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Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study.

Combined oral contraceptives, oral hormone replacement therapy and thrombophilias are recognised risk factors for venous thromboembolism in women. The objective of this study was to assess the risk of thromboembolism among women with thrombophilia who are taking oral contraceptives or hormone replacement therapy, conducting a systematic review and metaanalysis. Of 201 studies identified, only nine met the inclusion criteria. Seven studies included pre-menopausal women on oral contraceptives and two studies included peri-menopausal women on hormone replacement therapy. For oral contraceptive use, significant associations of the risk of venous thromboembolism were found in women with factor V Leiden (OR 15.62; 95%CI 8.66 to 28.15); deficiencies of antithrombin (OR 12.60; 95%CI 1.37 to 115.79), protein C (OR 6.33; 95%CI 1.68 to 23.87), or protein S (OR 4.88; 95%CI 1.39 to 17.10), elevated levels of factor VIIIc (OR 8.80; 95%CI 4.13 to 18.75); and factor V Leiden and prothrombin G20210A (OR 7.85; 95%CI 1.65 to 37.41). For hormone replacement therapy, a significant association was found in women with factor V Leiden (OR 13.16; 95%CI 4.28 to 40.47). Although limited by the small number of studies, the findings of this study support the presence of interaction between thrombophilia and venous thromboembolism among women taking oral contraceptives. However, further studies are required to establish with greater confidence the associations of these, and other, thrombophilias with venous thromboembolism among hormone users.

Adult↗

A two-year clinical study of the effects of two triphasic oral contraceptives on plasma lipids.

OBJECTIVE: Oral contraceptive formulations can alter plasma lipid and lipoprotein levels; however, lower-dose triphasic tablets show only minimal metabolic effects during 6 or 12 cycles of use. Involvement of lipids in chronic cardiovascular conditions, plus long-term use of oral contraceptive tablets, prompted this first 24-cycle study of the effect of triphasic formulations on young women. METHODS: 69 women assigned randomly to an ethinyl estradiol/levonorgestrel formulation (Triphasil) or an ethinyl estradiol/norethindrone formulation (Ortho 7/7/7) and 25 control women (no hormonal contraception) had blood sampled for lipids and lipoproteins pre-trial, and at 3- or 6-cycle intervals for 24 cycles. RESULTS: At cycle 24, control women experienced no significant change from baseline in any variable except apolipoprotein B (apo B). Plasma apo B increased 42% (P < .01), reflecting the LDL apo B increase (42%, P < .01). Both combination formulations significantly increased apo B (plasma, VLDL, IDL and LDL); the increases ranged between 47% and 84%. Plasma apo A1 rose (15%, P < .001) in the Ortho 7/7/7 group only. Plasma and LDL triglycerides were increased significantly (P < .001) by the norethindrone product, 43% and 81%, respectively, and plasma and LDL cholesterol, 14% and 28%, respectively. Cholesterol decreased in all other subfractions, including HDL (11%, P < .01). HDL cholesterol decreased significantly in the Triphasil group (8%, P < .05); no other cholesterol subfractions changed significantly. All cycle-24 lipid and lipoprotein values remained well within respective normal ranges. CONCLUSION: Although 2-year exposure to the triphasic oral contraceptive formulations changed the lipid risk factors for cardiovascular disease only within normal ranges, there remains potential for long-term health effects when compounded with other risk factors.

Adolescent↗

Decreased plasma tissue factor pathway inhibitor in women taking combined oral contraceptives.

Use of combined oral contraceptives (OC) is associated with a significant risk of thrombosis. The mechanisms of this effect are not clearly defined. Tissue factor pathway inhibitor (TFPI) is a circulating anti-coagulant that inhibits the earliest steps in activation of the extrinsic coagulation pathway. It plays a central role in control of coagulation but its contribution to the thrombotic risk associated with OC has not been assessed. Plasma TFPI antigen and activity, factor VIIa, prothrombin fragments 1&2, von Willebrand antigen, fibrinogen, and low density lipoprotein cholesterol were measured by standard assays in women taking OC (aged 16 to 45 years, n = 40) and age-matched women not taking OC (controls, n = 40). Plasma TFPI antigen did not vary significantly across the menstrual cycle in controls. Women on OC had a 25% reduction in plasma TFPI antigen (median 51.0 ng/ml; 95% confidence intervals [CI] 37.5 to 85.5; control 68.0 ng/ml, CI 61.0 to 95.0; P < 0.001) and a 29% reduction in TFPI activity (78.5 U/ml, CI 57.5 to 107.5; control 111.0 U/ml, CI 79.5 to 171.0; P < 0.001) compared to controls. Plasma factor VIIa activity and prothrombin fragments 1&2 were also significantly increased in women using OC (both P < 0.001), indicating activation of the extrinsic coagulation pathway. These results demonstrate that normal cyclic variations in estrogen and/or progesterone do not significantly alter plasma TFPI levels. However, estrogens and/or progestogens in OC result in activation of the extrinsic coagulation pathway and significantly reduce plasma TFPI, its major circulating inhibitor. Reduced plasma TFPI levels may underlie the thrombotic effects of OC.

Adolescent↗

[Coronary thrombosis on oral contraception (author's transl)].

A case of myocardial infarction observed in a 27 years old female taking an oestrogen-progestogen combination for contraception, who died suddenly two months after the resection of a left ventricular aneurysm, provided unprecedented anatomical documents. Their histological examination allowed to state the thrombotic mechanism of the coronary occlusion and brought arguments in favour of an alteration of the coronary arterial wall in the form of thickening of the intima, likely to have been the starting point of this thrombosis.

Adult↗

Elevation of plasma neurophysin in women on oral contraceptives.

The effect of oral contraceptives on the neurohypophysis was demonstrated by changes in the plasma level of a posterior pituitary protein. neurophysin. Neurophysins are intraneuronal proteins associated with oxytocin and vasopressin. They have been shown to be released into the bloodstream. The resting plasma level of neurophysin in normal nonpregnant women is 0.69 ng/ml+/-0.7 SD. In women on oral contraceptives, the plasma level is 6.4 ng/ml+/-4.2 SD (P<0.001). Estrogen rather than progesterone causes the elevated neurophysin. The effect is observed within 12-24 h of estrogen administration and disappears 3-11 days after estrogen is discontinued. The results indicate that oral contraceptives act on the neurohypophysis and that estrogen is a potent pharmacologic stimulus useful in studying synthesis and release of neurophysin.

Adult↗

Clinical evaluation of a new oral contraceptive, 'Pregnon'.

'Pregnon', a new oral contraceptive containing 1 mg. lynestrenol and 0.05 mg. ethinyl oestradiol, was administered cyclically to 639 women of fertile age over a total of 9,159 cycles. There were no pregnancies. In most cases the withdrawal bleeding resembled normal menstruation. The incidence of metrorrhagia was relatively low and when it did occur it was usually confined to the early treatment cycles and was of very limited duration. The objective and subjective tolerance was excellent.

Adolescent↗

Riboflavin deficiency in women taking oral contraceptive agents.

The effect of oral contraceptive agents (OCA) on riboflavin nutritional status of women of child-bearing age in a low socioeconomic population was studied. For a control group, 100 women in the same age and socioeconomic group using alternate forms of contraception were selected. Riboflavin deficiency was determined by measuring erythrocyte glutathione reductase activity, a reliable index of the deficiency. None of the women was on vitamin supplements or had clinical conditions effecting dietary intake or utilization. Eleven of 100 women in the control group had biochemical evidence of deficiency. This compared to 24 of 56 OCA users who were deficient. The frequency of deficiency increased among those on OCA for longer periods of time. Thirteen of 17 OCA users for 3 years or more, compared to 11 of 39 users under 3 years were deficient. There were no discernable dietary differences between the groups. These studies demonstrate that riboflavin deficiency is a problem of women in the lower socioeconomic level in the child-bearing age. The use of OCA aggravates the prevalence of deficiency.

Adolescent↗