Thyrotoxicosis in Pregnancy

Due to the intrinsic TSH-like activity of human chorionic gonadotrophin (hCG), many healthy euthyroid pregnant women have reduced serum TSH values. Gestational transient thyrotoxicosis (i.e. increased serum free T4 and subnormal TSH) is seen in 1.4 % of pregnant women, mostly when hCG levels are above 70-80,000 IU/l (57). In one recently reported case, thyrotoxicosis was related to a TSH-R mutation increasing its responsiveness to hCG (57a). Thyrotoxicosis and other thyroid diseases during or after pregnancy are discussed in Chapter 14.

Thyrotoxicosis may be induced by hCG stimulation during molar pregnancy and also by trophoblastic tumors in males and in females. hCG is composed of an alpha -subunit, identical to the alpha -subunit in pituitary glycoprotein hormones such as LH, FSH and TSH, and a ß- subunit which is specific for hCG. There is structural homology with the ß-subunit of TSH. However, the ß-hCG unit is larger in that it is composed of 147 aminoacids while that of TSH consists of 110 aminoacids, and has additional carbohydrate residues on the COOH terminus.

TSH like activity of hCG: Weak thyrotropic activity of hCG was found in hCG prepared from pregnancy urine, using a mouse thyrotropin bioassay (58). In another study (59) hCG was purified from molar tissue and had intrinsic TSH bioactivity in the mouse bioassay, although 4000 times less than that of human TSH on a molar basis. Despite this weak activity in hydatidiform mole disease, hCG is produced in sufficient amounts to induce hyperthyroidism. In a study of 20 patients (60) with gestational trophoblastic neoplasia 2 patients were judged to be overtly thyrotoxic, and this was confirmed by elevated serum T4 levels. These 2 patients had extremely high serum (3,220,000 IU/l and 6,720,000 IU/l) and urine hCG levels which correlated closely with TSH-like activity exerted by the serum of these patients in a mouse thyroid bioassay. Patients with moderately (110,000 - 310,000 IU/l) increased serum hCG levels due to trophoblastic neoplasia were euthyroid. In studies using thyroids from different species to test for hCG intrinsic TSH activity, it was found that the mouse thyroid was much more sensitive to stimulation by hCG, whereas the human thyroid was relatively insensitive (61). In another study on the activity of hCG on the human thyroid gland (62), 1.0 IU hCG was found roughly equivalent to 0.27 m IU hTSH. hLH also has intrinsic thyroid stimulating activity, but lower than hCG. 1.0 IU hLH was found equivalent to 44 m IU hTSH. This lower potency of hCG is caused by the C-terminal extension of the ß-subunit that interferes with its binding to the receptor. This extension is lacking in the ß-subunit of hLH, its structure being otherwise almost identical to that of hCG. (63) Carboxy peptidase digestion of hCG, cleaving aminoacid residues 142-145 from the ß-subunit, leads to a dramatic increase in its capacity to stimulate adenylate cyclase in human thyroid membranes (64). A variant of hCG, lacking the C-terminus of the ß-subunit due to enzymatic cleavage has been identified in pregnancy serum and molar tissue (65). Human hCG not only stimulated the mouse thyroid but also displaced human TSH from the plasma membrane receptor of follicular cells (61,62,66). In studies using human thyroid membranes 67 or a cell line transfected with the human TSH receptor (68), desialylated forms of human hCG exhibited stronger inhibition of TSH mediated cAMP responses than native hCG. Both TSH binding, and TSH induced adenylate cyclase stimulation were found more effectively inhibited by desialylated variants of hCG than unmodified hCG (69) From these and other studies it seems that the biological effect of hCG is predominantly confined to hCG containing little or no sialic acid. hCG has also been found to increase iodide uptake in cultured FRTL-5 cells and also causes a dose related increment of adenylate cyclase activity and thymidine uptake (70,71).

In 1955 Tisné and co-workers described a patient with molar pregnancy that had increased thyroidal uptake of radioactive iodine and clinical signs of hyperthyroidism (cited by Hershman and Higgins(72). Earlier reports (73-76) also described molar pregnancy in combination with hyperthyroidism and in all cases a rapid return to normal thyroid function occurred after removal of the mole. The effect of removal of molar tissue on serum T4, serum T3, bioassayable TSH, and hCG (by immunoassay) is shown in Figure 13-8 (below) (77). The patient was pre-treated with iodide. After removal of the tumor there was a rapid normalization of serum T4, T3, serum TSH, and hCG. From the parallelism of thyroid stimulating and hCG activity it was concluded that the same molecule, i.e. hCG, possessed both gonadotrophic and thyrotropic activity. In a later study (72), 2 patients with hydatidiform mole were described with severe hyperthyroidism and rapid disappearance of hyperthyroidism after removal of the mole. The youngest patient described so far was 17years of age (72a) A thyroid stimulator was extracted from the serum of one patient that differed biologically and immunologically from TSH, from hCG found in normal placentas and from thyroid stimulating immunoglobulins. The conclusion that the molar thyrotropin differed from normal placenta hCG was based on differences in antigenic properties and molecular size. hCG extracted from hydatidiform moles contained less sialic acid and was biologically more active than normal pregnancy hCG(78). In Figure 13-9 (below) the relationship is shown between bioassayable TSH and serum T3 values in patients with molar pregnancy. In this study with the exception of one patient, there is a very high correlation between the two parameters, suggesting a causal relationship between serum thyrotropin activity and thyroid function. A similar correlation between serum hCG levels and thyroid stimulating activity in both serum and urine was found in two women who had widely metastatic choriocarcinoma and marked hyperthyroidism (60). In another patient with gestational choriocarcinoma serum thyroid stimulating activity correlated precisely with serum T4, with the ß- subunit of human hCG, and with the quantitation of the host tumor burden (79). Sera from five patients with hydatidiform mole before treatment showed increased stimulating activity in CHO-hTSHR cells that decreased promptly after evacuation of the tumor (79a).

Figure 13-8. The effect of 1 g of sodium iodide (NAI) and surgical removal of the molar tissue (O.R.) on the circulating levels of serum T4, T3, hCG (immunoassay) and TSH (bioassay) in a patient with hydatidiform mole induced thyrotoxicosis (taken from ref. 77, with permission).

Figure 13-9. Relationship between T3 serum levels and bioassayable serum TSH activity in 9 patients with hydatidiform mole induced thyrotoxocosis. The correlation coefficient for 8 patients (except x) is 0.94 (taken from ref. 77, with permission).

The clinical syndrome of hyperthyroidism associated with choriocarcinoma in the male is extremely rare, but several reports have appeared in the literature. Orgiazzi et al. (80) cite four cases from the literature and reported a patient who had choriocarcinoma of the colon associated with gynecomastia and hyperthyroidism. Thyroid stimulating activity, measured by mouse bioassay, was detected in the serum. Serum thyroid stimulating activity was partly inactivated by antibovine-TSH antiserum, but was completely neutralized by anti-hCG antiserum. The clinical picture of patients with trophoblastic hyperthyroidism is that of thyrotoxicosis, lacking the characteristic features belonging to Graves' disease (ophthalmic disease, pretibial myxedema and acropachy). hCG-levels are mostly above 300,000 U/l. The thyrotoxicosis is usually not severe because of its shorter duration. (For review see also 80a)

Obviously, removal of the tumor, if feasible, should be carried out as soon as possible. Treatment with antithyroid drugs does not produce euthyroidism rapidly, and patients are therefore also treated preoperatively with oral sodium ipodate 1 g/day, or saturated potassium iodide 3 x 10 drops daily or sodium iodide 0.5 g i.v. every 8 hours. Propranolol may be added to the regimen and additional supportive therapy, replacing fluids and electrolytes, may be necessary. In patients who are not suitable for surgery because of metastatic disease, antithyroid drug treatment using propylthyiouracil or methimazole in combination with chemotherapy is the best treatment available. 131-I therapy is also possible. If hyperthyroidism is so severe that development of thyroid crisis after surgery is possible, anti-thyroid drug treatment should be combined with iodide and propranolol pre-treatment.