Extensions, validation, and clinical applications of a feedback control system simulator of the hypothalamo-pituitary-thyroid axis
Open accessAbstract
BACKGROUND: We upgraded our recent feedback control system (FBCS) simulation model of human thyroid hormone (TH) regulation to include explicit representation of hypothalamic and pituitary dynamics, and updated TH distribution and elimination (D&E) parameters. This new model greatly expands the range of clinical and basic science scenarios explorable by computer simulation. METHODS: We quantified the model from pharmacokinetic (PK) and physiological human data and validated it comparatively against several independent clinical data sets. We then explored three contemporary clinical issues with the new model: combined triiodothyronine (T(3))/thyroxine (T(4)) versus T(4)-only treatment, parenteral levothyroxine (L-T(4)) administration, and central hypothyroidism. RESULTS: Combined T(3)/T(4) therapy--In thyroidectomized patients, the L-T(4)-only replacement doses needed to normalize plasma T(3) or average tissue T(3) were 145 microg L-T(4)/day or 165 microg L-T(4)/day, respectively. The combined T(4) + T(3) dosing needed to normalize both plasma and tissue T(3) levels was 105 microg L-T(4) + 9 microg T(3) per day. For all three regimens, simulated mean steady-state plasma thyroid-stimulating hormone (TSH), T(3), and T(4) was within normal ranges (TSH: 0.5-5 mU/L; T(4): 5-12 microg/dL; T(3): 0.8-1.9 ng/mL). Parenteral T(4) administration--800 microg weekly or 400 microg twice weekly normalized average tissue T(3) levels both for subcutaneous (SC) and intramuscular (IM) routes of administration. TSH, T(3), and T(4) levels were maintained within normal ranges for all four of these dosing schemes (1x vs. 2x weekly, SC vs. IM). Central hypothyroidism--We simulated steady-state plasma T(3), T(4), and TSH concentrations in response to varying degrees of central hypothyroidism, reducing TSH secretion from 50% down to 0.1% of normal. Surprisingly, TSH, T(3), and T(4) plasma concentrations remained within normal ranges for TSH secretion as low as 25% of normal. CONCLUSIONS: Combined T(3)/T(4) treatment--Simulated standard L-T(4)-only therapy was sufficient to renormalize average tissue T(3) levels and maintain normal TSH, T(3), and T(4) plasma levels, supporting adequacy of standard L-T(4)-only treatment. Parenteral T(4) administration-TSH, T(3), and T(4) levels were maintained within normal ranges for all four of these dosing schemes (1x vs. 2x weekly, SC vs. IM), supporting these therapeutic alternatives for patients with compromised L-T(4) gut absorption. Central hypothyroidism--These results highlight how highly nonlinear feedback in the hypothalamic-pituitary-thyroid axis acts to maintain normal hormone levels, even with severely reduced TSH secretion.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
For the majority of hypothyroid patients, standard L-T4-only therapy should be sufficient to reach normal triiodothyronine tissue concentrations.
“By mathematical modeling and computer simulations, it could be demonstrated that for the majority of hypothyroid patients standard l-T4-only therapy should be sufficient to reach normal triiodothyronine tissue concentrations (28, 29)”
From Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research (2016) · cites this paper as [29]
The Results (page unavailable) report that an L-T4-only dose normalized simulated lumped-tissue T3 in thyroidectomized subjects. The paper does not establish that standard L-T4-only therapy is sufficient for the majority of hypothyroid patients; that extends the simulation beyond its stated population and dosing conditions. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMany models focus on various aspects of the HPT axis, but models that specifically simulate the molecular regulations in thyroid follicles are still uncommon.
“While there are many models focusing on various aspects of the HPT axis (180, 273–275), models that specifically simulate the molecular regulations in thyroid follicles are still uncommon.”
From Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion (2022) · cites this paper as [275]
Ratios of T3 to T4 in combination therapy ranging from 1:3 to 1:17 have been reported.
“Ratios ranging from 1:3 to 1:17 have been reported in several articles (150–153).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [153]
As simulated by the model, a dose of 800 μg weekly or 400 μg twice weekly can maintain serum T3, T4, and TSH in the target range in patients with athyreosis.
“As simulated by the model, a dose of 800 µg weekly or 400 µg twice weekly can maintain serum T3, T4, and TSH in the target range in patients with athyreosis.”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [153]
A novel feedback control system simulator developed by Eisenberg et al was quantified from pharmacokinetic and physiological human data and was validated against several independent clinical data sets.
“In 2008, a novel feedback control system simulator was developed by Eisenberg et al (153). The model was quantified from pharmacokinetic and physiological human data and was validated against several independent clinical data sets.”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [153]
Subcutaneous injection produces smaller fluctuations in TSH levels and slower release into the circulation than intramuscular injection.
“SC injection produces smaller fluctuations in TSH levels and slower release into the circulation than IM injection (153).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [153]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
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
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
SAAM II: Simulation, analysis, and modeling software for tracer and pharmacokinetic studies
Barrett, P. H. R., Bell, B. M., Cobelli, C., Golde, H., Schumitzky, A., Vicini, P., & Foster, D. M. (1998) · Metabolism · doi:10.1016/s0026-0495(98)90064-6 · Cited by 445 · see citing works
Thyroid-Pituitary Interaction: Feedback Regulation of Thyrotropin Secretion by Thyroid Hormones
Bleich, H. L., Moore, M. J., & Larsen, P. R. (1982) · New England Journal of Medicine · doi:10.1056/nejm198201073060107 · Cited by 357 · see citing works
Silva, J. E., & Larsen, P. R. (1978) · Journal of Clinical Investigation · doi:10.1172/jci109041 · Cited by 209 · see citing works
Physiological variations in thyroid hormones: physiological and pathophysiological considerations
Fisher, D. A. (1996) · Clinical Chemistry · doi:10.1093/clinchem/42.1.135 · Cited by 207 · see citing works
Jacquez, J. A., & Greif, P. (1985) · Mathematical Biosciences · doi:10.1016/0025-5564(85)90098-7 · Cited by 205 · see citing works
Silva, J. E., & Larsen, P. R. (1977) · Science · doi:10.1126/science.199941 · Cited by 198 · see citing works
Spectrum of Pituitary Alteration with Mild and Severe Thyroid Impairment* †
Bigos, S. T., Ridgway, E. C., KOURIDES, I. A., & Maloof, F. (1978) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-46-2-317 · Cited by 184 · see citing works
Deiodination of Thyroid Hormone by Human Liver
Visser, T. J., Kaptein, E., Terpstra, O. T., & Krenning, E. P. (1988) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-67-1-17 · Cited by 121 · see citing works
Torres, M., Ramirez, L., Simkin, P. H., Braverman, L. E., & Emerson, C. H. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.4.7405 · Cited by 115 · see citing works
Huysmans, D. A., Nieuwlaat, W., Erdtsieck, R. J., SCHELLEKENS, A. P. M., Bus, J. W., Bravenboer, B., & Hermus, A. R. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.10.6869 · Cited by 109 · see citing works
Are Bioequivalence Studies of Levothyroxine Sodium Formulations in Euthyroid Volunteers Reliable?
Blakesley, V., Awni, W., Locke, C., Ludden, T., Granneman, G. R., & Braverman, L. E. (2004) · Thyroid · doi:10.1089/105072504773297867 · Cited by 85 · see citing works
Effects of hydrocortisone on pulsatile pituitary glycoprotein secretion
Samuels, M. H., Luther, M., Henry, P., & Ridgway, E. C. (1994) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.78.1.8288706 · Cited by 84 · see citing works
Self-citationPatel, Y., Pharoah, P. O. D., Hornabrook, R. W., & Hetzel, B. S. (1973) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-37-5-783 · Cited by 82 · see citing works
Estimation of the Secretion Rate of Thyrotropin in Man*
Odell, W. D., Utiger, R. D., Wilber, J. F., & Condliffe, P. G. (1967) · Journal of Clinical Investigation · doi:10.1172/jci105601 · Cited by 75 · see citing works
Metabolic Clearance and Production Rates of Human Thyrotropin
Ridgway, E. C., Weintraub, B. D., & Maloof, F. (1974) · Journal of Clinical Investigation · doi:10.1172/jci107630 · Cited by 66 · see citing works
Recombinant Human Thyrotropin Is a Potent Stimulator of Thyroid Function in Normal Subjects1
Ramirez, L., Braverman, L. E., White, B., et al. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.9.4205 · Cited by 62 · see citing works
Huysmans, D. A. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.85.10.3592 · Cited by 59 · see citing works
Sharifi, J., & Germain, D. L. S. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)42310-1 · Cited by 54 · see citing works
Recombinant Human Thyrotropin Is a Potent Stimulator of Thyroid Function in Normal Subjects
Ramirez, L. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.82.9.2836 · Cited by 49 · see citing works
Nielsen, V. E., Bonnema, S. J., & Hegedűs, L. D. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-031783 · Cited by 47 · see citing works
DIETRICH, J. W., TESCHE, A., PICKARDT, C. R., & MITZDORF, U. (2004) · Cybernetics and Systems · doi:10.1080/01969720490443354 · Cited by 44 · see citing works
Effects of Glutathione on Iodothyronine 5′-Deiodinase Activity*
GOSWAMI, A., & Rosenberg, I. N. (1988) · Endocrinology · doi:10.1210/endo-123-1-192 · Cited by 38 · see citing works
Patterns of Pulsatile Pituitary Glycoprotein Secretion in Central Hypothyroidism and Hypogonadism*
Samuels, M. H., Lillehei, K. O., Kleinschmidt-DeMasters, B. K., Stears, J. C., & Ridgway, E. C. (1990) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-70-2-391 · Cited by 37 · see citing works
Self-citationPulsatile TSH Secretion during 48-Hour Continuous TRH Infusions
Samuels, M. H., Henry, P., Luther, M., & Ridgway, E. C. (1993) · Thyroid · doi:10.1089/thy.1993.3.201 · Cited by 34 · see citing works
Self-citationUEDA, S., Takamatsu, J., Fukata, S., TANAKA, K., Shimizu, N., Sakata, S., Yamaji, T., Kuma, K., & Ohsawa, N. (1996) · Thyroid · doi:10.1089/thy.1996.6.563 · Cited by 32 · see citing works
New questions regarding bioequivalence of levothyroxine preparations: A Clinician's response
Green, W. L. (2005) · The AAPS Journal · doi:10.1208/aapsj070107 · Cited by 32 · see citing works
Neuroendocrine control of thyroid secretion in living systems: A feedback control system model
DisTeafano, J. J., & Stear, E. B. (1968) · Bulletin of Mathematical Biology · doi:10.1007/bf02476936 · Cited by 32 · see citing works
L-T <sub>4</sub> Bioequivalence and Hormone Replacement Studies via Feedback Control Simulations
Eisenberg, M., Samuels, M., & DiStefano, J. J. (2006) · Thyroid · doi:10.1089/thy.2006.16.1279 · Cited by 31 · see citing works
L-T 4 Bioequivalence and Hormone Replacement Studies via Feedback Control Simulations
Eisenberg, M. C., Samuels, M. H., & DiStefano, J. J. (2006) · Thyroid · doi:10.1089/thy.2006.0144 · Cited by 30 · see citing works
Self-citationSERUM TRIIODOTHYRONINE IN HEALTH AND DISEASE
Patel, Y., & Burger, H. (1973) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1973.tb01720.x · Cited by 28 · see citing works
Parenteral thyroxine administration
Hays, M. T. (2007) · Thyroid · doi:10.1089/thy.2006.0283 · Cited by 27 · see citing works
Variation in serum levels of T3, T4, FT4 and TSH during thyroxine replacement therapy
Wennlund, A. (1986) · European Journal of Endocrinology · doi:10.1530/acta.0.1130047 · Cited by 23 · see citing works
A dynamical model of the pulsatile secretion of the hypothalamo-pituitary-thyroid axis
Li, G., Liu, B., & Liu, Y. (1995) · Biosystems · doi:10.1016/0303-2647(94)01484-o · Cited by 21 · see citing works
Direct Radioimmunoassay of Nuclear 3,5,3′ Triiodothyronine in Rat Anterior Pituitary
Larsen, P. R., Bavli, S. Z., Castonguay, M., & Jove, R. (1980) · Journal of Clinical Investigation · doi:10.1172/jci109713 · Cited by 21 · see citing works
Hays, M. T., & McGUIRE, R. A. (1980) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-51-5-1112 · Cited by 17 · see citing works
Human Thyrotrophic Hormone Kinetics and Effects in Euthyroid Males
Kuku, S. F., Harsoulis, P., Kjeld, M., & Fraser, T. (1975) · Hormone and Metabolic Research · doi:10.1055/s-0028-1093789 · Cited by 16 · see citing works
DiStefano, J. J., & Mak, P. H. (1979) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1979.236.3.r137 · Cited by 15 · see citing works
Self-citationA new mathematical model of hypothalamo-pituitary-thyroid axis
Liu, Y., Liu, B., Xie, J., & Liu, Y. X. (1994) · Mathematical and Computer Modelling · doi:10.1016/0895-7177(94)90042-6 · Cited by 13 · see citing works
DiStefano, J. J., & Stear, E. B. (1968) · Journal of Theoretical Biology · doi:10.1016/0022-5193(68)90003-9 · Cited by 12 · see citing works
Self-citationRegulation of thyrotropin secretion by 3,5,3'-triiodothyronine and thyroxine.
Larsen, P. R. (1981) · PubMed · Cited by 5 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- [12]Jaquez JA. Greif P. Numerical parameter identifiability, estimatability: integrating identifiability, estimatability, optimal sampling design. Math Biosci. 1985;77 [Google Scholar]
- [24]Sarapura VD. Samuels MH. Ridgway EC. Thyroid-stimulating hormone. In: Melmed S, editor. The Pituitary. Second. Blackwell Science; Malden, MA: 2002. pp. 187–229. [Google Scholar]
- [34]Dietrich JW. Tesche A. Pickardt CR. Mitzdorf U. Fractal properties of the thyrotropic feedback control implications of a nonlinear model compared with empirical data. In: Trappl R, editor. Cybernetics and Systems. Austrian Society for Cybernetic Studies; Vienna: 2002. pp. 329–34. [Google Scholar]
Cited by
Sorted by citations
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
Dietrich, J. W., Landgrafe-Mende, G., Wiora, E., Chatzitomaris, A., Klein, H. H., Midgley, J. E. M., & Hoermann, R. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00057 · Cited by 164 · see citing works
“By mathematical modeling and computer simulations, it could be demonstrated that for the majority of hypothyroid patients standard -T4-only therapy should be sufficient to reach normal triiodothyronine tissue concentrations (28, 29), but that substitutionwith -T3may be beneficial to reduce the withdrawal period befo…”
BackgroundTSH and thyrotropic agonists: key actors in thyroid homeostasis
Dietrich, J. W., Landgrafe, G., & Fotiadou, E. H. (2012) · Journal of Thyroid Research · doi:10.1155/2012/351864 · Cited by 146 · 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
Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion
Jing, L., & Zhang, Q. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.992883 · Cited by 61 · see citing works
Levothyroxine: conventional and novel drug delivery formulations.
Liu, H., Li, W., Zhang, W., Sun, S., & Chen, C. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnac030 · Cited by 63 · see citing works
Berberich, J., Dietrich, J. W., Hoermann, R., & Müller, M. A. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00091 · Cited by 55 · see citing works
Goede, S. L., Leow, M. K.-S., Smit, J. W. A., & Dietrich, J. W. (2014) · Mathematical Biosciences · doi:10.1016/j.mbs.2014.01.001 · Cited by 50 · see citing works
Single-Dose T3 Administration: Kinetics and Effects on Biochemical and Physiological Parameters
Jonklaas, J., Burman, K. D., Wang, H., & Latham, K. R. (2015) · Therapeutic Drug Monitoring · doi:10.1097/ftd.0000000000000113 · Cited by 49 · see citing works
TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T <sub>4</sub> Bioequivalence
Eisenberg, M., & Distefano, J. J. (2009) · Thyroid · doi:10.1089/thy.2008.0148 · Cited by 43 · see citing works
Goede, S. L., Leow, M. K.-S., Smit, J. W. A., Klein, H. H., & Dietrich, J. W. (2014) · Bulletin of Mathematical Biology · doi:10.1007/s11538-014-9955-5 · Cited by 30 · see citing works
DiStefano, J., & Jonklaas, J. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00746 · Cited by 28 · see citing works
Self-citationBen-Shachar, R., Eisenberg, M., Huang, S. A., & DiStefano, J. J. (2012) · Thyroid · doi:10.1089/thy.2011.0355 · Cited by 16 · see citing works
Self-citation
- Authors
- Eisenberg, M., Samuels, M., & DiStefano, J. J.
- Affiliations
- University of California, Los Angeles (US)
- Oregon Health & Science University (US)
- Venue
- Thyroid
- Publisher
- SAGE Publications
- Published
- 2008-10
- Volume
- 18
- Issue
- 10
- Pages
- 1071-1085
- ISSN
- 1050-7256 (ISSN-L)
- 1557-9077
- PMC
- PMC2962855
- OpenAlex
- W2075932932
- Cited by
- 65
- References
- 42
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 5 · 2023: 7 · 2022: 5 · 2021: 3 · 2019: 3 · 2018: 1 · 2017: 5 · 2016: 4 · 2015: 2 · 2014: 7 · 2013: 6 · 2012: 2
- FWCI
- 1.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Thyroid (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- Directorate for Biological Sciences
- National Institute of General Medical Sciences (T32GM008185)
- 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 › Adrenal Hormones and Disorders
- Keywords
- hypothalamic-pituitary-thyroid axis, thyroid hormone regulation, triiodothyronine, thyroxine, levothyroxine, central hypothyroidism, thyroidectomy, thyroid-stimulating hormone
- MeSH terms
- Brain, Computer Simulation, Feedback, Humans, Hypothalamo-Hypophyseal System, Hypothyroidism, Iodide Peroxidase, Kinetics, Models, Biological, Thyroid Gland, Thyroidectomy, Thyroxine, Triiodothyronine, Hormone Replacement Therapy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
