Oral contraception in diabetic women. A cross-over study on serum and high density lipoprotein (HDL) lipids and diabetes control during progestogen and combined estrogen/progestogen contraception. Contraception in perimenopausal women with diabetes mellitus. Investigation of the influence of two low-dose monophasic oral contraceptives containing 20 micrograms ethinylestradiol/75 micrograms gestodene and 30 micrograms ethinylestradiol/75 micrograms gestodene, on lipid metabolism in an open randomized trial. Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol compared with one containing levonorgestrel and ethinylestradiol on haemostasis, lipids and carbohydrate metabolism. A double-blind comparative study of the effects of a 23-day oral contraceptive regimen with 20 microg ethinyl estradiol and 75 microg gestodene and a 21-day regimen with 30 microg ethinyl estradiol and 75 microg gestodene on hemostatic variables, lipids, and carbohydrate metabolism. Oral contraceptives in diabetic women: metabolic effects of four compounds with different estrogen/progestogen profiles. A 1-year randomized study to evaluate the effects of a dose reduction in oral contraceptives on lipids and carbohydrate metabolism: 20 microg ethinyl estradiol combined with 100 microg levonorgestrel. Effect of norethisterone and levonorgestrel in low-dose multiphasic oral contraceptives on serum lipids. Triphasic Randomized Clinical Trial: Comparison of effects on carbohydrate metabolism.
Twenty-three young women with insulin-dependent diabetes were randomly allocated to contraceptive treatment with either a progestogen only (Lynestrenol 0.5 mg) (LYN) or a combined oral contraceptive (OC) (ethinyl estradiol 50 micrograms + lynestrenol 2.5 micrograms) (EE + LYN). After six months treatment the medication was withdrawn for at least two months, after which the patients were placed on the other preparation. Diabetes control and serum and high density lipoprotein (HDL) lipids were assessed before and after 1, 3 and 6 months of treatment. Low-dose LYN administration did not alter the insulin requirement, blood glucose or body weight while the combined EE + LYN treatment increased the insulin requirement (p less than 0.01) without altering blood glucose or body weight. Low-dose LYN reduced serum triglycerides (p less than 0.001), serum cholesterol (p less than 0.001) and serum phospholipids (p less than 0.01) without affecting HDL lipids, while EE + LYN gave an inconsistent increase in serum triglycerides (p less than 0.01) but no change in HDL lipids. These findings confirm our earlier results and we conclude that EE + LYN influences diabetes control slightly more (although still not seriously) than the low-dose LYN. It is suggested that insulin-dependent diabetics (in contrast to non-diabetics) are more sensitive to the influence of 19-norprogestogens than to alkylated estrogens, with respect to lipid metabolism. To assess the effect of combined oral contraceptives (COCs) and intrauterine devices (IUDs) on carbohydrate and lipid metabolism and hemostasis in perimenopausal diabetic women.
                The open randomized study included a total of 113 diabetic women using COCs with different estrogen/progestogen profiles - ethinylestradiol (EE) 20 microg/desogestrel 150 microg, EE 30 microg/desogestrel 150 microg and EE 30 microg/gestodene 75 microg - and levonorgestrel-releasing or copper IUDs. Average daily insulin requirements, levels of glycosylated hemoglobin, total cholesterol, triglycerides, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, the state of coagulation hemostatis and fibrinolytic activity were determined at baseline and after 3, 6, 9 and 12 months of contraception. The control group was composed of 40 age-matched diabetic women who did not use any methods of contraception.
                Neither COCs nor IUDs influenced glycosylated hemoglobin and had little or no influence on the elevation in the requirements for insulin preparations. The majority of the preparations did not exert any unfavorable effect on the blood lipid profile. Taking COCs was accompanied by increased intravascular activation of blood platelets and to a lesser degree by alterations in parameters of hemostatic homeostasis. The use of IUDs had a neutral effect on blood coagulation and fibrinolysis systems.
                Comparing lipid levels and hemostatic variables as a function of glycosylated hemoglobin level, we conclude that diabetes control has greater influence on these parameters than the type and dose of steroids involved in the contraceptive devices. An open comparison at a single center was performed in volunteers (n = 58) randomly allocated to two treatment groups, one receiving tablets containing 20 micrograms ethinylestradiol (EE) + 75 micrograms gestodene, and the other 30 micrograms EE + 75 micrograms gestodene. The study consisted of three treatment-free pre-cycles, followed by thirteen 28-day treatment cycles. Analysis of results revealed that there were no statistically significant differences between the two groups with regard to the plasma levels of HDL-cholesterol and its subfractions, LDL-cholesterol and apolipoproteins. There was, however, a trend toward a more favorable effect on HDL-cholesterol in the 20 micrograms EE group, where levels increased by 3% compared with the 30 micrograms EE group, where levels decreased by 9%. There was a statistically significant difference between the adjusted mean values of total triglycerides in the two groups in favor of the 20 micrograms EE group (+21%), compared with the 30 micrograms EE group (+64%) (p = 0.029). Two serious adverse events were reported (lymphadenopathy and vertigo), but neither were considered to be causally related to either study medication. The formulation containing 75 micrograms gestodene and 20 micrograms EE was shown to be a reliable and well tolerated oral contraceptive, with a favorable lipid profile. To compare the effects of a combined oral contraceptive (COC) containing nomegestrol acetate and 17β-oestradiol (NOMAC/E2) on haemostasis, lipids, carbohydrate metabolism, C-reactive protein (CRP) and sex hormone-binding globulin (SHBG) with those of a COC containing levonorgestrel and ethinylestradiol (LNG/EE).
                In a randomised, open-label study, 121 healthy women, 18-50 years of age, were randomly assigned to receive NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen (n=60) or LNG/EE (150 μg/30 μg) in a 21/7-day regimen (n=61) for six cycles. The primary outcome was the change from baseline to cycle 6 for all indices.
                All parameters were similar at baseline between the two groups. Over six cycles, NOMAC/E2 had less effect on most haemostatic indices than LNG/EE. Lipids were essentially unchanged with NOMAC/E2, whereas with LNG/EE high-density lipoprotein cholesterol decreased and low-density lipoprotein cholesterol and triglycerides slightly increased. NOMAC/E2 induced negligible changes in glucose and insulin parameters, in contrast to LNG/EE. A much smaller increase in CRP was observed with NOMAC/E2 than with LNG/EE. NOMAC/E2 was associated with a greater increase in SHBG.
                The monophasic COC NOMAC/E2 had less influence on haemostasis, lipids and carbohydrate metabolism than the COC LNG/EE. In this double-blind study we compared the influence of two oral contraceptives, a 23-day regimen with 20 microg ethinyl estradiol and 75 microg gestodene (23-day 20/75) and a 21-day regimen with 30 microg ethinyl estradiol and 75 microg gestodene (21-day 30/75), on hemostatic variables, lipids, and carbohydrate metabolism. The volunteers received the preparations daily for six 28-day cycles. Hemostatic variables and lipids were measured at baseline and after six treatment cycles. Carbohydrate metabolism was assessed by determination of the area under the curve (AUC) of carbohydrate parameters after oral glucose tolerance tests performed at baseline and after three treatment cycles. Data from 33 volunteers in each group were obtained. No significant differences between the effects of both treatments on the hemostatic system were detected. Neither the overall change of all hemostatic variables from baseline to treatment Cycle 6 [defined as primary target variable in the study] nor the change of any of the individual hemostatic parameters differed significantly between the treatment groups. Likewise, no significant nor clinically relevant differences in the effects of both treatments on the volunteers' lipid profiles were detected. The data on carbohydrate variables suggested a slightly more favorable influence of the 23-day 20/75 regimen. The increase of the glucose AUCs after three cycles tended to be stronger with the 21-day 30/75 regimen than with the 23-day 20/75 regimen. In addition, the AUCs for insulin and C-peptide were slightly reduced after three cycles with the 23-day 20/75 regimen but slightly increased with the 21-day 30/75 regimen. Both study treatments were safe and well tolerated by the volunteers as shown by the nature and frequency of adverse events, the routine laboratory examinations, and the physical and gynecological examinations. Both preparations provided adequate contraceptive reliability. The only pregnancy during treatment was attributable to intake errors. In conclusion, the prolongation of the treatment phase of an oral contraceptives with 20 microg ethinyl estradiol does not evoke more pronounced metabolic effects than a conventional 21-day regimen with 30 microg ethinyl estradiol. The metabolic effects of four oral contraceptives with different estrogen/progestogen profiles (monophasic nonalkylated estrogen/norethindrone, low-dose monophasic ethinyl estradiol (EE2)/norethindrone, progestogen only treatment with norethindrone, and triphasic EE2/levonorgestrel) were examined in insulin-dependent diabetic women. During the 6-month study period, no differences were found in fasting plasma glucose, 24-hour insulin requirements, glycated hemoglobin, free fatty acids, low-density lipoprotein cholesterol concentrations, or high-density lipoprotein cholesterol/total cholesterol ratio between the patients in each treatment group. Compared with the nonalkylated estrogen/norethindrone and the triphasic EE2/levonorgestrel formulations, the low-dose EE2/norethindrone combination resulted in small but significant increases in plasma triglyceride and very low-density lipoprotein cholesterol levels (P less than 0.01), which seemed unfavorable from a clinical point of view. Norethindrone-only treatment appeared to be an appropriate alternative to both the nonalkylated estrogen/norethindrone combination and the triphasic EE2/levonorgestrel formulations. To evaluate the impact on lipid and carbohydrate variables of a combined one-third ethinyl estradiol (EE)/levonorgestrel (LNG) dose reduction in oral contraceptives.
                In an open-label, randomized study, a dose-reduced oral contraceptive containing 20 microg EE and 100 microg LNG (20 EE/100 LNG) was compared with a reference preparation containing 30 microg EE and 150 microg LNG (30 EE/150 LNG). One-year data from 48 volunteers were obtained.
                We found a decrease of HDL2 cholesterol and increases of low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol and total triglycerides in both treatment groups from baseline to the 13th treatment cycle. Although for four of six variables, the changes in the 20 EE group were lower compared with the 30 EE group, none of the differences between the two treatments were statistically significant. The median values for the fasting levels of insulin, C-peptide and free fatty acids slightly increased or remained unchanged while the fasting glucose levels slightly decreased after 13 treatment cycles. While the glucose area under the curve (AUC) (0-3 h) was similar in both groups during the OGTT, the insulin AUC(0-3 h) was less increased in the 20 EE/100 LNG group compared with the 30 EE/150 LNG group. None of the differences between the treatment groups for any of the carbohydrate metabolism variables were statistically significant at any time point. Both study treatments were safe and well tolerated by the volunteers.
                Similar effects on the lipid and carbohydrate profiles were found for both preparations. The balanced one-third EE dose reduction in this new oral contraceptive caused slightly lower, but insignificant, changes in the lipid and carbohydrate variables compared with the reference treatment. In a parallel, multicenter study in Norway and Finland involving a total of 196 healthy women (mean age 22.4 years, range 18-30), the effects on serum lipids and lipoproteins of two multiphasic oral contraceptives containing ethinyl estradiol (EE) but different progestins were examined. One formulation contained EE 35 micrograms and norethisterone (NET) 0.5 mg on days 1-7 and days 17-21 and elevated NET 1.0 mg during the midphase (days 8-16). The other formulation contained EE 30 micrograms on days 1-6 and days 12-21 and 40 micrograms on days 7-11 and phased levonorgestrel (LGN): 50 micrograms (days 1-6), 75 micrograms (days 7-11) and 125 micrograms (days 12-21). Both formulations induced significant elevation of total cholesterol (6.7 and 4.1%), Apo B (8.1 and 7.0%) as well as HDL (6.4 and 3.7%) for the EE/NET and EE/LGN formulation respectively. Mean serum levels of triglycerides were significantly elevated (58 and 47%). However, all mean serum lipid and lipoprotein values remained within the normal range, and no change in the calculated cholesterol ratio (HDL/total cholesterol) nor lipoprotein ratio (HDL/(HDL+LDL)) was observed. No significant difference between the formulations could be detected with respect to the effect on serum lipids and lipoproteins measured. The change in total cholesterol was smaller than reported in many studies of monophasic preparations. Taken together, these data suggest that only small alterations in lipid metabolism are elicited by these oral contraceptives. One hundred thirty women were randomly assigned to treatment with one of three triphasic oral contraceptives and 43 women using nonhormonal methods served as controls for a 6-month study of the metabolic effects of these formulations. One of the oral contraceptives contained ethinyl estradiol and levonorgestrel, and the other two contained ethinyl estradiol and norethindrone. Compared with pretreatment assessment, all three triphasic oral contraceptives produced small increases in the mean plasma glucose levels that were statistically significant but clinically unimportant. No subjects had abnormal glucose response curves in glucose tolerance test results. Compared with pretreatment assessment, all of the oral contraceptive preparations produced small increases in the mean insulin levels at 3 months but not at 6 months. Overall there were no statistically significant differences among the three formulations in their effects on carbohydrate metabolism as measured by glucose or insulin levels after 6 months of treatment.
The four included randomised controlled trials in this systematic review provided insufficient evidence to assess whether progestogen-only and combined contraceptives differ from non-hormonal contraceptives in diabetes control, lipid metabolism and complications. Three of the four studies were of limited methodological quality, sponsored by pharmaceutical companies and described surrogate outcomes. Ideally, an adequately reported, high-quality randomised controlled trial analysing both intermediate outcomes (that is glucose and lipid metabolism) and true clinical endpoints (micro- and macrovascular disease) in users of combined, progestogen-only and non-hormonal contraceptives should be conducted. However, due to the low incidence of micro- and macrovascular disease and accordingly the large sample size and long follow-up period needed to observe differences in risk, a randomised controlled trial might not be the ideal design.