Download Menstrual Cycle Patterns and Breast Cancer

[CANCER RESEARCH 38, 4021-4024,
0008-5472/78/0038-OOOOS02.00
November
1978]
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
Using a data set of women who longitudinally recorded
menstrual and reproductive events, we examined men
strual cycle characteristics in relationship to early and
late menarche, early and late menopause, and deferred
parity, three variables epidemiologically related to breast
cancer incidence. Women with late onset of menarche
had longer and more variable cycles in the 10 years after
menarche than did those with early onset. Women with
late onset of menopause had longer and more variable
cycles in the premenopausal interval than did those with
early onset. Cumulative fertility in women after marriage
did not differ according to cycle length and variance. Late
menopause may be a breast cancer risk factor due to
relative estrogen excess and progesterone lack as re
flected in longer, more varied cycle patterns. Observed
cycle differences between women with early and late
menarche await further study of the endocrine physiology
of the menstrual cycle in those groups.
arche and late menopause might have a longer or exagger
ated phase of irregular menstrual cycles and thus a longer
time of relative estrogen excess. We also theorized that the
association of late age at first pregnancy with increased
breast cancer risk was at least in part a manifestation of
involuntary infertility that might be related to abnormalities
of menstrual cycle length and, by inference, inadequate
luteal-phase progesterone production.
With some evidence that relative estrogen excess in the
face of inadequate progesterone is related to the pathogen
esis of hormone-responsive neoplasms (3) and the pre
sumption that this abnormal physiological state could be
inferred from alteration in menstrual cycle patterns, we
hypothesized that early menarche, late menopause, and
late first parity would be associated with such an increased
frequency of menstrual cycle abnormalities. If this held
true, not only might knowledge of pathogenesis improve,
but also women at special risk of breast cancer might be
identified according to cycle patterns for rigorous early
detection programs.
Introduction
Methods
A large body of evidence relates reproductive function
and reproductive hormones to breast cancer. In particular,
epidemiological studies have repeatedly demonstrated al
tered breast cancer risk related to menarchal and menopausal age and to age at first parity (3). While each of these
represents a major event in a woman's reproductive life and
is accompanied by an important change in the endocrine
environment, there has been no interpretation that explains
the risk factors in terms of concomitant hormonal changes.
Knowledge of the mechanism by which endocrine events
alter breast cancer risk would contribute greatly to our
understanding of the underlying pathogenesis of the dis
ease.
In 1974 we formulated an hypothesis attempting to ex
plain some of the epidemiologically derived breast cancer
risk factors in terms of altered reproductive physiology (5).
We had observed that insufficient corpus luteum progester
one production was a common manifestation of disordered
follicular maturation at several stages of reproductive life
and in some infertile women (7). These disorders resulted
in a hormonal environment of estrogen sufficiency in the
absence of the regular, cyclic increases in progesterone
that occur during each normal menstrual cycle. The years
immediately following menarche and immediately prior to
menopause are times when menstrual cycles are most
irregular (10). We suggested that women with early men1 Presented at the John E. Fogarty International Center Conference on
Hormones and Cancer, March 29 to 31, 1978, Bethesda, Md. Supported by
Grant CA-15104 from the National Cancer Institute.
2 To whom requests for reprints should be addressed.
NOVEMBER
To examine the relationship between abnormal cycle
patterns and age at menarche, menopause, and first parity,
we utilized the data set of the Menstrual and Reproductive
History Research Program (10). Beginning in 1934 Dr. A. E.
Treloar enrolled female students from the University of
Minnesota to record menstrual cycle intervals and repro
ductive events through life. Participating women were given
calendars on which they noted all days of vaginal bleeding
and reported related contraceptive, reproductive, and med
ical events. Many returned information each year until
menopause. In addition, many daughters of the original
subjects were enrolled from the time of menarche. To date,
nearly 5000 women have participated, although some
dropped out and others have significant gaps in the conti
nuity of their records.
The results below include data collected through 1975
from all women with sufficient menstrual and reproductive
information for the stage of reproductive life under study.
Subjects taking oral contraceptives or with any gynecolog
ical surgery that might interfere with cycle patterns were
excluded from analysis.
Results
Median 2-year mean cycle length and variance were
examined for the immediate postmenarchal years of women
with different ages at menarche (Chart 1). In the first 2 years
after menarche, there was a consistent positive association
between age at menarche and mean cycle length (p = 0.01,
analysis of variance). This association was lost between 3
1978
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4021
R. B. Wallace et al.
and 10 years after menarche, except for the late-menarche
group, which had consistently longer mean cycles for 10
years after menarche. Table 1 shows the specific findings
for cycle means and standard deviations in the 2-year
interval after menarche. The group with menarche at age
15 to 16 years also showed the greatest cycle variance over
the 10-year study interval.
The relationship between age at natural menopause and
mean cycle length during the years immediately preceding
menopause was examined in Chart 2. There was a signifi
cantly positive correlation between age at menopause and
both cycle length and standard deviation in the 2 years
prior to menopause (p = 0.03). This relationship held in the
third and fourth years prior to menopause (p = 0.02),
although the magnitude of the differences was considerably
less and no relationship was found 5 years or more before
menopause. Table 2 shows specific findings of cycle length
and variance in the 2 years prior to menopause according
to menopausal age.
To determine whether fertility is deferred in association
with unusual cycles, we contrasted the cumulative propor
tion of subjects becoming pregnant in the first 5 years of
marriage according to cycle length and variance during the
2 years prior to marriage. Women who conceived prior to
marriage and those reporting the use of any contraception
were eliminated from the analysis.
For women married between ages 20 and 24, there was
no relationship between cycle characteristics before mar
riage and cumulative proportion becoming pregnant, which
was about 90% within 5 years of marriage (Table 3). For
so
70
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t
50
S
40
<JJ
X
O
5 30
I
20
0
9-10
7-8
5-6
3-4
Years Prior to Menopause
Chart 2. Mean menstrual cycle length prior to menopause according to
age of menopause.
Table 2
Mean cycle length and standard deviation in the 2 years prior to
menopause, according to menopausal age
Menopausal
age
(yr)s
44
45-46
50-54
55 +No.
of sub
jects15
(days)56.9
length
89
164
18Cycle
60.5 ±48.1
68.2 ±54.0
77.9 ±64.0
±46.5"
Mean ±S.D.
Table 3
Cumulative proportion of women pregnant
according to mean cycle length and standard
years before marriage
Marriage age was 20 to 24 years.
ofsub
after marriage
deviation in the 2
pregnant at following
marriage1yr0.540.420.520.450.430.522yr0.850.630.670.6
times after
jects26174215813825Proportion
yr0.960.880.900.840.910.885yr
Meancyclelength
(days)£2627-3536+Mean
o
S.D.(days)s22-67
cycle
s
I"
30
+No.
29
3-4
5-6
7-8
Years After Menarche
Chart 1. Median 2-year mean cycle length after menarche according to
age at menarche.
Table 1
Mean menstrual cycle length and standard deviation according
age at menarche in the 2-year interval after menarche
Age at men
(yr)10-1112131415-16"
arche
of sub
length
jects21871096021Cycle (days)34.1
±11.4°35.2
14.636.4
±
13.138.6
±
16.548.4
±
±23.0
S.D.4022No.
Mean ±
to
women married between ages 25 and 29, there was a trend
toward a decreased cumulative pregnancy rate among
those whose premarriage mean cycle lengths were less
than 27 or more than 34 days (Chart 3; Table 4). These
results were not statistically significantly different from the
5-year pregnancy rate among women with premarriage
mean cycle lengths of 27 to 34 days (p = 0.1), and no
difference was found in cumulative pregnancy rate accord
ing to premarital cycle standard deviation.
Discussion
In women of mature reproductive age, menstruation is a
consequence of an orderly process of follicular maturation,
ovulation, corpus luteum function, and regression, events
CANCER
RESEARCH
VOL.
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38
Cycle Patterns and Breast Cancer Risk
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 radioimmunoassay of pituitary and ovarian hormones showed that the
absent fluctuation of the basal body temperature was in
deed
associated with subnormal corpus luteum progester
I 0.6
one secretion (8, 9, 12). Other studies had demonstrated
i
inadequate corpus luteum function in normal-length or
05
short menstrual cycles occurring at regular intervals in
0
young women some of whom were infertile, and inferences
12345
Years After Marriage
of inadequate corpus luteum function had been made in
infertile regularly menstruating women based on hormonal
Chart 3. Cumulative proportion of women pregnant after marriagi ac
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.
marriage1yr0.500.500.620.490.510.502yr0.610.760.620.750.740.553yr0.710.850.760.840.810.824
times after
ofc
We did discern differences in cycle characteristics in
ih-ouujects28170216912622Proportion
i
women with early versus late menarche and menopause,
yr0.790.900.760.880.870.825yr0.790.910.760.880.880.92
and the finding of increased cycle variability in women with
Meancyclelength
later menopause was consistent with our hormonal hypoth
(days)s
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
cases menstruation was preceded by only a few days of
S.D.(days)<22-6>6No.
cycle
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.
Our data clearly showed a relationship between age at
Longitudinal studies of menstrual cycle length and variabil
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
with early menarche established a pattern of regular cycle
and before menopause (10). Analysis of the data collected
intervals more promptly than did women with late men
in the Menstrual and Reproductive History Research Pro
arche, who as a group had persistently longer and more
gram enabled us to determine whether there were differ
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
some modification of our hypothesis. Since there is appar
differences observed between these groups could be cor
ently no correlation between age at menarche and meno
related with independently determined hormonal character
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
that of a woman's first 20 menstrual cycles 35% are associ
(5).
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 0.3°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
rI °7
NOVEMBER
1978
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4023
ñ.B. Wallace et al.
cycles with an abnormal estrogen-progesterone relation
ship. We cannot determine from our data whether the
proportion of cycles that are associated with deficient
corpus luteum function differs in women with early and late
menarche is known.
While one suggestive trend was noted, in general, study
subjects did not differ in cumulative proportion in becoming
pregnant after marriage according to prior cycle length or
variability characteristics. We did not find information re
garding cycle length that would support our hypothesis or
that would indicate an abnormality in reproductive function
preceding pregnancy. It is possible, however, that our
methods and sample size were not large or sensitive
enough to detect relative infertility in the study cohort.
Clearly, fertility is to a considerable extent determined by
cultural and social characteristics as well as any of the
biological or constitutional factors that may act as facilita
tors or impediments to conception. In addition, we had no
way of discerning that proportion of infertility attributable
to male factors.
In this analysis we have examined only simple measures
of cycle patterns, means, and variance. It is possible that a
single or a small number of episodes of prolonged amenorrhea may be of more pathophysiological importance than
are deviations from average cycle length of, for example, 1
week.
In addition to these studies concerning the association of
menstrual cycle alterations with the various breast cancer
risk factors, we are currently attempting to recontact the
members of the study cohort to determine whether breast
cancer occurred. We will then conduct an empirical analy
sis of breast cancer risk according to various cycle patterns.
Should there be an association of patterns of menstrual
cycle length with increased breast cancer risk, the possibil
4024
ity of identifying groups for rigorous early detection may be
quite realistic.
Acknowledgments
We are grateful to Dr. Stanley G. Korenman for his helpful suggestions
and discussion.
References
1. Dodson, k. S., MacNaughton, M. C., and Coutis, J. R. T. Infertility in
Women with Apparently Ovulatory Cycles. Brit. J. Obstet. Gynaecol., 82:
615-624, 1975.
2. Jones. G. S. The Luteal Phase Defect. Fertility Sterility. 27: 351-356,
1976.
3. MacMahon, B.. Cole. P.. and Brown. J. Etiology of Human Breast
Cancer-A Review. J. Nati. Cancer Inst., 50. 21-42, 1973.
4. Ross, G.T.. Cargille, C. M., Lipsett, M. B., Rayford, P. I., Marshall, J. R.,
Strott, C. A., and Rodbard, D. Pituitary and Gonadal Hormones in
Women during Spontaneous and Induced Ovulatory Cycles. Recent
Progr. Hormone Res., 26. 1-62, 1970.
5. Sherman, B. M., and Korenman, S. G. Inadequate Corpus Luteum
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The Short Luteal Phase. J. Clin. Endocrinol. Metab.. 38: 89-93, 1974.
7. Sherman, B. M., and Korenman, S. G. Hormonal Characteristics of the
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CANCER
RESEARCH
VOL. 38
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Menstrual Cycle Patterns and Breast Cancer Risk Factors
Robert B. Wallace, Barry M. Sherman, Judy A. Bean, et al.
Cancer Res 1978;38:4021-4024.
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