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Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats.
Open accessAbstract
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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“Normalization of T3 concentrations in Lu required even higher infusion doses of T4 than normalization of T3 in L.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
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“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Circulating T4, T3, and TSH, and concentrations of T4 and T3 in different tissues as function of the T4 dose
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“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Circulating T4, T3, and TSH, and concentrations of T4 and T3 in different tissues as function of the T4 dose
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“As may be seen, the degree of increase of T4 and T3 was not the same for all tissues studied.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Circulating T4, T3, and TSH, and concentrations of T4 and T3 in different tissues as function of the T4 dose
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“we did not detect appreciable 5'D-I activity in Cx, Cb, and BAT.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
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“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
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“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
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“Even so, T3 may still be low in some tissues.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
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“In animals with normal circulating T4 and T3 the concentrations of the latter iodothyronine are lower than nor- mal in both P1 and L.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
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“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Concentrations of T4 and T3 in different tissues as function of circulating T4 and T3
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“The activity of the inner-ring 5D-I1 was 2,022±473 fmol I-/h per mg protein in Cx of the control rats.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Concentrations of T4 and T3 in different tissues as function of circulating T4 and T3
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“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
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“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Circulating T4, T3, and TSH, and concentrations of T4 and T3 in different tissues as function of the T4 dose
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“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Concentrations of T4 and T3 in different tissues as function of circulating T4 and T3
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“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).”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Concentrations of T4 and T3 in different tissues as function of circulating T4 and T3
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“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
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“Activities increased twofold in the rats receiving 8.0 HIg T4/ 100 gram BW per day.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Concentrations of T4 and T3 in different tissues as function of circulating T4 and T3
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“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Concentrations of T4 and T3 in different tissues as function of circulating T4 and T3
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“Skeletal muscle T3 was also normal in animals with low circulating T3 levels, but with higher than normal concentrations of T4 in the tissue.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
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“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Methods
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- Also stated in: § Circulating T4, T3, and TSH, and concentrations of T4 and T3 in different tissues as function of the T4 dose · plain
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“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).”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Concentrations of T4 and T3 in different tissues as function of circulating T4 and T3
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“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Abstract
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“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Methods
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“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Circulating T4, T3, and TSH, and concentrations of T4 and T3 in different tissues as function of the T4 dose
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“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”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Concentrations of T4 and T3 in different tissues as function of circulating T4 and T3
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“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Concentrations of T4 and T3 in different tissues as function of circulating T4 and T3
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“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
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“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Concentrations of T4 and T3 in different tissues as function of circulating T4 and T3
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In the paper
“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
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In the paper
“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Circulating T4, T3, and TSH, and concentrations of T4 and T3 in different tissues as function of the T4 dose
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
What the sources say
- Not matchedcites [52]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [53]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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In the paper
“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
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- The authors state this as an assumption: Normalization of the iodothyronine content of a tissue would be followed by normalization of the biological effects.
In the paper
“If the amount of available T3 is insufficient, T4 occupies the receptor, and exerts a biological effect (46).”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
What the sources say
- Not matchedcites [46]
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“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).”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Introduction
What the sources say
- Not matchedcites [1]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites (2)(3)(4)(5)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Reverse T3 is a potent reversible inhibitor of 5 'D-II (50) and might locally reach inhibitory concentrations in vivo.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
What the sources say
- Not matchedcites [50]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“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”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Introduction
What the sources say
- Not matchedcites [2]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [3]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [4]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [5]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“The oral administration of L-thyroxine (27, 28) is at present the widely accepted and recommended form of replacement therapy of hypothyroidism in humans.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Introduction
What the sources say
- Not matchedcites [27]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [28]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Not matched
In the paper
“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).”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
What the sources say
- Not matchedcites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“Moreover, rat-cultured astrocytes do not sulfate T3, but only the deiodination products of T3 (56).”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
What the sources say
- Not matchedcites [56]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
What the sources say
- Not matchedcites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Circulating T4, T3, and TSH, and concentrations of T4 and T3 in different tissues as function of the T4 dose
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one. The quote only partly states this claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- 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.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Sulfotransferase activity is not only high in liver and kidney, but also in the brain (54,55).”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
What the sources say
- Not matchedcites [54]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [55]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“This could be in agreement with the reported finding that BAT represents and important source of systemic T3 ( 23, 24).”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
What the sources say
- Not matchedcites [23]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [24]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Introduction
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“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”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Introduction
What the sources say
- Not matchedcites [6]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [7]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
What the sources say
- Not matchedcites [55]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
What the sources say
- Not matchedcites [59]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“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).”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
What the sources say
- Not matchedcites [2]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [3]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [4]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [5]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [1]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“This is usually considered adequate to achieve stable thyroid hormone concentrations (27).”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
What the sources say
- Not matchedcites [27]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measured
The cited source says what the claim attributes to it.
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“Although the cause is unclear, there is evidence that “tissue T3 lack” may be responsible.”
In the citing paper
“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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
“In animals with normal circulating T4 and T3”
§ Replacement Therapy for Hypothyroidism with Thyroxine Alone Does Not Ensure Euthyroidism in All Tissues, as Studied in Thyroidectomized Rats > Discussion
“the concentrations of the latter iodothyronine are lower than nor- mal in both P1 and L.”
Citations
Cites
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 316,394
Ingbar, S. H. (1965) · Archives of Internal Medicine · doi:10.1001/archinte.1965.03870060154035 · Cited by 1,745
Larsen, P. R., Silva, J. E., & Kaplan, M. M. (1981) · Endocrine Reviews · doi:10.1210/edrv-2-1-87 · Cited by 546
de Escobar, G. M., PASTOR, R., Obregón, M.-J., & del Rey, F. E. (1985) · Endocrinology · doi:10.1210/endo-117-5-1890 · Cited by 356
Self-citationFish, 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
CRANTZ, F. R., SILVA, J. E., & LARSEN, P. R. (1982) · Endocrinology · doi:10.1210/endo-110-2-367 · Cited by 340
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
Self-citationSilva, J. E., & Larsen, P. R. (1978) · Journal of Clinical Investigation · doi:10.1172/jci109041 · Cited by 208
Silva, J. E., & Larsen, P. R. (1985) · Journal of Clinical Investigation · doi:10.1172/jci112239 · Cited by 207
Cerebral cortex responds rapidly to thyroid hormones
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Bianco, A. C., Carvalho, S. D., Carvalho, C. R. F., Rabelo, R., & Moriscot, A. S. (1998) · Endocrinology · doi:10.1210/endo.139.2.5737 · Cited by 47
Hypothalamic type II iodothyronine deiodinase: a light and electron microscopic study
Diano, S., Leonard, J. L., Meli, R., Esposito, E., & Schiavo, L. (2003) · Brain Research · doi:10.1016/s0006-8993(03)02692-1 · Cited by 46
Biondi, B., Bartalena, L., Chiovato, L., Lenzi, A., Mariotti, S., Pacini, F., Pontecorvi, A., Vitti, P., & Trimarchi, F. (2016) · Journal of Endocrinological Investigation · doi:10.1007/s40618-016-0511-z · Cited by 44
Metadata
- Authors
- Escobar-Morreale, H. F., Obregón, M. J., Escobar del Rey, F., & Morreale de Escobar, G.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Venue
- Journal of Clinical Investigation
- Published
- 1995-12-01
- Volume
- 96
- Issue
- 6
- Pages
- 2828-2838
- ISSN
- 0021-9738 (ISSN-L)
- 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
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.
A language model drew the claims from the paper on 2026-10-27, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-27 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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 ›
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