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Genetic Relationships Between Early Menopause and the Behaviour of Theca Interna During Follicular Atresia

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Genetic Relationships Between Early Menopause and the Behaviour of Theca Interna During Follicular Atresia Human Reproduction, Vol.0, No.0, pp. 1–3, 2020 doi:10.1093/humrep/deaa173 OPINION Genetic relationships between early Downloaded from https://academic.oup.com/humrep/advance-article/doi/10.1093/humrep/deaa173/5892245 by Univ of Rochester Library user on 26 August 2020 menopause and the behaviour of theca interna during follicular atresia Raymond J. Rodgers1,* and Joop S.E. Laven2 1Robinson Research Institute, School of Medicine, The University of Adelaide, Adelaide, SA 5005, Australia 2Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynaecology, Erasmus University Medical Center, Rotterdam, Netherlands *Correspondence address. Robinson Research Institute, School of Medicine, The University of Adelaide, Adelaide, SA 5005, Australia. E-mail: [email protected] Submitted on April 26, 2020; resubmitted on May 24, 2020; editorial decision on June 8, 2020 ABSTRACT: Genetic variants are known to contribute to about 50% of the heritability of the age of menopause and recent studies sug- gest that genes associated with genome maintenance are involved. The idea that increased rates of follicular atresia could lead to depletion of the primoridial follicle reserve and early menopause has also been canvassed, but there is no direct evidence of this. In studies of the transcriptomics of follicular atresia, it was found that in the theca interna, the largest group of genes are in fact down-regulated and associ- ated with ‘cell cycle and DNA replication’, in contrast with the up-regulation of apoptosis-associated genes which occurs in granulosa cells. Many of the genes down-regulated in the theca interna are the same as or related to the genes in loci associated with early menopause. From these findings, we suggest that early menopause could be due to increased rates of follicular atresia initiated from the theca interna. Key words: menopause / follicle / atresia / genetics / genome maintenance . Early menopause . studies (GWAS), 29 contained one or more DNA damage response . and genome maintenance genes within 500 kb, and these genes were . Menopause in women is the age-dependent permanent end of ovula- . the nearest genes in 18 of these loci. These genes are also linked with tion and menstrual cycles. It is due to a reduction in the number of . longevity and ageing (Laven et al.,2016; Niedernhofer et al.,2018). ovarian follicles and on average occurs at age of 51 years. Early meno- . Thus it was suggested that premature ageing of soma could be respon- pause is defined as menopause occurring between ages 40 and 45 . sible for the occurrence of early menopause (Laven et al.,2016), but . years (Laven et al., 2016). In about 1% of women, it can occur prema- . the mechanism of how this process of ageing and the genome mainte- turely, earlier than 40 years old (Luborsky et al.,2003). Women are . nance genes are mechanistically linked to menopause is not known. diagnosed with premature ovarian insufficiency if they have secondary . Premature ovarian insufficiency (or failure) is also indicated by a pre- amenorrhoea for at least 4 months before 40 years of age and FSH . mature reduction in the number of ovarian primordial follicles and this . levels above 40 IU/l. Premature ovarian insufficiency is considered as a . can be caused by genetics, autoimmunity or toxins (Rebar, 2009; multifactorial, heterogeneous condition and the specific underlying . Cooper et al.,2011; Jiao et al.,2018). Genes associated with growth cause remains unclear in most of the affected women. However, vari- . and development of follicles or meiosis are linked to about 20–25% of ous genetic causes have been determined, and associations with auto- . cases (Qin et al., 2015; Patino~ et al.,2017; Jiao et al.,2018; Venturella immune diseases and environmental factors, such as smoking, have . et al.,2019). Other studies have obviously focused on follicular dynam- . been reported (Daan et al.,2016). Moreover, sometimes premature . ics and considered early menopause to be associated with either the ovarian insufficiency is part of syndrome, like Turner syndrome, but in . formation of fewer follicles during ovarian development or subse- . the majority of cases, it is not syndromic. Genetic variants are known . quently enhanced rates of either follicular activation or follicular atresia, to contribute to about 50% of the heritability of the age of natural . all of which will lead to an earlier loss of ovarian primordial follicle re- . menopause (Perry et al.,2013). Recent investigations into the genetics . serve (Pelosi et al.,2015). The effects of chemicals such as cigarette of early menopause suggest that genes associated with DNA repair . smoke and chemotherapy and autoimmunity are also well known to . are involved (Day et al., 2015; Laven et al.,2016; Horikoshi et al., . affect ovarian primordial follicle reserve and hence the onset of meno- 2018). Specifically of the 44 loci identified by genome-wide association . pause (Shelling, 2010; Pelosi et al.,2015; Torrealday et al.,2017). VC The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: [email protected] 2 Rodgers and Laven Table I Genes in common between follicular atresia and early menopause. Genes associated with early menopausea Genes down-regulated in theca interna during atresiab ............................................................................................................................................................................................................................ BRCA1 Breast cancer 1. DNA repair and homologous recombination BRCA1 Downloaded from https://academic.oup.com/humrep/advance-article/doi/10.1093/humrep/deaa173/5892245 by Univ of Rochester Library user on 26 August 2020 FANCI Fanconi anaemia complementation group I. Inter-strand crosslink repair FANCI KNTC1 Kinetochore associated 1. Chromosome segregation KNTC1 RAD51 Homologous recombination and inter-strand crosslink repair RAD51AP1 RAD51-Associated Protein 1 CDK12 Cyclin-dependent kinase 12 CDK1 Cyclin-dependent kinase 1 CHEK2 Checkpoint kinase 2 CHEK1 Checkpoint kinase 1 MCM8 Minichromosome maintenance 8. Homologous recombination repair factor MCM2 Minichromosome maintenance 2, 3, 4, 5, 6 MCM3 MCM4 MCM5 MCM6 POLG DNA polymerase gamma, catalytic subunit POLE2 DNA polymerase epsilon 2, accessory subunit aLaven et al. (2016). bHatzirodos et al. (2014b). Follicular atresia . 12 of these genes down-regulated in the theca interna upon atresia . (Hatzirodos et al.,2014b) are the same or related to 8 of the 37 Follicular atresia occurs as a means of reducing the numbers of follicles . DNA repair genes found in loci associated with early menopause ovulating and controlling the timing of ovulation during a reproductive . (Laven et al.,2016)(Table I). cycle (Byskov, 1978). It involves cell death and during follicle growth . and development, the order of susceptibility to death is the oocyte, . then both the theca interna and membrana granulosa, and lastly at the . Idea late antral stages, just the membrana granulosa (Clark et al.,2004). It . has been proposed previously that increased rates of follicular atresia . From these findings, we hypothesise that one mechanism by which . early menopause occurs is via the theca interna and the process of fol- lead to increased rates of primordial follicle activation and eventually . licular atresia. How would this operate? Presumably as proposed pre- depletion of the ovarian primordial follicle reserve leading to early . menopause, however, there is no direct evidence of this (Pelosi et al., . viously, the genes associated with genome maintenance are less . 2015). Indirect evidence is supported by the relationships between the . effective in women who prematurely age and have early menopause declining numbers of primordial follicles and the reduction in the size . (Laven et al., 2016). It they were also less effective in the theca . of the reserve of small antral follicles with ageing (Monniaux et al., . interna, their follicles would be more prone to undergo follicular atre- . sia. Increased rates of follicular atresia in turn would lead to increased 2014). Also, some chemotherapy agents primarily damage growing fol- . licles, leading to increased rates of activation of dormant primordial fol- . rates of primordial follicle activation to produce more growing follicles . to replace those undergoing atresia. This in turn would lead to an ear- licles, in turn leading to an earlier reduction in the primordial follicle . reserve and hence early menopause (Kalich-Philosoph et al.,2013; . lier depletion of the primordial follicle reserve and hence an earlier . menopause. Wang et al.,2019). When recently reviewing published literature of follicular atresia . (Hatzirodos et al.,2014a,b), it became apparent that there is a po- . How could this be tested? tential connection with the genetics of early menopause. In studies . of the transcriptomics of bovine follicular atresia, it was found that . Firstly, it would be necessary to confirm the bovine data by conducting in the theca interna, the largest group of genes were in fact down- . a study of transcriptomics of human theca interna during atresia. This regulated and associated with ‘cell cycle and DNA replication’ . would use RNA-seq to identify all of the genes involved in atresia; the (Hatzirodos et al.,2014b). This was in complete contrast to the up- . bovine data were
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