Dynamics of 24-hour endogenous cortisol secretion and clearance in primary hypothyroidism assessed before and after partial thyroid hormone replacement

Although various abnormalities of hypothalamic pituitary adrenal function have been reported in primary hypothyroidism, neither 24-h patterns of pulsatile cortisol release nor estimation of its endogenous secretion and clearance rates have been fully investigated in this clinical setting. We studied pulsatile and circadian patterns of cortisol secretion in six hypothyroid men [mean free T₄ index, 0.59 ± 0.22 (±SE); mean TSH, >50 mU/L] by sampling blood at 20-min intervals for 24 h before (unreplaced) and then after 5-7 months of partial replacement treatment with levo-T₄. Compared to a normal group, hypothyroid men had significantly elevated 24-h mean serum concentrations of cortisol (419 vs. 254 nmol/L; P < 0.001), with no change in serum cortisol-binding globulin concentrations. Cluster analysis of cortisol time series revealed a normal pulse frequency, with significant increases in mean peak amplitude (527 us. 331 nmol/L; P = 0.001), mean interpulse valley concentrations (384 vs. 204 nmol/L; P < 0.05), and mean prepeak nadir concentrations (298 vs. 166 nmol/L; P < 0.05). Cosinor analysis showed preserved circadian rhythmicity (i.e. normal mean circadian amplitude of cortisol release) in hypothyroidism, with a significant delay in the timing of circadian acrophases and an increase in the mesor (mean). Analysis of data by a multiple parameter deconvolution method demonstrated a normal 24-h endogenous cortisol production rate in the presence of significantly prolonged subject-specific half-life of cortisol disappearance (155 vs. 73 min; P < 0.05). Partial replacement therapy with levo-T₄ caused significant decreases in 1) mean 24-h serum cortisol concentrations (419 vs. 323 nmol/L; P < 0.05); 2) mean cortisol peak amplitudes (527 vs. 375 nmol/L; P < 0.05); 3) mean prepeak nadir concentrations (298 vs. 221 nmol/L; P < 0.05); and 4) mean half-life of cortisol disappearance (155 vs. 112 min; P < 0.0019). In summary, the present study of cortisol secretory dynamics in hypothyroid men has shown elevated mean 24-h serum concentrations of cortisol with preserved circadian rhymicity and normal endogenous production rates, but prolonged half-lives of cortisol disappearance. In conjunction with normal serum cortisol-binding globulin concentrations, these largely reversible findings suggest that significant hypercortisolemia in primary hypothyroidism is primarily due to decreased metabolic clearance of cortisol and a presumptive decrease in the negative feedback effect of cortisol on the hypothalamo-pituitary axis.