Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 2938

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn

The use of hormonal contraception and its protective role

against endometrial and ovarian cancer
Grigoris F. Grimbizis, MD, PhD, Assistant Professor, Basil C. Tarlatzis, MD,
PhD, Professor and Chairman *
1st Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Nea Efkarpia,
Ring Road, 54603-Thessaloniki, Greece

Keywords:
Hormonal contraception has a protective effect over ovarian and
hormonal contraception endometrial cancer development. Relative risk of ovarian cancer
oral contraceptives decreases by w20% for each 5 years of use; it is w50% for 15 years
ovarian cancer of use and decreasing with further use. The protective effect
endometrial cancer gained declines as time passes from its last use, but a signicant
non-contraceptive benets effect remains a long time after ceasing. The effect is independent
primary protection from the type of formulation used. Hormonal contraceptives do
not protect from mucinous types of ovarian tumours. Relative risk
reduction of endometrial cancer is even higher; the estimated
relative risk decrease is w50% with 4 years of use, w70% with 12
years of use and decreasing with further use. After ceasing oral
contraception, the risk begins to rise from its reduced levels but it
is still w50% even after >20 years after its last use. Hormonal
contraception could be used for primary protection from ovarian
and endometrial cancer development.
2009 Elsevier Ltd. All rights reserved.

Hormonal contraception has been introduced in the early 1960s and they have become a dominant
form of female contraception in most developed countries. It is estimated that more than 300 million of
women have used them.1 In United Kingdom, w25% of women aged 1649 years and in USA w20% of
women aged 1544 years take oral contraceptives. The percentages are even higher in younger
population, reaching in UK w60% of women aged 1624 years.2 Often, oral-contraceptive users do it for
prolonged periods and at a time of their life of good health while a great proportion of them are pushed
by their doctors to do so for the non-contraceptive benets of them. Apart from protection from an

* Corresponding author. Tel.: 30 2310 991508; fax: 30 2310 991510.

E-mail addresses: grimbi@med.auth.gr (G.F. Grimbizis), basil.tarlatzis@gmail.com (B.C. Tarlatzis).

1521-6934/$ see front matter 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bpobgyn.2009.08.010
30 G.F. Grimbizis, B.C. Tarlatzis / Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 2938

undesired pregnancy and the risks of pregnancy termination, the relation of these drugs with cancer is
extremely important.1
Ovarian cancer represents a common and rather aggressive type of gynaecological cancer, being
responsible for most of the deaths from gynaecological malignancies.3 Hormonal contraception is
associated with alterations in the biological activity of the ovaries, causing reversible anovulation, as
well as by changes in pituitary function by reducing the levels of gonadotrophins and, consequently, of
ovarian sex steroids. This might reduce the risk of ovarian cancer development. It is true that from past
several years a benecial effect on ovarian cancer risk has been supposed. This supposed protective
effect of hormonal contraception over ovarian cancer might have serious public health implications:
since advances in screening and early diagnosis of ovarian cancer are limited, primary prevention
resulting from hormonal contraception use would be a major progress.3,4
Endometrial cancer has not the unfavourable prognosis of ovarian cancer. However, it has a higher
prevalence than that of ovarian cancer, thus having greater public health signicance.5 Hormonal
contraception seems to be associated with alterations in the mitotic activity of the endometrium and,
as a result, it might alter the risk of endometrial cancer development.5
Nevertheless, after so many years in use, the association of ovarian and endometrial cancers with
oral contraception remains an extremely challenging issue to be answered. Malignancies become
common in women aged above 40 years while oral contraceptives are used mainly by women aged
between 20 and 30 years: this elapsed time makes it difcult to design proper epidemiological studies
with well-studied population. Furthermore, women may use different formulations of oral contra-
ceptives for various periods in their lifetime and the time between cessation of hormonal contraceptive
use and cancer development might differ widely as well. Moreover, ovarian cancer is a histologically
heterogeneous group of tumours with varying invasiveness. These parameters may impact on the
effect of hormonal contraceptives on ovarian and endometrial cancer risk.4,5
This review article aims to estimate the effect of hormonal contraception use on ovarian and
endometrial cancer risk as well as to clarify the role of several parameters that might affect this effect.

Ovarian cancer

Ovarian cancer risk in oral-contraceptive users and the relation with the duration of use

Nowadays, there is a substantial body of epidemiological data examining the relationship between
hormonal contraception and ovarian cancer. Beral, on behalf of the Collaborative Group on Epidemi-
ological Studies of Ovarian Cancer,4 recently has published a collaborative re-analysis of data from 45
epidemiological cohort and case-control studies including 23 257 women with ovarian cancer and
87 303 controls from 21 countries. In total, 31% (7308) of the women with ovarian cancer and 37%
(32717) of the controls had used oral contraceptives and the average duration of use was 4.4 and 5.0
years, respectively. The overall relative risk (RR; stratied by study, age, parity and hysterectomy) for
ever users versus never users was found to be 0.73 (95% condence interval (CI): 0.700.76, p < 0.0001)
(Table 1). Furthermore, the longer the duration of use the lower the risk for ovarian cancer develop-
ment. The overall relative risk decreased by 20% (95% CI: 1823%, p < 0.0001) for each 5 years of use; in
women who had taken oral contraceptives for w15 years, the risk for ovarian cancer was almost halved
and decreasing with further use. It is important to note that the gradual decrease in ovarian cancer risk
observed with increasing duration of use was statistically signicant (p < 0.00001) and seems to start
after at least 1 year of treatment; less than 1-year users versus non-users (mean 0.4 years) had an RR of
1.0 (95% CI: 0.911.10), users for 14 years (mean 2.4 years) had an RR of 0.78 (95% CI: 0.730.83), users
for 59 years (mean 6.8 years) had an RR of 0.64 (95% CI: 0.590.69), users for 1014 years (mean 11.6
years) had a relative risk of 0.56 (95% CI: 0.500.62) and, nally, users for 15 years or more (mean 18.3
years) had a relative risk of 0.42 (95% CI: 0.360.49).
There are also two more recent cohort studies6,7 whose data are not included in the aforementioned
collaborative re-analysis. The Oxford-Family Planning Association (Oxford-FPA) contraceptive study
includes 17 032 women recruited at 17 family planning clinics in England and Scotland at ages 2539
years between 1968 and 1974.6 Some early data on the ovarian cancer incidence in relation to oral
contraceptives have already been published,8 and they have been included in the re-analysis of the
 G.F. Grimbizis, B.C. Tarlatzis / Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 2938 31

Collaborative Group on Epidemiological Studies of Ovarian Cancer.4 However, the latest ndings till the
end of 2004 based on much larger numbers of cases and longer follow-up have recently been
published, including a total of 540 000 woman-years of observation and 58 ovarian cancer cases in the
control group and 48 cases in the oral contraceptives group.6 The overall ovarian cancer relative risk for
ever users versus never users in this study was found to be 0.5 (95% CI: 0.30.7) (Table 1). Furthermore,
this group of investigators found that ovarian cancer risk is signicantly lower in women on oral
contraceptives for more than 4 years, suggesting that a minimum period of use may be necessary to
obtain their protective effect.
The Royal College of General Practitioners oral contraceptive study started in 1968 and, over
a period of 14 months, 23 377 women who were using oral contraceptives and 23 796 women who had
never used them were recruited.7 The latest results including a total of 339 000 woman-years of
observation for never users and 744 000 woman-years for ever users have recently been published. The
mean duration of oral contraceptive use in the study was 44 months. A statistically signicant reduced
ovarian cancer risk (relative risk (RR) 0.51, 95% CI: 0.330.78) was found in ever users of oral contra-
ceptives as compared with never users (Table 1). Furthermore, a statistically signicant gradual
decrease (p 0.0015) with increasing duration of oral contraceptives use was observed: for oral
contraceptive users of <48 months the RR was 0.58 (95% CI: 0.331.04), for users of 4996 months it
was 0.57 (95% CI: 0.301.07) and for users of 97 months the RR was 0.38 (95% CI: 0.160.88).
It seems, therefore, that the use of hormonal contraception has a protective effect over ovarian
cancer development.4,6,7 It is also important to note that a benecial effect seems to exist in women
with a family history or a genetic predisposition to ovarian cancer.9 Narod et al.10 conducted a study on
207 women with a genetic predisposition to ovarian cancer (179 carriers of BRCA1 and 28 carriers of
BRCA2) and 161 sister controls. They found an overall RR (adjusted for geographic area of residence,
age, parity and age at rst birth) of 0.5 (95% CI: 0.30.8) for ever users versus never users. The RR was
even lower with increasing duration of use: for >6 years users it was 0.4 (95% CI: 0.20.7). McGuire
et al.11 have studied ovarian cancer risk in a case control study of 36 BRCA1 carriers with ovarian cancer,
381 non-carriers cases and 568 population controls. A statistically signicantly reduced RR (adjusted
for age, ethnicity and parity) was found for ever users versus never users among non-carriers (RR 0.55,
95% CI: 0.410.75) and a reduced, although not reaching statistical signicance, the RR among carriers
(RR 0.54, 95% CI: 0.261.13). However, the RR for ovarian cancer was statistically signicantly reduced
for use 7 years both in BRCA1 carriers (RR 0.22, 95% CI: 0.070.71) and in non-carriers (RR 0.43, 95%
CI: 0.300.63). A trend for reduced ovarian cancer development was also found in a case-control study
conducted by Whittemore et al., 12 including 147 ovarian cancer cases and 304 controls with BRCA1 and
MRCA2 mutations. The RR was 0.85 for ever users versus never users (95% CI: 0.531.40) and that for
6 years of use 0.62 (95% CI: 0.351.10). However, Modan et al.,13 in a case-control study including 240
ovarian cancer cases carriers of BRCA1 and BRCA2 592 ovarian non-carriers cases and 2257 controls,
failed to nd any protective effect of oral contraceptives on BRCA carriers. The RR for ever users versus
never users, as expected, was 0.53 (95% CI: 0.340.54) in non-carriers but it was 1.07 (95% CI: 0.63
1.83) in carriers. A limitation of the study is thought to be the absence of any information on carrier
status in controls.

Protective effect according to the age of rst use of oral contraceptives and the interval from last use

Another interesting question is whether the protective effect gained with the use of oral contra-
ceptives remains unchanged through womans life or reduces as time passes from the last use of oral
contraceptives.4,6,7 In the re-analysis of the Collaborative Group on Epidemiological Studies of Ovarian
Cancer,4 it was found that the more recent the use of oral contraceptives the lower the RR of ovarian
cancer. The proportional decline in RR per 5 years of oral contraceptive use was found to be 29% for
those who had stopped use <10 years previously, 19% for those who had ceased use 1019 years
previously and 15% for those who had ceased use 2029 years previously (p for trend 0.004). For >30
years elapsed time, there were not sufcient data for permanent conclusions since these patients took
oral contraception for short periods in their life (early periods of oral contraception), but it seems that
even in these patients a reduced risk might exist (Table 2). It is also important to note that the longer
the duration of use the higher the protection irrespective of the time elapsed from ceasing (Table 2).
32 G.F. Grimbizis, B.C. Tarlatzis / Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 2938

Table 1
Ovarian cancer risk and hormonal contraception: epidemiological studies.

Study Study design Population Follow-up Mean duration RR (95% CI)

of use
Collaborative Group Re-analysis of 45 Cases: - Cases: 4.4 years 0.73 (0.700.76)
4
on Ovarian Cancer epidemiological cohort 23257 Controls: 5.0 years
21 Countries and case-control studies Controls:
in case-control design 87303
7
Hannaford et al Cohort Study Ever users: Ever users: 44 months 0.51(0.330.78)
UK Recruitment: 23377 744000
1968-1969 Never users: women-years
23796 Never users:
339000
women-years
6
Vessey and Painter Cohort Study Ever and never Ever users: NR 0.5 (0.30.7)
UK Recruitment: users: 17032 353000
1968-1974 women-years
Never users:
187000
women-years

Furthermore, despite the initial perception that the protective effect lasts only for a certain period of
a womans life after use of oral contraceptives, it seems that a signicant effect remains a long time
after ceasing.4
Data analysis of the Royal College of General Practitioners Study7 by time since last use of oral
contraception has similar ndings; there was a statistically signicant (p for trend 0.041) decline in
the risk of ovarian cancer with longer time since last use. However, the protective effect was found for
at least 15 years after stopping, with reduced (although statistically non-signicant) RR observed still
after longer time intervals. It is impressive that the ndings of the Oxford-Family Planning Association
(Oxford-FPA) contraceptive study6 were in the same direction; there was a trend towards increasing
ovarian cancer risk with time elapsed since oral contraception discontinuation but, a statistically
signicant in this study, protective effect still exists even in the longest interval group (>20 years).
Another parameter that was studied is whether the age of onset of oral contraception plays a role in
ovarian cancer risk protection. When duration of use and time since last use were taken into account in the
collaborative re-analysis of the epidemiological studies of ovarian cancer,4 the age of onset of oral
contraception seems to play no role on the protection from ovarian cancer risk, not even the age of last use.

Table 2
Ovarian cancer risk in ever users versus never users of oral contraceptives by time since last use and duration of use. Adapted
from reference. 4

Ever-users Duration of oral contraceptives use Decline in risk %

for every 5 years
<5 years 5-9 years 10 years
of use (95% CI)
Current or use <10 years previously
Relative risk (95% CI) 0.57 (0.50-0.64) 0.88 (0.75-1.04) 0.52 (0.43-0.64) 0.39 (0.33-0.47) 28.9 (23.0-34.3)
Mean duration of use 5.8 years 1.7 years 7.2 years 14.7 years

Last use 1019 years previously

Relative risk (95% CI) 0.67 (0.62-0.73) 0.85 (0.75-0.97) 0.62 (0.53-0.73) 0.51 (0.44-0.59) 19.4 (14.2-24.2)
Mean duration of use 5.6 years 1.6 years 6.9 years 13.8 years

Last use 20-29 years previously

Relative risk (95% CI) 0.76 (0.710.97) 0.81 (0.740.89) 0.69 (0.600.78) 0.60 (0.510.72) 15.1 (8.521.2)
Mean duration of use 4.6 years 1.8 years 6.7 years 11.8 years

Last use 30 years previously

Relative risk (95% CI) 0.86 (0.760.97) 0.83 (0.730.95) Insufcient data Insufcient data Insufcient data
Mean duration of use 2.5 years 1.5 years

All relative risks were adjusted for study, age, parity and hysterectomy.
 G.F. Grimbizis, B.C. Tarlatzis / Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 2938 33

Protective effect according to the formulations of oral contraceptives

During the past decades, new formulations of oral contraceptives containing fewer amounts of
oestrogen and progestins as well as new progestins come on the market. It is obvious that most of the
epidemiological studies involved women who primarily have used older formulations containing
higher doses of oestrogen (50 mg) and progestins.7 This is due to the fact that ovarian cancer usually
develops in the age of 50s after oral contraception use. Although, low-dose pills effectively suppress
ovulation, they might have a different effect in suppression of gonadotropin levels and, thus, their
protective effect could be different from the older higher-dose preparations.4,14
An answer to this question was attempted in the collaborative re-analysis of the epidemiological
studies of ovarian cancer4 by dividing the women according to the mid-year of use in 1960s, 1970s and
1980s; oral contraceptives typically used in 1980s contained less than one half of the dose of those
typically used in the 1960s with those used in the 1970s being in the middle. The investigators found
that for a given time since last use, the calendar year of use had no effect on the ovarian cancer risk.
Thus, they concluded that the lower-dose oral contraceptives have a similar protective effect on ovarian
cancer risk.4
Similar nding were reported by Ness et al.14 in their case-control study, who found that ovarian
cancer risk reduction was similar in women who started oral contraception before 1972, between 1972
and 1980 and after 1980. However, this group of investigators attempted a direct answer by further
dividing cases and controls in those taken high oestrogen/high progestin and those taken low
oestrogen/low progestin formulations; they found an identical RR in the low-dose users (RR 0.5, 95%
CI: 0.30.6) and in the high-dose ones (RR 0.5, 95% CI: 0.30.7).

Protective effect according to the tumour histology

As already mentioned, ovarian cancer represent a heterogeneous group of tumours with varying
invasiveness. An interesting question is whether hormonal contraception has the same protective
effect irrespective of tumour type. In the collaborative re-analysis of the epidemiological studies of
ovarian cancer,4 a sub-analysis of the ovarian cancer cases according to the histological subtype has
been made; data for histological subtype were available in 33 out of 45 epidemiological studies
including 17 099 out of 23 257 cases. It should be noted that, among these women, ovarian cancer risk
declined by 21% for each 5 years of hormonal contraception use, which is similar to the 20% observed in
all women, thus indicating that the results were representative of the whole population.
The protective effect for every 5 years use of hormonal contraception was broadly similar for
epithelial and non-epithelial tumours (Table 3). However, among the epithelial tumours, there was
heterogeneity across histological types (test for heterogeneity p 0.0007). This was due to the fact that
hormonal contraception seems to have little or no effect on mucinous types of ovarian tumours
whereas the protective effect seems to be almost similar in the other types (serous, endometroid and
clear cells) of epithelial tumours. Furthermore, the ndings did not differ when mucinous and serous
ovarian cancer cases were divided according to their invasiveness in malignant and borderline ones
(Table 3). It seems, therefore, that the proportional risk reduction is similar between the different
histological types irrespective of their invasiveness, with the exception of mucinous tumours whose
incidence seems to be affected very marginally.4

Endometrial cancer

Endometrial cancer risk in oral-contraceptive users and relation with the duration of use

Published epidemiological data support the notion that the use of oral contraceptives has
a protective effect over endometrial cancer development. Schlesselman5 has published a meta-analysis
of epidemiological published until 1996; a total of 10 case-control studies including 1728 cases and
6243 controls and one cohort study including in total w440 000 woman-years of observation were
meta-analysed whereas ve case-control studies and one cohort study were not included due to
ineligibility (Table 4). A statistically reduced RR for endometrial cancer was observed, and this RR was
34 G.F. Grimbizis, B.C. Tarlatzis / Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 2938

Table 3
4
Reduction in ovarian cancer risk for every 5 years use according to ovarian tumours histology. Adapted from reference.

Histological type Cases Decline in risk for

every 5 years of use (SE)
All with recorded histology 17099 20.5 (1.9)
Epithelial
Clear cell 740 21.3 (7.3)
Endometroid 1994 27.1 (4.8)
Mucinous 2027 4.0 (4.7)
Mucinous malignant 1412 6.7 (5.8)
Mucinous borderline 615 1.5 (7.7)
Serous 7131 20.9 (2.7)
Serous malignant 6263 22.1 (2.9)
Serous borderline 868 13.0 (6.8)
Other/mixed 3436 20.8 (3.9)
Non-epithelial 589 19.7 (10.8)
Malignant/not specied 1182 25.8 (7.8)

Percent reduction in the risk was adjusted for study, age, parity and hysterectomy.

negatively associated with the duration of oral contraceptive use as found by regression analysis of the
data; the equation for endometrial cancer RR estimation according to the years of use was found to be
RRdur exp[0.0230.493  ln(years 1)] where exp denotes exponential function and ln natural
logarithm. Thus, the estimated RR reduction for endometrial cancer in oral contraceptive users is 56%
with 4 years of use, 67% with 8 years of use and 72% with 12 years of use (RR 0.44, 0.33 and 0.28,
respectively, p for trend < 0.0001).
A statistically signicant reduced risk for uterine cancer was also found in the Oxford-FPA
contraceptive study.6 Till the end of 2004, during 540 000 woman-years of observation, 50 uterine
body cancer cases were observed in the control and 27 cases in the oral contraceptives group (Table 4).
The overall uterine cancer RR for ever users versus never users in this study was found to be 0.3 (95% CI:
0.20.6). Furthermore, this group of investigators also found that the association of RR of uterine cancer
with the duration of oral contraceptives use was negative and statistically signicant; the estimated RR
was 0.6 (0.31.1) for up to 48 months users, 0.4 (0.20.8) for 4996 months users and 0.1 (0.00.4) for
97 months users (p for trend < 0.001). The protective effect seems to be signicantly lower in women

Table 4
Endometrial and/or uterine body cancer risk and hormonal contraception: epidemiological studies.

Study Study design Population Follow-up Mean duration RR (95% CI)

of use
Schlesselman 5 Meta-analysis 10 Case-control 1 Cohort study 4 to 12 years 0.44 to 0.28
Endometrial & of 10 case-control studies Ever users: (p < 0.0001)
uterine cancer/6 and 1 cohort study Cases: 1728 182900
Countries Controls: 6243 women-years
Never users:
257000
women-years
6
Vessey and Painter Cohort Study Ever and Ever users: NR 0.3 (0.20.6)
Uterine/UK Recruitment: never users: 353000
1968-1974 17032 women-years
Never users:
187000
women-years
7
Hannaford et al Cohort Study Ever users: Ever users: 44 months 0.47 (0.270.81)
Uterine/UK Recruitment: 23377 744000
1968-1969 Never users: women-year
23796 Never users:
339000
women-years
 G.F. Grimbizis, B.C. Tarlatzis / Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 2938 35

taken oral contraceptives for more than 4 years, suggesting that a minimum period of use may be
necessary to obtain their protective effect.5
The results of the Royal College of General Practitioners oral contraceptive study7 were similar as
well. For a mean duration of 44 months use, a statistically signicant (adjusted for age, parity, smoking,
social status and hormone replacement therapy) reduced uterine body cancer risk (RR 0.47, 95% CI:
0.270.81) was found in ever users of oral contraceptives as compared with never users. Furthermore,
a statistically signicant gradual decrease (p for trend 0.0287) with increasing duration of oral
contraceptives use was observed; oral contraceptive users of <48 months had an RR of 0.60 (95% CI:
0.301.21), users of 4996 months had an RR of 0.14 (95% CI: 0.080.58) and users of 97 months had
an RR of 0.57 (95% CI: 0.271.19).

Protective effect according to the interval from last use of oral contraceptives

A part of the apparent protective effect gained from the use of oral contraceptives seems to be lost as
time passes from their last use. In the meta-analysis of the 11 epidemiological studies,5 it was found
that the more recent the use of oral contraceptives the lower the RR of endometrial cancer. The
equation for endometrial RR estimation according to the years since last use (recency of use) was found
to be RRrec exp [1.721 0.346  ln(years 1)] where exp denotes exponential function and ln
natural logarithm. It seems, therefore, that after ceasing oral contraception the risk of endometrial
cancer begins to rise from its reduced levels; the estimated RR was 0.33, 0.41 and 0.51 for 5, 10 and 20
years of discontinuation, respectively (p for trend 0.011). However, it should be noted that even after
>20 years of ceasing the protective effect is still statistically signicant and almost 50% below that of
women who have never used oral contraceptives. It is also important to note that a signicant nding
of this meta-analysis5 is that the longer the duration of use the higher the protection irrespective of the
time elapsed from ceasing.
The ndings from the Royal College of General Practitioners Study7 were analogous; a statistically
signicant (p for trend 0.041) decline in the RR (adjusted for age, parity, smoking, social status and
hormone replacement therapy) of uterine body cancer was observed as the interval since oral
contraceptives last use increases. However, the protective effect was found to last for at least 20 years
after stopping with reduced (although statistically non-signicant) RR observed still after longer time
intervals. It is remarkable that the ndings of the Oxford-FPA contraceptive study6 were similar. There
was a statistically signicant (p for trend < 0.05) decline in the protective effect over uterine cancer as
time elapsed since oral contraception discontinuation (estimated RR 0.1, 0.4 and 0.5 for 412, 1220
and >20 years of discontinuation, respectively). However, in this study, a statistically signicant
protective effect still existed even in the longest interval group; the RR for users of >20 years was 0.5
(95% CI: 0.30.9). These data support the notion that the protective effect of oral contraceptives over
endometrial cancer development seems to be persistent.57

Biological explanation of the protective effect

The biological mechanism through which hormonal contraception exerts its protective effect is
based on the current theories of ovarian and endometrial carcinogenesis. According to the incessant
ovulation hypothesis, rst proposed by Fathalla in the early 1970s15 for the explanation of ovarian
carcinogenesis, it was supposed that defective cellular repair after ovulation represents the major risk
factor for ovarian cancer.15,16 However, more recent ndings led to the assumption that ovarian cancer
development is attributed to either activated proto-oncogenes or inactivated tumour-suppressor
genes.17,18 It seems, therefore, that abnormalities of genomic DNA quantity and quality and the
resulting defective cellular repair during ovarian healing process after ovulation is the causal factor
and, thus, incessant ovulation as proposed by Fathalla is related rather to the disease manifestation
than to disease aetiology.19
Consequently, the protective effect of oral contraceptives over ovarian cancer development seems to
be attributed to the resulting anovulation during their use not allowing genetic predisposition cellular
repair defects to be expressed.19 This also explains the time-dependent effect of their use as well as the
observed protective effect in women with a family history or a genetic predisposition to ovarian cancer.
36 G.F. Grimbizis, B.C. Tarlatzis / Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 2938

Table 5
Cumulative incidence of endometrial per 100000 women in oral contraceptive users for 4, 8 and 12 years and in never users.
Adapted from reference. 5

Oral contraception use Estimated number of cases per 100000 women (95% CI)

Age 2054 years Age 2074 years

USA Japan USA Japan

Never users 447 136 2396 473
4 years use 283 (203394) 86 (62119) 1696 (11852427) 328 (230469)
8 years use 241 (180322) 73 (5597) 1522 (10932118) 292 (211405)
12 years use 213 (165277) 65 (5084) 1417 (10371937) 271 (199368)

Prolonged and unremitting mitotic activity of the endometrium due to unopposed oestrogenic
stimulation seems to underlie the development in most of the cases of endometrial adenocarcinoma.20
The use of oral contraceptives seems to suppress endometrial mitotic activity and, thus, reduce the risk
of cancer development.5 This explains the time-dependent effect of oral contraception as well as the
loss of a part of the protective effect as time passes from its last use and oestrogenic stimulation and
any pathophysiologic disturbances associated with it.21

Public health implications

Ovarian cancer is an aggressive and fatal disease. Advances in early diagnosis and screening seem to
be very slow and, despite progresses in ovarian cancer treatment, long-term survival mortality rates
remain poor.3 Endometrial cancer is a common gynaecological malignancy having serious public
health importance as well.5 Thus, the primary protection that could be offered from use of hormonal
contraception seems to be useful.
However, the main question to be answered is whether the overall risk from cancer is affected since
it is also known that hormonal contraception increases the risk mainly of cervical and less of central
nervous system cancers.6,7 It is important that both large cohort epidemiological studies found a net
overall protection from cancer development from hormonal contraception use. Hannaford et al.7
estimated that the overall absolute reduction in risk of any cancer among oral contraceptive ever users
versus never users was 1045 cases (depending on the database used) per 100 000 woman-years.
Moreover, Vessey and Painter6 in a pooled re-analysis of data for cervical, uterine and ovarian cancer in
ever users versus never users have found an overall RR of 0.7 (95% CI: 0.50.8). It seems, therefore, that
the benecial effect of hormonal contraception on uterine and ovarian cancer outweighs the harmful
effect on cervical cancer.6,7
Furthermore, Beral and colleagues in their collaborative report have suggested that during the past
50 years some 200 000 cases of ovarian cancer and 100 000 deaths have been already prevented from
the use of oral contraceptives.4 The same authors have calculated that, at the current ovarian cancer
incidence rates and oral contraceptive users, almost 30 000 ovarian cancer cases could be prevented
every year.4
Interestingly, Schelesseman5 has calculated the estimated cumulative incidence of endometrial
cancer through age 74 years (Table 5). In USA, never users of oral contraceptives have an estimated
cumulative incidence of 2.4% while users for 4, 8 and 12 years have an expected reduction in the
incidence to 1.7%, 1.5% and 1.4%, respectively.
These ndings set a new standard in primary protection from endometrial and ovarian malig-
nancies and seem to have important public health implications.25 It should also be noted that primary
protection from cervical cancer could based on vagination for HPV.

Conclusions

Hormonal contraception seems to be associated with a statistically signicant protective effect for
ovarian and endometrial cancer development. The ovarian cancer RR seems to decrease by 20% for each
 G.F. Grimbizis, B.C. Tarlatzis / Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 2938 37

5 years of use and for women who had taken oral contraceptives for w15 years the risk for ovarian
cancer is almost halved and decreasing with further use. A minimum period of 1-year use is necessary
to obtain the protective effect. A benecial effect seems also to exist in women with a family history or
a genetic predisposition to ovarian cancer, but further studies are needed to fully elucidate this issue.
The protective effect gained with oral contraceptives declines as time passes from their last use. The
more recent the use of oral contraceptives the lower the RR of ovarian cancer. However, the longer the
duration of use the higher the protection irrespective of the time elapsed from ceasing. Furthermore,
despite the initial perception that the protective effect lasts only for a certain period of womans life
after oral contraceptives use, it seems that a signicant effect remains a long time after ceasing. The
protective effect seems to be independent from the type of oral contraceptives formulation. Further-
more, the protection from ovarian cancer is similar among the different histological types irrespective
of their invasiveness with the exception of mucinous types.
The protective effect of oral contraceptives seems to be even higher for endometrial cancer. The
estimated RR reduction in oral contraceptive users is w50% with 4 years of use and it is increasing to
w70% with 12 years of use. After discontinuing oral contraception, the risk of endometrial cancer
begins to rise from its reduced levels. However, it should be noted that even after >20 years of
discontinuation, the protective effect is still statistically signicant and almost 50% below that of
women who have never used oral contraceptives. Moreover, the longer the duration of use the higher
the protection irrespective of the time elapsed from discontinuation. It is still obscure if this protective
effect is similar among the different histological types and if the different oral contraceptive formu-
lations have a different degree of protection.
Importantly, the use of hormonal contraception might set a new standard for primary protection
from gynaecological malignancies.

Practice points

Ovarian cancer risk and oral contraception

 The ovarian cancer RR decreases by 20% for each 5 years of oral contraceptive use and it is
almost 50% for 15 years of use.
 A minimum period of 1-year use seems to be necessary to obtain a marginally signicant
protective effect.
 A benecial effect seems also to exist in women with a genetic predisposition to ovarian
cancer development.
 The protective effect gained with hormonal contraception reduces as time passes from its last
use, but a signicant effect remains for a long time after ceasing.
 The longer the duration of use the higher the protection, irrespective of the time passed from
ceasing.
 The protective effect is similar between the different histological types, with the exception of
mucinous tumours.
 The protective effect is similar with the use of different formulations.

Endometrial cancer risk and oral contraception

 The estimated RR decrease for endometrial cancer is w50% for 4 years of oral contraceptive
use and w70% for 12 years of use.
 A minimum period of use is necessary to obtain the protective effect.
 After ceasing oral contraception, the risk of endometrial cancer begins to rise from its reduced
levels.
 The protective effect is still w50% below that of never users, even after >20 years of ceasing.
 The protective effect according to the different types of endometrial tumours is not known.
 The protective effect according to the different formulations is not known.
38 G.F. Grimbizis, B.C. Tarlatzis / Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 2938

Research agenda

 To estimate the minimum period of oral contraceptives use necessary to obtain the
protective effect for ovarian and endometrial cancer.
 To estimate the protection that remains long after ceasing hormonal contraception.
 To estimate the effect of different formulations mainly on endometrial and more systemat-
ically on ovarian cancer.
 To estimate the protective effect according to the different histological types of endometrial
tumours.
 To further investigate if oral contraception could be used as a standard in primary protection
from ovarian and endometrial cancer.

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