High GDF-8 in follicular fluid is associated with a low pregnancy rate in IVF patients with PCOS

in Reproduction
Authors:
Lanlan Fang Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

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Sijia Wang Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

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Yiran Li Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

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Yiping Yu Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

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Yuxi Li Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

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Yang Yan Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

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Jung-Chien Cheng Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

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Ying-Pu Sun Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

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Correspondence should be addressed to L Fang or Y-P Sun; Email: fanglly@163.com or syp2008@vip.sina.com

*(L Fang and S Wang contributed equally to this work)

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Polycystic ovary syndrome (PCOS) is the most common cause of female infertility. Growth differentiation factor-8 (GDF-8) is expressed in the ovary and can be detected in human follicular fluid which provides an important microenvironment for maintaining physiological functions of the ovarian follicle. To date, the relationship between GDF-8 levels in follicular fluid and the risk of PCOS is completely unknown. In the present study, we show that during the process of the controlled ovarian hyperstimulation (COH), serum GDF-8 levels are higher on the day of gonadotropin administration and 14 days after embryo transfer in in vitro fertilization (IVF) patients with PCOS than they are in IVF patients without PCOS. Importantly, GDF-8 levels in follicular fluid at oocyte retrieval are also higher in PCOS patients than in non-PCOS patients. Treatment of primary human granulosa-lutein (hGL) cells with GDF-8 downregulates StAR protein expression and the inhibition is more pronounced in hGL cells from PCOS patients than it is in cells from non-PCOS patients. Importantly, high GDF-8 levels and low progesterone (P4) levels were associated with poor pregnancy outcomes in PCOS patients. Our results provide the first evidence that aberrant expression of GDF-8 in the follicular fluid of PCOS patients results in abnormal P4 expression, which leads to poor pregnancy outcomes.

 

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  • Arpaci H 2019 Major determinants of circulating myostatin in polycystic ovary syndrome. Experimental and Therapeutic Medicine 17 13831389. (https://doi.org/10.3892/etm.2018.7080)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Caburet S, Fruchter RB, Legois B, Fellous M, Shalev S & Veitia RA 2017 A homozygous mutation of GNRHR in a familial case diagnosed with polycystic ovary syndrome. European Journal of Endocrinology 176 K9K14. (https://doi.org/10.1530/EJE-16-0968)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chang HM, Fang L, Cheng JC, Klausen C, Sun YP & Leung PC 2015 Growth differentiation factor 8 down-regulates PENTRAXIN 3 in human granulosa cells. Molecular and Cellular Endocrinology 404 8290. (https://doi.org/10.1016/j.mce.2015.01.036)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chang HM, Pan HH, Cheng JC, Zhu YM & Leung PCK 2016a Growth differentiation factor 8 suppresses cell proliferation by up-regulating CTGF expression in human granulosa cells. Molecular and Cellular Endocrinology 422 917. (https://doi.org/10.1016/j.mce.2015.11.009)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chang HM, Fang L, Cheng JC, Taylor EL, Sun YP & Leung PC 2016b Effects of growth differentiation factor 8 on steroidogenesis in human granulosa-lutein cells. Fertility and Sterility 105 520528. (https://doi.org/10.1016/j.fertnstert.2015.10.034)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chang HM, Fang Y, Liu PP, Cheng JC, Yang X & Leung PC 2016c Connective tissue growth factor mediates growth differentiation factor 8-induced increase of lysyl oxidase activity in human granulosa-lutein cells. Molecular and Cellular Endocrinology 434 186198. (https://doi.org/10.1016/j.mce.2016.07.007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chen MJ, Han DS, Yang JH, Yang YS, Ho HN & Yang WS 2012 Myostatin and its association with abdominal obesity, androgen and follistatin levels in women with polycystic ovary syndrome. Human Reproduction 27 24762483. (https://doi.org/10.1093/humrep/des209)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Clark BJ, Wells J, King SR & Stocco DM 1994 The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). Journal of Biological Chemistry 269 2831428322.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Devoto L, Christenson LK, McAllister JM, Makrigiannakis A & Strauss JF 3rd 1999 Insulin and insulin-like growth factor-I and -II modulate human granulosa-lutein cell steroidogenesis: enhancement of steroidogenic acute regulatory protein (StAR) expression. Molecular Human Reproduction 5 10031010. (https://doi.org/10.1093/molehr/5.11.1003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Doldi N, Gessi A, Destefani A, Calzi F & Ferrari A 1998 Polycystic ovary syndrome: anomalies in progesterone production. Human Reproduction 13 290293. (https://doi.org/10.1093/humrep/13.2.290)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Doldi N, Marsiglio E, Destefani A, Gessi A, Merati G & Ferrari A 1999 Elevated serum progesterone on the day of HCG administration in IVF is associated with a higher pregnancy rate in polycystic ovary syndrome. Human Reproduction 14 601605. (https://doi.org/10.1093/humrep/14.3.601)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS & Legro RS 2015 Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocrine Reviews 36 487525. (https://doi.org/10.1210/er.2015-1018)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Erickson GF, Magoffin DA, Garzo VG, Cheung AP & Chang RJ 1992 Granulosa cells of polycystic ovaries: are they normal or abnormal? Human Reproduction 7 293299. (https://doi.org/10.1093/oxfordjournals.humrep.a137638)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fan X, Gaur U, Sun L, Yang D & Yang M 2017 The growth differentiation factor 11 (GDF11) and myostatin (MSTN) in tissue specific aging. Mechanisms of Ageing and Development 164 108112. (https://doi.org/10.1016/j.mad.2017.04.009)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fang L, Chang HM, Cheng JC, Yu Y, Leung PC & Sun YP 2015 Growth differentiation factor-8 decreases StAR expression through ALK5-mediated Smad3 and ERK1/2 signaling pathways in luteinized human granulosa cells. Endocrinology 156 46844694. (https://doi.org/10.1210/en.2015-1461)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fang L, Yu Y, Zhang R, He J & Sun YP 2016 Serum GDF-8 levels change dynamically during controlled ovarian hyperstimulation in patients undergoing IVF/ICSI-ET. Scientific Reports 6 28036. (https://doi.org/10.1038/srep28036)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fang L, Yu Y, Li Y, Wang S, Zhang R, Guo Y, Li Y, Yan Y & Sun YP 2019 Human chorionic gonadotropin-induced amphiregulin stimulates aromatase expression in human granulosa-lutein cells: a mechanism for estradiol production in the luteal phase. Human Reproduction 34 20182026. (https://doi.org/10.1093/humrep/dez171)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Grade CVC, Mantovani CS & Alvares LE 2019 Myostatin gene promoter: structure, conservation and importance as a target for muscle modulation. Journal of Animal Science and Biotechnology 10 32. (https://doi.org/10.1186/s40104-019-0338-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Khosravi S & Leung PC 2003 Differential regulation of gonadotropin-releasing hormone (GnRH)I and GnRHII messenger ribonucleic acid by gonadal steroids in human granulosa luteal cells. Journal of Clinical Endocrinology and Metabolism 88 663672. (https://doi.org/10.1210/jc.2002-020866)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Knight PG & Glister C 2006 TGF-beta superfamily members and ovarian follicle development. Reproduction 132 191206. (https://doi.org/10.1530/rep.1.01074)

  • Li Q, Yang G, Wang Y, Zhang X, Sang Q, Wang H, Zhao X, Xing Q, He L & Wang L 2011 Common genetic variation in the 3′-untranslated region of gonadotropin-releasing hormone receptor regulates gene expression in cella and is associated with thyroid function, insulin secretion as well as insulin sensitivity in polycystic ovary syndrome patients. Human Genetics 129 553561. (https://doi.org/10.1007/s00439-011-0954-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin TT, Chang HM, Hu XL, Leung PCK & Zhu YM 2018 Follicular localization of growth differentiation factor 8 and its receptors in normal and polycystic ovary syndrome ovaries. Biology of Reproduction 98 683694. (https://doi.org/10.1093/biolre/ioy029)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • McCartney CR & Marshall JC 2016 CLINICAL PRACTICE. Polycystic ovary syndrome. New England Journal of Medicine 375 5464. (https://doi.org/10.1056/NEJMcp1514916)

  • McPherron AC & Lee SJ 1997 Double muscling in cattle due to mutations in the myostatin gene. PNAS 94 1245712461. (https://doi.org/10.1073/pnas.94.23.12457)

  • McPherron AC, Lawler AM & Lee SJ 1997 Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 387 8390. (https://doi.org/10.1038/387083a0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Peng C, Fan NC, Ligier M, Vaananen J & Leung PC 1994 Expression and regulation of gonadotropin-releasing hormone (GnRH) and GnRH receptor messenger ribonucleic acids in human granulosa-luteal cells. Endocrinology 135 17401746. (https://doi.org/10.1210/endo.135.5.7956897)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Practice Committee of the American Society for Reproductive Medicine 2015 Current clinical irrelevance of luteal phase deficiency: a committee opinion. Fertility and Sterility 103 e27e32. (https://doi.org/10.1016/j.fertnstert.2014.12.128)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Qiao J & Feng HL 2011 Extra- and intra-ovarian factors in polycystic ovary syndrome: impact on oocyte maturation and embryo developmental competence. Human Reproduction Update 17 1733. (https://doi.org/10.1093/humupd/dmq032)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Raja-Khan N, Urbanek M, Rodgers RJ & Legro RS 2014 The role of TGF-beta in polycystic ovary syndrome. Reproductive Sciences 21 2031. (https://doi.org/10.1177/1933719113485294)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rotterdam ESHRE/ASRM‐sponsored PCOS consensus workshop group 2004 Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Human Reproduction 19 4147. (https://doi.org/10.1093/humrep/deh098)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Stamatiades GA & Kaiser UB 2018 Gonadotropin regulation by pulsatile GnRH: signaling and gene expression. Molecular and Cellular Endocrinology 463 131141. (https://doi.org/10.1016/j.mce.2017.10.015)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Stocco DM & Clark BJ 1996 Regulation of the acute production of steroids in steroidogenic cells. Endocrine Reviews 17 221244. (https://doi.org/10.1210/edrv-17-3-221)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Valdes JA, Flores S, Fuentes EN, Osorio-Fuentealba C, Jaimovich E & Molina A 2013 IGF-1 induces IP3 -dependent calcium signal involved in the regulation of myostatin gene expression mediated by NFAT during myoblast differentiation. Journal of Cellular Physiology 228 14521463. (https://doi.org/10.1002/jcp.24298)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Venetis CA, Kolibianakis EM, Papanikolaou E, Bontis J, Devroey P & Tarlatzis BC 2007 Is progesterone elevation on the day of human chorionic gonadotrophin administration associated with the probability of pregnancy in in vitro fertilization? A systematic review and meta-analysis. Human Reproduction Update 13 343355. (https://doi.org/10.1093/humupd/dmm007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Venetis CA, Kolibianakis EM, Bosdou JK & Tarlatzis BC 2013 Progesterone elevation and probability of pregnancy after IVF: a systematic review and meta-analysis of over 60 000 cycles. Human Reproduction Update 19 433457. (https://doi.org/10.1093/humupd/dmt014)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Witchel SF, Oberfield SE & Peña AS 2019 Polycystic ovary syndrome: pathophysiology, presentation, and treatment with emphasis on adolescent girls. Journal of the Endocrine Society 3 15451573. (https://doi.org/10.1210/js.2019-00078)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zuloaga R, Fuentes EN, Molina A & Valdes JA 2013 The cAMP response element binding protein (CREB) is activated by insulin-like growth factor-1 (IGF-1) and regulates myostatin gene expression in skeletal myoblast. Biochemical and Biophysical Research Communications 440 258264. (https://doi.org/10.1016/j.bbrc.2013.09.067)

    • PubMed
    • Search Google Scholar
    • Export Citation