Abstract
The aim is to study the association of estrogen receptor α (ERα) and estrogen receptor β (ERβ) gene polymorphisms and diplotypes with ovarian response to follicle-stimulating hormone (FSH) stimulation and the hormone levels [FSH, luteinizing hormone (LH), E2] at the third day of the menstrual cycle. Three hundred women undergoing medically assisted reproduction and 300 women with at least one spontaneous pregnancy participated in the study. ERα PvuII and XbaI polymorphisms as well as ERβ AluI polymorphism were genotyped. The FSH, LH, and E2 levels were determined at the third day of the menstrual cycle, while the follicular size, the follicle, and oocyte numbers were recorded during oocyte retrieval. PvuII CC, XbaI GG, and AluI GG women were characterized by increased amounts of large follicles compared to PvuII TT, XbaI AA, and AluI AA women (p = 0.045, 0.01, and 0.033, respectively). The PvuII CC/XbaI GG diplotype was also significantly associated with higher large follicle numbers compared to the PvuII TT/XbaI AA diplotype (p = 0.024). However, no associations were observed between ER gene polymorphisms and the hormonal profile, the follicle/oocyte numbers, and the pregnancy rates. ERα and ERβ genetic variants were associated with ovarian response to standard gonadotropin stimulation of women undergoing in-vitro fertilization affecting mainly the follicular growth.
Similar content being viewed by others
References
S.A. Tonetta, G.S. diZerega, Intragonadal regulation of follicular maturation. Endocr. Rev. 10, 205–229 (1989)
X.N. Wang, G.S. Greenwald, Synergistic effects of steroids with FSH on folliculogenesis, steroidogenesis and FSH- and hCG-receptors in hypophysectomized mice. J. Reprod. Fertil. 99, 403–413 (1993)
J.J. Ireland, J.S. Richards, Acute effects of estradiol and follicle-stimulating hormone on specific binding of human [125I]iodofollicle-stimulating hormone to rat ovarian granulosa cells in vivo and in vitro. Endocrinology 102, 876–883 (1978)
L. Speroff, M.A. Fritz, Clinical Gynecologic Endocrinology and Infertility (Lippincott Williams & Wilkins, Philadelphia, 2005)
S.C. Hewitt, K.S. Korach, Progesterone action and responses in the alphaERKO mouse. Steroids 65, 551–557 (2000)
D.B. Lubahn, J.S. Moyer, T.S. Golding, J.F. Couse, K.S. Korach, O. Smithies, Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc. Natl. Acad. Sci. USA 90, 11162–11166 (1993)
D.W. Schomberg, J.F. Couse, A. Mukherjee, D.B. Lubahn, M. Sar, K.E. Mayo, K.S. Korach, Targeted disruption of the estrogen receptor-alpha gene in female mice: characterization of ovarian responses and phenotype in the adult. Endocrinology 140, 2733–2744 (1999)
J.H. Krege, J.B. Hodgin, J.F. Couse, E. Enmark, M. Warner, J.F. Mahler, M. Sar, K.S. Korach, J.A. Gustafsson, O. Smithies, Generation and reproductive phenotypes of mice lacking estrogen receptor beta. Proc. Natl. Acad. Sci. USA 95, 15677–15682 (1998)
E. Hatzi, I. Bouba, A. Galidi, L. Lazaros, N. Xita, P. Sakaloglou, G. Kolios, E. Bairaktari, A. Kaponis, K. Zikopoulos, A. Tsatsoulis, I. Georgiou, Association of serum and follicular SHBG levels and SHBG(TAAAA)n polymorphism with follicle size in women undergoing ovarian stimulation. Gynecol. Endocrinol. 27, 27–32 (2011)
L. Lazaros, S. Markoula, N. Xita, S. Giannopoulos, P. Gogou, G. Lagos, A. Kyritsis, I. Georgiou, Association of estrogen receptor-alpha gene polymorphisms with stroke risk in patients with metabolic syndrome. Acta Neurol. Scand. 117, 186–190 (2008)
L.A. Lazaros, N.V. Xita, A.I. Kaponis, K.A. Zikopoulos, N.I. Plachouras, I.A. Georgiou, Estrogen receptor alpha and beta polymorphisms are associated with semen quality. J. Androl. 31, 291–298 (2010)
J.S. Richards, Maturation of ovarian follicles: actions and interactions of pituitary and ovarian hormones on follicular cell differentiation. Physiol. Rev. 60, 51–89 (1980)
I. Georgiou, M. Konstantelli, M. Syrrou, I.E. Messinis, D.E. Lolis, Oestrogen receptor gene polymorphisms and ovarian stimulation for in vitro fertilization. Hum. Reprod. 12, 1430–1433 (1997)
C. Sundarrajan, W. Liao, A.C. Roy, S.C. Ng, Association of oestrogen receptor gene polymorphisms with outcome of ovarian stimulation in patients undergoing IVF. Mol. Hum. Reprod. 5, 797–802 (1995)
S. Altmäe, K. Haller, M. Peters, O. Hovatta, A. Stavreus-Evers, H. Karro, A. Metspalu, A. Salumets, Allelic estrogen receptor 1 (ESR1) gene variants predict the outcome of ovarian stimulation in in vitro fertilization. Mol. Hum. Reprod. 13, 521–526 (2007)
O.U. Ayvaz, A. Ekmekçi, V. Baltaci, H.I. Onen, E. Unsal, Evaluation of in vitro fertilization parameters and estrogen receptor alpha gene polymorphisms for women with unexplained infertility. J. Assist. Reprod. Genet. 26, 503–510 (2009)
F. de Castro, F.J. Morón, L. Montoro, J.J. Galán, D.P. Hernández, E.S. Padilla, R. Ramírez-Lorca, L.M. Real, A. Ruiz, Human controlled ovarian hyperstimulation outcome is a polygenic trait. Pharmacogenetics 14, 285–293 (2004)
Y.S. Choi, S.H. Kim, S.Y. Ku, B.C. Jee, C.S. Suh, Y.M. Choi, J.G. Kim, S.Y. Moon, Efficacy of ER-alpha polymorphisms and the intrafollicular IGF system for predicting pregnancy in IVF-ET patients. Gynecol. Obstet. Invest. 67, 73–80 (2009)
R. Boudjenah, D. Molina-Gomes, A. Torre, M. Bergere, M. Bailly, F. Boitrelle, S. Taieb, R. Wainer, M. Benahmed, P. de Mazancourt, J. Selva, F. Vialard, Genetic polymorphisms influence the ovarian response to rFSH stimulation in patients undergoing in vitro fertilization programs with ICSI. PLoS One 7, e38700 (2012)
M. Putnik, C. Zhao, J.A. Gustafsson, K. Dahlman-Wright, Effects of two common polymorphisms in the 3′ untranslated regions of estrogen receptor beta on mRNA stability and translatability. BMC Genet. 10, 55 (2009)
B.S. Hurst, K.K. Leslie, The role of oestrogen in follicular development. Mol. Hum. Reprod. 3, 643–645 (1997)
C. Hegele-Hartung, P. Siebel, O. Peters, D. Kosemund, G. Müller, A. Hillisch, A. Walter, J. Kraetzschmar, K.H. Fritzemeier, Impact of isotype-selective estrogen receptor agonists on ovarian function. Proc. Natl. Acad. Sci. USA 101, 5129–5134 (2004)
K.S. Korach, Insights from the study of animals lacking functional estrogen receptor. Science 266, 1524–1527 (1994)
A.M. van Heusden, H.J. Coelingh Bennink, B.C. Fauser, FSH and ovarian response: spontaneous recovery of pituitary–ovarian activity during the pill-free period versus exogenous recombinant FSH during high-dose combined oral contraceptives. Clin. Endocrinol. (Oxf) 56, 509–517 (2002)
Y. Chen, X. Li, J. Li, A novel approach for haplotype-based association analysis family data. BMC Bioinform. 18, S45 (2010)
Acknowledgments
The authors would like to thank Dr. I. Bouba for her contribution in the laboratory work-up.
Conflict of interest
The authors have no conflicts of interest or financial ties to disclose.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lazaros, L., Pamporaki, C., Vlahos, N. et al. The follicular outcome after standard gonadotropin stimulation is associated with ERα and ERβ genotypes. Endocrine 47, 930–935 (2014). https://doi.org/10.1007/s12020-014-0249-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-014-0249-3