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• W2897336055 abstract "Infertility, may be a harbinger for future health risk in women, including early mortality. Fertility status itself could serve as an early biomarker, (present in a woman's reproductive years) for risk stratification later in life. The relationship between infertility and early mortality involves the impact of nulliparity on future adverse health events, potential sequelae from the underlying cause(s) of infertility, the risks of fertility treatments, as well as the potential for risk reduction from a healthy pregnancy. This complex interplay coupled with difficulties ascertaining infertility on a population level has presented unique challenges to assessing infertility and early mortality risk. With further study, a better understanding the role of fertility status in health at various stages of life may provide unique opportunities for surveillance and risk reduction. Infertility, may be a harbinger for future health risk in women, including early mortality. Fertility status itself could serve as an early biomarker, (present in a woman's reproductive years) for risk stratification later in life. The relationship between infertility and early mortality involves the impact of nulliparity on future adverse health events, potential sequelae from the underlying cause(s) of infertility, the risks of fertility treatments, as well as the potential for risk reduction from a healthy pregnancy. This complex interplay coupled with difficulties ascertaining infertility on a population level has presented unique challenges to assessing infertility and early mortality risk. With further study, a better understanding the role of fertility status in health at various stages of life may provide unique opportunities for surveillance and risk reduction. Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/38187-26725 Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/38187-26725 Fertility has long been associated with vitality, longevity, and general well-being. While Kirkwood's Disposal Soma Theory and William's antagonistic pleiotropy hypothesis both postulate a tradeoff between fertility and longevity (1Lithgow G.J. Kirkwood T.B. Mechanisms and evolution of aging.Science. 1996; 273: 80Crossref PubMed Scopus (100) Google Scholar, 2Williams G. Pleiotropy, natural selection, and the evolution of sensescence.Evolution. 1957; 11: 398-411Crossref Google Scholar) humans appear to have superceded expectations with multiple cohort and population-based studies suggesting a positive correlation between fertility and longevity in both historical and contemporary settings (3Mitteldorf J. Female fertility and longevity.Age. 2010; 32: 79-84Crossref PubMed Scopus (22) Google Scholar). Just as fertility may be a marker of longevity for women, infertility, may be a harbinger for future health risk, including early mortality. While there are multiple contributors to health status including genetics, epigenetics, environmental influences, concomitant co-morbidities, and lifestyle factors, fertility status itself could serve as an early biomarker, (present in a woman's reproductive years) for risk stratification later in life. The interplay between fertility, parity, and long-term health is complex and multi-faceted. While we have looked to historical population cohorts to analyze birth and mortality trends, with the advent of assisted reproductive technologies in the 20th century, patterns in family building have shifted, and with it, the ripple effect on long-term health in both women and men remains to be seen. A better understanding of this relationship between fertility status and future health risk is critical as more women seek guidance to understand their fertility and general health status, and as the generation of children born after IVF come to adulthood and move through their reproductive years. To date, there are no studies that examine the relationship between infertility and mortality on a population level likely due to challenges ascertaining infertility as the exposure of interest (defined as attempting conception for at least 12 months in women <35 years-old, and for at least 6 months in women ≥35 years-old). While the association between nulliparity and mortality has been examined, the assumption that nulliparity is an appropriate surrogate for infertility is overly simplistic. An examination of in the association of infertility and early mortality involves consideration of not only of the impact of nulliparity on future adverse health events, but also potential sequelae from the underlying cause(s) of infertility, the risks of fertility treatments, as well as the potential for risk reduction from a healthy pregnancy. Indeed, understanding the role of fertility status in health at various stages of life may provide unique opportunities for surveillance and risk reduction. Perturbations in both female (4Zeng Y. Ni Z.M. Liu S.Y. Gu X. Huang Q. Liu J.A. et al.Parity and all-cause mortality in women and men: a dose-response meta-analysis of cohort studies.Sci Rep. 2016; 6: 19351Crossref PubMed Scopus (43) Google Scholar) and male (5Capogrosso P. Ventimiglia E. Boeri L. Cazzaniga W. Chierigo F. Montorsi F. et al.Male infertility as a proxy of the overall male health status.Minerva Urol Nefrol. 2018; 70: 286-299PubMed Google Scholar, 6Eisenberg M.L. Li S. Behr B. Cullen M.R. Galusha D. Lamb D.J. et al.Semen quality, infertility and mortality in the USA.Hum Reprod. 2014; 29: 1567-1574Crossref PubMed Scopus (129) Google Scholar, 7Latif T. Kold Jensen T. Mehlsen J. Holmboe S.A. Brinth L. Pors K. et al.Semen Quality as a predictor of subsequent morbidity: a Danish cohort study of 4,712 men with long-term follow-up.Am J Epidemiol. 2017; 186: 910-917Crossref PubMed Scopus (67) Google Scholar) reproductive function have been linked to cancer, cardiovascular disease, and mortality. Several epidemiological studies have suggested that nulliparity is associated with an increased risk of all-cause mortality (8Barclay K. Keenan K. Grundy E. Kolk M. Myrskyla M. Reproductive history and post-reproductive mortality: a sibling comparison analysis using Swedish register data.Soc Sci Med. 2016; 155: 82-92Crossref PubMed Scopus (47) Google Scholar, 9Jaffe D.H. Eisenbach Z. Manor O. The effect of parity on cause-specific mortality among married men and women.Matern Child Health J. 2011; 15: 376-385Crossref PubMed Scopus (31) Google Scholar, 10Jacobsen B.K. Knutsen S.F. Oda K. Fraser G.E. Parity and total, ischemic heart disease and stroke mortality. The Adventist Health Study, 1976-1988.Eur J Epidemiol. 2011; 26: 711-718Crossref PubMed Scopus (33) Google Scholar, 11Cooper G.S. Baird D.D. Weinberg C.R. Ephross S.A. Sandler D.P. Age at menopause and childbearing patterns in relation to mortality.Am J Epidemiol. 2000; 151: 620-623Crossref PubMed Scopus (49) Google Scholar, 12Simons L.A. Simons J. Friedlander Y. McCallum J. Childbearing history and late-life mortality: the Dubbo study of Australian elderly.Age Ageing. 2012; 41: 523-528Crossref PubMed Scopus (22) Google Scholar, 13Jaffe D.H. Neumark Y.D. Eisenbach Z. Manor O. Parity-related mortality: shape of association among middle-aged and elderly men and women.Eur J Epidemiol. 2009; 24: 9-16Crossref PubMed Scopus (47) Google Scholar). A recent meta-analysis of 18 studies including 2,813,481 participants demonstrated a pooled relative risk of all-cause mortality of 1.19 (95% confidence interval [CI] 1.03–1.38) among nulliparous women compared to those with 1 or more live births (4Zeng Y. Ni Z.M. Liu S.Y. Gu X. Huang Q. Liu J.A. et al.Parity and all-cause mortality in women and men: a dose-response meta-analysis of cohort studies.Sci Rep. 2016; 6: 19351Crossref PubMed Scopus (43) Google Scholar). These findings are likely driven by the increased risk of cardiovascular disease-related death observed amongst nulliparous women when compared to their parous counterparts (hazard ratio 2.43, 95% CI 1.49–3.96) (13Jaffe D.H. Neumark Y.D. Eisenbach Z. Manor O. Parity-related mortality: shape of association among middle-aged and elderly men and women.Eur J Epidemiol. 2009; 24: 9-16Crossref PubMed Scopus (47) Google Scholar). As cardiovascular disease is intimately related to circulating levels of reproductive hormones as well as hormone replacement (14Rossouw J.E. Anderson G.L. Prentice R.L. LaCroix A.Z. Kooperberg C. Stefanick M.L. et al.Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.JAMA. 2002; 288: 321-333Crossref PubMed Scopus (13746) Google Scholar) it is plausible that unique disruptions of these hormones by disease processes that lead to infertility, and for some, unintended nulliparity, may explain the unique risk of cardiovascular disease-related mortality observed. Beyond cardiovascular health, abnormal estrogen and progesterone profiles have been implicated in hormone-sensitive cancers including breast, ovarian, and endometrial cancer (15Dumesic D.A. Lobo R.A. Cancer risk and PCOS.Steroids. 2013; 78: 782-785Crossref PubMed Scopus (132) Google Scholar, 16Kim H.S. Kim T.H. Chung H.H. Song Y.S. Risk and prognosis of ovarian cancer in women with endometriosis: a meta-analysis.Br J Cancer. 2014; 110: 1878-1890Crossref PubMed Scopus (172) Google Scholar, 17Kim J.J. Kurita T. Bulun S. progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer.Endocr Rev. 2013; 34: 130-162Crossref PubMed Scopus (295) Google Scholar, 18Yue W. Wang J. Li Y. Fan P. Liu G. Zhang N. et al.Effects of estrogen on breast cancer development: role of estrogen receptor independent mechanisms.Int J Cancer. 2010; 127: 1748-1757Crossref PubMed Scopus (86) Google Scholar); thus, it is likely that altered profiles observed amongst nulliparous women may be implicated in cancer-related mortality. Additionally, nulliparity has been associated with limitation of activity for health reasons and faster acquisition of those limitations suggesting an adverse effect on functional status in addition to specific disease processes (19Read S. Grundy E. Wolf D.A. Fertility history, health, and health changes in later life: a panel study of British women and men born 1923-49.Popul Stud. 2011; 65: 201-215Crossref Scopus (44) Google Scholar). It is plausible that the relative risks attributable to nulliparity and infertility are different depending upon the underlying etiology of why a woman may have chosen not to bear children versus been unable to bear children due to either lack of access to treatment or unsuccessful treatment. As nulliparity is a state that describes a heterogenous cross-section of the population and may include heterosexually partnered women who have elected to not have children, women who are not in a relationship with a male partner, transgender female-to-male as well those with a history of infertility, it is important to consider both parity and fertility status as related but potentially independent contributors to the assessment of future health risk. In an interesting parallel to these findings, several studies have observed an association between later maternal age at birth and exceptional longevity. An analysis of New England Centenarian Study cohort demonstrated that women who gave birth to a child after the age of 40 had four times greater odds of being a centenarian compared to women from the same birth cohort who had their last child at younger ages (20Perls T.T. Alpert L. Fretts R.C. Middle-aged mothers live longer.Nature. 1997; 389: 133Crossref PubMed Scopus (139) Google Scholar). A nested case-control study using Long Life Family Study data found that women who had their last child beyond the age of 33 years had twice the odds of survival to the top 5th percentile of survival of their birth cohorts compared to women who had their last child by 29 years of age (odds ratio [OR] 2.08, 95%CI 1.13–3.92 for age between 33 and 37 years and OR 1.92, 95% CI 1.03–3.68 for age>37 years) (21Sun F. Sebastiani P. Schupf N. Bae H. Andersen S.L. McIntosh A. et al.Extended maternal age at birth of last child and women's longevity in the Long Life Family Study.Menopause. 2015; 22: 26-31Crossref PubMed Scopus (36) Google Scholar). In contrast an analysis of over 20,000 women from the Women's Health Initiative cohort demonstrated that while odds of longevity were significantly higher in women with later age at first childbirth (adjusted OR 1.11, 95% CI 1.02–1.21 for age 25 years or older vs. younger than 25 years) there was no difference in longevity based on age at last birth (22Shadyab A.H. Gass M.L. Stefanick M.L. Waring M.E. Macera C.A. Gallo L.C. et al.Maternal age at childbirth and parity as predictors of longevity among women in the United States: The Women's Health Initiative.Am J Public Health. 2017; 107: 113-119Crossref PubMed Scopus (20) Google Scholar). While some have interpreted these findings to suggest that pregnancy at advanced maternal ages is not only possible, but may be associated with increased longevity, it should be noted that these studies were performed amongst women in population-based cohorts and may not reflect the longevity or health status of women who have pregnancies at advanced maternal ages made possible by fertility treatments; certainly, further study of in contemporary cohorts are needed to understand these associations. To understand the mechanisms of infertility's potential association with early mortality one need only look to the most common causes of infertility for biologic plausibility. There are several pathologic processes associated with infertility whose systemic effects can lead to chronic morbidity and adverse events later in life. Indeed, amongst the most common causes of infertility including polycystic ovary syndrome (PCOS), endometriosis, fibroids, and diminished ovarian reserve there are disruptions in systemic pathways that may be implicated in future morbidity. PCOS is the most common endocrine disorder amongst women of reproductive age and is associated with chronic anovulation, androgen excess, and metabolic perturbations (23Dumesic D.A. Oberfield S.E. Stener-Victorin E. Marshall J.C. Laven J.S. Legro R.S. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome.Endocr Rev. 2015; 36: 487-525Crossref PubMed Scopus (442) Google Scholar). Women with PCOS, as compared with age- and body mass index-matched women without the syndrome, appear to have a higher risk of insulin resistance, hyperinsulinemia, glucose intolerance, dyslipidemia, and an increased prothrombotic state, possibly resulting in a higher rate of type 2 diabetes mellitus, fatty liver disease, subclinical atherosclerosis, vascular dysfunction, obstructive sleep apnea, cardiovascular disease, and endometrial hyperplasia (24Randeva H.S. Tan B.K. Weickert M.O. Lois K. Nestler J.E. Sattar N. et al.Cardiometabolic aspects of the polycystic ovary syndrome.Endocr Rev. 2012; 33: 812-841Crossref PubMed Scopus (198) Google Scholar). Interestingly, in a United Kingdom cohort study of women with PCOS, while there was an increased risk of death from diabetes (OR 3.6, 95% CI 1.5–8.4, there was no difference in all-cause mortality noted (standardized mortality ratio 0.90, 95% CI 0.69–1.17). Notably, this was relatively small cohort (data based on 59 deaths) suggesting there may have been insufficient sample size to detect meaningful associations (25Pierpoint T. McKeigue P.M. Isaacs A.J. Wild S.H. Jacobs H.S. Mortality of women with polycystic ovary syndrome at long-term follow-up.J Clin Epidemiol. 1998; 51: 581-586Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar). Similar correlations with systemic disease have been suggested in endometriosis and uterine fibroids. Endometriosis, a chronic benign gynecologic disease characterized by endometrial glands and stroma present outside the uterine lining, affects 10% of women and is a major cause of chronic pelvic pain and infertility (26Dunselman G.A. Vermeulen N. Becker C. Calhaz-Jorge C. D'Hooghe T. De Bie B. et al.ESHRE guideline: management of women with endometriosis.Hum Reprod. 2014; 29: 400-412Crossref PubMed Scopus (1316) Google Scholar, 27Practice Committee of the American Society for Reproductive MEndometriosis and infertility: a committee opinion.Fertil Steril. 2012; 98: 591-598Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar). Both underlying inflammation and molecular alterations of multiple organ systems have been implicated in the role of endometriosis in other chronic diseases (28Kvaskoff M. Mu F. Terry K.L. Harris H.R. Poole E.M. Farland L. et al.Endometriosis: a high-risk population for major chronic diseases?.Hum Reprod Update. 2015; 21: 500-516Crossref PubMed Scopus (193) Google Scholar). Endometriosis has been associated cardiovascular risk factors including increased endothelial dysfunction and atherosclerosis (29Santoro L. D'Onofrio F. Campo S. Ferraro P.M. Tondi P. Campo V. et al.Endothelial dysfunction but not increased carotid intima-media thickness in young European women with endometriosis.Hum Reprod. 2012; 27: 1320-1326Crossref PubMed Scopus (40) Google Scholar, 30Santoro L. D'Onofrio F. Flore R. Gasbarrini A. Santoliquido A. Endometriosis and atherosclerosis: what we already know and what we have yet to discover.Am J Obstet Gynecol. 2015; 213: 326-331Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). Additionally, endometriosis has been linked to an increased risk of certain subtypes of ovarian cancer (specifically endometrioid and clear cell ovarian carcinoma) (16Kim H.S. Kim T.H. Chung H.H. Song Y.S. Risk and prognosis of ovarian cancer in women with endometriosis: a meta-analysis.Br J Cancer. 2014; 110: 1878-1890Crossref PubMed Scopus (172) Google Scholar, 31Wang C. Liang Z. Liu X. Zhang Q. Li S. The association between endometriosis, tubal ligation, hysterectomy and epithelial ovarian cancer: meta-analyses.Int J Environ Res Public Health. 2016; 13Crossref Scopus (36) Google Scholar). Interestingly, while several reports have hypothesized a potential link between endometriosis and cardiovascular risk, there are no studies that have interrogated these questions on a population level. Similarly, uterine fibroids (also known as leiomyomas or myomas) are benign uterine tumors with an estimated incidence of 20% to 40% in women during their reproductive years (32Bulun S.E. Uterine fibroids.N Eng J Med. 2013; 369: 1344-1355Crossref PubMed Scopus (368) Google Scholar). More than 70% of women with symptomatic fibroids will report symptoms of heavy menstrual bleeding, and are these women are 2.3 times more likely to experience chronic anemia than women without fibroids (33Fuldeore M.J. Soliman A.M. Patient-reported prevalence and symptomatic burden of uterine fibroids among women in the United States: findings from a cross-sectional survey analysis.Int J Womens Health. 2017; 9: 403-411Crossref PubMed Scopus (21) Google Scholar). As chronic anemia has been associated with an increased risk of mortality from acute coronary syndromes, stroke, and all cause-mortality, fibroids maybe associated with an increased risk for all-cause mortality for women later in life (34Lawler P.R. Filion K.B. Dourian T. Atallah R. Garfinkle M. Eisenberg M.J. Anemia and mortality in acute coronary syndromes: a systematic review and meta-analysis.Am Heart J. 2013; 165: 143-153.e145Crossref PubMed Scopus (108) Google Scholar, 35Lee G. Choi S. Kim K. Yun J.M. Son J.S. Jeong S.M. et al.Association of hemoglobin concentration and its change with cardiovascular and all-cause mortality.J Am Heart Assoc. 2018; 7: 1-9Crossref Scopus (40) Google Scholar, 36Barlas R.S. Honney K. Loke Y.K. McCall S.J. Bettencourt-Silva J.H. Clark A.B. et al.Impact of hemoglobin levels and anemia on mortality in acute stroke: analysis of UK Regional Registry Data, Systematic Review, and Meta-Analysis.J Am Heart Assoc. 2016; 5: 1-16Crossref Scopus (70) Google Scholar). Finally, as early menopause has been linked to increased risk of osteoporosis and cardiovascular disease, diminished ovarian reserve and premature ovarian insufficiency may be associated with increased risk of early mortality. Diminished ovarian reserve which is diagnosed based on high follicle stimulating hormone levels, low antimüllerian hormone levels, low antral follicle count, or poor response to fertility treatment (37Ferraretti A.P. La Marca A. Fauser B.C. Tarlatzis B. Nargund G. Gianaroli L. et al.ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria.Hum Reprod. 2011; 26: 1616-1624Crossref PubMed Scopus (1109) Google Scholar), is thought to be on a spectrum of ovarian dysfunction that may culminate in premature ovarian insufficiency for some women (38Cohen J. Chabbert-Buffet N. Darai E. Diminished ovarian reserve, premature ovarian failure, poor ovarian responder--a plea for universal definitions.J Assist Reprod Genet. 2015; 32: 1709-1712Crossref PubMed Scopus (107) Google Scholar, 39Verit F.F. Yildiz Zeyrek F. Zebitay A.G. Akyol H. Cardiovascular risk may be increased in women with unexplained infertility.Clin Exp Reprod Med. 2017; 44: 28-32Crossref PubMed Scopus (21) Google Scholar, 40Tani A. Yamamoto S. Maegawa M. Kunimi K. Matsui S. Keyama K. et al.Arterial stiffness is increased in young women with endometriosis.J Obstet Gynaecol Journal Inst Obstetrics Gynaecol. 2015; 35: 711-715Crossref Scopus (14) Google Scholar). While most women experience menopause between the ages of 45 and 55 years, approximately 5% of women will enter menopause between the ages of 40 and 45 years, and 1% of women will enter menopause before the age of 40 (41Miro F. Parker S.W. Aspinall L.J. Coley J. Perry P.W. Ellis J.E. Sequential classification of endocrine stages during reproductive aging in women: the FREEDOM study.Menopause. 2005; 12: 281-290Crossref PubMed Scopus (34) Google Scholar, 42Luborsky J.L. Meyer P. Sowers M.F. Gold E.B. Santoro N. Premature menopause in a multi-ethnic population study of the menopause transition.Hum Reprod. 2003; 18: 199-206Crossref PubMed Scopus (281) Google Scholar). With respect to osteoporosis-related fracture risk, the data are inconsistent and time-dependent. While early menopause compared to natural menopause is associated with an increase in fracture rates compatible with the associated bone loss (43Vega E.M. Egea M.A. Mautalen C.A. Influence of the menopausal age on the severity of osteoporosis in women with vertebral fractures.Maturitas. 1994; 19: 117-124Abstract Full Text PDF PubMed Scopus (27) Google Scholar, 44van der Klift M. de Laet C.E. McCloskey E.V. Johnell O. Kanis J.A. Hofman A. et al.Risk factors for incident vertebral fractures in men and women: the Rotterdam Study.J Bone Miner Res Official Journal Am Soc Bone Mineral Res. 2004; 19: 1172-1180Crossref PubMed Scopus (151) Google Scholar) one cohort study demonstrated 50% more fractures with early menopause until 70 years old, while another suggested increased fracture risk only after age 70 years (45Gardsell P. Johnell O. Nilsson B.E. The predictive value of bone loss for fragility fractures in women: a longitudinal study over 15 years.Calcif Tissue Int. 1991; 49: 90-94Crossref PubMed Scopus (117) Google Scholar, 46van Der Voort D.J. van Der Weijer P.H. Barentsen R. Early menopause: increased fracture risk at older age.Osteoporos Int. 2003; 14: 525-530Crossref PubMed Scopus (137) Google Scholar). With respect to cardiovascular health, multiple studies have demonstrated that menopause before 45 years is associated with increased risk of cardiovascular disease (47Kannel W.B. Hjortland M.C. McNamara P.M. Gordon T. Menopause and risk of cardiovascular disease: the Framingham study.Ann Intern Med. 1976; 85: 447-452Crossref PubMed Scopus (1128) Google Scholar), angina (48Parashar S. Reid K.J. Spertus J.A. Shaw L.J. Vaccarino V. Early menopause predicts angina after myocardial infarction.Menopause. 2010; 17: 938-945Crossref PubMed Scopus (22) Google Scholar), heart failure (49Ebong I.A. Watson K.E. Goff Jr., D.C. Bluemke D.A. Srikanthan P. Horwich T. et al.Age at menopause and incident heart failure: the Multi-Ethnic Study of Atherosclerosis.Menopause. 2014; 21: 585-591Crossref PubMed Scopus (57) Google Scholar), and early mortality (50Parker W.H. Feskanich D. Broder M.S. Chang E. Shoupe D. Farquhar C.M. et al.Long-term mortality associated with oophorectomy compared with ovarian conservation in the nurses' health study.Obstet Gynecol. 2013; 121: 709-716Crossref PubMed Scopus (293) Google Scholar, 51Shuster L.T. Rhodes D.J. Gostout B.S. Grossardt B.R. Rocca W.A. Premature menopause or early menopause: long-term health consequences.Maturitas. 2010; 65: 161-166Abstract Full Text Full Text PDF PubMed Scopus (460) Google Scholar). Notably, much of the data regarding early menopause and cardiovascular risk is extrapolated from studies including women with surgical menopause which may be a different pathogenic process than the more indolent diminished ovarian reserve or premature ovarian insufficiency. While hormone replacement therapy in women with premature ovarian insufficiency has been shown to restore endothelial dysfunction and reduce the impact of relative estrogen deficiency on bone health (52Cartwright B. Robinson J. Seed P.T. Fogelman I. Rymer J. Hormone replacement therapy versus the combined oral contraceptive pill in premature ovarian failure: a randomized controlled trial of the effects on bone mineral density.J Clin Endocrinol Metab. 2016; 101: 3497-3505Crossref PubMed Scopus (85) Google Scholar, 53Kalantaridou S.N. Naka K.K. Papanikolaou E. Kazakos N. Kravariti M. Calis K.A. et al.Impaired endothelial function in young women with premature ovarian failure: normalization with hormone therapy.J Clin Endocrinol Metab. 2004; 89: 3907-3913Crossref PubMed Scopus (199) Google Scholar), the impact on early mortality has not been well established. Furthermore, while diminished ovarian reserve has been shown to correlate with markers of cardiovascular disease risk (54Chu M.C. Rath K.M. Huie J. Taylor H.S. Elevated basal FSH in normal cycling women is associated with unfavourable lipid levels and increased cardiovascular risk.Hum Reprod. 2003; 18: 1570-1573Crossref PubMed Scopus (58) Google Scholar, 55Pal L. Bevilacqua K. Zeitlian G. Shu J. Santoro N. Implications of diminished ovarian reserve (DOR) extend well beyond reproductive concerns.Menopause. 2008; 15: 1086-1094Crossref PubMed Scopus (43) Google Scholar) the association of diminished ovarian reserve with cardiovascular events and early mortality has not been established. Indeed, this will become increasingly relevant in the era of direct-to-consumer medical testing, as more women both with and without a history of infertility seek fertility testing. Further study of the role of surrogates for ovarian reserve as biomarkers for future health risk with consideration of infertility and parity is warranted to identify which women with infertility or abnormal parameters may be at greatest risk. Beyond individual infertility diagnoses, it is important to consider the temporal effect of a pathogenic process on the development of disease later in life. Ideally, a screening test for detection or surveillance of disease should be inexpensive, easy to administer/detect, reliable, valid, and detect disease in a pre-clinical phase to have greatest utility. Having a marker of future disease like fertility status that manifests well before the onset of disease, may offer a unique opportunity for surveillance and potential risk reduction. A systematic review integrating genomics and data from the literature to analyze common genes and molecular mechanisms shared by diseases demonstrated that known causes of infertility not only share particular genes and/or molecular pathways with other disease processes associated with long-term morbidity, but they have distinct clinical relationships with other diseases appearing after infertility is manifested. These relationships include but are not limited to: an association between osteoporosis, mood disorders, dementia, and premature ovarian failure; breast/ovarian cancer and diminished ovarian reserve, specifically in those with BRCA1/2 mutations; ovarian cancer (clear cell, endometrioid, and low-grade serous), melanoma, and non-Hodgkin's lymphoma and endometriosis; and endometrial/ovarian cancer and unexplained infertility (56Tarin J.J. Garcia-Perez M.A. Hamatani T. Cano A. Infertility etiologies are genetically and clinically linked with other diseases in single meta-diseases.Reprod Biol Endocrinol. 2015; 13: 31Crossref PubMed Scopus (59) Google Scholar). These findings were the result of a novel approach that aims to search common pathogenic mechanisms that link diseases together in a single meta-disease instead of the traditional approach of splitting phenotypes attributable to sequence variation in the human genome and specific environmental influences) into discrete disease entities. As such, the findings, while intriguing, are largely hypothesis generating, and require validation from larger studies. Thus, while there is a dearth of population-based data on the long-term outcomes of women with infertility and its underlying causes, there is convincing biologic plausibility for increased risk of early mortality attributable to infertility. Further population-based studies are needed to better characterize this potential risk. The 21st century has also seen a shift in population trends in family building as well as utilization of assisted reproductive technologies wh" @default.
• W2897336055 created "2018-10-26" @default.
• W2897336055 creator A5066763006 @default.
• W2897336055 date "2018-10-01" @default.
• W2897336055 modified "2023-10-16" @default.
• W2897336055 title "Infertility: a marker of future health risk in women?" @default.
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• W2897336055 doi "https://doi.org/10.1016/j.fertnstert.2018.08.058" @default.
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