Third-trimester estradiol is associated with isolated maternal hypothyroxinemia and attenuated TSH-FT4 coupling: evidence from rats and human astrocytes.

Introduction: Isolated maternal hypothyroxinemia (IMH), defined by low free thyroxine (FT4) with thyroid-stimulating hormone (TSH) within the reference range, is a clinically relevant thyroid phenotype in late pregnancy, when estradiol (E2) rises sharply. We tested whether third-trimester E2 is associated with IMH and whether complementary animal and cell data are compatible with a proposed model of pituitary adaptation. Methods: In 200 women at ≥28 gestational weeks (IMH, n = 100; euthyroid, n = 100), multivariable regression assessed associations of log2(E2) with IMH and FT4 after adjustment for gestational age and maternal age. Complementary experimental studies used gestational-stage Wistar rats, ovariectomized Wistar rats with 17β-E2 replacement, and Human Astrocytes treated with T4 ± E2 ± ICI 182,780. Results: Higher E2 was associated with IMH (OR 2.93 per doubling) and lower FT4 (-1.74 pmol/L per doubling), whereas the adjusted TSH-FT4 association was not statistically significant. In rats, late gestation and E2 replacement were associated with lower serum FT4, no statistically significant increase in TSH, lower pituitary T4, and higher pituitary Dio2 and Oatp1c1; in the OVX+E2 model, the pituitary T3/T4 ratio was also higher. In Human Astrocytes, E2 increased DIO2/OATP1C1 expression and the supernatant T3/T4 ratio, and ICI attenuated these effects, indicating estradiol responsiveness in a glial-like human cell system. Discussion: Together, these findings are compatible with altered local thyroid hormone handling under high-E2 conditions, but pituitary thyroid hormone metabolism was not directly assessed in the clinical cohort. The proposed model of pituitary adaptation should therefore be regarded as exploratory and hypothesis-generating rather than as a demonstrated human mechanism.