Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-78c5997874-4rdpn Total loading time: 0 Render date: 2024-11-15T11:19:34.678Z Has data issue: false hasContentIssue false

Chapter 7 - Optimal IVF Protocols for Women over 40 and Low Functional Ovarian Reserve

from Section 5 - Optimal Deployment of ART beyond 40

Published online by Cambridge University Press:  15 September 2022

By
David H. Barad  and
Norbert Gleicher
Edited by
Dimitrios S. Nikolaou  and
David B. Seifer
Dimitrios S. Nikolaou
Affiliation:
Chelsea and Westminster Hospital, London
David B. Seifer
Affiliation:
Yale Reproductive Medicine, New Haven, CT
Get access

Summary

As women age, their response to ovulation induction is progressively diminished due to the continuous depletion of primordial follicles and to changes in the ovarian endocrine/paracrine microenvironment. While many couples faced with the reality of a diagnosis of low functional ovarian reserve may turn to the use of donor gametes to achieve a pregnancy, some still feel the need to try on their own, despite a poor prognosis. For such women careful preparation and hormonal priming in the months prior to beginning an IVF cycle can increase their chance of a successful outcome. Optimal treatment of these patients differs from the usual treatment of women with normal ovarian reserve in every aspect and needs to be highly individualized.

Keywords

Agingin vitro fertilizationovulation inductionovarian reservefunctional ovarian reserveovarian insufficiencypremature ovarian insufficiencyfolliculogenesisatresiaandrogenDHEAhuman growth hormoneplatelet rich plasma (PRP)
Type
Chapter
Information
Optimizing the Management of Fertility in Women over 40 , pp. 81 - 97
Publisher: Cambridge University Press
Print publication year: 2022

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Gleicher, N, Kushnir, VA, Weghofer, A, Barad, DH. The “graying” of infertility services: an impending revolution nobody is ready for. Reprod Biol Endocrinol 2014; 12: 63.Google Scholar
Ethics Committee of American Society for Reproductive Medicine. Fertility treatment when the prognosis is very poor or futile: a committee opinion. Fertil Steril 2012; 98(1): e6–9.CrossRefGoogle Scholar
Gleicher, N, Vega, MV, Darmon, SK, et al. Live-birth rates in very poor prognosis patients, who are defined as poor responders under the Bologna criteria, with nonelective single embryo, two-embryo, and three or more embryos transferred. Fertil Steril 2015; 104(6): 1435–41.Google Scholar
Leridon, H. Can assisted reproduction technology compensate for the natural decline in fertility with age? A model assessment. Hum Reprod 2004; 19(7): 1548–53.CrossRefGoogle ScholarPubMed
Gleicher, N, Weghofer, A, Barad, DH. Defining ovarian reserve to better understand ovarian aging. Reprod Biol Endocrinol 2011; 9: 23.Google Scholar
Findlay, JK, Dunning, KR, Gilchrist, RB, Hutt, KJ, Russell, DL, Walters, KA. Chapter 1 - Follicle selection in mammalian ovaries. In: Leung, PCK, Adashi, EY, eds. The Ovary (Third Edition): Academic Press; 2019: 3–21.Google Scholar
Prasasya, RD, Mayo, KE. Chapter 2 - Regulation of follicle formation and development by ovarian signaling pathways. In: Leung, PCK, Adashi, EY, eds. The Ovary (Third Edition): Academic Press; 2019: 23–49.CrossRefGoogle Scholar
Kushnir, VA, Seifer, DB, Barad, DH, Sen, A, Gleicher, N. Potential therapeutic applications of human anti-Müllerian hormone (AMH) analogues in reproductive medicine. J Assist Reprod Genet 2017; 34(9): 1105–13.Google Scholar
Kim, H-A, Choi, J, Park, CS, et al. Post-chemotherapy serum anti-Müllerian hormone level predicts ovarian function recovery. Endocr Connect 2018; 7(8): 949–56.Google Scholar
van Zonneveld, P, Scheffer, GJ, Broekmans, FJ, et al. Do cycle disturbances explain the age-related decline of female fertility? Cycle characteristics of women aged over 40 years compared with a reference population of young women. Hum Reprod 2003; 18(3): 495–501.CrossRefGoogle ScholarPubMed
Prizant, H, Gleicher, N, Sen, A. Androgen actions in the ovary: balance is key. J Endocrinol 2014; 222(3): R141–51.Google Scholar
Sen, A, Prizant, H, Hammes, SR. Understanding extranuclear (nongenomic) androgen signaling: what a frog oocyte can tell us about human biology. Steroids 2011; 76(9): 822–8.Google Scholar
Sen, A, Prizant, H, Light, A, et al. Androgens regulate ovarian follicular development by increasing follicle stimulating hormone receptor and microRNA-125b expression. Proc Natl Acad Sci U S A 2014; 111(8): 3008–13.CrossRefGoogle ScholarPubMed
Schulman, RA, Dean, C. Solve it with supplements : the best herbal and nutritional supplements to prevent and heal more than 100 common health problems. Emmaus, Pa.: Rodale; 2007.Google Scholar
Zwain, IH, Yen, SSC. Dehydroepiandrosterone: biosynthesis and metabolism in the brain. Endocrinology 1999; 140(2): 880–7.Google Scholar
Chen, F, Knecht, K, Birzin, E, et al. Direct agonist/antagonist functions of dehydroepiandrosterone. Endocrinology 2005; 146(11): 4568–76.Google Scholar
Gleicher, N, Kim, A, Weghofer, A, et al. Hypoandrogenism in association with diminished functional ovarian reserve. Hum Reprod 2013; 28(4): 1084–91.Google Scholar
Gleicher, N, Barad, DH. Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR). Reprod Biol Endocrinol 2011; 9: 67.CrossRefGoogle ScholarPubMed
Gleicher, N, Kushnir, VA, Barad, DH. Chapter 24 - The ovarian factor in assisted reproductive technology. In: Leung, PCK, Adashi, EY, eds. The Ovary (Third Edition): Academic Press; 2019: 379–401.CrossRefGoogle Scholar
Sen, A, Hammes, SR. Granulosa cell-specific androgen receptors are critical regulators of ovarian development and function. Mol Endocrinol 2010; 24(7): 1393–403.Google Scholar
Gallagher, LM, Owen, LJ, Keevil, BG. Simultaneous determination of androstenedione and testosterone in human serum by liquid chromatography-tandem mass spectrometry. Ann Clin Biochem 2007; 44(Pt 1): 48–56.Google Scholar
Shohat-Tal, A, Sen, A, Barad, DH, Kushnir, V, Gleicher, N. Genetics of androgen metabolism in women with infertility and hypoandrogenism. Nat Rev Endocrinol 2015; 11(7): 429–41.Google Scholar
Wojciechowska, A, Osowski, A, Jóźwik, M, Górecki, R, Rynkiewicz, A, Wojtkiewicz, J. Inositols’ importance in the improvement of the endocrine-metabolic profile in PCOS. Int J Mol Sci 2019; 20(22): 5787.CrossRefGoogle ScholarPubMed
Showell, MG, Mackenzie-Proctor, R, Jordan, V, Hodgson, R, Farquhar, C. Inositol for subfertile women with polycystic ovary syndrome. Cochrane Database Syst Rev 2018; 12: CD012378.Google ScholarPubMed
Surrey, ES. Management of the poor responder: the role of GnRH agonists and antagonists. J Assist Reprod Genet 2007; 24(12): 613–19.Google Scholar
Barad, DH, Kim, A, Kubba, H, Weghofer, A, Gleicher, N. Does hormonal contraception prior to in vitro fertilization (IVF) negatively affect oocyte yields? A pilot study. Reprod Biol Endocrinol 2013; 11: 28.Google Scholar
Smulders, B, van Oirschot, SM, Farquhar, C, Rombauts, L, Kremer, JA. Oral contraceptive pill, progestogen or estrogen pre-treatment for ovarian stimulation protocols for women undergoing assisted reproductive techniques. Cochrane Database Syst Rev 2010;1: CD006109.Google Scholar
Farquhar, C, Rombauts, L, Kremer, JA, Lethaby, A, Ayeleke, RO. Oral contraceptive pill, progestogen or oestrogen pretreatment for ovarian stimulation protocols for women undergoing assisted reproductive techniques. Cochrane Database Syst Rev 2017; 5: CD006109.Google Scholar
Farquhar, C, Rombauts, L, Kremer, JA, Lethaby, A, Ayeleke, RO. Oral contraceptive pill, progestogen or oestrogen pretreatment for ovarian stimulation protocols for women undergoing assisted reproductive techniques. Cochrane Database Syst Rev 2017; 5: CD006109-CD.Google Scholar
Fanchin, R, Cunha-Filho, JS, Schonauer, LM, Kadoch, IJ, Cohen-Bacri, P, Frydman, R. Coordination of early antral follicles by luteal estradiol administration provides a basis for alternative controlled ovarian hyperstimulation regimens. Fertil Steril 2003; 79(2): 316–21.Google Scholar
Reynolds, KA, Omurtag, KR, Jimenez, PT, Rhee, JS, Tuuli, MG, Jungheim, ES. Cycle cancellation and pregnancy after luteal estradiol priming in women defined as poor responders: a systematic review and meta-analysis. Human Reprod 2013; 28(11): 2981–9.Google Scholar
Kuczynski, A. Anti-aging potion or poison? The New York Times 1998; April 12, Sect. 1.Google Scholar
Liu, H, Bravata, DM, Olkin, I, et al. Systematic review: the safety and efficacy of growth hormone in the healthy elderly. Ann Intern Med 2007; 146(2): 104–15.Google Scholar
Duffy, JM, Ahmad, G, Mohiyiddeen, L, Nardo, LG, Watson, A. Growth hormone for in vitro fertilization. Cochrane Database Syst Rev 2010; 1: CD000099.Google Scholar
Cozzolino, M, Cecchino, GN, Troiano, G, Romanelli, C. Growth hormone cotreatment for poor responders undergoing in vitro fertilization cycles: a systematic review and meta-analysis. Fertil Steril 2020; 114(1): 97–109.CrossRefGoogle ScholarPubMed
Bortoletto, P, Spandorfer, S. Growth hormone: in search of the Holy Grail for poor responders (or a felony). Fertil Steril 2020; 114(1): 63–4.Google Scholar
Kasapoğlu, I, Seli, E. Mitochondrial dysfunction and ovarian aging. Endocrinology 2020; 161(2).CrossRefGoogle ScholarPubMed
Wang, T, Zhang, M, Jiang, Z, Seli, E. Mitochondrial dysfunction and ovarian aging. Am J Reprod Immunol 2017; 77(5): e12651.Google Scholar
Bentov, Y, Yavorska, T, Esfandiari, N, Jurisicova, A, Casper, RF. The contribution of mitochondrial function to reproductive aging. J Assist Reprod Genet 2011; 28(9): 773–83.Google Scholar
Kalén, A, Appelkvist, E-L, Dallner, G. Age-related changes in the lipid compositions of rat and human tissues. Lipids 1989; 24(7): 579–84.Google Scholar
Ben-Meir, A, Burstein, E, Borrego-Alvarez, A, et al. Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging. Aging Cell 2015; 14(5): 887–95.Google Scholar
Bentov, Y, Casper, RF. The aging oocyte--can mitochondrial function be improved? Fertil Steril 2013; 99(1): 18–22.Google Scholar
Gat, I, Blanco Mejia, S, Balakier, H, Librach, CL, Claessens, A, Ryan, EA. The use of coenzyme Q10 and DHEA during IUI and IVF cycles in patients with decreased ovarian reserve. Gynecol Endocrinol 2016; 32(7): 534–7.CrossRefGoogle ScholarPubMed
Pantos, K, Nitsos, N, Kokkali, G, et al. Ovarian rejuvenation and folliculogenesis reactivation in peri-menopausal women after autologous platelet-rich plasma treatment. Abstracts of the 32nd Annual Meeting of the European Society of Human Reproduction and Embryology, Helsinki, Finland. Hum Reprod 2016: i301.Google Scholar
Fabi, S, Sundaram, H. The potential of topical and injectable growth factors and cytokines for skin rejuvenation. Facial Plast Surg 2014; 30(02): 157–71.Google Scholar
Xie, X, Zhang, C, Tuan, RS. Biology of platelet-rich plasma and its clinical application in cartilage repair. Arthritis Res Ther 2014; 16(1): 204.Google Scholar
Macaulay, IC, Carr, P, Gusnanto, A, Ouwehand, WH, Fitzgerald, D, Watkins, NA. Platelet genomics and proteomics in human health and disease. J Clin Invest 2005; 115: 3370–7.Google Scholar
McRedmond, JP, Park, SD, Reilly, DF, et al. Integration of proteomics and genomics in platelets: a profile of platelet proteins and platelet-specific genes. Mol Cell Proteomics 2004; 3: 133–44.CrossRefGoogle ScholarPubMed
Watson, SP, Bahou, WF, Fitzgerald, D, Ouwehand, W, Rao, AK, Leavitt, AD. ISTH platelet physiology subcommittee: mapping the platelet proteome: a report of the ISTH platelet physiology subcommittee. J Thromb Haemost 2005; 3: 2098–101.CrossRefGoogle ScholarPubMed
Sills, ES, Wood, SH. Autologous activated platelet-rich plasma injection into adult human ovary tissue: molecular mechanism, analysis, and discussion of reproductive response. Biosci Rep 2019; 39(6): BSR20190805.CrossRefGoogle ScholarPubMed
Farimani, M, Heshmati, S, Poorolajal, J, Bahmanzadeh, M. A report on three live births in women with poor ovarian response following intra-ovarian injection of platelet-rich plasma (PRP). Mol Biol Rep 2019; 46(2): 1611–16.Google Scholar
Hosseini, L, Shirazi, A, Naderi, MM, et al. Platelet-rich plasma promotes the development of isolated human primordial and primary follicles to the preantral stage. Reprod Biomed Online 2017; 35(4): 343–50.Google Scholar
Sills, ES, Rickers, NS, Li, X, Palermo, GD. First data on in vitro fertilization and blastocyst formation after intraovarian injection of calcium gluconate-activated autologous platelet rich plasma. Gynecol Endocrinol 2018; 34(9): 756–60.Google Scholar
Bidet, M, Bachelot, A, Bissauge, E, et al. Resumption of ovarian function and pregnancies in 358 patients with premature ovarian failure. J Clin Endocrinol Metab 2011; 96(12): 3864–72.CrossRefGoogle ScholarPubMed
Gulati, SC, Van Poznak, C. Pregnancy after bone marrow transplantation. J Clin Oncol 1998; 16(5): 1978–85.CrossRefGoogle ScholarPubMed
Loren, AW, Chow, E, Jacobsohn, DA, et al. Pregnancy after hematopoietic cell transplantation: a report from the late effects working committee of the Center for International Blood and Marrow Transplant Research (CIBMTR). Biol Blood Marrow Transplant 2011; 17(2): 157–66.Google Scholar
Akahori, T, Woods, DC, Tilly, JL. Female fertility preservation through stem cell-based ovarian tissue reconstitution in vitro and ovarian regeneration in vivo. Clin Med Insights Reprod Health 2019; 13: 1179558119848007.CrossRefGoogle ScholarPubMed
Herraiz, S, Buigues, A, Diaz-Garcia, C, et al. Fertility rescue and ovarian follicle growth promotion by bone marrow stem cell infusion. Fertil Steril 2018; 109(5): 908–18 e2.Google Scholar
Liu, R, Zhang, X, Fan, Z, et al. Human amniotic mesenchymal stem cells improve the follicular microenvironment to recover ovarian function in premature ovarian failure mice. Stem Cell Res Ther 2019; 10(1): 299.Google Scholar
Pandian, Z, McTavish, AR, Aucott, L, Hamilton, MP, Bhattacharya, S. Interventions for ‘poor responders’ to controlled ovarian hyper stimulation (COH) in in-vitro fertilisation (IVF). Cochrane Database Syst Rev 2010; (1): CD004379.Google Scholar
Al‐Inany, HG, Youssef, MA, Ayeleke, RO, Brown, J, Lam, WS, Broekmans, FJ. Gonadotrophin‐releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev 2016; (4): CD001750.Google Scholar
Kamath, MS, Maheshwari, A, Bhattacharya, S, Lor, KY, Gibreel, A. Oral medications including clomiphene citrate or aromatase inhibitors with gonadotropins for controlled ovarian stimulation in women undergoing in vitro fertilisation. Cochrane Database Syst Rev 2017; (11): CD008528.Google Scholar
Dahhan, T, Balkenende, E, van Wely, M, Linn, S, Goddijn, M. Tamoxifen or letrozole versus standard methods for women with estrogen‐receptor positive breast cancer undergoing oocyte or embryo cryopreservation in assisted reproduction. Cochrane Database Syst Rev 2013; (11): CD010240.Google Scholar
Check, JH. The multiple uses of ethinyl estradiol for treating infertility. Clin Exp Obstet Gynecol 2010; 37(4): 249–51.Google ScholarPubMed
Mochtar, MH, Danhof, NA, Ayeleke, RO, Van der Veen, F, van Wely, M. Recombinant luteinizing hormone (rLH) and recombinant follicle stimulating hormone (rFSH) for ovarian stimulation in IVF/ICSI cycles. Cochrane Database Syst Rev 2017; (5): CD005070.Google Scholar
Youssef, MA, van Wely, M, Mochtar, M, et al. Low dosing of gonadotropins in in vitro fertilization cycles for women with poor ovarian reserve: systematic review and meta-analysis. Fertil Steril 2018; 109(2): 289–301.Google Scholar
Barad, DH, Kushnir, VA, Lee, HJ, Lazzaroni, E, Gleicher, N. Effect of inter-cycle interval on oocyte production in humans in the presence of the weak androgen DHEA and follicle stimulating hormone: a case-control study. Reprod Biol Endocrinol 2014; 12: 68.Google Scholar
Barad, DH, Gleicher, N. Increased oocyte production after treatment with dehydroepiandrosterone. Fertil Steril 2005; 84(3): 756.Google Scholar
Wu, YG, Barad, DH, Kushnir, VA, et al. Aging-related premature luteinization of granulosa cells is avoided by early oocyte retrieval. J Endocrinol 2015; 226 (3): 167–80.Google Scholar
Wu, YG, Barad, DH, Kushnir, VA, et al. With low ovarian reserve, Highly Individualized Egg Retrieval (HIER) improves IVF results by avoiding premature luteinization. J Ovarian Res 2018; 11(1): 23.Google Scholar
Gleicher, N, Kushnir, VA, Darmon, S, Albertini, DF, Barad, DH. Older women using their own eggs? Issue framed with two oldest reported IVF pregnancies and a live birth. Reprod Biomed Online 2018; 37(2): 172–7.Google Scholar
Glujovsky, D, Farquhar, C, Quinteiro Retamar, AM, Alvarez Sedo, CR, Blake, D. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane Database Syst Rev 2016; (6): CD002118.Google Scholar
Xiao, JS, Healey, M, Talmor, A, Vollenhoven, B. When only one embryo is available, is it better to transfer on Day 3 or to grow on? Reprod Biomed Online 2019; 39(6): 916–23.Google Scholar
Kissin, DM, Kulkarni, AD, Kushnir, VA, Jamieson, DJ, National ARTSSG. Number of embryos transferred after in vitro fertilization and good perinatal outcome. Obstet Gynecol 2014; 123(2 Pt 1): 239–47.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×