Infertility, ovulation, induced ovulation, and female cancers

Early menarche and late menopause increase the risk of breast cancer. Endogenous progesterone, together with estrogens, is related to the risk of breast cancer, as is the combination of estrogens and progestins in menopause hormone replacement therapy. Regular menstrual cycles increase breast cancer risk, and the risk is reduced for women with menstrual irregularities. Nulliparous and infertile women have also an increased risk of breast cancer. A few studies from the USA, Europe, and Israel have addressed the issue of use of fertility drugs and the risk of breast cancer. Their overall results show no consistent association, and the variation can be largely explained by chance alone. Ovulation has also been related to ovarian cancer risk. In a combined analysis of two Italian case-control studies including 1822 cases and 4631 controls, compared with the lowest quartile of number of ovulatory cycles, the relative risks (RR) were 1.6, 1.7, and 1.8 for subsequent quartiles. The association between menstrual cycle patterns and ovarian cancer risk is however more complex than defined by the number of ovulations only. With reference to induced ovulation, it is now possible to exclude a RR over 2 among ever users of fertility drugs, but a minor role of specific drugs on specific groups of women remains open for further investigation. These include nulligravidae, who have an increased baseline risk of ovarian cancer. Endometrial cancer risk is increased not only in nulliparae, but also in women with history of infertility and polycystic ovary syndrome (PCOS), particularly in pre-menopause. This is attributed to anovulation, which leads to continuous exposure to estrogens insufficiently counterbalanced by progesterone. With reference to induced ovulation, results for endometrial cancer are suggestive of an association for fertility drugs and specifically clomiphene, with RRs between 1.6 and 6 in various studies. An association between clomiphene and endometrial cancer risk is plausible, given its similarities with tamoxifen, which has been related to excess endometrial cancer risk.