THE EFFECT OF ORAL CONTRACEPTIVES ON SERUM LIPIDS

Transcription

1 FERTn.rry AND STERn.rry Copyright 1971 by The Williams & Wilkins Co. Vol. 22, No.9, September 1971 Printed in U.S.A. THE EFFECT OF ORAL CONTRACEPTIVES ON SERUM LIPIDS J. G. SCHENKER, M.D., A. PINSON, M.Sc., AND W. Z. POLISHUK, M.D. Department of Obstetric-Gynecology, and Laboratory of Surgical Research, Hadassah University Hospital, Jerusalem, Israel ". During the latter part of human pregnancy, total lipids, cholesterol, triglycerides (TG), phospholipids, and free fatty acids of serum increase progressively and reach peak values immediately before delivery. 1-3 Administration of female sex hormones is known to affect the metabolism of lipids and their concentration in plasma. 4, 5 The effect of oral contraceptives which contain both synthetic estrogens and progestagens on plasma lipids has been studied with some contradictory results. 6-8 We have studied the effects of different oral contraceptive preparations on the level of serum total lipids, cholesterol, and triglycerides in relation to the duration of treatment and the steroid composition of the oral contraceptive used. MATERIAL AND METHODS Serum total lipids, cholesterol, and triglycerides were determined in 441. These included 375 healthy, ambulant female subjects, aged years (mean 23.6 years), who were taking various oral contraceptives, both combined and sequential, and did not manifest clinical side effects. A control group consisted of 66 healthy women whose ages ranged from years (mean 22.1 years), who were taking no medication. The type and steroid composition of the various oral contraceptives used is shown in Table 1. The duration of therapy and number of patients is shown in Table 2. Total lipids, total cholesterol, and triglycerides were determined in serum samples, drawn in the morning before breakfast, and following a fasting period of at Received for publication February 8, least 12 hr. Fluctuating lipid level following meals was thus minimized. Total lipids were determined according to the method of Kunkel, Ahrens, and Eisenmenger. 9 Cholesterol was analyzed by the method of Zak et al 10 Serum TG was selectively extracted by the isopropanol-heptane solvent of Dole. 11 The upper heptane layer was rendered free of no -TG glycerolipids by washing with the lower 58%. Aqueous isopropanol layer and the TG-glycerol were assayed after hydrolysis by a modification of the chromotropic acid method of Lambert and Neish. 12 Statistical evaluation of the data for each group included calculation of the mean standard deviation and standard error of the mean. The significance of the difference between the mean was calculated by Student's t test. RESULTS Table 3 shows fasting serum levels of total lipids, cholesterol, and triglycerides in the test and control group. A mean value for serum total lipids was 596 mg./100 ml in the control group, while patients taking oral contraceptives had a mean of 712 mg./ 100 ml (p < 0.001). In subjects taking oral contraceptives the mean serum triglycerides showed a marked increase from 70 mg./100 ml to 122 mg./100 ml, while there was no significant change in mean cholesterol concentration. There was no difference in the mean total lipids, cholesterol, and triglycerides levels in patients taking combined and sequential preparations, and no significant difference among those taking different steroid compositions of the "Pill" (Table 3 and 4).

2 September 1971 ORAL CONTRACEPTIVES 605 Proprietary name Manufacturer TABLE 1. Composition of Oral Contraceptive Tablets Davs of cycle Prostagen Dose Estrogen Dose Gynovlar Schering, 5-25 N orthisterone 3.0 Ethynyl W. Germany acetate estradiol Metrulen-M Searle, 5-25 Ethynodial 1.0 Mestranol England diacetate Nogest-S Ikapharm, 5-19 Ethynyl Israel estradiol -24 Medroxy- 5.0 Ethynyl progesterone estradiol Sequelan Teva, Israel 5-19 Mestranol Northynodrel 5.0 Mestranol mg. mg. TABLE 2. Duration of Therapy with Various Oral Contraceptives patients on contraceptive preparations Total cycles Per cent Gynov- Metru- No- Seque- patients lar len-m gest-s len Total There is no direct correlation between the duration of contraceptive therapy and serum lipid values (Fig. 1, Table 4). The rise in serum total lipids and triglycerides appeared during the first cycles of treatment and then a plateau was attained. The apparent progressive increase observed after 37 cycles of medication is statistically not significant. There is some nonstatistically significant increase in total cholesterol concentration after 1 year of treatment (Fig. 1, Table 4). DISCUSSION The serum total lipids, and triglycerides changes in patients with oral contraceptive therapy are somewhat similar to those seen in the last two trimesters of pregnancy, but there are quantitative differences In pregnancy, the serum lipids, cholesterol, and serum TG are notably elevated, while in our test group the elevation of total lipids and TG was marked without parallel increase in total cholesterol concentration. For both the serum total lipids and TG, the difference between the controls and the subjects on oral contraceptive therapy was statistically significant (p < 0.001). Changes in the total lipids and TG concentration were not dependent upon the time of medication. The rise in serum lipids and TG appeared in the 2nd or 3rd cycles of oral contraceptive medication in most subjects tested while a statistically significant increase in cholesterol level was not observed after 1 year of treatment. (Fig. 1, Table 4). The exact mechanism responsible for hypertriglyceridemia during oral contraceptive therapy remains conjectural. It may result from dietary or increased endogenous synthesis or decreased plasma TG removal, or a combination of both factors. 13 It is of interest that we have not found a difference in the total lipid and TG levels with the different steroid preparations used. While Brody et al. 14 studying "Anovlar" and "Volidan," have shown that different combinations may differ in their action on serum phospholipids. Nearly the same mean values were obtained when comparing the serum lipid concentrations in subjects taking the different estrogen-progestin combinations, Metrulen, Gynovlar, and Sequelan. Although it is known that it

3 . 606 SCHENKER ET AL. Vol. 22 TABLE 3. Serum Total Lipids, Cholesterol, and Triglvcerides in Test and Control Groups p' Metrulen-M Control Gynovlar p No- 4-1 p Seque- 5-1 p gest-s Ian 6. All test 6-1 p groups Total lipids (mg./iooml.) ± 24t ± 21 Total cholesterol (mg./iooml.) ± 8.3 ± 7.2 Triglycerides ± 10.2 ± 12.1 * Determinations by Student's t test. t Values given are mean ± S.E. :j: N.S., not sigoificant ± N.S.:j: 196 ± ± ± 26 ± 19 2 N.S. 0 6 N.S. 1 7 N.S. ± 8.3 ± ± 9.7 ± ± N.S. ± ± 10.9 TABLE 4. Mean Value of Serum Total Lipids (Lip_), Cholesterol (Chol.), and Triglycerides (TO) According to Duration of Therapy with Various Oral Contraceptives cycles Gynovlar Chol. TG Metrulen Lip. Chol. TG Nogest-S Lip. Chol. TG Sequelan Lip. Chol. TG TOTAL CHOLESTEROL, TRIGLYCERIDES mg /l00ml 300 l'o llo 240 llo loa '80 / I f- --f---i---f TOTAL LIPIDS r / TOTAL CHOLESTEROL J ~ ~_~_t--~----f-j,--f TOTAL LIPIDS rna/100 ml '60,lO ' <0 ( / TAI&LVCERIDES f _-L--f---L --t I ;[;---r--- - r I /I U Number of cycles FIG. L Serum lipids according to the duration of contraceptive therapy. is impossible to compare the biologic effects of the different estrogen"progestin combinations, we have found the same mean lipid content in patients taking Gynovlar and Nogest-S. In the latter combination the estrogenic agent is the same as in Gynovlar, mainly ethynyl estradiol, but in different amounts, while the progestagen is different. Previous studies suggested that the estrogen in the oral contraceptives are respon- I.-

4 September 1971 ORAL CONTRACEPTIVES 607., sible for the adverse effect on lipid metabolism. 15, 16 Elevated serum triglycerides were found in premenopausal women treated with estrogens, 14, 15 but not in oophorectomized subjects. 17 Progesterone administration had no significant effect on the serum lipids. 17 This last statement was supported by Larsson-Cohn, Berlin, and Vikrot,18 that no alterations in triglycerides, total cholesterol, and free fatty acids were found in women taking low-dose gestagens as contraceptives. Our [mdings of no change in total cholesterol levels during contraceptive treatment confirm earlier reports,6, 18, 19 but are contradictory to other studies. 7,8 Estrogen has been reported to diminish the cholesterol, phospholipid ratio by increasing serum phospholipid concentration and/or lowering serum cholesterol levels. In hypercholesterolemic subjects, estrogen administration lowers serum cholesterol concentrations. SUMMARY Serum total lipids, cholesterol, and triglycerides were estimated in subjects taking different oral contraceptives. A marked rise in serum total lipids and triglycerides was seen in those taking contraceptives, while there was no significant change in cholesterol concentration. There was no direct correlation between the duration of contraceptive therapy and serum lipid values, and no significant difference among those taking different steroid compositions of the "Pill." The mechanism of the adverse effect of oral contraceptives on lipid metabolism is discussed. REFERENCES 1. VON STUDNITZ, W. Studies on serum lipids and lipoproteins in pregnancy. Scand J Clin Lab Invest 7:829, DE ALVAREZ, R R, GAISER, D. F., SIMILSINS, D. M., SMITH, E. K., AND BRATVOLD, G. E. Serial studies of serum lipids in normal pregnancy. AmerJ Obstet Gynec 77:743, I'ETIERS, J. P., HEINEMAN, M., AND MAN, E. B. The lipids of serum in pregnancy. J Clin Invest 30:388, Russ, E. M., EDER, A., AND BARR, D. P. Influence of gonadal hormones on protein-lipid relationships in human plasma. Arner J Med 19:4, OLIVER, M. F., AND BoYD, G. S. The influence of the sex hormones on the circulating lipids in coronary sclerosis. Circulation 13:82, PINCUS, G. In Control of Fertility. Acad. Press, New York, 1965, p AURELL, M., CRAMER, K., AND RYBO, G. Serum lipids and lipoproteins during long term administration of oral contraceptives. Lancet 1 :251, WYNN, V., DOAR, J. W. H., AND MILLS, G. L. Some effects of oral contraceptives on serum lipid and lipoprotein levels. Lancet 2:7, KUNKEL, H. G., AHRENS, E. H., AND EISENMEN GER, W. J. Application of turbidimetric methods for estimation of gamma globulin and total lipid to the study of patients with liver disease. Gastroenterology 11 :499, ZAK, B., DICKENMAN, R C., WHITE, E. G., BUR NETT, H., AND CHERNEY, P. J. Rapid estimation of free and total cholesterol. Arner J Clin Path 24:1307, DOLE, V. P., AND MEINERTZ, H. Microdetermination of long-chain fatty acids in plasma and tissues. J Bioi Chern 235:2595, LAMBERT, M., AND NEISH, A. Rapid method for estimation of glycerol in fermentation solutions. Canad J Res 28:83, HAZZARD, W. R, SPIGER, M. J., BAGDADE, J. D., AND BIERMAN, E. L. Studies on the mechanism of increased plasma triglycerides levels induced by oral contraceptives. New Eng J Med 280:471, BRODY, S., HOGDAHL, A. M., NILSSON, L., SVAN BORG, A., AND VIKROT, O. The effect of some ovulation inhibitors on the lipid metabolism. Acta Med Scand 179:501, GERSHBERG, H., HULSE, M., AND JAVIER, Z. Hypertriglycerilemia during treatment with estrogen and oral contraceptives. Obstet Gynec 31 (Suppl.) 186:189, BARTON, G. M. G. AND FREEMAN, P. R Oral contraceptives and serum lipids. J Obstet Gynaec Brit Cornrn 77:551, SVANBORG, A., AND VIKROT, O. The effect of estradiol and progesterone on plasma lipids in oophorectomized women. Acta Med Scand 179: 615, LARSSON-COHN, M., BERLIN, R, AND VIKROT, O. Effects of combined and low dose gestagen oral

5 ) \ SCHENKER ET AL. Vol. 22 contraceptives on plasma lipids. Acta Endocr (Kobenhavn) 63:717, CORREDOR, D. G., MANDELSOHN, L. V., SABEH, G., SUNDER, J. M., AND DAWOVSKI, T. S. Serum lipids during oral contraceptive exposure. Clin Pharmacol Ther 11:188, FuRMAN, R. H., ALAUPOVIC, P., AND HOWARD, R. P. Effects of androgens and estrogens on serum lipids and the composition and concentration of serum lipoproteins in normolipemic and hyperlidemic states. Progr Biochem Pharmacol 2:215, 1967.