Skip to main content
Log in

Tight interplay in early pregnancy between follistatin and anti-mullerian hormone in women with polycystic ovarian syndrome (PCOS)

  • Gynecologic Endocrinology and Reproductive Medicine
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

Follistatin levels increase during the course of pregnancy and may play a role in ovarian arrest, reflected by the simultaneous decrease of anti-mullerian-hormone (AMH) levels. The aim of the study was to investigate AMH and follistatin levels during the hormonal window at the beginning of pregnancy. Since both parameters are described as deregulated in polycystic ovarian syndrome (PCOS), subgroup analysis of PCOS patients may additionally elucidate their interplay and effects on ovarian activity.

Methods

Serum samples were retrospectively analyzed using the AMH Gen II ELISA and the Human Follistatin Quantikine ELISA Kit. Samples were collected longitudinally from 57 patients (32 with PCOS and 25 controls) before conception and during the first trimester. In 18 patients, measurements from the early and the late first trimester were available. Potential associations of AMH and follistatin levels with PCOS-related parameters were compared between the subgroups as well as longitudinally before and in the first trimester of pregnancy. For statistical analysis, the Spearman’s correlation, Wilcoxon test, t test, Friedman test and multiple linear regression analysis was performed.

Results

In contrast to AMH, follistatin levels differed not between controls and PCOS patients before and in pregnancy. In both subgroups, AMH levels significantly decreased and follistatin levels significantly increased in longitudinally performed measurements before conceiving and in the first trimester of pregnancy.

Conclusion

Follistatin levels are not suited as a biomarker for PCOS, but could be involved in suppressing ovarian activity, as reflected by AMH levels at the beginning of pregnancy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Ueno N, Ling N, Ying SY, Esch F, Shimasaki S, Guillemin R (1987) Isolation and partial characterization of follistatin: a single-chain Mr 35,000 monomeric protein that inhibits the release of follicle-stimulating hormone. Proc Natl Acad Sci USA 84(23):8282–8286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Nakamura T, Takio K, Eto Y, Shibai H, Titani K, Sugino H (1990) Activin-binding protein from rat ovary is follistatin. Science 247(4944):836–838

    Article  CAS  PubMed  Google Scholar 

  3. Nakamura T, Hasegawa Y, Sugino K, Kogawa K, Titani K, Sugino H (1992) Follistatin inhibits activin-induced differentiation of rat follicular granulosa cells in vitro. Biochim Biophys Acta 1135(1):103–109

    Article  CAS  PubMed  Google Scholar 

  4. Xiao S, Farnworth PG, Findlay JK (1992) Interaction between activin and follicle-stimulating hormone-suppressing protein/follistatin in the regulation of basal inhibin production by cultured rat granulosa cells. Endocrinology 131(5):2365–2370

    Article  CAS  PubMed  Google Scholar 

  5. Findlay JK (1993) An update on the roles of inhibin, activin, and Follistatin as local regulators of folliculogenesis. Biol Reprod 48(1):15–23

    Article  CAS  PubMed  Google Scholar 

  6. Guo Q, Kumar TR, Woodruff T, Hadsell LA, DeMayo FJ, Matzuk MM (1998) Overexpression of mouse follistatin causes reproductive defects in transgenic mice. Mol Endocrinol 12(1):96–106

    Article  CAS  PubMed  Google Scholar 

  7. Cate RL, Mattaliano RJ, Hession C, Tizard R, Farber NM, Cheung A, Ninfa EG, Frey AZ, Gash DJ, Chow EP et al (1986) Isolation of the bovine and human genes for Müllerian inhibiting substance and expression of the human gene in animal cells. Cell 45(5):685–698

    Article  CAS  PubMed  Google Scholar 

  8. Weenen C, Laven JS, Von Bergh AR, Cranfield M, Groome NP, Visser JA et al (2004) Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod 10(2):77–83

    Article  CAS  PubMed  Google Scholar 

  9. Durlinger AL, Visser JA, Themmen AP (2002) Regulation of ovarian function: the role of anti-Müllerian hormone. Reproduction 124(5):601–609

    Article  CAS  PubMed  Google Scholar 

  10. Matzuk MM, Finegold MJ, Mishina Y, Bradley A, Behringer RR (1995) Synergistic effects of inhibins and müllerian-inhibiting substance on testicular tumorigenesis. Mol Endocrinol 9(10):1337–1345

    CAS  PubMed  Google Scholar 

  11. Köninger A, Kauth A, Schmidt B, Schmidt M, Yerlikaya G, Kasimir-Bauer S et al (2013) Anti-Mullerian-hormone levels during pregnancy and postpartum. Reprod Biol Endocrinol 11:60

    Article  PubMed  PubMed Central  Google Scholar 

  12. Köninger A, Schmidt B, Mach P, Damaske D, Nießen S, Kimmig R et al (2015) Anti-Mullerian-Hormone during pregnancy and peripartum using the new Beckman Coulter AMH Gen II Assay. Reprod Biol Endocrinol 13:86

    Article  PubMed  PubMed Central  Google Scholar 

  13. Köninger A, Schmidt B, Damaske D, Birdir C, Enekwe A, Kimmig R et al (2017) Follistatin during pregnancy and its potential role as an ovarian suppressing agent. Eur J Obstet Gynecol Reprod Biol 212:150–154

    Article  PubMed  Google Scholar 

  14. Wakatsuki M, Shintani Y, Abe M, Liu ZH, Shitsukawa K, Saito S (1996) Immunoradiometric assay for follistatin: serum immunoreactive follistatin levels in normal adults and pregnant women. J Clin Endocrinol Metab 81(2):630–634

    CAS  PubMed  Google Scholar 

  15. Rae K, Hollebone K, Chetty V, Clausen D, McFarlane J (2007) Follistatin serum concentrations during full-term labour in women—significant differences between spontaneous and induced labour. Reproduction 134(5):705–711

    Article  CAS  PubMed  Google Scholar 

  16. Pigny P, Merlen E, Robert Y, Cortet-Rudelli C, Decanter C, Jonard S et al (2003) Elevated serum level of anti-mullerian hormone in patients with polycystic ovary syndrome: relationship to the ovarian follicle excess and to the follicular arrest. J Clin Endocrinol Metab 88(12):5957–5962

    Article  CAS  PubMed  Google Scholar 

  17. Köninger A, Koch L, Edimiris P, Enekwe A, Nagarajah J, Kasimir-Bauer S, Kimmig R, Strowitzki T, Schmidt B (2014) Anti-Mullerian Hormone: an indicator for the severity of polycystic ovarian syndrome. Arch Gynecol Obstet 290(5):1023–1030

    Article  PubMed  Google Scholar 

  18. 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. Hum Reprod 27(8):2476–2483

    Article  CAS  PubMed  Google Scholar 

  19. Teede H, Ng S, Hedger M, Moran L (2013) Follistatin and activins in polycystic ovary syndrome: relationship to metabolic and hormonal markers. Metabolism 62(10):1394–1400

    Article  CAS  PubMed  Google Scholar 

  20. Norman RJ, Milner CR, Groome NP, Robertson DM (2001) Circulating follistatin concentrations are higher and activin concentrations are lower in polycystic ovarian syndrome. Hum Reprod 16(4):668–672

    Article  CAS  PubMed  Google Scholar 

  21. Chen MJ, Chen HF, Chen SU, Ho HN, Yang YS, Yang WS (2009) The relationship between follistatin and chronic low-grade inflammation in women with polycystic ovary syndrome. Fertil Steril 92(6):2041–2044

    Article  CAS  PubMed  Google Scholar 

  22. Eldar-Geva T, Spitz IM, Groome NP, Margalioth EJ, Homburg R (2001) Follistatin and activin A serum concentrations in obese and non-obese patients with polycystic ovary syndrome. Hum Reprod 16(12):2552–2556

    Article  CAS  PubMed  Google Scholar 

  23. Fujiwara T, Sidis Y, Welt C, Lambert-Messerlian G, Fox J, Taylor A, Schneyer A (2001) Dynamics of inhibin subunit and follistatin mRNA during development of normal and polycystic ovary syndrome follicles. J Clin Endocrinol Metab 86(9):4206–4215

    Article  CAS  PubMed  Google Scholar 

  24. Erickson GF, Chung DG, Sit A, DePaolo LV, Shimasaki S, Ling N (1995) Follistatin concentrations in follicular fluid of normal and polycystic ovaries. Hum Reprod 10(8):2120–2124

    Article  CAS  PubMed  Google Scholar 

  25. Shimasaki S, Koga M, Buscaglia ML, Simmons DM, Bicsak TA, Ling N (1989) Follistatin gene expression in the ovary and extragonadal tissues. Mol Endocrinol 3(4):651–659

    Article  CAS  PubMed  Google Scholar 

  26. Keelan JA, Marvin KW, Sato TA, McCowan LM, Coleman M, Evans LW et al (1999) Concentrations of activin A, inhibin A and Follistatin in human amnion, choriodecidual and placental tissues at term and preterm. J Endocrinol 163(1):99–106

    Article  CAS  PubMed  Google Scholar 

  27. Hansen JS, Rutti S, Arous C, Clemmesen JO, Secher NH, Drescher A, Gonelle-Gispert C, Halban PA, Pedersen BK, Weigert C, Bouzakri K, Plomgaard P (2016) Circulating follistatin is liver-derived and regulated by the glucagon-to-insulin ratio. J Clin Endocrinol Metab 101(2):550–560

    Article  CAS  PubMed  Google Scholar 

  28. Wilson KM, Smith AI, Phillips DJ (2006) Stimulatory effects of lipopolysaccharide on endothelial cell activin and follistatin. Mol Cell Endocrinol 253(1–2):30–35

    Article  CAS  PubMed  Google Scholar 

  29. Keelan JA, Zhou RL, Evans LW, Groome NP, Mitchell MD (2000) Regulation of activin A, inhibin A, and follistatin production in human amnion and choriodecidual explants by inflammatory mediators. J Soc Gynecol Investig 7(5):291–296

    Article  CAS  PubMed  Google Scholar 

  30. Turcotte LM, DeFor TE, Newell LF, Cutler CS, Verneris MR, Wu J, Howard A, MacMillan ML, Antin JH, Vercellotti GM, Slungaard A, Blazar BR, Weisdorf DJ, Panoskaltsis-Mortari A, Holtan SG (2018) Donor and recipient plasma follistatin levels are associated with acute GvHD in Blood and Marrow Transplant Clinical Trials Network 0402. Bone Marrow Transplant 53(1):64–68

    Article  CAS  PubMed  Google Scholar 

  31. 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. Hum Reprod 19(1):41–47

    Article  Google Scholar 

  32. Ferriman D, Gallwey JD (1961) Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 21:1440–1447

    Article  CAS  PubMed  Google Scholar 

  33. Ludwig E (1977) Classification of the types of androgenetic alopecia (common baldness) occurring in the female sex. Br J Dermatol 9:7247–7254

    Google Scholar 

  34. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419

    Article  CAS  PubMed  Google Scholar 

  35. R Core Team. R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna. ISBN 3-900051-07-0, URL: http://www.R-project.org/

  36. Ying SY, Becker A, Swanson G, Tan P, Ling N, Esch F et al (1987) Follistatin specifically inhibits pituitary follicle stimulating hormone release in vitro. Biochem Biophys Res Commun 149(1):133–139

    Article  CAS  PubMed  Google Scholar 

  37. Shikone T, Matzuk MM, Perlas E, Finegold MJ, Lewis KA, Vale W, Bradley A, Hsueh AJ (1994) Characterization of gonadal sex cord-stromal tumor cell lines from inhibin-alpha and p53-deficient mice: the role of activin as an autocrine growth factor. Mol Endocrinol 8(8):983–995

    CAS  PubMed  Google Scholar 

  38. Stanford JL, Hartge P, Brinton LA, Hoover RN, Brookmeyer R (1987) Factors influencing the age at natural menopause. J Chronic Dis 40(11):995–1002

    Article  CAS  PubMed  Google Scholar 

  39. Farahmand M, Tehrani FR, Pourrajabi L, Najafi M, Azizi F (2013) Factors associated with menopausal age in Iranian women: Tehran Lipid and Glucose Study. J Obstet Gynaecol Res 39(4):836–841

    Article  PubMed  Google Scholar 

  40. Li L, Wu J, Pu D, Zhao Y, Wan C, Sun L, Shen CE et al (2012) Factors associated with the age of natural menopause and menopausal symptoms in Chinese women. Maturitas 73(4):354–360

    Article  PubMed  Google Scholar 

  41. Parazzini F, Progetto Menopausa Italia Study Group (2007) Determinants of age at menopause in women attending menopause clinics in Italy. Maturitas 56(3):280–287

    Article  PubMed  Google Scholar 

  42. Yaden BC, Croy JE, Wang Y, Wilson JM, Datta-Mannan A, Shetler P, Milner A, Bryant HU, Andrews J, Dai G, Krishnan V (2014) Follistatin: a novel therapeutic for the improvement of muscle regeneration. J Pharmacol Exp Ther 349(2):355–371

    Article  PubMed  Google Scholar 

  43. Wang L, Qi H, Baker PN, Zhen Q, Zeng Q, Shi R, Tong C, Ge Q (2017) Altered circulating inflammatory cytokines are associated with anovulatory polycystic ovary syndrome (PCOS) women resistant to clomiphene citrate treatment. Med Sci Monit 23:1083–1089

    Article  PubMed  PubMed Central  Google Scholar 

  44. Craig LB, Ke RW, Kutteh WH (2002) Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss. Fertil Steril 78(3):487–490

    Article  PubMed  Google Scholar 

  45. Chen MJ, Yang WS, Chen HF, Kuo JJ, Ho HN, Yang YS, Chen SU (2010) Increased follistatin levels after oral contraceptive treatment in obese and non-obese women with polycystic ovary syndrome. Hum Reprod 25(3):779–785

    Article  CAS  PubMed  Google Scholar 

  46. Dasgupta S, Pisapati S, Kudugunti N, Kathragadda A, Godi S, Reddy MB (2012) Does follistatin gene have any direct role in the manifestation of polycystic ovary syndrome in Indian women? J Postgrad Med 58:190–193

    Article  CAS  PubMed  Google Scholar 

  47. Urbanek M, Wu X, Vickery KR, Kao LC, Christenson LK, Schneyer A, Legro RS, Driscoll DA, Strauss JF 3rd, Dunaif A, Spielman RS (2000) Allelic variants of the follistatin gene in polycystic ovary syndrome. J Clin Endocrinol Metab 85(12):4455–4461

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the laboratory staff and the nurses of the University Hospital of Essen, Department of Gynecology and Obstetrics, for technical assistance and data documentation. We are grateful to Dr. Florence Witte for English editing and critical reading of the manuscript.

Funding

This study was funded by the University of Duisburg-Essen.

Author information

Authors and Affiliations

Authors

Contributions

A.Kö: project development, data collection, data analysis, manuscript writing; A.Ka: data collection, data analysis, biochemical analysis; PM: data analysis; BS: data analysis, manuscript editing; TS: data analysis, manuscript editing; RK: project development; AG: project development, manuscript writing.

Corresponding author

Correspondence to Angela Köninger.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interests.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the national research committee and with the 1964 Helsinki Declaration and its later amendments. The study was approved by the Research Ethics Committee of the Faculty of Medicine, University Duisburg-Essen, Germany (No. 11-4643).

Informed consent

Written informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Köninger, A., Kampmeier, A., Mach, P. et al. Tight interplay in early pregnancy between follistatin and anti-mullerian hormone in women with polycystic ovarian syndrome (PCOS). Arch Gynecol Obstet 297, 1307–1316 (2018). https://doi.org/10.1007/s00404-018-4718-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00404-018-4718-4

Keywords

Navigation