0021-972x/92/7402-0260$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright 0 1992 by The Endocrine Society

Vol. 74, No. 2 Printed in U.S.A.

Human Chorionic Gonadotropin for Thyroid-Stimulating Activity Normal Pregnancy Serum* R. L. KENNEDY, H. GRIFFITHS

J. DARNE,

M. COHN,

A. PRICE,

May not be Responsible in

R. DAVIES,

A. BLUMSOHN,

AND

Departments of Medicine (R.L.K., R.D.), Obstetrics & Gynaecology (J.D., M.C.), and Clinical (A.P., A.B., H.G.), Northern General Hospital, Sheffield, United Kingdom

ABSTRACT. Although hCG can activate thyroid cells in culture there is considerable doubt as to whether it is responsible for the changes in thyroid function which occur during normal pregnancy. Thyroid-stimulating activity (TSA), measured usina iodide uptake into FRTL-5 cells, was demonstrated in 32/5i (63%) first and 15/29 (52%) third trimester sera. Free T, was increased (P < 0.601) and TSH decreased (P < 0.01) in”fnst trimester. In the early pregnancy group there was a positive correlation between hCG and TSA (r = 0.594, P < 0.001) and a negative correlation between hCG and TSH (r = -0.329, P < 0.02). In third trimester hCG concentration was often below that required to produce TSA in vitro and TSA could not be neutralized by antibodies to hCG. There was no correlation between hCG and TSH or thyroid hormones in the third trimester. In 26 women TSA decreased in parallel with serum hCG

T

HERE is controversy surrounding the role of hCG as a thyroid regulator during normal pregnancy (1). The molecule competes with TSH for binding sites on thyroid membranes (2, 3). Some studies have suggested that hCG is a weak stimulator of CAMP production in human thyroid cells (4, 5) while other studies, including our own, have failed to demonstrate such an activity (3, 6). This and the poor correlation between hCG concentration and thyroid function casts considerable doubt on the hypothesis that hCG is a physiologically important thyroid regulator in pregnancy. In early pregnancy, when hCG concentration is highest, free thyroid hormone concentrations are modestly increased (7-9) and TSH is relatively suppressed (8-10). These effects are consistent with thyroid stimulation by hCG and there is, indeed, some direct evidence for such Received May 20, 1991. Address correspondence and requests for reprints to: Dr. R. L. Kennedy, Department of Medicine, Clinical Sciences Centre, Northern General Hospital, Herries Road, Sheffield S5 7AU, United Kingdom. * Financial SUDDOI~ for this work is from the Universitv of Sheffield and from the research fund of the Northern General Hospital, Sheffield.

Chemistry

concentration after termination of pregnancy (P < 0.001). Free T3 also decreased (P < 0.01) and TSH increased (PC 0.05) after termination. TSA persisted in many patients even after hCG was either very low or undetectable. Purified hCG stimulated iodide uptake in a concentrationdependent manner. Stimulation of iodide uptake by TSH was inhibited by the simultaneous presence of low concentrations of hCG while activity was restored with high concentrations. hCG may contribute to the thyroid changes in early pregnancy. However the poor correlation between TSA and thyroid tests suggests that other factors may be involved. The partial agonist activity of hCG may account for some of the inconsistencies observed but TSA in serum from late pregnancy or after termination of pregnancy is almost certainly due to another hormone or growth factor. (J Clin Endocrinol Metab 74: 260265, 1992)

an action (11). Although hCG may not activate human thyroid cells in vitro, it can undoubtedly activate the rat thyroid line FRTL-5 (12-14). We, and others, have shown that pregnancy serum contains thyroid-stimulating activity (TSA) and that this activity may be related to hCG (15-18). These studies have focussed on first trimester of pregnancy although Yoshikawa et al. (16) demonstrated TSA in 12 out of 13 third trimester sera. The latter observation is puzzling since serum hCG concentration is much lower in third trimester and the prevailing thyroid status is, if anything, one of compensated hypothyroidism with decreased free thyroid hormone concentrations (7, 10, 19) and increased serum TSH (10, 20). The aim of this work was to document the prevalence of TSA in normal pregnancy and to examine its relationship with thyroid function. We have also performed a sequential study in 26 women before and after termination of pregnancy. Since the thyroid in pregnancy is exposed simultaneously to hCG and TSH, we have studied the effect of combinations of these hormones on FRTL-5 cells in vitro.

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THYROID

Materials

STIMULATION

and Methods

Patients

The cross-sectionalstudy included 51 first trimester and 29 third trimester patients recruited sequentially from the antenatal booking clinic at the Northern General Hospital, Sheffield. The first trimester patients had a mean ageof 25.2 yr (16-44) and a mean gestation of 64 days (42-84). The third trimester patients had a meanageof 26.4 yr (16-30) and a meangestation of 35 weeks(31-40). None had a personal or family history of endocrine or autoimmune diseaseand there were no features of these on examination. The controls were 45 females of comparableage and with spontaneousmenstrual cycles. The sequential study included 26 primigravid patients requesting termination of pregnancy. At entry into the study the mean agewas 22.0 yr (18-28) and the mean gestation 69 days (5686). Again there was no evidence of endocrine or autoimmune disease.Thesepatients were studiedbefore suction termination of pregnancy as well as 7 and 28 days after. After informed consent, 20 ml venous blood were withdrawn, allowed to clot, and serumseparatedand wasstored in aliquots at -20 C before assay. Hormone

Measurements

Thyroid hormoneswere measuredby RIA-total Tq and TS (Amersham),free Tq (Mallinckrodt), free TS (Diagnostic Products Ltd.) and Tq binding globulin (TBG, Behring). TSH was measuredusing an immunoradiometric assay (detection limit 0.1 mu/L) with reagents supplied by North East ThamesRegionImmunoassayUnit. Purified hCG (batch 75/537-First International ReferencePreparation) did not cross-reactin the TSH assay.hCG was measuredby immunoradiometric assay suppliedby Serono Diagnostics (detection limit 2 III/L). The assayrecognizesthe intact hCG moleculeand free B-chains. It doesnot cross-reactwith TSH. The coefficient of variation for all assaysusedwas lessthan 10%. The normal, nonpregnant rangesfor Tq and Ts were 62-143 and 0.8-2.7 nmol/L, respectively, for free Tq and free Ta 7.7-20.6 and 2.2-6.8 pmol/L, respectively, for TBG 10.0-30.0 mg/L and for TSH 0.38-4.5 mu/L. For the sequentialstudy hCG was measuredby an in-house assaywhich measuresonly intact hCG. The assay was a sequential doublemonoclonal antibody enzyme-linked immunosorbent assayusing clonesBIO-ICG-003 and BIO-OlOH (BiogenesisLimited, U.K.). There was no cross-reactivity with other glycoprotein hormonesand cross-reactivity with free flchain of hCG wasminimal (

Human chorionic gonadotropin may not be responsible for thyroid-stimulating activity in normal pregnancy serum.

Although hCG can activate thyroid cells in culture there is considerable doubt as to whether it is responsible for the changes in thyroid function whi...
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