Dual control of pituitary thyroid stimulating hormone secretion by thyroxine and triiodothyronine in athyreotic patients

Abstract

Background: Patient responses to levothyroxine (LT4) monotherapy vary considerably. We sought to differentiate contributions of FT4 and FT3 in controlling pituitary thyroid stimulating hormone (TSH) secretion.

Methods: We retrospectively assessed the relationships between TSH and thyroid hormones in 319 patients with thyroid carcinoma through 2914 visits on various LT4 doses during follow-up for 5.5 years (median, IQR 4.2, 6.9). We also associated patient complaints with the relationships.

Results: Under varying dose requirements (median 1.84 µg/kg, IQR 1.62, 2.11), patients reached TSH targets below 0.4, 0.1 or 0.01 mIU/l at 73%, 54% and 27% of visits. While intercept, slope and fit of linearity of the relationships between lnTSH and FT4/FT3 varied between individuals, gender, age, LT4 dose and deiodinase activity influenced the relationships in the cohort (all p < 0.001). Deiodinase activity impaired by LT4 dose significantly affected the lnTSH-FT4 relationship. Dose increase and reduced conversion efficiency displaced FT3-TSH equilibria. In LT4-treated patients, FT4 and FT3 contributed on average 52% versus 38%, and by interaction 10% towards TSH suppression. Symptomatic presentations (11%) accompanied reduced FT3 concentrations (-0.23 pmol/l, p = 0.001) adjusted for gender, age and BMI, their relationships being shifted towards higher TSH values at comparable FT3/FT4 levels.

Conclusions: Variation in deiodinase activity and resulting FT3 levels shape the TSH-FT4 relationship in LT4-treated athyreotic patients, suggesting cascade control of pituitary TSH production by the two hormones. Consequently, measurement of FT3 and calculation of conversion efficiency may identify patients with impaired biochemistry and a resulting lack of symptomatic control.

Keywords: TSH feedback control; deiodinase; levothyroxine treatment; set point; thyroid homeostasis; triiodothyronine.

Figures

Figure 1.

Relationships between FT4 (a), FT3 (b), and TSH (c) and weight-adjusted LT4 dose, stratified by quartiles of deiodinase activity. The main panels show crude relationships obtained by locally weighted scatterplot smoothing in each strata. The inserts are derived by a linear mixed model (see Methods), fitting natural splines to the interaction of deiodinase activity with LT4 dose. The interaction term was significant (p < 0.001) for all relationships, indicating a change in slope, not a strictly parallel shift. The distribution of the deiodinase strata is shown in (d). The shaded area surrounding the curves indicates 95% confidence interval in this and other figures. FT3, free triiodothyronine; FT4, free thyroxine; LT4, levothyroxine; TSH, thyroid stimulating hormone; BW, body weight.

Figure 2.

Relationship between TSH and FT4 or FT3, stratified by quartiles of deiodinase activity (a, c), administered LT4 dose (b) or FT3 concentrations (d). The main panel shows the crude relationship obtained by locally weighted scatterplot smoothing in each strata over the full range. The inserts are restricted to the nonhypothyroid range, fitted by a mixed model using natural splines for the independent variable and its interaction with the respective strata after adjusting for gender, age and body mass index (except if dose was already weight-adjusted). The curves shown are significantly different (see Results). FT3, free triiodothyronine; FT4, free thyroxine; LT4, levothyroxine; TSH, thyroid stimulating hormone.

Figure 3.

Relationships between TSH and FT4 or FT3 at symptomatic versus asymptomatic presentations. The main panel shows the crude relationships obtained by locally weighted scatterplot smoothing in each group over the full range. The inserts are restricted to the nonhypothyroid range, fitted by a mixed model adjusted for FT4/FT3, gender, age and BMI. Responses in symptomatic patients were significantly shifted to the right (FT4: p = 0.03, FT3: p = 0.007). BMI, body mass index; FT3, free triiodothyronine; FT4, free thyroxine; TSH, thyroid stimulating hormone.