SummaryBackgroundMenarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women.MethodsIndividual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression.FindingsBreast cancer risk increased by a factor of 1·050 (95% CI 1·044–1·057; p<0·0001) for every year younger at menarche, and independently by a smaller amount (1·029, 1·025–1·032; p<0·0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45–54 years 1·43, 1·33–1·52, p<0·001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women's year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p<0·006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p<0·01 for both comparisons).InterpretationThe effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women's total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours.FundingCancer Research UK.

SummaryBackgroundPublished findings on breast cancer risk associated with different types of menopausal hormone therapy (MHT) are inconsistent, with limited information on long-term effects. We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence.MethodsPrincipal analyses used individual participant data from all eligible prospective studies that had sought information on the type and timing of MHT use; the main analyses are of individuals with complete information on this. Studies were identified by searching many formal and informal sources regularly from Jan 1, 1992, to Jan 1, 2018. Current users were included up to 5 years (mean 1·4 years) after last-reported MHT use. Logistic regression yielded adjusted risk ratios (RRs) comparing particular groups of MHT users versus never users.FindingsDuring prospective follow-up, 108 647 postmenopausal women developed breast cancer at mean age 65 years (SD 7); 55 575 (51%) had used MHT. Among women with complete information, mean MHT duration was 10 years (SD 6) in current users and 7 years (SD 6) in past users, and mean age was 50 years (SD 5) at menopause and 50 years (SD 6) at starting MHT. Every MHT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use and were greater for oestrogen-progestagen than oestrogen-only preparations. Among current users, these excess risks were definite even during years 1–4 (oestrogen-progestagen RR 1·60, 95% CI 1·52–1·69; oestrogen-only RR 1·17, 1·10–1·26), and were twice as great during years 5–14 (oestrogen-progestagen RR 2·08, 2·02–2·15; oestrogen-only RR 1·33, 1·28–1·37). The oestrogen-progestagen risks during years 5–14 were greater with daily than with less frequent progestagen use (RR 2·30, 2·21–2·40 vs 1·93, 1·84–2·01; heterogeneity p<0·0001). For a given preparation, the RRs during years 5–14 of current use were much greater for oestrogen-receptor-positive tumours than for oestrogen-receptor-negative tumours, were similar for women starting MHT at ages 40–44, 45–49, 50–54, and 55–59 years, and were attenuated by starting after age 60 years or by adiposity (with little risk from oestrogen-only MHT in women who were obese). After ceasing MHT, some excess risk persisted for more than 10 years; its magnitude depended on the duration of previous use, with little excess following less than 1 year of MHT use.InterpretationIf these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50–69 years by about one in every 50 users of oestrogen plus daily progestagen preparations; one in every 70 users of oestrogen plus intermittent progestagen preparations; and one in every 200 users of oestrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great.FundingCancer Research UK and the Medical Research Council.

In a Norwegian, prospective study we investigated breast cancer risk in relation to age at, and time since, childbirth, and whether the timing of births modified the risk pattern after delivery. A total of 23 890 women of parity 5 or less were diagnosed with breast cancer during follow-up of 1.7 million women at ages 20 -74 years. Results, based on Poisson regression analyses of person-years at risk, showed long-term protective effects of the first, as well as subsequent, pregnancies and that these were preceded by a short-term increase in risk. The magnitude and timing of this adverse effect differed somewhat by birth order, maternal age at delivery and birth spacing. No transient increase in risk was seen shortly after a first birth below age 25 years, but an early first birth did not prevent a transient increase in risk after subsequent births. In general, the magnitude of the adverse effect was strongest after pregnancies at age 30 years or older. A wide birth interval was also related to a more pronounced adverse effect. Increasing maternal age at the first and second childbirth was associated with an increase in risk in the long run, whereas no such long-term effect was seen with age at higher order births. British Journal of Cancer (2005) From the numerous studies of reproductive history and breast cancer risk, there is a consensus that an early first birth and increasing number of full-term births are associated with a longterm reduction in risk (National Cancer Institute, 2003). However, a transient increase in risk after first birth has also been found, with a peak in risk within 5 years after delivery (Pathak, 2002; National Cancer Institute, 2003). This pattern may be due to a growth enhancing effect of oestrogens during pregnancy on premalignant breast cells (Henderson and Bernstein, 1991). It is likely that the susceptibility of the breast tissue cells increase with age. Thus, an adverse effect may be more pronounced after a pregnancy at an older age. However, few studies have investigated whether the risk pattern after pregnancy differs by maternal age at the childbirth, or whether subsequent pregnancies exert an independent adverse effect and whether birth spacing affects the risk pattern.The present study aimed to obtain detailed information on associations between breast cancer risk and timing of births based on follow-up information for 1 691 555 Norwegian women of parity 0 -5, including 22 890 breast cancer cases at ages 20 -74 years. MATERIAL AND METHODSThe present study includes all Norwegian women born in the period 1925 to 1979, who had been residents of Norway for some period after 1960 and thus were included in the Norwegian Population Registry. The present data set is an update (until 1 January 2000) and extension of our previous data set (Albrektsen et al, 1994(Albrektsen et al, , 1995 with information on reproductive history (date of birth for each live born child) and breast cancer. Detailed information on the linking between data from national registers has been given previously ...

In a cohort of 19,731 Norwegian postmenopausal women, the authors analyzed relations between the age at natural menopause and all-cause mortality. A total of 18,533 women died during the 37 years of follow-up from 1961 to 1997. An inverse relation was found between the age at menopause and the all-cause mortality rate (p = 0.003). The strength of the association was moderate, however, with 1.6% (95% confidence interval: 0.6, 2.7) reduced mortality per 3 years' increase in age at menopause. The impact appeared to be stronger in women with an attained age of less than 70 years (3.7% reduction in risk) than in women aged 80 years or more (1.0%). The inverse relation could not be explained by extreme mortality rates in women with very early (<40 years) or late (>55 years) menopause or by possible confounding variables like birth cohort, place of residence, occupational category (own or husband's occupation), body mass index, age at menarche, and first and last delivery or parity. The smoking prevalence was low in the underlying population, and the use of hormone replacement therapy was very rare. The authors conclude that age at natural menopause is inversely related to all-cause mortality.

Associations between reproductive factors and risk of ovarian cancer were examined in a prospective study of 60,565 women in Norway. A total of 445 women were diagnosed as having ovarian cancer during follow-up, from 1961 through 1980. The highest risk was observed among nulliparous women, and the risk decreased significantly with increasing parity. The estimated odds ratio for women with 5 or more births compared with one birth was 0.46, after adjustment for age, urban/rural place of residence and occupational class. Neither age at first or last birth, nor age at menarche or menopause, nor marital status, showed significant associations with ovarian cancer risk after adjustment for parity. The apparent protective effect of high parity was observed for epithelial as well as non-epithelial cancers, and for the separate histological types of epithelial cancer except mucinous cystadenocarcinomas.