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

Escobar-Morreale, H F; Obregón, M J; Escobar del Rey, F; Morreale de Escobar, G

doi:10.1172/jci118353

Cited by 287Thyroid Disorders and TreatmentsThyroid and Parathyroid SurgeryThyroid Cancer Diagnosis and Treatment

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

Open access

Escobar-Morreale, H F, Obregón, M J, Escobar del Rey, F, Morreale de Escobar, G·1995·Journal of Clinical Investigation

DOI 10.1172/jci118353PMC PMC185993

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Abstract

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.

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Claims the paper makes

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Findingnone given
Normalization of T3 concentrations in lung required even higher infusion doses of T4 than normalization of T3 in liver.
“Normalization of T3 concentrations in Lu required even higher infusion doses of T4 than normalization of T3 in L.”
Quote in the paperSubstantial claim
Findingown data
Cerebral cortex T3 homeostasis was independent of plasma T4 and T3 levels and of T4 levels in the cortex.
“This excellent T3 homeostasis was independent of plasma T4 and T3 levels, and of T4 levels in the Cx, which were low with 0.2 to 0.8 Iug T4/ 100 grams BW per day, and elevated with doses of 1.0 to 8.0 Mg T4/ 100 grams BW per day.”
Quote in the paperSubstantial claim
Findingown data
The lowest dose resulting in normal circulating T4 (0.6 ug T4/100g/day) resulted in normal T4 concentrations in heart, lung, spleen, and cerebellum, although higher doses were needed to normalize liver and kidney T4.
“Thus, the lowest of such doses, namely 0.6 Mg T4/ 100 grams BW per day, resulted in normal T4 concentrations in the heart, lung, spleen, and cerebellum, although higher doses were needed to normalize liver and kidney T4.”
Quote in the paperSubstantial claim
Findingown data
The degree of increase of T4 and T3 was not the same for all tissues studied.
“As may be seen, the degree of increase of T4 and T3 was not the same for all tissues studied.”
Quote in the paperSubstantial claim
Findingown data
We did not detect appreciable 5'D-I activity in cerebral cortex, cerebellum, and BAT.
“we did not detect appreciable 5'D-I activity in Cx, Cb, and BAT.”
Quote in the paperSubstantial claim

Findingown data
Administration of T4 alone to thyroidectomized rats does not result in both normal T4 and T3 simultaneously in all tissues at any of the 10 doses tested.
“It is evident from the present results that possibility (a) is not met, as the administration of T4 alone to thyroidectomized rats does not result in both normal T4 and T3 simultaneously in all tissues at any of the 10 doses tested.”
Quote in the paperSubstantial claim
Findingreasoning
The findings for BAT T3 were similar to those for lung T3, inasmuch as BAT T3 reached normal values when plasma T3 was higher than normal.
“The findings for BAT T3 were similar to those for lung T3, inasmuch as BAT T3 reached normal values when plasma T3 was higher than normal.”
Quote in the paperNot a substantial claim
Findingreasoning
T3 may still be low in some tissues at the 1.6 μg T4/100 g BW per day dose.
“Even so, T3 may still be low in some tissues.”
Quote in the paperSubstantial claim
Findingnone given
In animals with normal circulating T4 and T3, the concentrations of T3 are lower than normal in both P1 and L.
“In animals with normal circulating T4 and T3 the concentrations of the latter iodothyronine are lower than nor- mal in both P1 and L.”
Quote in the paperSubstantial claim
Findingown data
A normal plasma T4 level does not ensure that T3 is normal in tissues, with the notable exception of Cx and Cb, and possibly K, Mu, and S.
“Fig. 5 A-2 illustrates the finding that a normal plasma T4 level concentration does not ensure that T3 is normal in tissues, with the notable exception of Cx and Cb, and possibly K, Mu, and S.”
Quote in the paperSubstantial claim
Findingown data
Cerebral cortex T3 remained within normal limits over a 20-fold increase in T4 infusion doses, from 0.4 to 8.0 μg T4/100 g BW per day.
“Cerebral cortex T3 remained within normal limits over a 20-fold increase in the T4 infusion doses, namely from 0.4 to 8.0 tg T4/ 100 gram BW per day.”
Quote in the paperSubstantial claim
Findingown data
Cerebral T3 homeostasis is unique: it is normal even with plasma T4 and T3 levels clearly in a hypothyroid range.
“Fig. 5, B-J-B-3 stress the unique homeostasis of cerebral T3, which is normal even with plasma T4 and T3 levels which are clearly in a hypothyroid range.”
Quote in the paperSubstantial claim
Findingown data
Cerebral cortex T3 concentrations were low in thyroidectomized rats infused with placebo or 0.2 ug T4/100g/day, but normal with doses from 0.4 to 8.0 ug T4/100g/day, except mildly elevated at 1.6.
“Cerebral cortex T3 concentrations were low in thyroidectomized rats infused with placebo or 0.2 ,ug T4/ 100 grams BW per day, but presented normal T3 levels with doses ranging from 0.4 to 8.0 ,tg T4/ 100 grams BW per day (with the exception of mildly elevated levels in the group of thyroidectomized rats infused with 1.6 Mug T4/ 100 grams BW per day).”
Quote in the paperSubstantial claim
Findingreasoning
Normal T3 concentrations in many tissues required either supraphysiological concentrations of T4 in the tissue, elevated activities of iodothyronine deiodinases, or both.
“Normal T3 concentrations in many tissues required either supraphysiological concentrations of T4 in the tissue, elevated activities of iodothyronine deiodi- nases, or both.”
Quote in the paperSubstantial claim
Findingown data
The dose needed to ensure a normal concentration of each iodothyronine was not the same for all tissues studied.
“Moreover, the dose needed to ensure a normal concentration of each iodothyronine (see Table III) was not the same for all tissues studied.”
Quote in the paperSubstantial claim
Findingown data
Cerebral cortex 5'D-II markedly increased in thyroidectomized rats to 209±14 fmol I-/h per mg protein, compared to 33±2 in controls.
“Cerebral cortex 5 'D-II markedly increased in the thyroidectomized rats to 209±14 fmol I-/h per mg protein, as compared to 33±2 fmol I-/h per mg protein in controls animals.”
Quote in the paperSubstantial claim
Findingown data
In most tissues, the dose of T4 needed to ensure normal T3 levels resulted in supraphysiological T4 concentrations.
“Moreover, in most tissues, the dose of T4 needed to ensure normal T3 levels resulted in supraphysiological T4 concentrations.”
- Also stated in: § Circulating T4, T3, and TSH, and concentrations of T4 and T3 in different tissues as function of the T4 dose · plain
  “Conversely, supraphysiological T4 levels were needed to normalize T3 levels in most tissues.”
Quote in the paperSubstantial claim
Findingown data
Normalization of lung T3 in thyroidectomized, T4-infused rats requires supraphysiological circulating T3.
“On the contrary, normalization of lung T3 in the thyroidectomized, T4-infused rats requires supraphysiological circulating T3.”
Quote in the paperSubstantial claim
Findingown data
The concentration of T3 may still be low in some tissues, such as Lu and BAT, even when infusion of thyroidectomized rats with T4 has resulted in normal plasma T3.
“Fig. 5 A-3 summarizes the finding that the concentration of T3 may still be low in some tissues, such as Lu and BAT, even when infusion of the thyroidectomized rats with T4 has resulted in normal plasma T3.”
Quote in the paperSubstantial claim
Findingown data
T3 did not increase in BAT above the normal range even at the highest plasma T4 and T3 levels attained in the present study (3.5 and 2.5 times mean control values, respectively).
“Despite this, the interpolated values shown in the lower panels of Fig. 5 indicate that T3 did not increase in BAT above the normal range even at the highest plasma T4 and T3 levels attained in the present study, namely 3.5 and 2.5 times the mean control values, respectively.”
Quote in the paperSubstantial claim
Findingown data
Triiodothyronine in lung was lower than normal even when normal plasma T3 levels were reached.
“Triiodothyronine in Lu was lower than normal even when normal plasma T3 levels were reached.”
Quote in the paperSubstantial claim
Findingown data
The present study confirmed a marked increase in cerebral cortex 5'D-II activity of hypothyroid rats.
“This finding is in conceptual agreement with the marked increase in cerebral Thyroid Hormone Tissue Levels in Thyroidectomized Rats on Thyroxine cortex 5 'D-II activity of hypothyroid rats (49), as measured in vitro, and confirmed in the present study.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [49]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Findingown data
Normal tissue T4 levels were achieved with lower T4 doses than those needed to normalize tissue T3.
“In general, normal tissue T4 levels were achieved with lower T4 doses than the ones needed to normalize tissue T3.”
Quote in the paperSubstantial claim
Findingown data
In most tissues, normal concentrations of T4 are not reached until the dose of T4 is sufficient to result in normal circulating T4.
“In most tissues, normal concentrations of T4 are not reached until the dose of T4 is sufficient to result in normal circulating T4.”
Quote in the paperSubstantial claim
Findingown data
Cortex, brown adipose tissue, and cerebellum maintained T3 homeostasis over a wide range of plasma T4 and T3 levels.
“Notable exceptions were the cortex, brown adipose tissue, and cerebellum, which maintained T3 ho- meostasis over a wide range of plasma T4 and T3 levels.”
- Also stated in: § Circulating T4, T3, and TSH, and concentrations of T4 and T3 in different tissues as function of the T4 dose · plain
  “Notable exceptions are, however, the Cx, BAT, and Cb, tissues which showed a remarkable degree of independence from plasma T4 and T3 levels: normal or near normal T3 concentrations were found over a wide range of T4 doses.”
Quote in the paperSubstantial claim
Findingown data
Lung and BAT T3 were still low when plasma T3 was normal.
“Lung and BAT T3 were still low when plasma T3 was normal.”
Quote in the paperSubstantial claim
Findingown data
In several tissues T3 only became normal when normal or supraphysiological plasma T3 concentrations were reached.
“In several tissues T3 only became normal when normal or supraphysiological plasma T3 concentrations were reached.”
Quote in the paperSubstantial claim
Findingown data
No statistically significant changes reproducible in both experiments were observed in inner-ring 5D-III activity in cerebral cortex of thyroidectomized rats on placebo or T4 infusion.
“The activity of the inner-ring 5D-I1 was 2,022±473 fmol I-/h per mg protein in Cx of the control rats.No statistically significant changes which were reproducible in both experiments were observed in the thyroidectomized rats on placebo or T4 infusion.”
Quote in the paperSubstantial claim
Findingown data
Triiodothyronine concentrations in BAT were low in rats infused with placebo or 0.2 and 0.4 ug/100g/day and normal with most doses from 0.6 to 8.0 ug T4/100g/day.
“Triiodothyronine concentrations in BAT were low in rats infused with placebo or with 0.2 and 0.4 Mg/100 grams BW and normal with most of the doses ranging from 0.6 to 8.0 Mg T4/100 grams BW per day.”
Quote in the paperSubstantial claim
Findingown data
Present results confirm for normal adult female rats the tight homeostasis of T3 concentrations in the cerebral cortex when T4 is provided to the hypothyroid animal, already described for the rat fetus and adult pregnant rat.
“Present results confirm for nor- mal adult female rats the tight homeostasis of T3 concentrations in the Cx when T4 is provided to the hypothyroid animal, al- ready described for the rat fetus (22) and adult pregnant rat (48).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [22]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [48]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Interpretationreasoning
It seems unlikely that the slight inhibition of 5'D-II, observed only for animals on the two highest doses of T4, would be enough to counteract the very marked increase in the concentration of T4 in the cerebral cortex.
“It seems unlikely that the slight inhibition of 5 'D-II, which was only observed for the animals on the two highest doses of T4, would be enough to counteract the very marked increase in the concentration of T4 in the Cx.”
Quote in the paperSubstantial claim
Interpretationown data
Of the tissues studied, cerebral cortex showed a very efficient homeostasis of its T3 concentrations, providing metabolic protection of this organ against wide changes in thyroid hormone availability.
“Of the tis- sues studied, Cx showed a very efficient homeostasis of its T3 concentrations, providing metabolic protection of this organ against wide changes in thyroid hormone availability.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Normalization of the iodothyronine content of a tissue would be followed by normalization of the biological effects.
Interpretationown data
Interpolated values calculated from the curves best fitting the individual data support the conclusion that infusion of T4 alone, even at doses not tested in the present study, is inadequate to normalize tissue T4 and T3.
“The interpolated values calculated from the curves best fitting the individual data also support the conclusion that infusion of T4 alone, even at doses which were not tested in the present study, is inadequate to normalize tissue T4 and T3.”
Quote in the paperSubstantial claim
Interpretationreasoning
The changes of cerebral cortex 5'D-II activity do not appear to offer an adequate explanation for the maintenance of cerebral cortex T3 homeostasis in rats infused with very high doses of T4, which resulted in supraphysiological cerebral cortex T4, plasma T4, and plasma T3 levels.
“The changes of cerebral cortex 5 'D-II activity do not, however, appear to offer an adequate explanation for the maintenance of cerebral cortex T3 homeostasis in rats infused with very high doses of T4, which resulted in supraphysiological cerebral cortex T4, plasma T4, and plasma T3 levels.”
Quote in the paperSubstantial claim
Premisecitation
Preliminary data show that combined infusion of T4 and T3, in a molar ratio similar to that of thyroidal production, does ensure both normal T4 and T3 in all tissues.
“The infusion of T3 to thyroidectomized rats is also inade- quate to ensure normal T3 levels simultaneously in plasma and all tissues (57), whereas preliminary data show that the com- bined infusion of T4 and T3, in a molar ratio similar to that of the thyroidal production, does ensure both normal T4 and T3 in all tissues (58).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [58]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Interpretationreasoning
Compensatory regulatory mechanisms are inadequate to at least ensure normal concentrations of T3 in all tissues, even at the expense of excessive T4 concentrations.
“They are also inadequate to at least ensure normal concentrations of T3 in all tissues, even at the expense of excessive T4 concentra- tions.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Normalization of the iodothyronine content of a tissue would be followed by normalization of the biological effects.
Interpretationreasoning
It is highly unlikely that both normal T4 and T3 simultaneously in all tissues would have been achieved with an intermediate T4 dose, possibly between 1.0 and 1.6 μg T4/100 g BW per day.
“It is also highly unlikely that this would have been achieved with an intermedi- ate dose, possibly between 1.0 and 1.6 Ag T4/100 gram BW per day.”
Quote in the paperSubstantial claim
Interpretationreasoning
The measured changes in lung 5'D-I activity do not afford an explanation for the low lung T3, unless locally generated T3 is rapidly exported into the circulation.
“The measured changes in lung 5 'D-I activity do not afford an explanation for this finding, unless locally generated T3 is rapidly exported into the circulation.”
Quote in the paperSubstantial claim
Interpretationown data
When T4 alone is administered as replacement therapy to thyroidectomized rats, compensatory regulatory mechanisms are unable to provide both normal T4 and T3 concentrations simultaneously in plasma and all tissues.
“In summary, when T4 alone is administered as replacement therapy to thyroidectomized rats, compensatory regulatory mechanisms are unable to provide both normal T4 and T3 con- centrations simultaneously in plasma and all tissues.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Normalization of the iodothyronine content of a tissue would be followed by normalization of the biological effects.
Interpretationreasoning
Even if SD-III activity remained unchanged, the amount of rT3 generated by inner-ring deiodination of T4 would increase with increasing amounts of available substrate.
“Even if SD-Ill activity remained unchanged, the amount of rT3 generated by inner-ring deiodination of T4 would increase with in- creasing amounts of available substrate.”
Quote in the paperNot a substantial claim
Premisecitation
Extranuclear effects of T4 have been described.
“Extranuclear effects of T4 have, however, been described (44).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [44]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Premisecitation
T4 might contribute to nuclear thyroid hormone receptor occupancy, although to a much lesser degree than T3.
“Moreover, T4 might contribute to nuclear thyroid hormone re- ceptor occupancy, although to a much lesser degree than T3 (45).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [45]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Interpretationcitation
The differences between continuous subcutaneous infusion and usual daily oral T4 delivery might not be very great if mean residence time for T4 in both species is considered.
“The differences between these two types of delivery, however, might not be very great if we consider the mean residence time for T4 in both species, namely 310 and 17.4 h in humans and rats, respectively (40).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [40]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Interpretationown data
Neither plasma T4 nor plasma T3 levels alone permit prediction of the degree of change in T4 and T3 concentrations in tissues.
“It is evident that neither plasma T4 nor plasma T3 levels alone permit prediction of the degree of change in T4 and T3 concentrations in tissues: not only are the tissue to plasma T4 and T3 ratios different for different tissues, but they may also change for a single tissue as a function of the plasma iodothyronine level.”
Quote in the paperSubstantial claim
Premisecitation
Infusion of T3 to thyroidectomized rats is also inadequate to ensure normal T3 levels simultaneously in plasma and all tissues.
“The infusion of T3 to thyroidectomized rats is also inade- quate to ensure normal T3 levels simultaneously in plasma and all tissues (57), whereas preliminary data show that the com- bined infusion of T4 and T3, in a molar ratio similar to that of the thyroidal production, does ensure both normal T4 and T3 in all tissues (58).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [57]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Interpretationreasoning
In hypothyroid conditions, the activity of liver 5'D-I does not appear to contribute to the normalization of plasma-derived T3 in other tissues.
“Thus, in hypothyroid conditions, the activ- ity of liver 5 'D-I does not appear to contribute to the normaliza- tion of plasma-derived T3 in other tissues.”
Quote in the paperSubstantial claim
- Rests on an assumption: Liver 5'D-I plays an important role in the generation of T3 and T4, and the liver is an important source of systemic T3.
Study design and conductcitation
The 12-13-d infusion period is several days longer than the minimum time needed to achieve a steady state situation in hypothyroid rats.
“The 12-13-d infusion period is several days longer than the minimum time needed to achieve a steady state situation in hypothyroid rats (16, 17).”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [16]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [17]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The quote only partly states this claim. 4
May combine two claims. 40
Classified as probably not a substantial claim. 10

The quote only partly states this claim.
Findingown data
The activity of inner-ring 5D-III in cerebral cortex of control rats was 2,022±473 fmol I-/h per mg protein.
“The activity of the inner-ring 5D-I1 was 2,022±473 fmol I-/h per mg protein in Cx of the control rats.”
Quote in the paperNot a substantial claim
May combine two claims.
Findingown data
The changes in the activity of liver 5'D-I measured in the present study agree with those expected from previous investigations: activity decreases in the thyroidectomized rat and then increases towards normal values, that are not reached until liver and plasma T3 are normal and plasma and liver T4 are increased approximately twofold.
“The changes in the activity of liver 5'D-I measured in the present study agree with those expected from previous investigations: activity decreases in the thyroidectomized rat and then increases towards normal values, that are not reached until liver and plasma T3 are normal and plasma and liver T4 are increased approximately twofold.”
Quote in the paperNot a substantial claim
May combine two claims.
Findingown data
Skeletal muscle T4 was already normal in thyroidectomized rats infused with only 0.4 ug T4/100g/day, a dose insufficient to normalize circulating T4.
“An interesting exception is the skeletal muscle, where T4 was already normal in the thyroidectomized rats infused with only 0.4 Mig T4/100 grams BW per day, a dose which is insufficient to normalize circulat- ing T4.”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
Liver 5'D-I activity decreased from control values of 52±4 to 16±12 pmol I-/min per mg protein in placebo-infused thyroidectomized rats, and increased towards normal in rats on 1.0 or 1.6 ug T4/100g/day.
“Liver 5'D-I activity decreased from controls values of 52±4 to 16±12 pmol I-/min per mg protein in the placebo-infused thyroidectomized rats, and increased towards normal activities in the thyroidectomized rats on 1.0 or 1.6 jtg T4/ 100 gram BW per day.”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
The relationship between plasma T3 and plasma T4 in thyroidectomized rats is not linear; the closest fit was a power function T3 = 2.62 * T4^0.75 (d.f.=49, R2=0.96, P<0.001).
“The relationship is not the linear one expected if the changes in circulating T3 were of the same magnitude as those of T4.The closest fit to the individual paired plasma data was found for the power function: T3 = 2.62 * T4075, (with d.f.= 49, R2 = 0.96, and P < 0.001).”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
The 1.0 μg T4/100 g BW per day dose results in normal circulating T4 and T3, but plasma TSH is still elevated, and T3 is low in most tissues.
“The first of these two doses results in normal circulating T4 and T3, but plasma TSH is still elevated, and T3 low in most tissues.”
Quote in the paperSubstantial claim
The quote only partly states this claim.
Findingown data
Lung 5'D-I activity increased twofold in rats receiving 8.0 ug T4/100g/day.
“Activities increased twofold in the rats receiving 8.0 HIg T4/ 100 gram BW per day.”
Quote in the paperNot a substantial claim
May combine two claims.
Findingown data
A normal circulating T4 level does not necessarily ensure that T4 is normal in all tissues: T4 in Mu and Cb are higher than expected from plasma T4, whereas T4 tends to be low in H, and possibly K and L.
“circulating T4 level (Fig. 5 A-i) does not necessarily ensure that T4 is normal in all tissues: T4 in Mu and Cb are higher than expected from plasma T4, whereas T4 tends to be low in H, and possibly K and L.”
Quote in the paperSubstantial claim
May combine two claims.
Findingnone given
Skeletal muscle T3 was normal in animals with low circulating T3 levels, but with higher than normal concentrations of T4 in the tissue.
“Skeletal muscle T3 was also normal in animals with low circulating T3 levels, but with higher than normal concentrations of T4 in the tissue.”
Quote in the paperNot a substantial claim
May combine two claims.
Findingown data
Plasma TSH was elevated in thyroidectomized rats infused with placebo or T4 at 0.2 to 1.0 ug/100g/day, normal at 1.6, and low at higher doses.
“Plasma TSH was elevated in the rats infused with placebo or T4 at doses from 0.2 to 1.0 ,g T4/100 grams BW per day, normal in the rats infused with 1.6 tzg T4/100 grams”
- Also stated in: § Circulating T4, T3, and TSH, and concentrations of T4 and T3 in different tissues as function of the T4 dose · plain
  “low in the animals infused with higher doses.”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
Most curves fitting tissue T4 or T3 concentrations to circulating T4 and T3 levels are not linear, with exponents in power functions ranging from 0.68 to 1.66.
“Most of the curves fitting the tissue T4 or T3 concentrations to the circulating T4 and T3 levels are not linear, although the exponent in the power functions ranged from 0.68 to 1.66, and the curves are almost linear (an exponent = 1.0 corresponds to a linear function).”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
No single dose of T4 restored normal plasma thyrotropin, T4, and T3, as well as T4 and T3 in all tissues, or at least restored T3 simultaneously in plasma and all tissues.
“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.”
- Also stated in: § Introduction · plain
  “As will be seen, none of the 10 doses of T4 which we tested was adequate to ensure simultaneously a normal thyroid status of all the tissues studied.”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
Plasma T3 was normal only with T4 doses of 1.0 and 1.6 ug/100g/day, remaining low with lower doses and elevated with higher doses.
“only reached normal levels with the doses of 1.0 and 1.6 ,ig T4/ 100 grams BW per day, remaining low in the rats infused with lower doses of T4 or placebo, and elevated with higher doses of T4.”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
Plasma T4 was low in thyroidectomized rats infused with placebo or T4 at 0.2 and 0.4 ug/100g/day, normal at 0.6, 0.8, and 1.0, and elevated at 1.6, 2.0, 3.0, 4.0, and 8.0.
“Plasma T4 was low in the groups of thyroidectomized rats infused with placebo or with T4 at doses of 0.2 and 0.4 ,tg/ 100 grams BW per day, normal in the groups infused with 0.6, 0.8, and 1.0 jtg T4/100 grams BW per day, and elevated in the groups infused with 1.6, 2.0, 3.0, 4.0, and 8.0 ,4g T4/ 100 grams BW per day.”
Quote in the paperNot a substantial claim
May combine two claims. The quote only partly states this claim.
Findingown data
Cerebral cortex 5'D-II activity decreased when T4 was infused, with normal values at 0.6 to 3.0 ug T4/100g/day, and decreased to 6.3±0.3 fmol I-/h per mg protein at 4.0 and 8.0.
“The activity of this enzyme decreased when T4 was infused, normal values being found in the thyroidectomized rats infused with 0.6 to 3.0 4g T4/100 gram BW per day, and decreased to 6.3±0.3 fmol I-/h per mg protein in the thyroidectomized rats”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
The tissue-to-plasma T4 and T3 ratios are different for different tissues and may change for a single tissue as a function of plasma iodothyronine level.
“not only are the tissue to plasma T4 and T3 ratios different for different tissues, but they may also change for a single tissue as a function of the plasma iodothyronine level.”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
Normalization of T3 is achieved in the cerebral cortex when circulating T4 is half that of normal control animals, and T4 in the cerebral cortex is one-third.
“Normalization of T3 is achieved in the Cx when circulating T4 is half that of normal control animals, and T4 in the Cx is one-third.”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
Lung 5'D-I activity decreased from control values of 557±17 to 144±9 fmol I-/h per mg protein in placebo-infused thyroidectomized rats, and increased in T4-infused rats, being within normal range at 1.0 to 4.0 ug T4/100g/day.
“Lung 5 'D-I activity also decreased from controls values of 557+17 to 144±9 fmol I-/h per mg protein in the placebo- infused thyroidectomized rats.Activities increased in T4-in- fused thyroidectomized rats and were within the normal range in those infused with 1.0 to 4.0 ,4g T4/100 gram BW per day.”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
An unexpected finding was that skeletal muscle T4 became normal in rats on a T4 dose which was insufficient to ensure normal plasma T4, and became higher than normal in animals with normal circulating T4.
“An unexpected finding was that skeletal muscle T4 became normal in rats on a T4 dose which was insufficient to ensure normal plasma T4, and became higher than normal in animals with normal circulating T4.”
Quote in the paperNot a substantial claim
May combine two claims.
Findingown data
Cerebellar T3 was low in rats infused with placebo, 0.2, 0.4, and 0.6 ug T4/100g/day, normal with 0.8 to 3.0, and elevated with 4.0 and 8.0.
“Cerebellar T3 was low in rats infused with placebo, 0.2, 0.4, and 0.6 Mg T4/ 100 grams BW per day, normal with 0.8 to 3.0 Mug T4/ 100 grams BW per day, and elevated with 4.0 and 8.0 Mtg T4/100 grams BW per day.”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation
Sulfation of T4 and T3 leads to the formation of sulfo-conjugates, which greatly enhances their inner-ring and outer-ring deiodination, both sulfo-conjugates being much better substrates for the selenocysteine-containing 5'D-I than the parent iodothyronine.
“Regarding the latter, sulfation of T4 and T3 leads to the forma- tion of the sulfo-conjugates, which greatly enhances their inner- ring and outer-ring deiodination, both sulfo-conjugates being much better substrates for the selenocisteine-containing 5 'D-I than the parent iodothyronine (52, 53).”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [52]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [53]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown data
Even if normalization of tissue T3 is considered an adequate criterion to assess tissue euthyroidism, a normal thyroid status is not achieved simultaneously for all tissues when T4 alone is infused.
“Even if these possibilities are disregarded and normalization of tissue T3 is considered as an adequate criterion to assess tissue euthyroidism, it is clear from the present results that a normal thyroid status is not achieved simultaneously for all tissues when T4 alone is infused.”
Quote in the paperSubstantial claim
- The authors state this as an assumption: Normalization of the iodothyronine content of a tissue would be followed by normalization of the biological effects.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation
If the amount of available T3 is insufficient, T4 occupies the receptor and exerts a biological effect.
“If the amount of available T3 is insufficient, T4 occupies the receptor, and exerts a biological effect (46).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [46]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation
The molar ratio of T4 to T3 secreted by the thyroid gland is 14:1 in adult humans and 6:1 in adult male rats.
“The molar ratio of the two iodothyronines, as secreted by the gland, has been calculated as 14:1 in adult humans (1), with the corresponding mean value obtained for the adult male rat being 6:1 (2)(3)(4)(5).”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [1]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites (2)(3)(4)(5)
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationreasoning
The dose of T4 needed to normalize thyroid hormone concentrations is different for each tissue, pointing to the existence of tissue-specific regulatory mechanisms.
“The dose of T4 needed to normalize thyroid hormone concentrations is different for each tissue, thus pointing to the existence of tissue-specific regulatory mechanisms.”
Quote in the paperSubstantial claim
May combine two claims.
Premisecitation
Reverse T3 is a potent reversible inhibitor of 5'D-II and might locally reach inhibitory concentrations in vivo.
“Reverse T3 is a potent reversible inhibitor of 5 'D-II (50) and might locally reach inhibitory concentrations in vivo.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [50]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Premisecitation
The relative contribution of T3 derived from the circulation and T3 generated locally from T4 is not the same for all tissues in the rat and may change in opposite manner in the same or different tissues during the life cycle or with alterations in thyroid hormone status, metabolic imbalances, treatments with drugs, etc.
“The relative contribution of T3 derived as such from the circulation and T3 generated locally from T4 has been measured for many tissues in the rat: it is not the same for all tissues and may, moreover, change in opposite manner in the same or different tissues during the life cycle, or when the animal is faced with alterations in thyroid hormone status, metabolic im- balances, treatments with d”
Quote in the paperSubstantial claim0 of 10 sources checked
- cites [2]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [3]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [4]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [5]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [12]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [13]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [14]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [15]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [16]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [17]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Classified as probably not a substantial claim.
Premisecitation
The oral administration of L-thyroxine is at present the widely accepted and recommended form of replacement therapy of hypothyroidism in humans.
“The oral administration of L-thyroxine (27, 28) is at present the widely accepted and recommended form of replacement therapy of hypothyroidism in humans.”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [27]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [28]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Premisecitation
In rat liver, plasma-derived T3 and T3 generated locally from T4 are in different compartments with respect to nuclear receptor binding, with practically all nuclear T3 appearing to be plasma derived.
“It has also been reported for the rat liver that plasma-derived T3 and T3 generated locally from T4 are in different compartments with respect to nuclear receptor binding: practically all of the nuclear T3 appears to be plasma derived (18).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [18]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Premisecitation
Rat-cultured astrocytes do not sulfate T3, but only the deiodination products of T3.
“Moreover, rat-cultured astrocytes do not sulfate T3, but only the deiodination products of T3 (56).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [56]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Premisecitation
Local conversion of T4 to T3 generates a very minor proportion of T3 in thigh muscle of hypothyroid rats (1.5-3.7%) and none in euthyroid animals.
“Local conversion of T4 to T3 generates a very minor proportion of T3 in thigh muscle of hypothyroid rats (1.5-3.7%) and none in euthyroid animals (16), and does not afford an explanation for the latter finding.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [16]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims. The quote only partly states this claim.
Study design and conductreasoning
BAT T4 values might be questioned because of the proximity of the interscapular BAT pads to the osmotic pump and possible external contamination with T4; therefore T4 values in BAT are not shown in further figures and tables.
“These T4 values might be questioned because of the proximity of the interscapular BAT pads to the site where the osmotic pump is implanted, and from which it is only separated by an easily punctured thin layer of connective tissue.Although care was taken at autopsy to avoid contact between the BAT pads and fluid surrounding the T4- containing pumps, some external contamination with T4 might have”
Quote in the paperNot a substantial claim
May combine two claims.
Interpretationreasoning
Decreased activity of liver 5'D-I would have a T4-sparing effect and might contribute to the normalization of locally generated T3 in tissues with important local production of T3 from T4, such as Cx.
“This decreased activity of liver 5 'D-I would have a T4-sparing effect and might contrib- ute to the normalization of locally generated T3 in tissues with important local production of T3 from T4, such as Cx.”
Quote in the paperSubstantial claim
- Rests on an assumption: Liver 5'D-I plays an important role in the generation of T3 and T4, and the liver is an important source of systemic T3.
May combine two claims.
Interpretationreasoning
When T4 is given daily, the patient receives 13 doses within the period of mean T4 residence time; fluctuations of serum T4 are likely to be buffered.
“When T4 is given daily, the patient receives 13 doses within the period of mean T4 residence time; fluctuations of serum T4 are likely to be buf- fered.”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation
Sulfotransferase activity is high in liver and kidney, and also in the brain.
“Sulfotransferase activity is not only high in liver and kidney, but also in the brain (54,55).”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [54]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [55]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
BAT represents an important source of systemic T3.
“This could be in agreement with the reported finding that BAT represents and important source of systemic T3 ( 23, 24).”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [23]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [24]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S4 (based). May combine two claims.
Interpretationreasoning
Tissues that derive most of their T3 from the circulation would have normal T3 concentrations when circulating T3 levels are normal, whereas tissues deriving all or most of their T3 by local generation from T4 would have normal T3 concentrations when plasma T4 is normal or somewhat elevated, provided the physiological responses to changes in thyroid status of the different deiodinases and of other
“Despite the many gaps in our knowledge, it would appear likely that those tissues which derive most of their T3 from the circulation would have normal concentrations of T3 when circulating T3 levels are normal, whereas those tissues deriving all or most of their T3 by local generation from T4 would have normal T3 concentrations when plasma T4 is normal or somewhat elevated, provided the ph”
Quote in the paperNot a substantial claim
May combine two claims.
Premisecitation
Triiodothyronine generated locally from T4 is not necessarily in rapid or complete equilibrium with circulating T3 in all tissues, and therefore cannot be readily quantified from serum T3 levels and the tissue-to-plasma T3 ratio.
“Studies from our laboratory (6, 7), however, questioned this assumption.Triiodothyronine generated locally from T4 is not necessarily in rapid or complete equilibrium with circulating T3 in all tissues, and therefore cannot be readily quantified from serum T3 levels and the tissue to plasma T3 ratio for that tissue, as determined”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [6]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [7]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation
Brain microsomes appear to metabolize T3S poorly, and less rapidly than T3, contrary to findings in the liver.
“This is in conceptual agreement with the finding that brain microsomes appear to metabolize T3S poorly, and less rapidly than T3 (55), contrary to findings in the liver.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [55]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationreasoning
A 12-d infusion period in the rat would be equivalent to 16.6 times the mean T4 residence time; this would be roughly equivalent to 5,146 h in man, or 7 mo of treatment.
“If we again take the mean residence time in both species as a plausible basis for comparisons, a 12-d infusion period in the rat would be equivalent to 16.6 times the mean T4 residence time; this would be roughly equivalent to 5,146 h in man (16.6-310 h), or 7 mo of treatment.”
Quote in the paperSubstantial claim
May combine two claims.
Premisecitation
Peripheral compensatory mechanisms do not provide adequate circulating levels of both T4 and T3 in hypothyroid patients on T4; for similar plasma levels of T3 and TSH, patients on T4 replacement therapy present higher circulating T4 than normal controls.
“There are data, however, which strongly suggest that present main conclusions are relevant for patients, inasmuch as peripheral compensatory mechanisms do not provide adequate circulating levels of both T4 and T3 in hypothyroid patients on T4: for similar plasma levels of T3 and TSH (59) patients on T4 replacement therapy present higher circulating T4 than normal controls.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [59]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationreasoning
This situation is the same as found in the present experimental study, and suggests that similarities may well exist as regards tissue concentrations of T3 and T4.
“This situation is the same we have found in the present experimental study, and suggests that similarities may well exist as regards tissue concentrations of T3 and T4.”
Quote in the paperSubstantial claim
May combine two claims.
Premisecitation
The relative importance of thyroidal T3 secretion versus T3 generation from T4 is likely to be greater in rats than humans, as the molar ratio of T4 to T3 in thyroidal secretion is about 6:1 in rats and 14:1 in humans.
“The relative importance of thyroidal T3 secretion versus T3 generation from T4 is likely to be greater in rats than humans, as the molar ratio of T4 to T3 in the respective thyroidal secre- tion is -6:1 (2-5), and 14:1 (1).”
Quote in the paperSubstantial claim0 of 5 sources checked
- cites [2]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [3]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [4]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [5]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [1]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
This is usually considered adequate to achieve stable thyroid hormone concentrations.
“This is usually considered adequate to achieve stable thyroid hormone concentrations (27).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [27]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationreasoning
This might be roughly equivalent in the rat to 13 doses during a 17.4-h period, which may be considered almost equivalent to constant infusion.
“This might be roughly equivalent in the rat to 13 doses during a 17.4-h period, which may be considered almost equivalent to constant infusion.”
Quote in the paperSubstantial claim

45 of 45

The paper relies on this without support.
The thyroidectomized rat infused with T4 is a valid model for human T4 replacement therapy.
“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.”
“It therefore appeared of interest to clarify directly whether, or not, using T4 alone a euthyroid status is ensured simultaneously for all tissues.”
The paper relies on this without support.
Normal tissue T4 and T3 concentrations are a valid measure of euthyroidism in those tissues.
“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.”
“As will be seen, none of the 10 doses of T4 which we tested was adequate to ensure simultaneously a normal thyroid status of all the tissues studied.”
The authors state this as an assumption.
Normalization of the iodothyronine content of a tissue would be followed by normalization of the biological effects.
“The latter criterion assumes that normalization of the iodothyronine content of the tissue would be followed by normalization of the biological effects.”
The paper relies on this without support.
Liver 5'D-I plays an important role in the generation of T3 and T4, and the liver is an important source of systemic T3.
“Liver 5 'D-I plays an important role in the generation of T3 and T4, and the L is an important source of systemic T3.”

4 of 4

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?

LT4 therapy given to hypothyroid rats did not achieve normal serum T3 levels, nor did it result in normal T3 levels in all tissues sampled.
“Seminal studies from the Escobar-Morreale group first showed that LT4 therapy given to hypothyroid rats did not achieve normal serum T3 levels, nor did it result in normal T3 levels in all tissues sampled (2).”
From Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document (2021) · cites this paper as [2]
The Results section (page unavailable) reports that the T4 dose producing normal circulating T4 and T3 was insufficient to normalize T3 in most tissues, supporting the tissue-level claim. But it also explicitly says plasma T3 was normal at a dose of 1.0 μg T4/100 g body weight per day, so the claim that LT4 therapy did not achieve normal serum T3 is incorrect. (LLM, conf=0.92)
Experimental — accuracy not yet measured
In experimental animals, tissue T3 content could be normalized only by combined administration of T4 and T3, not by T4 alone.
“In 1996, 25 years ago, Escobar-Morreale et al. [1,2] reported that only combined treatment with thyroxine (T4) and triiodothyronine (T3) restored euthyroidism (as judged by normal T4 and T3 tissue contents) simultaneously in all tissues of thyroidectomized rats.”
From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [1]
The Discussion reports that T4 alone did not normalize T4 and T3 simultaneously in all tissues of thyroidectomized rats. It also says that combined T4/T3 infusion did so, but identifies that finding as preliminary data; the citing sentence presents it as an established result. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Most studies in the literature used lower T4:T3 dose ratios, in the order of 5:1 to 10:1.
“Most studies in the literature used lower T4:T3 dose ratios, in the order of 5:1 to 10:1, which might be more effective but also liable to more side effects [1].”
From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [1]
The Discussion (page not available) says a proposed 14:1 T4:T3 ratio would be higher than the 4:1 ratio previously used clinically, supporting the general point that earlier ratios were lower. It does not establish that most studies used 5:1 to 10:1, or address the suggested effectiveness and side effects of those ratios. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Lower T4:T3 dose ratios might be more effective but also liable to more side effects.
“Most studies in the literature used lower T4:T3 dose ratios, in the order of 5:1 to 10:1, which might be more effective but also liable to more side effects [1].”
From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [1]
The Discussion (page not provided) says a 4:1 T4:T3 ratio had previously been used clinically and suggests a higher ratio, possibly 14:1. It does not say that most studies used ratios of 5:1 to 10:1, or that lower ratios might be more effective or cause more side effects. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Preclinical studies of thyroidectomised rats treated with levothyroxine indicate that plasma and tissue tri-iodothyronine are not normalised despite normalisation of serum TSH, whereas this was the case when treated with levothyroxineliothyronine combination therapy in the physiological ratio for rats.
“Additionally, preclinical studies of thyroidectomised rats treated with levothyroxine indicate that plasma and tissue tri-iodothyronine are not normalised despite normalisation of serum TSH, whereas this was the case when treated with levothyroxineliothyronine combination therapy in the physiological ratio for rats.175”
From Hypothyroidism (2024) · cites this paper as [175]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured

Administration of L-T4 alone to thyroidectomised rats does not, at any dose tested, result in normal T4 and T3 concentrations simultaneously in all tissues.
“Administration of L-T4 alone to thyroidectomised rats does not, at any dose tested, result in normal T4 and T3 concentrations simultaneously in all tissues (which can be taken as one criterion for defining euthyroidism) [32] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [32]
Thyroidectomized rats reached euthyroidism only after normalization of serum T3 levels.
“Similar phenomena were also observed in thyroidectomized rats, which reached euthyroidism only after normalization of serum T3 levels (146).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [146]
Experimental data from three decades ago suggested that areas of localised hypothyroidism may exist in LT4-treated rodents with hypothyroidism, and addition of T3 to LT4 corrected this situation.
“In addition, experimental data from three decades ago suggested that areas of”
From A review of the safety of triiodothyronine in combination with levothyroxine for the management of hypothyroidism (2024) · cites this paper as [18]
There is evidence that "tissue T3 lack" may be responsible for persistent symptoms in some hypothyroid subjects on LT4.
“Although the cause is unclear, there is evidence that “tissue T3 lack” may be responsible.”
From Designing a combined liothyronine (LT3), L- thyroxine (LT4) trial in symptomatic hypothyroid subjects on LT4 - the importance of patient selection, choice of LT3 and trial design (2023) · cites this paper as [17]
LT4 therapy given to hypothyroid rats did not achieve normal serum T3 levels, nor did it result in normal T3 levels in all tissues sampled.
“Seminal studies from the Escobar-Morreale group first showed that LT4 therapy given to hypothyroid rats did not achieve normal serum T3 levels, nor did it result in normal T3 levels in all tissues sampled [2].”
From Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document (2021) · cites this paper as [2]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

Plasma T3 described as both normal and below normal
Minor
The discussion describes the same animals as having normal circulating T3 and lower-than-normal T3 in plasma ("P1").

1 of 1

PROTEIN MEASUREMENT WITH THE FOLIN PHENOL REAGENT
Lowry, O. H., Rosebrough, N., Farr, A. L., & Randall, R. (1951) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)52451-6 · Cited by 315,771 · see citing works
The Thyroid Gland.
Ingbar, S. H. (1965) · Archives of Internal Medicine · doi:10.1001/archinte.1965.03870060154035 · Cited by 1,745 · see citing works
Relationships between Circulating and Intracellular Thyroid Hormones: Physiological and Clinical Implications*
Larsen, P. R., Silva, J. E., & Kaplan, M. M. (1981) · Endocrine Reviews · doi:10.1210/edrv-2-1-87 · Cited by 546 · see citing works
Effects of Maternal Hypothyroidism on the Weight and Thyroid Hormone Content of Rat Embryonic Tissues, before and after Onset of Fetal Thyroid Function*
de Escobar, G. M., PASTOR, R., Obregón, M.-J., & del Rey, F. E. (1985) · Endocrinology · doi:10.1210/endo-117-5-1890 · Cited by 361 · see citing works
Self-citation
Replacement Dose, Metabolism, and Bioavailability of Levothyroxine in the Treatment of Hypothyroidism
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
An Analysis of the Sources and Quantity of 3,5,3′-Triiodothyronine Specifically Bound to Nuclear Receptors in Rat Cerebral Cortex and Cerebellum*
CRANTZ, F. R., SILVA, J. E., & LARSEN, P. R. (1982) · Endocrinology · doi:10.1210/endo-110-2-367 · Cited by 340 · see citing works
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.
Calvo, R. M., Obregón, M.-J., de Oña, C. R., del Rey, F. E., & de Escobar, G. M. (1990) · Journal of Clinical Investigation · doi:10.1172/jci114790 · Cited by 322 · see citing works
Self-citation
Contributions of Plasma Triiodothyronine and Local Thyroxine Monodeiodination to Triiodothyronine to Nuclear Triiodothyronine Receptor Saturation in Pituitary, Liver, and Kidney of Hypothyroid Rats
Silva, J. E., & Larsen, P. R. (1978) · Journal of Clinical Investigation · doi:10.1172/jci109041 · Cited by 209 · see citing works
Potential of brown adipose tissue type II thyroxine 5'-deiodinase as a local and systemic source of triiodothyronine in rats.
Silva, J. E., & Larsen, P. R. (1985) · Journal of Clinical Investigation · doi:10.1172/jci112239 · Cited by 207 · see citing works
Cerebral cortex responds rapidly to thyroid hormones
Leonard, J. L., Kaplan, M. M., Visser, T. J., Silva, J. E., & Larsen, P. R. (1981) · Science · doi:10.1126/science.7291997 · Cited by 206 · see citing works
Pituitary nuclear 3,5,3’-triiodothyronine and thyrotropin secretion: an explanation for the effect of thyroxine
Silva, J. E., & Larsen, P. R. (1977) · Science · doi:10.1126/science.199941 · Cited by 198 · see citing works
The Contribution of Local Tissue Thyroxine Monodeiodination to the Nuclear 3,5,3′- Triiodothyronine in Pituitary, Liver, and Kidney of Euthyroid Rats*
SILVA, J. E., DICK, T. E., & LARSEN, P. R. (1978) · Endocrinology · doi:10.1210/endo-103-4-1196 · Cited by 189 · see citing works
Thyroidal and peripheral production of 3,5,3'-triiodothyronine in humans by multicompartmental analysis
Pilo, A., Iervasi, G., Vitek, F., Ferdeghini, M., Cazzuola, F., & Bianchi, R. (1990) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1990.258.4.e715 · Cited by 185 · see citing works
Thyroxine-dependent modulation of actin polymerization in cultured astrocytes. A novel, extranuclear action of thyroid hormone.
Siegrist-Kaiser, C. A., Juge-Aubry, C. E., Tranter, M. P., Ekenbarger, D. M., & Leonard, J. L. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)34121-3 · Cited by 157 · see citing works
Evidence for Two Tissue-specific Pathways for In Vivo Thyroxine 5′-Deiodination in the Rat
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CIRCADIAN AND 30 MINUTES VARIATIONS IN SERUM TSH AND THYROID HORMONES IN NORMAL SUBJECTS
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Concentration of l-Thyroxine and l-Triiodothyronine Specifically Bound to Nuclear Receptors in Rat Liver and Kidney
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Thyroid Hormones and 5’-Deiodinase in the Rat Fetus Late in Gestation: Effects of Maternal Hypothyroidism*
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Sulfation Preceding Deiodination of Iodothyronines in Rat Hepatocytes
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Are Iodine-Deficient Rats Euthyroid*
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Direct assessment of brown adipose tissue as a site of systemic tri-iodothyronine production in the rat
Fernandez, J. A., Mampel, T., Villarroya, F., & Iglesias, R. (1987) · Biochemical Journal · doi:10.1042/bj2430281 · Cited by 59 · see citing works
Pituitary and Plasma Thyrotropin, Thyroxine, and Triiodothyronine after Hyperthyroidism
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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
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EXCHANGE OF TRIIODOTHYRONINE DERIVED FROM THYROXINE WITH CIRCULATING TRIIODOTHYRONINE AS STUDIED IN THE RAT*
Obregón, M.-J., Roelfsema, F., de Escobar, G. M., del Rey, F. E., & Querido, A. (1979) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1979.tb02085.x · Cited by 44 · see citing works
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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
der Elst, J. P. S.-V., & van der Heide, D. (1990) · Endocrinology · doi:10.1210/endo-127-4-1656 · Cited by 41 · see citing works
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Effects of Streptozocin-Induced Diabetes and Food Restriction on Quantities and Source of T4 and T3 in Rat Tissues
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The Contribution of Local Thyroxine Monodeiodination to Intracellular 3,5,3′-Triiodothyronine in Several Tissues of Hyper thyroid Rats at Isotopic Equilibrium*
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In vivo effects of flavonoid EMD 21388 on thyroid hormone secretion and metabolism in rats
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β and αAdrenergic Mechanisms Are Involved in Regulation of Rat Pineal Type II Thyroxine 5'- Deiodinase Activity during Development*
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The Influence of Partial Food Deprivation on the Quantity and Source of Triiodothyronine in Several Tissues of Athyreotic Thyroxine-Maintained Rats*
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der Elst, J. P. S.-V., & van der Heide, D. (1990) · Endocrinology · doi:10.1210/endo-126-1-186 · Cited by 23 · see citing works
Thyroxine treatment and the recovery of pyramidal cells of the cerebral cortex from changes induced by juvenile‐onset hypothyroidism
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Homeostasis of brain T3 in rat fetuses and their mothers: effects of thyroid status and iodine deficiency.
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A study of the 3,5,3'-triiodothyronine sulfation activity in the adult and the fetal rat
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Utiger, R. D. 1989. Hypothyroidism. In Endocrinology, 2nd Edition. L. J. DeGroot, editor. W. B. Saunders Co., Philadelphia. 702-721.
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Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement
Jonklaas, J., Bianco, A. C., Bauer, A. J., Burman, K. D., Cappola, A. R., Celi, F. S., Cooper, D. S., Kim, B. W., Peeters, R. P., Rosenthal, M. S., et al. (2014) · Thyroid® · doi:10.1089/thy.2014.0028 · Cited by 1,928 · see citing works
“This has been demonstrated in vitro by utilizing LT4 infusion in animals, during which some tissues were demonstrated to be relatively T3-deficient even though all were exposed to the same plasma T3 and T4 concentrations and in some cases had normal serum TSH levels (338,361).”
Influential
Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases
Bianco, A. C., Salvatore, D., Gereben, B., Berry, M. J., & Larsen, P. R. (2002) · Endocrine Reviews · doi:10.1210/edrv.23.1.0455 · Cited by 1,853 · see citing works
Thermogenic Mechanisms and Their Hormonal Regulation
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Thyroid Function Is Associated with Components of the Metabolic Syndrome in Euthyroid Subjects
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Thyroid Hormones and Brain Development
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A Moderate and Transient Deficiency of Maternal Thyroid Function at the Beginning of Fetal Neocorticogenesis Alters Neuronal Migration
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2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism
Wiersinga, W. M., Duntas, L., Fadeyev, V., Nygaard, B., & Vanderpump, M. P. J. (2012) · European Thyroid Journal · doi:10.1159/000339444 · Cited by 427 · see citing works
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Cloning of the mammalian type II iodothyronine deiodinase. A selenoprotein differentially expressed and regulated in human and rat brain and other tissues.
Croteau, W., Davey, J. C., Galton, V. A., & Germain, D. L. S. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118806 · Cited by 372 · see citing works
Thyroid hormones states and brain development interactions
Ahmed, O. M., El‐Gareib, A. W., El-Bakry, A. M., El-Twab, S. M. A., & Ahmed, R. G. (2007) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2007.09.011 · Cited by 339 · see citing works
Deiodinases and their intricate role in thyroid hormone homeostasis
Luongo, C., Dentice, M., & Salvatore, D. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0218-2 · Cited by 332 · see citing works
Common Variation in the DIO2 Gene Predicts Baseline Psychological Well-Being and Response to Combination Thyroxine Plus Triiodothyronine Therapy in Hypothyroid Patients
Panicker, V., Saravanan, P., Vaidya, B., Evans, J., Hattersley, A. T., Frayling, T. M., & Dayan, C. M. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-1301 · Cited by 327 · 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
Thyroid hormone transporters—functions and clinical implications
Bernal, J., Guadaño‐Ferraz, A., & Morte, B. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.66 · Cited by 293 · see citing works
Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat.
Escobar-Morreale, H. F., del Rey, F. E., Obregón, M. J., & de Escobar, G. M. (1996) · Endocrinology · doi:10.1210/endo.137.6.8641203 · Cited by 261 · see citing works
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Triiodothyronine Levels in Athyreotic Individuals During Levothyroxine Therapy
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Combined Thyroxine/Liothyronine Treatment Does Not Improve Well-Being, Quality of Life, or Cognitive Function Compared to Thyroxine Alone: A Randomized Controlled Trial in Patients with Primary Hypothyroidism
Walsh, J. P., Shiels, L., Lim, E. M., Bhagat, C. I., Ward, L. C., Stuckey, B. G. A., Dhaliwal, S. S., Chew, G. T., Bhagat, M. C., & Cussons, A. J. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030249 · Cited by 210 · see citing works
American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models: Report of the American Thyroid Association Task Force on Approaches and Strategies to Investigate Thyroid Hormone Economy and Action
Bianco, A. C., Anderson, G., Forrest, D., Galton, V. A., Gereben, B., Kim, B. W., Kopp, P. A., Liao, X. H., Obregon, M. J., Peeters, R. P., et al. (2014) · Thyroid · doi:10.1089/thy.2013.0109 · Cited by 205 · see citing works
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Treatment for primary hypothyroidism: current approaches and future possibilities
Vaidya, B., Chakera, A. J., & Pearce, S. H. S. (2011) · Drug Design Development and Therapy · doi:10.2147/dddt.s12894 · Cited by 202 · see citing works
Combined Levothyroxine Plus Liothyronine Compared With Levothyroxine Alone in Primary Hypothyroidism: A Randomized Controlled Trial
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
Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine
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Combined Therapy with Levothyroxine and Liothyronine in Two Ratios, Compared with Levothyroxine Monotherapy in Primary Hypothyroidism: a Double-Blind, Randomized, Controlled Clinical Trial
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Thyroid Hormone Replacement Therapy in Primary Hypothyroidism: A Randomized Trial Comparing <scp>l</scp>-Thyroxine plus Liothyronine with <scp>l</scp>-Thyroxine Alone
Escobar-Morreale, H. F., Botella-Carretero, J. I., Gómez-Bueno, M., Galán, J. M., Barrios, V., & Sancho, J. (2005) · Annals of Internal Medicine · doi:10.7326/0003-4819-142-6-200503150-00007 · Cited by 182 · see citing works
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Is a Normal TSH Synonymous With “Euthyroidism” in Levothyroxine Monotherapy?
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Thyroid Hormone Homeostasis and Action in the Type 2 Deiodinase-Deficient Rodent Brain during Development
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Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document
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Effect of Different Starting Doses of Levothyroxine on Growth and Intellectual Outcome at Four Years of Age in Congenital Hypothyroidism
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Clinical practice guidelines for the management of hypothyroidism
Brenta, G., Vaisman, M., Sgarbi, J. A., Bergoglio, L., de Andrada, N. C., Bravo, P. P., Orlandi, A. M., & Graf, H. (2013) · Arquivos Brasileiros de Endocrinologia & Metabologia · doi:10.1590/s0004-27302013000400003 · Cited by 161 · see citing works
Treatment of Hypothyroidism with Combinations of Levothyroxine plus Liothyronine
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Self-citation
Replacement therapy with levothyroxine plus triiodothyronine (bioavailable molar ratio 14 : 1) is not superior to thyroxine alone to improve well‐being and cognitive performance in hypothyroidism
Siegmund, W., Spieker, K., Weike, A. I., Giessmann, T., Modess, C., Dabers, T., Kirsch, G., Sänger, E., Engel, G., Hamm, A. O., et al. (2004) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2004.02050.x · Cited by 152 · see citing works
Pregnant rat uterus expresses high levels of the type 3 iodothyronine deiodinase
Galton, V. A., Martinez, E., Hernández, A., Germain, E. A. S., Bates, J. M., & Germain, D. L. S. (1999) · Journal of Clinical Investigation · doi:10.1172/jci6073 · Cited by 152 · see citing works
DIO2 Thr92Ala Reduces Deiodinase-2 Activity and Serum-T3 Levels in Thyroid-Deficient Patients
Castagna, M. G., Dentice, M., Cantara, S., Ambrosio, R., Maino, F., Porcelli, T., Marzocchi, C., Garbi, C., Pacini, F., & Salvatore, D. (2017) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2016-2587 · Cited by 151 · see citing works
The Starting Dose of Levothyroxine in Primary Hypothyroidism Treatment: A Prospective, Randomized, Double-blind Trial
Roos, A., Linn-Rasker, S. P., van Domburg, R. T., Tijssen, J. P., & Berghout, A. (2005) · Archives of Internal Medicine · doi:10.1001/archinte.165.15.1714 · Cited by 150 · see citing works
Thyroid Hormone Replacement Therapy
Wiersinga, W. M. (2001) · Hormone Research in Paediatrics · doi:10.1159/000048140 · Cited by 150 · see citing works
Defending plasma T3 is a biological priority
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Scope and limitations of iodothyronine deiodinases in hypothyroidism
Gereben, B., McAninch, E. A., Ribeiro, M. O., & Bianco, A. C. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.155 · Cited by 146 · see citing works
Tissue Thyroid Hormone Levels in Critical Illness
Peeters, R. P., van der Geyten, S., Wouters, P. J., Darras, V. M., van Toor, H., Kaptein, E., Visser, T. J., & Van den Berghe, G. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-1013 · Cited by 145 · see citing works
Primary hypothyroidism and quality of life
Hegedüs, L., Bianco, A. C., Jonklaas, J., Pearce, S. H., Weetman, A. P., & Perros, P. (2022) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00625-8 · Cited by 144 · see citing works
Hypothyroidism and Depression
Dayan, C. M., & Panicker, V. (2013) · European Thyroid Journal · doi:10.1159/000353777 · Cited by 144 · see citing works
Homeostatic control of the thyroid-pituitary axis: perspectives for diagnosis and treatment
Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00177 · Cited by 143 · see citing works
Thyroxine Replacement Attenuates Hypothyroxinemia, Hearing Loss, and Motor Deficits Following Developmental Exposure to Aroclor 1254 in Rats
Goldey, E. S., & Crofton, K. M. (1998) · Toxicological Sciences · doi:10.1006/toxs.1998.2495 · Cited by 142 · see citing works
Partial Substitution of Thyroxine (T4) with Tri-Iodothyronine in Patients on T4Replacement Therapy: Results of a Large Community-Based Randomized Controlled Trial
Saravanan, P., Simmons, D. J., Greenwood, R., Peters, T. J., & Dayan, C. M. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1672 · Cited by 136 · see citing works
Thyroid Hormones Affect Neurogenesis in the Dentate Gyrus of Adult Rat
Ambrogini, P., Cuppini, R., Ferri, P., Mancini, C., Ciaroni, S., Voci, A., Gerdoni, E., & Gallo, G. (2005) · Neuroendocrinology · doi:10.1159/000087648 · Cited by 136 · see citing works
Fasting-Induced Increase in Type II Iodothyronine Deiodinase Activity and Messenger Ribonucleic Acid Levels Is Not Reversed by Thyroxine in the Rat Hypothalamus1
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Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat.
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Regulation of Iodothyronine Deiodinase Activity as Studied in Thyroidectomized Rats Infused with Thyroxine or Triiodothyronine1
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Presence of L-Thyroxine and 3,5,3′-Triiodo-L-thyronine in Tissues from Thyroidectomized Rats*
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Conversion of thyroxine to 3,5,3'-triiodothyronine in several rat tissues in vivo: the effect of hypothyroidism
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Authors: Escobar-Morreale, H. F., Obregón, M. J., Escobar del Rey, F., & Morreale de Escobar, G.
Affiliations: Consejo Superior de Investigaciones Científicas (ES)
ORCID: Escobar-Morreale, H F
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 1995-12-01
Volume: 96
Issue: 6
Pages: 2828-2838
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci118353
PMC: PMC185993
OpenAlex: W2048245477
Cited by: 287
References: 51
Citations by year: 2026: 7 · 2025: 11 · 2024: 8 · 2023: 4 · 2022: 10 · 2021: 8 · 2020: 18 · 2019: 14 · 2018: 14 · 2017: 12 · 2016: 13 · 2015: 19 · 2014: 10 · 2013: 10 · 2012: 9
FWCI: 3.05
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
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 › Thyroid Cancer Diagnosis and Treatment
Keywords: hypothyroidism, thyroxine replacement, triiodothyronine, iodothyronine deiodinase, thyroidectomized rats, brown adipose tissue, cerebellum, cerebral cortex, liver, lung
MeSH terms: Animals, Brain, Adipose Tissue, Brown, Cerebellum, Cerebral Cortex, Female, Hypothyroidism, Iodide Peroxidase, Organ Specificity, Reference Values, Thyroidectomy, Thyrotropin, Thyroxine, Triiodothyronine, Rats, Wistar, Rats

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

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