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The Triphasic Randomized Clinical Trial was a multicenter, open-label, controlled, 6-month study to determine the influence of three currently marketed triphasic oral contraceptives on lipid and carbohydrate metabolism, cyclic bleeding profiles, and other adverse drug experiences. The study protocol mandated four clinic visits: an initial visit during which study eligibility was determined, a second visit during which baselines were obtained for lipid and carbohydrate parameters, and visits at 3 and 6 months while taking the study drug. The study enrolled healthy women between the ages of 18 and 35 years who were within 20% of their ideal body weight and who had a history of normal and regular menstrual cycles. Patients were randomly assigned to one of three treatment groups: 51 patients to Tri-Levlen, 50 patients to Ortho-Novum 7/7/7, and 56 patients to Tri-Norinyl. The control group consisted of 49 patients using nonhormonal forms of birth control. Eighty-eight percent (181/206) of the patients completed all four visits and were considered evaluable for subsequent analyses.
In a cross-sectional study that aimed to identify risk factors for diabetes, 1290 consecutive, healthy, nonpregnant women of child-bearing age were examined in a center for preventive medicine. An in-depth interview about menses, use of oral contraceptives, and menopause was performed. Plasma glucose at fasting and 2 hours after a 75 gm glucose load, glycated hemoglobin A1c, fasting plasma insulin, total plasma cholesterol, and triglycerides were measured. Compared with nonusers taking no progestogens, oral contraceptive users (n = 431; 33.4%) were younger (p less than 0.001) and leaner (p less than 0.001). After adjustment for age and body mass index, oral contraceptive users had higher 2-hour plasma glucose (p less than 0.001), higher fasting plasma insulin (p less than 0.01), and higher triglycerides levels (p less than 0.01). Fasting plasma glucose, glycated hemoglobin A1c, and total cholesterol did not significantly differ between the two groups. In relation to dosage and types of steroid components, few differences have been found between high-dose and low-dose oral contraceptives or according to the estrogen-progestogen balance of the preparations. Use of oral contraceptives appears to induce an increase of insulin-resistance markers, which have recently been cited as risk factors for ischemic vascular diseases. These markers should be carefully monitored in oral contraceptive users.
Women with recent gestational diabetes mellitus were randomly assigned to one of two low-dose oral contraceptives to evaluate the effect of low-dose oral contraceptives on carbohydrate and lipid metabolism. A cohort of similar women requesting a non-oral-contraceptive method served as controls. The two oral contraceptives studied were ethinyl estradiol (0.035 mg)-norethindrone (0.40 mg) and ethinyl estradiol (0.030 to 0.040 mg)-levonorgestrel (0.050 to 0.125 mg). A 75 gm, 2-hour oral glucose tolerance test and a fasting lipid profile (total cholesterol, triglyceride, high- and low-density lipoprotein cholesterols) were performed at entry, after 3 months, and after 6 to 13 months of treatment. The prevalence of diabetes at 6 to 13 months (27/156 patients) was not significantly different between groups (non-oral-contraceptive group, 17%; ethinyl estradiol-norethindrone, 15%; ethinyl estradiol-levonorgestrel, 20%). When examined by prior gestational diabetes mellitus class, diabetes mellitus was present in 7% of prior class A1 and 29% of women with prior class A2 disease (p less than 0.001). Mean cholesterol and low-density lipoprotein cholesterol levels were significantly improved in all three groups at 3 months and at 6 to 13 months, whereas triglycerides remained unchanged. There were no differences in cholesterol, low-density lipoprotein cholesterol, or triglycerides levels between the groups. After 6 to 13 months, there was a significant increase in high-density lipoprotein cholesterol in the ethinyl estradiol-norethindrone group compared with the ethinyl estradiol-levonorgestrel and non-oral-contraceptive groups.
In order to determine the metabolic effects of long-term use of the injectable contraceptive norethisterone oenanthate, plasma glucose and serum insulin concentrations were studied in two groups of women who had used the method continuously for at least five years. Group 1 comprised 24 subjects, from whom only fasting blood samples were taken. Despite similar plasma glucose concentrations to those of the controls, the subjects had significantly increased serum insulin concentrations (164.5 (39.9) v 120.3 (34.3) pmol/l, p less than 0.01). In addition the insulin:glucose ratios were also significantly increased (34.3 (8.5) v 24.6 (6.7), p less than 0.01), consistent with decreased insulin sensitivity. Group 2 comprised 13 of the original 24 subjects who also had an oral glucose tolerance test. Basal plasma glucose concentrations were similar in the subjects and their controls, whilst the significantly increased insulin:glucose ratios (35.0 (7.7) v 28.7 (5.6), p less than 0.05) were consistent with the results of the larger group. Following oral glucose challenge, plasma glucose concentrations, serum insulin concentrations and insulin:glucose ratios were similar in the subjects and their controls throughout the test. Thus, long-term use of norethisterone oenanthate injections is associated with a decrease in peripheral insulin sensitivity. However, these changes are not associated with any evidence of oral glucose intolerance.
Two hundred and ten healthy young women volunteered to take a combined oral contraceptive (OC) and to have glucose tolerance in insulin secretion measured in a projected 3-year study with roughly annual investigations. Although the dropout rate was high, glucose tolerance was noted to deteriorate progressively and insulin secretion to rise initially, but thereafter they remained constant. Eventually, insulin levels were lower than would have been expected from the prevailing glucose values. This combination of steroids produced marked insulin resistance to which the pancreas could respond by further insulin secretion. It is suggested that levonorgestrel is too strong a progestin for routine use in the combined OC, and it is recommended that its dose be reduced further or that weaker progestins such as norethindrone be used.
Blood glucose and pyruvate, plasma insulin, and glucagon levels as well as erythrocyte insulin receptors were measured during an oral glucose tolerance test in 38 normal women before and after 6 months' use of one of three new oral contraceptives containing low doses of 19 nortestosterone-derived progestogens, levonorgestrel, and desogestrel. A slight deterioration of glucose tolerance was observed, with the area under the glucose curve increasing by only 7%, 9%, and 12% after Ovidol (Aaciphar SA, Brussels, Belgium), Marvelon (Organon, SA, Brussels, Belgium), and Trigynon (Schering SA, Brussels, Belgium) administration, respectively. We did not find any argument in favor of the development of a state of insulin resistance in women using these compounds, because erythrocyte receptor binding was not modified and plasma insulin responses to glucose were decreased. The glucose-induced suppression of plasma glucagon levels seemed less effective for treatment with the desogestrel-containing preparations than with the levonorgestrel-containing oral contraceptives.
BACKGROUND: Oral contraceptives can induce changes in lipid and carbohydrate metabolism similar to those associated with an increased risk of coronary heart disease, including increased serum triglyceride, low-density lipoprotein (LDL) cholesterol, and insulin levels and decreased high-density lipoprotein (HDL) cholesterol levels. In this study, we examined whether modification of the type or dose of progestin in oral-contraceptive preparations diminishes these changes. METHODS: We measured plasma lipoprotein levels and performed oral glucose-tolerance tests in a cross section of 1060 women who took one of nine types of oral contraceptives for at least three months and 418 women who took none. Seven of the contraceptive formulations contained various doses and types of progestin: levonorgestrel in low (150 micrograms), high (250 micrograms), and triphasic (50 to 125 micrograms) doses; norethindrone in low (500 micrograms), high (1000 micrograms), and triphasic (500 to 1000 micrograms) doses; and a new progestin, desogestrel, in one dose (150 micrograms). All seven contained 30 to 40 micrograms of ethinyl estradiol. Two additional formulations contained progestin alone. RESULTS: As compared with controls, women taking combination drugs did not have increased serum total cholesterol levels but did have increases of 13 to 75 percent in fasting triglyceride levels. Levels of LDL cholesterol were reduced by 14 percent in women taking the combination containing desogestrel and by 12 percent in those taking low-dose norethindrone. Levels of HDL cholesterol were lowered by 5 percent and 16 percent by the combinations containing low-dose and high-dose levonorgestrel, respectively; these decreases were due to reductions of 29 percent and 43 percent, respectively, in the levels of HDL subclass 2. The combination pill containing high-dose norethindrone did not affect HDL cholesterol levels, whereas that containing low-dose norethindrone increased HDL cholesterol levels by 10 percent. The desogestrel combination increased HDL cholesterol levels by 12 percent. Levels of apolipoproteins A-I, A-II, and B were generally increased by combination drugs. Depending on the dose and type of progestin, combination drugs were associated with plasma glucose levels on the glucose-tolerance test that were 43 to 61 percent higher than in controls, insulin responses 12 to 40 percent higher, and C-peptide responses 18 to 45 percent higher. Progestin-only formulations had only minor metabolic effects. CONCLUSIONS: The appropriate dose and type of progestin may reduce the adverse effects of oral contraceptives on many metabolic markers of risk for coronary heart disease. Progestin-only formulations or combinations containing desogestrel or low-dose norethindrone were associated wtih the most favorable profiles.
The responses of serum glucose, insulin, and lipids to a glucose load were compared in two groups of college-age women fed two different carbohydrate diets. One group of women took oral contraceptives (OC) and the other group had never taken OC. Two experimental diets supplied approximately 13% of the calories from protein, 36% from fat, and 51% from carbohydrate. Of the carbohydrate, 84% was either sucrose or wheat starch. Each diet was fed for 4 weeks in a cross-over design. The subjects were given a glucose load dose, 1 g/kg of body weight, before and after each dietary period. Serum glucose, insulin, and lipids were measured before and 30, 60, 120, and 180 minutes after the load dose. Serum insulin was significantly affected by the type of carbohydrate in the diet (p less than .01). The sucrose diet generally gave lower insulin levels in response to the glucose load. Serum triglyceride levels were significantly higher (p less than .01) in users than nonusers of OC. Serum free fatty acids and total lipids were not significantly affected by OC use. There was no effect of different carbohydrates on any of the serum lipid parameters. Significant responses from fasting levels were observed for serum glucose, insulin, and triglyceride levels (p less than .01).
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Controlled clinical investigations of a three-phase, low-dose oral contraceptive combination of levonorgestrel and ethinyl estradiol were conducted at 17 sites in the United States and 60 sites in the United Kingdom. A day 1 start in cycle one with no backup contraception was used. A total of 3546 female volunteers participated in 35,036 cycles. Medication was missed in 2688 (7.7%) cycles. Nine pregnancies were reported for an uncorrected use-effectiveness rate of 0.33 per 100 woman-years. Cycle control was excellent, bleeding irregularities were minimal, and the incidence of side effects was very low. No clinically significant variations in blood pressure means or weight means were observed. Carbohydrate and lipid metabolism studies were limited to 6 months and showed minimal alterations. Subject compliance with the preparation was excellent. It is concluded that this triphasic oral contraceptive with its varying ratios of levonorgestrel and ethinyl estradiol is an effective, predictable, and well-tolerated combination oral contraceptive.
OBJECTIVE: To examine the effects of a sugar-only (SO) beverage vs one containing a mixed-nutrient (MN) composition on energy expenditure and feelings of hunger and satiety. HYPOTHESIS: A beverage containing a mixed macronutrient composition will lead to greater thermic effect of food and feelings of fullness than an isocaloric beverage containing only sugar. RESEARCH METHODS AND PROCEDURES: Adults were randomly assigned to receive a 2510 kJ (600 kcal) SO liquid formula followed by an isovolumic, isoenergetic, MN liquid formula with an energy distribution of 17% protein, 67% carbohydrates as sucrose and corn syrup solids, and 16% fat, or vice versa, in a crossover design. The carbohydrate source in the two beverages was identical: 1:1 ratio of sucrose and corn syrup solids (25 dextrose equivalents). The thermic response was calculated as the 7 h deviation from resting metabolic rate (RMR). Subjects provided hunger/satiety ratings and other related information by visual analog scales at regular intervals throughout the study period. RESULTS: In all, 20 subjects completed the protocol; one was removed from the thermic effect analysis due to discrepant RMRs. Following beverage ingestion, SO and MN liquid meals produced 7 h thermic effects of (X+/-s.e.m.) 274.1+/-27.6 kJ (65.5+/-6.6 kcal) and 372.0+/-33.9 kJ (88.9+/-8.1 kcal), respectively, resulting in a significant (P<0.01) difference between meals (Delta=97.9+/-35.1 kJ [23.4+/-8.4 kcal]). Analysis of satiety ratings using area under the curve analysis showed greater feelings of satiety (P<0.05) with MN compared to SO consumption. Also, subjects felt that they could eat less (P<0.05) after consumption of the MN vs SO beverage. DISCUSSION: In comparison to MN beverages, SO beverages are associated with a relatively high-energy retention without accompanying subjective hunger/fullness compensations, suggesting a basis for their role in long-term unintentional weight gain in healthy adults.
Effects of Trigynon, a triphase low-dose oral contraceptive, containing ethinylestradiol and l-norgestrel in various proportions, on testosterone binding globulin, transcortin, thyroxine, free testosterone, free cortisol and free thyroxine as well as on plasma lipids and glucose tolerance were studied in 12 normal women treated for 3-6 months. Trigynon appears to have dominant estrogenic effects as evidenced from the increase in transport proteins and the decrease in free testosterone concentration. Plasma lipids were not significantly influenced; glucose tolerance was slightly, but not significantly decreased.
Metabolic changes were investigated in two groups of women using oral contraceptives for 5 to 16 years. Blood samples were taken during the last cycle of oral contraceptive use and three months post-treatment. One group had used a monthly oral contraceptive (MOC, 3mg quinestrol and 10mg 16-methylene chlormadinone acetate) and the second group a daily oral contraceptive (DOC, 35 micrograms ethynylestradiol and 0.625 mg norethisterone). During treatment there were increases in serum total cholesterol and triglycerides but not HDL-C, in plasma total cortisol but not in renin activity, angiotensin II or urinary free cortisol excretion, in hemoglobin and some coagulation factors but not Factor X or antithrombin III, platelet function or fibrinolysis. The area under the blood glucose concentration-time curve, but not that for serum insulin, was slightly increased and there was no change in fasting blood sugar concentrations. All metabolic parameters, except plasma cortisol, which had shown an increase on treatment, had decreased to control levels within 3 months. Ovulation returned promptly in all women, the mean time being 70 days for Group MOC and 44 days for Group DOC. Thus, in spite of the long duration of use of the oral contraceptives, metabolic changes were minor.
In a group of 33 healthy women, among whom 15 utilized the combined oral contraceptive pill, and 18 utilized the progesterone oral pill (ethynodiol diacetate, 0.5 mg, Femulen, we have examined the percentage of glycohemoglobin (Hb A1). In the progesterone oral pill users the percentage of Hb A1 remained unchanged, that is 5.4% before, and 5.2% 3-6 mth after using it, whereas in women taking the combined oral contraceptive pill the values increased from 5.9% before to a mean of 8.7% after 3-6 mth after administration. This increase seems to be related to the estrogen of the which, as in pregnancy, may induce glucose intolerance. From this study it may be seen that, despite its disadvantages such as reduced effectiveness and menstrual disruption, the progesterone-only pill is preferable. At the same time, the screening by the Hb A1 evaluation, a sure, inexpensive and easily performed procedure, makes it possible to detect a nonsuspected diabetes or a borderline diabetes and thus to change the contraception method used for another method.
Norethisterone acetate, medroxyprogesterone acetate and levonorgestrel were administered to oophorectomised women to evaluate the effects they have on lipid metabolism. Blood samples were drawn after a 3 wk period without hormone therapy and after 3 wk on each progestogen. Serum and lipoprotein lipids were followed and an oral glucose tolerance test with blood glucose and plasma insulin determinations were performed. The nortestosterone derivatives, norethisterone acetate and levonorgestrel, decreased high density lipoprotein cholesterol as well as alpha-lipoproteincholesterol, while the 17-hydroxyprogesterone derivative medroxyprogesterone acetate did not. Norethisterone acetate and medroxyprogesterone acetate impaired glucose tolerance. A difference between nortestosterone derivatives and 17-hydroxyprogesterone derivatives having an effect on high density lipoproteins is suggested.
Seven normal premenopausal women were studied before (control) and after 3 and 6 months of oral contraceptive agent (OCA) administration (30 micrograms ethinyl estradiol plus 150 micrograms levonorgestrel). The plasma glucose responses during 75-g oral glucose tolerance tests were not altered by the OCA, but the 3- and 6-month plasma insulin responses significantly exceeded control values (P less than 0.05). On a separate morning a constant iv infusion of [3H]3-glucose was given throughout a 2-h basal period and during two successive 2-h euglycemic clamp procedures at iv insulin delivery rates of 10 and 40 mU/m2.min, respectively. Endogenous glucose production rates (milligrams per kg/min) were not altered after 3 or 6 months of OCA administration. Peripheral glucose utilization rates were expressed as M (milligrams per kg/min) or the ratio of M over the prevailing plasma insulin concentration (M/I). One or both parameters were significantly reduced below control values at both insulin infusion rates after 3 months (P less than 0.05), but returned toward control values after 6 months. Serum androgen concentrations were reduced or not altered by OCA administration. We conclude that insulin resistance induced by OCA administration is manifested by reduced peripheral tissue insulin sensitivity and may ameliorate with time. This effect does not relate consistently to total plasma insulin responses during oral glucose tolerance tests or to elevated serum androgen concentrations.