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Oral Contraceptives and Cancer Risk - Illustrated Article

Oral contraceptives (OCs) first became available to American women in the early 1960s. The convenience, effectiveness, and reversibility of action of birth control pills (popularly known as "the pill") have made them the most popular form of birth control in the United States. However, concerns have been raised about the role that hormones play in a number of cancers, and how hormone-based OCs might contribute to their development.

This fact sheet addresses only what is known about OC use and the risk of developing cancer. It does not deal with the role of hormones in postmenopausal hormone therapy or the most serious side effect of OC use-the increased risk of cardiovascular disease for certain groups of women.

Oral Contraceptives
Currently, two types of OCs are available in the United States. The most commonly prescribed OC contains two man-made versions of natural female hormones (estrogen and progesterone) that are similar to the hormones the ovaries normally produce. Estrogen stimulates the growth and development of the uterus at puberty, causes the endometrium (the inner lining of the uterus) to thicken during the first half of the menstrual cycle, and causes changes in breast tissue at puberty and at childbirth.

Progesterone, which is produced during the last half of the menstrual cycle, prepares the endometrium to receive the egg. If the egg is fertilized, progesterone secretion continues, preventing release of additional eggs from the ovaries. For this reason, progesterone is called the "pregnancy-supporting" hormone, and scientists believe that it has valuable contraceptive effects. The man-made progesterone used in OCs is called progestogen or progestin.

The second type of OC available in the United States is called the minipill. It contains only a progestogen. The minipill is less effective in preventing pregnancy than the combination pill, so it is prescribed less often.

Because medical research suggests that cancers of the female reproductive organs depend on naturally occurring sex hormones for their development and growth, scientists have been investigating a possible link between OC use and cancer risk. Researchers have focused a great deal of attention on OC users over the past 40 years. This scrutiny has produced a wealth of data on OC use and the development of certain cancers, although results of these studies have not always been consistent.

Breast Cancer
A woman's risk of developing breast cancer depends on several factors, some of which are related to her natural hormones. Hormonal factors that increase the risk of breast cancer include conditions that allow high levels of hormones to persist for long periods of time, such as early age at first menstruation (before age 12), late age at menopause (after age 55), having children after age 30, and not having children at all. A woman's risk of breast cancer increases with the amount of time she is exposed to hormones.

Because many of the risk factors for breast cancer are related to natural hormones, and because OCs work by manipulating these hormones, there has been some concern about the possible effects of medicines such as OCs on breast cancer risk, especially if women take them for many years. Sufficient time has elapsed since the introduction of OCs to allow investigators to study large numbers of women who took birth control pills for many years, beginning at a young age, and to follow them as they became older. Two major studies are described below.

Women's CARE Study
The Women's Contraceptive and Reproductive Experience (Women's CARE) study examined the use of OCs as a risk factor for breast cancer in women ages 35 to 64. Researchers interviewed 4,575 women who were diagnosed with breast cancer between 1994 and 1998, and 4,682 women who did not have breast cancer. Investigators collected detailed information about the participants' use of OCs, reproductive history, health, and family history. The results, which were published in 2002, indicated that current or former use of OCs among women ages 35 to 64 did not significantly increase the risk of breast cancer. The findings were similar for white and black women. Factors such as longer periods of use, higher doses of estrogen, initiation of OC use before age 20, and OC use by women with a family history of breast cancer were not associated with an increased risk of the disease. The data also provided evidence that former OC use does not increase the risk of breast cancer later in life.

Collaborative Group on Hormonal Factors in Breast Cancer Study
A 1996 analysis of worldwide epidemiologic data found that women who were current or recent users of birth control pills had a slightly elevated risk of developing breast cancer. However, 10 years or more after they stopped using OCs, their risk of developing breast cancer returned to the same level as if they had never used birth control pills.

To conduct this analysis, the researchers examined the results of 54 studies conducted over the previous 25 years. The analysis involved 53,297 women with breast cancer and 100,239 women without breast cancer. More than 200 researchers participated in this combined analysis of their original studies, which represented about 90 percent of the epidemiological studies throughout the world that had investigated the possible relationship between OCs and breast cancer.

The return of risk to normal levels after 10 years or more of not taking OCs was consistent regardless of family history of breast cancer, reproductive history, geographic area of residence, ethnic background, differences in study design, dose and type of hormone, and duration of use. The change in risk also generally held true for age at first use; however, for reasons that were not fully understood, there was a continued elevated risk among women who had started to use OCs before age 20.

OCs and Collaborative Analyses of Breast Cancer in Younger Women
Although in general there does not appear to be an association between OC use and most breast cancers, OC use may increase the risk of early-onset breast cancer (breast cancer that is diagnosed before age 40). Data from collaborative analyses have suggested that OC use is most strongly related to breast cancer in younger women. These findings indicate that OCs may promote the growth of newly developing tumors.

Ovarian and Endometrial Cancers
Studies have consistently shown that using OCs reduces the risk of ovarian cancer. Researchers estimate that the risk is reduced by 5 to 10 percent for each additional year of use. For example, the Cancer and Steroid Hormone Study (CASH), which was conducted by the Centers for Disease Control and Prevention, found that the longer a woman had used OCs, the lower her risk of ovarian cancer. The decrease in risk persisted long after OC use stopped. The risk-reducing effect of OCs appeared in both older and younger women, and in women with and without children. At this time, it is uncertain whether the effect occurs in women who have certain genetic changes that make them more susceptible to developing ovarian cancer. Several hypotheses have been offered to explain how oral contraceptives might protect against ovarian cancer, such as a reduction in the number of ovulations a woman has during her lifetime, but the exact mechanism is still not known.

Researchers have also found that OC users have a reduced risk of endometrial cancer. Findings from the CASH study and other reports show that combination OC use can protect against the development of endometrial cancer. The level of risk reduction is greater in women who have used OCs for a longer time, and the protection apparently persists after women have stopped taking OCs.

The reduction in risk of ovarian and endometrial cancers from OC use does not apply to the sequential type of pill, in which each monthly cycle contains 16 estrogen pills followed by 5 estrogen-plus-progesterone pills. (Sequential OCs were taken off the market in 1976, so few women have been exposed to them.) Researchers believe OCs reduce ovarian and endometrial cancer risk only when the estrogen content of birth control pills is balanced by progestogen in the same pill.

Cancer of the Cervix
There is some evidence that long-term use of OCs may increase the risk of cancer of the cervix (the narrow, lower portion of the uterus). The results of studies conducted by National Cancer Institute scientists and other researchers support a relationship between extended use of the pill (5 or more years) and a slightly increased risk of cervical cancer. However, the exact nature of the association between OC use and risk of cervical cancer remains unclear.

One reason that the association is unclear is that two of the major risk factors for cervical cancer (early age at first intercourse, especially age 16 or younger, and a history of multiple sex partners) are related to sexual behavior. Because these risk factors may be different between women who use OCs and those who have never used them, it is difficult for researchers to determine the exact role that OCs may play in the development of cervical cancer.

Human Papillomavirus
The two major risk factors mentioned above that contribute to the development of cervical cancer are also risk factors that contribute to the development of human papillomavirus (HPV) infection in the cervix. Of the more than 100 types of HPV, over 30 types can be passed from one person to another through sexual contact. HPV is one of the most common sexually transmitted diseases. Certain HPVs, particularly HPV type 16, are known to cause cervical cancer. Compared to non-OC users, women who use OCs may be less likely to use barrier methods of contraception (such as condoms). Because condoms are partially effective in preventing HPV infection, OC users who do not use condoms may be at increased risk of becoming infected with HPV. Therefore, the increased risk of cervical cancer that some studies found to be caused by prolonged OC use may actually be the result of HPV infection.

Researchers are studying whether other factors such as multiple births and the use of OCs work together with sexually transmitted agents (such as HPVs) in the development of cervical cancer. Findings from an analysis of 10 studies suggested that long-term use of OCs may increase the risk of cervical cancer by up to 4 times in women who are infected with HPV. Researchers continue to investigate the exact nature of the relationship between OC use and cancer of the cervix.

OC product labels have been revised to inform women of the possible risk of cervical cancer. The product labels also warn that birth control pills do not protect against human immunodeficiency virus (HIV) and other sexually transmitted diseases such as HPV, chlamydia, and genital herpes.

Liver Tumors
There is some evidence that OCs may increase the risk of certain malignant (cancerous) liver tumors. However, the risk is difficult to evaluate because of different patterns of OC use and because these tumors are rare in American women (the incidence is approximately 2 cases per 100,000 women). A benign (non-cancerous) tumor of the liver called hepatic adenoma has also been found to occur, although rarely, among OC users. These tumors do not spread, but they may rupture and cause internal bleeding.

Reducing Risks Through Screening
Studies have found that breast cancer screening with mammograms reduces the number of deaths from breast cancer for women age 40 to 69. Women who are at increased risk for breast cancer should seek medical advice about when to begin having mammograms and how often to be screened. A high-quality mammogram, with a clinical breast exam (an exam done by a professional health care provider), is the most effective way to detect breast cancer early.

Abnormal changes in the cervix can often be detected by a Pap test and treated before cancer develops. Women who have begun to have sexual intercourse or are age 21 should check with their doctor about having a Pap test.

Women who are concerned about their risk for cancer are encouraged to talk with their health care provider.

Source: National Cancer Institute

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