Menstrual Cycle Patterns and Breast Cancer Risk Factors1

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[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.Â¡

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

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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 Â£ interval after menarche. The group with menarche at age t 50 15 to 16 years also showed the greatest cycle variance over

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 Â±46.5" tion of subjects becoming pregnant in the first 5 years of 45-46 89 60.5 Â±48.1 marriage according to cycle length and variance during the 50-54 164 68.2 Â±54.0 2 years prior to marriage. Women who conceived prior to 55 +No. 18Cycle 77.9 Â±64.0 marriage and those reporting the use of any contraception Mean Â±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)Â£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 Â±11.4Â°35.2 Â±14.636.4 Discussion Â±13.138.6 Â±16.548.4 In women of mature reproductive age, menstruation is a Â±23.0 consequence of an orderly process of follicular maturation, S.D.4022No.Mean Â± ovulation, corpus luteum function, and regression, events

CANCER RESEARCH VOL. 38

was frequently absent from the irregular cycles of postmenarchal 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 Â°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). Other studies had demonstrated 05 inadequate corpus luteum function in normal-length or short menstrual cycles occurring at regular intervals in 0 12345 young women some of whom were infertile, and inferences Years After Marriage of inadequate corpus luteum function had been made in Chart 3. Cumulative proportion of women pregnant after marriagi ac infertile regularly menstruating women based on hormonal cording to mean cycle length prior to marriage. studies or the findings of premenstrual endometrial biopsy (1, 2, 6). Inadequate corpus luteum function has also been Table 4 described in some women with features of the polycystic Cumulative proportion of women pregnant after marriage ovarian syndrome, a disorder associated with infertility and according to mean cycle length and standard deviation in the 2 increased breast cancer risk (3, 5). In all of these situations years before marriage when the luteal-phase plasma progesterone concentration Marriage age was 25 to 29 years. was subnormal, estradici concentrations in the range were pregnant at following observed in menstruating women. ofc marriage1yr0.500.500.620.490.510.502yr0.610.760.620.750.740.553yr0.710.850.760.840.810.824times after iih-ouujects28170216912622Proportion We did discern differences in cycle characteristics in yr0.790.900.760.880.870.825yr0.790.910.760.880.880.92women with early versus late menarche and menopause, Meancyclelength and the finding of increased cycle variability in women with (days)s later menopause was consistent with our hormonal hypoth 2627-3536 esis. In related studies we showed that the irregular vaginal bleeding in perimenopausal women was the result of irreg +Mean ular maturation of residual ovarian follicles (8). In many cycleS.D.(days)<22-6>6No. cases menstruation was preceded by only a few days of limited progesterone secretion or in some instances by a rise and fall of estradiol unaccompanied by a detectable increase in progesterone, examples of anovulatory bleed ing. Late menopausal age is also a risk factor for endome trial cancer which may also be related to persistent estrogen accompanied by well-defined hormonal changes (4, 7). stimulation. Longitudinal studies of menstrual cycle length and variabil Our data clearly showed a relationship between age at ity have shown the greatest stability during the middle years menarche and menstrual cycle length and variance; how of reproductive life and the most variation after menarche ever, it was opposite to the direction predicted. Women and before menopause (10). Analysis of the data collected with early menarche established a pattern of regular cycle in the Menstrual and Reproductive History Research Pro intervals more promptly than did women with late men gram enabled us to determine whether there were differ arche, who as a group had persistently longer and more ences in menstrual cycle patterns in women with early variable cycles for up to 10 years after menarche. Thus, versus late menarche, early versus late menopause, and while cycle differences exist between women with early and early versus late age at first parity. We proposed that late menarche, interpretation of this observation requires differences observed between these groups could be cor some modification of our hypothesis. Since there is appar related with independently determined hormonal character ently no correlation between age at menarche and meno istics and inferences made regarding the endocrine patho- pause, one possibility is that women with early menarche physiology of the breast cancer risk that accompanies early have a greater number of menstrual cycles and thus a menarche, late menopause, and late age at first parity. greater cumulative hormone exposure. More specifically, we predicted that a situation of relative In this study our hormonal hypothesis was testable only estrogen sufficiency and absent or inadequate, regular as far as luteal-phase insufficiency might be manifest by progesterone secretion would be associated with early some alteration in menstrual cycle length or variance, and menarche, late menopause, and involuntary infertility (i.e., it is possible that such defects occur in women with entirely late age at first pregnancy) and that they might be indicated regular menstrual histories. By longitudinal analysis of by the demonstration of abnormal cycle length and variance basal body temperature records, Vollman (11) has shown (5). that of a woman's first 20 menstrual cycles 35% are associ That hypothesis was based on several observations. ated with monophasic records indicating poor corpus lu When determination of basal body temparatures was added teum function. This incidence decreased to 25% in the to studies of menstrual cycle length, the thermal shift, an second 20 cycles and to 10% in the third 20 cycles. Thus increase of about 0.3Â°Cor more in the basal temperature women with early menarche not only have earlier and more that occurs during the second half of the menstrual cycle, prolonged exposure to sex steroids but also may well have

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Downloaded from cancerres.aacrjournals.org on October 4, 2021. © 1978 American Association for Cancer Research. Ã±.B. Wallace et al. cycles with an abnormal estrogen-progesterone relation ity of identifying groups for rigorous early detection may be ship. We cannot determine from our data whether the quite realistic. proportion of cycles that are associated with deficient corpus luteum function differs in women with early and late Acknowledgments menarche is known. We are grateful to Dr. Stanley G. Korenman for his helpful suggestions While one suggestive trend was noted, in general, study and discussion. subjects did not differ in cumulative proportion in becoming pregnant after marriage according to prior cycle length or References variability characteristics. We did not find information re garding cycle length that would support our hypothesis or 1. Dodson, k. S., MacNaughton, M. C., and Coutis, J. R. T. Infertility in Women with Apparently Ovulatory Cycles. Brit. J. Obstet. Gynaecol., 82: that would indicate an abnormality in reproductive function 615-624, 1975. preceding pregnancy. It is possible, however, that our 2. Jones. G. S. The Luteal Phase Defect. Fertility Sterility. 27: 351-356, methods and sample size were not large or sensitive 1976. 3. MacMahon, B.. Cole. P.. and Brown. J. Etiology of Human Breast enough to detect relative infertility in the study cohort. Cancer-A Review. J. Nati. Cancer Inst., 50. 21-42, 1973. Clearly, fertility is to a considerable extent determined by 4. Ross, G.T.. Cargille, C. M., Lipsett, M. B., Rayford, P. I., Marshall, J. R., cultural and social characteristics as well as any of the Strott, C. A., and Rodbard, D. Pituitary and Gonadal Hormones in Women during Spontaneous and Induced Ovulatory Cycles. Recent biological or constitutional factors that may act as facilita Progr. Hormone Res., 26. 1-62, 1970. tors or impediments to conception. In addition, we had no 5. Sherman, B. M., and Korenman, S. G. Inadequate Corpus Luteum Function: A Pathophysiological Interpretation of Human Breast Cancer way of discerning that proportion of infertility attributable Epidemiology. Cancer, 33: 1306-1312, 1974. to male factors. 6. Sherman, B. M., and Korenman, S. G. Measurement of Plasma LH, FSH, In this analysis we have examined only simple measures Estradici and Progesterone in Disorders of the Human Menstrual Cycle: The Short Luteal Phase. J. Clin. Endocrinol. Metab.. 38: 89-93, 1974. of cycle patterns, means, and variance. It is possible that a 7. Sherman, B. M., and Korenman, S. G. Hormonal Characteristics of the single or a small number of episodes of prolonged amen- Human Menstrual Cycle throughout Reproductive Life. J. Clin. Invest., orrhea may be of more pathophysiological importance than 55:699-706, 1975. 8. Sherman, B. M., West, J. H., and Korenman, S. G. The Menopausal are deviations from average cycle length of, for example, 1 Transition: Analysis of LH, FSH, Estradici and Progesterone Concentra week. tions during Menstrual Cycles of Older Women. J. Clin. Endocrinol. Metab..42: 629-636, 1976. In addition to these studies concerning the association of 9. Strott, C. A., Cargille, C. M., Ross, G. T., and Lipsett, M. B. The Short menstrual cycle alterations with the various breast cancer Luteal Phase. J. Clin. Endocrinol. Metab., 30: 246-261, 1970. risk factors, we are currently attempting to recontact the 10. Treloar, A. E., Boynton, R. E., Behn. B. G., and Brown, B. W. Variation of the Human Menstrual Cycle through Reproductive Life. Intern. J. members of the study cohort to determine whether breast Fertility, 12: 77-126, 1967. cancer occurred. We will then conduct an empirical analy 11. Vollman, R. F. The Menstrual Cycle, 193 pp. Philadelphia: W. B. Saunders Company, 1977. sis of breast cancer risk according to various cycle patterns. 12. Winter, J. S. D., and Faiman, C. The Development of Cyclic Pituitary- Should there be an association of patterns of menstrual Gonadal Function in Adolescent Females. J. Clin. Endocrinol. Metab., cycle length with increased breast cancer risk, the possibil 37: 714-718, 1973.

4024 CANCER RESEARCH VOL. 38

Robert B. Wallace, Barry M. Sherman, Judy A. Bean, et al.

Cancer Res 1978;38:4021-4024.

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