Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology

Regulation of functional and regressing stages of corpus luteum development in mice. Role of reactive oxygen species

Valeria A. Sander A , Lidia Piehl B , Graciela B. Facorro B , Emilio Rubín de Celis B and Alicia B. Motta A C

A Laboratorio de Fisiopatología Ovárica – Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)/ Departamento de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.

B Cátedra de Física, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.

C Corresponding author. Email:

Reproduction, Fertility and Development 20(7) 760-769
Submitted: 15 March 2008  Accepted: 15 June 2008   Published: 1 August 2008


The endocrine and immune systems modulate ovarian function. The aim of the present work was to compare the status of various modulating factors in two well-defined stages of corpus luteum (CL) development (the functional stage and the regressing stage) by means of a gonadotropin-synchronised mouse model. At the regressing stage of CL development, we found that ovarian tissue showed increased prostaglandin (PG) F and diminished PGE levels concomitantly with enhanced protein abundance of ovarian cyclooxygenase 2, the inducible isoform of the limiting enzyme of PG synthesis. We also found both enhanced lipid peroxidation and enhanced total superoxide dismutase activity, as well as inhibited catalase activity and inhibited total hydroxyl radical scavenger capacity, when compared with ovaries at the functional stage. In addition, at the regressing stage we observed an increased percentage of CD8+ (cytotoxic/suppressor) T-cells and a decreased percentage of CD4+ (helper) T-cells from ovarian-draining lymph nodes. Also, the serum interleukin (IL)-2, IL-4 and IL-10 were diminished as compared with the functional stage. We conclude that a pro-oxidant status together with a pro-inflammatory response is responsible for the loss of luteal function.

Additional keywords: cytokines, luteal regression, oxidative stress.


Agarwal A. Gupta S. Sharma R. 2005 Role of oxidative stress in female reproduction. Reprod. Biol. Endocrinol. 3 28 doi:10.1186/1477-7827-3-28 Pubmed Abstract

Al-Gubory K. H. Bolifraud P. Germain G. Nicole A. Ceballos-Bicot I. 2004 Antioxidant enzymatic defence systems in sheep corpus luteum throughout pregnancy. Reproduction 128 767 774 doi:10.1530/REP.1.00389 Pubmed Abstract

Al-Gubory K. H. Ceballos-Picot I. Nicole A. Bolifraud P. Germain G. Michaud M. Mayeur C. Blachier F. 2005 Changes in activities of superoxide dismutase, nitric oxide synthase, glutathione-dependent enzymes and the incidence of apoptosis in sheep corpus luteum during the estrous cycle. Biochim. Biophys. Acta 1725 348 357 Pubmed Abstract

Arosh J. A. Banu S. K. Chapdelaine P. Madore E. Sirois J. Fortier M. A. 2004 Prostaglandin biosynthesis, transport, and signalling in corpus luteum: a basis for autoregulation of luteal function. Endocrinology 145 2551 2560 doi:10.1210/EN.2003-1607 Pubmed Abstract

Bauer M. Reibiger I. Spanel-Borowski K. 2001 Leucocyte proliferation in the bovine corpus luteum. Reproduction 121 297 305 doi:10.1530/REP.0.1210297 Pubmed Abstract

Best C. L. Pudney J. Welch W. R. Burger N. Hill J. A. 1996 Localization and characterization of white blood cell populations within the human ovary throughout the menstrual cycle and menopause. Hum. Reprod. 11 790 797 Pubmed Abstract

Brännström M. Fridén B. 1997 Immune regulation of corpus luteum function. Semin. Reprod. Endocrinol. 15 363 370 Pubmed Abstract

Bukulmez O. Arici A. 2000 Leukocytes in ovarian function. Hum. Reprod. Update 6 1 15 doi:10.1093/HUMUPD/6.1.1 Pubmed Abstract

Cannon M. J. Pate J. L. 2003 The role of major histocompatibility complex molecules in luteal function. Reprod. Biol. Endocrinol. 10 1 93

Cannon M. J. Davis J. S. Pate J. L. 2007 Expression of costimulatory molecules in the bovine corpus luteum. Reprod. Biol. Endocrinol. 5 5
doi:10.1186/1477-7827-5-5 Pubmed Abstract

Dias A. L. Brigagão M. R. Colepicolo P. Siqueira A. M. Silva E. G. Paula C. R. 2006 Superoxide dismutase in Cryptococcus neoformans varieties gattii, grubi, and neoformans. Mem. Inst. Oswaldo Cruz 101 107 109 doi:10.1590/S0074-02762006000100021

Duarte A. I. Santos M. S. Oliveira C. R. Rego A. C. 2005 Insulin neuroprotection against oxidative stress in cortical neurons – involvement of uric acid and glutathione antioxidant defenses. Free Radic. Biol. Med. 39 876 889 doi:10.1016/J.FREERADBIOMED.2005.05.002 Pubmed Abstract

Endo T. Yamamoto H. Tanaka S. 1988 Effect of prostaglandins (PGs) on progesterone production by human cultured luteal cells and their ability of PGs production. Nippon Naibunpi Gakkai Zasshi 64 687 697 Pubmed Abstract

Estevez A. Tognetti T. Luchetti C. Sander V. Motta A. 2003 Sequence of interleukin 1beta actions on corpus luteum regression: relationship with inducible cyclooxygenase and nitric oxide synthase expression. Reproduction 126 639 645 doi:10.1530/REP.0.1260639 Pubmed Abstract

Faas M. Bouman A. Moesa H. Heineman M. J. Leij L. D. Schuiling G. 2000 The immune response during the luteal phase of the ovarian cycle: a Th2-type response? Fertil. Steril. 74 1008 1013 doi:10.1016/S0015-0282(00)01553-3 Pubmed Abstract

Farina M. G. Billi S. Sordelli M. S. Ribeiro M. L. Di Girolamo G. Lombardi E. Franchi A. M. 2006 Nitric oxide (NO) inhibits prostaglandin E2 9-ketoreductase (9-KPR) activity in human fetal membranes. Prostaglandins Other Lipid Mediat. 79 260 270 doi:10.1016/J.PROSTAGLANDINS.2006.02.004 Pubmed Abstract

Foyouzi N. Cai Z. Sugimoto Y. Stocco C. 2005 Changes in the expression of steroidogenic and antioxidant genes in the mouse corpus luteum during luteolysis. Biol. Reprod. 72 1134 1141 doi:10.1095/BIOLREPROD.104.037598 Pubmed Abstract

Gadsby J. E. Balapure A. K. Britt J. H. Fitz T. A. 1990 Prostaglandin F2a receptors on enzyme dissociated pig luteal cells throughout the estrous cycle. Endocrinology 126 787 795 Pubmed Abstract

Garrel C. Ceballos-Picot I. Germain G. Al-Gubory K. H. 2007 Oxidative stress-inducible antioxidant adaptive response during prostaglandin F2alpha-induced luteal cell death in vivo. Free Radic. Res. 41 251 259 doi:10.1080/10715760601067493 Pubmed Abstract

Glimcher L. H. Murphy K. M. 2000 Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes Dev. 14 1693 1711 Pubmed Abstract

Gutteridge J. M. C. 1995 Lipid peroxidation and antioxidants as biomarkers of tissue damage. Clin. Chem. 41 1819 1828 Pubmed Abstract

Hansel W. 1996 Special topics in the theriogenology, no. 2: the bovine corpus luteum. Theriogenology 45 1265 1266 doi:10.1016/0093-691X(96)00097-0 Pubmed Abstract

Hashii K. Fujiwara H. Yoshioka S. Kataoka N. Yamada S. Hirano T. Mori T. Fujii S. Maeda M. 1998 Peripheral blood mononuclear cells stimulate progesterone production by luteal cells derived from pregnant and non-pregnant women: possible involvement of interleukin-4 and interleukin-10 in corpus luteum function and differentiation. Hum. Reprod. 13 2738 2744 Pubmed Abstract

Hla T. Neilson K. 1992 Human cyclooxygenase-2 cDNA. Proc. Natl. Acad. Sci. USA 89 7384 7388 doi:10.1073/PNAS.89.16.7384 Pubmed Abstract

Hurwitz A. Finci-Yeheskel Z. Milwidsky A. Mayer M. 2002 Regulation of cyclooxygenase activity and progesterone production in the rat corpus luteum by inducible nitric oxide synthase. Reproduction 123 663 669 doi:10.1530/REP.0.1230663 Pubmed Abstract

Knickerbocker J. J. Wiltbank M. C. Niswender G. D. 1988 Mechanisms of luteolysis in domestic livestock. Domest. Anim. Endocrinol. 5 91 107 doi:10.1016/0739-7240(88)90011-2 Pubmed Abstract

Komatsu K. Manabe N. Kiso M. Shimabe M. Miyamoto H. 2003 Changes in localization of immune cells and cytokines in corpora lutea during luteolysis in murine ovaries. J. Exp. Zoolog. A Comp. Exp. Biol. 296 152 159 Pubmed Abstract

Kotwica J. Skarzynski D. Mlynarczuk J. Rekawiecki R. 2003 Role of prostaglandin E2 in basal and noradrenaline-induced progesterone secretion by the bovine corpus luteum. Prostaglandins Other Lipid Mediat. 70 351 359 doi:10.1016/S0090-6980(02)00149-1 Pubmed Abstract

Krusche C. A. Vloet T. D. Herrler A. Black S. Beier H. M. 2002 Functional and structural regression of the rabbit corpus luteum is associated with altered luteal immune cell phenotypes and cytokine expression patterns. Histochem. Cell Biol. 118 479 489 Pubmed Abstract

Lawler D. F. Hopkins J. Watson E. D. 1999 Immune cell populations in the equine corpus luteum throughout the oestrous cycle and early pregnancy: an immunohistochemical and flow cytometric study. J. Reprod. Fertil. 117 281 290 Pubmed Abstract

Lu F. X. Abel K. Ma Z. Rourke T. Lu D. Torten J. McChesney M. Miller C. J. 2002 The strength of B cell immunity in female rhesus macaques is controlled by CD8+ T cells under the influence of ovarian steroid hormones. Clin. Exp. Immunol. 128 10 20 doi:10.1046/J.1365-2249.2002.01780.X Pubmed Abstract

Luchetti C. G. Solano M. E. Sander V. Arcos M. L. B. Gonzalez C. Girolamo G. D. Chiocchio S. Cremaschi G. Motta A. B. 2004 Effects of dehydroepiandrosterone on ovarian cystogenesis and immune function. J. Reprod. Immunol. 64 59 74 doi:10.1016/J.JRI.2004.04.002 Pubmed Abstract

McCracken J. A. Custer E. E. Lamsa J. C. 1999 Luteolysis: a neuroendocrine-mediated event. Physiol. Rev. 79 263 323

Medina K. L. Kincade P. W. 1994 Pregnancy-related steroids are potential negative regulators of B lymphopoiesis. Proc. Natl. Acad. Sci. USA 91 5382 5386
doi:10.1073/PNAS.91.12.5382 Pubmed Abstract

Medina K. L. Smithson G. Kincade P. W. 1993 Supression of B lymphopoeisis during normal pregnancy. J. Exp. Med. 178 1507 1515 doi:10.1084/JEM.178.5.1507 Pubmed Abstract

Minegishi K. Tanaka M. Nishimura O. Tanigaki S. Miyakoshi K. Ishimoto H. Yoshimura Y. 2002 Reactive oxygen species mediate leukocyte-endothelium interactions in prostaglandin F2alpha-induced luteolysis in rats. Am. J. Physiol. Endocrinol. Metab. 283 E1308 E1315 Pubmed Abstract

Misra H. P. Fridovich I. 1972 The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J. Biol. Chem. 247 3170 3175 Pubmed Abstract

Motta A. B. Estevez A. Franchi A. Perez-Martinez S. Farina M. Ribeiro M. L. Lasserre A. Gimeno M. F. 2001 Regulation of lipid peroxidation by nitric oxide and PGF2alpha during luteal regression in rats. Reproduction 121 631 637 doi:10.1530/REP.0.1210631 Pubmed Abstract

Nakamura T. Sakamoto K. 2001 Reactive oxygen species up-regulates cyclooxygenase-2, p53, and Bax mRNA expression in bovine luteal cells. Biochem. Biophys. Res. Commun. 284 203 210 doi:10.1006/BBRC.2001.4927 Pubmed Abstract

Nilsson N. Carlsten H. 1994 Estrogen induces suppression of natural killer cell cytotoxicity and augmentation of polyclonal B cell activation. Cell. Immunol. 158 131 139 doi:10.1006/CIMM.1994.1262 Pubmed Abstract

Pate J. L. Landis Keyes P. 2001 Immune cells in the corpus luteum: friends or foes? Reproduction 122 665 676 doi:10.1530/REP.0.1220665 Pubmed Abstract

Riley J. C. Behrman H. R. 1991 In vivo generation of hydrogen peroxide in the rat corpus luteum during luteolysis. Endocrinology 128 1749 1753

Ristimaki A. Jaatinen R. Ritvos O. 1997 Regulation of prostaglandin F2 alpha receptor expression in cultured human granulosa-luteal cells. Endocrinology 138 191 195
doi:10.1210/EN.138.1.191 Pubmed Abstract

Sander V. Luchetti C. G. Solano M. E. Elia E. Di Girolamo G. Gonzalez C. Motta A. B. 2006 Role of the n,n′-dimethylbiguanide metformin in the treatment of female prepuberal BALB/c mice hyperandrogenized with dehydroepiandrosterone. Reproduction 131 591 602 doi:10.1530/REP.1.00941 Pubmed Abstract

Sawada M. Carlson J. C. 1991 Rapid plasma membrane changes in superoxide radical formation, fluidity, and phospholipase A2 activity in the corpus luteum of the rat during induction of luteolysis. Endocrinology 128 2992 2998 Pubmed Abstract

Smith W. L. Meade E. A. DeWitt D. L. 1994 Interactions of PGH synthase isozymes-1 and -2 with NSAIDs. Ann. N. Y. Acad. Sci. 744 50 57 doi:10.1111/J.1749-6632.1994.TB52723.X Pubmed Abstract

Solano M. E. Elia E. Luchetti C. G. Sander V. Di Girolamo G. Gonzalez C. Motta A. B. 2006 Metformin prevents embryonic resorption induced by hyperandrogenisation with dehydroepiandrosterone in mice. Reprod. Fertil. Dev. 18 533 544 doi:10.1071/RD05099 Pubmed Abstract

Sugimoto Y. Yamasaki A. Segi E. Tsuboi K. Aze Y. et al. 1997 Failure of parturition in mice lacking the prostaglandin F receptor. Science 277 681 683 doi:10.1126/SCIENCE.277.5326.681 Pubmed Abstract

Sugino N. Shimamura K. Tamura H. Ono M. Nakamura Y. Kato H. 1996 Involvement of stimulatory effect of prostaglandin F2 alpha on superoxide radical production by macrophages in corpus luteum regression. Nippon Sanka Fujinka Gakkai Zasshi 48 393 398 Pubmed Abstract

Sugino N. Karube-Harada A. Taketani T. Sakata A. Nakamura Y. 2004 Withdrawal of ovarian steroids stimulates prostaglandin F2a production through nuclear factor-κB activation via oxygen radicals in human endometrial stromal cells: potential relevance to menstruation. J. Reprod. Dev. 50 215 225 doi:10.1262/JRD.50.215 Pubmed Abstract

Tam N. N. C. Ghatak S. Ho S.-M. 2003 Sex hormone-induced alterations in the activities of antioxidant enzymes and lipid peroxidation status in the prostate of noble rats. Prostate 55 1 8 doi:10.1002/PROS.10169 Pubmed Abstract

Wang H. Z. , Wu Y. F. , Shen W. X. , Zhon W. , and Gong Y. T. (1991). The hormonal control of human luteal cells. In ‘Growth Factor in Fertility Regulation’. (Eds F. P. Hasseltine and J. K. Findley.) pp. 99–113. (Cambridge University Press: New York.)

Weems Y. S. Bridges P. J. Tanaka Y. Sasser R. G. LeaMaster B. R. Vincent D. L. Weems C. W. 1997 PGE1 or PGE2 not LH regulates secretion of progesterone in vitro by the 88–90 day ovine corpus luteum of pregnancy. Prostaglandins 53 337 353 doi:10.1016/0090-6980(97)00037-3 Pubmed Abstract

Weller C. L. Collington S. J. Hartnell A. Conroy D. M. Kaise T. Barker J. E. Wilson M. S. Taylor G. W. Jose P. J. Williams T. J. 2007 Chemotactic action of prostaglandin E2 on mouse mast cells acting via the PGE2 receptor 3. Proc. Natl. Acad. Sci. USA 104 11 712 11 717 doi:10.1073/PNAS.0701700104 Pubmed Abstract

Wiltbank M. C. Ottobre J. S. 2003 Regulation of intraluteal production of prostaglandins. Reprod. Biol. Endocrinol. 1 91 doi:10.1186/1477-7827-1-91

Export Citation Cited By (10)