Hysterectomy and thyroid cancer risk: A systematic review and meta-analysis

Background Incidence rates of thyroid cancer have increased. Recent studies findings suggest that women who underwent a hysterectomy have an elevated relative risk of thyroid cancer. The aim of our meta-analysis is to summarize the evidence about the association between hysterectomy and thyroid cancer risk. Methods PubMed, Web of Science, and Scopus database were searched for studies published up to 5 September 2023. The PRISMA statement was followed. Heterogeneity was explored with Q statistic and the I2 statistic. Publication bias was assessed with Begg's and Egger's tests. Results Sixteen studies met the criteria. The pooled analysis showed a significantly 64% increment of thyroid cancer risk in association with any hysterectomy (OR 1.64, 95% CI 1.48–1.81; I2 = 28.68%, p = 0.156). Hysterectomy without oophorectomy was a stronger predictor of risk than hysterectomy with oophorectomy. The pooled analysis of data regarding hysterectomy without oophorectomy showed a statistically significant increment of thyroid cancer risk by 59%. Hysterectomy with oophorectomy was associated with an increase of thyroid cancer risk of 39% (OR 1.39, 95% CI 1.16–1.67; I2 = 42.10%, p = 0.049). Significant publication bias was not detected. Conclusions Our findings help with decision making around these surgeries.


Introduction
Thyroid cancer (TC) is the most common endocrine malignancy.Incidence rates of thyroid cancer have increased considerably during the last two decades.It is threefold as common in women as in men (10.1 per 100,000 women and 3.1 per 100,000 men).In both sexes, incidence rates were five times higher in high and very high Human Development Index countries than in low and medium Human Development Index countries [1].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) [2,3].There is no clear evidence of an association between reproductive or hormonal factors and thyroid cancer [4].
Hysterectomy is the most common gynaecologic surgery performed in women worldwide.Although it is the elective surgical procedure for treatment of uterine cancer, over 90% of procedures are associated to symptomatic benign gynaecological conditions (uterine fibroids, endometriosis, or unusual uterine bleeding) [5].Often hysterectomy may also include the removal of both ovaries (bilateral salpingesoophorectomy: BSO), a procedure that substantially reduce the risk of ovarian cancer [5].The incidence rate of hysterectomy is decreasing over time in most countries, even though hysterectomies per 100,000 women swing among countries, in fact in 2018 it ranged from 12 in Denmark to 291 in Czech Republic [6].Although considered safe, hysterectomy complications may occur which include infectious, venous thromboembolic and genitourinary and gastrointestinal tract injury [7].Since both hysterectomy and BSO have the potential to induce evident changes in hormone levels [8], they can influence the risk of hormones related cancers.Discordant results regarding the association of hysterectomy-BSO with breast cancer risk were reported in several studies.In some cases, the breast cancer risk was lower after hysterectomy while no relation was observed in others [9].Instead, in a previous meta-analysis an evident increment of risk in association with hysterectomy has been reported for both colorectal and kidney cancers [10,11].Oophorectomy was also found to act as a risk factor for primary liver cancer [12].
Caini and colleagues have found that hysterectomy may play a role in the aetiology of thyroid cancer.Their review included four studies and didn't stratify hysterectomy by oophorectomy status [13].
Recently, several epidemiological studies have investigated the possible effect of hysterectomy, with or without BSO, on thyroid cancer risk with contrasting results.
Therefore, the present systematic review and meta-analysis was carried out to summarize and better understand the published epidemiologic evidence regarding the association between hysterectomy and thyroid cancer risk.

Methods
We conducted this systematic review and meta-analysis according to the "preferred reporting items for systematic reviews and meta-analyses" (PRISMA) [14].This research may be exempt from formal ethics review.

Search strategy and study selection
A comprehensive literature search, without restrictions, was carried out until 5 September 2023 through PubMed, Web of Science, and Scopus databases to identify all the original articles on the association between hysterectomy and thyroid cancer risk.The following key words were used: hysterectomy AND (cancer OR tumour OR neoplasia OR "neoplastic disease" OR neoplasm) AND thyroid.In addition, to identify additional relevant publications, we manually examined the reference lists of included articles and recent relevant reviews.Study search results, initial duplication, search review and study selection were managed using Zotero (www.zotero.org).

Inclusion and exclusion criteria
The inclusions criteria, organized on PICO model, were: was the association between hysterectomy and thyroid cancer in women.In particular: -Population: Female Population; -Intervention: any type of hysterectomy (with and without oophorectomy); -Comparison: No hysterectomy; -Outcomes: thyroid cancer, in particular, to search the databases, we used the following words: (cancer OR tumour OR neoplasia OR "neoplastic disease" OR neoplasm) AND thyroid; -S: case-control, prospective, or cross-sectional study design; -Finally, we included only articles, which reported a risk estimation (odds ratio, OR; relative risk, RR; or hazard ratio, HR) with 95% confidence intervals (CIs).
The exclusion criteria were: -article not in English; -some article type, such as case studies, commentaries and reviews; -not reporting the association and/or the risk estimate between hysterectomy and thyroid cancer risk.
When there were several publications from the same study, the one with the largest sample was selected.Foreach potentially included study, two investigators independently conducted the selection, data abstraction, and quality assessment.Disagreements were resolved by discussion or in consultation with a third author.Although it is useful to have background information, reviews and meta-analyses were excluded.No studies were excluded based on weakness of design or data quality.

Quality assessment
The study quality was assessed by a 9-star system, based on the Newcastle-Ottawa Scale (NOS) method [15]; the maximum score was 9 and a total score of ≥7 was used to indicate a high-quality study.To avoid selection bias, no study was excluded because of the quality criteria.Two authors individually performed the quality evaluation of each selected study and disagreements were settled by a joint reevaluation with a third author.

Data extraction
From the included studies, we extracted the following information: first author's last name, year of publication, country, study design and name, sample size (number of cases, controls, cohort size and incident cases), duration of follow-up for cohort studies, population characteristics (age, hysterectomy, reasons of surgery),whether the surgery included also unilateral/bilateral salpingo-ophorectomy (USO/BSO), age at surgery, risk estimates for the different categories of surgery (OR/ RR/HR) with 95% CI sand adjustment of confounding factors.When multiple estimates were reported in the article, we abstracted those that adjusted for the most confounding factors.The outcome of interest in this study is thyroid cancer (TC).

Statistical analysis
The association between hysterectomy and thyroid cancer risk in women was evaluated by version 3.0 of the ProMeta statistical program (IDoStatistics-Internovi, Cesena, Italy).For overall estimation, the relative risk and hazard ratio were taken as an approximation of the OR, and the meta-analysis was performed as if all types of ratio were ORs.We used the random effects model to calculate the summary OR and 95% confidence interval.Stratified analysis by study design (cohort and case-control studies), surgery categories (any hysterectomy, hysterectomy without oophorectomy, hysterectomy-BSO and hysterectomy-USO) and age at surgery (in the case of hysterectomy without oophorectomy) was also performed.
The chi-square-based Cochran's Q statistic and the I2 statistic were used to evaluate heterogeneity in results across studies [16].The I2 statistic yields results ranged from 0%to 100% (I2 = 0-25%, no heterogeneity; I2 = 25-50%, moderate heterogeneity; I2 = 50-75%, large heterogeneity; and I2 = 75-100%, extreme heterogeneity) [17].Results of the meta-analysis may be biased if the probability of publication is dependent on the study results.The methods of Begg and Mazumdar [18] and the methods of Egger et al. [19] were used to detect publication bias.Both methods were tested for funnel plot asymmetry.The former was based on the rank correlation between the effect estimates and their sampling variances, and the latter was based on a linear regression of a standard normal deviate on its precision.If a potential bias was detected, we further conducted a sensitivity analysis to assess the robustness of combined effect estimates, and the possible influence of the bias, and to have the bias corrected [18,19].We also conducted a sensitivity analysis to investigate the influence of a single study on the overall risk estimate, by omitting one study in each turn.We considered the funnel plot to be asymmetrical, if the intercept of Egger's regression line deviated from zero, with a p-value <0.05.

Studies selection
From the primary literature search through PubMed (n = 183), Web of Science (n = 131) and Scopus (n = 541) databases, and after removing duplicates (n = 260), we identified 595 records for title and abstract revision (Fig. 1).Among these, 580 articles were excluded because they did not investigate the association between hysterectomy and thyroid cancer risk.Fifteen articles were subjected to full-text revision.Manual searching of reference lists of both selected articles and recent relevant reviews led to the identification of 3 additional items.Subsequently, 2 articles were excluded because they did not report the risk estimation.Therefore, at the end of the selection process, 16 studies were included in the systematic review and meta-analysis [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35].

Meta-analysis
Fifteen out of 16 articles included in the systematic review were used for the overall risk estimation.One study [25] was excluded because it reported the same results, on the same population, of a previous publication [28] carried out by the same authors.Pulling together the data of the 13 studies reporting the risk in association with "any hysterectomy" we found a 64% increment of thyroid cancer risk (OR 1.64, 95% CI 1.48-1.81)(Fig. 2A) (Table 2).
Stratifying the analysis according to the method used for hysterectomy assessment, we observed a cancer risk increment of 62% and 67% for the self-reported and for the hospital record, respectively (Table 2).Stratifying by study design, we observed a cancer risk increment of 57% for the case-control and 64% for the cohort studies with a moderate heterogeneity (I 2 : 49.01) for cohort studies (Table 2).Similarly, when considering the effect of "hysterectomy without oophorectomy" we observed a 59% increment of thyroid cancer risk (OR 1.59, 95% CI 1.43-1.77;I 2 : 31.32) (Fig. 2B) (Table 2).In this case, it was possible to calculate the risk as a function of age at surgery with an increment of 81% and 38% for age < 45 and > 45 years, respectively (Table 2).The pooled analysis of data on hysterectomy with oophorectomy (14 studies) and the risk of thyroid cancer showed association (OR 1.39, 95% CI 1.16-1.67;I 2 : 42.10%, p = 0.049) (Table 2).An increment of thyroid cancer risk was also observed when hysterectomy was associated to BSO (OR 1.46, 95% CI 1.19-1.77)with a moderate heterogeneity (I 2 : 49.94) (Fig. 2C) (Table 2).No effect was reported when hysterectomy was associated to USO (OR 0.99, 95% CI 0.62-1.57)(Table 2).

Publication bias
No significant publication bias was detected with Egger's or Beggs method (Table 2) and analysing the symmetry of funnel plots (Fig. 3).

Main finding of this study
The incidence of thyroid cancer continues to increase globally,1 presenting a challenge in identifying unestablished risk factors.Current meta-analysis provides a significant update of Caini's study [13].We found that hysterectomy, with or without oophorectomy, was associated with an elevated relative risk of developing thyroid cancer.Convincing results were obtained both in case-control and cohort studies.Thyroid cancer risk was increased by 64% for women undergoing hysterectomy in comparison to no surgery.Hysterectomy without oophorectomy was a stronger predictor of risk than hysterectomy with oophorectomy (59% vs 39%).Furthermore, hysterectomy associated to BSO increased the risk by 46% while we found no association between hysterectomy associated to USO and thyroid cancer risk.This last finding should be considered with caution as it is obtained from a small number of studies in which partial ovarian removal was considered.We also found association between hysterectomy and risk of thyroid cancer in relation to the age in which the woman underwent hysterectomy: women with hysterectomy without oophorectomy had increased risk of thyroid cancer with decreasing age at surgery.In any case, these data are of particular importance and could help in the decision-making process regarding these surgeries in terms of thyroid cancer risk.

What is already known on this topic
The biological mechanism underlying the association between hysterectomy and thyroid cancer is unclear, although both hormonal and iatrogenic factors have been suggested.Furthermore, the effect of gynaecological surgery has been shown to be associated to an alteration of lipid peroxidation levels, which may induce DNA damage and promote mutations in proto-oncogenes and tumour suppressor genes [36].
Thyroid cancer is the most common endocrine malignancy and female hormones can contribute to modulate cellular proliferation and cell cycle progression through receptor-mediated transcriptional mechanisms [37][38][39]; moreover, previous studies reported the expression of progesterone and estrogenic receptors in thyroid cancer in  various degrees [40].
Evidence suggests that oestrogens may contribute to gender differences in the immune pathways [41].and response [42], even though the role of sex hormones in the immunologic escape of cancer remains unclear [43].
ERs belong to the nuclear receptor superfamily, which act as transcription factors.Oestrogen binding to the nuclear receptors is responsible for a nuclear translocation, with the consequent activation of genomic pathways and the transcription of multiple target genes.ERα promotes DNA transcription, while ERβ inhibits it; ERα plays a role in tumorigenesis by stimulating cell proliferation, while ERβ seems to have a significant antitumor activity [45].
In a study that examined association of endogenous sex hormone levels with hysterectomy, oophorectomy status, age or years since menopause, it was demonstrated that androgen levels were greatly decreased in women who undergo simple hysterectomy in comparison with natural menopause.In addition, testosterone levels were 40% lower in hysterectomized women with bilateral oophorectomy compared to not hysterectomized women, with intermediate levels of testosterone observed in hysterectomized women with ovarian conservation [46].
These results demonstrate that ovaries remain a critical source of androgen throughout the lifespan of a woman.Since both hysterectomy with oophorectomy and hysterectomy without oophorectomy have the potential to induce evident changes in hormone levels, they can also influence the risk of hormones related cancers.Further studies are needed to evaluate the effects of hormone replacement after oophorectomy.
The adverse association between hysterectomy and thyroid cancer may be a consequence of the underling conditions leading up to hysterectomy.The most common diagnosis associated with hysterectomy are uterine fibroids, abnormal uterine bleeding, prolapsed, endocrine disorders and endometriosis [47].Indeed, it has been demonstrated that endometriosis was associated with a higher risk of thyroid cancer [48].
The carcinogenic potential of conditions that lead to a hysterectomy is poorly understood, but hypothesized to be multidimensional in aetiology, involving hormonal, genetic and immunological factors [49].
Finally, it is necessary to consider that women undergoing hysterectomy are more medicalized and therefore more in touch with the health care system and more concerned about their own health, so they may have a higher likelihood of being diagnosed with thyroid cancer than the general population.

Strengths and limitations
Sensitivity and publication bias analyses revealed that our results are stable.Moreover, in our systematic review have been included many cohort studies, of good quality, that reinforce our results.It is important to notice that the number of people that have been considered by our systematic review is 7.575.968and that the meta-analysis showed a consistently results of 64% increment of thyroid cancer risk in association with any type of hysterectomy.
The principal weakness of our study, instead, is that, even if a high agreement was registered between self-reported hysterectomy data (i.e.year of surgery) and hospital records in studies that validated exposure information, for several studies the hysterectomy status was not verified with medical records and it is self-reported only [49][50][51][52].Actually, selfreported hysterectomy history is a reliable data, instead it is necessary to pay attention to the interpretation of self-reported oophorectomy history.An incorrect self-reported oophorectomy status could lead to a misclassification error of predictor groups, which may invalidate results.Moreover, most of women in our studies were Caucasians, so our conclusions may not be applicable to other ethnic groups.

Conclusions
Oophorectomy or hysterectomy should be proposed to women who have a high-penetrance susceptibility genes for ovarian cancer and/or endometrial cancer, because of the high life-time risk of developing these types of cancers [53], while women who are not at high risk of ovarian cancer or endometrial cancer, the gynaecological surgery should be a careful choice, because of the increasing risk of thyroid cancer, as find in our study, and of colorectal and kidney cancer's risk, as reported in two previous meta-analysis [10,11].
Our review was able to account risk factors for thyroid cancer, however, other confounding factors should be taken in consideration, such as indications for hysterectomy, type of hysterectomy (mini- invasive as laparoscopic, vaginal, or robotic and invasive as abdominal hysterectomy) and an eventual substitutive hormone therapy given in case of ovariectomy, which can influence woman cancer history.Despite challenges, additional studies are needed to determine the biological mechanisms of these associations and cohort studies with prolonged follow-up are essential to verify our findings.
In conclusion, our findings from this meta-analysis suggest that women undergoing hysterectomy have an increased relative risk of thyroid cancer.This relative risk depends on frequency of hysterectomy and thyroid cancer, however, the proportion of thyroid cancers attributable to hysterectomy may be substantial, given that approximately 45% of women are estimated to undergo this procedure by the age of 70 years.

Fig. 1 .
Fig. 1.PRISMA flowchart of studies selection about the association between hysterectomy and risk of thyroid cancer.

Fig. 2 .
Fig. 2. Forest Plot; 2 A) Any type of hysterectomy and thyroid cancer risk; 2B) Any type of hysterectomy without oophorectomy and thyroid cancer risk; 2C) Any type of hysterectomy with bilateral oophorectomy and thyroid cancer risk.

Fig. 3 .
Fig. 3. Funnel Plot; 3 A) Any type of hysterectomy and thyroid cancer risk; 3B) Any type of hysterectomy without oophorectomy and thyroid cancer risk; 3C) Any type of hysterectomy with bilateral oophorectomy and thyroid cancer risk.

Table 1
Characteristics of studies on hysterectomy in association with thyroid cancer risk.

Table 1
[27]tinued ) Quality Score; b Body Mass Index; c Socio-Economic Indexes for Areas; d Index of Relative Socioeconomic Disadvantage; e Polycystic Ovarian Syndrome; f Menopausal Hormone Therapy; g Excluded from meta-analysis because included in Altman et al.[27] a R. Fabiani et al.

Table 2
Results of stratified analysis of the thyroid cancer risk estimates according to the oophorectomy condition.aThe risk estimates were calculated using the random-effects model; b Number of data used to calculate the risk; c Bilateral Salpingo Oophorectomy; d Unilateral Salpingo Oophorectomy.