M A Marcello et al.

Obesity and thyroid cancer 21:5 T255–T271

Thematic Review

Obesity and thyroid cancer

Marjory Alana Marcello, Lucas Leite Cunha, Fernando Assis Batista and Correspondence
Laura Sterian Ward should be addressed
to M A Marcello
Laboratory of Cancer Molecular Genetics (Gemoca), Faculty of Medical Sciences, University of Campinas Email
(FCM- Unicamp), Rua Tessália Vieira de Camargo 126, Barão Geraldo, Campinas, São Paulo 13083-970, Brazil marjoryam@gmail.com

Abstract
Many studies have provided observational data on the association of obesity and thyroid Key Words
cancers, but only few of them propose mechanisms that would permit a better under- " obesity
standing of the causal molecular mechanisms of this association. Considering that there is an " oncology
increasing incidence of both obesity and thyroid cancers, we need to summarize and link " molecular biology
recent studies in order to characterize and understand the contribution of obesity-related
factors that might affect thyroid cancer development and progression. Adipose tissue is
involved in many vital processes, including insulin sensitivity, angiogenesis, regulation of
Endocrine-Related Cancer

energy balance, activation of the complement system, and responses such as inflammation.
Although these processes have their own molecular pathways, they involve the same
molecules through which obesity and adipose tissue might exert their roles in
carcinogenesis, not only affecting MAPK and PI3K or even insulin pathways, but also
recruiting local inflammatory responses that could result in disease formation and
progression. This review describes five important issues that might explain the link between
excessive weight and thyroid cancer: thyroid hormones, insulin resistance, adipokines,
inflammation, and sexual hormones. Endocrine-Related Cancer
(2014) 21, T255–T271

Introduction
Overweight and/or obesity have been consistently related
to the development and progression of different types of
cancers during the last decades. An extensive review
published a few years ago estimated that approximately
20% of all cancers might be caused by excessive weight
(overweight or obesity) (Wolin et al. 2010). Both the
International Agency for Research on Cancer (IARC) and
the World Cancer Research Fund (WRCF) recognize solid
evidence that postmenopausal breast cancer, endometrial
cancer, colon cancer, esophageal adenocarcinoma, kidney
cancer, liver cancer, pancreatic cancer, prostate cancer,
thyroid cancers, leukemia, non-Hodgkin lymphoma, and
myeloma are related to overweight and obesity with respect
to development, treatment, and progression of the disease
(IARC 2002, World Cancer Research Fund & American
Institute for Cancer Research 2007, Wolin et al. 2010,
De Pergola et al. 2013). However, because of the differences
in the etiological factors related to different types of
tumors and the variety of mechanisms involved in
excessive weight conditions, cancers might be related to
weight variations by distinct and complex pathways.
Many efforts have been made to understand the possible
mechanisms underlying these associations, and it has been
strongly suggested that endometrial and postmenopausal
breast cancers are linked to obesity by endogenous estrogen
levels (Begg et al. 1987, Kaaks et al. 2002, Renehan et al. 2008,
Hvidtfeldt et al. 2012, Strong et al. 2013), whereas cancers of
the gallbladder, and esophagus, lymphomas, and myelomas
might be influenced by inflammation, which, itself, is very
closely related to obesity (Renehan et al. 2008, Lodh et al.
2012, Kavanagh et al. 2013, Li et al. 2013, Wang et al. 2013). In
patients with pancreatic and colon cancers, the evidence

http://erc.endocrinology-journals.org
DOI: 10.1530/ERC-14-0070
q 2014 Society for Endocrinology
Published by Bioscientifica Ltd.
Printed in Great Britain
This paper forms part of a special thematic review section on New concepts and
challenges in thyroid cancer. The guest editor for this section was Laura Ward,
Universidade Estadual de Campinas, Brazil. She from
Downloaded was not involved in the
Bioscientifica.com athandling of 12:53:39AM
07/06/2019
this paper, on which she is listed as an author. via free access
 Thematic Review M A Marcello et al.
indicates a major role of insulin pathways linking the
development of the disease with obesity (Renehan et al.
2008, Sun et al. 2013, Wolpin et al. 2013).
Concerning thyroid tumors, although many observa-
tional studies have been reporting a correlation between
excessive weight and thyroid malignancy (Zhao et al.
2012), the mechanisms behind this correlation are not
fully understood and a causal mechanism has not yet
been established. In this review, we aim to present clinical
data regarding the association of obesity and overweight
with thyroid cancer and the latest findings on the possible
pathophysiological pathways that underlie this
association.
Obesity, BMI, and thyroid cancer
Epidemiological data
The World Health Organization (WHO) uses the BMI,
a measure of weight relative to height (kg/m2) to indicate
body fat, and recommends a median BMI in the range
Endocrine-Related Cancer
of 21–23 kg/m2 for optimal health. The general indication
for subjects is to maintain the BMI in the range of 18.5–
24.9 kg/m2, as a large number of studies have proved that
there is an increased risk of comorbidities for BMIs ranging
from 25.0 to 29.9 kg/m2, and moderate to severe risk of
comorbidities for subjects with a BMI of over 30 kg/m2
(WHO 2009). In fact, the WHO estimates that, at the
present time, 65% of the world’s population live in
countries where overweight and obesity cause more
diseases and deaths than malnutrition (WHO 2009). The
worldwide prevalence of obesity has almost doubled
between 1980 and 2008 (Ogden et al. 2006), and although
more recent studies have shown a tendency towards
stabilization of the growing rates of obesity (Flegal et al.
2012, Perez Rodrigo 2013), the general rates of overweight
and obesity remain very high in the population (Perez
Rodrigo 2013). The WHO reported that over 50% of the
population of America, the Eastern Mediterranean, and
Europe were overweight in 2008 (Perez Rodrigo 2013).
Obesity and overweight have long been recognized
as triggers for many diseases, such as hypertension, hyper-
cholesterolemia, diabetes, insulin resistance (IR), and
different types of cancers. Like obesity, thyroid cancer has
been showing a worldwide increase in incidence during the
last decades (Davies & Welch 2006, Chen et al. 2009, Agate
et al. 2012, Jung et al. 2012, Wang & Wang (In Press)). This
increase is mainly due to differentiated thyroid carcinomas
(DTCs), and more specifically due to papillary thyroid
carcinomas (PTCs) (Pellegriti et al. 2013). PTCs are indolent
http://erc.endocrinology-journals.org q 2014 Society for Endocrinology
DOI: 10.1530/ERC-14-0070 Printed in Great Britain
Obesity and thyroid cancer 21:5 T256
cancers, and most of them are not likely to progress or cause
death (Brito et al. 2013). Although the incidence of thyroid
cancers has presented a marked increase, the mortality rates
have remained stable indicating that a pool of formerly
undiagnosed tumors would possibly never present a clinical
evolution (Davies & Welch 2006). However, the reasons
why DTC incidence has been increasing are still contro-
versial (Ward & Graf 2008). A series of studies have claimed
that this was only a matter of diagnosis (Davies & Welch
2006, Grodski et al. 2008, Sprague et al. 2008), but the
increasing incidence does not comprise only tumors less
than 1 cm of extent favored by better imaging tests, but also
larger tumors, making it difficult to believe that changes in
incidence are exclusively due to improvements in diagnosis
and health access (Enewold et al. 2009). Thus, it is possible
to propose the hypothesis that we are dealing with an
increasing exposure to risk factors that might contribute to
this noticeable surge. Among the well-documented and
recognized risk factors for DTCs are previous radiation
exposure, iodine intake, familial history of thyroid dis-
orders, hormonal and reproductive factors, TSH levels, and,
more recently, the genetic profile; presence of inflam-
mation and also BMI have been included to the list of
potential risk factors for thyroid cancers (Agate et al. 2012).
Association between overweight and thyroid cancer:
observational studies
The relationship between overweight and cancers has
long been investigated, and the first available studies date
back to the 1940s. In 1987, during the decade when the first
obesity boom was reported, Albanes (1987) reviewed a series
of studies concerning the relationship between overweight
and different cancer types and observed that subjects with
high relative body weight or high caloric intake were at a
higher risk of developing breast, colon, rectum, prostate,
endometrium, kidney, cervix, ovary, thyroid, and gallblad-
der cancers. But in the case of thyroid cancers, it was only
after the year 2000 that larger studies started to appear with
the first solid evidence (Pappa & Alevizaki 2013).
There are two different types of observational studies
concerning the relationship between obesity and thyroid
cancer: in the first one, thyroid cancer prevalence has been
looked for in obese patients and, in the second one,
patients with thyroid cancer are searched for obesity.
These approaches give different information and pictures,
but it is important to observe that obesity can be an
epiphenomenon of the thyroid cancer disease, reducing
therefore the relevance of the second type of studies,
although there is no evidence that thyroid cancer induces
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 07/06/2019 12:53:39AM
via free access
 Thematic Review M A Marcello et al.
important metabolic alterations. Most of the observa-
tional studies quoted in this revision are large cohorts of
obese subjects.
Dal Maso et al. (2000) analyzed 12 case–control
studies performed during the 1990s, including 2056
females and 417 males with thyroid cancer, and found
a weak relationship of the BMI at diagnosis and an
increased risk of thyroid cancer in females (ORZ1.2),
but no association in males. Although some other authors
have shown associations of food intake with the risk of
thyroid cancers (Franceschi et al. 1990, 1991, Shah 1999),
this first review only considered anthropometric factors,
not including any data regarding eating habits or
other possible factors that could be related to obesity
and cancer risk. However, it provided the rationale for
further studies. Back at that time, there were scarce
studies focusing on the mechanisms of obesity-related
thyroid cancers.
During the next decade (2001–2010), many studies
investigated the relationship between excessive weight
and cancers and, although a considerable number of
Endocrine-Related Cancer
them were not specifically designed for thyroid cancers,
many authors presented data on the relationship between
DTCs and obesity. These studies included larger cohorts
and, by the end of the decade, the mechanisms that
would link DTCs and overweight/obesity started to
appear as objects of investigation. Samanic et al. (2004)
investigated a large cohort of US male veterans (3 668 486
whites and 832 214 blacks) with a diagnosis of obesity
and their risk for the development of different types of
cancers over almost 30 years. The primary goal of the
authors was to identify differences in the risk of cancers
between white and black subjects, and the authors
reported that both white and black obese men presented
a higher risk of developing thyroid cancers (RRZ1.4; 95%
CIZ1.09–1.81 and RRZ1.92; 95% CIZ1.09–3.4 respect-
ively) (Samanic et al. 2004). In an interesting study, Boru
and colleagues analyzed an Italian cohort of 1333 obese
patients who were considering bariatric surgery. Out of
these patients, 43 (3.2%) presented with different types of
cancer either before, during, or after the obesity treat-
ment. Thyroid cancer was the second most frequent,
affecting 8 (18.60%) out of the 43 patients with
malignancies, indicating that severely obese subjects
are at a higher risk of developing thyroid carcinomas
(Boru et al. 2005).
Engeland et al. (2006) analyzed a very large cohort of
subjects (2 000 947) followed for an average of 23 years.
During this time, 3046 thyroid cancer cases were diagnosed
and 1415 of them were either overweight or obese.
http://erc.endocrinology-journals.org q 2014 Society for Endocrinology
DOI: 10.1530/ERC-14-0070 Printed in Great Britain
Obesity and thyroid cancer 21:5 T257
The risk of thyroid cancer (all the types together) increased
moderately with an increase in the BMI of one unit in both
women (RRZ1.02; 95% CIZ1.01–1.03) and men (RRZ
1.03; 95% CIZ1.00–1.05). The authors verified that obese
women were at a higher risk of PTCs (RRZ1.19; 95% CIZ
1.01–1.41) or follicular thyroid carcinomas (FTCs) (RRZ
1.63; 95% CIZ1.24–2.15), but at a lower risk of medullary
thyroid carcinomas (MTCs) (RRZ0.35; 95% CIZ0.16–
0.79), demonstrating, for the first time, to our knowledge,
that the association of obesity with thyroid cancers was
stronger for DTCs. Men did not present a higher risk of
DTCs, probably because the number of cases included was
limited (Engeland et al. 2006). As a matter of fact, several
studies have reported these differences between obese men
and women and their risk of thyroid cancer, allowing
speculation regarding hormone effects or the insufficiency
of male cases analyzed, as thyroid cancer incidence is
higher in women (Pappa & Alevizaki 2013). Other
subsequent studies showed associations of weight, BMI,
body surface area, and/or overweight/obesity and DTCs,
demonstrating that these parameters elevated the risk of
developing these cancers (Brindel et al. 2009, Mijovic et al.
2009, Clero et al. 2010, Leitzmann et al. 2010). However, as
stated by Wolin, Carson, and Colditz in a great review of
the association of obesity and cancers, by the year 2010,
there were still only a few inconclusive studies about the
mechanisms linking overweight/obesity and thyroid
cancer (Wolin et al. 2010), although some authors had
started outlining insulin-related pathways (Haddad et al.
2002, Rezzonico et al. 2008, 2009, Akinci et al. 2009,
Cheng et al. 2010a).
During the current decade, several authors have been
studying the relationship between excessive weight and
cancer and trying to propose mechanisms underlying this
relationship, based on the advances made by molecular
biologists. Kitahara et al. (2011) published three large
pooled analyses of cohort studies on the roles of obesity,
the amount of exercise performed, and waist circumfer-
ence (Kitahara et al. 2012a,b,c) in thyroid cancers. In
these studies, all including very large cohorts, the authors
demonstrated that overweight and obese subjects,
compared with normal-weight subjects, presented a
higher risk of developing thyroid cancers (HRZ1.20;
95% CIZ1.04–1.38 and HRZ1.53; 95% CIZ1.31–1.79
respectively) (Kitahara et al. 2011). In addition, subjects
with a BMI of 25 kg/m2 or more who declared the greatest
amount of physical activity presented a higher risk of
thyroid cancer (HRZ1.34; 95% CIZ1.09–1.64) (Kitahara
et al. 2012a,b). Studying some anthropometric parameters,
Kitahara and colleagues demonstrated that a large waist
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 07/06/2019 12:53:39AM
via free access
 Thematic Review M A Marcello et al.
circumference (over 102 cm in men and over 88 cm in
women) increased the risk of thyroid cancer not only in
men (HRZ1.79; 95% CIZ1.21–2.63) but also in women
(HRZ1.54; 95% CIZ1.05–2.26) (Kitahara et al. 2012c),
indicating that central adiposity might exert an effect on
hormonal balance and metabolism which might increase
the risk of thyroid cancer. In 2012, two other studies with
very large cohorts demonstrated the association of
excessive weight with thyroid cancers as well. Rinaldi
et al. (2012) studied 343 765 females and 146 824 males,
with 566 incident thyroid cancers, demonstrating an
association of obesity with thyroid cancer risk in women
(HR highest versus lowest quintileZ1.41; 95% CIZ1.03–
1.94), but not a significant one for men. Zhao, in a meta-
analysis of five studies, including a total of 809 941
subjects and 5154 thyroid cancer patients, demonstrated
that excessive weight was associated with an increased
risk of thyroid cancers (ORZ1.18; 95% CIZ1.11–1.25).
Both overweight and obesity were risk factors for
thyroid cancers, although overweight represented a
slightly smaller risk than obesity (ORZ1.13; 95%
Endocrine-Related Cancer
CIZ1.04– 1.22 – for overweight and ORZ1.29; 95%
CIZ1.18–1.41 for obesity) (Zhao et al. 2012). During the
same year, our group demonstrated that excessive weight
(BMI O25 kg/m2) was associated with an increased
risk of DTCs (ORZ3.787; 95% CIZ1.12–6.81) and that
this increased risk could be due to the excess calorie
ingestion (ORZ5.89; 95% CIZ3.12–11.10), characterized
by the excessive ingestion of proteins (ORZ4.60; 95%
CIZ1.63–12.95) and carbohydrates (ORZ4.90; 95%
CIZ2.59–9.28) (Marcello et al. 2012a).
In 2013, Kim and colleagues showed that obesity was
not only associated with an increased risk of thyroid
cancers, but could also exert an influence on tumor
presentation. They reported that a 5-kg/m2 increase in
the BMI was associated with PTCs O1 cm (ORZ1.31;
P!0.001), microscopic extrathyroidal invasion (ORZ
1.23; PZ0.006), and advanced tumor/node/metastases
(TNM) stage (ORZ1.30; PZ0.003) (Kim et al. 2013a).
Some other authors have been reinforcing the data on the
relationship between obesity and thyroid cancer, and the
most recent studies have focussed on the possible links for
this association, such as diabetes and/or IR (Shih et al.
2012, Tseng 2013), cytokines (Cheng et al. 2012, 2013,
Di Cristofano 2013), diet (Kim et al. 2013b), anthropo-
metric factors (Kim et al. 2013c), and even genetic variants
that might affect susceptibility to thyroid cancers
(Kitahara et al. 2012a,b). The main results presented in
this section are summarized in Table 1.
http://erc.endocrinology-journals.org q 2014 Society for Endocrinology
DOI: 10.1530/ERC-14-0070 Printed in Great Britain
Obesity and thyroid cancer 21:5 T258
Understanding the underlying mechanisms:
where do we stand?
Five important factors might explain the connection
between excessive weight and thyroid cancer: thyroid
hormones, IR, adipokines, inflammation, and sexual
hormones (Fig. 1), but do we understand how they
interfere with thyroid cells and tissue biology?
Thyroid hormones
Some studies with euthyroid subjects have shown
evidence that regional obesity and a tendency to weight
gain are associated with slight variations in thyroid
function (Knudsen et al. 2005, Fox et al. 2008). A negative
association between BMI and serum free thyroxine (T4)
levels was reported (Knudsen et al. 2005), with lower
T4 levels being associated with fat accumulation (Knudsen
et al. 2005, Alevizaki et al. 2009). A moderate increase in
triiodothyronine (T3) levels observed in obese subjects
(Reinehr et al. 2006, De Pergola et al. 2007, Nannipieri et al.
2009) has been explained by a higher conversion of T4 to
T3 as a compensatory mechanism for fat accumulation
to improve energy expenditure (De Pergola et al. 2007).
Positive associations were also observed between free
T3 level and both waist circumference and BMI in obese
patients (De Pergola et al. 2007). Some cross-sectional
studies in euthyroid subjects demonstrated a positive
association between serum TSH and BMI (Manji et al.
2006, Fox et al. 2008). Potential stimulators of TSH
production, explaining the increase in TSH in obese
patients, include hormonal mediators of adipose tissue,
especially leptin (Rosenbaum et al. 2000, Sari et al. 2003).
Apart from modulating food intake and energy expendi-
ture, leptin acts as a neuroendocrine regulator of the
hypothalamic–pituitary–thyroid axis by regulating the
expression of TRH in the paraventricular nucleus; leptin
secretion by adipose tissue will then be stimulated by TSH
(Menendez et al. 2003, Oge et al. 2005, Feldt-Rasmussen
2007, Santini et al. 2010). Leptin may also affect
deiodinases, activating the T4 to T3 conversion (Zimmer-
mann-Belsing et al. 2003, Reinehr 2010).
In addition to the association between TSH and BMI,
there is a clinical association between higher serum TSH
levels and an increased risk of malignancy in human
thyroid nodules (Fiore & Vitti 2012) and advanced stage of
the disease (McLeod et al. 2013). As TSH is the major
stimulator of thyrocyte proliferation, this hormone could
be directly involved in thyroid carcinogenesis in obese
subjects (Hard 1998). In fact, the binding of TSH to its
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 07/06/2019 12:53:39AM
via free access
 Thematic Review M A Marcello et al. Obesity and thyroid cancer 21:5 T259

Table 1 Summary of observational studies relating excess weight and thyroid cancer risk

References Study design Population studied Main findings

Dal Maso et al. (2000)
Samanic et al. (2004)
Boru et al. (2005)
Engeland et al. (2006)
Brindel et al. (2009)
Endocrine-Related Cancer
Pooled analysis of 2056 female and 417 male patients, The heaviest women and men were at a higher
12 case–control 3358 female and 965 male
studies controls
Cohort study 4 500 700 US male veterans
(3 668 486 whites; 832 214 blacks)
diagnosed as obese
Cohort 1333 severely obese patients
(369 males and 964 females)
Cohort 2 000 947 persons (963 523 men
and 1 037 424 women) 3046 cases
of thyroid cancer
Case–control 219 thyroid cancer cases (195
women/24 men) and 359 controls Highest quartile of BMI before diagnosis: 2.3
(315 women and 44 men)
risk of thyroid cancer (ORZ1.2 and ORZ1.5
respectively)
Weight at diagnosis was a risk factor
(ORZ1.20) in women
BMI at diagnosis increased the risk of thyroid
cancer by 1.2 in women
White and black obese veterans were at a
higher risk of developing thyroid cancer
when compared with non-obese subjects
White: HRZ1.4
Black: HRZ1.9
Thyroid cancer as the second most common
malignancy (18.6% of the malignant cases)
Obese women were at a higher risk of PTCs
(RRZ1.19) or FTCs (RRZ1.63), but at a
lower risk of MTCs (RRZ0.35)
Increased risk only in women
more risk for thyroid cancer
Higher risk in overweight or obese women at

age 18 compared with normal lifelong

Mijovic et al. (2009)
Clero et al. (2010)
Leitzmann et al. (2010)
Kitahara et al. (2011)
Kitahara et al. (2012a,b)
Kitahara et al. (2012c)
Rinaldi et al. (2012)
Zhao et al. (2012)
Marcello et al. (2012a)
Kim et al. (2013a)
weight women (ORZ6.2)
Cross-sectional 253 patients with indeterminate Women !45 years had higher malignancy
FNABs rates when obese (65%) versus 54%
(non-obese)
Pooled analysis 554 cases (65 men and 489 women) Patients with a greater body surface area
and 776 controls presented more risk of thyroid cancer. OR for
womenZ3.97 and for menZ4.06
Cohort 484 326 men and women from the Higher risk in obese compared with normal-
USA, 352 cases of thyroid cancer weight men (HRZ1.89), especially for PTCs
(ORZ1.49)
Pooled analysis of 413 979 women and 434 953 men. Overweight and obesity compared with
five prospective 768 women and 388 men with normal-weight increased the risk of thyroid
studies thyroid cancer cancer (HRZ1.20 and HRZ1.53 respectively)
Pooled analysis of 362 342 men, 312 149 women. Subjects with excess weight with the greatest
five prospective 308 men and 510 women with amount of physical activity presented a
studies a primary thyroid cancer higher risk of thyroid cancer (HRZ1.34)
Cohort 125 347 men and 72 363 women. Large waist circumference increased the risk of
106 men and 105 women with thyroid cancer not only in men (HRZ1.79)
thyroid cancer but also in women (HRZ1.54)
Cohort 343 765 female and 146 824 male Association of obesity with thyroid cancer risk
participants 566 thyroid cancer in women (HRZ1.41)
patients
Meta-analysis 809 941 subjects and 5154 thyroid Excessive weight (overweight and obesity)
cancer patients increased the risk of thyroid cancers
(ORZ1.18)
When the groups were separated:
Overweight: ORZ1.13
Obese: ORZ1.29
Case–control 115 DTC cases and 103 controls Excessive weight increased the risk of DTCs by
more than three times (ORZ3.78)
Retrospective 2057 patients with PTCs Increase in the BMI was associated with
PTCs O1 cm (ORZ1.31), microscopic
extrathyroidal invasion (ORZ1.23), and
advanced TNM stage (ORZ1.30)

PTC, papillary thyroid cancer; HR, hazard ratio; OR, odds ratio; FNAB, fine needle aspiration biopsy; FTC, follicular thyroid carcinoma; MTC,
medullary thyroid carcinoma.

http://erc.endocrinology-journals.org q 2014 Society for Endocrinology Published by Bioscientifica Ltd.

DOI: 10.1530/ERC-14-0070 Printed in Great Britain
Downloaded from Bioscientifica.com at 07/06/2019 12:53:39AM
via free access
 Thematic Review M A Marcello et al.
TSH
Thyroid
cancer
Estrogen
Adipokines Inflammation
Obesity
Insulin
resistance
Figure 1
Endocrine-Related Cancer
Schematic representing the main factors that might explain the relation-
ship between obesity and thyroid cancer and the possible interactions
among them.
receptor (TSHR) increases the intracellular levels of cAMP
and activates proliferation pathways, including PI3K–AKT
and RAS–BRAF pathways (Takada et al. 1990, Xing 2013).
Mitogenic effects of TSH on follicular thyroid cells have
been demonstrated using in vitro and animal models (Farid
et al. 1994, Zielke et al. 1999, Rivas & Santisteban 2003).
TSH also interacts with other growth factors such as
insulin (Rapp et al. 2006). In IR, a clinical condition
frequently present in obesity, insulin stimulates TSH
production promoting proliferation of thyroid cancer
cells (Hard 1998, Hursting et al. 2008).
Based on the important role of TSH in thyroid cell
proliferation, a recent study has evaluated the serum TSH
levels in two mouse groups that spontaneously develop
thyroid cancer: one fed on a high-fat diet and another on
a low-fat diet. However, no significant difference in serum
TSH levels between the two groups was found, indicating
that the tumor growth and anaplastic change observed in
the obese mouse group occur independent of alterations of
TSH level (Kim et al. 2013b).
Clinical studies also did not show an association
between serum TSH and thyroid cancer. Two prospective
studies evaluated serum TSH levels in obese and non-obese
subjects. One study showed an increased risk of thyroid
cancer in obese subjects, but this risk was unrelated to serum
TSH levels (PZ0.831) (Han et al. 2013). Another study,
http://erc.endocrinology-journals.org q 2014 Society for Endocrinology
DOI: 10.1530/ERC-14-0070 Printed in Great Britain
Obesity and thyroid cancer 21:5 T260
aiming to evaluate the prevalence of thyroid nodules in
morbidly obese women, showed significantly higher TSH
levels in this group when compared with a group of normal-
weight and/or slightly overweight women (P!0.0001), but
the prevalence of thyroid nodules was significantly lower in
obese women (P!0.0001) (Cappelli et al. 2012).
In summary, the existing data neither support nor
rule out the involvement of TSH hormone as an etio-
pathogenic element in the association between obesity
and thyroid cancer.
IR and the role of IGF1
Back in 1992, Vassilopoulou-Sellin and colleagues
reported the case of a girl with thyroid cancer and severe
IR also associated with acanthosis nigricans (Vassilopou-
lou-Sellin et al. 1992), but it was only after the year 2000
that studies relating IR and thyroid cancer started to
appear. IR is a condition in which the body produces
sufficient insulin to take up and use glucose, but the
sensitivity to this insulin is impaired or selective, thus
causing pancreatic b-cells to upregulate insulin pro-
duction as a compensatory mechanism, which results in
hyperinsulinemia. There are several studies linking hyper-
insulinemia and the risk and/or aggressiveness of color-
ectal, pancreatic, liver, esophageal, breast, and
endometrial cancers (Gunter et al. 2008, Arcidiacono
et al. 2012, Inoue & Tsugane 2012, Qiu et al. 2012, Zhan
et al. 2013). Thyroid nodules follow the same trend
(Rezzonico et al. 2008). Rezzonico and colleagues studied
111 euthyroid women divided into four groups: G1,
subjects with IR and obesity; G2, obese women without
IR; G3, normal-weight subjects without IR; and G4,
normal-weight women without IR. Subjects with IR (G1
and G3) presented a higher frequency of thyroid nodules
(50 and 61% respectively) when compared with members
of groups G2 and G4 (23.8 and 16.1% respectively). In
addition, about 30% of the subjects in G1 and G3
presented with larger nodules (O1 cm), whereas only
5 and 7% of the subjects in G2 and G4 presented with such
nodules (Rezzonico et al. 2008). In order to verify if IR
would specifically be increased in DTC patients, apart from
other thyroid nodules, the same group further investi-
gated 20 DTC women and 20 euthyroid subjects,
observing that 50% of DTC patients but only 10% of the
control group presented with IR; they suggested that IR
could be an important risk factor for DTCs (Rezzonico et al.
2009). Not only the Argentinean group has reported the
association of IR with thyroid nodules, but other studies in
Turkish and Italian populations have also shown that
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 07/06/2019 12:53:39AM
via free access
 Thematic Review M A Marcello et al.
nodular thyroid disease might be related to higher HOMA-
IR (an index to measure IR) and metabolic syndrome
(MetS) (Ayturk et al. 2009, Yasar et al. 2011, Rendina et al.
2012, Balkan et al. 2014). Rezzonico et al. (2011)
investigated the effect of metformin, an anti-diabetic
medication, on thyroid hyperplasia. The authors followed
66 women with hyperplasia and IR for 6 months and
divided them into four groups: G1 (nZ14), for those who
received only metformin as treatment; G2 (nZ18),
subjects who received both L-T4 and metformin; G3
(nZ19), patients treated only with L-T4; and G4 (nZ15),
women who did not receive any kind of medication.
After 6 months, subjects in G1 and G2 presented a
significant reduction in nodular size, while the G3 and
G4 patients did not present with size-altered nodules
(Rezzonico et al. 2011). These results reinforced the
importance of IR in nodular thyroid disease and also
provided evidence that IR diagnosis and its concurrent
treatment may be beneficial. But what could be the
molecular mechanisms involved?
The insulin signal transduction is dependent on two
Endocrine-Related Cancer
insulin receptors: IR-A (which has greater affinity for
insulin-like growth factors 1 and 2 (IGF1 and IGF2),
although it also recognizes insulin), and IR-B (insulin
specific) (Artim et al. 2012). Blood glucose homeostasis in
healthy subjects requires a very delicate adjustment of
insulin production by pancreatic b-cells and insulin-
mediated glucose uptake in tissues (Kern et al. 1990,
Dimitriadis et al. 2008). The first step in insulin receptor
activation results in the phosphorylation and recruitment
of several molecules which ultimately lead to the down-
stream upregulation of the AKT/mTOR/PI3K and ERK/
RAS/MAPK pathways, the two main signaling cascades
involved in cancer proliferation and survival (Guo 2013).
Hence, insulin receptors are also directly involved in the
expression and effects of IGF1 and IGF2, both already
related to thyroid cancers (Vella et al. 2001).
The stimulation of the IGF1 axis may cause different
effects, as it is involved in inflammation, IR, diabetes, and
cancer (Djiogue et al. 2013). IGF1 is a protein with a high
level of conservation through species, probably due to its
participation in vital processes such as the regulation of
cell proliferation according to food availability (Longo &
Finch 2003). Like TSH, IGF1 is also essential for thyroid
cell growth and thyroid formation (Eggo et al. 1990). There
are several reports associating the overexpression of IGF1
and IGF1 receptor (IGF1R) with thyroid enlargement
and goiter development, supporting the hypothesis of an
effect of IGF1 on thyroid cells (Cheung & Boyages 1997,
Clement et al. 2001, Kimura et al. 2001, Volzke et al. 2007).
http://erc.endocrinology-journals.org q 2014 Society for Endocrinology
DOI: 10.1530/ERC-14-0070 Printed in Great Britain
Obesity and thyroid cancer 21:5 T261
In a recent report, Ock and colleagues have shown that in
the absence of the IGF1R, neither TSH-induced thyrocyte
hypertrophy occurs nor is goitrogen administration
effective in promoting thyroid hypertrophy. The authors
also observed that short-term treatment using IGF1
induces AKT activation, which may induce the TSH-
stimulated IGF1R/mTOR/S6 signaling pathways in
cultured thyrocytes (Ock et al. 2013).
While IGF1 is related to many events beyond IR, IGF2
plays its role through its binding to insulin receptors and
the participation in the above-mentioned pathways
(Djiogue et al. 2013). IGF2 receptor (IGF2R) may also play
an important role in human cancers. In fact, mutations that
cause loss of function of IGF2R gene have already been
reported for breast, ovarian, lung, oral epithelial, and
squamous cell carcinomas (Cheng et al. 2009).
Inflammation
For many years, adipose tissue was considered as a measly
deposit of fat in our body. Today, adipose tissue is under-
stood as a dynamic gland and the diverse range of molecules
produced by adipocytes includes proteins involved in lipid
metabolism, insulin sensitivity, the alternative complement
system, vascular hemostasis, blood pressure regulation,
angiogenesis, the regulation of energy balance, and acute-
phase response, as well as inflammation (Trayhurn & Wood
2004). Adipose tissue may be considered a component of the
immune system, as it expresses receptors for many immune
molecules (Fruhbeck 2006, Schaffler & Scholmerich 2010) in
addition to producing immune molecules that can be
released into circulation. These molecules may provide
favorable conditions that support a pro-tumor immune
microenvironment, indicating that obesity-dependent
inflammation may be the link between obesity and cancer.
But what are these molecules? How do they associate with
obesity and cancer?
In addition to adipocytes, adipose tissue contains
stromovascular cells that are active producers of molecules
that may influence the immune response. Aiming to
characterize changes that happen in adipose tissue with
increasing adiposity, Weisberg and colleagues profiled the
transcript expression in adipose tissue from several groups
of mice. They found that the expression of 1304
transcripts correlated significantly with body mass and
many of these transcripts were characteristic of macro-
phages. In fact, immunohistochemical analysis of adipose
tissue revealed that the percentage of cells expressing
macrophage markers was significantly and positively
correlated with both adipocyte size and body mass,
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 07/06/2019 12:53:39AM
via free access
 Thematic Review M A Marcello et al.
indicating an association between macrophage infiltration
and development of obesity (Weisberg et al. 2003).
It has been proposed that pro-inflammatory
T-lymphocytes are present in visceral adipose tissue and
may contribute to local inflammatory cell activation
before the appearance of macrophages, indicating that
these cells could play an important role in the initiation
and perpetuation of adipose tissue inflammation
(Kintscher et al. 2008). Both M1 and M2 macrophages
can be found in adipose tissue. M1 macrophages are
stimulated by IFNg or lipopolysaccharide and are able
to produce pro-inflammatory cytokines. Conversely, M2
macrophages are related to humoral immune response
and are able to produce anti-inflammatory cytokines, such
as IL10 (Gordon & Taylor 2005). In this scenario, local
hypoxia in obesity may promote the M2 to M1 switching
(Catalan et al. 2013). Interestingly, these macrophages are
responsible for almost all adipose tissue TNFa (TNF)
expression and significant amounts of iNOS (NOS2) and
IL6 expression (Weisberg et al. 2003).
TNFa is a cytokine that is believed to mediate tumor
Endocrine-Related Cancer
cytotoxicity and is a potent inducer of new blood vessel
growth (angiogenesis) (Leibovich et al. 1987). Liu et al.
(2012) demonstrated that diet-induced obesity produces
an elevation in colonic TNFa levels and instigates a
number of alterations in the key components within the
Wnt signaling pathway, which have a pro-transforma-
tional nature, indicating that the Wnt pathway could be
the mechanism by which obesity increases the risk of
colorectal cancer. TNFa has an anti-proliferative action in
a human PTC cell line through a receptor-mediated
mechanism (Pang et al. 1994). Exposure of PTC cell lines
to TNFa resulted in the development of progressively
increasing loss of the TNFa-induced anti-proliferation,
termed resistance (Pang et al. 1996). Probably, the high
TNFa exposure provided by obesity may induce TNFa
resistance that facilitates thyroid tumor progression.
IL6 is a pleiotropic cytokine. It interferes with growth
and differentiation and some results indicate that IL6
might increase the risk of certain cancers such as those
that originate from breast, liver, prostate, colon, and
esophagus (Ghosh & Ashcraft 2013). However, the role of
IL6 in thyroid cancer is still confusing. Using human
thyroid cancer-derived cell lines, Couto and colleagues
determined that IL6/gp130/JAK signaling is responsible
for STAT3 activation. STAT3 deficiency led to more
proliferative and larger tumors, indicating that, at least
in the context of thyroid cancer, STAT3 is paradoxically a
negative regulator of tumor growth (Couto et al. 2012). An
anaplastic thyroid cancer cellline secretes high levels of
http://erc.endocrinology-journals.org q 2014 Society for Endocrinology
DOI: 10.1530/ERC-14-0070 Printed in Great Britain
Obesity and thyroid cancer 21:5 T262
IL6 (Chang et al. 2003). Despite only a few results linking
IL6 directly to thyroid cancer, IL6 may be important for
the inflammatory microenvironment in thyroid carcino-
genesis, and this microenvironment has already been
proven to have an influence on DTC development and
progression (Lumachi et al. 2010, Cunha et al. 2013).
Adipokines: the link among obesity, IR, and
inflammation?
Our body produces cytokines in order to respond to
aggressive or non-proper features. These molecules influ-
ence activation, growth, and differentiation of several
different target cells. Adipokines or adipocytokines are a
subset of cytokines produced by the adipose tissue (Cunha
et al. 2013). They are involved not only in immune
responses, but also in the regulation of appetite and energy
balance, insulin sensitivity, angiogenesis, blood pressure
regulation, and lipid metabolism (Kwon & Pessin 2013).
Obesity, per se, is already related to an inflammatory state,
but the presence of IR might enhance this inflammation,
by decreasing the production of anti-inflammatory
molecules, such as adiponectin, and producing pro-
inflammatory adipokines, such as leptin and resistin,
which will lead to the stimulation or blockage of several
other immunological molecules, thus, promoting an
optimal environment for tumor growth and development
(Catalan et al. 2013).
Adiponectin is an adipokine with strong anti-
inflammatory properties. It is produced exclusively by
adipocytes; pro-inflammatory factors such as TNFa, IL6,
and ROS can exert a regulatory effect on adiponectin
expression (Li et al. 2009). This adipokine is able to
improve insulin sensitivity, influence cell proliferation,
and regulate the balance of anti- and pro-inflammatory
molecules and cells, such as TNFa, IL10, macrophages,
T-cells, and NK-cells, always aiming to control inflam-
mation (Yokota et al. 2000, Kumada et al. 2004, Takemura
et al. 2007). In order to develop these functions,
adiponectin binds to two different receptors: AdipoR1
and AdipoR2. These receptors have an important role in
improving the insulin signaling on target cells, through
the increase in AMPK activity and PPARa and PGCa, also
indirectly leading to a reflex on the AKT/mTOR/PI3K and
MAPK pathways, well known due to their regulation of cell
proliferation (Hall et al. 2009). In addition, during this
process, adiponectin also influences the immune system
through NFkB regulation (Obeid & Hebbard 2012). Owing
to its complex anti-proliferative and inflammation-
restraining functions, adiponectin has been suggested to
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 07/06/2019 12:53:39AM
via free access
 Thematic Review M A Marcello et al.
have anti-neoplastic properties in some types of cancers.
In recent years, several authors have been demonstrating
association of adiponectin with breast, endometrial,
prostate, colorectal, liver, pancreatic, and gastric cancers,
as well as some hematological types of leukemia,
lymphoma, and myeloma (Obeid & Hebbard 2012). In
2011, Mitsiades and colleagues demonstrated that adipo-
nectin levels are in serum inversely correlated with DTCs,
exerting a protective effect against the development of this
cancer. Furthermore, the authors demonstrated that
thyroid tissues express ADIPOR1 and ADIPOR2, facilitat-
ing the entrance and the functioning of adiponectin in the
thyroid (Mitsiades et al. 2011), indicating that adiponectin
is not only expressed, but also functional in thyroid cells.
Another recent study has demonstrated that adiponectin
receptors might be important for DTCs. Comparing tissues
of primary PTCs with metastatic tissues, Cheng et al.
(2013) reported that 27% of primary tumors expressed
ADIPOR1 and 47% expressed ADIPOR2. When tissues
were negative for both receptors, tumors were significantly
associated with extrathyroidal invasion, multicentricity,
Endocrine-Related Cancer
and higher TNM stage, indicating that the expression of
adiponectin receptors is associated with a better prognosis.
Leptin is another adipokine predominantly secreted
by adipose tissue, although it can also be produced by
skeletal muscle, stomach, and plasma (Piya et al. 2013).
Leptin is structurally similar to other cytokines, such as
IL2, IL6, and granulocyte-colony-stimulating factor
(G-CSF), a characteristic that makes leptin capable of
participating in similar cellular and organic processes,
such as the control of food intake through satiety
sensation, regulation of energy expenditure, the acti-
vation of monocytes and macrophages, stimulation of
VEGF, angiogenesis, cell proliferation, and the suppres-
sion of anti-inflammatory cytokines (Kwon & Pessin
2013). The induction of leptin responses and effects
involves its binding to leptin receptor b (ObR), leading
to the activation of intracellular signals through JAK2,
STAT3, and AMPK (Kwon & Pessin 2013). These molecules
will then regulate several pathways of pivotal importance
to cancers, such as the AKT/mTOR/PI3K and ERK/MAPK
pathways, involved in cell growth and survival; COX2,
IL1, and NFkB, related to inflammation; and VEGFs,
involved in angiogenesis (Surmacz 2013). Thus, leptin
interacts with several factors that participate in diverse
carcinogenic stages, and its relationship with breast,
prostate, colorectal, hepatocellular, pancreatic, and lung
cancers, as well as thyroid cancer, has consistently been
demonstrated in the literature (Dutta et al. 2012, Vansaun
2013). Concerning thyroid cancers, and more specifically
http://erc.endocrinology-journals.org q 2014 Society for Endocrinology
DOI: 10.1530/ERC-14-0070 Printed in Great Britain
Obesity and thyroid cancer 21:5 T263
DTCs, leptin and OBR (LEPR) expression were first
demonstrated by Cheng et al. (2010b), who found them
associated with a high risk of lymph node metastases.
Other groups have also reported the involvement of leptin
in the clinical phenotype of DTCs, and it has been
suggested that leptin may affect the migration of thyroid
cells, collaborating for a worse prognosis and metastasis
formation (Cheng et al. 2010a, 2011, 2012, Kim et al.
2013b, Zhang et al. 2013).
Resistin is an adipokine produced by human mono-
cytes and macrophages, as well as adipocytes (Kwon &
Pessin 2013). Its name is derived from the fact that it was
primarily related to IR by the suppression of insulin-
mediated signaling in rat adipocytes (Steppan et al. 2005),
but in humans this association is not always present.
Actually, in humans, resistin has diverse functions in
proliferative, anti-apoptotic, pro-inflammatory, and pro-
angiogenic events (Hlavna et al. 2011, Piya et al. 2013).
Inflammatory cytokines such as IL1b, IL6, TNFa, and LPS
may induce resistin expression, but, conversely, resistin has
been demonstrated to stimulate the production of IL6 and
TNFa through the NFkB signaling pathway (Bokarewa et al.
2005). In addition to its action on the immune system
molecules, resistin can also bind to TLR4, activating JNK
and p38 MAPK, to induce IR (Benomar et al. 2013). Owing
to its ability to regulate immune molecule production and
its indirect regulatory effect on the MAPK pathway and
other proliferative events, resistin has been investigated in
human cancers. Its expression has been linked to the
increased proliferation of prostate cancer by the stimu-
lation of the AKT/mTOR pathway (Kim et al. 2011). Resistin
has also been linked to breast, endometrial, colorectal,
hepatocellular, pancreatic, and lung cancers (Hlavna et al.
2011, Jiang et al. 2012, Dalamaga et al. 2013, Duan et al.
2013, Kuo et al. 2013, Stewart et al. 2013).
Preliminary data from our group indicate that quanti-
fication of serum leptin, adiponectin, resistin, and ghrelin
might provide an excellent tool for diagnosis malignancy in
thyroid nodules (Marcello et al. 2012b). We observed that
DTC patients had lower levels of adiponectin in serum
(2.46G0.84) when compared with patients with benign
nodules (3.03G1.73; P!0.0001). Leptin, on the other
hand, was higher in DTCs (9.82G0.70) than in benign
cases (1.95G0.67; P!0.0001). Similarly, resistin levels were
higher in patients with DTCs (14.80G1.53) than in
patients with benign nodules (1.99G0.66; P!0.0001).
Ghrelin levels differed between DTC (84.56G24.02) and
benign patients (133.57G18.00; P!0.0001). The receiver
operating characteristic (ROC) curves for all the cytokines
showed that the concentrations of serum adiponectin,
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 07/06/2019 12:53:39AM
via free access
 Thematic Review M A Marcello et al. Obesity and thyroid cancer 21:5 T264

leptin, resistin, and ghrelin distinguished benign from
malignant nodules with 76, 100, 100, and 96% accuracy
respectively (Marcello et al. 2012b; Fig. 2). In a deeper
investigation, we were able to show that these cytokines
helped to discriminate follicular patterned lesions. The
follicular variant of PTC (FVPTC) could be distinguished
from follicular adenomas (FA) by adiponectin (P!0.05),
leptin (P!0.001), and ghrelin levels; and from goiters by
serum leptin (P!0.001), resistin (P!0.001), and ghrelin
(P!0.001) levels. FA differed from follicular carcinomas
and the classic PTCs (CPTCs) with respect to leptin
(P!0.001) and ghrelin (P!0.001) levels. The CPTCs
differed from FA with respect to leptin (P!0.01) and
ghrelin (P!0.01) levels and from goiters with regard to
leptin (P!0.001), resistin (P!0.001), and ghrelin
(P!0.01) levels. These results indicate that the peripheral
blood measurement of serum adiponectin, leptin, resistin,
and ghrelin levels, using simple and reliable ELISAs, may
represent a new alternative approach to the diagnosis and
management of thyroid nodules MA Marcello, A Calixto,
LL Cunha, MB Martins, AC Vasques, BC Geloneze and
LS Ward, unpublished observations).
Gender
The relationship between thyroid cancers and gender is
long known, as all the available literature have reported a
higher thyroid cancer incidence among women. In fact,

1.00 d 10
Adiponectin

Serum concentrations (µg/ml)

0.80 8

0.60 6
Sensitivity

0.40 4
Endocrine-Related Cancer

0.20 2
Adiponectin

0.00 0
0.0 0.2 0.4 0.6 0.8 1.0 DTC Benign Controls
specificity
Specificity

d
1.00 1.00
Leptin
Serum concentrations (ng/ml)

0.80 0.80
Sensitivity

0.60 0.60

0.40 0.40

0.20 0.20
Leptin

0.00 0.00
0.0 0.2 0.4 0.6 0.8 1.0 DTC Benign Controls
specificity
Specificity

d
1.00 60
Resistin
Serum concentrations (ng/ml)

50
0.80

40
Sensitivity

0.60
30
0.40
20

0.20
10
Resistin

0.00 0
0.0 0.2 0.4 0.6 0.8 1.0 DTC Benign Controls
specificity
Specificity

Figure 2
Box plots showing the serum concentrations of the adipokines studied and ROC curves showing the very high specificity and sensitivity of these adipokines.

http://erc.endocrinology-journals.org q 2014 Society for Endocrinology Published by Bioscientifica Ltd.

DOI: 10.1530/ERC-14-0070 Printed in Great Britain
Downloaded from Bioscientifica.com at 07/06/2019 12:53:39AM
via free access
 Thematic Review M A Marcello et al.
the Brazilian National Cancer Institute (INCA) estimates
that 2.9% of the new cases of cancer (do not include skin
cancers – not melanoma) affecting women in Brazil in
2014 will correspond to thyroid cancers. This incidence
rate drops to only 0.4% in men (INCA 2014). In a recent
review, Pellegriti et al. (2013) have shown that the
incidence rates of thyroid cancer among women have
grown considerably more than that for men in countries
such as Denmark, Finland, France, Israel, Italy, Japan,
Spain, Switzerland, United Kingdom, and the USA.
In 1979, considering the follow-up of 600 patients,
Cady et al. (1979) observed that women who had thyroid
cancers before menopause presented with less aggressive
tumors, in comparison with women diagnosed after
menopause. Several subsequent studies with large cohorts
have proven a strong association of thyroid diseases and,
more specifically, thyroid cancers with female gender;
in addition, many reports describe differences in thyroid
cancer comportment in men and women (McTiernan et al.
1984, Ron et al. 1987, Galanti et al. 1996, Truong et al.
2005, Leux et al. 2012). But how do estrogen and/or
Endocrine-Related Cancer
reproductive hormones influence thyroid cancers?
Even though the thyroid carcinogenesis model that
is widely accepted and consolidated indicates a major role
of mutations in members of the MAPK and PI3K/AKT
pathways, accumulating evidence indicates that these
inherited or somatic alterations are not sufficient to
characterize tumors, and the microenvironment where
this tumor is inserted is of extreme importance for tumor
phenotypes (Cunha et al. 2013). Estrogen might influence
this microenvironment.
Banu et al. (2001) first demonstrated that both
testosterone and estradiol had effects on the proliferation
of human PTC and FTC cell cultures and that these two
cell lines presented receptors (ERa and ERb) for the studied
hormones. These receptors are responsible for the func-
tions of estrogen, and they have opposite functions with
respect to cell proliferation and survival. ERa acts as
a stimulator of proliferation and suppressor of apoptosis,
whereas ERb acts as an adjuvant for cell differentiation and
stimulates apoptosis (Di Vito et al. 2011). Investigations
with thyroid cancer cell lines and also some human
thyroid tumors have demonstrated the expression of ERs
in thyroid tumor cells, both neoplastic and non-neoplastic,
indicating that thyroid cells are likely to experience effects
of estrogen or ERs (Lee et al. 2005, Zeng et al. 2007, 2008).
In fact, the administration of estrogen has been associated
with thyroid cell growth and proliferation and also with
some changes in other markers of proliferation, growth,
and angiogenesis, demonstrating not only the
http://erc.endocrinology-journals.org q 2014 Society for Endocrinology
DOI: 10.1530/ERC-14-0070 Printed in Great Britain
Obesity and thyroid cancer 21:5 T265
intracellular role of estradiol and ERs, but also their role
in the transcription of other genes (Tangjitgamol et al.
2005, Zeng et al. 2007, Chen et al. 2008, Ranks et al. 2009,
Kavanagh et al. 2010, Kumar et al. 2010, Rajoria et al. 2010,
Kamat et al. 2011). A recent study has demonstrated
crosstalk between ER and PPARg, indicating that levels of
expression of ERa (ESR1) and ERb (ESR2) are related to
PPARg levels in the cell. Chu and colleagues demonstrated
that there is an inverse relationship between PPARg and
ERs. Also, these authors demonstrated that while cells that
presented ERa activation were able to control the
inhibitory effect of PPARg on cellular functions, activation
of ERb led to apoptosis. When the interaction between ERb
and PPARg was tested, molecules such as caspase 3 and
apoptosis-inducing factor were expressed, indicating that
the crosstalk between ERb and PPARg could be a target for
DTC therapy (Chu et al. 2013).
It is certainly important to understand these complex
molecular mechanisms, but how do they relate to obesity
and obesity-related cancers?
Although the molecular relationship between estro-
gen and thyroid cancers has been largely investigated, the
literature is a lot scarcer when obesity is involved. The
relationship between obesity and waist circumference is a
crucial point for the understanding of the relationships
between obesity, estrogen and cancer. The National
Institute of Health (NIH) in the USA, following the WHO
recommendations, considers that overweight or obese
subjects presenting waist circumference over 102 cm
(men) and over 88 cm (women) are at an extremely high
risk of developing several types of disease, especially the
ones related to metabolism of glucose (WHO 2011). After
the first sexual differentiation, during the teenage years,
two other very important aspects also contribute to body fat
distribution: reproductive status and age, which can be
connected in women. Pregnancy, for example, is associated
with gains in central and visceral adiposity post partum,
augmenting women’s waist circumference and dislocating
fat accumulation to the upper part of the body (Lassek &
Gaulin 2006). In the same way, menopause is associated
with an increase in fat mass and a redistribution of fat to the
abdominal area, indicative of two important protagonists:
hormones and aging (Toth et al. 2000). Although steroid
hormones may have more influence in women than in
men, the age factor is of extreme importance for both.
Ford et al. (2003) demonstrated that the waist circum-
ference increases with the age in both genders, indicating
that after a certain moment in time, waist changes will
be nearly equivalent and the differences between men
and women will disappear. Kitahara et al. (2012c)
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 07/06/2019 12:53:39AM
via free access
 Thematic Review M A Marcello et al.
described an influence of the large waist circumferences
on DTCs, but this is the first association of waist
circumference with thyroid cancers. This association
might be justified by the fact that fat accumulation,
specifically in the abdominal region, might lead to a
hypertrophy of adipocytes or even impair their functions.
Adipose tissue is involved in many vital processes,
including insulin sensitivity, angiogenesis, regulation of
energy balance, activation of the complement system, and
responses such as inflammation (Trayhurn & Wood 2004).
Although these processes have their own molecular
pathways, they involve the same molecules through
which obesity and adipose tissue might exert their role
in carcinogenesis, not only affecting MAPK and PI3K or
even insulin pathways, but also recruiting local inflam-
matory responses that could result in disease formation
and progression.
Summary/conclusions
Endocrine-Related Cancer
In this review, we attempted to summarize and discuss
available data in order to better understand obesity-related
thyroid cancers. Although recent reports have described a
slight decrease in the prevalence of obesity, these data
might be considered with caution, as methodologies for the
evaluation of these data are different from the ones used in
the past. Furthermore, the incidence of thyroid cancers is
still rising and a better characterization of the relationship
between obesity and thyroid cancers could help in the
establishment of new preventive measures and also in
identification of new specific targets for cancer therapy,
improving not only the quality of health services but also
patients’ quality of life, which remains our main goal.
Declaration of interest
The authors declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of the review.
Funding
We thank the National Council for Scientific and Technological Develop-
ment (CNPq) – Brazil for the grants 141299/2011-8 and 475673/2013-1,
which allowed the realization of this paper.
Author contribution statement
All authors of this review have directly participated in the planning,
analysis, and writing of the article. All authors of this review have read and
approved the final version submitted.
http://erc.endocrinology-journals.org q 2014 Society for Endocrinology
DOI: 10.1530/ERC-14-0070 Printed in Great Britain
Obesity and thyroid cancer 21:5 T266
Acknowledgements
We thank Etna Macário of the Faculty of Medical Sciences for her valuable
suggestions and insights in the English review. We also thank Murilo
Meneghetti for his help with the tables and figures.
References
Agate L, Lorusso L & Elisei R 2012 New and old knowledge on differentiated
thyroid cancer epidemiology and risk factors. Journal of Endocrinological
Investigation 35 3–9.
Akinci M, Kosova F, Cetin B, Aslan S, Ari Z & Cetin A 2009 Leptin levels
in thyroid cancer. Asian Journal of Surgery 32 216–223. (doi:10.1016/
S1015-9584(09)60397-3)
Albanes D 1987 Caloric intake, body weight, and cancer: a review. Nutrition
and Cancer 9 199–217. (doi:10.1080/01635588709513929)
Alevizaki M, Saltiki K, Voidonikola P, Mantzou E, Papamichael C &
Stamatelopoulos K 2009 Free thyroxine is an independent predictor
of subcutaneous fat in euthyroid individuals. European Journal of
Endocrinology 161 459–465. (doi:10.1530/EJE-09-0441)
Arcidiacono B, Iiritano S, Nocera A, Possidente K, Nevolo MT, Ventura V,
Foti D, Chiefari E & Brunetti A 2012 Insulin resistance and cancer risk:
an overview of the pathogenetic mechanisms. Experimental Diabetes
Research 2012 789174. (doi:10.1155/2012/789174)
Artim SC, Mendrola JM & Lemmon MA 2012 Assessing the range of kinase
autoinhibition mechanisms in the insulin receptor family. Biochemical
Journal 448 213–220. (doi:10.1042/BJ20121365)
Ayturk S, Gursoy A, Kut A, Anil C, Nar A & Tutuncu NB 2009 Metabolic
syndrome and its components are associated with increased thyroid
volume and nodule prevalence in a mild-to-moderate iodine-
deficient area. European Journal of Endocrinology 161 599–605.
(doi:10.1530/EJE-09-0410)
Balkan F, Onal ED, Usluogullari A, Tuzun D, Ozdemir D, Inancli SS, Ersoy R
& Cakir B 2014 Is there any association between insulin resistance and
thyroid cancer?: a case control study Endocrine 45 55–60. (doi:10.1007/
s12020-013-9942-x)
Banu KS, Govindarajulu P & Aruldhas MM 2001 Testosterone and
estradiol have specific differential modulatory effect on the prolifer-
ation of human thyroid papillary and follicular carcinoma cell lines
independent of TSH action. Endocrine Pathology 12 315–327.
(doi:10.1385/EP:12:3:315)
Begg L, Kuller LH, Gutai JP, Caggiula AG, Wolmark N & Watson CG 1987
Endogenous sex hormone levels and breast cancer risk. Genetic
Epidemiology 4 233–247. (doi:10.1002/gepi.1370040402)
Benomar Y, Gertler A, De Lacy P, Crepin D, Hamouda HO, Riffault L &
Taouis M 2013 Central resistin overexposure induces insulin resistance
through Toll-like receptor 4. Diabetes 62 102–114. (doi:10.2337/
db12-0237)
Bokarewa M, Nagaev I, Dahlberg L, Smith U & Tarkowski A 2005 Resistin,
an adipokine with potent proinflammatory properties. Journal of
Immunology 174 5789–5795. (doi:10.4049/jimmunol.174.9.5789)
Boru C, Silecchia G, Pecchia A, Iacobellis G, Greco F, Rizzello M & Basso N
2005 Prevalence of cancer in Italian obese patients referred for
bariatric surgery. Obesity Surgery 15 1171–1176. (doi:10.1381/
0960892055002284)
Brindel P, Doyon F, Rachedi F, Boissin JL, Sebbag J, Shan L, Chungue V,
Bost-Bezeaud F, Petitdidier P, Paoaafaite J et al. 2009 Anthropometric
factors in differentiated thyroid cancer in French Polynesia:
a case–control study. Cancer Causes & Control 20 581–590.
(doi:10.1007/s10552-008-9266-y)
Brito JP, Morris JC & Montori VM 2013 TOO MUCH MEDICINE. Thyroid
cancer: zealous imaging has increased detection and treatment of low
risk tumours. BMJ 347. (doi:10.1136/bmj.f4706)
Cady B, Sedgwick CE, Meissner WA, Wool MS, Salzman FA & Werber J 1979
Risk factor analysis in differentiated thyroid cancer. Cancer 43 810–820.
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 07/06/2019 12:53:39AM
via free access
 Thematic Review M A Marcello et al.
(doi:10.1002/1097-0142(197903)43:3!810::AID-CNCR2820430306
O3.0.CO;2-B)
Cappelli C, Pirola I, Mittempergher F, De Martino E, Casella C, Agosti B,
Nascimbeni R, Formenti A, Rosei EA & Castellano M 2012 Morbid
obesity in women is associated to a lower prevalence of thyroid
nodules. Obesity Surgery 22 460–464. (doi:10.1007/s11695-011-0410-5)
Catalan V, Gomez-Ambrosi J, Rodriguez A & Fruhbeck G 2013 Adipose
tissue immunity and cancer. Frontiers in Physiology 4 275. (doi:10.3389/
fphys.2013.00275)
Chang JW, Yeh KY, Shen YC, Hsieh JJ, Chuang CK, Liao SK, Tsai LH &
Wang CH 2003 Production of multiple cytokines and induction of
cachexia in athymic nude mice by a new anaplastic thyroid carcinoma
cell line. Journal of Endocrinology 179 387–394. (doi:10.1677/
joe.0.1790387)
Chen GG, Vlantis AC, Zeng Q & van Hasselt CA 2008 Regulation of
cell growth by estrogen signaling and potential targets in thyroid
cancer. Current Cancer Drug Targets 8 367–377. (doi:10.2174/
156800908785133150)
Chen AY, Jemal A & Ward EM 2009 Increasing incidence of differentiated
thyroid cancer in the United States, 1988–2005. Cancer 115 3801–3807.
(doi:10.1002/cncr.24416)
Cheng I, Stram DO, Burtt NP, Gianniny L, Garcia RR, Pooler L,
Henderson BE, Le Marchand L & Haiman CA 2009 IGF2R missense
single-nucleotide polymorphisms and breast cancer risk: the multi-
ethnic cohort study. Cancer Epidemiology, Biomarkers & Prevention 18
1922–1924. (doi:10.1158/1055-9965.EPI-09-0253)
Cheng SP, Yin PH, Chang YC, Lee CH, Huang SY & Chi CW 2010a
Endocrine-Related Cancer
Differential roles of leptin in regulating cell migration in thyroid cancer
cells. Oncology Reports 23 1721–1727. (doi:10.3892/or_00000817)
Cheng SP, Chi CW, Tzen CY, Yang TL, Lee JJ, Liu TP & Liu CL 2010b
Clinicopathologic significance of leptin and leptin receptor expressions
in papillary thyroid carcinoma. Surgery 147 847–853. (doi:10.1016/
j.surg.2009.11.004)
Cheng SP, Yin PH, Hsu YC, Chang YC, Huang SY, Lee JJ & Chi CW 2011
Leptin enhances migration of human papillary thyroid cancer cells
through the PI3K/AKT and MEK/ERK signaling pathways. Oncology
Reports 26 1265–1271. (doi:10.3892/or.2011.1388)
Cheng SP, Liu CL, Hsu YC, Chang YC, Huang SY & Lee JJ 2012 Regulation
of leptin receptor expression in human papillary thyroid cancer cells.
Biomedicine & Pharmacotherapy 66 469–473. (doi:10.1016/j.biopha.
2012.03.008)
Cheng SP, Liu CL, Hsu YC, Chang YC, Huang SY & Lee JJ 2013 Expression
and biologic significance of adiponectin receptors in papillary thyroid
carcinoma. Cell Biochemistry and Biophysics 65 203–210. (doi:10.1007/
s12013-012-9419-1)
Cheung NW & Boyages SC 1997 The thyroid gland in acromegaly:
an ultrasonographic study. Clinical Endocrinology 46 545–549.
(doi:10.1046/j.1365-2265.1997.1680985.x)
Chu R, van Hasselt A, Vlantis AC, Ng EK, Liu SY, Fan MD, Ng SK, Chan AB,
Liu Z, Li XY et al. 2013 The cross-talk between estrogen receptor and
peroxisome proliferator-activated receptor g in thyroid cancer. Cancer
120 142–153. (doi:10.1002/cncr.28383)
Clement S, Refetoff S, Robaye B, Dumont JE & Schurmans S 2001 Low TSH
requirement and goiter in transgenic mice overexpressing IGF-I and
IGF-I receptor in the thyroid gland. Endocrinology 142 5131–5139.
(doi:10.1210/endo.142.12.8534)
Clero E, Leux C, Brindel P, Truong T, Anger A, Teinturier C, Diallo I, Doyon F,
Guenel P & de Vathaire F 2010 Pooled analysis of two case–control
studies in New Caledonia and French Polynesia of body mass index
and differentiated thyroid cancer: the importance of body surface area.
Thyroid 20 1285–1293. (doi:10.1089/thy.2009.0456)
Couto JP, Daly L, Almeida A, Knauf JA, Fagin JA, Sobrinho-Simoes M, Lima J,
Maximo V, Soares P, Lyden D et al. 2012 STAT3 negatively regulates
thyroid tumorigenesis. PNAS 109 E2361–E2370. (doi:10.1073/pnas.
1201232109)
http://erc.endocrinology-journals.org q 2014 Society for Endocrinology
DOI: 10.1530/ERC-14-0070 Printed in Great Britain
Obesity and thyroid cancer 21:5 T267
Cunha LL, Marcello MA & Ward LS 2014 The role of the inflammatory
microenvironment in thyroid carcinogenesis. Endocrine-Related Cancer
21 R85–R103. (doi:10.1530/ERC-13-0431)
Dalamaga M, Sotiropoulos G, Karmaniolas K, Pelekanos N, Papadavid E &
Lekka A 2013 Serum resistin: a biomarker of breast cancer in
postmenopausal women? Association with clinicopathological charac-
teristics, tumor markers, inflammatory and metabolic parameters Clinical
Biochemistry 46 584–590. (doi:10.1016/j.clinbiochem.2013.01.001)
Dal Maso L, La Vecchia C, Franceschi S, Preston-Martin S, Ron E, Levi F,
Mack W, Mark SD, McTiernan A, Kolonel L et al. 2000 A pooled analysis
of thyroid cancer studies. V. Anthropometric factors. Cancer Causes &
Control 11 137–144. (doi:10.1023/A:1008938520101)
Davies L & Welch HG 2006 Increasing incidence of thyroid cancer in the
United States, 1973–2002. Journal of the American Medical Association
295 2164–2167. (doi:10.1001/jama.295.18.2164)
De Pergola G, Ciampolillo A, Paolotti S, Trerotoli P & Giorgino R 2007
Free triiodothyronine and thyroid stimulating hormone are directly
associated with waist circumference, independently of insulin resist-
ance, metabolic parameters and blood pressure in overweight and
obese women. Clinical Endocrinology 67 265–269. (doi:10.1111/
j.1365-2265.2007.02874.x)
De Pergola G, Nardecchia A, Giagulli VA, Triggiani V, Guastamacchia E,
Minischetti MC & Silvestris F 2013 Obesity and heart failure. Endocrine,
Metabolic & Immune Disorders Drug Targets 13 51–57. (doi:10.2174/
1871530311313010007)
Di Cristofano A 2013 Obesity and thyroid cancer: is leptin the (only) link?
Endocrinology 154 2567–2569. (doi:10.1210/en.2013-1567)
Dimitriadis G, Maratou E, Boutati E, Kollias A, Tsegka K, Alevizaki M,
Peppa M, Raptis SA & Hadjidakis DJ 2008 IGF-I increases the
recruitment of GLUT4 and GLUT3 glucose transporters on cell surface
in hyperthyroidism. European Journal of Endocrinology 158 361–366.
(doi:10.1530/EJE-07-0532)
Di Vito M, De Santis E, Perrone GA, Mari E, Giordano MC, De Antoni E,
Coppola L, Fadda G, Tafani M, Carpi A et al. 2011 Overexpression of
estrogen receptor-a in human papillary thyroid carcinomas studied by
laser- capture microdissection and molecular biology. Cancer Science
102 1921–1927. (doi:10.1111/j.1349-7006.2011.02017.x)
Djiogue S, Nwabo Kamdje AH, Vecchio L, Kipanyula MJ, Farahna M,
Aldebasi Y & Seke Etet PF 2013 Insulin resistance and cancer: the role of
insulin and IGFs. Endocrine-Related Cancer 20 R1–R17. (doi:10.1530/
ERC-12-0324)
Duan XF, Tang P, Li Q & Yu ZT 2013 Obesity, adipokines and
hepatocellular carcinoma. International Journal of Cancer 133
1776–1783. (doi:10.1002/ijc.28105)
Dutta D, Ghosh S, Pandit K, Mukhopadhyay P & Chowdhury S 2012
Leptin and cancer: pathogenesis and modulation. Indian
Journal of Endocrinology and Metabolism 16 S596–S600. (doi:10.4103/
2230-8210.103041)
Eggo MC, Bachrach LK & Burrow GN 1990 Interaction of TSH, insulin and
insulin-like growth factors in regulating thyroid growth and function.
Growth Factors 2 99–109. (doi:10.3109/08977199009071497)
Enewold L, Zhu K, Ron E, Marrogi AJ, Stojadinovic A, Peoples GE &
Devesa SS 2009 Rising thyroid cancer incidence in the United
States by demographic and tumor characteristics, 1980–2005.
Cancer Epidemiology, Biomarkers & Prevention 18 784–791.
(doi:10.1158/1055-9965.EPI-08-0960)
Engeland A, Tretli S, Akslen LA & Bjorge T 2006 Body size and thyroid
cancer in two million Norwegian men and women. British
Journal of Cancer 95 366–370. (doi:10.1038/sj.bjc.6603249)
Farid NR, Shi Y & Zou M 1994 Molecular basis of thyroid cancer.
Endocrine Reviews 15 202–232. (doi:10.1210/edrv-15-2-202)
Feldt-Rasmussen U 2007 Thyroid and leptin. Thyroid 17 413–419.
(doi:10.1089/thy.2007.0032)
Fiore E & Vitti P 2012 Serum TSH and risk of papillary thyroid cancer in
nodular thyroid disease. Journal of Clinical Endocrinology and Metabolism
97 1134–1145. (doi:10.1210/jc.2011-2735)
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 07/06/2019 12:53:39AM
via free access
 Thematic Review M A Marcello et al.
Flegal KM, Carroll MD, Kit BK & Ogden CL 2012 Prevalence of obesity
and trends in the distribution of body mass index among US adults,
1999–2010. Journal of the American Medical Association 307 491–497.
(doi:10.1001/jama.2012.39)
Ford ES, Mokdad AH & Giles WH 2003 Trends in waist circumference
among US adults. Obesity Research 11 1223–1231. (doi:10.1038/
oby.2003.168)
Fox CS, Pencina MJ, D’Agostino RB, Murabito JM, Seely EW, Pearce EN &
Vasan RS 2008 Relations of thyroid function to body weight:
cross-sectional and longitudinal observations in a community-based
sample. Archives of Internal Medicine 168 587–592. (doi:10.1001/
archinte.168.6.587)
Franceschi S, Talamini R, Fassina A & Bidoli E 1990 Diet and epithelial
cancer of the thyroid gland. Tumori 76 331–338.
Franceschi S, Levi F, Negri E, Fassina A & La Vecchia C 1991 Diet and
thyroid cancer: a pooled analysis of four European case–control studies.
International Journal of Cancer 48 395–398. (doi:10.1002/
ijc.2910480315)
Fruhbeck G 2006 Intracellular signalling pathways activated by leptin.
Biochemical Journal 393 7–20. (doi:10.1042/BJ20051578)
Galanti MR, Hansson L, Lund E, Bergstrom R, Grimelius L, Stalsberg H,
Carlsen E, Baron JA, Persson I & Ekbom A 1996 Reproductive history
and cigarette smoking as risk factors for thyroid cancer in women:
a population-based case–control study. Cancer Epidemiology, Biomarkers
& Prevention 5 425–431.
Ghosh S & Ashcraft K 2013 An IL-6 link between obesity and cancer.
Frontiers in Bioscience 5 461–478. (doi:10.2741/E628)
Gordon S & Taylor PR 2005 Monocyte and macrophage heterogeneity.
Endocrine-Related Cancer
Nature Reviews. Immunology 5 953–964. (doi:10.1038/nri1733)
Grodski S, Brown T, Sidhu S, Gill A, Robinson B, Learoyd D, Sywak M, Reeve T
& Delbridge L 2008 Increasing incidence of thyroid cancer is due to
increased pathologic detection. Surgery 144 1038–1043. (doi:10.1016/
j.surg.2008.08.023)
Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Rohan TE, Manson JE,
Howard BV, Wylie-Rosett J, Anderson GL, Ho GY et al. 2008 Insulin,
insulin-like growth factor-I, endogenous estradiol, and risk of colorectal
cancer in postmenopausal women. Cancer Research 68 329–337.
(doi:10.1158/0008-5472.CAN-07-2946)
Guo S 2013 Insulin signaling, resistance, and the metabolic syndrome:
insights from mouse models to disease mechanisms. Journal of
Endocrinology 220 T1–T23. (doi:10.1530/JOE-13-0327)
Haddad FH, Malkawi OM, Omari AA, Izzat AS, Khassrof HM, Faiad LM,
Okla AL & Jamil AN 2002 Diabetes and infarcted papillary thyroid
cancer. Saudi Medical Journal 23 467–470.
Hall J, Roberts R & Vora N 2009 Energy homoeostasis: the roles of adipose
tissue-derived hormones, peptide YY and ghrelin. Obesity Facts 2
117–125. (doi:10.1159/000208517)
Han JM, Kim TY, Jeon MJ, Yim JH, Kim WG, Song DE, Hong SJ, Bae SJ,
Kim HK, Shin MH et al. 2013 Obesity is a risk factor for thyroid
cancer in a large, ultrasonographically screened population. European
Journal of Endocrinology 168 879–886. (doi:10.1530/EJE-13-0065)
Hard GC 1998 Recent developments in the investigation of thyroid
regulation and thyroid carcinogenesis. Environmental Health Perspectives
106 427–436. (doi:10.1289/ehp.98106427)
Hlavna M, Kohut L, Lipkova J, Bienertova-Vasku J, Dostalova Z, Chovanec J
& Vasku A 2011 Relationship of resistin levels with endometrial cancer
risk. Neoplasma 58 124–128. (doi:10.4149/neo_2011_02_124)
Hursting SD, Lashinger LM, Wheatley KW, Rogers CJ, Colbert LH,
Nunez NP & Perkins SN 2008 Reducing the weight of cancer:
mechanistic targets for breaking the obesity-carcinogenesis link.
Best Practice & Research. Clinical Endocrinology & Metabolism 22 659–669.
(doi:10.1016/j.beem.2008.08.009)
Hvidtfeldt UA, Gunter MJ, Lange T, Chlebowski RT, Lane D, Farhat GN,
Freiberg MS, Keiding N, Lee JS, Prentice R et al. 2012 Quantifying
mediating effects of endogenous estrogen and insulin in the relation
between obesity, alcohol consumption, and breast cancer.
http://erc.endocrinology-journals.org q 2014 Society for Endocrinology
DOI: 10.1530/ERC-14-0070 Printed in Great Britain
Obesity and thyroid cancer 21:5 T268
Cancer Epidemiology, Biomarkers & Prevention 21 1203–1212.
(doi:10.1158/1055-9965.EPI-12-0310)
IARC 2002 Weight Control and Physical Activity. Lyon: IARC Press.
INCA M 2014 Estimativa 2014 – Incidência de Câncer no Brasil.
Rio de Janeiro: MS/INCA. http://www.slideshare.net/MinSaude/
estimativa-cancer2014
Inoue M & Tsugane S 2012 Insulin resistance and cancer: epidemiological
evidence. Endocrine-Related Cancer 19 F1–F8. (doi:10.1530/ERC-12-0142)
Jiang CY, Wang W, Yin YL, Yuan ZR & Wang LB 2012 Expression of the
adipocytokine resistin and its association with the clinicopathological
features and prognosis of pancreatic ductal adenocarcinoma. Oncology
Letters 4 960–964. (doi:10.3892/ol.2012.865)
Jung CK, Lubin JH, Brenner AV, Little MP, Sigurdson AJ & Nikiforov YE
2012 The increase in papillary thyroid cancer incidence in the US
during the last four decades is accompanied by a high and stable
frequency of BRAF mutations and a sharp increase in NRAS mutations.
Modern Pathology 25 S2 146A.
Kaaks R, Lukanova A & Kurzer MS 2002 Obesity, endogenous hormones,
and endometrial cancer risk: a synthetic review. Cancer Epidemiology,
Biomarkers & Prevention 11 1531–1543.
Kamat A, Rajoria S, George A, Suriano R, Shanmugam A, Megwalu U,
Prakash PB, Tiwari R & Schantz S 2011 Estrogen-mediated angiogenesis
in thyroid tumor microenvironment is mediated through VEGF
signaling pathways. Archives of Otolaryngology-Head & Neck Surgery 137
1146–1153. (doi:10.1001/archoto.2011.194)
Kavanagh DO, McIlroy M, Myers E, Bane F, Crotty TB, McDermott E,
Hill AD & Young LS 2010 The role of oestrogen receptor a in human
thyroid cancer: contributions from coregulatory proteins and the
tyrosine kinase receptor HER2. Endocrine-Related Cancer 17 255–264.
(doi:10.1677/ERC-09-0216)
Kavanagh ME, O’Sullivan KE, O’Hanlon C, O’Sullivan JN, Lysaght J &
Reynolds JV 2013 The esophagitis to adenocarcinoma sequence;
the role of inflammation. Cancer Letters 345 182–189. (doi:10.1016/
j.canlet.2013.08.017)
Kern M, Wells JA, Stephens JM, Elton CW, Friedman JE, Tapscott EB,
Pekala PH & Dohm GL 1990 Insulin responsiveness in skeletal muscle
is determined by glucose transporter (Glut4) protein level. Biochemical
Journal 270 397–400.
Kim HJ, Lee YS, Won EH, Chang IH, Kim TH, Park ES, Kim MK, Kim W &
Myung SC 2011 Expression of resistin in the prostate and its
stimulatory effect on prostate cancer cell proliferation. BJU International
108 E77–E83. (doi:10.1111/j.1464-410X.2010.09813.x)
Kim HJ, Kim NK, Choi JH, Sohn SY, Kim SW, Jin SM, Jang HW, Suh S,
Min YK & Chung JH 2013a Associations between body mass index
and clinico-pathological characteristics of papillary thyroid cancer.
Clinical Endocrinology 78 134–140. (doi:10.1111/j.1365-2265.
2012.04506.x)
Kim WG, Park JW, Willingham MC & Cheng SY 2013b Diet-induced
obesity increases tumor growth and promotes anaplastic change in
thyroid cancer in a mouse model. Endocrinology 154 2936–2947.
(doi:10.1210/en.2013-1128)
Kim MR, Kim SS, Huh JE, Lee BJ, Lee JC, Jeon YK, Kim BH, Kim SJ, Wang SG,
Kim YK et al. 2013c Neck circumference correlates with tumor size and
lateral lymph node metastasis in men with small papillary thyroid
carcinoma. Korean Journal of Internal Medicine 28 62–71. (doi:10.3904/
kjim.2013.28.1.62)
Kimura T, Van Keymeulen A, Golstein J, Fusco A, Dumont JE & Roger PP
2001 Regulation of thyroid cell proliferation by TSH and other factors:
a critical evaluation of in vitro models. Endocrine Reviews 22 631–656.
(doi:10.1210/edrv.22.5.0444)
Kintscher U, Hartge M, Hess K, Foryst-Ludwig A, Clemenz M, Wabitsch M,
Fischer-Posovszky P, Barth TF, Dragun D, Skurk T et al. 2008
T-lymphocyte infiltration in visceral adipose tissue: a primary event in
adipose tissue inflammation and the development of obesity-mediated
insulin resistance. Arteriosclerosis, Thrombosis, and Vascular Biology 28
1304–1310. (doi:10.1161/ATVBAHA.108.165100)
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 07/06/2019 12:53:39AM
via free access
 Thematic Review M A Marcello et al.
Kitahara CM, Platz EA, Freeman LE, Hsing AW, Linet MS, Park Y, Schairer C,
Schatzkin A, Shikany JM & Berrington de Gonzalez A 2011 Obesity and
thyroid cancer risk among U.S. men and women: a pooled analysis of
five prospective studies. Cancer Epidemiology, Biomarkers & Prevention 20
464–472. (doi:10.1158/1055-9965.EPI-10-1220)
Kitahara CM, Neta G, Pfeiffer RM, Kwon D, Xu L, Freedman ND,
Hutchinson AA, Chanock SJ, Sturgis EM, Sigurdson AJ et al. 2012a
Common obesity-related genetic variants and papillary thyroid cancer
risk. Cancer Epidemiology, Biomarkers & Prevention 21 2268–2271.
(doi:10.1158/1055-9965.EPI-12-0790)
Kitahara CM, Platz EA, Beane Freeman LE, Black A, Hsing AW, Linet MS,
Park Y, Schairer C & Berrington de Gonzalez A 2012b Physical activity,
diabetes, and thyroid cancer risk: a pooled analysis of five prospective
studies. Cancer Causes & Control 23 463–471. (doi:10.1007/s10552-012-
9896-y)
Kitahara CM, Platz EA, Park Y, Hollenbeck AR, Schatzkin A & Berrington
de Gonzalez A 2012c Body fat distribution, weight change during
adulthood, and thyroid cancer risk in the NIH-AARP Diet and Health
Study. International Journal of Cancer 130 1411–1419. (doi:10.1002/
ijc.26161)
Knudsen N, Laurberg P, Rasmussen LB, Bulow I, Perrild H, Ovesen L &
Jorgensen T 2005 Small differences in thyroid function may be
important for body mass index and the occurrence of obesity in
the population. Journal of Clinical Endocrinology and Metabolism 90
4019–4024. (doi:10.1210/jc.2004-2225)
Kumada M, Kihara S, Ouchi N, Kobayashi H, Okamoto Y, Ohashi K,
Maeda K, Nagaretani H, Kishida K, Maeda N et al. 2004 Adiponectin
Endocrine-Related Cancer
specifically increased tissue inhibitor of metalloproteinase-1 through
interleukin-10 expression in human macrophages. Circulation 109
2046–2049. (doi:10.1161/01.CIR.0000127953.98131.ED)
Kumar A, Klinge CM & Goldstein RE 2010 Estradiol-induced proliferation
of papillary and follicular thyroid cancer cells is mediated by estrogen
receptors a and b. International Journal of Oncology 36 1067–1080.
(doi:10.3892/ijo_00000629)
Kuo CH, Chen KF, Chou SH, Huang YF, Wu CY, Cheng DE, Chen YW,
Yang CJ, Hung JY & Huang MS 2013 Lung tumor-associated dendritic
cell-derived resistin promoted cancer progression by increasing
Wolf–Hirschhorn syndrome candidate 1/Twist pathway.
Carcinogenesis 34 2600–2609. (doi:10.1093/carcin/bgt281)
Kwon H & Pessin JE 2013 Adipokines mediate inflammation and insulin
resistance. Frontiers in Endocrinology 4 71. (doi:10.3389/fendo.
2013.00071)
Lassek WD & Gaulin SJ 2006 Changes in body fat distribution in relation
to parity in American women: a covert form of maternal depletion.
American Journal of Physical Anthropology 131 295–302. (doi:10.1002/
ajpa.20394)
Lee ML, Chen GG, Vlantis AC, Tse GMK, Leung BCH & van Hasselt CA 2005
Induction of thyroid papillary carcinoma cell proliferation by estrogen
is associated with an altered expression of Bcl-xL. Cancer Journal 11
113–121. (doi:10.1097/00130404-200503000-00006)
Leibovich SJ, Polverini PJ, Shepard HM, Wiseman DM, Shively V & Nuseir N
1987 Macrophage-induced angiogenesis is mediated by tumour
necrosis factor-a. Nature 329 630–632. (doi:10.1038/329630a0)
Leitzmann MF, Brenner A, Moore SC, Koebnick C, Park Y, Hollenbeck A,
Schatzkin A & Ron E 2010 Prospective study of body mass index,
physical activity and thyroid cancer. International Journal of Cancer 126
2947–2956. (doi:10.1002/ijc.24913)
Leux C, Truong T, Petit C, Baron-Dubourdieu D & Guenel P 2012 Family
history of malignant and benign thyroid diseases and risk of thyroid
cancer: a population-based case–control study in New Caledonia.
Cancer Causes & Control 23 745–755. (doi:10.1007/s10552-012-9944-7)
Li S, Shin HJ, Ding EL & van Dam RM 2009 Adiponectin levels and risk
of type 2 diabetes: a systematic review and meta-analysis. Journal of
the American Medical Association 302 179–188. (doi:10.1001/
jama.2009.976)
http://erc.endocrinology-journals.org q 2014 Society for Endocrinology
DOI: 10.1530/ERC-14-0070 Printed in Great Britain
Obesity and thyroid cancer 21:5 T269
Li Y, Zhang J & Ma H 2013 Chronic inflammation and gallbladder cancer.
Cancer Letters 345 242–248. (doi:10.1016/j.canlet.2013.08.034)
Liu Z, Brooks RS, Ciappio ED, Kim SJ, Crott JW, Bennett G, Greenberg AS &
Mason JB 2012 Diet-induced obesity elevates colonic TNF-a in mice and
is accompanied by an activation of Wnt signaling: a mechanism for
obesity-associated colorectal cancer. Journal of Nutritional Biochemistry
23 1207–1213. (doi:10.1016/j.jnutbio.2011.07.002)
Lodh M, Goswami B, Gupta N, Patra SK & Saxena A 2012 Assessment of
oxidative stress and inflammatory process in patients of multiple
myeloma. Indian Journal of Clinical Biochemistry 27 410–413.
(doi:10.1007/s12291-012-0222-y)
Longo VD & Finch CE 2003 Evolutionary medicine: from dwarf model
systems to healthy centenarians? Science 299 1342–1346. (doi:10.1126/
science.1077991)
Lumachi F, Basso SM & Orlando R 2010 Cytokines, thyroid diseases and
thyroid cancer. Cytokine 50 229–233. (doi:10.1016/j.cyto.2010.03.005)
Manji N, Boelaert K, Sheppard MC, Holder RL, Gough SC & Franklyn JA
2006 Lack of association between serum TSH or free T4 and body
mass index in euthyroid subjects. Clinical Endocrinology 64 125–128.
(doi:10.1111/j.1365-2265.2006.02433.x)
Marcello MA, Sampaio AC, Geloneze B, Vasques AC, Assumpcao LV &
Ward LS 2012a Obesity and excess protein and carbohydrate
consumption are risk factors for thyroid cancer. Nutrition and Cancer 64
1190–1195. (doi:10.1080/01635581.2012.721154)
Marcello MA, Araujo P, Calixto A, Vasques AJ, Tincani AJ, Geloneze B &
Ward LS 2012b Serum adiponectin and ghrelin levels may help to
identify malignancy in thyroid nodules. In 82nd American Thyroid
Association Annual Meeting. Ed ATA. Québec City, Canada:
Mary Ann Liebert, Inc.
McLeod DS, Cooper DS, Ladenson PW, Ain KB, Brierley JD, Fein HG,
Haugen BR, Jonklaas J, Magner J, Ross DS et al. 2013 Prognosis of
differentiated thyroid cancer in relation to serum TSH and thyro-
globulin antibody status at time of diagnosis. Thyroid 24 35–42.
(doi:10.1089/thy.2013.0062)
McTiernan AM, Weiss NS & Daling JR 1984 Incidence of thyroid cancer in
women in relation to reproductive and hormonal factors. American
Journal of Epidemiology 120 423–435.
Menendez C, Baldelli R, Camina JP, Escudero B, Peino R, Dieguez C &
Casanueva FF 2003 TSH stimulates leptin secretion by a direct effect on
adipocytes. Journal of Endocrinology 176 7–12. (doi:10.1677/joe.0.1760007)
Mijovic T, How J, Pakdaman M, Rochon L, Gologan O, Hier MP, Black MJ,
Young J, Tamilia M & Payne RJ 2009 Body mass index in the evaluation
of thyroid cancer risk. Thyroid 19 467–472. (doi:10.1089/
thy.2008.0386)
Mitsiades N, Pazaitou-Panayiotou K, Aronis KN, Moon HS, Chamberland JP,
Liu X, Diakopoulos KN, Kyttaris V, Panagiotou V, Mylvaganam G et al.
2011 Circulating adiponectin is inversely associated with risk of thyroid
cancer: in vivo and in vitro studies. Journal of Clinical Endocrinology and
Metabolism 96 E2023–E2028. (doi:10.1210/jc.2010-1908)
Nannipieri M, Cecchetti F, Anselmino M, Camastra S, Niccolini P,
Lamacchia M, Rossi M, Iervasi G & Ferrannini E 2009 Expression of
thyrotropin and thyroid hormone receptors in adipose tissue of
patients with morbid obesity and/or type 2 diabetes: effects of weight
loss. International Journal of Obesity 33 1001–1006. (doi:10.1038/
ijo.2009.140)
Obeid S & Hebbard L 2012 Role of adiponectin and its receptors in cancer.
Cancer Biology & Medicine 9 213–220. (doi:10.7497/j.issn.2095-3941.2012.
04.001)
Ock S, Ahn J, Lee SH, Kang H, Offermanns S, Ahn HY, Jo YS, Shong M,
Cho BY, Jo D et al. 2013 IGF-1 receptor deficiency in thyrocytes impairs
thyroid hormone secretion and completely inhibits TSH-stimulated
goiter. FASEB Journal 27 4899–4908. (doi:10.1096/fj.13-231381)
Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ & Flegal KM
2006 Prevalence of overweight and obesity in the United States,
1999–2004. Journal of the American Medical Association 295 1549–1555.
(doi:10.1001/jama.295.13.1549)
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 07/06/2019 12:53:39AM
via free access
 Thematic Review M A Marcello et al.
Oge A, Bayraktar F, Saygili F, Guney E & Demir S 2005 TSH influences serum
leptin levels independent of thyroid hormones in hypothyroid and
hyperthyroid patients. Endocrine Journal 52 213–217. (doi:10.1507/
endocrj.52.213)
Pang XP, Yoshimura M, Wang J & Dubinett SM 1994 TNF-a-induced
antiproliferation is not dependent on the autocrine action of TGF-b 1 in
a thyroid cancer cell line. Lymphokine and Cytokine Research 13 93–97.
Pang XP, Ross NS & Hershman JM 1996 Alterations in TNF-a signal
transduction in resistant human papillary thyroid carcinoma cells.
Thyroid 6 313–317. (doi:10.1089/thy.1996.6.313)
Pappa T & Alevizaki M 2013 Obesity and thyroid cancer: a clinical update.
Thyroid 24 190–199. (doi:10.1089/thy.2013.0232)
Pellegriti G, Frasca F, Regalbuto C, Squatrito S & Vigneri R 2013 Worldwide
increasing incidence of thyroid cancer: update on epidemiology and
risk factors. Journal of Cancer Epidemiology 2013 965212. (doi:10.1155/
2013/965212)
Perez Rodrigo C 2013 Current mapping of obesity. Nutrición Hospitalaria
28 (Supplement 5) 21–31. (doi:10.3305/nh.2013.28.sup5.6915)
Piya MK, McTernan PG & Kumar S 2013 Adipokine inflammation and
insulin resistance: the role of glucose, lipids and endotoxin.
Journal of Endocrinology 216 T1–T15. (doi:10.1530/JOE-12-0498)
Qiu J, Yang R, Rao Y, Du Y & Kalembo FW 2012 Risk factors for breast cancer
and expression of insulin-like growth factor-2 (IGF-2) in women with
breast cancer in Wuhan City, China. PLoS ONE 7 e36497. (doi:10.1371/
journal.pone.0036497)
Rajoria S, Suriano R, Shanmugam A, Wilson YL, Schantz SP, Geliebter J &
Tiwari RK 2010 Metastatic phenotype is regulated by estrogen in
Endocrine-Related Cancer
thyroid cells. Thyroid 20 33–41. (doi:10.1089/thy.2009.0296)
Ranks JB, Feliciano D & Kansakar E 2009 Expression of estrogen receptor,
progesterone receptor, and vascular endothelial growth factor-A in
thyroid cancer. American Surgeon 75 785–789 discussion 789.
Rapp K, Schroeder J, Klenk J, Ulmer H, Concin H, Diem G, Oberaigner W &
Weiland SK 2006 Fasting blood glucose and cancer risk in a cohort of
more than 140,000 adults in Austria. Diabetologia 49 945–952.
(doi:10.1007/s00125-006-0207-6)
Reinehr T 2010 Obesity and thyroid function. Molecular and Cellular
Endocrinology 316 165–171. (doi:10.1016/j.mce.2009.06.005)
Reinehr T, de Sousa G & Andler W 2006 Hyperthyrotropinemia in obese
children is reversible after weight loss and is not related to lipids.
Journal of Clinical Endocrinology and Metabolism 91 3088–3091.
(doi:10.1210/jc.2006-0095)
Rendina D, De Filippo G, Mossetti G, Zampa G, Muscariello R, Benvenuto G,
Vivona CL, Ippolito S, Galante F, Lombardi G et al. 2012 Relationship
between metabolic syndrome and multinodular non-toxic goiter in
an inpatient population from a geographic area with moderate iodine
deficiency. Journal of Endocrinological Investigation 35 407–412.
(doi:10.3275/7842)
Renehan AG, Tyson M, Egger M, Heller RF & Zwahlen M 2008 Body-mass
index and incidence of cancer: a systematic review and meta-analysis of
prospective observational studies. Lancet 371 569–578. (doi:10.1016/
S0140-6736(08)60269-X)
Rezzonico J, Rezzonico M, Pusiol E, Pitoia F & Niepomniszcze H 2008
Introducing the thyroid gland as another victim of the insulin
resistance syndrome. Thyroid 18 461–464. (doi:10.1089/thy.2007.0223)
Rezzonico JN, Rezzonico M, Pusiol E, Pitoia F & Niepomniszcze H 2009
Increased prevalence of insulin resistance in patients with differen-
tiated thyroid carcinoma. Metabolic Syndrome and Related Disorders 7
375–380. (doi:10.1089/met.2008.0062)
Rezzonico J, Rezzonico M, Pusiol E, Pitoia F & Niepomniszcze H 2011
Metformin treatment for small benign thyroid nodules in patients with
insulin resistance. Metabolic Syndrome and Related Disorders 9 69–75.
(doi:10.1089/met.2010.0026)
Rinaldi S, Lise M, Clavel-Chapelon F, Boutron-Ruault MC, Guillas G,
Overvad K, Tjonneland A, Halkjaer J, Lukanova A, Kaaks R et al. 2012
Body size and risk of differentiated thyroid carcinomas: findings from
http://erc.endocrinology-journals.org q 2014 Society for Endocrinology
DOI: 10.1530/ERC-14-0070 Printed in Great Britain
Obesity and thyroid cancer 21:5 T270
the EPIC study. International Journal of Cancer 131 E1004–E1014.
(doi:10.1002/ijc.27601)
Rivas M & Santisteban P 2003 TSH-activated signaling pathways in thyroid
tumorigenesis. Molecular and Cellular Endocrinology 213 31–45.
(doi:10.1016/j.mce.2003.10.029)
Ron E, Kleinerman RA, Boice JD Jr, LiVolsi VA, Flannery JT & Fraumeni JF Jr
1987 A population-based case–control study of thyroid cancer.
Journal of the National Cancer Institute 79 1–12. (doi:10.1093/jnci/79.1.1)
Rosenbaum M, Hirsch J, Murphy E & Leibel RL 2000 Effects of changes in
body weight on carbohydrate metabolism, catecholamine excretion,
and thyroid function. American Journal of Clinical Nutrition 71
1421–1432.
Samanic C, Gridley G, Chow WH, Lubin J, Hoover RN & Fraumeni JF Jr
2004 Obesity and cancer risk among white and black United States
veterans. Cancer Causes & Control 15 35–43. (doi:10.1023/B:CACO.
0000016573.79453.ba)
Santini F, Galli G, Maffei M, Fierabracci P, Pelosini C, Marsili A, Giannetti M,
Castagna MG, Checchi S, Molinaro E et al. 2010 Acute exogenous TSH
administration stimulates leptin secretion in vivo. European Journal of
Endocrinology 163 63–67. (doi:10.1530/EJE-10-0138)
Sari R, Balci MK, Altunbas H & Karayalcin U 2003 The effect of body weight
and weight loss on thyroid volume and function in obese women.
Clinical Endocrinology 59 258–262. (doi:10.1046/j.1365-2265.2003.
01836.x)
Schaffler A & Scholmerich J 2010 Innate immunity and adipose tissue
biology. Trends in Immunology 31 228–235. (doi:10.1016/j.it.2010.
03.001)
Shah SH 1999 Imbalance diet: a risk factor for thyroid cancer. Journal of the
Pakistan Medical Association 49 130.
Shih SR, Chiu WY, Chang TC & Tseng CH 2012 Diabetes and thyroid
cancer risk: literature review. Experimental Diabetes Research 2012
578285. (doi:10.1155/2012/578285)
Sprague BL, Andersen SW & Trentham-Dietz A 2008 Thyroid cancer
incidence and socioeconomic indicators of health care access. Cancer
Causes & Control 19 585–593. (doi:10.1007/s10552-008-9122-0)
Steppan CM, Wang J, Whiteman EL, Birnbaum MJ & Lazar MA 2005
Activation of SOCS-3 by resistin. Molecular and Cellular Biology 25
1569–1575. (doi:10.1128/MCB.25.4.1569-1575.2005)
Stewart PA, Luks J, Roycik MD, Sang QX & Zhang J 2013 Differentially
expressed transcripts and dysregulated signaling pathways and
networks in African American breast cancer. PLoS ONE 8 e82460.
(doi:10.1371/journal.pone.0082460)
Strong AL, Strong TA, Rhodes LV, Semon JA, Zhang X, Shi Z, Zhang S,
Gimble JM, Burow ME & Bunnell BA 2013 Obesity associated
alterations in the biology of adipose stem cells mediate enhanced
tumorigenesis by estrogen dependent pathways. Breast Cancer
Research 15 R102. (doi:10.1186/bcr3569)
Sun A, Liu R & Sun G 2013 Insulin therapy and risk of colorectal
cancer: an updated meta-analysis of epidemiological studies. Current
Medical Research and Opinion 30 423–430. (doi:10.1185/03007995.
2013.858622)
Surmacz E 2013 Leptin and adiponectin: emerging therapeutic targets
in breast cancer. Journal of Mammary Gland Biology and Neoplasia 18
321–332. (doi:10.1007/s10911-013-9302-8)
Takada K, Amino N, Tada H & Miyai K 1990 Relationship between
proliferation and cell cycle-dependent Ca2C influx induced by a
combination of thyrotropin and insulin-like growth factor-I in rat
thyroid cells. Journal of Clinical Investigation 86 1548–1555.
(doi:10.1172/JCI114874)
Takemura Y, Ouchi N, Shibata R, Aprahamian T, Kirber MT, Summer RS,
Kihara S & Walsh K 2007 Adiponectin modulates inflammatory
reactions via calreticulin receptor-dependent clearance of early
apoptotic bodies. Journal of Clinical Investigation 117 375–386.
(doi:10.1172/JCI29709)
Tangjitgamol S, Ramirez PT, Sun CC, See HT, Jhingran A, Kavanagh JJ &
Deavers MT 2005 Expression of HER-2/neu, epidermal growth factor
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 07/06/2019 12:53:39AM
via free access
 Thematic Review M A Marcello et al.
receptor, vascular endothelial growth factor, cyclooxygenase-2,
estrogen receptor, and progesterone receptor in small cell and large cell
neuroendocrine carcinoma of the uterine cervix: a clinicopathologic
and prognostic study. International Journal of Gynecological Cancer 15
646–656. (doi:10.1111/j.1525-1438.2005.00121.x)
Toth MJ, Tchernof A, Sites CK & Poehlman ET 2000 Effect of menopausal
status on body composition and abdominal fat distribution.
International Journal of Obesity and Related Metabolic Disorders 24
226–231. (doi:10.1038/sj.ijo.0801118)
Trayhurn P & Wood IS 2004 Adipokines: inflammation and the pleiotropic
role of white adipose tissue. British Journal of Nutrition 92 347–355.
(doi:10.1079/BJN20041213)
Truong T, Orsi L, Dubourdieu D, Rougier Y, Hemon D & Guenel P 2005 Role
of goiter and of menstrual and reproductive factors in thyroid cancer: a
population-based case–control study in New Caledonia (South Pacific),
a very high incidence area. American Journal of Epidemiology 161
1056–1065. (doi:10.1093/aje/kwi136)
Tseng CH 2013 Diabetes and thyroid cancer mortality: a 12-year
prospective follow-up of Taiwanese. European Journal of Clinical
Investigation 43 595–601. (doi:10.1111/eci.12086)
Vansaun MN 2013 Molecular pathways: adiponectin and leptin signaling
in cancer. Clinical Cancer Research 19 1926–1932. (doi:10.1158/
1078-0432.CCR-12-0930)
Vassilopoulou-Sellin R, Cangir A & Samaan NA 1992 Acanthosis nigricans
and severe insulin resistance in an adolescent girl with thyroid cancer:
clinical response to antineoplastic therapy. American Journal of Clinical
Oncology 15 273–276. (doi:10.1097/00000421-199206000-00019)
Vella V, Sciacca L, Pandini G, Mineo R, Squatrito S, Vigneri R & Belfiore A
Endocrine-Related Cancer
2001 The IGF system in thyroid cancer: new concepts. Molecular
Pathology 54 121–124. (doi:10.1136/mp.54.3.121)
Volzke H, Friedrich N, Schipf S, Haring R, Ludemann J, Nauck M, Dorr M,
Brabant G & Wallaschofski H 2007 Association between serum insulin-
like growth factor-I levels and thyroid disorders in a population-based
study. Journal of Clinical Endocrinology and Metabolism 92 4039–4045.
(doi:10.1210/jc.2007-0816)
Wang Y & Wang W 2012 Increasing incidence of thyroid cancer in
Shanghai, China, 1983–2007. Asia-Pacific Journal of Public Health
[in press]. (doi:10.1177/1010539512436874)
Wang F, Meng W, Wang B & Qiao L 2013 Helicobacter pylori-induced gastric
inflammation and gastric cancer. Cancer Letters 345 196–202.
(doi:10.1016/j.canlet.2013.08.016)
Ward LS & Graf H 2008 Thyroid cancer: increased occurrence of the disease
or simply in its detection? Arquivos Brasileiros de Endocrinologia e
Metabologia 52 1515–1516. (doi:10.1590/S0004-27302008000900018)
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL &
Ferrante AW Jr 2003 Obesity is associated with macrophage
accumulation in adipose tissue. Journal of Clinical Investigation 112
1796–1808. (doi:10.1172/JCI200319246)
WHO 2009 Global Health Risks. Mortality and Burden of Disease Attributable to
Selected Major Risks. Geneva: WHO Press.
http://erc.endocrinology-journals.org q 2014 Society for Endocrinology
DOI: 10.1530/ERC-14-0070 Printed in Great Britain
Obesity and thyroid cancer 21:5 T271
WHO 2011 Waist Circumference and Waist–hip Ratio: Report of a WHO Expert
Consultation. Geneva 8–11 December 2008. Geneva: WHO Press.
Wolin KY, Carson K & Colditz GA 2010 Obesity and cancer. Oncologist 15
556–565. (doi:10.1634/theoncologist.2009-0285)
Wolpin BM, Bao Y, Qian ZR, Wu C, Kraft P, Ogino S, Stampfer MJ, Sato K,
Ma J, Buring JE et al. 2013 Hyperglycemia, insulin resistance, impaired
pancreatic b-cell function, and risk of pancreatic cancer. Journal of the
National Cancer Institute 105 1027–1035. (doi:10.1093/jnci/djt123)
World Cancer Research Fund & American Institute for Cancer Research
2007 Food, Nutrition, Physical Activity, and the Prevention of Cancer: a
Global Perspective. Washington, DC: American Institute for Cancer
Research.
Xing M 2013 Molecular pathogenesis and mechanisms of thyroid cancer.
Nature Reviews. Cancer 13 184–199. (doi:10.1038/nrc3431)
Yasar HY, Ertugrul O, Ertugrul B, Ertugrul D & Sahin M 2011 Insulin
resistance in nodular thyroid disease. Endocrine Research 36 167–174.
(doi:10.3109/07435800.2011.593011)
Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N,
Kihara S, Funahashi T, Tenner AJ, Tomiyama Y et al. 2000
Adiponectin, a new member of the family of soluble defense collagens,
negatively regulates the growth of myelomonocytic progenitors and
the functions of macrophages. Blood 96 1723–1732.
Zeng Q, Chen GG, Vlantis AC & van Hasselt CA 2007 Oestrogen mediates
the growth of human thyroid carcinoma cells via an oestrogen
receptor – ERK pathway. Cell Proliferation 40 921–935. (doi:10.1111/
j.1365-2184.2007.00471.x)
Zeng Q, Chen GG, Vlantis AC, Tse GM & van Hasselt CA 2008 The
contributions of oestrogen receptor isoforms to the development of
papillary and anaplastic thyroid carcinomas. Journal of Pathology 214
425–433. (doi:10.1002/path.2297)
Zhan Y, Wang J, Ma Y, Liu Z, Xu H, Lu S & Lu B 2013 Serum insulin-like,
growth factor binding protein-related protein 1 (IGFBP-rP1) and
endometrial cancer risk in Chinese women. International Journal of
Cancer 132 411–416. (doi:10.1002/ijc.27622)
Zhang GA, Hou S, Han S, Zhou J, Wang X & Cui W 2013 Clinicopatho-
logical implications of leptin and leptin receptor expression in papillary
thyroid cancer. Oncology Letters 5 797–800.
Zhao ZG, Guo XG, Ba CX, Wang W, Yang YY, Wang J & Cao HY 2012
Overweight, obesity and thyroid cancer risk: a meta-analysis of cohort
studies. Journal of International Medical Research 40 2041–2050.
(doi:10.1177/030006051204000601)
Zielke A, Hoffmann S, Plaul U, Duh QY, Clark OH & Rothmund M 1999
Pleiotropic effects of thyroid stimulating hormone in a differentiated
thyroid cancer cell line. Studies on proliferation, thyroglobulin
secretion, adhesion, migration and invasion. Experimental and
Clinical Endocrinology & Diabetes 107 361–369. (doi:10.1055/
s-0029-1212127)
Zimmermann-Belsing T, Brabant G, Holst JJ & Feldt-Rasmussen U 2003
Circulating leptin and thyroid dysfunction. European Journal of
Endocrinology 149 257–271. (doi:10.1530/eje.0.1490257)
Received in final form 20 March 2014
Accepted 14 April 2014
Made available online as an Accepted Preprint
16 April 2014
Published by Bioscientifica Ltd.
Downloaded from Bioscientifica.com at 07/06/2019 12:53:39AM
via free access