Median-lower normal levels of serum thyroxine are associated with low triiodothyronine levels and body temperature in patients with central hypothyroidism
Abstract
Objective: Although it has been recommended that serum free thyroxine (FT 4) levels should be targeted to middle-upper normal levels during levothyroxine (l-T 4) replacement therapy in patients with central hypothyroidism (CeH), the rationale has not been clarified. Methods: A retrospective single-center study enrolled 116 patients with hypothyroidism (CeH,n=32; total thyroidectomy (Tx),n=22; primary hypothyroidism (PH),n=33; and control benign thyroid nodule (C),n=29). The patients had received l-T 4 therapy at the Kobe University Hospital between 2003 and 2013. They were stratified according to serum FT 4 level (≥1.10 or <1.10 ng/dl), and body temperature (BT), serum free triiodothyronine (FT 3) levels, FT 3/FT 4 ratio, and lipid profiles were compared. The effect of GH replacement therapy on thyroid function was also analyzed. Results: FT 3 levels and FT 3/FT 4 ratios were significantly lower in patients with CeH than in patients with PH (P<0.05) or C (P<0.05). In patients with FT 4<1.10 ng/dl, BT was significantly lower in patients with CeH (P=0.002) and Tx (P=0.005) than in patients with PH, whereas no differences were found in patients with FT 4≥1.10 ng/dl. In patients with CeH, FT 3 levels were higher in those with GH replacement therapy (P=0.018). Conclusion: In CeH, patients with median-lower normal levels of serum FT 4 exhibited lower serum FT 3 levels and lower BT. These results support the target levels of serum FT 4 as middle-upper normal levels during l-T 4 replacement therapy in patients with CeH.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Concentrations of FT4 in the upper part of normal range might represent an appropriate target in most treated CeH patients.
“Several groups [49, 56, 58, 60] reported that concentrations of FT4 in the upper part of normal range might represent an appropriate target in most treated CeH patients (Recommendation 26).”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [60]
Cites
Identification and Importance of Brown Adipose Tissue in Adult Humans
Cypess, A. M., Lehman, S., Williams, G., Tal, I., Rodman, D., Goldfine, A. B., Kuo, F. C., Palmer, E. L., Tseng, Y.-H., Doria, A., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810780 · Cited by 4,399 · see citing works
Feldmann, H. M., Golozoubova, V., Cannon, B., & Nedergaard, J. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2008.12.014 · Cited by 1,318 · see citing works
Association between premature mortality and hypopituitarism
Tomlinson, J., Holden, N., Hills, R., Wheatley, K., Clayton, R., Bates, A., Sheppard, M., & Stewart, P. (2001) · The Lancet · doi:10.1016/s0140-6736(00)04006-x · Cited by 1,006 · see citing works
The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue
de Jesus, L. A., Carvalho, S. D., Ribeiro, M. O., Schneider, M. J., Kim, S.-W., Harney, J. W., Larsen, P. R., & Bianco, A. C. (2001) · Journal of Clinical Investigation · doi:10.1172/jci200113803 · Cited by 537 · see citing works
Bunevičius, R., Kažanavičius, G., Žalinkevičius, R., & Prange, A. J. (1999) · New England Journal of Medicine · doi:10.1056/nejm199902113400603 · Cited by 482 · see citing works
Estradiol Regulates Brown Adipose Tissue Thermogenesis via Hypothalamic AMPK
de Morentin, P. B. M., González‐García, I., Martins, L., Lage, R., Fernández-Mallo, D., Martínez‐Sánchez, N., Ruíz-Pino, F., Liu, J. T., Morgan, D. A., Pinilla, L., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.03.031 · Cited by 452 · see citing works
Fish, L. H., Schwartz, H. L., Cavanaugh, J., Steffes, M. W., Bantle, J. P., & Oppenheimer, J. H. (1987) · New England Journal of Medicine · doi:10.1056/nejm198703263161302 · Cited by 353 · see citing works
Levothyroxine Therapy in Patients with Thyroid Disease
Mandel, S. J., Brent, G. A., & Larsen, P. R. (1993) · Annals of Internal Medicine · doi:10.7326/0003-4819-119-6-199309150-00009 · Cited by 324 · see citing works
Levothyroxine Monotherapy Cannot Guarantee Euthyroidism in All Athyreotic Patients
Gullo, D., Latina, A., Frasca, F., Le Moli, R., Pellegriti, G., & Vigneri, R. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022552 · Cited by 307 · see citing works
Grozinsky-Glasberg, S., Fraser, A., Nahshoni, E., Weizman, A., & Leibovici, L. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-0448 · Cited by 296 · see citing works
Central Hypothyroidism: Pathogenic, Diagnostic, and Therapeutic Challenges
Persani, L. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-1616 · Cited by 295 · see citing works
The Deiodination of the Iodothyronines and of Their Derivatives in Man
Engler, D., & Burger, A. (1984) · Endocrine Reviews · doi:10.1210/edrv-5-2-151 · Cited by 237 · see citing works
Health Care–Associated Bloodstream Infections
Kaye, K. S., Friedman, N. D., & Sexton, D. J. (2003) · Annals of Internal Medicine · doi:10.7326/0003-4819-139-3-200308050-00018 · Cited by 232 · see citing works
Clyde, P. W., Harari, A. E., Getka, E. J., & Shakir, K. M. M. (2003) · JAMA · doi:10.1001/jama.290.22.2952 · Cited by 195 · see citing works
Triiodothyronine induces UCP-1 expression and mitochondrial biogenesis in human adipocytes
Lee, J., Takahashi, N., Yasubuchi, M., Kim, Y., Hashizaki, H., Kim, M., Sakamoto, T., Goto, T., & Kawada, T. (2011) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00010.2011 · Cited by 176 · see citing works
Jørgensen, J. O. L., Møller, J., Laursen, T., Ørskov, H., Christiansen, J. S., & Weeke, J. (1994) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1994.tb01826.x · Cited by 162 · see citing works
Alexopoulou, O., Beguin, C., De Nayer, P., & Maiter, D. (2004) · European Journal of Endocrinology · doi:10.1530/eje.0.1500001 · Cited by 135 · see citing works
Ferretti, E., Persani, L., Jaffrain-Rea, M.-L., Giambona, S., Tamburrano, G., & Beck-Peccoz, P. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.3.5553 · Cited by 134 · see citing works
Ito, M., Miyauchi, A., Morita, S., Kudo, T., Nishihara, E., Kihara, M., Takamura, Y., Ito, Y., Kobayashi, K., Miya, A., et al. (2012) · European Journal of Endocrinology · doi:10.1530/eje-11-1029 · Cited by 133 · see citing works
EFFECT OF SINGLE DOSE DEXAMETHASONE ON THE CONCENTRATION OF SERUM TRIIODOTHYRONINE IN MAN
Duick, D. S., Warren, D. W., Nicoloff, J. T., Otis, C. L., & CROXSON, M. S. (1974) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-39-6-1151 · Cited by 114 · see citing works
Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism
Wiersinga, W. M. (2014) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.258 · Cited by 114 · see citing works
Slawik, M., Klawitter, B., Meiser, E., Schories, M., Zwermann, O., Borm, K., Peper, M., Lubrich, B., Hug, M. J., Nauck, M., et al. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-0297 · Cited by 113 · see citing works
Agnihothri, R. V., Courville, A. B., Linderman, J. D., Smith, S., Brychta, R., Remaley, A., Chen, K. Y., Simchowitz, L., & Celi, F. S. (2014) · Thyroid · doi:10.1089/thy.2013.0055 · Cited by 94 · see citing works
Portes, E. S., Oliveira, J. H. A., Maccagnan, P., & Abucham, J. (2000) · Clinical Endocrinology · doi:10.1046/j.1365-2265.2000.01071.x · Cited by 81 · see citing works
Shimon, I., Cohen, O., Lubetsky, A., & Olchovsky, D. (2002) · Thyroid · doi:10.1089/105072502760339406 · Cited by 72 · see citing works
Landsberg, L., Young, J. B., Leonard, W. R., Linsenmeier, R. A., & Turek, F. W. (2009) · Metabolism · doi:10.1016/j.metabol.2009.02.017 · Cited by 65 · see citing works
Butler, P. W., Smith, S. M., Linderman, J. D., Brychta, R. J., Alberobello, A. T., Dubaz, O. M., Luzon, J. A., Skarulis, M. C., Cochran, C. S., WESLEY, R. A., et al. (2010) · Thyroid · doi:10.1089/thy.2010.0244 · Cited by 60 · see citing works
Clinical Features of Accidental Hypothermia, With Some Observations on Thyroid Function
Rosin, A. J., & Exton‐Smith, A. N. (1964) · BMJ · doi:10.1136/bmj.1.5374.16 · Cited by 51 · see citing works
Sesmilo, G. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.86.4.1518 · Cited by 39 · see citing works
Thyroid Morphology and Function in Adults with Untreated Isolated Growth Hormone Deficiency
Alcântara, M. R. S., Salvatori, R., Alcântara, P. R. S., Nóbrega, L. M. A., Campos, V. S., Oliveira, E. C. O., Oliveira, M. H. S., Souza, A. H. O., & Aguiar-Oliveira, M. H. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-2555 · Cited by 34 · see citing works
Developmentally defined regulation of thyroid hormone metabolism by glucocorticoids in the rat
der Geyten, S. V., & Darras, V. (2005) · Journal of Endocrinology · doi:10.1677/joe.1.05974 · Cited by 29 · see citing works
Sesmilo, G., Simó, O., Choque, L., Casamitjana, R., Puig-Domingo, M., & Halperin, I. (2011) · Endocrinología y Nutrición · doi:10.1016/j.endonu.2010.09.006 · Cited by 18 · see citing works
Hypopituitarism: replacement of adrenal, thyroid, and gonadal axes
Howlett, T. A. (2011) · doi:10.1093/med/9780199235292.003.2083 · Cited by 1 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Persani, L., Brabant, G., Dattani, M., Bonomi, M., Feldt-Rasmussen, U., Fliers, E., Gruters, A., Maiter, D., Schoenmakers, N., & van Trotsenburg, A. S. P. (2018) · European Thyroid Journal · doi:10.1159/000491388 · Cited by 222 · see citing works
Fertility Awareness-Based Methods for Women's Health and Family Planning
Duane, M., Stanford, J. B., Porucznik, C. A., & Pilar Vigil, P. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.858977 · Cited by 74 · see citing works
Central hypothyroidism and its role for cardiovascular risk factors in hypopituitary patients
Feldt-Rasmussen, U., & Klose, M. (2016) · Endocrine · doi:10.1007/s12020-016-1047-x · Cited by 43 · see citing works
Thyroid function related symptoms during levothyroxine monotherapy in athyreotic patients
Ito, M., Miyauchi, A., Hisakado, M., Yoshioka, W., Kudo, T., Nishihara, E., Kihara, M., Ito, Y., Miya, A., Fukata, S., et al. (2019) · Endocrine Journal · doi:10.1507/endocrj.ej19-0094 · Cited by 17 · see citing works
Ito, M., Kawasaki, M., Danno, H., Kohsaka, K., Nakamura, T., Hisakado, M., Yoshioka, W., Kasahara, T., Kudo, T., Nishihara, E., et al. (2019) · Thyroid · doi:10.1089/thy.2019.0135 · Cited by 16 · see citing works
Manens, L., Grison, S., Bertho, J., Lestaevel, P., Guéguen, Y., Benderitter, M., Aigueperse, J., & Souidi, M. (2016) · Journal of Radiation Research · doi:10.1093/jrr/rrw067 · Cited by 14 · see citing works
Iglesias, P. (2025) · Endocrine Practice · doi:10.1016/j.eprac.2025.02.004 · Cited by 8 · see citing works
Castets, S., Albarel, F., Bachelot, A., Brun, G., Bouligand, J., Briet, C., Quoc, E. B., Cazabat, L., Chabbert‐Buffet, N., Christin‐Maître, S., et al. (2024) · Annales d Endocrinologie · doi:10.1016/j.ando.2024.03.001 · Cited by 5 · see citing works
Petunina, N. A., Trukhina, L. V., & Martirosian, N. S. (2019) · Terapevticheskii arkhiv · doi:10.26442/00403660.2019.10.000358 · Cited by 1 · see citing works
Persani, L., Brabant, G. E., Dattani, M., Bonomi, M., Feldt‐Rasmussen, U., Fliers, E., Grüters, A., Maiter, D. M., Schoenmakers, N. A., & van Trotsenburg, A. S. P. (2019) · Yearbook of pediatric endocrinology · doi:10.1530/ey.16.3.16 · Cited by 1 · see citing works
AKDENİZ, D. D., & Öztop, M. B. (2021) · Journal of Basic and Clinical Health Sciences · doi:10.30621/jbachs.916680
When to decide on testosterone replacement despite dopamine agonist therapy in male prolactinomas?
Fukuoka, H. (2024) · Pituitary · doi:10.1007/s11102-024-01457-1
Self-citationTan, H., Liu, Y., & Cholekho, S. (2025) · IntechOpen eBooks · doi:10.5772/intechopen.1005432
Oi-Yo, Y., Urai, S., Yamamoto, M., Tomofuji, S., Ohmachi, Y., Sasaki, Y., Bando, H., Takahashi, M., Iguchi, G., Harada, R., et al. (2026) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgag153
Self-citation
- Authors
- Hirata, Y., Fukuoka, H., Iguchi, G., Iwahashi, Y., Fujita, Y., Hari, Y., Iga, M., Nakajima, S., Nishimoto, Y., Mukai, M., Hirota, Y., Sakaguchi, K., Ogawa, W., & Takahashi, Y.
- Affiliations
- Kobe University Hospital (JP)
- Corresponding author
- Fukuoka, Hidenori
- Venue
- European Journal of Endocrinology
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-08
- Volume
- 173
- Issue
- 2
- Pages
- 247-256
- ISSN
- 0804-4643 (ISSN-L)
- 1479-683X
- OpenAlex
- W2100595276
- Cited by
- 14
- References
- 33
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2022: 1 · 2021: 1 · 2019: 4 · 2018: 1 · 2016: 2
- FWCI
- 0.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Keywords
- central hypothyroidism, levothyroxine replacement, free triiodothyronine, body temperature, FT3/FT4 ratio, growth hormone replacement therapy, total thyroidectomy, primary hypothyroidism, lipid profile
- MeSH terms
- Adult, Aged, Body Temperature, Female, Humans, Hypothyroidism, Male, Middle Aged, Retrospective Studies, Thyroxine, Triiodothyronine, Biomarkers
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
