clinical Implications

Abstract

To explore whether possible differences in central nervous system neuromodulators contribute to the differential presentation of affective symptomatology in Cushing's disease and major depression, we examined the levels of immunoreactive CRH and ACTH in the cerebrospinal fluid (CSF) of 11 patients with Cushing's disease, a patient with ectopic ACTH secretion, 34 patients with major depression, and 60 healthy subjects. We elected to measure these peptides not only because both are classically involved in pituitary-adrenal regulation, but also because their primarily arousal-producing and anorexigenic behavioral effects in experimental animals suggest that they may play a role in the symptom complex of depressive syndromes. We also explored whether the CSF levels of these peptides were more helpful in determining the often difficult differential diagnosis between major depression and Cushing's disease than the plasma ACTH response to ovine CRH, a currently used but somewhat insensitive laboratory means of distinguishing these disorders. CSF levels of immunoreactive CRH and ACTH were significantly lower in Cushing's disease patients [21.9 +/- 2.7 and 15.4 +/- 1.8 pg/mL, (mean +/- SEM), respectively] compared to patients with major depression [38.4 +/- 2.3 pg/mL (P less than 0.01) and 24.5 +/- 1.6 pg/mL (P less than 0.01), respectively] and controls [38.4 +/- 1.6 pg/mL (P less than 0.001) and 26.3 +/- 1.1 pg/mL (P less than 0.001), respectively]. The coexistence of high plasma ACTH and low CSF ACTH in Cushing's disease yielded a CSF/plasma ACTH ratio consistently less than that in depressed patients, with only 2 of 31 subjects comprising both groups showing values that overlapped. In contrast, 9 of the combined patients showed ACTH responses to ovine CRH that overlapped. These data suggest that differences in centrally directed CRH secretion may account for the differential presentation of the dysphoric syndromes seen in major depression and Cushing's disease. Hence, the classic form of major depression (melancholia), is often associated with evidence of pathological hyperarousal, such as intense anxiety, sleeplessness, and anorexia, while that of Cushing's disease is associated with evidence of pathological hyperarousal, including hyperphagia, fatigue, and inertia. Moreover, measurement of the CSF/plasma ACTH ratio may serve as a clinically useful adjunct to the ovine CRH stimulation test and other laboratory measures in determining the differential diagnosis between major depression and Cushing's disease.

Increased corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine nuclei of depressed suicide men

“…The majority of these studies measured CRH levels from the CSF of depressed patients, and although several reports found elevated CSF CRH levels in the depressed subjects, 9-11 a number of other studies failed to replicate these findings. [15][16][17] The inconsistency among these studies may be attributable to differences in methodology, Figure 4 Representative color-enhanced immunoautoradiographic images of CRH-IR concentrations in specific pontine nuclei of a matched control (a) and depressed subject (b) pair. The red outlined regions correspond to the specific pontine nuclei sampled for CRH-IR.…”

“…For example, a blunted ACTH response to exogenous CRH administration, [6][7][8] increased CRH cerebrospinal fluid (CSF) levels, [9][10][11] increased numbers of CRHimmunoreactive 12 and CRH mRNA-containing paraventricular hypothalamic neurons 13 and decreased binding sites of CRH receptors in the frontal cortex of depressed subjects 14 represent some of the biochemical changes that support the hypothesis of hyperactivity of CRH function in depression. However, other studies have failed to document changes in CSF CRH levels, [15][16][17] brain tissue levels of CRH 18,19 or CRH receptor binding sites in the cortex of depressed subjects 19,20 and thus do not support the CRH hyperactivity hypothesis of depression. With the exception of the reports documenting alterations in CRH substrates in the paraventricular nucleus of the hypothalamus and in the frontal cortex, there has been no additional direct evidence for CRH hyperactivity in other brain regions of depressed subjects.…”

Effects of corticotrophin-releasing hormone, vasopressin and insulin-like growth factor-I on proliferation of and adrenocorticotrophic hormone secretion by canine corticotrophic adenoma cells in vitro

“…This is in concordance with results from earlier studies. In man and dog, it has been shown that the excessive ACTH secretion in Cushing's disease is not caused by persistent hyperstimulation of corticotropes by CRH (29,38), and canine ACTH-producing tumours have been shown to be relatively insensitive to stimulation by hypothalamic hormones in vitro (39).…”

Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states

“…73 In a study of the 30-h pattern of CSF CRH levels in severely depressed inpatient melancholic subjects and controls, we found inappropriately 'normal' integrated 30-h CSF CRH concentrations despite significant hypercortisolism and around-the-clock elevations of CSF NE 74 ( Figure 4). Because the overall pool of CSF CRH and plasma ACTH levels are glucocorticoid suppressible, 75 we previously suggested that quantitatively 'normal' CSF CRH and plasma ACTH levels in the face of hypercortisolism are, nevertheless, inappropriate for the patients' degree of hypercortisolism. 76 Our reasoning was as follows: we compared levels of CSF CRH in patients with depression associated with Cushing's disease (a pituitary disorder), who had matching degrees of hypercortisolism.…”

“…To further support the premise of a decrement in hypothalamic ACTH secretion in Cushing's disease due to longstanding hypercortisolism, we found that, compared to controls, their CSF CRH levels were profoundly suppressed. 75 We were then ready to study patients with affective disorder. To determine whether patients with atypical depression show evidence of a centrally mediated hypoactivity of the HPA axis, we first studied patients with depression of seasonal affective disorder, a syndrome virtually identical to that of atypical depression.…”