Identifying opportunities for cancer prevention during preadolescence and adolescence: puberty as a window of susceptibility.
ABSTRACT Early life exposures during times of rapid growth and development are recognized increasingly to impact later life. Epidemiologic studies document an association between exposures at critical windows of susceptibility with outcomes as diverse as childhood and adult obesity, timing of menarche, and risk for hypertension or breast cancer.
This article briefly reviews the concept of windows of susceptibility for providers who care for adolescent patients.
The theoretical bases for windows of susceptibility is examined, evaluating the relationship between pubertal change and breast cancer as a paradigm, and reviewing the underlying mechanisms, such as epigenetic modification.
The long-term sequela of responses to early exposures may impact other adult morbidities; addressing these exposures represents an important challenge for contemporary medicine.
- SourceAvailable from: Mohamed A Yassin[Show abstract] [Hide abstract]
ABSTRACT: The American Academy of Pediatrics recommends that young people between the ages of 11 and 21 years should be seen annually by their pediatricians, since annual checkups can be an important opportunity for health evaluation and anticipatory guidance. Parents of infants and young children are accustomed to regularly visiting a pediatrician for their child's checkups. Unfortunately, when children reach the teen years, these annual checkups may decrease in frequency. In routine check-ups and medical office visits, particular attention should be paid to the possibility of a developmental or endocrine disorder. Early diagnosis and treatment may prevent medical complications in adulthood and foster age-appropriate development. Our purpose is to acquaint readers with the concept, based on current scientific understanding, that some endocrine disorders may be associated with a wide range of deleterious health consequences including an increased risk of hypertension and hyperlipidemia, increased risk of coronary artery disease, type 2 diabetes, significant anxiety and lack of self-esteem. Understanding the milestones and developmental stages of adolescence is essential for pediatricians and all other health providers who care for adolescents. Treating adolescents involves knowledge of a variety of medical, social and legal information; in addition, close working relationships must be established within the adolescent's network to create an effective care system. In summary, we underline the importance of a periodic endocrine checkup in adolescents in order to identify endocrine problems early and develop an approach to treatment for those patients who need help during this time. Indications for endocrine referral for professional and other healthcare providers are also included. These lists are clearly not intended to be comprehensive, but will hopefully serve as a guide for specific clinical circumstances.Iranian Journal of Endocrinology and Metabolism 11/2014; 18(1):27-37.
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ABSTRACT: Significant left-right (L-R) differences in tumor incidence and disease outcome occur for cancers of paired organs, including the breasts; however, the basis for this laterality is unknown. Here, we show that despite their morphologic symmetry, left versus right mammary glands in wild-type mice have baseline differences in gene expression that are L-R independently regulated during pubertal development, including genes that regulate luminal progenitor cell renewal, luminal cell differentiation, mammary tumorigenesis, tamoxifen sensitivity and chemotherapeutic resistance. In MMTV-cNeu(Tg/Tg) mice, which model HER2/Neu-amplified breast cancer, baseline L-R differences in mammary gene expression are amplified, sustained or inverted in a gene-specific manner and the mammary ductal epithelium undergoes L-R asymmetric growth and patterning. Comparative genomic analysis of mouse L-R mammary gene expression profiles with gene expression profiles of human breast tumors revealed significant linkage between right-sided gene expression and decreased breast cancer patient survival. Collectively, these findings are the first to demonstrate that mammary glands are lateralized organs, and, moreover, that mammary glands have L-R differential susceptibility to HER2/Neu oncogene-mediated effects on ductal epithelial growth and differentiation. We propose that intrinsic molecular laterality may have a role in L-R asymmetric breast tumor incidence and, furthermore, that interplay between the L-R molecular landscape and oncogene activity may contribute to the differential disease progression and patient outcome that are associated with tumor situs.Oncogene advance online publication, 9 June 2014; doi:10.1038/onc.2014.149.Oncogene 06/2014; · 8.56 Impact Factor
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ABSTRACT: There is a large amount of literature regarding the benefits of the Mediterranean diet in the adult population; however, there is growing curiosity about the individuals who naturally adhere to those principles early in life. The “Evaluation of Dietary Habits in Adolescents”, carried out by the National Research Council of Italy in 2009, is a survey that aimed to assess the dietary habits and lifestyles of Italian adolescents and their adherence to the Mediterranean diet. We hypothesized that there would be differences across regions, with a higher adherence in Southern Italy compared to Northern Italy based on geography. The survey was conducted in three different geographic locations in Italy and included a convenience sample of adolescents who attended either a middle or high school. The participants were asked to fill out a questionnaire concerning demographic data, lifestyle factors, and eating patterns, and scores were assigned according to adherence to the Mediterranean diet, as calculated using Trichopoulou’s Mediterranean diet scale. The final sample included 565 adolescents, between 12 and 19 years of age, who attended school in the North-East, North-West, or Southern regions of Italy in 2009. According to the findings, 38.6% of the respondents had scores indicating a low adherence to the Mediterranean diet, while only 14% had scores showing a high adherence. Teenagers from the Southern region showed the highest adherence. Those with a high adherence to the Mediterranean diet consumed higher quantities of fiber, iron, Vitamin B6, Vitamin C, folic acid, Vitamin A, Vitamin D, and monounsaturated fats.Nutrition Research 08/2014; · 2.59 Impact Factor
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: firstname.lastname@example.org (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 are severalepidemiologic
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
levelsare 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.
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