Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

37.The Adrenal Cortex in Thyrotoxicosis

Robert G. Dluhy

Thyrotoxicosis has several effects on adrenocortical function and the metabolism of adrenocortical hormones, serving especially to accelerate the latter. Patients with thyrotoxicosis therefore have more rapid cortisol clearance than do normal subjects (Figs. 37.1 and 37.2). The function of the hypothalamic–pituitary–adrenal axis is normal; corticotropin (ACTH) and cortisol secretion increase to meet the need for more cortisol resulting from the increased clearance rate. Therefore, patients with thyrotoxicosis have normal serum ACTH and cortisol concentrations. If hypothalamic, pituitary, or adrenal function is impaired, however, the patient's serum cortisol concentrations are low.

FIGURE 37.1. The relationship between the serum concentrations and the secretion and clearance rates of cortisol in normal subjects and in patients with thyrotoxicosis. In normal subjects, the serum concentration (SC) of cortisol reflects its secretion at the time of measurement. The SC is dependent on two factors: the cortisol secretion rate (SR) and the rate at which cortisol is metabolized, that is, the metabolic clearance rate (MCR) of cortisol. In patients with thyrotoxicosis, the hepatic clearance of cortisol is accelerated due to augmentation of Δ4,5-reductase activity (see Fig. 37.3). If normal feedback relationships are preserved, the endogenous cortisol secretion rate increases and serum cortisol concentrations are normal.

FIGURE 37.2. Disappearance of cortisol from plasma after its intravenous administration to a single normal subject, a patient with hypothyroidism (myxedema), and a patient with thyrotoxicosis. The slowing and acceleration, respectively, of the plasma half-life (t1/2) of cortisol are evident. In this study, the results were similar after infusion of tracer doses of 14C-cortisol. (From Peterson RE. The influence of the thyroid on adrenal cortical function. J Clin Invest 1958;37:736, with permission.)


FIGURE 37.3. Alterations in hepatic metabolism of cortisol in thyrotoxicosis. Cortisol is inactivated primarily by reduction of the α,β-unsaturated ketone region in ring A, yielding 5α- and 5β-dihydrocortisol, which are inactive. These reactions are catalyzed by hepatic Δ4,5-steroid reductases. Subsequently 3-keto reduction of dihydrocortisol yields the tetrahydrohydroxy metabolites. Thyroid hormone increases the activity of these reductases. As a result, in thyrotoxicosis there is an overall increase in the metabolic clearance of cortisol, as well as a qualitative alteration in the pattern of metabolites produced, with a small increase in the fraction of cortisol metabolized to tetrahydrocortisone, a small increase in the allotetrahydrocortisol fraction, and a decrease in the fraction of tetrahydrocortisol. There are two isoforms of 11β-hydroxysteroid dehydrogenase (11β-HSD): type 1, which is located in the liver and acts as a reductase, thereby converting cortisone to cortisol; and type 2, which is located in the kidneys and acts as a dehydrogenase, converting cortisol to cortisone. Thyrotoxicosis results in a decrease in the reductase activity of 11β-HSD type 1 and therefore a decrease in hepatic conversion of cortisone to cortisol. The result is an accumulation of cortisone, which is biologically inactive. Thyrotoxicosis does not alter the conjugation of cortisol metabolites with glucuronic acid in the liver.

The larger and smaller arrows indicate changes in cortisol metabolism, as compared with normal.

Conversely, glucocorticoids affect a variety of thyroid functions, such as thyrotropin (TSH) secretion, the production and clearance of thyroxine (T4), peripheral conversion of T4 to triiodothyronine (T3), renal clearance of iodide, and the production or clearance of serum thyroid hormone–binding proteins.

Finally, thyroid and adrenal function may be altered by concurrent disease processes, particularly autoimmune diseases, beyond the aforementioned hormonal interactions. Additional potential interactions include those resulting from the alterations in both adrenal and thyroid function that occur during acute and chronic illness (see section on nonthyroidal illness in Chapter 11).


In vitro, glucocorticoids act synergistically with T3 to increase growth hormone (GH) production by pituitary tumor cells. The affinity of the T3 nuclear receptors for T3 in these cells is reduced by 50% in the absence of cortisol (1). Other interactions between thyroid hormones and glucocorticoids, for example, effects on the messenger RNAs (mRNAs) for the receptors for the two hormones and on GH gene expression, also have been reported (2,3,4). Thyroid hormone and glucocorticoid receptors are encoded by genes that are members of a single family, and the two types of receptors have some structural similarity. In one study of GH3 cells (a pituitary tumor cell line), T3 increased glucocorticoid action by increasing glucocorticoid receptor mRNA concentrations (4). A reciprocal action of glucocorticoids on T3 receptor mRNA was not found, even though T3 action in GH3 cells is augmented by glucocorticoids. In contrast to these interactions of glucocorticoids and thyroid hormone on GH secretion, there is no evidence for interactions in pituitary thyrotrophs or corticotrophs or in other tissues. In addition, some negative findings have emerged. For example, patients with either primary cortisol resistance (due to inactivating mutations of the glucocorticoid receptor) or the cortisol hyperreactive syndrome have normal serum TSH and thyroid hormone concentrations, and the responsiveness of their tissues to T4 and T3 is normal (5,6).


Neither ACTH nor cortisol is a major regulator of pituitary TSH secretion (7), and the release of ACTH and TSH is governed by separate hypothalamic signals (8,9). Thus, under physiologic conditions in humans, there is no functionally important feedback of cortisol on circadian TSH secretion, even though serum cortisol concentrations are lowest when serum TSH concentrations are highest in the late evening. On the other hand, moderate to high doses of glucocorticoids inhibit thyrotropin-releasing hormone (TRH)-induced TSH secretion and reduce mean 24-hour serum TSH concentrations and the nocturnal surge in TSH secretion. Patients with Cushing's syndrome have similar changes in TSH secretion (10). These changes are caused by a decrease in TSH pulse amplitude. TSH secretion returns to normal after the glucocorticoid is discontinued or Cushing's syndrome is treated; however, TSH secretion partially escapes from suppression during long-term glucocorticoid exposure so that hypothyroidism does not occur (11). The actions of glucocorticoids that affect TSH secretion occur at the level of both the hypothalamus and the pituitary (11,12).


In animals, thyrotoxicosis causes adrenocortical enlargement, but it does not occur in hypophysectomized animals given thyroid hormone, indicating that the effect of thyroid hormone is indirect. In early studies of patients with thyrotoxicosis, urinary 17-ketosteroid excretion was usually low and 17-hydroxycorticosteroid excretion was slightly high; both were low in patients in patients with hypothyroidism. Subsequent studies revealed that the metabolism of cortisol and other steroids is accelerated in thyrotoxicosis and slowed in hypothyroidism (13). These metabolic abnormalities are discussed in the next section with respect to the C21 steroids cortisol and aldosterone.


Infused cortisol is cleared from the circulation at an accelerated rate in thyrotoxicosis, but not in other hypermetabolic states (13) (Fig. 37.2). The miscible pool of cortisol is normal, whereas the fractional turnover rate of the pool per unit time (metabolic clearance rate) and the secretion rate are increased (14); the latter occurs as a result of an increase in the number of cortisol secretory episodes. The raised cortisol secretion rate accounts for the increase in urinary 17-hydroxycorticoid excretion. These abnormalities are corrected after restoration of a euthyroid state by appropriate treatment (13). In hypothyroidism, the opposite changes occur, again with a normal cortisol pool size (Fig. 37.2); the reduced cortisol secretion rate is concordant with low urinary 17-hydroxycorticoid excretion, and treatment with thyroid hormone restores cortisol metabolism to normal (13).

In thyrotoxicosis, the normal pool of cortisol may be regarded as concordant with the normal serum cortisol concentrations. Serum corticosteroid-binding globulin concentrations are also normal, indicating that serum free cortisol concentrations should be normal. The latter is confirmed by the finding of normal urinary cortisol excretion. Therefore, thyrotoxicosis is not associated with abnormal adrenocortical function from the point of view of the peripheral tissues (13).

Thyrotoxicosis accelerates the disposal rate of endogenous or exogenous cortisol by accelerating reduction of ring A of the steroid molecule, chiefly by stimulating Δ 4,5-steroid reductase activity in hepatic microsomes; this is the rate-limiting step in hepatic degradation of glucocorticoids (Fig. 37.3). The clearance of one of these metabolites, tetrahydrocortisone, in patients with thyrotoxicosis is normal. This finding indicates that the next step in the disposal of tetrahydrocortisone (and other ring A–reduced cortisol metabolites), which is conjugation with glucuronic acid, is normal (13).

Thyrotoxicosis not only influences the overall rate of cortisol degradation but also affects its metabolism qualitatively (Fig. 37.3). It increases the fraction of cortisol metabolized to 11-keto as opposed to 11β-hydroxy compounds; the quantities of tetrahydrocortisone and cortolones rise, whereas those of tetrahydrocortisol and cortols decline (13). T4 also regulates hepatic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) mRNA and activity levels (15), although variable results have been reported in different species (16). In humans, thyrotoxicosis decreases the conversion of cortisone to cortisol (17), leading to accumulation of cortisone, which is biologically inactive (13). As a result, the ratio of tetrahydrocortisone to tetrahydrocortisol in urine is increased. Because these urinary cortisol metabolites provide an assessment of peripheral thyroid hormone action, a low or normal ratio in patients with high serum T4concentrations has been used as a marker of thyroid hormone resistance (17) (see Chapter 81). Cortisone, like cortisol, is also disposed of at an accelerated rate in thyrotoxicosis, as are corticosterone, deoxycorticosterone, aldosterone (see the next section Section 38), and most other steroids.


In patients with thyrotoxicosis, basal serum cortisol concentrations and the responses to ACTH and insulin-induced hypoglycemia are usually normal. However, in patients with severe long-standing thyrotoxicosis, low-dose ACTH testing revealed significantly lower mean increments in serum cortisol concentrations, as compared with the increments when the patients were euthyroid (18). This effect of sustained thyrotoxicosis to diminish adrenocortical reserve is unlikely to be of clinical importance. Nevertheless, in patients with thyrotoxic crisis who have hypotension, treatment with hydrocortisone is the standard of practice because of the possibility of diminished adrenal reserve (relative adrenal insufficiency) or undiagnosed concomitant Addison's disease (see Chapter 43).

The responses of counterregulatory hormones to insulin-induced hypoglycemia in thyrotoxicosis are variable; serum glucagon responses are increased, ACTH responses are slightly increased, and GH responses are blunted. Serum glucose concentrations increase more rapidly after hypoglycemia in patients with thyrotoxicosis, as compared with normal subjects, most likely due to the heightened glucagon response (19).

Basal plasma epinephrine and norepinephrine concentrations are normal or slightly reduced, respectively, in patients with thyrotoxicosis (20) (see Chapter 38). The plasma epinephrine response to insulin-induced hypoglycemia is normal, whereas that of norepinephrine is reduced, consistent with a selective action of thyroid hormones on the sympathoadrenal system (20).


In patients with thyrotoxicosis, the metabolic clearance rate of aldosterone is slightly increased, resulting in a compensatory increase in aldosterone secretion; serum concentrations of aldosterone are usually normal (13,21,22). In addition to increasing the hepatic degradation of aldosterone, thyrotoxicosis is associated with other alterations in the function of the renin–angiotensin–aldosterone system (Table 37.1). Plasma renin activity basally and in response to upright posture is increased, probably caused by increased activity of the β-adrenergic nervous system (22,23). Serum angiotensin-converting enzyme concentrations are increased (24). Finally, serum angiotensinogen concentrations are increased (25), probably as a result of increased transcription of the angiotensinogen gene or increased stability of its mRNA (26). As a result of the increase in serum angiotensinogen, the generation of angiotensin peptides is increased, because the serum concentration of angiotensinogen is near the Michaelis constant (Km) of the proteolytic activity of renin. The actions of thyroid hormone on the production of angiotensinogen may contribute to the increased plasma renin activity in thyrotoxicosis. None of these changes is of clinical importance, nor do the changes underlie the cardiovascular manifestations of thyrotoxicosis, which are dominated by heightened adrenergic activity (see Chapter 31).


Hepatic clearance of aldosterone: increased

Plasma renin activity: high

Serum angiotensin-converting enzyme activity: increased

Serum aldosterone concentrations: normala

Serum angiotensinogen concentrations: high

a Serum aldosterone concentrations: variable, probably due to varying states of sodium and potassium balance and the severity of thyrotoxicosis.

Thus, the regulation of aldosterone secretion in patients with thyrotoxicosis reflects thyroid hormone–induced alterations in hepatic steroid metabolism, and to a lesser extent independent actions on the renin–angiotensin–aldosterone system. In addition, patients with thyrotoxicosis may have low total-body potassium stores as a result of the kaliuretic effects of thyroid hormone; potassium depletion independently results in increased plasma renin activity and decreased production of aldosterone (27,28). These variables, as well as overall sodium balance and the severity of thyrotoxicosis, mean that the results of studies of the renin–angiotensin–aldosterone system are variable in patients with thyrotoxicosis. In general, plasma renin activity is increased (22,23), whereas basal serum aldosterone concentrations are normal, but they may be high or low (22,29,30). The serum aldosterone response to exogenous ACTH is normal (22,29), but the response to exogenous angiotensin II is blunted (29). The altered relationship between plasma renin activity and aldosterone secretion may reflect potassium depletion; in one study, oral potassium loading corrected the abnormalities (22). Despite these alterations, the overall function of the renin–angiotensin–aldosterone system is preserved in thyrotoxicosis, so blood pressure regulation and sodium homeostasis are nearly always normal.


Men with thyrotoxicosis have high serum estradiol concentrations, as a result of increased extraglandular conversion of androstenedione to estradiol, and some have gynecomastia (see Chapter 39). In addition, serum sex hormone–binding globulin concentrations are high, leading to increases in serum total testosterone and estradiol concentrations and concomitant decreases in the clearance rate of both steroids (31). In human hepatoma cells, the mRNA for sex hormone–binding globulin is increased by T3, suggesting that it increases expression of the gene for the binding protein (32).

The increase in hepatic Δ 4,5-steroid reductase activity that occurs in thyrotoxicosis described above extends to androgens (Fig. 37.3). The result is a shift in the pattern of testosterone and androstenedione metabolism; the formation and urinary excretion of androsterone are increased, and those of etiocholanolone are decreased (13).


1. DeNayer P, Dozin B, Vandeput Y, et al. Altered interaction between triiodothyronine and its nuclear receptors in absence of cortisol: a proposed mechanism for increased thyrotropin secretion in corticosteroid deficiency states. Eur J Clin Invest 1987; 17:106.

2. Brent GA, Harney JW, Moore DD, et al. Multihormonal regulation of the human, rat, and bovine growth hormone promoters: differential effects of 3′,5′-cyclic adenosine monophosphate, thyroid hormone, and glucocorticoids. Mol Endocrinol 1988;2: 792.

3. Brent GA. The molecular basis of thyroid hormone action. N Engl J Med 1994;331:847.

4. Williams GR, Franklyn JA, Sheppard MC. Thyroid hormone and glucocorticoid regulation of receptor and target gene mRNAs in pituitary GH3 cells. Mol Cell Endocrinol 1991;80:127.

5. Malchoff CD, Javier EC, Malchoff DM, et al. Primary cortisol resistance presenting as isosexual precocity. J Clin Endocrinol Metab 1990;70:503.

6. Iida S, Nakamura Y, Fujii H, et al. A patient with hypocortisolism and Cushing's syndrome-like manifestations: cortisol hyperreactive syndrome. J Clin Endocrinol Metab 1990;70:729.

7. Brabant A, Brabant G, Schuermeyer T, et al. The role of glucocorticoids in the regulation of thyrotropin. Acta Endocrinol (Copenh) 1989;121:95.

8. Alford FP, Baker HWG, Burger HG, et al. Temporal patterns of integrated plasma hormone levels during sleep and wakefulness. I: Thyroid-stimulating hormone, growth hormone and cortisol. J Clin Endocrinol Metab 1973;37:841.

9. Van Cauter E, Leclercq R, Vanhaelst L, et al. Simultaneous study of cortisol and TSH daily variations in normal subjects and patients with hyperadrenalcorticism. J Clin Endocrinol Metab 1974;39:645.

10. Adriaanse R, Brabant G, Endert E, et al. Pulsatile thyrotropin secretion in patients with Cushing's syndrome. Metabolism 1994; 43:782.

11. Nicoloff JT, Fisher DA, Appleman MD. The role of glucocorticoids in the regulation of thyroid function in man. J Clin Invest 1970;49:1922.

12. Wilber JF, Utiger RD. The effect of glucocorticoids on thyrotropin secretion. J Clin Invest 1969;48:2096.

13. Peterson RE. Metabolism of adrenal cortical steroids. In: Christy NP, ed. The human adrenal cortex. New York: Harper & Row, 1971:137.

14. Gallagher TF, Hellman L, Finkelstein J, et al. Hyperthyroidism and cortisol secretion in man. J Clin Endocrinol Metab 1972;34: 919.

15. Whorwood CB, Sheppard MC, Stewart PM. Tissue specific effects of thyroid hormone on 11β-hydroxysteroid dehydrogenase gene expression. J Steroid Biochem Molec Biol 1993;46(5): 539.

16. Ricketts ML, Shoesmith KJ, Hewison M, et al. Regulation of 11β-hydroxysteroid dehydrogenase type 1 in primary culture of rat and human hepatocytes. J Endocrinol 1998;156:159.

17. Taniyama M, Honma K, Ban Y. Urinary cortisol metabolites in the assessment of peripheral thyroid hormone action: application for diagnosis of resistance to thyroid hormone. Thyroid 1993;3:229.

18. Tsatsoulis A, Johnson EO, Kalogera CH, et al. The effect of thyrotoxicosis on adrenocortical reserve. Eur J Endocrinol 2000;142: 231.

19. Moghetti P, Castello R, Tosi F, et al. Glucose counterregulatory response to acute hypoglycemia in hyperthyroid human subjects. J Clin Endocrinol Metab 1994;78:169.

20. Coulombe P, Dussault JH, Walker P. Catecholamine metabolism in thyroid diseases. II. Norepinephrine secretion rate in hyperthyroidism and hypothyroidism. J Clin Endocrinol Metab 1977; 44:1185.

21. Luetscher JA Jr, Camargo CA, Cohen AP, et al. Observations on metabolism of aldosterone in man. Ann Intern Med 1963; 59:1.

22. Cain JP, Dluhy RG, Williams GH, et al. Control of aldosterone secretion in hyperthyroidism. J Clin Endocrinol Metab 1973; 36:365.

23. Resnick LM, Laragh JH. Plasma renin activity in syndromes of thyroid hormone excess and deficiency. Life Sci 1982;30:585.

24. Brent GA, Hershman JM, Reed AW, et al. Serum angiotensin-converting enzyme in severe nonthyroidal illnesses associated with low serum thyroxine concentration. Ann Intern Med 1984; 100:680.

25. Dzau VJ, Hermann HC. Hormonal regulation of angiotensinogen synthesis. Life Sci 1982;30:577.

26. Deschepper CF, Hong-Brown LQ. Hormonal regulation of the angiotensinogen gene in liver and other tissues. In: Raizada MK, Phillips MI, Sumners C. eds. Cellular and molecular biology of renin-angiotensin system. Boca Raton, FL: CRC Press, 1993: 152.

27. Dluhy RG, Underwood RH, Williams GH. Influence of dietary potassium on plasma renin activity in normal man. J Appl Physiol 1970;28:299.

28. Dluhy RG, Axelrod L, Underwood RH, et al. Studies of the control of plasma aldosterone concentration in normal man. II. Effect of dietary potassium and acute potassium infusion. J Clin Invest 1972;51:1950.

29. Kigoshi T, Kaneko M, Nakano S, et al. Aldosterone response to various stimuli in hyperthyroidism: in vivo and in vitro studies. Folia Endocrinol Jpn 1993;69:609.

30. Shigematsu S, Iwasaki T, Aizawa T, et al. Plasma atrial natriuretic peptide, plasma renin activity and aldosterone during treatment of hyperthyroidism due to Graves' disease. Horm Metab Res 1989; 21:514.

31. Ridgway EC, Longcope C, Maloof F. Metabolic clearance and blood production rates of estradiol in hyperthyroidism. J Clin Endocrinol Metab 1975;41:491.

32. Barlow JW, Crowe TC, Cowen NL, et al. Stimulation of sex hormone-binding globulin mRNA and attenuation of corticosteroid-binding globulin mRNA by triiodothyronine in human hepatoma cells. Eur J Endocrinol 1994;130:166.