Cyril Y. Bowers

The identity of chemical and hormonal properties of the thyrotropin releasing hormone and pyroglutamyl-histidyl-proline amide

Abstract The structure of L-pyroglutamyl- l -histidyl- l -proline amide (I) is in agreement with all Qf the known chemical and hormonal properties of the thyrotropin releasing hormone (TIM) from porcine hypothalami. This structural interpretation is probably applicable to the THE of other mammalian species, and is chemically based on the chromatographic identity in seventeen diversified systems and is biologically based on a quantitative comparison of the hormonal activities of the natural and synthetic products. This formulation of structure represents the elucidation of the first of the hypothalamic hormones that have been sought for so long.

Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ

Recent progress in the field of energy homeostasis was triggered by the discovery of adipocyte hormone leptin and revealed a complex regulatory neuroendocrine network. A late addition is the novel stomach hormone ghrelin, which is an endogenous agonist at the growth hormone secretagogne receptor and is the motilin‐related family of regulatory peptides. In addition to its ability to stimulate GH secretion and gastric motility, ghrelin stimulates appetite and induces a positive energy balance leading to body weight gain. Leptin and ghrelin are complementary, yet antagonis¬tic, signals reflecting acute and chronic changes in energy balance, the effects of which are mediated by hypothalamic neuropeptides such as neuropeptide Y and agouti‐related peptide. Endocrine and vagal affer¬ent pathways are involved in these actions of ghrelin and leptin. Ghrelin is a novel neuroendocrine signal possessing a wide spectrum of biological activities that illustrates the importance of the stomach in providing input into the brain. Defective ghrelin signaling from the stomach could contribute to abnormalities in en¬ergy balance, growth, and associated gastrointestinal and neuroendocrine functions.—Inui, A., Asakawa, A., Bowers, C. Y., Mantovani, G., Laviano, A., Meguid, M. M., Fujimiya, M. Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endo¬crine organ.

Prolactin and thyrotropin release in man by synthetic pyroglutamyl-histidyl-prolinamide

Abstract Synthetic pyroglutamyl-histidyl-prolinamide or thyrotropin-releasing-hormone (TRH) stimulates secretion of prolactin (PRL) as well as thyrotropin (TSH) but has no consistent effect on serum levels of growth hormone (GH), luteinizing hormone (LH) or follicle stimulating hormone (FSH) in man. After intravenous injection of as little as 10 μg TRH, both serum PRL and TSH levels rise rapidly. The PRL and TSH response was greater in normal women than in normal men and both responses were greatly enhanced in hypothyroid patients and virtually abolished in hyperthyroid patients. The possibility that p-Glu-His-Pro-NH2 is also a “natural physiological” regulator of PRL in man is evident.

Thyrotrophin and prolactin release in prolonged critical illness: dynamics of spontaneous secretion and effects of growth hormone-secretagogues†

Infusion of GH secretagogues appears to be a novel endocrine approach to reverse the catabolic state of critical illness, through amplification of the endogenously blunted GH secretion associated with a substantial IGF‐I rise. Here we report the dynamic characteristics of spontaneous nightly TSH and PRL secretion during prolonged critical illness, together with the concomitant effects exerted by the administration of GH‐secretagogues, GH‐releasing hormone (GHRH) and GH‐releasing peptide‐2 (GHRP‐2) in particular, on night‐time TSH and PRL secretion.

Intracerebroventricular growth-hormone-releasing peptide-6 stimulates eating without affecting plasma growth hormone responses in rats

The purpose of this study was to determine the effect of intracerebroventricular (i.c.v.) injections of a synthetic, opioid-related hexapeptide, growth-hormone-releasing peptide-6 (GHRP-6), on stimulation of eating by rats and to correlate this aspect of feeding behavior with the peripheral plasma growth hormone (GH) response to the administered peptide. GHRP-6 dissolved in 5 microL of saline was injected into the lateral ventricles of sated, adult, male, Sprague-Dawley rats in doses from 0 pmol (saline only) to 1000 pmol. For 1 hour after injection, the occurrence of eating was noted, and specimens of arterial blood were collected at 0, 15, 30, and 60 minutes. The plasma was assayed for GH. A nearly linear, statistically significant (p < 0.01) dose-response relationship between the dose of GHRP-6 and the incidence of eating was noted. The mean change from baseline of plasma GH during the 60 minutes after injection was not dose-related (p > 0.2, p > 0.1, and p > 0.1 at 15, 30, and 60 minutes, respectively). We conclude that GHRP-6 given intracerebroventricularly to sated, adult, male, Sprague-Dawley rats stimulates eating and suggest that it does so by some mechanism that is independent of its GH-releasing property.

The combined administration of GH-releasing peptide-2 (GHRP-2), TRH and GnRH to men with prolonged critical illness evokes superior endocrine and metabolic effects compared to treatment with GHRP-2 alone

objective Central hyposomatotrophism, hypothyroidism and hypogonadism are present concomitantly in men with prolonged critical illness. This study evaluated the impact of combined treatment with GH‐releasing peptide‐2 (GHRP‐2), TRH and GnRH for 5 days compared with GHRP‐2 + TRH and with GHRP‐2 alone.

Late Endocrine Effects of Administering Monosodium Glutamate to Neonatal Rats

Rats were injected with monosodium 1-glutamate (MSG) daily for the 1st 5 days of life and allowed to mature. This is known to cause selective destruction of neurons in the retina and in the arcuate nucleus of the hypothalamus. The adult animals had a significant increase in body fat without an increase in weight, a marked reduction in pituitary, thyroid, adrenal, gonadal and prostate weights. Pituitary, hypothalamic and serum thyrotropin (TSH) were significantly reduced in the males. Serum growth hormone (GH) was markedly reduced in both sexes and the serum prolactin (Prl) was increased significantly in females. FSH did not appear to be abnormal and the LH may have been increased in the males. Serum T4 was significantly reduced in females. The fertility of the females was normal, but treated males mated with normal females showed a marked reduction in fertility and, although the litter sizes of the offspring were normal, the birth weights of the pups of both sexes were significantly reduced. These persistent alterations in neuroendocrine function indicate that lesions produced by neonatal MSG treatment provide a convenient model for studying hypothalamic function.

Interactions of growth hormone secretagogues and growth hormone-releasing hormone/somatostatin.

The class of novel synthetic compounds termed growth hormone secretagogues (GHSs) act in the hypothalamus through, as yet, unknown pathways. We performed physiologic and histochemical studies to further understand how the GHS system interacts with the well-established somatostatin (SRIF)/growth hormone-releasing hormone (GHRH) neuroendocrine system for regulating pulsatile GH secretion. Comparison of the GH-releasing activities of the hexapeptide growth hormone-releasing peptide-6 (GHRP-6) and GHRH administered intravenously to conscious adult male rats showed that the pattern of GH responsiveness to GHRP-6 was markedly time-dependent, similar to that observed with GHRH. Immunoneutralization of endogenous SRIF reversed the blunted GH response to GHRP-6 at trough times, suggesting that GHRP-6 neither disrupts nor inhibits the cyclical release of endogenous hypothalamic SRIF. By striking contrast, passive immunization with anti-GHRH serum virtually obliterated the GH responses to GHRP-6, irrespective of the time of administration. These findings suggest that the GHSs do not act by altering SRIF release but, rather, stimulate GH release via GHRH-dependent pathways. Our dual chromogenic and autoradiographic in situ hybridization experiments revealed that a subpopulation of GHRH mRNA-containing neurons in the arcuate (Arc) nucleus and ventromedial nucleus (VMN) of the hypothalamus expressed the GHS receptor (GHS-R) gene. These results provide strong anatomic evidence that GHSs may directly stimulate GHRH release into hypophyseal portal blood, and thereby influence GH secretion, through interaction with the GHS-R on GHRH-containing neurons. Altogether, these findings support the notion that an additional neuroendocrine pathway may exist to regulate pulsatile GH secretion, possibly through the influence of the newly discovered GHS natural peptide, ghrelin.

Demonstration and characterization of the specific binding of growth hormone-releasing peptide to rat anterior pituitary and hypothalamic membranes

Since the growth hormone-releasing peptide (GHRP), His-D-Trp-Ala-Trp-D-Phe-Lys-NH2, was found to specifically release growth hormone by a complementary but yet not clearly defined action on the pituitary as well as the hypothalamus, in vitro studies have been performed to demonstrate and characterized GHRP binding sites on peripheral membranes of both the rat anterior pituitary and hypothalamus. Optimum binding assay conditions were established using [125I]Tyr-Ala-GHRP as the radioligand. The membrane binding sites were specific, reversible, saturable and time, temperature, pH and concentration dependent. Computerized analyses of competition experiments suggested two classes of binding sites in both pituitary and hypothalamic membranes. The maximum specific binding was observed at pH 5.0 than the physiological pH in both tissues. Pretreatment of the membranes with trypsin prevented specific binding. The increase in Bmax was statistically significant and showed a 2.0- to 8.9-fold and 5.8- to 11.2-fold in pituitary and hypothalamus, respectively, whereas the affinity constants (Kds) were not significant. Of the synthetic and natural neuropeptides that influence the release of GH from somatotrophs, only (D-Lys3)GHRP, substance P antagonists and growth hormone-releasing factor analog were potent inhibitors of GHRP binding in both tissues.

Pituitary responsiveness to GH-releasing hormone, GH-releasing peptide-2 and thyrotrophin-releasing hormone in critical illness.

OBJECTIVE Protein hypercatabolism and preservation of fat depots are hallmarks of critical illness, which is associated with blunted pulsatile GH secretion and low circulating IGF‐I, TSH, T4 and T3. Repetitive TRH administration is known to reactivate the pituitary‐thyroid axis and to evoke paradoxical GH release in critical illness. We further explored the hypothalamic‐pituitary function in critical illness by examining the effects of GH‐releasing hormone (GHRH) and/or GH‐releasing peptide‐2 (GHRP‐2) and TRH administration.