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.
Introduction
Delayed childbearing brings forth a unique problem in women. Unlike males who possess a renewing population of spermatogonial cells, females begin life with ultimately a finite number of oocytes. Oocytes eventually comprise a pool of primordial follicles that diminish in number throughout a woman’s lifetime (McGee & Hsueh 2000). Although, the quantity of this discrete population of oocytes in the follicle pool constitutes the ovarian reserve, both the number and quality of oocytes impact reproductive potential and aging (Tal & Seifer 2017, ASRM 2020). Despite the widely accepted dogma that the oocyte pool is determinate, some reports suggest that new oocytes can form and contribute to the ovarian reserve (Johnson et al. 2004). Such studies may hold potential promise for the field of reproductive medicine. However, it is unclear whether these new cells can function as oocytes (Wood & Rajkovic 2013). Gametogenesis begins during fetal development in females, and by mid-gestation, the number of oocytes reaches a maximum number of approximately 6–7 million (Allen 2010). After reaching this peak, there is a stage of pronounced oocyte atresia that decreases the oocyte number to approximately 2 million at birth. The process of atresia gradually leads to a decline in the follicle pool, and by puberty, approximately 400,000 primordial follicles remain. Ultimately, the number of primordial follicles decreases to approximately 1000 at menopause. Newer models of reproductive aging in women, which take into account data from older studies, propose that attrition of the non-growing follicle pool continually increases with age and does not abruptly change (Hansen et al. 2008). The changes that occur in this dynamic cohort of oocytes correlate with the changes in fertility over the course of a woman’s reproductive life, which become most clinically apparent when a woman reaches her mid to late 30s and beyond (Wallace & Kelsey 2010, Tal & Seifer 2017).
Multiple factors, including chromosomal, genetic, mitochondrial, and cytoplasmic, impact the quantity and quality of oocytes in the ovarian reserve (Fig. 1). The effects of these factors on the ovarian reserve and fertility also vary among different women of similar ages (te Velde & Pearson 2002, Hansen et al. 2008). Current research has been focused on determining the factors that are most important to ovarian health. One goal of these studies is to elucidate the molecular mechanisms underlying the changes in ovarian reserve, oocyte viability, and oocyte health. Although current diagnostic tools exist, their accuracy in assessing ovarian reserve remains a significant area of debate. In addition, once the ovarian reserve has diminished markedly, few treatments other than assisted reproductive technologies are effective in treating resulting infertility. Thus, there is potential for the development of better diagnostic tools and improved treatments in the field of reproductive medicine. In this survey of the literature, we broadly review molecular mechanisms of ovarian aging, recent developments in the reproductive field, and prospective directions.
A multitude of physiological factors can diminish the quantity and quality of the ovarian reserve and lead to ovarian aging. Each factor is explained further under subheadings in the text.
Citation: Reproduction 162, 2; 10.1530/REP-21-0022
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 gestation and continues until birth (AlAsiri et al. 2015) Oocytes in the primordial follicles remain arrested in the diplotene stage of prophase I during meiosis until the onset of puberty (Picton 2001, Hansen et al. 2008). These primordial follicles are the origin of the ovarian reserve (Fig. 2). Ultimately, follicles containing oocytes arrested in prophase I have one of three following outcomes: they undergo atresia, remain quiescent, or become recruited to grow. A majority of the follicles undergo atresia, a mechanism of apoptotic cell death. Atresia reduces the follicle population significantly from approximately 7 million to 2 million at birth (Baker 1963, Picton 2001). Other follicles remain dormant and are recruited throughout a woman’s reproductive life. Finally, primordial follicles that enter the growth phase, in a process known as initial recruitment, develop into secondary follicles and, eventually, antral follicles (McGee & Hsueh 2000). Most antral follicles undergo atresia. However, some are spared by recruitment and activation, processes that are cyclically regulated under the hormonal influence at the onset of puberty (McGee & Hsueh 2000, Picton 2001, te Velde & Pearson 2002).
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.
Citation: Reproduction 162, 2; 10.1530/REP-21-0022
Beginning at menarche, with each menstrual cycle, the non-dominant antral follicles become atretic and are degraded to nourish the dominant follicle, which will ovulate (Baker 1963). The process of atresia leads to a significant loss of oocytes as women age and is not well understood. Atresia may occur as a protective mechanism to eliminate poor-quality oocytes that cannot be fertilized. The earliest studies of follicular atresia estimate that 99% of human oocyte loss occurs by this mechanism (McGee 2006, Hunt & Hassold 2008). Though the cause of this increased apoptosis has not yet been elucidated, it is certainly a contributing factor to the loss of oocytes during a woman’s reproductive life. Pools of follicles that are not degraded become recruited and activated to grow. Protein kinase B (AKT), mammalian target of rapamycin (mTOR), and signaling pathways downstream of these initial activators contribute to the growth of follicles with each menstrual cycle (reviewed in Hsueh et al. 2015). Activation also induces other morphological changes of follicles that result in maturation of part of the oocyte pool; a portion of the pool remains quiescent. The mTOR serine/threonine kinase, in particular, is crucial to help maintain female fertility, as it signals this selective activation process (McGee & Hsueh 2000, Picton 2001). After activation and growth, the granulosa cells of the secondary follicle secrete estrogens, which lead to ovarian follicle growth and ultimately ovulation. Following the release of the egg, the follicle transitions to become the corpus luteum. If the ovulated egg is fertilized, the corpus luteum will persist into early pregnancy; if not, the follicle will undergo luteal regression. Each month, progression through this cycle is mainly controlled by varying concentrations of estrogen, progesterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) (McGee & Loucks 1993).
By menopause, the primordial follicle pool decreases to about 1000. These changes in follicle number result in increased activation, leading to a significant increase in the rate of loss of the remaining follicles, likely through atresia (Hansen et al. 2008). At the end of the menopausal transition, there is a complete loss of follicles. The majority of women reach menopause around the ages of 49–52 (te Velde et al. 1998, Takahashi & Johnson 2015). The decline in ovarian reserve, ovarian aging, and the onset of menopause are inevitable and occur with age in all women. However, the rate at which these events ensue and primordial follicles are lost varies (Tal & Seifer 2017). Though much of menopause is well characterized, the molecular basis of ovarian aging is far less understood. It is clear that reproductive ability in women ultimately ceases with age, but the mechanism(s) that underly this process remains uncertain.
Diminished ovarian reserve (DOR) is a term used to describe a clinically significant decline in ovarian reserve. Women with DOR have regular menses but exhibit decreased fecundity and responsiveness to exogenous ovarian hormone stimulation compared to women of similar ages (ASRM 2020). Ten percent of women who present to an infertility clinic in the United States are diagnosed with DOR, and these women have considerably lower success rates with assisted reproductive technologies (ART) (Tal & Seifer 2017, Pastore et al. 2018). More recent data reveal that up to 32% of women in the United States who undergo in vitro fertilization are diagnosed with DOR. The age at which DOR becomes clinically apparent varies among women, making it difficult to predict if and when a woman will be affected. This is unlike primary ovarian insufficiency (POI), a condition that becomes clinically apparent in women younger than 40. Although less common, POI, formerly called premature ovarian failure (POF) or premature menopause, also results in a decline in oocyte number (Collins et al. 2017). POI has been proposed to exist as a continuum of changes in ovarian function that includes an 'occult' state in which women have reduced fecundity but normal FSH levels and regular menses, a 'biochemical' state with reduced fecundity, elevated FSH levels but regular menses, and finally, an 'overt' state with reduced fecundity, elevated FSH, and irregular or lack of menses (Welt 2008, Pastore et al. 2018). Women with POI have a failure of ovarian function and infertility, too. Unlike women with DOR, women with POI exhibit cessation of menses for at least 3 months to 4 months with postmenopausal levels of FSH (>40 IU/L) (Collins et al. 2017). Although POI and DOR are different in onset and clinical presentations, they share some of the same genetic mutations that are believed to contribute to ovarian aging (Bodega et al. 2006, Greene et al. 2014). Additionally, some women with DOR still reach menopause at an earlier age of less than 45 years, suggesting clinical overlap between the two conditions. These conditions have also been studied in mice as a model organism, and quantification of the ovarian follicle pool, litter size, and oocyte quality are parameters commonly used to evaluate DOR and POI in comparison to these disorders in women. For example in mice, CHTF18(chromosome transmission fidelity factor 18) has been demonstrated to play a crucial role in female fertility and assuring the quantity and quality of the ovarian reserve (Holton et al. 2020). Chtf18−/− female mice exhibit age-dependent subfertility with fewer offspring beginning at 6 months of age compared to WT females. Ovaries of Chtf18−/− females also have fewer follicles at all stages of folliculogenesis, and the follicle pools are nearly depleted by 6 months of age. Oocytes of poor quality result in aneuploid eggs. Thus, the Chtf18−/−female phenotypes resemble that of DOR in women (Holton et al. 2020). Utilizing oocyte and DNA samples from patients with POI or DOR, and model organisms as investigative tools, has helped elucidate mechanisms of ovarian aging.
Cohesion, meiotic recombination, and the spindle assembly checkpoint
Chromosomal cohesion
Mechanisms that ensure accurate meiotic division and chromosome segregation are essential during oocyte development to prevent aneuploidy. Aneuploidy resulting from chromosome mis-segregation can lead to miscarriage, congenital anomalies, and infertility. Therefore, it is critical that sister chromatids remain together until anaphase. Cohesins are multi-protein complexes that mediate cohesion between sister chromatid arms and at centromeres during both mitosis and meiosis (reviewed in Brooker & Berkowitz 2014). Studies in mice have shown that with increasing female age, chromosome cohesion in oocytes naturally deteriorates (Chiang et al. 2010, 2011). Cohesins in older oocytes are more susceptible to removal by separase, a cysteine protease that cleaves the cohesin subunit REC8 (Uhlmann et al. 2000, Waizenegger et al. 2000). Decreased cohesion leads to a greater frequency of chromosome mis-segregation, premature chromatid separation, and aneuploidy (Chiang et al. 2010,2011, Holton et al. 2020). Meiotic cohesins have also been shown to decrease in human oocytes with age (Duncan et al. 2012, Tsutsumi et al. 2014).
Shugoshin-like 2 (SGO2, formerly SGOL2) is a conserved protein that protects centromeric cohesion from degrading during mitosis and meiosis (Kitajima et al. 2004, Salic et al. 2004). SGO2 localizes to centromeres and prevents separase from cleaving cohesin until the metaphase to anaphase transition. Notably, SGO2 expression decreases in oocytes with advancing age (Lister et al. 2010, Rattani et al. 2013). Depletion of SGO2 in mouse oocytes causes loss of centromeric cohesion during anaphase I, leading to premature separation of sister chromatids; depletion also affects proper kinetochore-microtubule (K-MT) attachments, as well as spindle assembly checkpoint (SAC) silencing (discussed further subsequently) (Rattani et al. 2013). SGO2is vital in maintaining proper chromosomal alignment before division and protecting cohesion at centromeres to ensure accurate chromosome segregation (Rattani et al. 2013).
Deterioration of cohesion in older mouse oocytes also results in erroneous K-MT attachments during meiosis (Shomper et al. 2014, Nakagawa & FitzHarris 2017). Oocytes from aged mice had significantly more erroneous K-MT attachments than those from younger mice during meiosis I and meiosis II (Shomper et al. 2014). The impact of cohesion loss on attachments was especially significant during meiosis II (Shomper et al. 2014). Loss of cohesion during meiosis II in older mouse oocytes caused K-MT misattachments, leading to chromosome lagging and mis-segregation. In aged MI oocytes, changes in spindle dynamics were the main cause of erroneous K-MT attachments (Nakagawa & FitzHarris 2017). Altered spindle dynamics increased susceptibility to transient multipolar spindles, leading to erroneous K-MT attachments and mis-segregation even in intact sister chromatid pairs (Nakagawa & FitzHarris 2017). Live time-lapse imaging of spindle assembly in young and old mouse oocytes revealed that initially 90% of young oocytes formed normal bipolar spindles compared to 50% of old oocytes (Nakagawa & FitzHarris 2017). Instead, older mouse oocytes transiently developed multipolar spindles consisting of unstable microtubules in a disorganized manner. Multipolar spindles had significantly fewer correct kinetochore attachments compared to bipolar spindles, and this led to mis-segregation and oocyte aneuploidy (Nakagawa & FitzHarris 2017). Although the duration of meiosis I was not significantly different between older and younger oocytes, there was a delay in establishing correct K-MT attachments in older oocytes. Thus, cohesion loss or altered MT dynamics each cause erroneous K-MT attachments, mis-segregation, and ultimately aneuploidy. Errors such as these contribute to pregnancy loss and are consistent with the reported increased frequency of Trisomy 21 in offspring of older women (Handel & Schimenti 2010, Nagaoka et al. 2012, Jones & Lane 2013). Recent studies have suggested that K-MT defects in aged oocytes are more extreme in human oocytes than those observed in mouse oocytes (reviewed in Mihajlović & FitzHarris 2018). In human oocytes, the distance between sister kinetochores was increased with age in both meiosis I and meiosis II. In some instances, the distance led to a 90-degree rotation of homologous chromosomes which resulted in mis-segregation (Zielinska et al. 2015, Mihajlović & FitzHarris 2018). The authors speculate that unlike in mouse oocytes, in human oocytes, interkinetochore distances, in addition to multiple other factors, contribute to aneuploidy seen with ovarian aging (Cimini et al. 2001, Zielinska et al. 2015).
Meiotic recombination
One of the distinguishing and critical features of meiosis is the process of homologous recombination. This process, including the formation of DNA double-strand breaks (DSBs) and repair as crossovers between homologous chromosomes, gives rise to the genetic diversity of the gametes and ultimately offspring (Handel & Schimenti 2010). Meiotic crossovers, cytologically seen as chiasmata, form direct physical contacts between nonsister chromatids of homologous chromosomes, allowing the exchange of genetic information. However, when crossovers occur too close to the centromere, there is an increased risk of mis-segregation. In fact, kinetochore proteins that suppress the occurrence of crossovers too proximal to the centromere have been identified in lower eukaryotes (Vincenten et al. 2015). Studies have also reported the dramatic increase in aneuploidy secondary to recombination errors with increased maternal age. Studies of recombination frequencies of chromosome 21 have shown that younger women have an increase in proximal and distal recombination events. However, older women have more exchanges closer to the centromere, resulting in mis-segregation and aneuploidy (Lamb et al. 2005, Ghosh et al. 2009). Both human and mouse studies suggest that errors in the position or frequency of recombination events impact aneuploidy rates (Chiang et al. 2012). As a result of mis-segregation, near the end of a woman’s reproductive life, at least 50% of pregnancies are trisomic or monosomic (Wang et al. 2017a).
Based on data from human oocytes, meiotic segregation errors and aneuploidy have been postulated to result from crossover maturation inefficiency (CMI) (Wang et al. 2017a). CMI is proposed to occur when recombination intermediates fail to become mature crossovers. Interestingly, it is inferred to occur uniquely in 25% of recombination intermediates in human oocytes and may be a major contributing factor to chromosome mis-segregation (Wang et al. 2017a). At least 10% of pregnancies are trisomic or monosomic usually due to oocyte aneuploidy (Nagaoka et al. 2012). Meanwhile, mis-segregation in male germ cells is more rare, occurring only about 2–5% of the time. In fact, the more frequent occurrence of aneuploidy in females than males is likely due, in part, to female-specific maturation inefficiency (Wang et al. 2017a). Additionally, CMI in females is hypothesized to affect crossover recombination patterns, leading to increased aneuploidy, especially with increased age.
Spindle assembly checkpoint
During cell division, the spindle assembly checkpoint (SAC) monitors attachments of chromosomes to the spindle. The SAC prevents the onset of anaphase until all chromosomes are correctly attached to the spindle. Errors in attachment activate the SAC, causing the cell cycle to arrest. In oocytes of young mice, inhibition of the SAC and monopolar spindle 1 (MPS1), a kinase and component of the SAC, results in reduced securin levels, a phenotype typical of oocytes of old mice (Nabti 2017). Securin is a protein that interacts with separase to inhibit cohesin cleavage. Ultimately, inhibition of MPS1 in mice leads to early sister chromatid separation. On the contrary, overexpression of MPS1 decreases the frequency of premature sister chromatid separation. In human oocytes, the SAC can be inactivated by loss of centromeric cohesion (Lagirand-Cantaloube et al. 2017). With advancing age, as centromeric cohesion decreases, the activity and the stringency of the SAC decrease as well. The compromised SAC is less able to respond to DNA damage, resulting in premature sister chromatid separation and aneuploidy (discussed below in DNA damage) (Chiang et al. 2010,2012 Nagaoka et al. 2011, 2012, Marangos et al. 2015, Vincenten et al. 2015, Lagirand-Cantaloube et al. 2017, Wang et al. 2017a).
Other components of the SAC when impaired also contribute to increased aneuploidy with advancing female age. Budding-uninhibited-by-benzimidazole (BUB1) and BUB1-related (BUBR1) protein kinases localize to kinetochores upon activation of the SAC (Lagirand-Cantaloube et al. 2017). Decreased localization of BUB1 and BUBR1 have been shown to correlate with aneuploidy in aged human oocytes (Lagirand-Cantaloube et al. 2017). The SAC, BUB1, BUBR1, and MPS1 all aid in monitoring proper spindle and chromosome attachment. Theoretically, manipulating different components of the SAC could lead to new therapeutic approaches for age-related female aneuploidy.
Breast cancer-associated 1 (BRCA1), a tumor suppressor gene, has also been implicated in spindle assembly and the SAC. Earlier studies revealed that BRCA1 colocalizes with γ-tubulin at spindle poles during meiosis in mouse oocytes (Pan et al. 2008, Xiong et al. 2008). Decreasing or depleting BRCA1 in mouse oocytes leads to severely impaired spindle formation and chromosome mis-alignment, resulting in chromosome mis-segregation and aneuploidy (Pan et al. 2008, Xiong et al. 2008). Similarly, aged mouse oocytes demonstrate decreased BRCA1 expression, leading to aberrant spindle formation and chromosome misalignment. These findings are also consistent with age-related differences demonstrated in global gene expression of oocytes and eggs (Pan et al. 2008). Interestingly, differences in expression of genes involved in spindle assembly, the SAC, and chromosome alignment were also shown (Pan et al. 2008), Although the SAC appears to be an important safeguard against aneuploidy even with advancing maternal age, studies in mice indicate that defective SAC function is not a primary cause of female age-related aneuploidy (Duncan et al. 2009). However, impaired function of the SAC with age is likely an important contributing factor.
DNA damage, telomeres, reactive oxygen species, and mitochondrial dysfunction
DNA damage
As organisms age, cellular mechanisms that repair DNA damage become less effective. Decreased efficacy of DNA repair mechanisms leads to DNA damage, altered DNA repair, and accumulation of mutations (Gorbunova et al. 2007). In oocytes, this could result in poor quality, apoptosis, and ultimately infertility and miscarriage. In the presence of DNA damage, cells activate a coordinated mechanism called the DNA damage response (DDR), which activates different repair processes to correct the damage. Activation of the DDR during meiosis can lead to the elimination of oocytes with unrepaired meiotic DSBs above a threshold level; this has been shown to occur in mice via the TRP53 and TAp63 pathways (Rinaldi et al. 2020). The DDR also coordinates with the SAC so that both of these cell cycle checkpoints are able to identify most of the DNA damage that occurs (Collins & Jones 2016). Among the types of DNA damage, DSBs are the most detrimental to cells, often leading to cell death if left unrepaired (Collins & Jones 2016). Both physically and chemically induced DSBs activate the SAC and arrest oocytes in metaphase I. The arrest blocks APC/C activity and stabilizes securin. Thus, the SAC is critical in preventing DNA damage including DSBs in oocytes (Collins & Jones 2016).
In addition to roles related to spindle assembly and the SAC, BRCA genes have functions in DNA repair. BRCA1, and its closely related tumor suppression gene BRCA2, are both involved in the repair of ataxia-telangiectasia-mutated (ATM)-mediated DSBs in oocytes (Yoshida & Miki 2004, Titus et al. 2013, Lin et al. 2017b). They do so by regulating the transcription of DNA repair genes. Through hyperphosphorylation events by a multitude of kinases, the proteins encoded by BRCA1 and BRCA2 repair DSBs via homologous recombination (HR) (Yoshida & Miki 2004). Studies have scrutinized the role of BRCA1 and BRCA2 in ovarian aging and have found that gene mutations in both mice and humans are associated with an age-related decline in ovarian reserve (Titus et al. 2013, Lin et al. 2017b). Brca1-deficient female mice had decreased reproductive potential, lower numbers of primordial follicles compared to WT females. Follicles of older Brca1-deficient ovaries also had increased DSBs compared to WT controls (Titus et al. 2013). In women with BRCA1-mutations, mean serum anti-mullerian hormone (AMH) levels were significantly lower, consistent with diminished ovarian reserve (Titus et al. 2013). BRCA1 mRNA and protein expression were also decreased in oocytes of older women compared to younger women (Titus et al. 2013). The impact of BRCA1 and BRCA2 mutations on ovarian reserve has also been studied in women (Lin et al. 2017b). Unaffected carriers of BRCA1 and BRCA2 mutations were shown to have an age-related decline in the number of primordial follicles consistent with decreased ovarian reserve. This rate of decline was much faster than that observed in the control group without BRCA1 or BRCA2 mutations (Lin et al. 2017b). Interestingly, oocytes of carriers with only BRCA1 mutations showed increased DSBs (Lin et al. 2017b). These studies suggest and highlight the importance of DNA repair and BRCA1 and BRCA2 functionin delaying ovarian aging (Titus et al. 2013, Lin et al. 2017b).
Another component essential to the repair of DSBs is checkpoint kinase 2 (CHK2) (Bolcun-Filas et al. 2014). CHK2 is a serine/threonine-protein kinase that aids in checkpoint signaling during the progression of the cell cycle in mitosis and meiosis. CHK2 is activated by ataxia-telangiectasia mutated (ATM) kinase in the presence of DSBs and plays an important role in culling the ovarian follicle pool, especially oocytes with unrepaired or induced DSBs or those with unsynapsed homologous chromosomes (Bolcun-Filas et al. 2014, Rinaldi et al. 2017). Errors detected by CHK2activate the TRP53/TAp63 pathway to eliminate defective oocytes (Bolcun-Filas et al. 2014, Rinaldi et al. 2017). Chk2-null mice are fertile and possess similar numbers of oocytes as WT mice. Mice that are doubly deficient in Chk2 and other genes necessary for DSB repair showed partial rescue of oocyte elimination compared to mice singly deficient in these repair genes. Since not all oocytes are rescued in these double mutants, CHK2 is not essential for the elimination of all defective oocytes; this suggests that other mechanisms are also necessary to repair DSBs in oocytes. Nevertheless, CHK2 plays an important role in DNA damage repair and in ensuring the development of undamaged healthy oocytes. Thus, as oocytes age, surveillance mechanisms of DNA damage are crucial in maintaining the quality of oocytes and female fertility.
Telomere length and telomerase activity
Telomeres, present at chromosome ends in eukaryotes, consist of tandem DNA repeat sequences. They act in concert with proteins and RNA molecules to preserve chromosome integrity (Venkatesan et al. 2017). In most cell types in the human body, DNA is lost with each cycle of DNA replication as a result of telomere shortening. Some cells, including oocytes, possess the enzyme telomerase to help extend telomeric DNA (Keefe et al. 2015). Telomerase is an RNA-dependent DNA polymerase (also known as reverse transcriptase) that ensures the proper DNA replication of the highly repetitive sequences of telomeres (Venkatesan et al. 2017). Telomere length is known to directly correlate with both reproductive life span and life expectancy ( Keefe et al. 2007, Kalmbach et al. 2013).
Comparison of telomere lengths in the leukocytes of women revealed that telomeres are shorter in postmenopausal women than those of a similar age but still menstruating (Gray et al. 2014). In fact, women with longer telomeres were found to enter menopause up to 3 years later than in those with shorter telomeres (Gray et al. 2014). This suggests that menopause may occur after telomere shortening bypasses or reaches a specific length. As such, quantification of telomere length in leukocytes could potentially be used as a biomarker of reproductive aging (Gray et al. 2014).
A study of women undergoing IVF suggested that telomere length may also predict oocyte quality and be associated with aneuploidy in human embryos (Treff et al. 2011). Aneuploid embryonic cells were found to possess significantly less telomere DNA than euploid embryonic cells. This highlights the significant role of telomeres in genomic stability. This also suggests that decreased telomere length may be associated with aneuploidy in oocytes and early-stage embryos (Treff et al. 2011). Therefore, oocytes and early embryos with shorter telomere lengths may be an indicator of improper chromosome segregation, leading to aneuploidy (Treff et al. 2011). Thus, in the future, it may be possible to improve IVF success rates by selecting oocytes and embryos based on telomere length (Treff et al. 2011). However, further studies are needed to determine a possible correlation between telomere length and oocyte and embryo quality.
Telomere length and telomerase activity have also been associated with specific age-related conditions. Studies in human granulosa cells indicate that telomerase homeostasis, the combination of telomere loss and repair, correlates with POI in young women (Butts et al. 2009). Specifically, in women 37 years old and younger, a lack of telomerase activity in human granulosa cells was associated with ovarian insufficiency. Women with 'biochemical' POI, an intermediate stage of POI characterized by irregular but spontaneous menstrual periods and elevated serum FSH levels ranging from 10 to 40 IU/L, had reduced telomerase activity and shorter telomere lengths in their follicle granulosa cells as well as peripheral blood leukocytes (Butts et al. 2009, Xu et al. 2017). Women with biochemical POI also had about 50% less telomerase activity and telomere length in these cells compared to women without POI of the same age (Xu et al. 2017). Thus, telomere length and telomerase activity may have a significant impact on ovarian aging, and perhaps these parameters could be used to study changes and decline of ovarian function.
ROS and mitochondrial dysfunction
Reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) have been shown to impact cellular aging in the human body, including in the female reproductive tract (Rizzo et al. 2012). Importantly, studies have suggested that excess ROS may negatively impact ovarian aging. ROS are highly reactive compounds containing oxygen such as superoxide anions, hydrogen peroxide, and hydroxyl radicals. ROS form endogenously from the metabolism of oxygen during cellular processes. Normally, cells are able to eliminate excess ROS (Remacle et al. 1995). When overproduced, these compounds cause oxidative stress and cellular damage. High concentrations of ROS in cells lead to mitochondrial and nuclear DNA damage and apoptosis (Rizzo et al. 2012). These types of damage have been shown to adversely affect ovarian follicle development and ovulation (Guerin et al. 2001, Rizzo et al. 2009, 2012). In fact, ROS may be lethal to cells but is a normal part of ovarian aging (reviewed in Rizzo et al. 2012). In mice, long-term oxidative stress caused by ROS has been associated with decreased follicle and oocyte quality without affecting oocyte quantity (Shi et al. 2016). Ovaries of ozone-exposed mice showed high levels of ROS and oxidized metabolites. Consistent with these findings, ozone-exposed female mice had smaller and fewer litters compared to controls. However, serum estrogen levels were no different between the two groups while serum testosterone and progesterone levels were decreased in ozone-exposed females. Although markers of ovarian reserve, including the size of the primordial follicle pool and expression levels of anti-mullerian hormone (AMH), also did not change (Shi et al. 2016). The authors propose that long-term moderate oxidative damage decreased the fertility and fecundity potential of mice (Shi et al. 2016). In a separate study, mice that were exposed to ozone and fed with the antioxidant N-acetyl-L-cysteine (NAC) had better quality oocytes than those of ozone-exposed mice not given NAC (Liu et al. 2012). Specifically, NAC-treated mice ovulated greater numbers of intact oocytes and yielded significantly increased numbers of blastocysts compared to unexposed mice that ovulated more fragmented or lysed oocytes. Interestingly, NAC treatment also increased oocyte telomere length, telomerase activity, and expression of genes associated with telomerase activity (Liu et al. 2012). Collectively, these studies suggest that oxidative damage caused by ROS may impact reproductive potential by decreasing the quality of ovarian follicles and oocytes, and that antioxidants may prevent oxidative damage and delay oocyte aging (Liu et al. 2012, Shi et al. 2016).
Mitochondrial DNA (mtDNA) damage and dysfunction have also been associated with ovarian aging. Mitochondrial DNA is uniquely inherited by the offspring directly from oocyte mitochondria. In females, the mtDNA copy number increases from approximately 200 to 100,000 as oogenesis progresses. Each mitochondrion contains about 2–10 copies (Keefe et al. 2015, Wang et al. 2017b). The mitochondrial-free radical theory of aging puts forth the notion that high levels of ROS cause oxidative damage, leading to mtDNA mutations in cells; this negatively affects the production and function of electron transport chain proteins (Harman 1956, Keefe et al. 2015, Wang et al. 2017b). Since mitochondria have limited DNA repair mechanisms, mitochondrial mutations accumulate in cells with age at an exponential rate, almost 25 times that of nuclear DNA (Lynch et al. 2006). Accrual of mtDNA mutations has been proposed to compromise oxidative phosphorylation and increase ROS, resulting in increased mtDNA copy number to offset these effects. Thus, mtDNA copy number and ATP content have been used as parameters to assess aging in oocytes, too. Although mtDNA mutations and oxidative damage resulting from high levels of ROS have been thought to contribute to ovarian aging, studies have been conflicting. Previous studies that analyzed mitochondrial DNA deletions using nested PCR techniques found no relationship between mtDNA mutations in oocytes or embryos and a woman’s age (Brenner et al. 1998). However, more recent research suggests that an elevated mtDNA copy number in oocytes is more closely correlated with ovarian aging (Keefe et al. 2007, 2015, Wang et al. 2017b). Day 3 and day 5 preimplantation embryos from older women undergoing IVF were found to have higher mtDNA copy numbers compared to those from younger women when analyzed by array comparative genomic hybridization, PCR, and next-generation sequencing (Fragouli et al. 2015). In addition, aneuploid embryos from women, regardless of age, were found to have increased mtDNA copy numbers compared to euploid embryos (Fragouli et al. 2015). Consequently, women with increased mtDNA copy numbers of their embryos had decreased implantation rates with IVF (Fragouli et al. 2015, Seli 2016, Ravichandran et al. 2017). These findings suggest that increased mtDNA copy number is associated with decreased embryo viability and quality (Wang et al. 2017b). However, conflicting studies have found no significant correlation between mtDNA copy number and implantation rate (Treff et al. 2017, Victor et al. 2017, Klimczak et al. 2018, Kim & Seli 2019). Other studies demonstrate that low copy numbers of mtDNA are associated with ovarian aging (Bonomi et al. 2012, Keefe et al. 2015). In particular, women with POI were found to have lower copy numbers of mtDNA in peripheral blood cells compared to women of the same age with normal ovarian reserve (Bonomi et al. 2012). Surprisingly, in the same study, women with a poor response to exogenous ovarian stimulation were found to have intermediate levels of mtDNA. A separate study in mouse oocytes found that low copy numbers of mtDNA had minimal effect on oocyte and embryo development until copy numbers were lower than that found in human oocytes (Keefe et al. 2015). Although there is potential for utilizing mtDNA copy numbers in a clinical setting, further studies are needed to determine the absolute impact on ovarian aging.
Genetic factors
Genetic factors play an important role in ovarian aging as indicated by studies suggesting that the ages of menarche and natural menopause are heritable (Snieder et al. 1998, de Bruin et al. 2001, Murabito et al. 2005, He & Murabito 2014). A few of the most well-studied genes are mentioned in this section (Table 1). The earliest studies of genetic factors that demonstrate a clear association between ovarian aging and genetic factors identified a premutation of FMR1 in women with POI (Man et al. 2017). Currently, it is unclear whether mutations in FMR1 decrease ovarian function due to changes during the development of the primordial germ cell population and/or attrition of the oocyte pool during a woman’s life (Reyniers et al. 1993, Man et al. 2017). A mutation in FMR1 is associated with fragile X syndrome, an X-linked dominant genetic disorder characterized by intellectual disabilities and physical abnormalities. The mutation is an expansion of the trinucleotide sequence CGG beyond a normal number of approximately 5–40 in the 5’ UTR of the FMR1 gene, and expansion of the repeat occurs in successive generations within a family (Reyniers et al. 1993, Man et al. 2017). The mutation is characterized by the number of expanded CGG repeats: intermediate corresponds to approximately 40–55 CGG repeats, premutation about 55–200 repeats, and a full mutation greater than 200 repeats. A full mutation results in DNA hypermethylation, leading to silencing of FMR1 and loss of FMR protein (FMRP) expression (Cronister et al. 1991, Devys et al. 1993, Tassone et al. 2000, Juncos et al. 2011). Less than 200 CGG repeats confer low to normal FMRP expression. Premutation of FMR1 is responsible for 2–11% of POI cases in the Caucasian population, a 20-fold increased risk compared to women without a mutation (Hipp et al. 2016). Interestingly, the premutation of FMR1 was more strongly associated with POI than intermediate expansions of CGG repeats (Bodega et al. 2006). Approximately 75% of women were able to have at least one child with or without the help of infertility treatments. A study of women with FMR1 premutations undergoing IVF had a statistically significant, but weakly associated, decreased responsiveness to ovarian stimulation and lower fertilization rates compared to women with >100 CGG repeats (Banks et al. 2016).
Well-studied genes that when mutated or deleted in humans and/or mice impair ovarian function and impact oocyte quantity and/or quality.
| Gene (human) | Function | Physiologic consequence of mutation in humans | Phenotype caused by deletion/mutation in mice | References |
|---|---|---|---|---|
| FMR1 | RNA-binding polysome-associated protein | Premutation POI | Early decline in reproduction; reduced litter size; reduced follicle survival; ovarian mitochondria abnormalities | Bodega et al. (2006), Pastore et al. (2012), Elizur et al. (2014), Gleicher et al. (2015), Banks et al. (2016), Conca Dioguardi et al. (2016), Hipp et al. (2016), Mok-Lin et al. (2018), |
| MYADML | Myeloid-associated differentiation marker like pseudogene function in oogenesis unknown |
POI | No studies documented in mice. | Schuh-Huerta et al. (2012a) |
| MCM8 | Mini chromosome maintenance complex- initiation of DNA replication, formation of replication fork | Gonadal dysgenesis POI | Defective meiotic recombination; subfertility; Impaired gametogenesis | Maiorano et al. (2005), Lutzmann et al. (2012), Schuh-Huerta et al. (2012b), Stolk et al. (2012), Al Asiri et al. (2015) |
| POLG | Catalytic subunit of mtDNA polymerase | Phenotype caused by deletion/mutation in mice | mtDNA mutations accumulation; age-related phenotypes; subfertility | Luoma et al. (2004), Trifunovic et al. (2004), Pagnamenta et al. (2006), Stolk et al. (2012) |
| NOBOX | Transcription factor for oogenesis | POI | Accelerated postnatal oocyte loss; arrest of ovarian follicle development at the primordial stage | Rajkovic et al. (2004), Lin et al. (2017a) |
| FIGLA | Transcription factor in oocyte gene expression | POI | Sterility; small, underdeveloped ovaries; depletion of oocytes | Rankin & Dean (2000), Soyal et al. (2000), Zhao et al. (2008), Tosh et al. (2015) |
POI, primary ovarian insufficiency.
Although FMR1 has been most implicated with POI, other studies have revealed a more general role for this gene in ovarian aging. Different ranges of CGG repeats have been associated with varying degrees of decline in ovarian reserve. While prior studies suggested that individuals without a mutation in FMR1 (CGG repeats < 40) show no clinical phenotype, more recent studies suggest an association with diminished ovarian reserve (Pastore et al. 2012, Elizur et al. 2014, Gleicher et al. 2015,). In fact, fewer than 26 CGG repeats in FMR1 may have the most negative impact on ovarian aging and infertility. Analysis of young oocyte donors demonstrated that women with CGG repeats of < 26 showed accelerated reductions in serum AMH levels compared to women with greater copy numbers (Gleicher et al. 2015). These results suggest the importance of FMR1 in ovarian aging even when CGG trinucleotide repeats are considered to be in the 'normal' range of < 40 ( Elizur et al. 2014, Gleicher et al. 2015, Banks et al. 2016). Although the loss of FMRP expression leads to fragile X syndrome, the mechanisms by which lower levels of FMRP impact ovarian aging are not yet known.
Interestingly, genetic studies in humans and mice have revealed genes with noncanonical functions in the processes of folliculogenesis, ovarian follicle pool maintenance, and ovarian aging. Genome-wide association studies (GWAS) have identified candidate genes that are implicated in ovarian aging. One of the earliest GWA studies to examine ovarian aging evaluated genetic variants associated with FSH and AMH, hormonal biomarkers of ovarian reserve. This study, performed in a population of Caucasian and African American women aged 25–45, revealed a significant correlation between variants near and within the myeloid associated differentiation marker-like (MYADML) gene and serum FSH levels (Schuh-Huerta et al. 2012a); some variants of MYADML were associated with higher serum FSH, while other variants were associated with lower serum FSH (Schuh-Huerta et al. 2012a). Fewer genetic variants were found to correlate with AMH levels in both Caucasian and African American women. In addition, both FSH and AMH levels were more variable and less strongly associated with age in African American women compared to in Caucasian women (Schuh-Huerta et al. 2012a).
A large meta-analysis of GWA studies by Stolk et al. found an association between the age of natural menopause and minichromosome maintenance complex component 8 (MCM8), a gene subsequently demonstrated to have functions in fertility and folliculogenesis (Stolk et al. 2012). MCM8 encodes a DNA helicase that has previously been shown to function in homologous recombination in mice (Maiorano et al. 2005, Lutzmann et al. 2012). In a separate GWA study evaluating ovarian reserve and reproductive lifespan, women with a specific SNP in MCM8 (rs16991615) were shown to reach menopause approximately 1 year later than women without this DNA variant. These women also had higher antral follicle counts by pelvic ultrasound (Schuh-Huerta et al. 2012b). Other studies utilizing whole-exome sequencing revealed MCM8 mutations in families of individuals with gonadal dysgenesis and POI (Maiorano et al. 2005, Lutzmann et al. 2012, AlAsiri et al. 2015 ). In fact, these findings support prior studies of MCM8 in mice. Targeted deletion of MCM8 in mice caused defective meiotic recombination, subfertility, and impaired gametogenesis in both female and male mice (Lutzmann et al. 2012). MCM8-deficient female mice had smaller ovaries containing fewer, as well as apoptotic oocytes compared to WT controls. Adult ovaries of MCM8-deficient female mice had aberrant-appearing follicles that were arrested in the primary stage of follicle development. Collectively, these findings demonstrate the importance of MCM8 in ovarian function and suggest a role in ovarian aging.
POLG, another novel gene identified by genetic studies in humans and mice, has also been associated with ovarian aging (Trifunovic et al. 2004, Stolk et al. 2012). POLG encodes the alpha subunit of DNA polymerase gamma that functions in the synthesis of mtDNA (Luoma et al. 2004, Pagnamenta et al. 2006). Previously, POLG mutations have been identified in patients with an associated inherited mitochondrial disorder (Luoma et al. 2004). A study examining this condition in individuals from seven families of different ethnic backgrounds found that women who possessed a specific mutation in POLG (Y955C) also had POI (Luoma et al. 2004). A subsequent study found the same POLG mutation in three generations of women with dominantly inherited POI (Pagnamenta et al. 2006). Mice with a homozygous knock-in mutation expressing a proof-reading-deficient PolgA, which encodes the catalytic subunit of Polg, displayed accumulation of mtDNA mutations, age-related phenotypes, and subfertility. Intriguingly, most mutant females had only one or two litters of normal size each, and none had litters after 20 weeks of age (Trifunovic et al. 2004).
The newborn ovary homeobox (NOBOX) is a gene expressed in primordial germ cells, oocytes, and granulosa cells. It is essential for regulating the transcription of genes that are critical in early oocyte differentiation (Rajkovic et al. 2004, Bouilly et al. 2015). Recent studies have also demonstrated the importance of NOBOX in women with POI (Bouilly et al. 2015, 2016). Six percent of women with POI were found to be heterozygous for a mutation in NOBOX (Bouilly et al. 2015). In another study of European women with idiopathic POI, 6.5% of women were heterozygous for NOBOX variants. Additionally, a truncating variant of NOBOX that causes a loss-of-function mutation on the transcriptional activation of GDF9, a known target of NOBOX, was identified in women with POI (Lin et al. 2017a). This novel variant of NOBOX, when inherited in a homozygous manner, results in a compromised DNA binding domain of the protein and impaired transcriptional activation. In addition, this truncation results in aberrant G2/M checkpoint control, which suggests that NOBOX may be important for cell-cycle control (Lin et al. 2017a). Previous studies in Nobox-deficient mice have shown accelerated postnatal oocyte loss and arrest of ovarian follicle development at the primordial stage. At birth, histomorphometric analyses showed Nobox-deficient mice had no loss of germ cells. However, by day 7, ovaries had fewer oocytes, fewer primary follicles, and no secondary follicles. By day 14 postnatally, ovaries were almost devoid of oocytes (Rajkovic et al. 2004). Consistent with these findings, accelerated loss of oocytes in Nobox-deficient females resulted in infertility (Rajkovic et al. 2004).
Factor in the germline alpha (Figla, formerly FIGα) encodes a helix-loop-helix transcription factor that regulates oocyte-specific genes and folliculogenesis in mammals (Soyal et al. 2000). Figla regulates oocyte-specific gene expression postnatally, particularly the expression of Zona Pellucida (ZP)1, ZP2, and ZP3. These genes encode proteins that comprise the zona pellucida, a specialized glycoprotein layer surrounding the developing oocyte and preimplanatation embryo (Rankin & Dean 2000, Soyal et al. 2000). Studies have identified mutations of FIGLA in women with POI (Zhao et al. 2008, Tosh et al. 2015). Seven unique variants of FIGLA were identified in a study of 219 Indian women with POI (Tosh et al. 2015). In a separate study of Chinese women with POI, a missense mutation and a deletion of FIGLA were present in 2% of women with POI (Zhao et al. 2008). Mutations in FIGLA caused premature termination of translation and disrupted the formation of primordial follicles (Zhao et al. 2008). Figla-null female mice are sterile, possessing small ovaries that are depleted of oocytes. In the absence of Figla, oocytes cannot develop to maturity (Soyal et al. 2000). Although gonadogenesis occurs normally during embryonic development in both Figla-null females and males, primordial follicles fail to form in Figla-null ovaries following birth (Soyal et al. 2000).
Protein metabolism dysregulation and microenvironmental alterations in the ovary
Dysregulation of protein metabolism in oocytes during the crucial period of oogenesis has been suggested to be deleterious to oocyte quality (Duncan & Gerton 2018). In a novel study using RNA-Seq, single growing follicles from reproductively young and aged female mice were analyzed to investigate the effects of age on cellular processes in the oocyte. Follicles from older females had increased numbers of nucleoli and ribosomes and disrupted protein metabolism compared to follicles from younger mice (Duncan et al. 2017). Consequently, older oocytes showed increased expression of specific proteins such as fibrillarin, an rRNA methyltransferase that alters ribosome function and is also known to be overexpressed in breast and prostate cancers in mice and humans (Duncan et al. 2017). Alterations during the early oogenesis period have a clear impact on oocyte quality and reproductive potential.
Fibrosis of ovarian stroma, caused by an accumulation of extracellular matrix, has also been associated with ovarian aging (Briley et al. 2016). When connective tissue from the ovaries of mice was stained with picrosirius red (PSR), the ovaries from older mice aged 22 months showed increased staining intensity compared to ovaries from younger mice aged 6 weeks. This suggested that with advancing reproductive age, there was increased ovarian fibrosis (Briley et al. 2016). In this study, oocytes of older mice had increased expression of genes associated with chronic inflammation including more multinucleated macrophage giant cells (Briley et al. 2016). These findings emphasize the importance of the stromal microenvironment in reproductive aging.
The presence of inflammation in the microenvironment has also been shown to play a role in ovarian aging. With age, there is increased low-grade, chronic inflammation that contributes to the development of age-related diseases (Foley et al. 2021). Inflammation in the ovary of mice has been suggested to impact the number and quality of oocytes (Zhang et al. 2020, Foley et al. 2021, Lliberos et al. 2021b). Examination of whole ovaries throughout the lifespan of mice revealed that specific macrophage markers were increased in old ovaries compared to young ovaries (Zhang et al. 2020). This is consistent with the presence of more proinflammatory cytokines, macrophages, and collagen, which may contribute to the inhospitable, inflammatory microenvironment in aging ovaries (Foley et al. 2021). Interestingly, when factors that contribute to an inflammation state in mice were suppressed, macrophage infiltration was reduced and follicle reserves were maintained with aging (Lliberos et al. 2021a). In humans, metabolic syndrome, particularly that resulting from obesity, worsens with increasing age and has been shown to contribute to the increase in the extrinsic and intrinsic inflammatory state (Kase et al. 2020). The consequence of this includes an increased risk for the development of cancer including ovarian and endometrial cancers. Thus both follicles and the ovarian microenvironment likely contribute to a decline in oocyte quality with aging. The extent of this multifactorial impact on oocyte quality and ovarian aging warrants further investigation.
Quality over quantity
Current measures of reproductive aging rely heavily on markers of follicle quantity. However, the potential use of these biomarkers has come under scrutiny in a recent study of the association between hormonal biomarkers of ovarian reserve and infertility (Steiner et al. 2017). In this study of reproductive-aged women without a history of infertility, diminished markers of follicle quantity were, in fact, not associated with a lower probability of conceiving. Women with markers of diminished ovarian reserve had similar predicted probabilities of conceiving as women with normal hormonal values (Steiner et al. 2017). Another study found similar conclusions in reproductive-aged women with a history of one or two miscarriages. AMH levels were not associated with clinical pregnancy loss (Zarek et al. 2016). Women with low AMH levels had similar rates of pregnancy loss compared to women with normal or high AMH levels. These findings highlight the limitations of current biomarkers that are being used to counsel women about their reproductive potential (Zarek et al. 2016). The importance of evaluating oocyte quality over quantity and its effects on ovarian aging are an area of research that must further be investigated.
Conclusions
The field of ovarian biology continues to evolve and expand at a remarkable pace as new areas of research investigate female fertility and ovarian aging. Recent studies have provided a deeper understanding of the mechanisms of ovarian aging and the diverse factors that impact it including deterioration of chromosomal cohesion, DNA damage and mitochondrial dysfunction, telomere shortening, genetic mutations, and alterations in protein metabolism and the stromal microenvironment. These factors influence both the quantity and quality of the ovarian reserve. With a greater number of women seeking fertility counseling and infertility treatment, methods to evaluate and protect the ovarian reserve, and ultimately, mitigate ovarian aging have become increasingly important to study. In fact, recently, there has been a substantial investigative effort to further elucidate measures of oocyte quality over quantity, as markers of the diminished ovarian reserve may not be an accurate representation of a woman’s reproductive potential. As the aging population continues to increase, it is also critical to investigate further the complex relationship between somatic and ovarian aging and its consequences on the reproductive and general health of women. This review provides a broad survey and insight into mechanisms of ovarian aging, as well as potential areas to explore further to gain a better understanding of the complexities of the ovarian reserve.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This work was supported by the National Institutes of Health (NIH) R01 GM106262 grant and the American Society for Reproduction 2020 Research Grant to K.M.B.
Author contribution statement
K B and L W conceived of the work. L W, S P, and K B wrote and edited the manuscript.
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