Impact of infertility and assisted reproductive technology on cancer risk

Ovarian stimulation drugs, in particular those used in assisted reproductive technology (ART) treatments for infertility, have been suspected to influence cancer risk. In addition, infertility per se may be a risk factor for some cancer types. The focus of this thesis project was to examine the risk of breast and gynecological cancers among infertile women and women treated with ovarian stimulation.

The four studies included in this thesis aimed to investigate: if ovarian stimulation may alter mammographic density (study I), if the use of ART influences the risk of breast cancer (study II), borderline ovarian tumors (BOT) or ovarian cancer (study III), and if infertility is associated with the risk of breast, ovarian or endometrial cancer (study IV). The first study was based on data from a screening-based cohort and the other three studies used information from Swedish population-based registers.

Study I evaluated whether having a history of infertility or ovarian stimulation were associated with mammographic density, which is a strong risk factor for breast cancer. In studies II and III, cancer risk was examined among parous women who gave birth in Sweden between 1982 and 2012, comparing risks in women who had given birth following ART to that of parous women with and without infertility. In study II, breast cancer risk was also evaluated among women born 1960–1992, comparing the risk in women exposed to ovarian stimulation in 2005 or later to that of unexposed women with and without infertility. In study IV, the risk of breast, ovarian and endometrial cancer was assessed in women born 1942– 1992, comparing the risk in women diagnosed with infertility, ovulatory disturbances or endometriosis to that of women with none of these diagnoses.

Although mammographic density was higher in women with a history of infertility, in particular among women exposed to ART, there was no association between infertility or ovarian stimulation and breast cancer risk. Ovarian cancer risk was higher among women diagnosed with infertility, endometriosis, and in a subpopulation of women with ovulatory disorders. Women who had given birth following ART treatments had a higher risk of ovarian cancer and BOT, which was partly explained by infertility. Endometrial cancer risk was higher among women diagnosed with infertility or ovulatory disturbances, but not in women with endometriosis.

In conclusion, the findings suggest that infertile women have a higher risk of ovarian and endometrial cancer, but not breast cancer. The possible increase in ovarian tumor risk following ART treatments needs to be investigated further, since the results were based on a small number of exposed cases and may be confounded by the underlying causes of infertility.

List of scientific papers

I. Lundberg FE, Johansson ALV, Rodriguez-Wallberg K, Brand JS, Czene K, Hall P and Iliadou AN. Association of infertility and fertility treatment with mammographic density in a large screening-based cohort of women: a cross-sectional study. Breast Cancer Research 2016;18:36.
https://doi.org/10.1186/s13058-016-0693-5

II. Lundberg FE, Iliadou AN, Rodriguez-Wallberg K, Bergh C, Gemzell- Danielsson K, Johansson ALV. Ovarian stimulation and risk of breast cancer in Swedish women. Fertility and Sterility 2017;108(1):137-144.
https://doi.org/10.1016/j.fertnstert.2017.05.010

III. Lundberg FE, Johansson ALV, Rodriguez-Wallberg K, Gemzell-Danielsson K, Iliadou AN. Assisted reproductive technology and risk of ovarian cancer and borderline tumors in parous women. [Manuscript]

IV. Lundberg FE, Iliadou AN, Rodriguez-Wallberg K, Gemzell-Danielsson K, Johansson ALV. Infertility and risk of breast or gynecological cancer. [Manuscript]