Advertisement

Steuerung der Hypophysenfunktion durch das Gonadotropin-Releasing Hormon (GnRH) und dessen Analoga

  • L. Kiesel
  • B. Runnebaum
Conference paper

Abstract

The physiological actions and clinical applications of gonadotropin-releasing hormon (GnRH) and its analogues have received increasing attention within the past few years. The hypothalamic decapeptide GnRH stimulates the syntheseis and secretion of luteinizing hormon (LH) and follicle-stimulating hormon (FSH), responsible for the cyclic changes and ovarian steroid production of the female menstrual cycle. The intracellular pathway through which GnRH stimulates pituitary gonadotroph function is receptor-mediated and calcium dependent. Recently we and others have focused our attention on the transmembrane signaling involved in GnRH action. The native hormone GnRH binds to specific receptors on the surface of the pituitary cell membrane. This receptor is coupled to the formation of second messengers participating in hormonal exocytosis. The activation of the GnRH receptor will cause the hydrolysis of phos-phoinositides within 5 seconds. The breakdown of these membrane lipids will produce inositolphosphates and diacylglycerol. We have identified specific membrane-bound receptors for inositol-1,4,5-triphosphate in pituitary cells. Inositolphosphates can rapidly release calcium from intracellular stores or promote calcium influx. The release of gonadotropins and the function of pituitary gonadotrophs is highly calcium-dependent. In vitro experiments have demonstrated that GnRH stimulation will activate the liberation of arachidonic acid from lipid stores and this fatty acid is readily metabolized to lipoxygenase products such as leuko-trienes in the pituitary cell. Leukotrienes are potent mediators and modulators of GnRH action. A further pathway in the cascade of signal transduction appears to be relevant in the pituitary. This involves the translocation and activation of the calcium- and phospholipid-dependent proteinkinase C. The activation of this enzyme by phorbolesters can induce a prolongued gonadotropin secretion in vitro. These aforementioned second messengers participate in signal transduction of GnRH-induced LH and FSH secretion. At present, however, it quite unclear how the different cascades orchestrate hormonal exocytosis.

GnRH-analogues have a paradoxical effect on gonadotroph function. The long-term action of potent GnRH analogues will result in the down-regulation of

GnRH-receptors and will cause desensitisation of the pituitary. In vitro experiments suggest that down-regulation of GnRH-receptors may represent only one aspect of the phenomenon of desensitisation due to prolongued action of GnRH in vivo and in vitro. Several other intracellular sites of action have been proposed including the uncoupling of the GnRH-receptor from the guanine nucleotide regulatory protein and from phospholipase C. Desensitisation evoked by GnRH-agonist is preceded by a short phase of receptor up-regulation and pituitary stimulation. GnRH antagonists will act on the pituitary by competitive binding to the GnRH-receptor without inducing the synthesis or secretion of gonadotropins.

The application of GnRH-anlogues produces thereby a reversible inhibition of gonadotroph function and ovarian suppression. Their use has opened a wide field of medical treatment of hormone dependent the benign and malignant diseases in gynecology.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literatur

  1. Clayton RN, Catt KJ (1981) Gonadotropin-releasing hormone receptors: characterization, physiological regulation and relationship to reproductive function. Endocr Rev 2:186–209PubMedCrossRefGoogle Scholar
  2. Helm K, Kiesel L, Rabe T, Runnebaum B (1988) Desensitization of pituitary cells by gonadotropin-releasing hormone in vitro. In: Runnebaum B, Rabe T, Kiesel L (eds) Female Contraception. Springer, Berlin, pp 184–191CrossRefGoogle Scholar
  3. Huckle WR, Conn PM (1987) The relationship between gonadotropin-releasing hormone-stimulated luteinizing hormone release and inositol phosphate production: studies with calcium antagonists and proteinkinase C activators. Endocrinology 120:160–169PubMedCrossRefGoogle Scholar
  4. Kiesel L, Bertges K, Rabe T, Runnebaum (1986) Gonadotropin-releasing hormone enhances polyphosphoinositide hydrolysis in rat pituitary cells. Biochem Biophys Res Commun 134:861–867PubMedCrossRefGoogle Scholar
  5. Kiesel, L. Lukàcs GL, Eberhardt I, Runnebaum B, Spät A (1987a) Effect of inositol 1,4,5-tri-phosphate and GTP on calcium release from pituitary microsomes. FEBS Lett 217:85–88PubMedCrossRefGoogle Scholar
  6. Kiesel L, Przylipiak A, Rabe T, Runnebaum B (1987b) Leukotrienes stimulate gonadotropin-release in vitro. Gynecol Endocrinol 1:25–35CrossRefGoogle Scholar
  7. Kiesel L, Rabe T, Helm K, Maier C, Runnebaum B (1988) Potency of contraceptive progestins to inhibit luteinizing hormone secretion in vitro. In: Runnebaum B, Rabe T, Kiesel L (eds) Female Contraception. Springer, Berlin, pp 192–205CrossRefGoogle Scholar
  8. Naor Z, Leifer AM, Catt KJ (1980) Calcium-dependent actions of gonadotropin-releasing hormone on pituitary guanosine 3’,5’-monophosphate production and gonadotropin release. Endocrinology 107:1428–1445Google Scholar
  9. Naor Z, Kiesel L, Vanderhoek J, Catt KJ (1985) Mechanism of action of gonadtropin-releasing hormone: role of lipoxygenase products of arachidonic acid in luteinizing hormone release. J Steroid Biochem 23:711–717PubMedCrossRefGoogle Scholar
  10. Nishizuka Y (1984) The role of proteinkinase C in cell surface signal transduction and tumor promotion. Nature 308:693–698PubMedCrossRefGoogle Scholar
  11. Smith, Vale (1981) Desensitization of gonadotropin-releasing hormone observed in superfused pituitary cells on cytodex beads. Endocrinology 108:752–759PubMedCrossRefGoogle Scholar
  12. Vanderhoek JY, Kiesel L, Naor Z, Bailey JM, Catt KJ (1984) Arachidonic acid metabolism in gonadotroph-enriched pituitary cells. Prostaglandins Leukotrienes Med 15:375–385CrossRefGoogle Scholar
  13. Wildt L (1987) Die endokrine Kontrolle des menstruellen Zyklus. In: Diedrich K (Hrsg) Neue Wege in Diagnostik und Therapie der weiblichen Sterilität. Enke, Stuttgart, S 1–25Google Scholar

Copyright information

© Springer-Verlag, Berlin Heidelberg New York 1991

Authors and Affiliations

  • L. Kiesel
    • 1
  • B. Runnebaum
    • 1
  1. 1.Abteilung für Gynäkologische EndokrinologieUniversitäts-FrauenklinikHeidelbergDeutschland

Personalised recommendations