Identifying Opportunities for Cancer Prevention During Preadolescence and
Adolescence: Puberty as a Window of Susceptibility
Frank M. Biro, M.D.a,*, and Julianna Deardorff, Ph.D.b
aDepartment of Pediatrics, University of Cincinnati College of Medicine; Division of Adolescent Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
bMaternal and Child Health Program, King Sweesy and Robert Womack Endowed Chair in Medical Science & Public Health, School of Public Health, University of California,
Article history: Received May 2, 2012; Accepted September 18, 2012
Keywords: Developmental plasticity; Thrifty phenotype; Windows of susceptibility; Puberty; Obesity
A B S T R A C T
Purpose: Early life exposures during times of rapid growth and development are recognized
increasingly to impact later life. Epidemiologic studies document an association between expo-
sures at critical windows of susceptibility with outcomes as diverse as childhood and adult obesity,
timing of menarche, and risk for hypertension or breast cancer.
Methods: This article briefly reviews the concept of windows of susceptibility for providers who
care for adolescent patients.
Results: The theoretical bases for windows of susceptibility is examined, evaluating the rela-
tionship between pubertal change and breast cancer as a paradigm, and reviewing the underlying
mechanisms, such as epigenetic modification.
Conclusions: The long-term sequela of responses to early exposures may impact other adult
morbidities; addressing these exposures represents an important challenge for contemporary
? 2013 Society for Adolescent Health and Medicine. All rights reserved.
This article provides an
care providers with adoles-
cent patients. It examines
associating early life expo-
sures with adult disorder-
susing the paradigms of
pubertal change and breast
susceptibility to environ-
Over the past several decades, there has been an increasing
awareness that early life events may shape developmental
trajectories and thereby impact later health . For example,
adult diseases, such as breast cancer and ischemic heart disease,
are believed to have origins in the early stages of life, and in
recent years the study of breast cancer etiology has moved
toward studying events during childhood . Adolescence has
received little attention, despite the important behavioral,
cognitive, and physical developmental changes that occur during
this period. In this rapidly evolving area of study, several
frameworks have been forwarded to explain these findings,
incorporating diverse disciplines and perspectives that impact
physical and mental health issues at the individual as well as
public health level. These models are not mutually exclusive, yet
often emphasize a specific perspective on antecedents or
outcomes. This article will review briefly the literature that
explores the factors in early life that impact the physiologic
changes associated with puberty and how these influence adult
morbidity using breast cancer as a paradigm.
Birth weight perhaps has been the most studied early life
factorimpacting laterhealth. Both lowerand higher birth weight,
long-term outcomes across the life course. The impact of fetal
Publication of this article was supported by the Centers for Disease Control and
Prevention. Supported, in part, by U01 ES-12770 (NCI and NIEHS), and UL1
RR026314 (USPHS); U01 ES019453 and U01 ES012801 (NCI and NIEHS).
The authors report no potential conflicts of interest.
* Address correspondence to: Frank M. Biro, M.D., Department of Pediatrics,
University of Cincinnati College of Medicine, Director, Division of Adolescent
Medicine, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue
(ML-4000), Cincinnati, OH 45229.
E-mail address: email@example.com (F.M. Biro).
1054-139X/$ e see front matter ? 2013 Society for Adolescent Health and Medicine. All rights reserved.
Journal of Adolescent Health 52 (2013) S15eS20
undernutrition has been recognized for several decades. Obser-
vations of three cohortsdchildren born during the Dutch famine
of 1944, bornwithin theHertfordshire (UK)district between1911
and 1930, and selected from the Helsinki Birth Cohort of
1934e44dhave led researchers to note the association between
small size at birth and during infancy and later increased
morbidity and mortality. The increased rates of adverse health
outcomesincluded thoseforcoronaryheartdisease[3e7]; stroke
[7,8]; insulin resistance ; and type 2 diabetes mellitus ;
adiposity [11,12], especially visceral fat distribution ; meta-
bolic syndrome (associated with both low birth weight and
maternal obesity ; and osteoporosis . The increased rates
, often called the “Barker hypothesis,” as described below.
Nutritional excess during pregnancy has also been linked to
adverse outcomes from childhood through adulthood, especially
for development of obesity and type 2 diabetes . Studies
found that maternal triglyceride levels were associated with
newborn weight  and that the strongest prenatal predictor of
pediatric overweight and adiposity is maternal body mass index
(BMI) . Studies also found positive associations between birth
size and cord insulin-like growth factor (IGF)-1 levels [19,20], as
well as cord leptin levels , and between birth weight with
adolescent height and lower age of menarche [21,22].
Observations of the association between higher infant death
resistance  led Barker and colleagues to develop the “thrifty
phenotype” hypothesis. That is, the prenatal environment has
nephron number, to enhance postnatal success in an anticipated
energy-limited environment. However, the infant encounters an
imbalance that occurs between the prenatal and postnatal envi-
adverse consequences. This is described as a “programmed” effect
that results from a permanent or long-term change in structure or
function through metabolic imprintingand/orepigenetic changes,
acting at critical period of early life. This concept was incorporated
into developmental plasticity, defined as variations in develop-
mental pathways that are triggered by environmental events
during sensitive periods in development , which others call
critical windows of sensitivity  (or windows of susceptibility).
Several different models have been proposed to explain these
genotype  as well as thrifty phenotype ; developmental
plasticity ; ecobiodevelopmental framework ; life history
theory ; adaptive calibration model; and developmental
origins of adult disease . A similar perspective is the predictive
adaptive response, which is a response to an environmental factor
that may not be of immediate benefit but made in expectation of
a future environment ; environment could include not only in
utero factors, but also postnatal psychosocial, nutritional, or
chemical exposures. These responses carry costs, as suggested by
growth or energy storage would reduce resources for other traits,
such as tissue repair processes. These adaptations are considered
the basis of the adverse consequences of fetal undernutrition and
maternal overnutrition, leading to the fetal origins of adult disease
. As discussed later, the adaptations in structure and function
are long-term or permanent, and there is increasing evidence that
epigenetic mechanisms may be responsible, prompting some to
suggest that, rather than a thrifty genotype  or thrifty pheno-
type , the underlying mechanism is the thrifty epigenotype,
incorporating both hypotheses through proposing epigenetic
variations to enhance energy storage and utilization . These
hypotheses resulted in a renewed interest in exposures that occur
at periods of increased susceptibility, such as during fetal devel-
opment and puberty. For example, Barker noted the relationship
adult hypertension .Brenner suggested that small-for-
gestational-age status may be associated with decreased nephron
colleagues reviewed the role of fetal programming on adult
hypertension and kidney disease and suggested several explana-
kidney,increasedexposure to fetalglucocorticoids,andalterations
in the renin-angiotensin system .
Pubertal Milestones and Relative Timing of Puberty
Puberty represents an important developmental window of
vulnerability to environmental exposures. Puberty is a time of
rapid and profound change, including (re)activation of the
adrenal axes, an acceleration in height velocity and achieve-
ment of the pubertal peak height velocity, changes in body
composition, the development of secondary sexual characteris-
tics, and the achievement of fertility. The temporal relationships
between these events are shown in Figure 1, and compared with
timing of breast development. During puberty, there is rapid
expansion and differentiation of breast stem cells, as discussed
later, which occurs contemporaneously with reactivation of the
hypothalamic-pituitary-ovarian axis, the onset of the pubertal
growth spurt, and the time of maximal accrual of bone mineral
content. The temporal relationships between these factors may
suggest shared or underlying biologic mechanisms.
The timing of puberty may serve as a sensitive indicator of
in age at menarche, which is correlated to onset of puberty, is
attributable to direct or additive genetic effects [38,39]. Recent
reviews reported that there are 42 loci associated with timing of
puberty but noted that these loci make a small contribution
(3.6%e6.1%) to the variability of age at onset [40,41]. Greater BMI
during childhood is associated with earlier age at menarche
[42,43]; this association may be related to greater levels of leptin
reflecting sufficient energy stores  or other mechanisms
associated with visceral adiposity [45,46]. Parent et al. reviewed
other factors that could impact variability in timing of puberty:
they include genetic factors and intrauterine environment, as
noted previously; nutritional intake; climatic exposures; light-
dark cycle; and exposure to endocrine-disrupting chemicals .
Psychosocial Factors and Puberty
In addition to metabolic and biologic exposures, studies have
linked timing of puberty in girls to adversity in the psychosocial
realm. Consistent with evolutionary life history theory, Belsky
and colleagues  posited that when girls encountered
F.M. Biro and J. Deardorff / Journal of Adolescent Health 52 (2013) S15eS20
conditions that were not favorable for survival (i.e., environ-
mental stressors), it was generally adaptive for them to become
reproductively mature at earlier ages . Empirical evidence
has confirmed that childhood adversity accelerates girls’
pubertal development . In countries that have adequate
nutrition, such as the United States, lower socioeconomic status
has been associated with earlier menarche, although effects may
vary depending on race/ethnicity . In addition, harsh-
conflictual family dynamics and poor parent-child attachment
predict earlier maturation, whereas warm and supportive family
conditions forecast later puberty among girls [51e54]. The
absence of a biological father also has been associated with
earlier pubertal timing, such that girls with no father in the home
prepubertally are about twice as likely to experience menarche
earlier than age 12 years than those with a father present
[52,54e58]. Studies of stepfathers have yielded inconsistent
findings, and there is no evidence to suggest that a mother’s
absence influences puberty; however, the presence of siblings
may play a role in delaying menarche [55,59].
The role that prepubertal BMI may play in mediating associ-
ations between adverse family factors and girls’ pubertal devel-
opment is somewhat unclear. Some studies suggest that the
influence of father absence on girls’ pubertal development is
mediated by BMI , whereas other studies do not note BMI as
a mediator [56,61]. Future research is needed to further explore
whether BMI or other measures of body composition (e.g.,
visceral adiposity) may help explain associations between
adverse family factors and girls’ pubertal timing.
Pubertal Events and Breast Cancer
Recently, attention has been turned toward the associations
between early life events, pubertal changes, and risk for breast
cancer in adulthood. Although exposures across the life span
have been linked to breast cancer risk , the mechanisms
underlying the relationship remain unclear. During puberty,
mammary growth occurs through exponential cellular prolifer-
ation and differentiation, suggesting a stem-like cell with
regenerative capacity , and the mammary gland undergoes
extensive changes. Primary ducts grow and divide with forma-
tion of terminal end buds, which further divide into smaller
alveolar buds and form the lobule type 1 unit. There is additional
growth and differentiation into lobules 2 and 3 throughout
puberty and into adulthood (Figure 1). Of note, breast epithelium
exhibits maximal proliferative activity during the luteal phase of
the menstrual cycle, and the highest level of cell proliferation is
observed in undifferentiated lobule type 1 . Full differentia-
tion into lobule type 4 occurs as a result of pregnancy, with
permanent alterations in gene expression pattern. These
pregnancy-associated changes have been hypothesized to result
in cells that are more refractory to environmental exposures
[64,65], unlike the earlier progenitor cells that are believed to be
the cellular target for potential carcinogens and is proposed as
the mechanism underlying decreased risk for breast cancer with
earlier age at first full-term pregnancy . For example, local
girls 19 years or younger when the Nagasaki and Hiroshima atom
bombs were dropped were more likely than local adults to
develop breast cancer ,suggesting an increased susceptibility
for younger women to the effects of radiation.
There areseveral epidemiologic
pubertal events and risk of breast cancer, including age of
menarche, growth factors (height and height velocity), and bone
mineral density. Epidemiologic studies support up to 30%
increased risk withyoungerage at menarche [2,68e72]. A pooled
analysis reported that for each year that age of menarche was
delayed, the risk of premenopausal breast cancer was reduced by
Figure 1. Pubertal milestones and breast development.
F.M. Biro and J. Deardorff / Journal of Adolescent Health 52 (2013) S15eS20
9%, and risk of postmenopausal breast cancer was reduced by 4%
. Menarche is one of the most well-established risk factors
for breast cancer, in part because the age at which menarche
occurred can be recalled years later . Young age at onset of
menarche is associated with young age at onset of breast
development and with young age during the pubertal growth
spurt. Young age during the pubertal growth spurt is associated
with greater growth velocity . Of note, obese and tall children
have greater levels of IGF-1 in response to growth hormone than
do short and normal-weight children , and IGF-1 may
mediate the relationship between menarche and breast cancer. A
recent study noted that the age at menarche was associated with
risk of breast cancer, but not when age at peak growth was
included in the analysis: this study found that risk for breast
cancer increased 11% for every 5-cm increase in adult height .
Similarly, if a woman reached her maximum height at or before
age 12 years, her risk of breast cancer increased by 1.4 .
Several studies documented the relationship between greater
bone mineral density and later development of breast cancer
[78e82]. Of note, the majority of bone mineral content is
deposited during the teenage years, peaking shortly after the age
at peak height velocity .
With regard to the concept of “windows of susceptibility,”
important factors may expand the window or lead to more
intense exposures. For example, early maturation leads to longer
duration of puberty and to a greater peak height velocity. That is,
early age at onset of puberty is associated with longer interval
between onset of puberty and menarche [84e86] and therefore
longer time for completion of puberty , with an increased
risk for perturbation during cell proliferation and differentiation.
Similarly, early age at onset of puberty is associated with greater
height velocity (and IGF-1 levels) [84,87]; and greater IGF-1
levels are associatedwith greater
density [88,89], another factor associated with risk of breast
cancer. In addition, the risk of breast cancer (and several other
cancers) increases with greater height , with a 1.17 increased
risk for every 10 cm of adult height. As noted earlier, greater BMI
is associated with earlier maturation in girls, and earlier matu-
ration is associated with higher BMI and increased risk of obesity.
An analysis from the Bogalusa Heart Study found that greater
childhood BMI was associated with earlier pubertal onset, and
earlier puberty with greater BMI as an adult, but the relationship
suggested that childhood BMI was the major factor . A recent
review suggests how IGF-1 might impact risk of cancer : the
action of IGF-I promotes tumor growth and mitosis, inhibits
apoptosis, and induces endothelial growth factor. Multiple
reviews discuss the association of obesity and several different
cancers , and as well as the underlying mechanisms for this
association, which include pro-inflammatory cytokines .
It is important to consider a life course approach in the care of
the adolescent. There is limited evidence, however, for inter-
ventions to decrease risk of later breast cancer in children and
adolescents. Multiple studies have documented an increased risk
of breast cancer with exposure to ionizing radiation during
childhood and adolescence, both from survivors of nuclear
bombs , as well as lower dose exposures , including serial
radiographs for scoliosis, especially with a family history of
breast cancer . These studies would suggest that minimizing
childrenand adolescents toionizing radiation exposurewould be
beneficial. Another potential exposure is alcohol; in a review of
dietary factors and breast cancer, alcohol was the only consistent
factor associated with increased risk , perhaps mediated
through the association of alcohol with increased breast density.
Although the literature is somewhat inconsistent, soy intake may
be beneficial, with some studies citing intake during childhood
 or during adulthood . Physical activity levels mayalso be
protective, and a case-control study noted that physical activity
at ages 14 to 20 years decreased risk of breast cancer . The
relationship between hormonal contraceptives and breast cancer
is controversial, although risk in younger users with BRCA1 and
BRCA2 mutations may be increased modestly .
This article provides a brief reviewof a rapidlyevolving fieldof
inquiry, the developmental basis of adult disease, with an
emphasis on the concepts of developmental plasticity and
windows of susceptibility. We have focused on one adult disease,
breast cancer, to discuss how changes during puberty may be
particularly important for later disease. This is especially relevant
for health providers of adolescents, who are familiar with a life
course model of health, but may be unaware of studies from early
life research or on adult outcomes. Early life factors may impact
pubertal changes and predisposition to specific adult morbidities
and mortality. The long-term changes may be mediated through
epigenetic changes, as well as or resulting in, structural and
functional changes to organs and body systems, and are imple-
term sequela of these responses to early exposures may apply to
several other adult morbidities and addressing these exposures
represent an important challenge for contemporary medicine.
 Godfrey KM, Gluckman PD, Hanson MA. Developmental origins of meta-
bolic disease: Life course and intergenerational perspectives. Trends
Endocrinol Metab 2010;21:199e205.
 Okasha M, McCarron P, Gunnell D, et al. Exposures in childhood, adoles-
cence and early adulthood and breast cancer risk: A systematic review of
the literature. Breast Cancer Res Treat 2003;78:223e76.
 Andersen LG, Ängquist L, Eriksson JG, et al. Birth weight, childhood body
mass index and risk of coronary heart disease in adults: Combined
historical cohort studies. PLoS One 2010;5:e14126.
 Barker DJP, Osmond C. Infant mortality, childhood nutrition, and ischae-
mic heart disease in England and Wales. Lancet 1986;327:1077e81.
risk ofdeath from ischaemic heart disease: Cohort study of 15,000 Swedish
men and women born 1915-29. BMJ 1998;317:241e5.
 Osmond C, Barker D, Winter P, et al. Early growth and death from
cardiovascular disease in women. BMJ 1993;307:1519e24.
 Rich-Edwards JW, Stampfer MJ, Manson JAE, et al. Birth weight and risk of
cardiovascular disease in a cohort of women followed up since 1976. BMJ
 Frankel S, Elwood P, Smith GD, et al. Birthweight, body-mass index in
middle age, and incident coronary heart disease. Lancet 1996;348:
 Fabricius-Bjerre S,Jensen RB, Færch K,et al. Impactof birth weight and early
infant weight gain on insulin resistance and associated cardiovascular risk
factors in adolescence. PLoS One 2011;6:e20595. Epub 2011 Jun 2.
 Hales CN, Barker DJP. Type 2 (non-insulin-dependent) diabetes mellitus:
The thrifty phenotype hypothesis. Diabetologia 1992;35:595e601.
 Kensara OA, Wootton SA, Phillips DI, et al. Fetal programming of body
composition: Relation between birth weight and body composition
measured with dual-energy X-ray absorptiometry and anthropometric
methods in older Englishmen. Am J Clin Nutr 2005;82:980e7.
 Meas T, Deghmoun S, Armoogum P, et al. Consequences of being born
small for gestational age on body composition: An 8-year follow-up
study. J Clin Endocrinol Metab 2008;93:3804e9.
 Rolfe EDL, Loos RJF, Druet C, et al. Association between birth weight and
visceral fat in adults. Am J Clin Nutr 2010;92:347e52.
 Boney CM, Verma A, Tucker R, et al. Metabolic syndrome in childhood:
Association with birth weight, maternal obesity, and gestational diabetes
mellitus. Pediatrics 2005;115:e290e6.
 Cooper C, Fall C, Egger P, et al. Growth in infancy and bone mass in later
life. Ann Rheum Dis 1997;56:17e21.
F.M. Biro and J. Deardorff / Journal of Adolescent Health 52 (2013) S15eS20
 Heerwagen MJR, Miller MR, Barbour LA, et al. Maternal obesity and fetal
metabolic programming: A fertile epigenetic soil. Am J Physiol Regul
Integr Comp Physiol 2010;299:R711e22.
 Di Cianni G, Miccoli R, Volpe L, et al. Maternal triglyceride levels and
newborn weight in pregnant women with normal glucose tolerance.
Diabetic Med 2005;22:21e5.
 Catalano PM, Farrell K, Thomas A, et al. Perinatal risk factors for childhood
obesity and metabolic dysregulation. Am J Clin Nutr 2009;90:1303e13.
 Boyne MS, Thame M, Bennett FI, et al. The relationship among circu-
lating insulin-like growth factor (IGF)-I, IGF-binding proteins-1 and -2,
and birth anthropometry: A prospective study. J Clin Endocrinol Metab
 Vatten LJ, Nilsen ST, Odegård RA, et al. Insulin-like growth factor I and
leptin in umbilical cord plasma and infant birth size at term. Pediatrics
 Romundstad PR, Vatten LJ, Nilsen TIL, et al. Birth size in relation to age at
menarche and adolescent body size: Implications for breast cancer risk.
Int J Cancer 2003;105:400e3.
 Öberg S, Cnattingius S, Sandin S, et al. Birth weight-breast cancer revis-
ited: Is the association confounded by familial factors? Cancer Epidemiol
Biomarkers Prev 2009;18:2447e52.
 Barker DJ, Winter PD, Osmond C, et al. Weight in infancy and death from
ischaemic heart disease. Lancet 1989;2:577e80.
 Bateson P, Barker D, Clutton-Brock T, et al. Developmental plasticity and
human health. Nature 2004;430:419e21.
 Selevan SG, Kimmel CA, Mendola P. Identifying critical windows of
exposure for children’s health. Environ Health Perspect 2000;108:451e5.
 Neel JV. Diabetes mellitus: A “thrifty” genotype rendered detrimental by
“progress”? Am J Hum Genet 1962;14:353e62.
 Shonkoff JP. Building a new biodevelopmental framework to guide the
future of early childhood policy. Child Development 2010;81:357e67.
 Stearns SC. Life history evolution: Successes, limitations, and prospects.
 Barker DJP. The developmental origins of adult disease. J Am Coll Nutr
 Gluckman PD, Hanson MA. Developmental origins of disease paradigm: A
mechanistic and evolutionary perspective. Pediatr Res 2004;56:311e7.
 de Boo HA, Harding JE. The developmental origins of adult disease
(Barker) hypothesis. Aust N Z J Obstet Gynaecol 2006;46:4e14.
 Barker DJP, Eriksson JG, Forsen T, et al. Fetal origins of adult disease:
Strength of effects and biological basis. Int J Epidemiol 2002;31:1235e9.
 Stöger R. The thrifty epigenotype: An acquired and heritable predisposi-
tion for obesity and diabetes? Bioessays 2008;30:156e66.
 Brenner B, Garcia D, Anderson S. Glomeruli and blood pressure. Less of
one, more the other? Am J Hypertens 1988;1:335e47.
 Zandi-Nejad K, Luyckx VA, Brenner BM. Adult hypertension and kidney
disease. Hypertension 2006;47:502e8.
timing: Expert panel research needs. Pediatrics 2008;121:S192e207.
 Herman-Giddens ME, Slora EJ, Wasserman RC, et al. Secondary sexual
characteristics and menses in young girls seen in office practice: A study
from the Pediatric Research in Office Settings Network. Pediatrics 1997;
 Kaprio J, Rimpelä A, Winter T, et al. Common genetic influences on BMI
and age at menarche. Hum Biol 1995;67:739e53.
 Treloar SA, Martin NG. Age at menarche as a fitness trait: Nonadditive
genetic variance detected in a large twin sample. Am J Hum Genet 1990;
 Elks CE, Perry JR, Sulem P, et al. Thirty new loci for age at menarche
identified by a meta-analysis of genome-wide association studies. Nat
 He C, Murabito JM. Genome-wide association studies of age at menarche
and age at natural menopause. Molec Cell Endocrinol 2012. http://
dx.doi.org/10.1016/j.mce.2012.05.003. [Epub ahead of print].
 Freedman DS, Khan LK, Serdula MK, et al. Relation of age at menarche to
race, time period, and anthropometric dimensions: The Bogalusa Heart
Study. Pediatrics 2002;110:e43.
 Kaplowitz PB. Link between body fat and the timing of puberty. Pediatrics
 Burt Solorzano CM, McCartney CR. Obesity and the pubertal transition in
girls and boys. Reproduction 2010;140:399e410.
 Ahmed ML, Ong KK, Dunger DB. Childhood obesity and the timing of
puberty. Trends Endocrinol Metabol 2009;20:237e42.
 Jasik CB, Lustig RH. Adolescent obesity and puberty: The “perfect storm.”
Ann N Y Acad Sci 2008;1135:265e79
 Parent AS, Teilmann G, Juul A, et al. The timing of normal puberty and the
age limits of sexual precocity: Variations around the world, secular
trends, and changes after migration. Endocr Rev 2003;24:668e93.
 Belsky J, Steinberg L, Draper P. Childhood experience, interpersonal
development, and reproductive strategy: An evolutionary theory of
socialization. Child Dev 1991;62:647e70.
 Ellis BJ. Timing of pubertal maturation in girls: An integrated life history
approach. Psychol Bull 2004;130:920e58.
 Braithwaite D, Moore DH, Lustig RH, et al. Socioeconomic status in rela-
tion to early menarche among black and white girls. Cancer Causes
 Belsky J, Steinberg L, Houts RM, et al. The development of reproductive
strategy in females: Early maternal harshness –> earlier menarche –>
increased sexual risk taking. Dev Psychol 2010;46:120e8.
 Ellis BJ, McFadyen-Ketchum S, Dodge KA, et al. Quality of early family
relationships and individual differences in the timing of pubertal matu-
ration in girls: A longitudinal test of an evolutionary model. J Pers Soc
 Saxbe DE, Repetti RL. Brief report: Fathers’ and mothers’ marital rela-
tionship predicts daughters’ pubertal development two years later.
J Adolesc 2009;32:415e23.
 Tither JM, Ellis BJ. Impact of fathers on daughters’ age at menarche:
A genetically and environmentally controlled sibling study. Dev
 Bogaert AF. Age at puberty and father absence in a national probability
sample. J Adolesc 2005;28:541e6.
 Deardorff J, Ekwaru JP, Kushi LH, et al. Father absence, body mass index,
and pubertal timing in girls: Differential effects by family income and
ethnicity. J Adolesc Health 2011;48:441e7.
 Quinlan RJ. Father absence, parental care, and female reproductive
development. Evol Hum Behav 2003;24:376e90.
 Romans S, Martin J, Gendall K, et al. Age of menarche: The role of some
psychosocial factors. Psychol Med 2003;33:933e9.
 Milne FH, Judge DS. Brothers delay menarche and the onset of sexual
activity in their sisters. Proc Biol Sci 2011;278:417e23.
 Ellis BJ, Essex MJ. Family environments, adrenarche, and sexual maturation:
A longitudinal test of a life history model. Child Dev 2007;78:1799e817.
 Bogaert AF. Menarche and father absence in a national probability sample.
J Biosoc Sci 2008;40:623e36.
 Visvader JE. Keeping abreast of the mammary epithelial hierarchy and
breast tumorigenesis. Genes Dev 2009;23:2563e77.
 Russo J, Hu YF, Yang X, et al. Developmental, cellular, and molecular basis
of human breast cancer. J Natl Cancer Inst Monogr 2000;27:17e37.
 Russo J, Mailo D, Hu YF, et al. Breast differentiation and its implication in
cancer prevention. Clin Cancer Res 2005;11:931se6s.
 Russo J, Moral R, Balogh GA, et al. The protective role of pregnancy in
breast cancer. Breast Cancer Res 2005;7:131e42.
 Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem
cells. Nature 2001;414:105e11.
 Land CE, Tokunaga M, Koyama K, et al. Incidence of female breast cancer
among atomic bomb survivors, Hiroshima and Nagasaki, 1950-1990. Radiat
 Clavel-Chapelon F. Differential effects of reproductive factors on the risk
of pre- and postmenopausal breast cancer. Results from a large cohort of
French women. Br J Cancer 2002;86:723e7.
 Garland M, Hunter DJ, Colditz GA, et al. Menstrual cycle characteristics and
history of ovulatory infertility in relation to breast cancer risk in a large
cohort of US women. Am J Epidemiol 1998;147:636e43.
 Kelsey JL, Gammon MD, John EM. Reproductive factors and breast cancer.
Epidemiol Rev 1993;15:36e47.
risk in nulliparous women. Breast Cancer Res Treat 1995;33:55e61.
 Petridou E, Syrigou E, Toupadaki N, et al. Determinants of age at menarche
as early life predictors of breast cancer risk. Int J Cancer 1996;68:193e8.
 Cooper R, Blell M, Hardy R, et al. Validity of age at menarche self-reported
in adulthood. J Epidemiol Community Health 2006;60:993e7.
 Biro FM, McMahon RP, Striegel-Moore R, et al. Impact of timing of
pubertal maturation on growth in black and white female adolescents:
The National Heart, Lung, and Blood Institute Growth and Health Study.
J Pediatr 2001;138:636e43.
 Bouhours-Nouet N, Gatelais F, Boux de Casson F, et al. The insulin-like
growth factor-I response to growth hormone is increased in prepu-
bertal children with obesity and tall stature. J Clin Endocrinol Metab
 Ahlgren M, Melbye M, Wohlfahrt J, et al. Growth patterns and the risk of
breast cancer in women. Int J Gynecol Cancer 2006;16(Suppl 2):569e75.
 Li CI, Littman AJ, White E. Relationship between age maximum height is
attained, age at menarche, and age at first full-term birth and breast
cancer risk. Cancer Epidemiol Biomarkers Prev 2007;16:2144e9.
 Cauley JA, Lucas FL, Kuller LH, et al. Bone mineral density and risk of
breast cancer in older women: The Study of Osteoporotic Fractures
Research Group. JAMA 1996;276:1404e8.
 Hadji P, Gottschalk M, Ziller V, et al. Bone mass and the risk of breast
cancer: The influence of cumulative exposure to oestrogen and repro-
ductive correlates. Results of the Marburg breast cancer and osteoporosis
trial (MABOT). Maturitas 2007;56:312e21.
F.M. Biro and J. Deardorff / Journal of Adolescent Health 52 (2013) S15eS20
 Kalder M, Jäger C, Seker-Pektas B, et al. Breast cancer and bone mineral Download full-text
density: The Marburg Breast Cancer and Osteoporosis Trial (MABOT II).
 Kuller LH, Cauley JA, Lucas L, et al. Sex steroid hormones, bone mineral
density, and risk of breast cancer. Environ Health Perspect 1997;105:
 Zhang Y, Kiel DP, Kreger BE, et al. Bone mass and the risk of breast cancer
among postmenopausal women. N Engl J Med 1997;336:611e7.
 Baxter-Jones ADG, Faulkner RA, Forwood MR, et al. Bone mineral accrual
from 8 to 30 years of age: An estimation of peak bone mass. J Bone Miner
 Biro FM, Huang B, Crawford PB, et al. Pubertal correlates in black and
white girls. J Pediatr 2006;148:234e40.
 de Ridder CM, Thijssen JH, Bruning PF, et al. Body fat mass, body fat
distribution, and pubertal development: A longitudinal study of physical
and hormonal sexual maturation of girls. J Clin Endocrinol Metab 1992;
 Marti-Henneberg C, Vizmanos B. The duration of puberty in girls is related
to the timing of its onset. J Pediatr 1997;131:618e21.
 Sandhu J, Smith GD, Holly J, et al. Timing of puberty determines serum
insulin-like growth factor-I in late adulthood. J Clin Endocrinol Metab
 Byrne C, Colditz GA, Willett WC, et al. Plasma insulin-like growth factor
(IGF) I, IGF-binding protein 3, and mammographic density. Cancer Res
 Renehan AG, Zwahlen M, Minder C, et al. Insulin-like growth factor (IGF)-
I, IGF binding protein-3, and cancer risk: Systematic review and meta-
regression analysis. Lancet 2004;363:1346e53.
 Green J, Cairns BJ, Casabonne D, et al. Height and cancer incidence in the
Million Women Study: Prospective cohort, and meta-analysis of prospec-
tive studies of height and total cancer risk. Lancet Oncol 2011;12:785e94.
 Freedman D, Khan L, Serdula M, et al. The relation of menarcheal age to
obesity in childhood and adulthood: The Bogalusa heart study. BMC
 Renehan AG, Tyson M, Egger M, et al. Body-mass index and incidence of
cancer: A systematic review and meta-analysis of prospective observa-
tional studies. Lancet 2008;371:569e78.
 Lorincz AM, Sukumar S. Molecular links between obesity and breast
cancer. Endocr Relat Cancer 2006;13:279e92.
 Tokunaga M, Norman Jr JE, Asano M, et al. Malignant breast tumors
among atomic bomb survivors, Hiroshima and Nagasaki, 1950-74. J Natl
Cancer Inst 1979;62:1347e59.
 Shore RE. Low-dose radiation epidemiology studies: Status and issues.
Health Phys 2009;97:481e6.
 Ronckers CM, Doody MM, Lonstein JE, et al. Multiple diagnostic X-rays for
spine deformities and risk of breast cancer. Cancer Epidemiol Biomarkers
 Michels KB, Mohllajee AP, Roset-Bahmanyar E, et al. Diet and breast
cancer: A review of the prospective observational studies. Cancer 2007;
 Korde LA, Wu AH, Fears T, et al. Childhood soy intake and breast cancer
risk in Asian American women. Cancer Epidemiol Biomarkers Prev 2009;
 Lee SA, Shu XO, Li H, et al. Adolescent and adult soy food intake and
breast cancer risk: Results from the Shanghai Women’s Health Study.
Am J Clin Nutr 2009;89:1920e6.
 Kruk J. Lifetime physical activity and the risk of breast cancer: A case-
control study. Cancer Detect Prev 2007;31:18e28.
 Brohet RM, Goldgar DE, Easton DF, et al. Oral contraceptives and breast
cancer risk in the international BRCA1/2 carrier cohort study: A report
from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating
Group. J Clin Oncol 2007;25:3831e6.
F.M. Biro and J. Deardorff / Journal of Adolescent Health 52 (2013) S15eS20