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Neuroanatomical Pathways for Thyroid Hormone Feedback in the Human Hypothalamus
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CONTEXT: Recent findings point to an increasing number of hypothalamic proteins involved in the central regulation of thyroid hormone feedback. The functional neuroanatomy of these proteins in the human hypothalamus is largely unknown at present. OBJECTIVE: The aim of this study was to report the distribution of type II and type III deiodinase (D2 and D3) as well as the recently identified T(3) transporter, monocarboxylate transporter 8 (MCT8), in the human hypothalamus. DESIGN: The study included enzyme activity assays, immunocytochemical studies, and mRNA in situ hybridizations in postmortem human hypothalamus (n = 9). RESULTS: D2 immunoreactivity is prominent in glial cells of the infundibular nucleus/median eminence, blood vessels, and cells lining the third ventricle. By contrast, both D3 and MCT8 are expressed by neurons of the paraventricular (PVN), supraoptic, and infundibular nucleus (IFN). In support of these immunocytochemical data, D2 and D3 enzyme activities are detectable in the mediobasal human hypothalamus. Combined D2, D3, MCT8, and thyroid hormone receptor immunohistochemistry and TRH mRNA in situ hybridization clearly showed that D3, MCT8, and thyroid hormone receptor isoforms are all expressed in TRH neurons of the PVN, whereas D2 is not. CONCLUSIONS AND IMPLICATIONS: Based on these findings, we propose three possible routes for thyroid hormone feedback on TRH neurons in the human PVN: 1) local thyroid hormone uptake from the vascular compartment within the PVN, 2) thyroid hormone uptake from the cerebrospinal fluid in the third ventricle followed by transport to TRH neurons in the PVN or IFN neurons projecting to TRH neurons in the PVN, and 3) thyroid hormone sensing in the IFN of the mediobasal hypothalamus by neurons projecting to TRH neurons in the PVN.
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“In the hypothalamus, DIO2 is expressed in glial cells and tanycytes and DIO3 is expressed in neurons of the paraventricular nucleus (PVN), supraoptic nucleus (SON) and IFN [14].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [14]
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“Hypothalamic TRH is also modulated by glucocorticoids, as high glucocorticoid levels suppress the pituitary response to TRH in man [69], while a postmortem study in human hypothalamus showed that glucocorticoid treatment is associated with downregulation of TR neurons in the human PVN [14].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [14]
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“In addition, tanycytes are richly replete in the thyroid hormone transporters, MCT8 and OATP1C1 (Figure 7, C and D) (51,101,102), that facilitate the entry of T 4 from the circulation or CSF and the release of the generated T 3 into the neuropil or CSF.”
From Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions (2014) · cites this paper as [101]
In the citing paper
“The location of tanycytes at the blood-brain and CSFbrain barriers and their high expression of thyroid hormone transporters place them in a strategic position to extract T 4 from the bloodstream or CSF.”
From Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions (2014) · cites this paper as [101]
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Metadata
- Authors
- Alkemade, A., Friesema, E. C., Unmehopa, U. A., Fabriek, B. O., Kuiper, G. G., Leonard, J. L., Wiersinga, W. M., Swaab, D. F., Visser, T. J., & Fliers, E.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Erasmus MC (NL)
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Fliers, Eric
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2005-07
- Volume
- 90
- Issue
- 7
- Pages
- 4322-4334
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2126000321
- Cited by
- 146
- References
- 50
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 4 · 2023: 7 · 2022: 4 · 2021: 5 · 2020: 6 · 2019: 6 · 2018: 1 · 2017: 7 · 2016: 10 · 2015: 7 · 2014: 7 · 2013: 6 · 2012: 12
- FWCI
- 7.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- thyroid hormone feedback, hypothalamus, type 2 deiodinase, type III deiodinase, MCT8, thyroid hormone transporters, paraventricular nucleus, arcuate nucleus, median eminence, thyroid hormone receptor, mediobasal hypothalamus, postmortem brain
- MeSH terms
- Adult, Aged, Aged, 80 and over, Feedback, Female, Humans, Hypothalamus, Immunohistochemistry, Iodide Peroxidase, Male, Middle Aged, Pituitary Gland, Anterior, Receptors, Thyroid Hormone, Thyroid Hormones, In Situ Hybridization, Monocarboxylic Acid Transporters, Symporters
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