Compliance, counseling and satisfaction with oral contraceptives: a prospective evaluation.

CONTEXT: Oral contraceptive users' risk of accidental pregnancy may be higher than it should be, because of inconsistent pill-taking. However, few reliable data are available on pill users' everyday experiences with their method, especially characteristics that may affect consistency of use. METHODS: Two months after initiating or resuming oral contraceptive use, a nationwide sample of 943 women completed questionnaires examining their compliance with instructions for proper use, the quality of their interactions with their provider, their satisfaction with the method, and the frequency and costs of visits or calls to their providers because of pill-related side effects. Regression analyses were used to determine the factors associated with compliance difficulties and method dissatisfaction. RESULTS: In all, 47% of users missed one or more pills per cycle, and 22% missed two or more. Women who lacked an established pill-taking routine, who did not read and understand all of the informational material accompanying the pill package, or who experienced spotting or heavy bleeding had increased odds of missing two or more pills per cycle. Method satisfaction was most likely among women who were aware of the pill's noncontraceptive benefits, were satisfied with their relationship with their provider, had used the pill in the past and experienced few side effects. Some 22% of users called their provider at least once about pill-related side effects, and 9% made at least one visit for this reason; these women spent $25 and $62, respectively, to treat side effects. CONCLUSIONS: Improving pill use is a shared responsibility of the provider, the patient and, to a lesser degree, pill manufacturers. Awareness of potential difficulties such as inadequate counseling is a key step in helping women use oral contraceptives effectively.

PIP: The Organon Contraceptive Use Study, a prospective cohort study (1994-96) of 943 US women (mean age, 25 years) recruited through private medical practices, Planned Parenthood clinics, and a health maintenance organization, examined oral contraceptive (OC) use patterns. 95% of study participants began or switched to a new OC brand at study enrollment. At follow up 2 months after enrollment, 47% of pill users reported missing 1 or more pill per cycle and 22% missed 2 or more pills in each cycle. Those who missed 1 or more pill were significantly more likely than those who did not to lack an established pill-taking routine, not to have read or understood the informational material accompanying the pill, and to have experienced spotting or heavy bleeding. 34% rated the OC as a very good method and another 30% considered it a good method. Method satisfaction was significantly higher among OC users who were aware of the pill's noncontraceptive health benefits, had a good relationship with their OC provider, had used the pill in the past, and experienced few side effects. 22% of OC recipients called their provider at least once about pill-related side effects and 9% visited at least once for this reason; these women spent US$25 and $62, respectively, to treat side effects. Recommended, to increase patient compliance and satisfaction with OCs, are measures such as counseling on potential side effects, evaluations of consistency of use at all follow-up contacts, and attention to the quality of the provider-client relationship.

Oral contraceptives did not affect biochemical folate indexes and homocysteine concentrations in adolescent females.

OBJECTIVE: The study was designed to determine the impact of currently available oral contraceptive agents (OCAs), smoking, and alcohol on biochemical indexes of folate and vitamin B-12 in adolescent females. DESIGN: Subjects completed a 3-day weighed food record along with a detailed lifestyle questionnaire that included questions on OCA, cigarette, and alcohol use. After subjects had fasted overnight, blood samples were collected and analyzed for levels of serum and red blood cell (RBC) folate and serum B-12 and homocysteine. SUBJECTS/SETTINGS: Two hundred twenty-nine adolescent females (aged 14 to 20 years) were recruited from southern Ontario, Canada, by advertisements in newspapers, high schools, universities, shopping malls, adolescent drop-in centers, and community groups. STATISTICAL ANALYSES PERFORMED: Multiple regression models were used to determine the effect of lifestyle factors and covariates (e.g., dietary folate intake, supplemental folate intake, and age) on biochemical indexes. RESULTS: OCA use, alcohol use, and smoking were not significantly associated with lower serum or RBC folate levels, after controlling for folate intake. Serum homocysteine levels were not associated with smoking or OCA use; however, we estimated a 13% higher concentration among alcohol users than nonusers. Smoking and alcohol use were not associated with serum B-12 levels, but OCA use was associated with an estimated 33% lower serum B-12 level than nonuse. APPLICATIONS: Our findings provide no evidence to suggest that currently available OCAs have a negative impact on the folate status of adolescent females; thus, dietary advice designed to specifically encourage an increase in folate intake among adolescents who use OCAs is not supported. In contrast, serum B-12 levels were lower among OCA users than nonusers, which suggests that an interaction between OCA and some vitamins may persist. The suboptimal biochemical folate indexes of smokers may have more to do with the dietary quality of smokers than previously appreciated. Thus, efforts to improve dietary folate intakes of adolescents who smoke may be an important strategy for improving the folate status of young women.

PIP: The impact of oral contraceptive (OC) use, smoking, and alcohol drinking on biochemical indexes of folate and vitamin B-12 was investigated in 229 adolescents 14-20 years old recruited from advertisements in Ontario, Canada. Subjects completed a life-style questionnaire and a 3-day, weighed food record, followed by overnight fasting and the collection of blood samples. Of the 48 participants (21%) who were OC users, 30 had used the pill for more than 12 months. Only 37 adolescents (16%) smoked, but 94 (60%) had consumed alcohol in the month preceding the study. Median daily intake of folate and vitamin B-12 (including intake from supplements) was 215 mcg and 1.9 mcg, respectively. OC use, smoking, and alcohol consumption were not significantly associated with lower serum or red blood cell folate levels, after controlling for folate intake. Serum homocysteine levels were not correlated with smoking or OC use, but were 13% higher among alcohol drinkers than nondrinkers. Finally, although smoking and alcohol use were not associated with serum B-12 levels, OC use was linked with an estimated 33% lower serum B-12 level than was nonuse. These findings fail to validate concerns that OC use has a negative impact on the folate status of adolescent females, but suggest a need to improve the dietary folate intake of young women who smoke.

Shortened pill-free interval delivered by new 20 mcg pill. Organon's Mircette scheduled for U.S. debut this summer.

PIP: The new low-dose oral contraceptive (OC), Mircette, is the first pill to shorten the hormone-free interval. The dosing regimen begins with 21 days of 20 mcg of ethinyl estradiol and 150 mcg of desogestrel; the last 7 days start with 2 days of placebo, followed by 5 days of 10 mcg of ethinyl estradiol. These 5 days of ethinyl estradiol are expected to oppose the effect of any follicle-stimulating hormone in promoting growth of a follicle in the estimated 20% of pill takers who are close to ovulation at the end of each pill-free interval. The efficacy trial, which included more than 1000 women followed for 18 menstrual cycles, reported a Pearl index of 1.02. Breakthrough bleeding occurred in 3.5% of the 18 cycles. Less than 3% of women discontinued Mircette use because of menstruation-related side effects. The small amount of estrogen provided by Mircette during the last 5 days of the cycle helps prevent the withdrawal headaches many users of OCs with a longer hormone-free interval experience. Mircette will become available in the US in July 1998.^ieng

Use of oral contraceptives and serum beta-carotene.

OBJECTIVE: Antioxidants, in particular carotenoids, may influence the risk for cardiovascular disease. This study investigates the influence of oral contraceptives (OC) on the serum concentration of beta-carotene, which may in turn affect the risk of cardiovascular diseases due to its antioxidative impact. DESIGN: Cross-sectional epidemiologic study. Examinations included a detailed questionnaire on medical history and lifestyle factors, a 7 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 (n = 610). RESULTS: Overall, the use of OC was negatively associated with serum beta-carotene concentration in bi- and multivariable analyses after adjustment for age, smoking, alcohol consumption, dietary intake of beta-carotene, use of vitamin supplements, body mass index, pregnancies, and serum concentrations of total triglyceride and cholesterol. A strong interaction between OC use and age on beta-carotene concentration was observed. While no relationship between OC use and serum beta-carotene was seen in the youngest age-group (18-24 y), there was a modest but significant negative association between OC use and beta-carotene levels among 25-34 y old women. The use of OC was associated with a strong decrease in beta-carotene levels among 35-44 y old women. The interaction between OC use and age could partly be explained by age dependent use of OC with higher estrogen content. CONCLUSIONS: OC use seems to be strongly related to serum beta-carotene levels, particularly among women above the age of 35. Further studies are needed to clarify the underlying mechanisms of this association and its implications for health risks of OC use.

PIP: Beta-carotene, a provitamin with antioxidant effects, may substantially reduce the risk of coronary artery disease and acute myocardial infarction. A cross-sectional epidemiologic study involving 610 West German women 18-44 years of age indicates that oral contraceptive (OC) use has a negative impact on serum levels of beta-carotene. 195 respondents (32%) were current OC users, 322 (53%) were past users, and 91 (15%) had never used OCs. Median serum beta-carotene levels were significantly lower in current OC users (25.1 mcg/dl) than in past (32.5 mcg/dl) and never users (31.2 mcg/dl). The percentage of women with beta-carotene levels below the desirable value of 21.5 mcg/dl was significantly higher in the current OC use group (34%) than in the 2 other groups combined (21%), yielding an overall odds ratio (OR) of 1.9 (95% confidence interval, 1.3-2.8). The strength of the association between OC use and decreased beta-carotene increased with age (OR of 1.5 for women 18-24 years, 1.9 for those 25-34 years, and 3.4 for 35-44-year old women). In addition, the decrease of beta-carotene was larger for OCs containing 50 mcg of ethinyl estradiol than for low-dose formulations. Also observed were significant associations between serum beta-carotene levels and smoking, alcohol intake, body mass index, triglycerides, nutrient intake, and total cholesterol levels. Although further studies are required to identify the mechanisms underlying the OC-beta-carotene association and define its implications for women's health, OC users should be advised to consume vegetables rich in beta-carotene.

[Clinical effectiveness of Marvelon]. / Analiza kliniczna stosowania Marvelonu.

Clinical results of a new contraceptive pills--Marvelon (Organon) were studied. 32 women, ages 30 +/- 5 years, participated in the study during at least 6 cycles. Marvelon was good tolerated and subjective side-effects were very low. The cycles were regular, duration of withdrawal bleeding was 3-5 days and the amount of the blood lost were unchanged or milder. Marvelon didn't affect body weight and blood pressure. Favourable lipid profile--increased a mean level of HDL-Cholesterol and decreased a mean level of LDL-Cholesterol were noticed. Pearl Index was 0,0.

PIP: Marvelon is an oral contraceptive of the third generation of contraceptives introduced in the 1980s. These preparations contain progestagens (desogestrel, gestodene, and norgestimate) and ethinyl estradiol. Marvelon contains .03 mg of ethinyl estradiol and .15 mg of desogestrel. The results of clinical use of Marvelon (made by Organon), were studied in 32 women aged 30 +or- 5 years in the course of at least six cycles. Marvelon was well tolerated and the subjective side effects were minor. The cycles were regular and withdrawal bleeding lasted 3-5 days. The duration of menstrual cycles with the use of Marvelon constituted 27-30 days. The amount of bleeding did not change in 26 women, while it became less in 6 women. Marvelon did not affect body weight and blood pressure. The weight of the patients varied within the limit of +or- 2 kg. It produced a favorable lipid profile by increasing the mean level of high density lipoprotein (HDL) cholesterol and lowering the mean level of low density lipoprotein (LDL) cholesterol. The level of HDL cholesterol was 1.56 mmol/l in cycle 0 compared with 1.85 in cycle 6. The average level of LDL cholesterol was statistically lower in the 6th cycle of Marvelon use (2.73 mmol/l) in comparison to cycle 0 (3.29 mmol/l). Marvelon did not significantly influence the values of glucose, total cholesterol, and triglycerides. The Pearl Index was 0.0.

Clinical comparison of two low-dose oral contraceptives, Minulet and Mercilon, in women over 30 years of age.

A comparative study of two low-dose oral contraceptives, gestodene (GES) 75 mcg/ethinyl oestradiol (EE) 30 mcg and desogestrel (DES) 150 mcg/EE 20 mcg, was conducted in women over 30 years of age. This randomised, open-label study was organised in Denmark, Italy, New Zealand and United Kingdom. A total of 505 women received GES/EE and 501 received DES/EE for 6 consecutive menstrual cycles. The two groups were comparable in terms of demographic and gynaecologic characteristics at baseline. However, the menstrual flow length was slightly longer in the GES/EE group before the start of the treatment. The mean age (+/- SD) was 35 +/- 4 years in the GES/EE group and 35 +/- 5 years in the DES/EE group. The subjects in the GES/EE group contributed data for a total of 2800 cycles and those in the DES/EE group, data for 2796 cycles. There were no pregnancies on medication with either preparation. The results showed that there were significantly more normal cycles in the GES/EE group for cycles 1 to 6. Irregular bleeding between withdrawal bleeds occurred in 10% of GES/EE and 18.5% of DES/EE cycles. Absence of all bleeding was reported in 29 (1%) and 63 (2%) cycles, respectively. The incidence of missed pills was low in both groups (11% of cycles). No significant differences were observed in cycle length or withdrawal bleeding episode length. Withdrawal bleeding mean intensity was statistically significantly greater with GES/EE. However, for both preparations, the mean intensity was close to light bleeding. No clinically significant differences were noted in weight, blood pressure, Papanicolaou smears or laboratory data. Sixty-eight (13.5%) subjects in the GES/EE group and 64 (12.8%) in the DES/EE group discontinued before the end of the study. Among them, 37 (7%) and 40 (8%) in the respective groups withdrew because of adverse reactions. There was no difference between groups in terms of primary reasons for withdrawal. The most frequently reported complaints that led to discontinuation in both groups were headache, nausea and metrorrhagia. Breast tenderness led to the discontinuation of 1 subject in the GES/EE group and 3 in the DES/EE group. These results show excellent cycle control, efficacy and very low rate of side effects with both GES/EE and DES/EE. These low-dose oral contraceptives could be well suited to healthy nonsmoking women requiring contraception up to the age of menopause.

PIP: At 66 sites in Denmark, Italy, New Zealand, and the UK, clinicians randomly allocated 1006 women 30 years old, some of whom were in their early 50s, into 1 of 2 groups receiving a low-dose oral contraceptive (OC): Minulet containing 75 mcg gestodene (GES)/30 mcg ethinyl estradiol (EE) and Mercilon containing 150 mcg desogestrel (DES)/20 mcg EE. The study aimed to compare these 2 low-dose OCs to help physicians prescribe an OC that could be continued into later years. Before treatment, the 2 groups had similar demographic and gynecologic characteristics. The mean menstrual flow length in the GES/EE group was longer than that of the DES/EE group (4.7 days vs. 4.5 days; p = .035) though. None of the women during 2800 cycles of GES/EE use and 2796 cycles of DES/EE use conceived, even though women forgot to take at least 1 pill in 11% of cycles. The GES/EE OC had significantly better cycle control than did the DES/EE OC. For example, the GES/EE group was more likely to have normal cycles than the DES/EE group (84-93% vs. 73-83%; p .001). The DES/EE group experienced a significantly lower withdrawal bleeding mean intensity than the GES/EE group in all 6 cycles, but the bleeding for both groups was close to light bleeding. The 2 groups were similar in weight, blood pressure, Papanicolaou smears, and laboratory data. Discontinuation rates for the GES/EE and DES/EE groups were 13.5% and 12.8%, respectively. Adverse reactions accounted for discontinuation in 7% of the GES/EE group and 8% of the DES/EE group. The major complaints leading to discontinuation were headache, nausea, and breakthrough bleeding. Both GES/EE and DES/EE had very good cycle control and efficacy and a very low rate of side effects. These results suggest that both these low-dose OCs would be acceptable for healthy nonsmoking women needing contraception up to menopause.

Comparative profiles of reliability, cycle control and side effects of two oral contraceptive formulations containing 150 micrograms desogestrel and either 30 micrograms or 20 micrograms ethinyl oestradiol.

OBJECTIVE: To compare two oral contraceptive pills, both containing 150 micrograms desogestrel, but with either 20 micrograms (Mercilon) or 30 micrograms (Marvelon/Desolett) ethinyl oestradiol (EE), regarding reliability, cycle control and side effect profile. DESIGN: A double blind, randomised, multicentre study over one year with follow up after three, six and 12 months. The women noted tablet intake and all bleedings on specifically designed diary cards. SETTING: University clinics, central hospitals and private gynaecological practices in Norway, Sweden and Denmark. SUBJECTS: One thousand women aged 18 to 40 years requesting oral contraceptive pills. MAIN OUTCOME MEASURES: Reliability, cycle control, side effects, blood pressure, body weight and haemoglobin. RESULTS: In a total of 4543 cycles with the 20 micrograms EE dose pill and 4688 cycles with the 30 micrograms EE dose pill, the number of pregnancies ascribed to method failure were 0 and 2, respectively. Irregular bleeding (break-through bleeding or spotting) was significantly more frequent with the 150/20 combination in about two-thirds of the cycles randomly distributed over the one year of the study. Mean blood pressure decreased slightly, particularly in the group on the 150/20 combination (about 1 mmHg), whereas mean body weight increased approximately 0.5 kg in the group with the 150/30 combination after 12 months. Haemoglobin did not change. Side effects other than bleeding problems were rare, but dizziness and mood changes were more frequent in the group on the 150/20 combination. Due to side effects, more women on the 150/20 combination discontinued the study during the one to three and four to six month periods, and women on this pill were also less positive about continuing the study drug at the end of the trial. CONCLUSIONS: Both pills have high contraceptive reliability and are well tolerated, but with the 150/20 combination the cycle control is less effective. However, in view of the potentially increased safety profile of the 150/20 combination, many women can be expected to accept some additional discomfort due to irregular bleeding.

PIP: A double-blind, randomized, multicenter study compared 2 combined oral contraceptives containing 150 mcg desogestrel and either 30 mcg (Marvelon/Desolett) or 20 mcg (Mercilon) of ethinyl estradiol, focusing on reliable pregnancy prevention and cycle control. The women were 300 Norwegians, 500 Swedes, and 200 Danes, 52% of whom switched from a prior brand of pill. Women completed bleeding diaries: all bleeding that did not start in the 7-day tablet-free interval and last for 7 or fewer days was considered irregular bleeding, either breakthrough bleeding or spotting. The 2 groups were similar except that those taking the 150/20 combination were slightly older. There were 2 pregnancies with the 20 mcg combination and 3 with the 30 mcg pill, 2 of which were considered method failures. In 8573 cycles analyzed there were more instances of irregular bleeding and amenorrhea with the 20 mcg pill than with the 30 mcg pill. Duration of breakthrough bleeding was not significantly different. Irregular bleeding was also more common n women switching from another brand of pill to a lower estrogen dose pill. Blood pressure decreased slightly on the 20 mcg ill and body weight rose slightly on the 30 mcg pill, but hemoglobin did not change. More women dropped out or chose not to continue taking the 150/20 mcg pill because of side effects, usually irregular bleeding, mood changes, dizziness, or weight gain. Despite these differences, there were enough women who tolerated the lower dose combination pill to merit continuing to take it.

Hemostatic and metabolic effects of lowering the ethinyl-estradiol dose from 30 mcg to 20 mcg in oral contraceptives containing desogestrel.

The metabolic and hemostatic effects of two oral contraceptives containing 150 mcg desogestrel and 20 mcg ethinyl-estradiol (EE) (MERCILON) or 30 mcg EE (MARVELON) were compared in order to examine the effect of reducing the EE dose in contraceptive pills. Forty-nine women participated in this randomized study during 6 cycles. In both groups, there was a significant increase in triglycerides, HDL-cholesterol and apoprotein A1; the same increase was observed for SBP and CBG. Slight and transient variations of fasting blood glucose levels were seen in the 30 mcg EE group and in the two groups for fasting insulin levels. The increase in renin substrate was significantly higher with the 30 mcg EE than with the 20 mcg EE pill. In both groups, plasminogen increased significantly, but antithrombin III, total and free protein S and fibrinogen decreased significantly only in women taking the 30 mcg EE pill, whereas there was no significant change in the 20 mcg EE group. Reducing the dose of EE in oral contraceptives from 30 mcg to 20 mcg minimizes their impact on renin substrate and hemostatic parameters.

Epilepsy and pregnancy.

PIP: According to a London physician, women with epilepsy taking antiepileptic drugs can take combined oral contraceptives (OCs). It is usual to recommend a combined OC preparation containing at least 50 mcg of estrogen (Ovran) from patients taking enzyme-inducing antiepileptic drugs; this can be increased to 60 mcg by taking 2 30 mcg pills, and if necessary to 80 mcg. To ensure that ovulation is inhibited, the blood progesterone concentration can be measured on day 21 of the 1st cycle. The higher doses of estrogen should be accompanied by higher doses of progestogen. The commonest fetal malformations are cleft lip and palate and congenital heart disease, usually septal defects. These abnormalities may be caused by all the major antiepileptic drugs. Phenytoin has been particularly implicated and may cause minor defects in up to 30% of infants and major defects in about 5%. The incidence of cleft palate and heart defects with phenytoin is 1.8% compared with 0.7% in the general population. With sodium valproate, neural tube defects occur in about 1.5% of pregnancies. Present evidence suggests that carbamazepine is the safest drug. Folic acid supplements reduce the risk of neural tube defects in women at risk, therefore women taking antiepileptic drugs who are contemplating pregnancy should be given a small folic acid supplement or a diet rich in folate. To reduce the risk of bleeding in the perinatal period, pregnant women taking enzyme-inducing antiepileptic drugs should be given oral phytomenadione (vitamin K1) 20 mg daily for at least 1 week before delivery. Vitamin K1 should be given to the newborn immediately after delivery. Only phenobarbitone and primidone might be contraindicated for breast feeding. Mothers with uncontrolled major epilepsy should not be left alone with small children. If there is already 1 sibling with epilepsy the risk of inheriting epileptic liability rises to about 10% and if both parent have epilepsy the risk is 15-20%.^ieng

The safety of oral contraceptives: epidemiologic insights from the first 30 years.

Because oral contraceptives are used by tens of millions of healthy women, their safety for short-term and long-term use is an important issue that has been examined in a large number of epidemiologic studies. These studies have become more rigorous and have increased in size and analytic sophistication over the years. Although breast cancer remains the most important safety concern, the bulk of recent data suggests that oral contraceptives have no overall impact on a woman's risk of developing this disease. The results are less clear on the risk of cervical cancer and its precursors because of methodologic problems. However, the newer oral contraceptive formulations no longer appear to be associated with an increased risk of myocardial infarction or stroke.

PIP: Studies show that OCs have several benefits besides prevention of pregnancy. They protect against ovarian and endometrial cancer, pelvic inflammatory disease, and ectopic pregnancy. OCs also prevent iron deficiency anemia, primary dysmenorrhea, functional ovarian cysts, and benign breast disease. They may even protect against some benign uterine tumors, osteoporosis, toxic shock syndrome, and rheumatoid arthritis. Despite many concerns, some large studies have not identified an overall effect of OCs on breast cancer, but subgroup analyses showed increased risk in 30-34 year old women and in women with 1 child. A reanalysis of a large US study indicated an increase risk of breast cancer in nulliparous women with increasing use of OCs by young women. Cervical cancer is the leading cancer of women in developing countries which emphasizes the need to examine the link between OC use and cervical cancer. Several studies show an increased risk of cervical cancer. Several studies show an increased risk of cervical cancer in long term OC users. In 1 study, long term use meant 5 years. Yet these studies did not adequately address confounding factors such as smoking and sexual behavior. 3 case control studies in the US and the UK found an increased risk of liver cancer among OC users, yet a large case control study in developing countries did not find a link between OC use and liver cancer. Studies of high dose OCs found considerable increased risks of cardiovascular disease in OC users, but they did not take into account cigarette smoking which indeed increases the risk. Further health practitioners today do a more thorough job of identifying underlying medical problems before prescribing OCs. Moreover estrogen doses have fallen 10 fold since the original OCs. Finally, despite a transient delay, women who take OCs experience a return to fertility at the same rate as those who use other contraceptives.

A cross-over study of three oral contraceptives containing ethinyloestradiol and either desogestrel or levonorgestrel.

A randomised cross-over trial was performed to compare the pharmacodynamic actions of three low-dose oral contraceptives (OCs): Marvelon (150 micrograms desogestrel (DSG)+ 30 micrograms ethinyloestradiol (EE)), Mercilon (150 micrograms DSG + 20 micrograms EE) and Microgynon (150 micrograms levonorgestrel (LNG) + 30 micrograms EE). None of the OCs produced any significant changes in serum cholesterol, LDL-C and apoprotein B. Triglycerides were increased by the desogestrel OCs but not by Microgynon. The latter however increased the glucose and insulin responses to a glucose tolerance test whereas Marvelon and Mercilon had no effect. HDL-C increased with Marvelon, was unchanged with Mercilon and was decreased with Microgynon. Apoprotein AII was increased by all three OCs but only the DSG OCs increased apoprotein AI. All OCs produced similar increases in caeruloplasmin but the increase in SHBG was much greater with Marvelon and Mercilon than with Microgynon. Testosterone was reduced more with Microgynon than with the DSG OCs. Many of the changes reflect the strong anti-oestrogenic action of LNG on metabolic parameters compared to DSG. Except for the effect on HDL-C, there was little difference between Marvelon and Mercilon on metabolic parameters and this complements the findings from large-scale clinical trials of the two OCs. Mercilon, therefore provides a very satisfactory alternative to Marvelon.

PIP: 12 healthy volunteers attending the family planning clinic at Shanghai, First Maternity and Infant China, Hospital, enrolled in the study, Oral contraceptives (OCs) were prescribed: Marvelon (150 mcg of desogestrel--DSG), Mercilon (150 mcg of DSG), and Microgynon (150 mcg of levonorgestrel--LNG). The patients were divided into 6 groups of 2 persons each in a randomized cross-over study. OCs were taken on day 6 of the cycle up to day 21, then stopping for 7 days. Each OC was used for 3 months. During the pretreatment cycle between days 6 and 9 of the follicular phase and 21 and 22 of the luteal phase a blood sample was taken after fasting for determination of lipids, sex hormone binding globulin (SHGB), ceruloplasmin, and testosterone. After glucose loading, significant increases of glucose and insulin occurred at 1, 2, and 3 hours during treatment with Microgynon only. The ratio for total areas of insulin to glucose did not change significantly nor did glycosilated hemoglobin A1 levels. Serum triglyceride concentrations increased significantly for both Marvelon (27%-43%) and Mercilon (29-40%). Serum high density lipoprotein (HDL) cholesterol concentrations were significantly elevated with Marvelon but less so with Mercilon, while HDL-C decreased significantly with Microgynon. The serum low density lipoprotein (LDL) cholesterol changes were not significant, but LDL-C concentrations declined with DSG formulations and increased with Microgynon. Apoprotein A1 and A2 increased significantly for both Marvelon and Mercilon. Apoprotein A2 increased with Microgynon. Serum SHBG increased markedly with Marvelon (335-380%). Serum testosterone concentrations decreased significantly (33.2-40.4% with Microgynon) and so did ceruloplasmin values. The antiestrogenic effect of strong LNG in Microgynon produced significant metabolic changes. The effect of 30 mcg EE in Marvelon and 20 mcg EE of Mercilon was equal.

Effects of low and high dose oral contraceptives on blood coagulation and thrombogenesis induced by vascular subendothelium exposed to flowing human blood.

We investigated the effect of oral contraceptives with low and high estrogen concentration on blood coagulation and thrombogenesis, induced by vascular subendothelium of rabbit aorta exposed to flowing human blood. Twenty healthy women intending to take oral contraceptives were studied [1] before drug ingestion (control), and subsequently during the intake of oral contraceptives with [2] low estrogen content (20 micrograms ethinyl estradiol and 150 micrograms desogestrel per day) and [3] high estrogen content (50 micrograms ethinyl estradiol and 125 micrograms desogestrel per day). All experiments were performed between day 17 and 21 of the menstrual cycle and drug effects were studied during the third tablet cycle. Deposition of fibrin, platelets and platelet thrombi on vascular subendothelium was tested at a defined blood flow and wall shear rate (10 ml/min, 650 s-1) and was quantified by morphometrical techniques. Treatment with the low and high dose contraceptive increased the plasma levels of ethinyl estradiol (728 +/- 139 and 1438 +/- 212 vs. 0 fmol/l [low and high dose vs. control], means +/- SEM, P less than 0.001) and fibrinogen (2.3 +/- 0.1 and 2.6 +/- 0.1 vs. 2.0 +/- 0.1 g/l, P less than 0.05); and decreased antithrombin III activity (95 +/- 3 and 92 +/- 3 vs. 101 +/- 3 %, P less than 0.05). Fibrin deposition on vascular subendothelium was enhanced by the high dose contraceptive only (47 +/- 4 vs. 35 +/- 4 % coverage of the subendothelial surface with fibrin, high dose vs. control, P less than 0.05). The subendothelial deposition of platelets and platelet thrombi was not changed by contraceptive treatment. These results indicate that treatment with high dose contraceptives leads to an increase of fibrin-subendothelial interactions, whereas low dose contraceptives do not significantly alter the blood-subendothelium interactions. observed in this ex vivo model of thrombogenesis.

Exercise and "the pill": putting a rumor to rest.

PIP: Every once in a while, female athletes hear the rumor that oral contraceptives (OCs) keep them from performing their best. Yet, studies that have tried to evaluate the effects of OCs on physically active women have not been conclusive. This rumor probably started with the initial, higher-dose formulations instead of with the current biphasic or triphasic OCs. Side effects of the higher-dose OCs included weight gain, nausea, fatigue, headaches, and increased risks of hypertension, thromboembolism, and changes in glucose and lipid metabolism. Current OCs minimize these side effects and the risk of complications. In fact, the aerobic exercise female athletes undergo most likely neutralizes the negative effects of OCs on coagulation and lipid metabolism. Further, OCs may even improve athletic performance because they can decrease bleeding, the risk of iron deficiency, and frequency of cramps. Moreover, athletes can use OCs to orchestrate their menstrual cycles around competitive meets. Some studies with small sample sizes show that athletes on OCs experience a slight reduction in functional aerobic capacity and endurance capability. A Swedish study of female soccer players reported that OC users suffer fewer traumatic injuries than nonusers. It is difficult to attribute this to OCs, because there is considerable psychological control over sports performance. A sports physician in Hawaii is aware of rumors that OCs induce sluggishness or fatigue during certain days of the month, but he does not know a female athlete who believes this. The head trainer of the US Olympic Committee says that many female Olympic athletes use OCs. Strenuous exercise, considerable weight loss, and possibly other stress factors induce athletic amenorrhea, especially in adolescent females. In many cases, OCs can treat it. They are especially needed to minimize the risk of reduced bone density and musculoskeletal injury.^ieng

Fertility after contraception or abortion.

There is a very small correlation, if any, between the prior use of OCs and congenital malformations, including Down's syndrome. There are few, if any, recent reports on masculinization of a female fetus born to a mother who took an OC containing 1 mg of a progestogen during early pregnancy. However, patients suspected of being pregnant and who are desirous of continuing that pregnancy should not continue to take OCs, nor should progestogen withdrawal pregnancy tests be used. Concern still exists regarding the occurrence of congenital abnormalities in babies born to such women. The incidence of postoperative infection after first trimester therapeutic abortion in this country is low. However, increasing numbers of women are undergoing repeated pregnancy terminations, and their risk for subsequent pelvic infections may be multiplied with each succeeding abortion. The incidence of prematurity due to cervical incompetence or surgical infertility after first trimester pregnancy terminations is not increased significantly. Asherman's syndrome may occur after septic therapeutic abortion. The pregnancy rate after treatment of this syndrome is low. The return of menses and the achievement of a pregnancy may be slightly delayed after OCs are discontinued, but the fertility rate is within the normal range by 1 year. The incidence of postpill amenorrhea of greater than 6 months' duration is probably less than 1%. The occurrence of the syndrome does not seem to be related to length of use or type of pill. Patients with prior normal menses as well as those with menstrual abnormalities before use of OCs may develop this syndrome. Patients with normal estrogen and gonadotropin levels usually respond with return of menses and ovulation when treated with clomiphene. The rate for achievement of pregnancy is much lower than that for patients with spontaneous return of menses. The criteria for defining PID or for categorizing its severity are diverse. The incidence of PID is higher among IUD users than among patients taking OCs or using a barrier method. The excess risk of PID among IUD users, with the exception of the first few months after insertion, is related to sexually transmitted diseases and not the IUD. Women with no risk factors for sexually transmitted diseases have little increased risk of PID or infertility associated with IUD use. There appears to be no increased risk of congenital anomalies, altered sex ratio, or early pregnancy loss among spermicide users. All present methods of contraception entail some risk to the patient. The risk of imparied future fertility with the use of any method appears to be low.(ABSTRACT TRUNCATED AT 400 WORDS)

PIP: This is a comprehensive review of the risk of infertility or adverse effects on pregnancy outcome, such as chromosomal or congenital birth defects, amenorrhea, pelvic inflammatory disease (PID), or spontaneous abortion, after use of oral contraceptives, IUDs, induced abortion or spermicides. The sequelae reported for orals are chromosomal abnormalities, the VACTERL anomalies, masculinization of female fetus, Down's syndrome and post-pill amenorrhea. Several large studies found no increased risks for birth defects, although the risk of malformations when pregnant women inadvertently take the pill in early pregnancy was high in 1 of 2 such studies. Masculinization was reported with high dose combined hormone treatment and in 2 infants of a woman who took Enovid. the bulk of recent studies on secondary amenorrhea indicate that it is rare, but just as likely to occur in women with prior normal or abnormal menstrual patterns. One study found that amenorrhea is 7.7 times more likely to develop in women who took the pill to regulate menses. It is recommended that women with amenorrhea be screened for pituitary tumors and counseled before prescribing pills, and that those who fail to ovulate after stopping the pill be treated at least 6 months with clomiphene. A massing of all studies on the impact of 1st trimester induced abortion on subsequent fertility, premature delivery and spontaneous abortion, shows all relative risks around 1.0. After multiple abortions, the results are conflicting. In contrast, prior series analyzing illegal abortion have an unquestioned adverse effect on fertility and pregnancy outcome. Asherman's syndrome, a rare disorder of intrauterine adhesions, menstrual abnormalities, infertility and habitual abortion, has been associated with D & C abortion concurrent with pelvic sepsis, or traumatic pregnancy with D & C. This condition can be treated with moderate success. The bulk of IUD studies conclude that there is no overall decrement in fertility, while some disaggregated studies point the Dalkon shield as a higher risk and copper IUDs as a lower risk. PID and its consequences are now considered related to the immediate post-insertion time frame, or specifically to women who are at risk of contracting sexually transmitted disease, i.e., those with multiple partners, those with prior PID and nulliparas. Comprehensive review of current large series on spermicides shows no relationship between their use and spontaneous abortion or congenital malformation.

Generalized peliosis hepatis and cirrhosis after long-term use of oral contraceptives.

Peliosis hepatis, a condition characterized by the presence of blood-filled lacunar spaces in the liver, has been described primarily in patients on androgenic steroid medication and patients with tuberculosis. It has never been reported as a complication of the use of oral contraceptives, except in association with and localized in contraceptive-induced hepatic tumors. The present report concerns a 43-yr-old woman with generalized peliosis hepatis that developed during long-term use of oral contraceptives. Extensive examination did not reveal a hepatic tumor. Liver cirrhosis and portal hypertension developed, although the oral contraceptives had been withdrawn. She finally underwent successfully an orthotopic liver transplantation.

PIP: A case report is presented of a 43-year-old woman with generalized peliosis hepatitis that developed during longterm use of oral contraceptives (OCs). The patient had been in good health until the last 2 years when she began to experience vague epigastric pains and a feeling of abdominal distension. Several months prior to admission, she had started to complain of itching and fatigue. There was no history of dark urine, white stools, or hepatitis. On physical examination, no jaundice or cutaneous stigmata of chronic liver disease were observed. Laboratory studies showed a normal erythrocyte sedimentation rate and hematological blood count. A radionuclide study of the liver showed hepatomegaly; especially the left lobe was enlarged. A computerized tomographic scan of the liver showed multiple areas of decreased density in both of the enlarged lobes. There was no evidence of a tumor. Selective transfemoral angiography of the celiac artery also showed hepatic enlargement but no signs of a space-occupying lesion. At laparoscopy, the liver was grossly enlarged and had a lumpy appearance, but again there were no signs of a tumor. No evidence of veno-occlusive disease or hepatocellular adenoma was found. The diagnosis was peliosis hepatitis. The OCs were withdrawn, and the patient was discharged. Regular follow-up in the outpatient department showed no decrease in the size of the liver. The alkaline phosphatase level rose. The fatigue became worse, and cholestyramine was prescribed for progressive itching. In September 1980, the patient was admitted for reevaluation. A repeated CT scan and angiography of the liver again yielded no evidence of a tumor. Esophagoscopy showed the presence of varices grade 2. The liver at laparoscopy had the same appearance as it had in 1976. Histological examination of a biopsy specimen showed occasional dilated sinusoids and locally marked periportal and intralobular fibrosis. No regeneration nodules were found. The diagnosis was liver fibrosis. The patient's condition deteriorated gradually in the following years. She experienced increasing fatigue. Steatorrhea developed, and the patient lost weight. She needed increasing doses of cholestyramine and oral supplementation of vitamins A, D, and K. She was admitted for a 3rd time in February 1985. Esophagoscopy revealed varices grade 4. A CT scan of the liver showed no change. The patient successfully underwent an orthotopic liver transplantation in January 1987. The diagnosis of peliosis hepatis was well documented in this patient.

Drug interactions with oral contraceptives: compilation and analysis of an adverse experience report database.

Over 700 alleged OC/drug interactions were reported for antituberculous drugs, other antibiotics, anticonvulsants, antidepressants, and analgesics. Fewer than ten reports of OC/drug interactions were found involving antihistamines, thyroid hormone, vitamin C, antacids, ulcer medication, or diuretics. These may represent a set of OC/drug interaction problems that need to brought into medical awareness. Pregnancy is the first event reported when OCs appear to interact with another drug. However, menstrual disturbances are reported more often. BTB is the most frequently reported menstrual disturbance: it has been considered a warning signal that OC efficacy may be compromised. In such circumstances, contraceptive backup may be warranted. Reports of interference with OC efficacy have been most common for drugs used to treat tuberculosis, epilepsy, and depression, so patients and their physicians should be aware of potential problems. However, the average woman is more likely to encounter antibiotics, analgesics, and antihistamines, and current package inserts contain appropriate warnings. In recent years, prescriptions for low-estrogen OCs have outnumbered those for high-dose preparations. Many physicians became concerned that there was an increased risk of OC drug failure with the low-dose products. The database does not seem to suggest that this has happened. The dose of estrogen is not correlated with total adverse experience reports, time of appearances of the first adverse experience reports, or rate of reporting of the interactions. Likewise, reports of potential interactions with menstrual disturbances are not correlated with lower estrogen doses in OCs. There is, however, an association between low-estrogen OCs and recently reported pregnancies attributed to OC/drug interactions.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: Given the large numbers of oral contraceptive (OC) users, coupled with the prevalence of use of antibiotics, antidepressants, anticonvulsants, and anticoagulants, there is a need for a comprehensive analysis of potential OC/drug interactions. This review includes a compilation of a database of all the adverse experience reports contained in the literature, results voluntarily reported to Syntex, and a survey of clinical and animal studies in this field. Over 700 alleged OC/drug interactions were reported for antituberculous drugs, other antibiotics, anticonvulsants, antidepressants, and analgesics. Fewer than 10 reports of OC/drug interactions were found involving antihistamines, thyroid hormones, vitamin C, antacids, ulcer medication, or diuretics. The greatest number of incidents (256) involved antibiotics; of these, antituberculous drugs accounted for 76% of the total. Of the 713 cases involving possible interference with the efficacy of OCs, only 21% resulted in pregnancies; 41% reported menstrual disturbances and 38% reported no problems at all. 94% of the cases of adverse OC/drug interactions involved higher-dose (50 mcg or more) estrogen OCs. Likewise, reports of potential interactions with menstrual disturbances are not correlated with lower estrogen doses in OCs. There is, however, an association between low-estrogen OCs and recently reported pregnancies attributable to OC/drug interactions. Breakthrough bleeding was the most commonly reported menstrual disturbance and may constitute a warning sign of adverse OC/drug interactions.

Carbohydrate metabolism in women who used oral contraceptives containing levonorgestrel or desogestrel: a 6-month prospective study.

Blood glucose and pyruvate, plasma insulin, and glucagon levels as well as erythrocyte insulin receptors were measured during an oral glucose tolerance test in 38 normal women before and after 6 months' use of one of three new oral contraceptives containing low doses of 19 nortestosterone-derived progestogens, levonorgestrel, and desogestrel. A slight deterioration of glucose tolerance was observed, with the area under the glucose curve increasing by only 7%, 9%, and 12% after Ovidol (Aaciphar SA, Brussels, Belgium), Marvelon (Organon, SA, Brussels, Belgium), and Trigynon (Schering SA, Brussels, Belgium) administration, respectively. We did not find any argument in favor of the development of a state of insulin resistance in women using these compounds, because erythrocyte receptor binding was not modified and plasma insulin responses to glucose were decreased. The glucose-induced suppression of plasma glucagon levels seemed less effective for treatment with the desogestrel-containing preparations than with the levonorgestrel-containing oral contraceptives.

Systemics.

PIP: This discussion of systemics covers oral contraceptives (OCs), injectables, depot medroxyprogesterone acetate (DMPA), known as Depo-Provera; and Norplant implants and injectable microspheres of norethisterone (NET). To minimize the side effects of OCs, pharmaceutical companies have worked to get OCs with the lowest possible dose of hormones that is still effective. Family Health International (FHI) has conducted several studies around the world comparing low-dose and standard-dose pills. A new FHI study will determine the acceptability of switching from standard-dose to low-dose pills. FHI also is undertaking a study of OCs with and without iron supplements among women with low hemoglobin counts to see if 7 days of iron each month causes a rise in the hemoglobin and if side effects are higher for the group taking iron supplements. The estrogen component of combined OCs has been associated with suppression of lactation. This is of serious concern, particularly for breastfeeding women with no alternative method of feeding their infants. While increasing the risk of some diseases (such as myocardial infarction and stroke), OCs provide protection from others. Over 100,000 Latin American women use injectable steroidal contraceptives. The World Health Organization (WHO) and FHI are collaborating on a study to compare 2 injectables. The study will evaluate effectiveness, side effects, and user satisfaction for each formulation. A new FHI study in Costa Rica addresses the question of whether longterm users of OCs or Depo-Provera run an increases risk of breast cancer or cervical cancer. The short-term safety and efficacy of Norplant implants has been established, and it has been approved for marketing in Finland. The primary objectives of FHI's clinical trials are to introduce the NORPLANT implant system into countries with no previous experience with this method and to determine overall acceptability of the method in different patient populations. By 1985 or early 1986, FHI will initiate studies in several Latin American countries. Every woman receiving the NORPLANT system will be followed up every 6 months for 5 years, the life of the system. Animals studies of the NET microspheres are concluding. There are plans to test it in a small number of women.^ieng

The effect of oral contraceptive formulation and field-workers: a cautionary tale.

This paper examines oral contraceptive continuation rates and reported side effects in a large scale clinical research project conducted in Sri Lanka. The project evaluated standard- and low-dose pills used with and without vitamin supplements. Differences in continuation rates and perception of side effects are used to illustrate the impact that family planning field-workers can have on women's use of oral contraceptives.

PIP: The article reports the results of a large-scale clinical research project conducted in Sri Lanka in 1977-81 that was designed to address 3 issues: 1) whether oral contraceptives (OCs) with estrogen doses of 50 mcg and progestagen doses of 1 mg should be replaced by lower-dose preparations; 2) whether a multivitamin tablet taken in conjunction with OCs can reduce OC side effects and increase continuation rates; and 3) whether a recruitment and delivery system using young village women as house-to-house motivators and contraceptive suppliers can be a successful, cost-effective mechanism of family planning service delivery. Differences in continuation between OC types and in terms of vitamin supplementation versus nonsupplementation were generally inconsistent and nonsignificant. However, there were marked differences in continuation rates among the 3 study sites (Colombo, Matara, and Puttalam) which appeared to reflect the different attitudes and practices of fieldworkers in these areas. Fieldworkers in the urban area of Colombo, the study site with the highest continuation rate, were highly trained, well supervised, and did not have to travel as far as their counterparts in the other 2 study areas. 12-month termination rates in Colombo were significantly higher for low-dose compared to standard-dose OCs; again, this finding is considered to be more reflective of the greater skill and diligence of field workers assigned to follow up standard-dose clients than of properties of the 2 forms of OCs. In Matara, standard-dose only users had higher continuation and fewer side effects than study treatment acceptors in general or than standard dose placebo acceptors; in Puttalam, they had lower continuation and more side effects. The substantial differences in Puttalam are entirely explained as an artifact of the geographic assignment of fieldworkers: a home visiting team did not work in the standard-dose only area. These findings indicate that differences in the setting in which treatment is provided, especially in the quality of field personnel, are often far more important to treatment success than the contraceptive methods themselves.

Oral contraceptives and the cobalamin (vitamin B12) metabolism.

The mean concentrations of serum (S)-cobalamin (vitamin B12) and S-unsaturated B12 binding capacity (UBBC) were significantly decreased in 101 women (mean age: 30.4 years) taking oral contraceptives (OC) of the combination type, compared to 113 controls. OC users more frequently showed decreased concentrations of S-cobalamin (less than 200 pmol/l) than did their controls. However, the incidence of particularly low concentrations (less than 150 pmol/l) in OC users was not increased. To study a possible dose-dependent effect, 27 women (mean age: 50.5 years) given high-dose estrogen preparations (1-4 mg estrogen) were compared with 31 controls. The two groups showed no difference with regard to S-cobalamin, but the mean S- and plasma-UBBC levels were significantly decreased in the high-dose estrogen group. 12 OC users with decreased S-cobalamin (less than 200 pmol/l), 9 OC users with normal S-cobalamin and 10 controls were studied more intensively. The mean hemoglobin concentration was significantly decreased in those OC users having decreased S-cobalamin. On the contrary, the absorption and excretion of radiolabeled cobalamin and the concentrations of erythrocyte-folate, S-iron and -transferrin did not show any difference between the groups, and all results were normal, by and large. No characteristic changes in plasma volume were found. It is concluded that routine measurement of S-cobalamin in women taking OC is not justified.

PIP: This study investigated the incidence and etiology of cobalamin (vitamin B12) deficiency in oral contraceptive (OC) users. Mean concentrations of serum (S)-cobalamin and S-unsaturated B12 binding capacity were significantly decreased in 101 women who had been taking combination OCs with an estrogen content of 50 mcg for at least the past 6 months compared to 113 controls who had not used OCs for at least the past 6 months. However, the incidence of particularly low concentrations of S-cobalamin (under 150 pmol/1) was not increased in OC users. To investigate the possibility of a dose-dependent effect, 27 women who wrere using high-dose estrogen OCs with an estrogen content of 1-4 mg were compared with 31 controls who had not used sex steroids. Although the group showed no difference in terms of S-cobalamin concentrations, mean serum and plasma-unsaturated B12 binding capacity levels were significantly decreased in the high-dose estrogen group. When 12 OC users with decreased S-cobalamin (under 200 pmol/1), 9 OC users with normal S-cobalamin, and 10 controls were studied more extensively, the mean hemoglobin concentration was found to be significantly decreased in OC users with decreased S-cobalamin levels. The absorption and excretion of radiolabeled cobalamin and concentrations of erythrocyte-folate, S-iron, and S-transferrin remained normal in all 3 groups and no changes in plasma volume were observed. it is concluded that the decreased S-cobalamin levels found in OC users are caused by a decreased S-unsaturated vitamin B12 binding capacity, possibly reflecting a lowering of the white blood cell count. Routine measurement of S-cobalamin in OC users is not recommended.