Skip to main content

Advertisement

Log in

Do young women with unexplained infertility show manifestations of decreased ovarian reserve?

  • Assisted Reproduction Technologies
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

To investigate whether unexplained infertility at a young age demonstrates manifestations of decreased ovarian reserve.

Methods

A total of 100 women were divided into two equally sized groups. The study group comprised women aged ≤ 37 years diagnosed with unexplained infertility, and the control group included age-matched women with either mechanical factor or severe male factor infertility.

Results

Both groups were comparable in their basic characteristics. Overall, women with unexplained infertility presented with inferior ovarian reserve results set against women of the control group. The number of ≥ 14-mm follicles on the day of hCG administration was significantly lower in the study compared with the control group (7.0 ± 4.5 vs. 10.4 ± 4.1 follicles, respectively, P < 0.001). Likewise, basal serum FSH was higher in the study compared with the control group (8.4 ± 5.5 vs. 6.4 ± 1.7 IU/L, respectively, P = 0.015), while antral follicle count was lower (10.9 ± 6.6 vs. 16.2 ± 6.6 follicles, respectively, P < 0.001). Furthermore, women with unexplained infertility required a higher total dose of FSH for ovarian stimulation (2,923 ± 1,701 vs. 2,196 ± 941 IU/L, respectively, P = 0.010), but exhibited a lower number of retrieved oocytes (9.3 ± 6.3 vs. 15.6 ± 7.9 oocytes, respectively, P < 0.001), alongside a lower number of achieved embryos (5.3 ± 4.0 vs. 8.0 ± 4.7 embryos, respectively, P = 0.002). Interestingly, the cumulative clinical pregnancy rate was not significantly different between the two groups (44% vs. 58%, respectively, P = 0.163).

Conclusions

Young women ≤ 37 years of age with unexplained infertility have clear manifestations of sub-optimal ovarian reserve set against controls. Our findings suggest that unexplained infertility at a young age may be a risk factor for developing poor ovarian response, specifically as a quantitative, rather than a qualitative, risk factor.

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.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Practice Committee of the American Society for Reproductive Medicine. Effectiveness and treatment for unexplained infertility. Fertil Steril. 2006;86:S111–4. https://doi.org/10.1016/j.fertnstert.2006.07.1475.

    Article  Google Scholar 

  2. Pandian Z, Gibreel A, Bhattacharya S. In vitro fertilisation for unexplained subfertility. Cochrane Database Syst Rev. 2015;(11):CD003357. https://doi.org/10.1002/14651858.CD003357.pub4.

  3. Guzick DS, Sullivan MW, Adamson GD, Cedars MI, Falk RJ, Peterson EP, et al. Efficacy of treatment for unexplained infertility. Fertil Steril. 1998;70:207–13. https://doi.org/10.1016/S0015-0282(98)00177-0.

    Article  CAS  PubMed  Google Scholar 

  4. Collins JA, Burrows EA, Willan AR. The prognosis for live birth among untreated infertile couples. Fertil Steril. 1995;64:22–8. https://doi.org/10.1016/S0015-0282(16)57650-X.

    Article  CAS  PubMed  Google Scholar 

  5. Somigliana E, Paffoni A, Busnelli A, Filippi F, Pagliardini L, Vigano P, et al. Age-related infertility and unexplained infertility: an intricate clinical dilemma. Hum Reprod. 2016;31:1390–6. https://doi.org/10.1093/humrep/dew066.

    Article  PubMed  Google Scholar 

  6. Martyn FM, McAuliffe FM, Beggan C, Downey P, Flannelly G, Wingfield MB. Excisional treatments of the cervix and effect on subsequent fertility: a retrospective cohort study. Eur J Obstet Gynecol Reprod Biol. 2015;185:114–20. https://doi.org/10.1016/j.ejogrb.2014.12.004.

    Article  PubMed  Google Scholar 

  7. Cakmak H, Taylor HS. Implantation failure: molecular mechanisms and clinical treatment. Hum Reprod Update. 2011;17:242–53. https://doi.org/10.1093/humupd/dmq037.

    Article  CAS  PubMed  Google Scholar 

  8. Lyons RA, Saridogan E, Djahanbakhch O. The reproductive significance of human fallopian tube cilia. Hum Reprod Update. 2006;12:363–72. https://doi.org/10.1093/humupd/dml012.

    Article  CAS  PubMed  Google Scholar 

  9. Younis JS, Laufer N. Peritoneal fluid in the pouch of Douglas: strategically located and affecting reproductive events. Fertil Steril. 2015;104:831–2. https://doi.org/10.1016/j.fertnstert.2015.08.010.

    Article  PubMed  Google Scholar 

  10. Wang C, Swerdloff RS. Limitations of semen analysis as a test of male fertility and anticipated needs from newer tests. Fertil Steril. 2014;102:1502–7. https://doi.org/10.1016/j.fertnstert.2014.10.021.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Younis JS. The Bologna criteria for poor ovarian response; has the job been accomplished? Hum Reprod. 2012;27:1874–6. https://doi.org/10.1093/humrep/des118.

  12. Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L. ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011;26:1616–24. https://doi.org/10.1093/humrep/der092.

    Article  CAS  PubMed  Google Scholar 

  13. Younis JS, Ben-Ami M, Ben-Shlomo I. The Bologna criteria for poor ovarian response: a contemporary critical appraisal. J Ovarian Res. 2015;8(76):76. https://doi.org/10.1186/s13048-015-0204-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. te Velde E, Habbema D, Leridon H, Eijkemans M. The effect of postponement of first motherhood on permanent involuntary childlessness and total fertility rate in six European countries since the 1970s. Hum Reprod. 2012;27:1179–83. https://doi.org/10.1093/humrep/der455.

  15. Smith S, Pfeifer SM, Collins JA. Diagnosis and management of female infertility. JAMA. 2003;290:1767–70. https://doi.org/10.1001/jama.290.13.1767.

    Article  CAS  PubMed  Google Scholar 

  16. Hamilton JA, Cissen M, Brandes M, Smeenk JM, De Bruin JP, Kremer JA, et al. Total motile sperm count: a better indicator for the severity of male factor infertility than the WHO sperm classification system. Hum Reprod. 2015;30:1110–21. https://doi.org/10.1093/humrep/dev058.

    Article  CAS  PubMed  Google Scholar 

  17. Younis JS, Radin O, Mirsky N, Izhaki I, Majara T, Bar-Ami S, et al. First polar body and nucleolar precursor body morphology is related to the ovarian reserve of infertile women. Reprod BioMed Online. 2008;16:851–8. https://doi.org/10.1016/S1472-6483(10)60152-6.

    Article  PubMed  Google Scholar 

  18. Van Royen E, Mangelschots K, De Neubourg D, Valkenburg M, Van de Meerssche M, Ryckaert G, et al. Characterization of a top quality embryo, a step towards single-embryo transfer. Hum Reprod. 1999;14:2345–9.

    Article  PubMed  Google Scholar 

  19. Seckin B, Turkcapar F, Ozaksit G. Elevated day 3 FSH/LH ratio: a marker to predict IVF outcome in young and older women. J Assist Reprod Genet. 2012;29(3):231–6.

    Article  PubMed  Google Scholar 

  20. Goverde AJ, McDonnell J, Schats R, Vermeiden JPW, Homburg R, Lambalk CB. Ovarian response to standard gonadotrophin stimulation for IVF is decreased not only in older but also in younger women in couples with idiopathic and male subfertility. Hum Reprod. 2005;20:1573–7. https://doi.org/10.1093/humrep/deh827.

    Article  CAS  PubMed  Google Scholar 

  21. Broekmans FJ, De Ziegler D, Howles CM, Gougeon A, Trew G, Olivennes F. The antral follicle count: practical recommendations for better standardization. Fertil Steril. 2010;94:1044–51. https://doi.org/10.1016/j.fertnstert.2009.04.040.

    Article  PubMed  Google Scholar 

  22. Randolph JF, Ginsburg KA, Leach RE, Blacker CM, Moghissi KS, Diamond MP, et al. Elevated early follicular gonadotropin levels in women with unexplained infertility do not provide evidence for disordered gonadotropin-releasing hormone secretion as assessed by luteinizing hormone pulse characteristics. Fertil Steril. 2003;80:320–7. https://doi.org/10.1016/S0015-0282(03)00612-5.

    Article  PubMed  Google Scholar 

  23. Kok HS, Van Asselt KM, Van Der Schouw YT, Grobbee DE, Te Velde ER, Pearson PL, et al. Subfertility reflects accelerated ovarian ageing. Hum Reprod. 2003;18:644–8. https://doi.org/10.1093/humrep/deg126.

    Article  PubMed  Google Scholar 

  24. De Boer EJ, Den Tonkelaar I, Te Velde ER, Burger CW, Klip H, Van Leeuwen FE. A low number of retrieved oocytes at in vitro fertilization treatment is predictive of early menopause. Fertil Steril. 2002;77:978–85. https://doi.org/10.1016/S0015-0282(02)02972-2.

    Article  PubMed  Google Scholar 

  25. Nikolaou D, Lavery S, Turner C, Margara R, Trew G. Is there a link between an extremely poor response to ovarian hyperstimulation and early ovarian failure? Hum Reprod. 2002;17:1106–11. https://doi.org/10.1093/humrep/17.4.1106.

    Article  CAS  PubMed  Google Scholar 

  26. Beckers NGM, Macklon NS, Eijkemans MJC, Fauser BC. Women with regular menstrual cycles and a poor response to ovarian hyperstimulation for in vitro fertilization exhibit follicular phase characteristics suggestive of ovarian aging. Fertil Steril. 2002;78:291–7. https://doi.org/10.1016/S0015-0282(02)03227-2.

    Article  PubMed  Google Scholar 

  27. Lawson R, El-Toukhy T, Kassab A, Taylor A, Braude P, Parsons J, et al. Poor response to ovulation induction is a stronger predictor of early menopause than elevated basal FSH: a life table analysis. Hum Reprod. 2003;18:527–33. https://doi.org/10.1093/humrep/deg101.

    Article  CAS  PubMed  Google Scholar 

  28. Szmidt NA, Bhattacharya S, Maheshwari A. Does poor ovarian response to gonadotrophins predict early menopause? A retrospective cohort study with minimum of 10-year follow-up. Hum Fertil. 2016;19:212–9. https://doi.org/10.1080/14647273.2016.1221149.

    Article  CAS  Google Scholar 

  29. Hvidman HW, Bentzen JG, Thuesen LL, Lauritsen MP, Forman JL, Loft A, et al. Infertile women below the age of 40 have similar anti-Müllerian hormone levels and antral follicle count compared with women of the same age with no history of infertility. Hum Reprod. 2016;31:1034–45. https://doi.org/10.1093/humrep/dew032.

    Article  CAS  PubMed  Google Scholar 

  30. Greenwood EA, Cedars MI, Santoro N, Eisenberg E, Kao CN, Haisenleder DJ, et al. Antimüllerian hormone levels and antral follicle counts are not reduced compared with community controls in patients with rigorously defined unexplained infertility. Fertil Steril. 2017;108:1070–7. https://doi.org/10.1016/j.fertnstert.2017.09.015.

    Article  CAS  PubMed  Google Scholar 

  31. Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update. 2006;12:685–718.

    Article  CAS  PubMed  Google Scholar 

  32. Broer SL, van Disseldorp J, Broeze KA, Dolleman M, Opmeer BC, Bossuyt P, et al. Added value of ovarian reserve testing on patient characteristics in the prediction of ovarian response and ongoing pregnancy: an individual patient data approach. Hum Reprod Update. 2013;19:26–36. https://doi.org/10.1093/humupd/dms041.

    Article  PubMed  Google Scholar 

  33. Lambalk CB, van Disseldorp J, de Koning CH, Broekmans FJ. Testing ovarian reserve to predict age at menopause. Maturitas. 2009;63:280–91. https://doi.org/10.1016/j.maturitas.2009.06.007.

    Article  CAS  PubMed  Google Scholar 

  34. La Marca A, Dondi G, Sighinolfi G, Giulini S, Papaleo E, Cagnacci A, et al. The ovarian response to controlled stimulation in IVF cycles may be predictive of the age at menopause. Hum Reprod. 2014;29:2530–5. https://doi.org/10.1093/humrep/deu234.

    Article  CAS  PubMed  Google Scholar 

  35. Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW, Behre HM, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2010;16(3):231–45.

    Article  PubMed  Google Scholar 

  36. Land JA, Yarmolinskaya MI, Dumoulin JC, Evers JL. High-dose human menopausal gonadotropin stimulation in poor responders does not improve in vitro fertilization outcome. Fertile Steril. 1996;65(5):961–5.

    Article  CAS  Google Scholar 

  37. Roest J, van Heusden AM, Mous H, Zeilmaker GH, Verhoeff A. The ovarian response as a predictor for successful in vitro fertilization treatment after the age of 40 years. Fertile Steril. 1996;66(6):969–73.

    Article  CAS  Google Scholar 

  38. Lashen H, Ledger W, Lopez-Bernal A, Barlow D. Poor responders to ovulation induction: is proceeding to in-vitro fertilization worthwhile? Hum Reprod. 1999;14(4):964–9.

    Article  CAS  PubMed  Google Scholar 

  39. Raga F, Bonilla-Musoles F, Casañ EM, Bonilla F. Recombinant follicle stimulating hormone stimulation in poor responders with normal basal concentrations of follicle stimulating hormone and oestradiol: improved reproductive outcome. Hum Reprod. 1999;14(6):1431–4.

    Article  CAS  PubMed  Google Scholar 

  40. Garcia-Velasco JA, Isaza V, Requena A, Martínez-Salazar FJ, Landazábal A, Remohí J, et al. High doses of gonadotrophins combined with stop versus non-stop protocol of GnRH analogue administration in low responder IVF patients: a prospective, randomized, controlled trial. Hum Reprod. 2000;15(11):2292–6.

    Article  CAS  PubMed  Google Scholar 

  41. Weissman A, Farhi J, Royburt M, Nahum H, Glezerman M, Levran D. Prospective evaluation of two stimulation protocols for low responders who were undergoing in vitro fertilization-embryo transfer. Fertil Steril. 2003;79(4):886–92.

    Article  PubMed  Google Scholar 

  42. Macklon NS, Stouffer RL, Giudice LC, Fauser BC. The science behind 25 years of ovarian stimulation for in vitro fertilization. Endocr Rev. 2006;27(2):170–207.

    Article  PubMed  Google Scholar 

  43. Tazegül A, Görkemli H, Ozdemir S, Aktan TM. Comparison of multiple dose GnRH antagonist and minidose long agonist protocols in poor responders undergoing IVF. Arch Gynecol Obstet. 2008;278(5):467–72.

    Article  CAS  PubMed  Google Scholar 

  44. Broekmans FJ, Soules MR, Fauser BC. Ovarian aging: mechanisms and clinical consequences. Endocr Rev. 2009;30(5):465–93.

    Article  CAS  PubMed  Google Scholar 

  45. Mukherjee T, Copperman AB, Lapinski R, Sandler B, Bustillo M, Grunfeld L. An elevated day three follicle-stimulating hormone:luteinizing hormone ratio (FSH:LH) in the presence of a normal day 3 FSH predicts a poor response to controlled ovarian hyperstimulation. Fertile Steril. 1996;65(3):588–93.

    Article  CAS  Google Scholar 

  46. Barroso G, Oehninger S, Monzó A, Kolm P, Gibbons WE, Muasher SJ. High FSH:LH ratio and low LH levels in basal cycle day 3: impact on follicular development and IVF outcome. J Assist Reprod Genet. 2001;18(9):499–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Shrim A, Elizur SE, Seidman DS, Rabinovici J, Wiser A, Dor J. Elevated day 3 FSH/LH ratio due to low LH concentrations predicts reduced ovarian response. Reprod Biomed Online. 2006;12(4):418–22.

    Article  CAS  PubMed  Google Scholar 

  48. Liu KE, Greenblatt EM. Elevated day 3 follicle-stimulating hormone/luteinizing hormone ratio >or=2 is associated with higher rates of cancellation in in vitro fertilization-embryo transfer cycles. Fertile Steril. 2008;90(2):297–301.

    Article  CAS  Google Scholar 

  49. Brodin T, Bergh T, Berglund L, Hadziosmanovic N, Holte J. High basal LH levels in combination with low basal FSH levels are associated with high success rates at assisted reproduction. Hum Reprod. 2009;24(11):2755–9.

    Article  CAS  PubMed  Google Scholar 

  50. Lyu SW, Kim JW, Choi CH, Seok HH, Yoon TK, Kim A. Impact of high basal FSH/LH ratio in women with normal FSH levels on in vitro fertilization outcomes. Gynecol Endocrinol. 2013;29(5):424–9.

    Article  CAS  PubMed  Google Scholar 

  51. Simoni M, Nieschlag E, Gromoll J. Isoforms and single nucleotide polymorphisms of the FSH receptor gene: implications for human reproduction. Hum Reprod Update. 2002;8(5):413–21.

    Article  CAS  PubMed  Google Scholar 

  52. Perez Mayorga M, Gromoll J, Behre HM, Gassner C, Nieschlag E, Simoni M. ovarian response to follicle-stimulating hormone (FSH) stimulation depends on the FSH receptor genotype. J Clin Endocrinol Metab. 2000;85(9):3365–9.

    CAS  PubMed  Google Scholar 

  53. de Koning CH, Benjamins T, Harms P, Homburg R, van Montfrans JM, Gromoll J, et al. The distribution of FSH receptor isoforms is related to basal FSH levels in subfertile women with normal menstrual cycles. Hum Reprod. 2006;21(2):443–6.

    Article  CAS  PubMed  Google Scholar 

  54. Sudo S, Kudo M, Wada S, Sato O, Hsueh AJ, Fujimoto S. Genetic and functional analyses of polymorphisms in the human FSH receptor gene. Mol Hum Reprod. 2002;8(10):893–9.

    Article  CAS  PubMed  Google Scholar 

  55. Behre HM, Greb RR, Mempel A, Sonntag B, Kiesel L, Kaltwasser P, et al. significance of a common single nucleotide polymorphism in exon 10 of the follicle-stimulating hormone (FSH) receptor gene for the ovarian response to FSH: a pharmacogenetic approach to controlled ovarian hyperstimulation. Pharmacogenet Genomics. 2005;15(7):451–6.

    Article  CAS  PubMed  Google Scholar 

  56. Lindgren I, Bååth M, Uvebrant K, Dejmek A, Kjaer L, Henic E, et al. Combined assessment of polymorphisms in the LHCGR and FSHR genes predict chance of pregnancy after in vitro fertilization. Hum Reprod. 2016;31(3):672–83.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Johnny S. Younis.

Ethics declarations

Conflict of interests

The authors declare they have no conflict of interest.

Ethical approval

Approval and waiver of written informed consent to retrieve and analyze the data was obtained from the Institutional Review and Ethical Committee of Poriya Medical Center. No additional interventions were performed to the routine clinical and laboratory standards in our unit.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abrahami, N., Izhaki, I. & Younis, J.S. Do young women with unexplained infertility show manifestations of decreased ovarian reserve?. J Assist Reprod Genet 36, 1143–1152 (2019). https://doi.org/10.1007/s10815-019-01467-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-019-01467-0

Keywords

Navigation