Peter J. Snyder
Thyrotoxicosis affects the secretion of most pituitary hormones, but because the clinical consequences are not so great as are those in hypothyroidism, the abnormalities of pituitary hormone secretion have not been studied as well as those in hypothyroidism. The effects of thyrotoxicosis on the secretion of growth hormone (GH) and prolactin are discussed in this chapter; the effects on the secretion of vasopressin, corticotropin, and follicle-stimulating hormone and luteinizing hormone are discussed elsewhere (see Chapters 33,37 and 39, respectively).
GROWTH HORMONE
Clinical Manifestations
Children with thyrotoxicosis may grow more rapidly than normal children. In one study of five children studied before and during antithyroid treatment, the height ages were all more than 3 standard deviations (SD) above the mean for normal children (1). The children's bone ages also were accelerated and to a similar degree; the relationship of bone age to height age remained normal. Consequently, when the children were treated, it appeared that their final heights would be normal.
Hormonal Abnormalities
Growth acceleration in children with thyrotoxicosis suggests that their GH secretion might be greater than normal. In one study of adults, both the production rate and metabolic clearance rate of GH were higher in thyrotoxic patients and lower in hypothyroid patients than in normal subjects (2). In eight patients with thyrotoxicosis, the mean (± SD) GH production rate was 529±242 ng/min, as compared with 347±173 ng/min in 22 normal subjects and 160±69 ng/min in six patients with hypothyroidism. Serum GH concentrations, however, are lower in thyrotoxic patients than in normal subjects. This decrease is not due to a lower serum concentration of GH-binding protein, because the concentrations were similar in 15 thyrotoxic patients and 19 normal subjects (3). Serum GH concentrations increase in response to deep sleep to a lesser degree in thyrotoxic children and adolescents than in normal subjects and increase when patients are treated with propylthiouracil (4) (Fig. 36.1). Likewise, the increase in serum GH concentrations in response to insulin-induced hypoglycemia is less in thyrotoxic children and adults than in normal subjects (5,6,7), especially in those with severe thyrotoxicosis (6). The serum GH response to growth hormone releasing hormone (GH-RH) also is less than normal in thyrotoxic patients, and it increases during antithyroid treatment (8,9), suggesting that the increased GH production rate is not due to increased stimulation by GH-RH.
FIGURE 36.1. Serum GH concentrations during stages III and IV of sleep in a patient when thyrotoxic (A) and later after treatment when euthyroid (B). (From Sasaki N, Tsuyusaki T, Nakamura H, et al. Sleep-related growth hormone release in thyrotoxic patients before and during propylthiouracil therapy. Endocrinol Jpn 1985;32:39, with permission.)
The low serum GH concentrations, despite the increased production rate, are probably the result of the increased metabolic clearance rate (2). In fact, studies of GH secretion in seven thyrotoxic patients, based on measurements of serum GH concentrations at 10-minute intervals for 24 hours and deconvolution analysis (which removes the effect of metabolic clearance mathematically), revealed more frequent GH secretory bursts, a larger mass of GH released per burst, and a fourfold higher GH production rate than in seven normal subjects (10). Because GH secretion is greater than normal in thyrotoxicosis, the increase in linear growth in thyrotoxic children could be a GH effect. Thyroid hormone appears to act directly on somatotroph cells to stimulate GH secretion. In rats, triiodothyronine (T3) activates the promoter region of the GH gene (11), an action that requires the expression of the transcription factor Pit-1 (12).
The finding of higher than normal serum insulin-like growth factor-1 concentrations in thyrotoxic patients [mean (±SD) 259±34 µg/L] and a decrease to normal (189±15 µg/L) during antithyroid drug treatment (13) suggests that there is a greater than normal effect of GH in thyrotoxicosis. These results do not, however, exclude the possibility that increased linear growth in thyrotoxicosis could be due at least partly to a direct effect of thyroid hormone on bone.
PROLACTIN
Clinical Manifestations
Galactorrhea is a manifestation of hypothyroidism, and therefore one might expect that difficulty in lactation would occur in postpartum women with thyrotoxicosis who attempt to nurse; however, this has not been reported, and it seems likely that prolactin secretion and serum prolactin concentrations in women with thyrotoxicosis are sufficient for normal lactation. In addition, postpartum thyroiditis, the most common cause of thyrotoxicosis at this time, usually begins several months after delivery and is mild and transient (see Chapter 27). Women with thyrotoxicosis who need antithyroid drug treatment can nurse their infants safely (see Chapter 45).
Hormonal Abnormalities
Secretion of prolactin in thyrotoxicosis is similar to that of GH in that the production rate and metabolic clearance rate are somewhat greater than normal, but serum prolactin concentrations are less than normal. In one study, the mean (±SD) production rate of prolactin in six patients with thyrotoxicosis was 504±91 µg/day and in six normal subjects was 367±144 µg/day (14). Not only are basal serum prolactin concentrations slightly lower in thyrotoxic patients, but so too are their serum prolactin responses to thyrotropin-releasing hormone (Fig. 36.2). Both basal and stimulated serum prolactin concentrations return to normal when the patients are treated (15) (Fig. 36.2). The serum prolactin response to arginine is also decreased in both women and men with thyrotoxicosis (16). The mechanism by which thyroid hormone suppresses prolactin secretion may involve an interaction with the activating response element and an inhibitory element on the promoter region of the human prolactin gene (17). So far, no physiologic or clinical consequences of these abnormalities are known.
FIGURE 36.2. Mean (±5E) serum prolactin responses to thyrotropin-releasing hormone (TRH) in 10 patients when they were thyrotoxic (•, before treatment) and when they were euthyroid (○, during treatment). (From Snyder PJ, Jacobs LS, Utiger RD, Daughaday WH. Thyroid hormone inhibition of the prolactin response to thyrotropin-releasing hormone. J Clin Invest 1973;52:2324, with permission.)
REFERENCES
1. Schlesinger S, MacGillivray MH, Munschauer RW. Acceleration of growth and bone maturation in childhood thyrotoxicosis. Pediatrics 1973;83:233.
2. Taylor AL, Finster JL, Mintz DH. Metabolic clearance and production rates of human growth hormone. J Clin Invest 1969; 48:2349.
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4. Sasaki N, Tsuyusaki T, Nakamura H, et al. Sleep-related growth hormone release in thyrotoxic patients before and during propylthiouracil therapy. Endocrinol Jpn 1985;32:39.
5. Burgess JA, Smith BR, Merimee TJ. Growth hormone in thyrotoxicosis: effect of insulin-induced hypoglycemia. J Clin Endocrinol 1966;26:1257.
6. Giustina G, Reschini E, Valentini F, et al. Growth hormone and cortisol responses to insulin-induced hypoglycemia in thyrotoxicosis. J Clin Endocrinol 1971;32:571.
7. Katz HP, Youlton R, Kaplan SL, et al. Growth and growth hormone. III. Growth hormone release in children with primary hypothyroidism and thyrotoxicosis. J Clin Endocrinol 1969;29: 346.
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10. Iranmanesh A, Lizarralde G, Johnson ML, et al. Nature of altered growth hormone secretion in hyperthyroidism. J Clin Endocrinol Metab 1991;72:108.
11. 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.
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13. Miell JP, Taylor AM, Zini M, et al. Effects of hypothyroidism and hyperthyroidism on insulin-like growth factors (IGFs) and growth hormone- and IGF-proteins. J Clin Endocrinol Metab 1993;76:950.
14. Cooper DS, Ridgway EC, Kliman B, et al. Metabolic clearance and production rates of prolactin in man. J Clin Invest 1979;64: 1669.
15. Snyder PJ, Jacobs LS, Utiger RD, et al. Thyroid hormone inhibition of the prolactin response to thyrotropin-releasing hormone. J Clin Invest 1973;52:2324.
16. Ciccarelli D, Zini M, Grottoli S, et al. Impaired prolactin response to arginine in patients with hyperthyroidism. Clin Endocrinol 1994;41:371.
17. Pernasetti F, Cacavelli L, Van der Weerdt C, et al. Thyroid hormone inhibits the human prolactin gene promoter by interfering with activating protein-1 and estrogen stimulations. Mol Endocrinol 1997;11:986.