[CANCER RESEARCH 38, 4021-4024, November 1978] 0008-5472/78/0038-OOOOS02.00 Menstrual Cycle Patterns and Breast Cancer Risk Factors1 Robert B. Wallace,2 Barry M. Sherman, Judy A. Bean, James P. Leeper, and Alan E. Treloar Departments of Preventive Medicine and Environmental Health [P. B. W.,J.A. B.,J. P. L.] and Internal Medicine [B. M.S.], University of Iowa, Iowa City, Iowa 52242, and Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, North Carolina 27514 [A. E. T.¡ Abstract arche and late menopause might have a longer or exagger ated phase of irregular menstrual cycles and thus a longer Using a data set of women who longitudinally recorded time of relative estrogen excess. We also theorized that the menstrual and reproductive events, we examined men association of late age at first pregnancy with increased strual cycle characteristics in relationship to early and breast cancer risk was at least in part a manifestation of late menarche, early and late menopause, and deferred involuntary infertility that might be related to abnormalities parity, three variables epidemiologically related to breast of menstrual cycle length and, by inference, inadequate cancer incidence. Women with late onset of menarche luteal-phase progesterone production. had longer and more variable cycles in the 10 years after With some evidence that relative estrogen excess in the menarche than did those with early onset. Women with face of inadequate progesterone is related to the pathogen late onset of menopause had longer and more variable esis of hormone-responsive neoplasms (3) and the pre cycles in the premenopausal interval than did those with sumption that this abnormal physiological state could be early onset. Cumulative fertility in women after marriage inferred from alteration in menstrual cycle patterns, we did not differ according to cycle length and variance. Late hypothesized that early menarche, late menopause, and menopause may be a breast cancer risk factor due to late first parity would be associated with such an increased relative estrogen excess and progesterone lack as re frequency of menstrual cycle abnormalities. If this held flected in longer, more varied cycle patterns. Observed true, not only might knowledge of pathogenesis improve, cycle differences between women with early and late but also women at special risk of breast cancer might be menarche await further study of the endocrine physiology identified according to cycle patterns for rigorous early of the menstrual cycle in those groups. detection programs. Introduction Methods A large body of evidence relates reproductive function To examine the relationship between abnormal cycle and reproductive hormones to breast cancer. In particular, patterns and age at menarche, menopause, and first parity, epidemiological studies have repeatedly demonstrated al tered breast cancer risk related to menarchal and menopau- we utilized the data set of the Menstrual and Reproductive History Research Program (10). Beginning in 1934 Dr. A. E. sal age and to age at first parity (3). While each of these represents a major event in a woman's reproductive life and Treloar enrolled female students from the University of Minnesota to record menstrual cycle intervals and repro is accompanied by an important change in the endocrine ductive events through life. Participating women were given environment, there has been no interpretation that explains calendars on which they noted all days of vaginal bleeding the risk factors in terms of concomitant hormonal changes. and reported related contraceptive, reproductive, and med Knowledge of the mechanism by which endocrine events ical events. Many returned information each year until alter breast cancer risk would contribute greatly to our menopause. In addition, many daughters of the original understanding of the underlying pathogenesis of the dis subjects were enrolled from the time of menarche. To date, ease. nearly 5000 women have participated, although some In 1974 we formulated an hypothesis attempting to ex dropped out and others have significant gaps in the conti plain some of the epidemiologically derived breast cancer nuity of their records. risk factors in terms of altered reproductive physiology (5). The results below include data collected through 1975 We had observed that insufficient corpus luteum progester from all women with sufficient menstrual and reproductive one production was a common manifestation of disordered information for the stage of reproductive life under study. follicular maturation at several stages of reproductive life Subjects taking oral contraceptives or with any gynecolog and in some infertile women (7). These disorders resulted ical surgery that might interfere with cycle patterns were in a hormonal environment of estrogen sufficiency in the excluded from analysis. absence of the regular, cyclic increases in progesterone that occur during each normal menstrual cycle. The years immediately following menarche and immediately prior to Results menopause are times when menstrual cycles are most Median 2-year mean cycle length and variance were irregular (10). We suggested that women with early men- examined for the immediate postmenarchal years of women with different ages at menarche (Chart 1). In the first 2 years 1 Presented at the John E. Fogarty International Center Conference on after menarche, there was a consistent positive association Hormones and Cancer, March 29 to 31, 1978, Bethesda, Md. Supported by Grant CA-15104 from the National Cancer Institute. between age at menarche and mean cycle length (p = 0.01, 2To whom requests for reprints should be addressed. analysis of variance). This association was lost between 3 NOVEMBER 1978 4021 Downloaded from cancerres.aacrjournals.org on October 4, 2021. © 1978 American Association for Cancer Research. R. B. Wallace et al. and 10 years after menarche, except for the late-menarche so group, which had consistently longer mean cycles for 10 70 years after menarche. Table 1 shows the specific findings Q. for cycle means and standard deviations in the 2-year Q 60 £ interval after menarche. The group with menarche at age t 50 15 to 16 years also showed the greatest cycle variance over <JJ S 40 the 10-year study interval. X O The relationship between age at natural menopause and 5 30 mean cycle length during the years immediately preceding I menopause was examined in Chart 2. There was a signifi 20 0 cantly positive correlation between age at menopause and 9-10 7-8 5-6 3-4 both cycle length and standard deviation in the 2 years Years Prior to Menopause prior to menopause (p = 0.03). This relationship held in the Chart 2. Mean menstrual cycle length prior to menopause according to third and fourth years prior to menopause (p = 0.02), age of menopause. although the magnitude of the differences was considerably less and no relationship was found 5 years or more before Table 2 menopause. Table 2 shows specific findings of cycle length Mean cycle length and standard deviation in the 2 years prior to and variance in the 2 years prior to menopause according menopause, according to menopausal age to menopausal age. Menopausal of sub To determine whether fertility is deferred in association age(yr)s jects15 length(days)56.9 with unusual cycles, we contrasted the cumulative propor 44 ±46.5" tion of subjects becoming pregnant in the first 5 years of 45-46 89 60.5 ±48.1 marriage according to cycle length and variance during the 50-54 164 68.2 ±54.0 2 years prior to marriage. Women who conceived prior to 55 +No. 18Cycle 77.9 ±64.0 marriage and those reporting the use of any contraception Mean ±S.D. were eliminated from the analysis. For women married between ages 20 and 24, there was Table 3 no relationship between cycle characteristics before mar Cumulative proportion of women pregnant after marriage riage and cumulative proportion becoming pregnant, which according to mean cycle length and standard deviation in the 2 was about 90% within 5 years of marriage (Table 3). For years before marriage Marriage age was 20 to 24 years. pregnant at following ofsub marriage1yr0.540.420.520.450.430.522yr0.850.630.670.640.670.643yr0.880.790.860.740.830.844times after jects26174215813825Proportion yr0.960.880.900.840.910.885yr0.960.890.900.860.920.88 Meancyclelength (days)£2627-3536+Mean o cycleS.D.(days)s22-67 s I" 30 +No. 29 3-4 5-6 7-8 women married between ages 25 and 29, there was a trend Years After Menarche toward a decreased cumulative pregnancy rate among Chart 1. Median 2-year mean cycle length after menarche according to those whose premarriage mean cycle lengths were less age at menarche. than 27 or more than 34 days (Chart 3; Table 4). These results were not statistically significantly different from the Table 1 5-year pregnancy rate among women with premarriage Mean menstrual cycle length and standard deviation according to age at menarche in the 2-year interval after menarche mean cycle lengths of 27 to 34 days (p = 0.1), and no difference was found in cumulative pregnancy rate accord Age at men of sub ing to premarital cycle standard deviation. arche(yr)10-1112131415-16" jects21871096021Cycle length(days)34.1 ±11.4°35.2 ±14.636.4 Discussion ±13.138.6 ±16.548.4 In women of mature reproductive age, menstruation is a ±23.0 consequence of an orderly process of follicular maturation, S.D.4022No.Mean ± ovulation, corpus luteum function, and regression, events CANCER RESEARCH VOL. 38 Downloaded from cancerres.aacrjournals.org on October 4, 2021. © 1978 American Association for Cancer Research. Cycle Patterns and Breast Cancer Risk was frequently absent from the irregular cycles of postmen- archal and premenopausal women (11). Detailed character ization of the hormonal changes during menstrual cycles in postmenarchal and perimenopausal women by radioimmu- r noassay of pituitary and ovarian hormones showed that the I °7 absent fluctuation of the basal body temperature was in deed associated with subnormal corpus luteum progester I 0.6 i one secretion (8, 9, 12).