A primer on the hormone-free interval for combined oral contraceptives.

BACKGROUND: The dosing, schedules, and other aspects of combined oral contraceptive (COC) design have evolved in recent years to address a variety of issues including short- and long-term safety, bleeding profiles, and contraceptive efficacy. In particular, several newer formulations have altered the length of the hormone-free interval (HFI), in order to minimize two key undesired effects that occur during this time: hormone-withdrawal-associated symptoms (HWaS) and follicular development. OBJECTIVE: This primer reviews our current understanding of the key biological processes that occur during the HFI and how this understanding has led to changes in the dosing and schedule of newer COC formulations. MAIN MESSAGE: In brief, HWaS are common, underappreciated, and a likely contributor to COC discontinuation; because of this, shortening the HFI and/or supplementing with estrogen during the progestin-free interval may provide relief from these symptoms and improve adherence. A short HFI (with or without estrogen supplementation) may also help maintain effective follicular suppression and contraceptive efficacy, even when the overall dose of estrogen throughout the cycle is low. CONCLUSIONS: Taken together, the available data about HWaS and follicular activity during the HFI support the rationale for recent COC designs that use a low estrogen dose and a short HFI. The availability of a variety of COC regimens gives physicians a range of choices when selecting the most appropriate COC for each woman's particular priorities and needs.

New contraceptive eligibility checklists for provision of combined oral contraceptives and depot-medroxyprogesterone acetate in community-based programmes.

Community-based services (CBS) have long used checklists to determine eligibility for contraceptive method use, in particular for combined oral contraceptives (COCs) and the 3-month injectable contraceptive depot-medroxyprogesterone acetate (DMPA). As safety information changes, however, checklists can quickly become outdated. Inconsistent checklists and eligibility criteria often cause uneven access to contraceptives. In 1996, WHO produced updated eligibility criteria for the use of all contraceptive methods. Based on these criteria, new checklists for COCs and DMPA were developed. This article describes the new checklists and their development. Several rounds of expert review produced checklists that were correct, comprehensible and consistent with the eligibility requirements. Nevertheless, field-testing of the checklists revealed that approximately half (48%) of the respondents felt that one or more questions still needed greater comprehensibility. These findings indicated the need for a checklist guide. In March 2000, WHO convened a meeting of experts to review the medical eligibility criteria for contraceptive use. The article reflects also the resulting updated checklist.

Effect of 1995 pill scare on rates of venous thromboembolism among women taking combined oral contraceptives: analysis of general practice research database.

OBJECTIVE: To compare the incidence of venous thromboembolism among women taking combined oral contraceptives before and after the October 1995 pill scare. DESIGN: Analysis of General Practice Research Database. SETTING: United Kingdom, January 1993 to December 1998. SUBJECTS: Women aged 15-49 taking combined oral contraceptives. MAIN OUTCOME MEASURES: Incidence of venous thromboembolism. RESULTS: Use of so called "third generation" combined oral contraceptives fell from 53% during January 1993 to October 1995 to 14% during November 1995 to December 1998. There was no significant change in the incidence of venous thromboembolism between the two periods after age was adjusted for (incidence ratio 1.04, 95% confidence interval 0.78 to 1.39). CONCLUSIONS: The findings are not compatible with the assertion that third generation oral contraceptives are associated with a twofold increase in risk of venous thromboembolism compared with older progestogens.

PIP: In October 1995 the UK Committee on Safety of Medicines advised that combined oral contraceptives (OCs) containing either gestodene or desogestrel were associated with twice the risk of venous thromboembolism compared with older products. This study was conducted to compare the incidence of venous thromboembolism among women taking combined OCs before and after the October 1995 pill scare. Using data from the General Practice Research Database, a total of 304 practices were analyzed. Overall, results show that use of third-generation combined OCs fell from 53% during the period of January 1993 to October 1995 to 14% during the period of November 1995 to December 1998. No significant change was noted in the incidence of venous thromboembolism between the two periods after age was adjusted for (incidence ratio, 1.04; 95% confidence interval, 0.78-1.39). Based on these findings, it is concluded that third-generation OCs are not associated with a twofold increase in risk of venous thromboembolism compared with older progestogens.

Oral contraceptives and fatal pulmonary embolism.

In a national case-control study of fatal pulmonary embolism in New Zealand women of childbearing age, we estimated that current users of combined oral contraceptives had a relative risk of 9.6 (95% CI 3.1-29.1). From national distribution data, the absolute risk of death from pulmonary embolism in current users was estimated to be 10.5 per million woman-years.

PIP: This national case-control study examined relative risk of fatal pulmonary embolism in childbearing-aged New Zealand women who use combined oral contraceptives (OCs). A total of 36 cases were identified from deaths between January 1990 and August 1998. Information about medical and contraceptive histories from the group practice and any family planning clinic records, were obtained by the same approach for cases and controls. Overall, it was estimated that users of combined OCs had a relative risk of 9.6 (95% confidence interval, 3.1-29.1). However, from the national distribution data, the absolute risk of death from pulmonary embolism in users was estimated to be 10.5 (6.2-16.6) per million woman-years. This death rate was higher than expected, because the annual incidence of venous thromboembolism in OC users has been estimated at 1 or 2 per 10,000 women, with a case fatality rate of only 1-2%. Given these findings, the authors concluded that deaths from pulmonary embolism are rare among OC users, but the absolute risk should still be considered as clinically important and significant to public health.

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.

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.

Choices: "the pill" combined oral contraceptive.

PIP: This article offers substantial information on combined oral contraceptives (COCs). It is noted that such pills contain two hormones, an estrogen and a progestin. COCs prevent ovulation and make the lining of the uterus thinner, when correctly and consistently used, with a reported failure rate of 1/1000 women. An important benefit of COC use is that it decreases a woman's risk of ovarian cancer, endometrial cancer, benign breast masses, and ovarian cysts. Other advantages include a decrease in menstrual cramps and pain, reduction of menstrual blood loss and a woman's risk for anemia, and fertility control. Some of the disadvantages of COC use include side effects and lack of protection against HIV virus. In the US, these pills are available from doctors, nurse practitioners, nurse-midwives, health departments, and family planning clinics.^ieng

Importance of levonorgestrel dose in oral contraceptives for effects on coagulation.

Combined oral contraceptives show clear differences in effect on the tissue factor-initiated coagulation test of activated protein C resistance, which is dependent on the presence and dosage of levonorgestrel. Multiphasic levonorgestrol oral contraceptives differ from monophasic contraceptives and resemble third-generation contraceptives.

PIP: The significance of levonorgestrel dose in oral contraceptives for effects on coagulation is presented. A study in Germany was conducted to test the activated protein C resistance and assess the differences induced by various combined oral contraceptives (COCs). A resistance to activated protein C of monophasic COCs with desogestrel, gestodene, or norgestimate close to the value of women heterozygous for factor V Leiden was confirmed. Higher concentrations of levonorgestrel counteract the increase in resistance. Thus, monophasic and multiphasic COCs with levonogestrel were distinguished according to their effects on tissue-factor-initiated resistance to activated protein C. A more detailed comparison of in-vitro coagulation effects and epidemiology will further assess the plausibility and mechanisms of resistance in relation to activated protein C acquired by COC use and venous thromboembolism.

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.

Consensus conference on combination oral contraceptives and cardiovascular disease.

PIP: At the June 1998 conference of the International Federation of Fertility Societies (IFFS), a consensus was reached that there is no reason to advise selective prescribing of oral contraceptives (OCs) containing different progestins on the basis of their effects on cardiovascular disease. All currently available low-dose OCs, regardless of their progestin component, are more beneficial for a woman's short- or long-term health than the alternative of use of no contraception or use of a less effective method. The usual precautions in selecting appropriate candidates for OC use should be applied. This consensus was reached after several investigators presented the results of their studies on OC use and cardiovascular risk to an IFFS panel. Consolidation of the available research evidence produced annual cardiovascular mortality rates per 100,000 among women 15-24 years old of 1.2 in OC non-users, 2.1 in users of second-generation OCs, and 1.8-2.3 in users of third-generation OCs; among women 35-44 years old, these rates were 9.2, 20.4, and 15.5-17.8, respectively.^ieng

The differential risk of oral contraceptives: the impact of full exposure history.

Previous discussions have indicated that the small increases of risk of venous thromboembolism (VTE) associated with newer combined oral contraceptives (third generation, containing desogestrel and gestodene) may be attributed to bias due to cohort effects. In a case-control analysis, this may produce an overestimate of risk of newer preparations. In 10 centres in Germany and the UK, the Transnational Study analysed data from 502 women aged 16-44 years with VTE, and from 1864 controls matched for 5-year age group and region. Information on lifetime exposure history from all subjects was added to the dataset used in previous analyses and entered into a Cox regression model with time-dependent covariates. Based on 17 622 continuous exposure episodes comprising 47 914 person-years of observation, the adjusted hazard ratio (equivalent to odds ratio, OR) of VTE for the comparison of current users of third-generation versus current users of second-generation (primarily levonorgestrel compounds) combined oral contraceptives was 0.8 (0.5 to 1.3). The OR obtained in standard case-control analysis had been 1.5 (1.1 to 2.1). Adjustment for past exposures includes more information and appears more valid than the standard cross-sectional analysis. Using this approach, the Transnational Study data show no evidence for an increased risk of VTE with third- compared with second-generation combined oral contraceptives.

PIP: This transnational study examined the risk of venous thromboembolism (VTE) associated with combined oral contraceptives (OCs). The study analyzed data on 502 women aged 16-44 years with VTE and 1864 controls from 10 centers in Germany and the UK from 1 January, 1993, to 20 October, 1995. Information on lifetime exposure history from all subjects was added to the data set used in previous analyses and entered into a Cox regression model with time-dependent covariates. Based on 17,622 continuous exposure episodes comprising 47914 person-years of observation, the adjusted hazard ratio of VTE for the comparison of current users of third-generation versus current users of second-generation combined OCs was 0.8 (0.5-1.3). The OR obtained in standard case-control analysis had been 1.5 (1.1-2.1). Adjustment for past exposures includes more information and appears more valid than the standard cross-sectional analysis. Using this approach, the transnational study data show no evidence for an increased risk of VTE with third-generation compared with second-generation combined OCs.

Oral contraceptives and myocardial infarction: results of the MICA case-control study.

OBJECTIVES: To determine the association between myocardial infarction and use of different types of oral contraception in young women. DESIGN: Community based case-control study. Data from interviews and general practice records. SETTING: England, Scotland, and Wales. PARTICIPANTS: Cases (n=448) were recruited from women aged between 16 and 44 who had suffered an incident myocardial infarction between 1 October 1993 and 16 October 1995. Controls (n=1728) were women without a diagnosis of myocardial infarction matched for age and general practice. MAIN OUTCOME MEASURES: Odds ratios for myocardial infarction in current users of all combined oral contraceptives stratified by their progestagen content compared with non-users; current users of third generation versus second generation oral contraceptives. RESULTS: The adjusted odds ratio for myocardial infarction was 1.40 (95% confidence interval 0.78 to 2. 52) for all combined oral contraceptive users, 1.10 (0.52 to 2.30) for second generation users, and 1.96 (0.87 to 4.39) for third generation users. Subgroup analysis by progestagen content did not show any significant difference from 1, and there was no effect of duration of use. The adjusted odds ratio for third generation users versus second generation users was 1.78 (0.66 to 4.83). 87% of cases were not exposed to an oral contraceptive, and 88% had clinical cardiovascular risk factors or were smokers, or both. Smoking was strongly associated with myocardial infarction: adjusted odds ratio 12.5 (7.29 to 21.5) for smoking 20 or more cigarettes a day. CONCLUSIONS: There was no significant association between the use of oral contraceptives and myocardial infarction. The modest and non-significant point estimates for this association have wide confidence intervals. There was no significant difference between second and third generation products.

PIP: The association between myocardial infarction and use of oral contraceptives (OCs) was investigated in a case-control study conducted in England, Scotland, and Wales. 448 women 16-44 years old who had suffered an incident myocardial infarction during 1991-95 were identified from general practice records and matched by age and general practice with 1728 healthy controls. 85% of cases were not taking OCs in the 3 months before their myocardial infarction. The adjusted odds ratio (OR) for myocardial infarction was 1.40 (95% confidence interval [CI], 0.78-2.52) for all combined OC users, 1.10 (95% CI, 0.52-2.30) for users of second-generation formulations, and 1.96 (95% CI, 0.87-4.39) for third-generation OCs. Subgroup analysis by progestogen content did not show any significant difference from 1, and there was no effect of duration of OC use. 88% of cases had clinical cardiovascular risk factors or were smokers, or both. The adjusted OR for third-generation vs. second-generation OC users was 1.78 (95% CI, 0.66-4.83). The adjusted OR was 12.5 (95% CI, 7.29-21.5) among women who smoked 20 or more cigarettes a day. These findings indicate that OCs, including third-generation formulations, do not increase a woman's risk of myocardial infarction. Women who are concerned about their cardiovascular health should be urged to stop smoking, however.

Divergent effects of weight reduction and oral anticonception treatment on adrenergic lipolysis regulation in obese women with the polycystic ovary syndrome.

The influence of weight reduction and female sex hormones on the regulation of lipolysis was investigated in isolated abdominal sc adipocytes from 20 obese hyperandrogenic women with polycystic ovary syndrome (PCOS). Nine PCOS women were reinvestigated after 8-12 weeks of weight reduction therapy (WR) with a very low calorie diet, inducing a mean loss of 8 +/- 3 kg, and 8 PCOS women were reinvestigated after 12 weeks of treatment with combined oral contraceptives (OC), containing ethinyl estradiol and norethisterone; the remaining 3 subjects were drop-outs. Both WR and OC normalized hyperandrogenicity. WR caused a 50% reduction of basal lipolysis rate and a 5- to 7-fold increased noradrenaline and terbutaline sensitivity (P < 0.02); the latter could be ascribed to a 2-fold increased beta2-adrenoceptor density (P < 0.02) as determined with radioligand binding. There was no change with regard to dobutamine (beta1-adrenoceptor sensitivity) or clonidine, (alpha2-adrenoceptor sensitivity) or to beta1-adrenoceptor density. OC treatment did not influence the basal lipolysis rate or beta2- or alpha2-adrenoceptor sensitivity, but lowered the beta1-adrenoceptor sensitivity 7-fold (P < 0.03) without a reduction in beta1-adrenoceptor density. The OC treatment effect was not observed when forskolin and dibutyryl cAMP, acting on adenylate cyclase or protein kinase A, respectively, were used, suggesting a partial uncoupling of beta1-adrenoceptors. WR therapy, but not OC therapy, caused, in addition to changes in lipolysis function, improved in vivo insulin sensitivity and lower plasma noradrenaline levels. These findings suggest that factors other than hyperandrogenicity modulate lipolysis regulation in obese subjects with PCOS. Disturbances in sympathetic pathways could be of pathogenic importance.

Breast cancer risk: perception versus reality.

Evidence that breast cancer is hormonally mediated has fueled women's concern that use of oral contraceptives (OC) will increase their risk of developing the disease. A recent reanalysis of combined worldwide epidemiologic evidence regarding the relationship between breast cancer risk and use of combination OC provides reassurance that there is little or no association between OC use and breast cancer. Ten or more years after discontinuation of OC use, there is no difference in cumulative risk of breast cancer among OC ever-users and never-users. The risk of breast cancer diagnosis is slightly elevated in current OC users and remains slightly elevated until about 10 years after OC discontinuation. Once recency of use is taken into account, other characteristics have little additional effect. There is no increase in breast cancer risk with increasing dose or duration of OC use and no difference in risk related to type of estrogen or progestin used. Moreover, those breast cancers diagnosed in OC ever-users were found to be significantly more likely to be localized than those diagnosed in same-age never-users.

PIP: A recent survey of US women 40-50 years old with no history of breast cancer found that women's perceptions of their risk of developing and dying of breast cancer exceeded the actual risk. Evidence that breast cancer is hormonally mediated has raised concerns that oral contraceptive (OC) use increases a woman's risk of developing the disease. This concern has been fueled by the observation that the increasing diagnosis of breast cancer in many countries has occurred in tandem with widespread OC use. However, a reanalysis by the UK Imperial Cancer Research Fund Epidemiology Unit of worldwide epidemiologic data revealed little or no evidence of a link between OC use and breast cancer. 10 or more years after discontinuation of OCs, there is no difference in cumulative breast cancer risk between OC ever-users and nonusers. Breast cancer risk among ever-users was not affected by duration of OC use, age at first use, parity, family history, or the dose or type of OC. Moreover, breast cancers diagnosed in OC ever-users are significantly less advanced and more likely to be localized to the breast than those in never-users. It may be that current or recent OC users are receiving more breast examinations and therefore have the opportunity for early diagnosis and improved prognosis.

Oral contraceptive health benefits: perception versus reality.

Many women remain unaware of classic oral contraceptive (OC) noncontraceptive health benefits even as new health advantages emerge from experience and research. An extensive body of evidence has established that OC protect women against dysmenorrhea and menorrhagia, menstrual cycle irregularities, iron deficiency anemia, ectopic pregnancy, pelvic inflammatory disease, ovarian cysts, benign breast disease, endometrial cancer, and ovarian cancer. In addition, the FDA has stated for the first time that an OC-triphasic norgestimate/35 micrograms ethinyl estradiol--is an effective treatment for moderate acne vulgaris. OC use also appears to prevent osteopenia in hypoestrogenic women. In addition to these noncontraceptive health benefits, OC have proven valuable in the management of a variety of gynecologic disorders, including dysfunctional uterine bleeding, persistent anovulation, premature ovarian failure, functional ovarian cysts, pelvic pain (including secondary dysmenorrhea), mittelschmerz, endometriosis, and the control of bleeding in women with blood dyscrasias. Educating healthcare providers and women about these important noncontraceptive health benefits will result in increased compliance, greater continuation, and fewer unintended pregnancies.

PIP: Many US women remain unaware of the noncontraceptive health benefits associated with oral contraceptive (OC) use. An extensive body of research has established that OCs protect women against dysmenorrhea and menorrhagia, menstrual cycle irregularities, iron deficiency anemia, ectopic pregnancy, pelvic inflammatory disease, ovarian cysts, benign breast disease, and endometrial and ovarian cancer. More recent studies have suggested that OCs can be used for the treatment of acne vulgaris and the prevention of osteopenia in hypoestrogenic women. In addition to these classic and emerging noncontraceptive health benefits, many clinicians prescribe OCs for the treatment of common gynecologic conditions such as dysfunctional uterine bleeding, polycystic ovarian syndrome, premature ovarian failure, pelvic pain, mittelschmertz, endometriosis, and control of bleeding in women with blood dyscrasias. If OC acceptors are educated about these benefits, contraceptive compliance and continuation are likely to improve.

Patterns of contraception in UK women with Type 1 diabetes mellitus: a GP database study.

AIM: To establish the patterns of contraceptive prescribing for women aged 15-49 with Type 1 diabetes mellitus (DM) and compare them with the patterns in women without diabetes. METHODS: This was a cross-sectional study using a UK primary care database. RESULTS: Nine hundred and thirty-eight women with a diagnosis of Type 1 DM were identified. A comparison group of women aged 15-49 without diabetes (n = 10000) were randomly selected from the database. Twenty-five per cent of the women with diabetes and 32% without diabetes were prescribed a hormonal contraceptive in 1994. Women with Type 1 DM were more likely to be prescribed a combined oral contraceptive than a progestogen only pill (POP) but were 2.12 (95% CI 1.65-2.72) times more likely to be prescribed a POP than women without diabetes and were less likely to be prescribed a combined pill - odds ratio 0.53 (95% CI 0.44-0.64). The pregnancy rate in women with Type 1 DM over the age of 25 years was lower than for women without diabetes. Women under 25 years with Type 1 DM seemed more likely to record a pregnancy. CONCLUSIONS: Differences between women with Type 1 DM and those without diabetes highlight the variation in the way that GPs and patients evaluate the risks and benefits when deciding on contraception.

PIP: This cross-sectional study using a UK primary care database establishes the patterns of contraceptive prescribing for women aged 15-49 with Type 1 diabetes mellitus (DM) and compares them with the patterns in women without DM. A total of 938 Type 1 DM women were identified and a comparison group of women without diabetes (n = 10,000) were randomly selected from the database. Statistical analysis showed that 25% of the Type 1 DM women and 32% of those without diabetes were prescribed a hormonal contraceptive in 1994. Type 1 DM women were more likely to be prescribed a combined oral contraceptive than a progestogen-only pill (POP). However, they were 2.12 (95% CI, 1.65-2.72) times more likely to be prescribed a POP and less likely to be prescribed a combined pill (odds ratio, 0.53; 95% CI, 1.65-0.64) compared to women without diabetes. In addition, the pregnancy rates in Type 1 DM women over the age of 25 years were lower than in women without diabetes. This finding suggests that Type 1 DM women under age 25 appear more likely to record a pregnancy. In conclusion, differences between Type 1 DM women and those without diabetes highlight the variation in the way that general practitioners and patients evaluate the risks and benefits when deciding on contraception.

Contraception and cardiovascular disorders.

PIP: Prescribing contraceptives for women with underlying medical conditions requires careful attention from practitioners. This article reviews current knowledge on the metabolic effects and cardiovascular risks associated with use of combined oral contraceptives (OCs). OCs exert effects on lipids, high- and low-density lipid cholesterol, serum triglycerides, hemostasis, insulin resistance and hyperinsulinemia, and hypertension, all of which may have implications for ischemic heart disease, cerebrovascular accidents, and venous thromboembolism. Also discussed are alternative contraceptive methods for women with contraindications to OC use. Preconception counseling is especially important to provide women with information on the likely impact of their disease on pregnancy outcome and of pregnancy on their disease.^ieng

Decreased plasma tissue factor pathway inhibitor in women taking combined oral contraceptives.

Use of combined oral contraceptives (OC) is associated with a significant risk of thrombosis. The mechanisms of this effect are not clearly defined. Tissue factor pathway inhibitor (TFPI) is a circulating anti-coagulant that inhibits the earliest steps in activation of the extrinsic coagulation pathway. It plays a central role in control of coagulation but its contribution to the thrombotic risk associated with OC has not been assessed. Plasma TFPI antigen and activity, factor VIIa, prothrombin fragments 1&2, von Willebrand antigen, fibrinogen, and low density lipoprotein cholesterol were measured by standard assays in women taking OC (aged 16 to 45 years, n = 40) and age-matched women not taking OC (controls, n = 40). Plasma TFPI antigen did not vary significantly across the menstrual cycle in controls. Women on OC had a 25% reduction in plasma TFPI antigen (median 51.0 ng/ml; 95% confidence intervals [CI] 37.5 to 85.5; control 68.0 ng/ml, CI 61.0 to 95.0; P < 0.001) and a 29% reduction in TFPI activity (78.5 U/ml, CI 57.5 to 107.5; control 111.0 U/ml, CI 79.5 to 171.0; P < 0.001) compared to controls. Plasma factor VIIa activity and prothrombin fragments 1&2 were also significantly increased in women using OC (both P < 0.001), indicating activation of the extrinsic coagulation pathway. These results demonstrate that normal cyclic variations in estrogen and/or progesterone do not significantly alter plasma TFPI levels. However, estrogens and/or progestogens in OC result in activation of the extrinsic coagulation pathway and significantly reduce plasma TFPI, its major circulating inhibitor. Reduced plasma TFPI levels may underlie the thrombotic effects of OC.

PIP: This article reports the findings of a study that determined whether use of oral contraceptive (OC) is associated with significant changes in plasma tissue factor pathway inhibitor (TFPI), which may contribute to thrombotic risk. Plasma TFPI antigen and activity, factor VIIa, prothrombin fragments 1 and 2, von Willebrand antigen, fibrinogen, and low density lipoprotein cholesterol were measured by standard assays in 40 women aged 16-45 taking OCs and 40 age-matched women not taking OCs. Results revealed that the plasma TFPI antigen did not vary significantly across the menstrual cycle in controls. Women on OCs had a 25% reduction in plasma TFPI antigen (median, 51.0 ng/ml; 95% confidence interval (CI), 37.5-85.5; controls, 68.0 ng/ml; CI, 61.0-95.0) and a 29% reduction in TFPI activity (78.5 U/ml; CI, 57.5-107.5; controls, 111.0 U/ml; CI, 79.5-171.0) compared to controls. Plasma factor VIIa activity and prothrombin fragments 1 and 2 were also significantly increased in women using OCs, indicating activation of the extrinsic coagulation pathway. These results demonstrate that normal cyclic variations in estrogen and/or progesterone do not significantly alter plasma TFPI levels. However, estrogens and/or progesterone in OCs result in activation of the extrinsic coagulation pathway and significantly reduce plasma TFPI, its major circulation inhibitor. In conclusion, reduced plasma TFPI levels may underlie the thrombotic effects of OCs.

The trimonthly combination oral contraceptive regimen: is it cost effective?

The extended use of combination oral contraceptive pills (COCPs) to decrease the frequency of withdrawal bleeding can be convenient and beneficial to women. We conducted a cost-effective analysis comparing the standard regimen (21 days of estrogen/progestin) to a trimonthly regimen (84 days of estrogen/progestin) followed by a pill-free week for 1-year. The economic savings for patient out-of-pocket expenses from decreased sanitary product usage as a result of nine fewer withdrawal bleeding episodes is offset by the cost of three extra packages of COCPs from the trimonthly regimen. On the basis of an average use of 18 tampons per month, the trimonthly regimen is cost effective when the patient cost per package of pills is less than $9.45. The trimonthly regimen is also cost effective when the sanitary product usage is in the higher range; an above average use of 48 tampons per month is cost effective when the patient cost per package of pills is less than $25.20. Therefore, the trimonthly regimen may be useful for women with menorrhagia, but for the average women, the qualitative benefits of less frequent withdrawal bleeding need to be weighed against an increase in cost.

PIP: The extended use of combination oral contraceptives (COCs) to decrease the frequency of withdrawal bleeding can be convenient and beneficial to women. The authors conducted a cost-effective analysis comparing the standard regimen (21 days of estrogen/progestin) to a trimonthly regimen (84 days of estrogen/progestin) followed by a pill-free week for 1-year. The economic savings for patient out-of-pocket expenses from decreased sanitary product usage as a result of 9 fewer withdrawal bleeding episodes is offset by the cost of three extra packages of COCs from the trimonthly regimen. On the basis of an average use of 18 tampons per month, the trimonthly regimen is cost-effective when the patient cost per package of pills is less than $9.45. The trimonthly regimen is also cost-effective when the sanitary product usage is in the higher range; an above average use of 48 tampons per month is cost-effective when the patient cost per package of pills is less than $25.20. Therefore, the trimonthly regimen may be useful for women with menorrhagia, but for the average women, the qualitative benefits of less frequent withdrawal bleeding need to be weighed against an increase in cost.

Ovulatory potential of preovulatory sized follicles during oral contraceptive treatment.

The ovulatory potential of preovulatory follicles was studied in five women taking monophasic gestodene pills containing 20 micrograms of ethinyl estradiol. After one normal pill cycle, follicles were allowed to grow to 16 mm in diameter by deliberate extension of the pill-free period. Once the size of the leading follicle reached 16 mm, the women resumed oral contraceptives for the following 21 days to investigate whether ovulation can be inhibited by late onset of the pill. In addition, 100 micrograms of gonadotropin releasing hormone analog was given intravenously on the third pill day to induce ovulation. Follicular growth and activity were monitored by ultrasonography and by serum concentrations of ethinyl estradiol, progesterone, luteinizing hormone, and follicle stimulating hormone from the last pill day of the first cycle until the end of the second pill intake of 21 days. An increase in luteinizing hormone secretion started before intravenous administration of a gonadotropin releasing hormone analog in all women, eventually leading to ovulation in four of five women. One woman developed an unruptured follicle. Thus, the ovulatory potential of a 16-mm functional follicle cannot be inhibited by reintroduction of pills containing 20 micrograms ethinyl estradiol and 75 micrograms of gestodene.

PIP: The ovulatory potential of preovulatory follicles was studied in five women taking monophasic gestodene pills containing 20 mcg of ethinyl estradiol. After one normal pill cycle, follicles were allowed to grow to 16 mm in diameter by deliberate extension of the pill-free period. Once the size of the leading follicle reached 16 mm, the women resumed oral contraceptives for the following 21 days to investigate whether ovulation can be inhibited by late onset of the pill. In addition, 100 mcg of gonadotropin releasing hormone analog was given intravenously on the third pill day to induce ovulation. Follicular growth and activity were monitored by ultrasonography and by serum concentrations of ethinyl estradiol, progesterone, luteinizing hormone, and follicle stimulating hormone from the last pill day of the first cycle until the end of the second pill intake of 21 days. An increase in luteinizing hormone secretion started before intravenous administration of a gonadotropin releasing hormone analog in all women, eventually leading to ovulation in four of five women. One woman developed an unruptured follicle. Thus, the ovulatory potential of a 16-mm functional follicle cannot be inhibited by reintroduction of pills containing 20 mcg ethinyl estradiol and 75 mcg of gestodene.