Octanoylated ghrelin (1-28) (intact ghrelin) is rapidly and easily degraded to desoctanoyl forms or smaller fragments (degraded ghrelin). Plasma levels of intact and degraded ghrelin were examined in 30 patients with anorexia nervosa (AN) (body mass index, 8.81-22.4 kg/m(2)) and 16 age-matched healthy women using several assay methods. Plasma levels of ghrelin measured using immunocomplex transfer-enzyme immunoassay, which specifically detects intact ghrelin, were lower in AN than controls. Plasma ghrelin levels in AN measured using the active ghrelin ELISA kit, which is advertised as specifically detecting intact ghrelin, did not differ significantly from controls. Plasma levels of desoctanoyl ghrelin using the desacyl-ghrelin ELISA kit, N-terminus ghrelin using the ghrelin active RIA kit, and C-terminus ghrelin using the ghrelin total RIA kit were significantly higher in AN than controls, and displayed significant negative correlations with body mass index. Plasma levels of ghrelin determined using immunocomplex transfer-enzyme immunoassay or active ghrelin ELISA during iv glucose infusion were suppressed in both AN and controls, whereas plasma levels of degraded ghrelin levels were not significantly decreased in AN. Plasma levels of intact ghrelin are therefore not higher in AN than controls, whereas degraded forms of ghrelin are elevated in AN. Rapid suppression of plasma intact ghrelin, but not degraded ghrelin, occurs in AN in response to glucose infusion. The profiles of intact and degraded forms of ghrelin in plasma of AN patients differ from those of healthy women.

The effects of thyroidectomy (Tx) and thyroxine replacement (T4Rx) on pituitary growth hormone (GH) secretion and hypothalamic GH-releasing hormone (GRH) concentration were compared to define the mechanism of hypothyroid-associated GH deficiency.Thyroidectomized rats exhibited a complete loss of pulsatile GH secretion with extensive reduction in GRH responsiveness and pituitary GH content. Cultured pituitary cells from Tx rats exhibited reduced GRH sensitivity, maximal GH responsiveness, and intracellular cyclic AMP accumulation to GRH, while somatostatin (SRIF) suppressive effects on GH secretion were increased. Hypothalamic GRH content was also markedly reduced. T4Rx completely restored hypothalamic GRH content and spontaneous GH secretion despite only partial recovery of pituitary GH content, GRH and SRIF sensitivity, and intracellular cyclic AMP response to GRH.The results indicate multiple effects of hypothyroidism on GH secretion and suggest that a critical role of T4 in maintaining normal GH secretion, in addition to restoring GH synthesis, is related to its effect on hypothalamic GRH.

Loss of MSH6 occurred during the progression from an atypical prolactinoma to a pituitary carcinoma, which may have caused resistance to TMZ treatment. This case suggests that preserving MSH6 function is essential for responsiveness to TMZ treatment in MGMT-negative and p53-mutated atypical pituitary adenoma or pituitary carcinoma.

GH-releasing factor (GRF) is a hypothalamic peptide that stimulates the secretion of pituitary GH. The possibility of feedback effects of GRF within the central nervous system was studied in conscious freely moving male rats with indwelling iv and intracerebroventricular (icv) cannulae. Animals were injected icv or iv with 10 ng-10 micrograms human (h) GRF(1-40)-OH (hGRF-40) or GRF(1-44)-NH2 (hGRF-44), and blood samples were obtained every 10-20 min from 1000-1400 h. GH secretion was pulsatile, with major secretory peaks at around 1200 h in most control animals. When 10 ng hGRF-40 were injected icv at 1100 h, immediately before the expected onset of the spontaneous GH secretory burst, GH secretion was suppressed during the following 2-h period. An iv injection of 10 ng hGRF-40 was without effect. In contrast, when 1 microgram hGRF-40 was injected icv or iv, plasma GH levels peaked at 20 and 10 min, respectively, and returned toward baseline shortly thereafter. The spontaneous GH secretory pulse after 1 microgram hGRF-40 (icv or iv) was suppressed in proportion to the magnitude of the GH secretory response to GRF (r = 0.78, p less than 0.01), and the prolongation of the interval between the injection of GRF and the subsequent spontaneous GH surge was directly related to the GH response to GRF (r = 0.85, p less than 0.001). The icv or iv injection of a larger dose of either hGRF-40 or hGRF-44 (10 micrograms) at 1100 h also resulted in marked and comparable increases in plasma GH levels, with peaks at 20 min (icv) and 10 min (iv) after injection. No changes in behavior or plasma glucose were observed up to 3 h after icv injection of any of the doses of hGRF-40 or of hGRF-44. The suppressive effect of centrally administered hGRF-40 (10 ng) on GH secretion was blocked by the iv administration of a specific antisomatostatin serum immediately before the injection of hGRF. These results demonstrate a dual action of GRF on spontaneous GH secretion and indicate the presence of an inhibitory feedback system within the central nervous system for the regulation of GH secretion which is mediated by hypothalamic somatostatin.

The role of central corticotropin-releasing factor (CRF) in the regulation growth hormone (GH) secretion was studied in freely moving conscious male rats with indwelling intra-atrial and intracerebroventricular (i.c.v.) cannulae. GH measurements in blood samples obtained every 20 min from 10.00 to 14.00 h in control animals injected with saline either intravenously (i.v.) or into the lateral cerebral ventricle revealed that spontaneous GH secretion was pulsatile, and occurred regularly at around 12.00 h. When ovine CRF (10 µg) was injected i.c.v., spontaneous GH secretion was inhibited (mean plasma GH [11.20–13.00 h]: 20 ± 7 ng/ml vs. control: 126 ± 22 ng/ml, p < 0.01). In contrast, the intravenous injection of CRF (10 µg) did not affect spontaneous GH secretion (mean plasma GH [11.20–13.00 h]: 162 ± 25 ng/ml vs. control: 193 ± 31 ng/ml). This GH suppressive action of central CRF was blocked by the i.v. injection (0.5 ml) of antisomatostatin serum (AS), but not of normal sheep serum (NS), (mean plasma GH [11.20–13.00 h]: NS + CRF: 15 ± 2 ng/ml vs. AS + CRF: 202 ± 30 ng/ml, p < 0.01). The mean plasma GH value [11.20–13.00 h] in animals receiving AS and CRF was not significantly different from those in animals receiving saline (i.v.) together with AS. These results suggest a potential inhibitory role of central CRF in the regulation of spontaneous GH secretion in the rat which is mediated by the stimulation of hypothalamic somatostatin.

The effect of intraventricular administration of prostaglandin (PG)D2 on pulsatile LH release was studied in castrated conscious rats. The administration of 5 micrograms of PGD2 into the lateral ventricle inhibited pulsatile discharge of LH secretion, in contrast to the stimulatory effect of PGE2. Intraventricular administration of 13,14-dihydro-15-keto-PGD2, a metabolite of PGD2, had no significant effect. Intravenous administration of 100 micrograms of PGD2 caused only a slight decrease in LH secretion. Intravenous administration of naloxone, a specific opiate antagonist, blocked the suppressive effect of PGD2 on Lh release. These results suggest that PGD2 plays an inhibitory role in pulsatile LH secretion in castrated male rats and that opiate receptors are involved in the PGD2-induced inhibition of LH secretion.

GH release decreases with aging in primates. However, it is unclear whether the age-related decrease in GH release is due to a decrease in stimulatory GHRH or an increase in inhibitory somatostatin (SS) from the hypothalamus. In the present study, we measured the release of GHRH and SS in the stalk-median eminence of conscious aged (n = 7, 27.0 +/- 0.7 yr old) and young adult female monkeys (n = 12, 5.0 +/- 0.3 yr old) using the push-pull perfusion method. Mean GHRH levels during morning (0600-1200 h) and evening (1800-2400 h) in aged monkeys were 3- to 4-fold lower than in young monkeys. Pulse analysis indicated that pulse frequency, pulse amplitude, and baseline GHRH release in aged monkeys were much lower than in young adults. In contrast, mean SS levels in aged monkeys during mornings and evenings were 2-fold higher than in young monkeys. Pulse analyses indicated that amplitude and baseline levels of SS were significantly higher in aged monkeys than in young adults. There were no significant changes in the pulse frequency of SS release. Therefore, the aging-related decrease in GH release is due to a substantial decrease in GHRH release and an increase in SS release from the hypothalamus.

The effects of vasoactive intestinal polypeptide (VIP), TRH, dopamine, and rat median eminence extract on GH release from GH-secreting pituitary adenomas were studied in vitro using a sensitive superfusion method. Dispersed pituitary tumor cells obtained from three patients with acromegaly were placed in a superfusion column, and the amounts of GH in the superfusate were determined. The addition of VIP (10(-6) M) to the perfusion system resulted in a marked increase in GH release in all three cases, and a dose-response relationship in VIP (10(-8) 10(-6) M) induced GH secretion was observed in one case studied. TRH (10(-7) M) and median eminence extract (1 equivalent/ml) also caused an abrupt and marked increase in GH release in all of the experiments. The infusion of either dopamine (10(-7) M) or bromocriptine (10(-7) M) inhibited GH secretion. These results suggest that VIP as well as TRH stimulate GH secretion by a direct action on GH-secreting pituitary tumor cells in at least some acromegalic patients.