Cancer Causes Control DOI 10.1007/s10552-015-0546-z
REVIEW ARTICLE
Menstrual and reproductive history and use of exogenous sex hormones and risk of thyroid cancer among women: a meta-analysis of prospective studies Saverio Caini • Bianca Gibelli • Domenico Palli Calogero Saieva • Massimilano Ruscica • Sara Gandini
•
Received: 27 November 2014 / Accepted: 27 February 2015 Ó Springer International Publishing Switzerland 2015
Abstract Purpose Thyroid cancer has a higher incidence in women than in men, and it has been hypothesized that hormonal factors may explain such disparity. We performed a metaanalysis of observational prospective studies to investigate the association between menstrual and reproductive variables and exogenous hormone use and the risk of thyroid cancer among women. Methods We calculated summary relative risks and 95 % confidence intervals (95 % CI) using random effect models. Results Overall, 5,434 thyroid cancer cases from twentyfour papers were included. Increasing age at first pregnancy/birth (SRR 1.56, 95 % CI 1.01–2.42) and hysterectomy (SRR 1.43, 95 % CI 1.15–1.78) were associated with thyroid cancer risk. Women that were in menopause at
Electronic supplementary material The online version of this article (doi:10.1007/s10552-015-0546-z) contains supplementary material, which is available to authorized users. S. Caini (&) D. Palli C. Saieva Unit of Molecular and Nutritional Epidemiology, Institute for Cancer Research and Prevention (ISPO), Via delle Oblate 2, 50139 Florence, Italy e-mail: [email protected]; [email protected] B. Gibelli Department of Head and Neck Surgery, Thyroid Cancer Unit, European Institute of Oncology, Milan, Italy M. Ruscica Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy S. Gandini Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
enrolment had a reduced thyroid cancer risk (SRR 0.79, 95 % CI 0.62–1.01). No other menstrual, reproductive, and hormonal variable was associated with thyroid cancer risk. Conclusions Menstrual and reproductive factors may play a role in the etiology of thyroid cancer, possibly through the mediation of estrogen receptors. Keywords Menstrual factors Reproductive factors Hormone use Thyroid cancer Meta-analysis List of abbreviations 95 % CI 95 % confidence intervals ER Estrogen receptors SRR Summary relative risk OC Oral contraceptives HRT Hormone replacement therapy
Introduction The incidence of thyroid cancer has been increasing since the 1970s worldwide [1] and has nearly tripled between 1975 and 2009 in the USA [2]. While this rise in incidence is partly explained by excess diagnosis, a true increase in incidence also exists, the reasons of which are, however, still unclear [3]. Thyroid cancer has an incidence three times higher in women than in men and is the ninth most frequent tumor among females worldwide [4]. Few established risk factors for thyroid cancer are known (such as radiotherapy treatment of the neck area, family history of thyroid cancer, some hereditary conditions, and excess body weight) [5, 6], none of which can account but for a marginal part of the
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differences in thyroid cancer incidence by gender, due to either low absolute prevalence, little differences in prevalence by gender, or small associated relative risks. A possible exception is benign thyroid disease (including hyperand hypothyroidism, goiter, nodules, and autoimmune thyroiditis), which is highly prevalent [7], more frequent among women than men [8], and associated with a strongly increased risk of subsequent thyroid cancer [9]. Despite this, the attributable risk of thyroid cancer risk due to benign thyroid disease does not exceed 20 % [10], and female gender is associated with thyroid cancer risk also after adjusting by it [11]. Based on epidemiological data, it has long been speculated that hormonal and reproductive factors (including age at menarche, age at menopause, age at first birth, or age at last birth) may play a role in determining or modulating the risk of thyroid cancer [12]. This hypothesis is supported by experimental data as well, such as the promoting effect exerted by estrogens on the growth of thyroid cancer cells through a pathway mediated by estrogens receptors alpha (ER-a) and beta (ER-b) [13, 14]. The association between menstrual and reproductive factors and use of exogenous hormones [i.e., oral contraceptives (OC) or hormone replacement therapy (HRT)] and thyroid cancer risk has been investigated in several studies. Most studies published until the first half of the last decade had a case–control design [15, 16], which may be affected by recall bias for both putative causal exposures and confounding variables. Conversely, several studies with a prospective design (cohort, case-cohort, and nested case–control studies) have been appearing during recent years, despite with inconsistent findings [17–20]. We performed a systematic literature search and metaanalysis of observational prospective studies to summarize the best available evidence for the association between menstrual and reproductive variables and use of exogenous hormones and the risk of thyroid cancer among women.
Materials and methods Search of papers and inclusion criteria We planned and conducted a systematic literature search and subsequent analysis of data according to MOOSE guidelines for meta-analysis of observational studies [21]. We searched reports published before 31 July 2014 in the following databases: PUBMED, Ovid Medline, EMBASE, Google Scholar, ISI Web of Knowledge, Open Grey, and Grey Literature Report. The search was conducted by using any combination of the MESH terms for the exposures of interest (listed in Table 1) and ‘‘thyroid cancer.’’
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We obtained the full copy of all papers that were considered as potentially eligible for the present meta-analysis on the basis of the abstract. We searched for additional papers in the reference list of retrieved papers and of previously published reviews and meta-analyses. Two authors (SC and SG) independently read and decided on eligibility of selected papers (based on criteria listed below; all conflicts were resolved by discussion). We considered for inclusion in the present meta-analysis all studies with a prospective design, i.e., all studies in which information on exposures of interest and potential confounders was collected before the occurrence of thyroid cancer. Included in this definition are cohort studies (both general population [20] and special exposure cohorts [22] were allowed) and case–control or case-cohort studies nested within established cohorts. Instead, we excluded purely retrospective case–control studies, as well as ecological studies, case reports, reviews, and editorials. Papers were included in the meta-analysis that reported, or allowed to estimate, a measure of relative risk for the association between any exposure of interest and the risk of thyroid cancer among women, along with 95 % confidence intervals (95 % CI) or another measure of statistical uncertainty (variance, standard error, or exact p values). We used the publication with the largest number of thyroid cancer cases whenever there was an overlap (whether partial or total) of the study sample between two or more otherwise eligible papers. No language, time, or geographical restrictions were applied. Data extraction and statistical analysis We collected and inputted into a specially designed dataset the following information from each paper: publication year; country of study; study design; source of study participants; number and mean/median age (whatever was available) of thyroid cancer cases, cohort members, or controls (for nested case–control studies); first and last year at diagnosis of thyroid cancer; average years of follow-up; percent of thyroid cancer cases belonging to papillary, follicular, or other histotype; whether the study had a matched design and variables used for matching; how the information on exposures was obtained (self-administered questionnaire, face-to-face interview, medical records, etc.); and variables used for statistical adjustment. For each association of interest, we transformed the most adjusted estimate of relative risk (and corresponding confidence intervals) available in each paper into log relative risks, and calculated the corresponding variance by using the formula proposed by Greenland [23]. As thyroid is a relatively rare disease, we made no distinction between the different measures of relative risk (incidence rate ratio, risk ratio, odds ratio, and standardized incidence ratio). We
Cancer Causes Control Table 1 Variables of interest in the meta-analysis of menstrual, reproductive, and hormonal factors and thyroid cancer risk History of menstruation
Childbearing and breastfeeding
Use of exogenous sex hormones
Age at menarche
Ever pregnant/parous
History of use of OC
History of ovariectomy
Irregular menstrual cycle
Number of pregnancies/births
Age began using OC
History of hysterectomy
Menopausal status
Outcome of first pregnancy
Age ended using OC
Age at hysterectomy
Menopause type
Age at first pregnancy/birth
Duration of OC use
Time since hysterectomy
Age at menopause
Age at last pregnancy/birth
Time since last used OC
History of use of IUD
Time since menopause
Other variables
Time since last pregnancy/birth
History of use of HRT
Age began using IUD
History of abortion/miscarriage
Type of HRT
Duration of IUD use
History of stillbirth
Age began using HRT
History of tubal sterilization
Ever breastfeeding
Age ended using HRT
Age at tubal sterilization
Duration of breastfeeding
Duration of HRT use
Time since tubal sterilization
Time since last used HRT
History of infertility Use of fertility drugs History of in vitro fertilization
OC oral contraceptives, HRT hormone replacement therapy, IUD intrauterine device
calculated an unadjusted measure of relative risk (and evaluate its standard error by using Woolf’s formula) from crude tabular data, if available, when no adjusted estimate was reported in the text. We pooled study-specific estimates using random effect models through maximum likelihood estimation [24]. Summary relative risks (SRR) and respective 95 % CI were calculated for the association between each variable of interest (for which at least three estimates from independent studies were available) and thyroid cancer risk. The available estimates were pooled together, and a single SRR was calculated, for each of the following pairs of variables: ‘‘ever pregnant’’ and ‘‘ever parous’’; ‘‘number of pregnancies’’ and ‘‘number of births’’; and ‘‘history of abortion’’ and ‘‘history of miscarriage.’’ This was done to increase the statistical power and/or because it was unsure which variable of the pair was actually used in some papers. When it was possible to calculate a SRR, we also produced a forest plot including all available estimates, the SRR and its 95 % CI. For some variables of interest (for instance, age at menopause), there were papers reporting estimates that were obtained by using a reference category different from that used in the majority of papers (for instance, women of intermediate age instead of women youngest age). When this occurred, we used raw data (if available) to calculate an unadjusted estimate with the latter as reference category, and performed a sensitivity analysis to assess whether this procedure influenced the results. If raw data were not available, the paper was not used to calculate the SRR for that variable. The homogeneity of the effects across studies was assessed using the I2 statistics, which can be interpreted as
the proportion of total variation across studies that is attributable to heterogeneity [25]. The larger the value of I2, the greater the heterogeneity; a value of I2 below 50 % is considered as an acceptable degree of heterogeneity. We used meta-regression and subgroup analysis to quantify the proportion of between-study heterogeneity that is accounted for by several study variables, including country, study design, study population, adjustment for confounding factors, and others [23]. Meta-regression was also used to assess the effect on between-study heterogeneity of appropriate statistical methods and correct reporting of results, according to the STROBE checklist for observational epidemiologic studies [26]. We also performed a sensitivity analysis by examining changes in results produced by the exclusion of each study. We evaluated whether there was a publication bias against negative studies by using the Macaskill test, which is the most powerful option when less than 20 studies are used to calculate a SRR [27]. All the statistical analyses were conducted using R software, version 2.12.2 (http://www.r-project.org), and SAS software (SAS Institute Inc., Cary, NC; version 9.2).
Results We obtained the full copy of 92 papers (Fig. 1): Of these, twenty-six matched all inclusion criteria. However, the papers by Yli-Kuha [28] and Ka¨lle´n [29] could not be used to calculate any SRR as they were the only two papers providing estimates for the variable ‘‘history of in vitro fertilization,’’ and did not report on any other variable of interest. Therefore, the papers that were finally used for the
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Cancer Causes Control Fig. 1 Flowchart of the selection process for the studies included in the meta-analysis for the association between menstrual, reproductive, and hormonal factors and risk of thyroid cancer among women
meta-analysis were twenty-four [11, 17–20, 22, 30–47]: All were prospective cohort studies except the paper by Galanti et al. [45], which is a nested case–control study, and that by Wong et al. [17], which has a case-cohort design. Other characteristics of papers that were included are shown in Table 2 and in Supporting Table. Overall, 5,434 thyroid cancer cases diagnosed during over 18 million years of follow-up between 1935 and 2011 were available for analyses. The percentage of thyroid cancer cases belonging to the papillary and to another (including follicular) or unknown histotype in the papers for which this information was available was 69.6 % and, respectively, 30.4 %. We report in Table 3 the summary relative risk, their 95 % confidence intervals, and the value of the I2 statistics for the association between menstrual, reproductive, and hormonal variables (for which three or more independent estimates were available) and the risk of thyroid cancer
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among women. Forest plots are available in ESM Appendix. Neither age at menarche nor age at menopause was associated with thyroid cancer risk. The borderline significant 20 % reduction (I2 = 0 %) in thyroid cancer risk for women that were post-menopausal (compared to perior premenopausal) at enrolment disappeared after dropping the paper by Zamora-Ros et al. [30], from which we could only use an unadjusted estimate. Parity did not affect the risk of thyroid cancer among women, nor did having ever had an abortion and/or a miscarriage. Instead, increasing age at first pregnancy/birth was associated with an increasing risk of thyroid cancer, the SRR being 1.56 (95 % CI 1.01–2.42, I2 = 35 %) for those in the oldest versus youngest age group. Sensitivity analysis revealed that this result was highly dependent on the study by Wong et al. [17], the only reporting a
Cancer Causes Control Table 2 Main characteristics of studies included in the meta-analysis of menstrual, reproductive, and hormonal factors and thyroid cancer risk References
Country
Brinton et al. [47]
USA
Akslen et al. [46]
Norway
Galanti et al. [45]
Sweden
Persson et al. [44]
Sweden
Luoto et al. [43]
Finland
Modan et al. [42]
Israel
Iribarren et al. [11] Luoto et al. [41]
USA Finland
No. thyroid cancer
First and last year of follow-up
Mean/median follow-up (years)
2,335
1935–1981
19.4
124
63,090
1961–1989
na
1,409
&1,700,000
1943–1984
na
25
22,597
1977–1991
13.0
71
25,382
1963–1993
20.5
8
2,496
1964–1991
21.4
123 118
204,964 17,900
1964–1997 1986–1997
20.0 6.0
6
No. cohort
Althuis et al. [38]
USA
18
8,422
1965–1999
18.8
Navarro Silvera et al. [39]
Canada
169
89,835
1980–2000
15.9
Neale et al. [40]
Sweden
986
1,234,967
1961–1996
na
Rosenblatt et al. [37]
China
153
267,400
1989–2000
8.6
Wong et al. [17]
China
130
3,187
1989–1998
na
Hannibal et al. [36]
Denmark
29
54,362
1963–2000
8.8
Dorjgochoo et al. [34]
China
83
66,661
1997–2007
7.5
Pham et al. [18]
Japan
86
37,986
1988–1997
10.0
Rosenblatt et al. [35]
China
161
267,400
1989–2000
9.3
Meinhold et al. [22]
USA
242
69,506
1983–2006
15.8
Horn-Ross et al. [19]
USA
233
117,646
1995–2007
na
Schonfeld et al. [33]
USA
312
187,865
1995–2006
9.3
Kabat et al. [20]
USA
296
145,007
1993–2011
12.7
Sungwalee et al. [32] Braganza et al. [31]
Thailand USA
17 127
10,767 70,047
1990–2011 1993–2006
14.2 11.0
Zamora-Ros et al. [30]
Europe
508
345,157
1992–2009
11.0
significant association: After dropping this paper, the SRR was 1.25 (95 % CI 0.90–1.74, I2 = 0 %). The use of both OC and HRT and having ever had a diagnosis of infertility did not increase nor reduce the risk of thyroid cancer. Women who had undergone hysterectomy had an increased risk (SRR 1.43, 95 % CI 1.15–1.78, I2 = 47 %) of developing a thyroid cancer later in life. The heterogeneity decreased (I2 = 0 %) and the SRR fell to a borderline significant 1.34 (95 % CI 0.97–1.85) after dropping the paper by Luoto et al. [43] published in 1997. We found no evidence of publication bias against negative studies for any variable of interest.
Discussion We presented here the results of a meta-analysis of prospective studies on the association of menstrual and reproductive history and use of exogenous sex hormones and thyroid cancer risk, based on over 5,000 cases during more than 18 million person-years. We found a statistically significant risk effect of later age at first pregnancy/birth
and history of hysterectomy and a borderline significant inverse association for being in menopause at enrolment. No other menstrual, reproductive, and hormonal variable was convincingly associated with thyroid cancer risk. In particular, we were unable to replicate findings originating from case–control studies on age at menarche and use of oral contraceptives [15, 16]. Some variables of interest (such as use of exogenous hormones) and several potential confounding factors for the studied associations may be subject to recall bias, which may easily explain the discrepancies between retrospective and prospective studies. Overall, the role played by menstrual, reproductive, and hormonal variables on the risk of thyroid cancer seems to be modest, and cannot explain but a small share of the growth in thyroid cancer incidence over recent years and of the differences in incidence by gender. Yet, our results deserve careful attention because of their public health implication and their potential to shed light on the etiological mechanisms leading to thyroid cancer. Estrogen receptors can be found on both normal [48] and neoplastic thyroid cells [13, 49]. In physiology, ERs seem to be involved in the function of the thyroid gland,
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Cancer Causes Control Table 3 Summary relative risks and 95 % confidence intervals (95 % CI) for the association between menstrual, reproductive, and hormonal characteristics and risk of thyroid cancer among women Category
No. studies
No. thyroid cancer
SRR
Lower 95 % CI
Upper 95 % CI
I2 (%)
Age at menarche
Oldest versus youngest
11
2,244
1.02
0.90
1.16
31
Menopausal status at enrolment Age at menopause
Post- versus premenopausal Oldest versus youngest
4 5
1,042 1,157
0.79 1.19
0.62 0.79
1.01 1.78
0 0
Variable History of menstruation
Reproduction and breastfeeding History of pregnancies/births
Ever versus never
8
1,163
0.91
0.75
1.10
0
No. of pregnancies/births (reference: nulliparous women)
Many versus none
9
3,139
0.84
0.56
1.25
13
No. of pregnancies/births (reference: uniparous women)
Many versus one child
6
1,652
1.02
0.78
1.34
33
Age at first pregnancy/birth
Oldest versus youngest
11
2,848
1.56
1.01
2.42
35
Age at last pregnancy/birth History of abortion/miscarriage
Oldest versus youngest Ever versus never
4 4
1,858 915
1.91 1.11
0.78 0.87
4.65 1.42
0 0
Use of exogenous sex hormones History of use of OC
Ever versus never
10
1,959
0.99
0.87
1.13
0
Duration of OC use
Longest versus shortest
9
2,021
0.86
0.69
1.06
33
History of use of HRT
Ever versus never
8
1,802
1.05
0.89
1.24
14
History of hysterectomy
Ever versus never
4
615
1.43
1.15
1.78
47
History of infertility
Ever versus never
4
540
1.49
0.89
2.47
38
Other variables
2
I proportion of total variation in study estimates that is due to heterogeneity OC oral contraceptives, HRT hormone replacement therapy
mainly at puberty, in early pregnancy and breastfeeding [50, 51]. Beta-human chorionic gonadotropin plays a role in the normal physiology of the thyroid gland showing a strong thyroid-stimulating hormone-like effect in early pregnancy [52]. An inappropriate activation of ERs may also be caused by some chemicals (sometimes referred to as ‘‘xenoestrogens’’) with an endocrine disruptor activity [53]. A continuous activation of the ERs (by endogenous hormones or pollutants) may stimulate the growth of thyroid tissue and lead to development and progression of well differentiated (hence, with favorable prognosis) cancers. This could explain the risk effect that we found for a later age at first pregnancy/birth, and the borderline inverse association with younger age at menopause. A reason for the risk effect of the history of hysterectomy on thyroid cancer risk may be found in the frequent association of uterine leiomyomas (a leading cause of hysterectomy) and thyroid nodules [54]. The latter association is not surprising, given the role of estrogens in the physiology and pathology of both the thyroid gland and the uterus. Thyroid cancer incidence has grown steeply during past 40 years, especially among women [2]. The refinement of diagnostic techniques has allowed an early diagnosis of potentially lethal cancers, but also led to detect many cancers that would have never progressed toward clinical
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stage. Parallel to this, a true growth in incidence has occurred as well during recent years, the causes of which are, however, poorly understood [3, 53]. The activation of ERs of thyroid gland cells by endogenous hormones, endocrine disruptors, or other chemicals may account for a part of it, possibly along with an increased exposure to medical radiations and environmental pollutants [55], intake of endocrine disruptors through diet or water [55], overweight and obesity [56], and other causes yet to be identified. Ongoing and future research should primarily aim at improving our understanding of underlying mechanisms of carcinogenesis of thyroidal gland. Acknowledgments This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector. Conflict of interest interest to disclose.
The authors declare they have no conflicts of
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REVIEW ARTICLE
Menstrual and reproductive history and use of exogenous sex hormones and risk of thyroid cancer among women: a meta-analysis of prospective studies Saverio Caini • Bianca Gibelli • Domenico Palli Calogero Saieva • Massimilano Ruscica • Sara Gandini
•
Received: 27 November 2014 / Accepted: 27 February 2015 Ó Springer International Publishing Switzerland 2015
Abstract Purpose Thyroid cancer has a higher incidence in women than in men, and it has been hypothesized that hormonal factors may explain such disparity. We performed a metaanalysis of observational prospective studies to investigate the association between menstrual and reproductive variables and exogenous hormone use and the risk of thyroid cancer among women. Methods We calculated summary relative risks and 95 % confidence intervals (95 % CI) using random effect models. Results Overall, 5,434 thyroid cancer cases from twentyfour papers were included. Increasing age at first pregnancy/birth (SRR 1.56, 95 % CI 1.01–2.42) and hysterectomy (SRR 1.43, 95 % CI 1.15–1.78) were associated with thyroid cancer risk. Women that were in menopause at
Electronic supplementary material The online version of this article (doi:10.1007/s10552-015-0546-z) contains supplementary material, which is available to authorized users. S. Caini (&) D. Palli C. Saieva Unit of Molecular and Nutritional Epidemiology, Institute for Cancer Research and Prevention (ISPO), Via delle Oblate 2, 50139 Florence, Italy e-mail: [email protected]; [email protected] B. Gibelli Department of Head and Neck Surgery, Thyroid Cancer Unit, European Institute of Oncology, Milan, Italy M. Ruscica Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy S. Gandini Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
enrolment had a reduced thyroid cancer risk (SRR 0.79, 95 % CI 0.62–1.01). No other menstrual, reproductive, and hormonal variable was associated with thyroid cancer risk. Conclusions Menstrual and reproductive factors may play a role in the etiology of thyroid cancer, possibly through the mediation of estrogen receptors. Keywords Menstrual factors Reproductive factors Hormone use Thyroid cancer Meta-analysis List of abbreviations 95 % CI 95 % confidence intervals ER Estrogen receptors SRR Summary relative risk OC Oral contraceptives HRT Hormone replacement therapy
Introduction The incidence of thyroid cancer has been increasing since the 1970s worldwide [1] and has nearly tripled between 1975 and 2009 in the USA [2]. While this rise in incidence is partly explained by excess diagnosis, a true increase in incidence also exists, the reasons of which are, however, still unclear [3]. Thyroid cancer has an incidence three times higher in women than in men and is the ninth most frequent tumor among females worldwide [4]. Few established risk factors for thyroid cancer are known (such as radiotherapy treatment of the neck area, family history of thyroid cancer, some hereditary conditions, and excess body weight) [5, 6], none of which can account but for a marginal part of the
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differences in thyroid cancer incidence by gender, due to either low absolute prevalence, little differences in prevalence by gender, or small associated relative risks. A possible exception is benign thyroid disease (including hyperand hypothyroidism, goiter, nodules, and autoimmune thyroiditis), which is highly prevalent [7], more frequent among women than men [8], and associated with a strongly increased risk of subsequent thyroid cancer [9]. Despite this, the attributable risk of thyroid cancer risk due to benign thyroid disease does not exceed 20 % [10], and female gender is associated with thyroid cancer risk also after adjusting by it [11]. Based on epidemiological data, it has long been speculated that hormonal and reproductive factors (including age at menarche, age at menopause, age at first birth, or age at last birth) may play a role in determining or modulating the risk of thyroid cancer [12]. This hypothesis is supported by experimental data as well, such as the promoting effect exerted by estrogens on the growth of thyroid cancer cells through a pathway mediated by estrogens receptors alpha (ER-a) and beta (ER-b) [13, 14]. The association between menstrual and reproductive factors and use of exogenous hormones [i.e., oral contraceptives (OC) or hormone replacement therapy (HRT)] and thyroid cancer risk has been investigated in several studies. Most studies published until the first half of the last decade had a case–control design [15, 16], which may be affected by recall bias for both putative causal exposures and confounding variables. Conversely, several studies with a prospective design (cohort, case-cohort, and nested case–control studies) have been appearing during recent years, despite with inconsistent findings [17–20]. We performed a systematic literature search and metaanalysis of observational prospective studies to summarize the best available evidence for the association between menstrual and reproductive variables and use of exogenous hormones and the risk of thyroid cancer among women.
Materials and methods Search of papers and inclusion criteria We planned and conducted a systematic literature search and subsequent analysis of data according to MOOSE guidelines for meta-analysis of observational studies [21]. We searched reports published before 31 July 2014 in the following databases: PUBMED, Ovid Medline, EMBASE, Google Scholar, ISI Web of Knowledge, Open Grey, and Grey Literature Report. The search was conducted by using any combination of the MESH terms for the exposures of interest (listed in Table 1) and ‘‘thyroid cancer.’’
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We obtained the full copy of all papers that were considered as potentially eligible for the present meta-analysis on the basis of the abstract. We searched for additional papers in the reference list of retrieved papers and of previously published reviews and meta-analyses. Two authors (SC and SG) independently read and decided on eligibility of selected papers (based on criteria listed below; all conflicts were resolved by discussion). We considered for inclusion in the present meta-analysis all studies with a prospective design, i.e., all studies in which information on exposures of interest and potential confounders was collected before the occurrence of thyroid cancer. Included in this definition are cohort studies (both general population [20] and special exposure cohorts [22] were allowed) and case–control or case-cohort studies nested within established cohorts. Instead, we excluded purely retrospective case–control studies, as well as ecological studies, case reports, reviews, and editorials. Papers were included in the meta-analysis that reported, or allowed to estimate, a measure of relative risk for the association between any exposure of interest and the risk of thyroid cancer among women, along with 95 % confidence intervals (95 % CI) or another measure of statistical uncertainty (variance, standard error, or exact p values). We used the publication with the largest number of thyroid cancer cases whenever there was an overlap (whether partial or total) of the study sample between two or more otherwise eligible papers. No language, time, or geographical restrictions were applied. Data extraction and statistical analysis We collected and inputted into a specially designed dataset the following information from each paper: publication year; country of study; study design; source of study participants; number and mean/median age (whatever was available) of thyroid cancer cases, cohort members, or controls (for nested case–control studies); first and last year at diagnosis of thyroid cancer; average years of follow-up; percent of thyroid cancer cases belonging to papillary, follicular, or other histotype; whether the study had a matched design and variables used for matching; how the information on exposures was obtained (self-administered questionnaire, face-to-face interview, medical records, etc.); and variables used for statistical adjustment. For each association of interest, we transformed the most adjusted estimate of relative risk (and corresponding confidence intervals) available in each paper into log relative risks, and calculated the corresponding variance by using the formula proposed by Greenland [23]. As thyroid is a relatively rare disease, we made no distinction between the different measures of relative risk (incidence rate ratio, risk ratio, odds ratio, and standardized incidence ratio). We
Cancer Causes Control Table 1 Variables of interest in the meta-analysis of menstrual, reproductive, and hormonal factors and thyroid cancer risk History of menstruation
Childbearing and breastfeeding
Use of exogenous sex hormones
Age at menarche
Ever pregnant/parous
History of use of OC
History of ovariectomy
Irregular menstrual cycle
Number of pregnancies/births
Age began using OC
History of hysterectomy
Menopausal status
Outcome of first pregnancy
Age ended using OC
Age at hysterectomy
Menopause type
Age at first pregnancy/birth
Duration of OC use
Time since hysterectomy
Age at menopause
Age at last pregnancy/birth
Time since last used OC
History of use of IUD
Time since menopause
Other variables
Time since last pregnancy/birth
History of use of HRT
Age began using IUD
History of abortion/miscarriage
Type of HRT
Duration of IUD use
History of stillbirth
Age began using HRT
History of tubal sterilization
Ever breastfeeding
Age ended using HRT
Age at tubal sterilization
Duration of breastfeeding
Duration of HRT use
Time since tubal sterilization
Time since last used HRT
History of infertility Use of fertility drugs History of in vitro fertilization
OC oral contraceptives, HRT hormone replacement therapy, IUD intrauterine device
calculated an unadjusted measure of relative risk (and evaluate its standard error by using Woolf’s formula) from crude tabular data, if available, when no adjusted estimate was reported in the text. We pooled study-specific estimates using random effect models through maximum likelihood estimation [24]. Summary relative risks (SRR) and respective 95 % CI were calculated for the association between each variable of interest (for which at least three estimates from independent studies were available) and thyroid cancer risk. The available estimates were pooled together, and a single SRR was calculated, for each of the following pairs of variables: ‘‘ever pregnant’’ and ‘‘ever parous’’; ‘‘number of pregnancies’’ and ‘‘number of births’’; and ‘‘history of abortion’’ and ‘‘history of miscarriage.’’ This was done to increase the statistical power and/or because it was unsure which variable of the pair was actually used in some papers. When it was possible to calculate a SRR, we also produced a forest plot including all available estimates, the SRR and its 95 % CI. For some variables of interest (for instance, age at menopause), there were papers reporting estimates that were obtained by using a reference category different from that used in the majority of papers (for instance, women of intermediate age instead of women youngest age). When this occurred, we used raw data (if available) to calculate an unadjusted estimate with the latter as reference category, and performed a sensitivity analysis to assess whether this procedure influenced the results. If raw data were not available, the paper was not used to calculate the SRR for that variable. The homogeneity of the effects across studies was assessed using the I2 statistics, which can be interpreted as
the proportion of total variation across studies that is attributable to heterogeneity [25]. The larger the value of I2, the greater the heterogeneity; a value of I2 below 50 % is considered as an acceptable degree of heterogeneity. We used meta-regression and subgroup analysis to quantify the proportion of between-study heterogeneity that is accounted for by several study variables, including country, study design, study population, adjustment for confounding factors, and others [23]. Meta-regression was also used to assess the effect on between-study heterogeneity of appropriate statistical methods and correct reporting of results, according to the STROBE checklist for observational epidemiologic studies [26]. We also performed a sensitivity analysis by examining changes in results produced by the exclusion of each study. We evaluated whether there was a publication bias against negative studies by using the Macaskill test, which is the most powerful option when less than 20 studies are used to calculate a SRR [27]. All the statistical analyses were conducted using R software, version 2.12.2 (http://www.r-project.org), and SAS software (SAS Institute Inc., Cary, NC; version 9.2).
Results We obtained the full copy of 92 papers (Fig. 1): Of these, twenty-six matched all inclusion criteria. However, the papers by Yli-Kuha [28] and Ka¨lle´n [29] could not be used to calculate any SRR as they were the only two papers providing estimates for the variable ‘‘history of in vitro fertilization,’’ and did not report on any other variable of interest. Therefore, the papers that were finally used for the
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Cancer Causes Control Fig. 1 Flowchart of the selection process for the studies included in the meta-analysis for the association between menstrual, reproductive, and hormonal factors and risk of thyroid cancer among women
meta-analysis were twenty-four [11, 17–20, 22, 30–47]: All were prospective cohort studies except the paper by Galanti et al. [45], which is a nested case–control study, and that by Wong et al. [17], which has a case-cohort design. Other characteristics of papers that were included are shown in Table 2 and in Supporting Table. Overall, 5,434 thyroid cancer cases diagnosed during over 18 million years of follow-up between 1935 and 2011 were available for analyses. The percentage of thyroid cancer cases belonging to the papillary and to another (including follicular) or unknown histotype in the papers for which this information was available was 69.6 % and, respectively, 30.4 %. We report in Table 3 the summary relative risk, their 95 % confidence intervals, and the value of the I2 statistics for the association between menstrual, reproductive, and hormonal variables (for which three or more independent estimates were available) and the risk of thyroid cancer
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among women. Forest plots are available in ESM Appendix. Neither age at menarche nor age at menopause was associated with thyroid cancer risk. The borderline significant 20 % reduction (I2 = 0 %) in thyroid cancer risk for women that were post-menopausal (compared to perior premenopausal) at enrolment disappeared after dropping the paper by Zamora-Ros et al. [30], from which we could only use an unadjusted estimate. Parity did not affect the risk of thyroid cancer among women, nor did having ever had an abortion and/or a miscarriage. Instead, increasing age at first pregnancy/birth was associated with an increasing risk of thyroid cancer, the SRR being 1.56 (95 % CI 1.01–2.42, I2 = 35 %) for those in the oldest versus youngest age group. Sensitivity analysis revealed that this result was highly dependent on the study by Wong et al. [17], the only reporting a
Cancer Causes Control Table 2 Main characteristics of studies included in the meta-analysis of menstrual, reproductive, and hormonal factors and thyroid cancer risk References
Country
Brinton et al. [47]
USA
Akslen et al. [46]
Norway
Galanti et al. [45]
Sweden
Persson et al. [44]
Sweden
Luoto et al. [43]
Finland
Modan et al. [42]
Israel
Iribarren et al. [11] Luoto et al. [41]
USA Finland
No. thyroid cancer
First and last year of follow-up
Mean/median follow-up (years)
2,335
1935–1981
19.4
124
63,090
1961–1989
na
1,409
&1,700,000
1943–1984
na
25
22,597
1977–1991
13.0
71
25,382
1963–1993
20.5
8
2,496
1964–1991
21.4
123 118
204,964 17,900
1964–1997 1986–1997
20.0 6.0
6
No. cohort
Althuis et al. [38]
USA
18
8,422
1965–1999
18.8
Navarro Silvera et al. [39]
Canada
169
89,835
1980–2000
15.9
Neale et al. [40]
Sweden
986
1,234,967
1961–1996
na
Rosenblatt et al. [37]
China
153
267,400
1989–2000
8.6
Wong et al. [17]
China
130
3,187
1989–1998
na
Hannibal et al. [36]
Denmark
29
54,362
1963–2000
8.8
Dorjgochoo et al. [34]
China
83
66,661
1997–2007
7.5
Pham et al. [18]
Japan
86
37,986
1988–1997
10.0
Rosenblatt et al. [35]
China
161
267,400
1989–2000
9.3
Meinhold et al. [22]
USA
242
69,506
1983–2006
15.8
Horn-Ross et al. [19]
USA
233
117,646
1995–2007
na
Schonfeld et al. [33]
USA
312
187,865
1995–2006
9.3
Kabat et al. [20]
USA
296
145,007
1993–2011
12.7
Sungwalee et al. [32] Braganza et al. [31]
Thailand USA
17 127
10,767 70,047
1990–2011 1993–2006
14.2 11.0
Zamora-Ros et al. [30]
Europe
508
345,157
1992–2009
11.0
significant association: After dropping this paper, the SRR was 1.25 (95 % CI 0.90–1.74, I2 = 0 %). The use of both OC and HRT and having ever had a diagnosis of infertility did not increase nor reduce the risk of thyroid cancer. Women who had undergone hysterectomy had an increased risk (SRR 1.43, 95 % CI 1.15–1.78, I2 = 47 %) of developing a thyroid cancer later in life. The heterogeneity decreased (I2 = 0 %) and the SRR fell to a borderline significant 1.34 (95 % CI 0.97–1.85) after dropping the paper by Luoto et al. [43] published in 1997. We found no evidence of publication bias against negative studies for any variable of interest.
Discussion We presented here the results of a meta-analysis of prospective studies on the association of menstrual and reproductive history and use of exogenous sex hormones and thyroid cancer risk, based on over 5,000 cases during more than 18 million person-years. We found a statistically significant risk effect of later age at first pregnancy/birth
and history of hysterectomy and a borderline significant inverse association for being in menopause at enrolment. No other menstrual, reproductive, and hormonal variable was convincingly associated with thyroid cancer risk. In particular, we were unable to replicate findings originating from case–control studies on age at menarche and use of oral contraceptives [15, 16]. Some variables of interest (such as use of exogenous hormones) and several potential confounding factors for the studied associations may be subject to recall bias, which may easily explain the discrepancies between retrospective and prospective studies. Overall, the role played by menstrual, reproductive, and hormonal variables on the risk of thyroid cancer seems to be modest, and cannot explain but a small share of the growth in thyroid cancer incidence over recent years and of the differences in incidence by gender. Yet, our results deserve careful attention because of their public health implication and their potential to shed light on the etiological mechanisms leading to thyroid cancer. Estrogen receptors can be found on both normal [48] and neoplastic thyroid cells [13, 49]. In physiology, ERs seem to be involved in the function of the thyroid gland,
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Cancer Causes Control Table 3 Summary relative risks and 95 % confidence intervals (95 % CI) for the association between menstrual, reproductive, and hormonal characteristics and risk of thyroid cancer among women Category
No. studies
No. thyroid cancer
SRR
Lower 95 % CI
Upper 95 % CI
I2 (%)
Age at menarche
Oldest versus youngest
11
2,244
1.02
0.90
1.16
31
Menopausal status at enrolment Age at menopause
Post- versus premenopausal Oldest versus youngest
4 5
1,042 1,157
0.79 1.19
0.62 0.79
1.01 1.78
0 0
Variable History of menstruation
Reproduction and breastfeeding History of pregnancies/births
Ever versus never
8
1,163
0.91
0.75
1.10
0
No. of pregnancies/births (reference: nulliparous women)
Many versus none
9
3,139
0.84
0.56
1.25
13
No. of pregnancies/births (reference: uniparous women)
Many versus one child
6
1,652
1.02
0.78
1.34
33
Age at first pregnancy/birth
Oldest versus youngest
11
2,848
1.56
1.01
2.42
35
Age at last pregnancy/birth History of abortion/miscarriage
Oldest versus youngest Ever versus never
4 4
1,858 915
1.91 1.11
0.78 0.87
4.65 1.42
0 0
Use of exogenous sex hormones History of use of OC
Ever versus never
10
1,959
0.99
0.87
1.13
0
Duration of OC use
Longest versus shortest
9
2,021
0.86
0.69
1.06
33
History of use of HRT
Ever versus never
8
1,802
1.05
0.89
1.24
14
History of hysterectomy
Ever versus never
4
615
1.43
1.15
1.78
47
History of infertility
Ever versus never
4
540
1.49
0.89
2.47
38
Other variables
2
I proportion of total variation in study estimates that is due to heterogeneity OC oral contraceptives, HRT hormone replacement therapy
mainly at puberty, in early pregnancy and breastfeeding [50, 51]. Beta-human chorionic gonadotropin plays a role in the normal physiology of the thyroid gland showing a strong thyroid-stimulating hormone-like effect in early pregnancy [52]. An inappropriate activation of ERs may also be caused by some chemicals (sometimes referred to as ‘‘xenoestrogens’’) with an endocrine disruptor activity [53]. A continuous activation of the ERs (by endogenous hormones or pollutants) may stimulate the growth of thyroid tissue and lead to development and progression of well differentiated (hence, with favorable prognosis) cancers. This could explain the risk effect that we found for a later age at first pregnancy/birth, and the borderline inverse association with younger age at menopause. A reason for the risk effect of the history of hysterectomy on thyroid cancer risk may be found in the frequent association of uterine leiomyomas (a leading cause of hysterectomy) and thyroid nodules [54]. The latter association is not surprising, given the role of estrogens in the physiology and pathology of both the thyroid gland and the uterus. Thyroid cancer incidence has grown steeply during past 40 years, especially among women [2]. The refinement of diagnostic techniques has allowed an early diagnosis of potentially lethal cancers, but also led to detect many cancers that would have never progressed toward clinical
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stage. Parallel to this, a true growth in incidence has occurred as well during recent years, the causes of which are, however, poorly understood [3, 53]. The activation of ERs of thyroid gland cells by endogenous hormones, endocrine disruptors, or other chemicals may account for a part of it, possibly along with an increased exposure to medical radiations and environmental pollutants [55], intake of endocrine disruptors through diet or water [55], overweight and obesity [56], and other causes yet to be identified. Ongoing and future research should primarily aim at improving our understanding of underlying mechanisms of carcinogenesis of thyroidal gland. Acknowledgments This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector. Conflict of interest interest to disclose.
The authors declare they have no conflicts of
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