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Previous reports speculated that vascular events could be related to the development of antibodies against synthetic steroids contained in oral contraceptives or other hormonal treatments. This study describes original immunoassays designed to detect antisynthetic steroid antibodies. In a first step, the assays were characterized and validated using animal-raised antisteroid antibodies. In a second step, a population of 88 oral contraceptive users, 47 of them having developed a vascular thrombosis during synthetic steroid use and 41 serving as healthy control users, were tested. Detection of antibodies against ethinylestradiol, levonorgestrel, norethisterone, cyproterone acetate, and gestodene showed that the values obtained in normal oral contraceptive users as well as thrombosis patients are very low, and show no statistically significant difference between the two groups tested. Taken together, these data indicate that the "immunological hypothesis" related to antisteroid antibodies is unlikely to explain the pathogenesis of vascular events in oral contraceptive users.

To test an immunological hypothesis proposed to explain the pathogenesis of cerebrovascular thrombosis in steroid users, circulating immune complexes were assayed in the sera from 6 control subjects, 14 ever users of oral contraceptive having developed a neurological ischaemic accident, and 7 patients with the same clinical history during use of other sex steroid not containing ethinylestradiol. Beaumont's ammonium sulfate and polyethylene glycol precipitation methods, together with a specific method of isolation of circulating immune complexes using affinity chromatography on Protein A, were used. Radioactivity from labeled ethinylestradiol added to the sera before precipitation was monitored in the precipitates to detect anti-ethinylestradiol antibodies. There were no significant differences for these parameters in the three groups. However, protein content and 3H-EE activity in the precipitates were equally and dramatically reduced after affinity chromatography in the three groups. These latter results do not support the presence of antibodies against ethinylestradiol in steroid users with cerebrovascular thrombosis. Moreover, our data suggest a lack of specificity of Beaumont's method for the isolation of immune complexes containing anti-ethinylestradiol antibodies.

The changes in plasma hormone levels were evaluated in matched healthy female volunteers investigated before and after 6 months' use of three new oral contraceptives (OCs): TrigynonR (n = 13), a triphasic OC containing low doses of ethinylestradiol (EE) + levonorgestrel (LNg); MarvelonR (n = 14), a monophasic OC containing low doses of EE + desogestrel (DOG, a new progestogen derived from LNg); and OvidolR (n = 10), a sequential OC containing higher doses (50 micrograms) of EE + DOG. Serum levels of FSH, LH, estradiol and progesterone were decreased in all cases to levels incompatible with ovulation. Prolactin concentrations were unchanged. Sex hormone binding globulin (SHBG) and Transcortin (CBG) levels were significantly increased by all three OCs (Ovidol greater than Marvelon greater than Trigynon); free testosterone levels decreased significantly while free cortisol concentrations remained unchanged. Collectively, these data indicate that (a) all three OCs are effective ovulation inhibitors, (b) Ovidol and Marvelon have greater estrogenic effects than Trigynon, (c) LNg is more effective than DOG in reducing the EE-induced increase in SHBG levels, and (d) free testosterone levels are equally well suppressed by all three Ocs.

Changes in serum lipid and lipoprotein levels were evaluated in a randomized prospective study conducted in matched healthy young women before and after 6 months' use of three oral contraceptives (OCs): Trigynon (preparation A, n = 13), a triphasic OC containing low doses of ethinylestradiol (EE) and levonorgestrel (LNG); Marvelon (preparation B, n = 14), a monophasic OC containing low doses of EE + Desogestrel (DOG, a new progestogen derived from LNG); and Ovidol (preparation C, n = 11), a sequential OC containing higher doses (50 micrograms) of EE + DOG. After 6 months of use, total triglyceride levels were non-significantly increased by preparations A (+ 29% from basal values) and B (+21%), and very significantly increased by preparation C (+90%). Total cholesterol and phospholipids were unchanged by preparations A and B, whereas phospholipids were significantly increased by preparation C. However, HDL-cholesterol, LDL-cholesterol and their epidemiologically important ratios (HDL-chol:total-chol; LDL-chol:HDL-chol) were kept unchanged by all preparations tested. Apolipoprotein A-1 (Apo A-1) was slightly but significantly increased by all three preparations whereas apolipoprotein B (Apo B) was significantly decreased by preparation B. All ratios Apo A-1:Apo B were accordingly ("favorably") increased, especially during treatment with preparation B. In conclusion, the triphasic OC containing low doses of LNG does not induce obvious, clinically significant, alterations of lipid metabolism, and it is also the case for the low-dose monophasic combination of EE + DOG. The higher-dose sequential preparation of EE + DOG behaves as a more estrogenic compound, increasing total triglyceride concentrations above the normal range.

For various metabolic and clinical reasons, it has been strongly advocated to reduce the dose of both the estrogen and progestogen components of oral contraceptives (OCs). In this study, we compared after 6 months of treatment, the action on various hormonal parameters of a standard-dose combined OC containing ethinylestradiol (EE) 0.050 mg and levonorgestrel (LNg) 0.250 mg and a low-dose triphasic combination containing a 59% reduced amount of the same steroids. Hormonal measurements in the last 3 days of OC intake indicated that basal levels of FSH and LH were less inhibited by the low-dose preparation, while PRL levels were unchanged. However, gonadal function was effectively inhibited by both high and low dose OCs, as demonstrated by equally low levels of E2, E1, P and 17-P. Consequently, no residual gonadal function could be anticipated from the observed low steroid concentrations. These results corroborated other studies (reviewed in this paper) in which serial hormonal measurements also revealed a complete lack of follicular maturation during low-dose triphasic OC treatment. Moreover, inhibition of circulating levels of A, DHEA, DHEAS, free T and DHT was similarly obtained with both preparations. Collectively, these data indicate that ovarian function is as effectively inhibited by a low-dose triphasic preparation as by a higher, standard-dose OC containing the same steroids.