Using epidemiological data to guide clinical practice: review of studies on cardiovascular disease and use of combined oral contraceptives

OBJECTIVE: To explore the usefulness of epidemiological data to guide clinical practice by seeking an answer to the question "What is the risk of cardiovascular disease among users of currently available, low dose, combined oral contraceptives who are aged less than 35 years, do not smoke, and do not have a medical condition known to increase the risk of vascular disease?" DESIGN: Review of all relevant published studies identified from the library of references held by Royal College of General Practitioners' Manchester Research Unit, checking of reference lists of identified studies, and Medline search. MAIN OUTCOME MEASURES: Identification of methodologically sound studies able to address the specific clinical question. RESULTS: Our literature search identified 74 papers about the relation between current use of combined oral contraceptives and cardiovascular disease: 23 papers reporting risk of venous thromboembolism, 22 on ischaemic stroke, 13 on haemorrhagic stroke or subarachnoid haemorrhage, 13 on all stroke, and 33 on myocardial infarction. Only five papers provided information that directly addressed our clinical question; all related to the risk of venous thromboembolism. Fourteen of the discarded papers probably had the potential to answer our clinical question. CONCLUSIONS: Much of the epidemiological data about the risk of cardiovascular disease in users of combined oral contraceptives is not useful to clinicians. Some of the discarded data could be made more useful to clinicians by reanalysis. This situation is unlikely to be unique to use of contraceptives.     

Secondary amenorrhoea and oral contraceptives

Extirpation of the endolymphatic anlage of the ear vesicle or that part of the ear placode which develops into the endolymphatic anlage in chick embryos, resulted in the absence of the endolymphatic system. In specimens of which the endolymphatic anlage was removed on the fourth day, healing of the wound was completed soon after the fifth day of incubation. Most of these experimental animals developed endolymphatic hydrops at a later stage. However, where healing was delayed after the fifth day, the open wound acted as an escape route for the endolymph (thus preventing further closure) which at that stage (or soon after) reached an appreciable volume.     

Pharmacology of oral contraceptives

Oral contraceptives include two types of steroids; ethinyl-estradiol as the main estrogenic component which dose vary from 20 to 50 micrograms per tablet (mostly 30 to 35 micrograms) and progestins essentially derivatives of 19 nortestosterone. Derivatives of 19 norprogesterone such as nomegestrol acetate or ST 1435 are not used as oral contraceptives but are being evaluated through parenteral administration, e.g. implants or transdermal systems. The assessment of the pharmacological properties of these progestins indicate a high antigonadotropic and a high antiestrogenic properties for levonorgestrel and for the newer gestagens as well. Therefore very low doses are being used in the current oral contraceptives. However, there is a lower margin of security with the low dose contraceptives than with previous standard combinations and especially when concomitant medications are ingested such as enzyme-inducing agents. Selection of contraceptive methods should be discussed when specific co-medications are necessary.     

Potencies of oral contraceptives

Oral contraceptives are combinations of estrogens and progestogens or, in the case of the mini-pills, progestogens alone. With specific test procedures in laboratory animals or human subjects, it is possible to assign potency evaluations to the components relative to the progestational, estrogenic, or antiestrogenic activities of the progestogen or to the estrogenic potencies of the estrogenic component. It might even be possible to quantify the synergistic effects of the estrogen on the progestational agent. Unfortunately, however, it is impossible now to amalgamate such assay results into single estimates of the potencies of the combinations (either the combination products per se or the combination tablets of sequential products). For example, an over-all estrogenic potency of a combination preparation would involve the integration of contributions form the estrogen itself plus the estrogenic products of metabolism of the progestogen minus the antagonistic effect of the progestational agent, if any. These factors cannot now be quantified independently, much less merged into a single figure of clinical significance. Further, even if it were possible to produce such an estimate, it is unlikely that the evaluation would be meaningful in relation to any putative side effect or adverse reaction, i.e., the alleged thrombogenic effects of oral contraceptives cannot currently be related directly to any measure of potency that will allow prediction of these clinical conditions from laboratory models. Any evaluation of the potential of a given contraceptive to produce a specific side effect will depend upon data generated with specific regard to that adverse reaction and the individual product in question.     

Anti-nidation activity of oral contraceptives

The antinidatory activity of the oral contraception is generally unknown: the contraceptive pill mainly prevents the gametes from meeting. However, pregnancies under pill indicate conception of embryos. Besides, missed pills protocols sometimes record ovulatory escape. We suggest the computation of an Embryo Destruction Index (EDI), in order to measure the antinidatory effect of two categories of oral contraceptives: combined estroprogestatives and microprogestatives.     

Oestrogen-progestogen oral contraceptives and urinary calcium excretion

To examine the effects of age and use of oestrogen-progestogen oral contraceptive agents (OCA) on urinary calcium excretion, 24 h urine collections were obtained from 525 women aged 16-69 years during a health survey, and measurements made of the amounts of calcium, creatinine, sodium, potassium and magnesium excreted. Younger women using OCA excreted more potassium and creatinine but less calcium, and less calcium and magnesium relative to creatinine, than corresponding controls using no OCA. Older women excreted less creatine, but significantly greater amounts of calcium, sodium, potassium and magnesium relative to creatinine than younger women. It is postulated that the diminished urinary calcium excretion observed in women using OCA resulted from suppression of bone resorption by oestrogens in OCA.     

Tumors of the liver and oral contraceptives

In this editorial, the authors review the body of literature dealing with primary tumors of the liver (hepatomas) that occur in women using oral contraceptives; since 1972 reports of 23 such cases have been published. The affected women ranging in age from 22 to 52 years, and most reported that they had used the "combined pill." The women had been using the pill for a mean duration of 5 years; there was no direct association between the duration of pill use and the appearance of the hepatoma. Diagnosis of the tumor was made either by liver scan or by intra-abdominal arteriography. Since it was possible to palpate the tumor in 10 patients, the authors emphasize the importance of continuous medical supervision of women who are using oral contraceptives. Treatment may be conservative or surgical; in this series, 20 of the patients underwent surgery despite the risks of considerable operative morbidity. The mechanism leading to the appearance of hepatomas in these women is not clear, although it is certain that it is related to the liver's role in the metabolism of hormones. The authors note that only 23 cases of hepatoma have been reported among the more than 20 million women using the pill; the frequency of the tumor in the general population of women of reproductive age must be examined before concluding that there is a direct association between the appearance of the tumor and use of the pill.     

Liver damage from low-dose oral contraceptives

OBJECTIVE: To study whether the decrease in the content of oestrogen and gestagen in modern low-dose oral contraceptives (OC) has yielded a lower incidence of adverse liver reactions, and to describe the biochemical pattern of the adverse liver reactions from low-dose OC. DESIGN: We surveyed all liver reactions from OC reported to SADRAC (Swedish Adverse Drug Reactions Advisory Committee) from 1966 to 1989. MAIN OUTCOME MEASURE: Incidence of reported adverse liver reactions (number of reported adverse reactions/OC sales in defined daily dose [DDD]). RESULTS: There was a sharp decline in the number of reports during the studied period, suggesting changes in reporting habits. However, there was also a significantly lower incidence of reports for medium-compared to high-oestrogen dose OC, and a further decrease, albeit non-significant, in incidence with low-oestrogen dose OC. Furthermore, in three comparisons of pairs of OC that differed only in the gestagen dose, there was a strong trend towards a higher reporting rate with higher gestagen dose. Cholestatic and hepatocellular liver enzyme patterns were equally frequent in patients with adverse reactions from low-dose oestrogen OC. There was no report of liver tumours related to use of low-oestrogen dose OC. CONCLUSION: There seems to be a decrease in the incidence of adverse liver reactions related to lower contents of both oestrogen and gestagens in OC of the combined-preparation type.     

Amenorrhea following the use of oral contraceptives

Clinical aspects and the incidence of the various underlying etiologic factors were studied in 86 patients with post-oral contraceptive amenorrhea. Patients were divided into two groups according to the presence or absence of detectable galactorrhea. Group I was composed of 55 amenorrheic patients without detectable galactorrhea and group II included 31 patients with amenorrhea associated with galactorrhea. Both groups were comparable for age, gravidity, duration of intake of oral contraceptives, and duration of amenorrhea. The incidence of previous oligomenorrhea and late menarche was high in both groups. The most striking difference between the two groups was in the incidence of pituitary prolactin-secreting tumor--32% among patients with galactorrhea and less than 2% among patients without galactorrhea. Identification of galactorrhea and accurate diagnosis of its causes are mandatory for successful management of postpill amenorrhea.     

Veno-occlusive disease of the liver associated with oral contraceptives: case report and review of literature

This report concerns a young woman who, after taking a contraceptive preparation orally for three years, developed the Budd-Chiari syndrome as the result of a widespread chronic obliterative process involving the intrahepatic efferent venous system. Her prolonged course, which failed to respond to an end-to-side portacaval shunt procedure, mimicked chronic hepatitis evolving to cirrhosis. Additional noteworthy features were the presence of two small benign hepatic adenomas, observed both at biopsy and at necropsy, a lesion recently recognized as a complication of anovulatory drugs, and widespread hepatic calcifications found at autopsy.     

The relationship between oral contraceptives and adolescent sexual behavior

The AAMD Adaptive Behavior Scale, Public School Revision, was administered to 2,618 elementary-school children from 7 to 13 years of age. The sample of children included White, Black, and Spanish-surname groups from regular and special-education classes. Factor analyses of domain scores indicated four dimensions of adaptive behavior: Functional Autonomy, Interpersonal Adjustment, Social Responsibility, and Intrapersonal Adjustment. Comparison of factor structure across school classification and age groups revealed the same four dimensions for all groups. Implications for the assessment of adaptive behavior were discussed.     

Newer oral contraceptives and the risk of venous thromboembolism

Over the past 5 years, a large collaborative study of chemically-induced mutation has been performed using the four bacterial strains Salmonella typhimurium TA102 and TA2638 and Escherichia coli WP2/pKM101 and WP2 uvrA/pKM101 in order to compare the specific spectrum of response to chemicals and to evaluate the usefulness (sensitivity) of each strain. Following the two collaborative studies to test the chemicals in category 1, chemicals previously judged as positive only in E. coli WP2 strains and derivatives of these chemicals, and category 2, oxidative agents or crosslinking agents, 22 compounds of category 3 consisting of 10 nonmutagenic carcinogens and another 12 chemicals were selected in this study. Twenty participating laboratories tested each compound in the same method as previous reports. In the group of nonmutagenic carcinogens, no chemical induced revertant colonies of any strain tested. In the group of other chemicals, response to the chemicals was similar in TA102 and WP2 uvrA/pKM101. Overall, in the three collaborative studies, a total of 79 compounds were tested. No difference in qualitative response to the four strains was observed for 71% (56/79) of the test chemicals. The combination of strains providing the greatest number of positive responses was WP2 uvrA/pKM101 with TA102; 84% (66/79) of the test chemicals elicited the same qualitative response in these two strains. Therefore, it is suggested that WP2 uvrA/pKM101 and TA102 can be included as a part of the standard tester strains for detection of mutagenic activity of chemicals.     

Cerebral thrombosis and oral contraceptives. A case-control study

To assess the influence of oral contraceptives (OC) on the risk of cerebral thrombosis and transient cerebral ischemic attacks, a 5-year case-control study including all Danish hospitals was conducted. All women 15-44 years old who suffered a cerebral thromboembolic attack (CTA) during the period 1994-95 and 1200 age matched control subjects were included. Of 309 patients and 1200 control subjects questionnaires sent out, 271 patients (87.7%) and 1074 control subjects (89.5%) responded and agreed to participate. After exclusion of women with nonvalid diagnoses, previous thromboembolic diseases, or current pregnancy, 219 patients and 1041 control subjects were available for analysis. After confounder control and with nonusers as reference, current users of first generation OC (50 micrograms of ethinyl estradiol [EE] or estrans) had an odds ratio (OR) of CTA of 1.86 (95% confidence interval [CI] 0.88-3.92); users of second generation OC (levonorgestrel or norgestimate) had an OR of 2.37 (1.35-4.16); and users of third generation OC (desogestrel or gestodene) had an OR of 1.32 (0.78-2.22). Users of OC with 50, 30-40, or 20 micrograms EE had OR of 2.65 (1.11-6.34), 1.60 (1.05-2.43), and 1.59 (0.57-4.58), respectively. Odds ratios for specific progestin types were as follows: estrans 1.37 (0.60-3.13), levonorgestrel 2.43 (1.40-4.21), norgestimate 7.09 (1.87-26.8), desogestrel 1.62 (0.72-3.63), and gestodene 1.24 (0.67-2.30). Duration of use was without significant influence on the risk and the OR were constant across the age bands. Compared with women who had never used OC, former users had an OR of CTA of 0.95 (0.66-1.51). In conclusion, use of OC with 50 micrograms of EE and OC with second generation progestins increased the risk of CTA significantly. OC with third generation progestins did not have any significant influence on the risk of CTA. The risk of CTA among former users of OC was not increased.