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Decreased Hypothalamic Thyrotropin-Releasing Hormone Gene Expression in Patients with Nonthyroidal Illness¹

Department of Endocrinology and Metabolism (E.F., W.M.W.), Academic Medical Center of the University of Amsterdam, 1100 DE Amsterdam, The Netherlands; and Graduate School of Neurosciences Amsterdam (E.F., S.E.F.G., D.F.S.), Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Eric Fliers, M.D., Department of Endocrinology and Metabolism, Academic Medical Center of the University of Amsterdam, PO box 22700, 1100 DE Amsterdam, The Netherlands. E-mail: e.fliers{at}amc.uva.nl

Changes in hypothalamus-pituitary-thyroid function occur in patients with a variety of illnesses and are referred to as the euthyroid sick syndrome or nonthyroidal illness (NTI). In NTI, serum concentrations of T₃ decrease to low, or even undetectable, levels without giving rise to elevated concentrations of TSH. We hypothesized that decreased activity of TRH-producing cells in the paraventricular nucleus (PVN) contributes to the persistence of low TSH levels.

To test this hypothesis, we collected a series of formalin-fixed, paraffin-embedded hypothalami of patients whose plasma concentrations of T₃, T₄, and TSH had been measured in a blood sample taken less than 24 h before death. Quantitative TRH messenger RNA in situ hybridization (intraassay coefficient of variation: 13%) was performed in the PVN.

Total TRH messenger RNA in the PVN showed a positive correlation with serum T₃ (r = 0.66; P < 0.05) and with logTSH (r = 0.64; P < 0.05), but not with T₄ (r = -0.02; P = 0.95). This is the first study to correlate premortem serum concentrations of thyroid hormones with postmortem gene expression of identified neurons in the human hypothalamus. The results suggest an important role for TRH cells in the pathogenesis of NTI.

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