Carbohydrate metabolism prospectively studied in women using a low-estrogen oral contraceptive for six months

CONTRACEPTION

CARBOHYDRATE METABOLISM PROSPECTIVELY STUDIED IN WOMEN USING A LOW-ESTROGEN ORAL CONTRACEPTIVE FOR SIX MONTHS

W.N. Spellacy, M.D.* W.C. Buhi, M.S. S.A. Birk, R.N., B.S.

The Department of Obstetrics and Gynecology at the University of Florida College of Medicine Gainesville, Florida 32610

*Present Address and for Reprints Department of Obstetrics and Gynecology, The Abraham Lincoln School of Medicine, 840 South Wood Street, Chicago, Illinois 60612

ABSTRACT Twenty-four women were prospectively evaluated for their carbohydrate metabolic status before and after six months of using an oral contraceptive containing 0.035 mg ethinyl estradiol and 0.4 mg of At each testing,a lOO-gm oral glucose load was adminnorethindrone. istered and blood glucose and plasma insuli_n values were measured Nineteen women with "normal" control tests over a three-hour period. demonstrated a significant decrease in their fasting glucose vall:es and two of these women (10.5%) had a slight deterioration of their There were no other significant glucose or insulin glucose curves. They had no change in weight and there was a significant changes. reduction in their blood pressure during the treatment time. Five women had "borderline abnormal" control glucose tests, and four of these (80%) improved during the six months of treatment, and two of them (40%) became "normal." Thus, there is no evidence of an adverse effect of this low-estrogen oral contraceptive on carbohydrate metabolism during six months of therapy. Accepted

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10,

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CONTRACEPTION INTRODUCTION

Continued surveillance of women using oral contraceptives has disclosed the fact that metabolic changes occur with time. These changes result in elevations of blood pressure, blood glucose, and blood triglycerides (1). Following the discovery of these alterations, there was a widespread concern that atherogenesis might be accelerated and that blood vessel diseases would become more frequent in users following long durations of use. Recently, epidemiologic studies have shown that myocardial infarction is more common in women using these drugs for five or more years (2,3). In an attempt to reduce these potential problems, new formulations have been produced which contain lower amounts of estrogen. This report describes prospective studies of carbohydrate metabolism in women using a low-estrogen type oral contraceptive for six months' time.

METHODS

Twenty-four women attending a Family Planning Clinic volunteered to participate in this study. Each woman had decided to use oral contraceptives and after this study was explained to them, each signed an informed consent which had been approved by the University Committee The women were all at least three months on Human Experimentation. postpartum or had not been using steroid contraceptives for that length The testing has already been described and will therefore of time. only be briefly outlined (4). Each woman was brought to the metabolic laboratory at 0800 after having ingested a high carbohydrate diet for They were each fasting for at least ten the three preceding days. hours and were kept at rest during the test. After an antecubital venous blood sample was drawn, they were each given a solution conRepeat venous blood samples taining 100 gms of glucose to drink. The were then drawn at 0.5, 1, 2 and 3 hours after the glucose load. women were then given a low-estrogen oral contraceptive co t ining Pa? 0.035 mg of ethinyl estradiol and 0.4 mg of norethindrone . They were instructed to take the pills daily and they were seen regularly The women all returned for drug refills and to answer questions. for an identical repeat metabolic test at the end of six months of Each woman served as her own control (with a pre- and posttherapy. treatment test) thus giving matched-pair data. The All of the blood samples were divided between two tubes. first contained sodium fluoride and potassium oxylate and was mixed well; later the glucose content was measured in duplicate (5,6). The other aliquot was mixed with heparin, centrifuged and the plasma Later all of the plasma samples from removed and frozen at -2O'C. (a) The oral contraceptive Ovcon (R) was kindly Johnson Company of Evansville, Indiana.

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the two tests on each subject were analyzed in duplicate for their insulin content using a modified solid-phase radioimmun say procedure in order to eliminate interassay variations (7,8). ?V The original glucose tolerance test (curve was classified by the Wilkerson point score method. Only four oE the glucose values were used for this classification (fasting 1,2, and 3 hours). Thus, if the curve had zero points it was termed "normal", if it had 0.5 to 1.5 points it was termed "borderline abnormal" (9). There were no "abnormal" control curves which would require 2.0 or more points. There were nineteen women with "normal" control tests and five with "borderline abnormal" control tests and the subjects were then analyzed in those two subgroups. All of these data were put on punch cards and analyzed with the aid of a computer. Calculations were made of the means, standard deviations, standard errors, and ,Student's t values for matched-pair data. The probability values were taken from two-tailed tables and only values less than 0.05 were considered significant. The women in the study were similar to those in most family planning studies. In the "normal" subgroup the mean age was 21.9 Z! S.E.M. 0.8 years and their mean parity was 1.1 2 S.E.?i. 0.3 Their mean control weight was 137.6 f S.E.M. 5.2 and their mean six-month weight was 140.1 ? S.E.M. 5.6 which was not signiEicantly different (t=0.322). Their mean control systolic blood pressure was 118.9 ? S.E.M. 1.7 and at six months it was 103.8 2 S.E.M. 2.7 an3 this was a significant reduction (t=4.709 p
RESULTS

I.

Blood Glucose A.

"Normal" Subgroup The statistical studies of the blood glucose results for the nineteen women with the "normal"contro1 test are given in Table I, and the mean values are shown in Figure 1. It can be seen that there was a significant lowering of the fasting glucose value at the sixmonth treatment test and none of the other values were significantly altered. The individual glucose curves were also analyzed and there were two (10.5%) that changed into the "borderline abnormal"

(b) The human insulin used as a standard in these assays was Lot No. 516-734-B33 which was generously supplied by Dr. Mary Root of the Lilly Research Laboratories of Indianapolis, Indiana.

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140

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150-

140-

130 -

120-

M A*p

70

-

60

-

501

1 IOOgm I FASTING

ORAL

GLUCOSE

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6 MONTHS

LOAD

I

I

1

I

I

2

3

IN

i

< 0.005

0.5

TIME

Figure 1

CONTROL -

HOURS

Mean f S.E.M. blood glucose values in mg/dl for 'tnormall' women tested before and after using an oral contraceptive containing 0.035 mg ethinyl estradiol and 0.4 mg norethindrone for six months (N=19).

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classification,

having

0.5 and 1.5 points.

"Borderline Abnormal" Subgroup The Wilkerson point scores for the two glucose tolerance tests in each of these patients are shown in Table II. It can be seen that four (80%) of the tests changed classification with two (40%) of them becoming "normal." There were no significant changes in the group glucose levels. B.

2.

Plasma

Insulin The statistical studies of the plasma insulin results for the "normal" subgroup are given in Table III and the mean values are plotted in Figure 2. It can be seen that there were no significant changes and this was also true for the data from the "borderline abnormal" subgroup. DISCUSSION Studies of the secondary metabolic effects of oral contraceptives have been of increasing interest to all because of the possible relationship of these changes to an accelerated vascular aging process in women The studies demonstrating an increased risk of myousing these drugs. cardial infarction and presumably atherogenesis in OC users were have been alarming (2,3). Almost all of these metabolic investigations carried out in women using drugs containing 50 or more micrograms of type products are now widely marketed estrogen (1). Newer low-estrogen and have acceptable pregnancy rates so it seemed advisable to investigate their metabolic effects (10). Few studies have been published on the effects of low-estrogen type oral contraceptives on carbohydrate metabolism and most of them used The prospective studies by Wynn and coworkthe progestogen norgestrel. ers over three months' time noted no glucose alterations, but there were elevations of the plasma insulin levels (11). Cross-sectional studies by Wynn et al. with 30 pig ethinyl estradiol plus norgestrel showed an elevation of both blood glucose and plasma insulin levels (12). Hausmann and associates studied fifteen women using a drug with 30 micrograms of ethinyl estradiol and norgestrel and also noted a significant rise in insulin but no change in blood glucose levels (13). The crosssectional fasting data by Briggs and Briggs on women taking ethinyl estradiol and norgestrel noted no alterations in glucose (14). An earlier study from this laboratory demonstrated no deterioration in carbohydrate metabolism in women treated for only three months' to time (4). The study reported here now extends these observations six months and these data confirm the fact that no deterioration occurred when 35 micrograms of ethinyl estradiol was taken with norethindrone. Indeed, there was a significant reduction in the fasting blood glucose levels for the "normal" women and improvement in the glucose curve classfication for most of the"borderline abnormal" women.

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WILKCRSON POINT SCORES FRO\!THE ORAL GLUCOSI''TOLERANCETCST' OK lQO!CNDCFORI:AND AFTER SIX IlONTfIS OF TRl,4'l?lENT WITH AN OR41,CONTRACCPTIVE CONTAINING 0.0:.5mg ETHJNYL ESTRADIOL AND 0.1 mg NORETHINDICONI. i\=5)

Glucose Curve Wilkerson Point Score Control

?-lean S.C.bl. t P

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0.5

0

O..i

0

0.5

1.5

1.0

0.5

1.5

1.0

0. n 0. 3 Not significant

143

%

e

,

0.371

N .L. $ k

t

P

N.S.

0.525

25.3

137.7

0.5

N.S.

1.513

12.1

114.7

1

Control

-'N.S. indicates -not significant

4.5

21.0

Mean

S.E.M.

Fasting

Time

Test

N.S.

0.457

10.3

106.0

2

N.S.

0.162

12.9

72.0

3

I

3.7

23.2

Fasting

18.9

154.2

0.5

1

18.8

148.9

Six-Month

STATISTICAL STUDIES OF PLASMA INSULIN IN vUNITS/ml FOR "NORMAL" WOMEN USING AN ORAL CONTRACEPTIVE CONTAINING 0.035 mg ETHINYL ESTRADIOL AND 0.4 mg NORETHINDRONF FOR SIX MONTHS (N=19)

TABLE III

12.4

113.4

2

8.7

74.5

3

p

CONTRACEPTION

-c 2

1-- T.

150c

CONTROL 6 MONTH

$ 50 51 d Int ”

1 FASTING

1 100 am ORAL GLUCOSE

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2

I

0.5

TIME

Figure 2

LOAD 3

IN HOURS

Mean 2 S.E.?l.plasma insulin values in pIJnits/mlfor "normal" women tested before and after using an oral contraceptive containing 0.035 mg ethinyl estradiol and 0.4 mg norethindrone for six months (N=19).

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These results are interesting because similar studies with just the progestogen norethindrone have demonstrated that there was a deterioration of carbohydrate metabolism during a six-month period of Studies with high-dose estrogen-containing oral contracepuse (15). tives also showed a deterioration of carbohydrate metabolism (1). Studies with estrogen alone in both animals and humans have demonstrated a biphasic effect, that is, low doses tend to improve carbohydrate metabolism whereas higher doses are associated with a deterioration (16). It would thus appear from the present study, that the reduced estrogen dose in this OC was enough to counterbalance the mild progestogen effect and that the net result is a stable to slightly improved carbohydrate metabolic state. More potent progestogens such as norgestrel do not appear to be counterbalanced by the low dosage of estrogen, however If these results hold with increased patient numbers and longer (11-14). durations of use, then a clear advantage seems apparent from this lowFinally, prolonged follow-up will be necessary estrogen formulation. to see if clinical differences in conditions such as atherogenesis can be recognized.

ACKNOWLEDGMENT

The authors would like to thank Mrs. M. Rountree for her help with these studies and Ms. E. Wells for her assistance in preparing this manuscript.

SUPPORT

These studies were supported Company of Evansville, Indiana.

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by a grant

from the Mead Johnson

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REFERENCES

1.

Carbohydrate metabolism in male infertility and Spellacy, W.N.: female fertility-control patients. Fertil Steril 27:1132-1141 (1976).

2.

Mann, J.I., Vessey, M.P., Thorogood, M., and Doll, R.: Myocardial infarction in young women with special reference to oral ccntraceptive practice. Brit Med J 2:241-245 (1975).

3.

Royal College of General Practitioners: Mortality traceptive users. Lancet 2:727-731 (1377).

4.

Spellacy, W.N., Buhi, W.C., and Birk, :S.A.: Carbohydrate metabolism in women using a low-estrogen or.31 contraceptive for three months. Obstet Gynec (In press).

5.

Nelson, N.: Photometric adaptation of Somogyi method for determination of glucose. J Biol Chem 153:375-380 (1944).

6.

Somogyi, (1945)

M.:

Determination

of blood

sugar.

among oral con-

3 Biol Chem 160:69-73

Goetz, F.C., Greenberg, B.Z., Ells. J., and Meinert, C.: A simple immunoassay for insulin: Application to human and dog plasma. J Clin Endocr 23:1237-1246 (1963). Herbert, charcoal (1965).

V., Lau, K., Gottlieb, C.W., and Bleicher, S.J.: Coated immunoassay of insulin. J Clin Endocr 25:1375-1384

Wilkerson, H.L.C.: Diagnosis: Oral glucose tolerance tests in Diagnosis and treatment. (T.S. Danowski, -diabetes mellitus: Editor) American Diabetes Association Inc., New York, 1964, p '31-34. 10.

Sartoretto, J.N., Ortega-Recio, J.C., Moraes, R., and Filho, F.N.: Clinical studies with a low dose estrogen-progestogen combination. Contraception 15:563-570 (1977).

11.

Wynn, V., Adams, P., Oakley, N., and Seed, M.: Metabolic investigations in women taking 30 pgm ethinyl estradiol plus 150 ug d-norgestrel. Excerpta-Medica Int Cong Series 344:47-57 (1974).

12.

Wynn, V., Adams, P.W., Godsland, I., Melrose, J., Niththyananthan,R. Oakley, N.W., and Seed, M.: Comparison of effects of different combined oral-contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1:1045-1049 (1979).

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Hausmann, L., Goebel, K.M., Klshn, D., and Kaffarnik, H.: Insulin-und proinsulin-sekretion be: Anwendung ant: konzeptioneller steroide. Klin Wschr 53:853-860 (1975).

14.

Briggs, M.H. and Briggs, 14.: Clinical and biochemical investigations of an ultra low-dose combination type oral contraceptive. Curr Med Res Opinion 3:618-623 (1976).

15.

Spellacy, W.N., Buhi, W.C., Birk, S.A., and McCreary, S.A.: Metabolic studies in women taking norethindrone for 6 months' time (measurements of blood glucose, insulin and triglyceride concentrations). Fert Steril 24:419-425 (1973).

16.

Spellacy, W.N.: contraceptives.

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A review of carbohydrate metabolism and the oral Am J Obstet Gynec 104:448-460 (1969).

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