Serum Triiodothyronine, Thyroxine and Thyroid-Stimulating Hormone in Endemic Goiter: A Comparison of Goitrous and Nongoitrous Subjects in New Guinea†

Patel, Yogesh C.; Pharoah, P. O. D.; Hornabrook, R. W.; Hetzel, Basil S.

doi:10.1210/jcem-37-5-783

Cited by 80 publications

(34 citation statements)

References 20 publications

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“…This could explain the circumstances in the iodine-deficient rat where an apparently euthyroid state is associated with a low plasma T4, normal plasma T3, and an elevated TSH (17,43). Similar arguments can be applied to explain why patients with endemic goiter, a high plasma TSH, and normal plasma T3 can appear euthyroid as well as why patients with early thyroid dysfunction with reduced plasma T4, normal plasma T3, and elevated TSH are often asvmptomatic in metabolic terms (44)(45)(46)(47). It would appear that the presence of a system in the thyrotroph responsive to decreases in either plasma T, or T4 would provide maximum protection against the onset of metabolic hypothyroidism in tissues such as the liver and kidney whether the threat to the euthyroid state is a result of primary thyroid disease or iodine deficiency.…”

Section: Specific Experimetital Protocolsmentioning

confidence: 91%

Contributions of Plasma Triiodothyronine and Local Thyroxine Monodeiodination to Triiodothyronine to Nuclear Triiodothyronine Receptor Saturation in Pituitary, Liver, and Kidney of Hypothyroid Rats

Silva¹,

Larsen²

1978

J. Clin. Invest.

209

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A B S T R A C T Inijections of triiodothyronine (T3)and thyroxine (T4) into chronically hypothyroid rats were used to evaluate the contribution of intracellular T4 to T3 conversion to nuclear T3 in pituitary, liver, and kidney, and to correlate the occupancy of pituitary nuclear T3 receptors with inhibition of thyroid-stimulating hormone (TSH) release. Injection of a combination of 70 ng T3 and 400 ng T4/100 g body wt resulted in plasma T3 concentrations of 45+7 ng/dl (mean±+-SD) and 3.0±0.4,ug/dl T43 h later. At that plasma T3 level, the contribution of plasma T3 to the nuclear receptor sites resulted in saturation of 34±7% for pituitary, 27±5% for liver, and 33+2% for kidney. In addition to the T3 derived from plasma T3, there was additional T3 derived from intracellular monodeiodination of T4 in all three tissues that resulted in total nuclear occuipancy (as percent saturation) of 58±11% (pituitary), 36±8% (liver), and 41+11% (kidney), respectively. The percent contribution of T3 derived from cellular T4 added 41% of the total nuclear T3 in the pituitary which was significantly higher than the contribution of this source in the liver (24%) or the kidney (19%). 3 h after intravenous injection of increasing doses of T3, the plasma T3 concentration correlated well with both the change in TSH and the nuclear occupancy, suggesting a linear relationship between the integrated nuclear occupancy by T3 and TSH release rate. The contribution of intrapituitary T4 to T3 conversion to nuclear T, was accompanied by an appropriate decrease in TSH, supporting the biological relevance of nuclear T3. Pretreatment of the animals with 6-n-propylthiouracil before T4 injection decreased neither the nuclear T3 derived from intrapituitary T4 nor the subsequent decrease in TSH.These results indicate that intracellular monodeiodination of T4 contributes substantially to the nuclear T3 in the pituitary of the hypothyroid rat, and suggest a linear inverse relationship between nuclear receptor occupancy by T3 in the pituitary and TSH release rate. The data further indicate that T4 to T3 monodeiodination is considerably more important as a source of nuclear T3 in the pituitary than in the liver and kidney. This provides a mechanism whereby the TSH secretion could respond promptly to a decrease in thyroid secretion (predominantly T4) before a decrease in plasma T3 would be expected to lead to significant metabolic hypothyroidism. INTRODUCTIONThere is considerable indirect evidence suggesting that interaction of triiodothyronine (T3)l with a specific

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Section: Specific Experimetital Protocolsmentioning

confidence: 91%

Contributions of Plasma Triiodothyronine and Local Thyroxine Monodeiodination to Triiodothyronine to Nuclear Triiodothyronine Receptor Saturation in Pituitary, Liver, and Kidney of Hypothyroid Rats

Silva¹,

Larsen²

1978

J. Clin. Invest.

209

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“…With D2 upregulated, we expect k 4 to increase in hypothyroidism. We show in Appendix 2 that k 4 goes from k 4 & k 3 in euthyroids (where k 3 is the T 3 transport rate into the brain) to k 4 & 6k 3 in extreme hypothyroidism, based on data in rats and humans (3)(4)(5)(21)(22)(23)(24)(25). To bridge these two ranges, we replaced the parameter k 4 with a smooth sigmoid transition function, designated f 4 (T 3B ) in Eq.…”

Section: Brain Submodel Refinements In Extreme Primary Hypothyroidismmentioning

confidence: 99%

TSH Regulation Dynamics in Central and Extreme Primary Hypothyroidism

Eisenberg

Santini

Marsili

et al. 2010

Thyroid

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Background: Thyrotropin (TSH) changes in extreme primary hypothyroidism include increased secretion, slowed degradation, and diminished or absent TSH circadian rhythms. Diminished rhythms are also observed in central hypothyroid patients and have been speculated to be a cause of central hypothyroidism. We examined whether TSH secretion saturation, previously suggested in extreme primary hypothyroidism, might explain diminished circadian rhythms in both disorders. Methods: We augmented and extended the range of our published feedback control system model to reflect nonlinear changes in extreme primary hypothyroidism, including putative TSH secretion saturation, and quantified and validated it using multiple clinical datasets ranging from euthyroid to extreme hypothyroid (postthyroidectomy). We simulated central hypothyroidism by reducing overall TSH secretion and also simulated normal TSH secretion without circadian oscillation, maintaining plasma TSH at constant normal levels. We also utilized the validated model to explore thyroid hormone withdrawal protocols used to prepare remnant ablation in thyroid cancer patients postthyroidectomy. Results: Both central and extreme primary hypothyroidism simulations yielded low thyroid hormone levels and reduced circadian rhythms, with simulated daytime TSH levels low-to-normal for central hypothyroidism and increased in primary hypothyroidism. Simulated plasma TSH showed a rapid rise immediately following triiodothyronine (T 3 ) withdrawal postthyroidectomy, compared with a slower rise after thyroxine withdrawal or postthyroidectomy without replacement. Conclusions: Diminished circadian rhythms in central and extreme primary hypothyroidism can both be explained by pituitary TSH secretion reaching maximum capacity. In simulated remnant ablation protocols using the extended model, TSH shows a more rapid rise after T 3 withdrawal than after thyroxine withdrawal postthyroidectomy, supporting the use of replacement with T 3 prior to 131 I treatment. IntroductionT wo well-known hallmarks of normal thyrotropin (TSH) dynamics are high sensitivity to small changes in circulating thyroid hormone (TH) and circadian oscillations. TSH changes in extreme primary hypothyroidism include increased TSH secretion, slowed degradation (1), effects of compensatory changes in deiodinase activity, particularly type 2 deiodinase (D2) upregulation in brain (2-5), and diminished or absent circadian rhythms (6)(7)(8). Although the mechanism is unknown, diminished circadian rhythms also are observed in central hypothyroidism. Indeed, they are speculated to be one cause of the disease (6,7,9), although multiple factors may contribute to central hypothyroidism, including mutations in the thyrotropin releasing hormone (TRH) or TSH gene and improper glycosylation, among others (10-12).We address these issues here by augmenting and extending a human TH feedback control system simulation model (13,14) into the extreme hypothyroid range, supported by human data in this range. We examine whether saturation o...

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“…While hormone level changes of the magnitude seen in our simulations are unlikely to be harmful to patients taking relatively low doses of L-T 4 , they could pose a problem for patients taking larger doses, such as those undergoing hormone-suppression therapy for cancer (12). Further, much of the tablet stability data we used for predicting outcomes via simulation=data comparisons were generated under fairly ideal conditions, and L-T 4 tablet stability is known to be sensitive to factors such as light, temperature, and moisture (32)(33)(34)(35)(36)(37). The stability data we used (19) were generated in idealized, controlled environments, at normal temperature and relative humidity, with tablets kept in sealed containers with desiccants.…”

Section: L-t 4 Stability and Lot-by-lot Differencesmentioning

confidence: 99%

TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T₄Bioequivalence

Eisenberg¹,

DiStefano²

2009

Thyroid

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Background: FDA Guidance for pharmacokinetic (PK) testing of levothyroxine (L-T 4 ) for interbrand bioequivalence has evolved recently. Concerns remain about efficacy and safety of the current protocol, based on PK analysis following supraphysiological L-T 4 dosing in euthyroid volunteers, and recent recalls due to intrabrand manufacturing problems also suggest need for further refinement. We examine these interrelated issues quantitatively, using simulated what-if scenarios testing efficacy of a TSH-based protocol and tablet stability and absorption, to enhance precision of L-T 4 bioequivalence methods. Methods: We use an updated simulation model of human thyroid hormone regulation quantified and validated from data that span a wide range of normal and abnormal thyroid system function. Bioequivalence: We explored a TSH-based protocol, using normal replacement dosing in simulated thyroidectomized patients, switching brands after 8 weeks of full replacement dosing. We simulated effects of tablet potency differences and intestinal absorption differences on predicted plasma TSH, T 4 , and triiodothyronine (T 3 ) dynamics. Stability: We simulated effects of potency decay and lot-by-lot differences in realistic scenarios, using actual tablet potency data spanning 2 years, comparing the recently reduced 95-105% FDA-approved potency range with the original 90-110% range. Results: A simulated decrease as small as 10-15% in L-T 4 or its absorption generated TSH concentrations outside the bioequivalence target range (0.5-2.5 mU=L TSH), whereas T 3 and T 4 plasma levels were maintained normal. For a 25% reduction, steady-state TSH changed 300% (from 1.5 to 6 mU=L) compared with <25% for both T 4 and T 3 (both within their reference ranges). Stability: TSH, T 4 , and T 3 remained within normal ranges for most potency decay scenarios, but tablets of the same dose strength and brand were not bioequivalent between lots and between fresh and near-expired tablets. Conclusions: A pharmacodynamic TSH-measurement bioequivalence protocol, using normal L-T 4 replacement dosing in athyreotic volunteers, is likely to be more sensitive and safer than current FDA Guidance based on T 4 PK. The tightened 95-105% allowable potency range for L-T 4 tablets is a significant improvement, but otherwise acceptable potency differences (whether due to potency decay or lot-by-lot inconsistencies) may be problematic for some patients, for example, those undergoing high-dose L-T 4 therapy for cancer.

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Serum Triiodothyronine, Thyroxine and Thyroid-Stimulating Hormone in Endemic Goiter: A Comparison of Goitrous and Nongoitrous Subjects in New Guinea†

Cited by 80 publications

References 20 publications

Contributions of Plasma Triiodothyronine and Local Thyroxine Monodeiodination to Triiodothyronine to Nuclear Triiodothyronine Receptor Saturation in Pituitary, Liver, and Kidney of Hypothyroid Rats

Contributions of Plasma Triiodothyronine and Local Thyroxine Monodeiodination to Triiodothyronine to Nuclear Triiodothyronine Receptor Saturation in Pituitary, Liver, and Kidney of Hypothyroid Rats

TSH Regulation Dynamics in Central and Extreme Primary Hypothyroidism

TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T₄Bioequivalence

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Serum Triiodothyronine, Thyroxine and Thyroid-Stimulating Hormone in Endemic Goiter: A Comparison of Goitrous and Nongoitrous Subjects in New Guinea†

Cited by 80 publications

References 20 publications

Contributions of Plasma Triiodothyronine and Local Thyroxine Monodeiodination to Triiodothyronine to Nuclear Triiodothyronine Receptor Saturation in Pituitary, Liver, and Kidney of Hypothyroid Rats

Contributions of Plasma Triiodothyronine and Local Thyroxine Monodeiodination to Triiodothyronine to Nuclear Triiodothyronine Receptor Saturation in Pituitary, Liver, and Kidney of Hypothyroid Rats

TSH Regulation Dynamics in Central and Extreme Primary Hypothyroidism

TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T4Bioequivalence

Contact Info

Product

Resources

About

TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T₄Bioequivalence