HYPERTHYROIDISM DUE TO INAPPROPRIATE TSH SECRETION
Normal or even elevated serum TSH, in combination with clinical hyperthyroidism, and increased serum thyroid hormone levels, may be seen in the presence of a TSH secreting pituitary tumor or selective partial pituitary resistance to thyroid hormone.
SELECTIVE TISSUE RESISTANCE OF THE PITUITARY TO THYROID HORMONE
This syndrome is described in Chapter 16 and is probably part of the continuous spectrum of the syndromes of thyroid hormone resistance in which the resistance is predominant at the pituitary level. Since the pituitary is selectively resistant to thyroid hormone, the set-point of the pituitary, i.e. the specific TSH: thyroid hormone ratio needed to ensure normal thyroid gland activation, is set at a higher level of serum thyroid hormone concentration. The other body tissues appear more sensitive to thyroid hormones, and the clinical picture of thyrotoxicosis develops. Eye symptoms and other characteristics specific for Graves' disease are absent. This syndrome may be inherited in an autosomal dominant mode. Since there is no pituitary tumor, the ratio of TSH alpha-subunits to total TSH is less than 1, whereas in a TSH producing pituitary tumor (see below) this ratio is usually above 1.
HYPERTHYROIDISM DUE TO A TSH SECRETING PITUITARY ADENOMA
Hyperthyroidism due to a TSH secreting pituitary tumor is rare. In 1978 Tolis et al. (103) reviewed the literature and found that between 10 - 20 patients had been reported. In 1983 another review found 17 women and 16 men with hyperthyroidism due to a TSH producing pituitary tumor (104)
The criteria that are required to confirm this entity are the following. The patient is clinically thyrotoxic while serum levels of free T4 and/or free T3 are elevated and serum TSH concentration is normal or increased. Visualization of the pituitary by magnetic resonance imaging shows a pituitary tumor. The concentration of TSH alpha -subunits in blood is above normal, as is the ratio of TSHalpha /TSH (104a). Pituitary TSH adenoma produce normal forms of TSH but secrete them in variable amount and differing biological activity, explaining the variable degree of hyperthyroidism in these patients (104b) In a study of 9 patients it was found that the mean delay to a correct diagnosis was 6.2 years1(06) Seven of these patients were wrongly treated for presumed primary hyperthyroidism with either thionamides, radioactive iodine or even by thyroidectomy, prior to the final diagnosis. Although in principle this thyrotoxicosis is not accompanied by eyesigns, unilateral exophthalmos may ensue from a thyrotropin secreting pituitary tumor due to invasion of one orbit (107).
When the diagnosis is established, patients should have treatment of the pituitary tumor. This usually consists of surgery plus external radiation. This approach however is not always successful (107). A relapse was seen in 4 of 5 operated and postoperatively irradiated patients during follow-up of 3.5 - 6 years. Another report (108) described a relapse in all 4 similarly treated patients. When the tumor is a macroadenoma, its behavior tends to be aggressive. The prognosis is better in patients with microadenomas(106). Better results with macroadenomas were reported by Smallridge and Smith (104). All patients had large adenomas. Eight out of 9 were cured by surgery plus external radiation, whereas 8 of 16 were cured by surgery alone and 1 out of 4 by radiation alone. Normalization of the elevated biologic to immunologic ratio of serum TSH after operation points to successful treatment of the adenoma (106). From these results a combination therapy consisting of surgery and irradiation seems imperative, at least in TSH-producing macroadenomas. As these tumors may become invasive early treatment is advised.
Administration of dopamine agonists or of somatostatin analogues are useful to shrink the tumor and in surgical failures (104a,109-113). The slow release formulation of the somatostatin analog lanreotide has recently been used in treating a series of 18 patients with pituitary thyrotropin secreting adenomas which had induced hyperthyroidism. In all cases with two or three monthly injections, there was control of hyperthyroidism with mild side effects such as abdominal cramps and diarrhea. There was no significant change in adenoma size. The lanreotide in this formulation appears to be an effective medical therapy for TSH-secreting adenomas. (113a) Long term treatment with lanreotide and cabergoline has also been successful (113b).
Autosomal dominantly inherited non-autoimmune hyperthyroidism was originally described by Duprez et al (114). In 2 kindred's activating germline mutations, Val 509 Ala and Cys 672 Tyr respectively, involving the third and seventh transmembrane segment of the thyrotropin receptor, were found. A third mutation (Phe 631 Leu) was described in a similar patient with congenital hyperthyroidism (114a). Since this was not found in parental DNA, it represented a neo mutation. 114b When mutant receptor gene constructs were transfected into COS cells, constitutive cAMP accumulation was observed (114,114a). Several other gain of function mutations have been recognized, all localized in exon 10 which encodes for the entire trans-membrane region of the TSH receptor. Recently a germline mutations in the extra-cellular portion of the TSH receptor were found to cause congenital hyperthyroidism (114b,114c). It is noteworthy that similar, but somatic, mutations are found in toxic adenoma tissue (see section "toxic adenoma" this chapter). The syndrome is fully discussed in Chapter 16a.
