The use of hormonal contraception and its protective role against endometrial and ovarian cancer

Article Outline

• Abstract
• Ovarian cancer
  • Ovarian cancer risk in oral-contraceptive users and the relation with the duration of use
  • Protective effect according to the age of first use of oral contraceptives and the interval from last use
  • Protective effect according to the formulations of oral contraceptives
  • Protective effect according to the tumour histology
• Endometrial cancer
  • Endometrial cancer risk in oral-contraceptive users and relation with the duration of use
  • Protective effect according to the interval from last use of oral contraceptives
• Biological explanation of the protective effect
• Public health implications
• Conclusions
• References
• Copyright

Hormonal contraception has a protective effect over ovarian and endometrial cancer development. Relative risk of ovarian cancer decreases by ∼20% for each 5 years of use; it is ∼50% for 15 years of use and decreasing with further use. The protective effect gained declines as time passes from its last use, but a significant effect remains a long time after ceasing. The effect is independent 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 ∼50% with 4 years of use, ∼70% 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 ∼50% even after >20 years after its last use. Hormonal contraception could be used for primary protection from ovarian and endometrial cancer development.

Keywords: hormonal contraception, oral contraceptives, ovarian cancer, endometrial cancer, non-contraceptive benefits, primary protection

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, ∼25% of women aged 16–49 years and in USA ∼20% of women aged 15–44 years take oral contraceptives. The percentages are even higher in younger population, reaching in UK ∼60% of women aged 16–24 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 benefits of them. Apart from protection from an 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 beneficial 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 significance.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 difficult to design proper epidemiological studies with well-studied population. Furthermore, women may use different formulations of oral contraceptives 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.

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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 Epidemiological 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; stratified by study, age, parity and hysterectomy) for ever users versus never users was found to be 0.73 (95% confidence interval (CI): 0.70–0.76, p<0.0001) (Table 1). Furthermore, the longer the duration of use the lower the risk for ovarian cancer development. The overall relative risk decreased by 20% (95% CI: 18–23%, p<0.0001) for each 5 years of use; in women who had taken oral contraceptives for ∼15 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 significant (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: 0.91–1.10), users for 1–4 years (mean 2.4 years) had an RR of 0.78 (95% CI: 0.73–0.83), users for 5–9 years (mean 6.8 years) had an RR of 0.64 (95% CI: 0.59–0.69), users for 10–14 years (mean 11.6 years) had a relative risk of 0.56 (95% CI: 0.50–0.62) and, finally, users for 15 years or more (mean 18.3 years) had a relative risk of 0.42 (95% CI: 0.36–0.49).

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

There are also two more recent cohort studies^*6, ^*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 25–39 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 Collaborative Group on Epidemiological Studies of Ovarian Cancer.⁴ However, the latest findings 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: 0.3–0.7) (Table 1). Furthermore, this group of investigators found that ovarian cancer risk is significantly 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 significant reduced ovarian cancer risk (relative risk (RR) 0.51, 95% CI: 0.33–0.78) was found in ever users of oral contraceptives as compared with never users (Table 1). Furthermore, a statistically significant 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: 0.33–1.04), for users of 49–96 months it was 0.57 (95% CI: 0.30–1.07) and for users of ≥97 months the RR was 0.38 (95% CI: 0.16–0.88).

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 beneficial 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 first birth) of 0.5 (95% CI: 0.3–0.8) 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: 0.2–0.7). 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 significantly reduced RR (adjusted for age, ethnicity and parity) was found for ever users versus never users among non-carriers (RR 0.55, 95% CI: 0.41–0.75) and a reduced, although not reaching statistical significance, the RR among carriers (RR 0.54, 95% CI: 0.26–1.13). However, the RR for ovarian cancer was statistically significantly reduced for use ≥7 years both in BRCA1 carriers (RR 0.22, 95% CI: 0.07–0.71) and in non-carriers (RR 0.43, 95% CI: 0.30–0.63). 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: 0.53–1.40) and that for ≥6 years of use 0.62 (95% CI: 0.35–1.10). 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 find any protective effect of oral contraceptives on BRCA carriers. The RR for ever users versus never users, as expected, was 0.53 (95% CI: 0.34–0.54) 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 first use of oral contraceptives and the interval from last use 

Another interesting question is whether the protective effect gained with the use of oral contraceptives remains unchanged through woman's 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 10–19 years previously and 15% for those who had ceased use 20–29 years previously (p for trend=0.004). For >30 years elapsed time, there were not sufficient 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). Furthermore, despite the initial perception that the protective effect lasts only for a certain period of a woman's life after use of oral contraceptives, it seems that a significant effect remains a long time after ceasing.⁴

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 of use (95% CI)
		<5 years	5-9 years	≥10 years
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 10–19 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 (0.71–0.97)	0.81 (0.74–0.89)	0.69 (0.60–0.78)	0.60 (0.51–0.72)	15.1 (8.5–21.2)
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 (0.76–0.97)	0.83 (0.73–0.95)	Insufficient data	Insufficient data	Insufficient data
Mean duration of use	2.5 years	1.5 years

All relative risks were adjusted for study, age, parity and hysterectomy.

Data analysis of the Royal College of General Practitioners' Study⁷ by time since last use of oral contraception has similar findings; there was a statistically significant (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-significant) RR observed still after longer time intervals. It is impressive that the findings 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 significant 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.

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 μg) 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 finding 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: 0.3–0.6) and in the high-dose ones (RR=0.5, 95% CI: 0.3–0.7).

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 findings 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

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

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 specified	1182	25.8 (7.8)

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

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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 ∼440 000 woman-years of observation were meta-analysed whereas five 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 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 RR_dur=exp[–0.023–0.493 × 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).

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

Study	Study design	Population	Follow-up	Mean duration of use	RR (95% CI)
Schlesselman5Endometrial & uterine cancer/6 Countries	Meta-analysis of 10 case-control and 1 cohort study	10 Case-control studies Cases: 1728 Controls: 6243	1 Cohort study Ever users: 182900 women-years Never users: 257000 women-years	4 to 12 years	0.44 to 0.28 (p<0.0001)
Vessey and Painter6Uterine/UK	Cohort Study Recruitment: 1968-1974	Ever and never users: 17032	Ever users: 353000 women-years Never users: 187000 women-years	NR	0.3 (0.2–0.6)
Hannaford et al7Uterine/UK	Cohort Study Recruitment: 1968-1969	Ever users: 23377 Never users: 23796	Ever users: 744000 women-year Never users: 339000 women-years	44 months	0.47 (0.27–0.81)

A statistically significant 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: 0.2–0.6). 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 significant; the estimated RR was 0.6 (0.3–1.1) for up to 48 months' users, 0.4 (0.2–0.8) for 49–96 months' users and 0.1 (0.0–0.4) for ≥97 months' users (p for trend<0.001). The protective effect seems to be significantly lower in women 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 significant (adjusted for age, parity, smoking, social status and hormone replacement therapy) reduced uterine body cancer risk (RR 0.47, 95% CI: 0.27–0.81) was found in ever users of oral contraceptives as compared with never users. Furthermore, a statistically significant 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: 0.30–1.21), users of 49–96 months had an RR of 0.14 (95% CI: 0.08–0.58) and users of ≥97 months had an RR of 0.57 (95% CI: 0.27–1.19).

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 RR_rec=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 significant and almost 50% below that of women who have never used oral contraceptives. It is also important to note that a significant finding of this meta-analysis⁵ is that the longer the duration of use the higher the protection irrespective of the time elapsed from ceasing.

The findings from the Royal College of General Practitioners' Study⁷ were analogous; a statistically significant (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-significant) RR observed still after longer time intervals. It is remarkable that the findings of the Oxford-FPA contraceptive study⁶ were similar. There was a statistically significant (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 4⁺–12, 12⁺–20 and >20 years of discontinuation, respectively). However, in this study, a statistically significant protective effect still existed even in the longest interval group; the RR for users of >20 years was 0.5 (95% CI: 0.3–0.9). These data support the notion that the protective effect of oral contraceptives over endometrial cancer development seems to be persistent.^*5, ^*6, ^*7

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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, first 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 findings 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.

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

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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 10–45 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: 0.5–0.8). It seems, therefore, that the beneficial 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.

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

These findings set a new standard in primary protection from endometrial and ovarian malignancies and seem to have important public health implications.², ^*3, ^*4, ^*5 It should also be noted that primary protection from cervical cancer could based on vagination for HPV.

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Conclusions 

Hormonal contraception seems to be associated with a statistically significant protective effect for ovarian and endometrial cancer development. The ovarian cancer RR seems to decrease by 20% for each 5 years of use and for women who had taken oral contraceptives for ∼15 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 beneficial 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 woman's life after oral contraceptives' use, it seems that a significant effect remains a long time after ceasing. The protective effect seems to be independent from the type of oral contraceptives formulation. Furthermore, 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 ∼50% with 4 years of use and it is increasing to ∼70% 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 significant 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 formulations have a different degree of protection.

Importantly, the use of hormonal contraception might set a new standard for primary protection from gynaecological malignancies.

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References 

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