THYROTROPIC ACTION OF HUMAN CHORIONIC-GONADOTROPIN

Hyperthyroidism or increased thyroid function has been reported in man y patients with trophoblastic tumors. In these cases, greatly increase d human chorionic gonadotropin (hCG) levels and suppressed TSH levels suggest that hCG has thyrotropic activity. Recent investigations have clarified the structural homology not only in the hCG and TSH molecule s but also in their receptors, and this homology suggests the basis fo r the reactivity of hCG with the TSH receptor. The clinical significan ce of the thyrotropic action of hCG is now also recognized in normal p regnancy and hyperemesis gravidarum. Highly purified hLH binds to reco mbinant hTSH receptor and is about 10 times as potent as purified hCG in increasing cAMP. The beta-subunits of hCG and hLH share 85% sequenc e identity in their first 114 amino acids but differ in the carboxy-te rminal peptide because hCG beta contains a 31-amino acid extension (be ta-CTP). A recombinant mutant hCG that lacks beta-CTP showed almost id entical potency to LH on stimulation of recombinant hTSH receptor. If intact hCG were as potent as hLH in regard to its thyrotropic activity , most pregnant women would become thyrotoxic. One of the roles of the beta-CTP may be to prevent overt hyperthyroidism in the first trimest er of pregnancy when a large amount of hCG is produced by the placenta . Nicked hCG preparations, obtained from patients with trophoblastic d isease or by enzymatic digestion of intact hCG, showed approximately 1 .5- to 2-fold stimulation of recombinant hTSH receptor compared with i ntact hCG. This suggests that the thyrotropic activity of hCG may be i nfluenced by the metabolism of the hCG molecule itself. Deglycosylatio n and/or desialylation of hCG enhances its thyrotropic potency. Basic hCG isoforms with lower sialic acid content extracted from hydatidifor m moles were more potent in activating adenylate cyclase, and showed h igh bioactivity/immunoactivity (B/I) ratio in CHO cells expressing hum an TSH receptors. This is consistent with the finding that the beta-CT P truncated hCG with higher thyrotropic potency is substantially degly cosylated and desialylated in the beta-subunit relative to intact hCG because all four O-linked glycosylation sites occur within the missing C-terminal extension. The desialylated hCG variant also interacts dir ectly with recombinant hTSH receptors transfected into human thyroid c ancer cells. There is thyroid-stimulating activity in sera of normal p regnant women, and this correlates with serum hCG levels. The thyroid gland of normal pregnant women may be stimulated by hCG to secrete sli ghtly excessive quantities of T-4 and induce a slight suppression of T SH, perhaps being about 1 mU/L less than nongravid levels, but not hig h enough to induce overt hyperthyroidism. Maternal thyroid glands may secrete more thyroid hormone during early pregnancy in response to the thyrotropic activity of hCG that overrides the normal operation of th e hypothalamic-pituitary-thyroid feedback system. Biochemical hyperthy roidism associated with hyperemesis gravidarum has been attributed to hCG. In patients with hyperemesis gravidarum, thyrotropic activity in serum correlated with hCG immunoreactivity, and the severity of vomiti ng as indicated by clinical and biochemical parameters correlated with the degree of thyroid stimulation. To understand the thyrotropic acti on of hCG, it is necessary to know whether hCG activates the same doma in of the TSH receptor as does TSH. The identification of the molecula r structure of the hCG isoform with the highest thyrotropic potency wi ll resolve the enigma of gestational thyrotoxicosis and the hyperthyro idism associated with trophoblastic disease and hCG-producing tumors.