Search tips
Search criteria 


Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. 1995 December; 96(6): 2828–2838.
PMCID: PMC185993

Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats.


We have studied whether, or not, tissue-specific regulatory mechanisms provide normal 3,5,3'-triiodothyronine (T3) concentrations simultaneously in all tissues of a hypothyroid animal receiving thyroxine (T4), an assumption implicit in the replacement therapy of hypothyroid patients with T4 alone. Thyroidectomized rats were infused with placebo or 1 of 10 T4 doses (0.2-8.0 micrograms per 100 grams of body weight per day). Placebo-infused intact rats served as controls. Plasma and 10 tissues were obtained after 12-13 d of infusion. Plasma thyrotropin and plasma and tissue T4 and T3 were determined by RIA. Iodothyronine-deiodinase activities were assayed using cerebral cortex, liver, and lung. No single dose of T4 was able to restore normal plasma thyrotropin, T4 and T3, as well as T4 and T3 in all tissues, or at least to restore T3 simultaneously in plasma and all tissues. Moreover, in most tissues, the dose of T4 needed to ensure normal T3 levels resulted in supraphysiological T4 concentrations. Notable exceptions were the cortex, brown adipose tissue, and cerebellum, which maintained T3 homeostasis over a wide range of plasma T4 and T3 levels. Deiodinase activities explained some, but not all, of the tissue-specific and dose related changes in tissue T3 concentrations. In conclusion, euthyroidism is not restored in plasma and all tissues of thyroidectomized rats on T4 alone. These results may well be pertinent to patients on T4 replacement therapy.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.7M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Pilo A, Iervasi G, Vitek F, Ferdeghini M, Cazzuola F, Bianchi R. Thyroidal and peripheral production of 3,5,3'-triiodothyronine in humans by multicompartmental analysis. Am J Physiol. 1990 Apr;258(4 Pt 1):E715–E726. [PubMed]
  • Schröder-van der Elst JP, van der Heide D. Thyroxine, 3,5,3'-triiodothyronine, and 3,3',5'-triiodothyronine concentrations in several tissues of the rat: effects of amiodarone and desethylamiodarone on thyroid hormone metabolism [corrected]. Endocrinology. 1990 Oct;127(4):1656–1664. [PubMed]
  • Schröder-van der Elst JP, van der Heide D. Effects of 5,5'-diphenylhydantoin on thyroxine and 3,5,3'-triiodothyronine concentrations in several tissues of the rat. Endocrinology. 1990 Jan;126(1):186–191. [PubMed]
  • Schröder-van der Elst JP, van der Heide D, Köhrle J. In vivo effects of flavonoid EMD 21388 on thyroid hormone secretion and metabolism in rats. Am J Physiol. 1991 Aug;261(2 Pt 1):E227–E232. [PubMed]
  • Schröder-van der Elst JP, van der Heide D. Effects of streptozocin-induced diabetes and food restriction on quantities and source of T4 and T3 in rat tissues. Diabetes. 1992 Feb;41(2):147–152. [PubMed]
  • Obregon MJ, Roelfsema F, Morreale de Escobar G, Escobar del Rey F, Querido A. Exchange of triiodothyronine derived from thyroxine with circulating triiodothyronine as studied in the rat. Clin Endocrinol (Oxf) 1979 Mar;10(3):305–315. [PubMed]
  • Silva JE, Larsen PR. Pituitary nuclear 3,5,3'-triiodothyronine and thyrotropin secretion: an explanation for the effect of thyroxine. Science. 1977 Nov 11;198(4317):617–620. [PubMed]
  • Larsen PR, Silva JE, Kaplan MM. Relationships between circulating and intracellular thyroid hormones: physiological and clinical implications. Endocr Rev. 1981 Winter;2(1):87–102. [PubMed]
  • Silva JE, Larsen PR. Contributions of plasma triiodothyronine and local thyroxine monodeiodination to triiodothyronine to nuclear triiodothyronine receptor saturation in pituitary, liver, and kidney of hypothyroid rats. Further evidence relating saturation of pituitary nuclear triiodothyronine receptors and the acute inhibition of thyroid-stimulating hormone release. J Clin Invest. 1978 May;61(5):1247–1259. [PMC free article] [PubMed]
  • Silva JE, Dick TE, Larsen PR. The contribution of local tissue thyroxine monodeiodination to the nuclear 3,5,3'-triiodothyronine in pituitary, liver, and kidney of euthyroid rats. Endocrinology. 1978 Oct;103(4):1196–1207. [PubMed]
  • Silva JE, Leonard JL, Crantz FR, Larsen PR. Evidence for two tissue-specific pathways for in vivo thyroxine 5'-deiodination in the rat. J Clin Invest. 1982 May;69(5):1176–1184. [PMC free article] [PubMed]
  • Crantz FR, Silva JE, Larsen PR. An analysis of the sources and quantity of 3,5,3'-triiodothyronine specifically bound to nuclear receptors in rat cerebral cortex and cerebellum. Endocrinology. 1982 Feb;110(2):367–375. [PubMed]
  • van Doorn J, van der Heide D, Roelfsema F. Sources and quantity of 3,5,3'-triiodothyronine in several tissues of the rat. J Clin Invest. 1983 Nov;72(5):1778–1792. [PMC free article] [PubMed]
  • van Doorn J, Roelfsema F, van der Heide D. Contribution fron local conversion of thyroxine to 3,5,3'-triiodothyronine to intracellular 3,5,3'-triiodothyronine in several organs in hypothyroid rats at isotope equilibrium. Acta Endocrinol (Copenh) 1982 Nov;101(3):386–396. [PubMed]
  • van Doorn J, van der Heide D, Roelfsema F. The contribution of local thyroxine monodeiodination to intracellular 3,5, 3'-triiodothyronine in several tissues of hyperthyroid rats at isotopic equilibrium. Endocrinology. 1984 Jul;115(1):174–182. [PubMed]
  • van Doorn J, van der Heide D, Roelfsema F. The influence of partial food deprivation on the quantity and source of triiodothyronine in several tissues of athyreotic thyroxine-maintained rats. Endocrinology. 1984 Aug;115(2):705–711. [PubMed]
  • Silva JE, Matthews PS. Production rates and turnover of triiodothyronine in rat-developing cerebral cortex and cerebellum. Responses to hypothyroidism. J Clin Invest. 1984 Sep;74(3):1035–1049. [PMC free article] [PubMed]
  • Ruiz de Oña C, Obregón MJ, Escobar del Rey F, Morreale de Escobar G. Developmental changes in rat brain 5'-deiodinase and thyroid hormones during the fetal period: the effects of fetal hypothyroidism and maternal thyroid hormones. Pediatr Res. 1988 Nov;24(5):588–594. [PubMed]
  • Calvo R, Obregón MJ, Ruiz de Oña C, Escobar del Rey F, Morreale de Escobar G. Congenital hypothyroidism, as studied in rats. Crucial role of maternal thyroxine but not of 3,5,3'-triiodothyronine in the protection of the fetal brain. J Clin Invest. 1990 Sep;86(3):889–899. [PMC free article] [PubMed]
  • Silva JE, Larsen PR. Potential of brown adipose tissue type II thyroxine 5'-deiodinase as a local and systemic source of triiodothyronine in rats. J Clin Invest. 1985 Dec;76(6):2296–2305. [PMC free article] [PubMed]
  • Fernandez JA, Mampel T, Villarroya F, Iglesias R. Direct assessment of brown adipose tissue as a site of systemic tri-iodothyronine production in the rat. Biochem J. 1987 Apr 1;243(1):281–284. [PubMed]
  • Obregon MJ, Pascual A, de Escobar GM, Escobar del Rey F. Pituitary and plasma thyrotropin, thyroxine, and triiodothyronine after hyperthyroidism. Endocrinology. 1979 May;104(5):1467–1473. [PubMed]
  • Morreale de Escobar G, Pastor R, Obregon MJ, Escobar del Rey F. Effects of maternal hypothyroidism on the weight and thyroid hormone content of rat embryonic tissues, before and after onset of fetal thyroid function. Endocrinology. 1985 Nov;117(5):1890–1900. [PubMed]
  • Morreale de Escobar G, Calvo R, Escobar del Rey F, Obregón MJ. Thyroid hormones in tissues from fetal and adult rats. Endocrinology. 1994 Jun;134(6):2410–2415. [PubMed]
  • Santisteban P, Obregon MJ, Rodriguez-Peña A, Lamas L, Del Rey FE, De Escobar GM. Are iodine-deficient rats euthyroid? Endocrinology. 1982 May;110(5):1780–1789. [PubMed]
  • Ruiz de Oña C, Morreale de Escobar G, Calvo R, Escobar del Rey F, Obregón MJ. Thyroid hormones and 5'-deiodinase in the rat fetus late in gestation: effects of maternal hypothyroidism. Endocrinology. 1991 Jan;128(1):422–432. [PubMed]
  • Obregón MJ, Ruiz de Oña C, Hernandez A, Calvo R, Escobar del Rey F, Morreale de Escobar G. Thyroid hormones and 5'-deiodinase in rat brown adipose tissue during fetal life. Am J Physiol. 1989 Nov;257(5 Pt 1):E625–E631. [PubMed]
  • LOWRY OH, ROSEBROUGH NJ, FARR AL, RANDALL RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed]
  • Campos-Barros A, Köhler R, Müller F, Eravci M, Meinhold H, Wesemann W, Baumgartner A. The influence of sleep deprivation on thyroid hormone metabolism in rat frontal cortex. Neurosci Lett. 1993 Nov 12;162(1-2):145–148. [PubMed]
  • Ruiz-Marcos A, Cartagena-Abella P, Martinez-Galan JR, Calvo R, Morreale de Escobar G, Escobar del Rey F. Thyroxine treatment and the recovery of pyramidal cells of the cerebral cortex from changes induced by juvenile-onset hypothyroidism. J Neurobiol. 1994 Jul;25(7):808–818. [PubMed]
  • García MD, Escobar del Rey F, Morreale de Escobar G. Thyrotropin-releasing hormone and thyroid hormone interactions on thyrotropin secretion in the rat: lack of inhibiting effects of small doses of triiodo-L-thyronine in the hypothyroid rat. Endocrinology. 1976 Jan;98(1):203–213. [PubMed]
  • Weeke J, Gundersen HJ. Circadian and 30 minutes variations in serum TSH and thyroid hormones in normal subjects. Acta Endocrinol (Copenh) 1978 Dec;89(4):659–672. [PubMed]
  • Baumgartner A, Campos-Barros A, Meinhold H. Thyroid hormones and depressive illness: implications for clinical and basic research. Acta Med Austriaca. 1992;19 (Suppl 1):98–102. [PubMed]
  • Rubio A, Osuna C, Guerrero JM. Beta- and alpha-adrenergic mechanisms are involved in regulation of rat pineal type II thyroxine 5'-deiodinase activity during development. Endocrinology. 1991 Mar;128(3):1661–1667. [PubMed]
  • Siegrist-Kaiser CA, Juge-Aubry C, Tranter MP, Ekenbarger DM, Leonard JL. Thyroxine-dependent modulation of actin polymerization in cultured astrocytes. A novel, extranuclear action of thyroid hormone. J Biol Chem. 1990 Mar 25;265(9):5296–5302. [PubMed]
  • Surks MI, Oppenheimer JH. Concentration of L-thyroxine and L-triiodothyronine specifically bound to nuclear receptors in rat liver and kidney. Quantitative evidence favoring a major role of T3 in thyroid hormone action. J Clin Invest. 1977 Sep;60(3):555–562. [PMC free article] [PubMed]
  • Pascual A, Montiel F, Aranda A. Effects of iopanoic acid on thyroid hormone receptor, growth hormone production, and triiodothyronine generation from thyroxine in pituitary GH1 cells. Endocrinology. 1987 Mar;120(3):1089–1096. [PubMed]
  • Morreale de Escobar G, Calvo R, Obregon MJ, Escobar del Rey F. Homeostasis of brain T3 in rat fetuses and their mothers: effects of thyroid status and iodine deficiency. Acta Med Austriaca. 1992;19 (Suppl 1):110–116. [PubMed]
  • Leonard JL, Kaplan MM, Visser TJ, Silva JE, Larsen PR. Cerebral cortex responds rapidly to thyroid hormones. Science. 1981 Oct 30;214(4520):571–573. [PubMed]
  • Obregon MJ, Larsen PR, Silva JE. The role of 3,3',5'-triiodothyronine in the regulation of type II iodothyronine 5'-deiodinase in the rat cerebral cortex. Endocrinology. 1986 Nov;119(5):2186–2192. [PubMed]
  • Balsam A, Ingbar SH. Observations on the factors that control the generation of triiodothyronine from thyroxine in rat liver and the nature of the defect induced by fasting. J Clin Invest. 1979 Jun;63(6):1145–1156. [PMC free article] [PubMed]
  • Otten MH, Mol JA, Visser TJ. Sulfation preceding deiodination of iodothyronines in rat hepatocytes. Science. 1983 Jul 1;221(4605):81–83. [PubMed]
  • Moreno M, Berry MJ, Horst C, Thoma R, Goglia F, Harney JW, Larsen PR, Visser TJ. Activation and inactivation of thyroid hormone by type I iodothyronine deiodinase. FEBS Lett. 1994 May 16;344(2-3):143–146. [PubMed]
  • Hurd RE, Santini F, Lee B, Naim P, Chopra IJ. A study of the 3,5,3'-triiodothyronine sulfation activity in the adult and the fetal rat. Endocrinology. 1993 Nov;133(5):1951–1955. [PubMed]
  • Santini F, Chopra IJ, Wu SY, Solomon DH, Chua Teco GN. Metabolism of 3,5,3'-triiodothyronine sulfate by tissues of the fetal rat: a consideration of the role of desulfation of 3,5,3'-triiodothyronine sulfate as a source of T3. Pediatr Res. 1992 Jun;31(6):541–544. [PubMed]
  • Esfandiari A, Gavaret JM, Lennon AM, Pierre M, Courtin F. Sulfation after deiodination of 3,5,3'-triiodothyronine in rat cultured astrocytes. Endocrinology. 1994 Nov;135(5):2086–2092. [PubMed]
  • Fish LH, Schwartz HL, Cavanaugh J, Steffes MW, Bantle JP, Oppenheimer JH. Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans. N Engl J Med. 1987 Mar 26;316(13):764–770. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation