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Chapter 2 - Biological Basis of Female Reproductive Aging: What Happens to the Ovaries and Uterus as They Age?

from Section 2 - Biological Basis of Female Reproductive Aging: What Happens to the Ovaries and the Uterus as they Age?

Published online by Cambridge University Press:  15 September 2022

By
Jacquelyn Shaw ,
Jennifer K. Blakemore  and
David L. Keefe
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
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Summary

The loss of oocytes and reduced oocyte quality contribute to age-associated ovarian decline and decreased fertility, which is at odds with the social trend toward delayed family building. Females are born with a finite cohort of germ cells, arrested from mid-gestation, and they progressively lose them throughout their reproductive lifespan, reaching a state of near depletion at menopause. Declining oocyte number, however, is not the sole culprit for age-related infertility. Oocyte competence, the ability to fertilize, develop, implant, and produce a live offspring, deteriorates more or less in concert with declining ovarian reserve. The uterus likely also plays a role, further hindering reproduction later in life, though additional studies are needed.

Keywords

Oocyte competenceovarian ageingmeiotic non-disjunctionchiasmata formationcohesion defectestelomete attritionreactive ogygene speciesmitochondriaamyloidsirtruinsreservatrol
Type
Chapter
Information
Optimizing the Management of Fertility in Women over 40 , pp. 19 - 26
Publisher: Cambridge University Press
Print publication year: 2022

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References

Schwartz, D, Mayaux, MJ. Female fecundity as a function of age: results of artificial insemination in 2193 nulliparous women with azoospermic husbands. Federation CECOS. N Engl J Med. 1982;306(7):404–6.Google Scholar
Gosden, RG. Maternal age: a major factor affecting the prospects and outcome of pregnancy. Ann N Y Acad Sci. 1985;442:45–57.Google Scholar
Matthews, TJ, Hamilton, BE. Delayed childbearing: more women are having their first child later in life. NCHS Data Brief. 2009(21):1–8.Google Scholar
Hurwitz, A, Adashi, EY. Ovarian follicular atresia as an apoptotic process: a paradigm for programmed cell death in endocrine tissues. Mol Cell Endocrinol. 1992;84(1–2):C19–23.Google Scholar
Marcozzi, S, Rossi, V, Salustri, A, De Felici, M, Klinger, FG. Programmed cell death in the human ovary. Minerva Ginecol. 2018;70(5):549–60.Google Scholar
Keefe, DL. Telomeres, reproductive aging, and genomic instability during early development. Reprod Sci. 2016;23(12):1612–5.Google Scholar
Keefe, DL, Liu, L. Telomeres and reproductive aging. Reprod Fertil Dev. 2009;21(1):10–4.Google Scholar
Kalmbach, KH, Antunes, DM, Kohlrausch, F, Keefe, DL. Telomeres and female reproductive aging. Semin Reprod Med. 2015;33(6):389–95.CrossRefGoogle ScholarPubMed
Lemoine, ME, Ravitsky, V. Sleepwalking into infertility: the need for a public health approach toward advanced maternal age. Am J Bioeth. 2015;15(11):37–48.Google Scholar
Liu, L, Keefe, DL. Nuclear origin of aging-associated meiotic defects in senescence-accelerated mice. Biol Reprod. 2004;71(5):1724–9.Google Scholar
Tatone, C, Amicarelli, F. The aging ovary–the poor granulosa cells. Fertil Steril. 2013;99(1):12–7.CrossRefGoogle ScholarPubMed
Forman, EJ, Treff, NR, Scott, RT, Jr. Fertility after age 45: From natural conception to assisted reproductive technology and beyond. Maturitas. 2011;70(3):216–21.Google Scholar
Bouzaglou, A, Aubenas, I, Abbou, H, Rouanet, S, Carbonnel, M, Pirtea, P, et al. Pregnancy at 40 years old and above: obstetrical, fetal, and neonatal outcomes. Is age an independent risk factor for those complications? Front Med (Lausanne). 2020;7:208.CrossRefGoogle ScholarPubMed
Adhikari, D, Zheng, W, Shen, Y, Gorre, N, Hamalainen, T, Cooney, AJ, et al. Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles. Hum Mol Genet. 2010;19(3):397–410.CrossRefGoogle ScholarPubMed
Nagaoka, SI, Hassold, TJ, Hunt, PA. Human aneuploidy: mechanisms and new insights into an age-old problem. Nat Rev Genet. 2012;13(7):493–504.CrossRefGoogle ScholarPubMed
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(6):685–718.Google Scholar
Munné, S, Cohen, J. Advanced maternal age patients benefit from preimplantation genetic diagnosis of aneuploidy. Fertil Steril. 2017;107(5):1145–6.Google Scholar
Battaglia, DE, Goodwin, P, Klein, NA, Soules, MR. Fertilization and early embryology: Influence of maternal age on meiotic spindle assembly oocytes from naturally cycling women. Hum Reprod. 1996;11(10):2217–22.Google Scholar
Cromie, GA, Smith, GR. Branching out: meiotic recombination and its regulation. Trends Cell Biol. 2007;17(9):448–55.Google Scholar
Maguire, MP. Is the synaptonemal complex a disjunction machine? J Hered. 1995;86(5):330–40.Google Scholar
Hassold, T, Hunt, P. To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet. 2001;2(4):280–91.CrossRefGoogle Scholar
Jessberger, R. Deterioration without replenishment–the misery of oocyte cohesin. Genes Dev. 2010;24(23):2587–91.Google Scholar
Liu, L, Keefe, DL. Defective cohesin is associated with age-dependent misaligned chromosomes in oocytes. Reprod Biomed Online. 2008;16(1):103–12.Google Scholar
Handyside, AH, Montag, M, Magli, MC, Repping, S, Harper, J, Schmutzler, A, 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):742–7.CrossRefGoogle ScholarPubMed
Liu, L. Ageing-associated aberration in meiosis of oocytes from senescence-accelerated mice. Hum Reprod. 2002;17(10):2678–85.Google Scholar
Hodges, CA, Revenkova, E, Jessberger, R, Hassold, TJ, Hunt, PA. SMC1β-deficient female mice provide evidence that cohesins are a missing link in age-related nondisjunction. Nat Genet. 2005;37(12):1351–5.Google Scholar
Xu, H, Beasley, MD, Warren, WD, Van Der Horst, GTJ, McKay, MJ. Absence of mouse REC8 cohesin promotes synapsis of sister chromatids in meiosis. Dev Cell. 2005;8(6):949–61.Google Scholar
De Lange, T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005;19(18):2100–10.Google Scholar
Kalmbach, KH, Fontes Antunes, DM, Dracxler, RC, Knier, TW, Seth-Smith, ML, Wang, F, et al. Telomeres and human reproduction. Fertil Steril. 2013;99(1):23–9.CrossRefGoogle ScholarPubMed
Keefe, DL, Franco, S, Liu, L, Trimarchi, J, Cao, B, Weitzen, S, et al. Telomere length predicts embryo fragmentation after in vitro fertilization in women—toward a telomere theory of reproductive aging in women. Am J Obstet Gynecol. 2005;192(4):1256–60.Google Scholar
Keefe, DL, Liu, L, Marquard, K. Telomeres and meiosis in health and disease. Cell Mol Life Sci. 2007;64(2):139–43.Google Scholar
Keefe, DL. Telomeres and genomic instability during early development. Eur J Med Genet. 2020;63(2):103638.Google Scholar
Wright, DL, Jones, EL, Mayer, JF, Oehninger, S, Gibbons, WE, Lanzendorf, SE. Characterization of telomerase activity in the human oocyte and preimplantation embryo. Mol Hum Reprod. 2001;7(10):947–55.Google Scholar
Robinson, LG, Jr., Pimentel, R, Wang, F, Kramer, YG, Gonullu, DC, Agarwal, S, et al. Impaired reproductive function and fertility preservation in a woman with a dyskeratosis congenita. J Assist Reprod Genet. 2020;37(5):1221–5.Google Scholar
Keefe, DL, Marquard, K, Liu, L. The telomere theory of reproductive senescence in women. Curr Opin Obstet Gynecol. 2006;18(3):280–5.Google Scholar
Keefe, DL, Niven-Fairchild, T, Powell, S, Buradagunta, S. Mitochondrial deoxyribonucleic acid deletions in oocytes and reproductive aging in women. Fertil Steril. 1995;64(3):577–83.CrossRefGoogle ScholarPubMed
Reynier, P, May-Panloup, P, Chretien, MF, Morgan, CJ, Jean, M, Savagner, F, et al. Mitochondrial DNA content affects the fertilizability of human oocytes. Mol Hum Reprod. 2001;7(5):425–9.CrossRefGoogle ScholarPubMed
May-Panloup, P, Chrétien, MF, Jacques, C, Vasseur, C, Malthièry, Y, Reynier, P. Low oocyte mitochondrial DNA content in ovarian insufficiency. Hum Reprod. 2005;20(3):593–7.Google Scholar
Navarro, PAAS, Liu, L, Keefe, DL. In vivo effects of arsenite on meiosis, preimplantation development, and apoptosis in the mouse. Biol Reprod. 2004;70(4):980–5.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
Henderson, SA, Edwards, RG. Chiasma frequency and maternal age in mammals. Nature. 1968;218(5136):22–8.Google Scholar
Polani, P, Crolla, J. A test of the production line hypothesis of mammalian oogenesis. Hum Genet. 1991;88(1):64–70.CrossRefGoogle ScholarPubMed
Engmann, L, Sladkevicius, P, Agrawal, R, Bekir, J, Campbell, S, Tan, S. Value of ovarian stromal blood flow velocity measurement after pituitary suppression in the prediction of ovarian responsiveness and outcome of in vitro fertilization treatment. Fertil Steril. 1999;71(1):22–9.Google Scholar
Ng, EHY, Tang, OS, Chan, CCW, Ho, PC. Ovarian stromal blood flow in the prediction of ovarian response during in vitro fertilization treatment. Hum Reprod. 2005;20(11):3147–51.Google Scholar
Lunenfeld, E, Schwartz, I, Meizner, I, Potashnik, G, Glezerman, M. Ovary and ovulation: intraovarian blood flow during spontaneous and stimulated cycles. 1996;11(11):2481–3.Google Scholar
Younis, JS, Haddad, S, Matilsky, M, Radin, O, Ben-Ami, M. Undetectable basal ovarian stromal blood flow in infertile women is related to low ovarian reserve. Gynecol Endocrinol. 2007;23(5):284–9.CrossRefGoogle ScholarPubMed
Berchowitz, LE, Kabachinski, G, Walker, MR, Carlile, TM, Gilbert, WV, Schwartz, TU, et al. Regulated formation of an amyloid-like translational repressor governs gametogenesis. Cell. 2015;163(2):406–18.CrossRefGoogle ScholarPubMed
Pimentel, RN, Navarro, PA, Wang, F, Robinson, LG, Jr., Cammer, M, Liang, F, et al. Amyloid-like substance in mice and human oocytes and embryos. J Assisted Reprod Genet. 2019;36(9):1877–90.Google Scholar
Duan, F-H, Chen, S-L, Chen, X, Niu, J, Li, P, Liu, Y-D, et al. Follicular fluid Aβ40 concentrations may be associated with ongoing pregnancy following in vitro fertilization. J Assisted Reprod Genet. 2014;31(12):1611–20.Google Scholar
Urieli-Shoval, S, Finci-Yeheskel, Z, Eldar, I, Linke, RP, Levin, M, Prus, D, et al. Serum amyloid A: expression throughout human ovarian folliculogenesis and levels in follicular fluid of women undergoing controlled ovarian stimulation. J Clin Endocrinol Metab. 2013;98(12):4970–8.Google Scholar
Michan, S, Sinclair, D. Sirtuins in mammals: insights into their biological function. Biochem J. 2007;404(1):1–13.Google Scholar
Morris, BJ. Seven sirtuins for seven deadly diseases of aging. Free Radic Biol Med. 2013;56:133–71.CrossRefGoogle ScholarPubMed
Di Emidio, G, Falone, S, Vitti, M, D’Alessandro, AM, Vento, M, Di Pietro, C, et al. SIRT1 signalling protects mouse oocytes against oxidative stress and is deregulated during aging. Hum Reprod. 2014;29(9):2006–17.Google Scholar
Manosalva, I, González, A. Aging changes the chromatin configuration and histone methylation of mouse oocytes at germinal vesicle stage. Theriogenology. 2010;74(9):1539–47.Google Scholar
Tatone, C, Di Emidio, G, Vitti, M, Di Carlo, M, Santini, S, D’Alessandro, AM, et al. Sirtuin functions in female fertility: possible role in oxidative stress and aging. Oxid Med Cell Longev. 2015;2015:659687.Google Scholar
Tatone, C, Di Emidio, G, Barbonetti, A, Carta, G, Luciano, AM, Falone, S, et al. Sirtuins in gamete biology and reproductive physiology: emerging roles and therapeutic potential in female and male infertility. Hum Reprod Update. 2018;24(3):267–89.Google Scholar
Selesniemi, K, Lee, HJ, Muhlhauser, A, Tilly, JL. Prevention of maternal aging-associated oocyte aneuploidy and meiotic spindle defects in mice by dietary and genetic strategies. Proc Natl Acad Sci U S A. 2011;108(30):12319–24.CrossRefGoogle ScholarPubMed
Liu, M, Yin, Y, Ye, X, Zeng, M, Zhao, Q, Keefe, DL, et al. Resveratrol protects against age-associated infertility in mice. Hum Reprod. 2013;28(3):707–17.CrossRefGoogle ScholarPubMed
Noci, I, Borri, P, Scarselli, G, Chieffi, O, Bucciantini, S, Biagiotti, R, et al. Morphological and functional aspects of the endometrium of asymptomatic post-menopausal women: does the endometrium really age? Hum Reprod. 1996;11(10):2246–50.CrossRefGoogle ScholarPubMed
Klein, J, Sauer, MV. Assessing fertility in women of advanced reproductive age. Am J Obstet Gynecol. 2001;185(3):758–70.Google Scholar
Craig, SS, Jollie, WP. Age changes in density of endometrial stromal cells of the rat. Exp Gerontol. 1985;20(2):93–7.Google Scholar
Hsueh, AJ, Erickson, GF, Lu, KH. Changes in uterine estrogen receptor and morphology in aging female rats. Biol Reprod. 1979;21(4):793–800.Google Scholar
Burack, E, Wolfe, JM, Lansing, W, Wright, AW. The effect of age upon the connective tissue of the uterus, cervix, and vagina of the rat. Cancer Res. 1941;1(3):227–35.Google Scholar
Finn, CA, Martin, L. The cellular response of the uterus of the aged mouse to oestrogen and progesterone. J Reprod Fertil. 1969;20(3):545–7.Google Scholar
Smith, AF. Ultrastructure of the uterine luminal epithelium at the time of implantation in ageing mice. J Reprod Fertil. 1975;42(1):183–5.Google Scholar
Bal, HS, Getty, R. Changes in the histomorphology of the uterus of the domestic pig (Sus scrofa domesticus) with advancing age. J Gerontol. 1973;28(2):160–72.Google Scholar
Adams, SM, Terry, V, Hosie, MJ, Gayer, N, Murphy, CR. Endometrial response to IVF hormonal manipulation: comparative analysis of menopausal, down regulated and natural cycles. Reprod Biol Endocrinol. 2004;2:21.Google Scholar
Amir, W, Micha, B, Ariel, H, Liat, LG, Jehoshua, D, Adrian, S. Predicting factors for endometrial thickness during treatment with assisted reproductive technology. Fertil Steril. 2007;87(4):799–804.Google Scholar
Lenton, EA, Landgren, BM, Sexton, L. Normal variation in the length of the luteal phase of the menstrual cycle: identification of the short luteal phase. Br J Obstet Gynaecol. 1984;91(7):685–9.Google Scholar
Meldrum, DR. Female reproductive aging–ovarian and uterine factors. Fertil Steril. 1993;59(1):1–5.Google Scholar
Oron, G, Hiersch, L, Rona, S, Prag-Rosenberg, R, Sapir, O, Tuttnauer-Hamburger, M, et al. Endometrial thickness of less than 7.5 mm is associated with obstetric complications in fresh IVF cycles: a retrospective cohort study. Reprod Biomed Online. 2018;37(3):341–8.CrossRefGoogle ScholarPubMed
Lean, SC, Derricott, H, Jones, RL, Heazell, AEP. Advanced maternal age and adverse pregnancy outcomes: A systematic review and meta-analysis. PloS One. 2017;12(10):e0186287.Google Scholar
Sheen, JJ, Wright, JD, Goffman, D, Kern-Goldberger, AR, Booker, W, Siddiq, Z, et al. Maternal age and risk for adverse outcomes. Am J Obstet Gynecol. 2018;219(4):390.e1-.e15.Google Scholar
Hapangama, DK, Kamal, A, Saretzki, G. Implications of telomeres and telomerase in endometrial pathology. Hum Reprod Update. 2017;23(2):166–87.Google ScholarPubMed
Cho, A, Park, SR, Kim, SR, Nam, S, Lim, S, Park, CH, et al. An endogenous anti-aging factor, sonic hedgehog, suppresses endometrial stem cell aging through SERPINB2. Mol Ther. 2019;27(7):1286–98.Google Scholar

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