Thromboembolism and oral contraceptives

A 1970 study by Fuertes-de la Haba et al. (Obstetrics and Gynecology 36: 597-602) on thromboembolism in Puerto Rican women taking oral contraceptives is criticized. Fuertes-de la Haba et al. interpreted their results as failing to corroborate previous publications indication an increased mortality rate from thromboembolic disorders in women using the oral contraceptive. Siegel indicates that the limitations in the study preclude the possibility of its affecting the understanding of the relationship of oral contraceptives to thromboembolic mortality. The data in the study were inadequate, the number of cases too small to give statistically valid results, and the follow-up of subjects was too faulty to allow accurate inferences.     

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 from 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.     

Potencies of oral contraceptives

This letter is a response to the discussion by Edgren and Sturtevant (125:1029, 1976) on potencies of oral contraceptives (OCs). It is agreed that the results of studies in animal models on OC potencies may not necessarily reflect true potencies in human subjects, however, these animal models do allow the evaluation of the biological effects and interactions of the components of OCs. Data obtained in animal studies are acknowledged to be valuable aids in the study of human diseases. Likewise, mouse uterine response to contraceptive steroids is 1 criterion to be used in evaluating steroid potency. As previously reported, the importance of the mouse uterine response is that the contribution of the progestin component to the total estrogenic potency of the OC is demonstrated.     

Smoking and oral contraceptives

The added risks of thromboembolic disease in pill users who also smoke cigarets are enumerated, then the physiological mechanisms explained. From retrospective studies it seems that heart attacks are more likely in women with oral contraception, smoking, obesity, hypertension, diabetes, and high cholesterol. With 1 of these factors the risk is 4-fold, with 2 factors 10-fold, and with 3 factors 78-fold, i.e., a synergic not additive effect. The progestagen in the pill is primarily responsible, acting by causing microthrombi. Strokes are more likely when headaches and hypertension, or oral contraception and smoking are present. Smoking is more often associated with hemorrhagic strokes, while hypertension increases risks of thrombotic and hemorrhagic strokes. The following effects of smoking are probably involved in thromboembolic disease: tachycardia, hypertension, peripheral vasoconstriction, carbon monoxide, inhibition of fibrinolysis, atherosclerosis, and increased blood viscosity.     

Interactions with oral contraceptives

The interaction of a range of different factors with the pharmacologic activity of oral contraceptives is reviewed. Pharmacokinetic interactions with oral contraceptives may occur (1) during absorption and extrahepatic circulation, (2) by interfering with protein binding, and (3) during hepatic metabolism. The hepatic mixed function oxidase system, which is mainly responsible for the metabolism of oral contraceptives, is affected by several different factors and is easily induced. Nutrition affects the activity of many drugs, but information regarding oral contraceptives is meager. Both pharmacokinetic and pharmacodynamic interactions, which may be synergistic or antagonistic, between the estrogen and gestagen components of oral contraceptives, are important, but there is no correlation between the rate of metabolism of the two components. Evidence suggests that some anticonvulsant, antibiotic, and antibacterial drugs may reduce the efficacy of oral contraceptives. Instances of interactions of other therapeutic agents are reported infrequently. The incidence of serious interactions is low and does not appear to have been reduced with low-dose oral contraceptives, probably because of large intersubject variability in the pharmacokinetics of oral contraceptives.     

Individualization of low-dose oral contraceptives. Pharmacological principles and practical indications for oral contraceptives

The contraceptive pill has been a revolution of the last 40 years. In Italy, however, it is much less widely used than in other countries. Explanations for this phenomenon range from religious implications and customs to misinformation and word-of-mouth communication of negative experiences. The oral contraceptive pill is often used to correct menstrual disorders, leading to poor results and side-effects. Recent advances in oral contraception have led to a substantial reduction in doses and side-effects. Low-dose pills contain minimal doses of progesterones and estrogens and ensure good control of the menstrual cycle. Although reduction of ethinyl estradiol (EE) concentrations has reduced the incidence of negative systemic side effects such as water retention, edema and swollen breasts, the low estrogen dose may be associated with spotting and hypomenorrhea or amenorrhea in the long term, as well as dyspareunia due to reduced vaginal trophism, which may induce women to suspend use of the drug. It is also true that only one type of estrogen is used in the pill, albeit at different doses, whereas the progesterone may differ and in many cases is the cause of common side-effects. The choice of progesterone therefore involves not only its effect on the endometrium in synergy with estrogen, but also possible residual androgenic activity which may have negative metabolic repercussions. Indeed, addition of a progesterone, especially androgen-derived, attenuates the positive metabolic effects of estrogen. Two new monophasic oral contraceptives were recently released. They contain 30 microg (Yasmin) or 20 muicrog (Yasminelle) EE and a new progesterone, drospirenone, derived from spirolactone, which has antiandrogenic and antimineralcorticoid activity similar to endogenous progesterone. Like progesterone, the drospirenone molecule is an aldosterone antagonist and has a natriuretic effect that opposes the sodium retention effect of EE. It may, therefore, help to prevent the water retention, weight gain and arterial hypertension often associated with oral contraceptive use. Recent comparative studies recorded weight loss that stabilized after 6 months of treatment with drospirenone/EE. Overweight women may therefore benefit from the formulation with 20 microg EE, whereas the formulation with at least 30 microg EE should be more appropriate for underweight women. Women with slight to moderate acne, the formulation with 30 microg EE has been found to be as effective as 2 mg cyproterone acetate combined with 35 micrig EE (Diane). Menstrual cycle characteristics, however, remain the main factor determining the choice of formulation. Randomised control studies comparing the new formulation with others containing second or third generation progesterones have found similar efficacy in cycle control and incidence of spotting. From this point of view, it is not advisable to prescribe more than 30 microg EE (Yasmin or Yasminelle) for women with normal menstrual cycles, whereas in cases of hypomenorrhea and/or amenorrhea at least this dose of EE plus drospirenone may be used. Women with hypermenorrhea run the risk of spotting if an inappropriate drug is chosen. A solution is to use 30 microg EE/drospirenone from day 5 of the cycle. To control so-called minor side-effects, the dose of EE must be appropriate. In women with premenstrual tension a dose of at least 30 microg EE associated with drospirenone reduces or even prevents symptoms. On the other hand, in cases of chronic headache or headache as a side-effect of oral contraceptive use, a lower dose of estrogen is beneficial, and doses below 20 microg may be used. Although the progesterone component is not considered to affect headache, good results have been obtained with drospirenone, the antimineralcorticoid effects of which reduce blood pressure and improve symptoms. Formulations with 20 microg EE and drospirenone are particularly indicated in women with pre-existing mastodynia, fibrocystic breast manifestations or who develop mastodynia as a side-effect of oral contraceptive use. Since high plasma concentrations of androgens have been recorded in these women, a progesterone with antiandrogen and antiedema activity can be beneficial. Finally, it is worth recalling that monophasic pills with low estrogen doses, such as the formulations mentioned above, ensure good mood control, reducing the depressive symptoms often associated with oral contraceptive use. In conclusion, formulations containing drospirenone are a valid alternative to conventional oral contraceptives for the personalisation of these drugs.     

Initial selection of oral contraceptives

A prospective, randomized trial compared client experiences with three popular oral contraceptives--Triphasil, Ortho-Novum 7/7/7 and Ortho-Novum 1/35. After one year, no significant relationship was found between the contraceptive prescribed and either breakthrough bleeding or satisfaction with the medication. The monophasic formulation, Ortho-Novum 1/35, was associated with amenorrhea more often.     

Non-contraceptive benefits of oral contraceptives

Numerous non-contraceptive benefits of combined oral contraceptive (OC) use have been identified. The risk of endometrial cancer is reduced by 20% after 1 year of use, 50% after 4 years of use, and 71% after 12 years of use compared with the risk among non-users and this protective effect persists up to 15 years after OC discontinuation. There is a 30% overall reduction in ovarian cancer risk (50% after 5 years of OC use) and the protective effect lasts at least 10 years after ending pill use. For cervical cancer, OC use is associated with a slight increase in risk, although other causative factors may be implicated. The risk of follicular ovarian cysts is reduced by about 50%, while that of cysts from the corpus luteum declines by as much as 80%. Combined OCs also reduce the risk of fibrocystic breast disease and fibroadenomas by about 25%. Both low- and high-dose OCs reduce pelvic inflammatory disease by up to 50% and, if OC users do develop this infection, it is generally less severe than in non-users. Also recorded has been a 90% reduction in risk of ectopic pregnancy. Since OCs shorten the menstrual period and amount of blood loss, they protect against iron-deficiency anemia. Finally, OC users have a 60% reduced risk of dysmenorrhea.     

Drug interaction with oral contraceptives

As drug interaction can play a part in altering biological effectiveness of the administered agents, effective menstrual control by oral contraceptives may be jeopardized by simultaneous therapy with other drugs. And, conversely, oral contraceptives may alter the biotransformation of other therapeutic agents. The clinical literature concerning with drug induced contraceptive failure is still limited and apart from 1 or 2 exceptions consists of case reports generally on few patients. In a well-controlled study, Hempel and Klinger administered different psychotropic drugs to women taking 0.05 mg ethinyloestradiol plus 1.0 mg norethisterone acetate without menstrual dysfunction. Phenobarbitone and carbamazepine most frequently provoked bleeding disorders. It has been suggested that various anti-epileptic drugs will reduce the effectiveness of oral contraceptive steroids. Phenytoin administered experimentally to 14 women on oral contraceptives provoked bleeding disorders in 3. Janz and Schmidt refer to 3 patients becoming pregnant while on anti-epileptic drugs and oral contraceptives. Primidone, phenobarbitone and ethosuccimide were implicated. Gagnaire et al. and Belaish et al. cite individual cases of conception in patients treated with anti-epileptics including primidone given alone. Rifampicin is the antibiotic most clearly implicated in menstrual disorders and conception in women taking sequential or combined oral contraceptives. The main site of interaction of oral contraceptives with other drugs is in the liver where they share the same metabolising enzymes.