Chronic Administration of Corticotropin-Releasing Factor Increases Pituitary Corticotroph Number*

Abstract

The effect of chronic administration of CRF on rat pituitary morphology was studied. Experimental animals received CRF (10 micrograms/day) over a period of 52 days by means of sc osmotic pumps changed at 10- to 14-day intervals. The average 0800 h plasma corticosterone levels in the treated animals were significantly greater than control values [7.52 +/- 0.99 (+/- SE) vs. 1.14 +/- 0.5 micrograms/dl; P less than 0.001]. The CRF-treated animals also had a significantly greater adrenal weight (16.44 +/- 1.38 vs. 12.24 +/- 0.85 mg; P less than 0.05) and lower thymus weight (164 +/- 12 vs. 248 +/- 27 mg; P less than 0.005). There was a marked increase in the number of ACTH-producing cells in the anterior pituitaries of the rats that received CRF (13.3 +/- 0.8% vs. 4.5 +/- 0.3% ACTH-producing cells; P less than 0.001), as determined by immunocytochemical methods. Corticotrophs of rats treated with CRF manifested a significant increase in nuclear area (24.0 +/- 0.7 vs. 21.4 +/- 0.4 micron 2; P less than 0.001) and an increased diameter of forming and storage granules (191.1 +/- 1.1 vs. 158.6 +/- 3.5 nm and 196.1 +/- 1.2 vs. 170.1 +/- 3.7 nm, respectively; P less than 0.001). There was no demonstrable increase in ACTH cell area. These data indicate that long term administration of CRF is capable of increasing the number of pituitary corticotrophs. It also supports the view that the corticotroph hyperplasia occurring after adrenalectomy, in unusual cases of ectopic CRF production, and in rare instances of Cushing's disease is a proliferative response to CRF.

Human and murine pituitary expression of leukemia inhibitory factor. Novel intrapituitary regulation of adrenocorticotropin hormone synthesis and secretion.

“…Dramatically increased intensity of ACTH-immunoreactive pituitary cells occurs through the end of the second trimester. In the rat, increased corticotroph proliferation occurs in response to CRH (37), and the mature adult pituitary cell population consists of 10-20% corticotrophs (35 (39,40). Using a 600-bp radiolabeled human cRNA excluding the first exon, the 400-bp protected human pituitary LIF mRNA detected in fetal pituitary tissue is consistent with divergent splicing of the human LIF gene, as has been suggested for the murine LIF gene (41).…”

Increased Pituitary Volume in Antipsychotic-Free and Antipsychotic-Treated Patients of the Æsop First-Onset Psychosis Study

“…Animal and clinical studies have demonstrated that HPA axis activation by corticotropinreleasing hormone (CRH) or by stress leads to an increase in the number and size of corticotropes in the pituitary gland (Asa et al, 1992;Carey et al, 1984;Gertz et al, 1987;Westlund et al, 1985). This increase in the size and numbers of corticotropes can increase pituitary volume in humans as Figure 3 Individual measures of pituitary volumes in first-episode patients (n ¼ 77; one subject on which we had no medication history was excluded from this analysis) divided by antipsychotic treatment (free, n ¼ 18; atypicals, n ¼ 26; typicals, n ¼ 33).…”

Impaired diurnal adrenal rhythmicity restored by constant infusion of corticotropin-releasing hormone in corticotropin-releasing hormone-deficient mice.

“…Constant infusion of CRH was performed as described (33). Groups of n ϭ 5-6 adult CRH KO female mice maintained on a 12:12 LD cycle (lights on at 0700, lights out at 1900) underwent subcutaneous osmotic minipump placement (ALZA Corp., Palo Alto, CA) and received infusion of either vehicle alone (1% acetic acid, 1 mg/ml ascorbate, and 10 mg/ml BSA) or daily doses of 0.1, 0.25, 0.5, or 1 g/d of CRH in vehicle.…”