Hyperthyroidism or increased thyroid function has been reported in many patients with
trophoblastic tumors. In these cases, greatly increased
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 molecules but also in their receptors, and this homology suggests the basis for the reactivity of hCG with the
TSH receptor. The clinical significance of the thyrotropic action of hCG is now also recognized in normal pregnancy and
hyperemesis gravidarum. Highly purified hLH binds to recombinant hTSH receptor and is about 10 times as potent as purified hCG in increasing cAMP. The beta-subunits of hCG and hLH share 85% sequence identity in their first 114
amino acids but differ in the carboxy-terminal
peptide because
hCG beta contains a 31-amino
acid extension (beta-
CTP). A recombinant mutant hCG that lacks beta-
CTP showed almost identical 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 trimester of pregnancy when a large amount of hCG is produced by the placenta. Nicked hCG preparations, obtained from patients with trophoblastic disease or by enzymatic digestion of intact hCG, showed approximately 1.5- to 2-fold stimulation of recombinant hTSH receptor compared with intact hCG. This suggests that the thyrotropic activity of hCG may be influenced by the metabolism of the hCG molecule itself. Deglycosylation and/or desialylation of hCG enhances its thyrotropic potency. Basic hCG
isoforms with lower
sialic acid content extracted from
hydatidiform moles were more potent in activating
adenylate cyclase, and showed high bioactivity/immunoactivity (B/I) ratio in CHO cells expressing human
TSH receptors. This is consistent with the finding that the beta-
CTP truncated hCG with higher thyrotropic potency is substantially deglycosylated 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 directly with recombinant hTSH receptors transfected into human
thyroid cancer cells. There is thyroid-stimulating activity in sera of normal pregnant women, and this correlates with serum hCG levels. The thyroid gland of normal pregnant women may be stimulated by hCG to secrete slightly excessive quantities of T4 and induce a slight suppression of TSH, perhaps being about 1 mU/L less than nongravid levels, but not high 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 the hypothalamic-pituitary-thyroid feedback system. Biochemical
hyperthyroidism associated with
hyperemesis gravidarum has been attributed to hCG. In patients with
hyperemesis gravidarum, thyrotropic in serum correlated with hCG immunoreactivity, and the severity of
vomiting as indicated by clinical and biochemical parameters correlated with the degree of thyroid stimulation. To understand the thyrotropic action of hCG, it is necessary to know whether hCG activates the same domain of the
TSH receptor as does TSH. The identification of the molecular structure of the hCG
isoform with the highest thyrotropic potency will resolve the enigma of gestational
thyrotoxicosis and the
hyperthyroidism associated with trophoblastic disease and hCG-producing
tumors.