The Pituitary-Thyroid Regulatory System

  • P. Reed Larsen
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 261)


The pituitary thyroid regulatory system is a classical example of a hypothalamic-pituitary-endocrine gland feedback loop. As one of the earliest such systems recognized and one which has proven to be so useful clinically, it has been widely studied. The critical elements in the system are shown in the diagram in Figure 1. The best recognized level of feedback regulation is that of thyroid hormone on pituitary thyrotropin (TSH) production. However, results of recent studies reviewed below demonstrate conclusively that there is also feedback regulation of thyrotropin-releasing hormone (TRH) synthesis by thyroid hormone. This complex system is exquisitely sensitive to changes in ambient thyroid hormone levels and serves to maintain the serum hormone concentration in an extremely narrow range in a given individual.


Thyroid Hormone Deiodinase Activity Iopanoic Acid Thyrotropin Secretion Thyroid Hormone Administration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    M. Szabo, N. Kovathana, K. Gordon, and L. A. Frohman, Effect of passive immunization with an antiserum to thyrotropin (TSH)-releasing hormone on plasma TSH levels in thyroidectomized rats, Endocrinology 102: 799 (1978).PubMedCrossRefGoogle Scholar
  2. 2.
    A. R. C. Harris, D. Christianson, M. S. Smith, S. L. Fang, L. E. Braverman, and A. G. Vagenakis, The physiological role of thyrotropin-releasing hormone in the regulation of thyroid-stimulating hormone and prolactin secretion in the rat, J Clin Invest 61: 441 (1978).PubMedCrossRefGoogle Scholar
  3. 3.
    M. Mori, I. Kobayashi, and K Wakabayashi, Suppression of serum thyrotropin (TSH) concentrations following thyroidectomy and cold exposure by passive immunization with antiserum to thyrotropin-releasing hormone (TRH) in rats, Metab 27: 1485 (1978).CrossRefGoogle Scholar
  4. 4.
    S. L. Lee, K. Stewart, and R. H. Goodman, J Biol Chem 263: 16604 (1988).PubMedGoogle Scholar
  5. 5.
    T. P. Segerson, J. Kauer, H. C. Wolfe, H. Mobtaker, P. Wu, I. M. D. Jackson, and R. M. Lechan, Thyroid hormone regulates TRH biosynthesis in the paraventricular nucleus of the rat hypothalamus, Science 238: 78 (1987).PubMedCrossRefGoogle Scholar
  6. 6.
    R. T. Zoeller, R. S. Wolff, and K. J. Koller, Thyroid hormone regulation of messenger ribonucleic acid encoding thyrotropin (TSH)-releasing hormone is independent of the pituitary gland and TSH, Molecular Endocrinol 2: 248 (1988).CrossRefGoogle Scholar
  7. 7.
    E. M. Dyess, T. P. Segerson, Z. Liposits, W. K. Paull, M. M. Kaplan, P. Wu, I. M. D. Jackson, and R. M. Lechan, Triiodothyronine exerts direct cell-specific regulation of thyrotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus, Endocrinology 123: 2291 (1988).PubMedCrossRefGoogle Scholar
  8. 8.
    A. Arimura and A. V. Schally, Increase in basal and thyrotropin-releasing hormone (TRH)-stimulated secretion of thyrotropin (TSH) by passive immunization with antiserum to somatostatin in rats, Endocrinology 98: 1069 (1976).PubMedCrossRefGoogle Scholar
  9. 9.
    M. Berelowitz, K. Maeda, S. Harris, and L. A. Frohman, The effect of alterations in the pituitary-thyroid axis on hypothalamic content and in vitro release of somatostatin-like immunoreactivity, Endocrinology 107: 24 (1980).PubMedCrossRefGoogle Scholar
  10. 10.
    J. E. Silva and P. R. Larsen, Peripheral metabolism of homologous thyrotropin in euthyroid and hypothyroid rats: acute effects of thyrotropinreleasing hormone, triiodothyronine, and thyroxine, Endocrinology 102: 1783 (1978).PubMedCrossRefGoogle Scholar
  11. 11.
    C. Y. bowers, K. L. Lee, and A. V. Schally, A study on the interaction of the thyrotropin-releasing factor and L-triiodothyronine: effects of puromycin and cycloheximide, Endocrinology 82: 75 (1968).PubMedCrossRefGoogle Scholar
  12. 12.
    W. Vale, R. Burgus, and R. Guillemin, On the mechanism of action of TRF: effects of cycloheximide and actinomycin on the release of TSH stimulated in vitro by TRF and its inhibition by thyroxine, Neuroendocrinology 3: 34 (1968).CrossRefGoogle Scholar
  13. 13.
    T. G. Gard, B. Bernstein, and P. R. Larsen, Studies on the mechanism of 3,5,3’-triiodothyronineinduced thyrotropin release in vitro, Endocrinology 108: 2046 (1981).PubMedCrossRefGoogle Scholar
  14. 14.
    R. J. Koenig, D. Senator, and P. R. Larsen, Phorbol esters as probes of the regulation of thyrotropin secretion, Biochem and Biophysical Res Com 125: 353 (1984).CrossRefGoogle Scholar
  15. 15.
    M. H. Perrone and P. M. Hinkle, Regulation of pituitary receptors for thyrotropin-releasing hormone by thyroid hormones, J Biol Chem 253: 5168 (1978).PubMedGoogle Scholar
  16. 16.
    J. A. Gurr and I. A. Kourides, Regulation of thyrotropin biosynthesis, J Biol Chem 258: 10208 (1983).PubMedGoogle Scholar
  17. 17.
    M. A. Shupnik and E. C. Ridgway, Triiodothyronine rapidly decreases transcription of the thyrotropin subunit genes in thyrotropic tumor explants, Endocrinology 117: 1940, 1985.PubMedCrossRefGoogle Scholar
  18. 18.
    F. E. Carr, E. C. Ridgway, and W. W. Chin, Rapid simultaneous measurement of rat a-and thyrotropin (TSH) ß-subunit messenger ribonucleid acids (mRNAs) by solution hybridization: regulation of TSH subunit mRNAs by thyroid hormones, Endocrinology 117: 1272 (1985).PubMedCrossRefGoogle Scholar
  19. 19.
    J. A. Franklyn, D. F. Wood, N. J. Balfour, D. B. Ramsden, K. Docherty, W. W. Chin, and M. C. Sheppard, Effect of hypothyroidism and thyroid hormone replacement in vivo on pituitary cytoplasmic concentrations of thyrotropin-a and a-subunit messenger ribonucleic acids, Endocrinology 120: 2279 (1987).PubMedCrossRefGoogle Scholar
  20. 20.
    F. E. Carr, L. R. Need, and W. W. Chin, Isolation and characterization of the rat thyrotropin p-subunit gene, J Biol Chem 262: 981 (1987).PubMedGoogle Scholar
  21. 21.
    O. Wolf, I. A. Kourides, and J. A. Gurr, Expression of the gene for the p subunit of mouse thyrotropin results in multiple mRNAs differing in their 5’-untranslated regions, J Biol Chem 262: 16596 (1987).Google Scholar
  22. 22.
    F. E. Wondisford, S. Radovick, J. M. Moates, S. J. Usala, and B. D. Weintraub, Isolation and characterization of the human thyrotropin p-subunit gene, J Biol Chem 263: 12538 (1988).PubMedGoogle Scholar
  23. 23.
    P. R. Larsen, J. W. Harney, aod D. D. Moore, Sequences required for cell-type specific thyroid hormone regulation of rat growth hormone promoter activity, J Biol Chem 261: 14373 (1986).PubMedGoogle Scholar
  24. 24.
    C. K. Glass, R. Franco, C. Weinberger, V. R. Albert, R. M. Evans, and M. G. Rosenfeld, A c-erb-A binding site in rat growth hormone gene mediates trans-activation by thyroid hormone, Nature 329: 738 (1987).PubMedCrossRefGoogle Scholar
  25. 25.
    R. J. Koenig, G. A. Brent, R. L. Warne, P. R. Larsen, and D. D. Moore, Thyroid hormone receptor binds to a site in the rat growth hormone promoter required for induction by thyroid hormone, Proc Natl Acad Sci USA 84: 5670 (1987).PubMedCrossRefGoogle Scholar
  26. 26.
    G. A. Brent, P. R. Larsen, J. W. Harney, R. J. Koenig, and D. D. Moore, Functional characterization of the rat growth hormone promoter elements required for induction by thyroid hormone with and without a cotransfected p type thyroid hormone receptor, J Biol Chem 264: 178 (1989).PubMedGoogle Scholar
  27. 27.
    G. Riesco, A. Taurog, P. R. Larsen, and L. Krulich, Acute and chronic response to iodine deficiency in rats, Endocrinology 100: 303 (1977).PubMedCrossRefGoogle Scholar
  28. 28.
    P. R. Larsen, Feedback regulation of thyrotropin secretion by thyroid hormones. Thyroid-pituitary interaction. N Engl J Med 306: 23 (1982).PubMedCrossRefGoogle Scholar
  29. 29.
    J. M. Connors and G. A. Hedge, Feedback effectiveness of periodic versus constant triiodothyronine replacement, Endocrinology 106: 911 (1980).PubMedCrossRefGoogle Scholar
  30. 30.
    P. R. Larsen and R. D. Frumess, Comparison of the biological effects of thyroxine and triiodothyronine in the rat, Endocrinology 100: 980 (1977).PubMedCrossRefGoogle Scholar
  31. 31.
    J. E. Silva and P. R. Larsen, Pituitary nuclear 3,5,3’-triiodothyronine and thyrotropin secretion: an explanation for the effect of thyroxine, Science 198: 617 (1977).PubMedCrossRefGoogle Scholar
  32. 32.
    J. E. Silva and P. R. Larsen, Contributions of plasma triiodothyronine and local thyroxine monodeiodination to triiodothyronine and nuclear triiodothyronine receptor saturation in pituitary, liver and kidney of hypothyroid rats. Further evidence relating saturation of pituitary nuclear triiodothyronine receptors and the acute inhibition of thyroid-stimulating hormone release, J Clin Invest 61: 1247 (1978).PubMedCrossRefGoogle Scholar
  33. 33.
    R. G. Cheron, M. M. Kaplan, and P. R. Larsen, Physiological and pharmacological influences on thyroxine to 3,5,3’-triiodothyronine conversion and nuclear 3,5,3’-triiodothyronine binding in rat anterior pituitary, J Clin Invest 64: 1402 (1979).PubMedCrossRefGoogle Scholar
  34. 34.
    P. R. Larsen, T. E. Dick, M. M. Markovitz, M. M. Kaplan, and T. G. Gard, Inhibition of intrapituitary thyroxine to 3,5,3’-triiodothyronine conversion prevents the acute suppression of thyrotropin release by thyroxine in hypothyroid rats, J Clin Invest 64: 117 (1979).PubMedCrossRefGoogle Scholar
  35. 35.
    P. R. Larsen, J. E. Silva, and M. M. Kaplan, Relationships between circulating and intracellular thyroid hormones: physiological and clinical implications, Endocrine Rev 2:87 (1981).CrossRefGoogle Scholar
  36. 36.
    T. J. Visser, M. M. Kaplan, J. L. Leonard, and P. R. Larsen, Evidence for two pathways of iodothyronine 5’-deiodination in rat pituitary that differ in kinetics, propylthiouracil sensitivity, and response to hypothyroidism, J Clin Invest 71: 992 (1983).PubMedCrossRefGoogle Scholar
  37. 37.
    R. J. Koenig and A. Y. Watson, Enrichment of rat anterior pituitary cell types by metrizamide density gradient centrifugation, Endocrinology 115: 317 (1984).PubMedCrossRefGoogle Scholar
  38. 38.
    R. J. Koenig, J. L. Leonard, D. Senator, N. Rappaport, A. Y. Watson, and P. R. Larsen, Regulation of thyroxine 5’-deiodinase activity by 3,5,3’-triiodothyronine in cultured rat anterior pituitary cells, Endocrinology 115: 324 (1984).PubMedCrossRefGoogle Scholar
  39. 39.
    R. N. Riskind, J. M. Kolodny, and P. R. Larsen, The regional hypothalamic distribution of type II 5’-monodeiodinase in euthyroid and hypothyroid rats, Brain Res 420: 194 (1987).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1989

Authors and Affiliations

  • P. Reed Larsen
    • 1
    • 2
  1. 1.The Thyroid DivisionHoward Hughes Medical InstituteBostonUSA
  2. 2.Department of Medicine Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA

Personalised recommendations