Immunoreactive Corticotropin-Releasing Hormone Present in Human Plasma May Be Derived from Both Hypothalamic and Extrahypothalamic Sources*

Abstract

Immunoreactive CRH concentrations were determined in human plasma using an immunoaffinity chromatographic extraction procedure and sensitive RIA. Immunoreactive CRH was detectable in the plasma of all normal subjects (mean +/- SD, 6.2 +/- 2.4 pg/mL; n = 15). Basal (0800-1000 h) plasma immunoreactive CRH levels were significantly lower in patients with Cushing's syndrome due to adrenal (2.8 +/- 1.1 pg/mL; n = 4) or pituitary adenomas (2.9 +/- 0.8 pg/mL; n = 5), in patients with hypothalamic hypopituitarism (3.2 +/- 0.9 pg/mL; n = 5), and in glucocorticoid-treated patients (3.9 +/- 1.9 pg/mL, n = 8). Basal plasma CRH levels were also low in patients with acromegaly (2.8 +/- 0.8 pg/mL; n = 14) and insulin-treated diabetic patients whose pituitary-adrenal function was normal (3.6 +/- 1.0 pg/mL; n = 12). In normal subjects plasma CRH levels increased after insulin-induced hypoglycemia; this response was abolished by the prior administration of dexamethasone. In contrast, basal plasma CRH levels were not affected by prior administration of metyrapone or dexamethasone. No evidence for diurnal variation in plasma immunoreactive CRH was found in normal subjects. In addition, in normal subjects oral glucose administration elicited a significant increase in plasma CRH (basal, 7.3 +/- 0.9 pg/mL; peak 30 min after glucose, 16.7 +/- 5.8 pg/mL; n = 5; P less than 0.05) without concomitant changes in ACTH. Gel filtration of extracts of pooled plasma from normal subjects revealed a major component of immunoreactive CRH in the position of synthetic rat CRH. Immunoreactive CRH-sized material had the same retention time as authentic rat CRH in a reverse phase high pressure liquid chromatography system. The content of immunoreactive CRH in human placenta, pancreas, and adrenal gland was much larger than that in hypothalamus. These findings suggest that immunoreactive CRH is present in peripheral plasma; the increase in plasma immunoreactive CRH after insulin-induced hypoglycemia may reflect stimulation of hypothalamic CRH release; the increase in plasma immunoreactive CRH after glucose administration may reflect extrahypothalamic CRH release; and the lack of diurnal variation in plasma immunoreactive CRH together with the lack of suppression of CRH by dexamethasone suggest that basal plasma CRH is of extrahypothalamic origin.

Placental corticotropin-releasing hormone may be a stimulator of maternal pituitary adrenocorticotropic hormone secretion in humans.

“…We recently reported the presence of immunoreactive CRH in human placental tissue and plasma of women during pregnancy, labor, and delivery (2)(3)(4). We also isolated and characterized placental CRH.…”

Lack of Correlation Between Immunoreactive Corticotropin‐Releasing Factor Concentration Profiles in Hypophysial‐Portal and Peripheral Plasma

“…In several reports it was assumed that peripheral irCRF-41 concentrations reflected, at least in part, hypothalamic secretion (13)(14)(15)17); however, this critical assumption has never been directly addressed experimentally. Our current observations demonstrated a striking lack of correspondence between secretion of hypothalamic irCRF-41 into the hypophysial-portal circulation and peripheral irCRF-41 levels in rats, suggesting that peripheral irCRF-41 was not a reliable index of central irCRF-41 secretory [ -G & z q (10,11,13). Neither removal of the predominant source of central irCRF-41 by electrolytic lesion of the PVN, nor acute transection of the in fundibular stalk significantly altered peripheral irCRF-4 1 concentration in the rat.…”

“…However, this approach requires acute anesthesia and surgery, thus precluding studies of the axis in a basal state or of examining the effects of emotional stressors on function. Alternative approaches, including transnasal collection of hypophysial-portal blood from the awake sheep (8,9) and peripheral sampling in a variety of species (10)(11)(12)(13)(14)(15)(16)(17) have been attempted. In the present study, we have critically evaluated the validity of peripheral irCRF-41 measurements as an index of hypothalamic secretory activity by comparing peripheral and hypophysial-portal plasma irCRF-41 concentrations under a variety of conditions.…”

“…However, the relative inaccessibility of this specialized vascular link in species other than the sheep (8,9) prevents direct determination of irCRF-41 secretory profiles in the circulation at this level in the unanesthetized, ambulatory animal. Several laboratories have reported the presence of irCRF-41 in human or rat peripheral plasma (10)(11)(12)(13)(14)(15)(16)(17). During pregnancy, peripheral irCRF-41 appears to be derived from the placenta (18)(19)(20).…”

“…During pregnancy, peripheral irCRF-41 appears to be derived from the placenta (18)(19)(20). The source of peripheral irCRF-41 in non-pregnant animals is unknown and it has been postulated that it may reflect, at least in part, hypothalamic irCRF-41 secretion (13,14,16,17); other sources include the gastrointestinal tract (21), the pancreas (22) and the adrenal gland (23,24). In the present study, the relationship between peripheral and hypophysial-portal plasma concentration profiles of irCRF-41 was evaluated by direct measurements in both circulatory compartments under a variety of experimental conditions.…”