Morphology and Biochemistry of Ovulation

 

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Abstract

The process of ovulation involves multiple and iterrelated genetic, biochemical, and morphological events: cessation of the proliferation of granulosa cells, resumption of oocyte meiosis, expansion of cumulus cell-oocyte complexes, digestion of the follicle wall, and extrusion of the metaphase-II oocyte. The present narrative review examines these interrelated steps in detail. The combined or isolated roles of the follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are highlighted. Genes indiced by the FSH genes are relevant in the cumulus expansion, and LH-induced genes are critical for the resumption of meiosis and digestion of the follicle wall. A non-human model for follicle-wall digestion and oocyte release was provided.

Resumo

O processo de ovulação envolve modificações genéticas, bioquímicas e morfológicas múltiplas e interrelacionadas: suspensão da proliferação das células da granulosa, reinício da meiose do oócito, expansão das células do complexo cumulus-oócito, digestão da parede folicular, e extrusão do oócito. Esta revisão narrativa examina em detalhes cada um desses eventos e os principais genes e proteínas envolvidos. Mais importante, a ação combinada ou isolada do hormônio folículo-estimulante (HFE) e do hormônio luteinizante (HL) é destacada. Detalha-se o papel do HFE na expansão do cumulus e do HL na digestão da parede folicular, permitindo a extrusão do oócito na superfície ovariana. Proveu-se um modelo não humano para explicar a digestão da parede folicular.

Publication History

Received: 03 September 2020

Accepted: 19 March 2021

Article published online:
27 July 2021

© 2021. Federação Brasileira de Ginecologia e Obstetrícia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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• References

• 1 Russell DL, Robker RL. Molecular mechanisms of ovulation: co-ordination through the cumulus complex. Hum Reprod Update 2007; 13 (03) 289-312 DOI: 10.1093/humupd/dml062.
  CrossrefPubMedGoogle Scholar
• 2 Fraser IS, Critchley HO, Munro MG, Broder M. Can we achieve international agreement on terminologies and definitions used to describe abnormalities of menstrual bleeding?. Hum Reprod 2007; 22 (03) 635-643 DOI: 10.1093/humrep/del478.
  CrossrefPubMedGoogle Scholar
• 3 Latham KE, Bautista FD, Hirao Y, O'Brien MJ, Eppig JJ. Comparison of protein synthesis patterns in mouse cumulus cells and mural granulosa cells: effects of follicle-stimulating hormone and insulin on granulosa cell differentiation in vitro. Biol Reprod 1999; 61 (02) 482-492 DOI: 10.1095/biolreprod61.2.482.
  CrossrefPubMedGoogle Scholar
• 4 Peng XR, Hsueh AJ, LaPolt PS, Bjersing L, Ny T. Localization of luteinizing hormone receptor messenger ribonucleic acid expression in ovarian cell types during follicle development and ovulation. Endocrinology 1991; 129 (06) 3200-3207 DOI: 10.1210/endo-129-6-3200.
  CrossrefPubMedGoogle Scholar
• 5 Haghighat N, Van Winkle LJ. Developmental change in follicular cell-enhanced amino acid uptake into mouse oocytes that depends on intact gap junctions and transport system Gly. J Exp Zool 1990; 253 (01) 71-82 DOI: 10.1002/jez.1402530110.
  CrossrefPubMedGoogle Scholar
• 6 Albertini DF, Combelles CM, Benecchi E, Carabatsos MJ. Cellular basis for paracrine regulation of ovarian follicle development. Reproduction 2001; 121 (05) 647-653 DOI: 10.1530/rep.0.1210647.
  CrossrefPubMedGoogle Scholar
• 7 de Medeiros SF, Gil-Junior AB, Barbosa JS, Isaías ED, Yamamoto MM. New insights into steroidogenesis in normo- and hyperandrogenic polycystic ovary syndrome patients. Arq Bras Endocrinol Metabol 2013; 57 (06) 437-444 DOI: 10.1590/s0004-27302013000600005.
  CrossrefPubMedGoogle Scholar
• 8 van den Hurk R, Zhao J. Formation of mammalian oocytes and their growth, differentiation and maturation within ovarian follicles. Theriogenology 2005; 63 (06) 1717-1751 DOI: 10.1016/j.theriogenology.2004.08.005.
  CrossrefPubMedGoogle Scholar
• 9 Richards JS, Russell DL, Ochsner S, Espey LL. Ovulation: new dimensions and new regulators of the inflammatory-like response. Annu Rev Physiol 2002; 64: 69-92 DOI: 10.1146/annurev.physiol.64.081501.131029.
  CrossrefPubMedGoogle Scholar
• 10 Schatten H, Sun QY. Centrosome dynamics during mammalian oocyte maturation with a focus on meiotic spindle formation. Mol Reprod Dev 2011; 78 (10-11): 757-768 DOI: 10.1002/mrd.21380.
  CrossrefPubMedGoogle Scholar
• 11 Espey LL. Ovulation as an inflammatory reaction--a hypothesis. Biol Reprod 1980; 22 (01) 73-106 DOI: 10.1095/biolreprod22.1.73.
  CrossrefPubMedGoogle Scholar
• 12 Park JY, Su YQ, Ariga M, Law E, Jin SL, Conti M. EGF-like growth factors as mediators of LH action in the ovulatory follicle. Science 2004; 303 (5658): 682-684 DOI: 10.1126/science.1092463.
  CrossrefPubMedGoogle Scholar
• 13 Ashkenazi H, Cao X, Motola S, Popliker M, Conti M, Tsafriri A. Epidermal growth factor family members: endogenous mediators of the ovulatory response. Endocrinology 2005; 146 (01) 77-84 DOI: 10.1210/en.2004-0588.
  CrossrefPubMedGoogle Scholar
• 14 Shimada M, Hernandez-Gonzalez I, Gonzalez-Robayna I, Richards JS. Paracrine and autocrine regulation of epidermal growth factor-like factors in cumulus oocyte complexes and granulosa cells: key roles for prostaglandin synthase 2 and progesterone receptor. Mol Endocrinol 2006; 20 (06) 1352-1365 DOI: 10.1210/me.2005-0504.
  CrossrefPubMedGoogle Scholar
• 15 Sirard MA, Desrosier S, Assidi M. In vivo and in vitro effects of FSH on oocyte maturation and developmental competence. Theriogenology 2007; 68 (Suppl. 01) S71-S76 DOI: 10.1016/j.theriogenology.2007.05.053.
  CrossrefPubMedGoogle Scholar
• 16 Ochsner SA, Day AJ, Rugg MS, Breyer RM, Gomer RH, Richards JS. Disrupted function of tumor necrosis factor-alpha-stimulated gene 6 blocks cumulus cell-oocyte complex expansion. Endocrinology 2003; 144 (10) 4376-4384 DOI: 10.1210/en.2003-0487.
  CrossrefPubMedGoogle Scholar
• 17 Joyce IM, Pendola FL, O'Brien M, Eppig JJ. Regulation of prostaglandin-endoperoxide synthase 2 messenger ribonucleic acid expression in mouse granulosa cells during ovulation. Endocrinology 2001; 142 (07) 3187-3197 DOI: 10.1210/endo.142.7.8268.
  CrossrefPubMedGoogle Scholar
• 18 Hizaki H, Segi E, Sugimoto Y, Hirose M, Saji T, Ushikubi F. et al. Abortive expansion of the cumulus and impaired fertility in mice lacking the prostaglandin E receptor subtype EP(2). Proc Natl Acad Sci U S A 1999; 96 (18) 10501-10506 DOI: 10.1073/pnas.96.18.10501.
  CrossrefPubMedGoogle Scholar
• 19 Yamashita Y, Hishinuma M, Shimada M. Activation of PKA, p38 MAPK and ERK1/2 by gonadotropins in cumulus cells is critical for induction of EGF-like factor and TACE/ADAM17 gene expression during in vitro maturation of porcine COCs. J Ovarian Res 2009; 2: 20 DOI: 10.1186/1757-2215-2-20.
  CrossrefPubMedGoogle Scholar
• 20 Richards JS, Hernandez-Gonzalez I, Gonzalez-Robayna I, Teuling E, Lo Y, Boerboom D. et al. Regulated expression of ADAMTS family members in follicles and cumulus oocyte complexes: evidence for specific and redundant patterns during ovulation. Biol Reprod 2005; 72 (05) 1241-1255 DOI: 10.1095/biolreprod.104.038083.
  CrossrefPubMedGoogle Scholar
• 21 Gao S, De Geyter C, Kossowska K, Zhang H. FSH stimulates the expression of the ADAMTS-16 protease in mature human ovarian follicles. Mol Hum Reprod 2007; 13 (07) 465-471 DOI: 10.1093/molehr/gam037.
  CrossrefPubMedGoogle Scholar
• 22 Dozortsev DI, Diamond MP. Luteinizing hormone-independent rise of progesterone as the physiological trigger of the ovulatory gonadotropins surge in the human. Fertil Steril 2020; 114 (02) 191-199 DOI: 10.1016/j.fertnstert.2020.06.016.
  CrossrefPubMedGoogle Scholar
• 23 Richards JS, Russell DL, Robker RL, Dajee M, Alliston TN. Molecular mechanisms of ovulation and luteinization. Mol Cell Endocrinol 1998; 145 (1-2): 47-54 DOI: 10.1016/s0303-7207(98)00168-3.
  CrossrefPubMedGoogle Scholar
• 24 Robker RL, Russell DL, Espey LL, Lydon JP, O'Malley BW, Richards JS. Progesterone-regulated genes in the ovulation process: ADAMTS-1 and cathepsin L proteases. Proc Natl Acad Sci U S A 2000; 97 (09) 4689-4694 DOI: 10.1073/pnas.080073497.
  CrossrefPubMedGoogle Scholar
• 25 Eppig JJ. Regulation by sulfated glycosaminoglycans of the expansion of cumuli oophori isolated from mice. Biol Reprod 1981; 25 (03) 599-608 DOI: 10.1095/biolreprod25.3.599.
  CrossrefPubMedGoogle Scholar
• 26 Calder MD, Caveney AN, Westhusin ME, Watson AJ. Cyclooxygenase-2 and prostaglandin E(2)(PGE(2)) receptor messenger RNAs are affected by bovine oocyte maturation time and cumulus-oocyte complex quality, and PGE(2) induces moderate expansion of the bovine cumulus in vitro. Biol Reprod 2001; 65 (01) 135-140 DOI: 10.1095/biolreprod65.1.135.
  CrossrefPubMedGoogle Scholar
• 27 Fülöp C, Szántó S, Mukhopadhyay D, Bárdos T, Kamath VR, Rugg MS. et al. Impaired cumulus mucification and female sterility in tumor necrosis factor-induced protein-6 deficient mice. Development 2003; 130 (10) 2253-2261 DOI: 10.1242/dev.00422.
  CrossrefPubMedGoogle Scholar
• 28 Coticchio G, Dal-Canto M, Guglielmo MC, Mignini-Renzini M, Fadini R. Human oocyte maturation in vitro. Int J Dev Biol 2012; 56 (10-12): 909-918 DOI: 10.1387/ijdb.120135gv.
  CrossrefPubMedGoogle Scholar
• 29 Sutton ML, Gilchrist RB, Thompson JG. Effects of in-vivo and in-vitro environments on the metabolism of the cumulus-oocyte complex and its influence on oocyte developmental capacity. Hum Reprod Update 2003; 9 (01) 35-48 DOI: 10.1093/humupd/dmg009.
  CrossrefPubMedGoogle Scholar
• 30 Gilchrist RB, Ritter LJ, Armstrong DT. Oocyte-somatic cell interactions during follicle development in mammals. Anim Reprod Sci 2004; 82-83: 431-446 DOI: 10.1016/j.anireprosci.2004.05.017.
  CrossrefPubMedGoogle Scholar
• 31 Gilchrist RB, Lane M, Thompson JG. Oocyte-secreted factors: regulators of cumulus cell function and oocyte quality. Hum Reprod Update 2008; 14 (02) 159-177 DOI: 10.1093/humupd/dmm040.
  CrossrefPubMedGoogle Scholar
• 32 Buccione R, Schroeder AC, Eppig JJ. Interactions between somatic cells and germ cells throughout mammalian oogenesis. Biol Reprod 1990; 43 (04) 543-547 DOI: 10.1095/biolreprod43.4.543.
  CrossrefPubMedGoogle Scholar
• 33 Eppig JJ, Wigglesworth K, Pendola F, Hirao Y. Murine oocytes suppress expression of luteinizing hormone receptor messenger ribonucleic acid by granulosa cells. Biol Reprod 1997; 56 (04) 976-984 DOI: 10.1095/biolreprod56.4.976.
  CrossrefPubMedGoogle Scholar
• 34 Hussein TS, Thompson JG, Gilchrist RB. Oocyte-secreted factors enhance oocyte developmental competence. Dev Biol 2006; 296 (02) 514-521 DOI: 10.1016/j.ydbio.2006.06.026.
  CrossrefPubMedGoogle Scholar
• 35 Teilmann SC. Differential expression and localisation of connexin-37 and connexin-43 in follicles of different stages in the 4-week-old mouse ovary. Mol Cell Endocrinol 2005; 234 (1-2): 27-35 DOI: 10.1016/j.mce.2004.10.014.
  CrossrefPubMedGoogle Scholar
• 36 Gittens JE, Kidder GM. Differential contributions of connexin37 and connexin43 to oogenesis revealed in chimeric reaggregated mouse ovaries. J Cell Sci 2005; 118 (Pt 21): 5071-5078 DOI: 10.1242/jcs.02624.
  CrossrefPubMedGoogle Scholar
• 37 Aktas H, Wheeler MB, First NL, Leibfried-Rutledge ML. Maintenance of meiotic arrest by increasing [cAMP]i may have physiological relevance in bovine oocytes. J Reprod Fertil 1995; 105 (02) 237-245 DOI: 10.1530/jrf.0.1050237.
  CrossrefPubMedGoogle Scholar
• 38 Tsafriri A, Chun SY, Zhang R, Hsueh AJ, Conti M. Oocyte maturation involves compartmentalization and opposing changes of cAMP levels in follicular somatic and germ cells: studies using selective phosphodiesterase inhibitors. Dev Biol 1996; 178 (02) 393-402 DOI: 10.1006/dbio.1996.0226.
  CrossrefPubMedGoogle Scholar
• 39 Bilodeau-Goeseels S. Cows are not mice: the role of cyclic AMP, phosphodiesterases, and adenosine monophosphate-activated protein kinase in the maintenance of meiotic arrest in bovine oocytes. Mol Reprod Dev 2011; 78 (10-11): 734-743 DOI: 10.1002/mrd.21337.
  CrossrefPubMedGoogle Scholar
• 40 Tsafriri A, Cao X, Ashkenazi H, Motola S, Popliker M, Pomerantz SH. Resumption of oocyte meiosis in mammals: on models, meiosis activating sterols, steroids and EGF-like factors. Mol Cell Endocrinol 2005; 234 (1-2): 37-45 DOI: 10.1016/j.mce.2004.09.009.
  CrossrefPubMedGoogle Scholar
• 41 Gilchrist RB, Smitz JEJ, Thompson JG. Current status and future trends of the clinical practice of human oocyte in vitro maturation. In: Gardner DK, Rizk BRMB, Falcone T. editors. Human assisted reproductive technology: future trends in laboratory & clinical practice. Cambridge: Cambridge University Press; 2011: 186-98
  Google Scholar
• 42 Zhang M, Su YQ, Sugiura K, Xia G, Eppig JJ. Granulosa cell ligand NPPC and its receptor NPR2 maintain meiotic arrest in mouse oocytes. Science 2010; 330 (6002): 366-369 DOI: 10.1126/science.1193573.
  CrossrefPubMedGoogle Scholar
• 43 Dalton CM, Carroll J. Biased inheritance of mitochondria during asymmetric cell division in the mouse oocyte. J Cell Sci 2013; 126 (Pt 13): 2955-2964 DOI: 10.1242/jcs.128744.
  CrossrefPubMedGoogle Scholar
• 44 Coticchio G, Dal Canto M, Renzini MM, Guglielmo MC, Brambillasca F, Turchi D. et al. Oocyte maturation: gamete-somatic cells interactions, meiotic resumption, cytoskeletal dynamics and cytoplasmic reorganization. Hum Reprod Update 2015; 21 (04) 427-454 DOI: 10.1093/humupd/dmv011.
  CrossrefPubMedGoogle Scholar
• 45 Kishimoto H, Hamada K, Saunders M, Backman S, Sasaki T, Nakano T. et al. Physiological functions of Pten in mouse tissues. Cell Struct Funct 2003; 28 (01) 11-21 DOI: 10.1247/csf.28.11.
  CrossrefPubMedGoogle Scholar
• 46 Sen A, Caiazza F. Oocyte maturation: a story of arrest and release. Front Biosci (Schol Ed) 2013; 5: 451-477 DOI: 10.2741/s383.
  CrossrefPubMedGoogle Scholar
• 47 Russell DL, Doyle KM, Ochsner SA, Sandy JD, Richards JS. Processing and localization of ADAMTS-1 and proteolytic cleavage of versican during cumulus matrix expansion and ovulation. J Biol Chem 2003; 278 (43) 42330-42339 DOI: 10.1074/jbc.M300519200.
  CrossrefPubMedGoogle Scholar
• 48 Curry Jr TE, Dean DD, Sanders SL, Pedigo NG, Jones PB. The role of ovarian proteases and their inhibitors in ovulation. Steroids 1989; 54 (05) 501-521 DOI: 10.1016/0039-128x(89)90044-5.
  CrossrefPubMedGoogle Scholar
• 49 Ogiwara K, Takano N, Shinohara M, Murakami M, Takahashi T. Gelatinase A and membrane-type matrix metalloproteinases 1 and 2 are responsible for follicle rupture during ovulation in the medaka. Proc Natl Acad Sci U S A 2005; 102 (24) 8442-8447 DOI: 10.1073/pnas.0502423102.
  CrossrefPubMedGoogle Scholar
• 50 Kurita T, Wang YZ, Donjacour AA, Zhao C, Lydon JP, O'Malley BW. et al. Paracrine regulation of apoptosis by steroid hormones in the male and female reproductive system. Cell Death Differ 2001; 8 (02) 192-200 DOI: 10.1038/sj.cdd.4400797.
  CrossrefPubMedGoogle Scholar
• 51 Smith RK, Carroll PM, Allard JD, Simon MA. MASK, a large ankyrin repeat and KH domain-containing protein involved in Drosophila receptor tyrosine kinase signaling. Development 2002; 129 (01) 71-82
  CrossrefPubMedGoogle Scholar