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.     

Correcting misconceptions about oral contraceptives

Although the majority of American women believe that oral contraceptives can cause serious health problems such as cancer or heart disease, the scientific literature does not support these beliefs. Oral contraceptives actually protect against endometrial and ovarian cancer. The increased incidence of cardiovascular disease in oral contraceptive users, including myocardial infarction, appears to be caused by thrombosis and not atherosclerosis. The studies suggesting an increased risk of cardiovascular disease in oral contraceptive users were published in the late 1970s and therefore used a data base of women ingesting formulations containing 50 micrograms of estrogen or more. More recently published data involving healthy women taking mainly lower estrogen dose preparations suggest that there is no increased incidence of myocardial infarction or stroke. Nearly all published studies indicate that there is no increased risk of myocardial infarction in former users of oral contraceptives. Animal data actually suggest that oral contraceptives may have a protective effect against atherosclerosis, even in the presence of lowered high-density lipoprotein levels. The low-dose triphasic and monophasic formulations are effective, safe methods of contraception that can be used by most healthy women of reproductive age.     

Orale Kontrazeptiva und Depression

Oral contraceptives are used worldwide by millions of women to prevent unwanted pregnancies. The efficiency, the health risks, the contraindications and the possible health benefits have all been well studied and documented. The question whether oral contraceptives have a negative impact on moods or lead to depressive symptoms remains controversial. On the biological level it looks as if the two components of combined hormonal contraceptives counteract each other. Oestrogens have more seroninergic and possibly antidepressant effects while progestins have an antiestrogenic and gabaergic action which may lead to negative mood symptoms. Based on empirical studies it seems that combined hormonal contraceptives do not lead to depressive symptoms in healthy women. In women with premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD) the situation is more complicated. Some studies have indicated that estrogen dominant preparations with androgenic progestogens may lead to more symptoms, while a combination of low dose EE with the progestogen drosperinone taken over a 24-day period seems to have a therapeutic effect. Women with major depression taking combined hormonal contraceptives have less depressive symptoms and comorbidities compared with non-users. Progestogen only contraception with MPA, LNG and NETA seems to lead to depressive moods in a considerable number of users.     

Oral contraceptive use and glucose metabolism in a national sample of women in the united states

OBJECTIVE: This study was undertaken to determine whether users of oral contraceptives in a nationally representative population of US women had elevated levels of measures of glucose metabolism. STUDY DESIGN: Cross-sectional data from the Third National Health and Nutrition Examination Survey (1988-1994) included hemoglobin A(1c) levels and fasting glucose, insulin, and C-peptide levels. Means were compared among those who had never used oral contraceptives, current users of oral contraceptives, and former users of oral contraceptives, with and without adjustment for potential confounders. RESULTS: The vast majority of current users of oral contraceptives were using low-dose estrogen formulations. The two most common preparations were a triphasic formulation containing 0. 035 mg ethinyl estradiol and 0.5, 0.75, and 1 mg norethindrone (23. 9%) and a monophasic formulation containing 0.035 ethinyl estradiol and 1 mg norethindrone (20.7%). Current users of oral contraceptives did not have elevated values for any of the four measures of glucose metabolism. Hemoglobin A(1c) level and fasting glucose, insulin, and C-peptide levels were not related to duration of current use, age at which use began, or major formulation type. Among women who were former users of oral contraceptives there was no evidence of higher values among those who had recently ceased use. CONCLUSION: Oral contraceptive formulations currently available in the United States are not associated with an adverse glucose metabolic profile.     

Long-term oral contraceptive use does not affect trabecular bone density

To determine whether long-term exposure to exogenous estrogen in oral contraceptives influences trabecular bone mass in premenopausal women, we studied 25 closely matched, healthy, premenopausal women, who were recruited from an active obstetrics and gynecology practice. Eleven women had never used oral contraceptives, and 14 women had used oral contraceptives for a minimum of 67 months. All oral contraceptive users had used preparations that provided a minimum of 50 micrograms mestranol per day. Trabecular bone density was determined by quantitative single-energy computerized tomography of the L1-3 lumbar vertebral bodies. Trabecular bone density was similar for both the control group and the oral contraceptive users, 160.6 +/- 6.9 versus 161.2 +/- 7.4 mg/ml, respectively. The power to detect a 15% difference in bone density between these two samples was 0.87. We concluded that long-term, premenopausal oral contraceptive use has no effect on vertebral bone density.     

Results of in vitro sperm penetration tests in cervical mucus under takings of the sequential oral contraceptive ovanon and sequilar (author's transl)

The in vitro penetrability of cervical mucus by sperm was investigated in women who were taking Ovanon or Sequilar. Measurements were made under constant experimental conditions on every day of the cycle. The depth of penetration differed strikingly between women with normal menstrual cycles and women taking the sequential hormonal contraceptives. The penetration depth was substantially less when Sequilar or Ovanon was used. The Sequilar induced cervical sperm barrier during the entire cycle was almost as strong as that observed when combined preparations are used. During the proliferative phase of the cycle the penetration depth allowed by Ovanon was less than that observed during normal cycles but greater than that seen with Sequilar. During the secretion phase no appreciable differences in the penetrability of cervical mucus between the two contraceptives was observed. The hypothetical relationship between these data and the problem of cervical carcinoma was described.     

Acoustic measures of vocal stability during different speech tasks in young women using oral contraceptives: a retrospective study.

OBJECTIVES: To compare objective voice measures of vocal stability during different speech tasks in women taking oral contraceptives to those in women not taking oral contraceptives. METHODS: Voice recordings obtained from 28 women, aged 20-30 years old, were used for the study. Eighteen of the women were taking some form of oral contraception at the time of the recording (OC women); ten women were not taking any oral contraceptive medication (NOC women). Measures related to pitch, vocal stability, and loudness were obtained from sustained vowel and paragraph reading tasks. RESULTS: The OC women demonstrated significantly higher pitch levels but lower values related to measures of vocal stability. CONCLUSIONS: The use of oral contraceptives appears to exert a positive influence upon vocal fold function. Women taking oral contraceptives demonstrate higher pitch levels and greater stability during phonation than do women not taking oral contraceptives. This improvement in vocal function is contributed to the more stable hormonal environment that occurs with the use of oral contraceptives.     

Problems of contraception in women with Wilson disease

Because of the constant progress in medical therapy, the fertility status of patients with Wilson's disease may be preserved. Contraceptive counselling is, therefore, essential to these women. Some contraceptive methods can have a negative influence on hepatic function or hepatic insufficiency may reduce the efficacy of other contraceptives. Different contraceptive options for patients with Wilson's disease are described. Second generation intrauterine devices with copper and estrogen-containing oral contraceptives are contraindicated. Spermatocide and barrier contraceptives and progesterone-only preparations can be safely used.     

Acoustic measures of vocal stability during different speech tasks in young women using oral contraceptives: a retrospective study

Objectives To compare objective voice measures of vocal stability during different speech tasks in women taking oral contraceptives to those in women not taking oral contraceptives. Methods Voice recordings obtained from 28 women, aged 20-30 years old, were used for the study. Eighteen of the women were taking some form of oral contraception at the time of the recording (OC women); ten women were not taking any oral contraceptive medication (NOC women). Measures related to pitch, vocal stability, and loudness were obtained from sustained vowel and paragraph reading tasks. Results The OC women demonstrated significantly higher pitch levels but lower values related to measures of vocal stability. Conclusions The use of oral contraceptives appears to exert a positive influence upon vocal fold function. Women taking oral contraceptives demonstrate higher pitch levels and greater stability during phonation than do women not taking oral contraceptives. This improvement in vocal function is contributed to the more stable hormonal environment that occurs with the use of oral contraceptives.     

Triphasic Randomized Clinical Trial: Comparison of effects on carbohydrate metabolism

One hundred thirty women were randomly assigned to treatment with one of three triphasic oral contraceptives and 43 women using nonhormonal methods served as controls for a 6-month study of the metabolic effects of these formulations. One of the oral contraceptives contained ethinyl estradiol and levonorgestrel, and the other two contained ethinyl estradiol and norethindrone. Compared with pretreatment assessment, all three triphasic oral contraceptives produced small increases in the mean plasma glucose levels that were statistically significant but clinically unimportant. No subjects had abnormal glucose response curves in glucose tolerance test results. Compared with pretreatment assessment, all of the oral contraceptive preparations produced small increases in the mean insulin levels at 3 months but not at 6 months. Overall there were no statistically significant differences among the three formulations in their effects on carbohydrate metabolism as measured by glucose or insulin levels after 6 months of treatment.     

Oral contraceptives, thrombosis and haemostasis

The use of oral contraceptives is a well-established acquired risk factor for venous thrombosis. In 1995, a number of epidemiological studies were published which suggested that women who use third generation oral contraceptives that contain desogestrel or gestodene as progestagen are exposed to a two- to threefold higher risk for venous thrombosis than women using second generation oral contraceptives which contain levonorgestrel. In this paper, the effects of oral contraceptives on the haemostatic system are discussed. It appears that plasma from oral contraceptive users is resistant to the anticoagulant action of activated protein C (APC). This phenomenon, called acquired APC resistance, is more pronounced in users of desogestrel or gestodene-containing oral contraceptives than in women who use oral contraceptive pills with levonorgestrel. On the basis of these observations, it was proposed that acquired APC resistance may be the mechanistic basis of the increased risk for venous thrombosis during oral contraceptive use and for the further increased thrombotic risk of third generation oral contraceptive users. Furthermore, the results of a recent cross-over study are discussed. This study indicated that a large number of other haemostatic parameters were changed during oral contraceptive use. Some of these changes were more pronounced on desogestrel-containing oral contraceptives. The cross-over study also showed that the increased fibrinolytic activity during OC use is counterbalanced by an enhanced activity of thrombin-activatable fibrinolysis inhibitor (TAFI), a protein that participates in the inhibition of fibrinolysis.     

Unwanted pregnancies: Understanding contraceptive use and benefits in adolescents and older women

The highest percentages of unintended pregnancies and the largest increases in births reported in the United States in recent years were in adolescents and in women more than 35 years of age. Increasing numbers of these women will require contraception to avoid unintended pregnancy. In adolescents the combined oral contraceptive agents protect fertility indirectly and exert favorable actions on menstrual dysfunction and certain hormone-related disorders such as acne and hirsutism. To avoid sexually transmitted disease, barrier protection should be used along with oral contraceptives until mutually monogamous, stable relationships are established. Healthy older women who are nonsmokers may also safely use currently available contraceptives. These agents have little impact on metabolic parameters linked to the development of cardiovascular disease. In addition to providing reliable contraception, oral contraceptives offer noncontraceptive benefits to older reproductive-age women, including control of abnormal bleeding and a reduction in the incidence of ovarian and endometrial cancers and other gynecologic pathology. Intrauterine devices and progestin implants are safe, effective, and underused in the United States. Progestin implants may have an additional role in patients for whom estrogen preparations are contraindicated. Counseling is very important before insertion because of the high rate of nuisance side effects. The contraception selection process must consider the efficacy and acceptability of the specific,method to avoid the probability of unintended pregnancy and the risk of sexually transmitted diseases. (Ann J OBSTEr GYNECOL 1993;168:2042-8.)     

Low-dose oral contraceptives lower plasma levels of apolipoprotein E

Three different oral contraceptive preparations were studied before and after a 3 month treatment period with respect to their effects on plasma lipoprotein parameters. A total of 58 healthy women requesting oral contraception were randomly assigned to three groups. Each woman received either monophasic preparations containing ethinylestradiol and desogestrel (M-DG); ethinylestradiol and gestodene (M-GD); or a triphasic preparation of ethinylestradiol and levonorgestrel (T-LN). As has been reported in other studies, the concentrations of total plasma cholesterol and apolipoproteins B and A-IV did not change significantly in any group. HDL cholesterol, triglycerides, apolipoproteins A-I and A-II increased or tended to increase. Despite the effects of the three hormone preparations on these lipoprotein parameters, however, each led to a highly significant decrease in apolipoprotein E plasma levels. Considering the recently reported observations that oral contraceptives increase the hepatic uptake of cholesterol-rich remnants, this decrease in apo-E plasma levels may in women that take oral contraceptives be directly correlated with increased hepatic lipoprotein metabolism.     

Endometriosis: current and future medical therapies

Endometriosis is a chronic inflammatory disease that responds to steroidal manipulation. Creation of a steady hormonal environment with inhibition of ovulation temporarily suppresses the ectopic implants and reduces the inflammatory status as well as the associated pain symptoms. Pharmacological management of endometriosis must be set within the framework of long-term therapeutic strategies. As the available drugs are not curative, treatments will need to be administered for years or until women desire a pregnancy. The various therapies studied have shown similar efficacy. Consequently, based on a more favourable profile in terms of safety, tolerability and cost, combined oral contraceptives and progestins should be considered as the first-line option, both as an alternative to surgery and as a postoperative adjuvant measure. Gonadotrophin-releasing hormone analogues, danazol and gestrinone should be used when progestins and oral contraceptives fail, are not tolerated or are contra-indicated. Future therapies for endometriosis must compare favourably with existing drugs before hypothesizing their implementation in current practice. Medical treatment is not indicated in women seeking conception because reproductive prognosis is not ameliorated.     

Venous thromboembolism in relation to oral contraceptive use

The relation of the risk of venous thromboembolism to the use of oral contraceptives was assessed in a hospital-based study of 61 women suffering from a first episode of idiopathic deep vein thrombosis or pulmonary embolism (cases) and 1278 women admitted for trauma or respiratory infections (controls). Twenty (33%) of the cases and 121 (9%) of the controls had used oral contraceptives within the previous month, yielding an age-adjusted relative risk estimate of 8.1 (95% confidence interval 3.7 to 18) for recent users relative to never-users. For women using oral contraceptives containing less than 50 micrograms estrogen, the relative risk estimate was 11 (3.7 to 22); for preparations with 50 micrograms estrogen, it was 5.5 (2.1 to 15); and for preparations with more than 50 micrograms estrogen, it was 11 (3.9 to 30). Past use of oral contraceptives was not associated with an increased risk. The data suggest that the risk of venous thromboembolism is increased for recent oral contraceptive users relative to nonusers, even if women use oral contraceptives containing low doses of estrogen. Confidence intervals were wide, however, so that a reduction in the risk for users of lower dose formulations relative to users of higher dose formulations cannot be ruled out. Selection bias, if present, would have resulted in overestimation of the relative risk, but should not have distorted the comparisons according to dosage.     

Macroprogestative contraception: advantages

Combined oral contraceptives (OCs) have nearly total efficacy when correctly used and good overall tolerance among most women under 40, but there are several significant contraindications to their use. Women with hypertension, hyperlipidemia, diabetes, minor mastopathy, or premenstrual tension should not use OCs containing estrogen. Macroprogestational OCs administered generally 20 days out of 28 are useful when an antiestrogen effect is sought or when metabolic anomalies are to be avoided. An antiestrogen effect may be desired for women over 40 suffering from relative or absolute hyperestrogenism, or for women with premenstrual syndrome, menorrhagia related to endometrial hyperplasia or other menstrual problems, or benign mastopathies. An antiestrogen effect may also be desired to prevent cellular pathologies common after age 40. Some anomalies of metabolism, blood pressure, and coagulation persist in users of combined OCs regardless of the dose or the compounds used in the formulation. Progestins derived from testosterone were the first to be used in contraception and provide good cycle control and antigonadotropic activity, along with a powerful antiestrogen effect. But they may have metabolic side effects and cause signs of hyperandrogenism. Progestins derived from progesterone have been studied in health women and in those with different risk factors. Chlormadinone acetate has been used in women at high vascular risk, and promegestone has been used in women with fibrocystic breast disorders. A study was also done on 36 healthy women for 6 months using nomegestrol acetate. The preliminary results were good but the numbers of women were small, they had no metabolic risk factors, and the treatment periods were short. The results thus cannot be extrapolated to subjects at risk or for use during longer periods. The only observed modifications (essentially declines in apoprotein A1 and elevation of antithrombine) were probably attributable to the decline in average estradiol levels and without significance for risk. A disadvantage of these methods is that they have not been authorized for marketing as contraceptives in France and no Pearl index is available. Although the incidence of menstrual problems is not well known, such problems appear to be relatively frequent. The hypoestrogenism often sought for women with gynecological pathologies is not necessarily desirable for women using these methods because of metabolic problems or age over 40. A sufficient estradiol level protects against premature bone loss and has important metabolic effects including better production HDL cholesterol. 18 women who experienced menstrual problems with macroprogestational contraceptives were given 5 mg/day of nomegestrol acetate in combination with transdermally administered estradiol. Clinical and metabolic tolerance were excellent, and no pregnancies occurred. Further study is warranted.     

Effects of low-dose oral contraceptives on sugar metabolism

The effects on carbohydrate metabolism by four low-dose oral contraceptives were evaluated in four low-dose oral contraceptives were evaluated-66 young women randomly divided in four groups. In the various preparations there were a different dosage of estrogen (ethinylestradiol) together different doses and types of progestogen (desogestrel, gestodene, cyproterone acetate). After six months of treatment, in all groups a slight increase of glycemic and insulinemic responses during OGTT was observed; the significance was achieved with the preparation containing cyproterone acetate alone. Glycated hemoglobin did not change. Our results suggest that these new low-dose oral contraceptives induced negligible metabolic side effects.     

Health benefits of oral contraceptives

A sizeable literature corroborates the multiple health benefits of oral contraceptive use. The first estrogen/progestin combination pills were marketed to treat a variety of menstrual disorders. Although currently used oral contraceptives no longer carry FDA-approved labeling for these indications, they remain important therapeutic options for a variety of gynecologic conditions. Well-established gynecologic benefits include a reduction in dysmenorrhea and menorrhagia, iron-deficiency anemia, ectopic pregnancy, and PID. Although older, higher-dose pills reduced the incidence of ovarian cysts, low-dose pills suppress follicular activity less consistently. Nevertheless, cycle-related symptoms, including functional cysts, dysmenorrhea, chronic pelvic pain, and ovulation pain (mittelschmerz), generally improve. Women with polycystic ovary syndrome note improvement in bleeding patterns and a reduction in acne and hirsutism. Symptoms from endometriosis also improve with oral contraceptive therapy. Current data suggest that oral contraceptive therapy increases bone density and that past use decreases fracture risk. Oral contraceptives also improve acne, a major health concern of young women. Oral contraceptives provide lasting reduction in the risk of two serious gynecologic malignancies--ovarian and endometrial cancer. The data with respect to ovarian cancer are compelling enough to recommend the use of oral contraceptives to women at high risk by virtue of family history, positive carrier status of the BRCA mutations, or nulliparity, even if contraception is not required. Health care providers must counsel women regarding these benefits to counteract deeply held public attitudes and misconceptions regarding oral contraceptive use. Messages should focus on topics of interest to particular groups of women. The fact that oral contraceptives increase bone mineral density and reduce ovarian cancer is of great interest to women in their forties and helps influence use and compliance in this group. In contrast, the beneficial effects of oral contraceptives on acne resonates with younger women. Getting the good news out about the benefits of oral contraceptives will enable more women to take advantage of their positive health effects.     

Effect of various oral contraceptive combinations on dysmenorrhea

The influence of different oral contraceptives on the prevalence and severity of dysmenorrhea was investigated in a representative sample of 19-year-old women from an urban Swedish population. The prevalence and severity of dysmenorrhea were significantly (p less than 0.01) reduced amongst users of progestogen-dominated oral contraceptives compared to a control group of women who used neither oral contraceptives nor an intrauterine device. However, there was no significant difference in the prevalence and severity of dysmenorrhea between users of oral contraceptives with low progestogen activity and the same control group. Thus, the relative progestogen activity of the oral contraceptive used appears to be of importance for the effective treatment of dysmenorrhea. Possible reasons for the superior therapeutic efficacy of progestogen-dominated oral contraceptives are discussed. Further studies are, however, necessary to evaluate the importance of the progestogen activity of oral contraceptives in the treatment of dysmenorrhea.     

Anti-fertility activities of sex hormones

The antifertility action of various sex hormones is discussed. 20 years ago it was determined that Norethynodrel and Norethindrone, newly synthesized progestins, were effective oral contraceptives in women, and that their action was attributed to inhibition of ovulation. The author, skeptical of their effectiveness and mode of action, began to study some non-steroidal compounds claimed to prevent pregnancy in laboratory animals when administered orally soon after mating. When these antiestrogens, Norethynodrel, H241, and other estrogenic compounds were subjected to tests in laboratory animals, it was found that all these compounds, with varying degree of potency, caused a rapid egg transport to the uterus and expulsion of eggs from the uterus, but that ethinyl estradiol was the most effective one in this respect. It was determined through a number of experiments that the mechanism of action of estrogen administered soon after mating can be attributed not only to the early arrival of eggs from the tube into the uterus before they are able to survive in the uterus, but also to the expulsion of eggs from the uterus. When progestins are administered before ovulation, the transportation of eggs is much earlier than normal. Degeneration of eggs also occurs during such treatment. Based on the fact that degeneration of eggs occurred when eggs at 1 stage of development were transferred into the uterus of an advanced stage as demonstrated in many species by numerous workers, the degeneration of eggs in progestin-treated animals can be expected. It is concluded that the effectiveness of steroidal oral contraceptives is due to their attack on several processes of reproduction: they not only inhibit ovulation, but can inhibit fertilization and also cause the degeneration of eggs. It is hoped that through further research, in the future new ways will be found to regulate fertility without hazardous side effects.