Gynecological Cancer and Contraceptive Pill

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Introduction

We do not have level-one evidence from

randomised clinical trials regarding the

association of use of the contraceptive pill with

malignancy. As few of the epidemiologicalstudies are sufficiently large to precisely estimate

the relative risks of cancer associated with the

use of the pill, more recent research has used the

tool of meta-analysis. Studies have also taken into

account issues such as the role of human

papillomavirus (HPV) in the aetiology of

cervical cancer and of BRCA gene mutation on

ovarian and breast cancer risk.

Oral contraceptive use began in 1960.The dose

of hormones in the pill changed considerably

during the 1970s and the 1980s and by the 1990s

they contained one-quarter of the dose of oestrogen and one-tenth the dose of progesto-

gen. Although limited, we now also have some

information regarding use of modern lower dose

pills

Breast cancer

As both oestrogen and progestogen can

accelerate the rate of breast epithelial division

leading to increased mutational change,they may

have the ability to promote breast cancers.

Over 30 case–control and cohort studies were

published during the 1970s and 1980s looking at

the association of oral contraceptives and breast

cancer. There were often inconsistent findings,

with an increase in breast cancer with different

subgroup analyses. These inconsistent results

were the stimulus for the Collaborative Group

Study, which put together the individual data on

over 53 000 women and 100 000 controls.1

Current and recent use of the pill affected breast

cancer risk. The relative risk of breast cancer

diagnosis was 1.24 for current users versus

nonusers and the breast cancers were 12% less

likely to have spread beyond the breast.

Recency of use of the pill was the important

factor. Risk increased soon after first exposure,

did not increase with duration of exposure and

returned to normal ten years after stopping.

Further analysis found no evidence that recent

pill users were more likely to report having had

a mammogram than never users, makingsurveillance bias less probable as an explanation

for the association.

This study and other results also suggest a

reduced risk of breast cancer for women aged

45–54 years several years after stopping the pill.2

This finding is similar to the effect of pregnancy

on breast cancer; an increase in risk short-term

which decreases and reverses with time.

Age

Women who have been taking the pill since it

became available in the 1960s are now entering

the age group with greatest breast cancer risk.

© 2004 Royal College of Obstetricians and Gynaecologists

REVIEW

The Obstetrician& Gynaecologist

2004;6:75–79

Keywords

breast cancer,cervical cancer,endometrial cancer,humanpapillomavirus,ovarian cancer,contraceptive pill

Gynaecological cancerand the contraceptive pill

Helen E Roberts

Research continues to expand our knowledge regarding therelationship between oral contraceptive pill use and gynaecologicalmalignancy. The combined contraceptive pill increases cervical cancerin those women who are human papillomavirus positive. Current andrecent use of the pill increases breast cancer incidence but thisincrease tends to disappear five to ten years after the pill is stopped.Some studies have suggested that this increased incidence is onlyamong women who have used the pill at a young age, when absolutenumbers are small and where risk has disappeared as these womenreach menopause. The protective effect of the pill for endometrialand ovarian cancer continues up to 20 years after stopping use.Although further data are required, low-dose pills may have a smallerimpact on breast cancer risk while continuing to protect forendometrial and ovarian cancer.

Author details

Helen E Roberts MB MPH FACSHP,

Senior Lecturer Women’s Health,

School of Medicine, University of

Auckland, Department of

Obstetrics and Gynaecology, 2ndFloor, National Women’s Hospital,

Claude Road, Epsom, Auckland,

New Zealand.

email: [email protected]

DOI:10.1576/toag.6.2.75.26981


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The National Institute of Child Health and

Human Development (NICHD) study was

developed to look at this group of women.This

US multicentre case–control study had sufficient

power to detect small increases in risk,

particularly for menopausal women. The use of

oral contraceptives for women age 35–64 years

for women with and without breast cancer wasexamined. Current users of the pill had a relative

risk of 1.0 and previous users 0.9.These relative

risks did not increase consistently with longer

periods of use, with high dose pills, in women

with a family history of breast cancer or in

women who had started using the pill less than

20 years of age.3 The study authors concluded

that current or former use of oral contraceptives

among women aged 35–64 years does not

significantly increase the risk of breast cancer.

This result differs from that in the CollaborativeGroup study,1 where the results included women

who were less than age 35 years at time of

diagnosis of breast cancer (9%). In the pooled

analysis of that study, breast cancer risk was

highest among women who were less than 35

years of age. Reanalysis of the data from the

Cancer and Steroid Hormone Study (CASH)

also suggested that the increase in risk of breast

cancer with pill use was confined to those who

had diagnosis at a younger age (20–34 years).4

However, the Norwegian–Swedish prospective

cohort study found current and recent use of the

pill for women aged 30–49 years to increase

breast cancer risk (RR1.6).5 Unlike the

Collaborative Group Study, this study also found

an increased risk of breast cancer in women who

had stopped the pill 15 years previously.

Family history

The Collaborative Group Study1 and that by

Marchbanks3 found that family history of breast

cancer did not influence the results regarding pill

use. However, there is no detail regarding this

history. A recent retrospective cohort studyreported that ever use by daughters and sisters of

women with breast cancer had a relative risk of

3.3; this increased risk was mainly caused when

there was a family history of more than five

blood relatives with breast or ovarian cancer.6

Women who carry the BRCA1 or BRCA2

mutation have a 50–80% lifetime risk of

developing breast cancer, usually occurring in

young women. One study on a large sample of

known BRCA carriers found that, compared

with BRCA carriers who had not used the pill,

BRCA1 carriers who had used the pill before1975 (OR 1.42), who had used it for at least five

years (OR 1.33) and who had used it before the

age of 30 years (OR 1.29) may have an increased

risk of breast cancer.7 The authors suggested that

pill use after the age of 30 years in women who

are carriers of this mutation is not likely to

increase the risk of breast cancer and can be used

to decrease the risk of ovarian cancer. However,

before we are able to give clear advice, the

impact of the pill on breast cancer use in carriers

of these mutations needs further clarification, asbreast cancer is more common in these high-risk

families than ovarian cancer.

Dose

Many of the studies reporting risks with different

doses of the pill have looked at lifetime exposure

instead of the more relevant exposure – recent

use of the pill.There were thus varying reports of

association, increased risk with high potency

progestogen content or high oestrogen content

or long-term use of high-dose oestrogen.8

Adose association was found when women aged

20–44 years were examined for use in the five

years prior to diagnosis. Pills containing more

than 35 micrograms of ethinyl oestradiol had a

relative risk of 1.99 compared with 1.27 for

preparations with less oestrogen. This relation-

ship was most pronounced for women younger

than 35 years. Low-potency oestrogen and

progestogen pills had the lowest risk.8 Progest-

ogen doses in current oral contraceptive are

thought to be equipotent.

Cervical cancer

Persistent infection with HPV is now accepted

as the major risk factor, with 99.7% of cervical

cancers containing high risk HPV types.9

However, not all women with HPV develop

cervical cancer and other factors such as

smoking and oral contraceptive hormones may

promote carcinogenesis. Hormone receptors

have been found in cervical tissue and steroids

are thought to bind to specific DNA sequences

to affect transcription of various genes.

The World Health Organization study in 1993

showed an association between the pill and

cervical cancer with relative risk of 1.2 for

invasive squamous cervical cancer and 1.5 for in

situ carcinoma.10

Human papillomavirus

Earlier studies were not able to take into account

biases relating to sexual behaviour, cervical

screening or HPV infection. As HPV became

recognised as the main aetiological factor for theacquisition of cervical cancer, research started to

look at the effect of contraceptive pill use in

those women who were HPV positive.

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The International Agency for Research on

Cancer (IARC) published a pooled analysis of

these studies in 200211 and a systematic review

also looked at recency of use together with HPV

status.12 This review included at least 80% of the

potentially available information worldwide,

12 531 women with cervical cancer from 28

studies. For all women, relative risks of 1.1, 1.6and 2.2 were found for use for less than five

years, five to nine years and ten or more years,

respectively. For women who were HPV positive

these relative risks were 0.9, 1.3 and 2.5,

respectively. Similar results were found for all

types of cancer, including squamous, adeno, in

situ and invasive cancers, and also when

adjustment was made for number of partners,

smoking, use of barrier methods and previous

cervical screening. Although the data on risk

after stopping the pill were limited,and there was

some heterogeneity between studies, there was asuggestion that the risk might decrease when the

pill was stopped.Women who had used the pill

for more than five years and who were either

current users or stopped using in the last eight

years had a relative risk of 2.1 compared with 1.4

for those who had stopped more than eight years

ago.

Associations with HPV negative women were

less marked, with confidence intervals crossing

one, and associations are difficult to interpret as

the numbers were small and they may have been

false negatives.

It is not thought that pill use increases the

acquisition or persistence of HPV, as the

prevalence of HPV infection does not appear to

increase with increasing duration of pill use.12 It

may, however, be a cofactor, promoting

progression to cervical intraepithelial neoplasia

and invasive cancer and an independent

multiplier of risk of similar magnitude to

smoking or being multiparous.

The systematic review by Smith et al.12 pointedout that it was not possible to determine the

dose of hormone used in most of the studies.

The majority of women were likely to have been

using higher dose pills.

Ovarian cancer

The majority of studies have shown that ever use

of the pill gives a protective effect for ovarian

cancer of the order of 40%. Length of pill use

appears to influence the degree of protection,

with a relative risk of 0.4 for more than five yearsof use in pooled European and US studies.13

Protection seemed to exist for women of any age

and parity. The European study showed that

protection existed ten years after stopping the

pill (RR 0.6) and the US study up to 20 years

(RR 0.5). Data are limited for longer durations.

A large data set of six European case–control

studies has given information regarding all time

factors: age at first use, duration of use and time

since last use.14 Again, a stronger reduction in risk(OR 0.5) was found for women who had used

the pill for more than five years.After allowance

for duration of use the reduced risk was similar

for women who had stopped the pill 20 or more

years ago compared with those who had stopped

ten or more years ago. No difference was found

between nulliparous or parous women, indi-

cating that the pill was unlikely to be simply an

indirect marker of parity and fertility. The

protective effect was present in women with or

without a family history of breast or ovarian

cancer.

Dose

It has been thought that the risk of ovarian

cancer in pill users may be reduced because

inhibiting ovulation decreases disruption of

ovarian epithelium. If this is the case then any

formulation of the combined pill will result in

the same risk reduction. However lower-dose

oral contraceptives may permit higher gonado-

trophin levels, which may elevate the risk of

ovarian cancer. Also, low potency progestogens

may confer a lesser protection, as animal research

and a review have suggested that the protective

effect is progestogen mediated.15 A US

population-based case–control study with 426

cases of ovarian cancer and 940 controls using

the pill is the largest study to date.16 This study

looked at this issue both from ovarian cancer

rates by date of initiation of pill use and by

hormone content (for about 60% of users ). Risk

reduction of 40% for ever use was the same for

initiation prior to 1972 and after 1980. Similarly,

risk reduction of 50% was found for both low-

dose (less than 50 micrograms of ethinyloestradiol) and high-dose ( more than 50

micrograms) pills. Similar protection was also

found for high- and low-dose progestogen

independent of the dose of oestrogen Longer

duration of use afforded greater protection (0.3

for ten or more years versus 0.7 for less than five

years). However, women who had ceased use 30

years before had the same protection as those

who had stopped the pill ten years previously

and protection seemed to be independent of age

of initiation. Other results from a large

population-based study suggest that formulationswith a higher progestogen dose gave greater

protection and others report that this was true

with higher oestrogen potency.8

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Family history

The Bosetti study found that the protective

effect of the pill on ovarian cancer also applied

to women with a family history of cancer.14

Where inherited risk has been more specifically

identified, i.e. the presence of the BRCA mutat-

ion, two studies have shown protection from pilluse and one has not.17

Endometrial cancer

Biological mechanisms exist for the potential

effects of hormones on endometrial cancer.

Oestrogen increases cellular proliferation and

induces the synthesis of oestradiol receptors in

the endometrium. Progestogens diminish these

effects and also increase the conversion of

oestradiol to oestrone,which has a lower affinity

for oestrogen receptors. Progestogens also reverse

endometrial hyperplasia caused by unopposed

oestrogen.

We have been aware of the protective effects of

the pill on endometrial cancer through early

studies such as CASH. Use for at least one year

gave a relative risk of 0.6 for women using the

pill, an effect which lasted for 15 years after

stopping.18

Duration of use rather than recency of use seems

to be the main influencing factor on the

protective effect of the pill and endometrialcancer.A more recent meta-analysis, with larger

numbers of cases, has confirmed this protective

effect after four, eight and twelve years of use.

Risk reductions are in the order of 56%, 67%,

and 72%, respectively.19 Other studies have also

shown a decreased risk of around 50% up to 20

years after stopping and this residual protective

effect lasts after the menopause when the risk of

endometrial cancer is higher.19

Age

Women’s risk of endometrial cancer increases as

they age.The CASH study found no difference

in effect between younger and older women.A

Swedish case–control study of postmenopausal

women (50–74 years) showed a 50% decreased

risk after three or more years of use and 80%

lower risk after ten years, benefits lasting up to 20

years after pill use.20

Dose

Twenty-one days of progestogen is important for

the protective effect of the pill on endometrialcancer. Sequential pills with only five to seven

days of progestogen had increased risks of

endometrial cancer and were removed from the

market in 1976. Available data give varying

information. One author states that the low

progestogen content of the pill does not

influence risk.13 Another found that it reduced

risk before the age of 45 years or that five years

of use were necessary for protection with low-

dose pills.19

Cancer mortality and pill use

The 25-year follow-up of the Royal College of

General Practitioners’ study looked at death

associated with pill use.21 The majority of

women in this study used pills containing more

than 50 micrograms of oestrogen. All-cause

mortality was similar for ever users and never

users and women who had stopped using the pill

over ten years previously.The number of deaths

from each type of cancer was small butdifferences were found in ovarian and cervical

cancer among current and recent users in the last

ten years.The relative risk of death from ovarian

cancer was 0.2 and for cervical cancer 2.5.There

was a weak suggestion that the protective effect

for ovarian cancer wore off. However, 15 years

after stopping the pill the relative risk still

suggested protection at 0.7.

Progestogen-only pill

Data on progestogen-only pill use and cancer are

more limited. The Collaborative Group Study

had 725 cases and 528 controls who had used the

progestogen-only pill. Pooled analysis showed a

relative risk of 1.1 for breast cancer with

progestogen-only pill use, a result of only

borderline signifiance.22 The progestogen-only

pill is also not thought to affect the risk of

cervical cancer.23

The progestogen-only pill has also been shown

to be protective for endometrial and ovarian

cancer but the numbers of women in these

studies were small.22

Conclusion

Absolute risks rather than relative risks are more

important from a public health point of view.

The Collaborative Study found that women

who first began using the pill before the age of

20 years had higher relative risks of having breast

cancer diagnosed while using the pill than those

women who started it at an older age group.1

However, this did not result in more cancers

being diagnosed, as the absolute risk of breastcancer is low for young women. The excess

number of breast cancers diagnosed between

starting pill use and for ten years after stopping

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among 10 000 women using the pill at 16–19

years, 20–24 years and 25–29 years was 0.5, 1.5

and 4.7, respectively. For these women who use

the pill at a young age the increased risk has

disappeared by the time they reach menopause

when breast cancer risks increase. Also, for

women using the pill at older ages, some research

suggests no increase in breast cancer with pilluse.3 Duration of use did not influence results.

From the public health point of view,

endometrial protection with pill use would

result in 979 fewer case per 100 000 US women

by the age of 75 years with 12 years of use. 24

However, this protection may be less relevant to

the individual.The probability of remaining free

of endometrial cancer through age 74 years is

about 97.6% for a woman in the USA.Using the

pill for 12 years increases that probability to

98.6%.2

The association of pill use with cervical cancer is

likely to have more effect in those countries with

no cervical screening programmes.Women with

cervical intraepithelial neoplasia should have

regular screening. The WHO has put these

women into category 2 (generally use the

method) for pill use. Women with previous

breast cancer are category 4 (method not to be

used), unless it is five years since diagnosis with

no recurrence, in which they are case category 3

(not usually recommended unless other methods

not acceptable).Women with previous ovarian or endometrial cancer, if still requiring contracept-

ion, are category 1 for pill use (use method).

Overall, assuming a modest risk of breast and

cervical cancer with pill use and a decreased risk

of ovarian and endometrial cancer (400 fewer

case for 100 000 women with eight years of use)

the net effect of pill use on cancer is negligible.13

Continuing information of risk with low-dose

pills is required, together with data on risk for

older women.Further research is needed to help

women at increased risk of familial cancers,including those caused by genetic factors not yet

identified, e.g. BRCAx genes. Data on hormone

receptor status of cancer and the effect of the pill

may also give further insight.

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Gynecological Cancer and Contraceptive Pill

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