Abstract
Endometriosis is a common gynecologic disease defined by the presence of endometrial-like tissue outside the uterine cavity. While its etiology is largely unknown, accumulating evidence suggests that inflammation plays a major role. Our objective was to investigate the association between peripheral blood leukocyte telomere length (LTL) and endometriosis using data from two large population-based studies, the New England Case-Control Study (NEC; n = 877) and the National Health and Nutrition Examination Survey (NHANES; n = 2268). NEC control participants were identified through a combination of random digit dialing, drivers’ license lists, and town resident lists. In NHANES, selection algorithms were used to identify a nationally representative sample. Blood samples and demographic, reproductive, and health-related information were available from both data sources. Endometriosis was defined as self-reported of physician-diagnosed endometriosis. LTL was measured using quantitative polymerase chain reaction. Multivariable logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the association between LTL and endometriosis. Shorter LTL was associated with greater odds of history of endometriosis. In NEC, women with the shortest LTL tertile compared with the longest had a 2.5-fold greater odds of endometriosis (ORT3/T1 = 2.56, 95% CI = 1.16–5.63; p value, test for linear trend = 0.02). The association was stronger among women who usually experienced moderate or severe menstrual pain (OR T3/T1 = 3.50, 95% CI = 1.12–10.97). In NHANES, the data suggested a similar but attenuated association (ORT3/T1 = 1.29, 95% CI = 0.85–1.96). The observed associations in NEC suggest that shorter LTL may be associated with greater odds of endometriosis. A better understanding of how LTL influences endometriosis risk could elucidate novel disease pathophysiology.
Similar content being viewed by others
Data Availability
The NHANES datasets are available online [https://www.cdc.gov/nchs/nhanes/index.htm]. The NEC data that support the findings of this study are available upon request and review by study leadership. The data are not publicly available due to them containing information that could compromise research participants’ privacy and consent.
References
McEachern MJ, Krauskopf A, Blackburn EH. Telomeres and their control. Annu Rev Genet. 2000;34:331–58.
von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci. 2002;27(7):339–44.
Aviv A. Telomeres and human aging: facts and fibs. Sci Aging Knowledge Environ. 2004;2004(51):pe43.
O'Donovan A, Pantell MS, Puterman E, Dhabhar FS, Blackburn EH, Yaffe K, et al. Cumulative inflammatory load is associated with short leukocyte telomere length in the Health, Aging and Body Composition Study. PLoS One. 2011;6(5):e19687.
Steer SE, Williams FM, Kato B, Gardner JP, Norman PJ, Hall MA, et al. Reduced telomere length in rheumatoid arthritis is independent of disease activity and duration. Ann Rheum Dis. 2007;66(4):476–80.
Shafrir AL, Farland LV, Shah DK, Harris HR, Kvaskoff M, Zondervan K, et al. Risk for and consequences of endometriosis: a critical epidemiologic review. Best Pract Res Clin Obstet Gynaecol. 2018;51:1–15.
Zondervan KT, Becker CM, Koga K, Missmer SA, Taylor RN, Vigano P. Endometriosis. Nat Rev Dis Primers. 2018;4(1):9.
Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–79.
Drosdzol-Cop A, Skrzypulec-Plinta V. Selected cytokines and glycodelin A levels in serum and peritoneal fluid in girls with endometriosis. J Obstet Gynaecol Res. 2012;38(10):1245–53.
Kianpour M, Nematbakhsh M, Ahmadi SM. C-reactive protein of serum and peritoneal fluid in endometriosis. Iran J Nurs Midwifery Res. 2012;17(2 Suppl 1):S115–9.
Mu F, Harris HR, Rich-Edwards JW, Hankinson SE, Rimm EB, Spiegelman D, et al. A prospective study of inflammatory markers and risk of endometriosis. Am J Epidemiol. 2018;187(3):515–22.
Dracxler RC, Oh C, Kalmbach K, Wang F, Liu L, Kallas EG, et al. Peripheral blood telomere content is greater in patients with endometriosis than in controls. Reprod Sci. 2014;21(12):1465–71.
Hapangama DK, Turner MA, Drury JA, Quenby S, Saretzki G, Martin-Ruiz C, et al. Endometriosis is associated with aberrant endometrial expression of telomerase and increased telomere length. Hum Reprod. 2008;23(7):1511–9.
Missmer SA. Why so null? Methodologic necessities to advance endometriosis discovery. Paediatr Perinat Epidemiol. 2019;33(1):26–7.
Vitonis AF, Titus-Ernstoff L, Cramer DW. Assessing ovarian cancer risk when considering elective oophorectomy at the time of hysterectomy. Obstet Gynecol. 2011;117(5):1042–50.
NHANES—National Health and Nutrition Examination Survey Homepage. Available from: https://www.cdc.gov/nchs/nhanes/. Accessed 27 Nov 2019.
Curtin LR, Mohadjer LK, Dohrmann SM, Montaquila JM, Kruszan-Moran D, Mirel LB, et al. The National Health and Nutrition Examination Survey: Sample Design, 1999-2006. Vital Health Stat 2. 2012;(155):1–39.
Terry KL, Tworoger SS, Vitonis AF, Wong J, Titus-Ernstoff L, De Vivo I, et al. Telomere length and genetic variation in telomere maintenance genes in relation to ovarian cancer risk. Cancer Epidemiol Biomarkers Prev. 2012;21(3):504–12.
Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res. 2002;30(10):e47.
Rosner B, Cook N, Portman R, Daniels S, Falkner B. Determination of blood pressure percentiles in normal-weight children: some methodological issues. Am J Epidemiol. 2008;167(6):653–66.
Rosner B. Percentage points for a generalized ESD many-outlier procedure. Technotromics. 1983;25:165–72.
Cawthon RM. Telomere length measurement by a novel monochrome multiplex quantitative PCR method. Nucleic Acids Res. 2009;37(3):e21.
Needham BL, Adler N, Gregorich S, Rehkopf D, Lin J, Blackburn EH, et al. Socioeconomic status, health behavior, and leukocyte telomere length in the National Health and Nutrition Examination Survey, 1999-2002. Soc Sci Med. 2013;85:1–8.
Parasar P, Ozcan P, Terry KL. Endometriosis: epidemiology, diagnosis and clinical management. Curr Obstet Gynecol Rep. 2017;6(1):34–41.
Johnson CL, Paulose-Ram R, Ogden CL, Carroll MD, Kruszon-Moran D, Dohrmann SM, et al. National health and nutrition examination survey: analytic guidelines, 1999-2010. Vital Health Stat 2. 2013;(161):1–24.
Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Malspeis S, Willett WC, et al. Reproductive history and endometriosis among premenopausal women. Obstet Gynecol. 2004;104(5 Pt 1):965–74.
Bendon CL, Becker CM. Potential mechanisms of postmenopausal endometriosis. Maturitas. 2012;72(3):214–9.
Pollack AZ, Rivers K, Ahrens KA. Parity associated with telomere length among US reproductive age women. Hum Reprod. 2018;33(4):736–44.
Augoulea A, Mastorakos G, Lambrinoudaki I, Christodoulakos G, Creatsas G. The role of the oxidative-stress in the endometriosis-related infertility. Gynecol Endocrinol. 2009;25(2):75–81.
Khan S, Chuturgoon AA, Naidoo DP. Telomeres and atherosclerosis. Cardiovasc J Afr. 2012;23(10):563–71.
Zvereva MI, Shcherbakova DM, Dontsova OA. Telomerase: structure, functions, and activity regulation. Biochemistry (Mosc). 2010;75(13):1563–83.
Haycock PC, Burgess S, Nounu A, Zheng J, Okoli GN, Bowden J, et al. Association between telomere length and risk of cancer and non-neoplastic diseases: a Mendelian randomization study. JAMA Oncol. 2017;3(5):636–51.
Nyholt DR, Low SK, Anderson CA, Painter JN, Uno S, Morris AP, et al. Genome-wide association meta-analysis identifies new endometriosis risk loci. Nat Genet. 2012;44(12):1355–9.
Rahmioglu N, Banasik K, Paraskevi C, Danning R, Galarneau G, Giri A, et al. Large-scale genome-wide association meta-analysis of endometriosis reveals 13 novel loci and genetically-associated comorbidity with other pain conditions. bioRxiv. 2018. https://doi.org/10.1101/406967version1, https://www.biorxiv.org/content/10.1101/406967v1. Accessed 31 Dec 2019.
Vasilopoulos E, Fragkiadaki P, Kalliora C, Fragou D, Docea AO, Vakonaki E, et al. The association of female and male infertility with telomere length (review). Int J Mol Med. 2019;44(2):375–89.
Hassett AL, Epel E, Clauw DJ, Harris RE, Harte SE, Kairys A, et al. Pain is associated with short leukocyte telomere length in women with fibromyalgia. J Pain. 2012;13(10):959–69.
Sibille KT, Langaee T, Burkley B, Gong Y, Glover TL, King C, et al. Chronic pain, perceived stress, and cellular aging: an exploratory study. Mol Pain. 2012;8:12.
Steward AM, Morgan JD, Espinosa JP, Turk DC, Patel KV. Chronic pain and telomere length in community-dwelling adults: findings from the 1999 to 2002 National Health and Nutrition Examination Survey. J Pain. 2017;18(12):1517–25.
Acknowledgments
The authors would like to thank the participants of the New England Case-Control Study and the National Health and Nutrition Examination Survey for their valuable contribution.
Funding
This work was supported by the Ovarian Cancer Research Fund Liz Tilberis Award. NS was supported by a 2017 BCE/Marriott Family Foundation Trainee Award. SAM and KLT were supported by NICHD grant R01 HD094842. The sponsor had no role in the study design, conduct of the study or data analysis, writing of the report, or decision to submit the article for publication.
Author information
Authors and Affiliations
Contributions
NS was responsible for formulation of the study hypotheses and study design, statistical analyses, result interpretation, manuscript writing, revision, and finalization. JY was responsible for study design, statistical analyses, manuscript revision, and finalization. AFV was responsible for data collection, development, and implementation of NEC; study analysis methods; statistical analyses; results interpretation; and manuscript revision and finalization. DWC was responsible for data collection, development, and implementation of NEC, and manuscript revision and finalization. LJT was responsible for data collection, development, and implementation of NEC, and manuscript revision and finalization. IDV was responsible for data generation in NEC data and manuscript finalization. SAM was responsible for analysis methods, results interpretation, and manuscript revision and finalization. KLT was responsible for study design and analysis methods, results interpretation, manuscript revision and finalization, and was also responsible for the overall conceptualization of study.
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Ethics Approval
For the New England Case-Control Study, the Human Subjects Review Committees at Brigham and Women’s Hospital and Dartmouth Medical School approved this study, and each participant provided informed consent. For National Health and Nutrition Examination Survey, the NCHS Research Ethics Review Board approved the study.
Code Availability
All statistical analyses were conducted using SAS; programs are available from the corresponding author upon request.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Sasamoto, N., Yland, J., Vitonis, A.F. et al. Peripheral Blood Leukocyte Telomere Length and Endometriosis. Reprod. Sci. 27, 1951–1959 (2020). https://doi.org/10.1007/s43032-020-00214-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s43032-020-00214-6