Connecting links between genetic factors defining ovarian reserve and recurrent miscarriages

  • Deepika Delsa Dean
  • Sarita Agarwal
  • Poonam Tripathi



Approximately 1–2% of the women faces three or more successive spontaneous miscarriages termed as recurrent miscarriage (RM). Many clinical factors have been attributed so far to be the potential risk factors in RM, including uterine anomalies, antiphospholipid syndrome, endocrinological abnormalities, chromosomal abnormalities, and infections. However, in spite of extensive studies, reviews, and array of causes known to be associated with RM, about 50% cases encountered by treating physicians remains unknown. The aims of this study were to evaluate recent publications and to explore oocyte-specific genetic factors that may have role in incidence of recurrent miscarriages.


Recent studies have identified common molecular factors contributing both in establishment of ovarian reserve and in early embryonic development. Also, studies have pointed out the relationship between the age-associated depletion of OR and increase in the risk of miscarriages, thus suggestive of an interacting biology. Here, we have gathered literature evidences in establishing connecting links between genetic factors associated with age induced or pathological OR depletion and idiopathic RM, which are the two extreme ends of female reproductive pathology.


In light of connecting etiological link between infertility and RM as reviewed in this study, interrogating the oocyte-specific genes with suspected roles in reproductive biology, in cases of unexplained RM, may open new possibilities in widening our understanding of RM pathophysiology.


Recurrent miscarriages Ovarian reserve Premature ovarian insufficiency Genetic Factors 



The author is thankful Council of Science and Industrial Research (CSIR)–New Delhi for providing her fellowship.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Royal College of Obstetricians and Gynaecologists (RCOG). The investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage. Green-top Guideline No. 17. Royal College of Obstetricians and Gynaecologists (RCOG), 2011.Google Scholar
  2. 2.
    Coulam CB. Epidemiology of recurrent spontaneous abortion. Am J Reprod Immunol. 1991;26:23–7.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Royal College of Obstetricians and Gynaecologists, Scientific Advisory Committee, Guideline No. 17. The Investigation and treatment of couples with recurrent miscarriage. 2011.Google Scholar
  4. 4.
    Macklon NS, Geraedts JP, Fauser BC. Conception to ongoing pregnancy: the 'black box' of early pregnancy loss. Hum Reprod Update. 2002;8(4):333–43.CrossRefPubMedGoogle Scholar
  5. 5.
    McNamee K, Dawood F, Farquharson R. Recurrent miscarriage and thrombophilia: an update. Curr Opin Obstet Gynecol. 2012;24:229–34.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Duckitt K, Qureshi A. Recurrent miscarriage. Clin Evid. 2011;2:1409.Google Scholar
  7. 7.
    American College of Obstetrics and Gynecologists Committee on Practice Bulletins: ACOG Practice Bulletin. Paper 40. Obstet Gynecol 2011.Google Scholar
  8. 8.
    Cohn DM, Goddijn M, Middeldorp S, et al. Recurrent miscarriage and antiphospholipid antibodies: prognosis of subsequent pregnancy. J Thromb Haemost. 2010;8:2208–13.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Patel BG, Lessey BA. Clinical assessment and management of the endometrium in recurrent early pregnancy loss. Semin Reprod Med. 2011;29:491–506.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Management of Recurrent Early Pregnancy Loss. Washington, DC: The American College of Obstetricians and Gynecologists; 2001. The American College of Obstetricians and Gynecologists. (ACOG Practice Bulletin No. 24).Google Scholar
  11. 11.
    Ali O, Hakimi I, Chanana A, et al. Grossesse sur utérus cloisonné menée à terme: à propos d’un cas avec revue de la literature. The Pan African Medical Journal. 2015;22:219.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Pluchino N, Drakopoulos P, Wenger JM, Petignat P, Streuli I, Genazzani AR. Hormonal causes of recurrent pregnancy loss (RPL). Hormones (Athens). 2014;13(3):314–22.CrossRefGoogle Scholar
  13. 13.
    Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98(5):1103–11.CrossRefGoogle Scholar
  14. 14.
    Jovanovic L, Knopp H, Kim H, et al. Elevated pregnancy losses at high and low extremes of maternal glucose in early normal and diabetic pregnancies: evidence for a protective adaptation in diabetes. Diabetes Care. 2005;28(5):1113–7.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Cleary-Goldman J, Malone FD, Lambert-Messerlian G, Sullivan L, Canick J, Porter TF, et al. Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol. 2008;112(1):85–92.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Sarkar D. Recurrent pregnancy loss in patients with thyroid dysfunction. Indian Journal of Endocrinology and Metabolism. 2012;16(2):S350–1.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Shah D, Nagarajan N. Luteal insufficiency in first trimester. Indian Journal of Endocrinology and Metabolism. 2013;17(1):44–9.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Laurino MY, Bennett RL, Saraiya DS, Baumeister L, Doyle DL, Leppig K, et al. Genetic evaluation and counseling of couples with recurrent miscarriage: recommendations of the National Society of genetic counselors. J Genet Couns. 2005;14(3):165–81.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Stephenson MD, Sierra S. Reproductive outcomes in recurrent pregnancy loss associated with a parental carrier of a structural chromosome rearrangement. Hum Reprod. 2006;21(4):1076–82.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Carp H, Guetta E, Dorf H, Soriano D, Barkai G, Schiff E. Embryonic karyotype in recurrent miscarriage with parental karyotypic aberrations. Fertil Steril. 2006;85(2):446–50.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Benedetto C, Tibaldi C, Marozio L, Marini S, Masuelli G, Pelissetto S, et al. Cervicovaginal infections during pregnancy: epidemiological and microbiological aspects. J Matern Fetal Neonatal Med. 2004;16(2):9–12.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Srinivas SK, Ma Y, Sammel MD, Chou D, McGrath C, Parry S, et al. Placental inflammation and viral infection are implicated in second trimester pregnancy loss. Am J Obstet Gynecol. 2006;195:797–802.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Katz-Jaffe MG, Surrey ES, Minjarez DA, Gustofson RL, Stevens JM, Schoolcraft WB.Google Scholar
  24. 24.
    Association of abnormal ovarian reserve parameters with a higher incidence of aneuploid blastocysts. Obstet Gynecol. 2013 ; 121(1):71–7.Google Scholar
  25. 25.
    Matthews TJ, Hamilton BE. Delayed childbearing: more women are having their first child later in life. NCHS Data Brief. 2009;21:1–8.Google Scholar
  26. 26.
    Nybo Anderson AM, Wohlfahrt J, Christens P, et al. Maternal age and fetal loss: population based register linkage study. BMJ. 2000;320:1708–12.CrossRefGoogle Scholar
  27. 27.
    Hassold T, Hall H, Hunt P. The origin of human aneuploidy: where we have been, where we are going. Hum Mol Genet. 2007;16:R203–8.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Nagaoka SI, Hassold TJ, Hunt PA. Human aneuploidy: mechanisms and new insights into an age-old problem. Nat Rev Genet. 2012;13:493–504.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Quenby S, Vince G, Farquharson R, Aplin J. OPINION Recurrent miscarriage: A defect in nature's quality control? Hum Reprod. Aug. 2002;17(8):1959–63.Google Scholar
  30. 30.
    Choi TY, Lee HM, Park WK, Jeong SY, Moon HS. Spontaneous abortion and recurrent miscarriage: a comparison of cytogenetic diagnosis in 250 cases. Obstet Gynecol Sci. 2014;57:518–25.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Kwinecka-Dmitriew B, Zakrzewska M, Latos-Bieleńska A, Skrzypczak J. Frequency of chromosomal aberrations in material from abortions. Ginekol Pol. 2010;81(12):896–901.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Wang YA, Farquhar C, Sullivan EA. Donor age is a major determinant of success of oocyte donation/recipient programme. Hum Reprod. 2012;27(1):118–25.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Sauer MV, Paulson RJ, Lobo RA. Pregnancy after age 50: application of oocyte donation to women after natural menopause. Lancet. 1993;341:321–3.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Sauer MV, Paulson RJ, Lobo RA. Pregnancy in women 50 or more years of age: outcomes of 22 consecutively established pregnancies from oocyte donation. Fertil Steril. 1995;64:111–5.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Antinori S, Versaci C, Gholami GH, Panci C, Caffa B. Oocyte donation in menopausal women. Hum Reprod. 1993;8:1487–90.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Check JH, Nowroozi K, Barnea ER, Shaw KJ, Sauer MV. Successful delivery after age 50: a report of two cases as a result of oocyte donation. Obstet Gynecol. 1993;81:835–6.PubMedGoogle Scholar
  37. 37.
    Sills ES, Anthony MM, Walsh PH. Ovarian reserve screening in infertility: practical applications and theoretical directions for research. Eur J Obstet Gynecol Reprod Biol. 2009;146(1):30–6.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    May-Panloup P, Ferré-L'Hôtellier V, Morinière C, Marcaillou C, Lemerle S, Malinge MC, et al. Molecular characterization of corona radiata cells from patients with diminished ovarian reserve using microarray and microfluidic-based gene expression profiling. Hum Reprod. 2012;27(3):829–43.PubMedCrossRefGoogle Scholar
  39. 39.
    El Toukhy T, Khalaf Y, Hart R, Taylor A. Braude P; young age does not protect against the adverse effects of reduced ovarian reserve—an eight year study. Hum Reprod. 2002;17(6):1519–24.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Maroulis GB. Effect of aging on fertility and pregnancy. Semin Reprod Endocrinol. 1991;9:165–75.CrossRefGoogle Scholar
  41. 41.
    Volarcik K, Sheean L, Goldfarb J, Woods L, Abdul-Karim FW, Hunt P. The meiotic competence of in-vitro matured human oocytes is influenced by donor age: evidence that folliculogenesis is compromised in the reproductively aged ovary. Hum Reprod. 1998;13:154–60.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Delhanty JD. Mechanisms of aneuploidy induction in human oogenesis and early embryogenesis. Cytogenet Genome Res. 2005;111:237–44. 192PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Pellestor F, Andre’ OB, Anahory T, Hamamah S. The occurrence of aneuploidy in human: lessons from the cytogenetic studies of human oocytes. Eur J Med Genet. 2006;49:103–16. 193PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Tsutsumi M, Fujiwara R, Nishizawa H, Ito M, Kogo H, Inagaki H, et al. Agerelated decrease of meiotic cohesins in human oocytes. PLoS One. 2014;9:e96710.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Atasever M, Soyman Z, Demirel E, Gencdal S, Kelekci S. Diminished ovarian reserve: is it a neglected cause in the assessment of recurrent miscarriage? A cohort study. Fertil Steril. 2016;105(5):1236–40.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Hansen KR, Knowlton NS, Thyer AC, Charleston JS, Soules MR, Klein NA. A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause. Hum Reprod. 2008;23:699–708.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Wallace WH, Kelsey TW. Human ovarian reserve from conception to the menopause. PLoS One. 2010;5(1):e8772.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Oktem O, Urman B. Understanding follicle growth in vivo. Hum Reprod. 2010;25(12):2944–54. ReviewCrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Ottolenghi C, Uda M, Hamatani T, Crisponi L, Garcia JE, KoM PG, et al. Aging of oocyte, ovary, and human reproduction. Ann N Y Acad Sci. 2004;1034:117–31.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Broekmans FJ, Knauff EA, te Velde ER, Macklon NS, Fauser BC. Female reproductive ageing: current knowledge and future trends. Trends Endocrinol Metab. 2007;18:58–65.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Chapman C, Cree L, Shelling AN. The genetics of premature ovarian failure: current perspectives. Int J Womens Health. 2015;7:799–810.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Qin Y, Jiao X, Simpson JL. Chen ZJ genetics of primary ovarian insufficiency: new developments and opportunities. Hum Reprod Update. 2015;21(6):787–808.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Hakim RB, Gray RH, Zacur H. Infertility and early pregnancy loss. Obstet Gynecol. 1995;172(5):1510–7.Google Scholar
  54. 54.
    Coulam CB. Association between infertility and spontaneous abortion. Am J Reprod Immunol. 1992;27(3–4):128–9.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Molo MW, Kelly M, Balos R, Mullaney K, Radwanska E. Incidence of fetal loss in infertility patients after detection of fetal heart activity with early transvaginal ultrasound. J Reprod Med. 1993;38(10):804–6.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Liu HC, Rosenwaks Z. Early pregnancy wastage in IVF (in vitro fertilization) patients. J In Vitro Fert Embryo Transf. 1991;8(2):65–72.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Cocksedge KA, Li TC, Saravelos SH, Metwally MA. Reappraisal of the role of polycystic ovary syndrome in recurrent miscarriage. Reprod BioMed Online. 2008;17(1):151–60.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Trogstad L, Magnus P, Moffett A, Stoltenberg C. The effect of recurrent miscarriage and infertility on the risk of pre-eclampsia. BJOG. 2009;116(1):108–13.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol. 1986;67:604–6.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Torrealday S, Kodaman P, Pal L. Premature Ovarian Insufficiency - an update on recent advances in understanding and management. F1000Research. 2017;6:2069.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Sato Y, Kawamura N, Kawamura K. Infertility Treatment in Primary Ovarian Insufficiency: Fertility Preservation and In Vitro Activation. J Gynecol Women’s Health. 2017; 7(1): JGWH.MS.ID.555704.Google Scholar
  62. 62.
    Qin Y, Choi Y, Zhao H, Simpson JL, Chen ZJ, Rajkovic A. NOBOX homeobox mutation causes premature ovarian failure. Am J Hum Genet. 2007;81(3):576–81.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Lourenço D, Brauner R, Lin L, De Perdigo A, Weryha G, et al. Mutations in NR5A1 associated with ovarian insufficiency. N Engl J Med. 2009;360(12):1200–10.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Rah H, Jeon YJ, Ko JJ, Kim JH, Kim YR, Cha SH, et al. Association of inhibin α gene promoter polymorphisms with risk of idiopathic primary ovarian insufficiency in Korean women. Maturitas. 2014;77(2):163–7.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Chand AL, Ponnampalam AP, Harris SE, et al. Mutational analysis of BMP15 and GDF9 as candidate genes for premature ovarian failure. Fertil Steril. 2006;86(4):1009–12.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Di Pasquale E, Beck-Peccoz P, Persani L. Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein- 15 (BMP15) gene. Am J Hum Genet. 2004;75(1):106–11.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Santos MG, Machado AZ, Martins CN, et al. Homozygous Inactivating Mutation in NANOS3 in Two Sisters with Primary Ovarian Insufficiency. Biomed Res Int. 2014;2014(787465):8.Google Scholar
  68. 68.
    Wu X, Wang B, Dong Z, Zhou S, Liu Z, Shi G, et al. A NANOS3 mutation linked to protein degradation causes premature ovarian insufficiency. Cell Death Dis. 2013;4:e825.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Tucker EJ, Grover SR, Bachelot A, Touraine P, Sinclair AH. Premature ovarian insufficiency: new perspectives on genetic cause and phenotypic Spectrum. Endocr Rev. 2016;37(6):609–35.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Fonseca DJ, Patiño LC, Suárez YC, et al. Next generation sequencing in women affected by nonsyndromic premature ovarian failure displays new potential causative genes and mutations. Fertil Steril. 2015;104(1):154–62. e2PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Aittomäki K, Lucena JL, Pakarinen P, et al. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell. 1995;82(6):959–68.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Caburet S, Arboleda VA, Llano E, Overbeek PA, Barbero JL, Oka K, et al. Mutant cohesin in premature ovarian failure. N Engl J Med. 2014;370(10):943–9.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Takebayashi K, Takakura K, Wang H, Kimura F, et al. Mutation analysis of the growth differentiation factor-9 and −9B genes in patients with premature ovarian failure and polycystic ovary syndrome. Fertil Steril. 2000;74:976–9.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Di Pasquale E, Rossetti R, Marozzi A, Bodega B, et al. Identification of new variants of human BMP15 gene in a large cohort of women with premature ovarian failure. J Clin Endocrinol Metab. 2006;91(5):1976–9.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Dixit H, Rao LK, Padmalatha V, Kanakavalli M, Deenadayal M, Gupta N, et al. Mutational screening of the coding region of growth differentiation factor 9 gene in Indian women with ovarian failure. Menopause. 2005;12(6):749–54.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Persani L, Rossetti R, Cacciatore C. Genes involved in human premature ovarian failure. J Mol Endocrinol. 2010;45(5):257–79.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Tiotiu D, Alvaro Mercadal B, Imbert R, Verbist J, Demeestere I, de Leener A, et al. Variants of the BMP15 gene in a cohort of patients with premature ovarian failure. Hum Reprod. 2010;25(6):1581–7.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Auclair S, Rossetti R, Meslin C, Monestier O, di Pasquale E, Pascal G, et al. Positive selection in bone morphogenetic protein 15 targets a natural mutation associated with primary ovarian insufficiency in human. PLoS One. 2013;8(10):e78199.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Ferrarini E, Russo L, Fruzzetti F, Agretti P, De Marco G, et al. Clinical characteristics and genetic analysis in women with premature ovarian insufficiency. Maturitas. 2013;74(1):61–7.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Dixit H, Rao LK, Padmalatha VV, Kanakavalli M, et al. Missense mutations in the BMP15 gene are associated with ovarian failure. Hum Genet. 2006;119(4):408–15.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Laissue P, Christin-Maitre S, Touraine P, Kuttenn F, Ritvos O, Aittomaki K, et al. Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure. Eur J Endocrinol. 2006;154(5):739–44.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Kovanci E, Rohozinski J, Simpson JL, Heard MJ, et al. Growth differentiating factor-9 mutations may be associated with premature ovarian failure. Fertil Steril. 2007;87(1):143–6.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Wang TT, Ke ZH, Song Y, Chen LT, Chen XJ, Feng C, et al. Identification of a mutation in GDF9 as a novel cause of diminished ovarian reserve in young women. Hum Reprod. 2013;28(9):2473–81.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Simpson CM, Robertson DM, Al-Musawi SL, Heath DA, et al. Aberrant GDF9 expression and activation are associated with common human ovarian disorders. J Clin Endocrinol Metab. 2014;99(4):E615–24.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Gode F, Gulekli B, Dogan E, Korhan P, Dogan S, Bige O, et al. Influence of follicular fluid GDF9 and BMP15 on embryo quality. Fertil Steril. 2011;95(7):2274–8.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Wu Y-T, Tang L, Cai J, Lu X-E, Xu J, Zhu X-M, et al. High bone morphogenetic protein-15 level in follicular fluid is associated with high quality oocyte and subsequent embryonic development. Hum Reprod. 2007;22(6):1526–31.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Li Y, Li RQ, Ou SB, Zhang NF, Ren L, Wei LN, et al. Increased GDF9 and BMP15 mRNA levels in cumulus granulosa cells correlate with oocyte maturation, fertilization, and embryo quality in humans. Reprod Biol Endocrinol. 2014;12:81.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Lee MT, Bonneau AR, Giraldez AJ. Zygotic genome activation during the maternal-to-zygotic transition. Annu Rev Cell Dev Biol. 2014;30:581–613.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Tadros W, Lipshitz HD. The maternal-to-zygotic transition: a play in two acts. Development. 2009;136:3033–42. Scholar
  90. 90.
    Langley AR, Smith JC, Stemple DL, Harvey SA. New insights into the maternal to zygotic transition. Development. 2014;141:3834–41.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Lu X, Gao Z, Qin D, Li L. A maternal functional module in the mammalian oocyte-to-embryo transition. Trends Mol Med. 2017;23(11):1014–23.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Matzuk MM, Burns KH, Viveiros MM, Eppig JJ. Intercellular communication in the mammalian ovary: oocytes carry the conversation. Science. 2002;296:2178–80.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Bettegowda A, Lee KB, Smith GW. Cytoplasmic and nuclear determinants of the maternal-to-embryonic transition. Reprod Fertil Dev. 2008;20(1):45–53.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Flach G, Johnson MH, Braude PR, Taylor RA, Bolton VN. The transition from maternal to embryonic control in the 2-cell mouse embryo. EMBO J. 1982;1:681–6.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Li L, Zheng P, Dean J. Maternal control of early mouse development. Development. 2010;137(6):859–70.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Huang JY, Su M, Lin SH, Kuo PL. A genetic association study of NLRP2 and NLRP7genes in idiopathic recurrent miscarriage. Hum Reprod. 2013;28(4):1127–34.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Qian J, Nguyen NMP, Rezaei M, Huang B, Tao Y, Zhang XF, et al. Biallelic PADI6 variants linking infertility, miscarriages, and hydatidiform moles. Eur J Hum Genet. 2018;26(7):1007–13.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Fogarty NME, McCarthy A, Snijders KE, Powell BE, Kubikova N, Blakeley P, et al. Genome editing reveals a role for OCT4 in human embryogenesis. Nature. 2017;550(7674):67–73.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Zhang P, Dixon M, Zucchelli M, Hambiliki F, Levkov L, Hovatta O, et al. Expression analysis of the NLRP gene family suggests a role in human preimplantation development. PLoS One. 2008;3(7):e2755.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Li L, Baibakov B, Dean J. A subcortical maternal complex essential for preimplantation mouse embryogenesis. Dev Cell. 2008;15(3):416–25.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Zhu K, Yan L, Zhang X, Lu X, Wang T, Yan J, et al. Identification of a human subcortical maternal complex. Mol Hum Reprod. 2015;21(4):320–9.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Wu G, Schöler HR. Role of Oct4 in the early embryo development. Cell Regeneration. 2014;3(1):7.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Joshi S, Davies H, Sims LP, Levy SE, Dean J. Ovarian gene expression in the absence of FIGLA, an oocyte-specific transcription factor. BMC Dev Biol. 2007;7:67.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Choi Y, Qin Y, Berger M, Ballow D, et al. Microarray analyses of newborn mouse ovaries lacking Nobox. Biol Reprod. 2007;77(2):312–9.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Choi Y, Rajkovic A. Characterization of NOBOX DNA binding specificity and its regulation of Gdf9 and Pou5f1 promoters. J Biol Chem. 2006;281(47):35747–56.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Tsuda M, Sasaoka Y, Kiso M, Abe K, Haraguchi S, Kobayashi S, et al. Conserved role of nanos proteins in germ cell development. Science. 2003;301:1239–41.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Stephanie A. Pangas, Aleksandar Rajkovic; transcriptional regulation of early oogenesis: in search of masters. Hum Reprod Update. 2006;12(1):65–76.CrossRefGoogle Scholar
  108. 108.
    Rajkovic A, Pangas SA, Ballow D, Suzumori N, Matzuk MM. NOBOX deficiency disrupts early folliculogenesis and oocyte-specific gene expression. Science. 2004;305:1157–9.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Tripurani SK, Lee K-B, Wang L, Wee G, Smith GW, Lee YS, et al. A novel functional role for the oocyte-specific transcription factor newborn ovary Homeobox (NOBOX) during early embryonic development in cattle. Endocrinology. 2011;152(3):1013–23.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Lim E-J, Choi Y. Transcription factors in the maintenance and survival of primordial follicles. Clinical and Experimental Reproductive Medicine. 2012;39(4):127–31. Scholar
  111. 111.
    Shin YH, Ren Y, Suzuki H, Golnoski KJ, Ahn HW, Mico V, et al. Transcription factors SOHLH1 and SOHLH2 coordinate oocyte differentiation without affecting meiosis I. J Clin Invest. 2017;127(6):2106–17. Scholar
  112. 112.
    Pangas SA, Choi Y, Ballow DJ, Zhao Y, Westphal H, Matzuk MM, et al. Oogenesis requires germ cell-specific transcriptional regulators Sohlh1 and Lhx8. Proc Natl Acad Sci U S A. 2006;103(21):8090–5. Scholar
  113. 113.
    Bouilly J, Beau I, Barraud S, Bernard V, Azibi K, Fagart J, et al. Identification of multiple gene mutations accounts for a new genetic architecture of primary ovarian insufficiency. J Clin Endocrinol Metab. 2016;101(12):4541–50.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Zhao S, Li G, Dalgleish R, Vujovic S, Jiao X, Li J, et al. Transcription factor SOHLH1 potentially associated with primary ovarian insufficiency. Fertil Steril. 2015;103(2):548–53. e5PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Qin Y, Jiao X, Dalgleish R, Vujovic S, Li J, et al. Novel variants in the SOHLH2 gene are implicated in human premature ovarian failure. Fertil Steril. 2014;101(4):1104–9. e6PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Ferrari I, Bouilly J, Beau I, Guizzardi F, Ferlin A, Pollazzon M, et al. Impaired protein stability and nuclear localization of NOBOX variants associated with premature ovarian insufficiency. Hum Mol Genet. 2016;25(23):5223–33.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Li L, Wang B, Zhang W, Chen B, Luo M, Wang J, et al. A homozygous NOBOX truncating variant causes defective transcriptional activation and leads to primary ovarian insufficiency. Hum Reprod. 2017;32(1):248–55.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Jiao X, Qin Y, Li G et al. Novel NR5A1 Missense Mutation in Premature Ovarian Failure: Detection in Han Chinese Indicates Causation in Different Ethnic Groups. Sun Q-Y, ed. PLoS ONE. 2013; 8(9):e74759.Google Scholar
  119. 119.
    Tosh D, Rani HS, Murty US, Deenadayal A, Grover P. Mutational analysis of the FIGLA gene in women with idiopathic premature ovarian failure. Menopause. 2015;22(5):520–6.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Liu L, Rajareddy S, Reddy P, du C, Jagarlamudi K, Shen Y, et al. Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a. Development. 2007;134:199–209.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Cunningham MA, Zhu Q, Hammond JM. FoxO1a can alter cell cycle progression by regulating the nuclear localization of p27kip in granulosa cells. Mol Endocrinol. 2004;18:1756–67.PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Vinci G, Christin-Maitre S, Pasquier M, et al. FOXO3a variants in patients with premature ovarian failure. Clin Endocrinol. 2008;68:495–7.Google Scholar
  123. 123.
    Watkins WJ, Umbers AJ, Woad KJ, Harris SE, et al. Mutational screening of FOXO3A and FOXO1A in women with premature ovarian failure. Fertil Steril. 2006;5:1518–21.CrossRefGoogle Scholar
  124. 124.
    Pisarska MD, Bae J, Klein C, Aaron J, Hsueh W. Forkhead L2 Is Expressed in the Ovary and Represses the Promoter Activity of the Steroidogenic Acute Regulatory Gene. Endocrinology. 2004;145(7):3424–33.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Crisponi L, Deiana M, Loi A, Chiappe F, Uda M, Amati P, et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet. 2001;27:159–66.PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Méduri G, Bachelot A, Duflos C, et al. FOXL2 mutations lead to different ovarian phenotypes in BPES patients: case report. Hum Reprod. 2010;25:235–43.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Nallathambi J, Moumné L, De Baere E, et al. A novel polyalanine expansion in FOXL2: the first evidence for a recessive form of the blepharophimosis syndrome (BPES) associated with ovarian dysfunction. Hum Genet. 2007;121:107–12.PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Harris SE, Chand AL, Winship IM, Gersak K, Aittomäki K, Shelling AN. Identification of novel mutations in FOXL2 associated with premature ovarian failure. Mol Hum Reprod. 2002;8(8):729–33.PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Laissue P, Lakhal B, Benayoun BA, Dipietromaria A, Braham R, Elghezal H, et al. Functional evidence implicating FOXL2 in non-syndromic premature ovarian failure and in the regulation of the transcription factor OSR2. J Med Genet. 2009;46:455–7.PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Salker M, Teklenburg G, Molokhia M et al. Natural Selection of Human Embryos: Impaired Decidualization of Endometrium Disables Embryo-Maternal Interactions and Causes Recurrent Pregnancy Loss. Vitzthum VJ, ed. PLoS ONE. 2010; 5(4):e10287.Google Scholar
  131. 131.
    Salker MS, Christian M, Steel JH, Nautiyal J, Lavery S, Trew G, et al. Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure. Nat Med. 2011;17:1509–13.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Salker MS, Nautiyal J, Steel JH, Webster Z, Šućurović S, Nicou M, et al. Disordered IL-33/ST2 activation in decidualizing stromal cells prolongs uterine receptivity in women with recurrent pregnancy. PLoS One. 2012;7(12):e52252.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Lucas ES, Dyer NP, Murakami K, Hou Lee Y, Chan YW, Grimaldi G, et al. Loss of endometrial plasticity in recurrent pregnancy loss. Stem Cells. 2016;34:346–56.PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Christian M, Zhang X, Schneider-Merck T, Unterman TG, Gellersen B, White JO, et al. Cyclic AMP-induced forkhead transcription factor, FKHR, cooperates with CCAAT/enhancer-binding protein β in differentiating human endometrial stromal cells. J Biol Chem. 2002;277:20825–32.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Labied S, Kajihara T, Madureira PA, Fusi L, Jones MC, Higham JM, et al. Progestins regulate the expression and activity of the Forkhead transcription factor FOXO1 in differentiating human endometrium. Mol Endocrinol. 2006;20(1):35–44.PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Kajihara T, Jones M, Fusi L, Takano M, Feroze-Zaidi F, Pirianov G, et al. Differential expression of FOXO1 and FOXO3a confers resistance to oxidative cell death upon endometrial decidualization. Mol Endocrinol. 2006;20(10):2444–55.PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Kajihara T, Brosens JJ, Ishihara O. The role of FOXO1 in the decidual transformation of the endometrium and early pregnancy. Med Mol Morphol. 2013;46(2):61–8.PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Bellessort B, Bachelot A, Heude É, Alfama G, Fontaine A, Le Cardinal M, et al. Role of Foxl2 in uterine maturation and function. Hum Mol Genet. 2015;24(11):3092–103.PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Governini L, Carrarelli P, Rocha AL, Leo VD, Luddi A, Arcuri F, et al. FOXL2 in human endometrium: Hyperexpressed in endometriosis. Reprod Sci. 2014;21(10):1249–55.PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Eozenou C, Vitorino Carvalho A, Forde N, Giraud-Delville C, Gall L, Lonergan P, et al. FOXL2 is regulated during the bovine estrous cycle and its expression in the endometrium is independent of conceptus-derived interferon tau. Biol Reprod. 2012;87(2):32.PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Popovici RM, Betzler NK, Krause MS, Luo M, Jauckus J, Germeyer A, et al. Gene expression profiling of human endometrial-trophoblast interaction in a coculture model. Endocrinology. 2006;147(12):5662–75.PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Elbaz M, Hadas R, Bilezikjian LM, Gershon E. Uterine Foxl2 regulates the adherence of the Trophectoderm cells to the endometrial epithelium. Reprod Biol Endocrinol. 2018;16:12.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Deepika Delsa Dean
    • 1
  • Sarita Agarwal
    • 1
  • Poonam Tripathi
    • 1
  1. 1.Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS)LucknowIndia

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