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Studies of Chlormadinone Acetate and Mestranol on Blood Glucose and Plasma Insulin. II. Twelfth Month Oral Glucose Tolerance Test*
Vol. 22, No.4, April 1971
FmTn.rrY AND STERILrrY
Copyright
@
Printed in U.S.A.
1971 by The Williams & Wilkins Co.
STUDIES OF CHLORMADINONE ACETATE AND MESTRANOL ON BLOOD GLUCOSE AND PLASMA INSULIN. II. TWELFrH MONTH ORAL GLUCOSE TOLERANCE TEST* W. N. SPELLACY, M.D., W. C. BURl, M.S., S. A. BIRK, B.S., R.N.,
AND
S. A. McCREARY, B.S.
Department of Obstetrics and Gynecology, University of Miami School of Medicine, Miami, Florida
In a previous article it was noted that carbohydrate metabolism was adversely affected in some women taking mestranol and chlormadinone acetate for 6 months' time. 1 The purpose of the present article is to extend these data by reporting blood glucose and plasma insulin levels during an oral glucose tolerance test on 53 women taking the same steroids for 12 months. PROCEDURE
The women were all volunteers from the family planning clinic at Jackson Memorial Hospital. The testing procedure has already been described. l Briefly, a standardized oral glucose (100 gm.) tolerance test was performed more than a month postpartum before the women were started on the drug. t This identical test was then repeated after 12 months of drug usage. The venous blood samples were drawn in a fasting state and at 0.5, 1, 2, and 3 hr. after the glucose ingestion. The blood for glucose determination was analyzed in duplicate by the method of Nelson and Somogyi. 2, 3 The plasma was assayed in duplicate for its insulin content by a modified solid-phase radioimmunoassay procedure. 4 , 5 The matched-pair data were then placed on • These studies were supported in part by funds from the Public Health Service, Consumer Protection and Environmental Health Service, Food and Drug Administration, and Department of Health, Education, and Welfare, under Contract CPF 69-32. t The drug used was CT-902-7E containing mestranol 0.1 mg. for 15 days, mestranol 0.1 mg. and chlormadinone acetate 1.5 mg. for 8 days, and 5 placebo tablets. This drug was kindly supplied by Dr. J. M. Maas of the Eli Lilly and Company, Indianapolis, Ind.
224
punch cards and appropriately analyzed with the aid of a computer. The women had a mean age of 22.7 years (S.E.M., 0.8; range, 14-37), and a mean parity of 2.5 (S.E.M., 0.3; range, 0-13). The predrug mean weight was 131.1 lb. (S.E.M., 3.2; range, 94-203), and the mean 12-month weight was 133.7 lb. (S.E.M., 3.9; range, 95-240). This difference was not significant (t = 1.6068). There were 27 women who gained weight and 24 women who lost weight during the year, and the others were unchanged. RESULTS
Blood Glucose. The 53 subjects were divided into three subgroups on the basis of the first control glucose tolerance test results utilizing the Wilkerson Point System 6 (see Table 1). On this basis there were 50 women in the normal subgroup, 2 women in the borderline abnormal subgroup, and 1 woman in the I).bnormal subgroup. The statistical studies of the blood glucose results for the total group and the normal subgroup are shown in Tables 2 and 3. The normal subgroup values are plotted in Fig. 1. It can be seen that there are no significant differences between the two test results. The fasting blood glucose decreased for 23 women, increased for 27 women, and remained unchanged for 3. The tolerance curves in the normal subgroup were changed in their Wilkerson ratings for 5 women (see Table 4). Thus, 10% of the curves became borderline abnormal at the I-year test, but none had become abnormal. The two women in the borderline ab-
t
April 1971
225
CHLORMADINONE ACETATE. II.
normal group had their glucose curve points change from I to 0 and 0.5 to 1.5, respectively. The I subject with the abnormal control curve had her points change from 2 to 0 after I year. Plasma Insulin. The statistical studies of the plasma insulin results for the total group and the normal subgroup are shown in Tables 5 and 6. The normal subgroup values are plotted in Fig. 2. There is a significant increase in the plasma insulin
levels at the I2-month test for all values except the I-hr. sample. Correlating Factors. Studies of the individual factors which might be associated with carbohydrate metabolic alterations in these women were done by determining the correlation coefficients between each change in glucose or insulin, and the continuous variables of age, parity, and weight
~
E
TABLE 1. The Wilkerson Point System for Interpreting the 3-hr 100-gm. Oral Glucose Tolerance Test" Time
Blood glucose
hr.
mg. %
Fasting 1 2 3
110 or more 170 or more 120 or more 110 or more
Points·
.-e
CONTROl 0----0 J2 MONTHS
140
8
~ 120 Ol
~
o~ 100 u ~
(5 80 o
o 9
1 0.5 0.5 1
~
60'~L-
__~~__~______~________~__
~~
~
TIME
* Definition, normal curve, 0 points; borderline abnormal curve, 0.5-1.5 points; abnormal curve, 2 or more points.
3 In
HOURS AFTER INGESTION
FIG. 1. Mean blood glucose levels in "normal" women before and after 12 months of treatment with a sequential oral contraceptive containing mestranol and chlormadinone acetate. The curves are not significantly different (N = 50).
TABLE 2. Statistical Studies of Blood Glucose Levels in mg./100ml. for Women Taking a Sequential Oral Contraceptive Containing Mestranol and Chlormadinone Acetate for 12 Months (N = 53) 12-month test
Control test
Parameters measured
state
At 0.5 hr.
At 1 hr.
At2 hr.
At3 hr.
Fasting state
At 0.5 hr.
At 1 hr.
At2 hr.
At3 hr.
Mean S.D. S.E.M. t
84.3 10.9 1.5 1.2662
120.2 23.6 3.2 0.2529
108.6 28.4 3.9 1.2281
90.4 17.0 2.3 1.3622
77.7 19.7 2.7 1.1005
82.1 8.9 1.2
121.1 24.7 3.4
105.6 26.8 3.7
94.6 21.9 3.0
77.9 20.3 2.8
P
N.S.*
N.S.
N.S.
N.S.
N.S.
Fasting
* N.S., not significant.
TABLE 3. Statistical Studies of Blood Glucose in mg./100 mi. for the Normal Subgroup Taking a Sequential Oral Contraceptive Containing Mestranol and Chlormadinone Acetate for 12 Months (N = 50) 12-month test
Control test Parameters measured
Fasting state
At 0.5 hr.
At 1 hr.
At2 hr.
At3 hr.
Fasting state
At 0.5 hr.
At 1 hr.
At2 hr.
At3 hr.
Mean S.D. S.E.M.
83.7 9.8 1.4 0.8688
117.5 21.4 3.0 0.9245
105.9 24.5 3.6 0.6854
90.2 16.4 2.3 1.4035
76.6 19.5 2.8 0.2343
82.2 9.0 1.3
120.9 25.2 3.6
104.8 27.2 3.9
94.4 22.1 3.1
77.2 20.0 2.8
P
N.S.*
N.S.
N.S.
N.S.
N.S.
* N.S., not significant .
226
Vol. 22
SPELLACY ET AL.
change. These results are shown in Table 7. It is interesting that several factors are significantly related. The factors which commonly are regarded as adverse factors for glucose tolerance (old age, high parity, and large weight gain) are associated with negative changes in blood glucose during the year of drug treatment. Conversely the large weight gain is also associated with large positive changes in insulin. In the studies of the effects of a history of family members having diabetes mellitus or the TABLE 4. Changes in the Glucose Tolerance Curve Between the Control and the 12-Month Test for "Normal" Women Taking a Sequential Oral Contraceptive Containing Mestranol and Chlormadinone Acetate (N = 50) Wilkerson points'
No. of women (control test)
No. of women (12-month test)
0 0.5 1.0 1.5 2
50 0 0 0 0
45 1 1 3 0
delivery of a large infant (greater than 9 lb.) or the delivery of a stillborn or anomalous infant, only two positive and significant relationships were found. These were the 140
e_
0----0
120
CONTROl 12 MONTHS • p < 0 os
.. p <
::§.
~Ol
100
"" 3-
80
:)
Z
60
20 o~~
__ ____ ______ ________ __
Fasting
~
~
~
0.5
~
2
3
TIME in HOURS AFTER INGESTION
FIG. 2. Mean plasma insulin levels in "nonnal" women before and after 12 months of treatment with a sequential oral contraceptive containing mestranol and chlonnadinone acetate (N = 50).
TABLE 5. Statistical Studies of Plasma Insulin Levels in p.U./ml. for Women Taking a Sequential Oral Contraceptive Containing Mestranol and Chlormadinone Acetate for 12 Months (N = 53) 12-month test
Control test Parameters measured
Mean S.D. S.E.M. p
Fasting state
At 0.5
At1
At 2
hr.
At3 hr.
Faating state
At 0.5 hr.
At 1 hr.
At2 hr.
At3 hr.
8.8 5.5 0.8 2.5474 <0.05
92.3 69.3 9.5 3.0014 <0.01
81.9 53.5 7.4 1.5484 N.S.*
65.7 42.9 5.9 2.8546 <0.01
40.4 31.4 4.3 3.2159 <0.01
10.8 6.7 0.9
120.8 79.7 11.1
98.1 69.8 9.6
85.1 62.9 8.7
55.2 48.9 6.7
hr.
hr.
* N.S., not significant.
TABLE 6. Statistical Studies of Plasma Insulin in Il.u./ml. for the Normal Subgroup Taking a Sequential Oral Contraceptive containing Mestranol and Chlormadinone Acetate for 12 Months (N = 50)
~ 12-month test
Control Test Parameters measured
Mean S.D. S.E.M. t p
Fasting state
At 0.5 hr.
At 1
At2
hr.
At3 hr.
Fasting state
At 0.5
8.8 5.7 0.8 2.6442 <0.05
93.9 70.9 10.0 3.2219 <0.01
80.1 51.1 7.3 1.9283 N.S.*
66.9 43.6 6.2 2.8126 <0.01
41.7 31.8 4.5 3.0334 <0.01
11.0 6.8 0.9
124.3 79.3 11.2
* N.S., not significant.
hr.
hr.
At1 hr.
At2
At3
100.2 70.9 10.0
87.1 64.1 9.2
56.5 49.6 7.0
hr.
hr.
April 1971
227
CHLORMADINONE ACl!TI'ATE. II.
TABLE 7. Significantly Associated Factors in Carbohydrate Metabolic Alterations in Women Taking a Sequential-Type Oral Contraceptive Containing Mestranol and Chlormadinone Acetate for 1 Year Regression line
Variable
p
1. Age and change in: a) 0.5-hr. glucose b) 2-hr. glucose c) 3-hr. glucose
y = - 29.290 + 1.454 x y = - 22.304 + 1.178 x y = -29.414 + 1.337 x
0.33 0.33 0.42
<0.01 <0.01 <0.002
2. Parity and change in: a) 0.5-hr. glucose b) 2-hr. glucose c) 3-hr. glucose
y = -5.179 + 3.558 x y = - 2.722 + 2.867 x y = - 5.998 + 2.757 x
0.29 0.29 0.31
<0.03 <0.04 <0.03
3. Weight change and change in: a) I-hr. glucose b) 2-hr. glucose c) 3-hr. glucose d) Fasting insulin e) 0.5-hr. insulin t) I-hr. insulin g) 3-hr. insulin
y y y y y y y
0.38 0.33 0.37 0.38 0.34 0.43 0.28
<0.007 <0.02 <0.007 <0.005 <0.01 <0.002 <0.04
= = = = = = =
correlations between the delivery of large infants and the elevation of the fasting blood glucose level (t = 2.0314; p < 0.05), and the elevation of the 3-hr. insulin level (t = 2.4007; p < 0.05). DISCUSSION
The present study was designed to evaluate the frequency with which abnormal carbohydrate metabolism develops in women taking a sequential oral contraceptive containing mestranol and chlormadinone acetate. In a previous article it was noted that 16.2% of women tested after 6 months had converted from a "normal" glucose curve to a "borderline abnormal" curve. l In the present study the group of women were tested at 12 months and 10% of the curves had changed from "normal" to "borderline abnormal." Again there were no abnormal curves. A review of the statistical studies from the normal subgroups having an oral glucose tolerance test at the 6- and 12-month tests shows that the blood glucose values are significantly elevated at only the 6month test, whereas the plasma insulin
-4.107 + 0.662 x - 2.322 + 0.585 x -1.241 + 0.593 x 1.599 + 0.191 x 24.448 + 1.896 x 12.318 +2.689 x 12.220 +0.815 x
levels are elevated at both times. 1 These results are in contrast to studies with intravenous glucose tolerance tests where the glucose values were unchanged at both 6 and 12 months and where the insulin was elevated at 6 but not 12 months. 7 • 8 It is well recognized that there is more insulin released in the oral than the intravenous test. 9 This is presumably because the oral glucose test stimulates gut factors which act at the fJ cell in addition to the glucose. The greater fJ cell stimulus of an oral glucose load could help explain the elevated insulin values at 12 months in the oral glucose-tested group as compared to the intravenous glucose-tested group. There does not appear to be any increase in the number of abnormal-type glucose curves with the use of this drug from 6-12 months. This group is continuing to take the drug, and repeated tests after longer durations of use will aid in determining its safety. SUMMARY
Blood glucose and plasma insulin levels were measured during an oral glucose tol-
228
SPELLACY ET AL.
erance test. The test was performed before receiving, and 12 months after using a sequential oral contraceptive containing mestranol and chlormadinone acetate. There was no statistical change in the group glucose values but 10% of the glucose curves went from "normal" to "borderline abnormal." The plasma insulin levels were significantly elevated for the group. The glucose and insulin changes were related to the age, parity, weight changes, and the delivery of excessively large infants. Acknowledgments. The authors wish to thank Mrs. J. Burney, Miss B. Keller, Miss M. McShan, Miss R. Dow, and Mrs. R. Cabal for their help in carrying out these studies. They would also like to acknowledge and thank Mrs. J. Cassady for her statistical consultation. REFERENCES 1. SPELLACY, W. N., BUHI, W. C., BIRK, S. A., AND MCCREARY, S. A. Studies of chIormadinone acetate and mestranol on blood glucose and plasma insulin. I. Six-month oral glucose tolerance test. Fertil Steril 22:217, 1971.
Vol. 22
2. NELSON, N. Photometric adaptation of Somogyi method for determination of glucose. J Bioi Chern 153:375, 1944. 3. SOMOGYI, M. Determination of blood sugar. J Bioi Chern 160:69, 1945. 4. 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, 1963. 5. HERBERT, V., LAu, K., GoTTLIER, C. W., AND BLEICHER, S. J. Coated charcoal immunoassay of insulin. J Clin Endocr 25:1375, 1965. 6. WILKERSON, H. L. C. "Diagnosis, oral glucose tolerance tests." In Diabetes Mellitus, Diagnosis and Treatment. American Diabetes Association, New York, 1964, p. 31. 7. SPELLACY, W. N., BUHI, W. C., AND BENDEL, R. P. Insulin and glucose studies after one year of treatment with a sequential-type oral contraceptive. Obstet Gynec 33:800, 1969. 8. SPELLACY, W. N., CARLSON, K. L., AND SCHADE, S. L. Effect of a sequential oral contraceptive on plasma insulin and blood glucose levels after six months' treatment. Arner J Obstet Gynec 101:672, 1968. 9. PERLEy, M. J., AND KIPNIS, D. M. Plasma insulin responses to oral and intravenous glucose: Studies in normal and diabetic subjects. J Clin Invest 46: 1954, 1967.
FmTn.rrY AND STERILrrY
Copyright
@
Printed in U.S.A.
1971 by The Williams & Wilkins Co.
STUDIES OF CHLORMADINONE ACETATE AND MESTRANOL ON BLOOD GLUCOSE AND PLASMA INSULIN. II. TWELFrH MONTH ORAL GLUCOSE TOLERANCE TEST* W. N. SPELLACY, M.D., W. C. BURl, M.S., S. A. BIRK, B.S., R.N.,
AND
S. A. McCREARY, B.S.
Department of Obstetrics and Gynecology, University of Miami School of Medicine, Miami, Florida
In a previous article it was noted that carbohydrate metabolism was adversely affected in some women taking mestranol and chlormadinone acetate for 6 months' time. 1 The purpose of the present article is to extend these data by reporting blood glucose and plasma insulin levels during an oral glucose tolerance test on 53 women taking the same steroids for 12 months. PROCEDURE
The women were all volunteers from the family planning clinic at Jackson Memorial Hospital. The testing procedure has already been described. l Briefly, a standardized oral glucose (100 gm.) tolerance test was performed more than a month postpartum before the women were started on the drug. t This identical test was then repeated after 12 months of drug usage. The venous blood samples were drawn in a fasting state and at 0.5, 1, 2, and 3 hr. after the glucose ingestion. The blood for glucose determination was analyzed in duplicate by the method of Nelson and Somogyi. 2, 3 The plasma was assayed in duplicate for its insulin content by a modified solid-phase radioimmunoassay procedure. 4 , 5 The matched-pair data were then placed on • These studies were supported in part by funds from the Public Health Service, Consumer Protection and Environmental Health Service, Food and Drug Administration, and Department of Health, Education, and Welfare, under Contract CPF 69-32. t The drug used was CT-902-7E containing mestranol 0.1 mg. for 15 days, mestranol 0.1 mg. and chlormadinone acetate 1.5 mg. for 8 days, and 5 placebo tablets. This drug was kindly supplied by Dr. J. M. Maas of the Eli Lilly and Company, Indianapolis, Ind.
224
punch cards and appropriately analyzed with the aid of a computer. The women had a mean age of 22.7 years (S.E.M., 0.8; range, 14-37), and a mean parity of 2.5 (S.E.M., 0.3; range, 0-13). The predrug mean weight was 131.1 lb. (S.E.M., 3.2; range, 94-203), and the mean 12-month weight was 133.7 lb. (S.E.M., 3.9; range, 95-240). This difference was not significant (t = 1.6068). There were 27 women who gained weight and 24 women who lost weight during the year, and the others were unchanged. RESULTS
Blood Glucose. The 53 subjects were divided into three subgroups on the basis of the first control glucose tolerance test results utilizing the Wilkerson Point System 6 (see Table 1). On this basis there were 50 women in the normal subgroup, 2 women in the borderline abnormal subgroup, and 1 woman in the I).bnormal subgroup. The statistical studies of the blood glucose results for the total group and the normal subgroup are shown in Tables 2 and 3. The normal subgroup values are plotted in Fig. 1. It can be seen that there are no significant differences between the two test results. The fasting blood glucose decreased for 23 women, increased for 27 women, and remained unchanged for 3. The tolerance curves in the normal subgroup were changed in their Wilkerson ratings for 5 women (see Table 4). Thus, 10% of the curves became borderline abnormal at the I-year test, but none had become abnormal. The two women in the borderline ab-
t
April 1971
225
CHLORMADINONE ACETATE. II.
normal group had their glucose curve points change from I to 0 and 0.5 to 1.5, respectively. The I subject with the abnormal control curve had her points change from 2 to 0 after I year. Plasma Insulin. The statistical studies of the plasma insulin results for the total group and the normal subgroup are shown in Tables 5 and 6. The normal subgroup values are plotted in Fig. 2. There is a significant increase in the plasma insulin
levels at the I2-month test for all values except the I-hr. sample. Correlating Factors. Studies of the individual factors which might be associated with carbohydrate metabolic alterations in these women were done by determining the correlation coefficients between each change in glucose or insulin, and the continuous variables of age, parity, and weight
~
E
TABLE 1. The Wilkerson Point System for Interpreting the 3-hr 100-gm. Oral Glucose Tolerance Test" Time
Blood glucose
hr.
mg. %
Fasting 1 2 3
110 or more 170 or more 120 or more 110 or more
Points·
.-e
CONTROl 0----0 J2 MONTHS
140
8
~ 120 Ol
~
o~ 100 u ~
(5 80 o
o 9
1 0.5 0.5 1
~
60'~L-
__~~__~______~________~__
~~
~
TIME
* Definition, normal curve, 0 points; borderline abnormal curve, 0.5-1.5 points; abnormal curve, 2 or more points.
3 In
HOURS AFTER INGESTION
FIG. 1. Mean blood glucose levels in "normal" women before and after 12 months of treatment with a sequential oral contraceptive containing mestranol and chlormadinone acetate. The curves are not significantly different (N = 50).
TABLE 2. Statistical Studies of Blood Glucose Levels in mg./100ml. for Women Taking a Sequential Oral Contraceptive Containing Mestranol and Chlormadinone Acetate for 12 Months (N = 53) 12-month test
Control test
Parameters measured
state
At 0.5 hr.
At 1 hr.
At2 hr.
At3 hr.
Fasting state
At 0.5 hr.
At 1 hr.
At2 hr.
At3 hr.
Mean S.D. S.E.M. t
84.3 10.9 1.5 1.2662
120.2 23.6 3.2 0.2529
108.6 28.4 3.9 1.2281
90.4 17.0 2.3 1.3622
77.7 19.7 2.7 1.1005
82.1 8.9 1.2
121.1 24.7 3.4
105.6 26.8 3.7
94.6 21.9 3.0
77.9 20.3 2.8
P
N.S.*
N.S.
N.S.
N.S.
N.S.
Fasting
* N.S., not significant.
TABLE 3. Statistical Studies of Blood Glucose in mg./100 mi. for the Normal Subgroup Taking a Sequential Oral Contraceptive Containing Mestranol and Chlormadinone Acetate for 12 Months (N = 50) 12-month test
Control test Parameters measured
Fasting state
At 0.5 hr.
At 1 hr.
At2 hr.
At3 hr.
Fasting state
At 0.5 hr.
At 1 hr.
At2 hr.
At3 hr.
Mean S.D. S.E.M.
83.7 9.8 1.4 0.8688
117.5 21.4 3.0 0.9245
105.9 24.5 3.6 0.6854
90.2 16.4 2.3 1.4035
76.6 19.5 2.8 0.2343
82.2 9.0 1.3
120.9 25.2 3.6
104.8 27.2 3.9
94.4 22.1 3.1
77.2 20.0 2.8
P
N.S.*
N.S.
N.S.
N.S.
N.S.
* N.S., not significant .
226
Vol. 22
SPELLACY ET AL.
change. These results are shown in Table 7. It is interesting that several factors are significantly related. The factors which commonly are regarded as adverse factors for glucose tolerance (old age, high parity, and large weight gain) are associated with negative changes in blood glucose during the year of drug treatment. Conversely the large weight gain is also associated with large positive changes in insulin. In the studies of the effects of a history of family members having diabetes mellitus or the TABLE 4. Changes in the Glucose Tolerance Curve Between the Control and the 12-Month Test for "Normal" Women Taking a Sequential Oral Contraceptive Containing Mestranol and Chlormadinone Acetate (N = 50) Wilkerson points'
No. of women (control test)
No. of women (12-month test)
0 0.5 1.0 1.5 2
50 0 0 0 0
45 1 1 3 0
delivery of a large infant (greater than 9 lb.) or the delivery of a stillborn or anomalous infant, only two positive and significant relationships were found. These were the 140
e_
0----0
120
CONTROl 12 MONTHS • p < 0 os
.. p <
::§.
~Ol
100
"" 3-
80
:)
Z
60
20 o~~
__ ____ ______ ________ __
Fasting
~
~
~
0.5
~
2
3
TIME in HOURS AFTER INGESTION
FIG. 2. Mean plasma insulin levels in "nonnal" women before and after 12 months of treatment with a sequential oral contraceptive containing mestranol and chlonnadinone acetate (N = 50).
TABLE 5. Statistical Studies of Plasma Insulin Levels in p.U./ml. for Women Taking a Sequential Oral Contraceptive Containing Mestranol and Chlormadinone Acetate for 12 Months (N = 53) 12-month test
Control test Parameters measured
Mean S.D. S.E.M. p
Fasting state
At 0.5
At1
At 2
hr.
At3 hr.
Faating state
At 0.5 hr.
At 1 hr.
At2 hr.
At3 hr.
8.8 5.5 0.8 2.5474 <0.05
92.3 69.3 9.5 3.0014 <0.01
81.9 53.5 7.4 1.5484 N.S.*
65.7 42.9 5.9 2.8546 <0.01
40.4 31.4 4.3 3.2159 <0.01
10.8 6.7 0.9
120.8 79.7 11.1
98.1 69.8 9.6
85.1 62.9 8.7
55.2 48.9 6.7
hr.
hr.
* N.S., not significant.
TABLE 6. Statistical Studies of Plasma Insulin in Il.u./ml. for the Normal Subgroup Taking a Sequential Oral Contraceptive containing Mestranol and Chlormadinone Acetate for 12 Months (N = 50)
~ 12-month test
Control Test Parameters measured
Mean S.D. S.E.M. t p
Fasting state
At 0.5 hr.
At 1
At2
hr.
At3 hr.
Fasting state
At 0.5
8.8 5.7 0.8 2.6442 <0.05
93.9 70.9 10.0 3.2219 <0.01
80.1 51.1 7.3 1.9283 N.S.*
66.9 43.6 6.2 2.8126 <0.01
41.7 31.8 4.5 3.0334 <0.01
11.0 6.8 0.9
124.3 79.3 11.2
* N.S., not significant.
hr.
hr.
At1 hr.
At2
At3
100.2 70.9 10.0
87.1 64.1 9.2
56.5 49.6 7.0
hr.
hr.
April 1971
227
CHLORMADINONE ACl!TI'ATE. II.
TABLE 7. Significantly Associated Factors in Carbohydrate Metabolic Alterations in Women Taking a Sequential-Type Oral Contraceptive Containing Mestranol and Chlormadinone Acetate for 1 Year Regression line
Variable
p
1. Age and change in: a) 0.5-hr. glucose b) 2-hr. glucose c) 3-hr. glucose
y = - 29.290 + 1.454 x y = - 22.304 + 1.178 x y = -29.414 + 1.337 x
0.33 0.33 0.42
<0.01 <0.01 <0.002
2. Parity and change in: a) 0.5-hr. glucose b) 2-hr. glucose c) 3-hr. glucose
y = -5.179 + 3.558 x y = - 2.722 + 2.867 x y = - 5.998 + 2.757 x
0.29 0.29 0.31
<0.03 <0.04 <0.03
3. Weight change and change in: a) I-hr. glucose b) 2-hr. glucose c) 3-hr. glucose d) Fasting insulin e) 0.5-hr. insulin t) I-hr. insulin g) 3-hr. insulin
y y y y y y y
0.38 0.33 0.37 0.38 0.34 0.43 0.28
<0.007 <0.02 <0.007 <0.005 <0.01 <0.002 <0.04
= = = = = = =
correlations between the delivery of large infants and the elevation of the fasting blood glucose level (t = 2.0314; p < 0.05), and the elevation of the 3-hr. insulin level (t = 2.4007; p < 0.05). DISCUSSION
The present study was designed to evaluate the frequency with which abnormal carbohydrate metabolism develops in women taking a sequential oral contraceptive containing mestranol and chlormadinone acetate. In a previous article it was noted that 16.2% of women tested after 6 months had converted from a "normal" glucose curve to a "borderline abnormal" curve. l In the present study the group of women were tested at 12 months and 10% of the curves had changed from "normal" to "borderline abnormal." Again there were no abnormal curves. A review of the statistical studies from the normal subgroups having an oral glucose tolerance test at the 6- and 12-month tests shows that the blood glucose values are significantly elevated at only the 6month test, whereas the plasma insulin
-4.107 + 0.662 x - 2.322 + 0.585 x -1.241 + 0.593 x 1.599 + 0.191 x 24.448 + 1.896 x 12.318 +2.689 x 12.220 +0.815 x
levels are elevated at both times. 1 These results are in contrast to studies with intravenous glucose tolerance tests where the glucose values were unchanged at both 6 and 12 months and where the insulin was elevated at 6 but not 12 months. 7 • 8 It is well recognized that there is more insulin released in the oral than the intravenous test. 9 This is presumably because the oral glucose test stimulates gut factors which act at the fJ cell in addition to the glucose. The greater fJ cell stimulus of an oral glucose load could help explain the elevated insulin values at 12 months in the oral glucose-tested group as compared to the intravenous glucose-tested group. There does not appear to be any increase in the number of abnormal-type glucose curves with the use of this drug from 6-12 months. This group is continuing to take the drug, and repeated tests after longer durations of use will aid in determining its safety. SUMMARY
Blood glucose and plasma insulin levels were measured during an oral glucose tol-
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erance test. The test was performed before receiving, and 12 months after using a sequential oral contraceptive containing mestranol and chlormadinone acetate. There was no statistical change in the group glucose values but 10% of the glucose curves went from "normal" to "borderline abnormal." The plasma insulin levels were significantly elevated for the group. The glucose and insulin changes were related to the age, parity, weight changes, and the delivery of excessively large infants. Acknowledgments. The authors wish to thank Mrs. J. Burney, Miss B. Keller, Miss M. McShan, Miss R. Dow, and Mrs. R. Cabal for their help in carrying out these studies. They would also like to acknowledge and thank Mrs. J. Cassady for her statistical consultation. REFERENCES 1. SPELLACY, W. N., BUHI, W. C., BIRK, S. A., AND MCCREARY, S. A. Studies of chIormadinone acetate and mestranol on blood glucose and plasma insulin. I. Six-month oral glucose tolerance test. Fertil Steril 22:217, 1971.
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2. NELSON, N. Photometric adaptation of Somogyi method for determination of glucose. J Bioi Chern 153:375, 1944. 3. SOMOGYI, M. Determination of blood sugar. J Bioi Chern 160:69, 1945. 4. 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, 1963. 5. HERBERT, V., LAu, K., GoTTLIER, C. W., AND BLEICHER, S. J. Coated charcoal immunoassay of insulin. J Clin Endocr 25:1375, 1965. 6. WILKERSON, H. L. C. "Diagnosis, oral glucose tolerance tests." In Diabetes Mellitus, Diagnosis and Treatment. American Diabetes Association, New York, 1964, p. 31. 7. SPELLACY, W. N., BUHI, W. C., AND BENDEL, R. P. Insulin and glucose studies after one year of treatment with a sequential-type oral contraceptive. Obstet Gynec 33:800, 1969. 8. SPELLACY, W. N., CARLSON, K. L., AND SCHADE, S. L. Effect of a sequential oral contraceptive on plasma insulin and blood glucose levels after six months' treatment. Arner J Obstet Gynec 101:672, 1968. 9. PERLEy, M. J., AND KIPNIS, D. M. Plasma insulin responses to oral and intravenous glucose: Studies in normal and diabetic subjects. J Clin Invest 46: 1954, 1967.