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Mechanisms of Ovarian Aging

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Mechanisms of Ovarian Aging 162 2 REPRODUCTIONREVIEW Mechanisms of ovarian aging Selena U Park1,3, Leann Walsh1 and Karen M Berkowitz 1,2 1Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA, 2Department of Obstetrics and Gynecology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA and 3Department of Obstetrics, Gynecology, and Reproductive Sciences, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA Correspondence should be addressed to K M Berkowitz; Email: [email protected] Abstract Ovarian aging in women correlates with the progressive loss of both the number and quality of oocytes. When these processes occur early or are accelerated, their clinical correlates are diminished ovarian reserve and/or premature ovarian insufficiency. Both these conditions have important consequences for the reproductive and general health of women, including infertility. Although there are many contributing factors, the molecular mechanisms underlying many of the processes associated with ovarian aging have not been fully elucidated. In this review, we highlight some of the most critical factors that impact oocyte quantity and quality with advancing age. We discuss chromosomal factors including cohesion deterioration and mis-segregation, errors in meiotic recombination, and decreased stringency of the spindle assembly checkpoint. DNA damage, telomere changes, reactive oxygen species and mitochondrial dysfunction as they relate to ovarian aging, and well-known gene mutations associated with primary ovarian insufficiency and diminished ovarian reserve are also discussed. Additionally, studies investigating recently acknowledged cytoplasmic factors associated with ovarian aging including protein metabolic dysregulation and microenvironmental alterations in the ovary are presented. We use both mouse and human studies to support the roles these factors play in physiologic and expedited ovarian aging, and we propose directions for future studies. A better understanding of the molecular basis of ovarian aging will ultimately lead to diagnostic and therapeutic advancements that would provide women with information to make earlier choices about their reproductive health. Reproduction (2021) 162 R19–R33 Introduction this peak, there is a stage of pronounced oocyte atresia that decreases the oocyte number to approximately Delayed childbearing brings forth a unique problem 2 million at birth. The process of atresia gradually in women. Unlike males who possess a renewing leads to a decline in the follicle pool, and by puberty, population of spermatogonial cells, females begin life approximately 400,000 primordial follicles remain. with ultimately a finite number of oocytes. Oocytes Ultimately, the number of primordial follicles decreases eventually comprise a pool of primordial follicles that to approximately 1000 at menopause. Newer models of diminish in number throughout a woman’s lifetime reproductive aging in women, which take into account (McGee & Hsueh 2000). Although, the quantity of data from older studies, propose that attrition of the non- this discrete population of oocytes in the follicle pool growing follicle pool continually increases with age and constitutes the ovarian reserve, both the number does not abruptly change (Hansen et al. 2008). The and quality of oocytes impact reproductive potential changes that occur in this dynamic cohort of oocytes and aging (Tal & Seifer 2017, ASRM 2020). Despite correlate with the changes in fertility over the course the widely accepted dogma that the oocyte pool is of a woman’s reproductive life, which become most determinate, some reports suggest that new oocytes clinically apparent when a woman reaches her mid can form and contribute to the ovarian reserve (Johnson to late 30s and beyond (Wallace & Kelsey 2010, Tal & et al. 2004). Such studies may hold potential promise Seifer 2017). for the field of reproductive medicine. However, it is Multiple factors, including chromosomal, genetic, unclear whether these new cells can function as oocytes mitochondrial, and cytoplasmic, impact the quantity (Wood & Rajkovic 2013). Gametogenesis begins during and quality of oocytes in the ovarian reserve (Fig. 1). fetal development in females, and by mid-gestation, The effects of these factors on the ovarian reserve and the number of oocytes reaches a maximum number of fertility also vary among different women of similar approximately 6–7 million (Allen 2010). After reaching ages (te Velde & Pearson 2002, Hansen et al. 2008). © 2021 Society for Reproduction and Fertility https://doi.org/10.1530/REP -21-0022 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via https://rep.bioscientifica.com Downloaded from Bioscientifica.com at 09/23/2021 10:09:57AM via free access -21-0022 R20 S Park and others From embryonic development to menopause During human embryonic development, by the seventh week of gestation, primordial germ cells (PGCs) migrate from the yolk sac endoderm to the gonadal ridge. PGCs synchronize their entrance into mitotic divisions throughout their migration. Upon reaching the gonads, PGCs differentiate into oogonia and continue mitotic proliferation. At about 11–12 weeks of gestation, oogonia enter meiosis and develop into primary oocytes. Primary oocytes then individually become encased by pregranulosa cells to form primordial follicles – a process that begins around the 20th week of Figure 1 A multitude of physiological factors can diminish the gestation and continues until birth (AlAsiri et al. 2015) quantity and quality of the ovarian reserve and lead to ovarian aging. Oocytes in the primordial follicles remain arrested in Each factor is explained further under subheadings in the text. the diplotene stage of prophase I during meiosis until the onset of puberty (Picton 2001, Hansen et al. 2008). Current research has been focused on determining These primordial follicles are the origin of the ovarian the factors that are most important to ovarian health. reserve (Fig. 2). Ultimately, follicles containing oocytes One goal of these studies is to elucidate the molecular arrested in prophase I have one of three following mechanisms underlying the changes in ovarian reserve, outcomes: they undergo atresia, remain quiescent, or oocyte viability, and oocyte health. Although current become recruited to grow. A majority of the follicles diagnostic tools exist, their accuracy in assessing ovarian undergo atresia, a mechanism of apoptotic cell death. reserve remains a significant area of debate. In addition, Atresia reduces the follicle population significantly from once the ovarian reserve has diminished markedly, approximately 7 million to 2 million at birth (Baker few treatments other than assisted reproductive 1963, Picton 2001). Other follicles remain dormant and technologies are effective in treating resulting infertility. are recruited throughout a woman’s reproductive life. Thus, there is potential for the development of better Finally, primordial follicles that enter the growth phase, diagnostic tools and improved treatments in the field of in a process known as initial recruitment, develop reproductive medicine. In this survey of the literature, into secondary follicles and, eventually, antral follicles we broadly review molecular mechanisms of ovarian (McGee & Hsueh 2000). Most antral follicles undergo aging, recent developments in the reproductive field, atresia. However, some are spared by recruitment and and prospective directions. activation, processes that are cyclically regulated under Figure 2 Schematic of folliculogenesis. During the stages of follicle development, granulosa cells (depicted by dashed lines) proliferate in layers around the growing oocyte. Many primordial and antral follicles undergo atresia during this process. Ovulation occurs when the egg is released at the time of follicle rupture during the antral follicle stage (antral cavity is depicted in blue). Following ovulation, a corpus luteum forms from the remaining antral follicle. If the egg is not fertilized, the follicle will undergo luteal regression and ultimately be degraded. Reproduction (2021) 162 R19–R33 https://rep.bioscientifica.com Downloaded from Bioscientifica.com at 09/23/2021 10:09:57AM via free access Mechanisms of ovarian aging R21 the hormonal influence at the onset of puberty (McGee reserve. Women with DOR have regular menses but & Hsueh 2000, Picton 2001, te Velde & Pearson 2002). exhibit decreased fecundity and responsiveness to Beginning at menarche, with each menstrual cycle, exogenous ovarian hormone stimulation compared to the non-dominant antral follicles become atretic and women of similar ages (ASRM 2020). Ten percent of are degraded to nourish the dominant follicle, which women who present to an infertility clinic in the United will ovulate (Baker 1963). The process of atresia leads States are diagnosed with DOR, and these women to a significant loss of oocytes as women age and is have considerably lower success rates with assisted not well understood. Atresia may occur as a protective reproductive technologies (ART) (Tal & Seifer 2017, mechanism to eliminate poor-quality oocytes that Pastore et al. 2018). More recent data reveal that up to cannot be fertilized. The earliest studies of follicular 32% of women in the United States who undergo in atresia estimate that 99% of human oocyte loss occurs by vitro fertilization are diagnosed with DOR. The age at this mechanism (McGee 2006, Hunt & Hassold
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