Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users and in [correction of who are] carriers of hereditary prothrombotic conditions. The Cerebral Venous Sinus Thrombosis Study Group

OBJECTIVE: To investigate whether users of oral contraceptives and in [corrected] carriers of a hereditary prothrombotic condition (factor V Leiden mutation, protein C, S, or antithrombin deficiency) have an increased risk of cerebral sinus thrombosis. DESIGN: Comparison of a prospective series of cases of cerebral sinus thrombosis with population data. SETTING: Neurological teaching hospitals from different regions in the Netherlands (cases) and a representative sample of the non-institutionalised Dutch population (controls). SUBJECTS: 40 women aged 18-54 years with cerebral sinus thrombosis (cases) and 2248 women aged 18-49 years (controls). MAIN OUTCOME MEASURE: Current use of oral contraceptives at the time of the thrombosis (cases) or at the time of the questionnaire (controls). Prevalences of a hereditary prothrombotic condition in patients and in the population with odds ratios. RESULTS: 34 of 40 (85%) women with cerebral sinus thrombosis used oral contraceptives, versus 1007 of 2248 (45%) of the control women; the age adjusted odds ratio was 13 (95% confidence interval 5 to 37). Seven of 36 patients (19%) had a prothrombotic deficiency, versus 7% expected in the population; this corresponds to a threefold to fourfold increase in risk. In women who used oral contraceptives and also carried a prothrombotic defect, the odds ratio for cerebral sinus thrombosis was about 30 relative to women who had neither risk factor. CONCLUSION: The use of oral contraceptives and being a carrier of a hereditary prothrombotic condition increase the risk of and interact in a multiplicative way in the development of cerebral sinus thrombosis.     

Estrogen-containing oral contraceptive agents. A basis for their thrombogenicity

The mechanism whereby estrogen-containing contraceptives facilitate thrombosis is obscure, and published data concerning their effect on antithrombin III are conflicting. Plasma samples were examined for the quantity of antithrombin III and activated factor X (Xa) inhibitory activity among 57 women receiving oral contraceptives and 48 controls. The quantity of antithrombin III in both groups was normal. In contrast, Xa inhibitory activity was significantly reduced (P less than .001) among patients taking oral contraceptives, compared to controls. Heparin sodium added to plasma from patients taking contraceptives raised Xa inhibitory activity toward or above normal without changing the quantity of antithrombin III. The effect of estrogen is not to decrease the quantity of plasma antithrombin III, but rather to diminish plasma Xa inhibitory activity, an effect that can be abolished by heparin.     

Intimal histolysis as an early stage of atherosclerotic involvement. Observations on the human coronary arteries

The effect of long term use of oral contraceptives on glucose tolerance was studied in 133 women. Oral contraceptives were taken for a period between 3 and 12 years. 25 women without any hormone treatment served as a control group. The intravenous glucose tolerance test (IVGTT) has indicated no pathological decrease of glucose tolerance, measured by k. The glucose tolerance test was performed on all subjects (0.33 Gm. of glucose per kg bodyweight). In one subject we diagnosticated a clinical diabetes. Two patients had a subclinical diabetes. After 10 years of treatment a significant decline was noted in k, also in women with family history of diabetes or a past obstetrics history. Several doubtfully pathological k-values were recorded in women more than 40 years of age. No significant relation could be established between parity and the developement of an abnormal glucose metabolism, while taking the drugs. The effect upon glucose tolerance is not related to the type of oral contraceptive. The evidence is not sufficient to warrant the elimination of oral contraceptives. In is suggested that at least in diabetes suspects, repeated controls of glucose tolerance be carried out during long term cyclic use of oral contraceptives.     

Consistent lack of association between breast cancer and oral contraceptives using either hospital or neighborhood controls

BACKGROUND: Case-control studies of oral contraceptive use and breast cancer have used neighborhood, population, or hospital controls. METHODS: To determine whether this association differs according to type of controls, interview data from 131 incident cases of breast cancer were compared with those of 189 hospital controls and 182 neighborhood controls Study subjects were white females recruited between 1973 and 1975 from among residents of Baltimore City and County ages 18 to 59 years. RESULTS: Adjusted relative odds of breast cancer related to ever versus never use of oral contraceptives were 1.0 and 0.8, using hospital and neighborhood controls, respectively. Relative odds did not increase proportionally to duration of oral contraceptive use or to progestogen potency. Although few subjects had used oral contraceptives for more than 2 years, almost all pill brands contained more than 49 micrograms of ethinyl estradiol or of mestranol. CONCLUSIONS: Results from the present study do not support the hypothesis that early preparations of oral contraceptives increased breast cancer risk among white women, regardless of whether controls are neighbors of the cases or hospital patients. However, its conclusions cannot be generalized to women who began taking the pill before their first full-term birth or took it for more than 2 years.     

Effect of various estrogen treatment schedules on antithrombin III levels

Antithrombin III levels were determined in 18 normal indiviuals of both sexes, 24 pregnant women (at term), 20 patients treated with oral contraceptives and 21 postmenopausal patients treated with Premarin. There was no sex difference in antithrombin III levels in the untreated control group. Pregnant women at term had the lowest levels of antithrombin III. The second lowest values were exhibited by women on oral contraceptives. Both of these groups differed significantly (p less than 0.05) from the controls. Premarin treated postmenopausal women had somewhat lower levels of antithrombin III than controls but these were statistically not significant.     

Oral contraceptive use in older women and fatal myocardial infarction

A previous study of women who had died from myocardial infarction and of a control group of women matched with them for age suggested a fivefold increase in the risk of death from myocardial infarction among users of oral contraceptive aged 40-44 years compared with women not using such preparations. Only a small proportion of women in the infarction and control groups had used oral contraceptives, however, so the margin of error was wide. We therefore investigated a further 54 women in this age group who died from myocardial infarction and compared their oral contraceptive histories with those of age-matched, living controls. Combination of the findings from the present investigation with the previous results have enabled a revised estimate of a threefold increase in risk to be made. Although this risk estimate is similar to that previously shown for a younger age group, the total mortality attributable to complications associated with the use of oral contraceptives remained considerably greater among women over the age of 40.     

An epidemiological study of the haemostatic and other effects of oral contraceptives

Factors V, VII and VIII (each determined by biological assay), fibrinogen, platelet count and adhesiveness, and fibrinolytic activity were measured in 234 white pre-menopausal women, of whom 57 (24%) were on oral contraceptives and 177 (76%) were not. Cholesterol, triglyceride and blood pressure levels were also recorded. In 20 of the women on oral contraceptives, and in an age-matched group of 20 who were not, prothrombin, factor X, antithrombin III and alpha 2-macroglobulin levels were determined, and factors VII and VIII were also measured immunologically. For the majority of the variables studied, the differences between those using and not using oral contraceptives were greater in younger than older women; in the case of factor VII (biological assay) and fibrinogen, the differences between the regression slopes on age were statistically significant, and mean values were substantially higher in those on oral contraceptives. There was also a significant difference between regression slopes on age for cholesterol. Mean levels of prothrombin, factors VII (immunological assay) and X, triglycerides and blood pressure were significantly higher, and mean levels of antithrombin III significantly lower, in those on oral contraceptives compared with those not. Overall, fibrinolytic activity was significantly higher in the women on oral contraceptives; this difference was, however, almost entirely due to the greatly increased fibrinolytic activity of the non-smokers on oral contraceptives, activity in the smokers on oral contraceptives being similar to that of the women not on these preparations. There were no significant differences in mean platelet count or adhesiveness, or in haemoglobin, packed cell volume, uric acid and blood sugar levels. Among the women on oral contraceptives, there was a significant negative correlation between factor VIII and fibrinolytic activity; this was largely due to five women all of blood groups A and B, in whom, besides high factor-VIII levels and poor fibrinolytic activity, other variables (e.g. fibrinogen) were raised in a direction that might be expected to favour thrombogenesis. It is possible that it is those women whose fibrinolytic activity does not increase in order to compensate for the effects of oral contraceptives on clotting factors, lipids and blood pressure, who are at special risk of thromboembolic episodes. The differential effects of oral contraceptives by age must be borne in mind in evaluating the effects of these preparations on the haemostatic and lipid systems.     

Behaviour of ujoviridin exposure test (ICG) in conjunction with application of hormonal contraceptives (author's transl)

The effects of Ovosiston, Non-Ovlon, Anacyclin, Eugynon, and Deposiston, all oral hormonal contraceptives, on 75 women in fertile age and on the half-life of Ujoviridin (ICG - indocyanine green) were studied prior to treatment as well as late in the second, sixth, and twelfth cycles of treatment. ICG half-life was found to be extended in the adaptation phase only in response to Deposiston. ICG is recommended for time-related diagnosis of liver changes in women on hormonal contraceptives.     

Hyperglycemia-induced circulating ICAM-1 increase in diabetes mellitus: the possible role of oxidative stress

Since the introduction of itraconazole in the Netherlands, the Netherlands Pharmacovigilance Foundation LAREB and the Inspectorate for Health Care received 15 reports of pill cycle disturbances and one of pregnancy occurring during simultaneous use of itraconazole and oral contraceptives. Twelve women used oral contraceptives containing ethinylestradiol and desogestrel. In these women, the withdrawal bleeding was either delayed or did not occur at all; one of these women reported a transiently positive pregnancy test after previous breakthrough bleedings. Three women who used a contraceptive containing ethinylestradiol and levonorgestrel had a breakthrough bleeding. One woman who used an oral contraceptive containing ethinylestradiol and cyproterone acetate became pregnant during the concomitant use of itraconazole. The possible mechanism involved remains to be explained. Although an influence of itraconazole on the reliability of oral contraceptives is uncertain, additional contraceptive measurements might be considered.     

Regulation of metabolic pathways in various groups of aboriginal populations of the European North (as exemplified by the thyroliberin test)]

Injectable progestogen-only contraceptives can be considered for the woman who is unwilling or unable to use oral contraceptives or an IUD. They have a very low failure rate. They appear to have few serious life-threatening side-effects. The woman does not have to remember to take a daily pill. The method requires little compliance from the client and is independent of patient error. Short-term uses include for partners of men undergoing vasectomy, women being immunised against rubella and for women awaiting sterilisation. Noristerat can be used immediately after an abortion or birth of a baby. Breast feeding is not inhibited. Main side-effects are menstrual irregularities and delayed return of fertility after use. It is essential that women are counselled about the method and its side-effects before injectable contraceptives are given.     

Doppler-derived left ventricular rate of pressure rise and inotropic requirements during mitral valve surgery

OBJECTIVE: Inherited resistance to activated protein C (APC resistance), which is caused by a single point mutation in the factor V gene, is a frequent risk factor for venous thromboembolism. The aim of this study was to determine the prevalence of APC resistance and other coagulation disorders in fertile women with venous thromboembolism and also the risk factors these women had been exposed to in connection with thromboembolic events. DESIGN: A retrospective, case-control study of 36 month duration. SETTING: The study was carried out at Blekinge Hospital, Karlskrona, Sweden. SUBJECTS: The study population comprised 27 fertile women age 16-47 years with thromboembolic complications, referred to the department of Internal Medicine at Blekinge Hospital in Karlskrona during a 36-month period. RESULTS: APC resistance was found in 10 out of 27 women. APC resistance was associated with treatment with oral contraceptives in five out of six women and with pregnancy in one of seven women. All women with resistance to APC developed venous thrombosis in association with a predisposing situation (risk situation) such as surgery, trauma, immobilization, pregnancy, inflammatory state or the use of oral contraceptives. Amongst women not resistant to APC, all but one developed thrombosis in connection with a risk situation. CONCLUSION: APC resistance was found to be highly prevalent amongst fertile women with a history of thromboembolic complication occurring during their use of oral contraceptives.     

When is it safe to switch from oral contraceptives to hormonal replacement therapy?

Women may continue to use oral contraceptives (OCs) into their 40's and 50's, but to date no method has been evaluated to ascertain their ovarian status, i.e., whether fertility and estrogen production have diminished sufficiently so they could be safely switched to hormonal replacement therapy. A group of 12 postmenopausal women who had been, for long periods of time, on a regimen of 3 back-to-back packages (i.e., 63 days on, 7 days off) of low-dose oral contraceptives have been studied. Secondly, a group of 9 perimenopausal women aged 36 to 47 were examined in the same manner. The third group consisted of early reproductive age women (arbitrarily divided into subsets aged 17-25 and 26-35 using low-dose OCs in the customary regimen) as normal controls. Blood samples were obtained on the last day of a pill cycle and at 7 days off the pill. In some menopausal women, blood samples were obtained at both 7 and 14 days off OCs. Serum was assayed by RIA for estradiol, FSH and LH. As expected in the young reproductive age women, estradiol levels increase at one week off the pill, together with a rebound in FSH and LH to follicular phase levels. In the perimenopausal group, there was a sharp distinction based on age. The women over 40 showed a more marked rise in FSH while those aged 36-40 showed a distinctly lesser response. Estradiol levels were variable, but tended to show some age grouping. Little diagnostic separation was observed for LH. In postmenopausal women, FSH levels were not always elevated at one week post-pill, and even in a second trial with sampling at one and two weeks off the OC, not all postmenopausal women showed a "menopausal" increase in FSH. The more uniform feature was that estradiol levels never increased above basal values. The study found that serum estradiol levels increase after a week off the pill in controls, but are unchanged at one and two weeks in the menopausal group. FSH levels rebound normally in reproductive age women and usually, but not always, increase substantially in postmenopausal women. After two weeks off OCs, an increased FSH and/or no change in basal estradiol levels is strong evidence that it is now safe (contraceptively speaking) to switch from OCs to standard hormone replacement regimens.     

Effect of oral contraceptive progestins on serum copper concentration

OBJECTIVES: Recent epidemiologic studies have shown an increased mortality from cardiovascular diseases in people with higher serum copper levels. Even though higher serum copper concentration in women using oral contraceptives is well known, there is still uncertainty about the influence of newer progestin compounds in oral contraceptives on serum copper concentration. This issue is of particular interest in the light of recent findings of an increased risk of venous thromboembolism in users of oral contraceptives containing newer progestins like desogestrel compared to users of other oral contraceptives. DESIGN: Cross-sectional epidemiologic study. Examinations included a detailed questionnaire on medical history and lifestyle factors, a seven day food record, and blood samples. SETTING: National health and nutrition survey among healthy people living in private homes in West Germany in 1987-1988. SUBJECTS: Nonpregnant and nonlactating women aged 18-44 y (n = 610). RESULTS: Overall, the use of oral contraceptives was positively associated with serum copper concentration in by bi- and multivariable linear regression models with log-transformed values of serum copper concentration as dependend variable and oral contraceptive preparations and potential confounding variables as independent variables. Serum copper concentration in women using oral contraceptives varied more strongly by different progestin compounds than by estrogen contents. The highest increase of serum copper was seen in women using oral contraceptives containing antiandrogen progestins (55%; 95% CI: 37-76%), followed by desogestrel (46%; 95% CI: 36-56%), norethisteron/lynestrenol (42%; 95% CI: 29-57%), and levonorgestrel (34%; 95% CI: 24-45%). CONCLUSION: While elevated serum copper concentration was found in users of all types of oral contraceptives, elevation was more pronounced among women taking oral contraceptives with antiandrogen effective progestins like antiandrogens or third generation oral contraceptives containing desogestrel. Further investigation is required to shed light on the possible role of high serum copper concentration in increasing cardiovascular or thrombotic risk of women using oral contraceptives.     

Clinical course and pathogenesis of oral contraceptive hypertension (author's transl)]

Oral contraceptives are of pathogenetic importance in hypertension of women aged 26 to 35 years. The hypertensive reaction occurs predominantly in those women who have hereditary predisposition in hypertension or diabetes mellitus, who suffer themselves from diabetes mellitus or who showed toxemia in preceding pregnancies. Experimental studies in rats indicated that oral contraceptive hypertension could be due to vascular lesions, produced by estrogen, and sodium retention, caused by progestogen. Our findings are not in agreement with the proposal that the hypertensive reaction in women is always reversible. It would be of advantage if oral contraceptives could be used, which contain no estrogen or at least estrogen in the lowest possible dose and which comprise progestogens without sodium-retaining effect.     

Solution shift performance in the elderly

Studies with animals indicate that there are cyclical changes in the monoamine oxidase (MAO) activity of brain and uterus, and that these changes may be due to changes in estrogen and progesterone levels. To determine if oral contraceptives (OC) alter the tissue MAO activity of healthy women, we measured platelet MAO activity in 7 control women and in 7 women who were receiving combination estrogen-progesterone OC. The platelet MAO of the control women and the women receiving OC did not differ with the use of tryptamine and serotonin as MAO substrates. The two groups did not differ with respect to the following: serum serotonin, plasma tryptophan, plasma tyrosine, and the urinary excretion of tryptamine, tyramine, serotonin, 5-hydroxyindoleacetic acid, creatinine, 17-hydroxycorticosteroids, 17-ketosteroids, and urinary free cortisol. The subjects receiving OC had higher plasma cortisol concentrations than the controls. Two women in the seventh month of uncomplicated pregnancy, who underwent these studies, had higher plasma cortisol and urinary 17-ketosteroid excretion than control subjects. In the remaining tests the results of pregnant subjects did not differ from those of control subjects. We conclude that tissue MAO activity is not altered by OC or pregnancy.     

Effect of oral contraceptives and vitamin B6 supplements on alanine and glycine metabolism

Plasma alanine or glycine concentrations and blood pyruvate were studied before and after oral administration of the two amino acids to women using estrogen-containing oral contraceptives and to a control group of women. Thirty oral contraceptive users and 14 controls received alanine loads (200 mg/kg of body weight). The two groups had similar fasting plasma alanine levels, but the fasting blood pyruvate was elevated in the contraceptive steroid-treated women. After alanine ingestion, the increases in plasma alanine were significantly lower in the oral contraceptive users. Both groups showed a rise in blood pyruvate; there were no differences in the increments above fasting values. Treatment with pyridoxine hydrochloride, 25 mg for 4 weeks, had not effect on the responses of 11 oral contraceptive users to alanine loading. Twenty-four oral contraceptive users and 14 controls were studied before and after a glycine load (140 mg/kg of body weight). The fasting plasma glycine levels were similar, but lesser increases after ingestion of the amino acid occurred in the oral contraceptive-treated group. Blood pyruvate concentrations in both oral contraceptive users and controls were unaffected by oral glycine loads.     

Migraine and stroke in young women: case-control study. The World Health Organisation Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception

OBJECTIVE: To investigate the association between migraine and ischaemic or haemorrhagic stroke in young women. DESIGN: Hospital based case-control study. SETTING: Five European centres participating in the World Health Organisation Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. SUBJECTS: 291 women aged 20-44 years with ischaemic, haemorrhagic, or unclassified arterial stroke compared with 736 age and hospital matched controls. INTERVENTION: Questionnaire. MAIN OUTCOME MEASURE: Self reported history of headaches. RESULTS: Adjusted odds ratios associated with a personal history of migraine were 1.78 (95% confidence intervals, 1.14 to 2.77), 3.54 (1.30 to 9.61), and 1.10 (0.63 to 1.94) for all stroke, ischaemic stroke, and haemorrhagic stroke respectively. Odds ratios for ischaemic stroke were similar for classical migraine (with aura) (3.81, 1.26 to 11.5) and simple migraine (without aura) (2.97, 0.66 to 13.5). A family history of migraine, irrespective of personal history, was also associated with increased odds ratios, not only for ischaemic stroke but also haemorrhagic stroke. In migrainous women, coexistent use of oral contraceptives or a history of high blood pressure or smoking had greater than multiplicative effects on the odds ratios for ischaemic stroke associated with migraine alone. Change in the frequency or type of migraine on using oral contraceptives did not predict subsequent stroke. Between 20% and 40% of strokes in women with migraine seemed to develop directly from a migraine attack. CONCLUSIONS: Migraine in women of childbearing age significantly increases the risk of ischaemic but not haemorrhagic stroke. The coexistence of oral contraceptive use, high blood pressure, or smoking seems to exert a greater than multiplicative effect on the risk of ischaemic stroke associated with migraine.     

Choice and follow-up of contraception without risk factor

Every young healthy and truly informed woman may use any contraceptive method. Teenagers have to avoid not only pregnancy but also AIDS and other sexually transmitted diseases. Therefore they may use condoms when aware of postcoital contraception or must use both condoms and oral contraceptives. Non smoker women over 40 may choose between combined oral contraceptives, high doses progestogens or IUDs. Whatever the age, newer preparations with desogestrel, norgestimate or gestodene will be preferentially used due to the absence of clinical and metabolic side-effects. Smokers before 35, nonsmoker women over 35 will be preferentially given pills with only 20 micrograms ethinyloestradiol.     

User characteristics and oral contraceptive compliance in Egypt

Results from the 1988 Egypt Demographic and Health Survey show that many women are not taking oral contraceptives in a manner that ensures full protection by the method. Reports from 1,258 current pill users show a range of incorrect use; 63 percent of women surveyed reported an interruption in their use of the pill in the past month, and of those women, only 40 percent took the correct action when they missed a pill. The majority (89 percent) did not wait the correct number of days between packs. Multivariate analysis revealed that rural women were more likely to take pills out of sequence, compared with their urban counterparts. Failure to take a pill within the previous month was strongly associated with the experience of side effects. The younger women surveyed were more likely to know the correct interval between pill packs than were older women; and women who wanted more children were more likely to know the correct interval than those who did not. The use patterns exhibited by the pill users may be the result of their receiving confusing, incorrect, or incomplete information, and highlight the need to provide women with accurate, updated, and comprehensible information about oral contraceptives.