CORRELATION OF CLINICAL PARAMETERS WITH GLUCOSE TOLERANCE TESTS IN WOMEN TAKING ORAL CONTRACEPTIVES

Transcription

1 FERTIUTY AND STERILITY Copyright 1974 The American Fertility Society Vol. 25, No.7, July 1974 Printed in U.S.A. CORRELATION OF CLINICAL PARAMETERS WITH GLUCOSE TOLERANCE TESTS IN WOMEN TAKING ORAL CONTRACEPTIVES KATA YUN VIRKAR, M.D., VILLI BARSIVALA, M.Sc., AND R. D. KULKARNI, M.D. Division of Applied Research, Institute for Research in Reproduction (Indian Council of Medical Research), Bombay, India, and Department of Pharmacology, Grant Medical CoUege, Bombay, India No drugs in the history of therapeutics have received as much attention as the oral contraceptives. Since the results of the first clinical trials were reported 17 years ago, medical literature has been flooded with reports about the efficacy and acceptability of these drugs. An increasing number of articles has begun to appear in leading medical journals about either their short-term or long-term adverse effects.1-3 Despite their shortcomings, the oral contraceptives are convenient, very effective, and are used by a large number of women. It is unlikely that such a method would be forsaken. Studies are therefore being continued on the side effects of the existing contraceptive steroids. By these efforts, adverse effects can be minimized. The present study was undertaken to investigate the effects of steroidal contraceptives on carbohydrate metabolism and to correlate any abnormal findings with various clinical parameters in order to determine criteria for a high risk group. MATERIALS AND METHODS The study group consisted of 1 parous women volunteers of child-bearing age, of the low socioeconomic class, and attending the Family Planning Clinics at the Institute for Research in Reproduction of the Indian Council of Medical Research. Received October 2, The women were divided into three groups: group 1 - control group using conventional contraceptives (eg, diaphragm, jelly, and condoms); group 2 - women using a combination contraceptive,ovral (Wyeth, Philadelphia) (ethinyl estradiol.5 mg +.5 mg norgestrel); group 3 - women using low dosage progestogen (Q.5 mg megestrol acetate daily). A detailed medical history including the age, parity, weight, family history of diabetes, and history of delivery of large babies was obtained (Table 1). Each patient was then briefly instructed to refrain from taking any medication for a week before the test, to consume a regular diet for at least 3 days before, and to fast the night before. The patients were kept in a reclining position throughout the test. An intravenous glucose tolerance test was performed on each woman using.5 gm/kg body weight as the glucose load. Serum glucose was analyzed by the glucose oxidase method using -Dianisidine. 4 A glucose tolerance test was considered to be abnormal if two or more of the following abnormalities were found: (1) fasting serum glucose over 15 mg%; (2) 1 minute sample over 26 mg%; or (3) 7 minute sample at least 15 mg% higher than fasting. The values of glucose tolerance thus obtained were then correlated with type and duration of therapy, age, parity, family history of diabetes, history of large

2 57 VIRKAR ETAL July 1974 TABLE 1. Clinical Data of the Women in the Study Average AverB4"e Average with'famil who had No. of age body weight no. of history or delivered Group women (years) (kg) children diabetes large babies (19-39) (35.4- (1-5) 58.9) 2 b (19-4) (36.3- (1-8) 65.) 3c (22-36) (35.- (1-6) 55.4) "These women were using low dosage of progestogen (megestrol acetate). "These women were using low dosage progesto gen (megestrol acetate). AVERAGE SERUM GLUCOSE MILLIGRAMS PERCENT WITH S.E.M.AFTER INTRAVENOUS GLUCOSE._,", Group 1 24 / '" Group 2 I.. _ " --- Group 3 I: -, 2:.. "1--, 4, ~~ I..., I. '",,... '.J:,. T"...,...,'... ~ TI ME IN MI NS. FIG_ 1. Average serum glucose milligrams percent with standard error of the mean after intravenous glucose_ babies, excessive weight gain, and changes in blood pressure. This was to determine which clinical parameter or parameters coupled with the intake of honnonal contraceptives played a major role toward glucose impainnent. RESULTS Type of therapy. Figure 1 indicates the average serum glucose responses after an intravenous glucose load of.5 gm/kg body weight in the three groups of women. There was no significant difference in the fasting levels in the three groups. However, the 1 minute and the 7 minute levels in group 2 differed significantly (P<.5 with Student's t test) from those in group 1. Group 3 did not show TABLE 2. Glucose Tolerance in Relation to Duration of Therapy No. of cycles TotaIno. Impaired Group of therapy of women response b (-48) 48 3d Control group. These women were using conventional contraceptives. cp<.5 (Fisher's exact probability test). dthese women were using low dosage progesto gen (megestrol acetate) abnormality c

3 Vol. 25, No.7 GLUCOSE TOLERANCE TESTS AND ORAL CONTRACEPTIVES 571 any significant difference from group 1 a t any level. Duration of therapy. Table 2 indicates the distribution pattern of patients showing impaired glucose tolerance in the three groups. The abnormality percentage in group 2 was significantly higher than that in group 1. However, there was practically no variation relating to duration of treatment within group 1. Group 3 did not show any difference. Age. A relationship between age and glucose tolerance impairment is shown in Table 3. In group 1, for women 18 to 3 years of age, the percentage of abnormality was 12.5%, while in group 2, it was 39.%. This was found to be statistically significant (P<.5 Student's t test). Group 3 showed the same percentage of abnormality as group 1. In the control group, for women 31 to 4 years of age, the abnormality percentage was higher. Parity. No correlation was found be- TABLE 3. Distribution of Patients Showing Impaired Glucose Tolerance in Relation to Age Group I" Group 2b Total Women with Total Women with Age no. of impaired abnonnal- no. of impaired abnonnal- (years) women tolerance ity women tolerance ity d "Control group. These women were using conventional contraceptives. "These women were using a combination contraceptive (Ovral). "These women were using low dosage progestogen (megestrol acetate). dp<o.5 (Fisher's exact probability test). Total no. of cases Group 3" Women with impaired abnonnaltolerance ity TABLE 4. Relation Between Parity and Impaired Glucose Tolerance in Group 2" Total no. of Abnonnal Parity women response abnonnality andover "Women in group 2 were using a combination contraceptive (Ovral). TABLE 5. Distribution Pattern of Patients with Impaired Glucose Tolerance and a History of Delivery of Large Babies with impaired glucose tolerance Total no. of with history and history of Group women of large babies large babies 1" b " 27 3 abnonnality 3 75 Control group. These women were using conventional contraceptives. "These women were using low dosage progesto gen (megestrol acetate).

4 572 VIRKAR ETAL July 1974 tween parity and abnonnal glucose tolerance (Table 4). History of large infants. Infants over 3.6 kg (7.9 lb) were classified as large in our study because the average birth weight of infants delivered by women of the lower socioeconomic class in public hospitals in Bombay is 2.5 kg (5.5 lb). In group 1, of the seven patients who had previously delivered large infants, two showed an abnormal glucose tolerance (Table 5). In group 2, of the four women who had previously delivered large babies, three showed an impaired glucose tolerance. Thus, group 2 differed significantly from group 1 in this respect. None of the women in group 3 with a history of having delivered large babies showed an impaired glucose tolerance. Family history of diabetes. A correlation between family history of diabetes and impaired glucose tolerance was obtained (Table 6). In group 1, of the six women with a family history of diabetes, only one woman showed an impaired tolerance. On the other hand, all seven women in group 2 with a family history of diabetes showed an impaired tolerance. Neither of the two women in group 3 with a family history of diabetes showed an impaired glucose tolerance. Gain in weight over 2.2 kg. An increase of 2.2 kg (4.9 lb) in weight when on oral contraceptive therapy was considered excessive. Table 7 indicates a relationship between excessive weight gain and abnormal glucose tolerance in women of groups 2 and 3. A substantial number of TABLE 6. Distribution Pattern of Patients with Impaired Glucose Tolerance and a Family History of Diabetes Group Total no. of women with family history of diabetes with impaired glucose response and history of familb dia etes I" b " 27 2 abnormality 'Control group. These women were using conventional contraceptives. cthese women were using low dosage progestogen (megestrol acetate). P<O.1 (Fisher's exact probability test). TABLE 7. Distribution Pattern of Patients in Groups 2 and 3 Showing Impaired Glucose Tolerance with weight gain <gcles of Total no. showing a and impaired Group erapy of women weight gain glucose tolerance b " "Over 2.2 kg (4.9 lb). cthese women were using low dosage progestogen (megestrol acetate). Weight Gain" and abnormality

5 Vol. 25, No.7 GLUCOSE TOLERANCE TESTS AND ORAL CONTRACEPTIVES 573 women in group 2 had gained over 2.2 kg and of these a very high percentage (59%) showed an impaired glucose tolerance. Only three of the 27 women in group 3 had gained over 2.2 kg and of these none had an abnormal glucose tolerance. Blood pressure. No correlation was found between impaired glucose tolerance and blood pressure changes recorded in these women. This was studied because a few women had shown an increase of blood pressure with an excessive weight gain when using hormonal contraceptives. DISCUSSION Reports of effects of gonadal steroids on carbohydrate metabolism have been contradictory. Several studies have shown that estrogen alone, or in combination with progestogens, can cause a decrease in glucose tolerance. 5,7 Some investigators have reported no change. 8,9 This inconsistency can be explained by the differences in the chemical structure and dose of the compound, and the sensitivity of the patient to the metabolic action of these agents. However, evidence indicates that glucose tolerance is diminished in women taking combination oral contraceptives. Our results confirm this. There is also controversy over whether low dosage progestogens are associated with an improvement in glucose tolerance/o or not." Our findings corroborate with the latter. Again, there is a disparity of opinion as to the susceptibility factors which may predispose women to an altered carbohydrate metabolism. Factors such as age, parity, abnormal obstetric history, and family history of diabetes have been the focus of study for many investigators. Age, parity, and previous infant birth weight have been said to play no role in altering glucose metabolism.12,ls We found that women taking the combination oral contraceptives showed an impairment in carbohydrate metabolism at a much earlier age when compared to the control group and the low dosage progestogen group. We found no correlation between parity and abnormal glucose curves, but did find a significant correlation between impairment in glucose metabolism in women who had delivered large babies and were taking combination contraceptives. There is no agreement among researchers even for factors such as duration of contraceptive use and family history of diabetes. Some authors feel that they do contribute to the metabolic abnormality and others feel that they do not. 5,12,15 We found no correlation between carbohydrate metabolism and duration of contraceptive use (ie, the abnormality percentage remained the same from 1 to 4 years). However, we found a significant correlation between excessive weight gain and family history of diabetes. Blood pressure changes showed no correlation with the impaired glucose tolerance. The significance of these abnormal glucose tolerance tests is debatable. As yet, no true diabetes has been found in the women having these abnormal test results. Also, the persistence after discontinuing oral contraceptive therapy should be taken into account. However, in six women with impaired tolerance, we found a marked improvement when therapy was discontinued. The answers, therefore, to these controversial issues can only be had with time and prolonged research. In the meantime, we advocate that carbohydrate metabolism should be monitored in all women taking combination oral contraceptives, who have a family history of diabetes, who have previously given birth to large babies, and who have gained excessive weight while on therapy. SUMMARY Glucose tolerance test results of 48

6 574 VIRKAR ETAL July 1974 women taking combination oral contraceptives and of 27 women taking low dosage progestogens were compared with those of a control group of 25 women using conventional contraceptives. Women on combination contraceptives showed a significantly higher percentage of abnormal glucose curves compared to the control. On the other hand, women on low dosage progestogens failed to show any difference. When these abnormal curves were correlated with various clinical parameters, combination contraceptive therapy was found to be positively correlated with family history of diabetes, history of birth of a large baby, and excessive weight gain. Acknowledgment. The authors wish to thank the social workers of the clinics for their help in motivating the women to volunteer for these studies. REFERENCES 1. Mcqueen EG: Hormonal steroid contraceptives adverse reactions. New Ethicals 11 (No. 12): 37, Mcqueen EG: Hormonal steroid contraceptives adverse reactions. New Ethicals and Medical Progress 7 (No. 12): 37, Carey HM: Principles of oral contraception. Side effects of oral contraceptives. Med J Aust 2: 1242, Hjelm M, de Verdier CH: Scand J Clin Lab Invest 15: 515, Javier Z, Gershbey H, Hulse M: Ovulatory supressants, estrogens and carbohydrate metabolism. Metabolism 17:443, Spellacy WN, Buhi WC, Spellacy CE, et al: Glucose, insulin and growth hormone studies in long term users of oral contraceptives. Am J Obstet Gynecol 16: 173, Wynn V, Doar JWH: Some effects of oral contraceptives on carbohydrate metabolism. Lancet 2:715, Di Paola G, Puchulu F, Fobin M: Oral contraceptives and carbohydrate metabolism. Am J Obstet Gynecol 11: 26, Beck P, Wells SA: Comparison of the mechanisms underlying carbohydrate intolerance in sub clinical diabetic women during pregnancy and during post partum oral contraceptive steroid treatment. J Olin Endocrinol Metab. 29:87, Clinch J, Turnbull AC, Khosla T: Effect of oral contraceptives on glucose tolerance. Lancet 1:857, Doar JWH, Wynn V: Oral contraceptives and glucose tolerance. Lancet 1: 1156, Wynn V, Doar JWH: Some effects of oral contraceptives on carbohydrate metabolism. Lancet 2:761, Peterson WF, Steel MW, Coyne RC: An~. alysis of the effect of ovulatory suppressants on glucose tolerance. Am J Obstet Gynecol 95:484, Boshell BR, Roddam RF, McAdams CL, et al: The effects of oral contraceptives on glucose tolerance. J Reprod Fertil 5 (Suppl): 77, Spellacy WN, Zartman ER, Buhi WC, et al: Cross sectional investigation of carbohydrate metabolism in women taking a sequential or combination type of oral contraceptive. South Med J 63: 152, 197