Ashim Final Figure 1

More than 10 million women in the United States (almost 20% of women between the ages of 15 and 44) take birth control pills as a means of contraception []. In 2013, more than 2.9 million American women were living with breast cancer, almost 300,000 women were diagnosed with breast cancer, and nearly 40,000 women lost their lives to breast cancer []. Troublingly, many studies spanning five decades have suggested that certain kinds of birth control pills may be increasing the risk of breast cancer. So, what exactly is known about the link between birth control pills and breast cancer?

Figure 1 ~ Multiple types of birth control pills available in the market. Images from [14,15,16]

Birth control pills – what are they, and how do they work?

Birth control pills come in various forms. The two most common forms contain either synthetic versions of the hormones estrogen and progestogen (sometimes referred to as progesterone or progestin) and are known as the “combined oral contraceptive pill,” or they contain progestogen only and are called the “minipill.” There are currently multiple types of these two common forms on the market (referred to as 1st-4th generation and mono-/multi-phasic) that differ in their doses and in the synthetic formulations of the two hormones []. The high dose pills contain over 50 micrograms of estrogen, moderate dose pills contain 30-35 micrograms of estrogen, and the low dose pills contain 20 micrograms of estrogen.

Despite the wide variation in specific composition, all currently available pills work primarily by preventing ovulation. During a normal menstrual cycle, the level of the hormone estrogen and progestogen surges mid-cycle. This causes the pituitary gland to release two hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which then cause the ovary to release a mature egg (ovulation). Birth control pills maintain a high concentration of estrogen and progesterone in the bloodstream, thereby preventing the hormones from peaking mid-cycle and thus blocking the release of FSH and LH from the pituitary gland and inhibiting ovulation []. In addition, the pills thicken the cervical mucus so that sperm cannot penetrate the cervical wall to get into the uterus, which also helps prevent fertilization [].

Figure 2 ~ How birth control pills work. (A) Birth control pills maintain high levels of estrogen and progestogen in the blood stream and inhibit release of hormones FSH and LH by pituitary gland, thus preventing ovulation. (B) Progestogen in the pills thickens the cervical mucus. Consequently, sperm cannot penetrate the uterine wall to reach the egg. Images from [17,18,19]

Hormones: Yin and Yang

Estrogen and progestogens are essential steroid hormones. In women, they are required for normal development of female sex organs and secondary sex characteristics, regulation of the menstrual cycle and reproduction, and many other essential physiological functions in the bones, brain, breasts, adipose tissue, and uterus.

However, many epidemiological studies have shown that prolonged exposure to estrogens may increase the risk of breast cancer. Longer lifetime exposure to high levels of these hormones due to early age at first menstruation and late age of menopause has been associated with increased risk of breast cancer []. Similarly, epidemiological observational studies and the Women’s Health Initiative clinical trial have shown that the combination estrogen and progestogen hormone therapy used to treat menopausal symptoms and osteoporosis in post-menopausal women increases the risk of breast cancer [].

Figure 3 ~ Estrogen and progestogens are required for normal development and function of multiple tissues. However, estrogen can also promote breast cancer development mostly via activation of growth factor pathways that prompt cells to divide. Images from [20,21,22,23,24,25].

In a laboratory setting, estrogen has been shown to be involved in the development and growth of breast cancer. Exposure to estrogen transforms normal breast cells into cancerous cells in cell cultures and rodent models []. The effect of progestogen is not as conclusive, as studies have shown both proliferative and anti-proliferative effects on breast cancer cells. Most studies conclude that the carcinogenic effect of estrogen is predominantly mediated by estrogen binding to its receptors and activating growth factor pathways that stimulate breast cell proliferation [].

Birth control pills and breast cancer

Because of the evidence linking hormone exposure to breast cancer, many epidemiological and observational studies have been conducted over the years to determine the effect of birth control pills on breast cancer risk. However, these studies do not come to the same conclusion. While the majority shows increased risk of breast cancer with the use of birth control pills, several studies also suggest no such increase.

In 1996, the first large scale meta-analysis — a work of research combining results from multiple studies — pooled 54 studies that involved a total of 53,297 women with breast cancer and 100,239 women without breast cancer. It showed that current and recent use of birth control pills (within the past 10 years) increased the relative risk of breast cancer by up to 25% [5,7]. (Note: The increase in risk reported in all the studies is relative risk, which means that, according to this study, for a 40-year old woman with no family history of breast cancer, the risk of breast cancer increases from 1.5% normally to 1.9% with use of birth control pills.) The relative risk was higher if women started taking the pills at a younger age; however, the duration of use had no effect. Nevertheless, when women had stopped taking the pills for 10 or more years, the risk returned to the same level as the ones who had never taken pills. The study included many women who took the first formulation of birth control pills, which had a very high dose of estrogen.

Yet another meta-analysis including 34 studies carried out by the Mayo Clinic in 2006 showed that use of birth control pills increased the relative risk of breast cancer in pre-menopausal women by 19%, and that the risk is highest if women used the pills before their first full-term pregnancy []. A more recent meta-analysis that included 20 studies from 1996 to 2011 showed similar results where current use of birth control pills increased the relative risk of breast cancer by up to 30% but there was no increased risk with past use (> 10 years since last use) for women between the ages of 40 and 49 [].

However, there are a few studies that have shown that there is no increase in breast cancer risk with long term past or current use of birth control pills. The Women’s Contraceptive and Reproductive Experiences (CARE) study that followed 4575 women between the age of 35 and 64 with breast cancer and 4682 women without breast cancer showed no increase in risk of breast cancer from both current and past use of birth control pills regardless of the duration of use, the age at first use, or the dose of estrogen. []. A few other studies have reported similar findings [].

There are several problems with all the studies discussed above. The studies are mostly observational studies where the participants self-reported their use of birth control pills. Therefore, there could be differences in the accuracy and completeness of information recalled by the participants. In a vast majority of the studies, women were taking birth control pills with higher doses of estrogen than currently used. In addition, most of the studies also do not evaluate how the pill’s estrogen dosage might affect breast cancer risk.

Figure 4 ~ Effect of birth control use on breast cancer risk. In the general population, breast cancer risk is very low, ~1.5 % for women age 30-40 []. Shown above are the effects of current and past birth control use as well as different estrogen doses on breast cancer risk from a variety of studies. Most of the studies are epidemiological observational studies and report the risk either as relative risk (RR) or odds ratio (OR). The relative risk is the ratio of the probability of breast cancer in women taking birth control pills compared to the probability of breast cancer in women not taking pills. An odds ratio provides the ratio of odds, rather than probability. For something with very low probability of happening (like breast cancer risk in young women), these two are usually the same. If RR or OR 1, then there is no association between use of birth control pills and risk of breast cancer, whereas, RR or OR > 1 imply increased risk of breast cancer with the use of birth control pills. In the figure, the estimated range of effects observed in the different studies is indicated by the length of the horizontal bars and the mean effect as the intersection between the different shades in the bars. The blue bars indicate no effect, whereas red bars indicate that there is increased risk of breast cancer. A two-fold increase in risk means that a woman is twice as likely to develop breast cancer; however, because risk is low to begin with, the overall risk will still be below 3%.

A new study published last month addresses many of these issues. The study compared 1,102 women between the ages of 20 and 49 diagnosed with breast cancer from 1990 to 2009 with 21,952 women without breast cancer, whose birth control pills usage histories (including the dose information) were obtained using electronic pharmacy records. The study showed that current and recent pill use increased the relative risk of breast cancer by 50% overall. The risk was highest with high (170%) or moderate doses (60%) of estrogen and certain formulations of progestogen (up to 210%), but there was no increased risk with low estrogen doses and most of the progestogens [9,10].

A few recent studies have also explored the risk of different subtypes of breast cancer with use of birth control pills. Alarmingly, the studies have shown that use of birth control pills increases the risk of a type of breast cancer called triple-negative, which is more common in younger women and is aggressive and difficult to treat. A study from the Fred Hutchinson Cancer Institute in 2009 showed that use of birth control pills for more than one year increased the risk of triple-negative breast cancer four-fold in women younger than 40 [5,6]. The study also showed that the risk conferred by longer duration of use and by more recent use was significantly higher for triple-negative breast cancer. Several other studies have shown similar results [11,12].

To take or not to take: what should women do?

Let us recap our findings. A vast majority of studies show that recent and current use of birth control pills increase the relative risk of breast cancer, although the study from last month showed that low dose pills do not increase the risk. However, the moderate dose pill, which 78% of women in the study were taking up until 2009, increased the risk by 60%. Still other birth control pills increased the risk even more than 200%. Some of the recent studies also reported an increased risk of triple negative breast cancer, which is more common in younger women. Since women taking the pills tend to be younger, the combination of findings that the pills increase breast cancer risk with current and recent use and increase the risk of triple negative breast cancer make it more troubling.

These percentages sound scary. However, this does not mean birth control pills should be withdrawn from the market. The studies report an increase in risk only with current and recent use. In fact, the risk goes away 10 years after women stop taking the pills. In addition, since the overall risk of breast cancer in women younger than 50 and without family history is less than 2% [], even with an increase of risk by 60%, the actual risk is still only 3%. Also, the majority of birth control pills used today contain a low dose of estrogen, which is likely to be safe [9,10]. Furthermore, birth control pills provide multiple health benefits like relief from menstrual disorders, reduced risk of pelvic inflammatory disease, improved bone mineral density, and also have been shown to slightly decrease the risk of ovarian cancer and endometrial cancer [], which must be weighed against the increased risk of breast cancer for any individual considering using oral birth control.

All medicines carry risks. To decide whether to proceed with a particular treatment, one should always consider the balance between benefits and risks. Birth control pills are one of the most effective means of contraception, not to mention their assorted other health benefits. Thus, women should discuss the benefits and risks with their doctors in order to choose the options that best fit their needs.

Ashim Subedee is a PhD candidate in the Biological and Biomedical Sciences Program at Harvard Medical School.

References

  1. Guttmacher Institute. Contraceptive Use in the United States. http://www.guttmacher.org/pubs/fb_contr_use.html
  2. American Cancer Society. Breast cancer fact and figures 2013-2014. http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-042725.pdf
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  13. Howlader N, Noone A, Krapcho M, Garshell J, Miller D, Altekruse S, Kosary C, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). (2013) SEER Cancer Statistics Review, 1975-2011, National Cancer Institute. Retrieved September 1, 2014.
  14. https://www.flickr.com/photos/lookcatalog/8602762713/in/photolist-58MNRk-JX7P3-8YaubV-fX7td-pf3F2-5ZQpBo-dvjU6B-bvz12v-9ePN6m-9dRGVj-nYAQS7-4p5b7B-bqBWXm-7YnFJX-a447rG-e7cpD4-cQ9nu-6LKs7q-2o9a7J-a446YW-cmuQB7-a8r2ZL-5bvVC2-8cPaLX/
  15. http://upload.wikimedia.org/wikipedia/commons/1/1d/Pilule_contraceptive.jpg
  16. Pituitary Gland: http://commons.wikimedia.org/wiki/File:Pituitary_gland_image.png
  17. Ovulation: http://en.wikipedia.org/wiki/Human_fertilization
  18. Uterus: “Blausen 0404 Fertilization” by BruceBlaus – Own work. Licensed under Creative Commons Attribution 3.0 via Wikimedia Commons – http://commons.wikimedia.org/wiki/File:Blausen_0404_Fertilization.png#mediaviewer/File:Blausen_0404_Fertilization.png
  19. Bone: http://commons.wikimedia.org/wiki/File:Left_tibia_-_close_up_-_posterior_view.png
  20. Brain: http://commons.wikimedia.org/wiki/File:PSM_V46_D167_Outer_surface_of_the_human_brain.jpg
  21. Breast: http://en.wikipedia.org/wiki/Mammary_gland#mediaviewer/File:Gray1172.png
  22. Uterus and Uterine tubes: http://en.wikipedia.org/wiki/Uterine_horns#mediaviewer/File:Illu_cervix.jpg
  23. Breast Cancer: http://en.wikipedia.org/wiki/Breast_cancer#mediaviewer/File:En_Breast_cancer_illustrations.gif
  24. Woman: http://pixabay.com/en/anatomy-woman-man-face-body-lips-254120/

 

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