Br Med J. 1970 April 25; 2(5703): 203–209.
Thromboembolic Disease and the Steroidal Content of Oral Contraceptives. A Report to the Committee on Safety of Drugs
W. H. W. Inman, M. P. Vessey, Barbro Westerholm, and A. Engelund
Reports of thromboembolism following the use of oral contraceptives received by drug safety committees in the United Kingdom, Sweden, and Denmark have been analysed to investigate possible differences in the risks associated with the various preparations. For this purpose the numbers of reports of thromboembolism attributed to each product were compared with the distribution that would have been expected from market research estimates of sales, assuming that all products carried the same risk.
A positive correlation was found between the dose of oestrogen and the risk of pulmonary embolism, deep vein thrombosis, cerebral thrombosis, and coronary thrombosis in the United Kingdom. A similar association was found for venous thrombosis and pulmonary embolism in Sweden and Denmark. No significant differences could be detected between sequential and combined preparations containing the same doses of oestrogen, nor between the two oestrogens, ethinyloestradiol and mestranol.
Certain discrepancies in the data suggest that the dose of oestrogen may not be the only factor related to the risk of thromboembolism; thus there was a significant deficit of reports associated with the combination of mestranol 100 μg. with norethynodrel 2•5 mg. and a significant excess of reports associated with the combination of ethinyloestradiol 50 μg. with megestrol acetate 4 mg. An excess of reports also occurred with other combined preparations containing megestrol acetate.
The data obtained in earlier epidemiological studies were re-examined and, though no trend was obvious in any one of them, the combined results showed an excess of cases of thromboembolism at the highest dose of oestrogen.
Lancet. 1976 Mar 6;1(7958):509-11.
Oral contraceptives, antithrombin- III activity, and postoperative deep-vein thrombosis.
Sagar S, Stamatakis JD, Thomas DP, Kakkar VV.
Deep-vein thrombosis (D.V.T.) was detected by the fibrinogen-uptake test in six out of a total of thirty-one young women undergoing emergency abdominal surgery who gave a history of recent oral contraceptive intake. In contrast, no D.V.T. developed in nineteen similar patients who were not on oral contraceptives (P less than 0.01). Plasma-antithrombin-III activity was significantly lower preoperatively in patients taking oral contraceptives; postoperative D.V.T. subsequently developed in three out of five patients with preoperative antithrombin-III activity below 50%. In seventy-eight dental patients undergoing molar extraction, antithrombin-III activity was measured before, during, and after operation. Activity fell in all patients during operation, but the fall was significantly greater in women taking oral contraceptives (P less than 0.01). The intra-operative fall in antithrombin-III activity was prevented by a small preoperative dose of subcutaneous heparin.
Am J Obstet Gynecol. 1975 Jul 15;122(6):688-92.
Conjugated estrogens and hypercoagulability.
von Kaulla E, Droegemueller W, von Kaulla KN.
A group of 11 menopausal women receiving 1.25 mg. of conjugated estrogens daily had coagulation tests to determine the development of hypercoagulability after taking 5 and 21 tablets. There was no essential change in thrombin generation or fibrinolytic activity as measured by euglobin lysis time. There was a shift toward hypercoagulability in all three parameters of the thrombelastograms. The decrease of the antithrombin III activity was not as pronounced following the administration of conjugated estrogens as had been the change associated with oral contraceptives. Fibrin monomers were observed in some women during the first week of Premarin therapy.
Arch Pathol. 1970 Jan;89(1):1-8.
Vascular lesions in women taking oral contraceptives.
Irey NS, Manion WC, Taylor HB.
Distinctive vascular lesions in association with thrombosis were found in arteries and veins in 20 relatively young women receiving oral contraceptives. These lesions were characterized by structural and histochemical changes in the intima and media. Occlusive thrombi were associated with relatively small, organized bases, the age of the latter measured in days to weeks. Nonocclusive and possibly earlier lesions were dominated by endothelial proliferation with minimal thrombus formation. It is postulated that this endothelial and intimal hyperplasia may be related to the steroids received and that it parallels similarly induced hyperplasias that have been found in cervical gland epithelium, in leiomyomas, and in a variety of mesenchymal derivatives under experimental conditions. Further control and experimental studies are required to clarify the possible relationship between these vascular lesions and oral contraceptives.
Br Med J. 1973 December 1; 4(5891): 507–512.
Cryptogenic Cerebral Embolism in Women Taking Oral Contraceptives
Karin Enzell and Gunnar Lindemalm
Fourteen women taking oral contraceptives were admitted during a five-year period because of acute cerebrovascular lesions. A diagnosis of major cerebral embolism was established in four of them. No source of embolism was found, and thorough investigation failed to reveal any predisposing illness. Cerebral embolism was a probable diagnosis in several of the remaining 10 patients. A comparison was made with the strokes occurring in women not taking contraceptive pills in corresponding age groups.
Lancet. 1973 Jun 23;1(7817):1399-404.
Oral contraceptives and venous thromboembolic disease, surgically confirmed gallbladder disease, and breast tumours. Report from the Boston Collaborative Drug Surveillance Programme.
[No authors listed]
A large survey of 24 hospitals was conducted to identify associations between commonly used drugs and various diseases. The results of 3 such studies–on venous thromboembolism, gall bladder disease, and breast tumors–are summarized in this article. Trained nurses in various hospital wards interviewed admissions, asking questions designed to determine smoking behavior, coffee and tea drinking, drug use, marital status, and parity and menopausal status, where appropriate. This report specifically centers on associations between oral contraceptive use and development of the 3 conditions under study. Women reported on in this portion of the study were aged 20-44 years. Compared with nonusers, the estimate of relative risk for thromboembolism in users was 11, and the estimated attack rate attributable to oral contraceptives was 60/100,000 users/year. For gall bladder disease (surgically confirmed) the corresponding relative risk estimate was 2.0, and the estimated annual attack rate was 79/100,000. The frequency of gall bladder disease in women under 35 years was significantly higher in oral contraceptive users of 6-12 months duration, compared with women who had taken the pills for longer periods. Breast cancer studies showed no evidence of a higher risk in oral contraceptive users relative to nonusers. In fact, a negative association between oral contraceptive use and breast tumors was found, and this was more pronounced in women with fibroadenoma of the breast. Most of the women surveyed for this report took low-dose estrogen formulations, but the role of dose to the above findings was not investigated.
The finding of a positive correlation between the dose of oestrogen and the risk of coronary thrombosis is of special interest since previous studies have failed to provide clear evidence of a relationship between oral contraceptives and this condition.
Am J Obstet Gynecol. 1987 Oct;157(4 Pt 2):1042-8.
Coagulation effects of oral contraception.
In Europe and North America, estrogen/progestogen oral contraception has been associated with an increase in venous thromboembolism, myocardial infarction, and stroke. These hazards are found mainly in smokers and in women over the age of 35. Venous thromboembolism appears to correlate with the estrogen dosage, and the arterial complications with both the estrogen and progestogen components. Blood coagulation and vascular thrombosis are intimately related. Estrogen/progestogen oral contraception affects blood clotting by increasing plasma fibrinogen and the activity of coagulation factors, especially factors VII and X; antithrombin III, the inhibitor of coagulation, is usually decreased. Platelet activity is also enhanced with acceleration of aggregation. These changes create a state of hypercoagulability that, to a large extent, appears to be counterbalanced by increased fibrinolytic activity. Studies of the oral contraceptives in current use show that the coagulation effects depend on the dosage of estrogen and the type of progestogen used in combination. Current research is aimed at finding the estrogen/progestogen formulations that induce the least changes in the coagulation system and other physiologic processes. In this respect, the new low-dose formulations are a major step forward and should reduce the risk of vascular thrombotic complications.
Lancet. 1980 May 24;1(8178):1097-101.
Oral contraceptives and thromboembolic disease: effects of lowering oestrogen content.
Böttiger LE, Boman G, Eklund G, Westerholm B.
The introduction of low-oestrogen oral contraceptives in Sweden and the concomitant disappearance of high-dose preparations did not result in a lowering of the mortality of fertile women from thromboembolic disease. Morbidity due to thromboembolism seems to have fallen, and the number of thromboembolic incidents reported to the Swedish Adverse Drug Reaction Committee decreased dramatically. The decrease was due exclusively to a reduction in venous thromboembolic disease: the frequency of arterial complications (cerebral and coronary) remained constant.
Estrogen has many pro-clotting effects, and one of them is a decreased activity of vascular plasminogen activator. K. E. Miller and S. V. Pizzo, “Venous and arterial thromboembolic disease in women using oral contraceptives,” Am. J. Obst. Gyn. 144, 824, 1982. -Ray Peat, PhD
Am J Obstet Gynecol. 1982 Dec 1;144(7):824-7.
Venous and arterial thromboembolic disease in women using oral contraceptives.
Miller KE, Pizzo SV.
Vascular plasminogen activator was measured by means of a new chromogenic assay in 24 women who had suffered from oral contraceptive-associated thrombotic disease and was compared to that in a control group of 78 premenopausal women. Vascular plasminogen activator levels were significantly reduced in the subjects who had venous thrombosis but not in the five women who had arterial thrombosis (0.04 +/- 0.03 versus 0.38 +/- 0.31, respectively) when compared to the levels in the control group (0.19 +/- 0.20). Since vascular activator levels distribute in a non-Gaussian manner, cases and controls were also stratified into deciles. Seventeen subjects who had suffered from venous thrombosis were stratified in the lowest three deciles, and two subjects, in the fourth and fifth deciles. Subjects who had suffered from arterial thrombosis were in the fourth or higher deciles. The conclusion is that, although there is a correlation between low levels of vascular plasminogen activator and venous thrombosis, no such correlation exists for arterial thrombosis.
"Being on the newest kinds of pills, which contain the progestin hormones drospirenone, desogestrel, or gestodene along with estrogen, doubled the risk again, making it six to seven times as high as women who weren't using hormonal forms of birth control." -Brenda Goodman, MA
"For women who had never used any hormonal birth control, about 3.7 out of 10,000 were diagnosed with a blood clot in a vein in a year's time. Being on an older-generation pill that contained an estrogen and the progestin hormone levonorgestrel roughly doubled that risk, to 7.5 women out of 10,000 followed for one year.
"So what did the research show? Estrogen plus progestin used for women who still had their uterus study was stopped in 2002 when the research indicated an increased risk of breast cancer, heart disease, stroke, blood clots and urinary incontinence. Of interest, the risk of colorectal cancer went down, as did hip fractures.
The study of women taking only estrogen was stopped in 2004 when it was found that there was an increased risk of strokes and blood clots. The risk of breast cancer was uncertain, and there was no change in the risk of colorectal cancer. Hip fracture risk was decreased." -Debbie Jackson, PhD