Endocrine

, Volume 49, Issue 2, pp 470–478 | Cite as

Autoshortloop feedback regulation of pulsatile gonadotropin-releasing hormone (GnRH) secretion by its metabolite, GnRH-(1–5)

  • Darwin O. Larco
  • Melissa Williams
  • Lauren Schmidt
  • Nick Sabel
  • Jason Lange
  • Michael J. Woller
  • T. J. Wu
Original Article
First Online:
Received:
Accepted:

Abstract

Given the central role of the decapeptide gonadotropin-releasing hormone (GnRH) in reproductive function, our long-term objective is to delineate the underlying mechanism regulating these reproductive processes. The outcome of GnRH secretion is in part dependent on the proteolytic metabolism of this decapeptide. In contrast to the belief that the metabolism of GnRH serves only as a degradative process that removes excess GnRH, we have shown that a metabolite of the decapeptide, GnRH-(1–5), can directly regulate GnRH gene expression and reproductive behavior. To further characterize the effect of GnRH-(1–5) on GnRH neuronal function, we determined whether GnRH-(1–5) can directly regulate GnRH secretion and pulsatility using an in vitro perifusion system. We compared the effect of GnRH-(1–5) on GnRH secretion in the immortalized GnRH neuron (GT1-7 cell line), whole rat hypothalamic explant, and enzymatically dispersed rat hypothalamic cells. Tissue preparations were perifused continuously for 9 h during which a 3-h challenge with GnRH-(1–5) was administered (4–6 h). The results show that treatment with GnRH-(1–5) increased (p < 0.05) the mean GnRH secretion and the amplitude of the pulses but not the pulse frequency. The present study supports the notion that GnRH-(1–5) is functionally capable of regulating the reproductive neuroendocrine system.

Keywords

Neuropeptides GnRH Hypothalamus Endopeptidase 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

The work was supported by the National Science Foundation (IBN-0315923 and IOS-1052288 and Department of Defense (CO85AX) (TJW); John P. Murtha Cancer Center Translational Fellowship (DOL); National Science Foundation (IOS- 0446112) (MJW); Beta Beta Beta National Fellowship (LS, NS, and CT). The opinions or assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Department of Defense or the Uniformed Services University of the Health Sciences.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

The experiments comply with the current laws of the United States in which they were performed.

References

  1. 1.
    A.-J. Silverman, I. Livne, J.W. Witkin, The gonadotropin-releasing hormone (GnRH) neuronal systems: immunocytochemistry and in situ hybridization, in The Physiology of reproduction, ed. by E. Knobil, J.D. Neill (Raven Press, New York, 1994)Google Scholar
  2. 2.
    L.V. DePaolo, R.A. King, A.J. Carrillo, In vivo and in vitro examination of an autoregulatory mechanism for luteinizing hormone-releasing hormone. Endocrinology 120(1), 272–279 (1987). doi: 10.1210/endo-120-1-272 CrossRefPubMedGoogle Scholar
  3. 3.
    D.K. Sarkar, In vivo secretion of LHRH in ovariectomized rats is regulated by a possible autofeedback mechanism. Neuroendocrinology 45(6), 510–513 (1987)CrossRefPubMedGoogle Scholar
  4. 4.
    A.M. Naylor, D.W. Porter, D.W. Lincoln, Inhibitory effect of central LHRH on LH secretion in the ovariectomized ewe. Neuroendocrinology 49(5), 531–536 (1989)CrossRefPubMedGoogle Scholar
  5. 5.
    Y.G. Han, S.S. Kang, J.Y. Seong, D. Geum, Y.H. Suh, K. Kim, Negative regulation of gonadotropin-releasing hormone and gonadotropin-releasing hormone receptor gene expression by a gonadotrophin-releasing hormone agonist in the rat hypothalamus. J. Neuroendocrinol. 11(3), 195–201 (1999)CrossRefPubMedGoogle Scholar
  6. 6.
    C. Roth, M. Schricker, M. Lakomek, A. Strege, I. Heiden, H. Luft, U. Munzel, W. Wuttke, H. Jarry, Autoregulation of the gonadotropin-releasing hormone (GnRH) system during puberty: effects of antagonistic versus agonistic GnRH analogs in a female rat model. J. Endocrinol. 169(2), 361–371 (2001)CrossRefPubMedGoogle Scholar
  7. 7.
    T.J. Wu, M.J. Glucksman, J.L. Roberts, S.K. Mani, Facilitation of lordosis in rats by a metabolite of luteinizing hormone releasing hormone. Endocrinology 147(5), 2544–2549 (2006). doi: 10.1210/en.2005-1646 CrossRefPubMedGoogle Scholar
  8. 8.
    T.J. Wu, S.K. Mani, M.J. Glucksman, J.L. Roberts, Stimulation of luteinizing hormone-releasing hormone (LHRH) gene expression in GT1-7 cells by its metabolite, LHRH-(1–5). Endocrinology 146(1), 280–286 (2005). doi: 10.1210/en.2004-0560 CrossRefPubMedGoogle Scholar
  9. 9.
    E.L. Baldwin, I.N. Wegorzewska, M. Flora, T.J. Wu, Regulation of type II luteinizing hormone-releasing hormone (LHRH-II) gene expression by the processed peptide of LHRH-I, LHRH-(1–5) in endometrial cells. Exp Biol Med (Maywood) 232(1), 146–155 (2007)Google Scholar
  10. 10.
    D.O. Larco, M. Cho-Clark, S.K. Mani, T.J. Wu, The metabolite GnRH-(1–5) inhibits the migration of immortalized GnRH neurons. Endocrinology 154(2), 783–795 (2013). doi: 10.1210/en.2012-1746 CrossRefPubMedGoogle Scholar
  11. 11.
    T.J. Wu, M.J. Gibson, M.C. Rogers, A.J. Silverman, New observations on the development of the gonadotropin-releasing hormone system in the mouse. J. Neurobiol. 33(7), 983–998 (1997)CrossRefPubMedGoogle Scholar
  12. 12.
    S. Wray, G. Hoffman, A developmental study of the quantitative distribution of LHRH neurons within the central nervous system of postnatal male and female rats. J. Comp. Neurol. 252(4), 522–531 (1986). doi: 10.1002/cne.902520408 CrossRefPubMedGoogle Scholar
  13. 13.
    S. Vella, J. Gussick, M. Woller, D. Waechter-Brulla, Modification of cell perifusion for extended study of hormone release in the rat pituitary. Methods Cell Sci. 23(4), 197–204 (2001)CrossRefPubMedGoogle Scholar
  14. 14.
    M. Woller, E. Nichols, T. Herdendorf, D. Tutton, Release of luteinizing hormone-releasing hormone from enzymatically dispersed rat hypothalamic explants is pulsatile. Biol. Reprod. 59(3), 587–590 (1998)CrossRefPubMedGoogle Scholar
  15. 15.
    M. Woller, S. Tessmer, D. Neff, A.A. Nguema, B.V. Roo, D. Waechter-Brulla, Leptin stimulates gonadotropin releasing hormone release from cultured intact hemihypothalami and enzymatically dispersed neurons. Exp Biol Med (Maywood) 226(6), 591–596 (2001)Google Scholar
  16. 16.
    Z. Liposits, I. Merchenthaler, W.C. Wetsel, J.J. Reid, P.L. Mellon, R.I. Weiner, A. Negro-Vilar, Morphological characterization of immortalized hypothalamic neurons synthesizing luteinizing hormone-releasing hormone. Endocrinology 129(3), 1575–1583 (1991)CrossRefPubMedGoogle Scholar
  17. 17.
    P.L. Mellon, J.J. Windle, P.C. Goldsmith, C.A. Padula, J.L. Roberts, R.I. Weiner, Immortalization of hypothalamic GnRH neurons by genetically targeted tumorigenesis. Neuron 5(1), 1–10 (1990)CrossRefPubMedGoogle Scholar
  18. 18.
    W.C. Wetsel, S.A. Eraly, D.B. Whyte, P.L. Mellon, Regulation of gonadotropin-releasing hormone by protein kinase-A and -C in immortalized hypothalamic neurons. Endocrinology 132(6), 2360–2370 (1993)PubMedGoogle Scholar
  19. 19.
    W.C. Wetsel, Z. Liposits, N.G. Seidah, S. Collins, Expression of candidate pro-GnRH processing enzymes in rat hypothalamus and an immortalized hypothalamic neuronal cell line. Neuroendocrinology 62(2), 166–177 (1995)CrossRefPubMedGoogle Scholar
  20. 20.
    W.C. Wetsel, M.M. Valença, I. Merchenthaler, Z. Liposits, F.J. López, R.I. Weiner, P.L. Mellon, A. Negro-Vilar, Intrinsic pulsatile secretory activity of immortalized luteinizing hormone-releasing hormone-secreting neurons. Proc. Natl. Acad. Sci. U.S.A. 89(9), 4149–4153 (1992)CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    M.J. Woller, J.K. McDonald, D.M. Reboussin, E. Terasawa, Neuropeptide Y is a neuromodulator of pulsatile luteinizing hormone-releasing hormone release in the gonadectomized rhesus monkey. Endocrinology 130(4), 2333–2342 (1992)PubMedGoogle Scholar
  22. 22.
    M.J. Woller, S. Meyer, A. Ada-Nguema, D. Waechter-Brulla, Dissecting autocrine effects on pulsatile release of gonadotropin-releasing hormone in cultured rat hypothalamic tissue. Exp Biol Med (Maywood) 229(1), 56–64 (2004)Google Scholar
  23. 23.
    G.R. Merriam, K.W. Wachter, Algorithms for the study of episodic hormone secretion. Am. J. Physiol. 243(4), E310–E318 (1982)Google Scholar
  24. 24.
    F. Kamel, J.A. Balz, C.L. Kubajak, V.A. Schneider, Effects of luteinizing hormone (LH)-releasing hormone pulse amplitude and frequency on LH secretion by perifused rat anterior pituitary cells. Endocrinology 120(4), 1644–1650 (1987). doi: 10.1210/endo-120-4-1644 CrossRefPubMedGoogle Scholar
  25. 25.
    J.E. Krause, J.P. Advis, J.F. McKelvy, Characterization of the site of cleavage of luteinizing hormone-releasing hormone under conditions of measurement in which LHRH degradation undergoes physiologically related change. Biochem. Biophys. Res. Commun. 108(4), 1475–1481 (1982)CrossRefPubMedGoogle Scholar
  26. 26.
    J.P. Advis, J.E. Krause, J.F. McKelvy, Luteinizing hormone-releasing hormone peptidase activities in discrete hypothalamic regions and anterior pituitary of the rat: apparent regulation during the prepubertal period and first estrous cycle at puberty. Endocrinology 110(4), 1238–1245 (1982). doi: 10.1210/endo-110-4-1238 CrossRefPubMedGoogle Scholar
  27. 27.
    T.J. Wu, A.R. Pierotti, M. Jakubowski, W.J. Sheward, M.J. Glucksman, A.I. Smith, J.C. King, G. Fink, J.L. Roberts, Endopeptidase EC 3.4.24.15 presence in the rat median eminence and hypophysial portal blood and its modulation of the luteinizing hormone surge. J. Neuroendocrinol. 9(11), 813–822 (1997)CrossRefPubMedGoogle Scholar
  28. 28.
    J.P. Bourguignon, M.L. Alvarez Gonzalez, A. Gerard, P. Franchimont, Gonadotropin releasing hormone inhibitory autofeedback by subproducts antagonist at N-methyl-D-aspartate receptors: a model of autocrine regulation of peptide secretion. Endocrinology 134(3), 1589–1592 (1994). doi: 10.1210/endo.134.3.8119202 PubMedGoogle Scholar
  29. 29.
    A.E. Herbison, S.M. Moenter, Depolarising and hyperpolarising actions of GABA(A) receptor activation on gonadotrophin-releasing hormone neurones: towards an emerging consensus. J. Neuroendocrinol. 23(7), 557–569 (2011). doi: 10.1111/j.1365-2826.2011.02145.x CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    S. Constantin, K.J. Iremonger, A.E. Herbison, In vivo recordings of GnRH neuron firing reveal heterogeneity and dependence upon GABAA receptor signaling. J. Neurosci. 33(22), 9394–9401 (2013). doi: 10.1523/JNEUROSCI.0533-13.2013 CrossRefPubMedGoogle Scholar
  31. 31.
    M. Cho-Clark, D.O. Larco, N.N. Semsarzadeh, F. Vasta, S.K. Mani, T.J. Wu, GnRH-(1–5) transactivates EGFR in Ishikawa human endometrial cells via an orphan G protein-coupled receptor. Mol. Endocrinol. 28(1), 80–98 (2014). doi: 10.1210/me.2013-1203 CrossRefPubMedGoogle Scholar
  32. 32.
    M. Matsumoto, T. Saito, J. Takasaki, M. Kamohara, T. Sugimoto, M. Kobayashi, M. Tadokoro, S. Matsumoto, T. Ohishi, K. Furuichi, An evolutionarily conserved G-protein coupled receptor family, SREB, expressed in the central nervous system. Biochem. Biophys. Res. Commun. 272(2), 576–582 (2000). doi: 10.1006/bbrc.2000.2829 CrossRefPubMedGoogle Scholar
  33. 33.
    D.K. Lee, T. Nguyen, K.R. Lynch, R. Cheng, W.B. Vanti, O. Arkhitko, T. Lewis, J.F. Evans, S.R. George, B.F. O’Dowd, Discovery and mapping of ten novel G protein-coupled receptor genes. Gene 275(1), 83–91 (2001)CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York (outside the USA)  2014

Authors and Affiliations

  • Darwin O. Larco
    • 1
  • Melissa Williams
    • 2
  • Lauren Schmidt
    • 2
  • Nick Sabel
    • 2
  • Jason Lange
    • 2
  • Michael J. Woller
    • 2
  • T. J. Wu
    • 1
  1. 1.Department of Obstetrics and GynecologyUniformed Services University of the Health SciencesBethesdaUSA
  2. 2.Department of Biological SciencesUniversity of Wisconsin-WhitewaterWhite WaterUSA

Personalised recommendations