ANTICANCER RESEARCH 40: 5995-6002 (2020)

doi:10.21873/anticanres.14620

Review

Estro-progestin Contraceptives and Risk

of Cervical Cancer: A Debated Issue
ANGIOLO GADDUCCI, STEFANIA COSIO and FRANCA FRUZZETTI

Department of Clinical and Experimental Medicine,

Division of Gynecology and Obstetrics, University of Pisa, Pisa, Italy

Abstract. Steroid contraceptive hormones may promote host genome may cause a high-grade cervical lesion and
human papilloma virus (HPV) - DNA integration into the then, an invasive cervical cancer (5). The genome of HPV
host genome, may bind to specific HPV-DNA sequences includes early genes (E1, E2, E4, E5, E6, E7) involved in the
within transcriptional regulatory regions, and may modulate regulation of the vegetative and productive phases of the
cell apoptosis. Most epidemiological studies, reported in this virus life cycle, late genes encoding the capsid proteins, and
narrative review, have shown that oral contraception is a non-coding regulatory region involved in transcription
associated with a 1.5-3.3-fold higher relative risk of cervical regulation and viral replication (6). The HPV E2 protein
carcer, but only in users for >5 years and especially in HPV- regulates the transcription of the E6 and E7 genes, whereas
positive women. The relative risk declines with increasing the malignant transformation triggered by HPV-DNA
time since last use and is not different from that of never integration into the host genome is accompanied by
users after >10 years. Ten-year oral contraceptive use from disruption of the E2 gene and deregulated expression of E6
the age of 20 years is associated with an increase in the and E7 (7). High-risk HPV E6 protein degrades the p53
cumulative incidence of invasive cervical cancer at the age protein and high-risk HPV E7 protein induces
of 50 years of approximately 1 case per 1,000. Oral phosphorylation and degradation of the retinoblastoma
contraception has a very small negative impact on the protein pRB, thus leading to the release of E2F family of
absolute risk of cancer of the uterine cervix. transcription factors and subsequent activation of genes
promoting cell proliferation (8).
Globocan estimates of incidence and mortality worldwide for Mechanisms used by HPV to escape immune surveillance
36 cancers in 185 countries have detected 569,847 new cases include the non-lytic replication that limits innate immune
of cervical cancer and 311,365 deaths due to this tumor in responses that would occur in response to cell death, the lack
2018 (1). It is caused by persistence of high-risk human of a viremic phase, the low expression of viral proteins until
papillomavirus (HPV) infection (2). HPV-16 is the most later stages of epithelial differentiation, and the down-
common type, responsible for about 55% of all tumors, HPV regulation of important receptors on cells of the innate immune
18 accounts for another 15%, and HPV types 31, 33, 35, 45, system (9). Furthermore, HPV inhibits the expression of
52, and 58 are responsible for an additional 18% of cases (3). proinflammatory proteins that are critical for activating
Most cervical cancers arise in the transformation zone (4). cytotoxic T cells.
Low-grade cervical lesions, generally harboring episomal Smoking, infection with other sexually transmitted agents
HPV, have a low risk of progression, whereas a minority of such as Clamydia trachomatis and human herpes simplex
persistent infections after integration of HPV-DNA into the virus, multiparity and hormonal contraception have been
investigated as cofactors for the development of high-grade
cervical lesions and invasive cervical cancer, whereas there
is a controversial evidence for a role of intrauterine device
Correspondence to: Angiolo Gadducci, MD, Department of Clinical (IUD) in HPV–related carcinogenesis (10-22). A recent US
and Experimental Medicine, Division of Gynecology and
retrospective cohort analysis of 10,674 women who received
Obstetrics, University of Pisa, Via Roma 56, Pisa, 56127, Italy. Tel:
+39 50992609, e-mail: a.gadducci@med.unipi.it IUDs reported that copper IUD users had a lower risk of
cervical neoplasms compared with levorgestrel-releasing
Key Words: Oral contraception, estrogen, progesterone, human IUD users [relative risk (RR)= 0.38, 95% confidence interval
papilloma virus (HPV), cervical cancer, review. (CI)=0.16-0.78] (20).

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In vivo studies have shown that estrogen may enhance the of the women who underwent conization after a minimum of
onset and progression of cervical cancer in human HPV 12 weeks (37). On multivariate analysis, condom use was
transgenic mouse models (23). The combination of low-dose found to be an independent predictor of CIN regression.
17β-estradiol and low-level HPV gene expression biases Oral contraceptives used in 1960s and 1970s contained
transformation zone reserve cells toward squamous cell rather higher doses of ethinylestradiol and different types and doses
than glandular cell differentiation (24). Transitional zone is five- of progestins than the currently used formulations, and long-
fold more sensitive to the induction of squamous cell term users would have probably started with higher dose oral
carcinogenesis by estrogen compared to other genital tract sites. contraceptives with a progressive switch to lower dose oral
Immunohistochemical studies on hysterectomy specimens from contraceptives pills (36). In this review, we critically
young women undergoing surgery for non-cervical benign analyzed the available literature data about oral contraception
uterine disease, have revealed that the expression of estrogen use and risk of carcinoma of the uterine cervix.
receptors and progesterone receptors is significantly higher in
the transformation zone compared with the ectocervix (25). Oral Contraception and HPV Infection
Steroid contraceptive hormones may also promote HPV-
DNA integration into the host genome, and may bind to Conflicting data are available in the literature regarding the
specific HPV-DNA sequences within transcriptional risk of HPV infection in oral contraceptive users (Table I).
regulatory regions, thus increasing or suppressing the In a population-based study including15,145 women aged
transcription of different genes and possibly modulating cell >15 years from 14 areas worldwide, Vaccarella et al. (38)
apoptosis (10-12, 14, 26, 27). Estrogen and progesterone detected no significant differences in HPV positivity between
increase the levels of apoptosis induced by HPV16 E2 and ever [odds ratio (OR)=1.08; 95%CI=0.94-1.25] and never
E7 proteins and therefore these hormones might protect cells users after adjustment for age, lifetime number of sexual
from malignant transformation (26). partners, and study area.
Conversely, in the absence of HPV-16 E2 protein Syrianen et al. (39), who assessed a cohort of 3,187
following HPV-DNA integration into the host genome, women enrolled in a Soviet Union screening trial, reported
steroid hormones could enhance carcinogenesis. that no contraceptive users, non-oral contraceptive users, and
Estrogens may be genotoxic agents that are hydroxylated oral contraceptive users had identical prevalence of high-risk
by a specific cytochrome P450 (28, 29). 4-hydroxyestrone and HPV.
16α-hydroxyestradiol are considered to be carcinogenic (30). Maucort-Boulch et al. (40) found that oral contraceptive use
Cervical cells, expecially those of the transformation zone, are was not associated with HPV persistence in 2,408 women with
able to 16α-hydroxylate estradiol, and both cervical and equivocal or mildly abnormal cytology followed for 24
foreskin cells immortalized with HPV-16 are greatly enhanced months. A cohort study on more than 12,000 Brazilian and
in the 16α-hydroxylation of estradiol compared with normal Argentinian women showed that the lenght of oral
cells (31). Moreover, in vitro studies have shown that 17beta- contraceptive use was not an independent predictor for high-
estradiol may enhance Bcl-2 expression and prevent oxidative risk HPV infections (41). A pooled analysis of 16,573 women
stress-induced apoptosis in keratinocytes (32). with cervical cancer and 35,509 controls from 24 studies
Experimental investigations in animal models of human worldwide confirmed that neither ever pill use nor use for >5
multiple sclerosis have shown that 17β-estradiol decreases years correlated significantly with high-risk HPV infection (RR
tumor necrosis factor-α, interferon-γ and interleukin -12 for HPV positive versus HPV negative=1.19, 95%CI=0.92-
production in mature dendritic cells (33) and that 17β- 1.52, and 1.21, 95%CI=0.89-1.63, respectively) (42).
estradiol-exposed dendritic cells inhibit the expansion of A Sweedish study on 972 women found no association
CD4+ T cells and increase the number of regulatory T cells between low-dose oral contraceptive use and HPV
and CD4+CD28– suppressor T cells (34). The altered infections, whereas high-dose oral contraceptives were an
dendritic cell function may contribute to the persistence of independent risk factor for these infections after adjustment
HPV by preventing infected cells from being eliminated by for age, number of lifetime sexual partners, number of sexual
cytotoxic T cells. partners during the last 6 months and age at sexual debut
The International Agency for Research on Cancer (IARC) (OR=2.8) (43).
has classified oral contraceptives as carcinogenic for the A prospective study on the natural history of HPV assessed
uterine cervix (35). Oral contraceptive users are more likely 1,070 HIV-negative Thai women aged 20-37 years who at
to be exposed to HPV than women using barrier methods enrollment had a prevalence of 19.8% and 11.5% of any HPV
(36). In a prospective population-based cohort study and high-risk HPV infections, respectively (14). After
including 170 patients aged 25-40 years with histologically adjustment for age, sexual behaviors, sexual transmitted
proven cervical intraepithelial neoplasia (CIN) 2-3, a infections and cytology, pill use for >6 years was associated
regression to ≤CIN1 in cone specimen was detected in 22% with a significantly increased RR of infection with any HPV

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Table I. Oral contraceptive use and risk of HPV infection.

Unchanged risk Increased risk

Vaccarella (38) Sikstrom (high-dose oral contraceptives) (43)

Marks (14) Cotton (44)
Syrianen (39) Rudolph (45)
Maucort-Boulch (40) Catarino (46)
Longatto-Filho (41)
Appleby (42)
Sikstrom (low-dose oral contraceptives) (43)

Table II. Oral contraceptive use and risk of cervical intraepithelial neoplasia (CIN).

Unchanged risk Increased risk

Syrianen (39) CIN2-3 Roura (15) CIN 3

Longatto-Filho (41) CIN1-3 Xu (18) CIN 2-3
Adhikari (49) CIN 1 (reduced risk) Loopik (21) CIN 3
Volpato (51) CIN 2-3 Volpato (51) CIN 1

(1.88, 95%CI=1.21-2.90) and any high risk-HPV (2.68, assessed the relationship between oral contraceptive use and
95%CI=1.47-4.88) compared to never users. The overall age- cervical atypias in a cohort of 999 originally non-HPV
standardised prevalence of high-risk HPV was 34.2% among vaccinated 16-17-year-old women participating in
5,038 UK women aged 20-59 years with a low-grade smear PATRICIA for 4 years. After adjusting for smoking and age
included in the Trial Of Management of Borderline and Other at sexual debut, the RR of CIN 1 in women who had started
Low-grade Abnormal smears [TOMBOLA] and the risk of this pill use for more than 1 year was 0.2 (95%CI=0.1-0.7)
infection was significantly related to current pill use on (Table II). Syrianen et al. (39) reported that no contraceptive
multivariate analysis (OR=1.54, 95%CI=1.30-1.84) (44). users, non-oral contraceptive users and oral contraceptive
Similarly, in a Mexican population-based study including users had the same incidence of cervical smear abnormalities
30,829 women aged 30-64 years, high- risk HPV positivity was and CIN histology. Oral contraception was a predictor of
11% and hormonal contracption was an independent risk factor HSIL or CIN2-3 in neither HPV-positive nor HPV-negative
for this infection (OR=1.10; 95%CI=1.01-1.20) (45). Hormonal women. According to Longatto-Filho et al. (41), the duration
contraception significantly correlated with HPV infection on of oral contraceptive use was associated neither with low-
multivariate analysis (OR=1.97, 95%CI=1.21-3.17) in two grade SIL (LSIL), atypical squamous cell of unknown
sequential Cameroonian studies including 838 women aged 25- significance (ASCUS) and high-grade SIL (HSIL) on
65 years with an overall HPV prevalence of 39% (46). cervical smear nor with high-grade CIN on histologic
In conclusion, there is no clear relationship between HPV samples. Oral contraception has not been found to increase
positivity and oral contraception. The limited data available, the relapse rate of CIN after conization (50).
the great heterogeneity among studies, the presence of A case-control study, including 101 women with HPV–
confounding factors (i.e. sexual activity and smoking habit), related cervical lesions and 101 controls, found that users of oral
and the use of different hormone contraceptive formulations contraceptives containing ethynyl-estradiol doses >0.03 mg had
do not allow firm conclusions to be drawn (47). a 2.1-fold higher risk of LSIL (p=0.036), but no increased risk
of HSIL and invasive cancer compared with never users (51).
Oral Contraception and Cervical Cancer The European Prospective Investigation into Cancer and
Nutrition (EPIC) showed that, in a cohort of 308,036
The PApilloma TRIal against Cancer In young Adults women, current oral contraceptive use was associated with a
(PATRICIA) is a double-blind, randomised study that has 1.8-fold higher RR (95%CI=1.4-2.4) of CIN 3 compared to
demonstrated the efficacy of HPV-16/18 AS04-adjuvanted never users (15).
vaccine against high-risk HPV infections and precancerous An Australian case-control study, including 886 women
lesions of the uterine cervix (48). Adhikari et al. (49) with CIN 2-3 and 3,636 controls aged 30-44 years, revealed

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Table III. Oral contraceptive use and risk of invasive cervical cancer.

Unchanged risk Increased risk

Lasey1 (57) Roura2 (15)

Moreno3 (56) Loopik4 (21)
Appleby2 (42)
Vessey5 (58)
Smith6 (59)
Hannaford7 (61)
Asthana8 (62)

1Associations between oral contraceptive use and invasive adenocarcinomas and squamous cell carcinomas disappeared after accounting for HPV
infection, sexual history, and cytological screening; 2use >5 years; 3use >5 years in HPV- positive women; 4use for at least 5 uninterrupted years;
5use >4 years; 6any duration of use for all women and use>5 years in HPV- positive women; 7use >97 months; 8use >2 years.

that current hormonal-contraceptive users had a higher risk HPV status and smoking habit, because of the retrospective
for CIN 2-3 than never users (OR=1.50, 95%CI=1.03-2.17) design of the study.
and that the risk increased with increasing duration of use An IARC multicentric case-control study assessed 1,853
(18). In fact, the OR for CIN 2-3 was 1.13 (95%CI=0.73- patients with cervical squamous cell cancer and 1,916 controls,
1.75), 1.51 (95%CI=1.00-2.72) and 1.82 (95%CI=1.22-2.72) of whom 1,676 and 255, respectively, were HPV-positive (56).
for <10 years, 10-14 years and ≥15 years of use (p <0.001). Women who had taken oral contraceptives for <5 years, 5-9
However, past users had the same risk as never users yearsor >10 years had an OR of 0.73 (95%Cl=0.52-1.03), 2.82
(OR=1.08, 95%CI=0.75-1.57), regardless of the time since (95%Cl=1.46-5.42) and 4.03 (95%CI=2.09-8.02) of developing
last use and the leght of use. cervical cancer compared with never users. The age at which
A Surveillance, Epidemiology, and End Results (SEER) women started to use oral contraceptives was not significantly
population-based case-control study, including 150 women associated with cervical cancer after adjustment for length of
with cervical adenocarcinoma in situ (ACIS) and 651 use. In women who had taken oral contraceptives for >5 years,
controls, revealed an increased incidence of ACIS in ever an increased risk persisted for 5-14 years after stopping use.
oral contraceptive users (OR=2.7; 95%CI=1.2-5.8) (52). The Therefore, long-term oral contraception could increase cervical
risk increased linearly with the length of use (p <0.001 for carcinoma risk in HPV-positive women.
trend), reaching an OR of 5.5 (95%CI=2.1-14.6) for a use of In a multicenter case-control study including 124 patients
>12 years. Long-term oral contraceptive use may contribute with cervical adenocarcinoma, 139 with cervical squamous
to the pathogenesis of cervical adenocarcinoma. However, cell carcinoma and 307 controls, oral contraceptive use was
we must take into consideration that this malignancy has a significantly associated with adenocarcinoma and weakly
wide histopathological spectrum and can be classified into 7 associated with squamous cell carcinoma (57). Adjustment for
subtypes (53, 54). No meaningful clinical data are currently HPV status, sexual history and screening, eliminated the
available as for the hormonosensitivity of each subtype. positive correlation between oral contraceptives and invasive
According to a meta-analysis of 16 case-control studies, adenocarcinoma, squamous cell carcinoma in situ and invasive
oral contraception was not a risk factor for cervical cancer squamous cell carcinoma and confirmed a positive association
(OR=1.12; 95%CI=0.90-1.38), except for Asian women only between current oral contraceptives and ACIS.
(OR=1.43; 95%CI=1.14-1.79) (55). The Oxford Family Planning Association contraceptive
Most papers have reported that a long-term use of oral study, including 17,032 women aged 25-39 years, found that
contraception is associated with a higher risk of invasive the RR of cervical cancer was 4.2 (95%CI=1.8-12.0) for ever
cervical cancer (15, 21, 42, 56-62) (Table III). oral contraceptive users versus non users, ranging from 2.9
A Ducth retrospective population-based cohort study, (95%CI=0.9-9.9), to 3.3 (95%CI=1.2-10.4) and to 6.1
which analyzed 702,037 women aged 29-44 years attending (95%CI=2.5-17.9), for an oral contraceptive use up to 48
a screening program, detected 6,705 cases of CIN 3 and 559 months, 49-96 months, and >97 months, respectively (58).
cases of cervical cancer after a median follow-up of 9.7 The assessement of 12,531 women with cervical
years (21). Oral contraceptive use correlated significantly carcinoma enrolled in 28 studies showed that oral
with an increased risk of CIN 3 (RR=2.77, 95%CI=2.65- contraceptive use for <5 years, 5-9 years, and >10 years was
3.00) and cervical cancer (RR=2.06, 95%CI=1.52-2.79). associated with a RR of this tumor of 1.1 (95%CI=1.1-1.2),
Unfortunately, the RR was not adjusted by sexual behaviour, 1.6 (95%CI=1.4-1.7) and 2.2 (95%CI=1.9-2.4) in all women,

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and, of 0.9 (95%CI=0.7-1.2), 1.3 (95%CI=1.0-1.9) and 2.5 in users for >5 years, and especially in HPV-positive women
(95%CI=1.6-3.9) in HPV-positive women, respectively (59). who should be encouraged to attend cervical screening
The results were similar for invasive and in situ cancers, as programmes accurately (15, 18, 21, 42, 56-63).
well as for squamous cell carcinoma and adenocarcinoma. The Royal College of General Practitioner’s oral
A reanalysis of individual data on 8,097 women with contraception study found that oral contraception to be
invasive squamous cell carcinoma, 1,374 women with associated with a 12% reduction in the RR (0.88, 95%=0.83-
invasive adenocarcinoma and 26,445 controls from 12 0.94) of any cancer (61). This study reported a significant
epidemiological studies, showed that in current oral reduction in the RR of endometrial cancer (0.58,
contraceptive users, there was an increased RR per each year 95%CI=0.42-0.79), ovarian cancer (0.54, 95%CI=0.40-0.71)
of use of 1.08 (95%CI=1.06-1.09) for squamous cell and large bowel cancer (0.72, 95%CI=0.58-0.90) and an
carcinoma and 1.07 (95%CI=1.04-1.11) for adenocarcinoma unchanged RR of gallbladder or liver cancer, lung cancer,
(60). A subsequent pooled analysis of 24 studies detected melanoma, and breast cancer. Conversely, a non-statistically
that among current users, the RR of invasive cervical cancer significant increase was detected in the RR of cancers of the
was 1.90 (95%CI= 1.69-2.13) for >5 year use versus never central nervous system (1.34, 95%CI=0.73-2.47) and uterine
use (42). The RR declined with increasing time since last use cervix (1.33, 95%CI=0.92-1.94). Cervical cancer risk
andwas not different from that of never users after >10 years. increased significantly only after 97 months.
Each year of use in current users was associated with a It has been calculated that 10 yearf of oral contraceptive
change in RR by a factor of 1.07 (95%CI=1.05-1.08). use from the age of 20 years is associated with an increase in
The Royal College of General Practitioner’s oral the cumulative incidence of invasive cervical cancer at the
contraception study, based on approximately 339,000 woman age of 50 years from 7.3 to 8.3 per 1,000 in less developed
years of observation for never users and 744,000 woman years countries and from 3.8 to 4.5 per 1,000 in more developed
for ever users, showed that oral contraception was associated countries (42). Therefore, the potential increase in terms of
with a non- statistically significant increase in RR of cervical absolute risk is very limited. Taking into consideration both
cancer (1.33, 95%CI=0.92-1.94) (61). The RR was 1.10 the overall harms and benefits, the World Health Organization
(95%CI=0.64-1.90), 1.45 (95%CI=0.84-2.49) and 2.73 does not recommend any change in oral contraceptive
(95%CI=1.61-4.61), for pill use <48 months, 46-96 months and practice as far as cervical carcinogenesis risk is concerned
>97 months, respectively. The RR progressively decreased (63). We must take into consideration that two very effective
after discontinuation, ranging from 1.99 (95%CI=1.26-3.15) to prevention strategies are available for cervical cancer, i.e.
1.25 (95%CI=0.65-2.39) to 0.65 (95%CI=0.23-1.83) for primary prevention with HPV vaccination and secondary
current or recent (<60 months) users, past users (61-120 prevention with HPV screening followed by treatment of
months) and long-term past users (>181 months), respectively. precancerous lesions (64, 65). Widespread coverage of both
The EPIC study detected that oral contraceptive use had a HPV vaccination and at least two cervical screenings in the
RR of cervical cancer of 2.0 (95%CI=1.3-3.0), 1.6 lifetime from 2020 onwards, has the potential to avoid up to
(95%CI=1.0-2.6) and 1.8 (95%CI=1.1-2.9), after a length of 12.5-13.4 million cases by 2069 and could obtain an average
use of 5-9 years, 10-14 years and >15 years, respectively (15). cervical cancer incidence of <4 per 100,000.
A recent review of 14 case-control and 5 cohort studies
reported that oral contraception was associated with a 1.51- Conflicts of Interest
fold higher risk of cervical cancer (95%CI=1.35-1.68) (62).
According to the length of use, there was a non-significantly The Authors declare no conflicts of interest in relation to this study.
increased incidence if the use was <2 years (OR=1.27;
95%CI=0.98-1.65). Conversely, a statistically significant Authors’ Contributions
increased risk was detected for an oral contraceptive use of
2-5 years (OR=1.34, 95%CI=1.20-1.50), 5-10 years Conceptualization, Writing – original draft: AG; Data curation, Formal
(OR=1.93, 95%CI=1.56-2.36) and >10 years (OR=2.24, analysis, Methodology, Writing-review & editing: AG, SC, FF.
95%CI=1.45-3.48), respectively (62). According to the
histological type, the risk was greater for adenocarcinoma References
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