A. Arimura

Gonadotropin-Releasing Hormone: One Polypeptide Regulates Secretion of Luteinizing and Follicle-Stimulating Hormones

A polypeptide isolated from porcine hypothalami stimulates the release of both luteinizing hormone and follicle-stimulating hormone from the pituitaries of several species. This polypeptide has been structurally identified as (pyro)Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 and synthesized. The natural and synthetic materials share biological properties. It appears that this peptide represents the hypothalamic hormone regulating the secretion of both luteinizing hormone and follicle-stimulating hormone.

Reduction of testicular luteinizing hormone/human chorionic gonadotropin receptors by [D-Trp6]-luteinizing hormone releasing hormone in hypophysectomized rats.

Abstract Adult and immature male rats were hypophysectomized and injected daily with saline or 0.2 or 2 μg of superactive Luteinizing Hormone Releasing Hormone (LHRH) agonist, [D-Trp 6 ]-LHRH subcutaneously for seven days - with, or without, concomitant treatment of 1 IU Human Chorionic Gonadotropin (hCG) or 50 IU Pregnant Mare Serum. The administration of [D-Trp 6 ]-LHRH reduced Luteinizing Hormone/Human Chorionic Gonadotropin receptors in all cases. The magnitude of this reduction was dose-related. As small a dose as 0.2 μg of the peptide resulted in approximately a 72% reduction of the receptors. The results suggest a direct action of [D-Trp 6 ]-LHRH on the testis. It also indicated that reduction of testicular Luteinizing Hormone/Human Chorionic Gonadotropin receptors by the peptide is not necessarily due to the over-stimulation of Luteinizing Hormone (LH) release from the pituitary through a “down regulation” mechanism.

The hypothalamus and reproduction.

Abstract This article has been designed to review recent developments in the field of hypothalamic hormones involved in the control of reproductive functions. A brief resume of early physiologic and anatomic studies was presented initially to give a better understanding of the concept of hypothalamic regulation of the release of gonadotropic hormones from the pituitary gland. Recently, an advance was achieved with the isolation from porcine hypothalami of a decapeptide which has both FSH-releasing hormone (FSH-RH) activity and LH-releasing hormone (LH-RH) activity. Its amino acid sequence was determined to be (pyro) gluhis-trp-ser-tyr-gly-leu-arg-pro-gly-NH 2 . The decapeptide corresponding to this structure was synthesized and shown to stimulate the release of LH and of FSH in laboratory and domestic animals and human beings. Natural and synthetic FSH-RH/LH-RH also stimulated the synthesis of both gonadotropins in tissue cultures of rat pituitaries in vitro. It was postulated that this decapeptide represents the hypothalamic hormone which regulates the release of both LH and FSH from the anterior pituitary gland. Complex effects of sex steroids on the release of LH and FSH were reviewed briefly. It was suggested that the over-all control of secretion of FSH and LH is most likely mediated by the interaction of hypothalamic FSH- and LH-releasing hormone with sex steroids. Clinical studies performed with natural and synthetic LH-RH/FSH-RH were reviewed. These studies, particularly induction of ovulation, suggest that LH-RH should find practical application in the treatment of sterility. Subsequent synthesis of LH-RH/FSH-RH by several laboratories and drug houses should provide enough material for large-scale clinical evaluation of this hormone. Some comments were made concerning probable clinical use of LH-RH. Finally, some speculations were offered about the possibility of developing new birth control methods based on LH-RH/FSH-RH, its analogues, or its derivatives.

Somatostatin analogs which inhibit glucagon and growth hormone more than insulin release

Abstract Three analogs of somatostatin, [ D -Cys14] -, [Ala2, D -Cys14] - and [ D -Trp8, D -Cys14] - somatostatin, were synthesized by the solid phase method, characterized by several means, and tested for their effects on the release of insulin, glucagon, and growth hormone. The peptides sharply suppressed the release of growth hormone in vitro and glucagon in vivo , but had less effect on insulin secretion in vivo . These analogs, particularly [ D -Trp8, D -Cys14] - somatostatin, could possibly be useful for the treatment of diabetes mellitus.

Reduction of LH-RH pituitary and estradiol uterine binding sites by a superactive analog of luteinizing hormone-releasing hormone☆

Abstract The ability of the Luteinizing Hormone-Releasing Hormone (LH-RH) analogs to displace LH-RH from its pituitary receptors was evaluated in vitro . The two superactive analogs tested showed higher potency than the antagonists and LH-RH itself, D-Trp6-LH-RH being the most potent. The LH-RH specific binding activity in the pituitary fluctuated throughout the age of the rats. The highest number of LH-RH binding sites were seen on day 35 of age (276 fmol × 10−2/pit) and an increment was induced by 0.05 μg D-Trp6-LH-RH (400 fmol × 10−2/pit). However, 1 μg D-Trp6-LH-RH reduced the binding of LH-RH at all the times studied. In the control animals the number of estradiol binding sites increased on day 42 of age, and 0.05 μg D-Trp6-LH-RH augmented them on day 35 of age. On the contrary, 1 μg D-Trp6-LH-RH diminished the estradiol uterine receptors at all the times studied. Similar results were obtained in the ovariectomized-hypophysectomized rats on day 35 of age. Our studies demonstrated a biphasic action of D-Trp6-LH-RH on LH-RH pituitary receptors and a direct effect on uterus which could be mediated through the uterine estradiol receptors.

Preoptic LH-RH and somatostatin in the rat median eminence. An experimental light and electron microscopic immunocytochemical study.

Glass microknife lesions and immunocytochemistry were used to evaluate luteinizing hormone-releasing hormone (LH-RH)- and somatostatin (SS)-immunoreactive pathways from the preoptic region to the rat median eminence. Cuts were so placed that axons of more caudally located neurons in the periventricular hypothalamic areas were spared. Light and EM observations of LH-RH-immunostained preparations indicated that following the midline periventricular cuts the density of LH-RH labelled axons and axon terminals in the ME appeared similar to that of nonlesioned animals. Following bilateral lateral hypothalamic cuts placed between the preoptic area and the ME, LH-RH immunostaining in the ME was markedly reduced. This provides evidence that the preponderance of LH-RH axons originating from the preoptic area reach the ME by a lateral hypothalamic route. In contrast to the LH-RH findings, midline lesions made using the same coordinates caused a noticeable reduction in SS immunostaining in the accurate nucleus and ME. There was either no change or only minimal change after the lateral cut. Somatostatin axons arising from the preoptic periventricular nucleus take a periventricular route and contribute to median eminence innervation, but much less extensively than the more caudally located somatostatin neurons in the hypothalamic periventricular nucleus [19].

Suppression of somatostatin levels in the hepatic portal and systemic plasma of the rat by synthetic human pancreatic polypeptide

Abstract Intravenous administration of synthetic human pancreatic polypeptide (hPP) with 36 amino acid residues significantly decreased immunoreactive somatostatin levels in both hepatic portal and systemic plasma in anesthetized rats. The effect of hPP on plasma somatostatin levels is acute. The results suggest that hPP may have a role in controlling somatostatin secretion from the gut and pancreas.

Luteinizing hormone-releasing hormone analogs lacking N-terminal pGlu ring structure

Abstract Six analogs of LH-RH lacking N-terminal pGlu ring structure, Gly 1 -LH-RH, formyl Gly 1 -LH-RH, acetyl Gly 1 -LH-RH, propionyl Gly 1 -LH-RH, palmitoyl Gly 1 -LH-RH and acetyl Ala 1 -LH-RH were synthesized. The Gly 1 analog was inactive, whereas acyl Gly 1 analogs except palmitoyl Gly 1 analog showed small but significant LH-RH activity in spite of the lack of the pyrrolidone ring structure. These findings suggest that the -CO-NHCHCO- group is the minimum necessary part of the pGlu residue to exhibit the biological activity.

Inhibition of the release of growth hormone in vitro by α-melanocyte stimulating hormone

Abstract A polypeptide isolated from porcine hypothalami was found to inhibit the release of growth hormone (GH) from isolated rat pituitaries. This polypeptide was identified chemically and biologically as α-MSH. Pure natural α-MSH isolated from beef posterior pituitary extracts and synthetic α-MSH also inhibit the release of GH in vitro . In addition, other substances not yet identified, present in porcine hypothalamic extracts, also share this property.

Dynamics of injected somatostatin in blood of patients with hepatic failure and acromegaly

Plasma somatostatin levels were measured by radioimmunoassay (RIA) at various times after rapid injection into the blood of 4 patients with acromegaly, 4 patients with hepatic failure, and 4 healthy subjects. In contrast to the single peak found in normal and acromegalic individuals, two distinct peaks were observed in each patient with liver failure. The first occurred at about the same time as that observed in the other two groups, but the second occurred about 3 min later. This second peak could not be distinguished immunologically from the intact somatostatin tetradecapeptide. The half-time disappearance of somatostatin in patients with hepatic failure was significantly longer than in the normal subjects. Acromegalic subjects tended to have the shortest half-time disappearance of the injected somatostatin and the highest peak level. The results are consistent with the possibility that altered metabolism and/or binding of somatostatin occurs in hepatic failure and in acromegaly.