Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Hum Reprod. 2022 Apr 1;37(4):838-847. doi: 10.1093/humrep/deab285.
STUDY QUESTION: Do fertility drugs increase the risk of thyroid cancer among infertile women? SUMMARY ANSWER: The use of most types of fertility drugs was not associated with an increased risk of thyroid cancer. WHAT IS KNOWN ALREADY: The incidence of thyroid cancer is higher for women than men, especially during reproductive years, indicating that reproductive hormones may be involved in the development of thyroid cancer. Only a few previous studies have examined the association between the use of fertility drugs and incidence of thyroid cancer and the results are inconclusive. STUDY DESIGN, SIZE, DURATION: A retrospective, population-based cohort study including all 146 024 infertile women aged 20-45 years and living in Denmark in the period 1995-2017. The women were followed from the date of entry in the cohort (i.e. date of first infertility diagnosis) until the occurrence of thyroid cancer or any other cancer (except non-melanoma skin cancer), death, emigration, total thyroidectomy or the end of follow-up (31 December 2018), whichever occurred first. The median length of follow-up was 11.3 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 167 women were diagnosed with thyroid cancer during the follow-up period. Information on the use of specific fertility drugs (clomiphene citrate, gonadotropins, hCGs, GnRH receptor modulators and progesterone), thyroid cancer, covariates and vital status was obtained from the Danish Infertility Cohort and various Danish national registers. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% CIs for thyroid cancer overall and for papillary thyroid cancer. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for the calendar year of infertility diagnosis, the highest obtained level of education, parity status, obesity or thyroid disease and mutual adjustment for other registered fertility drugs, no marked associations were observed between the use of clomiphene citrate, hCG, gonadotropins or GnRH receptor modulators and risk of overall or papillary thyroid cancer. However, ever use of progesterone was associated with an increased rate of both overall (HR 1.63; 95% CI 1.07-2.48) and papillary (HR 1.66, 95% CI 1.04-2.65) thyroid cancer after mutual adjustment for other specific fertility drugs. For most specific fertility drugs, we observed a tendency toward higher associations with thyroid cancer within the first 5 years after the start of drug use than after 5 years from the start of use. No marked associations were detected according to the cumulative dose for any of the specific fertility drugs. LIMITATIONS, REASONS FOR CAUTION: Despite a large study population, the statistical precision in some subgroup analyses may be affected due to the low number of thyroid cancer cases. Although we were able to adjust for a number of potential confounders, residual and unmeasured confounding may potentially have affected the observed associations, as we could not adjust for some factors that may influence the association between fertility drugs and thyroid cancer, including age at menarche and BMI. WIDER IMPLICATIONS OF THE FINDINGS: Although this study, which is the largest to date, provides reassuring evidence that there is no strong link between the use of fertility drugs and thyroid cancer incidence, we observed a modest increased thyroid cancer incidence after the use of progesterone. However, we cannot rule out that this is a chance finding and the potential association between the use of progesterone and thyroid cancer should therefore be investigated further in large epidemiological studies. The results of the present study provide valuable knowledge for clinicians and other health care personnel involved in the diagnosis and treatment of infertility. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by research grants from the Jascha Foundation and the Aase and Ejner Danielsens Foundation. B.N. received honoraria and/or non-financial support by Gedeon Richter Nordics AB, IBSA Nordic APS and Merck KGAA. The remaining authors have no competing interests. TRIAL REGISTRATION NUMBER: N/A.
研究问题：生育药物会增加不孕女性患甲状腺癌的风险吗？
总结答案：大多数类型的生育药物的使用与甲状腺癌风险的增加无关。
已知情况：甲状腺癌的发病率在女性中高于男性，尤其是在生育年龄，这表明生殖激素可能参与了甲状腺癌的发展。之前只有少数几项研究检查了生育药物的使用与甲状腺癌发病率之间的关系，结果尚无定论。
研究设计、大小和持续时间：这是一项回顾性、基于人群的队列研究，包括丹麦 1995 年至 2017 年间年龄在 20-45 岁之间的 146024 名不孕女性。这些女性从进入队列（即首次不孕诊断）的日期开始随访，直到发生甲状腺癌或任何其他癌症（除非黑色素瘤皮肤癌）、死亡、移民、全甲状腺切除术或随访结束（2018 年 12 月 31 日），以先发生者为准。中位随访时间为 11.3 年。
参与者/材料、设置、方法：在随访期间，共有 167 名女性被诊断患有甲状腺癌。生育药物（枸橼酸氯米酚、促性腺激素、hCG、促性腺激素释放激素受体调节剂和孕激素）、甲状腺癌、协变量和生存状态的信息均来自丹麦不孕队列和各种丹麦国家登记处。使用 Cox 比例风险回归模型计算了甲状腺癌总体和乳头状甲状腺癌的风险比（HR）和 95%置信区间。
主要结果和机会的作用：在调整了不孕症诊断的年份、最高获得的教育水平、产次、肥胖或甲状腺疾病以及其他已登记的生育药物的相互调整后，使用枸橼酸氯米酚、hCG、促性腺激素或促性腺激素释放激素受体调节剂与总体或乳头状甲状腺癌风险之间没有明显关联。然而，孕激素的使用与总体（HR 1.63；95%CI 1.07-2.48）和乳头状（HR 1.66，95%CI 1.04-2.65）甲状腺癌的风险增加有关，在相互调整了其他特定生育药物后。对于大多数特定生育药物，我们观察到在开始使用药物后的前 5 年内，与甲状腺癌的关联高于开始使用药物 5 年后。根据特定生育药物的累积剂量，未发现明显关联。
局限性、谨慎的原因：尽管研究人群庞大，但由于甲状腺癌病例数量较少，一些亚组分析的统计精度可能会受到影响。尽管我们能够调整许多潜在的混杂因素，但残余和未测量的混杂因素可能会影响观察到的关联，因为我们无法调整可能影响生育药物与甲状腺癌之间关联的一些因素，包括初潮年龄和 BMI。
研究结果的更广泛意义：尽管这项迄今为止最大的研究提供了令人放心的证据，表明生育药物的使用与甲状腺癌发病率之间没有很强的联系，但我们观察到使用孕激素后甲状腺癌发病率略有增加。然而，我们不能排除这是一个偶然发现，因此孕激素的使用与甲状腺癌之间的潜在关联应在大型流行病学研究中进一步研究。本研究的结果为参与不孕诊断和治疗的临床医生和其他医疗保健人员提供了有价值的知识。
研究资金/利益冲突：该研究得到了 Jascha 基金会和 Aase 和 Ejner Danielsens 基金会的研究资助。B.N. 因与 Gedeon Richter Nordics AB、IBSA Nordic APS 和 Merck KGAA 的关系而获得酬金和/或非财务支持。其余作者没有利益冲突。
临床试验注册号：无。
Cancer Causes Control. 2025-6-2
Zotero 插件