Research www. AJOG.

org

ONCOLOGY
Lifetime ovulatory cycles and ovarian cancer risk in 2 Italian
case-control studies
Claudio Pelucchi, ScD; Carlotta Galeone, ScD; Renato Talamini, ScD; Cristina Bosetti, ScD; Maurizio Montella, MD;
Eva Negri, ScD; Silvia Franceschi, MD; Carlo La Vecchia, MD

OBJECTIVE: Several factors that are related to ovulation are relevant to
ovarian cancer risk, but it is unclear whether they can be included in a
single definition of years of ovulation.
STUDY DESIGN: We considered data from 2 case-control studies of
ovarian cancer that were conducted in Italy and included 1822 histo-
logically confirmed cases and 4631 control subjects who were hospi-
talized for acute conditions.
RESULTS: As compared with the lowest quartile, the odds ratios of
ovarian cancer were 1.60 (95% CI, 1.31-1.95), 1.65 (95% CI, 1.34-
2.03), and 1.81 (95% CI, 1.47-2.23) for increasing quartiles of
lifetime ovulatory cycles. For 1 year of ovulation avoided, the con-
tinuous odds ratios were 0.975 (95% CI, 0.965-0.985) for total
ovulatory cycles, 0.91 (95% CI, 0.87-0.95) for parity-related
anovulations, 0.90 (95% CI, 0.76-1.06) for abortions, 0.92 (95%
CI, 0.87-0.97) for oral contraceptive use, 0.99 (95% CI, 0.96-1.03)
for age at menarche, and 0.97 (95% CI, 0.95-0.98) for age at
menopause. Women who reported high numbers of ovulatory cy-
cles and family history of ovarian/breast cancers had an odds ratio
of 3.27 (95% CI, 2.44-4.36).
CONCLUSION: This study found that pregnancy and oral contraceptive
use had a stronger protective effect on ovarian cancer than other
anovulatory factors.
Key words: case-control studies, epidemiologic investigation,
menstrual cycle, ovulation

Cite this article as: Pelucchi C, Galeone C, Talamini R, et al. Lifetime ovulatory cycles and ovarian cancer risk in 2 Italian case-control studies. Am J Obstet
Gynecol 2007;196:83.e1-83.e7

R eproductive, menstrual, and hor-

monal factors have long been re-
lated to ovarian carcinogenesis.1 In 1971,
Fathalla2 introduced the “incessant ovu-
lation” hypothesis, proposing that re-
From the Istituto di Ricerche
Farmacologiche “Mario Negri,” Milan, Italy
(Drs Pelucchi, Galeone, Bosetti, Negri, Dr
La Vecchia); Servizio di Epidemiologia e
Biostatistica, Centro di Riferimento
Oncologico, Aviano, Italy (Dr Talamini);
Servizio di Epidemiologia, Istituto Tumori
⬙Fondazione Pascale,” Naples, Italy (Dr
Montella); International Agency for
Research on Cancer, Lyon, France (Dr
Franceschi); Istituto di Statistica Medica e
Biometria, Università degli Studi di Milano,
Milan, Italy (Dr La Vecchia)
Received March 7, 2006; revised May 31,
2006; accepted June 20, 2006.
Reprints not available from the authors
This work was conducted with the support of
the Italian Association for Cancer Research,
the Italian League against Cancer and the
Italian Ministry of Education (PRIN 2005).
0002-9378/$32.00
© 2007 Mosby, Inc. All rights reserved.
doi: 10.1016/j.ajog.2006.06.088
peated ovulation stimulates cell prolifer-
ation and malignant transformation of
the ovarian epithelium. This hypothesis
was incorporated subsequently by Casa-
grande et al3 in a multistage model of
ovarian carcinogenesis, where relevant
tissue age was defined as the total dura-
tion of exposure to ovulation cycles.
Although several epidemiologic studies
have provided general confirmation of an
association between ovulatory cycles and
ovarian cancer,4-7 a number of these stud-
ies also raised doubts about the adequacy
of the theory by itself. In fact, variable risk
protections against ovarian cancer were
found for various anovulation-related fac-
tors that included late age at menarche,
early menopause, oral contraceptive (OC)
use, pregnancy, and breastfeeding, which
suggests that the protective effect may not
be attributable simply to the inhibition of
ovulatory cycles.8,9
Recently, 2 large case-control studies
tried to clear up the issue by analyzing
together ovulatory cycles and factors that
inhibit ovulation, according to age at
ovulatory exposure and menopausal sta-
tus. Purdie et al6 considered the effects of
age-specific ovulations on ovarian can-
cer risk in a study from Australia and
found the highest risk for ovulations in
the 20 to 29 years of age group (odds ra-
tio [OR], 1.20 for each ovulatory year
during this period). The corresponding
ORs for age groups 30 to 39 and 40 to 49
years were 1.06 and 1.04, respectively.
The effects of pregnancy and OC use
were somewhat greater than those of
other anovulatory factors. Likewise, a US
study reported a direct relation between
years of ovulatory cycles and ovarian
cancer risk (OR, 1.82, for ⬎34.1 as com-
pared with ⬍22.1 ovulatory years) and a
similar protective effect for various
anovulation-related factors.7 Further, a
stronger effect of years of ovulation
emerged for premenopausal women
(OR, 7.94, for ⬎34.1 as compared with
⬍22.1 ovulatory years).
It is now clear that several factors that
are related to ovulation are relevant to
ovarian cancer risk, particularly in pre-
menopausal women. However, it is still
unclear whether the influence of these
factors can be accounted for by a single
mechanism (ie, years of ovulation)

JANUARY 2007 American Journal of Obstetrics & Gynecology 83.e1

Research Oncology
rather than by other effects of parity, OC
use, and age at menarche and meno-
pause on ovarian carcinogenesis.10 To
give further insights on this issue, we
considered data that were derived from 2
large case-control studies of ovarian can-
cer and were conducted in Italy between
1983 and 1999.
M ATERIALS AND M ETHODS
In the first study (1983-1991), data were
collected in the greater Milan area,
northern Italy,11 on 971 women aged 22
to 74 years (median age, 54 years) and
2758 control subjects aged 23 to 74 years
(median age, 52 years). The second study
(1992-1999) was conducted in 4 Italian
areas: greater Milan; the provinces of
Pordenone, Padua, and Gorizia (North-
eastern Italy); the province of Latina
(central Italy); and the urban area of Na-
ples (southern Italy).12 Cases were 1031
women aged 18 to 79 years (median age,
56 years), and control subjects were 2411
women aged 17 to 79 years (median age,
57 years). In both studies, cases were
women who were admitted for incident,
histologically confirmed ovarian cancer
to the major teaching and general hospi-
tals in the areas under surveillance; con-
trol subjects were women who were ad-
mitted to the same hospitals as cases for
acute conditions that were not related to
gynecologic, hormonal, or neoplastic
diseases and who had not undergone bi-
lateral oophorectomy.
Among 5169 control subjects, 30% of
the women had traumatic conditions
(mostly fractures and sprains); 29% had
nontraumatic orthopedic disorders
(mostly low back pain and disc disor-
ders); 16% had acute surgical conditions
(mostly abdominal, such as acute appen-
dicitis or strangulated hernia), and 25%
had miscellaneous other illnesses (such
as eye, ear, and nose disorders). The dis-
tribution of control diagnoses was differ-
ent in the 2 studies; in each study, none
of the diagnosis group included ⬎34%
of control subjects. For both studies,
⬍5% of cases and control subjects who
were approached refused the interview,
and the response rates did not vary ma-
terially across hospitals and geographic
areas.
83.e2 American Journal of Obstetrics & Gynecology JANUARY 2007
All interviews were conducted in the
hospital, with the use of structured ques-
tionnaires that included information on
age, education and other socioeconomic
factors, anthropometric variables, smok-
ing habits, alcohol intake, coffee consump-
tion, food frequency, history of selected
diseases (including a number of gyneco-
logic and reproductive conditions), his-
tory of cancer in first-degree relatives, gy-
necologic and obstetric data, and a history
of the use of OC and hormone replace-
ment therapy (HRT) in menopause. Infor-
mation was obtained specifically on age at
menarche, age at menopause, number of
births, spontaneous and induced abor-
tions, and age at first pregnancy (ending
with both induced or spontaneous abor-
tion or childbirth) and at each birth. Data
were also elicited on lifelong history of use
of OC, HRT, and female hormone prepa-
rations for other indications.
With regard to menstrual and repro-
ductive factors, the 2 questionnaires dif-
fered in information on lactation his-
tory, which was collected only in the
second study, and menstrual cycle pat-
tern, which was collected from 1984 in
the first study and from the start in the
second study. Therefore, this informa-
tion was missing for 168 cases, 516 con-
trol subjects from the first study who
were not asked or did not answer the
question, for 8 cases, and 17 control sub-
jects from the second study who did not
answer the question.
We used self-reported information on
menopausal status and age at meno-
pause to classify women as premeno-
pausal or perimenopausal (these were
grouped together and from here on are
named “premenopausal”) and post-
menopausal. We classified all women
who were ⱖ 56 years old as postmeno-
pausal, independently of what declared
and all women who reported having the
first menopausal symptoms within the
year before the reference date as pre-
menopausal.
Women who declared to be premeno-
pausal, but reported hysterectomy
and/or unilateral oophorectomy (12
cases and 27 control subjects), were
considered premenopausal; similarly,
women who declared to be in postmeno-
pause and reported hysterectomy and/or
www.AJOG.org
unilateral oophorectomy before meno-
pause were given the age at menopause
that they declared (12 cases and 65 con-
trol subjects). We excluded from the
analyses 4 cases and 5 control subjects
who did not report their menopausal
status. Thus, we conducted the analysis
on 1822 cases and 4631 control subjects.
We calculated total years of menstrual
cycles by subtracting age at menarche
from age at the interview or diagnosis for
premenopausal women and from age at
menopause for postmenopausal women.
We estimated the lifetime ovulatory
period for every woman by subtracting
from the total years of menstrual cycles
the total years of any anovulatory period,
which was constituted by pregnancies,
abortions, the use of OCs, and lactation.
This latter value was based on self-re-
ported information that was obtained
for each birth. Nevertheless, we trun-
cated at a maximum of 6 months the du-
ration of lactation per birth, because
suppression of ovulation diminishes
with prolonged breastfeeding.4 We at-
tributed 3 anovulatory months for each
spontaneous or induced abortion, and 9
anovulatory months for each birth. Fi-
nally, we computed the lifetime number
of ovulatory cycles, multiplying the life-
time ovulatory period by the number of
cycles per year based on a woman’s de-
clared cycle length.
We derived OR of ovarian cancer and
the corresponding 95% confidence in-
tervals (CIs) using unconditional multi-
ple logistic regression, which was fitted
by the method of maximum likelihood.
The models included terms for study,
calendar year at interview, age, study
center, education, HRT use, family his-
tory of ovarian/breast cancer in first-de-
gree relatives, and, in turn, lifetime ovu-
latory cycles, parity, abortions, OC use,
menopausal status, and age at menarche.
We performed all the analyses using a
SAS software program (version 8.2; SAS
Institute, Cary, NC).
R ESULTS
Table 1 shows the distribution of cases
and control subjects according to se-
lected baseline characteristics. Cases had
a higher level of education than control
www.AJOG.org Oncology Research

TABLE 1
Distribution of 1822 cases of epithelial ovarian cancer and 4631 controls,* according to age and selected
characteristics (Italy, 1983-1999)
Variable Cases (%) Controls (%) OR† 95% CI OR‡ 95% CI
Age (y)
.......................................................................................................................................................................................................................................................................................................................................................................
⬍45 350 (19%) 1025 (22%)
.......................................................................................................................................................................................................................................................................................................................................................................
45-49 232 (13%) 559 (12%)
.......................................................................................................................................................................................................................................................................................................................................................................
50-54 294 (16%) 655 (14%)
.......................................................................................................................................................................................................................................................................................................................................................................
55-59 300 (16%) 667 (14%)
.......................................................................................................................................................................................................................................................................................................................................................................
60-64 286 (16%) 683 (15%)
.......................................................................................................................................................................................................................................................................................................................................................................
ⱖ65 360 (20%) 1042 (23%)
................................................................................................................................................................................................................................................................................................................................................................................
Education (y)
.......................................................................................................................................................................................................................................................................................................................................................................
⬍7 1004 (55%) 2688 (58%)
.......................................................................................................................................................................................................................................................................................................................................................................
7-12 432 (24%) 1203 (26%)
.......................................................................................................................................................................................................................................................................................................................................................................
ⱖ12 386 (21%) 740 (16%)
................................................................................................................................................................................................................................................................................................................................................................................
Family history of ovarian/
breast cancer
.......................................................................................................................................................................................................................................................................................................................................................................
§ §
No 1610 (89%) 4412 (95%) 1 1
.......................................................................................................................................................................................................................................................................................................................................................................
Yes 208 (11%) 219 (5%) 2.52 2.06, 3.10 2.44 1.99, 2.99
................................................................................................................................................................................................................................................................................................................................................................................
Menopausal status
.......................................................................................................................................................................................................................................................................................................................................................................
§ §
Before 647 (36%) 1671 (36%) 1 1
.......................................................................................................................................................................................................................................................................................................................................................................
After 1175 (64%) 2960 (64%) 0.89 0.71, 1.10 0.90 0.72, 1.12
................................................................................................................................................................................................................................................................................................................................................................................
* In some cases, the sum does not add up to the total because of missing values.
†
ORs and 95% CIs from multiple logistic regression that include terms for study, calendar year at interview, age, and study center.
‡
ORs from multiple logistic regression that include terms for study, calendar year at interview, age, study center, education, family history of ovarian and breast cancer in first-degree relatives, and
menopausal status (where appropriate).
§
Reference category.

subjects and reported more frequently a days, as compared with women with Table 3 reports the ORs of ovarian
history of ovarian/breast cancer in first- menstrual cycles of 26 to 30 days. With cancer and their 95% CI for 1 year of
degree relatives (OR, 2.44; 95% CI. 1.99, reference to the single anovulatory fac- ovulations avoided, according to the
2.99). tors, risk was inversely related to parity same factors considered in Table 2. The
Table 2 gives the distribution of cases (OR, 0.59; 95% CI, 0.47, 0.75 for ⱖ 4 continuous ORs of ovarian cancer were
and control subjects, the ORs of ovarian full-term pregnancies as compared with 0.975 for lifetime ovulatory cycles, 0.91
cancer, and the corresponding 95% CIs nulliparous women) and OC use (OR, for parity, 0.90 for abortions, 0.92 for OC
according to number of lifetime ovula- 0.75; 95% CI, 0.57, 0.98 for ⱖ 2 years of use, 0.99 for age at menarche, and 0.97
tory cycles and to each anovulatory fac- use). There was no significant associa- for age at menopause. The continuous
tor for all women and in strata of meno- tion between ovarian cancer risk and in- ORs in separate strata of menopausal
pausal status. As compared with women complete pregnancies (OR, 0.89 for ⱖ 2 status were not materially different.
in the lowest quartile of number of ovu- abortions) and age at menarche (OR, Table 4 shows the effect of interaction
latory cycles (⬍ 357; ie, ⬍ 27.5 ovulatory 0.95 for ⱖ 15 as compared with ⬍ 13 between the number of ovulatory cycles
years), the ORs were 1.60 (95% CI, 1.31, years). A direct relation emerged with and familiar predisposition to ovarian/
1.95), 1.65 (95% CI, 1.34, 2.03), and 1.81 age at menopause (OR, 1.54 for ⱖ 53 as breast cancers. As compared with
(95% CI, 1.47, 2.23), respectively, for in- compared with ⬍ 45 years). women with a number of lifetime ovula-
creasing quartiles of ovulatory cycles, There were no meaningful differences tory cycles below the median value and
with a significant trend in risk (P ⬍ between ovarian cancer risks that were with no family history of ovarian/breast
.0001). With regard to menstrual cycle observed among pre- and postmeno- cancers in first-degree relatives, the ORs
length, the ORs of ovarian cancer were pausal women because the ORs were were 1.25 for women with a high number
0.90 (95% CI, 0.53, 1.54) for women comparable according to number of of ovulations and no family history, 2.23
with cycles ⬍21 days and 0.57 (95% CI, ovulatory cycles and various anovulatory for women with a low number of ovula-
0.30, 1.08) for women with cycles ⱖ35 factors. tions and a positive family history, and

JANUARY 2007 American Journal of Obstetrics & Gynecology 83.e3

Research Oncology www.AJOG.org

TABLE 2
Distribution of 1822 cases of epithelial ovarian cancer and 4631 controls,* according to number of lifetime
ovulatory cycles and anovulatory factors (Italy, 1983-1999)
All women Premenopausal women Postmenopausal women
Cases:control Cases:control Cases:control
Variable subjects (n) OR 95% CI subjects (n) OR 95% CI subjects (n) OR 95% CI
No. of ovulatory cycles†
................................................................................................................................................................................................................................................................................................................................................................................
Undefined (irregular cycles) 86:248 1.24 0.93, 1.66 36:107 1.09 0.71, 1.67 50:141 1.42 0.95, 2.13
.......................................................................................................................................................................................................................................................................................................................................................................
⬍357 345:1169 1‡ 232:731 1‡ 113:438 1‡
.......................................................................................................................................................................................................................................................................................................................................................................
357-⬍429 456:1086 1.60 1.31, 1.95 175:399 1.49 1.08, 2.06 281:687 1.72 1.31, 2.24
.......................................................................................................................................................................................................................................................................................................................................................................
429-⬍481 456:1059 1.65 1.34, 2.03 106:270 1.31 0.88, 1.93 350:789 1.86 1.43, 2.42
.......................................................................................................................................................................................................................................................................................................................................................................
ⱖ481 479:1069 1.81 1.47, 2.23 98:164 1.91 1.24, 2.95 381:905 1.88 1.45, 2.44
.......................................................................................................................................................................................................................................................................................................................................................................
P trend§ ⬍.0001 .012 ⬍.0001
................................................................................................................................................................................................................................................................................................................................................................................
Menstrual cycle length (d)
................................................................................................................................................................................................................................................................................................................................................................................
Always irregular 86:248 0.84 0.64, 1.09 36:107 0.86 0.57, 1.30 50:141 0.82 0.58, 1.16
.......................................................................................................................................................................................................................................................................................................................................................................
⬍21 20:53 0.90 0.53, 1.54 4:24 0.44 0.15, 1.31 16.29 1.20 0.63, 2.27
.......................................................................................................................................................................................................................................................................................................................................................................
21-25 191:561 0.86 0.72, 1.03 84:239 0.91 0.69, 1.20 107:322 0.82 0.64, 1.04
.......................................................................................................................................................................................................................................................................................................................................................................
26-30 1436:3509 1‡ 475:1173 1‡ 961:2336 1‡
.......................................................................................................................................................................................................................................................................................................................................................................
31-34 77:210 0.87 0.66, 1.16 42:102 0.93 0.62, 1.40 35:108 0.85 0.56, 1.26
.......................................................................................................................................................................................................................................................................................................................................................................
ⱖ35 12:50 0.57 0.30, 1.08 6:26 0.58 0.23, 1.44 6:24 0.54 0.22, 1.36
.......................................................................................................................................................................................................................................................................................................................................................................
P trend§ .41 .80 .42
................................................................................................................................................................................................................................................................................................................................................................................
Parity (n)¶
.......................................................................................................................................................................................................................................................................................................................................................................
1‡ 1‡ 1‡
0.......................................................................................................................................................................................................................................................................................................................................................................
373:486 168:375 205:471
1.......................................................................................................................................................................................................................................................................................................................................................................
372:998 0.93 0.77, 1.11 146:408 0.85 0.64, 1.12 226:590 0.97 0.76, 1.22
2.......................................................................................................................................................................................................................................................................................................................................................................
626:1486 0.94 0.80, 1.11 224:542 0.93 0.71, 1.22 402:944 0.93 0.74, 1.15
3.......................................................................................................................................................................................................................................................................................................................................................................
278:720 0.76 0.62, 0.94 77:240 0.61 0.43, 0.89 201:480 0.81 0.63, 1.05
ⱖ4 173:581 0.59 0.47, 0.75 32:106 0.53 0.33, 0.87 141:475 0.59 0.45, 0.79
.......................................................................................................................................................................................................................................................................................................................................................................
P trend ⬍.001 .006 ⬍.001
................................................................................................................................................................................................................................................................................................................................................................................
Abortion (n)¶
.......................................................................................................................................................................................................................................................................................................................................................................
1‡ 1‡ 1‡
0.......................................................................................................................................................................................................................................................................................................................................................................
1300:3192 471:1156 829:2036
1.......................................................................................................................................................................................................................................................................................................................................................................
309:817 0.94 0.81, 1.10 104:298 0.96 0.74, 1.25 205:519 0.94 0.77, 1.14
ⱖ2 213:622 0.89 0.74, 1.06 72:217 0.95 0.70, 1.30 141:405 0.87 0.70, 1.09
.......................................................................................................................................................................................................................................................................................................................................................................
P trend .21 .44 .35
................................................................................................................................................................................................................................................................................................................................................................................
¶
OC use
.......................................................................................................................................................................................................................................................................................................................................................................
Never 1659:4159 1‡ 524:1293 1‡ 1135:2866 1‡
.......................................................................................................................................................................................................................................................................................................................................................................
⬍2 y 80:200 0.91 0.68, 1.21 59:161 0.91 0.65, 1.28 21:39 0.98 0.55, 1.76
.......................................................................................................................................................................................................................................................................................................................................................................
ⱖ2 y 83:272 0.75 0.57, 0.98 64:217 0.75 0.55, 1.02 19:55 0.78 0.44, 1.36
.......................................................................................................................................................................................................................................................................................................................................................................
P trend .04 .07 .45
................................................................................................................................................................................................................................................................................................................................................................................
at menarche (y)¶
Age .......................................................................................................................................................................................................................................................................................................................................................................
⬍13 778:1915 1‡ 347:773 1‡ 431:1142 1‡
.......................................................................................................................................................................................................................................................................................................................................................................
13-14 778:1991 0.97 0.86, 1.10 249:717 0.76 0.62, 0.93 529:1274 1.10 0.94, 1.30
.......................................................................................................................................................................................................................................................................................................................................................................
ⱖ15 266:725 0.95 0.80, 1.12 51:181 0.71 0.50, 1.00 215:544 1.06 0.86, 1.31
.......................................................................................................................................................................................................................................................................................................................................................................
P trend .49 .005 .40
................................................................................................................................................................................................................................................................................................................................................................................
at menopause (y)¶
Age .......................................................................................................................................................................................................................................................................................................................................................................
⬍45 153:547 1‡
.......................................................................................................................................................................................................................................................................................................................................................................
45-49 344:857 1.54 1.22, 1.96
.......................................................................................................................................................................................................................................................................................................................................................................
50-52 437:969 1.70 1.34, 2.15
.......................................................................................................................................................................................................................................................................................................................................................................
ⱖ53 241:587 1.54 1.18, 1.99
.......................................................................................................................................................................................................................................................................................................................................................................
P trend .002
................................................................................................................................................................................................................................................................................................................................................................................
* In some cases, the sum does not add up to the total because of missing values.
†
ORs adjusted for study, calendar year at interview, age, center, education, hormone replacement therapy use, and family history of ovarian and breast cancer in first degree relatives.
‡
Reference category.
§
Excluding undefined/irregular cycles category.
¶
ORs from multiple logistic regression including terms for study, calendar year at interview, age, center, education, hormone replacement therapy use, family history of ovarian and breast cancer
in first degree relatives, and, in turn, menopausal status, parity, abortion, oral contraceptive use, and age at menarche.
www.AJOG.org Oncology Research

TABLE 3
Continuous ORs* and 95% CIs, according to number of lifetime ovulatory cycles and anovulatory factors
(Italy, 1983-1999)
All women Premenopausal women Postmenopausal women
Variable OR 95% CI OR 95% CI OR 95% CI
No. of ovulatory cycles† 0.975 0.965, 0.985 0.979 0.961, 0.999 0.973 0.961, 0.985
................................................................................................................................................................................................................................................................................................................................................................................
‡
Parity 0.91 0.87, 0.95 0.88 0.81, 0.97 0.92 0.87, 0.96
................................................................................................................................................................................................................................................................................................................................................................................
‡
Abortion 0.90 0.76, 1.06 0.89 0.65, 1.21 0.91 0.75, 1.11
................................................................................................................................................................................................................................................................................................................................................................................
‡
OC use 0.92 0.87, 0.97 0.92 0.86, 0.98 0.92 0.82, 1.03
................................................................................................................................................................................................................................................................................................................................................................................
‡
Age at menarche 0.99 0.96, 1.03 0.93 0.87, 0.99 1.02 0.97, 1.06
................................................................................................................................................................................................................................................................................................................................................................................
‡
Age at menopause — — — — 0.97 0.95, 0.98
................................................................................................................................................................................................................................................................................................................................................................................
* The measurement unit was set at 1 ovulatory year avoided (ie, 13 ovulatory cycles).
†
ORs adjusted for study, calendar year at interview, age, center, education, hormone replacement therapy use, and family history of ovarian and breast cancer in first degree relatives.
‡
ORs from multiple logistic regression including terms of study, calendar year at interview, age, center, education, hormone replacment therapy use, family history of ovarian and breast cancer in
first degree relatives, and, in turn, menopausal status, parity, abortion, oral contraceptive use, and age at menarche.

3.27 for the combination of high number ger than that of a year delay of age at ovulations, which suggests a role that goes
of ovulations and positive family history. menarche or a year anticipation of age at beyond their anovulatory action. Also, dif-
menopause, which indicates that similar ferent types of OCs may have a different
C OMMENT anovulation-related factors have differ- impact on ovarian cancer risk. In the Can-
This uniquely large study confirmed the ent impacts on ovarian cancer risk.5,9,14 cer and Steroid Hormone study, ovarian
direct relation that had been observed in Our study gives additional support to cancer risk was lower among users of high-
previous epidemiologic investigations this hypothesis. Further, the protective progestin potency OC formulations than
between the number of lifetime ovula- effect of a pregnancy seems to be differ- among users of low-progestin formula-
tory cycles and the risk of ovarian cancer. ent at various ages,8,14-16 which suggests tions,17 although another study reported
We observed a 2.5% increase in risk for that (hormonal) factors other than ovu- contrasting results.18 A peculiarity of our
each additional ovulatory year. This re- lation itself are relevant to the process of population was the low proportion of ever
sult was comparable with findings from ovarian carcinogenesis. users of OC and their comparatively short
2 recent US and Australian case-control With reference to the effects of OCs, in a duration of use. Although this does not al-
studies that reported corresponding in- large case-control study from Australia, low us to provide meaningful data on the
creases of 3% and 6%, respectively.6,7 Siskind et al13 found a protection of OC effect of OC use alone, at the same time it
One of our main aims was to deter- use on ovarian cancer that persisted even provides the opportunity to evaluate the
mine whether ovarian cancer risks were after adjustment for the number of lifetime role of ovulatory cycles on ovarian cancer
comparable according to different
anovulatory factors. When we calculated TABLE 4
the risks separately for each factor, we ORs and 95% confidence intervals (CI) of epithelial ovarian cancer
found that pregnancies and OC use had a according to the combined effect of number of ovulatory cycles and
stronger effect on ovarian cancer (ie, familiar predisposition to ovarian/breast cancers (Italy, 1983-1999)
8%-10% decreased risk for each year of
Family history of ovarian/ No. of ovulatory cycles
ovulation avoided) than age at menarche breast cancers in first-
and menopause (ie, 1%-3% decreased degree relatives Less than median value Median value or more
risk) and than the total number of ovu-
No
latory cycles (ie, 2.5% decreased risk). ..............................................................................................................................................................................................................................................

Thus, our findings are only partly consis- Cases:control subjects* (n) 795:2391 815:2021
..............................................................................................................................................................................................................................................
† ‡
tent with the “incessant ovulation” hy- OR (95% CI) 1 1.25 (1.09, 1.42)
..............................................................................................................................................................................................................................................
pothesis, which implies that more com- Yes
..............................................................................................................................................................................................................................................
plex models of carcinogenesis should be Cases:control subjects* (n) 91:112 117:107
invoked. In particular, parity and OC use ..............................................................................................................................................................................................................................................
†
provided a stronger protective effect OR (95% CI) 2.23 (1.65-3.00) 3.27 (2.44, 4.36)
..............................................................................................................................................................................................................................................
than expected for anovulatory action * The sum does not add up to the total because of missing values.
†
alone.9,13 The influence of full-term Estimates from multiple logistic regression that include terms for study, calendar year at interview, age, center, education, and
HRT use.
pregnancy, which implies approximately ‡
Reference category.
1 year of anovulation, was much stron-

JANUARY 2007 American Journal of Obstetrics & Gynecology 83.e5

Research Oncology
risk in a population in which the single
anovulatory factors have different weights
than in other countries. Further, as a con-
sequence of the low use of OC, the average
ovulatory period of the women who were
included in our investigation (32.4 years
for cases, 31.3 years for control subjects)
was substantially higher than in previous
reports.
We found no meaningful differences
between ovarian cancer risks in strata of
menopausal status and age. Some studies
found a stronger protection of years of
ovulation in premenopausal women,7,19
which is consistent with the evidence of
the short-term protection of hormonal
factors on ovarian cancer and their late-
stage effect.20
We considered 2 additional aspects of
the analyses, 1 against and 1 in support of
the ovulation hypothesis. The aspect
against the ovulation hypothesis was the
absence of a systematic association and a
trend in risk between menstrual cycle
length and ovarian cancer. However, cy-
cles of ⬍ 25 or ⬎ 35 days of length may be
more frequently anovulatory.21 In support
was the fact that, when we limited the anal-
yses of age at menopause to women with
early menopause only (⬍ 45 years), as fer-
tility naturally declines with aging, the de-
crease in risk for each year of ovulation
avoided because of early menopause was
7% (95% CI, 2%, 13%), which is a similar
value to parity and OC use.
We critically considered strengths and
limitations of the study. Among the lat-
ter is the selection of control subjects that
was hospital-based, but this may well be
preferable in the analysis of reproductive
factors, because parity may influence re-
sponse rates in population control sub-
jects. Further, information on menstrual
and reproductive history proved to be
reliable among hospital control sub-
jects.22 Specific attention was paid to col-
lect the history of OC and HRT use in a
standardized way, and self-reported OC
history has been shown satisfactorily
valid.23 With further reference to possi-
ble bias, the method used to estimate the
number of ovulatory cycles was rather
imprecise. In fact, not all menstrual cy-
cles are ovulatory and vary within and
between women, according to age and
personal characteristics. However, this
83.e6 American Journal of Obstetrics & Gynecology JANUARY 2007
simple approach is the most commonly
used approach in epidemiologic investi-
gations and allows comparisons across
different studies. In the calculation of the
number of ovulatory cycles, we consid-
ered women with irregular cycles as a
separate category. In fact, Moorman et
al24 found that women who reported
long periods of missed or irregular cycles
had a 60% increased risk of ovarian can-
cer; therefore, episodes of anovulation
because of menstrual disturbances, con-
trary to those related to OC use and preg-
nancy, could increase ovarian cancer
risk. They hypothesized that other con-
ditions of the ovary could be responsible
for the increased risk of both menstrual
disturbances and ovarian cancer and
suggested to take into separate account
women with irregular periods when an-
alyzing lifetime ovulatory cycles. In any
case, in our study, women who reported
lifelong irregular cycles were not associ-
ated with ovarian cancer risk. Among the
strengths of the study are its large size,
which allowed us to obtain precise esti-
mates and to examine the interaction of
lifetime number of ovulatory cycles and
familiar predisposition to ovarian and
breast cancers, and the availability of de-
tailed information that permitted us to
consider the anovulatory factors for each
other.
In conclusion, because years of ovula-
tion is a combination of various factors
that are related to ovarian cancer risk, it
remains difficult to disentangle its role
from that of its components, and selected
reproductive and hormonal factors did not
support the “incessant ovulation” hypoth-
esis. Roles of progesterone stimulation, an-
drogen reduction, and/or suppression of
pituitary gonadotropin secretion21,25 are
among possible alternative explanations
for the stronger protective effect of preg-
nancy and OC use. f 15. Whittemore AS, Harris R, Itnyre J. Charac-
ACKNOWLEDGEMENT
We thank Mrs I. Garimoldi for editorial assis-
tance.
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