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Decreased Hypothalamic Thyrotropin-Releasing Hormone Gene Expression in Patients with Nonthyroidal Illness1
Abstract
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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“Indeed, reduced hypothalamic TRH expression, portal serum TRH and pituitary TSH content have been observed both in NTIS patients [65] and NTIS animal models [12, 19, 66, 67].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [65]
In the citing paper
“This concept was supported by a study reporting that deceased patients with NTIS had decreased TRH mRNA expression in the hypothalamic paraventricular nucleus, correlating with decreased ante mortem plasma TSH and T3 concentrations [65].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [65]
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“In addition, IL-1b administration to the cerebrospinal fluid in rats was associated with a proTRH mRNA content in the PVN that was inappropriately normal or reduced for the decreased concentration of circulating thyroid hormones ( 20 ).”
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Metadata
- Authors
- Fliers, E., Guldenaar, S. E. F., Wiersinga, W. M., & Swaab, D. F.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Corresponding author
- Fliers, Eric
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 1997-12
- Volume
- 82
- Issue
- 12
- Pages
- 4032-4036
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W1972866985
- Cited by
- 206
- References
- 4
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 3 · 2022: 5 · 2021: 8 · 2020: 3 · 2019: 7 · 2018: 6 · 2017: 6 · 2016: 8 · 2015: 4 · 2014: 14 · 2013: 12 · 2012: 8
- FWCI
- 3.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- low T3 syndrome, thyrotropin-releasing hormone, paraventricular nucleus, hypothalamus, hypothalamic-pituitary-thyroid axis, serum T3, thyroid-stimulating hormone
- MeSH terms
- Adult, Aged, Aged, 80 and over, Female, Humans, Hypothalamus, Male, Osmolar Concentration, Paraventricular Hypothalamic Nucleus, RNA, Messenger, Thyroid Diseases, Thyrotropin, Thyrotropin-Releasing Hormone, Triiodothyronine, Gene Expression, In Situ Hybridization
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