0021-972x/92/7402-0258$03.00/0 Journal of Clinical Endocrinology Copyright 0 1992 by The Endocrine

Editorial: Thyroid

and Metabolism Society

Role of Human Stimulator

Vol. 74, No. 2



The concept that hCG is a thyroid stimulator arose, in part, because of the association of hyperthyroidism with hydatidiform mole and choriocarcinoma, trophoblastic tumors that secrete large amounts of hCG. A thyroid stimulator extracted from the serum and molar tissue of a patient with severe hyperthyroidism and hydatidiform mole differed biologically and immunologically from pituitary TSH and the thyroid stimulator of Graves’ disease (1). Purification of the thyrotropic material extracted from hydatidiform moles led to copurification of hCG, and purified hCG had similar thyroidstimulating activity (TSA) in the McKenzie mouse bioassay (2). Nisula et al. (3) showed that highly purified hCG and its recombined subunits had intrinsic thyrotropic activity. hCG displaced TSH from its thyroid membrane receptor (4); hCG stimulated adenylate cyclase in human thyroid membranes (5); and injections of large amounts of commercial hCG into men caused release of thyroidal radioiodine (6). Others, however, found that the thyrotropic activity of purified hCG was difficult to demonstrate in human thyroid cell preparations in vitro and suggested that commercial hCG isolated from pregnancy urine contained another thyrotropic substance (7). Purified hCG was shown to have thyrotropic activity in cultured rat thyroid cells (8); it stimulated adenylate cyclase, increased iodide uptake, and increased growth of these cells. In this system, hTSH was much less potent than bovine TSH (bTSH). One unit of hCG was equivalent to 0.04 PU bTSH or to 0.7 PU hTSH. On a molar basis, hCG was about l/lo3 as potent as hTSH. Based on these data, a serum concentration of 50,000 U hCG/ L would be equivalent to 35 mU TSH/L. Such a concentration would cause severe hyperthyroidism. To explain this paradox, the hypothesis that the hTSH receptor discriminates against hCG has been proposed. The molecular basis for this discrimination is that the C-terminal tail on the P-subunit of hCG, which LH lacks, interferes with binding to the TSH receptor (5). In normal pregnancy, serum TSH levels are low when hCG levels are highest at 8-12 weeks of gestation (9-11).


in U.S.A.

as a

Free Tq and free T3 levels are higher at this time than later in pregnancy (10, 11). The thyrotropic activity of the serum is also higher at this time than at other times in gestation (10, 12). Based on these findings, several authors have theorized that hCG is a thyrotropin in normal pregnancy (10-12). Since TSH levels are only slightly suppressed in normal pregnancy, perhaps being 1 or 2 mU/L less than nongravid levels, one can theorize that 50,000 U hCG/L = 1 mU TSH/L. On this basis, hCG is only l/lo4 as potent as hTSH. In this issue, Kennedy and colleagues (13) have studied the TSA of serum from pregnant women tested in a system that measures iodide uptake of FRTL-5 rat cells. In their system, hCG and TSH caused a dose-related increment of iodide uptake. The system has a sensitivity of about 20,000 U hCG/L and 10 mU bTSH/L. Low concentrations of hCG inhibited the bioactivity of bTSH and this inhibitory effect was diminished when high concentrations of hCG were tested. The apparent conflict with another report that did not find inhibition of TSH action by hCG relates to the concentrations of hCG tested (8); low concentrations of hCG inhibit the action of TSH whereas high concentrations have an additive effect. Kennedy et al. (13) have shown that 63% of first trimester sera and 52% of third trimester sera had positive activity. The iodide uptake correlated with hCG levels using the first trimester data, but there was not a significant correlation using the third trimester data. A positive correlation between TSA and hCG was also found in another group of women who underwent termination of pregnancy, presumably early in gestation; 92% of them had detectable TSA. Neutralization of the TSA with polyclonal antibody to hCG was complete in two, partial in four, and absent in two of eight first trimester sera and absent in six third trimester sera. Based on these data the authors conclude the hCG may not be responsible for TSA in normal pregnancy serum. I differ with this conclusion and take the point of view that “the cup is half-full.” A nonspecific serum effect in this system may explain part of the discrepancies. Pregnancy serum may contain factors other than hCG which affect the assay. The excellent correlation of TSA with first trimester hCG levels and the neutralization of TSA in several samples by antibody to hCG are positive data

Received October l&1991. Address reprint requests to Jerome M. Hershman, M.D., Endocrinology-WlllD, West Los Angeles VA Medical Center, Los Angeles, California 90073. 258

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 19 November 2015. at 00:19 For personal use only. No other uses without permission. . All rights reserved.


which cannot be ignored. How can one explain the negative data? Is it assay nonspecificity, other factors in pregnancy sera, or the antagonistic effect of low concentrations of hCG? If hCG is not the placental thyrotropin, what is the nature of this thyroid stimulator? The best candidate may be a still uncharacterized molecular variant of hCG. hCG exists in isoforms which vary in carbohydrate content and possibly even in primary structure. Basic isoforms with diminished sialic acid content may be more potent thyrotropins. One may speculate that regulation of glycosylation of hCG may occur with secretion of forms having greater TSA early in pregnancy. There is increasing acceptance of the idea that maternal thyroid hormone may play a role in early fetal development before the onset of function of the fetal thyroid. Perhaps, hCG is the placental stimulator of maternal thyroid function at a time when the placenta is permeable to thyroid hormone and thyroid hormone is needed for fetal development. Additional work is needed to purify isoforms of hCG which may be more potent thyroid stimulators. New data are accumulating about the nature of the TSH receptor and its extracellular binding domain. The LH-hCG receptor is very similar to the TSH receptor. It is likely that hCG binds weakly to a stimulatory region of the TSH receptor and that hCG also binds to a region which blocks the action of TSH, analogous to the region which binds TSH-blocking antibody. This interaction of hCG with stimulatory and inhibitory receptor domains may explain the complex nature of the thyroid-regulating action of hCG. Jerome M. Hershman, MD. Endocrinology and Metabolism Division West Los Angeles V.A. Medical Center


References 1. Hershman JM, Higgins HP. Hydatidiform mole-a cause of clinical hyperthyroidism. New Engl J Med. 1971;284:573-577. 2. Kenimer JG, Hershman JM, Higgins HP. The thyrotropin in hydatidiform moles is human chorionic gonadotropin. J Clin Endocrinol Metab. 1975;40:482-491. 3. Nisula BC, Morgan FJ, Cantield RE. Evidence that chorionic gonadotropin has intrinsic thyrotropic activity. Biochem Biopphys Res Commun. 1974;59:86-91. 4. Azukizawa M, Kurtzman G, Pekary AE, Hershman JM. Comparison of the binding characteristics of bovine thyrotropin and human chorionic gonadotropin to thyroid plasma membranes. Endocrinology. 1977;101:1880-1889. 5. Carayon P, Lefort G, Nisula B. Interaction of human chorionic gonadotropin and human luteinizing hormone with human thyroid membranes. Endocrinology. 1980;106:1907-1916. 6. Sowers JR, Hershman JM, Carlson HE, Pekary AE. Effect of human chorionic gonadotropin on thyroid function in euthyroid men. J Clin Endocrinol Metab. 1978;47:898-901. 7. Amir SM, Endo K, Osathanondh R, Ingbar SH. Divergent responses by human and mouse thyroids to human chorionic gonadotropin in vitro. Mol Cell Endocrinol. 1985;39:31-37. 8. 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;67:74-79. 9. Braunstein GD, Hershman JM. Comparison of serum pituitary thyrotropin and chorionic gonadotropin concentrations throughout pregnancy. J Clin Endocrinol Metab. 1976;42:1123-1126. 10. Harada A, Hershman JM, Reed AW, et al. Comparison of thyroid stimulators and thyroid hormone concentrations in the sera of pregnant women. J Clin Endocrinol Metab. 1979;48:793-797. 11. Glinoer D, De Nayer P, Bourdoux P, et al. Regulation of maternal thyroid during pregnancy. J Clin Endocrinol Metab. 1990;71:276287. 12. Ballabio M, Poshyachinda M, Ekins RP. Pregnancy-induced changes in thyroid function; role of hCG as putative regulator of maternal thvroid. J Clin Endocrinol Metab. In Press. 13. Kennedy RL, Darne J, Cohn M, Price A, Davies R, Blumsohn A, Griffiths H. Human chorionic gonadotropin (hCG) may not be responsible or thyroid-stimulating activity (TSA) in normal pregnancy serum. J Clin Endocrinol Metab. 1992;72:258-63.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 19 November 2015. at 00:19 For personal use only. No other uses without permission. . All rights reserved.

Role of human chorionic gonadotropin as a thyroid stimulator.

0021-972x/92/7402-0258$03.00/0 Journal of Clinical Endocrinology Copyright 0 1992 by The Endocrine Editorial: Thyroid and Metabolism Society Role o...
211KB Sizes 0 Downloads 0 Views