The Effect of an Oral Contraceptive on Tests of Thyroid Function

Transcription

1 The Effect of an Oral Contraceptive on Tests of Thyroid Function DANIEL R. MISHELL, JR., M.D., STEPHEN Z. COLODNY, M.D., and LEONARD A. SWANSON, M.D. SEVERAL OF the oral ovulation-inhibiting progestational agents have been previously shown to alter the results of laboratory tests of thyroid function in euthyroid individuals. 5 9 Since these agents are currently being used by millions of women for family planning, and since the thyroid function tests are frequently performed as aids in clinical diagnosis, it is important to determine what alterations occur. The following study was performed in order to determine the effect of a combined oral progestin on five tests of thyroid function. MATERIALS AND METHODS The study group consisted of 21 parous women of childbearing age who were at least weeks postpartum and who had a history of regular menses. A detailed thyroid history was obtained, and each subject underwent a complete physical examination including careful examination of the thyroid gland. The five tests of thyroid function performed were: ( 1) radioactive iodine (RAI) uptake (at 2 and 24 hr.); (2) serum protein-bound iodine (PBI);* ( 3) thyroxine-iodine by column;* ( 4) triiodothyronine absorption test; and ( 5) serum cholesterol. Two baseline determinations of each of these tests, except the radioactive iodine uptake, were performed on each subject on separate days. The baseline tests and physical examination revealed that one patient was markedly hyperthyroid and another hypothyroid. Both of these patients, who were weeks postpartum, were removed from the study and referred for subsequent therapy. The remaining women were all found to be euthyroid (Table 1). Of these, 1 subjects were given the From the Departments of Obstetrics and Gynecology and of Radiology, Harbor General Hospital, Torrance, Calif., and the UCLA School of Medicine, Los Angeles, Calif. Supported by grants from the Ford Foundation and the Upjohn Company. *Performed by BioScience Laboratories, Van Nuys, Calif. 335

2 33 MISHELL ET AL. FERTILITY & STERILITY TABLE 1. Baseline Results of 5 Tests of Thyroid Function in 19 Patients Test Mean(%) Range Normal RAI uptake PBI 5.4 #-'g o-.o Thyroxine-iodine by column 4.5#-lg Triiodothyronine absorption Cholesterol 215 mg Q-250 study drug, 10 mg. of medroxyprogesterone acetate in combination with 0.05 mg. of ethinyl estradiol,* cyclically for 20 days in succession with intervals of 7 days without medication to permit menstruation. The thyroid function tests were repeated on each patient at various intervals of time. The results were calculated in terms of the period of time since the onset of therapy. The time periods used were: ( 1) the first week; ( 2) from the end of the first week to the end of the first month; ( 3) from the end of the first month to the end of 4 months; and ( 4) greater than 4 months after starting therapy. Within each time period, for each test, the mean value for the tests performed on individual patients was first calculated and then the mean value of the sum of the means of all patients tested was determined. RESULTS The results of the serum cholesterol determinations were extremely variable among individuals as well as among the group as a whole. The radioactive iodine uptake determinations were also extremely variable, precluding any evidence of drug effect. The remaining three tests, however, showed consistent changes in all patients studied. The serum PBI showed a very slight elevation within the first week of therapy and a definite further progression upward after 1 month of treatment (Table 2). Many of the values of this test performed after 1 month of drug therapy were in the hyperthyroid range. The results of the thyroxine-iodine by column also showed an insignificant upward change in the first week of therapy, but within the first month showed definitely elevated values, which persisted thereafter (Table 2). Again, many of the results of this test exceeded the normal values and reached the hyperthyroid range. The triiodothyronine absorption tests showed little change from baseline values within the first week of therapy, but there was a definite downward shift during the first month of treatment (Table 2). After 1 month of treatment, the entire range of nearly all of these values was below the lower *Supplied as Provest by The Upjohn Co., Kalamazoo, Mich.'

3 VoL. 20, No.2, 199 ORAL CoNTRACEPTIVE AND THYROID 337 TABLE 2. Determinations of Protein-bound Iodine, Thyroxine-Iodine, and Triiodothyronine Absorption at Various Intervals after Beginning Therapy No. of patients Interval (wk.) Mean change Range PROTEIN-BOUND IODINE LEVELS 10 9 < > THYROXINE-IODINE BY COLUMN DETERMINATIONS < >1, ,,_ VALUES OF TRIIODOTHYRONINE ABSORPTION TEST < > limit of normal of the baseline tests. The maximal depression was reached within 3 months after starting therapy. These determinations thus fell into the range associated with hypothyroidism. In individual patients tested, there was no significant change in the test results during any time period if the test was performed during the one week that the patients were not taking the drug. DISCUSSION These results indicate that the protein-bound iodine and thyroxine-iodine by column tests of thyroid function were not markedly altered during the first week of drug therapy but did show definite alterations by the end of the first month after starting medication. Williams et al. observed similar changes in PBI levels in women taking a combination of norethynodrel and mestranol. The present study shows that the triiodothyronine absorption test also was altered by the end of the first month of therapy with a further decrease in the values observed within the following 3-month period. Hollander et al. have shown that in normal males, medroxyprogesterone acetate alone does not alter the PBI or triiodothyronine red blood cell uptake. It is apparent, then, that it is the estrogen component, ethinyl estradiol, of this medication which is responsible for the alterations observed.

4 33 MISHELL ET AL. FERTILITY & STERILITY Alterations on tests of thyroid function have been previously observed in other hyperestrogenic conditions such as normal pregnancy and hydatidiform mole, 3 7 as well as in patients receiving exogenous estrogenic administration.1 4 Estrogens are known to elevate circulating levels of thyroxinebinding globulin ( TBG). 2 Florsheim and Faircloth showed that several oral ovulation-inhibiting drugs also cause an elevation in TBG. This rise in TBG will result in an elevation of the serum PBI as well as the measurement of thyroxine-iodine by column. In addition, the increase in thyroxine-binding protein makes available more binding sites for the exogenous radioactive triiodothyronine administered in vitro in the triiodothyronine absorption test. Thus, less of this radioactive triiodothyronine is absorbed by the resin sponge and the test result is correspondingly lowered. Alexander and Marmorston showed that as little as mg. of ethinyl estradiol produces a significant rise in the PBI. Since at least 0.05 mg. of ethinyl estradiol must be present to inhibit ovulation, and most of the oral contraceptive drugs in use today contain greater than this amount of estrogen, these agents will all produce changes in the tests of thyroid function. Since these alterations are caused by the estrogenic component of the combination pills, the newer sequential products will also produce these changes. Alterations in the tests of thyroid function are also found in postmenopausal women taking estrogens for.the prevention of some degenerative processes of aging. The data shown in this study indicate that patients taking oral contraceptive pills demonstrate significant changes in those thyroid function tests usually performed by clinicians as aids in diagnoses. These changes will occur within a relatively short time after the initial administration of the drug. The PBI and thyroxine-iodine by column tests reach levels that are usually associated with hyperthyroidism, while the triiodothyronine absorption test rapidly reaches levels consistent with the diagnosis of hypothyroidism. Because the use of estrogen therapy, either alone or in combination with progestins, is becoming much more frequent today, it is necessary for clinicians to be aware of the changes in the tests of thyroid function and to interpret them accordingly. Failure to realize the effect of estrogen on thyroid function tests may cause confusion and perhaps lead to erroneous diagnoses. SUMMARY Five tests of thyroid function were performed on a group of euthyroid women prior to and at intervals after the institution of oral contraceptive

5 VoL. 20, No.2, 199 ORAL CoNTRACEPTIVE AND THYROID 339 therapy consisting of a combination of medroxyprogesterone acetate and ethinyl estradiol. Definite alterations were observed in the protein-bound iodine, thyroxine-iodine by column, and triiodothyronine absorption tests. The former two were elevated and the latter depressed. The significance of these findings is discussed. Harbor General Hospital 1000 West Carson St. Torrance, Calif REFERENCES l. ALEXANDER, R. W., and MARMORSTON, J. Effects of two synthetic estrogens on the level of serum protein bound iodine in men and women with atherosclerotic heart disease. J Clin Endocr 21:243, DowLING, T. T., INGBAR, S. H., and FREINKEL, N. Iodine metabolism in hydatidiform mole and choriocarcinoma. I Clin Endocr 20: I, DowLING, T. T., FREINKEL, N., and INGBAR, S. H. The effect of estrogens upon the peripheral metabolism of thyroxine. J Clin Invest 39:1119, ENGSTROM, W. W., and MARKARDT, B. Influence of estrogen on thyroid function. J Clin Endocr 14:215, FLORSHEIM, \V. H., and FAIRCLOTH, M. A. Effects of oral ovulation inhibitors on serum protein bound iodine and thyroxine binding proteins. Proc Soc Exp Biol Med 117:5, HOLLANDER, C. S., GARCIA, A. M., STURGIS, S. H., and SLENKOW, H. A. Effects of an ovulatory suppressant on the serum protein bound iodine and the red cell uptake of radioactive triiodothyronine. New Eng J Med 29:501, RussELL, K. P. The current status of the protein-bound blood iodine in obstetrics and gynecology. Obstet Gynec Survey 9:157, SURAN, R. R. In Progress on Conception Control. Lippincott, Philadelphia, 19, p WILLIAMS, D. W., DENARDO, G. L., and ZELENIK, J. S. Thyroid function and Enovid. Obstet Gynec 27:232, 19.