Venous thromboembolic disease and combined oral contraceptives: A re-analysis of the MediPlus database.
(2/98)
In October 1995 the Committee on Safety of Medicines advised UK doctors and pharmacists that oral contraceptives containing desogestrel and gestodene were associated with double the risk of venous thromboembolic events (VTE) compared to pills containing other progestogens. In 1997 data was analysed from the MediPlus database of UK general practitioner records, which reported odds ratios for desogestrel and gestodene lower than that for levonorgestrel. Here the results of a more stringent nested case control analysis on the MediPlus database are reported. The study was larger and cases were verified. A crude incidence of idiopathic VTE was found amongst users of combined oral contraceptives of 4.6 per 10 000 exposed women years. Using levonorgestrel 150 microg + ethinyloestradiol 30 microg as reference, non-significant odds ratios of 1.1 (0.5-2.6) for desogestrel 150 microg + ethinyloestradiol 30 microg and 1.1 (0.5-2.4) for gestodene 75 microg + ethinyloestradiol 30 microg were found. The results of this study show no significant difference in risk between different formulations of combined oral contraceptive. (+info)
The differential risk of oral contraceptives: the impact of full exposure history.
(3/98)
Previous discussions have indicated that the small increases of risk of venous thromboembolism (VTE) associated with newer combined oral contraceptives (third generation, containing desogestrel and gestodene) may be attributed to bias due to cohort effects. In a case-control analysis, this may produce an overestimate of risk of newer preparations. In 10 centres in Germany and the UK, the Transnational Study analysed data from 502 women aged 16-44 years with VTE, and from 1864 controls matched for 5-year age group and region. Information on lifetime exposure history from all subjects was added to the dataset used in previous analyses and entered into a Cox regression model with time-dependent covariates. Based on 17 622 continuous exposure episodes comprising 47 914 person-years of observation, the adjusted hazard ratio (equivalent to odds ratio, OR) of VTE for the comparison of current users of third-generation versus current users of second-generation (primarily levonorgestrel compounds) combined oral contraceptives was 0.8 (0.5 to 1.3). The OR obtained in standard case-control analysis had been 1.5 (1.1 to 2.1). Adjustment for past exposures includes more information and appears more valid than the standard cross-sectional analysis. Using this approach, the Transnational Study data show no evidence for an increased risk of VTE with third- compared with second-generation combined oral contraceptives. (+info)
Recurrent use of newer oral contraceptives and the risk of venous thromboembolism.
(4/98)
The epidemiological studies that assessed the risk of venous thromboembolism (VTE) associated with newer oral contraceptives (OC) did not distinguish between patterns of OC use, namely first-time users, repeaters and switchers. Data from a Transnational case-control study were used to assess the risk of VTE for the latter patterns of use, while accounting for duration of use. Over the period 1993-1996, 551 cases of VTE were identified in Germany and the UK along with 2066 controls. Totals of 128 cases and 650 controls were analysed for repeat use and 135 cases and 622 controls for switching patterns. The adjusted rate ratio of VTE for repeat users of third generation OC was 0.6 (95% CI:0.3-1.2) relative to repeat users of second generation pills, whereas it was 1.3 (95% CI:0.7-2.4) for switchers from second to third generation pills relative to switchers from third to second generation pills. We conclude that second and third generation agents are associated with equivalent risks of VTE when the same agent is used repeatedly after interruption periods or when users are switched between the two generations of pills. These analyses suggest that the higher risk observed for the newer OC in other studies may be the result of inadequate comparisons of pill users with different patterns of pill use. (+info)
The oestrogenic effects of gestodene, a potent contraceptive progestin, are mediated by its A-ring reduced metabolites.
(5/98)
Gestodene (17 alpha-ethynyl-13 beta-ethyl-17 beta-hydroxy-4, 15-gonadien-3-one) is the most potent synthetic progestin currently available and it is widely used as a fertility regulating agent in a number of contraceptive formulations because of its high effectiveness, safety and acceptability. The observation that contraceptive synthetic progestins exert hormone-like effects other than their progestational activities, prompted us to investigate whether gestodene (GSD) administration may induce oestrogenic effects, even though the GSD molecule does not interact with intracellular oestrogen receptors (ER). To assess whether GSD may exert oestrogenic effects through some of its neutral metabolites, a series of experimental studies were undertaken using GSD and three of its A-ring reduced metabolites. Receptor binding studies by displacement analysis confirmed that indeed GSD does not bind to the ER, whereas its 3 beta,5 alpha-tetrahydro reduced derivative (3 beta GSD) interacts with a relative high affinity with the ER. The 3 alpha,5 alpha GSD isomer (3 alpha GSD) also binds to the ER, though to a lesser extent. The ability of the A-ring reduced GSD derivatives to induce oestrogenic actions was evaluated by the use of two different molecular bioassays: (a) transactivation of a yeast system co-transfected with the human ER alpha (hER alpha) gene and oestrogen responsive elements fused to the beta-galactosidase reporter vector and (b) transactivation of the hER alpha-mediated transcription of the chloramphenicol acetyl transferase (CAT) reporter gene in a HeLa cells expression system. The oestrogenic potency of 3 beta GSD was also assessed by its capability to induce oestrogen-dependent progestin receptors (PR) in the anterior pituitary of castrated female rats. The results demonstrated that 3 beta GSD and 3 alpha GSD were able to activate, in a dose-dependent manner, the hER alpha-mediated transcription of both the beta-galactosidase and the CAT reporter genes in the yeast and HeLa cells expression systems respectively. In both assays the 3 beta derivative of GSD exhibited a significantly greater oestrogenic effect than its 3 alpha isomer, while unchanged GSD and 5 alpha GSD were completely ineffective. Neither 3 beta GSD nor 3 alpha GSD exhibited oestrogen synergistic actions. Interestingly, the pure steroidal anti-oestrogen ICI-182,780 diminished the transactivation induced by 3 beta GSD and 3 alpha GSD in the yeast expression system. Furthermore, administration of 3 beta GSD resulted in a significant increase of oestrogen-dependent PR in the anterior pituitaries of castrated rats in comparison with vehicle-treated animals. The characteristics of the 3 beta GSD-induced PR were identical to those induced by oestradio benzoate. The overall results demonstrate that 3 beta GSD and its 3 alpha isomeric alcohol specifically bind to the ER and possess a weak intrinsic oestrogenic activity, whereas unmodified GSD does not. The data contribute to a better understanding of the GSD mechanism of action and allow the hypothesis to be advanced that the slight oestrogenlike effects attributable to GSD are mediated by its non-phenolic, tetrahydro reduced metabolites. (+info)
The progestin levonorgestrel induces endothelium-independent relaxation of rabbit jugular vein via inhibition of calcium entry and protein kinase C: role of cyclic AMP.
(6/98)
The progestin and oestrogen component of oral contraceptives have been involved in the development of venous thromboembolic events in women. In the present study we determined the vasoactive effects of sex steroids used in oral contraceptives in isolated preconstricted rabbit jugular veins in the presence of diclofenac and examined the underlying mechanisms. The natural hormone progesterone, the synthetic progestins levonorgestrel, 3-keto-desogestrel, gestodene and chlormadinone acetate, and the synthetic estrogen 17 alpha-ethinyloestradiol induced concentration-dependent relaxations of endothelium-intact veins constricted with U46619. Levonorgestrel also inhibited constrictions evoked by either a high potassium (K(+)) solution or phorbol myristate acetate (PMA) in the absence and presence of extracellular calcium (Ca(2+)). In addition, levonorgestrel depressed contractions evoked by Ca(2+) and reduced (45)Ca(2+) influx in depolarized veins. Relaxations to levonorgestrel in U46619-constricted veins were neither affected by the presence of the endothelium nor by the inhibitor of soluble guanylyl cyclase, NS2028, but were significantly improved either by the selective cyclic AMP phosphodiesterase inhibitor rolipram or in the absence of diclofenac, and decreased by the protein kinase A inhibitor, Rp-8-CPT-cAMPS. Rolipram also potentiated relaxations to levonorgestrel in PMA-constricted veins in the presence, but not in the absence of extracellular Ca(2+). Levonorgestrel increased levels of cyclic AMP and inhibited PMA-induced activation of protein kinase C in veins. These findings indicate that levonorgestrel caused endothelium-independent relaxations of jugular veins via inhibition of Ca(2+) entry and of protein kinase C activation. In addition, the cyclic AMP effector pathway contributes to the levonorgestrel-induced relaxation possibly by depressing Ca(2+) entry. (+info)
Effect of an oral contraceptive preparation containing ethinylestradiol and gestodene on CYP3A4 activity as measured by midazolam 1'-hydroxylation.
(7/98)
AIMS: To characterize the effect of an oral contraceptive (OC) containing ethinylestradiol and gestodene on the activity of CYP3A4 in vivo as measured by the 1'-hydroxylation of midazolam. METHODS: In this randomised, double-blind, cross-over trial nine healthy female subjects received either a combined OC (30 microg ethinylestradiol and 75 microg gestodene) or placebo once daily for 10 days. On day 10, a single 7.5 mg dose of midazolam was given orally. Plasma concentrations of midazolam and 1'-hydroxymidazolam were determined up to 24 h and the effects of midazolam were measured with three psychomotor tests up to 8 h. RESULTS: The combined OC increased the mean AUC of midazolam by 21% (95% CI 2% to 40%; P = 0.03) and decreased that of 1'-hydroxymidazolam by 25% (95% CI 10% to 41%; P = 0.01), compared with placebo. The metabolic ratio (AUC of 1'-hydroxymidazolam/AUC of midazolam) was 36% smaller (95% CI 19% to 53%; P = 0.01) in the OC phase than in the placebo phase. There were no significant differences in the Cmax, tmax, t(1/2) or effects of midazolam between the phases. CONCLUSIONS: A combined OC preparation caused a modest reduction in the activity of CYP3A4, as measured by the 1'-hydroxylation of midazolam, and slightly increased the AUC of oral midazolam. This study suggests that, at the doses used, ethinylestradiol and gestodene have a relatively small effect on CYP3A4 activity in vivo. (+info)
Prevention of postmenopausal osteoporosis with oestrogen replacement therapy and associated compounds: update on clinical trials since 1995.
(8/98)
Hormonal replacement therapy (HRT) is generally regarded as first choice for pharmacological prevention of osteoporosis in women. We reviewed recent studies of HRT regimens and selective oestrogen receptor modulators (SERMs), including controlled trials of at least one-year duration published since 1995 until February 2000 providing data on bone mineral density (BMD) or fractures. Natural and synthetic oestrogens exert a continuum of positive effects on BMD in a dose-dependent, though non-proportional, fashion independent of age and mode of administration. Bone loss may be largely prevented by 25 microg transdermal patch oestradiol, 0.3 mg conjugated equine or 0.3 mg esterified oestrogens. Progestogens neither attenuate nor augment the effect of oestrogens; sole use of tibolone prevents bone loss. Both the SERMs, tamoxifen and raloxifene, slightly increase BMD. There are no adequately powered fracture trials for any HRT regimen. Raloxifene 60 mg daily decreases the relative risk of vertebral fractures by at least 30%, as demonstrated by one 3-year fracture study of osteoporotic women. In conclusion, the recommendation to use oestrogen for postmenopausal osteoporosis, given both the lack of fracture trials and the rare trials on long-term use of HRT in (late) postmenopausal women, is not well supported. Fracture trials could overcome shortcomings of the current level of evidence. (+info)