pp 1-15 | Cite as

Oocyte Aging: The Role of Cellular and Environmental Factors and Impact on Female Fertility

  • Toka A. Ahmed
  • Sara M. Ahmed
  • Zaynab El-Gammal
  • Shaimaa Shouman
  • Ashrakat Ahmed
  • Ragaa Mansour
  • Nagwa El-BadriEmail author
Part of the Advances in Experimental Medicine and Biology book series


Female aging is one of the most important factors that impacts human reproduction. With aging, there is a natural decline in female fertility. The decrease in fertility is slow and steady in women aged 30–35 years; however, this decline is accelerated after the age of 35 due to decreases in the ovarian reserve and oocyte quality. Human oocyte aging is affected by different environmental factors, such as dietary habits and lifestyle. The ovarian microenvironment contributes to oocyte aging and longevity. The immediate oocyte microenvironment consists of the surrounding cells. Crosstalk between the oocyte and microenvironment is mediated by direct contact with surrounding cells, the extracellular matrix, and signalling molecules, including hormones, growth factors, and metabolic products. In this review, we highlight the different microenvironmental factors that accelerate human oocyte aging and decrease oocyte function. The ovarian microenvironment and the stress that is induced by environmental pollutants and a poor diet, along with other factors, impact oocyte quality and function and contribute to accelerated oocyte aging and diseases of infertility.

Graphical Abstract


Aging and longevity Human Microenvironment Oocytes 



Advanced glycation end products


Protein kinase B


B-cell lymphoma-2


Calmodulin-dependent protein kinase II




Cumulus cells


Cyclic guanosine monophosphate


Cumulus-oocyte complex


Cytochrome oxidase subunit 3


Coenzyme Q10


Connexin 43


Epidermal growth factor


EGF receptor


Fas-Associated protein with a Death Domain


Free α-subunit


Fas/Fas ligand


Forkhead box O


Follicle-stimulating hormone


Granulosa cells


Gonadotropin-releasing hormone


Glutathione peroxidase


Glutathione S transferase


Guanosine triphosphate


High-mobility group AT-hook 2

HPG axis

Hypothalamic-pituitary-gonadal axis


Inhibitor nuclear factor kappa B kinase subunit gamma


Insulin resistance


In vitro fertilization


Luteinising hormone


Long interspersed element


Mitogen-activated protein kinases


Meiotic metaphase II


Mitochondrial SOD


Maturation-promoting factor


Mitochondrial DNA




Nicotinamide adenine dinucleotide


Nuclear factor kappa B


Open reading frame


Polycystic ovary syndrome


Phosphodiesterase 3A

PGC-1 α

Proliferator-activated receptor coactivator-1α


Primordial germ cells


Phosphatidylinositol 3-kinase


Phosphatase and tensin homolog


Ras-related protein Rab-5B


Receptor for advanced glycation end products


Reactive oxygen species


Subunit A of succinate dehydrogenase


Soluble fasl


Silent information regulator-1


Superoxide dismutase



This work was supported by grant # 5300 from the Science and Technology. Development Fund.

Financial Disclosure

The authors report no financial conflicts to disclose.


  1. Agarwal A, Gupta S, Sharma RK (2005) Role of oxidative stress in female reproduction. Reprod Biol Endocrinol 3(1):28Google Scholar
  2. Albertini DF et al (2001) Cellular basis for paracrine regulation of ovarian follicle development. Reproduction 121(5):647–653Google Scholar
  3. Ames BN, Shigenaga MK, Hagen TM (1995) Mitochondrial decay in aging. Biochim Biophys Acta (BBA) - Mol Basis Dis 1271(1):165–170Google Scholar
  4. Amicarelli F et al (1999) Age-dependent ultrastructural alterations and biochemical response of rat skeletal muscle after hypoxic or hyperoxic treatments. Biochim Biophys Acta (BBA) - Mol Basis Dis 1453(1):105–114Google Scholar
  5. Aporntewan C et al (2011) Hypomethylation of intragenic LINE-1 represses transcription in cancer cells through AGO2. PLoS One 6(3):e17934Google Scholar
  6. Ashby J et al (2002) The effects of atrazine on the sexual maturation of female rats. Regul Toxicol Pharmacol 35(3):468–473Google Scholar
  7. Assou S et al (2013) MicroRNAs: new candidates for the regulation of the human cumulus–oocyte complex. Hum Reprod 28(11):3038–3049Google Scholar
  8. Attaran A, Maharaj R (2000) Ethical debate: doctoring malaria, badly: the global campaign to ban DDT. BMJ (Clin Res Ed) 321(7273):1403–1405Google Scholar
  9. Barbieri RL (2014) The endocrinology of the menstrual cycle. In: Human fertility. Springer, New York, pp 145–169Google Scholar
  10. Barja G (2002) Endogenous oxidative stress: relationship to aging, longevity and caloric restriction. Aging Res Rev 1(3):397–411Google Scholar
  11. Barja G (2004) Aging in vertebrates, and the effect of caloric restriction: a mitochondrial free radical production-DNA damage mechanism? Biol Rev Camb Philos Soc 79(2):235–251Google Scholar
  12. Ben-Meir A et al (2015) Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging. Aging Cell 14(5):887–895Google Scholar
  13. Boirie Y (2003) Insulin regulation of mitochondrial proteins and oxidative phosphorylation in human muscle. Trends Endocrinol Metab 14(9):393–394Google Scholar
  14. Boucret L et al (2015) Relationship between diminished ovarian reserve and mitochondrial biogenesis in cumulus cells. Hum Reprod 30(7):1653–1664Google Scholar
  15. Bretveld RW et al (2006) Pesticide exposure: the hormonal function of the female reproductive system disrupted? Reprod Biol Endocrinol 4(1):30Google Scholar
  16. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414(6865):813–820Google Scholar
  17. Brunet A et al (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303(5666):2011–2015Google Scholar
  18. Calabrese V et al (2010) Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders. Antioxid Redox Signal 13(11):1763–1811Google Scholar
  19. Carbone M et al (2003) Antioxidant enzymatic defences in human follicular fluid: characterization and age-dependent changes. MHR Basic Sci Reprod Med 9(11):639–643Google Scholar
  20. Chadwick RW et al (1988) Possible antiestrogenic activity of lindane in female rats. J Biochem Toxicol 3(3):147–158Google Scholar
  21. Collado M, Blasco MA, Serrano MJC (2007) Cellular senescence in cancer and aging. Cell 130(2):223–233Google Scholar
  22. da Silveira JC et al (2012) Cell-secreted vesicles in equine ovarian follicular fluid contain miRNAs and proteins: a possible new form of cell communication within the ovarian follicle. Biol Reprod 86(3):71Google Scholar
  23. Dale PO et al (1998) The impact of insulin resistance on the outcome of ovulation induction with low-dose follicle stimulating hormone in women with polycystic ovary syndrome. Hum Reprod 13(3):567–570Google Scholar
  24. Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116(2):205–219Google Scholar
  25. Danilovich N, Sairam MR (2002) Haploinsufficiency of the follicle-stimulating hormone receptor accelerates oocyte loss inducing early reproductive senescence and biological aging in mice. Biol Reprod 67(2):361–369Google Scholar
  26. de Haan N, Spelt M, Göbel R (2010) Reproductive medicine: a textbook for paramedics. Elsevier gezondheidszorg, AmsterdamGoogle Scholar
  27. Dhein J et al (1995) Autocrine T-cell suicide mediated by APO-1/(Fas/CD95). Nature 373(6513):438–441Google Scholar
  28. Dumollard R, Duchen M, Carroll J (2007) The role of mitochondrial function in the oocyte and embryo. Curr Top Dev Biol 77:21–49Google Scholar
  29. Dupont J, Scaramuzzi RJ (2016) Insulin signalling and glucose transport in the ovary and ovarian function during the ovarian cycle. Biochem J 473(11):1483–1501Google Scholar
  30. Eichenlaub-Ritter U et al (2004) Spindles, mitochondria and redox potential in aging oocytes. Reprod BioMed Online 8(1):45–58Google Scholar
  31. Eichenlaub-Ritter U et al (2011) Age related changes in mitochondrial function and new approaches to study redox regulation in mammalian oocytes in response to age or maturation conditions. Mitochondrion 11(5):783–796Google Scholar
  32. Farr SL et al (2004) Pesticide use and menstrual cycle characteristics among premenopausal women in the agricultural health study. Am J Epidemiol 160(12):1194–1204Google Scholar
  33. Filali M et al (2009) Oocyte in-vitro maturation: BCL2 mRNA content in cumulus cells reflects oocyte competency. Reprod BioMed Online 19:71–84Google Scholar
  34. Fragouli E, Wells D (2015) Mitochondrial DNA assessment to determine oocyte and embryo viability. In: Seminars in reproductive medicine. Thieme Medical Publishers, New YorkGoogle Scholar
  35. Fujino Y et al (1996) Ovary and ovulation: DNA fragmentation of oocytes in aged mice. Hum Reprod 11(7):1480–1483Google Scholar
  36. Garcia-Galiano D, Allen SJ, Elias CF (2014) Role of the adipocyte-derived hormone leptin in reproductive control. Horm Mol Biol Clin Invest 19(3):141–149Google Scholar
  37. Ge Z-J et al (2015) Oocyte aging and epigenetics. Reproduction 149(3):R103–R114Google Scholar
  38. Gerhart-Hines Z et al (2007) Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1α. EMBO J 26(7):1913–1923Google Scholar
  39. Gougeon A (1986) Dynamics of follicular growth in the human: a model from preliminary results. Hum Reprod 1(2):81–87Google Scholar
  40. Gougeon A (2005) The biological aspects of risks of infertility due to age: the female side. Rev Epidemiol Sante Publique 53:37–45Google Scholar
  41. Grabowski SR, Tortora GJ (2000) Principles of anatomy and physiology. Wiley, New York/ChichesterGoogle Scholar
  42. Grøndahl M et al (2010) Gene expression profiles of single human mature oocytes in relation to age. Hum Reprod 25(4):957–968Google Scholar
  43. Hall JE et al (2000) Decrease in gonadotropin-releasing hormone (GnRH) pulse frequency with aging in postmenopausal women. J Clin Endocrinol Metab 85(5):1794–1800Google Scholar
  44. Hamatani T et al (2004) Age-associated alteration of gene expression patterns in mouse oocytes. Hum Mol Genet 13(19):2263–2278Google Scholar
  45. Hasegawa K et al (2008) Sirt1 protects against oxidative stress-induced renal tubular cell apoptosis by the bidirectional regulation of catalase expression. Biochem Biophys Res Commun 372(1):51–56Google Scholar
  46. He W et al (2010) Sirt1 activation protects the mouse renal medulla from oxidative injury. J Clin Invest 120(4):1056–1068Google Scholar
  47. Hori YS et al (2013) Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress. PLoS One 8(9):e73875Google Scholar
  48. Huang J-C et al (2007) Changes in histone acetylation during postovulatory aging of mouse oocyte. Biol Reprod 77(4):666–670Google Scholar
  49. Itoh N et al (1991) The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66(2):233–243Google Scholar
  50. Iwamoto M et al (2005) Effects of caffeine treatment on aged porcine oocytes: parthenogenetic activation ability, chromosome condensation and development to the blastocyst stage after somatic cell nuclear transfer. Zygote 13(4):335–345Google Scholar
  51. Janny L, Menezo YJ (1996) Maternal age effect on early human embryonic development and blastocyst formation. Mol Reprod Dev 45(1):31–37Google Scholar
  52. Jensen TK et al (1999) Fecundability in relation to body mass and menstrual cycle patterns. Epidemiology 10(4):422–428Google Scholar
  53. Johnson MH, Everitt BJ (2000) Essential reproduction. Blackwell Science, Oxford, pp 69–87Google Scholar
  54. Ju ST et al (1995) Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 373(6513):444–448Google Scholar
  55. Jungheim ES, Moley KH (2010) Current knowledge of obesity's effects in the pre-and periconceptional periods and avenues for future research. Am J Obstet Gynecol 203(6):525–530Google Scholar
  56. Kao C-L et al (2010) Resveratrol protects human endothelium from H2O2-induced oxidative stress and senescence via SirT1 activation. J Atheroscler Thromb 17(9):970–979Google Scholar
  57. Kauppinen A et al (2013) Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal 25(10):1939–1948Google Scholar
  58. Kayagaki N et al (1995) Metalloproteinase-mediated release of human Fas ligand. J Exp Med 182(6):1777–1783Google Scholar
  59. Kirkwood T (1998) Ovarian aging and the general biology of senescence. Maturitas 30(2):105–111Google Scholar
  60. Kitagawa T et al (1993) Rapid accumulation of deleted mitochondrial deoxyribonucleic acid in postmenopausal ovaries. Biol Reprod 49(4):730–736Google Scholar
  61. Kujjo LL, Perez GI (2012) Ceramide and mitochondrial function in aging oocytes: joggling a new hypothesis and old players. Reproduction 143(1):1–10Google Scholar
  62. Lander HM et al (1997) Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem 272(28):17810–17814Google Scholar
  63. Lee H et al (2015) Prognostic and predictive values of EGFR overexpression and EGFR copy number alteration in HER2-positive breast cancer. Br J Cancer 112(1):103Google Scholar
  64. Li J et al (2017) Feedback inhibition of CREB signaling by p38 MAPK contributes to the negative regulation of steroidogenesis. Reprod Biol Endocrinol 15(1):19Google Scholar
  65. Liang H, Ward WF (2006) PGC-1α: a key regulator of energy metabolism. Adv Physiol Educ 30(4):145–151Google Scholar
  66. Lim J, Luderer U (2011) Oxidative damage increases and antioxidant gene expression decreases with aging in the mouse ovary. Biol Reprod 84(4):775–782Google Scholar
  67. Liu J et al (2012) Delay in oocyte aging in mice by the antioxidant N-acetyl-L-cysteine (NAC). Hum Reprod 27(5):1411–1420Google Scholar
  68. Lombard DB, Tishkoff DX, Bao J (2011) Mitochondrial sirtuins in the regulation of mitochondrial activity and metabolic adaptation. In: Histone Deacetylases: the Biology and Clinical Implication. Springer, Berlin, pp 163–188Google Scholar
  69. Louhio H et al (2000) The effects of insulin, and insulin-like growth factors I and II on human ovarian follicles in long-term culture. Mol Hum Reprod 6(8):694–698Google Scholar
  70. Luisi S et al (2005) Inhibins in female and male reproductive physiology: role in gametogenesis, conception, implantation and early pregnancy. Hum Reprod Update 11(2):123–135Google Scholar
  71. MacNaughton J et al (1992) Age related changes in follicle stimulating hormone, luteinizing hormone, oestradiol and immunoreactive inhibin in women of reproductive age. Clin Endocrinol 36(4):339–345Google Scholar
  72. Mamsen LS et al (2011) Germ cell numbers in human embryonic and fetal gonads during the first two trimesters of pregnancy: analysis of six published studies. Hum Reprod 26(8):2140–2145Google Scholar
  73. Manda K, Ueno M, Anzai K (2007) AFMK, a melatonin metabolite, attenuates X-ray-induced oxidative damage to DNA, proteins and lipids in mice. J Pineal Res 42(4):386–393Google Scholar
  74. Matsui M et al (1996) Early embryonic lethality caused by targeted disruption of the mouse thioredoxin gene. Dev Biol 178(1):179–185Google Scholar
  75. Matsumura R et al (1998) Glandular and extraglandular expression of the Fas-Fas ligand and apoptosis in patients with Sjogren’s syndrome. Clin Exp Rheumatol 16(5):561–568Google Scholar
  76. McReynolds S et al (2012) Impact of maternal aging on the molecular signature of human cumulus cells. Fertil Steril 98(6):1574–1580. e5Google Scholar
  77. Mehlmann LM (2005) Stops and starts in mammalian oocytes: recent advances in understanding the regulation of meiotic arrest and oocyte maturation. Reproduction 130(6):791–799Google Scholar
  78. Metwally M, Li T, Ledger WL (2007) The impact of obesity on female reproductive function. Obes Rev 8(6):515–523Google Scholar
  79. Mitsiades N et al (1998) Fas/Fas ligand up-regulation and Bcl-2 down-regulation may be significant in the pathogenesis of Hashimoto’s thyroiditis. J Clin Endocrinol Metab 83(6):2199–2203Google Scholar
  80. Monnot S et al (2013) Mutation dependance of the mitochondrial DNA copy number in the first stages of human embryogenesis. Hum Mol Genet 22(9):1867–1872Google Scholar
  81. Morris BJ (2013) Seven sirtuins for seven deadly diseases ofaging. Free Radic Biol Med 56:133–171Google Scholar
  82. Moschos S, Chan JL, Mantzoros CS (2002) Leptin and reproduction: a review. Fertil Steril 77(3):433–444Google Scholar
  83. Nemoto S, Fergusson MM, Finkel T (2005) SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. J Biol Chem 280(16):16456–16460Google Scholar
  84. Nestler JE (1997) Insulin regulation of human ovarian androgens. Hum Reprod 12(suppl_1):53–62Google Scholar
  85. Oktem O, Oktay K (2008) The ovary. Ann N Y Acad Sci 1127(1):1–9Google Scholar
  86. Oktem O, Urman B (2010) Understanding follicle growth in vivo. Hum Reprod 25(12):2944–2954Google Scholar
  87. Organization, W.H, W.H.O.M.o.S.A. Unit (2014) Global status report on alcohol and health, 2014. World Health Organization, GenevaGoogle Scholar
  88. Ottolenghi C et al (2004) Aging of oocyte, ovary, and human reproduction. Ann N Y Acad Sci 1034(1):117–131Google Scholar
  89. Pacella L et al (2012) Women with reduced ovarian reserve or advanced maternal age have an altered follicular environment. Fertil Steril 98(4):986–994. e2Google Scholar
  90. Pacella-Ince L, Zander-Fox D, Lane M (2014) Mitochondrial SIRT3 and its target glutamate dehydrogenase are altered in follicular cells of women with reduced ovarian reserve or advanced maternal age. Hum Reprod 29(7):1490–1499Google Scholar
  91. Perez GI, Tilly JL (1997) Cumulus cells are required for the increased apoptotic potential in oocytes of aged mice. Hum Reprod (Oxford, England) 12(12):2781–2783Google Scholar
  92. Perez GI et al (2000) Mitochondria and the death of oocytes. Nature 403(6769):500–501Google Scholar
  93. Perez GI et al (2005) A central role for ceramide in the age-related acceleration of apoptosis in the female germline. FASEB J 19(7):860–862Google Scholar
  94. Poulaki V, Mitsiades CS, Mitsiades N (2001) The role of Fas and FasL as mediators of anticancer chemotherapy. Drug Resist Updat 4(4):233–242Google Scholar
  95. Razi S et al (2016) Exposure to pistachio pesticides and stillbirth: a case-control study. Epidemiol Health 38:e2016016Google Scholar
  96. Richter T, von Zglinicki T (2007) A continuous correlation between oxidative stress and telomere shortening in fibroblasts. Exp Gerontol 42(11):1039–1042Google Scholar
  97. Robker RL et al (2009) Obese women exhibit differences in ovarian metabolites, hormones, and gene expression compared with moderate-weight women. J Clin Endocrinol Metab 94(5):1533–1540Google Scholar
  98. Robker RL, Wu LL-Y, Yang X (2011) Inflammatory pathways linking obesity and ovarian dysfunction. J Reprod Immunol 88(2):142–148Google Scholar
  99. Ruman J, Klein J, Sauer M (2003) Understanding the effects of age on female fertility. Minerva Ginecol 55(2):117–127Google Scholar
  100. Salmon AB, Richardson A, Pérez VI (2010) Update on the oxidative stress theory of aging: does oxidative stress play a role in aging or healthy aging? Free Radic Biol Med 48(5):642–655Google Scholar
  101. Sang Q et al (2013a) Identification of microRNAs in human follicular fluid: characterization of microRNAs that govern steroidogenesis in vitro and are associated with polycystic ovary syndrome in vivo. J Clin Endocrinol Metab 98(7):3068–3079Google Scholar
  102. Sang Q et al (2013b) Identification of microRNAs in human follicular fluid: characterization of microRNAs that govern steroidogenesis in vitro and are associated with polycystic ovary syndrome in vivo. J Clin Endocrinol Metab 98(7):3068–3079Google Scholar
  103. Santonocito M et al (2014) Molecular characterization of exosomes and their microRNA cargo in human follicular fluid: bioinformatic analysis reveals that exosomal microRNAs control pathways involved in follicular maturation. Fertil Steril 102(6):1751–1761. e1Google Scholar
  104. Santoro N et al (1998) Effects of aging and gonadal failure on the hypothalamic-pituitary axis in women. Am J Obstet Gynecol 178(4):732–741Google Scholar
  105. Sastre J et al (2002) Mitochondrial damage in aging and apoptosis. Ann N Y Acad Sci 959(1):448–451Google Scholar
  106. Scaglia H et al (1976) Pituitary LH and FSH secretion and responsiveness in women of old age. Acta Endocrinol 81(3):673–679Google Scholar
  107. Schettler T et al (1997) Generations at risk: how environmental toxicants may affect reproductive health in California. In: Generations at risk: how environmental toxicants may affect reproductive health in California. PSR. CALPIRG Charitable Trust, San FranciscoGoogle Scholar
  108. Selesniemi K et al (2011) Prevention of maternal aging-associated oocyte aneuploidy and meiotic spindle defects in mice by dietary and genetic strategies. Proc Natl Acad Sci U S A 108(30):12319–12324Google Scholar
  109. Shah DK et al (2011) Effect of obesity on oocyte and embryo quality in women undergoing in vitro fertilization. Obstet Gynecol 118(1):63–70Google Scholar
  110. Sliwowska JH et al (2014) Insulin: its role in the central control of reproduction. Physiol Behav 133:197–206Google Scholar
  111. Song C et al (2016) Melatonin improves age-induced fertility decline and attenuates ovarian mitochondrial oxidative stress in mice. Sci Rep 6:35165Google Scholar
  112. Sørensen AE et al (2016) MicroRNA species in follicular fluid associating with polycystic ovary syndrome and related intermediary phenotypes. J Clin Endocrinol Metab 101(4):1579–1589Google Scholar
  113. Stanford JS et al (2003) Regulation of the G2/M transition in oocytes of Xenopus tropicalis. Dev Biol 260(2):438–448Google Scholar
  114. Sukapan P et al (2014) Types of DNA methylation status of the interspersed repetitive sequences for LINE-1, Alu, HERV-E and HERV-K in the neutrophils from systemic lupus erythematosus patients and healthy controls. J Hum Genet 59(4):178Google Scholar
  115. Takeo S et al (2017) Age-associated deterioration in follicular fluid induces a decline in bovine oocyte quality. Reprod Fertil Dev 29(4):759–767Google Scholar
  116. Tamura H et al (2008) Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate. J Pineal Res 44(3):280–287Google Scholar
  117. Tanaka M et al (1995) Expression of the functional soluble form of human fas ligand in activated lymphocytes. EMBO J 14(6):1129–1135Google Scholar
  118. Tarlatzis BC, Zepiridis L (2003) Perimenopausal conception. Ann N Y Acad Sci 997(1):93–104Google Scholar
  119. Tatar M, Bartke A, Antebi A (2003) The endocrine regulation of aging by insulin-like signals. Science 299(5611):1346–1351Google Scholar
  120. Tatone C, Amicarelli F (2013) The aging ovary—the poor granulosa cells. Fertil Steril 99(1):12–17Google Scholar
  121. Tatone C et al (2008a) Cellular and molecular aspects of ovarian follicle aging. Hum Reprod Update 14(2):131–142Google Scholar
  122. Tatone C et al (2008b) Cellular and molecular aspects of ovarian follicle aging. Hum Reprod Update 14(2):131–142Google Scholar
  123. Tatone C et al (2010) Female reproductive dysfunction during aging: role of methylglyoxal in the formation of advanced glycation endproducts in ovaries of reproductively-aged mice. J Biol Regul Homeost Agents 24(1):63–72Google Scholar
  124. Tortoriello DV, McMinn J, Chua SC (2004) Dietary-induced obesity and hypothalamic infertility in female DBA/2J mice. Endocrinology 145(3):1238–1247Google Scholar
  125. Trikudanathan S (2015) Polycystic ovarian syndrome. Med Clin North Am 99(1):221–235Google Scholar
  126. Tumaneng K et al (2012) YAP mediates crosstalk between the Hippo and PI (3) K–TOR pathways by suppressing PTEN via miR-29. Nat Cell Biol 14(12):1322Google Scholar
  127. van Birgelen AP et al (1999) Toxicity of 3, 3′, 4, 4′-tetrachloroazoxybenzene in rats and mice. Toxicol Appl Pharmacol 156(3):206–221Google Scholar
  128. Van Blerkom J (2004) Mitochondria in human oogenesis and preimplantation embryogenesis: engines of metabolism, ionic regulation and developmental competence. Reproduction 128(3):269–280Google Scholar
  129. Van Blerkom J (2011) Mitochondrial function in the human oocyte and embryo and their role in developmental competence. Mitochondrion 11(5):797–813Google Scholar
  130. Van Blerkom J, Cox H, Davis P (2006) Regulatory roles for mitochondria in the peri-implantation mouse blastocyst: possible origins and developmental significance of differential Δψm. Reproduction 131(5):961–976Google Scholar
  131. Vanderhyden BC, Armstrong DT (1989) Role of cumulus cells and serum on the in vitro maturation, fertilization, and subsequent development of rat oocytes. Biol Reprod 40(4):720–728Google Scholar
  132. Wallace IR et al (2013) Sex hormone binding globulin and insulin resistance. Clin Endocrinol 78(3):321–329Google Scholar
  133. Wang X (2001) The expanding role of mitochondria in apoptosis. Genes Dev 15(22):2922–2933Google Scholar
  134. Wanichnopparat W et al (2013) Genes associated with the cis-regulatory functions of intragenic LINE-1 elements. BMC Genomics 14(1):205Google Scholar
  135. Watson LN et al (2012) Heparan sulfate proteoglycans regulate responses to oocyte paracrine signals in ovarian follicle morphogenesis. Endocrinology 153(9):4544–4555Google Scholar
  136. Whittingham DG, Siracusa G (1978) The involvement of calcium in the activation of mammalian oocytes. Exp Cell Res 113(2):311–317Google Scholar
  137. Wise PM et al (1997) Aging of the female reproductive system: a window into brain aging. Recent Prog Horm Res 52:279–303; discussion 303-5Google Scholar
  138. Wu YG et al (2007) The effects of delayed activation and MG132 treatment on nuclear remodeling and preimplantation development of embryos cloned by electrofusion are correlated with the age of recipient cytoplasts. Cloning Stem Cells 9(3):417–431Google Scholar
  139. Xu S et al (2011) Micro-RNA378 (miR-378) regulates ovarian estradiol production by targeting aromatase. Endocrinology 152(10):3941–3951Google Scholar
  140. Yanagimachi R, Chang MC (1961) Fertilizable life of golden hamster ova and their morphological changes at the time of losing fertilizability. J Exp Zool 148:185–203Google Scholar
  141. Yeung F et al (2004) Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 23(12):2369–2380Google Scholar
  142. Yin M et al (2012) Transactivation of microRNA-383 by steroidogenic factor-1 promotes estradiol release from mouse ovarian granulosa cells by targeting RBMS1. Mol Endocrinol 26(7):1129–1143Google Scholar
  143. Yooyongsatit S et al (2015) Patterns and functional roles of LINE-1 and Alu methylation in the keratinocyte from patients with psoriasis vulgaris. J Hum Genet 60(7):349Google Scholar
  144. Younglai EV, Holloway AC, Foster WG (2005) Environmental and occupational factors affecting fertility and IVF success. Hum Reprod Update 11(1):43–57Google Scholar
  145. Zhao C et al (2011) Early second-trimester serum miRNA profiling predicts gestational diabetes mellitus. PLoS One 6(8):e23925Google Scholar
  146. Zhu J et al (2015a) Cumulus cells accelerate oocyte aging by releasing soluble Fas ligand in mice. Sci Rep 5:8683Google Scholar
  147. Zhu J et al (2015b) Cumulus cells accelerate oocyte aging by releasing soluble Fas ligand in mice. Sci Rep 5:8683Google Scholar
  148. Zhu J et al (2016) The signaling pathways by which the Fas/FasL system accelerates oocyte aging. Aging (Albany NY) 8(2):291–303Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Toka A. Ahmed
    • 1
  • Sara M. Ahmed
    • 1
  • Zaynab El-Gammal
    • 1
  • Shaimaa Shouman
    • 1
  • Ashrakat Ahmed
    • 1
  • Ragaa Mansour
    • 2
  • Nagwa El-Badri
    • 1
    Email author
  1. 1.Center of excellence for stem cells and Regenerative MedicineZewail City of Science and TechnologyGizaEgypt
  2. 2.The Egyptian IVF-ET CenterCairoEgypt

Personalised recommendations