Abstract
Purpose
To determine whether Activin A affects the activation and survival of human primordial follicles in vitro.
Methods
Ovarian cortical biopsies from eight women undergoing elective caesarean sections or benign gynaecological procedures were taken and cut into small pieces (1–3 mm3), cultured in serum-free medium for 7 days with/without human recombinant Activin A at a concentration of either 50 or 100 ng/ml. Ovarian tissue were analysed by histology for follicle viability, development and density.
Result(s)
Significant activation of primordial follicles within cultured cortical tissue was observed after 7 days in control medium. However, medium supplemented with Activin A at 50 ng/ml resulted in significant inhibition of follicular activation. Increasing the concentration of Activin A to 100 ng/ml reversed the inhibitory effect. The effect of Activin A appeared to be specific to activation of non-growing (primordial) follicles into the growing population since no significant differences in follicle viability was observed between treatment groups.
Conclusion(s)
Activin A at a concentration of 50 ng/ml can inhibit the spontaneous activation of human primordial follicles in vitro indicating that this may be a component of the signalling mechanisms that maintain follicular quiescence.
Similar content being viewed by others
References
Scottish Intercollegiate Guidelines Network (SIGN) Long-term follow-up of survivors of childhood cancer. SIGN Publication No. 76. Edinburgh: SIGN 2004.
Edgar AB, Morris EM, Kelnar CJ, Wallace HB. Long-term follow-up of survivors of childhood cancer. Endocr Dev. 2009;15:59–80.
Meirow D, Schiff E. Appraisal of chemotherapy effects on reproductive outcome according to animal studies and clinical data. J Natl Cancer Inst Monogr. 2005;34:21–5.
Meirow D. Fertility preservation in cancer patients using stored ovarian tissue: clinical aspects. Curr Opin Endocrinol Diabetes Obes. 2008;15(6):536–47.
Telfer EE, McLaughlin M. Natural history of the mammalian oocyte. Reprod Biomed Online. 2007;15(3):288–95.
Eppig JJ, O’Brien MJ. Development in vitro of mouse oocytes from primordial follicles. Biol Reprod. 1996;54:197–207.
O’Brien MJ, Pendola JK, Eppig JJ. A revised protocol for in vitro development of mouse oocytes from primordial follicles dramatically improves their developmental competence. Biol Reprod. 2003;68:1682–6.
Telfer EE, McLaughlin M, Ding C, Thong KJ. A two-step serum-free culture system supports development of human oocytes from primordial follicles in the presence of activin. Hum Reprod. 2008;23:1151–8.
Fortune JE, Cushman RA, Wahl CM, Kito S. The primordial to primary follicle transition. Mol Cell Endocrinol. 2000;63(1–2):53–60.
Wandji SA, Srsen V, Voss AK, Eppig JJ, Fortune JE. Initiation in vitro of growth of bovine primordial follicles. Biol Reprod. 1996;55(5):942–8.
Hovatta O, Silye R, Abir R, Krausz T, Winston RM. Extracellular matrix improves survival of both stored and fresh human primordial and primary ovarian follicles in long-term culture. Hum Reprod. 1997;12:1032–6.
Hovatta O, Wright C, Krausz T, Hardy K, Winston RM. Human primordial, primary and secondary ovarian follicles in long-term culture: effect of partial isolation. Hum Reprod. 1999;14:2519–24.
Fortune JE, Kito S, Wandji SA, Srsen V. Activation of bovine and baboon primordial follicles in vitro. Theriogenology. 1998;49(2):441–9.
Rabinovici J, Spencer SJ, Doldi N, Goldsmith PC, Schwall R, Jaffe RB. Activin-A as an intraovarian modulator: actions, localization, and regulation of the intact dimer in human ovarian cells. J Clin Invest. 1992;89(5):1528–36.
Xu L. Regulation of Smad activities. Biochim Biophys Acta. 2006;1759(11–12):503–13.
Massagué J, Chen YG. Controlling TGF-beta signaling. Genes Dev. 2000;14(6):627–44.
Li S, Maruo T, Ladines-Llave CA, Samoto T, Kondo H, Mochizuki M. Expression of transforming growth factor-alpha in the human ovary during follicular growth, regression and atresia. Endocr J. 1994;41(6):693–701.
Zhao J, Taverne MA, van der Weijden GC, Bevers MM, van den Hurk R. Effect of activin A on in vitro development of rat preantral follicles and localization of activin A and activin receptor II. Biol Reprod. 2001;65:967–77.
Zhou Y, Sun H, Danila DC, Johnson SR, Sigai DP, Zhang X, et al. Truncated activin type I receptor Alk4 isoforms are dominant negative receptors inhibiting activin signaling. Mol Endocrinol. 2000;14(12):2066–75.
Ethier JF, Findlay JK. Roles of activin and its signal transduction mechanisms in reproductive tissues. Reproduction. 2001;121:667–75.
Findlay JK, Drummond AE, Dyson ML, Baillie DM, Robertson DM, Ethier JF. Recruitment and development of the follicle; the roles of the transforming growth factor-b superfamily. Mol Cell Endocrinol. 2002;191:35–43.
Thomas FH, Walters KA, Telfer EE. How to make a good oocyte: an update on in vitro models to study follicle regulation. Hum Reprod Update. 2003;9:1–15.
Mizunuma H, Liu X, Andoh K, Abe Y, Kobayashi J, Yamada K, et al. Activin from secondary follicles causes small preantral follicles to remain dormant at the resting stage. Endocrinology. 1999;140:37–42.
Yokota H, Yamada K, Liu X, Kobayashi J, Abe Y, Mizunuma H, et al. Paradoxical action of activin A on folliculogenesis in immature and adult mice. Endocrinology. 1997;138:4572–6.
Durlinger AL, Gruijters MJ, Kramer P, Karels B, Ingraham HA, Nachtigal MW, et al. Anti-Müllerian hormone inhibits initiation of primordial follicle growth in the mouse ovary. Endocrinology. 2002;143(3):1076–84.
Carlsson IB, Scott JE, Visser JA, Ritvos O, Themmen APN, Hovatta O. Anti-Müllerian hormone inhibits initiation of growth of human primordial ovarian follicles in vitro. Human Reprod. 2006;21:2223–7.
Gonzalez-Manchon C, Vale W. Activin-A, inhibin and transforming growth factor-beta modulate growth of two gonadal cell lines. Endocrinology. 1989;125(3):1666–72.
Myers M, van den Driesche S, McNeilly AS, Duncan WC. Activin A reduces luteinisation of human luteinised granulosa cells and has opposing effects to human chorionic gonadotropin in vitro. J Endocrinol. 2008;199(2):201–12.
Pangas SA, Woodruff TK. Activin signal transduction pathways. Trends Endocrinol Metab. 2000;11(8):309–14.
Roberts VJ, Barth S. el-Roeiy A, Yen SS: Expression of inhibin/activin subunits and follistatin messenger ribonucleic acids and proteins in ovarian follicles and the corpus luteum during the human menstrual cycle. Clin Endocrinol Metab. 1993;77(5):1402–10.
Pangas SA, Rademaker AW, Fishman DA, Woodruff TK. Localization of the activin signal transduction components in normal human ovarian follicles: implications for autocrine and paracrine signaling in the ovary. J Clin Endocrinol Metab. 2002;87:2644–57.
Jagarlamudi K, Liu L, Adhikari D, Reddy P, Idahl A, Ottander U, et al.: Oocyte-specific deletion of Pten in mice reveals a stage-specific function of PTEN/PI3K signaling in oocytes in controlling follicular activation. PLoS One. 2009; 9;4(7):e6186.
Reddy P, Liu L, Adhikari D, Jagarlamudi K, Rajareddy S, Shen Y, et al.: Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science 2008; 1;319(5863):611–3.
Oktay K, Karlikaya G, Akman O, Ojakian GK, Oktay M. Interaction of extracellular matrix and activin-A in the initiation of follicle growth in the mouse ovary. Biol Reprod. 2000;63(2):457–61.
Woodruff TK, Lyon RJ, Hansen SE, Rice GC, Mather JP. Inhibin and activin locally regulate rat ovarian folliculogenesis. Endocrinology. 1990;127(6):3196–205.
Acknowledgements
The authors thank Mr John Binnie for his outstanding technical assistance, and the women who took part in this research. We would also like to thank the Edinburgh Assisted Conception Unit for funding the project through its Endowment Fund.
Investigations on Human Subjects
This study was approved by the local ethics committee.
Conflict of Interest Statement
No conflict of interest for any of the submitting authors in reference to the submitted material.
Author information
Authors and Affiliations
Corresponding author
Additional information
Capsule This study observed a dose dependent inhibitory action of Activin A on the activation of human primordial follicles in vitro.
Rights and permissions
About this article
Cite this article
Ding, C.C., Thong, K.J., Krishna, A. et al. Activin A inhibits activation of human primordial follicles in vitro. J Assist Reprod Genet 27, 141–147 (2010). https://doi.org/10.1007/s10815-010-9395-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10815-010-9395-6