Thyrotropic Action of Human Chorionic Gonadotropin

Abstract

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 att...

Should human chorionic gonadotropine treatment increase thyroid volume?

“…These cases, considerably increased hCG levels and suppressed TSH levels suggest that hCG has thyrotropic activity. Human chorionic gonodotropine and human TSH belong to the biochemically closely related glycoprotein hormone family, they are potentially cross-reactive at the receptor level (8). In vitro, hCG has a weak intrinsic thyroid-stimulating activity, being able to stimulate iodine uptake, generation of cAMP, 3,5,3'-triodothyronine secretion, and even growth of thyroid cells (19)(20)(21).…”

“…These studies showed that hCG is the molar TSH and that 1 Unite hCG has intrinsic thyrotrophic activity equivalent to approximately 0.5 µU TSH in the Mouse bioassay (4). Additionally, hCG stimulates iodide uptake, adenylate cyclase, and DNA synthesis in cultured rat thyroid cells (8). Many investigations have detected that hCG and TSH share not only structural homology but also their receptors show structural similarity as well, and this homology suggests the basis for the reactivity of hCG with the TSH receptor (9,10).…”

The role of thyrostimulin and its potential clinical significance

“…However, LHR and FSHR are also orthologous with the DLRG1, but cannot bind to thyrostimulin. Furthermore, mammalian gonadotropins are capable of activating the teleost TSHR, whilst hCG possesses thyrotrophic abilities (Yoshimura and Hershman 1995;MacKenzie et al 2009). Consequently, the specifi city of TSHR for its ligands is not as high as that of other glycoprotein receptors.…”

Nausea and Vomiting of Pregnancy

“…22 f. HCG is the thyroid stimulator of pregnancy. 23 Numerous studies of thyroid hormones in pregnancy have established an association between transient biochemical hyperthyroidism and NVP. The degree of biochemical hyperthyroidism correlates closely with the severity of NVP.…”