|Year : 2014 | Volume
| Issue : 4 | Page : 571-576
Reproductive factors and risk of breast cancer: A Review
U Kapil1, AS Bhadoria1, N Sareen1, P Singh1, SN Dwivedi2
1 Department of Human Nutrition, All Institute of Medical Sciences, Ansari Nagar, New Delhi, India
2 Department of Biostatistics, All Institute of Medical Sciences, Ansari Nagar, New Delhi, India
|Date of Web Publication||1-Feb-2016|
Department of Human Nutrition, All India Institute of Medical Sciences, Ansari Nagar, New Delhi
Source of Support: None, Conflict of Interest: None
Breast cancer is one of the most common incident cancer and cause of death from cancer in women. It is known that several factors that influence hormonal status (e.g., age at first child birth) or are markers of change in hormonal status (e.g., age at menarche and age at menopause) are associated with the risk of breast cancer. Reproductive factors are known risk factors for breast cancer that probably act early in life. They point toward endogenous estrogens as likely player in the initiation, progression, and promotion of breast cancer. An attempt has been made in this article to review the scientific data published in Indexed journals on the role of reproductive factors in breast cancer.
Keywords: Breast cancer, menarche, menopause, reproductive factors
|How to cite this article:|
Kapil U, Bhadoria A, Sareen N, Singh P, Dwivedi S. Reproductive factors and risk of breast cancer: A Review. Indian J Cancer 2014;51:571-6
| » Introduction|| |
Breast cancer is one of the most common incident cancer and cause of death from cancer in women. Clinical, animal, and epidemiological studies have clearly demonstrated that breast cancer is a hormonally mediated disease and is caused by repeated exposure of breast cells to circulating ovarian hormones. It is known that several factors that influence hormonal status (e.g., age at first child birth) or are markers of change in hormonal status (e.g., age at menarche and age at menopause) are associated with the risk of breast cancer.,, A variety of constitutional risk factors have also been reported, such as nulliparity, early onset of menarche, delayed first birth, late menopause, and decreased parity. These risk factors are related to a longer period of exposure to estrogen.,,,, An attempt has been made in this article to review the scientific data published in Indexed journals on the role of reproductive factors in breast cancer. The studies were searched from Index Medicus and subsequently, the research studies were separated according to the various reproductive factors. The studies were reviewed in detail for the possible mechanism of reproductive factors in breast cancer.
The role of hormones in causation of breast cancer was advanced by Korenman with his estrogen window hypothesis which is important in this regard. It assumes that exposure to an environmental carcinogen during the two periods of unopposed estrogen activity is critical. Early menarche leads to an early opening of the first window, whereas nulliparity or delayed first pregnancy leads to its late closure. Late menopause and other factors such as obesity would prolong the opening of the second window. Early menarche and late menopause result in a substantial cumulative exposure to estrogens and the simultaneous presence of progesterone, an exposure theorized to increase the risk of breast cancer.
| » Age at Menarche|| |
Age at menarche and breast cancer risk are probably indirectly associated, with nutrition being the possible common factor. Research estimate that the risk of breast cancer can be reduced 10-20% for each year menarche is delayed.,, The results of a large study revealed that for each 2 year delay in onset of menstruation, breast cancer risk was reduced by about 10%. A case control study conducted in China revealed a statistically significant trends for increasing risk with decreasing age at menarche (P = 0.003). In a case control study conducted in the USA, Canada, and Israel, late age at menarche was associated with a lower risk among the pre-menopausal women but not among post-menopausal women. Results of another study revealed that women with menarchial age of 10 or 11 years showed a 2.2-fold risk of breast cancer compared to women who had their first menstrual period at age 12 or later. A hospital-based case control study, conducted in the USA, revealed higher than average risk of breast cancer among women with an early age at menarche (Odds Ratio (OR) = 1.4). Similar results have been shown by other studies.,,,,,,
A meta-analysis of three large case control studies of breast cancer from several Italian regions revealed that relative to women with menarche at age 15 or over, those with earlier menarche had a 20-30% higher breast cancer risk.
A cohort study conducted in Korea revealed that later age at menarche, 14 years or older, was inversely associated with the risk of breast cancer (Relative Risk (RR) = 0.8; 95% Confidence Interval (CI): 0.7-1.0). A series of reports on the hormonal patterns of a cohort of Finnish girls followed through puberty and into adulthood indicated that early menarche (before age 12) was associated with significantly higher estradiol levels in the adolescent period and with higher follicular phase estradiol levels in women aged 20-31 years.,
A possible explanation for the increase in breast cancer rates which has been occurring in recent years is decreasing age at menarche, due to improving nutritional status in adolescents.
| » Pregnancy|| |
Factors associated with pregnancy have also been considered to play some etiological role in the development of breast cancer. Pregnancy induces terminal differentiation of human breast glands, which may have a smaller proliferative component. The first pregnancy induces irreversible changes that either render the breast tissue itself less susceptible to induction of cancer or reduce the carcinogenic stimulus to the breast. Women produce substantial amounts of three major estrogens: Estrone (E1), estradiol (E2), and estriol (E3). Cole and MacMahon reviewed endocrinological data concerning the synthesis of these fractions. It was observed that during pregnancy, the total estrogen secretion rises considerably, with E3 increased to a far greater extent than E1 or E2. This is of interest because of the reduced risk of breast cancer associated with early pregnancy. It is also suggested that E3 may have lower carcinogenic potential than the other estrogens and hence, younger women with a low ratio of E3 to E1 and E2 are at high risk of breast cancer.,
Animal studies indicate that, after first pregnancy, the secretory cells of the breast gland, which have a longer cell cycle, are resistant to carcinogens, and have a more efficient DNA repair capacity.
The age at the birth of first child is also strongly associated with the incidence of breast cancer. It has been speculated that a full-term pregnancy at an early age may reduce the likelihood of tumor initiation, whereas a full-term pregnancy at a later age may promote the growth of existing tumor cells. The effect of the first pregnancy being more marked, the earlier it occurs might be explained by one or more of several mechanisms. First, a pregnancy at a young age, because of special characteristics of such pregnancies, may be particularly protective. Second, exposure to carcinogens may be particularly high in younger age pregnancy that would then exert its protective effect during a period which would otherwise be associated with high risk of tumor induction. Third, the first pregnancy may act as, or possibly is itself made possible, by a threshold, type of biological phenomenon which brings to an end a period of high risk of tumor induction, the earlier the pregnancy, the shorter would then be the period of risk and the lower the probability of induction.,
In a case control study conducted in seven areas of the world, the risk of breast cancer was found to increase with increase in the age at which a woman gave birth to the first child. Women having their first child when aged under 18 years have only about one-third the breast cancer risk compared to those whose first birth is delayed until the age of 35 years or more. A case control study conducted in China revealed a statistically significant trends for increasing risk with increasing age at first full-term pregnancy (P = 0.001). Another case control study conducted in the USA, Canada and Israel revealed that the risk of breast cancer increased with increasing age at first birth. An early age at first birth appeared to reduce the risk relative to no pregnancy, whereas a late age at first birth was associated with a higher risk than not having a full-term pregnancy.
In a case control study conducted among Turkish women, it was observed that early age at first child birth was associated with decreased breast cancer risk (OR = 0.34; 95% CI: 0.22-0.53). Another hospital-based case control study conducted in the USA revealed higher than average risk of breast cancer among women who had given birth to their first child at a relatively late age (OR = 1.8). In another case control study conducted in India, late age at marriage (30 years and above) and late age at first pregnancy (30 years and above) showed excess risks of 2.5 (95% CI: 1.0-6.6) and 5.4 (95% CI: 2.2-13.9) compared with women married at the age of 14 years and age at first pregnancy of ≤14 years.
A meta-analysis of three large case control studies of breast cancer from several Italian regions revealed that the risk of breast cancer was directly related to the age at first child birth (RR = 1.8 for more than or equal to 28 years versus less than 22 years).
A cohort study conducted in Sweden also found a positive association between a late age at first child birth and breast cancer. In a Norwegian prospective study, it was observed that the magnitude of adverse effect of breast cancer was the strongest after pregnancies at age 30 years or older. Results of another large population-based cohort study conducted in Denmark suggested that women who delay childbirth until older than age 30 years have a 2-fold increased risk of developing breast cancer compared with women younger than 20 years at first birth. The risk of breast cancer can be reduced further if early childbearing (less than 25 years) is followed by an additional birth, timely early in reproductive age.
A cohort study conducted in Korea revealed that late age at first birth increased the risk of breast cancer, when the first birth occurred after 29 years of age, women had an approximately 60% increase in the risk of breast cancer compared to women who had their first child at age 26 years or younger (RR = 1.6; 95% CI: 1.1-2.2). In another cohort study conducted among Japanese women, breast cancer risk tended to rise with increasing age at first delivery. It was observed that compared to women who had their first delivery before age 25, those who delayed this event until after 34 had a RR of 2.12 (95% CI: 0.72-6.21) and 3.33 (95% CI: 1.07-10.3) among the overall subjects and the menopausal, respectively.
| » Parity and Breast Cancer|| |
Parity has also been found to be associated with breast cancer risk. A population-based case control study conducted in Sweden found that higher parity was associated with a decrease in the risk of breast cancer. Results of another case control study conducted in China revealed a statistically significant trends for increasing risk with decreasing number of full-term pregnancies (P< 0.0001). A population-based case control study was conducted in two geographical areas of Germany. It was observed that breast cancer patients had a lower parity than the controls. In a hospital-based case control study conducted in the USA, higher than average risks were found among women who had never given birth to a child (OR = 1.3; 95% CI: 1.0-1.7).
In a case control study conducted in India, nulliparous women had a 2.2-fold higher risk (95% CI: 1.4-3.3) of breast cancer than parous women. Three or more pregnancies were associated with a 40-50% reduction in risk (P< 0.01). Results of a case control study conducted in the USA, Canada, and Israel revealed that high parity was associated with a reduction in the risk, parity ≥5 compared with parity 1-2, the RR estimate was 0.7 (95% CI: 0.5-1.0). In another case control study conducted in India, the results revealed that OR for breast cancer among pre-menopausal women was 2.9 (95% CI: 1.6-5.2) among nulliparous women as compared to parous women. Similarly, in the post-menopausal women, nulliparous women had an OR of 1.2 (95% CI: 0.8-2.0) compared to parous women.
A cohort study conducted in Sweden revealed that increasing number of maternities were associated with significantly reduced risk of breast cancer. In another population-based cohort study conducted among elderly women in the USA, a high number of live births were protective (hazard ratio = 0.67; 95% CI: 0.51-0.88) for five or more births compared with one or two. Results of a cohort study conducted among Japanese women revealed a significant decline in the risk of breast cancer with increasing parity among parous women. Women with four or more parities had a 69% lower risk of breast cancer than uniparous women.
| » Lactation and Breast Cancer|| |
An association between lactation and protection from breast cancer has also been postulated for a long time. The hypothesis that prolonged lactation protects against the development of breast cancer is one of the oldest and the most enduring hypotheses concerning the etiology of this neoplasm. Lactation increases the proportion of differentiated cells in the breast and using animal models, it has been demonstrated that differentiation of the cells of the mammary gland, prior to exposure to a carcinogen, protects them from malignant transformation. Lowered estrogen levels have been observed following full-term birth and lactation. Furthermore, in lactating women, cholesterol levels in breast fluid have been found to be low. Another postulated mechanism relates to the delay of onset of menses during lactation. This could reduce breast cancer risk because the risk may be positively correlated with the cumulative number of ovulatory cycles, since mitotic activity is enhanced in the luteal phase of the menstrual cycle. It has been suggested that lactation might reduce breast cancer risk by temporarily draining the breasts of potential chemical carcinogens and finally, the hormone oxytocin, which causes contraction of myoepithelial cells as a response to suction, has been reported to inhibit cell proliferation and tumor growth in animal models. There could be direct physical effects on the breast associated with lactation that might protect against breast cancer, such as changes in breast ductal epithelial cells in lactation of mechanical "flushing-out" of carcinogens.,,,,,,,
A nested case control study using the data from an Iceland cohort revealed that the controls had longer average duration of lactation as compared to the breast cancer patients. An inverse association between total duration of breastfeeding and breast cancer was also observed, with the adjusted OR = 0.77 per 6 months increase in duration of breastfeeding (95% CI: 0.59-1.00).
The results of a population-based case control study conducted in two geographical areas of Germany revealed that the risk of breast cancer decreased with increasing duration of breastfeeding (p for trend = 0.01) and the estimated RR was 0.6 (95% CI: 0.4-0.9) for 12-24 months of cumulative breastfeeding and 0.5 (95% CI: 0.3-1.1) for 25 months or more. Having breastfed each child on average of more than 3 months and up to 6 months decreased risk by 20%. The risk reduction associated with breastfeeding for more than 6 months on an average was 30%. There was a significant decreasing risk of breast cancer with increasing average length of breastfeeding per child and the OR for an additional month each child was breastfed on average was 0.96 (95% CI: 0.92-1.0). Results of a case control study conducted among Turkish women revealed that post-menopausal women with lactation longer than 48 months had reduced risk of breast cancer (OR = 0.36; 95% CI: 0.14-0.93).
 Other studies have also reported similar findings.,
A cohort study conducted in Korea revealed that compared to parous women who had no history of lactation, a period of lactation of 13-24 months, decreased the risk of breast cancer (RR = 0.7; 95% CI: 0.5-1.1), and this risk was decreased even further for those who breastfed for more than 24 months (RR = 0.6; 95% CI: 0.3-1.0).
| » Age at Menopause and Breast Cancer|| |
Women who experience menopause later have a prolonged ovarian activity which increases the risk of developing breast cancer.
It has been observed that for every 5-year difference in age at menopause, the risk of breast cancer changes by about 17%. In the post-menopausal period, when estrogen levels are low and progesterone is absent, rates of breast cell proliferation are very low. Researchers have revealed that women who experience menopause before the age of 45 years reduce their risk to about half that of women who continue to menstruate into their mid-50's and beyond.,,
A case control study conducted in Italy also revealed that the late age at menopause was a risk factor for breast cancer (OR = 1.2) for women more than or equal to 50 years of age as compared to women less than 50 years of age (95% CI: 0.7-2.1). In another case control study conducted in India, a 3-fold increased risk of breast cancer was noted in women who attained menopause between the age of 44-49 years. A hospital-based case control study conducted in the USA revealed that higher than average risks of breast cancer were found among women with a late age at menopause (OR = 2.7).
A meta-analysis of three large case control studies of breast cancer from several Italian regions revealed that the risk of breast cancer was directly related to the age at menopause (RR = 0.7 for less than 45 years vs. more than or equal to 50 years).
A prospective cohort study conducted in New York, USA revealed that the OR = 1.5 (95% CI: 0.7-3.1) for women having menopause at age more than 52 compared to women attaining menopause at less than 46 years. In another population-based cohort study conducted among elderly women in the USA, older age at menopause (p for trend = 0.07) conferred increased risk for women aged 75 or more years.
| » Oral Contraceptive Pills and Breast Cancer|| |
The use of OCP has also been found to be associated with the risk of breast cancer. A meta-analysis including 54 epidemiological studies showed that the relative risk of developing breast cancer was 1.24 for current users of oral contraceptives compared with never users. Similar results were observed for the population-based Doorlopend Onderzoek Mortaliteit cohort conducted in Denmark. In women older than 55 years, the use of OCP for more than 10 years was associated with a 2-fold increased risk of breast cancer (OR = 2.1; 95% CI: 1.1-4.0).
| » Other Hormonal Contraceptives|| |
The progestogen-only pill
The collaborative group study on hormonal factors in breast cancer found a non-significant 17% increase in the risk of breast cancer in women taking the progestogen-only pill. The evidence was based on a small number of cases. Even if the risk is real, it is probably lower than that for the combined pill, and may be negligible.
Injectable progestogens and hormone-releasing devices
Pooled data from several case-controlled studies show a non-significant excess risk of breast cancer with depot medroxyprogesterone., There is no apparent duration-of-use effect and the risk seems restricted to women under the age of 35. There is still some uncertainty as to whether recent use (within 5 years) of depot medroxyprogesterone is associated with a transient increase in the risk of breast cancer. There are no data on sub-dermal implants and the levonorgestrel-releasing intrauterine system.
| » Abortion and Breast Cancer|| |
Studies have revealed that the breast tumors of women who have spontaneous or induced abortion at a young age have a higher rate of cell proliferation and a higher frequency of aneuploid tumors compared with the tumors of other young women with breast cancer. During the first trimester of pregnancy, the breast is characterized by high mitotic activity and proliferation, and then in the mid to late pregnancy, cellular differentiation predominate. Therefore, it is plausible that those pregnancies that are not interrupted until the end of the first trimester could result in the breast containing a high number of undifferentiated cells, relative to the breasts of women whose abortion was induced early in pregnancy or those who had no abortion at all. Abortions leave the breast epithelium in a proliferative state with an increased susceptibility to carcinogenesis.,
In a case control study conducted in Greece, it was found that the prevalence of induced abortions was 39% and an elevated risk of breast cancer was associated with induced abortion (OR = 1.5; 95% CI: 1.28-1.84). In another case control study conducted in the USA, women who had been pregnant at least once, the risk of breast cancer in those who had experienced an induced abortion was 50% higher than among other women (95% CI: 1.2-1.9). The RR associated with having an induced abortion was 1.8 (95% CI: 1.2-2.9) in women younger than 35 years at diagnosis and/or reference date, it was 1.4 (95% CI: 1.0-1.9) in 35- to 44-year-old women. There was no increased risk of breast cancer associated with a spontaneous abortion (RR = 0.9; 95% CI: 0.7-1.2). However, other studies have observed no observation between abortion and cancer., A population-based case control study conducted in China suggested that a history of several induced abortions has little influence on breast cancer risk in Chinese women. It was found that after adjusting for confounding variables, there was no relation between ever having an induced abortion and breast cancer (OR = 0.9; 95% CI: 0.7-1.1). Women who had three or more induced abortions were not at increased risk of pre-menopausal breast cancer (OR = 0.9; 95% CI: 0.6-1.4) or post-menopausal breast cancer (OR = 1.3; 95% CI: 0.8-2.3).
Contrary to the findings reported above, a case control study conducted in Sweden revealed a reduced risk of breast cancer among women with a history of at least 1 compared to no abortions (adjusted OR = 0.84; 95% CI: 0.72-0.99). The adjusted OR decreased step-wise with number of abortions to 0.59 (95% CI: 0.34-1.03) for three or more compared to no abortions.
| » Conclusion|| |
Reproductive factors are known risk factors for breast cancer that probably act early in life. They point toward endogenous estrogens as likely player in the initiation, progression, and promotion of breast cancer., There is a need to have more scientific evidence to further increase our understanding of the role of reproductive factors in the etiology of breast cancer to expand opportunities for its prevention.
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