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Potential Intervention Targets in Utero and Early Life for Prevention of Hormone Related Cancers C

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Potential Intervention Targets in Utero and Early Life for Prevention of Hormone Related Cancers C Potential Intervention Targets in Utero and Early Life for Prevention of Hormone Related Cancers C. Mary Schooling, PhD,a, b Lauren C. Houghton, PhD,c Mary Beth Terry, PhDc abstract Hormone-related cancers have long been thought to be sensitive to exposures during key periods of sexual development, as shown by the vulnerability to such cancers of women exposed to diethylstilbestrol in utero. In addition to evidence from human studies, animal studies using new techniques, such as gene knockout models, suggest that an increasing number of cancers may be hormonally related, including liver, lung, and bladder cancer. Greater understanding of sexual development has also revealed the “mini-puberty” of early infancy as a key period when some sex hormones reach levels similar to those at puberty. Factors driving sex hormones in utero and early infancy have not been systematically identified as potential targets of intervention for cancer prevention. On the basis of sex hormone pathways, we identify common potentially modifiable drivers of sex hormones, including but not limited to factors such as obesity, alcohol, and possibly nitric oxide. We review the evidence for effects of modifiable drivers of sex hormones during the prenatal period and early infancy, including measured hormones as well as proxies, such as the second-to-fourth digit length ratio. We summarize the gaps in the evidence needed to identify new potential targets of early life intervention for lifelong cancer prevention. Strong associations between diethylstilbestrol exposure in utero and the subsequent risk of clear cell vaginal cancer offered the first epidemiologic evidence that a prenatal exposure, particularly a hormonal one, could lead to cancer later in life. 1 – 3 Endogenous hormones have been implicated in many cancers, including some of the most common cancers globally (breast and prostate) as well as some of the rarer cancers (endometrium, ovary, testis, thyroid, osteosarcoma, Ewing’s sarcoma, and rhabdomyosarcoma). 4 – 7 Key to interpreting the evidence base concerning the hormonal environment and cancer risk are specific issues of hormonal measurements, including the type (eg, direct as opposed to proxy indicators) and the timing (eg, adulthood versus in utero, infancy, childhood, and puberty), so that their effects can be understood within the context of their a CUNY School of Public Health and Hunter College, New York, New York; bSchool of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, People’s Republic of China; and cDepartment of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York Dr Schooling conceptualized the study, drafted the initial manuscript, and approved the fi nal manuscript as submitted; and Drs Houghton and Terry made substantial contributions to the conceptualization, reviewed and revised the manuscript, and approved the fi nal manuscript as submitted. DOI: 10.1542/peds.2015-4268E Accepted for publication Feb 16, 2016 Address correspondence to C. Mary Schooling, PhD, 2180 Third Ave, New York, NY 10035. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2016 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no fi nancial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of interest to disclose. Downloaded from www.aappublications.org/news by guest on September 25, 2021 SUPPLEMENT ARTICLE PEDIATRICS Volume 138 , Number s1 , November 2016 :e 20154268 modification by social, ecological, and associated with higher risk 13; notably levels similarly have a higher risk. 13 environmental factors. overweight and obese women have Despite the positive association of more anovulatory cycles. Thus, androgens in adults with breast The present review includes the hormonal mechanisms may explain cancer risk, this association is following: (1) a discussion of the the decreased risk from greater not always evident throughout limitations in the evidence base adiposity in the premenopausal years life. For example, epidemiologic concerning hormones and cancer; and the increased risk from greater studies generally show lower risk (2) a summary of the relevant adiposity in the postmenopausal of breast cancer in daughters of evidence that pertains to critical years. A similar hypothesis may pre-eclamptic pregnancies, 19, 20 periods of hormonal exposures in explain the inverse relationship when levels of cord androgens at carcinogenesis; and (3) an analysis between childhood body fatness birth could be higher in infants from of the potential drivers of hormonal and breast cancer risk, given that pre-eclamptic pregnancies than in levels. To illustrate the challenges the postmenarcheal anovulatory healthy pregnancies. 21, 22 As such, ahead and the gaps in the evidence period may be longer in obese androgens may have complex effects base, we start with the example girls. 14 Nevertheless, in the absence on breast cancer depending on the of breast cancer, one of the more of longitudinal studies that measure state of breast tissue (eg, developing, extensively studied hormonally hormones across the life course, the lactating, involuting) that generates driven cancers. potentially opposing trajectories different associations over the life of body size and hormone levels course; this hypothesis requires underlying these associations with confirmation. EVIDENCE FROM BREAST CANCER premenopausal and postmenopausal STUDIES breast cancer risk remain somewhat Even for breast cancer, which is the most extensively studied of the Much of the human evidence of an enigma. hormonally driven cancers, major concerning the role of hormones questions remain regarding the role stems from indirect evidence Global differences in breast of the timing of hormonal exposures rather than measurements of cancer incidence 15 have also led throughout life and the differences hormonal levels, particularly before to comparisons of direct and between estrogens and androgens menopause. Thus, the evidence proxy measures of the hormonal in carcinogenesis. More generally, from breast cancer studies can be environment. Some studies have the role of modifiable drivers of used to illustrate the gaps for both demonstrated lower levels of estrogen and androgens overall, the type and timing of hormonal estrogens in premenopausal and and at key life course stages, has not measurements. In postmenopausal postmenopausal Asian women been comprehensively delineated women, higher estrogen levels are compared with US women. 16, 17 to identify specific targets of linked with substantially increased However, premenopausal intervention for prevention of breast risk, such that women in the highest Mongolian women, who have a cancer and other hormonally related quintile of estradiol have double very low incidence of breast cancer, cancers. the risk of women in the lowest have higher circulating estrone quintile. 8 Adiposity may underlie and estradiol levels but lower this relationship 9 because, in the testosterone levels than women from LIMITATIONS OF THE EPIDEMIOLOGIC absence of ovarian estrogen after the United Kingdom. 18 These findings EVIDENCE BASE: MEASUREMENTS AND menopause, aromatization of suggest that the hormonal etiology DESIGN ISSUES steroids in adipose tissue increases of breast cancer is more complex estrogen that is in circulation and than originally hypothesized, likely The limited evidence base concerning bioavailable to the estrogen receptor involving androgens and estrogen. associations of directly measured in breast cells. Similarly, higher Androgens are metabolic precursors sex hormones with specific estrogen levels are associated with to estrogen, but evidence is mounting cancers stems from sex hormone a substantially increased risk of that androgens are independently measurements being expensive breast cancer in men, such that men implicated in premenopausal and and logistically challenging in in the highest quartile of estradiol postmenopausal breast cancer. large-scale epidemiologic studies. have more than double the risk Premenopausal women in the highest In men, the serum testosterone of men in the lowest quartile. 10 quartile of testosterone have a level varies throughout the day The association of estrogen with twofold higher risk of breast cancer and is ideally measured first thing premenopausal breast cancer is less compared with women in the lowest in the morning. In premenopausal well established. 11– 13 Higher levels of quartile, 11 and postmenopausal women, sex hormones vary during follicular-phase estrogens have been women with higher testosterone the menstrual cycle and are ideally Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 138 , number s1 , November 2016 S23 measured on the same day in characteristics (eg, anogenital cancer), hormones may also play a the menstrual cycle for all the distance [AGD], 31 second-to-fourth role. Knockout animal models have women in a study, or they require digit length [2d:4d] ratio).32 These recently provided a new means a sufficiently large random sample proxies have the advantage of ease of assessing specific physiologic with known date of last menstrual of recall and measurement, but mechanisms. These models suggest period to model variation during their relation with sex hormone that androgens
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