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The Hypothalamic-Pituitary-Thyroid Axis
Symposium on Current Concepts of Thyroid Disease
The Hypothalamic-Pituitary-Thyroid Axis Harold E. Carlson, M.D.,* and Jerome M. Hershman, M.D.**
Clinical and laboratory studies over the past 15 years have yielded a wealth of new information regarding the mechanisms of normal and abnormal regulation of thyroid function by the pituitary gland and, in turn, the control of pituitary thyrotropin (thyroid-stimulating hormone, TSH) secretion by the hypothalamus. Following a brief review of the normal anatomic and physiologic relationships involved in this regulation, we will examine the alterations in the system which may result from the presence of disease.
ANATOMY AND PHYSIOLOGY The secretion of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3 ) , by the thyroid gland is stimulated by TSH. This peptide hormone exerts its effect by binding to a specific receptor on the thyroid cell membrane;l binding of TSH activates the enzyme, adenyl cyclase, in the thyroid cell, which converts intracellular ATP to cyclic AMP. Cyclic AMP then initiates a series of biochemical events which ultimately result in stimulation of thyroid hormone production. Thyrotropin secretion, in turn, is stimulated by thyrotropin-releasing hormone (TRH). In 1969 the structure ofTRH was shown to be pyroglutamyl-histidyl-prolinamide, and this tripeptide was synthesized by several groups.2.13 TRH is produced by several hypothalamic nuclei and is secreted into the hypophyseal portal venous system which carries blood from the hypothalamus to the anterior pituitary. In the pituitary gland, TRH interacts with cell membrane receptors on the thyrotroph, resulting sequentially in activation of adenyl cyclase, increased production of cyclic AMP, and, finally, enhanced secretion of TSH.19. 25 • Assistant Professor of Medicine, UCLA School of Medicine; Assistant Chief, Endocrinology Section, Veterans Administration Wadsworth Hospital Center, Los Angeles, California ··Professor of Medicine, UCLA School of Medicine; Chief, Endocrinology Section, Veterans Administration Wadsworth Hospital Center, Los Angeles, California Supported by Veterans Administration Research Grants 3590-02 and 1289-01. Medical Clinics of North America- Vo!. 59, No. 5, September 1975
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Figure 1. Hypothalamic-pituitary-thyroid feedback system. Dashed arrows show inhibition and solid arrows stimulation. (Modified from Hershman, J. M., and Pittman, J. A., Jr.: New Eng. J. Med. 285:997-1006,1971, with permission.)
Feedback control of TSH secretion appears to operate at both the pituitary and hypothalamic levels. At the pituitary level, low levels of circulating thyroid hormones result in enhanced TSH secretion, while elevated concentrations of thyroid hormone suppress TSH secretionP Thyroid hormones also participate in feedback regulation of TRH secretion at the level of the hypothalamus, but these effects are, at present, unclear. Recently, feedback inhibition by thyroid hormones on the thyroid itself has been described;30 the importance of this autoregulation awaits further study. The thyroid hormone-TSH-TRH feedback system is illustrated in Figure l. While it is possible that supra-hypothalamic areas of the brain may further modify TRH secretion by the hypothalamus, such regulation is poorly understood. EFFECTS OF THYROTROPIN-RELEASING HORMONE IN NORMAL PERSONS Intravenous administration of synthetic TRH to normal human beings results in an increase in serum TSH, as measured by radioimmunoassay. TSH is elevated as early as 10 minutes following administration of TRH, and reaches a peak 15 to 30 minutes after administration of the releasing factor, followed by a decline to basal levels over the ensuing 1 to 4 hours (Fig. 2). Increasing intravenous doses of TRH produce increasing TSH responses over the range of 15 to 500 JLg; no additional response is seen with doses greater than 500 JLg. 14 The increased secretion of TSH results, as expected, in transient stimulation of the thyroid. Serum levels of T3 (measured by radioimmunoassay) increase about 70 per cent above basal levels 1 to 4 hours following TRH administration in euthyroid subjects, and serum T4 increases about 15 to 50 per cent.s In normal humans, TRH also stimu-
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lates the secretion of prolactin from the pituitary;18 the significance of this finding is unclear. Oral administration of synthetic TRH to normal subjects produces the same effects as when given intravenously, although much higher doses are needed (approximately 10 mg), and the stimulatory effects are more prolonged than those noted following intravenous injectionP Sideeffects following intravenous TRH have been frequent but mild. Lightheadedness, a flushed feeling, urge to urinate, mild nausea, and a peculiar taste may occur within 1 to 2 minutes after injection and clear rapidly over the following 5 minutes. Oral administration has been without side-effects of any sort.
OTHER FACTORS WHICH MAY AFFECT TSH SECRETION While basal levels of serum TSH do not change with increasing age in adults, a decreased TSH response to TRH has been noted in older euthyroid men in one study28 and in both sexes in another report.8 AI-
;-\
200
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TRH 100 SERUM TSH j1U/ml
+
· A~\
/
~.
50
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Figure 2. Serum thyrotropin (TSH) response to intravenous TRH in 2 hypothyroid patients (solid circles), three normal subjects (open circles), and one hyperthyroid patient with undetectable serum TSH (below dashed line). (From Hirshman, J. M.: New Eng. J. Med., 290:886-890, 1974.)
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though women of reproductive age tend to have higher TSH responses to TRH than men of the same age,!4 most studies have failed to show enhancement of TSH responses to TRH by short-term estrogen treatment in men. 3,32 Prolonged administration of glucocorticoids to normal subjects blunts or abolishes the response to TRH and may also lower basal levels of TSH.22 Somatostatin, a hypothalamic tetradecapeptide which inhibits pituitary growth hormone secretion, suppresses TRH-induced TSH release,27 while chronic L-dopa therapy, which may be given in Parkinson's disease, blocks both the TSH and prolactin responses to TRH.29 Administration of exogenous human growth hormone has also been reported to blunt the TSH response to TRH.26 A small diurnal variation in TSH secretion appears to be present in human beings with peak serum TSH levels preceding onset of sleep at about 11 :00 P.M. in some individuals or occurring at 4:00 to 6:00 A.M. in othersp,31 The magnitude of the variation is usually less than 1 to 2 /.L U per ml and thus of little importance in the interpretation of serum TSH measurements. Unlike various animal species and the human neonate, adult human beings do not augment their TSH secretion on exposure to cold.1I
PRIMARY HYPOTHYROIDISM When circulating levels of thyroid hormone are low because of primary thyroid failure, basal serum TSH concentration is elevated and the TSH response to TRH is enhanced (Fig. 2). However, since the elevated basal TSH level establishes the diagnosis, the TRH test is unnecessary. In occasional patients with borderline elevations of basal TSH, an exaggerated response to TRH may suggest the presence of hypothyroidism. TSH stimulation of thyroidal radioiodine uptake to differentiate primary from secondary hypothyroidism is now rarely performed, since the measurement of basal serum TSH is much easier and less costly. A few words of caution must be inserted about the absolute levels of serum TSH. In the early development of the radioimmunoassay of serum TSH, the mean normal basal level was 4 /.LU per ml and elevated levels were greater than 10 /.LU per ml. With recent improvements in methodology, the mean normal serum TSH in many laboratories is 2 /.LU per ml; values in excess of 6 /.LU per ml are clearly elevated. An elevated serum TSH concentration is the most sensitive laboratory index of primary hypothyroidism; however, elevated serum TSH cannot be used as an absolute indication of the diagnosis of primary hypothyroidism. There are at least three situations in which serum TSH is elevated in patients who appear to be clinically euthyroid and have normal serum levels of T4 and/or T 3 . These are (1) patients with mild chronic lymphocytic thyroiditis; (2) some patients previously treated with radioiodine for hyperthyroidism; (3) people residing in areas of severe iodine deficiency and endemic goiter. There may be other thyroid
THE HYPOTHALAMIC-PITUITARY- THYROID AXIS
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diseases in which serum TSH is elevated in a presumably euthyroid patient. The elevated serum TSH represents a pituitary response to an inadequate level of thyroid hormone reaching the pituitary receptors. In the euthyroid patient, this implies that the pituitary has a greater ability to respond to circulating levels of thyroid hormone than other tissues of the body, or that the threshold for detection of a low serum level of thyroid hormone is lower in the pituitary than in other tissues. Figure 3 illustrates this concept. Increased levels of serum TSH cause an increased thyroid response, shown as an increased level of serum thyroid hormone. The shaded area shows the normal ranges of serum thyroid hormone and TSH. If the serum TSH level were to be increased in response to some external stimulus, such as exogenous TRH, then thyroid hormone secretion would increase along the heavy line through the normal range. The dashed line shows the relationship between serum thyroid hormone and serum TSH in a patient with a diseased thyroid gland. For a given increment in serum TSH, there is a smaller increment in serum thyroid hormone in comparison with the normal thyroid gland. To maintain serum thyroid hormone levels in the midnormal range, the serum TSH is elevated. In a metaphoric sense, it takes more TSH to drive this diseased (or substrate-deprived) gland to function at a normal secretory level. Normal and slightly diseased glands can be stimulated by TSH and can be suppressed by thyroid hormone.
MONITORING SUPPRESSIVE THERAPY Euthyroid goitrous patients are often given exogenous thyroid hormone to suppress pituitary TSH secretion and, secondarily, thus reduce 20
15
TH 10
5
o TSH pU/ml
Figure 3. Response of normal and abnormal human thyroid glands to increasing concentrations of thyrotropin (TSH). The output of the thyroid is shown in arbitrary units of thyroid hormone (TH) on the ordinate, while serum TSH is shown on the abscissa.
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the size of the goiter. Since many euthyroid goitrous subjects have low or undetectable serum concentrations of TSH, suppression of basal serum TSH to undetectable levels does not assure adequacy of therapy. Measurement of thyroidal radioiodine uptake has in the past been used to monitor the degree of thyrotropin suppression. The TRH test offers an alternative means of assessment because suppressive doses of thyroid hormone will abolish the TSH response to TRH. The presence of any TSH response to TRH would be an indication to increase the dose of thyroid hormone.
PITUIT ARY DISEASE In disease states in which the pituitary gland is damaged or destroyed, producing secondary hypothyroidism, basal serum TSH is low and does not rise following the administration of TRH;12 similarly, the prolactin response to TRH may be deficient. Euthyroid patients with pituitary tumors may have normal basal serum TSH but a deficient TSH response to TRH, indicating decreased pituitary reserve of thyrotropinP' 14. 15 Acromegalic patients may show minimal or absent TSH responses to TRH, owing either to encroachment on normal pituitary tissue by the pituitary adenoma or to the suppressive effects of growth hormone on TSH secretion (see above).J5 Enlargement of the sella turcica may occur in primary hypothyroidism because of appropriate and expected hyperplasia of the thyrotrophs;20 thus, the finding of a large sella turcica in the presence of hypothyroidism does not necessarily signify hypopituitarism. Measurement of basal serum TSH will easily distinguish these two conditions. A few cases of TSH-secreting pituitary tumors have been described; such patients manifest clinical and laboratory evidence of hyperthyroidism, along with normal or elevated serum levels of TSH and the roentgenologic findings of a pituitary tumor.16
HYPOTHALAMIC DISEASE Testing with TRH has provided the basis for the diagnosis of hypothalamic lesions as a cause of hypothyroidism. Patients with hypothalamic hypothyroidism have deficient secretion of TRH with intact pituitary glands. In pure hypo thalamic disease with hypothyroidism, basal TSH levels are not elevated but rise following TRH administration. The peak TSH response is often delayed, occurring at 45 to 90 minutes rather than 30 minutes after TRH.26 However, examples of pituitary disease have been encountered in which the TSH response to TRH was normal or exaggerated. lO This finding is probably a consequence of suprasellar extension of the pituitary lesion with hypothalamic impairment. Hypothalamic hyperthyroidism, presumably caused by oversecretion of TRH, has been described in one subject;9 the hyperthyroidism
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was mild, as might be expected, since elevated thyroid hormone levels would, by feed-back inhibition on the pituitary, prevent any great increase in TSH secretion. A similar syndrome has been induced in laboratory animals by chronic administration of exogenous TRH.6
HYPERTHYROIDISM In the presence of high circulating concentrations of T4 and/or Ta, basal TSH is suppressed to undetectable levels and the response to TRH is blunted or abolished (Figure 2). Only minor increases in serum hormone levels appear necessary for nearly total suppression of the TSH response to TRH. Patients with euthyroid Graves' disease (infiltrative ocular disease without hyperthyroidism) often show lack of suppression of thyroidal radioiodine uptake following an 8 to 10 day course of Ta, 75 to 100 f,Lg per day. Most of these patients will also fail to show a TSH response to TRH;4 thus the TRH test may be of value in the diagnosis of this condition. Some patients with euthyroid Graves' disease may show normal or even exaggerated TSH responses to TRH; formal thyroid suppression testing should be performed in these patients, since abnormal results may still be found. 7
SUMMARY Although recent investigations have contributed greatly to our understanding of the function and regulation of the hypothalamic-pituitary-thyroid axis, much remains unclear. The influence of suprahypo thalamic areas of the brain on hypothalamic function, the nature of thyroid hormone feedback on the hypothalamus, and the physiologic significance of prolactin release by TRH are all topics requiring further study. The extensive experience which has been accumulated in the use of TRH as a diagnostic tool has led to its acceptance as a safe, convenient, rapid method of assessment of pituitary and thyroid function. It appears that TRH testing is useful in evaluation of pituitary TSH and prolactin reserve in patients with pituitary lesions; in the differentiation of pituitary and hypothalamic causes of hypothyroidism; in diagnosis of euthyroid Graves' disease; in the evaluation of the adequacy of TSH suppression in thyroid hormone therapy of nodular goiter; and possibly in the diagnosis of mild primary hypothyroidism.
REFERENCES 1. Amir, S. M., Carraway, T. F., and Kohn, L. D.: The binding of thyrotropin to isolated bovine thyroid plasma membranes. J. BioI. Chem., 248:4092-4100,1973. 2. Burgus, R., Dunn, T. F., Desiderio, D., et al.: Characterization of ovine hypothalamic hypophysiotropic TSH-releasing factor. Nature (Lond.), 226:321-325, 1970.
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3. Carlson, H. E., Jacobs, L. S., and Daughaday, W. H.: Growth hormone, thyrotropin, and prolactin responses to thyrotropin-releasing hormone following diethylstilbestrol pretreatment. J. Clin. EndocrinoI. Metab., 37:488-490,1973. 4. Chopra,1. J., Chopra, U., and Orgiazzi, J.: Abnormalities of hypothalamo-hypophysealthyroid axis in patients with Graves' ophthalmopathy. J. Clin. EndocrinoI. Metab., 37:955-967,1973. 5. Chopra,1. J., Ho, R. S., and Lam, R: An improved radioimmunoassay of triiodothyronine in serum: Its application to clinical and physiological studies. J. Lab. Clin. Med., 80: 729- 739, 1972. 6. Chopra,1. J., and Solomon, D. H.: Hyperthyroidism induced by thyrotropin-releasing hormone in mice. Endocrinology, 92:1731-1735,1973. 7. Clifton-Bligh, P., Silverstein, G. E., and Burke, G.: Unresponsiveness to thyrotropinreleasing hormone (TRH) in treated Graves' hyperthyroidism and in euthyroid Graves' disease. J. Clin. EndocrinoI. Metab., 38:531-538,1974. 8. Cuttelod, S., Lemarchand-Beraud, T., Magnenat, P., et al.: Effect of age and role of kidneys and liver on thyrotropin turnover in man. Metabolism, 23: 101-113, 1974. 9. Emerson, C. H., and Utiger, R D.: Hyperthyroidism and excessive thyrotropin secretion. New Eng. J. Med., 287:328-333,1972. 10. Faglia, G., Beck-Peccoz, P., Ambrosi, B., et al.: Prolonged and exaggerated elevations in plasma thyrotropin (HTSH) after thyrotropin releasing factor (TRF) in patients with pituitary tumors. J. Clin. EndocrinoI. Metab., 33 :999-1002, 1971. 11. Fisher, D. A., and Odell, W. D.: Effect of cold on TSH secretion in man. J Clin. EndocrinoI. Metab., 33:859-861,1971. 12. Fleischer, N., Lorente, M., Kirkland, J., et al.: Synthetic thyrotropin releasing factor as a test of pituitary thyrotropin reserve. J. Clin. EndocrinoI. Metab., 34 :617-624, 1972. 13. Folkers, K., Enzmann, F., Boler, J., et al.: Discovery of modification of the synthetic tripeptide-sequence of the thyrotropin releasing hormone having activity. Biochem. Biophys. Res. Commun., 37:123-126,1969. 14. Haigler, E. D., Jr., Pittman, J. A., Jr., Hershman, J. M., et aI.: Direct evaluation of pituitary thyrotropin reserve utilizing synthetic thyrotropin releasing hormone. J. Clin. EndocrinoI. Metab., 33:573-581,1971. 15. Hall, R, Ormston, B. J., Besser, G. M., et al.: The thyrotropin-releasing hormone test in diseases of the pituitary and hypothalamus. Lancet, 1: 759-762, 1972. 16. Hamilton, C. R, Jr., Adams, L. C., and Maloof, F.: Hyperthyroidism due to thyrotropinproducing pituitary chromophobe adenoma. New Eng. J. Med., 283:1077-1080,1970. 17. Hershman, J M., and Pittman, J. A.: Response to synthetic thyrotropin-releasing hormone in man. J. Clin. EndocrinoI. Metab., 31 :457-460, 1970. 18. Jacobs, L. S., Snyder, P. J., Wilber, J. F., Utiger, R D., and Daughaday, W. H.: Increased serum prolactin after administration of synthetic thyrotropin releasing hormone (TRH) in man. J. Clin. EndocrinoI. Metab., 33:996-998,1971. 19. Labrie, F., Barden, N., Poirier, G., and DeLean, A.: Binding of thyrotropin-releasing hormone to plasma membranes of bovine anterior pituitary gland. Proc. Nat. Acad. Sci., USA, 69:283-287,1972. 20. Lawrence, A. M., Wilber, J. F., and Hagen, T. C.: The pituitary and primary hypothyroidism. Arch. Intern. Med., 132:327-333,1973. 21. May, P. B., and Donabedian, R K.: Thyrotropin-releasing hormone (TRH) mediated thyroid-stimulating hormone (TSH) release from human anterior pituitary tissue in vitro. J. Clin. EndocrinoI. Metab., 36:605-607,1973. 22. Otsuki, M., Dakoda, M., and Baba, S.: Influence of glucocorticoids on TRF-induced TSH response in man. J. Clin. Endocrinol. Metab., 36:95-102, 1973. 23. Patel, Y. C., Alford, F. P., and Burger, H. G.: The 24-hour plasma thyrotrophin profile. Clin. Sci., 43:71-77,1972. 24. Pittman, J A., Jr., Haigler, E. D., Hershman, J. M., et aI.: Hypothalamic hypothyroidism. New Eng. J Med., 285:844-845,1971. 25. Poirier, G., Borden, N., Labrie, F., et aI.: Partial purification and some properties of adenyl cyclase and receptor for TRH from anterior pituitary gland. Proc. IV IntI. Congress Endocrinol., p. 85, Excerpta Medica International Congress Series No. 256, Amsterdam, 1972. 26. Root, A. W., Snyder, P. J., Rezvani, 1., et al.: Inhibition of thyrotropin-releasing hormonemediated secretion of thyrotropin by human growth hormone. J. Clin. Endocrinol. Metab., 36:103-107,1973. 27. Siler, T. M., Yen, S. S. C., Vale, W., et al.: Inhibition by somatostatin on the release of TSH induced in man by thyrotropin-releasing factor. J. Clin. Endocrinol. Metab., 38:742-745,1974. 28. Snyder, P. J., and Utiger, R D.: Response to thyrotropin releasing hormone (TRH) in normal man. J. Clin. Endocrinol. Metab., 34:380-385,1972.
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29. Spaulding, S. W., Burrow, G. N .. Donabedian, R., et al.: L-dopa suppression of thyrotropin releasing hormone response in man. J. Clin. EndocrinoL Metab., 35:182-185,1972. 30. Takasu, N., Sato, S., Tsukui, T., et al.: Inhibitory action of thyroid hormone on the activation of adenyl cyclase-cyclin AMP system by thyroid-stimulating hormone in human thyroid tissues from euthyroid subjects and thyrotoxic patients. J. Clin. EndocrinoL Metab., 39:772-778,1974. 31. VanCauter, E., Leclercq, R., Vanhaelst, L., et al.: Simultaneous study of cortisol and TSH daily variations in normal subjects and patients with hyperadrenal corticism. J. Clin. EndocrinoL Metab., 39:645-652,1974. 32. Woolf, P. D., Gonzalez-Barcena, D., Schalch, D. S., et al.: Lack of effect of steroids on thyrotropin-releasing hormone (TRH) mediated thyrotropin (TSH) release in man. NeuroendocrinoL, 13:56-62,1973/74.
Medical and Research Services Veterans Administration Wadsworth Hospital Center Los Angeles, California 90073
The Hypothalamic-Pituitary-Thyroid Axis Harold E. Carlson, M.D.,* and Jerome M. Hershman, M.D.**
Clinical and laboratory studies over the past 15 years have yielded a wealth of new information regarding the mechanisms of normal and abnormal regulation of thyroid function by the pituitary gland and, in turn, the control of pituitary thyrotropin (thyroid-stimulating hormone, TSH) secretion by the hypothalamus. Following a brief review of the normal anatomic and physiologic relationships involved in this regulation, we will examine the alterations in the system which may result from the presence of disease.
ANATOMY AND PHYSIOLOGY The secretion of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3 ) , by the thyroid gland is stimulated by TSH. This peptide hormone exerts its effect by binding to a specific receptor on the thyroid cell membrane;l binding of TSH activates the enzyme, adenyl cyclase, in the thyroid cell, which converts intracellular ATP to cyclic AMP. Cyclic AMP then initiates a series of biochemical events which ultimately result in stimulation of thyroid hormone production. Thyrotropin secretion, in turn, is stimulated by thyrotropin-releasing hormone (TRH). In 1969 the structure ofTRH was shown to be pyroglutamyl-histidyl-prolinamide, and this tripeptide was synthesized by several groups.2.13 TRH is produced by several hypothalamic nuclei and is secreted into the hypophyseal portal venous system which carries blood from the hypothalamus to the anterior pituitary. In the pituitary gland, TRH interacts with cell membrane receptors on the thyrotroph, resulting sequentially in activation of adenyl cyclase, increased production of cyclic AMP, and, finally, enhanced secretion of TSH.19. 25 • Assistant Professor of Medicine, UCLA School of Medicine; Assistant Chief, Endocrinology Section, Veterans Administration Wadsworth Hospital Center, Los Angeles, California ··Professor of Medicine, UCLA School of Medicine; Chief, Endocrinology Section, Veterans Administration Wadsworth Hospital Center, Los Angeles, California Supported by Veterans Administration Research Grants 3590-02 and 1289-01. Medical Clinics of North America- Vo!. 59, No. 5, September 1975
1045
1046
HAROLD
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CARLSON AND JEROME
M.
HERSHMAN
THYROID
Figure 1. Hypothalamic-pituitary-thyroid feedback system. Dashed arrows show inhibition and solid arrows stimulation. (Modified from Hershman, J. M., and Pittman, J. A., Jr.: New Eng. J. Med. 285:997-1006,1971, with permission.)
Feedback control of TSH secretion appears to operate at both the pituitary and hypothalamic levels. At the pituitary level, low levels of circulating thyroid hormones result in enhanced TSH secretion, while elevated concentrations of thyroid hormone suppress TSH secretionP Thyroid hormones also participate in feedback regulation of TRH secretion at the level of the hypothalamus, but these effects are, at present, unclear. Recently, feedback inhibition by thyroid hormones on the thyroid itself has been described;30 the importance of this autoregulation awaits further study. The thyroid hormone-TSH-TRH feedback system is illustrated in Figure l. While it is possible that supra-hypothalamic areas of the brain may further modify TRH secretion by the hypothalamus, such regulation is poorly understood. EFFECTS OF THYROTROPIN-RELEASING HORMONE IN NORMAL PERSONS Intravenous administration of synthetic TRH to normal human beings results in an increase in serum TSH, as measured by radioimmunoassay. TSH is elevated as early as 10 minutes following administration of TRH, and reaches a peak 15 to 30 minutes after administration of the releasing factor, followed by a decline to basal levels over the ensuing 1 to 4 hours (Fig. 2). Increasing intravenous doses of TRH produce increasing TSH responses over the range of 15 to 500 JLg; no additional response is seen with doses greater than 500 JLg. 14 The increased secretion of TSH results, as expected, in transient stimulation of the thyroid. Serum levels of T3 (measured by radioimmunoassay) increase about 70 per cent above basal levels 1 to 4 hours following TRH administration in euthyroid subjects, and serum T4 increases about 15 to 50 per cent.s In normal humans, TRH also stimu-
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lates the secretion of prolactin from the pituitary;18 the significance of this finding is unclear. Oral administration of synthetic TRH to normal subjects produces the same effects as when given intravenously, although much higher doses are needed (approximately 10 mg), and the stimulatory effects are more prolonged than those noted following intravenous injectionP Sideeffects following intravenous TRH have been frequent but mild. Lightheadedness, a flushed feeling, urge to urinate, mild nausea, and a peculiar taste may occur within 1 to 2 minutes after injection and clear rapidly over the following 5 minutes. Oral administration has been without side-effects of any sort.
OTHER FACTORS WHICH MAY AFFECT TSH SECRETION While basal levels of serum TSH do not change with increasing age in adults, a decreased TSH response to TRH has been noted in older euthyroid men in one study28 and in both sexes in another report.8 AI-
;-\
200
150
TRH 100 SERUM TSH j1U/ml
+
· A~\
/
~.
50
30
MINUTES
Figure 2. Serum thyrotropin (TSH) response to intravenous TRH in 2 hypothyroid patients (solid circles), three normal subjects (open circles), and one hyperthyroid patient with undetectable serum TSH (below dashed line). (From Hirshman, J. M.: New Eng. J. Med., 290:886-890, 1974.)
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though women of reproductive age tend to have higher TSH responses to TRH than men of the same age,!4 most studies have failed to show enhancement of TSH responses to TRH by short-term estrogen treatment in men. 3,32 Prolonged administration of glucocorticoids to normal subjects blunts or abolishes the response to TRH and may also lower basal levels of TSH.22 Somatostatin, a hypothalamic tetradecapeptide which inhibits pituitary growth hormone secretion, suppresses TRH-induced TSH release,27 while chronic L-dopa therapy, which may be given in Parkinson's disease, blocks both the TSH and prolactin responses to TRH.29 Administration of exogenous human growth hormone has also been reported to blunt the TSH response to TRH.26 A small diurnal variation in TSH secretion appears to be present in human beings with peak serum TSH levels preceding onset of sleep at about 11 :00 P.M. in some individuals or occurring at 4:00 to 6:00 A.M. in othersp,31 The magnitude of the variation is usually less than 1 to 2 /.L U per ml and thus of little importance in the interpretation of serum TSH measurements. Unlike various animal species and the human neonate, adult human beings do not augment their TSH secretion on exposure to cold.1I
PRIMARY HYPOTHYROIDISM When circulating levels of thyroid hormone are low because of primary thyroid failure, basal serum TSH concentration is elevated and the TSH response to TRH is enhanced (Fig. 2). However, since the elevated basal TSH level establishes the diagnosis, the TRH test is unnecessary. In occasional patients with borderline elevations of basal TSH, an exaggerated response to TRH may suggest the presence of hypothyroidism. TSH stimulation of thyroidal radioiodine uptake to differentiate primary from secondary hypothyroidism is now rarely performed, since the measurement of basal serum TSH is much easier and less costly. A few words of caution must be inserted about the absolute levels of serum TSH. In the early development of the radioimmunoassay of serum TSH, the mean normal basal level was 4 /.LU per ml and elevated levels were greater than 10 /.LU per ml. With recent improvements in methodology, the mean normal serum TSH in many laboratories is 2 /.LU per ml; values in excess of 6 /.LU per ml are clearly elevated. An elevated serum TSH concentration is the most sensitive laboratory index of primary hypothyroidism; however, elevated serum TSH cannot be used as an absolute indication of the diagnosis of primary hypothyroidism. There are at least three situations in which serum TSH is elevated in patients who appear to be clinically euthyroid and have normal serum levels of T4 and/or T 3 . These are (1) patients with mild chronic lymphocytic thyroiditis; (2) some patients previously treated with radioiodine for hyperthyroidism; (3) people residing in areas of severe iodine deficiency and endemic goiter. There may be other thyroid
THE HYPOTHALAMIC-PITUITARY- THYROID AXIS
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diseases in which serum TSH is elevated in a presumably euthyroid patient. The elevated serum TSH represents a pituitary response to an inadequate level of thyroid hormone reaching the pituitary receptors. In the euthyroid patient, this implies that the pituitary has a greater ability to respond to circulating levels of thyroid hormone than other tissues of the body, or that the threshold for detection of a low serum level of thyroid hormone is lower in the pituitary than in other tissues. Figure 3 illustrates this concept. Increased levels of serum TSH cause an increased thyroid response, shown as an increased level of serum thyroid hormone. The shaded area shows the normal ranges of serum thyroid hormone and TSH. If the serum TSH level were to be increased in response to some external stimulus, such as exogenous TRH, then thyroid hormone secretion would increase along the heavy line through the normal range. The dashed line shows the relationship between serum thyroid hormone and serum TSH in a patient with a diseased thyroid gland. For a given increment in serum TSH, there is a smaller increment in serum thyroid hormone in comparison with the normal thyroid gland. To maintain serum thyroid hormone levels in the midnormal range, the serum TSH is elevated. In a metaphoric sense, it takes more TSH to drive this diseased (or substrate-deprived) gland to function at a normal secretory level. Normal and slightly diseased glands can be stimulated by TSH and can be suppressed by thyroid hormone.
MONITORING SUPPRESSIVE THERAPY Euthyroid goitrous patients are often given exogenous thyroid hormone to suppress pituitary TSH secretion and, secondarily, thus reduce 20
15
TH 10
5
o TSH pU/ml
Figure 3. Response of normal and abnormal human thyroid glands to increasing concentrations of thyrotropin (TSH). The output of the thyroid is shown in arbitrary units of thyroid hormone (TH) on the ordinate, while serum TSH is shown on the abscissa.
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the size of the goiter. Since many euthyroid goitrous subjects have low or undetectable serum concentrations of TSH, suppression of basal serum TSH to undetectable levels does not assure adequacy of therapy. Measurement of thyroidal radioiodine uptake has in the past been used to monitor the degree of thyrotropin suppression. The TRH test offers an alternative means of assessment because suppressive doses of thyroid hormone will abolish the TSH response to TRH. The presence of any TSH response to TRH would be an indication to increase the dose of thyroid hormone.
PITUIT ARY DISEASE In disease states in which the pituitary gland is damaged or destroyed, producing secondary hypothyroidism, basal serum TSH is low and does not rise following the administration of TRH;12 similarly, the prolactin response to TRH may be deficient. Euthyroid patients with pituitary tumors may have normal basal serum TSH but a deficient TSH response to TRH, indicating decreased pituitary reserve of thyrotropinP' 14. 15 Acromegalic patients may show minimal or absent TSH responses to TRH, owing either to encroachment on normal pituitary tissue by the pituitary adenoma or to the suppressive effects of growth hormone on TSH secretion (see above).J5 Enlargement of the sella turcica may occur in primary hypothyroidism because of appropriate and expected hyperplasia of the thyrotrophs;20 thus, the finding of a large sella turcica in the presence of hypothyroidism does not necessarily signify hypopituitarism. Measurement of basal serum TSH will easily distinguish these two conditions. A few cases of TSH-secreting pituitary tumors have been described; such patients manifest clinical and laboratory evidence of hyperthyroidism, along with normal or elevated serum levels of TSH and the roentgenologic findings of a pituitary tumor.16
HYPOTHALAMIC DISEASE Testing with TRH has provided the basis for the diagnosis of hypothalamic lesions as a cause of hypothyroidism. Patients with hypothalamic hypothyroidism have deficient secretion of TRH with intact pituitary glands. In pure hypo thalamic disease with hypothyroidism, basal TSH levels are not elevated but rise following TRH administration. The peak TSH response is often delayed, occurring at 45 to 90 minutes rather than 30 minutes after TRH.26 However, examples of pituitary disease have been encountered in which the TSH response to TRH was normal or exaggerated. lO This finding is probably a consequence of suprasellar extension of the pituitary lesion with hypothalamic impairment. Hypothalamic hyperthyroidism, presumably caused by oversecretion of TRH, has been described in one subject;9 the hyperthyroidism
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was mild, as might be expected, since elevated thyroid hormone levels would, by feed-back inhibition on the pituitary, prevent any great increase in TSH secretion. A similar syndrome has been induced in laboratory animals by chronic administration of exogenous TRH.6
HYPERTHYROIDISM In the presence of high circulating concentrations of T4 and/or Ta, basal TSH is suppressed to undetectable levels and the response to TRH is blunted or abolished (Figure 2). Only minor increases in serum hormone levels appear necessary for nearly total suppression of the TSH response to TRH. Patients with euthyroid Graves' disease (infiltrative ocular disease without hyperthyroidism) often show lack of suppression of thyroidal radioiodine uptake following an 8 to 10 day course of Ta, 75 to 100 f,Lg per day. Most of these patients will also fail to show a TSH response to TRH;4 thus the TRH test may be of value in the diagnosis of this condition. Some patients with euthyroid Graves' disease may show normal or even exaggerated TSH responses to TRH; formal thyroid suppression testing should be performed in these patients, since abnormal results may still be found. 7
SUMMARY Although recent investigations have contributed greatly to our understanding of the function and regulation of the hypothalamic-pituitary-thyroid axis, much remains unclear. The influence of suprahypo thalamic areas of the brain on hypothalamic function, the nature of thyroid hormone feedback on the hypothalamus, and the physiologic significance of prolactin release by TRH are all topics requiring further study. The extensive experience which has been accumulated in the use of TRH as a diagnostic tool has led to its acceptance as a safe, convenient, rapid method of assessment of pituitary and thyroid function. It appears that TRH testing is useful in evaluation of pituitary TSH and prolactin reserve in patients with pituitary lesions; in the differentiation of pituitary and hypothalamic causes of hypothyroidism; in diagnosis of euthyroid Graves' disease; in the evaluation of the adequacy of TSH suppression in thyroid hormone therapy of nodular goiter; and possibly in the diagnosis of mild primary hypothyroidism.
REFERENCES 1. Amir, S. M., Carraway, T. F., and Kohn, L. D.: The binding of thyrotropin to isolated bovine thyroid plasma membranes. J. BioI. Chem., 248:4092-4100,1973. 2. Burgus, R., Dunn, T. F., Desiderio, D., et al.: Characterization of ovine hypothalamic hypophysiotropic TSH-releasing factor. Nature (Lond.), 226:321-325, 1970.
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3. Carlson, H. E., Jacobs, L. S., and Daughaday, W. H.: Growth hormone, thyrotropin, and prolactin responses to thyrotropin-releasing hormone following diethylstilbestrol pretreatment. J. Clin. EndocrinoI. Metab., 37:488-490,1973. 4. Chopra,1. J., Chopra, U., and Orgiazzi, J.: Abnormalities of hypothalamo-hypophysealthyroid axis in patients with Graves' ophthalmopathy. J. Clin. EndocrinoI. Metab., 37:955-967,1973. 5. Chopra,1. J., Ho, R. S., and Lam, R: An improved radioimmunoassay of triiodothyronine in serum: Its application to clinical and physiological studies. J. Lab. Clin. Med., 80: 729- 739, 1972. 6. Chopra,1. J., and Solomon, D. H.: Hyperthyroidism induced by thyrotropin-releasing hormone in mice. Endocrinology, 92:1731-1735,1973. 7. Clifton-Bligh, P., Silverstein, G. E., and Burke, G.: Unresponsiveness to thyrotropinreleasing hormone (TRH) in treated Graves' hyperthyroidism and in euthyroid Graves' disease. J. Clin. EndocrinoI. Metab., 38:531-538,1974. 8. Cuttelod, S., Lemarchand-Beraud, T., Magnenat, P., et al.: Effect of age and role of kidneys and liver on thyrotropin turnover in man. Metabolism, 23: 101-113, 1974. 9. Emerson, C. H., and Utiger, R D.: Hyperthyroidism and excessive thyrotropin secretion. New Eng. J. Med., 287:328-333,1972. 10. Faglia, G., Beck-Peccoz, P., Ambrosi, B., et al.: Prolonged and exaggerated elevations in plasma thyrotropin (HTSH) after thyrotropin releasing factor (TRF) in patients with pituitary tumors. J. Clin. EndocrinoI. Metab., 33 :999-1002, 1971. 11. Fisher, D. A., and Odell, W. D.: Effect of cold on TSH secretion in man. J Clin. EndocrinoI. Metab., 33:859-861,1971. 12. Fleischer, N., Lorente, M., Kirkland, J., et al.: Synthetic thyrotropin releasing factor as a test of pituitary thyrotropin reserve. J. Clin. EndocrinoI. Metab., 34 :617-624, 1972. 13. Folkers, K., Enzmann, F., Boler, J., et al.: Discovery of modification of the synthetic tripeptide-sequence of the thyrotropin releasing hormone having activity. Biochem. Biophys. Res. Commun., 37:123-126,1969. 14. Haigler, E. D., Jr., Pittman, J. A., Jr., Hershman, J. M., et aI.: Direct evaluation of pituitary thyrotropin reserve utilizing synthetic thyrotropin releasing hormone. J. Clin. EndocrinoI. Metab., 33:573-581,1971. 15. Hall, R, Ormston, B. J., Besser, G. M., et al.: The thyrotropin-releasing hormone test in diseases of the pituitary and hypothalamus. Lancet, 1: 759-762, 1972. 16. Hamilton, C. R, Jr., Adams, L. C., and Maloof, F.: Hyperthyroidism due to thyrotropinproducing pituitary chromophobe adenoma. New Eng. J. Med., 283:1077-1080,1970. 17. Hershman, J M., and Pittman, J. A.: Response to synthetic thyrotropin-releasing hormone in man. J. Clin. EndocrinoI. Metab., 31 :457-460, 1970. 18. Jacobs, L. S., Snyder, P. J., Wilber, J. F., Utiger, R D., and Daughaday, W. H.: Increased serum prolactin after administration of synthetic thyrotropin releasing hormone (TRH) in man. J. Clin. EndocrinoI. Metab., 33:996-998,1971. 19. Labrie, F., Barden, N., Poirier, G., and DeLean, A.: Binding of thyrotropin-releasing hormone to plasma membranes of bovine anterior pituitary gland. Proc. Nat. Acad. Sci., USA, 69:283-287,1972. 20. Lawrence, A. M., Wilber, J. F., and Hagen, T. C.: The pituitary and primary hypothyroidism. Arch. Intern. Med., 132:327-333,1973. 21. May, P. B., and Donabedian, R K.: Thyrotropin-releasing hormone (TRH) mediated thyroid-stimulating hormone (TSH) release from human anterior pituitary tissue in vitro. J. Clin. EndocrinoI. Metab., 36:605-607,1973. 22. Otsuki, M., Dakoda, M., and Baba, S.: Influence of glucocorticoids on TRF-induced TSH response in man. J. Clin. Endocrinol. Metab., 36:95-102, 1973. 23. Patel, Y. C., Alford, F. P., and Burger, H. G.: The 24-hour plasma thyrotrophin profile. Clin. Sci., 43:71-77,1972. 24. Pittman, J A., Jr., Haigler, E. D., Hershman, J. M., et aI.: Hypothalamic hypothyroidism. New Eng. J Med., 285:844-845,1971. 25. Poirier, G., Borden, N., Labrie, F., et aI.: Partial purification and some properties of adenyl cyclase and receptor for TRH from anterior pituitary gland. Proc. IV IntI. Congress Endocrinol., p. 85, Excerpta Medica International Congress Series No. 256, Amsterdam, 1972. 26. Root, A. W., Snyder, P. J., Rezvani, 1., et al.: Inhibition of thyrotropin-releasing hormonemediated secretion of thyrotropin by human growth hormone. J. Clin. Endocrinol. Metab., 36:103-107,1973. 27. Siler, T. M., Yen, S. S. C., Vale, W., et al.: Inhibition by somatostatin on the release of TSH induced in man by thyrotropin-releasing factor. J. Clin. Endocrinol. Metab., 38:742-745,1974. 28. Snyder, P. J., and Utiger, R D.: Response to thyrotropin releasing hormone (TRH) in normal man. J. Clin. Endocrinol. Metab., 34:380-385,1972.
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29. Spaulding, S. W., Burrow, G. N .. Donabedian, R., et al.: L-dopa suppression of thyrotropin releasing hormone response in man. J. Clin. EndocrinoL Metab., 35:182-185,1972. 30. Takasu, N., Sato, S., Tsukui, T., et al.: Inhibitory action of thyroid hormone on the activation of adenyl cyclase-cyclin AMP system by thyroid-stimulating hormone in human thyroid tissues from euthyroid subjects and thyrotoxic patients. J. Clin. EndocrinoL Metab., 39:772-778,1974. 31. VanCauter, E., Leclercq, R., Vanhaelst, L., et al.: Simultaneous study of cortisol and TSH daily variations in normal subjects and patients with hyperadrenal corticism. J. Clin. EndocrinoL Metab., 39:645-652,1974. 32. Woolf, P. D., Gonzalez-Barcena, D., Schalch, D. S., et al.: Lack of effect of steroids on thyrotropin-releasing hormone (TRH) mediated thyrotropin (TSH) release in man. NeuroendocrinoL, 13:56-62,1973/74.
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