Postoperative administration of monophasic combined oral contraceptives after laparoscopic treatment of ovarian endometriomas: a prospective, randomized trial.

OBJECTIVE: We sought to evaluate the efficacy of postoperative administration of monophasic, combined, low-dose oral contraceptives on endometrioma recurrence and on persistence-recurrence of associated pain symptoms after laparoscopic treatment of moderate-to-severe endometriosis. STUDY DESIGN: In a prospective, randomized trial 70 patients who were not attempting to conceive, aged 20 to 35 years, underwent laparoscopic excision of ovarian endometriomas, followed by either postoperative administration of low-dose cyclic oral contraceptives for 6 months or no treatment on the basis of a computer-generated sequence. At 3 and 6 months after surgery and then at 6-month intervals, both groups underwent ultrasonographic examination for possible evidence of endometrioma recurrence and for evaluation of the absence, persistence, or recurrence of pain symptoms. RESULTS: Two patients in the oral contraceptive group did not complete the study. After a mean follow-up of 22 months (range, 12-48 months), there were 2 (6.1%) endometrioma recurrences in the 33 patients who received postoperative oral contraceptives versus 1 (2.9%) recurrence in the 35 patients in the control group (not significant). The moderate-to-severe pain recurrence rate was 9.1% in the oral contraceptive group versus 17.1% in the control group (not significant). The mean time to recurrence of either symptoms or endometriomas was 18.2 months in the oral contraceptive group versus 12.7 months in the control group. The 12-month cumulative recurrence rate at life-table analysis was significantly lower for patients receiving oral contraceptives versus control subjects, whereas no significant difference was evident at 24 and 36 months. CONCLUSION: Postoperative administration of low-dose cyclic oral contraceptives does not significantly affect the long-term recurrence rate of endometriosis after surgical treatment. A delay in recurrence is evident at life-table analysis.

Evidence that treatment with monophasic oral contraceptive formulations containing ethinylestradiol plus gestodene reduces bone resorption in young women.

The aim of the study was to evaluate if a pill containing the same dose of the same type of progestin compound (gestodene, GES, 75 microg) but different doses of ethinylestradiol (EE2) (20 or 30 microg) differently influences specific markers of bone resorption (urinary levels of pyridinoline (PYR) and dexoxypyridinoline (D-PYR)). During the 12 months of the study a significant decrease of urinary levels of PYR and D-PYR was found in 2 groups of young post-adolescent women taking the pills with 20 and 30 microg of EE2 in comparison with control women (subjects of the same age group with normal menstrual cycle who did not use contraception). In women taking pills with 20 or 30 microg EE2, the levels of sex hormone-binding globulin (SHBG) significantly increased during treatment in comparison with baseline, whereas in the same time period no changes occurred in control women. These findings suggest that similar to the pill containing 30 microg EE2, the lower dosage of the EE2 pill (20 microg) is also capable of reducing bone resorption. Twenty and 30 microg EE2 pills exert the same biological estrogenic effect. In fact, SHBG levels significantly increased with both pills. However, an additional effect of the progestin compound that could act directly on progestin or estrogen receptors of bone cannot be excluded. Since contraception with a pill containing the lowest estrogen dose is associated with the lowest incidence of side effects, these findings further suggest a pill containing 20 microg EE2 for young post-adolescent women would be the best choice.

PIP: The aim of this study was to evaluate if a pill containing the same dose of the same type of progestin compound (gestodene, GES, 75 mcg) but different doses of ethinyl estradiol (EE2) (20 or 30 mcg) differently influences specific markers of bone resorption (urinary levels of pyridinoline (PYR) and dexoxypyridinoline (D-PYR). During the 12 months of the study a significant decrease of urinary levels of PYR and D-PYR was found in 2 groups of young postadolescent women taking the pills with 20 or 30 mcg EE2 in comparison with control women (subjects of the same age group with normal menstrual cycles who did not use contraception). In women taking pills with 20 or 30 mcg EE2, the levels of sex hormone-binding globulin (SHBG) significantly increased during treatment in comparison with baseline, whereas in the same time period no changes occurred in control women. These findings suggest that similar to the pill containing 30 mcg EE2, the lower dosage of the EE2 pill (20 mcg) is also capable of reducing bone resorption. 20 and 30 mcg EE2 pills exert the same biological estrogenic effect. In fact, SHBG levels significantly increased with both pills. However, an additional effect of the progestin compound that could act directly on progestin or estrogen receptors of bone cannot be excluded. Since contraception with a pill containing the lowest estrogen dose is associated with the lowest incidence of side effects, these findings further suggest that a pill containing 20 mcg EE2 would be the best choice for young postadolescent women.

Low-dose oral contraceptives and bone mineral density: an evidence-based analysis.

We reviewed studies of the association of oral contraceptive (OC) use and bone mineral density (BMD). We limited the review to studies of women using low-dose oral contraceptives and that measured BMD by bone densitometry. A total of 13 studies met the inclusion criteria. Nine of these showed a positive effect of OC use on BMD, and four did not show an association. However, none of the studies showed a decrease in BMD with OC use. We classified the level of evidence from each study according to the guidelines of the US Preventive Services Task Force. The level of evidence supporting a positive association between OC use and increased BMD is II-1. There is fair evidence (Category B) to support the position that OC use has a favorable effect on BMD. We made suggestions for a study design that could yield Level I evidence.

PIP: The authors reviewed studies of the association of oral contraceptive (OC) use and bone mineral density (BMD). They limited the review to studies of women using low-dose OCs and that measured BMD by bone densitometry. A total of 13 studies met the inclusion criteria; 9 of these showed a positive effect of OC use on BMD, and 4 did not show an association. However, none of the studies showed a decrease in BMD with OC use. They classified the level of evidence from each study according to the guidelines of the US Preventive Services Task Force. There is evidence supporting a positive association between OC use and increased BMD. There is fair evidence to support the position that OC use has a favorable effect on BMD. The authors made suggestions for a study design that could yield level I evidence.

An open-label, multicenter study to evaluate Yasmin, a low-dose combination oral contraceptive containing drospirenone, a new progestogen.

This open-label, multicenter study evaluated the efficacy, safety, and cycle control of Yasmin, a new low-dose, monophasic oral contraceptive containing the unique progestogen drospirenone (DRSP) 3 mg and ethinyl estradiol (EE) 30 microg. DRSP is a synthetic progestogen that has antiandrogenic and antimineralocorticoid effects. In this study, 326 women were evaluated and 220 (67%) completed all 13 treatment cycles. The corrected Pearl Index was 0. 407. Of the 151 subjects who experienced intermenstrual bleeding at any time during the study, the majority (64%) had bleeding during only one or two pill cycles. Breakthrough bleeding without spotting occurred in 1% of all cycles, spotting without breakthrough bleeding in 9.3% of all cycles, and breakthrough bleeding with spotting in 3% of all cycles. Amenorrhea was observed in 3% of all cycles. In all, 20 subjects (6%) discontinued participation in the study because of adverse events. No serious adverse events related to the study drug were reported. No clinically significant changes in weight, blood pressure, or lipids were reported. The impact of the new progestogen DRSP on the women's self-perception of menstrual health was also evaluated. Subjects reported that symptoms of water retention, negative affect, and increased appetite significantly improved at cycle 6 from baseline. This study demonstrates that Yasmin is an effective oral contraceptive that is safe and well tolerated.

Comparison of ovarian follicular activity during treatment with a monthly injectable contraceptive and a low-dose oral contraceptive.

Ovarian follicular development occurs during treatment with combined and progestin-only oral contraceptive (OC) pills and progestin-containing subdermal implants, and can be associated with the development of persistent functional cysts that may require surgical removal. Lunelle is a once-a-month injectable contraceptive containing estradiol cypionate 5 mg and medroxyprogesterone acetate 25 mg. A randomized, comparative study was undertaken to compare the effect on ovarian follicular activity associated with use of Lunelle and a low-dose OC. A total of 30 ovulatory subjects were randomly assigned to receive two cycles of treatment with either an OC containing ethinyl estradiol 20 microg and 0.1 mg levonorgestrel or Lunelle. During the second cycle of treatment, pelvic sonography was performed every 4 days, at which time the maximum follicle diameter was measured. Study end points were the presence of follicles >/=10, 20, and 30 mm. In all, 13 of 15 subjects in the OC group and 14 of 15 in the Lunelle group completed the study. Follicles measuring >/=10 mm were present in 11 of 13 (84.6%) in the OC users and in four of 14 (28.6%) in the Lunelle users (p <0.05). In the OC group, six of 13 subjects (46.1%) developed follicles >/=20 mm, and one of 13 (7.7%) developed follicles >/=30 mm. No subjects in the Lunelle group developed a follicle >/=20 mm in diameter. This study indicates that Lunelle is associated with a significantly lower incidence of ovarian follicular development compared to that of an OC containing 20 microg ethinyl estradiol and 0.1 mg levonorgestrel.

Examine use of low- and lower-dose OCs.

PIP: The use of 20-mcg oral contraceptives (OCs) is gaining ground, as more providers are using them in a wider range of women. A pharmaceutical market research firm has pegged US prescriptions of such pills at 14%, and Contraceptive Technology Update readers see an uptick in their use. A study that compared two 20-mcg pills against a 35-mcg formulation indicates that, while cycle control was similar among all three products, estrogenic side effects were 50% more common in women using the 35-mcg pill. A total of 463 women were randomized to use one of the three OC products, which were to be used for six menstrual cycles. In this three-way comparison, it was found that there were fewer estrogenic effects and equivalent cycle control and contraceptive efficacy in users of two 20-mcg ethinyl estradiol (EE) preparations as compared to women using a 35-mcg EE OC. However, proper pill taking is noted to be an important component in ensuring the effectiveness of any OC. Hence, clinicians should provide thorough education on pill usage with 20-mcg pills because they might be less forgiving of a missed pill in the daily regimen.^ieng

Providing combined OCs: examine special issues.

PIP: This article focuses on issues concerning the prescription and restriction of oral contraceptive (OC) use among smokers and new moms based on the findings from Contraceptive Technology's Update 2000 Contraception Survey involving family planning providers and clinicians. Overall, a majority (72%) of the providers restrict the pills to smokers aged 35-39 years, and 88.6% withhold the pills from smokers aged 40 and above. Providers believed that smoking increases the risk for developing cardiovascular disease; thus, all smokers are warned of that risk and are encouraged and advised to stop smoking. In addition, 42.5% of providers recommend new mothers to begin using the pills 4-6 weeks postpartum; and 45.1% say they start nursing mothers on progestin-only pills 4-6 weeks postpartum. Finally, half of survey participants chose Alesse, a 20 mcg pill, as their top choice for women who have experienced nausea on previous OC formulations.^ieng

Consider prescribing OCs for perimenopause use.

PIP: Contraceptive experts advise the use of low-dose (20-35 mcg estrogen) oral contraceptives (OCs) for perimenopausal patients because of their numerous advantages over hormone replacement therapy. Benefits include effective contraception, regular menses, treatment of menorrhagia and dysmenorrhea, reduction of vasomotor symptoms, higher bone density and fewer fractures, and prevention of ovarian and endometrial cancers. Although age limits for OC use for healthy nonsmoking women have been lifted for some time, certain providers still hesitate to prescribe OCs. Moreover, epidemiological studies confirm that low-dose pills are safe for healthy, nonsmoking women with normal blood pressure. More definitive research also found that the increased risk was mainly related to smoking rather than age. Since smoking is an important risk factor in OC use, pill use by smokers over 35 years old is contraindicated. Instead, it is suggested that they use progestin-only pills, IUDs, or barrier contraceptives for birth control. Another research indicates that women who use the pill can decrease their risk of postmenopausal fractures.^ieng

Does the pill affect bone mineral density?

PIP: According to the National Institutes of Health's Osteoporosis and Related Bone Diseases National Resource Center in Washington, DC, osteoporosis is a major public health threat for 28 million Americans, 80% of whom are women. It is noted that 1 of every 2 women over 50 years of age will have an osteoporosis-related fracture in her lifetime. In a retrospective review of medical literature which examined oral contraceptive (OC) user bone mineral density (BMD), evidence supports the hypothesis that low-dose OCs are associated with favorable effects on BMD. A total of 13 studies were included in the review; 9 of the studies showed a positive effect of OC use on BMD and 4 did not show an association. However, none of the studies indicated a decrease in BMD with OC use. Suggestions for a randomized controlled trial to gain definitive information on the literature are cited. In view of this, experts indicate that OC impact on BMD may best be demonstrated in hypoestrogenic women, including those with eating disorders, hypothalamic amenorrhea, and perimenopausal women.^ieng

Activity of the pituitary-ovarian axis in the pill-free interval during use of low-dose combined oral contraceptives.

This study was performed to evaluate pituitary-ovarian recovery in the pill-free interval during use of three low-dose combined oral contraceptives (COC). Either the estrogen component or the progestin component was comparable in the study groups, to evaluate their relative influence. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2) levels were measured and follicle number and size estimated by transvaginal sonography daily during the 7-day pill-free interval in 44 healthy volunteers using three different low-dose oral contraceptives. Healthy volunteers were enrolled using 20 micrograms ethinyl estradiol (EE) + 75 micrograms gestodene (GSD) (Harmonet, Wyeth-Lederle; n = 15), 20 micrograms EE + 150 micrograms desogestrel (DSG) (Mercilon, Organon n = 17), or 30 micrograms EE + 150 micrograms DSG (Marvelon, Organon, n = 12) given according to the usual regimen of one tablet daily during 3 weeks and 1 week pill-free interval. No ovulations were observed. Pituitary hormones were not statistically significantly different at the beginning of the pill-free interval between the study groups. FSH concentrations were significantly higher at the end of the pill-free interval in the 30 micrograms EE group compared with both 20 micrograms EE groups (7.0 [0.6-12.4] IU/L vs 4.9 [1.4-6.1] IU/L and 4.5 [2.4-7.4] IU/L; p = 0.001). In both 20 micrograms EE groups, a single persistent follicle (24 and 28 mm) was present in one subject. Follicle diameters were statistically significantly smaller at the beginning and at the end of the pill-free period in the 30 micrograms EE group compared with both 20 micrograms EE study groups. Dominant follicles (defined as follicle diameter > or = 10 mm) were observed at the end of the pill-free interval in both 20 micrograms EE groups (in 27% and 18% of women, respectively) but not in the 30 micrograms EE group. Finally, the area-under-the-curve for E2 was statistically significantly lower in the 30 micrograms EE group compared with both 20 micrograms EE groups. In conclusion, the EE content rather than the progestin component in the studied COC determined the extent of residual ovarian activity at the beginning of the pill-free interval. Dominant follicles were encountered only in the 20 micrograms EE study groups.

PIP: This article reports on a study that evaluated pituitary-ovarian recovery in the pill-free interval during a period of use of one of three low-dose combined oral contraceptives (COC). 44 female volunteers using low-dose oral contraception were subdivided into three groups in this comparative study: 15 women used 20 mcg ethinyl estradiol (EE) + 75 mcg gestodene; 17 used 20 mcg EE + 150 mcg desogestrel; 12 used 30 mcg EE + 150 mcg desogestrel. No ovulations were observed. Pituitary hormone levels between the study groups were not significantly different at the beginning of the pill-free interval. Follicle-stimulating hormone (FSH) concentrations were significantly higher at the end of the pill-free interval in the 30 mcg EE group than in both 20 mcg EE groups. In each of the 20 mcg EE groups, a single persistent follicle (24 mm and 28 mm, respectively) was found in 1 subject. In conclusion, the EE content rather than the progestin component in the studied COC determined the extent of residual ovarian activity at the beginning of the pill-free interval.

Benefits and risks of oral contraceptives.

The major benefits of modern low-dose oral contraceptives include relative safety and a high degree of efficacy, decreasing the need for abortion or surgical sterilization; reduced risks of bacterial (but not viral) pelvic inflammatory disease and of endometrial and ovarian cancer; improved menstrual regularity, with less dysmenorrhea and blood flow; and, when low-dose combination (not progestogen-only) oral contraceptives are used, reduced acne and hirsutism. Major risks are cardiovascular. Preliminary data from nonrandomized studies suggest that oral contraceptives containing third-generation progestogens are associated with increased risk of venous thromboembolism, particularly in carriers of the coagulation factor V Leiden mutation. The risk of arterial thrombosis, such as myocardial infarction or stroke, may be directly related to estrogen dose, particularly in women who have hypertension, smoke, or are >35 years old. Considering that only users aged >/=30 years who smoke >/=25 cigarettes/d have a higher estimated mortality rate than that of pregnant women, the benefits of oral contraceptives appear to outweigh their risks.

PIP: This article presents the benefits and risks of low-dose oral contraceptives (OCs). Most OCs contain a low-dose combination of ethinyl estradiol (or= 35 mcg) and a progestogen (0.1-1.5 mg, depending on the product type). OCs are relatively safe and effective when used for years; they control fertility in women and facilitate spontaneous sexual activity. Other benefits include: 1) improvement in the regularity of menses; 2) decrease in the incidence of dysmenorrhea; 3) circulation of blood flow; 4) reduction of the risks of ovarian and endometrial cancer; 5) inhibition of rheumatoid arthritis progression from mild to severe; and 6) when using low-dose combination (not progestogen-only) OCs, acne and hirsutism are reduced. However, there are also risks in using OCs. The risks associated with OC use are mostly cardiovascular. OCs containing third-generation progestogens are linked with an increased risk of venous thromboembolism. Moreover, acute myocardial infarction risk is great among smokers with hypertension, particularly among women older than 35 years; however, the risk decreases as the dosage of ethinyl estradiol decreases.

Hemostatic effects of smoking and oral contraceptive use.

This review addresses current knowledge of the effects of lower dose oral contraceptives (containing 35, 30, or 20 micrograms of ethinyl estradiol) on hemostasis in smoking and nonsmoking women. Evidence suggests that formulations containing 30 and 35 micrograms ethinyl estradiol induce a significant activation of coagulation, whereas oral contraceptive preparations with 20 micrograms ethinyl estradiol appear to have a negligible effect or no effect. In nonsmokers who take oral contraceptives any procoagulatory effects that may occur are counterbalanced by fibrinolytic effects. In smokers, however, compensatory fibrinolytic effects to offset the procoagulatory effects seen with 30-micrograms ethinyl estradiol oral contraceptive formulations are absent, shifting the hemostatic profile toward a hypercoagulable state. This suggests that a formulation with the lowest dose of ethinyl estradiol may be most suitable for smokers who wish to use this form of contraception.

PIP: This review addresses current knowledge of the effects of lower-dose oral contraceptives (OCs) (containing 35, 30, or 20 mcg of ethinyl estradiol) on hemostasis in smoking and nonsmoking women. Data showed that the OCs containing 30-35 mcg ethinyl estradiol influence a significant activation of coagulation parameters compared to the 20-mcg formulations, which appear to have little or no procoagulatory effect. However, procoagulatory effects of these OCs showed to be counterbalanced by the compensatory anticoagulation effects within the fibrinolytic system. This would indicate that most healthy women taking lower-dose OCs, particularly those containing 20 mcg ethinyl estradiol, are not at increased risk for thromboembolic disease. However, this compensatory activity of the fibrinolytic system does not occur in women who both smoke and use OCs. Studies documented that simultaneous smoking and OC use could lead to hypercoagulation. This suggests that OCs with the lowest effective dose of ethinyl estradiol are the best contraceptives for smokers.

Oral contraceptives and thrombosis. From risk estimates to health impact.

OBJECTIVE: The scientific debate on oral contraceptives (OCs) and thrombotic diseases continues unabated. The aim of this survey was to evaluate available scientific data on OCs and thrombotic diseases and to make tentative prescription recommendations of OCs to women with and without various thrombotic risk factors. CONSENSUS: In women 15-29 years old, venous thromboembolism is about twice as common as arterial complications. In women between 30 and 44 years, the number of arterial complications exceeds venous diseases by about 50%. The mortality from arterial diseases is 3.5 times higher than the number of deaths from venous diseases in women below 30 years, and 8.5 times higher in women 30-44 years old. A significant disability is more frequent in women suffering and surviving an arterial complication than in women with venous thromboembolism. Although many important scientific issues still have to be addressed, the available scientific data suggests a differential influence of OCs with second and third generation progestagens on the risk of venous and arterial diseases. OCs with second generation progestagens seem to confer a smaller increase in the risk of venous diseases and a higher increase in risk of arterial complications, compared with OCs containing third generation progestagens. The possible difference on the venous side seems to be smaller than primarily anticipated. RESULTS: Young women without any known risk factor for thrombotic diseases may use any low-dose OC. If OCs are prescribed to women with known risk factors for arterial thrombotic disease; e.g. smoking, diabetes, controlled hypertension, migraine without aura, family disposition of acute myocardial infarction (AMI) or thrombotic stroke, a low-dose pill with a third generation progestagen may have an advantage. If OCs are considered for women with risk factors for venous disease such as severe obesity, varicose veins, family history of VTE or with factor V Leiden mutation, a low-dose combined pill with a second generation progestagen may be preferable. In women above 30 years, OCs with third generation progestagens generally seem to confer less overall thrombotic morbidity, mortality and disability than OCs with second generation progestagens. These women should reconsider, however, the indication of combined OCs in the presence of significant risk factors of thrombotic diseases.

PIP: This article discusses available scientific data on oral contraceptives (OCs) and thrombotic diseases and provides tentative prescription recommendations of OCs to women, with and without various thrombotic risk factors. Several studies concerning OCs and venous thromboembolism (VTE), including the original studies serving as scientific databases, were presented. VTE was twice as common as arterial complications in women 15-29 years old, while arterial complications were 50% higher than VTE in women between 30 and 44 years of age. The mortality of arterial disease was 3.5 times higher than the number of deaths from venous disease in women below 30 years, and 8.5 times higher in women aged 30-44 years. The available scientific data suggests a differential influence of OCs with second and third generation progestagens on the risk of venous and arterial diseases. From this consensus, a low-dose OC was prescribed for young women without any known risk factor for thrombotic diseases. Women with a known risk factor for arterial thrombotic disease, a low-dose pill with a third generation progestogen, may have an advantage while a low-dose pill combined with a second generation progestogen was preferable for women with risk factors for venous disease. In women above 30 years, OCs with third generation progestagens generally seem to confer less overall thrombotic morbidity, mortality, and disability than OCs with second generation progestagens. These women should reconsider, however, the indication of combined OCs in the presence of significant risk factors of thrombotic diseases.

Estimates of the risk of cardiovascular death attributable to low-dose oral contraceptives in the United States.

OBJECTIVE: Our purpose was to estimate the annual risk of death in the United States from cardiovascular disease attributable to low-dose combination oral contraceptives. STUDY DESIGN: Estimates of the risk of death from cardiovascular disease attributable to low-dose oral contraceptives were modeled on data from studies published through 1997 and from age-specific mortality rates in the United States for 1993 and 1994. RESULTS: Attributable risk of death from cardiovascular disease resulting from oral contraceptive use is 0.06 and 3.0 per 100,000 nonsmokers 15 to 34 years of age and 35 to 44 years of age, respectively. In smokers this risk increases, respectively, to 1.73 and 19.4 per 100,000 users in these 2 age groups; however, 97% and 85% of this risk is due to the combined effects of smoking and using oral contraceptives. The attributable risk of death from cardiovascular disease in nonsmoking oral contraceptive users is lower than the risk of death from pregnancy in nonusers of oral contraceptives at all ages; however, among smoking oral contraceptive users more than 35 years of age, the excess risk of death from oral contraceptives is higher than the risk of death from pregnancy. CONCLUSION: There is virtually no excess attributable risk of death from cardiovascular disease related to oral contraceptive use in young women. However, smokers more than 35 years of age should use a nonestrogen contraceptive.

PIP: The annual risk of death in the US from cardiovascular disease attributable to low-dose combination oral contraceptives (OCs) was estimated through use of data from studies published in 1980-1997 and from age-specific mortality rates for 1993 and 1994. Four cardiovascular disease categories were included: myocardial infarction, venous thromboembolism and pulmonary embolism, ischemic stroke, and hemorrhagic stroke. The overall risk of death from cardiovascular disease among nonsmoking users of low-dose OCs is 0.06/100,000 women in the 15-34 year age group and 3.03/100,000 women in the 35-44 year age group. For young nonsmokers, the excess mortality risk associated with OC use is smaller than the risk of death from pregnancy, whether terminated by abortion or carried to term. Among OC users who smoke, the risk of cardiovascular mortality is 1.73/100,000 in 15-34 year olds and 19.4/100,000 in women 35-44 years old; however, 97% and 85% of this risk, respectively, is composed of the combined OC-smoking risk. Among smoking OC users over 35 years of age, the excess risk of death from OCs exceeds the risk of death from pregnancy. Young nonsmokers raise their risk of death from cardiovascular disease by less than 10% (0.60-0.65/100,000) by using OCs, while young women who do not use OCs increase their risk of death by 260% (0.60-1.57/100,000) by smoking cigarettes. For older women, the corresponding increases are 95% among nonsmoking OC users and 315% among smoking nonusers. These estimates indicate that women over 35 years of age who smoke should not be permitted to use either low- or high-dose OCs because of the excess attributable risk of death from cardiovascular disease.

Maximizing the use of the progestin minipill.

PIP: Although the progestin-only oral contraceptive (OC) is a safe, effective method for women who cannot use agents that include estrogen because they are breast-feeding or for another reason, it accounts for only 1-26% of the OC market in the US. The progestin-only OC is less effective than combined OCs, and about 5% of women who use rely on the progestin-only formulation and use it correctly will become pregnant in the first year. However, the added contraceptive effect of breast-feeding makes the method nearly 100% effective in lactating women. The progestin-only OC does not interfere with the quality or quantity of breast milk and causes fewer and milder side effects or adverse effects than combined OCs, with irregular bleeding being the most troublesome. The doses of progestin are even lower in the progestin-only OCs than in combined OCs, and the progestin is metabolized within 24 hours, so a back-up method of contraception must be used until the regular schedule has been reinstated for 48 hours if a woman misses a dose by more than 3 hours unless she is fully breast-feeding. The pills are taken daily, and the regimen can be started at any time in the menstrual cycle. Shorter and simpler labeling for the progestin-only OCs was accepted in 1995. The OCs can be given to women immediately postpartum and are a good choice for women who smoke or are over age 35 but should be avoided by women taking hepatic enzyme-inducing medications or by women with a history of gestational diabetes.^ieng

Does smoking affect efficacy of the pill? Ask the experts.

PIP: This article presents insights on the efficacy of oral contraceptives (OCs) in women who smoke. It presents opinions of three Contraceptive Technology Update board members, namely, Dr. Michael Rosenberg, Dr. Andrew Kaunitz, and Susan Wysocki. Two lines support that the anti-estrogenic effect of smoking reduces the effectiveness of OCs. First, several studies indicate that spotting and bleeding were more frequent in smokers. Smoking reduces estrogen levels in the body; hence smokers experience irregular bleeding with the pill. This is the reason why smokers are at a higher risk of developing osteoporosis in the later years. Breakthrough bleeding also demonstrates higher OC failure rates among smokers. A single study on the efficacy of OCs in smokers revealed a highly diminished effectiveness of the pill in this group. Second, laboratory analysis indicates that estrogen increases the catabolism of estrogen, providing a rationale for these observed effects. The use of low-dose pills in smokers is guided by safety concerns since smoking enhances the development of thrombosis. A balance of the safety and efficacy risks is necessary especially with the increasing use of low-dose OCs.^ieng

Finally, Japan swallows the pill.

PIP: The Health Minister, Sohei Miyashita, approved the production and sale of the low-dose oral contraceptive pill on June 16. The IUD with copper wire was also permitted. Both products will be sold in the market by Fall. Nine pharmaceutical companies filed applications for approval of manufacture and sale of pill between 1990 and 1991. Deliberations were suspended when the rate of HIV/AIDS infection increased because the pill was feared to lead a decrease in condom use. Critics also argued that it would lead to an increase in sexually transmitted diseases and unwanted side effects. The pill was defended against this charge by those who claimed that, as acquiring the pill would require a prescription, facilitating its availability would increase the number of women who would visit medical facilities and bring about a corresponding increase in the level of awareness of the dangers of infection. As to the pill¿s side effects, its defenders claimed that no other drug had been as extensively researched to reduce side effects as had the pill. Only after the drug to treat male erectile dysfunction, Viagra, had been approved did the pill regain attention. The Ministry of Health and Welfare has issued guidelines on the prescription and use of the pill in order to educate the public. What is important is that Japanese women now have the right to choose the pill as a contraceptive method. Places where they will be able to obtain the pill are also needed together with information and counseling on its use.^ieng

No link between OC use and heart attack.

PIP: A retrospective study conducted in England, Scotland, and Wales concluded that there is no significant increase in the risk of acute myocardial infarction (AMI/heart attack) in women who use modern low-estrogen dose oral contraceptives (OCs). The study matched 448 women aged 16-44 years who had suffered a heart attack with 1728 women in the control group. The leader of the study stated that women should be warned of the classical risk factors for AMI, particularly smoking, and not the OC that they are taking. Furthermore, researchers in the UK study revealed that of the women under age 45 years who suffered a heart attack, 87% were not taking an OC. Moreover, majority of these women had at least one or more known cardiovascular risk factors. In addition, the older studies clarified that the increase in risk for thrombotic diseases, including AMI, is applicable primarily to older high-dose OCs.^ieng

Efficacy, cycle control, and side effects of low- and lower-dose oral contraceptives: a randomized trial of 20 micrograms and 35 micrograms estrogen preparations.

Estrogen content represents a tradeoff between cycle control and side effects, but few direct comparisons of 20 and 30/35 micrograms preparations are available. To address this issue, we conducted a randomized, open-label multicenter clinical trial comparing Alesse (20 micrograms ethinyl estradiol [EE]), Mircette (20 micrograms EE), and Ortho Tri-Cyclen (35 micrograms EE) among 463 OC starters or switchers. Bloating, breast tenderness, and nausea were approximately 50% more common in women using 35 micrograms EE as compared to 20 micrograms EE preparations. Cycle control was similar in all products, although during the first two cycles among starters; users of Mircette and Ortho Tri-Cyclen (Tri-Cyclen) exhibited better cycle control than Alesse users. Discontinuation and pregnancy rates were not significantly higher in 35 micrograms EE users.

PIP: Estrogen content represents a tradeoff between cycle control and side effects, but few direct comparisons of 20 and 30/35 mcg preparations are available. To address this issue, researchers conducted a randomized, open-label multicenter clinical trial comparing Alesse (20 mcg ethinyl estradiol [EE]), Mircette (20 mcg EE), and Ortho Tri-Cyclen (35 mcg EE) among 463 oral contraceptive starters or switchers. Bloating, breast tenderness, and nausea were approximately 50% more common in women using 35 mcg EE as in those using 20 mcg EE preparations. Cycle control was similar in all products, although during the first two cycles among starters, users of Mircette and Ortho Tri-Cyclen (Tri-Cyclen) exhibited better cycle control than Alesse users. Discontinuation and pregnancy rates were not significantly higher in 35 mcg EE users.

Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study.

BACKGROUND: We have reported previously that, compared with use of second-generation oral contraceptives, the use of third-generation oral contraceptives is associated with increased resistance to the anticoagulant action of activated protein C (APC). Owing to the cross-sectional design of that study, these observations may have been subject to unknown bias or uncontrolled effects of the menstrual cycle. We aimed to overcome these sources of bias by doing a cycle-controlled randomised cross-over trial. METHODS: The response to APC in plasma was assessed in 33 women who received two consecutive cycles of a second-generation oral contraceptive (150 microg levonorgestrel and 30 microg ethinyloestradiol) or a third-generation oral contraceptive (150 microg desogestrel and 30 microg ethinyloestradiol), and who switched preparations after two pill-free cycles. Normalised APC sensitivity ratios were calculated by measurement of the effect of APC on thrombin generation in the plasma of these women and in pooled plasma from 90 controls. FINDINGS: Of the 33 women, five were excluded because not all required plasma samples were available. In the remaining 28 women, the normalised APC sensitivity ratio increased during treatment with both preparations. Compared with levonorgestrel, desogestrel-containing oral-contraceptive treatment caused a highly significant (p<0.0001) additional increase in normalised APC sensitivity ratio (0.51 [95% CI 0.37-0.66]). Normalised APC sensitivity ratios during oral-contraceptive treatment correlated with the values before oral-contraceptive use. INTERPRETATION: Oral-contraceptive treatment diminishes the efficacy with which APC down-regulates in-vitro thrombin formation. This phenomenon, designated as acquired APC resistance, is more pronounced in women using desogestrel-containing oral contraceptives than in women using levonorgestrel-containing preparations. Whether acquired APC resistance induced by oral contraceptives explains the increased risk of venous thromboembolism in oral-contraceptive users remains to be established.

PIP: This cycle-controlled randomized cross-over study examined the effects of a second-generation oral contraceptive (OC) containing levonorgestrel and a third-generation OC containing desogestrel on the anticoagulant action of activated protein C (APC) in the plasma. The response to APC in plasma was assessed in 28 women who received two consecutive cycles of a second-generation OC (150 mcg levonorgestrel and 30 mcg ethinyl estradiol) or a third-generation OC (150 mcg desogestrel and 30 mcg ethinyl estradiol), and who switched preparations after two pill-free cycles. Normalized APC sensitivity ratio was also taken from these women. Results showed that in the 28 women the normalized APC sensitivity ratio increased during treatment with both preparations. Compared with levonorgestrel, desogestrel-containing OC treatment caused a highly significant (p 0.0001) additional increase in normalized APC sensitivity ratio (0.51; 95% CI, 0.37-0.66). In conclusion, OC treatment diminishes the efficacy with which APC down-regulates in-vitro thrombin formation.