Role of Environmental Factors in the Timing of Puberty

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SUPPLEMENT ARTICLE

Role of Environmental Factors in the Timing

of Puberty

Susan Y. Euling, PhDa, Sherry G. Selevan, PhDa, Ora Hirsch Pescovitz, MDb, Niels E. Skakkebaek, MD, DMScc

aNational Center for Environmental Assessment, Office of Research and Development, US Environmental Protection Agency, Washington, DC;bDepartment of Pediatrics,

Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana;cUniversity Department of Growth and Reproduction, Rigshospitalet,

Blegdamsvej, Copenhagen, Denmark

The authors have indicated they have no financial relationships relevant to this article to disclose.

ABSTRACT

Puberty-timing measures have historically been used as indicators of adequate nu-trition and growth. More recently, these measures have been examined in relation to exposure to estrogenic or antiandrogenic agents, as well as other environmental factors. The scientific community has debated whether puberty timing is occurring earlier today than in the mid-1900s in the United States and, if so, whether envi-ronmental factors play a role; however, no one has asked a multidisciplinary panel to resolve this question. Thus, a multidisciplinary expert panel jointly sponsored by the US Environmental Protection Agency, the National Institute of Environmental Health Sciences, and Serono Symposia International was convened to examine the evidence of a secular trend, identify potential environmental factors of concern, and identify research needs regarding environmental factors and puberty timing at “The Role of Environmental Factors on the Timing and Progression of Puberty” workshop. The majority of the panelists concluded that the girls’ data are suffi-cient to suggest a secular trend toward earlier breast development onset and menarche from 1940 to 1994 but that the boys’ data are insufficient to suggest a trend during this same period. The weight-of-the-evidence evaluation of human and animal studies suggest that endocrine-disrupting chemicals, particularly the estrogen mimics and antiandrogens, and body fat are important factors associated in altered puberty timing. A change in the timing of puberty markers was considered adverse from a public health perspective. The panel recommended research areas to further our understanding of the relationships among environ-mental factors, puberty-timing outcomes, and other reproductive and adult dis-ease at the individual and population levels.

T

HE AGE OFpuberty has historically been used as a measure of health status of particular populations. From as early as the 1800s, data on the age of menarche have been collected and recorded in health records among specific populations in the United States1and Europe.2Declines in the age at menarche have been reported from

the late 1800s to the mid-1900s, and these declines have been attributed to improvements in nutrition occurring over the same period (Fig 1).3,4 Contemporary and historical studies of puberty timing have focused on girls’ age at menarche, in part because it is relatively easy to collect either retrospectively or prospectively. Puberty-timing measures used in studies have expanded in the past century to include measures that capture onset and progression of puberty (eg, Tanner stages) as well as completion.5–9

Although researchers disagree about whether children are entering and/or progressing through puberty earlier today than in the mid-1900s, some recent analyses of US cross-sectional data concluded that girls are reaching puberty earlier over this time span, as measured by age at breast development stage, pubic hair development stage, and/or age of menarche.10–14Conversely, other studies concluded that there is no compelling evidence of an earlier age of menarche when comparing data collected in the 1950s and 1960s with data collected between 1988 and 1994.15 Furthermore, for breast and pubic hair development, Sun et al16,17 argued that the studies cannot be

www.pediatrics.org/cgi/doi/10.1542/ peds.2007-1813C

doi:10.1542/peds.2007-1813C The views expressed in this article are those of the authors and do not necessarily reflect the views or policies of the US Environmental Protection Agency. Mention of trade names of commercial products does not constitute endorsement or recommendation for use.

Dr Selevan is currently a consultant in Silver Spring, Maryland.

Key Words

puberty, precocious puberty, growth and development, endocrine disruptors, body fat, environmental health, public health, environmental exposure, environmental pollutants

Abbreviation

EDC— endocrine-disrupting chemical

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adequately compared or that the degree of change is not significant. Far fewer studies of puberty timing in boys are available, but 2 recent studies suggested that male puberty timing is occurring earlier.18,19

Hypotheses to explain the proposed recent popula-tion-level changes in puberty timing from the mid-1900s to the present time are controversial. One prominent hypothesis is that exposure to endocrine-disrupting chemicals (EDCs) cause an earlier age of puberty.10,20,21EDCs are a class of chemicals that inter-fere with steroid hormone activity via a variety of modes of action, at a number of levels, and puberty timing has been identified as a sensitive marker of response to EDC exposure. Male and female puberty-timing end points are especially sensitive to in utero or peripubertal exposure to certain EDCs, particularly estrogens and antiandrogens in animal models.22,23 As-sociations between exposure to certain EDCs and pu-berty timing have been identified in some human studies as well.24,25The linkage between EDC exposure and puberty-timing outcomes at the level of the indi-vidual makes intuitive sense because the full spectrum of pubertal maturation events requires the activation of the pituitary-gonadal and hypothalamic-pituitary-adrenal axes in rodents, nonhuman primates, and humans. Furthermore, a change in the timing of a

single measure of puberty could result from exposure to an EDC that affects hormone activity at the target tis-sue.26,27In addition to the EDC hypothesis, other hypoth-eses include increasing obesity11,28,29 and increasing hy-perinsulinemia and insulin resistance,30but all of these hypotheses remain controversial.

The debate about the factors that are responsible for the proposed secular trend toward an earlier puberty stems from several sources. First, the question of whether a secular trend in puberty timing even exists in this time period continues to be debated. Second, the terms “puberty” and “puberty onset” have been used to indicate a variety of puberty markers (eg, “puberty onset” can indicate menarche to some and breast development to others), increasing confusion. Because puberty-timing markers can differ in their mechanistic underpinning, it is important to compare puberty-timing data for the same marker. Third, pu-berty timing is a consequence of a wide range of genetic31–33and environmental factors; thus extracting the contribution of environmental factors at the pop-ulation level is difficult. For example, racial/ethnic differences in the timing of puberty reflect both ge-netic and environmental factors (Table 1).18,19,34 Fi-nally, inherent biases in the different interest groups have tended to polarize the debate. Specifically,

iden-TABLE 1 Mean Ages at Onset of Pubic Hair, Breast Development, and Menarche for 3 Racial/Ethnic Groups of US Girls: NHANES III, 1988 –1994

Pubertal Event Non-Hispanic White Black Mexican American

Age, Mean (95% CI), y Age, Mean, ya Age, Mean (95% CI), y Age, Mean, ya Age, Mean (95% CI), y Age, Mean, ya

Pubic hairb 10.6 (10.4–10.9) 10.5 9.5 (9.2–9.8) 9.5 10.3 (10.1–10.6) 10.3

Breast developmentb 10.3 (10.0–10.5) 10.3 9.5 (9.3–9.8) 9.5 9.7 (9.4–9.9) 9.8

Menarcheb 12.6 (12.4–12.8) 12.7 12.2 (12.0–12.4) 12.1 12.2 (12.0–12.5) 12.2

Menarchec 12.7 (12.5–12.8) 12.7 12.4 (12.2–12.5) 12.3 12.5 (12.3–12.6) 12.5

NHANES III indicates Third National Health and Nutrition Examination Survey; CI, confidence interval. aEstimated with application of weights for the examination sample of NHANES III.

bEstimated by using probit model for the status quo data of the puberty measurements. cEstimated by using failure time model for the recalled age at menarche.

Adapted from Wu T, Mendola P, Buck GM.Pediatrics. 2002;110(4):755. 13 14 15 16 17 18

Calendar year

Age of menarche, y

1800 1820 1840 1860 1880 1900 1920 1940 1960 1980

FIGURE 1

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tification of a secular trend in puberty timing would have very different consequences for 2 main groups that are interested in this issue: health scientists and clinicians. For health scientists, the finding of a secular trend would identify a new public health concern for investigation of potential causes. For clinicians, the finding of a secular trend could influence the norma-tive guidelines for puberty timing. A finding of a sec-ular trend toward an earlier average age of puberty might lower the ages considered precocious, which in turn could potentially affect treatment protocols and/or decrease the number of children treated.35,36 Current US pediatric endocrinology guidelines cite age limits for precocious puberty as secondary sexual characteristics before 8 years of age for girls8 and before 9 years for boys,9but some have recommended reducing the US age limit for defining precocious pu-berty to breast or pubic hair development before 7 years in white girls and before 6 years in black girls.37 The US Environmental Protection Agency, the Na-tional Institute of Environmental Health Sciences, and Serono Symposia International convened an expert panel workshop to discuss and attempt to resolve some of these issues. Panelists represented a wide range of expertise, perspectives, and countries, includ-ing clinicians, epidemiologists, toxicologists, anthro-pologists, biologists, risk assessors, and statisticians. The goals of the workshop were to develop consensus, defined as characterizing areas of agreement and dis-agreement, on 2 main questions: (1) Are there suffi-cient data to suggest or establish a secular trend in the timing of puberty onset or progression in boys or girls from 1940 to 1994 in the United States? (2) What are the priority research needs for environmental factors and puberty timing for human and animal studies? The panel also considered the implication of its find-ings with respect to children’s health protection, in-cluding clinical guidelines for precocious and delayed puberty and children’s health risk assessment. This workshop is the only one, thus far, to have evaluated the data and come to consensus, across disciplines, viewpoints, and biases, on the evidence of a secular trend and the role of environmental factors in puberty timing in children.

The articles in this supplement describe some of the expert panel discussions and conclusions. Euling et al38summarize the expert panel findings assessing the data for evidence of a secular trend in puberty timing for data collected between 1940 and 1994. The major-ity of the panelists concluded that the data for girls are sufficient to suggest a secular trend toward an earlier age of breast development onset and/or menarche during this time frame. Almost all panelists agreed that the available data for boys were insufficient to draw conclusions. Buck Louis et al25 consider toxico-logic and epidemiotoxico-logic evidence linking environmen-tal factor exposure to alterations in puberty timing. The panel agreed that the weight of the evidence suggests that EDCs and body fat are the factors of greatest concern for both the individual and the gen-eral population. These discussions also identified

re-search recommendations: studies to identify critical windows of exposure in humans and longitudinal studies that examine environmental exposures, pu-berty markers, and hormonal measurements in com-bination (eg, National Children’s Study24). Kaplowitz39 reviews studies that examined the association of body fat with puberty timing. He describes several studies with a positive association between body fat and ear-lier puberty timing in girls and the need for additional studies to examine whether earlier puberty timing is the result or cause of a higher body fat. Golub et al40 consider evidence linking altered puberty timing with specific adult disease outcomes, highlighting the im-portance of alterations in puberty timing with regard to adult and children’s health. The panel concluded that an altered timing of puberty onset or progression, including isolated precocious breast development, was considered an adverse outcome; however, the incre-ment of change in puberty timing considered biolog-ically meaningful was not agreed on for either humans or an animal model. Finally, a recurring theme in the discussions was the value of multidisciplinary and in-ternational efforts to design and perform studies and analyze data.

These 4 articles provide a summary of the findings of the expert panel and, perhaps more important, illumi-nate gaps in our understanding of the interplay between genetic and environmental factors on puberty timing. Specific research needs highlighted in each article will allow us to understand better this important public health issue. Research recommendations focused on 3 areas: (1) studies to explore further the relationship between environmental factors and puberty timing, in-cluding basic research to understand the initiating event of puberty, longitudinal studies, and toxicology studies at dosages that are relevant to human exposure; (2) studies to explore further the relationship between pu-berty-timing alterations and adult disease, including an-imal and human studies of precocious puberty, delayed puberty, or isolated precocious breast development and later disease outcomes, particularly reproductive cancers (eg, breast development onset and breast cancer), and studies to determine the degree of change in puberty timing that is biologically meaningful with respect to later disease; and (3) methods development, including more sensitive puberty biomarkers with less variability in timing, especially for male puberty onset (eg, geno-mics methods, hormonal assays) and methods to dis-criminate more reliably fat from breast tissue. The goal of the recommended research is to develop a more com-plete picture of the complex interrelationships among dosage and time of exposure to environmental factors, genetic factors, puberty-timing outcomes, other repro-ductive outcomes, and adult disease, at the individual and population levels.

ACKNOWLEDGMENTS

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cooper-ative agreement 830774, the National Institute of Envi-ronmental Health Sciences, and Serono Inc.

We gratefully acknowledge Serono Symposia Inter-national and David Schlumper for organizing and holding “The Role of Environmental Factors on the Onset and Progression of Puberty” Expert Panel Work-shop held in Rosemont, Illinois, November 2003. In addition, we thank the other members of the expert panel: David Abbott, Carlos Bourdony, Jean-Pierre Bourguignon, Germaine Buck Louis, Farid Chehab, Gwen Collman, Ralph Cooper, Leo Dunkel, Paul Fos-ter, Beth Gladen, Mari Golub, L. Earl Gray, Mel Grum-bach, Marcia Herman-Giddens, John Himes, Anders Juul, Paul Kaplowitz, Carole Kimmel, Peter Lee, Rob-ert Lustig, Michele Marcus, Sergio Ojeda, Tony Plant, Ed Reiter, Steve Schrader, Richard Sharpe, Wolfgang Sippell, Thorkild Sørensen, Ana Soto, Shanna Swan, Jorma Toppari, Rochelle Tyl, Martin Wabitsch, Patri-cia Whitten, Selma Witchel. We also thank the work-shop observers.

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DOI: 10.1542/peds.2007-1813C

2008;121;S167

Pediatrics

Susan Y. Euling, Sherry G. Selevan, Ora Hirsch Pescovitz and Niels E. Skakkebaek

Role of Environmental Factors in the Timing of Puberty

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DOI: 10.1542/peds.2007-1813C

2008;121;S167

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Susan Y. Euling, Sherry G. Selevan, Ora Hirsch Pescovitz and Niels E. Skakkebaek

Role of Environmental Factors in the Timing of Puberty

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FIGURE 1

FIGURE 1

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TABLE 1Mean Ages at Onset of Pubic Hair, Breast Development, and Menarche for 3 Racial/Ethnic Groups of US Girls: NHANES III, 1988–1994

TABLE 1Mean

Ages at Onset of Pubic Hair, Breast Development, and Menarche for 3 Racial/Ethnic Groups of US Girls: NHANES III, 1988–1994 p.2