Marked changes in maternal thyroid activity occur in pregnancy. It has been suggested that hCG may stimulate maternal T4 secretion, given its in vitro thyrotropic activity ascribed to a significant degree of structural homology with TSH. In a longitudinal study of 32 normal pregnant women, we attempted to clarify the functional activity of the thyroid in early and late pregnancy and the possibility of a nonpituitary control on the thyroid. Total T4 and T4-binding globulin levels were increased from the first trimester onward. Free T4 levels did not differ in the first trimester from postpartum values, but were significantly decreased in second and third trimesters (P less than 0.001). A decrease in TSH levels was observed in the first trimester (0.72 +/- 0.09 vs. 1.23 +/- 0.12 mU/L; P less than 0.001), while second and third trimester values did not differ from those postpartum. A significant negative correlation (P less than 0.05) was observed between hCG and TSH levels in the earliest weeks (8-10) of the first trimester. No correlation was found between hCG and total T4 or free T4 levels. A stimulation of I- uptake in FRTL-5 cells was induced by first trimester serum, which also showed a different behavior at chromatofocusing, with a higher proportion of hCG eluting at acidic pIs compared to second trimester samples. However, neither hCG levels nor the amount of acidic hCG correlated with the thyroid-stimulating activity measured in vitro. Some correlation was found with the percentage of basic hCG (eluting at pI greater than 4.6), although these isoforms were equally present in first and second trimesters. The differing patterns of circulating hCG at various stages of gestation suggest that distinct hCG isoforms may regulate maternal thyroid activity.