Progesterone Therapy Increases Free Thyroxine Levels

Data From a Randomized Placebo-Controlled 12-Week Hot Flush Trial

P. Sathi; S. Kalyan; C. L. Hitchcock; M. Pudek; C. Prior

Disclosures

Clin Endocrinol. 2013;79(2):282-287. 

In This Article

Abstract and Introduction

Abstract

Objective 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.

Design 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.

Patients 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.

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

Results 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.

Conclusions 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.

Introduction

Women are more likely than men (P < 0.0001) to experience clinical thyroid problems.[1,2] The prevalence of TSH abnormalities increases with increasing age[2,3] and with lower socioeconomic status;[2] increasing age and lower socioeconomic status are also related to decreased progesterone production.[4] The increased prevalence of thyroid disturbances in women is likely related to women's more frequent autoimmune dysfunctions[3] and to interactions of thyroid hormones with estrogen.[5]

Normal thyroid function is important for reproductive health.[6] During pregnancy in women with treated hypothyroidism, the increase in TSH and decrease in Free thyroxine (FreeT4) levels have been attributed to estradiol-induced increased levels of circulating thyroid binding globulin (TBG), as well as to the effects of chorionic gonadotrophins.[7] Recent cross-sectional data suggest that lower mid-trimester FreeT4 levels are detrimental to the metabolic health of the mothers and also are inversely related to placental weight.[8]

Although understanding of estrogen's influences on thyroid function is extensive, especially during pregnancy,[6,7] little is known about thyroid function and progesterone. Several potential mechanisms link thyroid and progesterone actions: (1) common effects to increase core temperature and stimulate intermediary metabolism, (2) that TSH, chorionic and pituitary gonadotrophins include an identical alpha subunit, and (3) awareness that, when estradiol sits on its receptors, progesterone usually has complementary or opposing actions.[9,10] An additional potential mechanism for a progesterone–thyroid relationship is through cross-talk between the receptors for these steroids and mediators of gene transcription as both progesterone and thyroid are members of the steroid hormone superfamily.[11] Despite these plausible hypothetical relationships between the physiologies of the thyroid axis and progesterone, there are few studies of thyroid function in relationship to endogenous or exogenous progesterone.

Most of the available data about thyroid function and progesterone are with progestogens such as medroxyprogesterone that, like progesterone,[12] increase basal temperature.[13] Sparse evidence suggests that progesterone does not alter TBG.[6,14] However, two physiological studies of thyroid function during the follicular and luteal phases have been performed—one shows an increase in sleep metabolic rate in the luteal phase without changes in total T4, T3 or Free T4.[15] A second study showed an earlier nocturnal decrease in TSH in the luteal phase without report of other thyroid hormone levels.[16] One small randomized controlled trial found significantly lower TSH levels during progesterone therapy in postmenopausal women;[17] FreeT4 levels, however, were unchanged.[17]

In summary, progesterone appears not to stimulate TBG[6,14] as does oral estrogen[5] may play an undocumented additional role to estradiol in the pregnancy-related thyroid-function changes[18] and potentially may suppress TSH levels.[16,17] To better understand whether progesterone causes thyroid function changes, we performed analysis of the thyroid hormone axis during a 12-week placebo-controlled trial of oral micronized progesterone for treatment of vasomotor symptoms (VMS, hot flushes and night sweats).[19] Our purposes were to: first, identify whether there were any associations between thyroid hormone levels and VMS; if this thyroid–VMS association testing were negative, then secondly to assess whether thyroid function was altered by 12 weeks of progesterone or placebo therapy.

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