Stimulation of Thyroid Function by Human Chorionic Gonadotropin During Pregnancy: A Risk Factor for Thyroid Disease and a Mechanism for Known Risk Factors

Background: Thyroid autoimmunity is a major risk factor for gestational thyroid disease, and recently various other risk factors have been identified, including maternal age, body mass index (BMI) and parity. Human chorionic gonadotropin (hCG) is an important determinant of gestational thyroid function, yet it is unknown to what extent differences in hCG concentration affect the risk for thyroid disease. We have recently shown that thyroperoxidase antibody positivity impairs the thyroidal response to hCG stimulation, which may suggest that this is a mechanism through which thyroid autoimmunity acts as a risk factor for thyroid disease. Objective: The purpose of this study is to determine whether hCG is a risk factor for thyroid disease entities and whether recently identified risk factors for thyroid disease may influence the thyroidal response to hCG stimulation. Methods: Human chorionic gonadotropin, thyrotropin (TSH), and free thyroxine (FT4) were measured in 5435 pregnant women participating in a prospective cohort. The association of hCG with thyroid disease entities, and the association of known risk factors with thyroidal response to hCG stimulation were studied using multivariable linear regression models. Results: Higher hCG concentrations were associated with a higher risk of subclinical and overt hyperthyroidism. Lower hCG concentrations were associated with a higher risk of hypothyroxinemia. In contrast, hCG concentrations were not associated with subclinical hypothyroidism. Further analyses showed that in women with hypothyroxinemia, high hCG concentrations still suppressed TSH. However, in women with subclinical hypothyroidism, high hCG concentrations were not associated with higher FT4. Higher BMI, male fetal sex, and maternal parity >2 were associated with a lower thyroidal response to hCG stimulation. Conclusions: Human chorionic gonadotropin is associated with the risk of (subclinical) hyperthyroidism and hypothyroxinemia, but not with the risk of (subclinical) hypothyroidism. Women with hypothyroxinemia have a normal response to thyroidal stimulation by hCG, but this was abnormal in women with subclinical hypothyroidism. Known risk factors for thyroid dysfunction (BMI and parity), and also male fetal sex, are associated with a lower thyroidal response to hCG stimulation.