Jerome M. Hershman
Thyrotoxicosis occurs in patients with trophoblastic tumors, which are either hydatidiform moles or choriocarcinomas. Since the first report of thyrotoxicosis in women with a hydatidiform mole in 1955 (1), many additional cases have been reported (2,3,4,5,6,7). These reports revealed that the thyrotoxicosis disappeared rapidly after removal of the tumor, thus suggesting that the tumor produced a substance that caused the thyrotoxicosis. It is now clear that human chorionic gonadotropin (hCG) is the thyroid stimulator that causes thyrotoxicosis in patients with trophoblastic tumors.
In the United States, a hydatidiform mole occurs in about 1 in 1500 pregnancies, and is several times more common in Asian and Latin American countries. Choriocarcinoma occurs in 1 in 50,000 pregnancies in the United States and Europe; about one half of the cases occur in women with a previously diagnosed hydatidiform mole. Although thyrotoxicosis has been reported more often in women with a hydatidiform mole than in those with a choriocarcinoma, there have been many case reports of thyrotoxicosis in women with the latter (8,9,10,11), as well as in men with chorionic tumors of the testes (12,13,14).
The precise prevalence of thyrotoxicosis in patients with trophoblastic tumors is unknown. It was found in 5 of 20 women with trophoblastic tumors evaluated at a referral center in 1 year (15); 3 of these 5 women had a choriocarcinoma, and 2 had a hydatidiform mole. In another study, 30 of 52 women with gestational trophoblastic tumors were found to have thyrotoxicosis (2). In recent years, the routine use of ultrasonography during pregnancy has led to earlier diagnosis of hydatidiform moles when the tumor mass is smaller and thyrotoxicosis is less likely.
Hyperplacentosis, a rare nonneoplastic condition in which the placenta is enlarged and the serum hCG concentration is very high, may also cause thyrotoxicosis that remits promptly after delivery of the placenta (16).
GRADATIONS OF SEVERITY
In trophoblastic disease, the spectrum of alterations of thyroid function ranges from a small increase in serum free thyroxine (T4) and triiodothyronine (T3) concentrations, as evidenced by a low basal serum thyrotropin (TSH) concentration or a subnormal serum TSH response to thyrotropin-releasing hormone (TRH) (17), to moderate increases in serum free T4 and T3 concentrations with no symptoms of thyrotoxicosis, to marked increases with severe clinical thyrotoxicosis or even thyroid storm (4). The lack of clear clinical features of thyrotoxicosis in many patients with high serum free T4 and T3 concentrations may be attributable to the relatively brief duration of the increased thyroid function, so that there is insufficient time to develop overt clinical thyrotoxicosis (3,18). Also, the clinical manifestations of thyrotoxicosis may be overlooked because attention is focused on the toxemia that frequently accompanies the trophoblastic tumor. In addition, the toxemia may lower serum T3 concentrations, as occurs in patients with nonthyroidal illness (see section on nonthyroidal illness in Chapter 11). Thyrotoxic patients with trophoblastic tumors have a lower serum T3:T4 ratio than do patients with thyrotoxicosis caused by Graves' disease.
Whereas many women with trophoblastic tumors have few symptoms and signs of thyrotoxicosis, despite having high serum free T4 and T3 concentrations, others do have the typical clinical findings, including weight loss, muscle weakness, fatigue, excessive perspiration, heat intolerance, tachycardia, nervousness, and tremor. The thyroid gland is either not enlarged or only minimally enlarged; only rarely is it more than twice normal size. Ophthalmopathy is absent, in contrast with Graves' disease. In addition, there are characteristic features of the trophoblastic tumor. Abnormal vaginal bleeding during pregnancy is the usual presentation; more than 95% of women with trophoblastic tumors have uterine bleeding between the 6th and 16th week of pregnancy, and the size of the uterus is large for the duration of the gestation. Nausea, vomiting, and toxemia of pregnancy occur commonly in molar pregnancy and may obscure the symptoms and signs of thyrotoxicosis.
Most women with choriocarcinoma present within 1 year of the preceding conception. Although the tumor may be confined to the uterus, it is usually widely metastatic, involving the pelvis, liver, lungs, and even the brain. The lung metastases may cause cough, dyspnea, hemoptysis, or pleuritic pain. Cerebral metastases may cause focal neurologic signs or seizures. The diagnosis of metastatic cancer is usually obvious. As in women with a hydatidiform mole, there may be laboratory evidence of increased thyroid function without clinically evident thyrotoxicosis. In men, choriocarcinoma nearly always arises in the testes, and is usually widely metastatic (12,13,14). Gynecomastia is a common complaint in men with choriocarcinoma, although gynecomastia can occur in any man with thyrotoxicosis (see Chapter 39) (2).
Chorionic gonadotropin is secreted by both hydatidiform moles and by choriocarcinomas. Therefore, hCG serves as a marker for the tumor. For diagnosis and follow-up of these patients, serum hCG should be measured by an immunoassay that detects all the main forms of the molecule and its β-subunits. Patients with trophoblastic tumors have high serum hCG concentrations and urinary hCG excretion, with values that greatly exceed those found in normal pregnant women. In patients with trophoblastic tumors, serum hCG concentrations always exceed 100 U/mL, the peak concentration that occurs in pregnant women at 10 to 12 weeks' gestation, and they usually exceed 200 U/mL (5,10,11). Not all patients with trophoblastic tumors with high serum hCG concentrations have thyrotoxicosis, however.
The diagnosis of thyrotoxicosis, or increased thyroid function, is established by finding high serum free T4 and T3 concentrations. Trophoblastic tumors secrete less estrogen than normal placental tissue, so that the increase of serum thyroxine-binding globulin (TBG) concentrations is less in women with a molar pregnancy than in normal pregnant women (2). Thyroid radioiodine uptake is increased (3). Even when serum T4 and T3 concentrations are only slightly high, both serum TSH concentrations and serum TSH responses to TRH are low (17). TSH-receptor antibodies are not detectable, excluding Graves' disease as the cause of thyrotoxicosis in women with trophoblastic tumors.
Ultrasonography of the uterus reveals a characteristic “snowstorm” pattern in women with a hydatidiform mole, and it also provides an accurate indication of tumor volume within the uterus. The definitive diagnosis of hydatidiform mole or choriocarcinoma is based on the histopathology of the tissue removed by curettage or surgery.
Hyperemesis gravidarum is characterized by prolonged, severe nausea and vomiting in early pregnancy that lead to a loss of 5% of body weight, dehydration, and ketosis. It occurs in about 1.5% of pregnancies and is more common in Asian women than in white women. High serum free T4 and T3 concentrations are a common finding in women with hyperemesis gravidarum, having been reported in 25% to 75% of patients in various series (19,20,21,22,23,24,25,26). Women with hyperemesis and high serum free T4 and T3 concentrations have higher serum hCG concentrations than normal pregnant women (21,26). Their serum hCG concentrations correlate with the degree of elevation of serum free T4 and T3 concentrations and with serum thyroid-stimulating activity, as measured by bioassay. Vomiting is also more severe in women who have higher serum hCG concentrations, suggesting that another factor induced by hCG, perhaps estradiol, may be responsible for the vomiting (21). Although clinical features of thyrotoxicosis are usually absent, or overlooked, in women with hyperemesis gravidarum, some have clinically evident thyrotoxicosis, termed gestational thyrotoxicosis. Thyroid enlargement is rare. The thyrotoxicosis of hyperemesis gravidarum resolves spontaneously within several weeks as the vomiting disappears (19,25,27). Women with twin pregnancies have higher serum hCG concentrations than do women with singleton pregnancies, and are more likely to have hyperemesis gravidarum (28).
HUMAN CHORIONIC GONADOTROPIN
Human chorionic gonadotropin is composed of α- and β-subunits. The α-subunit is identical to the α-subunit of TSH, luteinizing hormone, and follicle-stimulating hormone. The β-subunit of hCG has considerable structural homology with the β-subunit of TSH, but it is larger because it contains a 21-amino-acid carboxy-terminal tail.
Material with thyroid-stimulating activity that has the characteristics of hCG can be extracted from hydatidiform moles and choriocarcinomas (9,29). The thyroid-stimulating activity of hCG has been demonstrated in mice, rats, chicks, and humans (29,30,31). Injection of large amounts of hCG (100,000 to 150,000 U) into normal men stimulates thyroid iodine release (30). In normal pregnant women, serum TSH concentrations decrease at 9 to 12 weeks of gestation when serum hCG concentrations are highest (see Chapter 80) (32,33,34), and 3% of pregnant women have transient subclinical thyrotoxicosis (low serum TSH and normal serum free T4 and free T3 concentrations) at that time (34). The high serum hCG concentrations correlate with increased thyroid-stimulating activity in a mouse bioassay (33). Serum thyroid-stimulating activity measured by a thyroid cell culture assay also is increased during the first trimester in normal pregnant women, and this activity was correlated with serum hCG and free T4 concentrations (35). The thyroid-stimulating activity of purified hCG is equivalent to about 0.2 µU of bovine TSH per unit of hCG in a mouse bioassay (34) and 0.04 µU bovine TSH per unit of hCG in a rat thyroid-cell bioassay (Fig. 26.1), but is equivalent to only 0.0013 µU of human TSH per unit of hCG in a human thyroid-cell bioassay (36). Nevertheless, this thyroid-stimulating activity may be substantial in patients with trophoblastic tumors, in whom serum hCG concentrations may be as high as 2,000 U/mL. Serum hCG and T3 concentrations were correlated in women with a hydatidiform mole (5), and in five women with trophoblastic thyrotoxicosis, serum hCG concentrations were correlated with serum T4, free T4, and T3 concentrations (15). The high serum concentrations of hCG in early pregnancy may worsen the thyrotoxicosis of Graves' disease (37).
FIGURE 26.1. Comparison of the effects of bovine thyrotropin (TSH) and purified human chorionic gonadotropin (hCG) on iodide uptake in cultured rat thyroid (FRTL-5) cells. Relative potencies are 1 U hCG = 0.72 µU human TSH = 0.042 µU bovine TSH. (From Hershman JM, Lee H-Y, Sugawara M, et al. Human chorionic gonadotropin stimulates iodide uptake, adenylate cyclase, and deoxyribonucleic acid synthesis in cultured rat thyroid cells. J Clin Endocrinol Metab 1988;67:74, with permission.)
The thyroid-stimulating activity of hCG has been elucidated by a variety of studies. Human chorionic gonadotropin inhibits the binding of labeled TSH to its plasma membrane receptors on thyroid follicular cells (38,39), and activates adenylyl cyclase in rat thyroid cells and cells transfected with human TSH receptors (39,40). Human chorionic gonadotropin increases iodide uptake (37) by increasing the expression of the sodium/iodide transporter on thyroid cells (41).
The hCG extracted from hydatidiform moles has greatly increased thyroid-stimulating potency, as compared with hCG extracted from normal placentas (6,42). This material is enriched in the more basic forms of the molecule that contain less sialic acid than does normal hCG (6,42). Asialo-hCG purified from a patient with choriocarcinoma had potent thyroid-stimulating activity in a bioassay that used human thyroid follicles (36). Although asialo-hCG has much greater thyroid-stimulating activity in vitro than sialylated hCG, the lack of sialic acid greatly accelerates its clearance from plasma and thus reduces its physiologic action (43). Recombinant mutant hCG lacking the carboxy-terminal tail of the β-subunit stimulates the human TSH receptor about 10-fold more potently than does intact hCG (39). Presumably, the long carboxy-terminal tail and the high sialic acid content reduce the ability of hCG to activate TSH receptors.
Although basic hCG that lacks sialic acid is more potent in vitro, women with hyperemesis gravidarum who have gestational thyrotoxicosis have high serum concentrations of acidic forms of hCG (44), and in them the acidic forms of hCG are correlated with the serum free T4 and free T3 concentrations (45). Human chorionic gonadotropin with increased sialic acid content has a longer serum half-life, which could increase its contribution to serum thyroid-stimulating activity.
MUTANT THYROID STIMULATING HORMONE–RECEPTOR
A woman with recurrent gestational thyrotoxicosis associated with hyperemesis gravidarum and a TSH-receptor mutation has been reported (46). Her mother had a similar history of hyperemesis and thyrotoxicosis during pregnancy. Study of the TSH receptor of the proband and her mother revealed an adenine to guanine substitution at codon 183 in exon 7 in one allele, resulting in substitution of arginine for lysine in the middle portion of the extracellular domain of the TSH receptor (see the section on the thyrotropin receptor in Chapter 10). The mutant TSH receptor was transfected into COS cells, and the cells were incubated with hCG. These cells were more sensitive to hCG than cells transfected with wild-type receptors, as measured by the cyclic adenosine monophosphate responses to hCG (Fig. 26.2). Thus, the gestational thyrotoxicosis in these two women was due to an exaggerated thyroid-stimulating action of hCG. No other family with a TSH receptor mutation of this type has been reported. Substitution of methionine, asparagine, or glutamine for the lysine at position 183 in the TSH receptor also increases its affinity for hCG (47).
FIGURE 26.2. Functional characteristics of the mutant thyrotropin receptor in COS cells showing the effect of stimulation of cyclic adenosine monophosphate production by graded concentrations of chorionic gonadotropin in cells transfected with wild-type or mutant TSH receptor. (From Rodien P, Bremont C, Sanson M-LR, et al. Familial gestational hyperthyroidism caused by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotropin. N Engl J Med 1998;339:1823.)
Surgical removal of the hydatidiform mole rapidly cures the thyrotoxicosis, as shown in Figure 26.3, and should be carried out as soon as possible. Other treatment of the thyrotoxicosis should be based on anticipation of the benefit of surgery. Propylthiouracil and methimazole can be given, but will have little immediate effect (see Chapter 45). Therapy with potassium iodide given orally will rapidly lower serum T4 and T3 concentrations (5). Propranolol and other β-adrenergic antagonist drugs are useful in controlling tachycardia and other symptoms of sympathetic activation, and other supportive measures such as fluid and electrolyte replacement should be administered as needed.
FIGURE 26.3. Serum thyroxine (T4), triiodothyronine (T3), thyrotropin (TSH), and human chorionic gonadotropin (hCG) concentrations in a 40-year-old woman with moderately severe thyrotoxicosis at 16 weeks gestation with a hydatidiform mole. She was given 1 g sodium iodide intravenously (NaI), and the hydatidiform mole was removed operatively (O.R.). There was a parallel fall in the serum hCG concentration, measured by radioimmunoassay, and in the serum molar TSH concentration, which was measured by a mouse bioassay. The patient's serum T4 and T3 concentrations also fell rapidly after removal of the mole. (From Higgins HP, Hershman JM, Kenimer JG, et al. The thyrotoxicosis of hydatidiform mole. Ann Intern Med 1975;83:307.)
Treatment of choriocarcinoma requires appropriate chemotherapy, which is best given in a specialized referral center. Cure of gestational choriocarcinoma cures the thyrotoxicosis (8,9,15). Unfortunately, patients with choriocarcinomas who have thyrotoxicosis usually have a large tumor mass, as indicated by high serum hCG concentrations, and therefore are less likely to be cured than the usual woman with choriocarcinoma, in whom the cure rate is greater than 90%. Nevertheless, several women with metastatic choriocarcinoma and thyrotoxicosis have achieved complete remission with chemotherapy. The prognosis for men with testicular choriocarcinoma and related hCG-secreting testicular tumors, however, is poor (13).
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