This section addresses reproductive factors during the course of a woman’s life in relation to risk of breast cancer. An underlying concept is that ovarian hormones initiate breast development and that subsequent monthly menstrualcycles induce regular breast cell proliferation. This pattern of cell division terminates with a natural menopause, as indicated by cessation of ovulation and menstrual periods.

Age at Menarche
Menarche represents the development of the mature hormonal environment of a young woman, and the onset of monthly cycling of hormones that induce ovulation, menstruation, and cell proliferation within the breast and endometrium. Earlier age at menarche has been consistently associated with increased risk of breast cancer. Most studies suggest that age at menarche is related to both premenopausal and postmenopausal breast cancer risk.

Although menarche is most clearly related to the onset of ovulation, some, but not all, studies suggest that hormone levels may be higher through the reproductive years among women who have early menarche. In addition, early menarche may be associated with more rapid onset of regular, ovulatory menstrual cycles and hence greater lifetime exposure to endogenous hormones. Whether the levels of ovarian hormones or their cyclic characteristics are the underlying influence on breast cancer risk is undetermined; both likely play a role.

Menstrual Cycle Characteristics
Shorter cycle length has been quite consistently related to greater risk of breast cancer, although not all studies support this relation. Shorter cycle length during ages 20 to 39 years may be associated with higher risk of breast cancer, perhaps because the shorter cycle length is associated with a greater number of cycles and more time spent in the luteal phase, when both estrogen and progesterone levels are high. Long and irregular cycles may also be related to reduced risk of breast cancer.

Ovulatory infertility, an indicator of infertility due to hormonal causes, has not been consistently related to risk of breast cancer, although one cohort study suggested a substantially lower risk among women with this condition (relative risk of 0.4 compared with women with no infertility history). The significant inverse association seen in this study may be due to the young age of the cohort and thoroughness of investigation of the cause of infertility in this group of health professionals.

Pregnancy and Age at First Full-Term Pregnancy
Nulliparous women are at increased risk of breast cancer compared with parous women. This risk is evident after age 40 to 45 years, but not for breast cancer diagnosed at younger ages. In the majority of epidemiologic studies, a younger age at first full-term pregnancy predicts a lower lifetime risk of breast cancer. The reduction in risk after pregnancy compared with nulliparity is not immediate but takes 10 to 15 years to manifest. In fact, risk of breast cancer is increased for the first decade after the first pregnancy. The proliferation of breast cells during the first pregnancy results in differentiation into mature breast cells prepared for lactation; this may also lead to growth of mutated cells and excess risk over the next decade. Epidemiologic evidence for the transient excess risk after the first pregnancy is consistent. Less clear is the presence of a transient increase in risk after subsequent pregnancies; some studies suggest an adverse effect, but others do not.

The first pregnancy is associated with permanent changes in the glandular epithelium and with changes in the biological properties of the mammary cells. After the differentiation of pregnancy, epithelial cells have a longer cell cycle and spend more time in G1, the phase that allows for DNA repair. The longer the interval from menarche to first pregnancy, the greater the adverse effect of the first pregnancy. The later the age at first full-term pregnancy, the more likely that DNA mistakes have occurred that will be propagated with the proliferation of mammary cells during pregnancy. The susceptibility of mammary tissue to carcinogens decreases after the first pregnancy, reflecting the differentiation of the mammary gland. This is seen in the age-dependent susceptibility of the breast to radiation, reviewed in the section Ionizing Radiation.

Number and Spacing of Births
A higher number of births is consistently related to lower risk of breast cancer; each additional birth beyond the first reduces long-term risk of breast cancer. Although in some analyses this has not been independent of earlier age at first birth, the overall evidence indicates an independent effect of greater parity. In addition to a protective effect of higher parity, several studies indicate that more closely spaced births are associated with lower lifetime risk of breast cancer. This may be due to the breast’s having less time to accumulate DNA damage before it attains maximal differentiation by repeated pregnancies.