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Role of Estrogen in Thyroid Function and Growth Regulation

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DOI: 10.4061/2011/875125 · Source: PubMed

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Journal of Thyroid Research
Volume 2011, Article ID 875125, 7 pages
doi:10.4061/2011/875125

Review Article
Role of Estrogen in Thyroid Function and Growth Regulation

Ana Paula Santin1 and Tania Weber Furlanetto1, 2

1 Postgraduation Program in Medicine and Medical Sciences, Federal University of Rio Grande do Sul,
90035-003 Porto Alegre, RS, Brazil
2 Divisão de Medicina Interna, Hospital de Clı́nicas de Porto Alegre, Universidade Federal do Rio Grande do Sul,

Rua Ramiro Barcellos 2350/700, 90035-903 Porto Alegre, RS, Brazil

Correspondence should be addressed to Tania Weber Furlanetto, taniafurlanetto@gmail.com

Received 14 January 2011; Accepted 24 February 2011

Academic Editor: Guillermo Juvenal

Copyright © 2011 A. P. Santin and T. W. Furlanetto. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.

Thyroid diseases are more prevalent in women, particularly between puberty and menopause. It is wellknown that estrogen (E) has
indirect effects on the thyroid economy. Direct effects of this steroid hormone on thyroid cells have been described more recently;
so, the aim of the present paper was to review the evidences of these effects on thyroid function and growth regulation, and its
mechanisms. The expression and ratios of the two E receptors, α and β, that mediate the genomic effects of E on normal and
abnormal thyroid tissue were also reviewed, as well as nongenomic, distinct molecular pathways. Several evidences support the
hypothesis that E has a direct role in thyroid follicular cells; understanding its influence on the growth and function of the thyroid
in normal and abnormal conditions can potentially provide new targets for the treatment of thyroid diseases.

1. Introduction (ER) alpha, and ER beta [7]. The isoform β is smaller

than the isoform α, and the DNA-binding domains of both
Thyroid diseases are more prevalent in women particularly subtypes are highly conserved. After binding of E2, ER
between puberty and menopause [1], and women are more forms a stable dimer that interacts with specific sequences
susceptible to the goitrogenic effect of iodine deficiency [2]. called estrogen response elements (EREs) to initiate the
Carcinomas of the thyroid are three-times more frequent transcription of target genes. Ligand-bound ERs can also
in women than in men, and the peak rates occur earlier interact with other transcription factors complexes and
in women [3]. These epidemiological data suggest a role of influence transcription of genes that do not harbor EREs.
estrogen in the pathogenesis of thyroid diseases. Third and fourth mechanisms of ERs regulatory actions
Estrogen has a well-known indirect effect on thyroid are, respectively, non-genomic and the ligand independent
economy, increasing the thyroxine binding globulin [4], and pathway. A variety of rapid signaling events such as activation
the need for thyroid hormone in hypothyroid women [5]. of kinases and phosphatases and increases in ion fluxes across
Direct effects of estrogen on thyroid cells have been described membranes has been described. These and other aspects of
more recently [6], so the aim of the present paper was to signaling and targets of ERs have been reviewed recently [7].
review the evidences of these effects on thyroid function and Recently, a transmembrane intracellular nonclassical ER
growth regulation, and its mechanisms. mediating rapid cell signaling was described, a G protein-
coupled receptor (GPCR), named GPR30 [8].
2. Estrogen and Its Receptors
17-β-estradiol (E2) is a lipophilic hormone with low- 2.1. Expression of ERs in Human Thyroid Tissue. Classically,
molecular weight that occurs naturally. Cellular signaling the presence of ER is fundamental for a direct action of
of estrogen is mediated classically upon the binding on estrogen in a given cell. ER has been described in both
two soluble intracellular nuclear receptors, estrogen receptor neoplastic and nonneoplastic human thyroid tissues, but
 2

Table 1: Estrogen receptor (ER) in human normal thyroid, and benign and malignant thyroid diseases.
Benign lesions Carcinoma
Study Method Normal All benign lesions All neoplastic lesions All carcinoma
Adenoma Goiter Papillary Follicular Medullary Anaplastic
Tavangar et al. [10]; 2007 IHC 8/37 31/130 37/119 2/18 0/35 0/12
Arain et al. [11];2003 IHC 0/25 0/9 0/8 0/19 0/10 0/4
Lewy-Trenda et al.[12]; 1998 IHC 2/19 0/20 4/8 3/5 0/4
Valle et al. [13]; 1998 RT-PCR 28/33 12/12 6/7 26/26 1/1 1/1 1/1
Bonacci et al. [14]; 1996 DCC 26/38 11/28 7/20
Jaklic et al. [15];1995 IHC 0/1 0/5 0/4 0/1
Colomer et al.[16];1996 IHC 1/7
Inoue et al. [17];1993 IHC 24/74
Inoue et al. [18];1993 IHC 18/70
Yane et al. [19];1994 RT-PCR 5/27
Yane et al. [20];1993 IHC 0/10 2/19 2/12 0/7
Hiasa et al. [21];1993 IHC 44/130 23/39 19/115 7/23 0/6
Diaz et al. [22];1991 IHC 20/30 23/30 11/20
Mizukami et al.[23];1991 IHC 8/18 4/8 47/62
Takeichi et al.[24];1991 IHC 11/12 1/6
Hong et al.[25];1991 IHC 1/27 1/20
Miki et al. [26]; 1990 DCC 0/14 12/46 7/23 5/11 2/12 6/20 0/1 1/1
Haruta et al.[27];1990 IHC 30/52 0/12
Chaudhuri et al.[28];1989 SDG 3/8 7/9 5/23 8/8 0/6
Money et al. [29];1989 IHC 20/22
Clark et al. [30];1985 SDG 14/15
Hampl [15];1985 RBA 0/8 0/5
Molteni et al. [37];1981 SDG 0/2 2/4
Data are shown as number of ER-positive samples/total number of samples. IHC: immunohistochemical assay; DCC: dextran-coated charcoal assay; RT-PCR: reverse transcriptase-polymerase chain reaction
technique; SDG: sucrose density gradient assay; RBA: radioligand binding assay.
Journal of Thyroid Research
Journal of Thyroid Research 3

Table 2: Estrogen receptors (ER) α and β in human normal thyroid, and benign and malignant thyroid diseases, by immunohistochemistry
(IHC).

All Benign lesions Carcinoma

Study Isoform All benign
carcinoma Adenoma Goiter Papillary Follicular Medullary Anaplastic
Vaiman et al.
ERα 0/34 0/150 0/90 0/6 0/4 0/5
[31]; 2010
ERβ 30/34 126/150 60/90 4/6 3/4 3/5
Winters et
ERα 1/1
al.[32]; 2010
Vannucchi et
ERα 12/38
al.[33]; 2010
Cho et al. [34];
ERα 10/11
2007
ERβ 8/11
Bléchet et al.
ERα 0/28
[35]; 2007
ERβ 26/28
Ceresini et al.
ERα 0/17 0/17
[36]; 2006
ERβ 17/17 14/17
Data are shown as number of ER-positive samples/total number of samples.

the results are discordant. Immunohistochemical assays, ERα/ERβ, suggesting a possible role in tumor growth and
with monoclonal antibodies, are the most commonly used progression. A few studies evaluated ERα and ERβ expression
methods for establishing receptor status. As may be seen in in normal and abnormal thyroid tissue, as shown in Table 2.
Table 1, some studies have found ER-positivity in normal and The effects of the agonists of ERα and ERβ, respectively,
abnormal thyroid tissue while others have not detected ER propyl-pyrazole-triol (PPT) and diarylpropionitrile (DPN),
protein in any tissue studied. This discrepancy could be due in the proliferation of thyroid cancer cell lines has been
to methodological issues; the development of monoclonal studied: PPT had a stimulatory effect, while inhibition of
antibodies against ER with high sensitivity and specificity, proliferation and DNA fragmentation were observed after
and others factors such as tissue fixation, tissue processing, DPN [45]. In the same study, small interference ribonucleic
interpretation of immunohistochemistry, and cutoffs for acid (siRNA) blocking ERα or ERβ demonstrated that knock-
positive results, could have contributed to the sensitivity of down of the ERα attenuated E2-mediated B-cell lymphoma
the techniques employed [9]. 2 (Bcl-2) expression, an important antiapoptotic protein,
while knockdown of the ERβ enhanced E2-induced Bcl-2
expression [45].
2.2. Expression of ERα and ERβ in Human Thyroid Tissue. ER
expression in human thyroid was first reported in 1981 [37].
ERα was first described in 1973 [38], and ERβ was identified 2.3. Expression of GPR30 in Thyroid Cells Lines. Growing
in 1996 [39], so only from this moment on it was possible to evidence suggests that estrogens are also able to exert non-
evaluate the relationship between isoforms of ERs in thyroid genomic events mediated by GPR30 [8]. Vivacqua and
tissue. An important role of different patterns of distribution colleagues analyzed the effects of E2 and the phytoestrogen
and expression of subtypes ERs in thyroid carcinoma has genistein in human follicular thyroid carcinoma cell lines,
been proposed: estrogen binding to ERα would promote WRO and FRO, and ARO, a human anaplastic thyroid
cell proliferation and growth, and, in contrast, ERβ would carcinoma cell line [46]. Both hormones stimulated in
promote apoptotic actions and other suppressive functions vitro proliferation of these cell lines through the GPR30
in thyroid tumors, as reviewed by Chen et al. [40]. Then, and mitogen-activated protein kinase signaling cascade [46].
ERα : ERβ ratio could have a role in the pathophysiology In other human benign and malignant thyroid tissue, the
of thyroid cancer [40], similar to that postulated for breast expression of GPR30 has not been studied.
cancer [41].
In differentiated thyroid follicular tumors, the expression 3. Response to E2 Stimulation In Vitro
of ERα has been associated with well-differentiated tumors
and reduced incidence of disease recurrence [54]. ERα 3.1. Proliferation. Several studies described proliferation of
protein [55] and ERα mRNA [19, 56] are expressed in thyroid cells induced by E2, as shown in Table 3. Some of
normal and neoplastic follicular cells of the thyroid. Also, the most commonly used assays are incorporation of bro-
the expression of ERα and ERβ was detected in human modeoxyuridine (BrdU) [6], 3-(4,5-dimethylthiazol-2-yl)-
medullary thyroid cancer [34] with an increased ratio of 2,5-diphenyl tetrazolium bromide (MTT) [45, 47, 50, 57],
4 Journal of Thyroid Research

Table 3: E2 effects on thyroid protein expression, function, and proliferation in vitro.

Erα Erβ Nis Iodide TG

Study Thyroid cells Presence of ERα/ERβ Proliferation
expression expression expression uptake mRNA
Kumar et al.[42]; 2010 NPA87 ERα+/ERβ+ ↑
KAT5 ERα+/ERβ+ ↑
WRO ERα+/ERβ+ ↑
Rajoria et al. [43]; 2010 BCPAP ERα+/ERβ+ ↑
Nthy-3-1 ERα+/ERβ+ ↑
Zeng et al. [44]; 2008 KAT5 ERα+/ERβ+ ↑ 0 ↑
FRO ERα+/ERβ+ 0 ↑ ↓
Zeng et al. [45]; 2007 KAT5 ERα+/ERβ+ ↑ 0 ↑
FRO ERα+/ERβ+ ↑ ↑ ↑
ARO ERα+/Erβ+ ↑ 0 ↑
Vivacqua et al. [46];
WRO ERα+/ERβ− ↑
2006
FRO ERα+/ERβ− ↑
ARO ERα−/ERβ− ↑
Lee et al. [47]; 2005 KAT5 ↑
Banu et al. [48]; 2001 NPA87 ER+ ↑ ↑
WRO ER+ ↓
Manole et al. [6]; 2001 HTC - TSHr ERα+/ERβ+ ↑ ↑ ↑
Goiter ERα+/ERβ+ ↑ ↑ ↑
XTC 133 ↑
Furlanetto et al. [49];
FRTL-5 ↑ ↓
2001
Furlanetto et al. [50];
FRTL-5 ERα+ ↑ ↓
1999
Nagy et al. [51]; 1999∗ Mng ↑
Ca ↑
Ade ↓
Del Senno et al. [52];
N ↑ ↑
1989∗∗
Ade ↑ ↑
Ca 0 0
Yang et al. [53]; 1988 TT ↑
Estrogen receptor (ER) +: presence of expression, –: absence of expression; NPA87, KAT5, and BCPAP: human papillary thyroid carcinoma cell lines; WRO
and FRO: human follicular thyroid carcinoma cell lines; Nthy-3-1: human normal transformed thyroid cell line; ARO: human anaplastic thyroid carcinoma
cell line; HTC-TSHr: human thyroid carcinoma cell line lacking endogenous TSH receptor; XTC-133: thyroid cancer cell line of Hurthle cell origin; FRTL-
5: Fischer rat thyroid cell line. Mng: multinodular goiter; Ca: carcinoma; Ade: adenoma; N: normal thyroid; TT: human medullary thyroid carcinoma cell
line; ↑: increase, ↓: decrease, and 0: no effect, after E2 exposure.: ∗ thyroid tissue obtained in surgical resection, under organotypic culture conditions for 48
hours;∗∗ suspension cultures of thyroid follicles.

[(3)H]-thymidine incorporation [48, 52, 53], and trypan and the iodide uptake [49]. E2 increased the thyroglobulin
blue solution [43]. Cotreatment with ICI182780, fulvestrant, gene expression in suspension cultures of human thyroid
an antagonist of E2 by inhibition and degradation of ER [58], follicles of adenoma and carcinoma [52]. These data are
significantly attenuated these proliferative effects. shown in Table 3. The opposite effects of E2 on the NIS
Based in these studies, E2 increases proliferation of gene expression and iodide uptake, in FRTL-5 cells, and
thyroid cells. the thyroglobulin gene expression, in suspension culture of
thyroid cells, could be due to the different systems studied;
it cannot be excluded that estradiol affects these genes
3.2. ER-Dependent Effects on Thyroid Differentiation Proteins. by different intracellular pathways. These results, together
Few studies evaluated E2 effect on gene transcription of with the increase in cell growth caused by estrogen, could
differentiation proteins in thyroid cells. In Fischer rat implicate this hormone in the pathogenesis of goiter and
derived thyroid cell line, FRTL-5, E2 treatment decreased thyroid carcinoma; nevertheless, as just one study evaluated
the sodium-iodide symporter (NIS) gene expression [50],
Journal of Thyroid Research 5

Table 4: Non-genomic estrogen effects on thyroid cells.

Study Cells GPR30 MAPK PI3k Cyclin D1 c-fos BcL-2 Bax

Kumar et al.[42]; 2010 NPA87 − ↑ ↑
KAT5 − ↑ ↑ ↑
WRO + ↑ ↑ ↑
Zeng et al. [45]; 2007 KAT5 ↑ ↓
FRO ↑ ↓
WRO ↑ ↓
Vivacqua et al. [46]; 2006 WRO + ↑ ↑ ↑
FRO + ↑ ↑ ↑
ARO + ↑ ↑ ↑
Manole et al. [6]; 2001 HTC-TSHr ↑ ↑
Goiter ↑ ↑
XTC 133 ↑ ↑
NPA87 and KAT5: human papillary thyroid carcinoma cell lines; WRO and FRO: human follicular thyroid carcinoma cell lines; HTC-TSHr: human thyroid
carcinoma cell line lacking endogenous TSH receptor; XTC-133: thyroid cancer cell line of Hurthle cell origin; Goiter: primary culture of human thyroid cells
isolated from goiter nodules. (+): presence of expression; (−) absence of expression; (↑): increase, (↓): decrease, and (0): no effects, after E2 exposure.

the effect of estrogen on thyroid differentiated proteins in Together, these results are very compelling, pointing
human thyroid tissue, more studies should be done to better to an ability of E2 to regulate genes mediating cell cycle
understand the role of estrogen in thyroid differentiated progression in thyroid cells, and potentially contributing to
protein expression. the pathogenesis of thyroid cancer or thyroid hyperplasia.

4. Conclusions
3.3. Non-Genomic Effects of E2. Some of the actions of
E2 in the proliferation of thyroid cells are mediated by There are evidences that estrogen may have direct actions in
the activation of signal transducing pathways, as shown in human thyroid cells by ER-dependent mechanisms or not,
Table 4. E2 can induce activation of phosphatidylinositol modulating proliferation, and function. Different patterns
3-kinase (PI3K) [42] and phosphorylation of extracellular of distribution, expression, and ratios of ERα and ERβ may
signal-regulated kinase 1/2 (ERK1/2) in follicular thyroid have a role in thyroid cancer cells proliferation, as well as
carcinoma cells, mainly due to interaction via membrane- in the outcome of thyroid cancer. Studying estrogen effects
associated ER [42, 45, 46]. PI3K and Erk1/2 signaling may on thyroid cells is a potential tool to better understand the
play a critical role in preventing apoptosis and inducing cell pathogenesis of thyroid diseases, and to develop targets to
cycle progression by induction of key genes expression [59]. its treatment. Further studies on the influence of E2 on the
Expression of early response genes and regulatory genes growth and function of the thyroid are needed, preferably
of the cell cycle are necessary for proliferation of cells. As E2 in primary culture of normal and abnormal human thyroid
has been demonstrated to stimulate the growth of thyroid cells.
cells, it is important to study the expression of key cell-cycle
genes such as cyclin D1 after stimulation with E2. Cyclin D1 Conflict of Interests
regulates the cell progression cycle facilitating G1 to S phase
transition and also has an estrogen-responsive regulatory The authors declare that there is no conflict of interests.
region [60], that is likely different from the canonical EREs.
Overexpression of cyclin D1 in thyroid malignancies has References
been reported [61–65], moreover, its expression has been
associated with an aggressive behavior in papillary thyroid [1] M. P. J. Vanderpump, W. M. G. Tunbridge, J. M. French et
microcarcinomas, because over 90% of the metastasizing al., “The incidence of thyroid disorders in the community:
microcarcinomas expressed cyclin D1 [66]. a twenty-year follow-up of the Whickham Survey,” Clinical
E2 significantly increased the expression of cyclin D1 in Endocrinology, vol. 43, no. 1, pp. 55–68, 1995.
a human thyroid carcinoma cell line lacking endogenous [2] P. Laurberg, K. M. Pedersen, A. Hreidarsson, N. Sigfusson, E.
Iversen, and P. R. Knudsen, “Iodine intake and the pattern
TSH receptor (HTC-TSHr cells), and in a thyroid cancer cell
of thyroid disorders: a comparative epidemiological study of
line of Hurthle cell origin (XTC-133), which was abolished thyroid abnormalities in the elderly in iceland and in Jutland,
by PD.098059 that blocked G0/G1 to S phases [6]. E2 Denmark,” Journal of Clinical Endocrinology and Metabolism,
upregulated cyclins A and D1, as well as the proto-oncogene vol. 83, no. 3, pp. 765–769, 1998.
c-fos, in WRO, FRO, and ARO cells [46]. Cyclin D1 was also [3] L. Enewold, K. Zhu, E. Ron et al., “Rising thyroid cancer
shown to be upregulated by E2 in KAT5, a papillary thyroid incidence in the United States by demographic and tumor
cancer cell line, and WRO cells [42]. characteristics, 1980–2005,” Cancer Epidemiology Biomarkers
6 Journal of Thyroid Research

and Prevention, vol. 18, no. 3, pp. 784–791, 2009. thyroid tumors,” Journal of Otolaryngology of Japan, vol. 96,
[4] Z. Ben-Rafael, J. F. Struass, B. Arendash-Durand, L. Mas- no. 5, pp. 787–790, 1993.
troianni, and G. L. Flickinger, “Changes in thyroid function [21] Y. Hiasa, H. Nishioka, Y. Kitahori et al., “Immunohistochem-
tests and sex hormone binding globulin associated with ical analysis of estrogen receptors in 313 paraffin section cases
treatment by gonadotropin,” Fertility and Sterility, vol. 48, no. of human thyroid tissue,” Oncology, vol. 50, no. 2, pp. 132–136,
2, pp. 318–320, 1987. 1993.
[5] B. M. Arafah, “Increased need for thyroxine in women [22] N. M. Diaz, G. Mazoujian, and M. R. Wick, “Estrogen-
with hypothyroidism during estrogen therapy,” New England receptor protein in thyroid neoplasms. An immunohisto-
Journal of Medicine, vol. 344, no. 23, pp. 1743–1749, 2001. chemical analysis of papillary carcinoma, follicular carcinoma,
[6] D. Manole, B. Schildknecht, B. Gosnell, E. Adams, and and follicular adenoma,” Archives of Pathology and Laboratory
M. Derwahl, “Estrogen promotes growth of human thyroid Medicine, vol. 115, no. 12, pp. 1203–1207, 1991.
tumor cells by different molecular mechanisms,” Journal of [23] Y. Mizukami, T. Michigishi, A. Nonomura, T. Hashimoto, M.
Clinical Endocrinology and Metabolism, vol. 86, no. 3, pp. Noguchi, and F. Matsubara, “Estrogen and estrogen receptors
1072–1077, 2001. in thyroid carcinomas,” Journal of Surgical Oncology, vol. 47,
[7] N. Heldring, A. Pike, S. Andersson et al., “Estrogen receptors: no. 3, pp. 165–169, 1991.
how do they signal and what are their targets,” Physiological [24] N. Takeichi, H. Ito, R. Haruta, T. Matsuyama, K. Dohi, and E.
Reviews, vol. 87, no. 3, pp. 905–931, 2007. Tahara, “Relation between estrogen receptor and malignancy
[8] C. M. Revankar, D. F. Cimino, L. A. Sklar, J. B. Arterburn, of thyroid cancer,” Japanese Journal of Cancer Research, vol. 82,
and E. R. Prossnitz, “A transmembrane intracellular estrogen no. 1, pp. 19–22, 1991.
receptor mediates rapid cell signaling,” Science, vol. 307, no. [25] G. S. Hong, I. T. Y. Sng, and K. C. Soo, “Oestrogen receptors
5715, pp. 1625–1630, 2005. in well differentiated thyroid cancers,” Annals of the Academy
[9] A. M. Gown, “Current issues in ER and HER2 testing by IHC of Medicine Singapore, vol. 20, no. 6, pp. 767–769, 1991.
in breast cancer,” Modern Pathology, vol. 21, no. 2, pp. S8–S15, [26] H. Miki, K. Oshimo, H. Inoue, T. Morimoto, and Y. Monden,
2008. “Sex hormone receptors in human thyroid tissues,” Cancer,
[10] S. M. Tavangar, M. Monajemzadeh, B. Larijani, and V. Hagh- vol. 66, no. 8, pp. 1759–1762, 1990.
panah, “Immunohistochemical study of oestrogen receptors [27] R. Haruta, H. Ito, N. Takeichi, T. Matsuyama, K. Dohi, and E.
in 351 human thyroid glands,” Singapore Medical Journal, vol. Tahara, “An immunohistochemical study of estrogen receptors
48, no. 8, pp. 744–747, 2007. in thyroid carcinoma,” Gan No Rinsho, vol. 36, no. 4, pp. 465–
[11] S. A. Arain, M. H. Shah, S. A. Meo, and Q. Jamal, “Estrogen 468, 1990.
receptors in human thyroid gland. An immunohistochemical [28] P. K. Chaudhuri and R. Prinz, “Estrogen receptor in normal
study,” Saudi Medical Journal, vol. 24, no. 2, pp. 174–178, 2003. and neoplastic human thryoid tissue,” American Journal of
[12] I. Lewy-Trenda, “Estrogen receptors in the malignant and Otolaryngology, vol. 10, no. 5, pp. 322–326, 1989.
benign neoplasms of the thyroid,” Polski Merkuriusz Lekarski, [29] S. R. Money, W. Muss, W. L. Thelmo et al., “Immunocyto-
vol. 5, no. 26, pp. 80–83, 1998. chemical localization of estrogen and progesterone receptors
[13] L. D. Valle, A. Ramina, S. Vianello, A. Fassina, P. Belvedere, in human thyroid,” Surgery, vol. 106, no. 6, pp. 975–979, 1989.
and L. Colombo, “Potential for estrogen synthesis and action [30] O. H. Clark, P. L. Gerend, and M. Davis, “Estrogen and
in human normal and neoplastic thyroid tissues,” Journal of thyroid-stimulating hormone (TSH) receptors in neoplastic
Clinical Endocrinology and Metabolism, vol. 83, no. 10, pp. and nonneoplastic human thyroid disease,” Journal of Surgical
3702–3709, 1998. Research, vol. 38, no. 2, pp. 89–96, 1985.
[14] R. Bonacci, A. Pinchera, P. Fierabracci, A. Gigliotti, L. [31] M. Vaiman, Y. Olevson, L. Habler, A. Kessler, S. Zehavi, and J.
Grasso, and C. Giani, “Relevance of estrogen and progesterone Sandbank, “Diagnostic value of estrogen receptors in thyroid
receptors enzyme immunoassay in malignant, benign and sur- lesions,” Medical Science Monitor, vol. 16, no. 7, pp. 203–207,
rounding normal thyroid tissue,” Journal of Endocrinological 2010.
Investigation, vol. 19, no. 3, pp. 159–164, 1996. [32] A. Winters, P. Friedlander, B. M. Jaffe, M. A. Khalek, K.
[15] B. R. Jaklic, J. Rushin, and B. C. Ghosh, “Estrogen and Moroz, and E. Kandil, “A postmenopausal woman with gross
progesterone receptors in thyroid lesions,” Annals of Surgical cystic disease fluid protein-15 and estrogen receptor-positive
Oncology, vol. 2, no. 5, pp. 429–434, 1995. recurrence of papillary thyroid cancer,” Thyroid, vol. 20, no.
[16] A. Colomer, J. V. Martı́nez-Mas, X. Matias-Guiu et al., 12, pp. 1413–1417, 2010.
“Sex-steroid hormone receptors in human medullary thyroid [33] G. Vannucchi, M. Perrino, S. Rossi et al., “Clinical and
carcinoma,” Modern Pathology, vol. 9, no. 1, pp. 68–72, 1996. molecular features of differentiated thyroid cancer diagnosed
[17] H. Inoue, K. Oshimo, H. Miki et al., “Immunohistochemical during pregnancy,” European Journal of Endocrinology, vol.
study of estrogen receptor and estradiol on papillary thyroid 162, no. 1, pp. 145–151, 2010.
carcinoma in young patients,” Journal of Surgical Oncology, [34] M. A. Cho, M. K. Lee, K. H. Nam et al., “Expression and role
vol. 53, no. 4, pp. 226–230, 1993. of estrogen receptor α and β in medullary thyroid carcinoma:
[18] H. Inoue, K. Oshimo, H. Miki, M. Kawano, and Y. Monden, different roles in cancer growth and apoptosis,” Journal of
“Immunohistochemical study of estrogen receptors and the Endocrinology, vol. 195, no. 2, pp. 255–263, 2007.
responsiveness to estrogen in papillary thyroid carcinoma,” [35] C. Bléchet, P. Lecomte, L. De Calan, P. Beutter, and S.
Cancer, vol. 72, no. 4, pp. 1364–1368, 1993. Guyétant, “Expression of sex steroid hormone receptors in C
[19] K. Yane, Y. Kitahori, N. Konishi et al., “Expression of the cell hyperplasia and medullary thyroid carcinoma,” Virchows
estrogen receptor in human thyroid neoplasms,” Cancer Archiv, vol. 450, no. 4, pp. 433–439, 2007.
Letters, vol. 84, no. 1, pp. 59–66, 1994. [36] G. Ceresini, S. Morganti, V. Graiani et al., “Estrogen recep-
[20] K. Yane, O. Tanaka, H. Miyahara, T. Matsunaga, Y. Kitahori, tor (ER)-β, but not ER-α, is present in thyroid vessels:
and Y. Hiasa, “Immunohistochemical study of epidermal immunohistochemical evaluations in multinodular goiter and
growth factor receptor and estrogen receptor in human papillary thyroid carcinoma,” Thyroid, vol. 16, no. 12, pp.
Journal of Thyroid Research 7

1215–1220, 2006. [52] L. Del Senno, E. Degli Uberti, S. Hanau, R. Piva, R. Rossi, and
[37] A. Molteni, R. L. Warpeha, L. Brizio-Molteni, and E. M. G. Trasforini, “In vitro effects of estrogen on tgb and c-myc
Fors, “Estradiol receptor-binding protein in head and neck gene expression in normal and neoplastic human thyroids,”
neoplastic and normal tissue,” Archives of Surgery, vol. 116, no. Molecular and Cellular Endocrinology, vol. 63, no. 1-2, pp. 67–
2, pp. 207–210, 1981. 74, 1989.
[38] E. V. Jensen and E. R. DeSombre, “Estrogen receptor interac- [53] K. Yang, C. E. Pearson, and N. A. Samaan, “Estrogen receptor
tion,” Science, vol. 182, no. 4108, pp. 126–134, 1973. and hormone responsiveness of medullary thyroid carcinoma
[39] S. Mosselman, J. Polman, and R. Dijkema, “ERβ: identification cells in continuous culture,” Cancer Research, vol. 48, no. 10,
and characterization of a novel human estrogen receptor,” pp. 2760–2763, 1988.
FEBS Letters, vol. 392, no. 1, pp. 49–53, 1996. [54] D. O. Kavanagh, M. McIlroy, E. Myers et al., “The role of
[40] G. G. Chen, A. C. Vlantis, Q. Zeng, and C. A. Van Hasselt, oestrogen receptor α in human thyroid cancer: contributions
“Regulation of cell growth by estrogen signaling and potential from coregulatory proteins and the tyrosine kinase receptor
targets in thyroid cancer,” Current Cancer Drug Targets, vol. 8, HER2,” Endocrine-Related Cancer, vol. 17, no. 1, pp. 255–264,
no. 5, pp. 367–377, 2008. 2010.
[41] A. M. Sotoca, H. Van den Berg, J. Vervoort et al., “Influence of [55] C. Lee et al., “Estrogen receptors and glucocorticoid receptors
cellular ERα/ERβ ratio on the ERα-agonist induced prolifera- in human well-differentiated thyroid cancer,” International
tion of human T47D breast cancer cells,” Toxicological Sciences, Journal of Molecular Medicine, vol. 2, no. 2, pp. 229–233, 1998.
vol. 105, no. 2, pp. 303–311, 2008. [56] C. Egawa, Y. Miyoshi, K. Iwao, E. Shiba, and S. Noguchi,
[42] A. Kumar, C. M. Klinge, and R. E. Goldstein, “Estradiol- “Quantitative analysis of estrogen receptor-α and -β messen-
induced proliferation of papillary and follicular thyroid cancer ger RNA expression in normal and malignant thyroid tissues
cells is mediated by estrogen receptors α and β,” International by real-time polymerase chain reaction,” Oncology, vol. 61, no.
Journal of Oncology, vol. 36, no. 5, pp. 1067–1080, 2010. 4, pp. 293–298, 2001.
[43] S. Rajoria, R. Suriano, A. Shanmugam et al., “Metastatic [57] T. Hoelting, S. Tezelman, A. E. Siperstein, Q. Y. Duh, and O. H.
phenotype is regulated by estrogen in thyroid cells,” Thyroid, Clark, “Biphasic effects of thyrotropin on invasion and growth
vol. 20, no. 1, pp. 33–41, 2010. of papillary and follicular thyroid cancer in vitro,” Thyroid, vol.
[44] Q. Zeng, G. G. Chen, A. C. Vlantis, G. M. Tse, and C. 5, no. 1, pp. 35–40, 1995.
A. Van Hasselt, “The contributions of oestrogen receptor [58] V. Marsaud, A. Gougelet, S. Maillard, and J.-M. Renoir,
isoforms to the development of papillary and anaplastic “Various phosphorylation pathways, depending on agonist
thyroid carcinomas,” Journal of Pathology, vol. 214, no. 4, pp. and antagonist binding to endogenous estrogen receptor α
425–433, 2008. (ERα), differentially affect ERα extractability, proteasome-
[45] Q. Zeng, G. G. Chen, A. C. Vlantis, and C. A. Van Hasselt, mediated stability, and transcriptional activity in human
“Oestrogen mediates the growth of human thyroid carcinoma breast cancer cells,” Molecular Endocrinology, vol. 17, no. 10,
cells via an oestrogen receptor-ERK pathway,” Cell Prolifera- pp. 2013–2027, 2003.
tion, vol. 40, no. 6, pp. 921–935, 2007. [59] M. Saji and M. D. Ringel, “The PI3K-Akt-mTOR pathway in
[46] A. Vivacqua, D. Bonofiglio, L. Albanito et al., “17β-Estradiol, initiation and progression of thyroid tumors,” Molecular and
genistein, and 4-hydroxytamoxifen induce the proliferation of Cellular Endocrinology, vol. 321, no. 1, pp. 20–28, 2010.
thyroid cancer cells through the G protein-coupled receptor [60] L. Altucci, R. Addeo, L. Cicatiello et al., “17β-estradiol induces
GPR30,” Molecular Pharmacology, vol. 70, no. 4, pp. 1414– cyclin D gene transcription, p36(D)-p34(cdk4) complex acti-
1423, 2006. vation and p105(Rb) phosphorylation during mitogenic stim-
[47] M. L. Lee, G. G. Chen, A. C. Vlantis, G. M. K. Tse, B. C. H. ulation of G-arrested human breast cancer cells,” Oncogene,
Leung, and C. A. Van Hasselt, “Induction of thyroid papillary vol. 12, no. 11, pp. 2315–2324, 1996.
carcinoma cell proliferation by estrogen is associated with an [61] S. Sporny, D. Slowinska-Klencka, and M. Ratynska, “Cyclin D1
altered expression of Bcl-xL,” Cancer Journal, vol. 11, no. 2, pp. expression in primary thyroid carcinomas,” Neuroendocrinol-
113–121, 2005. ogy Letters, vol. 26, no. 6, pp. 815–818, 2005.
[48] K. S. Banu, P. Govindarajulu, and M. M. Aruldhas, “Testos- [62] Y. Shi, M. Zou, E. Varkondi, A. Nagy, L. Kozma, and N. R.
terone and estradiol have specific differential modulatory Farid, “Cyclin D1 in thyroid carcinomas,” Thyroid, vol. 11, no.
effect on the proliferation of human thyroid papillary and 7, pp. 709–710, 2001.
follicular carcinoma cell lines independent of TSH action,” [63] F. Basolo, M. A. Caligo, A. Pinchera et al., “Cyclin D1
Endocrine Pathology, vol. 12, no. 3, pp. 315–327, 2001. overexpression in thyroid carcinomas: relation with clinico-
[49] T. W. Furlanetto, R. B. Nunes, A. M. I. Sopelsa, and R. M. pathological parameters, retinoblastoma gene product, and
B. Maciel, “Estradiol decreases iodide uptake by rat thyroid ki67 labeling index,” Thyroid, vol. 10, no. 9, pp. 741–746, 2000.
follicular FRTL-5 cells,” Brazilian Journal of Medical and [64] D. Lazzereschi, L. Sambuco, C. Carnuvale Scalzo et al., “Cyclin
Biological Research, vol. 34, no. 2, pp. 259–263, 2001. D1 and cyclin E expression in malignant thyroid cells and in
[50] T. W. Furlanetto, L. Q. Nguyen, and J. L. Jameson, “Estradiol human thyroid carcinomas,” International Journal of Cancer,
increases proliferation and down-regulates the sodium/iodide vol. 76, no. 6, pp. 806–811, 1998.
symporter gene in FRTL-5 cells,” Endocrinology, vol. 140, no. [65] S. Wang, R. V. Lloyd, M. J. Hutzler, M. S. Safran, N. A.
12, pp. 5705–5711, 1999. Patwardhan, and A. Khan, “The role of cell cycle regulatory
[51] N. Nagy, I. Camby, C. Decaestecker et al., “The influence of L- protein, cyclin D1, in the progression of thyroid cancer,”
triiodothyronine, L-thyroxine, estradiol-17β, the luteinizing- Modern Pathology, vol. 13, no. 8, pp. 882–887, 2000.
hormone-releasing hormone, the epidermal growth factor and [66] M. L. C. Khoo, S. Ezzat, J. L. Freeman, and S. L. Asa,
gastrin on cell proliferation in organ cultures of 35 benign “Cyclin D1 protein expression predicts metastatic behavior
and 13 malignant human thyroid tumors,” Journal of Cancer in thyroid papillary microcarcinomas but is not associated
Research and Clinical Oncology, vol. 125, no. 6, pp. 361–368, with gene amplification,” Journal of Clinical Endocrinology and
1999. Metabolism, vol. 87, no. 4, pp. 1810–1813, 2002.

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