Download PDF
Semin Reprod Med 2015; 33(03): 169-178
DOI: 10.1055/s-0035-1552585
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Shifting Paradigms in Diminished Ovarian Reserve and Advanced Reproductive Age in Assisted Reproduction: Customization Instead of Conformity

Beverly G. Reed
1   Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
,
Samir N. Babayev
1   Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
,
Orhan Bukulmez
1   Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas
› Author Affiliations
Further Information

Publication History

Publication Date:
02 June 2015 (online)

    Permissions and Reprints

Abstract

As women are increasingly delaying childbearing into their 30s and beyond, diminished ovarian reserve (DOR) and advanced reproductive age (ARA) patients are bound to become a large proportion of all assisted reproductive technology practices. Traditional controlled ovarian stimulation (COS) protocols for DOR and/or ARA have had some limited success, but pregnancy rates are lower and cycle cancellation rates are higher than their younger counterparts with normal ovarian reserve. Though many physicians have a selection of favorite standard protocols that they use, patients with DOR may require closer monitoring and customization of the treatment cycle to address the common problems that come with low ovarian reserve. Frequent issues that surface in women with DOR and/or ARA include poor follicular response, premature luteinizing hormone surge, and poor embryo quality. Limited published evidence exists to guide treatment for DOR. However, use of minimal or mild doses of gonadotropins, avoidance of severe pituitary suppression, and consideration for luteal phase stimulation and a “freeze all” approach are possible customized treatment options that can be considered for such patients who have failed more traditional COS protocols.

Keywords

diminished ovarian reserve - poor responder - advanced reproductive age - minimal stimulation - luteal phase stimulation
 

  • References

  • 1 Nabukera S, Wingate MS, Alexander GR, Salihu HM. First-time births among women 30 years and older in the United States: patterns and risk of adverse outcomes. J Reprod Med 2006; 51 (9) 676-682
    PubMedGoogle Scholar
  • 2 Martin JA, Hamilton BE, Osterman MJ, Curtin SC, Matthews TJ. Births: final data for 2013. Natl Vital Stat Rep 2015; 64 (1) 1-65
    PubMedGoogle Scholar
  • 3 Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod 1992; 7 (10) 1342-1346
    PubMedGoogle Scholar
  • 4 Dunson DB, Colombo B, Baird DD. Changes with age in the level and duration of fertility in the menstrual cycle. Hum Reprod 2002; 17 (5) 1399-1403
    CrossrefPubMedGoogle Scholar
  • 5 Rowe T. Fertility and a woman's age. J Reprod Med 2006; 51 (3) 157-163
    PubMedGoogle Scholar
  • 6 Seifer DB, Baker VL, Leader B. Age-specific serum anti-Müllerian hormone values for 17,120 women presenting to fertility centers within the United States. Fertil Steril 2011; 95 (2) 747-750
    CrossrefPubMedGoogle Scholar
  • 7 Wallace WH, Kelsey TW. Human ovarian reserve from conception to the menopause. PLoS ONE 2010; 5 (1) e8772
    CrossrefPubMedGoogle Scholar
  • 8 Battaglia DE, Goodwin P, Klein NA, Soules MR. Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. Hum Reprod 1996; 11 (10) 2217-2222
    CrossrefPubMedGoogle Scholar
  • 9 Angell RR. Aneuploidy in older women. Higher rates of aneuploidy in oocytes from older women. Hum Reprod 1994; 9 (7) 1199-1200
    PubMedGoogle Scholar
  • 10 Cramer SF, Patel A. The frequency of uterine leiomyomas. Am J Clin Pathol 1990; 94 (4) 435-438
    CrossrefPubMedGoogle Scholar
  • 11 Kuohung W, Jones GL, Vitonis AF , et al. Characteristics of patients with endometriosis in the United States and the United Kingdom. Fertil Steril 2002; 78 (4) 767-772
    CrossrefPubMedGoogle Scholar
  • 12 Muzii L, Achilli C, Lecce F , et al. Second surgery for recurrent endometriomas is more harmful to healthy ovarian tissue and ovarian reserve than first surgery. Fertil Steril 2015; 103 (3) 738-743
    CrossrefPubMedGoogle Scholar
  • 13 Oktay K, Oktem O. Ovarian cryopreservation and transplantation for fertility preservation for medical indications: report of an ongoing experience. Fertil Steril 2010; 93 (3) 762-768
    CrossrefPubMedGoogle Scholar
  • 14 Kushnir VA, Khanna P, Barad DH, Gleicher N. Establishment of comparative performance criteria for IVF centers: correlation of live birth rates in autologous and donor oocyte IVF cycles. Reprod Biol Endocrinol 2014; 12: 122
    CrossrefPubMedGoogle Scholar
  • 15 Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L ; ESHRE working group on Poor Ovarian Response Definition. ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod 2011; 26 (7) 1616-1624
    CrossrefPubMedGoogle Scholar
  • 16 Loutradis D, Drakakis P, Vomvolaki E, Antsaklis A. Different ovarian stimulation protocols for women with diminished ovarian reserve. J Assist Reprod Genet 2007; 24 (12) 597-611
    CrossrefPubMedGoogle Scholar
  • 17 Tarlatzis BC, Zepiridis L, Grimbizis G, Bontis J. Clinical management of low ovarian response to stimulation for IVF: a systematic review. Hum Reprod Update 2003; 9 (1) 61-76
    CrossrefPubMedGoogle Scholar
  • 18 Hofmann GE, Toner JP, Muasher SJ, Jones GS. High-dose follicle-stimulating hormone (FSH) ovarian stimulation in low-responder patients for in vitro fertilization. J In Vitro Fert Embryo Transf 1989; 6 (5) 285-289
    CrossrefPubMedGoogle Scholar
  • 19 Crosignani PG, Ragni G, Lombroso GC , et al. IVF: induction of ovulation in poor responders. J Steroid Biochem 1989; 32 (1B) 171-173
    CrossrefPubMedGoogle Scholar
  • 20 Scott RT, Navot D. Enhancement of ovarian responsiveness with microdoses of gonadotropin-releasing hormone agonist during ovulation induction for in vitro fertilization. Fertil Steril 1994; 61 (5) 880-885
    PubMedGoogle Scholar
  • 21 Hill MJ, McWilliams GD, Miller KA, Scott Jr RT, Frattarelli JL. A luteal estradiol protocol for anticipated poor-responder patients may improve delivery rates. Fertil Steril 2009; 91 (3) 739-743
    CrossrefPubMedGoogle Scholar
  • 22 Haas J, Zilberberg E, Machtinger R, Kedem A, Hourvitz A, Orvieto R. Do poor-responder patients benefit from increasing the daily gonadotropin dose during controlled ovarian hyperstimulation for IVF?. Gynecol Endocrinol 2015; 31 (1) 79-82
    CrossrefPubMedGoogle Scholar
  • 23 Baart EB, Martini E, Eijkemans MJ , et al. Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Hum Reprod 2007; 22 (4) 980-988
    CrossrefPubMedGoogle Scholar
  • 24 Handyside AH, Montag M, Magli MC , et al. Multiple meiotic errors caused by predivision of chromatids in women of advanced maternal age undergoing in vitro fertilisation. Eur J Hum Genet 2012; 20 (7) 742-747
    CrossrefPubMedGoogle Scholar
  • 25 Hill MJ, Levens ED, Levy G , et al. The use of recombinant luteinizing hormone in patients undergoing assisted reproductive techniques with advanced reproductive age: a systematic review and meta-analysis. Fertil Steril 2012; 97 (5) 1108-14.e1
    CrossrefPubMedGoogle Scholar
  • 26 Mochtar MH, , Van der Veen, Ziech M, van Wely M. Recombinant luteinizing hormone (rLH) for controlled ovarian hyperstimulation in assisted reproductive cycles. Cochrane Database Syst Rev 2007; 2 (2) CD005070
    PubMedGoogle Scholar
    • 27 Vuong TN, Phung HT, Ho MT. Recombinant follicle-stimulating hormone and recombinant luteinizing hormone versus recombinant follicle-stimulating hormone alone during GnRH antagonist ovarian stimulation in patients aged ≥35 years: a randomized controlled trial. Hum Reprod 2015; 30 (5) 1188-1195
      CrossrefPubMedGoogle Scholar
    • 28 Tabata C, Fujiwara T, Sugawa M , et al. Comparison of FSH and hMG on ovarian stimulation outcome with a GnRH antagonist protocol in younger and advanced reproductive age women. Reprod Med Biol 2015; 14: 5-9
      CrossrefPubMedGoogle Scholar
    • 29 Papaleo E, Vanni VS, Viganò P , et al. Recombinant LH administration in subsequent cycle after “unexpected” poor response to recombinant FSH monotherapy. Gynecol Endocrinol 2014; 30 (11) 813-816
      CrossrefPubMedGoogle Scholar
    • 30 Gomaa H, Casper RF, Esfandiari N, Chang P, Bentov Y. Addition of low dose hCG to rFSh benefits older women during ovarian stimulation for IVF. Reprod Biol Endocrinol 2012; 10: 55
      CrossrefPubMedGoogle Scholar
    • 31 Balasch J, Fábregues F, Peñarrubia J , et al. Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poor-responder IVF patients with normal basal concentrations of FSH. Hum Reprod 2006; 21 (7) 1884-1893
      CrossrefPubMedGoogle Scholar
    • 32 Kara M, Aydin T, Aran T, Turktekin N, Ozdemir B. Does dehydroepiandrosterone supplementation really affect IVF-ICSI outcome in women with poor ovarian reserve?. Eur J Obstet Gynecol Reprod Biol 2014; 173: 63-65
      CrossrefPubMedGoogle Scholar
    • 33 Poli E, Manfé S, Capuzzo D , et al. DHEA pre-treated patients, poor responders to a first IVF (ICSI) cycle: clinical results. Clin Exp Obstet Gynecol 2014; 41 (1) 5-9
      PubMedGoogle Scholar
    • 34 Yeung TW, Chai J, Li RH, Lee VC, Ho PC, Ng EH. A randomized, controlled, pilot trial on the effect of dehydroepiandrosterone on ovarian response markers, ovarian response, and in vitro fertilization outcomes in poor responders. Fertil Steril 2014; 102 (1) 108-115.e1
      CrossrefPubMedGoogle Scholar
    • 35 Duffy JM, Ahmad G, Mohiyiddeen L, Nardo LG, Watson A. Growth hormone for in vitro fertilization. Cochrane Database Syst Rev 2010; 4 (1) CD000099
      PubMedGoogle Scholar
    • 36 Eftekhar M, Aflatoonian A, Mohammadian F, Eftekhar T. Adjuvant growth hormone therapy in antagonist protocol in poor responders undergoing assisted reproductive technology. Arch Gynecol Obstet 2013; 287 (5) 1017-1021
      CrossrefPubMedGoogle Scholar
    • 37 Kim CH, You RM, Kang HJ , et al. GnRH antagonist multiple dose protocol with oral contraceptive pill pretreatment in poor responders undergoing IVF/ICSI. Clin Exp Reprod Med 2011; 38 (4) 228-233
      CrossrefPubMedGoogle Scholar
    • 38 Vlahos N, Papalouka M, Triantafyllidou O , et al. Dehydroepiandrosterone administration before IVF in poor responders: a prospective cohort study. Reprod Biomed Online 2015; 30 (2) 191-196
      CrossrefPubMedGoogle Scholar
    • 39 Xu B, Li Z, Yue J , et al. Effect of dehydroepiandrosterone administration in patients with poor ovarian response according to the Bologna criteria. PLoS ONE 2014; 9 (6) e99858
      CrossrefPubMedGoogle Scholar
    • 40 Venetis CA, Kolibianakis EM, Tarlatzi TB, Tarlatzis BC. Evidence-based management of poor ovarian response. Ann N Y Acad Sci 2010; 1205: 199-206
      CrossrefPubMedGoogle Scholar
    • 41 Madden JD, Milewich L, Parker Jr CR, Carr BR, Boyar RM, Mac Donald PC. The effect of oral contraceptive treatment on the serum concentration of dehydroisoandrosterone sulfate. Am J Obstet Gynecol 1978; 132 (4) 380-384
      CrossrefPubMedGoogle Scholar
    • 42 Griesinger G, Kolibianakis EM, Venetis C, Diedrich K, Tarlatzis B. Oral contraceptive pretreatment significantly reduces ongoing pregnancy likelihood in gonadotropin-releasing hormone antagonist cycles: an updated meta-analysis. Fertil Steril 2010; 94 (6) 2382-2384
      CrossrefPubMedGoogle Scholar
    • 43 Reichman DE, Zakarin L, Chao K, Meyer L, Davis OK, Rosenwaks Z. Diminished ovarian reserve is the predominant risk factor for gonadotropin-releasing hormone antagonist failure resulting in breakthrough luteinizing hormone surges in in vitro fertilization cycles. Fertil Steril 2014; 102 (1) 99-102
      CrossrefPubMedGoogle Scholar
    • 44 von Wolff M, Thaler CJ, Frambach T , et al. Ovarian stimulation to cryopreserve fertilized oocytes in cancer patients can be started in the luteal phase. Fertil Steril 2009; 92 (4) 1360-1365
      CrossrefPubMedGoogle Scholar
    • 45 Bedoschi GM, de Albuquerque FO, Ferriani RA, Navarro PA. Ovarian stimulation during the luteal phase for fertility preservation of cancer patients: case reports and review of the literature. J Assist Reprod Genet 2010; 27 (8) 491-494
      CrossrefPubMedGoogle Scholar
    • 46 Anderson RA, Kinniburgh D, Baird DT. Preliminary experience of the use of a gonadotrophin-releasing hormone antagonist in ovulation induction/in-vitro fertilization prior to cancer treatment. Hum Reprod 1999; 14 (10) 2665-2668
      CrossrefPubMedGoogle Scholar
    • 47 Kuang Y, Hong Q, Chen Q , et al. Luteal-phase ovarian stimulation is feasible for producing competent oocytes in women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment, with optimal pregnancy outcomes in frozen-thawed embryo transfer cycles. Fertil Steril 2014; 101 (1) 105-111
      CrossrefPubMedGoogle Scholar
    • 48 Fridén BE, Nilsson L. Gonadotrophin-releasing hormone-antagonist luteolysis during the preceding mid-luteal phase is a feasible protocol in ovarian hyperstimulation before in vitro fertilization. Acta Obstet Gynecol Scand 2005; 84 (8) 812-816
      CrossrefPubMedGoogle Scholar
    • 49 Winkler N, Bukulmez O, Hardy DB, Carr BR. Gonadotropin releasing hormone antagonists suppress aromatase and anti-Müllerian hormone expression in human granulosa cells. Fertil Steril 2010; 94 (5) 1832-1839
      CrossrefPubMedGoogle Scholar
    • 50 Xu B, Li Y. Flexible ovarian stimulation in a poor responder: a case report and literature review. Reprod Biomed Online 2013; 26 (4) 378-383
      CrossrefPubMedGoogle Scholar
    • 51 Kuang Y, Chen Q, Hong Q , et al. Double stimulations during the follicular and luteal phases of poor responders in IVF/ICSI programmes (Shanghai protocol). Reprod Biomed Online 2014; 29 (6) 684-691
      CrossrefPubMedGoogle Scholar
    • 52 Kucuk T, Sozen E. Luteal start of exogenous FSH in poor responder women. J Assist Reprod Genet 2007; 24 (12) 635-638
      CrossrefPubMedGoogle Scholar
    • 53 Revelli A, Chiadò A, Dalmasso P , et al. “Mild” vs. “long” protocol for controlled ovarian hyperstimulation in patients with expected poor ovarian responsiveness undergoing in vitro fertilization (IVF): a large prospective randomized trial. J Assist Reprod Genet 2014; 31 (7) 809-815
      CrossrefPubMedGoogle Scholar
    • 54 Macklon NS, Fauser BC. Mild stimulation in in vitro fertilization. Ann N Y Acad Sci 2003; 997: 105-111
      CrossrefPubMedGoogle Scholar
    • 55 Zarek SM, Muasher SJ. Mild/minimal stimulation for in vitro fertilization: an old idea that needs to be revisited. Fertil Steril 2011; 95 (8) 2449-2455
      CrossrefPubMedGoogle Scholar
    • 56 Zhang J, Chang L, Sone Y, Silber S. Minimal ovarian stimulation (mini-IVF) for IVF utilizing vitrification and cryopreserved embryo transfer. Reprod Biomed Online 2010; 21 (4) 485-495
      CrossrefPubMedGoogle Scholar
    • 57 Hu L, Bu Z, Guo Y, Su Y, Zhai J, Sun Y. Comparison of different ovarian hyperstimulation protocols efficacy in poor ovarian responders according to the Bologna criteria. Int J Clin Exp Med 2014; 7 (4) 1128-1134
      PubMedGoogle Scholar
    • 58 Kato K, Takehara Y, Segawa T , et al. Minimal ovarian stimulation combined with elective single embryo transfer policy: age-specific results of a large, single-centre, Japanese cohort. Reprod Biol Endocrinol 2012; 10: 35
      CrossrefPubMedGoogle Scholar
    • 59 D'Amato G, Caroppo E, Pasquadibisceglie A, Carone D, Vitti A, Vizziello GM. A novel protocol of ovulation induction with delayed gonadotropin-releasing hormone antagonist administration combined with high-dose recombinant follicle-stimulating hormone and clomiphene citrate for poor responders and women over 35 years. Fertil Steril 2004; 81 (6) 1572-1577
      CrossrefPubMedGoogle Scholar
    • 60 Takahashi K, Mukaida T, Tomiyama T, Goto T, Oka C. GnRH antagonist improved blastocyst quality and pregnancy outcome after multiple failures of IVF/ICSI-ET with a GnRH agonist protocol. J Assist Reprod Genet 2004; 21 (9) 317-322
      CrossrefPubMedGoogle Scholar
    • 61 Craft I, Gorgy A, Hill J, Menon D, Podsiadly B. Will GnRH antagonists provide new hope for patients considered ‘difficult responders’ to GnRH agonist protocols?. Hum Reprod 1999; 14 (12) 2959-2962
      CrossrefPubMedGoogle Scholar
    • 62 Check JH, Choe JK, Cohen R. Successful pregnancy following a single fresh embryo transfer in a 45-year-old woman whose early follicular phase serum follicle stimulating hormone was 29 mIU/ml. Clin Exp Obstet Gynecol 2011; 38 (4) 335-337
      PubMedGoogle Scholar
    • 63 Check JH, Chern R, Amui J. Successful pregnancy following in vitro fertilization embryo transfer in a 46-year-old woman with diminished oocyte reserve as evidenced by a high day 3 serum estradiol. Clin Exp Obstet Gynecol 2011; 38 (3) 209-210
      PubMedGoogle Scholar
    • 64 Schachter M, Friedler S, Raziel A, Strassburger D, Bern O, Ron-el R. Improvement of IVF outcome in poor responders by discontinuation of GnRH analogue during the gonadotropin stimulation phase—a function of improved embryo quality. J Assist Reprod Genet 2001; 18 (4) 197-204
      PubMedGoogle Scholar
    • 65 Yanagimachi R. Intracytoplasmic injection of spermatozoa and spermatogenic cells: its biology and applications in humans and animals. Reprod Biomed Online 2005; 10 (2) 247-288
      CrossrefPubMedGoogle Scholar
    • 66 Artini PG, Obino ME, Carletti E , et al. Conventional IVF as a laboratory strategy to rescue fertility potential in severe poor responder patients: the impact of reproductive aging. Gynecol Endocrinol 2013; 29 (11) 997-1001
      CrossrefPubMedGoogle Scholar
    • 67 Babayev SN, Park CW, Bukulmez O. Intracytoplasmic sperm injection indications: how rigorous?. Semin Reprod Med 2014; 32 (4) 283-290
      Article in Thieme ConnectPubMedGoogle Scholar
    • 68 Greco E, Litwicka K, Arrivi C , et al. Accumulation of oocytes from a few modified natural cycles to improve IVF results: a pilot study. J Assist Reprod Genet 2013; 30 (11) 1465-1470
      CrossrefPubMedGoogle Scholar
    • 69 Chatziparasidou A, Nijs M, Moisidou M , et al. Accumulation of oocytes and/or embryos by vitrification: a new strategy for managing poor responder patients undergoing pre implantation diagnosis. F1000 Res 2013; 2: 240
      PubMedGoogle Scholar
    • 70 Cobo A, Garrido N, Crespo J, José R, Pellicer A. Accumulation of oocytes: a new strategy for managing low-responder patients. Reprod Biomed Online 2012; 24 (4) 424-432
      CrossrefPubMedGoogle Scholar
    • 71 Shapiro BS, Daneshmand ST, Restrepo H, Garner FC, Aguirre M, Hudson C. Matched-cohort comparison of single-embryo transfers in fresh and frozen-thawed embryo transfer cycles. Fertil Steril 2013; 99 (2) 389-392
      CrossrefPubMedGoogle Scholar
    • 72 Roque M, Lattes K, Serra S , et al. Fresh embryo transfer versus frozen embryo transfer in in vitro fertilization cycles: a systematic review and meta-analysis. Fertil Steril 2013; 99 (1) 156-162
      CrossrefPubMedGoogle Scholar
    • 73 Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C. Clinical rationale for cryopreservation of entire embryo cohorts in lieu of fresh transfer. Fertil Steril 2014; 102 (1) 3-9
      CrossrefPubMedGoogle Scholar
    • 74 Barnhart KT. Introduction: are we ready to eliminate the transfer of fresh embryos in in vitro fertilization?. Fertil Steril 2014; 102 (1) 1-2
      CrossrefPubMedGoogle Scholar
    • 75 Practice Committee of Society for Assisted Reproductive Technology; Practice Committee of American Society for Reproductive Medicine. Elective single-embryo transfer. Fertil Steril 2012; 97 (4) 835-842
      CrossrefPubMedGoogle Scholar
    • 76 Papathanasiou A. Implementing the ESHRE ‘poor responder’ criteria in research studies: methodological implications. Hum Reprod 2014; 29 (9) 1835-1838
      CrossrefPubMedGoogle Scholar
    • 77 Frydman R, Nargund G. Mild approaches in assisted reproduction—better for the future?. Fertil Steril 2014; 102 (6) 1540-1541
      CrossrefPubMedGoogle Scholar