Gestational Trophoblastic Disease

CONTENTS I. The membrane receptors . . . . . . . . . . (I) Phylogenetic aspects of membrane receptors . . . . . (2) Selection or reinforcement of receptors in the course of phylogenesis . (3) Ontogenetic aspects of membrane receptors . . . . (4) Selection or amplification of receptors during ontogenesis . . (a ) The invertebrate model . . . . . . . (6) The vertebrate model . . . . . . . . . . . . . (a) The critical period . . . . . . . . (b) Duration of the critical period . . . . . . 11. The cytosol receptors . . . . . . . . .

Phylogeny and ontogeny of hormone receptors: the selection theory of receptor formation and hormonal imprinting

(Second of Two Parts) Circulating Thyroglobulin For several decades, thyroglobulin was thought to be confined to the thyroid gland. This view can no longer be defended since thyroglobulin has unque...

Control of Thyroglobulin Synthesis and Secretion

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.

Thyrotropic Action of Human Chorionic Gonadotropin

The present studies were undertaken to examine the factors that influence the growth of cells of endocrine gland origin, particularly the possible interactions between "nonspecific" growth factors and the trophic hormone for a target endocrine cell. As a model system, we explored the individual and conjoint effects of insulin-like growth factor-I (IGF-I) and TSH on the growth of FRTL5 cells, a nontransformed line of cloned rat thyroid follicular epithelium. In these cells, IGF-I and TSH each produced a dose-dependent enhancement of DNA synthesis and cell proliferation. When added together, IGF-I and TSH were markedly synergistic in stimulating DNA synthesis, producing increases in 3H-thymidine incorporation that were far greater than the sum of the effects of each alone. A similar effect of IGF-I was evident in the case of the stimulation of DNA synthesis produced by immunoglobulin G (IgG) preparations from the blood of patients with Graves' disease. Such IgG bind to the TSH receptor and mimic the actions of TSH therein. It is suggested, therefore, that there exist in the FRTL5 cell line at least two mechanisms for the regulation of growth, one activated at the level of the IGF-I receptor and the other at the level of the TSH receptor. When the two pathways are activated concurrently, a synergistic enhancement of DNA synthesis takes place. The findings indicate that the FRTL5 cell line is an excellent model in which to study these complex interactions and that IGF-I may be a determinant of thyroid cell growth, both normally and in certain thyroid diseases.

Insulin-like growth factor-I stimulates the growth of rat thyroid cells in culture and synergizes the stimulation of DNA synthesis induced by TSH and Graves'-IgG.

Sera of patients with Graves' disease contain immunoglobulins (IgG) that bind to thyroid plasma membranes, inhibiting thereby the binding of [125I]bovine TSH to its receptors [TSH-binding inhibitory IgG (TBII)], activate adenylate cyclase, or do both. In this report, we describe a new method for the extensive purification of IgG specific to the serum of patients with Graves' disease, using receptor purification as the isolation technique and the TBII assay as an index of activity. Human thyroid tissue was considered an undesirable source of receptor for two reasons. First, the IgG of sera of patients with Graves' disease almost always contain antimicrosomal and/or antithyroglobulin antibodies found in patients with other thyroid diseases, especially Hashimoto's thyroiditis. Second, many preparations of IgG from normal sera display TBII activity, suggesting that normal IgG also bind to human thyroid plasma membranes. Consequently, guinea pig fat cell membranes (FCM), which contain a high affinity receptor ...

Development and evaluation of a method for the partial purification of immunoglobulins specific for Graves' disease.

Others have reported that hCG has intrinsic thyrotropic activity in the mouse. To obtain evidence of whether hCG has stimulatory activity in the human thyroid, we have studied the interactions of crude and pure hCG with receptors in human thyroid membranes by assessing the ability of these preparations to inhibit the binding of bovine [125I]TSH ([125I]-bTSH) and to activate adenylate cyclase activity therein. On the assumption that all activity in crude hCG was due to hCG itself, studies of the displacement of [125I]bTSH at 4 C in 20 DIM Tris-Cl-0.5% bovine serum albumin, pH 7.45, revealed differing preparations of crude hCG to be approximately 10- to 40- fold more potent than pure hCG on a molar basis. Gonadotropic activities of crude and pure hCG were then standardized in a radioreceptor assay for hCG in rat testis. No major discrepancy between the in vivo bioactivity and the activity determined in vitro radioreceptor assay of these preparations was revealed. Lineweaver-Burk analysis showed the inhibiti...

In Vitro Responses to Crude and Purified hCG in Human Thyroid Membranes

Human chorionic gonadotropin and thyroid function in patients with hydatidiform mole

In view of the recent reports suggesting that human chorionic gonadotropin (hCG) may have intrinsic thyrotropic activity, the interaction of partially purified (hCG-c) and highly purified hCG (hCG-p) with bovine thyroid membranes was studied by assessing their ability both to inhibit the binding of 125I-labeled bovine thyrotropin (125I-bTSH) to thyroid membranes and to activate adenylate cycla'se therein. Both partially and highly purified hCG preparations inhibited the binding of 125I-bTSH, but hCG-c was approximately 24 times more potent than hCG-p. hCG-c also activated adenylate cyclase i n a dose-dependent manner, while hCG-p, in the same concentrations, had no effect. The content of hCG in hCG-c and hCG-p was measured by radioimmuno- and radioreceptor assays, and the results agreed quite closely with those reported by bioassay. Both preparations of hCG inhibited the binding of 125I-bTSH to bovine thyroid membranes in a non-competitive manner, as revealed by Lineweaver-Burk analysis. hCG-c could only ...

Interactions of bovine thyrotropin and preparations of human chorionic gonadotropin with bovine thyroid membranes.

Previously, we have shown that preparations of hCG bind to bovine thyroid membranes, as judged from their ability both to inhibit the binding of 125I-labeled bovine TSH (bTSH) and to activate adenylate cyclase (Amir, S. M., H. Uchimura, and S. H. Ingbar, J Clin Endocrinol Metab 45: 280, 1977). In the present studies, 125I-labeled, highly purified bTSH ([125I]bTSH) has been shown to bind specifically and saturably to receptors in a particulate fraction from rat testis. At 37 C, binding was rapid, reaching a maximum level in less than 15 min, but then declining markedly during the next several hours. At 22 C, binding reached a steady state after 2 h and remained unchanged for another 22 h. Binding of [125I]bTSH was greatest at pH 5.5, at which pH more than 50% of [125I]bTSH was bound in the presence of 330 μg/ml particulate protein, the concentration of protein that yielded maximum binding. Nevertheless, the majority of experiments were conducted at lesser protein concentrations and at physiological pH (7.4...

Syed M. Amir

Papers

Development and evaluation of a method for the partial purification of immunoglobulins specific for Graves' disease.

In Vitro Responses to Crude and Purified hCG in Human Thyroid Membranes

Human chorionic gonadotropin and thyroid function in patients with hydatidiform mole

Interactions of bovine thyrotropin and preparations of human chorionic gonadotropin with bovine thyroid membranes.

Binding of Bovine Thyrotropin to Receptors in Rat Testis and Its Interaction with Gonadotropins