Effect of Ovral, a combination type oral contraceptive agent, on vitamin A metabolism in rats.

When a typical combination-type oral contraceptive agent (Ovral, which contains 0.5 mg norgestrel and 0.05 mg ethinyl estradiol per tablet), is given to young female rats at 50 x the human dosage for an extended period, plasma vitamin A levels are elevated about 50%. The increase is mainly due to a higher steadystate level of retinol binding protein, and not to the presence of more lipoprotein-bound retinyl ester. In Ovral treated rats, the depletion of vitamin A from the liver, calculated as a linear rate, as a linear rate per unit body weight, or as a half-life, tends to be greater, although the differences are only marginally significant. The absorption, storage and short-term excretion patterns of a dose of radioactive vitamin A are not demonstrably affected by Ovral treatment.     

Pituitary response to LHRH stimulation in women on oral contraceptives.

Gonadotropic response to an LHRH bolus was tested on 12 patients who were taking two different contraceptive agents. Half of the subjects were on a short-term therapy, 2–3 months, and the other half were taking oral contraceptives for over three consecutive years. Six women who had a normal menstrual history and who had not taken any oral contraceptives for at least one year, served as controls. 150 ug LHRH was given intravenously during cycle day 20–25. Serum samples were obtained prior to bolus injection and at 20-minute intervals for two hours. Ovulation in control patients was confirmed by elevated serum progesterone. LH response in treated subjects was significantly lower than that of the controls. There were no differences between the long- and short-term groups. FSH response was not significantly altered in the treated groups. The suppression of LH response was greater in patients taking ethinyl estradiol preparation (Ovral) than in the patients taking mestranol preparation ($\text{Norinyl}\text{1}\text{50}$). No statistically significant differences were found in FSH response to LHRH in the two oral contraceptive groups.     

Effect of estrogen/progestin potency on clinical chemistry measures. The Lipid Research Clinics Program Prevalence Study

The effects of oral contraceptives of varied estrogen/progestin composition on clinical measurements of hepatic, thyroid, and renal function and carbohydrate metabolism were examined in 1,355 women in the Lipid Research Clinics Program Prevalence Study. In general, bilirubin and alkaline phosphatase levels are lower with both oral contraceptives and postmenopausal estrogen use, suggesting an estrogen effect. The least bilirubin reduction is seen with a progestin dominant oral contraceptive. A significant decrement in aspartate aminotransferase is observed in users of one high estrogen dose oral contraceptive and in postmenopausal Premarin users, while aspartate aminotransferase is higher in postmenopausal users of higher dose ethinyl estradiol. Globulins are slightly higher in all hormone use categories, suggesting an estrogen effect on hepatic secretion of this protein class into the circulation. Fasting glucose concentrations are generally slightly lower even in the progestin dominant oral contraceptives, where glucose intolerance has been described. Thyroxine concentrations are generally elevated in all women using oral contraceptives. A relationship to estrogen dose is seen in women with thyroxine concentrations greater than the 99th percentile and in postmenopausal estrogen users. Creatinine concentration is greater with the use of Ovral, a progestin dominant oral contraceptive, and lower with two estrogen dominant oral contraceptives and Premarin, suggesting a competitive effect of estrogen and progestin. Among the clinical laboratory tests considered here, oral contraceptive effects seem to be largely estrogen mediated with a suggestion of competitive effect of estrogen versus progestin only on bilirubin and creatinine levels. These observations differ from lipoproteins where opposing hormonal effects are more clearly reflected in changing lipoprotein concentrations.     

Extended regimens of the contraceptive vaginal ring versus hormonal oral contraceptives: effects on lipid metabolism

BackgroundCombined oral contraceptives used in an extended regimen have been studied because of their potential benefits; however, there have been few publications on extended regimens of contraceptive vaginal rings. The aim of this study was to assess the effects of these two extended regimens on the lipid metabolism of women using these contraceptive methods during 1 year.Study DesignThis prospective study enrolled 150 women: 75 used a vaginal contraceptive ring (11.7 mg etonogestrel and 2.7 mg ethinyl estradiol), and 75 used oral contraceptives (30 mcg ethinyl estradiol and 150 mg desogestrel). Both groups used their respective method for 84 days followed by a 7-day pause during 1 year. At baseline and every 3 months during the study period, blood was collected to assess total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides and apolipoprotein (apo) A-I and B. The analysis of variance test was used to analyze differences in the results of these exams over time.ResultsA total of 62 vaginal ring and 61 oral contraceptive users completed the study. There were no significant differences in the discontinuation rate, mean total cholesterol and fraction levels, apo B concentration or apo A-I/apo B ratio. Vaginal ring users had significantly higher apo A-1 levels than oral contraceptive users.ConclusionDespite the vaginal route of administration, the steroids released by the ring had the same effects on the lipid metabolism and lipoprotein levels typically seen with ethinyl estradiol given either by oral or parenteral routes.     

Efficacy of second versus third generation oral contraceptives in the treatment of hirsutism

OBJECTIVE: To compare second versus third generation combination oral contraceptives (OCs) in the treatment of hirsutism. METHODS: Women with hirsutism, as defined by a minimum Ferriman-Gallwey score of 10, were randomized in a double-blind fashion to receive an OC containing either ethinyl estradiol/desogestrel or ethinyl estradiol/levonorgestrel for 9 months of treatment. Ferriman-Gallwey scores, androgen levels and sex hormone-binding globulin were measured at baseline and every 3 months for the duration of the study. Hormones were measured in duplicate by radioimmunoassay. RESULTS: Of the 47 women enrolled, 24 were randomized to ethinyl estradiol/desogestrel and 23 were randomized to ethinyl estradiol/levonorgestrel. Mean sex hormone-binding globulin increased significantly in subjects using the desogestrel-containing contraceptive compared with the levonorgestrel-containing contraceptive. Ten subjects completed the 9 months of treatment in the levonorgestrel group and 11 completed the study in the desogestrel group. Mean free testosterone and 3alpha-androstanediol glucuronide decreased significantly in the group receiving ethinyl estradiol/desogestrel but not in the ethinyl estradiol/levonorgestrel group. Mean Ferriman-Gallwey scores decreased significantly in both treatment groups. Improvement in mean Ferriman-Gallwey score was 35.7 +/- 38.1% (p < 0.001) for the ethinyl estradiol/desogestrel arm and 33.4 +/- 27.3% (p < 0.001) for the ethinyl estradiol/levonorgestrel arm. There were no statistically significant differences found in the improvement of Ferriman-Gallwey scores between the two treatment arms, although the power to detect a difference was limited by the small sample size. CONCLUSIONS: Treatment of hirsute women with third generation OCs containing desogestrel results in a significant increase in sex hormone-binding globulin and decrease in free testosterone and 3alpha-androstanediol glucuronide. Both second and third generation OCs were clinically effective in treating hirsutism.     

Long-term effects of combined oral contraceptives on markers of endothelial function and lipids in healthy premenopausal women

The aim of this prospective cross-over study was to investigate the effect of two low-dosed oral contraceptives on markers of endothelial function and plasma lipids. Twelve healthy, nonsmoking women (mean age: 21.7 years) were recruited from the family planning clinic of the university hospital Zurich. For 6 months the participants received a treatment with two contraceptive pills containing 30 microg ethinyl estradiol/150 microg levonorgestrel (three cycles) and 30 microg ethinyl estradiol/75 microg gestodene (three cycles). Plasma levels of endothelin-1, nitric oxide, cholesterol, and HDL were measurement before and during treatment with both oral contraceptive treatments.No significant changes in the plasma levels of nitric oxide and endothelin-1, both important regulators of the vascular tone, were observed during oral contraceptive use. A significant negative correlation was found between nitric oxide and endothelin-1 and nitric oxide and cholesterol. There was a positive correlation between endothelin-1 and cholesterol. In conclusion, the investigated contraceptive pills did not cause major changes in circulating nitric oxide and endothelin-1 plasma levels.     

Hirsutism: metabolic effects of two commonly used oral contraceptives and spironolactone

Fifty-one hirsute women were randomly treated for nine months with ethinyl estradiol 35 ug plus norethindrone 0.4 mg or 30 ug ethinyl estradiol plus 1.5 mg norethindrone acetate if they needed contraception or spironolactone 200 mg daily if they did not. Metabolic evaluations in response to therapy demonstrated triglyceride elevations with the two oral contraceptives but not with spironolactone. While systolic blood pressure was lower with spironolactone, fasting insulin levels were higher as opposed to either low-dose oral contraceptive preparation. Ethinyl estradiol 30 ug plus 1.5 mg norethindrone acetate lowered 3-alpha-diol glucuronide levels, yet ethinyl estradiol 35 ug plus norethindrone 0.4 mg and spironolactone were more effective in lowering Ferriman-Gallwey Scores. Treatment strategies for hirsute women need to consider metabolic consequences as well as efficacy.     

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.     

Vitamin supplements to women using oral contraceptives (studies of vitamins B1, B2, B6 and A)

Additional requirement of pyridoxine, thiamin and riboflavin necessary to prevent a decline in the nutritional status of these vitamins in women using an oral contraceptive — Ovral (ethinyl estradiol 0.05 mg and dl-norgestrel 0.5 mg) was examined. Ten mg of pyridoxine daily could mitigate the defect in tryptophan metabolism to a large extent. This amount could prevent the defect in erythrocyte aspartate amino transferase activity. Daily supplements of 3 mg thiamin and 2 mg riboflavin could prevent the decline in the nutritional status of these vitamins. Higher amounts of riboflavin would, however, be required to correct the initial deficiency of the vitamin.     

Study of low-density lipoprotein receptor regulation by oral (steroid) contraceptives: desogestrel, levonorgestrel and ethinyl estradiol in JEG-3 cell line and placental tissue

BACKGROUND: The aim of this study was to compare in vitro the role of two oral contraceptives, desogestrel (a less androgenic derivative of levonorgestrel) and levonorgestrel--alone and in combination with ethinyl estradiol--on low-density lipoprotein (LDL) receptor regulation by assessing receptor protein expression and functional effectiveness. STUDY DESIGN: Placental tissue and cultured placental cells (JEG-3) were used to study the expression and endocytotic activity of LDL receptor protein. The expression of the receptor was assessed by immunocytochemistry and immunoblot assays with and without contraceptive challenge. Functioning activity of LDL receptor was studied by measuring the rate of uptake of LDL by placental cells. Quantification of LDL was based on the total cholesterol content of the lipoprotein. RESULTS: A combination of desogestrel (20 ng/mL of incubation medium) and ethinyl estradiol (10 ng/mL of incubation medium) maintained the LDL receptor at high level of expression and functioning mode. In contrast, the double-blind preparation of levonorgestrel (20 ng/mL) and ethinyl estradiol (10 ng/mL) had shown much lower expression as well as receptor-mediated LDL uptake. The concentration of contraceptives used in this study was similar to the prevailing concentration of oral contraceptives in clinical use. CONCLUSION: Higher expression of LDL receptor and enhanced rate of LDL uptake by the receptor protein projects the possibility that there might be less atherosclerosis-related disorders from the combination of desogestrol and ethinyl estradiol.     

Ethinyl estradiol in human milk and plasma after oral administration

In order to estimate the concentration of ethinyl estradiol in milk, four fully lactating women were given an oral contraceptive containing 50 μg ethinyl estradiol + 4 mg megestrol acetate, starting two months after delivery, and four women who wanted to stop nursing after a lactation period of 6–18 months were given one tablet of 500 μg ethinyl estradiol. Milk and blood samples were taken simultaneously after 3, 7, 11 and 23 hours. The concentration of ethinyl estradiol in plasma and milk were estimated by radioimmunoassay. The method for the assay of ethinyl estradiol in milk is evaluated in this paper.The concentration of ethinyl estradiol in milk from the women taking the oral contraceptive was below the detection limit of the assay. In the women taking 500 μg of ethinyl estradiol, the plasma:milk ratio of ethinyl estradiol was found to be about 100:25. The relative dose of ethinyl estradiol ingested by a fully nursed baby, when its mother takes an oral contraceptive containing 50 μg of ethinyl estradiol, has been calculated to be about 10 ng per day, which is 0.02 per cent of the dose given to the mother.     

A double-blind comparative study of the effects of a 23-day oral contraceptive regimen with 20 microg ethinyl estradiol and 75 microg gestodene and a 21-day regimen with 30 microg ethinyl estradiol and 75 microg gestodene on hemostatic variables, lipids, and carbohydrate metabolism.

In this double-blind study we compared the influence of two oral contraceptives, a 23-day regimen with 20 microg ethinyl estradiol and 75 microg gestodene (23-day 20/75) and a 21-day regimen with 30 microg ethinyl estradiol and 75 microg gestodene (21-day 30/75), on hemostatic variables, lipids, and carbohydrate metabolism. The volunteers received the preparations daily for six 28-day cycles. Hemostatic variables and lipids were measured at baseline and after six treatment cycles. Carbohydrate metabolism was assessed by determination of the area under the curve (AUC) of carbohydrate parameters after oral glucose tolerance tests performed at baseline and after three treatment cycles. Data from 33 volunteers in each group were obtained. No significant differences between the effects of both treatments on the hemostatic system were detected. Neither the overall change of all hemostatic variables from baseline to treatment Cycle 6 [defined as primary target variable in the study] nor the change of any of the individual hemostatic parameters differed significantly between the treatment groups. Likewise, no significant nor clinically relevant differences in the effects of both treatments on the volunteers' lipid profiles were detected. The data on carbohydrate variables suggested a slightly more favorable influence of the 23-day 20/75 regimen. The increase of the glucose AUCs after three cycles tended to be stronger with the 21-day 30/75 regimen than with the 23-day 20/75 regimen. In addition, the AUCs for insulin and C-peptide were slightly reduced after three cycles with the 23-day 20/75 regimen but slightly increased with the 21-day 30/75 regimen. Both study treatments were safe and well tolerated by the volunteers as shown by the nature and frequency of adverse events, the routine laboratory examinations, and the physical and gynecological examinations. Both preparations provided adequate contraceptive reliability. The only pregnancy during treatment was attributable to intake errors. In conclusion, the prolongation of the treatment phase of an oral contraceptives with 20 microg ethinyl estradiol does not evoke more pronounced metabolic effects than a conventional 21-day regimen with 30 microg ethinyl estradiol.     

Endometrial histology during use of a low-dose estrogen-desogestrel oral contraceptive with a reduced hormone-free interval

The object of the study was to determine the effect of a new low-dose ethinyl estradiol-desogestrel oral contraceptive on endometrial histology. The oral contraceptive regimen contained fixed doses of ethinyl estradiol (20 micrograms) and desogestrel (150 micrograms) for days 1-21, placebo on days 22 and 23, and ethinyl estradiol alone (10 micrograms) on days 24-28. Endometrial histology was assessed in tissue samples obtained during treatment cycles 13 and 14. All endometrial samples were sent to a central laboratory for processing and evaluation. No endometrial hyperplasia or metaplasia was found in the endometrial biopsy specimens obtained during cycles 13 and 14 in a subset of 12 women participating in a multicenter efficacy and safety study. These results suggest that this oral contraceptive regimen, which includes 5 days of unopposed ethinyl estradiol, is not associated with endometrial hyperplasia or metaplasia. The endometrial histologic findings observed in this study were similar to those observed during the use of 21-day combination oral contraceptive regimens.     

A comparative study of the metabolic effects of injectable and oral contraceptives

The metabolic effects of an injectable contraceptive, Depo-provera (medroxyprogesterone acetate), an oral contraceptive pill containing 50 micrograms ethinyl estradiol and 500 micrograms norgestrel and a control group (not on contraceptives) were compared in 3 groups, each comprising 32 women. The subjects were matched for race, age and parity. Mean duration of treatment was 41.7 +/- 18.3 months for Depo-provera and 59.6 +/- 29.0 months for the pill group. Glucose tolerance was impaired in both treatment groups. The combination pill showed more changes in both glucose tolerance and insulin response. Lipid levels remained unchanged in both treatment groups.     

Extended regimens of the vaginal contraceptive ring: cycle control

Background

Oral contraceptives used for extended periods of time have been extensively studied because of their potential benefits; however, there have been few publications on extended regimen of vaginal rings. The aim of this study was to compare the bleeding patterns of women using extended regimens of the vaginal ring or oral contraceptives.

Study Design

Prospective cohort involving 150 women: 75 used vaginal rings that release 120 mcg of etonogestrel and 15 mcg of ethinyl estradiol daily, and 75 took oral contraceptives containing ethinyl estradiol 0.3 mcg and desogestrel 150 mcg. Both groups used their respective contraceptive method over continuous periods of 84 days, followed by a 7-day pause, during 1 year.

Results

The total number of scheduled bleeding and spotting days decreased significantly during the 1-year period of the study for both methods (p=.001), and this decrease was significantly higher for oral contraceptive users. Similarly, during the study period, there was a significant reduction in the total number of unscheduled bleeding and spotting days for both methods (p=.01), but this decrease was significantly higher among vaginal ring users (p=.003).

Conclusion

Vaginal ring used on an extended regimen is a contraceptive method that offers good cycle control.     

Fertility regulation in nursing women: IV. Long-term influence of a low-dose combined oral contraceptive initiated at day 30 postpartum upon lactation and infant growth

The study was designed to test the long-term influence of a low-dose combined oral contraceptive upon lactation and infant growth when treatment was initiated at day 30 postpartum. The contraceptive tested contained ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg. Two control groups were formed by women who received an injectable placebo or a Copper T at day 30 postpartum. Women in the injectable placebo group received non-hormonal contraceptives at day 90 postpartum. An exacting list of requirements for admission and continuation in the study was applied to all groups. The oral contraceptive group had a significantly lower percentage of cases in full nursing from the 4th through the 10th postpartum month when compared to both control groups. The average absolute weight of infants in the oral contraceptive group was significantly lower at several ages when compared to the placebo group but not when compared to the Copper T group. No adverse side effects upon infant's health were detected. It was concluded that the oral contraceptive tested showed a moderate inhibitory influence upon lactation when treatment was initiated at the beginning of the second postpartum month.     

Effects of hormonal contraceptives on milk volume and infant growth: WHO Special Programme of Research and Development and Research Training in Human Reproduction

WHO conducted a three-centre study in Hungary and Thailand to evaluate the effects of hormonal contraception on lactation and infant growth. Women choosing oral contraceptives were randomly assigned to a combined oral contraceptive containing 30ug ethinyl estradiol and 150ug levonorgestrel (N=86) or a progestin-only preparation containing 75ug dl-norgestrel (N=85). Identical packaging and treatment schedules allowed double-blind observation. One-hundred-and-eleven women using no contraception or non-hormonal methods acted as controls. In the two Thai centres 59 women using depot-medroxyprogesterone acetate formed an additional comparison group. All subjects were healthy women with normal deliveries, whose infants had normal birth weights and satisfactory growth in the neonatal period.Breast milk volume was determined by pump expression using standardized procedures. Information was obtained on nursing frequency and supplementation, infant growth and morbidity. Pretreatment observations at 6 weeks post-partum were used as a baseline, and subjects were followed-up at 9, 12, 16, 20 and 24 weeks post-partum.Women using combined oral contraceptives had a decline in milk volume within 6 weeks of initiating treatment, whereas no significant decrease was observed in the other treatment groups. After 18 weeks of treatment, combined oral contraceptive users experienced a 41.9% decline in milk volume, compared to 12.0% with progestin-only minipills and 6.1% in the non-hormonal controls. The prevalence of complementary feeding and withdrawals due to inadequate milk supply were comparable in the four treatment groups. However, data were not available on the daily amounts of complementary feeds. There were no significant differences in growth of infants between treatment groups. Thus, women may have compensated for declines in milk volume by more supplementary feeding or by more prolonged and intense suckling episodes.We conclude that 30 ug estrogen-containing combined oral contraceptives impair milk secretion, but in the selected healthy group of mothers and children studied with the prevailing level of supplementary feeding, this did not adversely affect infant growth.     

Side effects and compliance with low- and conventional-dose oral contraceptives among adolescents

Oral contraceptives are the most popular birth control method for teenagers, yet many teens discontinue use of these contraceptives prematurely. The need to minimize any potential long-term medical complications from the use of contraceptive hormones must be balanced with the desirability of increasing acceptance of contraceptives by adolescents. There has been concern that the use of socalled “low-dose” estrogen preparations, although decreasing the likelihood of complications, may lead to side effects that make compliance less certain. The present study comparing two commonly used oral contraceptive preparations, one low dose, one conventional dose, tests the hypothesis that among adolescents an association exists between oral contraceptive side effects and compliance. Using a double-blind crossover method, 55 sexually active adolescent females received two months each of a preparation containing 35 μg ethinyl estradiol and 0.5 mg norethindrone and another containing 50 μg mestranol and 1.0 mg norethindrone. The 50-μg preparation was associated with fewer side effects when administered during the first two months. No differences in side effects were noted in the latter two months, but there was a slight increase in weight gain when compared with the 35-μg preparation. The most common side effect was intermenstrual bleeding with the 35-μg pill. There was no documented relationship between the occurrence of side effects and compliance.     

Influence of hormonal contraceptives on microbial flora of gingival sulcus

To determine a possible influence of two different hormonal contraceptives on bacterial microflora of gingival sulcus, subgingival plaque samples of 29 healthy women aged between 20 and 32 years were investigated bacteriologically before subjects took a contraceptive and 10 and 20 days after subjects started the medication. In 14 women, an oral contraceptive containing 0.02 mg ethinyl estradiol and 0.15 mg desogestrel (preparation A) was used, and 15 women took a contraceptive containing 0.03 mg ethinyl estradiol and 2.00 mg dienogest (preparation B) daily over 21 days. There were no changes in clinical parameters of the teeth investigated during 3 weeks of the study. The periodontopathogenic bacteria Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans were never detected throughout the study. On the other hand, the periodontopathogenic species Prevotella intermedia was found in plaque samples of 22 women. The content of this microorganism showed only a little change between the pretreatment period and plaque sampling after 10 days of contraceptive treatment, but a striking increase occurred after 20 days of contraceptive treatment, especially in the preparation A group. In this respect, there was a significant difference between preparations A and B.     

Biphasic versus triphasic oral contraceptives for contraception

Side effects caused by oral contraceptives discourage compliance with and continuation of oral contraceptives. A suggested disadvantage of biphasic oral contraceptive pills compared to triphasic oral contraceptive pills is an increase in breakthrough bleeding. We examined this potential disadvantage by conducting a systematic review comparing biphasic oral contraceptives with triphasic oral contraceptives in terms of efficacy, cycle control, and discontinuation because of side effects.We included randomized, controlled trials comparing any biphasic oral contraceptive with any triphasic oral contraceptive when used to prevent pregnancy. Only two trials of limited quality met our inclusion criteria. Larranaga compared two biphasic and one triphasic pills, each containing levonorgestrel and ethinyl estradiol. No important differences emerged, and the frequency of discontinuation because of medical problems was similar with all three pills. Percival-Smith compared a biphasic pill containing norethindrone (Ortho 10/11) with a triphasic pill containing levonorgestrel (Triphasil) and another triphasic pill containing norethindrone (Ortho 7/7/7). The biphasic pill had inferior cycle control compared with the levonorgestrel triphasic pill.The available evidence is limited and of poor quality; the internal validity of these trials is questionable. Given that caveat, the biphasic pill containing norethindrone was associated with inferior cycle control compared with the triphasic pill containing levonorgestrel. This suggests that the choice of progestin may be more important that the phasic regimen in determining bleeding patterns.