LIPID AND CARBOHYDRATE METABOLIC STUDIES AFI'ER ONE YEAR OF MEGESTROL ACETATE TREATMENT*

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1 FERTLTY AND STERLTY Copyright 1976 The American Fertility Society Vol. 27, No. 2, February 1976 Printed in U.S.A. LPD AND CARBOHYDRATE METABOLC STUDES AF'ER ONE YEAR OF MEGESTROL ACETATE TREATMENT* WLLAM N. SPELLACY, M.D., ROGER E. NEWTON, M.D.,t WLLAM C. BUH, M.S., AND SHARON A. BRK, B.S., R.N. Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, Florida 32610, and The Mead Johnson Research Center, Evansville, ndiana Few studies have concerned themselves with the metabolic effects of individual contraceptive steroids. 1 Such data are critical for a complete understanding of the secondary effects of oral contraceptives. The present investigation is an extension of previous work 2 with oral megestrol acetate (MA) (0.5 mg, provided by the Mead Johnson Research Center, Evansville, nd.). The lipid and carbohydrate metabolic parameters were investigated prospectively during 1 year of therapy. An oral glucose tolerance test was used as the stimulus. MATERALS AND METHbDS Twenty-two women participated in the study. All of the subjects were informed about the study and consented to participate. The protocol has been described previously. 2 Briefly, all subjects were investigated before steroid therapy was begun. Each subject was tested with a 3-hour, 100-gm oral glucose tolerance test in a fasting-resting state. They were then instructed to take the MA daily for contraception. Each woman was seen regularly to replace medication, to answer questions, and to be examined physically. Received July 3, *Supported in part by a grant from the Mead Johnson Research Center, Evansville, nd.; Ford Foundation Grant ; National nstitutes of Health Grant HL-14141; and Grant M69.87 from The Population Council of New York. tmead Johnson Research Center, Evansville, nd. 157 After 1 year of continuous daily oral steroid treatment, each subject was brought back to the research laboratory in a fasting state, and an identical repeat tolerance test was performed. Thus each woman served as her own control for the pre- and postdrug treatment tests. During the test, venous blood samples were obtained at the fasting and 0.5-, 1-, 2-, and 3-hour time periods. The paired blood samples from the two tests were later analyzed in duplicate for cholesterol, triglyceride, glucose, insulin, and growth hormone content by the methods previously described. 2-4 Since these were paired data, all of the information was placed on punch cards and analyzed with the aid of a computer for means, standard errors, differences, means of the differences, and Student's t-test values. The probabilities were calculated from two-tailed tables, and only values of less than 0.05 were considered significant. The women under study were characteristic of a family-planning population. The mean age was 24.6 years (± 1.1 SEM) and the mean parity was 2.7 (± 0.4 SEM). The mean control weight was pounds(± 6.2 SEM) and the mean 1-year weight was pounds (± 7.1 SEM), which were not significantly different (mean difference, 5.6 pounds; t= ). No significant complications were encountered during treatment or testing.

2 158 SPELLACY ET AL. February 1976 TABLE 1. Statistical Studies offasting Blood Lipids in Women before and after 1 Year of Oral Megestrol Acetate Treatment (N = 22) Lipid test Statistical analysis Cholesterol Triglyceride Control 1 Yr Control 1 Yr Mean SEM 10.2 Mean difference 10.3 t p NS RESULTS mg/100 ml NS Cholesterol. The statistical studies of the fasting cholesterol values are shown in Table 1. Although the mean value for the group increased 7.4% between the control and the 1-year time period, this change was not significant. Triglycerides. The results of the fasting triglyceride studies are also shown in Table 1, and again the change between the two tests was not significant. Glucose. The data from the two glucose tolerance tests are analyzed in Table 2 and the mean values are plotted in Figure 1. The fasting values were unchanged. There was a significant elevation of the values at 0.5 and 2 hours in the test after 1 year of therapy. None of the individual curves became abnormal. nsulin. The plasma insulin values for the group are analyzed in Table 3 and the mean values for the two tests are plotted in Figure 2. There were signifi- "E = ''' f' ' \ o,......, ' 100 =. 80 E... r '. 60 ORAl NGESTON = 100 im GLUCOSE :;;: 40 - CONTROL "" o---o 12 MONTHS 'p < O F. 0 5 ast1ng. TME N HOURS AFTER GLUCOSE NGESTON FG. 1. Mean values for blood glucose before and after 1 year's treatment of women with a daily, oral, 0.5-mg dose of megestrol acetate W = 22). cant elevations of all but the 0.5-hour value for the 1-year test. This is in marked contrast to the data obtained after only 6 months of treatment. 2 Growth Hormone. The mean fasting plasma growth hormone level for the control test was 6.4 ng/ml (± 1.7 SEM); after 1 year the mean level was 5.4 ng/ml (± 1.6 SEM). These differences were not significant (t= ). DSCUSSON A careful review of the literature dealing with steroid contraception and lipidcarbohydrate metabolism is confusing. Studies with different designs, different populations, and different steroids yield 'o TABLE 2. Statistical Studies of Blood Glucose Levels during an Oral Glucose Tolerance Test Performed in Women before and after 1 Year of Oral Daily Treatment with 0.5 mg of M egestrol Acetate (N = 22) Statistical analysis Control 1 Year Fasting 0.5 Hr 1 Hr 2 Hr 3 Hr Fasting 0.5 Hr 1 Hr 2Hr 3 Hr mg/100 ml Mean SEM Mean difference t p NS <0.05 NS <0.05 NS

3 Vol. 27, No.2 EFFECTS OF MEGESTROL ON METABOLSM 159 TABLE 3. Statistical Studies of Plasma nsulin Levels during an Oral Glucose Tolerance Test Performed in Women before and after 1 Year of Oral Daily Treatment with 0.5 mg of Megestrol Acetate (N = 22) Statistical analysis Control Fasting 0.5 Hr 1 Hr 2 Hr Mean SEM Mean difference t p <0.05 NS <0.05 < Year 3 Hr Fasting 0.5 Hr 1 Hr 2 Hr 3 Hr pll/ml <0.05 different results. 1 n addition, different investigators interpret the results in varying ways. t is clear that some parameters of both lipid and carbohydrate metabolism are altered by certain of the estrogen and progestogen steroids. 1 n order to define these drug effects more accurately, long-term prospective investigations of "normal" populations using individual steroids have been undertaken. Detailed analyses of both lipid and carbohydrate metabolism were made in the same group of women. n the present investigation no significant alterations in fasting cholesterol or triglyceride levels were detected. This is in keeping with the data reported after 6 months of study and the fact that most of the previously 120 e 100 ;;;- "'- 80., = :!!!: :., :E ,...a, o',..,.. ',, i :... <=> :..., * 'o :; : \ 5: \ / \ \ ol 1/ -\\\ \ \ o f - CONTROL o---o 12 MONTHS "p < 0.05 p < 0.01 Fasting TME N HOURS AFTER GLUCOSE NGESTON Fra. 2. Mean values for plasma insulin before and after 1 year's treatment of women with a daily, oral, 0.5-mg dose of megestrol acetate W = 22). reported studies associated t:p.e lipid alterations regularly with the estrogenic steroids. 1 The current data do show that certain parameters of carbohydrate metabolism are altered after 1 year of treatment. Although the blood glucose curves were only minimally affected, the plasma insulin levels, as measured by a radioimmunoassay technique, were significantly elevated after treatment. Since the fasting growth hormone levels and patient weights were not altered, it is unlikely that these ere involved in the mechanism of change. t would appear that MA increased peripheral insulin resistance and therefore more pancreatic f3-cell insulin was being released in order to maintain glucose homeostasis. These findings are in slight contrast to those reported after only 6 months of treatment, for at that time only minimal changes were noted in the glucose and insulin curves. 2 Other investigators have also studied the metabolic effects of MA. Pyorala and co-workers 5 administered 1 mg ofma plus 0.1 mg of ethinyl estradiol to six women for 5 days and noted no significant changes in the blood glucose values during an intravenous glucose tolerance test. Starup and associates 6 gave 5.0 mg ofma plus 0.1 mg of mestranol to 27 women for 1 year. They also noted no change in either the blood glucose or plasma insulin curves during an intravenous glucose tolerance test. Adams and Wynn 7 treated 31 women for 5.6 months (range, 3 to 18 months) with 0.5 mg of MA and did not

4 160 SPELLACY ET AL. February 1976 find any change in the glucose, insulin, pyruvate, cholesterol, or triglyceride levels during oral and intravenous glucose tolerance tests. Vermeulen et al.,8 however, administered 4.0 mg ofma plus 0.05 mg of ethinyl estradiol daily to 15 women for 12 to 16 months and conducted paired intravenous glucose tolerance tests. They noted an elevation of insulin levels at the fasting and 30- to 90-minute periods, while the glucose values were unchanged. The importance of these findings relates to four areas. First, this study points out the necessity for a long-term investigation, since the results appear to change with time. This should reaffirm the caution that must be exercised in comparing the literature, since grouping short-term (weeks) and long-term (years) study results is probably not valid. t is not surprising from other studies in the field of clinical pharmacology that the duration of treatment may have an effect on the results, as does drug type and dosage. Second, extrapolation of the results of investigations in which individual steroids were used to those in which combinations of steroids were used may not be possible. Both cumulative and synergistic effects are probable. Third, the basic mechanisms involved in contraceptive steroid-induced metabolic changes are still not understood. Whereas growth hormone and vitamin B 6 metabolism were once implicated, the results are now uncertain. 1 9 At one time the elevations in blood pyruvate levels accompanying oral treatment were suggested to represent a cortisol-like effect on the liver10; however, more recent data suggest that altered pyruvate levels could be related to a vitamin deficiency (B 1). 11 Thus, considerably more study of the mechanism of change is needed. Finally, the earlier studies implied that, principally, the 19- nor progestogens were involved in the carbohydrate changes. The present data suggest that all of the progestogens might be involved in the carbohydrate changes. The present data also imply that all of the progestogens must be carefully evaluated with regard to their effects on metabolism. SUMMARY A prospective study of lipid and carbohydrate metabolic parameters was made in 22 women who had taken a daily oral dose of 0.5 mg of megestrol acetate for contraception for 1 year. Studies of the fasting blood cholesterol and triglyceride levels demonstrated no significant change. A 3-hour oral glucose tolerance test was performed before and after 1 year of treatment. After therapy, the fasting blood glucose levels were normal but the 0.5- and 2-hour levels were elevated. All but one of the plasma insulin levels were elevated at the 1-year test. Since body weights and the fasting levels of plasma growth hormone were unchanged, they were probably not involved in the carbohydrate alteration. These results point out the need for long-term studies and the necessity for investigating the metabolic effects of all progestogen contraceptives. Acknowledgments. The authors thank Ms. S. McCreary and Mr. G. Harris for their help in these studies. They also thank Mrs. J annet Cassady for her help in the statistical analysis of these data. REFERENCES 1. Spellacy WN: Metabolic effects of oral contraceptives. Clin Obstet Gynecol17:53, Spellacy WN, Newton RE, Buhi WC, Birk SA: Carbohydrate and lipid studies during six months' treatment with megestrol acetate. Am J Obstet Gynecol116:1074, Spellacy WN, Ashbacher LV, Harris GK, Buhi WC: Total cholesterol content in maternal and umbilical vessels in term pregnancies. Obstet Gynecol 44:661, Spellacy WN, Carlson KL, Schade SL: Human growth hormone levels in normal subjects receiving an oral contraceptive. JAMA 202:451, 1967

5 Vol. 27, No.2 EFFECTS OF MEGESTROL ON METABOLSM Pyoriila K, Pyorala T, Lampinen V: Sequential oral contraceptive treatment and intravenous glucose tolerance. Lancet 2:776, Starup J, Date J, Deckert T: Serum insulin and intravenous glucose tolerance in oral contraception. Acta Endocrinol (Kbh) 58:537, Adams PW, Wynn V: The effect of a progestogen, megestrol acetate, on carbohydrate and lipid metabolism. J Obstet Gynaecol Br Commonw 79:744, Vermeulen A, Daneels R, Thiery M: Effects of oral contraceptives on carbohydrate metabolism. Diabetologia 6:519, Rose DP, Adams PW: Oral contraceptives and tryptophan metabolism: effects of oestrogen in low dose combined with progestogen and of a low-dose progestogen (megestrol acetate) given alone. J Clin Pathol 25:252, Doar JWH, Wynn V: Effects of obesity, glucocorticoid, and oral contraceptive therapy on plasma glucose and blood pyruvate levels. Br Med J 1:149, Briggs MH, Briggs M: Thiamine status and oral contraceptives. Contraception 11:151, 1975