For the past five decades, scientists have been attempting to establish a link between infertility and the risk of developing cancer. A recent study undertaken by the National Cancer Institute (NCI) at the National Institutes of Health (NIH) demonstrated the increased risk of infertility and cancer in women who were exposed to diethylstilbestrol (DES) in utero.1 Six decades since the first exposure to DES in pregnant women, the delayed gynecological effects of DES could be observed in their progeny.

Infertility manifests as a result of varying factors such as family history, irregular menstruation, as well as endocrine, autoimmune, and psychological disorders.2,3 It is estimated that about 7 million women will receive fertility treatments by 2025.4

Risk factors
Infertile women who demonstrate anovulation and polycystic ovaries are at risk of developing cancer.5 Use of fertility drugs that increase oocyte production (superovulation), and cause hormonal fluctuations may also be a risk factor for cancer.5,6 It has been shown that prolonged use of clomiphene citrate and gonadotropins for ovulation induction increases the risk for ovarian cancer.5,3 Hormones (e.g., gonadotropins, estrogen, progesterone), growth hormones (IGF-1), and genes (p53) are risk factors for breast and ovarian cancers. Case-control and cohort studies of the risks of ovarian cancer have shown that the longer the treatment to become pregnant, the higher the risk for ovarian cancer. The inability to become pregnant (nulligravid), inability to deliver a child (nulliparity), and endometriosis also pose significantly higher risks for cancer.3,5 Obesity and a high estrogen/progesterone ratio contribute to breast cancer risk.5 A recent study showed the association of high mammographic density with infertility, contributing to an increased risk of breast cancer.7 However, the effect of fertility medications on increasing risk of breast cancer is unclear. The role of hormones in increasing risk of breast cancer is also not very clear due to low statistical power in population studies.3 The following sections discuss the current research on the link between infertility and breast or ovarian cancer.

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Genetic links
Reduced ovarian reserve and infertility can be inferred from poor response to ovarian stimulation. The effect of BRCA1 mutation on primary ovarian insufficiency was shown by Oktay et al.8 Ovarian stimulation was carried out to preserve fertility in 126 women through embryo or oocyte cryopreservation. Based on the study criteria, 82 women were selected for testing of BRCA mutation status. Forty-seven women were selected for BRCA mutation testing. Fourteen of the women were BRCA mutation-positive, and 33 were BRCA mutation-negative. BRCA mutation status of 14 women was compared to their oocyte yield through ovarian stimulation. BRCA1 mutation was found in nine of the women, BRCA2 mutations in four of the women, and mutations in both genes were found in one woman. BRCA mutation-positive women showed a significantly low ovarian response rate (33.3%) compared to BRCA mutation-negative women (3.3%), and women who did not undergo BRCA testing (2.9%).