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

58.The Pituitary in Hypothyroidism

Peter J. Snyder

Hypothyroidism affects the secretion of all pituitary hormones. This chapter discusses the effects of hypothyroidism on the secretion of growth hormone (GH) and prolactin as well as the clinical consequences of these effects. The effects of hypothyroidism on the secretion of vasopressin, corticotropin, and follicle-stimulating hormone and luteinizing hormone are discussed elsewhere (see Chapters 55, 59, and 61, respectively).

GROWTH HORMONE

Clinical Features

Suspicion that hypothyroidism decreases GH secretion is based on the dramatic retardation of growth that occurs in children with hypothyroidism (see Chapter 75), followed by the equally dramatic increase in growth when they are treated with thyroid hormone. The degree of growth retardation, which may be severe, is accompanied by a corresponding decrease in bone age.

The growth curve of a child who has hypothyroidism (Fig. 58.1) is characterized by normal growth until onset of the hypothyroidism, then abrupt cessation of growth, and rapid catch-up growth after initiation of thyroid hormone replacement therapy. The final height may be normal, especially if treatment is begun before the anticipated age of puberty. Final height may be less than normal, however, if treatment is not begun until after the anticipated age of puberty because secretion of gonadal steroids, which increases after correction of the hypothyroidism, may cause epiphyseal closure before catch-up growth can occur.

FIGURE 58.1. The growth curve of a boy found to have primary hypothyroidism at age 11.5 years. Growth virtually ceased after age 9 years until the diagnosis was made. After treatment was initiated (arrow), growth resumed at an accelerated rate. To convert the serum thyroxine (T4) value to nM, multiply by 12.9. (Courtesy of Dr. Thomas Moshang, Children's Hospital of Philadelphia.)

Hormonal Abnormalities

The growth retardation caused by hypothyroidism appears to result from deficient secretion of GH as well as from impaired action of GH. Many but not all children with hypothyroidism have subnormal serum GH responses to insulin-induced hypoglycemia and arginine (1,2,3), and not all of those who have impaired responses have an increase in GH secretion after treatment with thyroid hormone.

Spontaneous GH secretion is usually greatest at night, especially during stages 3 and 4 of sleep, in normal children and young adults; therefore, it seems especially important that in a study of nocturnal serum GH concentrations in seven children with primary hypothyroidism, all had higher values after they were treated with thyroxine (T4) and were euthyroid; the mean serum GH concentration in the group increased more than twofold (4). The nocturnal pattern of GH secretion in one of the patients before and during thyroid hormone treatment is shown in Figure 58.2. The serum GH response to growth hormone–releasing hormone (GHRH) in two groups of hypothyroid adults increased twofold to threefold after treatment with thyroid hormone (5,6).

FIGURE 58.2. The nocturnal pattern of growth hormone secretion in a patient with primary hypothyroidism before (A) and during (B) treatment with thyroid hormone. The serum thyroxine (T4) and insulin-like growth factor-1 (IGF-1) concentrations at these times were 1.7 µg/dL and 0.11 U/mL and 9.9 µg/dL and 0.46 U/mL, respectively. To convert the serum T4 values to nM, multiply by 12.9. (From Chernausek SD, Turner R. Attenuation of spontaneous, noctural growth hormone secretion in children with hypothyroidism and its correlation with plasma insulin-like growth factor-1 concentrations. J Pediatr 1989; 114:968, with permission.)

The mechanism by which impaired GH secretion impairs growth in hypothyroidism is likely decreased production of insulin-like growth factor-1 (IGF-1). Normally, GH stimulates skeletal growth because it increases the production of IGF-1 by the liver and other tissues. Thyroid hormone treatment of three groups of patients, including both adults and children, with hypothyroidism increased the serum IGF-1 concentrations in each group twofold to fourfold (4,5,7). When six of the untreated hypothyroid patients in one group were given a single injection of GH, their serum IGF-1 concentrations increased fourfold (7). This increase suggests that hypothyroidism does not impair IGF-1 responsiveness to GH. By exclusion, these results suggest that decreased IGF-1 secretion results from decreased GH secretion, a conclusion corroborated by the decreased nocturnal serum GH concentrations in hypothyroid patients described previously (4).

Decreased GH secretion in hypothyroidism probably results from a direct effect of thyroid hormone deficiency on the pituitary somatotrophs and perhaps also from an effect on hypothalamic GHRH secretion. The marked improvement in GH responsiveness to GHRH administration when hypothyroid adults were treated with thyroid hormone (6) suggests that thyroid hormone directly affects GH secretion by the pituitary. The molecular mechanism by which thyroid hormone permits normal GH secretion is not clear, especially in humans. Although triiodothyronine (T3) increases the expression of the promoter region of the rat GH gene after transfection of rat pituitary tumor cells, it does not increase expression of the promoter region of the human GH gene when it is similarly transfected (8). This effect of T3 requires the presence of the transcription factor Pit1, which is expressed in somatotroph cells; without it, T3 inhibits the promoter (9).

The effect of thyroid hormone on GHRH secretion has not been studied in humans, but it has been studied in rats. Hypothyroidism in rats decreases the hypothalamic content of GHRH, but it increases GHRH messenger RNA content and GHRH release in vitro (10,11). These abnormalities are restored to normal by thyroid hormone and also by GH treatment, suggesting that the abnormal GHRH secretion in hypothyroidism is the result, not the cause, of decreased GH secretion. The effect of hypothyroidism on hypothalamic somatostatin has not been studied.

Hypothyroidism also impairs growth by impairing the response of cartilage to IGF-1. Administration of GH to children with hypothyroidism does not stimulate growth, even though serum IGF-1 concentrations increase. When cartilage is incubated in vitro, the addition of T3 to the incubation medium is necessary for the full effect of IGF-1. The diminished response of cartilage to GH also could be related to diminished GH receptors on cartilage cells, because the serum concentrations of GH-binding protein, which is the extracellular domain of the GH receptor, are less than normal in hypothyroidism and increase during treatment with thyroid hormone (12,13). Hypothyroidism, in summary, impairs growth by impairing the secretion of GH, which results in decreased IGF-1 secretion by the liver, as well as by impairing the response of cartilage to IGF-1 and possibly GH.

PROLACTIN

Clinical Features

Galactorrhea is the only clinical manifestation of the effect of hypothyroidism on prolactin secretion, although even this does not occur often. Galactorrhea occurred in about 5% of cases in three series of patients with hypothyroidism comprising 56 to 235 patients, but it did not occur in any of 1,005 patients in a fourth series (14). One factor that appears to influence which hypothyroid patients develop galactorrhea is the duration of their hypothyroidism. In one study, galactorrhea occurred in 7 of 27 women who had spontaneous hypothyroidism for an estimated mean duration of 72 months, but in none of 16 women who had iatrogenic hypothyroidism for an estimated mean duration of 7 months (15).

When galactorrhea occurs in patients with long-standing primary hypothyroidism who also have sellar enlargement attributable to thyrotroph hyperplasia, a prolactin-secreting adenoma may be diagnosed erroneously. This misdiagnosis has been reported in women who presented with amenorrhea and galactorrhea and had serum prolactin concentrations of 35 to 85 ng/mL. These values are compatible with small prolactin-secreting adenomas, which are what the women were thought to have when modest enlargement of their pituitary gland was seen by imaging (16,17). The true diagnosis, severe primary hypothyroidism causing pituitary enlargement as a result of thyrotroph hyperplasia and simultaneously causing hyperprolactinemia, was made in each of these women only when their serum T4 concentrations were found to be extremely low and their serum thyrotropin (TSH) concentrations quite high. The diagnosis was confirmed when treatment with T4 alone decreased the serum concentrations of TSH and prolactin and decreased the size of the pituitary gland to normal (Fig. 58.3).

FIGURE 58.3. A: An enlarged pituitary gland in a 24-year-old woman who presented with amenorrhea and galactorrhea and was found to have primary hypothyroidism and hyperprolactinemia. B: After treatment with thyroxine (T4) for 2 months, the patient's pituitary gland was no longer enlarged, and her serum thyrotropin concentration was normal. (From Groff TR, Shulkin BL, Utiger RD, et al. Amenorrhea-galactorrhea, hyperprolactinemia, and suprasellar pituitary enlargment as presenting features of primary hypothyroidism. Obstet Gynecol 1984;63 (suppl):86, with permission.)

Hormonal Abnormalities

The mechanism by which galactorrhea occurs in patients with hypothyroidism most likely is hyperprolactinemia, which is also the mechanism by which other causes of galactorrhea occur. When serum prolactin concentrations were measured in unselected patients with primary hypothyroidism, the values were normal in most patients but mildly supranormal in a few (18,19,20). In patients, nearly all of whom were women, with galactorrhea thought to be caused by hypothyroidism, values were normal to mildly supranormal (21,22,23). Even when the serum prolactin concentrations in hypothyroidism are supranormal, however, they are usually less than 100 ng/mL, and so a higher value should raise the suspicion of a prolactin-secreting adenoma. In one study of serum prolactin concentrations in hypothyroid men, the values were normal in magnitude, pulsatility, and circadian pattern (24), suggesting that hypothyroidism alone is not sufficient to cause hyperprolactinemia; rather, another stimulus, such as estrogen, is required. The strongest evidence for concluding that hypothyroidism is the cause of the hyperprolactinemia in patients who have both hypothyroidism and hyperprolactinemia is that their serum prolactin concentrations decline to normal when they are treated with thyroid hormone (14,16,17,25,26) (Fig. 58.4).

FIGURE 58.4. Serum prolactin (PRL) and thyrotropin (TSH) concentrations in a woman who presented with galactorrhea and primary hypothyroidism. When she was treated with triiodothyronine (T3), her serum prolactin and TSH concentrations decreased, and the galactorrhea disappeared. When treatment was discontinued, serum PRL and TSH concentrations both increased again. When treatment was resumed, both declined again. (From Onishi T, Miyai K, Aono T, et al. Primary hypothyroidism and galactorrhea. Am J Med 1977;63:373, with permission.)

The mechanism by which hypothyroidism causes hyperprolactinemia is not known, but it is probably due to a direct effect on the pituitary gland. Patients who are hypothyroid have greater than normal serum prolactin responses to thyrotropin-releasing hormone (TRH), and the responses decrease to normal during thyroid hormone therapy (18,19). The molecular mechanism by which thyroid hormone inhibits prolactin secretion may involve interaction with both activating and inhibitory elements in the proximal promoter region of the prolactin gene (27). Thyroid hormone may also influence prolactin secretion through an effect on TRH secretion, because T3 decreases the expression of the messenger RNA for the TRH precursor in the hypothalamus (28).

REFERENCES

1. Katz HP, Youltan R, Kaplan SL, et al. Growth and growth hormone. III. Growth hormone release in children with primary hypothyroidism and thyrotoxicosis. J Clin Endocrinol Metab 1969; 29:346.

2. MacGillivray MH, Aceto T, Frohman LA. Plasma growth hormone responses and growth retardation in hypothyroidism. Am J Dis Child 1968;115:273.

3. Root AW, Rosenfeld RL, Bongiovanni AM, et al. The plasma growth hormone response to insulin-induced hypoglycemia in children with retardation of growth. Pediatrics 1967;39:844.

4. Chernausek SD, Turner R. Attenuation of spontaneous, nocturnal growth hormone secretion in children with hypothyroidism and its correlation with plasma insulin-like growth factor I concentrations. Pediatrics 1989;114:968.

5. Valcavi R, Dieguez C, Preece M, et al. Effect of thyroxine replacement therapy on plasma insulin-like growth factor I levels and growth hormone responses to growth hormone releasing factor in hypothyroid patients. Clin Endocrinol (Oxf) 1987;27: 85.

6. Williams T, Maxon H, Thorner MO, et al. Blunted growth hormone (GH) response to GH-releasing hormone in hypothyroidism resolves in the euthyroid state. J Clin Endocrinol Metab 1985;61:454.

7. Chernausek SD, Underwood LE, Utiger RD, et al. Growth hormone secretion and plasma somatomedin-C in primary hypothyroidism. Clin Endocrinol (Oxf) 1983;19:337.

8. 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.

9. Palamino T, Barettino D, Aranda A. Role of GHF-1 in the regulation of the rat growth hormone gene promoter by thyroid hormone and retinoic acid receptors. J Biol Chem 1998;273: 27541.

10. Katakami H, Downs TR, Frohman LA. Decreased hypothalamic growth hormone-releasing hormone content and pituitary responsiveness in hypothyroidism. J Clin Invest 1987;77:1704.

11. Downs TR, Chomczynski P, Frohman LA. Effects of thyroid hormone deficiency and replacement on rat hypothalamic growth hormone (GH)–releasing hormone gene expression in vivo are mediated by GH. Mol Endocrinol 1990;4:402.

12. Amit T, Hertz P, Ish-Shalom S, et al. Effects of hypo- or hyperthyroidism on growth hormone-binding protein. Clin Endocrinol (Oxf) 1991;35:159.

 

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-binding proteins. J Clin Endocrinol Metab 1993;76:950.

14. Raber W, Gessi A, Nowotny P, et al. Hyperprolactinemia in hypothyroidism: clinical significance and impact of TSH normalization. Clin Endocrinol (Oxf) 2003;58:185.

15. Contreras P, Generini G, Michelsen H, et al. Hyperprolactinemia and galactorrhea: spontaneous versus iatrogenic hypothyroidism. J Clin Endocrinol Metab 1981;53:1036.

16. Groff TR, Shulkin BL, Utiger RD, et al. Amenorrhea-galactorrhea, hyperprolactinemia, and suprasellar pituitary enlargement as presenting features of primary hypothyroidism. Obstet Gynecol 1984;63:865.

17. Grubb MR, Chakeres D, Malarkey WB. Patients with primary hypothyroidism presenting as prolactinomas. Am J Med 1987; 83:765.

18. Refetoff S, Fang VS, Rapoport B, et al. Interrelationships in the regulation of TSH and prolactin secretion: effects of L-dopa, TRH and thyroid hormone in various combinations. J Clin Endocrinol Metab 1974;38:450.

19. 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.

20. Honbo KS, Van Herle AJ, Kellett KA. Serum prolactin levels in untreated primary hypothyroidism. Am J Med 1978;64:782.

21. Gomez F, Reyes Fl, Faiman C. Nonpuerperal galactorrhea and hyperprolactinemia. Am J Med 1977;62:648.

22. Kleinberg DL, Noel GL, Frantz AG. Galactorrhea: a study of 235 cases, including 48 with pituitary tumors. N Engl J Med 1977;296:589.

23. Tolis G, Somma M, Van Campenhout J, et al. Prolactin secretion in sixty-five patients with galactorrhea. Am J Obstet Gynecol 1974;118:91.

24. Iranmanesh A, Lizarralde G, Veldhuis JD. Robustness of the male lactotropic axis to the hyperprolactinemic stimulus of primary thyroidal failure. J Clin Endocrinol Metab 1992;74:559.

25. Boroditsky RS, Faiman C. Galactorrhea-amenorrhea due to primary hypothyroidism. Am J Obstet Gynecol 1973;116:661.

26. Onishi T, Miyai K, Aono T, et al. Primary hypothyroidism and galactorrhea. Am J Med 1977;63:373.

27. 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.

28. Dyess EM, Segerson TP, Liposits Z, et al. Triiodothyronine exerts direct cell-specific regulation of thyrotropin releasing hormone gene expression in the hypothalamic paraventricular nucleus. Endocrinology 1988;123:2291.