Reproductive factors can have an important effect on a woman’s risk for breast cancer by influencing her hormone levels, which, over a woman’s lifetime, can be associated with increased or decreased risk of breast cancer.
Factors associated with an increased risk of breast cancer risk include age at first period, whether or not a woman has had children, her age when she had her first child, her reproductive hormone levels and her age at menopause.
Age when periods started
Starting menstrual periods at a younger age is associated with an increased risk of breast cancer. Women who had their first period when younger than 12 years have a slightly higher risk of breast cancer than women who had their first period at 12 years or older.
The risk of breast cancer increases by about 5% for each year younger a woman is when she starts having periods. For example, someone whose periods start when she is 10 years old has about a 19% increased risk of breast cancer than someone who starts having periods when she is 13 years old.
The way in which age when periods start is associated with the risk of breast cancer probably relates to hormonal factors. Women who start having periods at a younger age have a higher lifetime exposure to the hormones oestrogen and progesterone. This can increase the risk of breast cancer.
Summary of the evidence
Evidence classification: Convincing
There is convincing evidence that earlier age when menstrual periods start (menarche) is associated with an increased risk of breast cancer.
The risk of breast cancer is estimated to increase by 5% (RR 1.05, 95% CI 1.04–1.06) for each year younger a woman is at menarche.[1]
Mechanisms
Early age at menarche increases a woman’s lifetime exposure to oestrogen and progesterone, which drive mitotic activity in the breast. A greater total extent of breast mitotic activity is thought to increase the risk of breast cancer.
Early age at menarche also increases the time between menarche and a woman’s first pregnancy, when breast cells undergo differentiation. Since undifferentiated breast cells are more likely to undergo malignant transformation, a longer period before cells differentiate is thought to increase the risk of breast cancer.
Evidence
The World Cancer Research Fund International/American Institute for Cancer Research (WCRF/AICR) lists early menarche as an established cause of breast cancer and states that ‘early menarche [before the age of 12]
increases lifetime exposure to oestrogen and progesterone and the risk of breast cancer’ and that ‘late menarche decreases the risk of breast cancer’.[2]
A large pooled analysis conducted by the Collaborative Group on Hormonal Factors in Breast Cancer used data from 117 international studies. Risk of breast cancer increased by a factor of 1.05 (95% confidence interval [CI] 1.044–1.057) for each year younger a woman was at menarche.1 The mean age of menarche was 13.1 years in the combined dataset. Compared with women aged 13 years at menarche, the relative risk (RR) for women aged 12, 11 and less than 11 years were 1.07 (95% CI 1.05–1.09), 1.09 (95% CI 1.06–1.12) and 1.19 (95% CI 1.13–1.25), respectively; and women aged 14, 15 and 16 years or older 0.98 (95% CI 0.96–1.00), 0.92 (95% CI 0.89–0.95) and 0.82 (95% CI 0.79–0.85), respectively.[1] The association was stronger for lobular than for ductal tumours, but there were no significant differences by oestrogen receptor status of the cancer.
Data from two more recent cohort studies[3,4] generally support these findings.
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Age when first child was born
Being older at the birth of a woman's first child is associated with an increased risk of breast cancer.
For each extra year older a woman is when she has her first child, the risk of breast cancer increases by about 3%. For example, women who have their first child when they are aged 30 years old have about a 20% higher risk of breast cancer than women who have their first child when they are 25–29 years old.
When a woman becomes pregnant for the first time, changes occur in cells in the breast which mean that these cells are less likely to become cancer cells. The younger a woman is when she becomes pregnant for the first time, the less chance there is for the cells in her breasts to become cancer cells. This may be one way that having a first child at a later age is associated with an increased risk of breast cancer.
In addition, full-term pregnancies reduce the levels of certain hormones in the body. This could also explain some of the association between age at birth of the first child and the risk of breast cancer.
Summary of the evidence
Evidence classification: Convincing
There is convincing evidence that older age at first birth is associated with an increased risk of breast cancer.
A woman’s risk of breast cancer is estimated to increase by about 3% for each year older she is at the birth of her first child (RR 1.03, 95% CI 1.02–1.05).[5]
Mechanisms
Before a woman’s first full-term pregnancy, the breast has a high proportion of undifferentiated epithelial cells.[6] These undifferentiated cells are more likely to undergo malignant transformation than terminally differentiated cells. The shorter the time between menarche (onset of menstruation) and first birth, the less time these undifferentiated breast cells are at risk of carcinogenesis.[5]
Full-term pregnancies also cause long-term reductions in levels of circulating sex hormones. This may contribute to the association between age at birth of the first child and the risk of breast cancer.[5]
Evidence
The World Cancer Research Fund International/American Institute for Cancer Research (WCRF/AICR) states that ‘a first pregnancy/birth over the age of 30 increases the risk of breast cancer’. The WCRF/AICR also noted that ‘pregnancy before the age of 30 decreases the risk of breast cancer’, overall indicating age at first birth as an established risk factor for breast cancer.[2]
A meta-analysis of five studies reported a relative risk (RR) for breast cancer overall of 1.20 (95% confidence interval [CI] 1.02–1.42) for women aged 30 years or older at first birth compared with women aged 25–29 years at first birth.[7]
A more recent meta-analysis of 3 cohort studies and 9 case–control studies did not report on a risk of breast cancer overall. It found that women aged >24 years compared with women aged ≤24 years at first birth had an increased risk of breast cancer of the luminal subtypes (RR 1.15, 95% CI 1.00–1.32).[8] No association was seen for HER2 or triple-negative subtypes of breast cancer.
Two large cohort studies have also found an increased risk of breast cancer in women who are older at birth of their first child. One found that women aged ≥35 years at first birth had an increased risk of oestrogen receptor-positive, progesterone receptor-positive (ER+PR+) breast cancer compared with women aged ≤19 years at first birth, but not of ER-PR- breast cancer.[2] In the Nurses Health Studies a dose–response relationship was observed between age at first birth and risk of breast cancer (RR per 1 year increase in age at first birth 1.03; 95% CI 1.02–1.03).[5] The association was seen for luminal A breast cancer but not for HER2+ breast cancer.
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Reproductive hormone levels
Higher levels of the naturally-occurring (endogenous) hormone oestrogen are associated with an increased risk of postmenopausal breast cancer.
Naturally-occurring hormones testosterone and insulin-like growth factor 1 (IGF-1) are also associated with an increased risk of breast cancer.
There is no conclusive evidence that naturally-occurring oestrogen is associated with an increased risk of premenopausal breast cancer. There is no conclusive evidence that the hormones progesterone, sex hormone binding globulin [SHBG] and prolactin are associated with an increased risk of breast cancer. Studies that have looked at these factors are limited and inconsistent.
Sex hormones (also known as steroid hormones) are produced naturally by women’s bodies and include oestrogens, progesterone and androgens (such as testosterone). These hormones affect sexual development during puberty, the menstrual cycle and reproduction. Levels of these hormones naturally decline when a woman goes through menopause.
The more a woman is exposed to oestrogen during her lifetime, the higher her risk of breast cancer. Longer exposure to oestrogen promotes the growth of breast cancer cells.
Summary of the evidence
Evidence classification
- Convincing:
- oestrogen (postmenopausal breast cancer),
- testosterone,
- insulin-like growth factor 1 [IGF-1]
- Inconclusive:
- oestrogen (premenopausal breast cancer),
- sex hormone binding globulin [SHBG]
- progesterone,
- prolactin
There is convincing evidence from large pooled analyses that higher circulating levels of oestrogen, testosterone, and IGF-1 are associated with an increased risk of postmenopausal breast cancer (OR 2.15, 95% CI 1.87–2.46[9]; OR 2.04, 95% CI 1.76–2.371, and OR 1.28, 95% CI 1.14–1.44[10]; for highest versus lowest levels, respectively).
The evidence for an association between circulating levels of oestrogen and risk of premenopausal breast cancer, progesterone and SHBG and risk of breast cancer, is inconclusive. Findings are inconsistent. For prolactin the evidence is limited in amount.
Mechanisms
Sex hormones or steroid hormones that occur naturally in women’s bodies (endogenous) include oestrogens, progesterone, and androgens such as testosterone. Levels of these hormones decline when a woman goes through menopause. Sex hormone binding globulin (SHBG) is a protein that binds oestrogen and testosterone, transports them in the bloodstream and influences their bioavailability to cells. Insulin-like growth factor 1 [IGF-1] is a hormone which plays an important role in childhood growth and development and is involved in adult metabolism.
A woman’s lifetime exposure to circulating oestrogen and progesterone appears to play a role in the development of breast cancer. Oestrogen, progesterone and growth factors such as IGF-1 promote proliferation of breast cells, decreased cell death (apoptosis) and possibly DNA damage.[11] In addition, research suggests that in breast cancer, the hormone progesterone can have a negative effect on cell growth.[15] Androgens have more complex actions, with both inhibitory and proliferative effects on breast cells.[12] Levels of SHBG are inversely related to BMI, and any effect of SHBG on breast cancer risk may be mediated through the level of body fat.[13] Prolactin might affect breast cancer risk by increasing cell proliferation and reducing apoptosis, as well as through synergistic effects with oestrogen and progesterone in the breast.[14,15]
Evidence
Endogenous steroid hormones and sex hormone binding globulin
The Endogenous Hormones and Breast Cancer Collaborative Group (EHBCCG) conducted a pooled analysis of individual participant data from 7 prospective studies among premenopausal women.[16] It found increased risk of breast cancer for circulating oestradiol (odds ratio [OR] for doubling of levels 1.19; 95% confidence interval [CI] 1.06–1.35), free oestradiol (OR 1.17; 95% CI 1.03–1.33), oestrone (OR 1.27, 95% CI 1.05–1.54) and testosterone (OR 1.18; 95% CI 1.03–1.35). However, there were inconsistent findings across the studies regarding oestrogens and an earlier pooled analysis of many of the same studies did not show an association between levels of oestrogens and risk of premenopausal breast cancer. Luteal phase progesterone and SHBG were not associated with breast cancer risk.[9]
The EHBCCG also analysed data from 18 prospective studies and found a positive association between levels of circulating oestradiol, oestrone and testosterone and risk of postmenopausal breast cancer, with approximately twice the odds of breast cancer for highest versus lowest levels of oestradiol, oestrone and testosterone.[17] An earlier analysis showed that SHBG was associated with a borderline decreased risk of postmenopausal breast cancer for the highest versus lowest levels.[10] Significant dose–response relationships were seen for all hormones.
Associations of breast cancer with endogenous oestrogens and androgens are strongest for oestrogen-receptor-positive (ER+) breast cancers, although associations have been reported with ER- breast cancers.
Prolactin
A prospective study has shown an increased breast cancer risk for higher prolactin measured within 10 years of breast cancer diagnosis (relative risk [RR] 1.20, 95% CI 1.03–1.40 for highest vs lowest quartiles).[14] The association was stronger for ER+ breast cancer and for postmenopausal women. Another cohort study also found a positive association between prolactin levels and risk of postmenopausal breast cancer (OR 1.29; 95% CI 1.05–1.58 for highest vs lowest quartile).[15] The risk was significant only in women who used postmenopausal hormone therapy.[15]
Insulin-like growth factor 1
In a pooled analysis of prospective cohort studies by the EHBCCG, plasma IGF-1 concentrations were associated with increased breast cancer risk for women in the highest versus the lowest quintile of IGF-1 concentration (OR 1.28; 95% CI 1.14–1.44).[18] The association was only significant for ER+ breast cancer.
More recent data from a cohort study have also shown an association only for ER+ breast cancer, and for ER+ postmenopausal but not premenopausal breast cancer.[19]
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Not having had children
Not having had children is associated with an increased risk of breast cancer.
Women who have not had any children have about a 16% greater risk of breast cancer than women who have had at least one child.
When a woman has a full-term pregnancy, changes occur in cells in the breast in preparation for breastfeeding. These changes are thought to make the cells less likely to become cancer cells. This might explain why women who have not had children have a higher risk of breast cancer than women who have had children.
Summary of the evidence
Evidence classification: Convincing
There is convincing evidence that not having had children is associated with an increased risk of breast cancer.
Women who have not had any children have about a 16% greater risk of breast cancer than women who have had at least one child.[7]
Mechanisms
Having children might decrease the risk of breast cancer through changes that occur in breast epithelial cells in preparation for lactation. These changes involve differentiation of epithelial cells, which is thought to make the cells less vulnerable to DNA damage.[19] This differentiation does not occur in women who have not had children, resulting in an increased risk of breast cancer compared with women who have had children.
Evidence
The World Cancer Research Fund International/American Institute for Cancer Research concluded that ‘not bearing children increases lifetime exposure to oestrogen and progesterone and the risk of breast cancer’ and listed ‘not bearing children’ as an established cause of breast cancer.[2]
Two meta-analyses have examined the association between number of children and breast cancer risk. The most recent, which reported on the association according to tumour subtype, found a significant protective effect of having had children for luminal breast cancer but not HER2+ or triple-negative breast cancer.[8] The other meta-analysis found that the relative risk of breast cancer in woman who had not had children compared with women who had had children was 1.16 (95% confidence interval [CI] 1.04–1.26), and that women with 3 or more births had a lower risk of breast cancer than women with none.[7]
A pooled analysis of data from 47 epidemiological studies in 30 countries reported that women with breast cancer had, on average, fewer births than did controls (2.2 vs. 2.6).[7] The relative risk of breast cancer decreased by 7% (95% CI 5–9%) for each birth.[7]
A cohort study found that women who had not had children had a greater risk of postmenopausal breast cancer than women who had had more than 1 child with the first birth before the age of 30 years.[3] In another cohort study, having had a full-term birth was associated with risk of oestrogen receptor-positive, progesterone receptor-positive (ER+PR+) breast cancer, with evidence of a dose–response relationship, but not with risk of ER-PR- breast cancer.[6]
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Age at menopause
Later age at menopause is associated with increased risk of breast cancer. Menopause occurs when a woman stops having periods. The average age of menopause in Australia is 51 years.
A woman’s risk of breast cancer increases by about 3% for each year older she is at menopause. For example, a woman who goes through menopause at the age of 55 years or older has about a 12% higher risk of breast cancer than a woman who is aged 50–54 years.
After menopause, the body produces less of the hormone oestrogen. If a woman goes through menopause later, her breast tissue is exposed to more oestrogen than if menopause occurs earlier. Longer exposure to oestrogen promotes the growth of breast cancer cells.
Summary of the evidence
Evidence classification: Convincing
There is convincing evidence that older age at menopause is associated with increased risk of breast cancer. A woman’s risk of breast cancer is estimated to increase by about 3% for each year older she is at menopause (RR 1.029, 95% CI 1.025‒1.034).[20]
Mechanisms
The median age of menopause in Australian women is 51 years.[20] During natural menopause, the body’s production of oestrogen and progesterone decreases. The later a woman goes through menopause, the longer her breast tissue is exposed to oestrogens released by the ovaries during her menstrual periods and the greater her lifetime exposure to oestrogen. The increased risk of breast cancer with later age at menopause is consistent with other evidence that factors that increase exposure to endogenous oestrogen increase the risk of breast cancer.
Evidence
A large pooled analysis was undertaken of 117 international studies that included 118,964 women with invasive breast cancer and 306,091 without the disease.[21] Among 35 cohort studies, risk of postmenopausal breast cancer increased by approximately 3% for every 1-year increase in age at menopause (relative risk [RR] 1.029; 95% confidence interval [CI] 1.025–1.034), with a dose-response relationship.
Women aged 55 years or older at menopause had a 12% higher risk of breast cancer than women aged 50–54 years at menopause (RR 1.12; 95% CI 1.07–1.17). The risk of breast cancer was correspondingly lower for women who experienced menopause at age less than 50 years. Women aged 45–49 years at menopause had a 14% lower risk of breast cancer than women aged 50 years or older at menopause (RR 0.86; 95% CI 0.84–0.89).[21]
This association was observed both for women with natural menopause and for women who had an induced menopause – for example, as a result of surgical removal of their ovaries.
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References
[1] Collaborative Group on Hormonal Factors in Breast Cancer (2012). Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncology 13(11):1141–1151.
[2] World Cancer Research Fund/American Institute for Cancer Research (2018). Continuous Update Project Expert Report 2018. Diet, nutrition, physical activity and breast cancer. London, UK.
[3] Dartois L, Fagherazzi G, Baglietto L, et al. (2016). Proportion of premenopausal and postmenopausal breast cancers attributable to known risk factors: estimates from the E3N‐EPIC cohort. International Journal of Cancer 138(10):2415–2427.
[4] Bodicoat DH, Schoemaker MJ, Jones ME, et al. (2014). Timing of pubertal stages and breast cancer risk: the Breakthrough Generations Study. Breast Cancer Research 16(1):R18.
[5] Sisti JS, Collins LC, Beck AH, et al. (2016). Reproductive factors in relation to molecular subtypes of breast cancer: results from the nurses’ health studies. International Journal of Cancer 138:2346–2356. doi:10.1002/ijc.29968
[6] Ritte R, Tikk K, Lukanova A, et al. (2013). Reproductive factors and risk of hormone receptor positive and negative breast cancer: a cohort study. BMC Cancer 13(1):584.
[7] Nelson HD, Zakher B, Cantor A, et al. (2012). Risk factors for breast cancer for women aged 40 to 49 years: a systematic review and meta-analysis. Annals of Internal Medicine 156(9):635–648.
[8] Lambertini M, Santoro L, Del Mastro L, et al. (2016). Reproductive behaviors and risk of developing breast cancer according to tumor subtype: a systematic review and meta-analysis of epidemiological studies. Cancer Treatment Reviews 49:65–76.
[9] Walker K, Bratton DJ, Frost C (2011). Premenopausal endogenous oestrogen levels and breast cancer risk: a meta-analysis. British Journal of Cancer 105(9):1451–7.
[10] Endogenous Hormones and Breast Cancer Collaborative Group (2002). Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. Journal of the National Cancer Institute 94(8):606–616.
[11] Fortner RT, Eliassen AH, Spiegelman D, et al. (2013) Premenopausal endogenous steroid hormones and breast cancer risk: results from the Nurses’ Health Study II. Breast Cancer Research 15: R19.
[12] Carroll JS, Hickey TE, Tarulli GA, et al. (2017). Deciphering the divergent roles of progestogens in breast cancer. Nature Reviews Cancer 17 (1):54–64
[13] Interagency Breast Cancer and Environmental Research Coordinating Committee (2013). Breast cancer and the environment: prioritizing prevention, report of the Interagency Breast Cancer and Environmental Research Coordinating Committee, National Institutes of Health, Bethesda, Maryland, https://www.niehs.nih.gov/about/assets/docs/ibcercc_full_508.pdf.
[14] Tworoger SS, Eliassen AH, Zhang X, et al. (2013). A 20-year prospective study of plasma prolactin as a risk marker of breast cancer development. Cancer Research 73(15):4810–4819.
[15] Tikk K, Sookthai D, Johnson T, et al. (2014). Circulating prolactin and breast cancer risk among pre- and postmenopausal women in the EPIC cohort. Annals of Oncology 25(7):1422–1428.
[16] Endogenous Hormones and Breast Cancer Collaborative Group (2013). Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies. Lancet Oncology 14(10):1009–1019.
[17] Endogenous Hormones and Breast Cancer Collaborative Group (2015). Steroid hormone measurements from different types of assays in relation to body mass index and breast cancer risk in postmenopausal women: reanalysis of eighteen prospective studies. Steroids 99:49–55.
[18] Endogenous Hormones and Breast Cancer Collaborative Group (2010). Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies. Lancet Oncology 11(6):530–542.
[18] Kaaks R, Johnson T, Tikk K, et al. (2014). Insulin-like growth factor 1 and risk of breast cancer by age and hormone receptor status: a prospective study within the EPIC cohort. International Journal of Cancer 134(11):2683–2690.
[19] Russo J, Moral R, Balogh GA, et al. (2005). The protective role of pregnancy in breast cancer. Breast Cancer Research 7(3):131–142.
[20] Do KA, Treloar SA, Pandeya N, Purdie D, Green AC, Heath AC & Martin NG (1998). Predictive factors of age at menopause in a large Australian twin study. Human Biology 70(6):1073–1091.
[21] Collaborative Group on Hormonal Factors in Breast Cancer (2012). Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet 13:1141–1151.
