People with type 1 diabetes have an increased risk for autoimmune thyroid disease, which is more common in women than in men according to at least one (1) but not all (2) studies. Exposures unique to women, such as pregnancy, exogenous estrogen, and menopause, have been linked to other autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus (3). However, studies examining such exposures in women with type 1 diabetes are unavailable.
Because the incidence of type 1 diabetes is increasing worldwide, it is important to determine the factors associated with comorbid conditions (4). We analyzed participants (n = 1,324) in the Diabetes Control and Complications Trial (DCCT), a randomized trial of intensive insulin therapy, and its follow-up, Epidemiology of Diabetes Interventions and Complications (EDIC). With the use of Cox regression models, we estimated hypothyroid risk associated with sex, age, DCCT treatment group, diabetes duration, microvascular complications, and hemoglobin A1c (HbA1c). Among women, we further examined parity, menopause, and estrogen use. We also report the cumulative incidences of other autoimmune diseases by sex.
Year 2 participant characteristics by incident hypothyroidism were similar in terms of BMI, diabetes duration, HbA1c, and microvascular complications. Parity, menopausal status, and estrogen use were also similar among women. By EDIC year 18, more women than men reported incident hypothyroidism (24.6 vs. 11.3%, P < 0.0001). Cumulative incidences of other autoimmune conditions, including pernicious anemia (17 women, 4 men) and adrenal disease (2 women, 2 men), were low.
Table 1 presents the risk of incident hypothyroidism associated with sex and other covariates. After multivariable adjustment, women had an increased hazard of hypothyroidism compared with men. Other covariates were not associated with increased hypothyroid risk. Among women, pregnancy, exogenous estrogen, and menopause were not associated with hypothyroidism.
To our knowledge, other studies have not examined female-specific exposures as risk factors for autoimmune disease among women with type 1 diabetes. In the current analysis, increased estrogen exposure was not associated with increased hypothyroid risk. Increased endogenous estradiol, as in pregnancy, or increased exogenous estradiol, as with estrogen use, did not significantly increase risk beyond baseline estradiol production. Other sex-specific exposures not related to sex hormones may also explain these differences.
The strengths of the study include a large cohort, high participant retention, and 18-year follow-up. However, DCCT/EDIC was not designed a priori to assess autoimmune disease. Self-reported disease represents clinically significant disease. However, autoantibody assays and hormone levels were not available to quantify subclinical disease, which leads to an underestimation of autoimmune disease.
In conclusion, in women with type 1 diabetes, the risk for hypothyroidism is not affected by exposure to pharmacologic estrogens, pregnancy, or menopause. Other diabetes-related factors were not associated with increased hypothyroid risk. Further research is needed to examine which exposures may increase this risk in women and whether such exposures are modifiable. Examination of sex-specific exposures and interactions with HLA types and antibody status to produce disease and how ascertainment for these diseases may differ by sex is needed.
Funding. The DCCT/EDIC has been supported by U01 Cooperative Agreement grants (1982–1993, 2011–2016) and contracts (1982–2011) with the Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (current grant numbers U01-DK-094176 and U01-DK-094157) and by the National Eye Institute, the National Institute of Neurological Disorders and Stroke, the Genetic Clinical Research Centers Program 1993–2007, and the Clinical and Translational Science Center Program (2006–present), Bethesda, MD. Additional support for this DCCT/EDIC collaborative study was provided by K23-DK-071552 and R01-DK-083297 (to C.K.).
Trial registration: ClinicalTrials.gov, NCT00360815 and NCT00360893.
The following industry contributors have had no role in the DCCT/EDIC study but have provided free or discounted supplies or equipment to support participants’ adherence to the study: Abbott Diabetes Care (Alameda, CA), Animas (Westchester, PA), Bayer Diabetes Care (North America Headquarters, Tarrytown, NY), Becton Dickinson (Franklin Lakes, NJ), CanAm (Atlanta, GA), Eli Lilly (Indianapolis, IN), LifeScan (Milpitas, CA), Medtronic Diabetes (Minneapolis, MI), Nova Diabetes Care (Billerica, MA), Omron (Shelton, CT), OmniPod Insulin Management System (Bedford, MA), Roche Diabetes Care (Indianapolis, IN), and Sanofi (Bridgewater, NJ).
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
Author Contributions. E.B. wrote the manuscript and researched data. A.V.S., M.P., R.L.D., B.H.B., P.A.C., C.C., M.E.L., H.W., D.M.N., and C.K. researched data and reviewed and edited the manuscript. C.K. is the guarantor of this work, and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Prior Presentation. Parts of this study were presented in poster form at the 72nd Scientific Sessions of the American Diabetes Association, Philadelphia, PA, 8–12 June 2012.