Semin Reprod Med 2007; 25(4): 235-242
DOI: 10.1055/s-2007-980217
Copyright © 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Genetics of Ovulation

JoAnne S. Richards1
  • 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
Further Information

Publication History

Publication Date:
26 June 2007 (online)


Ovulation is essential for reproductive success; many cases of infertility in women may be related to disruption of this critical and complex ovarian process. Recent gene profiling studies using rat, mouse, and human ovaries and cumulus oocyte complexes isolated prior to, during, and following luteinizing hormone (LH or human chorionic gonadotropin) -induced ovulation have unmasked a surprising diversity and staggering number of genes for which expression is altered in these tissues. Thus, impairment of this process could involve many factors not yet considered. Although some genes associated with inflammatory-like responses have been identified previously and shown to be obligatory for ovulation, others represent entirely new categories of genes. These include genes associated with innate immune responses and immune cell functions, neuronal cell activity, and novel signaling cascades. The innate immune and neuronal genes are expressed in cumulus cells not adhering immune cells. Thus, cumulus cells acquire immune cell-related functions. The neuronal-related genes may influence cumulus cell migration during formation of the hyaluronan-rich matrix. The factors stabilizing the matrix are essential for expansion of the cumulus oocyte complex and release of a fertilizable oocyte contained therein. Novel signaling molecules include members of the WNT/FRIZZLED family, the BMP family, and transcription factors. Some of these novel genes may become useful predictors of ovulation success and/or embryo health and viability.


  • 1 Espey L L. Ovulation as an inflammatory reaction-a hypothesis.  Biol Reprod. 1980;  22 73-106
  • 2 Espey L L, Richards J S. Temporal and spatial patterns of ovarian gene transcription following an ovulatory dose of gonadotropin in the rat.  Biol Reprod. 2002;  67 1662-1670
  • 3 Richards J S. Ovulation: New factors that prepare the oocyte for fertilization.  Mol Cell Endocrinol. 2005;  234 75-79
  • 4 Espey L L, Richards J S. Ovulation. 3rd ed. San Diego, CA; Academic Press, Elsevier 2006
  • 5 Jo M, Gieske M C, Payne C E et al.. Development and application of a rat ovarian gene expression database.  Endocrinology. 2004;  145 5384-5396
  • 6 Hernandez-Gonzalez I, Gonzalez-Robayna I J, Shimada M et al.. Gene expression profiles of cumulus cell oocyte complexes (COCs) during ovulation reveal cumulus cells express neuronal and immune-related genes: does this expand their role in the ovulation process?.  Mol Endocrinol. 2006;  20 1300-1321
  • 7 Assou S, Anahory T, Pantesco V, Le Carrour T, Pellestor F, Klein B, Reyftmann L, Dechaud H, De Vos J, Hamamah S. The human cumulus-oocyte complex gene-expression profile.  Human Reprod. 2006;  , on line
  • 8 Hizaki H, Segi E, Sugimoto Y et al.. Abortive expansion of the cumulus and impaired fertility in mice lacking the prostaglandin E receptor subtype EP2.  Proc Natl Acad Sci USA. 1999;  96 10501-10506
  • 9 Pakarainen T, Zhang F-P, Nurmi L, Poutanen M, Huhtaniemi I. Knockout of luteinizing hormone receptor abolishes the effects of follicle-stimulating hormone on preovulatory maturation and ovulation of mouse Graafian follicles.  Mol Endocrinol. 2005;  19 2591-2602
  • 10 Rao C V, Lei Z M. Consequences of targeted inactivation of LH receptors.  Mol Cell Endocrinol. 2002;  187 57-67
  • 11 Couse J F, Yates M M, Deroo B J, Korach K S. Estrogen receptor-β is critical to granulosa cell differentiation and ovulatory response to gonadotropins.  Endocrinology. 2005;  146 3247-3262
  • 12 Lydon J P, DeMayo F, Funk C R et al.. Mice lacking progesterone receptor exhibit reproductive abnormalities.  Genes Dev. 1995;  9 2266-2278
  • 13 Robker R L, Russell D L, Espey L L, Lydon J P, O'Malley B W, Richards J S. Progesterone-regulated genes in the ovulation process: ADAMTS-1 and cathepsin L proteases.  Proc Natl Acad Sci USA. 2000;  97 4689-4694
  • 14 Conneely O M, Mulac-Jericevic B, Lydon J P, DeMayo F J. Reproductive functions of the progesterone receptor isoforms: lessons from knockout mice.  Mol Cell Endocrinol. 2001;  179 97-103
  • 15 White R, Leonardsson G, Rosewell I, Jacobs M A, Milligan S, Parker M. The nuclear receptor co-repressor Nrip1 (RIP140) is essential for female fertility.  Nat Med. 2000;  6 1368-1373
  • 16 Tullet J MA, Pocock V, Steel J H, White R, Milligan S, Parker M G. Multiple signaling defects in the absence of RIP140 impair both cumulus expansion and follicle rupture.  Endocrinology. 2005;  146 4127-4137
  • 17 Wong W YW, Richards J S. Evidence for two antigenically distinct molecular weight variants of prostaglandin H synthase in the rat ovary.  Mol Endocrinol. 1991;  5 1269-1279
  • 18 Sirois J, Simmons D L, Richards J S. Hormonal regulation of messenger ribonucleic acid encoding a novel isoform of prostaglandin endoperoxide H synthase in rat preovulatory follicles.  J Biol Chem. 1992;  267 11586-11592
  • 19 Joyce I M, Pendola F L, O'Brien M, Eppig J J. Regulation of prostaglandin-endoperoxide synthase 2 messenger ribonucleic acid expression in mouse granulosa cells during ovulation.  Endocrinology. 2001;  142 3187-3197
  • 20 Davis B J, Lennard D E, Lee C A et al.. Anovulation in cyclo-oxygenase-2-deficient mice is restored by prostaglandin E2 and interleukin-1β.  Endocrinology. 1999;  140 2685-2696
  • 21 Park O-K, Mayo K. Transient expression of progesterone receptor messenger RNA in ovarian granulosa cells after the preovulatory luteinizing hormone surge.  Mol Endocrinol. 1991;  5 967-978
  • 22 Sriraman V, Sharma S C, Richards J S. Transactivation of the progesterone receptor gene in granulosa cells: Evidence that Sp1/Sp3 binding sites in the proximal promoter play a key role in luteinizing hormone inducibility.  Mol Endocrinol. 2003;  17 436-449
  • 23 Mulac-Jericevic B, Conneely O M. Reproductive tissue selective actions of progesterone receptors.  Reproduction. 2004;  128 139-146
  • 24 Takimoto G S, Tung L, Abdel-Hafiz H et al.. Functional properties of the N-terminal region of the progesterone receptors and their mechanistic relationship to structure.  J Steroid Biochem Mol Biol. 2003;  85 209-219
  • 25 Sriraman V, Richards J S. Cathepsin L gene expression and promoter activation in rodent granulosa cells.  Endocrinology. 2003;  145 582-589
  • 26 Sriraman V, Lohmann S, Mulders S, Richards J S. Induction of cGKII by LH and PR in the mouse ovary.  Mol Endocrinol. 2005;  , In press
  • 27 Doyle K MH, Russell D L, Sriraman V, Richards J S. Coordinate transactivation of the ADAMTS-1 gene by luteinizing hormone and progesterone receptor.  Mol Endocrinol. 2004;  18 2463-2478
  • 28 Hsieh M, Johnson M, Greenberg N M, Richards J S. Regulated expression of Wnt and Frizzled signals in the rodent ovary.  Endocrinology. 2002;  143 898-908
  • 29 Shimada M, Gonzalez-Robayna I, Hernandez-Gonzalez I, Richards J S. Paracrine and autocrine regulation of EGF-like factors in cumulus oocyte complexes and granulosa cells: key role for prostaglandin synthase 2 (Ptgs2) and progesterone receptor (Pgr).  Mol Endocrinol. 2006;  20 1352-1365
  • 30 Ko C, Gieske M C, Hahn Y et al.. Endothelin-2 in ovarian follicle rupture.  Endocrinology. 2006;  147 1770-1779
  • 31 Kim J, Sato M, Lydon J P, DeMayo F J, Bagchi I C, Bagchi M K. The peroxisome proliferator-activated receptor gamma is downstream of progesterone receptor and control ovulation in mice. Presented at: the 88th annual meeting of the Endocrine Society June 24-27, 2006 Boston, MA;
  • 32 Christian M, Tullet J M, Parker M G. Characterization of four autonomous repression domains in the corepressor receptor interacting protein 140.  J Biol Chem. 2004;  279 15645-15651
  • 33 Treuter E, Albrektsen T, Johansson L, Leers J, Gustafsson J A. A regulatory role for RIP140 in nuclear hormone receptor activation.  Mol Endocrinol. 1998;  12 864-881
  • 34 Park J-Y, Su Y-Q, Ariga M, Law E, Jin S-LC, Conti M. EGF-like growth factors as mediators of LH action in the ovulatory follicle.  Science. 2004;  303 682-684
  • 35 Conti M, Hsieh M, Park J-Y, Su Y-Q. Role of the epidermal growth factor network in ovarian follicles.  Mol Endocrinol. 2006;  20 715-723
  • 36 Hsieh M, Conti M. G-protein-coupled receptor signaling and the EGF network in endocrine systems.  Trends Endocrinol Metab. 2005;  16 320-326
  • 37 Ben-Ami I, Friemann S, Armon L, Dantes A, Ron-El R, Amsterdam A. Novel function of ovarian growth factors: combined studies by DNA microarray, biochemical and physiological approaches.  Mol Hum Reprod. 2006;  12 413-419
  • 38 Ben-Ami L, Freimann S, Armon L et al.. PGE2 up-regulates EGF-like factors biosynthesis in human granulosa cells: new insights into the coordination between PGE2 and LH in ovulation.  Mol Hum Reprod. 2006;  12 593-599
  • 39 Saavalainen K, Pasonen-Sappanen S, Dunlop T W, Tammi R, Tammi M I, Carlberg C. The human hyaluronan synthase 2 gene is a primary retinoic acid and epidermal growth factor responding gene.  J Biol Chem. 2005;  280 14636-14644
  • 40 Su Y-Q, Denegre J M, Wigglesworth K, Pendola F L, O'Brien M J, Eppig J J. Oocyte-dependent activation of mitogen-activated protein kinase (ERK1/2) in cumulus cells is required for the maturation of the mouse oocyte-cumulus cell complex.  Dev Biol. 2003;  263 126-138
  • 41 Fan H-Y, Sun Y-Q. Involvement of mitogen-activated protein kinase cascade during oocyte maturation and fertility in mammals.  Biol Reprod. 2004;  70 535-547
  • 42 Hsieh M, Lee D, Panigone S et al.. Luteinizing hormone-dependent activation of the epidermal growth factor network is essential for ovulation.  Mol Cell Biol. 2007;  25 1914-1924
  • 43 Ochsner S A, Russell D L, Richards J S. Decreased expression of tumor necrosis factor-α-stimulated gene 6 in cumulus cells of the cyclooxygenase-2 and EP2 null mice.  Endocrinology. 2003;  144 1008-1019
  • 44 Ochsner S A, Day A J, Breyer R M, Gomer R H, Richards J S. Disrupted function of tumor necrosis stimulated gene 6 blocks cumulus cell-oocyte complex function.  Endocrinology. 2003;  144 4376-4387
  • 45 Kahmann J D, O'Brien R, Werner J M et al.. Localization and characterization of the hyaluronan-binding site on the link module from human TSG-6.  Structure. 2000;  8 763-774
  • 46 Chen L, Mao S J, Larsen W J. Identification of a factor in fetal bovine serum that stabilizes the cumulus extracellular matrix. A role for a member of the inter-slpha-trypsin inhibitor family.  J Biol Chem. 1992;  267 12380-12386
  • 47 Mukhopadhyay D, Hascall V C, Day A J, Salustri A, Fulop C. Two distinct populations of tumor necrosis factor-stimulated gene-6 protein in the extracellular matrix of expanded mouse cumulus cell-oocyte complexes.  Arch Biochem Biophys. 2001;  394 173-181
  • 48 Carrette O, Nemade R V, Day A J, Brickner A, Larsen W J. TSG-6 is concentrated in the extracellular matrix of mouse cumulus oocyte complexes through hyaluronan and inter-alpha-inhibitor binding.  Biol Reprod. 2001;  65 301-308
  • 49 Chen L, Zhang H, Powers R W, Russell P T, Larsen W J. Covalent linkage between proteins of the inter-a-inhibitor family and hyaluronic acid sis mediated by a factor produced by granulosa cells.  J Biol Chem. 1996;  271 19409-19414
  • 50 Fulop C, Szanto S, Mukhopadhyay D et al.. Impaired cumulus mucification an female sterility in tumor necrosis factor-induced protein-6 deficient mice.  Development. 2003;  130 2253-2261
  • 51 Varani S, Elvin J A, Yan C et al.. Knockout of pentraxin 3, a downstream target of growth differentiation factor-9, causes female subfertility.  Mol Endocrinol. 2002;  16 1154-1167
  • 52 Salustri A, Garlanda C, Hirsch E et al.. PTX3 plays a key role in the organization of the cumulus oophorus extracellular matrix and in in vivo fertilization.  Development. 2004;  131 1577-1586
  • 53 Sato H, Kajikawa S, Kuroda S et al.. Impaired fertility in female mice lacking urinary trypsin inhibitor.  Biochem Biophys Res Comm. 2001;  281 1154-1160
  • 54 Zhuol L, Yoneda M, Zhao M et al.. Defect in SHAP-hyaluronan complex causes severe female infertility: A study by inaction of the bikunin gene in mice.  J Biol Chem. 2001;  276 7693-7696
  • 55 Camozzi M, Rusnati M, Bugatti A et al.. Identification of an antiangiogenic FGF-2binding stie in the N terminus of the soluble pattern recognition receptor, PTX3.  J Biol Chem. 2006;  281 22605-22613
  • 56 Yan C, Wang P, Demayo J et al.. Synergistic roles of bone morphogenic protein 15 and growth differentiation factor 9 in ovarian function.  Mol Endocrinol. 2001;  15 854-866
  • 57 Yoshino O, McMahon H E, Sharma S, Shimasaki S. A unique preovulatory expression pattern plays a key role in the physiological functions of BMP-15 in the mouse.  Proc Natl Acad Sci USA. 2006;  103 10678-10683
  • 58 Russell D L, Ochsner S A, Hsieh M, Mulders S, Richards J S. Hormone-regulated expression and localization of versican in the rodent ovary.  Endocrinology. 2003;  144 1020-1031
  • 59 Toole B P, Wight T N, Tammi M I. Hyaluronan-cell interactions in cancer and vascular disease.  J Biol Chem. 2002;  277 4593-4596
  • 60 Sandy J D, Westling J, Kenagy R D et al.. Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4.  J Biol Chem. 2001;  276 13372-13378
  • 61 Kuno K, Okada Y, Kawashima H et al.. ADAMTS-1 cleaves a cartilage proteoglycan, aggrecan.  FEBS Lett. 2000;  478 241-245
  • 62 Russell D L, Doyle K MH, Ochsner S A, Sandy J D, Richards J S. Processing and localization of ADAMTS-1 and proteolytic cleavage of versican during cumulus matrix expansion and ovulation.  J Biol Chem. 2003;  278 42330-42339
  • 63 Mittaz L, Russell D L, Wilson T et al.. ADAMTS-1 is essential for the development and function of the urogenital system.  Biol Reprod. 2004;  70 1096-1105
  • 64 Shindo T, Kurihara H, Kuno K et al.. ADAMTS-1: a metalloproteinase-disintegrin essential for normal growth, fertility and organ morphology and function.  J Clin Invest. 2000;  105 1345-1352
  • 65 Shozu M, Minami N, Yokoyama H, Inoue M, Kurihara H. ADAMTS1 is involved in normal follicular development, ovulatory process and organization of the medullary network in the ovary.  J Mol Endocrinol. 2005;  35 343-355
  • 66 Lee N V, Rodriguez-Manzanesque J C, Thai SN-M et al.. Fibulin-1 acts as a cofactor for the matrix metalloproteinase ADAMTS-1.  J Biol Chem. 2005;  280 34796-34804
  • 67 Richards J S, Hernandez-Gonzalez I, Gonzalez-Robayna I et al.. Regulated expression of ADAMTS family members in follicles and cumulus oocyte complexes: evidence for specific and redundant functions.  Biol Reprod. 2005;  72 1241-1255
  • 68 Somerville R P, Longpre J M, Jungers K A et al.. Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1.  J Biol Chem. 2003;  278 9503-9513
  • 69 Menke D B, Page D C. Sexually dimorphic gene expression in the developing mouse gonad.  Gene Expr Patterns. 2002;  2 359-367
  • 70 Boerboom D, Russell D L, Richards J S, Sirois J. Regulation of transcripts encoding ADAMTS-1 and progesterone receptor by human chorionic gonadotropin in equine preovulatory follicles.  J Mol Endocrinol. 2003;  31 413-485
  • 71 Madan P, Bridges P J, Komar C M et al.. Expression of messenger RNA for ADAMTS subtypes changes in the periovulatory follicle after the gonadotropin surge and during luteal development and regression in cattle.  Biol Reprod. 2003;  69 1506-1514
  • 72 Jo M, Komar C M, Fortune J E. Gonadotropin surge induces two separate increases in messenger RNA for progesterone receptor in bovine preovulatory follicles.  Biol Reprod. 2002;  67 1981-1988
  • 73 Tumilson B, Young K A, Stouffer R L. ADAMTS-1 mRNA is differentially expressed and regulated by LH in the primate corpus luteum. Presented at: the Society for the Study of Reproduction 36th Annual Meeting July 19-22, 2003 (abst 64)
  • 74 Shimada M, Hernandez-Gonzalez I, Gonzalez-Robanya I, Richards J S. Induced expression of pattern recognition receptors (PRRs) in cumulus oocyte complexes (COCs): novel evidence for innate immune-like cells functions during ovulation.  Mol Endocrinol. 2006;  20 3228-3239
  • 75 Baruah P, Dumitriu I E, Peri G et al.. The tissue pentraxin PTX3 limits C1q-mediated complement activation and phagocytosis of apoptotic cells by dendritic cells.  J Leukoc Biol. 2006;  80 87-95
  • 76 Reaven E, Luo Y, Nomoto A et al.. The selective pathway and a high-density lipoprotein receptor (SR-BI) in ovairan grnaulosa cells of the mouse.  Biochim Biophys Acta. 1999;  1436 565-576
  • 77 Chemes H. The phagocytic function of Sertoli cells: a morphological, biochemical and endocrinological study of lysosomes and acdi phosphatase localization in the rat testis.  Endocrinology. 1986;  119 1673-1681
  • 78 Hsieh M, Boerboom D, Shimada M et al.. Mice null for frizzled4 (Fzd4 - / - ) are infertile and exhibit impaired corpora lutea formation and function.  Biol Reprod. 2005;  73 1135-1146
  • 79 Zheng P, Vassena R, Latham K. Expression and downregulation of WNT signaling pathway genes in Rhesus monkey oocytes and embryos.  Mol Reprod Dev. 2006;  73 667-677
  • 80 McKenzie L J, Pangas S A, Carson S A et al.. Human cumulus granulosa cell gene expression: a predictor of fertilization and embryo selection in women undergoing IVF.  Hum Reprod. 2004;  19 2869-2874

JoAnne S RichardsPh.D. 

Department of Molecular and Cellular Biology, Baylor College of Medicine

One Baylor Plaza, Houston, TX 77030