Progesterone therapy increases free thyroxine levels--data from a randomized placebo-controlled 12-week hot flush trial

Thyroid hormones and progesterone both influence core temperature, metabolism and are crucial during pregnancy. Our objective was to discover whether progesterone therapy caused changes in thyroid physiology compared with placebo.

Post hoc analysis from a randomized (1:1) placebo-controlled 12-week trial of oral micronized progesterone (Progesterone, 300 mg/d at bedtime) for hot flushes (vasomotor symptoms, VMS) conducted in an academic medical centre.

Postmenopausal euthyroid, healthy (without cardiovascular diseases or risks) women, 1-11 years since last flow on no thyroid or ovarian hormone therapy with VMS participated.

Primary outcomes were final and 12-week changes in TSH, FreeT3 and FreeT4 on progesterone vs placebo.

Women with thyroid data (69 of 133 in original trial) were randomized to progesterone (n = 39) or placebo (n = 30)-baseline thyroid values were normal. There were no VMS-thyroid interactions-VMS Score (number × intensity) did not correlate with TSH, FreeT3 or FreeT4 (Spearman's rank correlations: -0.03 to -0.19, respectively; all P > 0.15). At 12 weeks on progesterone, TSH levels tended to be lower (1.7 mU) than on placebo (2.2), P = 0.06; FreeT4 levels were higher (16.4 pmol/l) than on placebo (15.3), P = 0.02. FreeT3 was unchanged throughout. Analysis of covariance showed a significant increase in FreeT4 on progesterone (+2.5 pmol/l; 1.9-3.0) vs on placebo (+1.7; 1.1-2.4) with 95% CI of difference = 0.8 pmol/l [0.0, 1.6], P = 0.04.

Progesterone caused a significant FreeT4 increase that was discovered during this randomized controlled VMS trial. The clinical importance of this increased FreeT4 level remains to be documented. Registered at ClinialTrials.gov#NCT00152438.