Women consuming oral contraceptives containing cyproterone acetate and ethinylestradiol show a higher risk of thyroid cancer than nonusers.

Oral contraceptives (OCs) are hormone-containing products used to prevent pregnancy. Inhibition of ovulation and prevention of sperm penetration into the cervix are the main mechanisms for avoiding pregnancy. [ 1 ] Prevention of ovulation is the main mechanism of contraceptives of combined oral contraceptives. The most common forms of oral contraceptives are synthetic female hormones – estrogen (E) and progesterone (P). This type of pill is called a combined oral contraceptive. Another form of oral contraceptives, such as minipill, contains progestin alone. Diane-35 (Bayer Weimer GmbH und Co., Weimer, Germany) is a combined form of an oral contraceptive containing 2 mg cyproterone acetate and 0.035 mg ethinylestradiol. Indications for Diane-35 include acne, seborrhea, hirsutism, polycystic ovarian syndrome, and pregnancy prevention. [ 2 ] Oral contraceptives increase the risk of breast and cervical cancers and decrease the risk of ovarian, endometrial, and colorectal cancers. [ 3 ] However, the risk of developing thyroid cancer after oral contraceptives is inconclusive. [ 4 – 6 ] Estrogen may play a role in the development and progression of certain types of thyroid cancer. [ 7 ] The thyroid gland expresses estrogen receptors (ERs), specifically ERα and ERβ. These receptors allow estrogen to bind and exert its effects on thyroid cells. [ 7 ] Thyroid cancer can be broadly classified into several types, including papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), medullary thyroid carcinoma, and anaplastic thyroid carcinoma. Estrogen’s role in thyroid cancer has been studied primarily in PTC and FTC, which are the most common types. [ 8 ] Estrogen can promote cell proliferation, inhibit cell death (apoptosis), and stimulate angiogenesis (formation of new blood vessels) in thyroid cancer cells. [ 9 ] These effects are mediated through estrogen receptors and various signaling pathways. Studies have suggested that estrogen may contribute to the growth and progression of thyroid cancer. Higher levels of estrogen have been associated with larger tumor size, increased lymph node metastasis, and advanced disease stage in PTC and FTC. [ 10 ] Some studies have suggested that longer exposure to estrogen over multiple menstrual cycles may increase the risk of thyroid cancer. [ 11 ] Estrogen exposure may modify the impact of ionizing radiation, a known risk factor for thyroid cancer, potentially enhancing its carcinogenic effects. [ 12 ] Further research is needed to gain a better understanding of the precise relationship between estrogen exposure and the development of thyroid cancer. In Taiwan, the incidence of thyroid cancer increased from 8.09 to 14.5 per 1000,000 persons between 2002 and 2012. [ 13 ] In a previous study, we found that the risk of thyroid cancer (adjusted incidence rate ratio: 1.80) increased after the consumption of infertility medication (clomiphene, estrogen, and progesterone) in people in Taiwan. [ 14 ] The female gender is prone to thyroid cancer which suggests sex steroid hormones may be elaborated in the occurrence of thyroid cancer. A large pooled analysis showed a weak association between several menstrual and reproductive factors (later age at menarche, abortion, and parity) and thyroid cancer. [ 15 ] Therefore, exploring exogenous estrogen exposure may provide more information. Diane-35 is the only combined form OC paid by National Health Insurance. Therefore, this study aimed to determine the association between Diane-35 and the risk of thyroid cancer. A population-based health insurance database was used to generate the data.

Conceptualization: Dah-Ching Ding. Data curation: Weishan Chen, Dah-Ching Ding. Formal analysis: Weishan Chen, Dah-Ching Ding. Funding acquisition: Weishan Chen. Methodology: Pei-Hsuan Lai. Software: Chung Y. Hsu. Supervision: Chung Y. Hsu, Jen-Hung Wang. Writing – original draft: Pei-Hsuan Lai, Weishan Chen, Dah-Ching Ding. Writing – review & editing: Dah-Ching Ding.

In 1996, the Taiwanese government initiated a national program called the National Health Insurance program that aimed to improve national health and medical care in Taiwan. The medical records were stored in the National Health Insurance Research Database, which contains information on patient demographics, diagnoses, examinations, drug prescriptions, and operations from all medical care settings for > 99% of the 23 million Taiwanese individuals. We analyzed data from the Longitudinal Health Insurance Database 2000, including all original claims data for 1 million beneficiaries randomly sampled from the registry of all beneficiaries enrolled in Taiwan’s National Health Insurance Program between January 1, 2000, and December 31, 2013. Disease diagnosis was coded using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). All data used in this study were anonymized before their use. Permission from the Taiwan National Health Insurance Department was required to access the raw data used in our study. The Research Ethics Committee at China Medical University and Hospital approved using NHRI-provided data for studies (institutional review board permit number: CMUH-104-REC2-115). The Research Ethics Committee at China Medical University and Hospital approved a waiver of informed consent. The study has been performed by the Declaration of Helsinki. All methods were carried out by relevant guidelines and regulations. The case cohort comprised women administered Diane-35 (anaplastic thyroid carcinoa code G03HB) between 2000 and 2012. Diane-35 was paid by insurance with the indications of polycystic ovarian disease, hirsutism, or menstrual irregularities. We selected 4 individuals not consuming Diane-35 as the control cohort through frequency matching with the study cohort by age (in 5-years intervals) and index year. The index date of the Diane-35 users was set as the first prescription date, and that of the controls was set as a random date after enrollment. Patients aged 65 years, diagnosed with all cancer (ICD-9-CM code: 140-208) before the index date, and diagnosed with any cancer before or 1 year after the index date were excluded (Fig. 1 ). Study flow chart. NHIRD = National Health Insurance Research Database. The confirmation of thyroid cancer (ICD-9-CM code: 193) events was based on the registry of catastrophic illness, a sub-data set of the NHIRD. Each patient was followed until a diagnosis of thyroid cancer was confirmed, until the patient was censored for loss at follow-up, death, withdrawal from the insurance system, or to the end of the follow-up (December 31, 2013). The related comorbidities included hypertension (ICD-9-CM code 401–405), diabetes (ICD-9-CM code 250), hyperlipidemia (ICD-9-CM code 272), stroke (ICD-9-CM code 430–438), coronary heart disease (ICD-9-CM code 410–414), congestive heart failure (ICD-9-CM codes 398.91, 402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, 425.4–425.9, and 428), chronic obstructive pulmonary disease (ICD-9-CM codes 491, 492, 493, and 496), endometriosis (ICD-9-CM code 617), and polycystic ovarian disease (PCOS, ICD-9-CM code 256.4) that occurred before the index date. The chi-square test was used to test the difference in the distribution of categorical variables between the 2 groups. Student t test was used to assess the difference in mean age and mean follow-up time for thyroid cancer. The incidence rate was calculated as 10,000 person-years. Hazard ratios and 95% confidence intervals (CIs) were estimated using the Cox proportional hazard model. Age was included as a continuous variable in the Cox model to account for adjustment. We used the Kaplan–Meier method to plot the cumulative incidence curves and log-rank tests to examine differences between the 2 cohorts. Statistical analyses were performed using SAS version 9.4, and data were plotted using R version 4.0. Statistical significance was set at P < .05.

A total of 49,325 subjects were included in this study; 9865 were Diane-35 users and 39,460 were Diane-35 nonusers. Table 1 presents the demographic and baseline clinical characteristics of the study population. The patients’ mean age was 33.5 ± 9.93 and 33.4 ± 10.3 years in the Diane-35 and comparison cohorts, respectively. The mean and standard difference of follow-up duration were 7.08 ± 3.63 and 7.04 ± 3.64 years for participants in the Diane-35 and comparison cohorts, respectively. The distribution of comorbidities in the Diane-35 and comparison groups was significantly different, such as hypertension (6.94% vs 5.84%), diabetes (2.97% vs 2.28%), hyperlipidemia (8.62% vs 5.94%), coronary heart disease (2.51% vs 1.82%), chronic obstructive pulmonary disease (5.26% vs 3.49%), endometriosis (12.0% vs 3.79%), and PCOS (7.73% vs 1.11%). Baseline characteristics of women in Diane-35 and comparison cohorts. CAD = coronary artery disease; CHF = congestive heart failure; COPD = chronic obstructive pulmonary disease, PCOS = polycystic ovarian disease. Table 2 compares the incidence rates of thyroid cancer in both cohorts based on age stratification. After adjusting for age and comorbidities, the hazard ratio of thyroid cancer in participants in the Diane-35 cohort was 1.91 (95% CI = 1.10–3.30), higher than that in participants in the comparison cohort for all ages. Furthermore, for patients aged 30 to 39 years, Diane-35 users had a significantly higher hazard ratio of thyroid cancer (adjusted hazard ratios = 5.58; 95% CI = 1.84–16.91) than those not consuming Diane-35. Risk of thyroid cancer in women consuming Diane-35 than those in comparison group. Model is adjusted by age and comorbidities listed in Table 1 . As shown in Figure 2 , the cumulative incidence of thyroid cancer was significantly higher in the Diane-35 cohort than in the comparison cohort (log-rank test, P = .03). Kaplan–Meier curves depict the cumulative incidence of thyroid cancer in the Diane-35 (dashed line) and comparison (solid line) cohorts matched by age and comorbidities.

The results of the present study showed that the incidence of thyroid cancer was 1.80-fold higher in Diane-35 users than in women in the comparison group. An elevated risk of thyroid cancer was observed. Although only 19 thyroid cancer cases developed in Diane-35 users, the study model was valid. In subgroup analysis, the 30 to 39 years age group showed a higher risk of developing thyroid cancer after consuming Diane-35 than the comparison group. The NIH-AARP Diet and Health Study found OC used for more than 10 years were inversely associated with the risk of thyroid cancer than never used. [ 16 ] Menopausal hormone therapy (MHT) was associated with an increased thyroid cancer risk compared with never users. [ 16 ] The previous meta-analysis included 6 cohort studies and 3 case-control studies that found no association between MHT and thyroid cancer risk. [ 17 ] MHT with E + P was associated with a decreased risk of thyroid cancer in a nationwide Swedish population-based cohort study. [ 18 ] Ever use or estrogen-only MHT among aged ≥ 45 years women were not associated with thyroid cancer. [ 19 ] In our study, a small population used Diane-35 as MHT. The MHT users (50–65 years) were not associated with thyroid cancer risk. Taken together, conflict data were noted regarding the association between MHT and thyroid cancer. A prospective cohort study also showed that OC users had a higher incidence rate of thyroid cancer than nonusers. [ 20 ] OC use was not associated with the risk of thyroid cancer in a prospective cohort study. [ 19 ] The previous meta-analysis showed that oral contraceptives failed to alter the risk of thyroid cancer. [ 6 ] A systematic review also failed to find a correlation between OC and thyroid cancer risk. [ 21 ] Another matched case-control study (292 pairs) also showed that OC is not associated with the risk of thyroid cancer. [ 22 ] Conversely, a meta-analysis of studies suggested a protective effect of prolonged oral contraceptives on developing thyroid cancer. [ 4 ] A population-based, case-control study showed that OC use was associated with a reduced risk of thyroid cancer. [ 15 ] In a subgroup analysis of our study, patients aged 30 to 39 years showed a higher risk of developing thyroid cancer after consuming Diane-35 than those in the comparison group. Taken together, conflict data were noted regarding the association between OC and thyroid cancer. A Danish nationwide cohort showed progesterone was associated with an increased risk of thyroid cancer. [ 23 ] The Taiwanese population cohort also found that the risk of thyroid cancer (adjusted incidence rate ratio: 1.80) increased after the consumption of infertility medication (clomiphene, estrogen, and progesterone) in women. [ 14 ] Basic research showed progesterone influences thyroid function and growth by upregulating related genes in thyroid cells. [ 24 ] The previous research also found a common expression of progesterone receptor (PR) in thyroid tumor tissue. [ 25 ] Another study showed that PR status did not affect the outcome of thyroid cancer. [ 26 ] In our study, Diane-35 contained cyproterone acetate might affect the risk of thyroid cancer. Taken together, progesterone might be associated with thyroid cancer on the findings from epidemiological and basic research. Regarding the duration of OC use, Wu and Zhu reported a significant inverse association between the longest and shortest duration of OC use and the risk of thyroid cancer. They also observed a linear relationship between the duration of OC use and thyroid cancer risk in a dose-response analysis. [ 27 ] Another study showed that OC use for 10 to 19 years decreased the risk of thyroid cancer. [ 28 ] In contrast, some studies failed to identify a trend for the duration of OC use. [ 5 , 15 ] Taken together, the longer the use of OC, the lower the risk of thyroid cancer. OC use-thyroid cancer relationship is complex, and comparing studies is difficult because it depends upon the types of OCs used, the recency of use, and whether one is evaluating pre- or post-menopausal cancer risk. In the present study, the distribution of PCOS in the 2 cohorts was significantly different. Few studies have attempted to identify cancer risk in patients with PCOS. A population-based cohort study reported that thyroid cancer risk was not affected by the presence of PCOS. [ 29 ] Nevertheless, PCOS tends to associate with an increased prevalence of autoimmune thyroid disease. [ 30 ] However, the relationship between chronic autoimmune thyroiditis and thyroid epithelial cancer remains controversial. [ 31 ] Therefore, the potential correlation between PCOS and thyroid cancer risk warrants further investigation. Moreover, in the present study, the obscure influence of the higher proportion of patients with PCOS in the Diane-35 user group should be interpreted carefully. In our study, the proportions of diabetes, hypertension, and hyperlipidemia among women in the Diane-35 cohort were larger than those in the comparison cohort. OCs are reported that may be related to hypertension, [ 32 ] diabetes, [ 33 ] and hyperlipidemia. [ 34 ] A larger portion of PCOS was also noted in the Diane-35 cohort, which may be associated with hyperlipidemia. [ 35 ] Nevertheless, in our analysis, these comorbidities were adjusted, and found the association between Diane-35 use and thyroid cancer. The biological plausibility of estrogen’s role in thyroid cancer stems from the fact that thyroid cells have estrogen receptors, which enable them to respond to estrogen signaling. [ 36 ] Estrogen can affect thyroid cell growth, proliferation, and survival through these receptors. [ 7 ] Moreover, estrogen metabolism enzymes, such as aromatase, are present in thyroid tissues, suggesting local estrogen production and modulation. [ 37 ] Age is an important factor in the interaction between estrogen and thyroid cancer risk. [ 16 ] The incidence of thyroid cancer is higher in women than men, and this gender disparity is most prominent during the reproductive years. The age-specific incidence rates of thyroid cancer tend to peak in women in their 40s and 50s, which is a time of hormonal fluctuations and declining ovarian function. [ 38 ] However, in our study, women aged 30 to 39 taking Diane-35 had a higher risk of thyroid cancer but not other age groups compared with non-Diane-35 users (Table 2 ). This might be caused by the influence of adding OC hormone (exogeneous hormone) on the oncogenesis of the thyroid gland in women aged 30 to 39. Nevertheless, this phenomenon needs further exploration. The present study has several strengths. First, the database covered 1 million people sampled from the entire population (23 million) in Taiwan. Second, all medical records were accurately recorded using the National Health Insurance Research Database. Third, an age-matched method was applied to the comparison cohort, which was the primary confounding factor. Fourth, the effect of only 1 OC, which does not represent all forms of OC, was explored in this study. Finally, the cohort used in this study was the most suitable model for exploring the association between OC and thyroid cancer. However, this study has several limitations. First, the database covers only 13 years, with a short follow-up duration (7.08 and 7.04 years in the Diane and comparison cohorts, respectively). Second, other confounding factors for thyroid cancer, such as lifestyle and behavioral factors (e.g., diet or exercise), were not recorded in the database. Third, comorbidities of thyroid cancer were identified using ICD-9-CM codes that may not always be precise. Therefore, these results should be interpreted cautiously due to their moderate statistical significance.

This nationwide, population-based, retrospective cohort study showed that consuming Diane-35 was associated with an increased risk of thyroid cancer. However, a larger population with a longer follow-up may be necessary to determine causality. Healthcare workers should counsel women who wish to use Diane-35 regarding their long-term potential health impact on the incidence of thyroid cancer.