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 and estrogen may the menstrual cycle. 18 In both sexes, levels at particular life stages has increase the risk of liver cancer, 35 measurement of sex hormones at not been well quantified. As such, and androgens may also increase the cancer diagnosis may not correspond these measures only provide a gross risk of cancer of the bladder, kidney, to lifetime exposure or the relevant indication that may not distinguish lung, and prostate. 36 However, time period for cancer induction between different sex hormones, or the corresponding epidemiologic because of changes at menopause give effects of hormones at all key evidence is limited. A proxy of in women and testosterone falling developmental periods. In addition, hormone exposure (ie, older age with age in men. 23 Moreover, serum the effects of androgens are rarely at menopause) is associated with testosterone level in men is largely studied, and fewer proxies are a higher risk of thyroid cancer in a measure of circulating gonadal available. However, the absence of women.37 Interestingly, proxies of in production relevant to clinical epidemiologic evidence should not utero sex hormone exposure, such as management, which may not indicate be taken as evidence of absence of a the 2d:4d ratio, have been positively total exposure to androgens because causal effect because use of poorly associated with breast cancer 38 but androgens are also produced in the measured exposures often biases not with hormonal cancers in men adrenal glands or produced and associations toward the null. On the such as testicular germ tumor 39 or used locally without circulating. 24 –26 contrary, the consistent presence of prostate cancer. 40, 41 Notably, the observed associations modest associations between crude of serum testosterone and of a proxies (eg, age at menarche) and Given the challenges and limitations correlate of total androgen exposure breast cancer risk suggests effects with the observational evidence, with cardiovascular disease of the underlying mechanisms, randomized controlled trials (RCTs) risk factors are different, suggesting which, if measured directly, might be of therapies known to modulate sex they are measuring different substantially larger with the role of hormones provide another means underlying constructs.27, 28 hormones underestimated. of establishing some effects of sex Insights about local hormone hormones on cancer. RCTs have not production have been key to the Observational evidence is clearly shown that administering development of the latest generation considerably more limited for other estrogen-only hormone therapy of antiandrogens in castration- hormone-related cancers, such as causes breast cancer, 42 but they have resistant prostate cancer. 29 Similarly, cancer of the endometrium, ovary, been too small to establish effects on in postmenopausal women, estrogen prostate, testis, and thyroid as well ovarian cancer, endometrial cancer, 43 produced and used locally may play as osteosarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, a role in breast cancer. 24 The ongoing and rhabdomyosarcoma. 4 – 7 Evidence or Ewing’s sarcoma. Estrogen development of analytic methods is also limited for cancers in which reduction via selected estrogen to assess the steroid metabolome sex differences in rates emerge at receptor modulators (SERMs) or in urine or blood will undoubtedly puberty, such as higher rates of aromatase inhibiters effectively facilitate obtaining a more bone and joint cancer in boys.33 prevents breast cancer, 44 but comprehensive steroid profile.30 Despite the more limited evidence, again these RCTs are too small Currently, a generally accepted direct the pubertal peak in osteosarcoma to comprehensively assess their biospecimen measure of exposure to and Ewing’s sarcoma is later in boys effectiveness for rarer cancers.45 The estrogen or androgens throughout than in girls, 34 suggestive of the specific reduction of endometrial life does not exist. influence of pubertal hormones even cancer by aromatase inhibitors, but for these rarer cancers. Several other not SERMs, 46, 47 however, suggests In the absence of direct cancers have higher rates in men a role (albeit complex) of sex comprehensive hormone than in women, such as cancer of the hormones. Androgen deprivation in measurements, sex hormone stomach, liver, bladder, and kidney, men is a well-established treatment exposures are often proxied by as well as lymphoma and leukemia, 15 for prostate cancer, but whether reproductive events, such as age which may well be due to differences androgen deprivation has an effect at puberty, age of first birth, age in nonhormonal risk factors. Even for on any other potentially androgen- of menopause, number of children cancers with a strong nonhormonal related cancers has not been or breastfeeding, or by physical risk factor (eg, hepatitis and liver comprehensively reported.

Downloaded from www.aappublications.org/news by guest on September 25, 2021 S24 SCHOOLING et al Studies using genetic variants related CRITICAL PERIODS FOR SEX 6 months. 61 In girls, estradiol levels to hormonal exposure provide HORMONES are low at birth but then increase another means of assessing the and fluctuate, before decreasing Levels of sex hormones are high role of hormones in cancer (ie, a in the second year of life. The in utero. Direct measurement of Mendelian randomization design). 48 processes generating these changes, fetal sex hormone levels is not their environmental drivers, their The challenge is that although genetic currently feasible, and manipulation purpose, and their long-term effects variants in hormonal pathways have of hormone levels in fetuses is 49–51 are poorly understood. Interestingly, been identified, few reliable unethical. Circulating fetal hormones this time period is also a stage of genetic predictors of androgens and originate from maternal, fetal, and very rapid growth. Whether infant estrogen levels have been isolated, placental sources. Information growth is associated with hormonal and whether the relevant genetic about the effects of hormones in cancers has rarely been investigated, variants affect hormones consistently utero is mainly gathered from although greater childhood height in utero, in infancy, at puberty, study of infants with exposure to is associated in boys with prostate and in adulthood is unknown. atypical hormone levels to inform cancer 72 and glioma, 73 and with Nevertheless, a recent Mendelian management of these conditions, thyroid cancer in both sexes. 74 randomization study has confirmed which may be most informative the causal role of postmenopausal regarding gross morphologic 49 Lifetime peak hormone levels are estradiol in endometrial cancer. development. Testosterone reaches attained at puberty. Menarche Genes in the estrogen pathway are its maximal value at 11 to 18 weeks is one of the longest known and associated with osteosarcoma,50 in male fetuses, when it is similar most well-established early life but genome-wide association studies to adult levels, 61 and contributes to risk factors for breast cancer. 13 (GWAS) have not identified genes the formation of masculine genitalia; Menarche is defined as an activated known to be associated with estrogen testosterone is also important hypothalamus-pituitary-ovarian as relevant to osteosarcoma, 52 in late gestation for testicular axis 14 and is often assumed to Ewing’s sarcoma, 53 thyroid cancer, 54 descent. 62 Most information about represent the first dose of estrogen or rhabdomyosarcoma. Genes sex hormones in utero comes from exposure in a woman’s life course. functionally associated with proxies, such as the 2d:4d ratio However, menarche is the final androgens are associated with or measurement of cord blood. milestone of the pubertal transition, prostate cancer51 but do not seem However, cord blood can be affected encompassing a complex, integrated to be related to leukemia, stomach by prenatal events and may only series of biological events, including cancer, liver cancer, bladder cancer, represent hormone levels at delivery, adrenarche (onset of adrenal or kidney cancer. 55 – 57 Genetic rather than throughout the fetal androgen production), thelarche polymorphisms in the 9p21 gene period.63 Higher birth weight has also (onset of breast development), region are associated with cancer been hypothesized to relate to higher and pubarche (onset of pubic hair estrogen exposure in utero, 64, 65 of the stomach, kidney, lung, breast, growth). In addition to the timing (or 58 although higher birth weight is and bladder, but the function of age) at each of these milestones, the associated with many hormone- this gene region is not currently well tempo of the transition (ie, the time related cancers 19, 66 but not all. 67 – 70 As understood. GWAS have essentially interval between each milestone) such, the association of birth weight generated agnostic correlations is also relevant to breast cancer with cancer risk is complex and and thus may not correspond to risk. In particular, earlier age at does not directly implicate specific a comprehensive set of causal thelarche (≤10 years compared with hormonal exposures in utero. 71 relations. For example, testosterone 11–12 years) and a longer interval Identifying the effects of birth weight is known from RCTs to increase between thelarche and menarche is analytically challenging and may hematocrit and hemoglobin levels.59 (≥2 years compared with 0 years) need to be considered in concert with However, the GWAS of red blood have recently been associated with the other key periods of hormonal cell traits does not include any a 20% higher risk of breast cancer development. genetic polymorphisms in the steroid in >100 000 women,75 independent pathway. 60 To what extent GWAS Levels of sex hormones are also of age at menarche and likely replicates known causal relations high during the mini-puberty of underestimated due to recall error. has not been assessed. Nevertheless, early infancy. In boys, testosterone Because the pubertal transition is genetic studies and Mendelian levels are low in cord blood, start to characterized by increasing levels of randomization studies are helping increase at 1 week, peak to pubertal androgens and estrogen from as early to clarify the role of sex hormones in levels at 1 to 3 months, and then as 6 years of age, the established cancer. fall to low prepubertal levels by menarche–breast cancer relationship

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 138 , number s1 , November 2016 S25 could also be a proxy for earlier be sex-specifically responsive to timing in boys 89 but not in girls. 90 hormonally related events. Previous environmental cues at specific life Experimental evidence in humans studies conducted with Bangladeshi stages, thus optimizing reproductive is necessarily limited. Experimental migrants to London collectively success in a given context. For evidence in male rats suggests that suggest that migration to the United example, extreme masculinity, fueled BPA reduces testosterone levels91 – 93 Kingdom as a child, specifically by high testosterone levels, seems to but may increase estrogen levels. 94 before puberty, is associated with an have been selected against in human Consistently, early BPA exposure elevated adult reproductive hormone history.82 As such, potential drivers reduces AGD.95 profile that is either comparable with of sex hormones may be identified Little evidence links phthalates or higher than white British adults, both empirically and theoretically with cancer. In utero, phthalates whereas migration as an adult is from the physiologic mechanisms are associated with shorter AGD 76 associated with a lower profile. For that enable responsiveness to and lower penile size in boys, 96, 97 example, luteal phase progesterone environmental indicators of and in utero exposure to phthalates levels were lower in premenopausal conditions relevant to reproduction. is associated with earlier pubertal Sylheti and migrant women than in Potential drivers of sex hormones, timing in girls. 90 Childhood exposure child migrants, second-generation and their role in hormonally related to phthalates is associated with later 77 migrants, and white British women. cancers, can be considered from both pubic hair development in girls, 98 Childhood concentrations of perspectives. and in utero exposure to phthalates is dehydroepiandrosterone sulfate associated with later pubertal timing were also elevated in first-generation 89 POTENTIAL DRIVERS OF SEX in boys. In rats in utero, phthalates child migrants compared with 99 HORMONES reduce testosterone levels and second-generation migrants and many measures of masculinization, 78 white British girls. These findings Endocrine Disruptors such as penile length, ventral suggest that there is a critical 100 It is well known that endocrine prostate weight, and AGD. window in early life affecting adult However, some of these findings have hormone levels. disruptors affect sex hormones, although the pathways, persistence, been difficult to reproduce or test in mechanistic models. 101 Although critical periods for and exact effects are not always hormonal exposures exist, exactly clear. Major man-made endocrine Dioxins were classified as a human how higher exposure during these disruptors include bisphenol A carcinogen by the International periods affects cancer risk and what (BPA), phthalates, dioxins, and other Agency for Research on Cancer in drives these exposures has not been persistent organic pollutants (POPs). 1997. Quasi-experimental studies delineated. The lack of knowledge BPA is positively associated with indicate that dioxin is a multisite 102 about the interrelation between in prostate cancer, 83 although the carcinogen, associated with breast 103,104 105 utero, infancy, and pubertal effects long-term association with other cancer, prostate cancer, 103 on sex hormone levels also means potentially hormone-related cancers possibly thyroid cancer, and 106 we do not know the optimal time for remains to be investigated. 84 The sarcoma, with little evidence intervention, nor the likely impact. lifetime effects of BPA are hard to regarding testis or endometrial One perspective that may provide establish because it only became cancer. However, a study found no insight is to place hormone commercially available in 1957; association of dietary dioxin with 107 exposures within the context of thus, those exposed in early life are breast cancer. Although dioxin the well-known tradeoff between only just reaching the age when may operate by many mechanisms, reproduction and longevity, 79 which cancer becomes more common, it seems to be associated with the may involve environmentally driven although the pattern of increasing pattern of cancers that might be strategies to optimize reproductive rates of testis cancer in young men expected of an estrogen-associated success that may differ for men and is consistent ecologically with the carcinogen. women, given sex-specific roles introduction of BPA. 85, 86 The Institute In adults, differences in sex hormones in reproduction. Women have to of Medicine was unable to draw a according to POP exposure can be focus on a few, ideally high-quality, firm conclusion about the role of difficult to determine,108 specimens, 80 whereas the stakes BPA in breast cancer.87 Evidence as are differences in sex hormones (ie, the potential rewards in terms of from observational studies suggests with related exposures (eg, descendants) are higher for men. 81 that BPA might raise 84 or decrease88 insecticides),109, 110 perhaps because This evolutionary biology perspective testosterone levels. Longitudinally of the difficulty with measuring suggests that reproductive effort, measured in utero exposure to BPA estrogen and androgens. Overall, and hence sex hormones, may is associated with later pubertal the effects of POPs on sex hormones

Downloaded from www.aappublications.org/news by guest on September 25, 2021 S26 SCHOOLING et al seem to be specific to the POP mechanism for “tuning” hormone adults suggests that diverse factors and the age of exposure, making levels in response to environmental modulate sex hormones, including effects difficult to unravel. POPs are conditions. Sex hormones are infections, 162, 163 social exclusion, 164 associated with breast cancer. 111 metabolized from cholesterol, 133, 134 and fatherhood165; whether similar and their metabolism pathways factors have effects in early life is Body Size play a role in hormonally related virtually unexplored. 49–51 Adiposity in men reduces cancers. Notably, catabolism testosterone, as interventions of estrogen and androgens occurs via major substance disposal that effectively and substantially NEXT STEPS reduce body fat in men also raise pathways (ie, glucuronidation, ′ testosterone levels, 112 – 115 probably by the uridine 5 -diphospho- Even for a cancer, such as breast because of reduced conversion of glucuronosyltransferase [UDP- cancer, that is well known to be testosterone to estrogen in adipose glucuronosyltransferase] enzymes, hormonally related, gaps in the tissue.115 Conversely, adiposity and sulfation), which are important evidence exist as to the lifetime in women may increase levels of pathways for elimination of drugs, effects of sex hormones and their testosterone. 116 dietary substances, toxins, and endogenous substances, and where drivers on risk over the life course Diet the disposal of 1 substance may affect from in utero exposures to old age. another. 135 –139 These catabolism Given the suggestive, but limited Alcohol may increase estrogen pathways have been studied in the evidence, testing common modifiable 117 levels. Intervention studies have context of drug–drug interactions, 140 exposures for their effects on also examined whether fat intake at are polymorphic,135, 141 estrogen and androgens in vitro, puberty affects pubertal hormones and are susceptible to epigenetic using metabolism and catabolism and found some effects on estrogens programming 142 by a variety of pathways, and then, as necessary, 118 119 in girls, but not adults, factors during early life.142, 143 in vivo experiments, might enable but no effects on sex hormones at Examination of the pathways classification of exposures that in 120 puberty in boys. However, fat suggests that many common early life might have long-lasting intake in men increases testosterone items may affect estrogen and/or effects on hormone levels and hence 121 levels. Soy protein consumption androgens via these pathways, such vulnerability to hormone-related may reduce testosterone levels in as cotinine, 144, 145 painkillers, 138,146, 147 cancers. Although the epidemiologic 122–124 men. Nitrates may also reduce and many dietary items, 148 including evidence on the role of hormones 125 testosterone levels. However, potentially vitamin A, 149, 150 cruciferous and cancer risk is limited (often to no systematic testing of dietary vegetables, 151, 152 citrus fruit,151 proxies of hormonal exposures and items to identify their effects on chili,153 sesame, 154 ginseng, 155, 156 a few critical periods throughout sex hormones has been conducted. and fatty acids (eg, linoleic acid). 157 life), the experimental data strongly Taking a broader perspective, women Although associations of various support a causal link between are known to stop menstruating similar risk factors with hormone hormonal levels and carcinogenesis. when energetic conditions are levels have been reported from For example, the effectiveness of 126 very limited. The question of high-quality studies, 158 –160 they SERMs in reducing the recurrence whether men’s reproductive axis are open to all the weaknesses of and incidence of breast cancer risk also responds to energetic conditions observational dietary epidemiologic suggest that further research specific 127 has less often been considered. analyses. 161 However, these specific to direct measurements of hormones, However, evidence exists for such physiologic pathways have not been and their drivers in early life, is responses; testosterone in men drops systematically studied from the essential in quantifying risk and 128–130 in response to undernutrition perspective of effects on estrogen and having a long-term impact on cancer and then rises again with improved androgens from early life exposures, risk reduction. The present article 131,132 nutrition. Moreover, although use of such physiology summarizes the major gaps that exist mechanisms for this response could be an effective method of in the evidence base for hormonal exist, whose elucidation could help preliminary screening to identify carcinogenesis. As the evidence base identify modulators of estrogen and factors in which early exposure might builds to support key time periods of androgens across the life course. have lifelong effects on hormone intervention to reduce risk, we have levels. A broad range of social and outlined ways of identifying potential Physiologic Pathways contextual factors could be relevant modifiable factors that may drive Sex hormone metabolism and to early life, and hence lifetime, sex hormonal levels as a first step for catabolism pathways provide a hormones, given that the evidence in investigation.

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Downloaded from www.aappublications.org/news by guest on September 25, 2021 Potential Intervention Targets in Utero and Early Life for Prevention of Hormone Related Cancers C. Mary Schooling, Lauren C. Houghton and Mary Beth Terry Pediatrics 2016;138;S22 DOI: 10.1542/peds.2015-4268E

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