Abstract
Purpose
The potential benefits of treating subclinical hypothyroidism (SCH) are unclear and still controversial. Thus, we surgically induced SCH in rats and evaluated the effects of thyroxine (T4) replacement on the gene expression levels of deiodinases and thyroid hormone (TH) transporters in different tissues.
Methods
SCH was induced by hemithyroid electrocauterization. The control animals underwent the same surgical procedure but were not subjected to electrocauterization (sham). After 14 days, half of the SCH animals were treated with T4 (SCH + T4). At the end of the experimental protocol, all of the rats were euthanized, serum hormone concentrations were measured, and RNA analyses were performed on different tissues and organs.
Results
Consistent with previous studies, we observed increased TSH levels, normal TH levels, and reduced hypothalamic TRH expression in the SCH group. Additionally, Dio2 mRNA expression was downregulated in the hippocampus and pituitary, and Dio1 was upregulated in the kidney and pituitary of the SCH animals. The changes in Dio3 expression were tissue-specific. Concerning TH transporters, Mct10 expression was upregulated in the pituitary, kidney, hypothalamus, and hippocampus, and Mct8 expression was downregulated in the kidney of the SCH group. Crym expression was upregulated in the kidney and pituitary. Notably, T4 replacement significantly attenuated serum TSH levels and reverted Dio1, Dio2, Mct10, and Crym expression in the pituitary, hippocampus, and kidney to levels that were similar to the sham group. Tissue-specific responses were also observed in the liver and hypothalamus.
Conclusion
Our results indicate that treatment of SCH should be considered before the appearance of clinical symptoms of hypothyroidism.
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References
Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI et al (2012) Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of clinical endocrinologists and the American Thyroid Association. Thyroid. 22(12):1200–1235
Zhou L, Ding S, Li Y, Wang L, Chen W, Bo T et al (2016) Endoplasmic reticulum stress may play a pivotal role in lipid metabolic disorders in a novel mouse model of subclinical hypothyroidism. Sci Rep 6
Akter N, Qureshi NK, Ferdous HS (2017) Subclinical hypothyroidism: a review on clinical consequences and management strategies. J Med 18(1):30–36
Cooper DS, Biondi B (2012) Subclinical thyroid disease. Lancet 379(9821):1142–1154
Pearce SHS, Brabant G, Duntas LH, Monzani F, Peeters RP, Razvi S et al (2014) 2013 ETA guideline: management of subclinical hypothyroidism. Eur Thyroid J 2(4):215–228
Cooper DS (2001) Subclinical hypothyroidism. N Engl J Med 345(4):260–265
Fatourechi V (2009) Subclinical hypothyroidism: an update for primary care physicians. Mayo Clin Proc 84(1):65–71
Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH et al (2004) Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 291(2):228–238
Villar HCCE, Saconato H, Valente O, Atallah AN (2007) Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database of Syst Rev 3:CD003419
Chu JW, Crapo LM (2001) The treatment of subclinical hypothyroidism is seldom necessary. J Clin Endocrinol Metab 86(10):4591–4599
Ge JF, Xu YY, Li N, Zhang Y, Qiu GL, Chu CH et al (2015) Resveratrol improved the spatial learning and memory in subclinical hypothyroidism rat induced by hemi-thyroid electrocauterization. Endocr J 62(10):927–938
Gibelli B, Dionisio R, Ansarin M (2015) Role of hemithyroidectomy in differentiated thyroid cancer. Curr Opin Otolaryngol Head Neck Surg 23(2):99–106
Bianco AC, Anderson G, Forrest D, Galton VA, Gereben B, Kim BW et al (2014) American thyroid association guide to investigating thyroid hormone economy and action in rodent and cell models. Thyroid. 24(1):88–168
Schmittgen DT, Livak KJ (2008) Analyzing real-time PCR data by the comparative CT method. Nat Protoc 3(6):1101–1108
Ge JF, Peng YY, Qi CC, Chen FH, Zhou JN (2014) Depression-like behavior in subclinical hypothyroidism rat induced by hemi-thyroid electrocauterization. Endocrine. 45(3):430–438
Maia AL, Goemann IM, Meyer ELS, Wajner SM (2011) Type 1 iodothyronine deiodinase in human and disease. J Endocrinol 209(3):283–297
Bianco AC, Kim BW (2006) Deiodinases: implications of the local control of thyroid hormone action. J Clin Invest 116(10):2571–2579
Gereben B, Salvatore D (2005) Pretranslational regulation of type 2 deiodinase. Thyroid. 15(8):855–864
Suzuki S, Mori JI, Kobayashi M, Inagaki T, Inaba H, Komatsu A et al (2003) Cell-specific expression of NADPH-dependent cytosolic 3,5,3′-triiodo-L-thyronine-binding protein (p38CTBP). Eur J Endocrinol 148(2):259–268
Mori JI, Suzuki S, Kobayashi M, Inagaki T, Komatsu AI, Takeda T et al (2002) Nicotinamide adenine dinucleotide phosphate-dependent cytosolic T3 binding protein as a regulator for T3-mediated transactivation. Endocrinology. 143(4):1538–1544
Suzuki S, Suzuki N, Mori JI, Oshima A, Usami S, Hashizume K (2007) μ-Crystallin as an intracellular 3,5,3′-triiodothyronine holder in vivo. Mol Endocrinol 21(4):885–894
Friesema ECH, Jansen J, Jachtenberg JW, Visser WE, Kester MHA, Visser TJ (2008) Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10. Mol Endocrinol 22(6):1357–1369
van Mullem AA, van Gucht ALM, Visser WE, Meima ME, Peeters RP, Visser TJ (2016) Effects of thyroid hormone transporters MCT8 and MCT10 on nuclear activity of T3. Mol Cell Endocrinol 437:252–260
Mebis L, Paletta D, Debaveye Y, Ellger B, Langouche L, D'Hoore A et al (2009) Expression of thyroid hormone transporters during critical illness. Eur J Endocrinol 161(2):243–250
Wittmann G, Szabon J, Mohácsik P, Nouriel SS, Gereben B, Fekete C et al (2015) Parallel regulation of thyroid hormone transporters OATP1c1 and MCT8 during and after endotoxemia at the blood-brain barrier of male rodents. Endocrinology. 156(4):1552–1564
Hu ZM, Zhuo XH, Shi YN, Liu X, Yuan JH, Li LY et al (2014) Iodine deficiency upregulates monocarboxylate transporter 8 expression of mouse thyroid gland. Chin Med J 127(23):4071–4076
Cheng SY, Leonard JL, Davis PJ (2010) Molecular aspects of thyroid hormone actions. Endocr Rev 31(2):139–170
Brent GA (2012) Mechanisms of thyroid hormone action. J Clin Invest 122(9):3035–3043
De Castro JPW, Fonseca TL, Ueta CB, McAninch EA, Abdalla S, Wittmann G et al (2015) Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine. J Clin Invest 125(2):769–781
Hernandez A, Morte B, Belinchon MM, Ceballos A, Bernal J (2012) Critical role of types 2 and 3 deiodinases in the negative regulation of gene expression by T 3 in the mouse cerebral cortex. Endocrinology. 153(6):2919–2928
Donzelli R, Colligiani D, Kusmic C, Sabatini M, Lorenzini L, Accorroni A et al (2016) Effect of hypothyroidism and hyperthyroidism on tissue thyroid hormone concentrations in rat. Eur Thyroid J. 5(1):27–34
Escobar-Morreale HF, Obregón MJ, Escobar Del Rey F, Morreale De Escobar G (1995) Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. J Clin Invest 96(6):2828–2838
Sawka AM, Cappola AR, Peeters RP, Kopp PA, Bianco AC, Jonklaas J (2019) Patient context and thyrotropin levels are important when considering treatment of subclinical hypothyroidism. Thyroid. 29(10):1359–1363
Bekkering GE, Agoritsas T, Lytvyn L, Heen AF, Feller M, Moutzouri E, Abdulazeem H, Aertgeerts B, Beecher D, Brito JP, Farhoumand PD, Singh Ospina N, Rodondi N, van Driel M, Wallace E, Snel M, Okwen PM, Siemieniuk R, Vandvik PO, Kuijpers T, Vermandere M (2019) Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ. 365:I2006
Feller M, Snel M, Moutzouri E, Bauer DC, de Montmollin M, Aujesky D, Ford I, Gussekloo J, Kearny PM, Mooijaart S, Quinn T, Scott D, Westendorp R, Rodondi N, Dekkers OM (2018) Association of thyroid hormone therapy with quality of life and thyroid-related symptoms in patients with subclinical hypothyroidism: a systematic review and meta-analysis. JAMA. 320(13):1349–1359
Acknowledgments
We would like to thank the Fundação Carlos Chagas, Filho de Amparo à Pesquisa do Estado de São Paulo (FAPESP), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes) for financial support and R2G English Editing Services (São Paulo, SP, Brazil) for reviewing and editing the manuscript.
Funding
This project was funded by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) to Janaina Sena de Souza (FAPESP #2017/07053-3 and #2018/22763-0) and to Gisele Giannocco (FAPESP #2017/23169-1) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes) for the fellowship granted to Kellen Carneiro Oliveira and Rodrigo Rodrigues da Conceição.
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This investigation was carried out in accordance with the “Guide for the Care and Use of Laboratory Animals” published by the US National Institutes of Health (NIH Publication No.85-23, revised 1996) and was approved by the institutional animal welfare committee in consonance with pertinent Brazilian legislation under Protocols number: 078, book 02.
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Oliveira, K.C., Laureano-Melo, R., da Conceição, R.R. et al. Thyroxine replacement modifies changes in deiodinase and thyroid hormone transporter expression induced by subclinical hypothyroidism in rats. Hormones 20, 101–110 (2021). https://doi.org/10.1007/s42000-020-00247-1
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DOI: https://doi.org/10.1007/s42000-020-00247-1