Ovarian cancer in the world: Epidemiology and risk factors

Abstract

Aim: Ovarian cancer is one of the most common gynecologic cancers that has the highest mortality rate. Considering the fact that knowledge on the incidence, mortality of ovarian cancer, as well as its risk factors is necessary for planning and preventing complications, this study was conducted with the aim of examining the epidemiology and risk factors of ovarian cancer in the world. Materials and methods: In order to access the articles, Medline, Web of Science Core Collection, and Scopus databases were searched from their start to the year 2018. Full-text, English observational studies that referred to various aspects of ovarian cancer were included in the study. Results: In total, 125 articles that had been published during the years 1925-2018 were entered into the study. Ovarian cancer is the seventh most common cancer among women. Increased risk factors of cancer have led to an upward trend in the incidence of cancer around the world. In 2018, 4.4% of entire cancer-related mortality among women was attributed to ovarian cancer. Although the incidence of cancer is higher among high Human Development Index (HDI) countries, the trend of mortality rate tends to be reversing. Various factors affect the occurrence of ovarian cancer, from which genetic factor are among the most important ones. Pregnancy, lactation, and oral contraceptive pills play a role in reducing the risk of this disease. Conclusion: This study provides significant evidence about ovarian cancer. Considering the heavy burden of ovarian cancer on women's health, preventive measures as well as health education and early detection in high risk groups of women are highly recommended. Although some risk factors cannot be changed, a focus on preventable risk factors may reduce the risk of ovarian cancer. More studies are needed to explore the role of unclear risk factors in ovarian cancer occurrence.

Full text

REVIEW
Ovarian cancer in the world: epidemiology and
risk factors
This article was published in the following Dove Press journal:
International Journal of Women's Health
Zohre Momenimovahed
1,2
Azita Tiznobaik
2,3
Safoura Taheri
4
Hamid Salehiniya
5,6
1
Department of Midwifery and
Reproductive Health, School of Nursing
and Midwifery, Qom University of
Medical Sciences, Qom, Iran;
2
Department of Midwifery and
Reproductive Health, School of Nursing
and Midwifery, Tehran University of
Medical Sciences, Tehran, Iran;
3
Department of Midwifery and
Reproductive Health, School of Nursing
and Midwifery, Hamedan University of
Medical Sciences, Hamedan, Iran;
4
Department of Midwifery and
Reproductive Health, School of Nursing
and Midwifery, Ilam University of Medical
Sciences, Ilam, Iran;
5
Social Determinants
of Health Research Center, Birjand
University of Medical Sciences, Birjand,
Iran;
6
Epidemiology and Biostatistics
Department, School of Public Health,
Tehran University of Medical Sciences,
Tehran, Iran
Aim: Ovarian cancer is one of the most common gynecologic cancers that has the highest
mortality rate. Considering the fact that knowledge on the incidence, mortality of ovarian
cancer, as well as its risk factors is necessary for planning and preventing complications, this
study was conducted with the aim of examining the epidemiology and risk factors of ovarian
cancer in the world.
Materials and methods: In order to access the articles, Medline, Web of Science Core
Collection, and Scopus databases were searched from their start to the year 2018. Full-text,
English observational studies that referred to various aspects of ovarian cancer were included
in the study.
Results: In total, 125 articles that had been published during the years 1925–2018 were
entered into the study. Ovarian cancer is the seventh most common cancer among women.
Increased risk factors of cancer have led to an upward trend in the incidence of cancer around
the world. In 2018, 4.4% of entire cancer-related mortality among women was attributed to
ovarian cancer. Although the incidence of cancer is higher among high Human Development
Index (HDI) countries, the trend of mortality rate tends to be reversing. Various factors affect
the occurrence of ovarian cancer, from which genetic factor are among the most important
ones. Pregnancy, lactation, and oral contraceptive pills play a role in reducing the risk of this
disease.
Conclusion: This study provides significant evidence about ovarian cancer. Considering the
heavy burden of ovarian cancer on women's health, preventive measures as well as health
education and early detection in high risk groups of women are highly recommended.
Although some risk factors cannot be changed, a focus on preventable risk factors may
reduce the risk of ovarian cancer. More studies are needed to explore the role of unclear risk
factors in ovarian cancer occurrence.
Keywords: Ovarian cancer, epidemiology, risk factor
Introduction
Cancer is the most common cause of mortality in most parts of the world,
1
and
currently is the most common impediment to achieving desirable life expectancy in
most countries.
2
Ovarian cancer is one of the most common gynecologic cancers
that rank third after cervical and uterine cancer.
2
It also has the worst prognosis and
the highest mortality rate.
3
Although ovarian cancer has a lower prevalence in
comparison with breast cancer, it is three times more lethal,
4
and it is predicted that,
by the year 2040, the mortality rate of this cancer will rise significantly.
2
The high
mortality rate of ovarian cancer is caused by asymptomatic and secret growth of the
tumor, delayed onset of symptoms, and lack of proper screening that result in its
Correspondence: Hamid Salehiniya
Social Determinants of Health Research
Center, Birjand University of Medical
Sciences, Birjand, Southern Khorasan,
Iran
Email alesaleh70@yahoo.com
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diagnosis in the advanced stages. Thus, silent killer is
a name that has been given to this cancer.
4–6
Like many cancers, the incidence of ovarian cancer varies
across the world.
7
The epidemiological diversity of ovarian
cancer in different regions can be attributed to the risk factors
that account for the occurrence of ovarian cancer.
8
The highest
prevalence of ovarian cancer is seen in non-Hispanic white
women (12.0 per 100,000), followed by Hispanic (10.3 per
100,000), non- Hispanic black (9.4 per 100,000), and Asian/
Pacific Islander women (9.2 per 100,000).
9
However, due to
differences in access to diagnostic and therapeutic services, the
mortality of ovarian cancer has a different pattern, and the
highest mortality rate is seen in African populations.
10
The
statistics show that between one third to two fifths of the total
cancer cases can be prevented by eliminating and reducing risk
factors.
2
Considering the fact that knowledge on the incidence,
mortality, and geographical diversity of ovarian cancer as well
as its risk factors is necessary for planning and preventing
complications, and since we could find no comprehensive
study on the risk factors of ovarian cancer in the world, the
aim of this study was to examine the trends in incidence and
mortality across the world and to present all possible factors
associated with OC.
Materials and methods
Search engines
In order to access the articles, Medline, Web of Science
Core Collection (Indexes = SCI-EXPANDED, SSCI, A &
HCI Timespan) and Scopus databases were searched from
their start to the year 2018.
Search strategy
At first, the search strategies were defined to increase valid-
ity of the review. In order to search the articles, a systematic
and accurate review of the published articles was carried out
by two researchers independently, and a list of potential
articles was prepared. The views of a specialist and expert
librarian were used to ensure the comprehensiveness of
searching strategies and reviewing resources. Searching for
articles was carried out with no time limit using keywords
such as; ovarian cancer, incidence, mortality, risk factor, and
a combination of them in English language. All keywords
were checked within PubMed Medical Subject Heading
(MeSH). Then, to ensure the adequacy of the search,
a manual search was also done in valid journals, followed
by a manual search for the references of full-text articles and
systematic reviews. All retrieved articles were entered into
a database in the Endnote X7.
Inclusion criteria
The criteria for entering the study included the following:
Full-text articles (retrospective and prospective cohort and
case-control studies), English language articles, the use of
keywords in the title or abstract (ovarian cancer, incidence,
mortality, risk factors, and a combination of these terms).
Exclusion criteria
Case reports, case series, systematic reviews, and animal
studies were excluded.
Results
Characteristics of the selected studies
In total, 145 articles that had been published during the years
1925–2018 were entered into the study. In the initial search,
588 articles were obtained from databases, and 46 articles were
extracted by manual search. After removing repetitive articles
using EndNote software, 493 articles were selected for review.
After reviewing the titles and abstracts, 322 articles that were
unrelated to the purpose of study and were not consistent with
the criteria of the study were removed. Furthermore, 26 articles
were also removed for scientific reasons (editorial: 5, qualita-
tive: 6, duplicate: 9, not available full text: 6). Finally, 145
articles that had been published during the years 1925–2018
were entered into the study (Figure 1).
The types of ovarian cancer
Different subtypes of ovarian cancer were discussed in
nine studies. Studies show that up to 90% of all OC have
epithelial origin and the remaining OC have non-epithelial
origin.
11–13
Among epithelial OC, 3% are mucinous and
others are non-mucinous.
14
Non-mucinous are further
found to have serous (70% of non-mucinous), endomter-
ioid (10%), clear cell (10%), and unspecified subtypes
(5%).
14–16
According to recent studies, serous carcinomas
are divided into two separate subtypes: high grade and low
grade.
17,18
Compared to epithelial cancers, non-epithelial
cancers are less invasive.
19
Incidence
Population growth, increased risk factors of cancer,
decreased pregnancy and duration of lactation, as well as
tube ligation have led to an upward trend in the incidence
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of cancer around the world.
2,20,21
Ovarian cancer is the
seventh most common cancer among women
2
and, in the
absence of protective factors, the lifetime risk of ovarian
cancer is about 2.7%.
21
According to Globoccan, 295,414
cases of ovarian cancer have been identified in 2018,
accounting for 3.4% of all cancer cases in women.
2
The
Age Standardized Rate (ASR) of ovarian cancer is esti-
mated to be 6.6 in 2018.
2
The incidence of epithelial
ovarian cancers varies in different age and race groups.
9
The incidence of this cancer is higher among transitioned
countries,
2
and approximately 30% of ovarian cancer cases
occur in European countries.
22
In 2012, the highest rates of
ovarian cancer occurred in China (14.60% of all cases),
India (11.33% of all cases), and the US (81.8% of all
cases).
22
In that year, 22,240 cases of ovarian cancer
were detected in the USalone.
9
Among the Asian coun-
tries, Singapore, Kazakhstan, and Brunei have the highest
standardized incidence rate of ovarian cancer.
23
Mortality
In 2018, 184,799 deaths occurred due to ovarian cancer,
accounting for 4.4% of the entire cancer-related mortality
among women.
2
Based on Globoccan 2018, the ASR of
ovarian cancer mortality is 3.9.
2
Although the incidence of
cancer is higher among high Human Development Index
(HDI) countries, the trend of mortality rate tends to be
reversing.
2
The highest mortality rate in Asia is seen in
India, and the mortality rate has decreased in Europe and
Databases searched
Medline: 353
Web of science: 132
Scopus: 103
Total recoreds indentified: n=588
Additional records identified
through other sources (n=46)
(Manual and bibliographic search)
493 records included after duplicates removed
IdentificationSearching
Eligibility
Included
322 records excluded based on title and abstract
171 articles assessed for
eligibility
145 studies included
in the synthesis
141 records excluded
26 articles excluded with reasons:
Editorial: 5
Qualitative: 6
Duplicate: 9
Not available full text: 6
Figure 1 Flowchart of the included eligible studies in review.
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North America in recent years, especially among young
people.
24
The mortality-to-incidence ratio is high among
African women, indicating their lack of access to suitable
treatment.
10
Two-thirds of ovarian cancer mortality is attribu-
table to high-grade serous carcinoma.
12
The FIGO’shighstage
at diagnosis and surgery,
25
and the presence of comorbidity
26
are among the most important predictors of high mortality in
ovarian cancer.
Risk factors
Table 1 shows factors related to ovarian cancer.
Demographic factor
Age
The epithelial ovarian cancer is an age-related disease,
and is considered mainly a postmenopausal disease.
10,27
Increased incidence of this cancer is more pronounced
in women over 65 years of age.
28
According to previous
studies, median age at diagnosis is 50–79 years.
27,29,30
The relationship between age and the outcome of ovar-
ian cancer is uncertain. Although many researchers have
pointed out that the younger age of ovarian cancer is
associated with the improved outcome,
29,31,32
other sta-
ted age is not an independent prognostic factor.
33
Older
age in this disease is associated with more advanced
disease and lower survival rate.
27,34
Older women are
treated less aggressively in contrast with younger ovar-
ian cancer patients, and, thus, survival is lower in these
group.
35
An age of over 64 years is one of the predic-
tors of mortality in people with ovarian cancer.
25
Reproductive factors
Menstrual-related factors
Tung et al
36
stated that non-mucinous tumors are strongly
associated with menstrual periods (odds ratio=1.5 for the
highest vs the lowest quartile) and ovulation cycles (odds
ratio=2.8 for the highest vs the lowest quartile). In numer-
ous studies, researchers indicated an inverse relationship
between ovulation cycles and the risk of ovarian
cancer.
37,38
The result of a case-control study showed that,
in women who have not had an ovulation cycle for 8.7
years, the risk of ovarian cancer was reduced by 4-times
(OR=0.23 [0.10–0.50]).
39
These findings support the theory
of “incessant ovulation”. Based on this theory, ovulation
without interruption can contribute to the incidence of ovar-
ian cancer by damaging the epithelium of ovaries; therefore,
any factor that contributes to the reduction of ovulation can
have a protective effect against ovarian cancer.
40
However,
Moorman et al
41
believed that, contrary to the lack of
ovulation due to pregnancy or the use of oral contracep-
tives, the lack of ovulation caused by menstrual disorders is
associated with an increased risk of ovarian cancer.
Table 1 Factors related to ovarian cancer in the world
Factors Protective Predisposing Controversial
Demographic Age ✓
Reproductive Menstrual-related factors ✓
Age of menarche and menopause ✓
Parity ✓
Pregnancy characteristics ✓
Higher age of childbirth ✓
Gynecologic Pelvic inflammatory disease ✓
Endometriosis ✓
Hormonal Contraceptive methods ✓
Hormone Replacement Therapy (HRT) ✓
Infertility treatments ✓
Genetic Family history ✓
BRCA mutations ✓
Lynch syndrome ✓
Lifestyle Nutrition and Diet ✓
Obesity and physical activity ✓
Alcohol, caffeine and cigarettes ✓
Other Lactation ✓
Lower socioeconomic status ✓
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Age of menarche and menopause
Although the result of some studies showed a relationship
between the early onset of menarche and risk of ovarian
cancer,
42,43
other researchers reported that age of
menarche and menopause has no effect on the risk of
ovarian cancer.
44–49
Parity
Results of several studies suggest that pregnancy has
a protective role against ovarian cancer.
38,45,49–52
Based on
the results of a case-control study, the risk of ovarian cancer
is reduced in women with live birth (P<0.001) or induced
abortion (P<0.05), and this risk decreases with an increase in
the number of live birth cases (P<0.001). The result of a case-
control study showed that, for every full-term pregnancy, OR
is equal to 0.76 [0.69–0.85] for non-mucinous tumors and
1.03 [0.88–1.21] for mucinous tumors.
53
The result ofa study
showed that increased pregnancy is associated with
a consistent reduction in the relative risk of invasive ovarian
cancer (odds ratio for each additional birth=0.81
[0.75–0.85]), epithelial cancer (0.81 [0.77–0.86]), stromal
cancer (0.84 [0.72–0.98]), and germ-cell cancer (0.71
[0.48–1.05]).
54
However, Poole et al
34
stated that pregnancy
decreases the risk of less aggressive disease compared to an
advanced disease.
Pregnancy characteristics
Jordan et al,
55
in a case-control study, showed that preterm
labor increases the risk of ovarian cancer (OR=1.48
[1.02–2.15]). This finding has been confirmed in Skold et al’s
56
study. The results of a study showed that the delivery of a male
infant is associated with a 2-times increase in the risk of
mucinous ovarian cancer (OR=2.19 [1.15–4.17]).
55
Mucci
et al
57
concluded that low birth weight among term infants
has a protective effect on the mother’s ovarian cancer, while
Skold et al
56
did not find any relationship between infant’s
weight and ovarian cancer. Skold et al
56
also rejected the role of
pre-eclampsia and multiple pregnancies in the occurrence of
cancer in the mother. However, Calderon-Margalit et al,
58
in
a cohort study, concluded that pre-eclampsia increases the risk
of ovarian cancer by more than 2-times (HR=2.59
[1.35–4.94]).
Age at childbirth
Results of a case-control study indicated that older age in
pregnancy is associated with a decreased risk of ovarian
cancer
59
relative to the number of pregnancies. This result
has been confirmed in other studies.
51,52,54
Adami et al
54
stated that, for every 5-year increase in the age at first
childbirth, the risk of ovarian cancer would be reduced by
up to 10% (OR=0.89 [0.84–0.94] epithelial cancer, 0.92
[0.77–1.10] stromal cancer, 0.92 [0.65–1.32] germ-cell
cancer, 0.93 [0.80–1.09] borderline tumors).
Gynecologic factors
Pelvic inflammatory disease
The role of inflammation and pelvic inflammatory disease
in the occurrence of ovarian cancer is controversial among
experts. Ness et al,
60
in a case-control study, supported the
hypothesis that suggests inflammation contributes to the
onset of ovarian cancer. On the other hand, Jia et al
61
concluded that events associated with inflammation in
the ovary (such as repairing the damaged ovary) are asso-
ciated with an increase in the release of cancer cells in the
tissues around the ovary. Thus, they stated that ovulation
and other events associated with inflammation in the ovary
contribute to an increased risk of ovarian cancer. In line
with this, a case-control study referred to the role of
chlamydia trachomatis infection in the development of
ovarian cancer.
62
Wong et al
63
stated that, although chla-
mydia trachomatis inflammation may contribute to the
development of ovarian cancer, chlamydia is a common
pathogen in the genital area, and it is difficult to determine
the exact relationship between the two. Merritt et al,
64
in
a case-control study in 2008, had an opposite view, and
stated that chronic inflammation has no role in the devel-
opment of ovarian cancer. Lin et al
65
reported that there is
a link between PID and ovarian cancer (HR=1.92
[1.27–2.92]). In a cohort study, Rusmussen et al
66
reported
that inflammation associated with serous ovarian cancer is
not associated with the risk of other types of ovarian
cancer. The result of another case-control study suggested
that, although there is a relationship between pelvic
inflammatory disease (PID) and ovarian cancer, this risk
is higher in the cases of recurrent PID (OR=1.88
[1.13–3.12], P=0.014).
67
Endometriosis
The relationship between endometriosis and ovarian
cancer has been shown in various studies through var-
ious mechanisms. The results of a cohort study showed
that, in people with endometrium, aging, living in urban
areas, low or high income, depression, pelvic infection,
and lack of childbearing increase the risk of ovarian
cancer.
68
In 1925, Sampson
69
proposed a link between
endometriosis and ovarian cancer based on the theory of
malignant changes of endometriosis. Inflammation and
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the PTEN, CTNNB1 (β-catenin), KRAS, microsatellite
instability, and ARID1A genes are involved in the
occurrence of endometriosis-associated ovarian
cancer.
70
THe results of a cohort study showed that
endometriosis increases the risk of ovarian cancer
(SIR=1.34 [1.16–1.55]) and this risk is higher in endo-
metrioid (SIR=1.64 [1.09–2.37]) and clear cells
(SIR=3.64 [2.36–5.38]).
71
Compared to other types of
ovarian cancer, endometriosis-associated ovarian cancer
is detected at a younger age and lower stages.
70
Melin
et al
72
stated that, although endometriosis increases the
risk of ovarian cancer (SIR=1.43 [1.19–1.71]), hyster-
ectomy may have a protective effect against ovarian
cancer before or at the time of endometriosis diagnosis.
Stewart et al,
73
in a cohort study, stated that nulliparous
women with endometriosis are 3-times more likely to
develop ovarian cancer (HR=3.11 [1.13–8.57]). They
stated that, although hysterectomy plays a protective
role against ovarian cancer, unilateral oophorectomy/
salpingo-oophorectomy without hysterectomy increases
the risk of ovarian cancer by 4-times (HR=4.23 [1.30–-
13.77]). Erzen and Kovacic
74
believed that the relation-
ship between endometriosis and ovarian cancer is
affected by the age of the patient. The incidence of
epithelial ovarian cancer in women with endometriosis
risesfrom4.99inlessthan30yearsto35.81inmore
than 50 years per 10,000 people per year.
75
In a case-
control study, researchers concluded that hyperestrogen-
ism or exogenous is a risk factor for the onset of
ovarian cancer after endometriosis.
76
Cottreau et al
77
believed that the use of danazol for the treatment of
endometriosis is associated with a 3.2-times increased
risk of ovarian cancer [1.2–8.5]. They stated that there
is no such a risk in the consumers of leuprolide/
nafarelin.
Ovarian cysts
Some types of benign ovarian cysts may act as a precursor
of malignant ovarian tumors. According to a case-control
study, ovarian cyst is associated with increased risk of
borderline ovarian tumors (OR=1.3 [0.9–1.8]), and this
risk increased among women who were undergoing
surgery.
78
In addition, complex ovarian cysts significantly
increase the risk of malignancy in postmenopause.
79
However in another study, complex cysts in postmenopau-
sal women were not the immediate precursors of ovarian
cancer.
80
Crayfold,
81
in a cohort of women, indicated that
removal of ovarian cysts was not associated with
a decrease in ovarian cancer related mortality.
Tubal ligation
The risk of ovarian cancer was reduced in women with
tubal ligation.
82–85
In a cohort study, tubal ligation was
associated with a 20% reduction in risk of high-grade
serous carcinoma.
86
Women with tubal ligation have
a decreased risk of invasive serous cancer (19%), invasive
mucinous cancer (32%), clear cell cancer (42%), and
endometrioid cancer (52%).
82,85
No association was
found between tubal ligation and low-grade serous
tumors.
82,86
Younger age at tubal ligation was not asso-
ciated with increased protective effects of this method.
82
A mechanical barrier for carcinogenic agents can reduce
ovarian cancer after tubal ligation.
87
Hormonal factors
Contraceptive methods
Results of most studies indicate that the use of oral
contraceptive methods is associated with a reduced risk
of all histological types of ovarian cancer.
36,51,88,89
Results of a case-control study in Canada indicated
that the use of hormonal contraceptive pills is associated
with a significant reduction in all histological types of
epithelial ovarian cancer, except for mucinous tumors.
Accordingtothefindings of this study, OR for
each year of use of these pills was 0.89 [0.85–0.93]
for non-mucinous tumors and 0.98 [0.93–1.04] for muci-
nous tumors.
53
The result of a case-control study
showed that oral contraceptive pill (OCP) decreases
the risk of fatal and advanced ovarian cancer compared
to less advanced cases.
34
Royar et al
89
stated that,
each year, use of combined oral contraceptive pills
reduces the risk of ovarian cancer by 7% (OR=0.93
[0.90–0.96]), and this reduction is more pronounced
during the first use at the age of less than 25 years.
Although there is an inverse relationship between the
time of using hormonal contraceptive pill, the age of its
use, and the risk of ovarian cancer, the duration of
consumption is more important.
51,59
This risk reduction
can persist for up to 10–15 years after the discontinua-
tion of pills,
90
however the protective effect of oral
contraception has not been proven in many studies.
50
In a case-control study, no relationship was found
between the use of contraceptive methods (except for
tube ligation) and the risk of ovarian cancer.
37
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Hormone replacement therapy (HRT)
The result of a case-control study showed that combined
estrogen-progesterone therapy after menopause does not
increase the risk of ovarian cancer.
91
Hempling et al
92
exam-
ined the effect of exposure to post-menopausal hormone
therapy, and stated that HRT is not associated with ovarian
cancer, even in long term use. However, Glud et al
93
stated
that oral hormone therapy is associated with an increased risk
of ovarian cancer in people who have not previously had
a hysterectomy. Researchers believe that the use of estro-
genic methods, especially for 10 years or more, is associated
with an increased risk of ovarian cancer.
94
The result of
a case-control study showed that, although hormone therapy
with estrogen alone increases the risk of ovarian cancer, it has
no significant effect on the survival of the patient.
95
Rossing
et al,
91
in a case-control study, stated that the progesterone
component of a combined hormone therapy reduces the risk
of ovarian cancer. Mørch et al
96
believed that, regardless of
the duration of use, formulation, estrogen dose, type of regi-
men, type of progesterone, and method of use, hormone
therapy is associated with an increased risk of ovarian cancer.
Infertility treatments
Ovarian cancer is a rare and, at the same time, a fatal disease.
Regardless of infertility treatments, nulliparity itself
97
and
infertility are risk factors of ovarian cancer, so it is difficult
to investigate the relationship between infertility treatment and
ovarian cancer. The “incessant ovulation theory”states that
ovulation without interruption can contribute to the develop-
ment of ovarian cancer by damaging the ovary epithelium,
and, therefore, any factor that contributes to the reduction of
ovulation can have a protective effect against ovarian cancer.
40
Several studies have indicated an association between the
increased risk of ovarian cancer and the use of clomiphene
citrate
98
and gonadotropin.
99
The results of a cohort study
showed an increase in ovarian cancer after exposure to clomi-
phene citrate, and indicated that the risk of ovarian cancer
increases with increasing dosage of clomiphene citrate among
nulliparous women.
98
The results of a case-control study
indicated that the use of ovulation-inducing drugs, especially
hMG, increases the risk of epithelial ovarian tumors.
100
Although several studies have suggested a relationship
between the risk of ovarian cancer and the use of ovulation-
inducing drugs, this risk was not significant in many
studies.
46,101–105
In a cohort study of 54,362 women, Jensen
et al
106
reported that the risk of ovarian cancer does not
increase with the use of clomiphene citrate, gonadotropins,
human chorionic gonadotrophin, and gonadotrophin releasing
hormone, and there is no relationship between duration of use,
duration of follow-ups, or pregnancy. Brinton et al (2001)
99
suggested that an increased risk of ovarian cancer among
people who take ovulation-inducing drugs requires a more
attention to the choice of individuals.
Genetic factors
Family history
The most important risk factor for ovarian cancer is a family
history ofbreast or ovarian cancer.
9
Personal history of breast
cancer is associated with an increase in the risk of ovarian
cancer (OR=3.7 [1.8–7.7]).
107
The results of a case-control
study showed that the risk of ovarian cancer increases in
women with a family history of breast, uterine, or ovarian
cancerintheirmotherorsister(P<0.001).
37
BRCA mutations
More than one-fifth of ovarian cancers are due to muta-
tions in tumor suppressor genes,
108
and 65–85% of inher-
ited ovarian tumors result from germline mutations in
BRCA genes.
109
Although the risk of ovarian cancer in
carriers of BRCA1 and BRCA2 mutations is less than 3%
by the age of 40, this risk increases to 10% by the age of
50.
12
The 10-year risk of developing ovarian cancer in
individuals with breast cancer is 12.7% and 6.8% in the
carriers of BRCA1 and BRCA2 mutation.
12
Cumulative
risk of ovarian cancer up to the age of 80 is 49% in
BRCA1 mutation carriers and 21% in BRCA2 mutation
carriers.
110
About 25% of breast cancer deaths in stage
I are due to the occurrence of ovarian cancer.
111
Salpingo-
oophorectomy in BRCA-positive individuals reduces the
risk of ovarian cancer by 75%.
112
Since, most epithelial
cancers originate from the fallopian tube, salpingectomy
decreases the risk of ovarian cancer by 35–50%.
113
Lynch syndrome
Lynch syndrome is an autosomal dominant cancer predis-
position syndrome that is responsible for 1–3% of all
colorectal cancer.
114
Lynch syndrome is responsible for
10–15% of the total inherited ovarian cancer cases,
115
and the lifetime risk of this cancer in individuals with
a family history of Lynch syndrome is 6–8%.
116
Most of
the ovarian cancers associated with Lynch syndrome are
non-mucinous, and 82–84% of them are in stage I or II.
115
Lynch occurs due to a hereditary mutation in one of the
four mismatch repair genes (MHL1,MSH2,MSH6, and
PMS2),
12
and MSH2 and MLH1 are the most common
mutations in these individuals.
117
The most common
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types of ovarian cancer in these individuals are endome-
trioid and clear cell ovarian cancers.
116
Lifestyle factors
Nutrition and diet
Accordingtothefindings of a case-control study, there is
a positive correlation between daily intake of fish and the
risk of ovarian cancer (P<0.05), and this correlation is negative
for daily intake of milk (P=0.05).
37,118
Results of a case-
control study showed that the risk of ovarian cancer is asso-
ciated with a higher cholesterol intake (OR=1.42 [1.03–1.97]),
and this risk is reduced by consumption of vegetables
(OR=0.77 [0.60–1.04]), vitamin supplement (OR=0.49
[0.30–0.81]), beta-carotene (OR=0.31 [0.11–0.91]), and
B-complex vitamins (OR=0.61 [0.36–1.05]).
119
McCann
et al
120
refer to the protective role of phytoestrogens in the
development of ovarian cancer, and believe that a plant-based
diet plays an important role in the reduction of hormone-
related cancers.
120,121
The results of a case-control study
showed that saturated fat is associated with an increased risk
of ovarian mucinous tumors.
53
Ong et al
122
revealed that an
increased concentration of vitamin D in plasma may reduce
the risk of ovarian cancer. This risk reduction is also seen in the
case of calcium and lactose consumption.
118
Obesity and physical activity
The results of a study showed that obesity reduces the risk of
survival in ovarian cancer (HR=3.40 [1.16–9.99]), and
increases the risk of death caused by the disease (HR=0.58
[0.35–0.96]).
123
Central adiposity is associated with an
increased risk of ovarian cancer, indicating the conversion
of androgen in the peripheral tissues.
124
Rodriguez et al
125
reported a 36% increase in the risk of ovarian cancer among
obese people who have never used postmenopausal estrogen
treatment, and stated that obesity and tallness increase the
mortality of ovarian cancer. Anderson et al,
126
in a cohort
study, reported that waist–hip ratio is associated with an
increased risk of ovarian cancer (RR=1.59 for high quartile
vs low quartile [1.05–2.40]). However, Kotsopoulos et al
127
stated that height, weight, and adiposity are not related to the
prognosis of ovarian cancer. Beehler et al
128
believed that the
relationship between obesity and risk of ovarian cancer is
related to menopause condition. Beehler et al,
128
in a case-
control study, showed that obesity before menopause is asso-
ciated with an increased risk of ovarian cancer (adjusted
OR=2.19 [1.49–4.04]), although it is not associated with the
risk of ovarian cancer at post-menopausal age. Leitzmann
et al
129
suggested that obesity, with its hormonal mechanism,
increases the risk of ovarian cancer and, in addition to that,
increases the mortality of affected individuals.
38
On the other
hand, researchers in a case-control study concluded that phy-
sical activity is associated with a reduction in the risk of
ovarian cancer.
130
However, this result has not been con-
firmed by other studies,
131,132
Anderson et al
126
stated that
leisure-time physical activity is associated with an increase in
the incidence of ovarian cancer (RR=:1.42 for high activity vs
low activity [1.03–1.97]).
Alcohol, caffeine, and cigarettes
Several researchers around the world believe that alcohol
does not increase the risk of ovarian cancer,
46,133–137
but
Goodman and Tung
138
argue that alcohol’s relation to
ovarian cancer is related to the type of alcohol. Schouten
et al
139
believed that drinking alcohol in the form of wine,
beer, or liquor is not associated with an increased risk of
ovarian cancer. However, the result of a case-control study
showed that caffeine and coffee consumption may increase
the risk of ovarian cancer in women before menopause.
135
Although many researchers believe that cigarette smok-
ing does not change the risk of ovarian cancer in women
before and after menopause,
135,140
Jordan et al
141
state that
smoking a pack of cigarettes daily for 20 years is associated
with a doubled risk of benign mucinous tumors, borderline
tumors, and malignant tumors (OR=2.7 [1.6–4.4] for benign
tumors, OR=2.7 [1.7–4.4] for borderline tumors, and
OR=2.1 [0.9–5.0] for malignant tumors). Gram et al,
142
in
a cohort study, showed that the length and amount of
smoking increases the risk of borderline tumors. Kim et al
38
believed that smoking increases the risk of death in people
with ovarian cancer by up to 25% (HR=1.25 [1.01–1.54]).
Marchbanks et al
143
stated that, although smoking increases
the risk of epithelial mucinous tumors (OR=2.9 [1.7–4.9]),
it is not associated with other histological types of ovarian
cancer. This result has also been confirmed in other
studies.
46,52,136,144–146
The age at smoking onset is not
associated with the risk of ovarian cancer.
147
Other
Lactation
Researchers have reported an inverse relationship between
the duration of breastfeeding, the number of breast-fed
children, and the risk of ovarian cancer.
50,148
Results of
a case-control study showed that lactation reduces the risk
of ovarian cancer by 22% (OR=0.78 [0.64–0.96]), and this
risk decreases with longer lactation period (OR=0.56
[0.32–0.98] for 18 months average duration of breastfeeding
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vs none). In this study, the most risk reduction was related
to endometrioid and clear cell ovarian cancers.
149
Tung
et al
36
were also in agreement with the views of other
researchers, and stated that the duration of lactation reduces
the risk of non-mucinous tumors (OR=: 0.4 for the highest
vs the lowest quartile). However, there was no such
a protective effect against mucinous tumors in this study.
Socioeconomic status
The socioeconomic status is one of the predictors of inci-
dence and survival of ovarian cancer.
150
Access to
healthcare,
151
patient awareness about the symptoms of
ovarian cancer, timely response to symptoms, lifestyle,
and underlying illnesses justify the link between socio-
economic status and ovarian cancer.
152
The result of
a case-control study showed a negative relationship
between educational level and the risk of ovarian
cancer.
153
In the Brewster et al’s
154
study, a weaker social
status was associated with the more advanced illness.
Conclusion
The aim of this study was to review the epidemiological
aspects and the risk factors of ovarian cancer in the world.
Ovarian cancer, as one of the major gynecological cancers,
kills many women around the world, and this mortality
varies from country to country. The findings of this study
showed that various factors affect the occurrence of ovar-
ian cancer, from which genetic, environmental and life-
style factors are among the most important ones. Many
factors such as pregnancy, lactation, and oral contraceptive
pills play a role in reducing the risk of this disease.
Disclosure
The authors report no conflicts of interest in this work.
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