Reproductive factors and subtypes of breast cancer defined by hormone receptor and histology.

Reproductive factors are associated with reduced risk of breast cancer, but less is known about whether there is differential protection against subtypes of breast cancer. Assuming reproductive factors act through hormonal mechanisms they should protect predominantly against cancers expressing oestrogen (ER) and progesterone (PR) receptors. We examined the effect of reproductive factors on subgroups of tumours defined by hormone receptor status as well as histology using data from the NIHCD Women's Contraceptive and Reproductive Experiences (CARE) Study, a multicenter case-control study of breast cancer. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) as measures of relative risk using multivariate unconditional logistic regression methods. Multiparity and early age at first birth were associated with reduced relative risk of ER + PR + tumours (P for trend=0.0001 and 0.01, respectively), but not of ER - PR - tumours (P for trend=0.27 and 0.85), whereas duration of breastfeeding was associated with lower relative risk of both receptor-positive (P for trend=0.0002) and receptor-negative tumours (P=0.0004). Our results were consistent across subgroups of women based on age and ethnicity. We found few significant differences by histologic subtype, although the strongest protective effect of multiparity was seen for mixed ductolobular tumours. Our results indicate that parity and age at first birth are associated with reduced risk of receptor-positive tumours only, while lactation is associated with reduced risk of both receptor-positive and -negative tumours. This suggests that parity and lactation act through different mechanisms. This study also suggests that reproductive factors have similar protective effects on breast tumours of lobular and ductal origin.

Hormone replacement therapy. Current controversies.

Hormone replacement therapy has had a controversial history since its introduction for medical use several decades ago. Current evidence indicates that users of hormone replacement therapy have an increased risk of venous thromboembolism, stroke, and coronary heart disease compared to non-users. Among users, the risk of breast cancer is modestly increased. This effect becomes apparent after 4 to 5 years use and primarily with use of combination estrogen plus progestin products. The risk of colorectal cancer is decreased with use of hormone replacement therapy. In addition, the risk of osteopenia and osteoporosis is decreased as is the risk of osteoporotic fracture.

Pharmacologic characteristics of progestins used for contraception and hormone replacement therapy, including new transdermal technologies.

Structural differences among progestins account for their unique properties. Pharmacologic principles should be used when considering the appropriate progestational agent to achieve both clinical and economic outcomes. Use of the same progestin in oral contraceptives (OCs) and hormone replacement therapy (HRT) allows for a seamless transition from OCs to HRT, while maintaining the health benefits of the OC. A pharmacologically based approach also has been used in developing the first transdermal contraceptive system, which is expected to be on the market in early 2002.

Managing the transition from oral contraceptives to hormone replacement therapy.

Oral contraceptives provide multiple benefits for perimenopausal women; their use results in considerable economic savings by managing vasomotor symptoms, preventing pregnancy, and improving future outcomes. Hormone replacement therapy provides many health benefits for menopausal women; a recently introduced constant estrogen/intermittent progestin regimen takes advantage of receptor dynamics and the extended half-life of norgestimate to provide a continuous progestational effect on the endometrium. The lower progestin dose may also decrease progestin-related side effects and contribute to increased adherence and treatment continuation.

Current perspectives on oral contraceptive use.

Oral contraceptives are one of the most highly effective forms of contraception and provide many short- and long-term noncontraceptive health benefits. They control menstrual cycle irregularities, such as breakthrough bleeding and amenorrhea, and are effective in treating dysfunctional uterine bleeding. In addition, for decades after oral contraceptive use is discontinued they are associated with substantial decreases in the risk of ovarian cancer (up to 80%) and of endometrial cancer (40%-50%), and nearly eliminate benign functional ovarian cysts. Long-term oral contraceptive use confers protection against benign breast disease and colorectal cancer, may help prevent rheumatoid arthritis, decreases ectopic pregnancy and hospitalizations for pelvic inflammatory disease, and helps preserve bone mineral density to reduce risk of fractures. Large bodies of evidence from extensive research have clarified the perceived association of oral contraceptive use with cardiovascular disease and with breast cancer. Findings indicate that there is no increased risk of myocardial infarction or stroke associated with oral contraceptive use in healthy, nonsmoking, normotensive women. Although there is a 3- to 4-fold increased risk of venous thromboembolism with current oral contraceptive use, the absolute risk is very small and is half that associated with pregnancy. Women of all reproductive ages, including perimenopausal women, can realize many health benefits through oral contraceptive use, including improved health status later in life.

Current perspectives on benefits and risks of hormone replacement therapy.

Hormone replacement therapy with estrogen alone or with added progestin relieves menopausal symptoms and physical changes associated with depleted endogenous estrogen levels. Estrogen replacement has also demonstrated a clear benefit in the prevention of osteoporosis. Hormone replacement therapy with added progestin maintains spinal bone density, protects against postmenopausal hip fractures, and provides these benefits even when therapy is started after age 60. More recently, additional benefits have emerged. Current estrogen and hormone replacement therapy users have a 34% reduction in the risk of colorectal cancer and a 20% to 60% reduction in the risk of Alzheimer's disease. Until recently, the body of evidence indicated that hormone replacement therapy with estrogen only reduced cardiovascular disease risk by 40% to 50% in healthy patients; whether the findings of 3 ongoing trials will change this conclusion is pending availability of the final results. The many benefits of estrogen and hormone replacement therapy must be weighed against a slight increase in the risk of breast cancer diagnosis with use for 5 or more years, but which disappears following cessation of therapy. Overall, estrogen and hormone replacement therapy improves the quality of life and increases life expectancy for most menopausal women.

Oral contraceptives: current status.

During the past four decades, oral contraceptives have remained a safe and effective method of birth control. Reductions in the estrogen and progestin dosages have significantly decreased the incidence of cardiovascular complications. The association between oral contraceptives and breast cancer appears to be primarily because of detection bias or possibly a promotional effect. Despite the changes in formulation, the problems related to side effects have not been totally solved. Because compliance and successful use is strongly affected by side effects, improvement in this area is probably the biggest challenge faced by developers of oral contraceptives. It is also clear that there are a growing number of significant noncontraceptive benefits that accrue in oral contraceptive users. Unfortunately, many women do not know about these benefits. Thus, one of the issues that providers need to continue to address is how to provide better information about oral contraceptives and contraception in general to patients.

Health economics of contraception.

Health economic analyses evaluate interventions from the standpoint of effectiveness and cost, important considerations in today's healthcare environment. Use of analytic cost-effectiveness approaches allows decision-makers to evaluate interventions in a more rational manner. With the use of sensitivity techniques, various scenarios can be evaluated, particularly as they relate to questions that have significant uncertainty. To date, there has been limited application of these methods to the area of contraception.

Contraceptive compliance.

Contraceptives are very effective when used and taken properly. Their effectiveness is limited by patient compliance with the prescribed regimens and contributes to unintended pregnancies. Multiple theories and models have been developed to address the issue of contraceptive compliance. This article will examine the consequences of noncompliance, potential reasons for noncompliance, and strategies for improving compliance in individual patients.

Cardiovascular issues with oral contraceptives: evidenced-based medicine.

Recent studies of current oral contraceptives indicate that the risk of cardiovascular sequelae is low in young (age 20-24 years) reproductive-aged women. Venous thromboembolism remains the one event that occurs in users independent of the presence of risk factors. However, the attributable risk is small, in the range of 7 to 18 events per 100,000 women annually. This risk is proportional to estrogen dose until the level of 30-35 microg is reached; type of progestin may also influence risk, though recent studies are controversial. Modifiable risk factors for venous thromboembolism include the presence of hemostatic disorders, especially factor V Leiden, and perhaps obesity. Stroke is even more uncommon, with an attributable risk of about 1.5 events per 100,000 women annually. Cigarette smoking and hypertension are modifiable risk factors for both ischemic and hemorrhagic stroke; use of preparations with 50 microg of estrogen or higher and migraine headaches are risk factors for ischemic stroke. Eliminating risk factors among users substantially reduces the risk of ischemic stroke and virtually eliminates the risk of hemorrhagic stroke. Myocardial infarction is rare among young women, occurring at a rate of about 0.2 event per 100,000 women annually. Oral contraceptive users who are non-smoking and normotensive do not have an increased risk of myocardial infarction. However, the presence of these risk factors along with age acts synergistically to increase the risk among oral contraceptive users.

Compliance and other issues in contraception.

About 5% of women in the United States (approximately three million) are not using contraception despite being at risk of unintended pregnancy. Teenagers have the highest rate of unintended pregnancy. Women 40 years and older most frequently terminate unintended pregnancy. Multiple theories and models, including the health belief model, the health decision model, the Prochaska change model, and the conviction-confidence model, have been developed to address choices and change in health behavior. Despite this information, current data on contraceptive compliance show considerable need for improvement. Side effects and patients' beliefs and preferences appear to influence strongly whether a method will be used appropriately. Systems improvements that address issues such as access and enhancement of provider-patient interaction appear to be areas of potential opportunity. Despite continued need for improvement, there is a paucity of information testing new approaches to improve contraceptive compliance.

The intrauterine contraceptive device: an often-forgotten and maligned method of contraception.

Although 90% of women at risk for unintended pregnancy in the United States use contraception, <1% of these women use the intrauterine contraceptive device. The mechanism of action of intrauterine contraceptive devices has been controversial, but several studies suggest that interference with sperm migration or function and with fertilization may be the most likely mechanisms. More important, there is lack of compelling evidence that the intrauterine contraceptive device acts as an abortifacient. The risk for pelvic inflammatory disease among users now appears to be extremely low, primarily as a result of better selection of candidates. A levonorgestrel-releasing intrauterine contraceptive device may offer some new therapeutic approaches for the treatment of certain gynecologic disorders. Although women who are not at risk for pelvic inflammatory disease or sexually transmitted diseases are appropriate candidates for the intrauterine contraceptive device, it appears that use can be expanded to selected nulliparous women and women with certain medical conditions.

Oral contraceptives: an update.

Oral contraceptives are used by large numbers of reproductive-aged women across the world. Recent data examining cardiovascular risk indicates a persistent risk for venous thromboembolism among all oral contraceptive users. This risk is enhanced by the presence of hemostatic disorders such as factor V Leiden. Whether the progestins gestodene and desogestrel also affect the risk of venous thromboembolism is controversial. Ischemic stroke is rare among users unless they smoke or have hypertension. Similarly, there appears to be no increased risk of hemorrhagic stroke among oral contraceptive users who do not have these risk factors present. Myocardial infarction is rare among oral contraceptive users. However, cigarette smoking coupled with age acts synergistically to substantially increase the risk of this disorder among oral contraceptive users. There is a small increase in risk of breast cancer among oral contraceptive users, although the risk disappears about 10 years after the last use of these preparations. Successful use of oral contraceptives appears to be significantly affected by side effects, understanding of the package insert and time of pill taking. Since serious sequelae are uncommon, improved compliance may be the most important challenge towards improving the use of oral contraceptives for the future.

Contraceptive sterilization: trends, options, and surprising new data.

PIP: In the US, 24% of women aged 15-50 rely on female or male sterilization for contraception. While all methods of sexual sterilization are highly effective, new data indicate that the risk of pregnancy after female sterilization varies according to type of procedure performed and the woman's age, but at 18.5/1000 procedures the risk is higher than previously believed. About 30% of all tubal sterilization failures result in ectopic pregnancy, with the greatest risk occurring 2-3 years after the procedure. Female sterilization can be performed at a time unrelated to conclusion of pregnancy or during the postpartum or postabortion periods using the minilaparotomy or laparoscopy surgical approach and surgical ligation or mechanical or electrical occlusion. Location of the vasa deferentia for occlusion in vasectomy can be achieved through two small incisions or with the no-scalpel method. Various methods are used to achieve occlusion. With a first-year pregnancy rate of only 0.15%, vasectomy is superior to female sterilization in terms of efficacy, safety, procedural complexity, and cost. The disadvantages of female sterilization include regret, the rare occurrence of surgical complications, a small risk of death (4/100,000), an increased risk of subsequent hysterectomy among younger women undergoing tubal ligation, and menstrual pain. Tubal sterilization, however, may protect against ovarian cancer. The few disadvantages associated with vasectomy include the small risk of immediate complications and regret. Because of the permanent nature of sterilization, effective counseling is important and should include presentation of information about the reversible, longterm contraceptive methods available to women.^ieng

The estrogen component of OCs: cardiovascular benefits and risks.

The relationship of oral contraceptive (OC) use to risk of venous thrombolism, stroke, and myocardial infarction continues to be evaluated. The estrogen component of combination OCs, which is primarily responsible for maintaining the endometrium and minimizing breakthrough bleeding (BTB) and spotting, was the initial focus of clinical and epidemiologic interest following early reports of an increased risk of vascular events with high-estrogen-dose formulations. OC estrogen continues to hold attention; current areas or interest include the relationship of estrogen to laboratory changes in hemostatic, lipid/lipoprotein, and carbohydrate variables, and, more important, to their possible clinical consequences. The historical view that OC-induced lipoprotein changes are responsible for observed increases in vascular risk in OC users is being debated, but the preponderance of evidence suggests that CO-related vascular disease is most likely due to thrombosis rather than atherosclerosis. This issue is made somewhat moot, however, by cumulative epidemiologic data indicating that although some combination OCs containing < or = 35 micrograms estrogen appear to produce a slight increase in the risk of venous thromboembolism, they have no adverse effect on the risk of myocardial infarction and minimal, if any, effect on the risk of stroke. The risks that may be associated with cigarette smoking and concomitant OC use have recently emerged as a somewhat contested issue relative to estrogen dose. Critical examination of the available information suggests that women over 35 years of age who smoke should be advised to use non-estrogen contraceptive methods and that smokers under age 35 may use any OC containing < 50 micrograms estrogen.

Practice guidelines for OC selection: update.

PIP: This report updates practice guidelines for oral contraceptive (OC) selection developed by US clinicians and researchers in 1996 on the basis of clinical experience, expert opinion, and a review of the research literature. The update was necessitated by the availability of new OC formulations, increased awareness of the range of noncontraceptive benefits of OCs, and emerging evidence linking OCs to cardiovascular and breast cancer risks. To facilitate the review, available OCs are categorized on the basis of low, medium, or high androgenic activity of the progestin component. Overall, the report recommends OC use as a first-choice method unless a woman has a clear contraindication, suffers intolerable side effects despite changes in the type of progestin or dose, or has difficulty taking the tablets consistently. Tables included in this report present the estrogen and progestin doses in all OCs currently available in the US; set forth guidelines for OC selection for different categories of women (e.g., adolescent, postpartum, perimenopausal) and to minimize OC-related side effects and adverse health effects; and offer recommendations to guide the formulation selection in women with pre-existing medical conditions, menstrual disorders, and other reproductive health problems.^ieng