help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Billig, H.
Right arrow Articles by Hsueh, A. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Billig, H.
Right arrow Articles by Hsueh, A. J.

Endocrinology, Vol 134, 245-252, Copyright © 1994 by Endocrine Society

ARTICLES

Gonadotropin-releasing hormone directly induces apoptotic cell death in the rat ovary: biochemical and in situ detection of deoxyribonucleic acid fragmentation in granulosa cells

H Billig, I Furuta and AJ Hsueh
Department of Gynecology and Obstetrics, Stanford University School of Medicine, California 94305-5317.

The majority of ovarian follicles undergo atresia through a mechanism involving apoptotic cell death. Although GnRH and its agonists have been shown to suppress ovarian growth and differentiation in hypophysectomized rats, studies on the induction of follicle atresia by GnRH are contradictory. In the present study, the direct effect of GnRH on the occurrence of apoptosis in the ovary was investigated in hypophysectomized estrogen-treated immature rats. Starting 2 days after operation and estrogen capsule implantation, rats were treated with a GnRH agonist (GnRHa; [desGly10,D-Phe6,Pro9-N-ethylamide] GnRH; 50 micrograms/injection, twice daily). Total ovarian DNA was isolated 48 h later, labeled at the 3'ends with [32P]dideoxy ATP, and size- fractionated. Compared to that in control animals, treatment with GnRHa increased DNA fragmentation in multiples of 180 basepairs, a hallmark of apoptosis, demonstrating that GnRH directly increases ovarian apoptotic cell demise. In contrast, FSH treatment (10 micrograms/injection, twice daily) decreased apoptotic DNA fragmentation, and the antiapoptotic effect of FSH was partially blocked by concomitant treatment with GnRHa. The apoptosis-inducing effect of GnRHa was time and dose dependent, with a significant increase seen after 24 h of treatment and a maximal 5.5-fold increase with 10 micrograms GnRHa/injection. Similar to studies using DNA isolated from whole ovaries, DNA obtained from isolated granulosa cells also showed a time- and dose-dependent increase in DNA fragmentation after GnRHa treatment. The effect on DNA fragmentation by GnRHa was mediated by ovarian GnRH receptors, because a potent GnRH receptor blocker, Azaline B, prevented GnRHa action. In addition, in situ end labeling of DNA using digoxigenin-dideoxy-UTP showed that DNA fragmentation was confined to the granulosa cells of preantral and antral follicles. No GnRHa-induced apoptosis was detected in granulosa cells of primary follicles or in thecal and interstitial cells. These data suggest that GnRH directly increases apoptotic cell death in the ovary, and the GnRH action is confined to the granulosa cells. These data provide a basis for future studies on the mechanism of follicular atresia and the regulation of ovarian endonuclease by GnRH.


This article has been cited by other articles:


Home page
 Reproductive SciencesHome page
C. Metallinou, B. Asimakopoulos, A. Schroer, and N. Nikolettos
Gonadotropin-Releasing Hormone in the Ovary
Reproductive Sciences, December 1, 2007; 14(8): 737 - 749.
[Abstract] [PDF]

Home page
 J Mol EndocrinolHome page
T. Ikemoto and M. K. Park
Comparative analysis of the pituitary and ovarian GnRH systems in the leopard gecko: signaling crosstalk between multiple receptor subtypes in ovarian follicles
J. Mol. Endocrinol., February 1, 2007; 38(2): 289 - 304.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
J. M. Wu, M. B. Zelinski, D. K. Ingram, and M. A. Ottinger
Ovarian Aging and Menopause: Current Theories, Hypotheses, and Research Models
Experimental Biology and Medicine, December 1, 2005; 230(11): 818 - 828.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
C. K. Cheng and P. C. K. Leung
Molecular Biology of Gonadotropin-Releasing Hormone (GnRH)-I, GnRH-II, and Their Receptors in Humans
Endocr. Rev., April 1, 2005; 26(2): 283 - 306.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
F. Parborell, G. Irusta, A. Vitale, O. Gonzalez, A. Pecci, and M. Tesone
Gonadotropin-Releasing Hormone Antagonist Antide Inhibits Apoptosis of Preovulatory Follicle Cells in Rat Ovary
Biol Reprod, March 1, 2005; 72(3): 659 - 666.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
L. E. C. Miles, A. C. Hanyaloglu, J. R. Dromey, K. D. G. Pfleger, and K. A. Eidne
Gonadotropin-Releasing Hormone Receptor-Mediated Growth Suppression of Immortalized L{beta}T2 Gonadotrope and Stable HEK293 Cell Lines
Endocrinology, January 1, 2004; 145(1): 194 - 204.
[Abstract] [Full Text] [PDF]

Home page
 Hum ReprodHome page
R. Depalo, L. Nappi, G. Loverro, S. Bettocchi, M. L. Caruso, A. M. Valentini, and L. Selvaggi
Evidence of apoptosis in human primordial and primary follicles
Hum. Reprod., December 1, 2003; 18(12): 2678 - 2682.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
H. Yang, G. K. Bhat, R. Wadley, K. L. Wright, B. M. Chung, J. A. Whittaker, A. M. Dharmarajan, and R. Sridaran
Gonadotropin-Releasing Hormone-Agonist Inhibits Synthesis of Nitric Oxide and Steroidogenesis by Luteal Cells in the Pregnant Rat
Biol Reprod, June 1, 2003; 68(6): 2222 - 2231.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
G. Irusta, F. Parborell, M. Peluffo, P. R. Manna, S. I. Gonzalez-Calvar, R. Calandra, D. M. Stocco, and M. Tesone
Steroidogenic Acute Regulatory Protein in Ovarian Follicles of Gonadotropin-Stimulated Rats Is Regulated by a Gonadotropin-Releasing Hormone Agonist
Biol Reprod, May 1, 2003; 68(5): 1577 - 1583.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
S. Khosravi and P. C. K. Leung
Differential Regulation of Gonadotropin-Releasing Hormone (GnRH)I and GnRHII Messenger Ribonucleic Acid by Gonadal Steroids in Human Granulosa Luteal Cells
J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 663 - 672.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
N. Danilovich and M. R. Sairam
Haploinsufficiency of the Follicle-Stimulating Hormone Receptor Accelerates Oocyte Loss Inducing Early Reproductive Senescence and Biological Aging in Mice
Biol Reprod, August 1, 2002; 67(2): 361 - 369.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
F. Parborell, A. Pecci, O. Gonzalez, A. Vitale, and M. Tesone
Effects of a Gonadotropin-Releasing Hormone Agonist on Rat Ovarian Follicle Apoptosis: Regulation by Epidermal Growth Factor and the Expression of Bcl-2-Related Genes
Biol Reprod, August 1, 2002; 67(2): 481 - 486.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. H. Kim, A. Wolfe, G. R. Smith, S. A. Tobet, and S. Radovick
Promoter Sequences Targeting Tissue-specific Gene Expression of Hypothalamic and Ovarian Gonadotropin-releasing Hormone in Vivo
J. Biol. Chem., February 8, 2002; 277(7): 5194 - 5202.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. M. M. Woo, C.-J. Tai, S. K. Kang, P. S. Nathwani, S. F. Pang, and P. C. K. Leung
Direct Action of Melatonin in Human Granulosa-Luteal Cells
J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4789 - 4797.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J.-Y. Park, J.-H. Park, H.-J. Park, J.-Y. Lee, Y.-I. Lee, K. Lee, and S.-Y. Chun
Stage-Dependent Regulation of Ovarian Pituitary Adenylate Cyclase-Activating Polypeptide mRNA Levels by GnRH in Cultured Rat Granulosa Cells
Endocrinology, September 1, 2001; 142(9): 3828 - 3835.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
V. Wallenius, K. Wallenius, M. Hisaoka, J. Sandstedt, C. Ohlsson, M. Kopf, and J.-O. Jansson
Retarded Liver Growth in Interleukin-6-Deficient and Tumor Necrosis Factor Receptor-1-Deficient Mice
Endocrinology, July 1, 2001; 142(7): 2953 - 2960.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
C. W. Xiao, K. Ash, and B. K. Tsang
Nuclear Factor-{{kappa}}B-Mediated X-Linked Inhibitor of Apoptosis Protein Expression Prevents Rat Granulosa Cells from Tumor Necrosis Factor {{alpha}}-Induced Apoptosis
Endocrinology, February 1, 2001; 142(2): 557 - 563.
[Abstract] [Full Text] [PDF]

Home page
 Hum ReprodHome page
A. L.L. Durlinger, P. Kramer, B. Karels, J.A. Grootegoed, J. Th.J. Uilenbroek, and A. P.N. Themmen
Apoptotic and proliferative changes during induced atresia of pre-ovulatory follicles in the rat
Hum. Reprod., December 1, 2000; 15(12): 2504 - 2511.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
P.J. Devine, C.M. Payne, M.K. McCuskey, and P.B. Hoyer
Ultrastructural Evaluation of Oocytes During Atresia in Rat Ovarian Follicles
Biol Reprod, November 1, 2000; 63(5): 1245 - 1252.
[Abstract] [Full Text]

Home page
 Biol. Reprod.Home page
E.Ch. Svensson, E. Markström, M. Andersson, and H. Billig
Progesterone Receptor-Mediated Inhibition of Apoptosis in Granulosa Cells Isolated from Rats Treated with Human Chorionic Gonadotropin
Biol Reprod, November 1, 2000; 63(5): 1457 - 1464.
[Abstract] [Full Text]

Home page
 Mol. Endocrinol.Home page
A. Bulling, F. D. Berg, U. Berg, D. M. Duffy, R. L. Stouffer, S. R. Ojeda, M. Gratzl, and A. Mayerhofer
Identification of an Ovarian Voltage-Activated Na+-Channel Type: Hints to Involvement in Luteolysis
Mol. Endocrinol., July 1, 2000; 14(7): 1064 - 1074.
[Abstract] [Full Text]

Home page
 Hum ReprodHome page
J. Dor, D. Bider, A. Shulman, J. Levron, S. Shine, S. Mashiach, and J. Rabinovici
Effects of gonadotrophin-releasing hormone agonists on human ovarian steroid secretion in vivo and in vitro--results of a prospective, randomized in-vitro fertilization study
Hum. Reprod., June 1, 2000; 15(6): 1225 - 1230.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
P. S. Nathwani, S. K. Kang, K. W. Cheng, K.-C. Choi, and P. C. K. Leung
Regulation of Gonadotropin-Releasing Hormone and Its Receptor Gene Expression by 17{beta}-Estradiol in Cultured Human Granulosa-Luteal Cells
Endocrinology, May 1, 2000; 141(5): 1754 - 1763.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
S. Y. Hsu and A. J. W. Hsueh
Tissue-Specific Bcl-2 Protein Partners in Apoptosis: An Ovarian Paradigm
Physiol Rev, April 1, 2000; 80(2): 593 - 614.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
C. P. Leo, S. Y. Hsu, S.-Y. Chun, H.-W. Bae, and A. J. W. Hsueh
Characterization of the Antiapoptotic Bcl-2 Family Member Myeloid Cell Leukemia-1 (Mcl-1) and the Stimulation of Its Message by Gonadotropins in the Rat Ovary
Endocrinology, December 1, 1999; 140(12): 5469 - 5477.
[Abstract] [Full Text]

Home page
 Endocr. Rev.Home page
L. Poretsky, N. A. Cataldo, Z. Rosenwaks, and L. C. Giudice
The Insulin-Related Ovarian Regulatory System in Health and Disease
Endocr. Rev., August 1, 1999; 20(4): 535 - 582.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
A. Chamson-Reig, O. P. Pignataro, C. Libertun, and V. A. R. Lux-Lantos
Alterations in Intracellular Messengers Mobilized by Gonadotropin-Releasing Hormone in an Experimental Ovarian Tumor
Endocrinology, August 1, 1999; 140(8): 3573 - 3580.
[Abstract] [Full Text]

Home page
 EndocrinologyHome page
I. L. Van Wezel, A. M. Dharmarajan, T. C. Lavranos, and R. J. Rodgers
Evidence for Alternative Pathways of Granulosa Cell Death in Healthy and Slightly Atretic Bovine Antral Follicles
Endocrinology, June 1, 1999; 140(6): 2602 - 2612.
[Abstract] [Full Text]

Home page
 Biol. Reprod.Home page
A. Weissman, L. Gotlieb, T. Colgan, A. Jurisicova, E. M. Greenblatt, and R. F. Casper
Preliminary Experience with Subcutaneous Human Ovarian Cortex Transplantation in the NOD-SCID Mouse
Biol Reprod, June 1, 1999; 60(6): 1462 - 1467.
[Abstract] [Full Text]

Home page
 EndocrinologyHome page
S. M. Quirk, D. A. Porter, S. C. Huber, and R. G. Cowan
Potentiation of Fas-Mediated Apoptosis of Murine Granulosa Cells by Interferon-{gamma}, Tumor Necrosis Factor-{alpha}, and Cycloheximide
Endocrinology, December 1, 1998; 139(12): 4860 - 4869.
[Abstract] [Full Text] [PDF]

Home page
 Ann. N. Y. Acad. Sci.Home page
B. MARCHETTI, F. GALLO, Z. FARINELLA, C. TIROLO, N. TESTA, C. ROMEO, and M. C. MORALE
Luteinizing Hormone-Releasing Hormone Is a Primary Signaling Molecule in the Neuroimmune Network
Ann. N.Y. Acad. Sci., May 1, 1998; 840(1): 205 - 248.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. Li, J.-M. Kim, P. Liston, M. Li, T. Miyazaki, A. E. Mackenzie, R. G. Korneluk, and B. K. Tsang
Expression of Inhibitor of Apoptosis Proteins (IAPs) in Rat Granulosa Cells during Ovarian Follicular Development and Atresia
Endocrinology, March 1, 1998; 139(3): 1321 - 1328.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
M. Heikinheimo, M. Ermolaeva, M. Bielinska, N. A. Rahman, N. Narita, I. T. Huhtaniemi, J. S. Tapanainen, and D. B. Wilson
Expression and Hormonal Regulation of Transcription Factors GATA-4 and GATA-6 in the Mouse Ovary
Endocrinology, August 1, 1997; 138(8): 3505 - 3514.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
B. C. J. M. Fauser and A. M. van Heusden
Manipulation of Human Ovarian Function: Physiological Concepts and Clinical Consequences
Endocr. Rev., February 1, 1997; 18(1): 71 - 106.
[Abstract] [Full Text]

Home page
 Reproductive SciencesHome page
A. Hurwitz, K. Ruutiainen-Altman, L. Marzella, L. Botero, M. Dushnik, and E. Y. Adashi
Follicular Atresia as an Apoptotic Process: Atresia-Associated Increase in the Ovarian Expression of the Putative Apoptotic Marker Sulfated Glycoprotein-2
Reproductive Sciences, July 1, 1996; 3(4): 199 - 208.
[Abstract] [PDF]

Home page
 Reproductive SciencesHome page
G. N. Piquette, J. L. Tilly, L. E. Prichard, C. Simon, and M. L. Polan
Detection of Apoptosis in Human and Rat Ovarian Follicles
Reproductive Sciences, October 1, 1994; 1(4): 297 - 301.
[Abstract] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 1994 by The Endocrine Society