Vol. 13 Issue 2, Spring 2008
Barbour S. Warren, BCERF Research Associate and Carol M. Devine, Associate Professor, Division of Nutritional Sciences
Accompanying a societal shift to delayed childbearing, there has been an increase in the number of couples seeking infertility treatment. Most studies of the short-term effects of infertility treatment among women have indicated that it is generally not associated with the risk of breast cancer. A number of different drugs have been used in these treatments; some studies have examined these drugs for an association with breast cancer risk. To date, the results of these studies show conflicting results, and more study is needed before the presence or absence of breast cancer risk can be determined. The long-term effects of infertility treatments on breast cancer risk are unknown. Most studies to date have evaluated treatment of less than 10 years duration and groups of women at ages where breast cancer is less common. Monitoring of women who have received infertility treatments should continue.
Infertility is common condition. Estimates of the percentage of women of reproductive age (15 to 44) who have not conceived a child after 12 months of trying, range between 8% and 20% (1, 2). A significant contributor to these estimates is the societal shift toward delayed childbearing over the last three decades. This shift is made clear by the changes in age-specific birth rates. Between 1970 and 2005, the birth rate among women aged 20 to 24 years declined 39% and the rate among women 25 to 29 years declined 20%. In contrast, the birth rate increased among women 30-34 years by 31%, among women 35-39 years by 46%, and among women 40-44 years by 12%. (3). There was also an increase in late age at first birth (a risk factor for breast cancer). Over the 16-year period from 1970 to 1986, the number of first births to mothers in their 30s more than quadrupled, while first births to women between ages 40 and 44 doubled.
Maternal age plays an important role in infertility. As women age there is a stepped decrease in fertility. Women are most fertile around age 20. From this age fertility steadily declines to about age 35, at which point it transitions into a stage of rapid decline. This step is followed by a dramatic fall after age 40, such that the likelihood of a failed pregnancy at age 45 is 75%. This is a more than six times the risk for women under 20.
Use of fertility services has increased greatly since their introduction in the late 1960s. The use of fertility drugs increased 1.9 fold between 1973 and 1991. Data from a 1995 survey by the U.S. Centers for Disease Control indicated that 17% of women 25 to 34 sought infertility services of some type. This value increased to 23% for women between ages 35 and 45 (4).
Possible associations between infertility treatment and breast cancer risk: direct and indirect effects
A number of breast cancer risk factors can possibly come into play with regard to breast cancer risk and infertility treatment. Breast cancer risk may be increased by factors associated with pregnancy and childbirth themselves, or through direct effects of the infertility treatments. Breast cancer risk factors associated with pregnancy and childbirth include pregnancy itself, age at first birth and maternal age for subsequent births. Pregnancy, while ultimately protective against breast cancer risk for younger mothers, is associated with an increase in breast cancer risk for a period of about 10 years following childbirth (5). This effect is especially prominent and may last longer in mothers older than 35 years. Maternal age has further importance. Age of first birth is well established to be associated with breast cancer risk and is related to a progressive increase in risk. Relative risks as large as 3.7 fold have been reported for comparisons of women at the extremes of reproductive age (6). A recent study of a cohort of 1.5 million Danish women strongly supports the idea that, above and beyond the effects of a first birth, all births to older mothers are associated with increased breast cancer risk. The investigators reported that while childbirth among young mothers (age 25 to 30) was associated with a decrease in breast cancer risk, childbirth among women older than age 30 was associated with a progressive increase in breast cancer risk as age at childbirth increased. The level of increase depended on the birth number; that is first, second, third, etc., but increased risk was associated with all births (7).
Most studies have reported a weak or no relationship between infertility itself and breast cancer risk. In addition, studies of different types of infertility showed no consistent associations with breast cancer risk (8-13). Direct effects of infertility treatments may have a role in breast cancer risk. The major goal of most infertility treatments is the stimulation of ovulation resulting in, for most protocols, “superovulation,” the maturation and release of multiple eggs from the ovary. It is well recognized that breast cancer risk is higher in women who undergo more ovulation cycles over a lifetime (14). This effect may result from changes associated with ovulation, which might potentially be greater during superovulation cycles. Alternatively, or in addition, ovulation stimulation affects estrogen and progestin levels. This may be important because increased exposure to estrogens and progestins has been clearly linked to increased breast cancer risk (15). Commonly used infertility drugs, that contain or affect the release of hormones controlling ovulation, lead to increased levels of estrogens and progestins (16, 17). However, it has also been argued that such changes do not attain high enough hormone levels or extend long enough to be likely to cause such deleterious effects (18).
On the other hand, two of the commonly used infertility drugs, clomophene citrate and human chorionic gonadotrophin, have been considered as preventive treatments for breast cancer (19, 20). Clomophene citrate has a similar structure and activity to the estrogen antagonist, tamoxifen. Tamoxifen is commonly used for adjuvant treatment of breast cancer and clomophene citrate has also been used in this manner. Studies in animals indicate that human chorionic gonadotrophin, a hormone produced during pregnancy, can have a protective effect against breast cancer and such use has been proposed for humans (21). Thus, these fertility drugs could potentially decrease breast cancer risk.
Infertility treatment and breast cancer risk: many study types and designs
A diverse collection of studies has examined infertility treatments and breast cancer risk. This includes five clinical case reports (22-26), four case-control (retrospective) studies (17, 27-29) and 16 cohort (prospective) studies (8-11, 24, 30-40). The design of the studies differed greatly. They differed in the sources of study participants: some focused on women undergoing in-vitro fertilization, some collected subjects from infertility clinics in general, and others examined women in existing cohorts. Differences also existed in how information was collected. The most accurate studies used medical records, while others used questionnaires and interviews with the women themselves.
Determination of risk requires the use of a comparison group. For example, to ideally examine the effects of infertility treatments on breast cancer risk, a group of infertile women with breast cancer who had received infertility treatment would be compared to an identical group of infertile women without breast cancer who had not received infertility treatment. Assembly of these ideal comparison groups is not possible, but if enough information about the breast cancer risk factor profiles is collected for both groups, the comparison can be adjusted to account for group differences. Since infertility may affect breast cancer risk, better designed studies in this area used infertile women as a comparison group, others used the general population. Some studies also did a better job of adjusting for other differences in breast cancer risk. One key risk factor in these studies was whether the women in both groups had had children and if so how many. This factor could differ greatly between the treated and the comparison groups. Only a few studies did this careful analysis. Finally, the studies also differed to a large extent in the number of women with breast cancer who were included in the analysis. Risk is a statistical calculation and, in general, the more subjects examined the more reliable the results. Most of the studies were limited by the fact that they studied less than 50 cases of breast cancer. Only a few of the studies had more than 100 cases.
Results of existing studies
Overall, the majority of the studies of associations between infertility treatment and breast cancer risk did not detect an association between the two. The results of the largest and best designed studies supported this result. However, since the follow-up time for the majority of these studies was less than 10 years, these studies have really only evaluated the short-term effects of these treatments. This is all the more important as several studies found increased risk of breast cancer among women that were monitored for more than 20 years. Studies that examined the association of specific infertility drugs and treatments with breast cancer risk had conflicting and inconclusive results; some studies reported increased breast cancer risk, others decreased risk, and still others no risk association among women who had those specific treatments for infertility. Inconclusive results were also reported for the examination of the risks associated with treatment dosages and number of treatment cycles.
Need for continued monitoring
Continued monitoring of infertility treatments is warranted for two reasons. First, most of the existing studies had short follow-up periods. Second, the majority of the study groups included mostly premenopausal women. Since 80% of breast cancer cases occur after menopause, a change in risk may not yet be apparent. Finally, monitoring should also include evaluation of different drugs and treatments. While most of the treatments do act on the same pathway for control of reproduction, this pathway is complex and the treatments are diverse. This means that specific treatments could have different effects on breast cancer risk.