AS165 - Subclinical Hypothyroidism and Risk of MI and Stroke

This page provides study documentation for AS165. For description of the specimen results, see Specimen Results Description (open to public). Data sets of the specimen results are included in the existing WHI datasets located on the WHI Data on this site (sign in and a completed Data Distribution Agreement are required; see details on the Data site).

Investigator Names and Contact Information

Carol E. Lorenz, PT, PhD, Associate Director, Center for Women’s Health Research, UNC School of Medicine


Diminished thyroid function is more common among women and with advancing age. Individuals with overt hypothyroidism usually have symptoms. The diagnosis is based on decreased thyroid hormone levels and increased thyroid stimulating hormone (TSH). Treatment is accomplished with thyroid hormone replacement. Laboratory testing also identifies individuals with elevated TSH and “normal” thyroid hormone levels. This circumstance, presumed to lie along the continuum of decreased thyroid function, has been termed subclinical or mild hypothyroidism (SCH). Individuals with these laboratory findings may or may not be symptomatic, and the need for treatment is unclear.1

SCH is of special interest in the context of cardiovascular disease (CVD) prevention research. Like overt hypothyroidism, SCH has been associated with atherosclerotic disease and myocardial infarction (MI). Subclinical hypothyroidism is common, with a prevalence of 10% or higher among post-menopausal women.2,3 However, knowledge about SCH and its relationship to risk of MI and stroke among post-menopausal women is scant and is based primarily on one cross-sectional study and two follow-up studies of comparatively small cohorts. The purpose of this study is to examine the association between subclinical thyroid dysfunction and subsequent risk of MI and stroke in a large prospective cohort of post-menopausal women, in order to assess potential benefits of screening in this population and to inform development of a randomized trial to directly evaluate CVD benefits of treatment.

Between 1993 and 1998, the Women’s Health Initiative (WHI) Observational Study enrolled 93,676 post-menopausal women in an ongoing prospective cohort that includes detailed annual follow-up of health status. Major health events, including MI and stroke, are documented by standardized review of medical records. Each participant has frozen serum samples archived from her baseline physical exam. By the time of the proposed research, the entire cohort will have five or more years under observation.

We propose to conduct a case-cohort analysis excluding women with known overt hypo- or hyperthyroidism, or with current use of medications that alter thyroid function, or with prior cardiovascular disease events at the time of enrollment. We will measure TSH in baseline samples from 800 participants who have had an incident MI, 750 with an incident ischemic stroke, and a randomly selected subcohort of 3,200 women matched for age, race/ethnicity, and clinical center. Samples with TSH ≥4.68 and ≤0.46 mIU/L (our assay’s reference interval) will be tested for free thyroxine (FT4) and thyroid peroxidase antibodies (TPOAb). These laboratory results, accompanied by annual data about medications and medical history will allow us to classify participants into categories that summarize their presumptive thyroid function status during the 5-year time frame of interest.

Doing so will allow us to answer the following primary research questions:

Among women in the WHI Observation Study cohort without history of thyroid disease, MI, or stroke:

RQ1.  Is subclinical hypothyroidism at baseline independently associated with risk of MI in the five years following enrollment?

RQ2   Is subclinical hypothyroidism at baseline independently associated with risk of ischemic stroke in the five years following enrollment?

Our secondary questions are:

RQ3   What form of association best describes the relationship between TSH, as a continuous measure, and risk of MI and stroke?

RQ4   What are the population correlates (i.e., race/ethnicity, BMI, hormone therapy, comorbidity) of SCH?

The proposed study has been approved by the WHI Design and Analysis Committee, because working within the WHI Observational Study will be a highly efficient and timely means of answering these questions of potentially critical importance to the health of older women. MI and stroke are the leading causes of death among post-menopausal women. SCH disproportionately affects older women and is common. If SCH is associated with even a modest increase in CVD risk, it could be responsible for thousands of deaths each year. Identifying such a link in a prospective study would lay the foundation for further preventive screening and intervention studies.


Some of the publications related to this ancillary study are:

Ms402 - Legrys VA, Funk MJ, Lorenz CE, Giri A, Jackson RD, Manson JE, Schectman R, Edwards TL, Heiss G, Hartmann KE. Subclinical hypothyroidism and risk for incident myocardial infarction among postmenopausal women. J Clin Endocrinol Metab. 2013 Mar 28. [Epub ahead of print]

For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Bibliography section of this website. To search for papers by study number, access the Simple Search, and enter the study number in the “Related Studies” field.