Semin Reprod Med 2020; 38(04/05): 256-262
DOI: 10.1055/s-0040-1721796
Review Article

Genetics of Menopause and Primary Ovarian Insufficiency: Time for a Paradigm Shift?

Joop S. E. Laven
1   Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus University Medical Center, Rotterdam, The Netherlands
› Author Affiliations

Abstract

This review summarizes the existing information concerning the genetic background of menopause and primary ovarian insufficiency (POI). There is overwhelming evidence that majority of genes are involved in double-strand break repair, mismatch repair, and base excision repair. The remaining loci were involved in cell energy metabolism and immune response. Gradual (or in case of rapid POI) accumulation of unrepaired DNA damage causes (premature) cell death and cellular senescence. This in turn leads to exhaustion of cell renewal capacity and cellular dysfunction in affected organs and eventually to aging of the entire soma. Similar erosion of the genome occurs within the germ cell line and the ovaries. Subsequently, the systemic “survival” response intentionally suppresses the sex-steroid hormonal output, which in turn may contribute to the onset of menopause. The latter occurs in particular when age-dependent DNA damage accumulation does not cease. Both effects are expected to synergize to promote (premature) ovarian silencing and install (early) menopause. Consequently, aging of the soma seems to be a primary driver for the loss of ovarian function in women. This challenges the current dogma which implies that loss of ovarian function initiates aging of the soma. It is time for a paradigm shift!



Publication History

Article published online:
01 March 2021

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 
  • References

  • 1 Wallace WH, Kelsey TW. Human ovarian reserve from conception to the menopause. PLoS One 2010; 5 (01) e8772
  • 2 Gajbhiye R, Fung JN, Montgomery GW. Complex genetics of female fertility. NPJ Genom Med 2018; 3: 29
  • 3 Gruhn JR, Zielinska AP, Shukla V. et al. Chromosome errors in human eggs shape natural fertility over reproductive life span. Science 2019; 365 (6460): 1466-1469
  • 4 Namazi M, Sadeghi R, Behboodi Moghadam Z. Social determinants of health in menopause: an integrative review. Int J Womens Health 2019; 11: 637-647
  • 5 Perry JR, Hsu YH, Chasman DI. et al; kConFab Investigators, ReproGen Consortium. DNA mismatch repair gene MSH6 implicated in determining age at natural menopause. Hum Mol Genet 2014; 23 (09) 2490-2497
  • 6 Laven JS. Genetics of early and normal menopause. Semin Reprod Med 2015; 33 (06) 377-383
  • 7 Desai S, Rajkovic A. Genetics of reproductive aging from gonadal dysgenesis through menopause. Semin Reprod Med 2017; 35 (02) 147-159
  • 8 Laven JSE, Visser JA, Uitterlinden AG, Vermeij WP, Hoeijmakers JHJ. Menopause: genome stability as new paradigm. Maturitas 2016; 92: 15-23
  • 9 Perry JR, Murray A, Day FR, Ong KK. Molecular insights into the aetiology of female reproductive ageing. Nat Rev Endocrinol 2015; 11 (12) 725-734
  • 10 van Asselt KM, Kok HS, Putter H. et al. Linkage analysis of extremely discordant and concordant sibling pairs identifies quantitative trait loci influencing variation in human menopausal age. Am J Hum Genet 2004; 74 (03) 444-453
  • 11 Murabito JM, Yang Q, Fox CS, Cupples LA. Genome-wide linkage analysis to age at natural menopause in a community-based sample: the Framingham Heart Study. Fertil Steril 2005; 84 (06) 1674-1679
  • 12 He C, Murabito JM. Genome-wide association studies of age at menarche and age at natural menopause. Mol Cell Endocrinol 2014; 382 (01) 767-779
  • 13 He C, Kraft P, Chasman DI. et al. A large-scale candidate gene association study of age at menarche and age at natural menopause. Hum Genet 2010; 128 (05) 515-527
  • 14 Yao G, He J, Kong Y. et al. Transcriptional profiling of long noncoding RNAs and their target transcripts in ovarian cortical tissues from women with normal menstrual cycles and primary ovarian insufficiency. Mol Reprod Dev 2019; 86 (07) 847-861
  • 15 Yang Y, Guo T, Liu R. et al. FANCL gene mutations in premature ovarian insufficiency. Hum Mutat 2020; 41 (05) 1033-1041
  • 16 Jiao X, Ke H, Qin Y, Chen ZJ. Molecular genetics of premature ovarian insufficiency. Trends Endocrinol Metab 2018; 29 (11) 795-807
  • 17 Day FR, Ruth KS, Thompson DJ. et al; PRACTICAL Consortium, kConFab Investigators, AOCS Investigators, Generation Scotland, EPIC-InterAct Consortium, LifeLines Cohort Study. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nat Genet 2015; 47 (11) 1294-1303
  • 18 Shen C, Delahanty RJ, Gao YT. et al. Evaluating GWAS-identified SNPs for age at natural menopause among Chinese women. PLoS One 2013; 8 (03) e58766
  • 19 Pyun JA, Kim S, Cho NH. et al. Genome-wide association studies and epistasis analyses of candidate genes related to age at menarche and age at natural menopause in a Korean population. Menopause 2014; 21 (05) 522-529
  • 20 Horikoshi M, Day FR, Akiyama M. et al. Elucidating the genetic architecture of reproductive ageing in the Japanese population. Nat Commun 2018; 9 (01) 1977
  • 21 Carty CL, Spencer KL, Setiawan VW. et al. Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study. Hum Reprod 2013; 28 (06) 1695-1706
  • 22 Coignet MV, Zirpoli GR, Roberts MR. et al. Genetic variations, reproductive aging, and breast cancer risk in African American and European American women: the Women's Circle of Health Study. PLoS One 2017; 12 (10) e0187205
  • 23 Shi J, Zhang B, Choi JY. et al. Age at menarche and age at natural menopause in East Asian women: a genome-wide association study. Age (Dordr) 2016; 38 (5-6): 513-523
  • 24 Perry JR, Corre T, Esko T. et al; ReproGen Consortium. A genome-wide association study of early menopause and the combined impact of identified variants. Hum Mol Genet 2013; 22 (07) 1465-1472
  • 25 França MM, Mendonca BB. Genetics of primary ovarian insufficiency in the next-generation sequencing era. J Endocr Soc 2019; 4 (02) bvz037
  • 26 Shi J, Wu L, Li B. et al. Transcriptome-wide association study identifies susceptibility loci and genes for age at natural menopause. Reprod Sci 2019; 26 (04) 496-502
  • 27 Niedernhofer LJ, Gurkar AU, Wang Y, Vijg J, Hoeijmakers JHJ, Robbins PD. Nuclear genomic instability and aging. Annu Rev Biochem 2018; 87: 295-322
  • 28 Sasaki H, Hamatani T, Kamijo S. et al. Impact of oxidative stress on age-associated decline in oocyte developmental competence. Front Endocrinol (Lausanne) 2019; 10: 811
  • 29 Dollé ME, Kuiper RV, Roodbergen M. et al. Broad segmental progeroid changes in short-lived Ercc1(-/Δ7) mice. Pathobiol Aging Age Relat Dis 2011; 1 DOI: 10.3402/pba.v1i0.7219.
  • 30 Milanese C, Bombardieri CR, Sepe S. et al. DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering. Nat Commun 2019; 10 (01) 4887
  • 31 Bacon ER, Mishra A, Wang Y, Desai MK, Yin F, Brinton RD. Neuroendocrine aging precedes perimenopause and is regulated by DNA methylation. Neurobiol Aging 2019; 74: 213-224
  • 32 Gast GC, Pop VJ, Samsioe GN. et al. Vasomotor menopausal symptoms are associated with increased risk of coronary heart disease. Menopause 2011; 18 (02) 146-151
  • 33 Woldringh GH, Frunt MH, Kremer JA, Spaanderman ME. Decreased ovarian reserve relates to pre-eclampsia in IVF/ICSI pregnancies. Hum Reprod 2006; 21 (11) 2948-2954
  • 34 Isik S, Ozcan HN, Ozuguz U. et al. Evaluation of ovarian reserve based on hormonal parameters, ovarian volume, and antral follicle count in women with type 2 diabetes mellitus. J Clin Endocrinol Metab 2012; 97 (01) 261-269
  • 35 Kim C, Karvonen-Gutierrez C, Kong S. et al. Antimüllerian hormone among women with and without type 1 diabetes: the Epidemiology of Diabetes Interventions and Complications Study and the Michigan Bone Health and Metabolism Study. Fertil Steril 2016; 106 (06) 1446-1452
  • 36 van Dorp W, van den Heuvel-Eibrink MM, de Vries AC. et al. Decreased serum anti-Müllerian hormone levels in girls with newly diagnosed cancer. Hum Reprod 2014; 29 (02) 337-342
  • 37 Brouwer J, Dolhain RJEM, Hazes JMW, Visser JA, Laven JSE. Reduced ovarian function in female rheumatoid arthritis patients trying to conceive. ACR Open Rheumatol 2019; 1 (05) 327-335
  • 38 Conley AC, Albert KM, Boyd BD. et al. Cognitive complaints are associated with smaller right medial temporal gray-matter volume in younger postmenopausal women. Menopause 2020; 27 (11) 1220-1227
  • 39 Labandeira-Garcia JL, Rodriguez-Perez AI, Valenzuela R, Costa-Besada MA, Guerra MJ. Menopause and Parkinson's disease. Interaction between estrogens and brain renin-angiotensin system in dopaminergic degeneration. Front Neuroendocrinol 2016; 43: 44-59
  • 40 Rocca WA, Gazzuola Rocca L, Smith CY. et al. Loss of ovarian hormones and accelerated somatic and mental aging. Physiology (Bethesda) 2018; 33 (06) 374-383
  • 41 Rocca WA, Grossardt BR, Shuster LT. Oophorectomy, menopause, estrogen, and cognitive aging: the timing hypothesis. Neurodegener Dis 2010; 7 (1-3): 163-166
  • 42 Younis JS, Iskander R, Fauser BCJM, Izhaki I. Does an association exist between menstrual cycle length within the normal range and ovarian reserve biomarkers during the reproductive years? A systematic review and meta-analysis. Hum Reprod Update 2020; 26 (06) 904-928
  • 43 Roman Lay AA, do Nascimento CF, Horta BL, Dias Porto Chiavegatto Filho A. Reproductive factors and age at natural menopause: a systematic review and meta-analysis. Maturitas 2020; 131: 57-64
  • 44 Sun F, Sebastiani P, Schupf N. et al. Extended maternal age at birth of last child and women's longevity in the Long Life Family Study. Menopause 2015; 22 (01) 26-31
  • 45 Jaffe D, Kogan L, Manor O, Gielchinsky Y, Dior U, Laufer N. Influence of late-age births on maternal longevity. Ann Epidemiol 2015; 25 (06) 387-391
  • 46 Sebastiani P, Bae H, Sun FX. et al. Meta-analysis of genetic variants associated with human exceptional longevity. Aging (Albany NY) 2013; 5 (09) 653-661
  • 47 Santos-Lozano A, Santamarina A, Pareja-Galeano H. et al. The genetics of exceptional longevity: insights from centenarians. Maturitas 2016; 90: 49-57
  • 48 Jaspers L, Kavousi M, Erler NS, Hofman A, Laven JS, Franco OH. Fertile lifespan characteristics and all-cause and cause-specific mortality among postmenopausal women: the Rotterdam Study. Fertil Steril 2017; 107 (02) 448-456.e1
  • 49 Jones OR, Scheuerlein A, Salguero-Gómez R. et al. Diversity of ageing across the tree of life. Nature 2014; 505 (7482): 169-173