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International Journal of
Environmental Research
and Public Health
Review
Impact of Sexual Activity on the Risk of Male Genital Tumors:
A Systematic Review of the Literature
Felice Crocetto 1, Davide Arcaniolo 2, Luigi Napolitano 1, * , Biagio Barone 1, Roberto La Rocca 1,
Marco Capece 1, Vincenzo Francesco Caputo 1, Ciro Imbimbo 1, Marco De Sio 2, Francesco Paolo Calace 1,2
and Celeste Manfredi 1,2
Citation: Crocetto, F.; Arcaniolo, D.;
Napolitano, L.; Barone, B.; La Rocca, R.;
Capece, M.; Caputo, V.F.; Imbimbo, C.;
De Sio, M.; Calace, F.P.; et al. Impact of
Sexual Activity on the Risk of Male
Genital Tumors: A Systematic Review
of the Literature. Int. J. Environ. Res.
Public Health 2021,18, 8500. https://
doi.org/10.3390/ijerph18168500
Academic Editor: David L. Rowland
Received: 7 July 2021
Accepted: 9 August 2021
Published: 11 August 2021
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Attribution (CC BY) license (https://
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1Urology Unit, Department of Neurosciences, Reproductive Sciences and Odontostomatology,
University of Naples “Federico II”, 80121 Naples, Italy; felice.crocetto@gmail.com (F.C.);
biagio193@gmail.com (B.B.); robertolarocca87@gmail.com (R.L.R.); drmarcocapece@gmail.com (M.C.);
vincitor@me.com (V.F.C.); ciro.imbimbo@unina.it (C.I.); frap.calace@gmail.com (F.P.C.);
manfredi.celeste@gmail.com (C.M.)
2Urology Unit, Department of Woman Child and of General and Specialist Surgery, University of Campania
“Luigi Vanvitelli”, 80121 Naples, Italy; davide.arcaniolo@gmail.com (D.A.);
marco.desio@unicampania.it (M.D.S.)
*Correspondence: nluigi89@libero.it
Abstract:
Most cancers are related to lifestyle and environmental risk factors, including smoking,
alcohol consumption, dietary habits, and environment (occupational exposures). A growing interest
in the association between sexual activity (SA) and the development of different types of tumors
in both men and women has been recorded in recent years. The aim of the present systematic
review is to describe and critically discuss the current evidence regarding the association between
SA and male genital cancers (prostatic, penile, and testicular), and to analyze the different theories
and biological mechanisms reported in the literature. A comprehensive bibliographic search in the
MEDLINE, Scopus, and Web of Science databases was performed in July 2021. Papers in the English
language without chronological restrictions were selected. Retrospective and prospective primary
clinical studies, in addition to previous systematic reviews and meta-analyses, were included. A
total of 19 studies, including 953,704 patients were selected. Case reports, conference abstracts, and
editorial comments were excluded. Men with more than 20 sexual partners in their lifetime, and
those reporting more than 21 ejaculations per month, reported a decreased risk of overall and less
aggressive prostate cancer (PCa). About 40% of penile cancers (PCs) were HPV-associated, with
HPV 16 being the dominant genotype. Data regarding the risk of HPV in circumcised patients are
conflicting, although circumcision appears to have a protective role against PC. Viral infections
and epididymo-orchitis are among the main sex-related risk factors studied for testicular cancer
(TC); however, data in the literature are limited. Testicular trauma can allow the identification
of pre-existing TC. SA is closely associated with the development of PC through high-risk HPV
transmission; in this context, phimosis appears to be a favoring factor. Sexual behaviors appear to
play a significant role in PCa pathogenesis, probably through inflammatory mechanisms; however,
protective sexual habits have also been described. A direct correlation between SA and TC has not
yet been proven, although infections remain the most studied sex-related factor.
Keywords: sexual activity; sex; prostate cancer; penile cancer; testicular cancer
1. Introduction
Sexual activity (SA) has long been a popular topic in different fields of medicine
due to its potential impact on health status. SA includes a variety of activities, such
as penetrative sex (anal and vaginal), oral sex, and masturbation, which could affect
the psychophysical condition of men [
1
]. The effect of SA on the health status and, in
particular, on the risk of developing tumors, has not been well clarified. A portion of
Int. J. Environ. Res. Public Health 2021,18, 8500. https://doi.org/10.3390/ijerph18168500 https://www.mdpi.com/journal/ijerph
Int. J. Environ. Res. Public Health 2021,18, 8500 2 of 16
the literature defines SA as a panacea, resulting in a positive influence on more than one
domain of health status. In this context, Cao et al. showed that SA may reduce the risk
of fatal coronary events and breast cancer, improving the quality of life, well-being, and
cognitive function [
2
]. In contrast, other research has highlighted the negative aspects of
SA, focusing on the risk of contracting sexually transmitted diseases (STDs), which may
be the primum movens of different types of cancer. For example, human papillomavirus
(HPV) infection is known to be a key risk factor for cervical tumors and a recognized risk
factor for cancer of the penis, vulva, vagina, anus, and oral cavity [
3
]. Another essential
aspect to consider in this context is the possible inflammation that can result, directly or
indirectly, from SA, which is a critical component of the tumor pathway. The available
literature reports that chronic inflammation increases the risk for several cancers through a
variety of mechanisms involving the tumor microenvironment [
4
]. More specifically, it is
hypothesized that inflammatory injury may favor carcinogenesis by causing cellular stress
and genomic damage via high production of ROS [
5
]. Evidence from a number of genetic,
epidemiological, and molecular studies suggests that inflammation plays a crucial role in
various stages of prostatic carcinogenesis and tumor progression [
6
]. The aim of the present
systematic review is to describe and critically discuss the current evidence regarding the
association between SA and male genital tumors (prostatic, penile, and testicular), focusing
on the different theories and biological mechanisms reported in the literature.
2. Materials and Methods
This analysis was conducted and reported according to the general guidelines rec-
ommended by the Primary Reporting Items for Systematic Reviews and Metanalyses
(PRISMA) statement [7].
The bibliographic search was performed in the MEDLINE (US National Library of
Medicine, Bethesda, MD, USA), Scopus (Elsevier, Amsterdam, The Netherlands), and
Web of Science (Thomson Reuters, Toronto, ON, Canada) databases in July 2021, without
chronological restrictions. The following terms were combined in a title–abstract search
to capture all relevant publications: (“sex” OR “sexual activity” OR “intercourse” OR
“masturbation” OR “anal sex” OR “oral sex”) AND ((“prostate” OR “prostatic”) OR (“testis”
OR “testicular”) OR (“penis” OR “penile”)) AND (“cancer” OR “tumor” OR “neoplasm”,
OR “lesion”). All articles identified from the literature search were screened by two
independent reviewers (B.B. and V.F.C.), with any discrepancies resolved by a third author
(D.A.). The reference lists of included papers were used to search for other relevant articles.
To assess the eligibility of the articles, PICOS (participants, intervention, compar-
ison, outcomes, study type) criteria were used [
8
]. PICOS criteria were set as follows:
participants—male patients; intervention—any form of sexual activity; comparison—not
applicable; outcome—cancer; study types—prospective and retrospective studies (con-
trolled and uncontrolled), systematic reviews, and meta-analyses. Only articles in English
describing at least 10 patients were selected. Preclinical studies exploring pathophysiology
mechanisms of cancer development were included. Conference abstracts and commentaries
were excluded.
The results were narratively reported, without performing a quantitative synthesis
of the data, due to the expected high heterogeneity of the studies. The following data
were extracted from clinical study: first author, publication year, study design, sample size,
and main findings. The quality of the included studies was assessed using the Newcastle–
Ottawa Scale (NOS) for non-randomized studies. Systematic reviews and meta-analyses
were analogously assessed using A Measurement Tool to Assess Systematic Reviews-2
(AMSTAR-2). Finally, the risk of bias was assessed using the ROBINS-I Tool for each of
non-randomized and randomized studies [
9
–
11
]. Ethical approval and patients’ consent
were not required for the present study.
Int. J. Environ. Res. Public Health 2021,18, 8500 3 of 16
3. Results
The search strategy revealed a total of 390 results. Screening of the titles and abstracts
revealed 306 papers that were eligible for inclusion. Further assessment of eligibility, based
on full-text articles, led to the exclusion of 287 papers. Finally, 19 studies involving a
total of 953,704 patients were included in the final analysis [
12
–
30
] (Figure 1). The main
characteristics of the selected studies are summarized in Table 1, and the assessment of the
risk of bias is reported in Figures 2and 3.
Int. J. Environ. Res. Public Health 2021, 18, 8500 5 of 17
Figure 1. PRISMA flow diagram for selection of studies.
Figure 1. PRISMA flow diagram for selection of studies.
Int. J. Environ. Res. Public Health 2021,18, 8500 4 of 16
Table 1. Main characteristics of the selected studies.
First Author and
Publication Year Study Design Sample Size Main Findings Study Quality
Prostate Cancer
Rosenblatt 2001 [16] Case-control 1456 Association between
sexual factor and PCa 5#
Spence 2014 [12] Case-control 3208
Reduction of risk of PCa
in men with
>20 sexual partners
No correlation between
Risk of PCa and age at
first sexual intercourse
No association between
STDs and PCa
8#
Papa 2017 [14] Case-control 2141 Inverse associations with
EF and PCa 6#
Crum 2004 [20]Prospective cohort
study 269
Positive correlation
between incidence of PCa
and duration of
HIV infection
6#
Cheng 2010 [18]Prospective cohort
study 68,675
Positive correlation
between prostatitis, STDs
and Pca
8#
Rider 2016 [13]Prospective cohort
study 31,925 Inverse association
between EF and PCa 7#
Sinnott 2018 [15]Prospective cohort
study 157 Inverse association
between EF and PCa 6#
Jian 2018 [17] Systematic Review 55,490
Positive association
between number of
female sexual partners,
age at first intercourse,
EF, and the risk of PCa
Intermediate *
Sun 2021 [19] Systematic Review 2780
Reduced risk of PCa
among people with
HIV/AIDS
High *
Penile Cancer
Iversen 1997 [23] Case-control 867
Not significant increased
of incidence of HPV
related cancers in partner
of patients with HPV
related cancer
5#
Daling 2005 [21] Case-control 808
Positive association
between HPV and
penile cancer
7#
Madsen 2008 [24] Case-control 293
Positive correlation
between oral sex as a risk
factor in PC
5#
Mirghani 2017 [22] Systematic Review 1356
Higher incidence of HPV
related cancers in partner
of patients with HPV
related cancer
Low *
Lekoane 2020 [25] Systematic Review 16,351
Positive correlation
between HIV
andHPV-related cancers
Intermediate *
Int. J. Environ. Res. Public Health 2021,18, 8500 5 of 16
Table 1. Cont.
First Author and
Publication Year Study Design Sample Size Main Findings Study Quality
Testicular Cancer
Algood 1988 [26]Prospective Cohort
study 86
Positive correlation
between Viral infections
(Epstein-Barr virus,
cytomegalovirus, and
hepatitis A and B viruses)
and TGCTs
6#
Kao 2016 [29] Case-control 4092
Positive association
between TGCTs
and Epididymoorchitis
8#
Garolla 2019 [27] Meta-analysis 285,878
Positive correlation
between viral infections
and risk of
developing TGCTs
High *
Trabert 1969 [30] Meta-analysis 1696
No association between
common infections
and TGCTs
Intermediate *
Grulich 2017 [28] Meta-analysis 476,149
Higher incidence of
cancers in people with
HIV/AIDS compared
with immunosuppressed
transplant recipients
High *
EF: ejaculatory frequency; HIV/AIDS: Human immunodeficiency Virus/Acquired Immune Deficiency Syndrome; HPV: human papillo-
mavirus; PCa: prostate cancer; STDs: sexually transmitted disease; PC: penile cancer; TGCTs: testicular germ cell tumors. * A Measurement
Tool to Assess Systematic Review-2 (AMSTAR-2), #Newcastle–Ottawa Scale (NOS).
Int. J. Environ. Res. Public Health 2021, 18, 8500 6 of 17
Figure 2. Risk of bias.
Figure 3. Risk of bias domains.
3.1. Prostate Cancer (PCa)
PCa is one of the most diagnosed cancers globally, with an estimated incidence of
1,276,000 new cancer cases and 359,000 deaths in 2018. Several risk factors have been es-
tablished (e.g., old age, family history, and African American ethnicity) [31–33]. PCa is the
neoplasia that has the greatest impact on the male population and is the most frequently
Figure 2. Risk of bias.
3.1. Prostate Cancer (PCa)
PCa is one of the most diagnosed cancers globally, with an estimated incidence of
1,276,000 new cancer cases and 359,000 deaths in 2018. Several risk factors have been
established (e.g., old age, family history, and African American ethnicity) [
31
–
33
]. PCa is
the neoplasia that has the greatest impact on the male population and is the most frequently
detected cancer globally for men over 50 years of age. Despite recent therapeutic advances,
PCa still represents a major urological disease associated with substantial morbidity and
mortality. The most important role in the development and maintenance of normal male
physiology is mediated by androgens. In particular, testosterone is a sex hormone that plays
important roles in the body via the libido, bone mass, fat distribution, muscle strength,
Int. J. Environ. Res. Public Health 2021,18, 8500 6 of 16
and mass, and also regulates spermatogenesis [
34
]. Recently, evidence has suggested
that sexual behaviors, such as number of sexual partners, sexual orientation, ejaculation
frequency (EF), gender of sexual partners, and impact of STDs, may play a role in PCa
pathogenesis. Spence et al. showed that men with more than 20 sexual partners (females
and males combined) in their lifetime had a decreased risk of overall and less aggressive
PCa (OR 0.78, 95% CI 0.61–1.00 and OR 0.75, 95% CI 0.57–0.99, respectively) [
12
]. In
addition, men considering themselves to be homosexual or bisexual had a slightly greater
PCa risk, compared to men who self-identified as heterosexual. In particular, several male
sexual partners were associated with an increased risk of PCa [
12
]. The pathophysiology
is not clear but it is thought that physical trauma of the prostate during receptive anal
intercourse and the major incidence of HIV could favor the development of PCa [
35
].
Rider et al. showed that men reporting
≥
21 ejaculations per month compared to subjects
with 4–7 ejaculations per month had a significantly lower risk of total PCa, with an HR
of 0.81 (95% CI 0.72–0.92) and 0.78 (95% CI 0.69–0.89) at 20–29 years and 40–49 years,
respectively [
13
]. Papa et al. described an inverse association between EF and PCa at age
30 to 39 (OR per 5-unit increase per week 0.83, 95% CI: 0.72–0.96) but not at ages 20 to 29 or
40 to 49 [
14
]. Several hypotheses were proposed to explain the correlation between EF and
PCa. In the prostatic acini, luminal secretion is rich in corpora amylacea, and the increase
in their number with age appears to be related to an increased incidence of PCa. A greater
level of sexual activity may lead to less accumulation of these bodies, which has been
supposed to have a carcinogenic effect [
36
,
37
]. Furthermore, EF regulates the expression of
several genes in the prostate tissue. Sinnot et al. reported that EF modifies some molecular
pathways, such as Ubiquitin Mediated Proteolysis (involved in cell cycle regulation), and
the Citrate Cycle pathway (involved in citrate production). Citrate production decreases in
PCa and increases in benign prostatic hyperplasia (BPH) [
15
]; moreover, it is known that
in early prostate tumorigenesis there is a metabolic switch from citrate secretion to citrate
oxidation [
38
]. Regarding sexual orientation, in 2002 Rosenblatt et al. showed that there
was no association between sexual orientation and PCa [
16
]. Finally, EF may be linked to the
alleviation of psychological tension and thus to the suppression of the central sympathetic
nervous system, which may reduce the stimulation of the division of the epithelial cells of
the prostate [
17
]. In addition, increased sexual activity can also be considered a risk factor
for PCa development. Multiple and lasting episodes of STDs may represent a high risk
for PCa development. It was proposed that gonorrhea and other bacterial infections may
cause PCa through prostate inflammation and atrophy, whereas viral infections may have
direct pro-oncogenetic properties or immunosuppressive effects [
18
]. In a meta-analysis
performed by Lian et al., involving 21 studies and 9965 patients with PCa, the authors
found a high incidence of tumors in patients with gonorrhea infection (OR 1.31, 95%
CI 1.14–1.52
), particularly in African American males (OR 1.32, 95% CI 1.06–1.65) [
39
]. Data
showed that HIV is associated with several genitourinary malignancies with an increased
incidence in the population with HPV infection [
40
]. Hessol et al. identified 32 cases of PCa
in a population of 14,000 adults in San Francisco between 1990 and 2001. The standardized
incidence was greater when compared to the general population [
41
]. A recent meta-
analysis by Sun et al., evaluating 27 articles and 2780 men with HIV/AIDS, showed a
decreased incidence of PCa in patients with HIV infection (SIR 0.76; 95%
CI, 0.64–0.91
;
p= 0.003
) [
19
]. Nevertheless, a significant correlation between PCa incidence and duration
of HIV infection (p= 0.047) has been previously demonstrated [
20
]. Among viruses, human
papillomavirus (HPV) infection is related to several cancers and is the most important
oncogenic virus. About 15% of all human cancers are caused by HPV and, specifically,
more than 60,000 cases of cervix, penile, vaginal, vulvar, anal, neck, and head cancers [
42
].
Chronic inflammation is the pathogenetic mechanism related to cancer. There are more
than 100 types of HPV; however, HPV 16 and HPV 18 are the most common oncogenetic
forms [
43
]. Although there are more than 200 types, only 40 are related to genital tract
infection. These types can be divided into two categories: low-risk HPV types (6, 11,
42, 43, and 44), causing genital warts; and high-risk HPV types (16, 18, 31, 33, 39, etc.),
Int. J. Environ. Res. Public Health 2021,18, 8500 7 of 16
causing cancer. HPV is the most common sexually transmitted virus, although non-sexual
transmission is also reported. Early beginning of sexual activity, several sexual partners,
use of oral contraceptives, low socioeconomic status, and smoking habit were found to
be the most important risk factors that contribute to HPV infection [
44
]. HPV infects
basal epithelial cells and, through the E6 and E7 oncoprotein, leads to cell transformation:
E6 binds and inactivates the p53 pathway, whereas E7 binds and inactivates pRb, p107,
and p130 tumor suppressor gene products. p53 and pRb are involved in cellular tumor
suppressor processes, such as cell cycle progression, DNA repair, apoptosis, differentiation,
senescence, and chromatin remodeling [45,46] (Figure 4).
Int. J. Environ. Res. Public Health 2021, 18, 8500 6 of 17
Figure 2. Risk of bias.
Figure 3. Risk of bias domains.
3.1. Prostate Cancer (PCa)
PCa is one of the most diagnosed cancers globally, with an estimated incidence of
1,276,000 new cancer cases and 359,000 deaths in 2018. Several risk factors have been es-
tablished (e.g., old age, family history, and African American ethnicity) [31–33]. PCa is the
neoplasia that has the greatest impact on the male population and is the most frequently
Figure 3. Risk of bias domains.
These two oncoproteins are able to bind p53, Bcl-2/surviving and retinoblastoma
proteins, respectively, which are related to the cellular cycle control. In a retrospective
study conducted in 2017, Glenn et al. identified HPV in 28 of 52 patients with an initial
benign prostate biopsy and who subsequently developed PCa. This virus was biologically
active and the higher prevalence of E7 protein suggested that HPV oncogenic activity was
an early phenomenon in prostate oncogenesis [
47
]. Yin et al., in a metanalysis of 24 studies
involving 971 patients and 1085 controls, showed that HPV infection significantly increased
the risk of PCa (OR = 2.27 (95% CI, 1.40–3.69) [48].
Int. J. Environ. Res. Public Health 2021,18, 8500 8 of 16
Int. J. Environ. Res. Public Health 2021, 18, 8500 8 of 17
vulvar, anal, neck, and head cancers [42]. Chronic inflammation is the pathogenetic mech-
anism related to cancer. There are more than 100 types of HPV; however, HPV 16 and
HPV 18 are the most common oncogenetic forms [43]. Although there are more than 200
types, only 40 are related to genital tract infection. These types can be divided into two
categories: low-risk HPV types (6, 11, 42, 43, and 44), causing genital warts; and high-risk
HPV types (16, 18, 31, 33, 39, etc.), causing cancer. HPV is the most common sexually
transmitted virus, although non-sexual transmission is also reported. Early beginning of
sexual activity, several sexual partners, use of oral contraceptives, low socioeconomic sta-
tus, and smoking habit were found to be the most important risk factors that contribute
to HPV infection [44]. HPV infects basal epithelial cells and, through the E6 and E7 onco-
protein, leads to cell transformation: E6 binds and inactivates the p53 pathway, whereas
E7 binds and inactivates pRb, p107, and p130 tumor suppressor gene products. p53 and
pRb are involved in cellular tumor suppressor processes, such as cell cycle progression,
DNA repair, apoptosis, differentiation, senescence, and chromatin remodeling [45,46]
(Figure 4).
Figure 4. Molecular mechanisms of HPV-induced carcinogenesis. E6 and E7 bind and inactivate the
p53 pathway, and pRb, p21, p27, p107, and p130 tumor suppressor gene products. This leads to cell
cycle disregulation and carcinogenesis. HPV: human papillomavirus.
These two oncoproteins are able to bind p53, Bcl-2/surviving and retinoblastoma pro-
teins, respectively, which are related to the cellular cycle control. In a retrospective study
conducted in 2017, Glenn et al. identified HPV in 28 of 52 patients with an initial benign
prostate biopsy and who subsequently developed PCa. This virus was biologically active
and the higher prevalence of E7 protein suggested that HPV oncogenic activity was an
early phenomenon in prostate oncogenesis [47]. Yin et al., in a metanalysis of 24 studies
involving 971 patients and 1085 controls, showed that HPV infection significantly in-
creased the risk of PCa (OR = 2.27 (95% CI, 1.40–3.69) [48].
3.2. Penile Cancer (PC)
Although PC is an uncommon tumor, its incidence is significantly higher in develop-
ing countries [49]. Globally, 26,300 new cases of penile cancer are diagnosed each year
[50]. Its prevalence varies between different populations, and the current opinion is that
Figure 4.
Molecular mechanisms of HPV-induced carcinogenesis. E6 and E7 bind and inactivate the
p53 pathway, and pRb, p21, p27, p107, and p130 tumor suppressor gene products. This leads to cell
cycle disregulation and carcinogenesis. HPV: human papillomavirus.
3.2. Penile Cancer (PC)
Although PC is an uncommon tumor, its incidence is significantly higher in develop-
ing countries [
49
]. Globally, 26,300 new cases of penile cancer are diagnosed each year [
50
].
Its prevalence varies between different populations, and the current opinion is that these
race effects are related to differences in sexual and behavior patterns [
51
]. Squamous
cell carcinoma (SCC) represents the majority of cases of PC, and up to 80% of cases are
localized at the glans and prepuce [
52
]. Penile cancer and its treatment may have a sig-
nificant impact on sexuality and intimacy, body image, urinary function, mental health,
and health-related quality of life (HRQOL) [
53
]. The recognized risk factors for PC include
poor penile hygiene, HPV infection, smoking, and chronic inflammatory conditions [
54
]. In
particular, HPV infection can result in a spectrum of genitourinary manifestations, ranging
from genital warts to PC [
21
]. Nationally representative surveys conducted in the USA
showed that HPV may achieve a prevalence of around 80% depending on parameters
of the population including age, sex, immune status, and sexual behavior [
22
]. To date,
over 200 HPV genotypes have been identified, which can be classified according to their
oncogenicity in high-risk genotypes, including HPV 16, 18, 33, and 35, whereas low-risk
genotypes include HPV 6 and 11 [
55
]. In about 50% of cases, multiple genotypes are present
at the same time. Although low-risk genotypes are the main cause of genital warts, they
are generally not related to PC [
56
]. In a recent systematic review, Parkin and Bray found
that about 40% of PCs were related to HPV, and the most frequent genotype was HPV
16. However, they also noted that this percentage may be overestimated by a coincident
presence of the virus, rather than a causal relationship [
50
]. The HPV infection process
appears to be based on the integration of HPV DNA into the human genome. This induces
a deregulated transcription of the viral oncogenes E6 and E7, chromosomal instability,
and genetic or epigenetic oncogenic alterations, leading to dysplasia and, potentially, to
carcinogenesis [
57
]. The transmission of HPV is facilitated by sexual intercourse through
mucosal contact or secretions. Based on this, several studies in recent years have inves-
tigated the potentially increased risk in partners of patients with a diagnosis of penile
cancer. A systematic review in 2017 by Mirghani et al. showed that, following the first
Int. J. Environ. Res. Public Health 2021,18, 8500 9 of 16
observation studies that showed a geographic correlation between rates of cervical and
penile cancers, several subsequent studies supposed a causality regarding the incidence
of cervical cancer in partners of patients diagnosed with penile cancer. This suggested
that partners of patients with HPV-related cancers also had a higher risk of developing
HPV-related cancers [
22
]. However, this study was subject to various limitations, as in-
dicated by the authors, and more recent studies did not show any higher risk in this
population, and thus did not confirm this hypothesis [
23
,
58
]. Another interesting study
about the role of sexual activity in the development of penile cancer was conducted by
Madsen et al., which showed a significant association between heterosexual oral-penis
sex and the risk of squamous PC. More specifically, the association with the number of
female partners performing oral sex (OR 3.65; 95% CI, 1.14–11.7; for
≥
3 versus 0 oral sex
partners,
p= 0.04
) was statistically significant in the multivariate analysis. This suggested
that oral sex could be an underestimated factor in HPV transmission increasing PC risk [
24
].
HPV is not the only sexually transmitted infection that can play a role in PC development;
thus, some authors also considered HIV infection as a potential risk factor for PC or other
HPV-related cancers. Although a clear mechanism has not yet been elucidated, HIV-related
immunosuppression probably plays an important role [
46
]. A 2016 estimate showed that
nearly 40 million people globally are living with HIV [
59
]. Its prevalence is concentrated
mostly in the African territories, whereas, in low prevalence territories such as Europe, the
virus is transmitted mainly in certain contexts, such as drug users, men who have sex with
men (MSM), sex workers, and transgender people [
59
]. In addition, it appears to be an
aggravating factor and an accelerator of disease progression [
25
,
60
]. Concerning predispos-
ing factors of disease progression, as in other cancers, chronic inflammation can play an
important role in creating a suitable microenvironment for PC development/progression.
In this context, studies have recorded a significant increase in the risk of PC among males
with phimosis [
21
]. Thus, during sexual arousal, the preputial epithelium stretches, thus
diminishing its already thin layer of keratin. During intercourse, this vulnerable structure
is directly exposed to the potentially infected partner’s secretions [
60
]. The preputial
cavity offers a hospitable environment for an infectious inoculum; moreover, it can be the
retention site of the epidermal cells, urine, and smegma, leading to chronic inflammation
and possible bacterial superinfection [
61
]. The available studies regarding the effect of
circumcision on the risk of contracting HPV are conflicting [
62
–
64
]. However, some papers
reported a lower incidence of PC in Jewish men [
65
] and a recent meta-analysis described
a strong protective effect of childhood/adolescent circumcision on invasive PC (OR 0.33;
95% CI 0.13–0.83) [
66
]. These data point to circumcision as an effective strategy for penile
tumor prevention. No study correlating penile trauma or sex-related microtrauma to the
onset of PC is available in the literature.
3.3. Testicular Cancer (TC)
TC is the most common solid tumor in males between 20 and 40 years, representing 1%
to 1.5% of cancer in males, and 5% of urologic tumors in general [
67
]. Among TCs, testicular
germ cell tumors (GCTs) represent 95% of malignant tumors, and are further clinically and
histologically subclassified into seminomas and non-seminomas. Non-seminoma tumors
are the more clinically aggressive subtype but, with current treatment, 5 year survival
rates exceed 70% [
68
]. The pathogenesis of this cancer is not fully clarified, but the rapid
increase in incidence suggests that critical changes in environmental factors may contribute
to the development of cancer [
69
]. Several risk factors have been proposed for TC, includ-
ing cryptorchidism, contralateral GCT, familial association, infertility, testicular atrophy,
trauma, surgery, socioeconomic status, environmental factors, occupational exposure to
noxious conditions, and Klinefelter syndrome [
67
]. Several trials involving controlled
studies, cancer registry reports, clinical case series, and case reports have explored these
factors. The data are relatively heterogeneous and the significance of some parameters
remains uncertain. Undescended testis (cryptorchidism), contralateral testicular GCT,
and familial testicular GCT are the only factors with an established evidence. Infertility,
Int. J. Environ. Res. Public Health 2021,18, 8500 10 of 16
twinship, and testicular atrophy are also associated with GCT risk, but the level of evidence
is clearly lower [
70
]. More recently, the literature has focused on the association between
inflammation and cancer, suggesting that it may play an important role in the occurrence
and progression of TC [
5
]. The relationship between inflammation and tumors can be
partly attributed to infections, with up to 20% of all cases of cancer globally associated
with microbial infections [
5
]. In particular, chronic inflammation has been founded to
mediate several diseases, such as as cardiovascular diseases, cancer, diabetes, arthritis,
Alzheimer’s disease, pulmonary diseases, and autoimmune diseases [
71
]. In tumorigenesis,
chronic inflammation is involved in different steps, including cellular transformation, pro-
motion, survival, proliferation, invasion, angiogenesis, and metastasis [
72
]. Inflammation
cells, such as macrophages and other leukocytes, produce several mutagenic agents, such
as reactive oxygen and nitrogen species, that cause mutation when they interact with
DNA. Furthermore, DNA damage is increased by tumor necrosis factor-alpha (TNF-
α
) and
macrophage migration inhibitory factors. The migration inhibitory factor is involved in
the p53 pathway, which causes an accumulation of oncogenic mutations and alteration
of the Rb-E2F pathway [
73
]. In the 1980s, Newell et al. and Algood et al. theorized the
possible causal relationship between viral infections and TGCT [
26
,
74
]. Most of the viruses
involved in STDs have an age-related prevalence that coincides with that observed in
TGCTs [
27
]. However, the literature does not show a clear and direct link between SA
and the development of TC. In recent years, several viruses potentially associated with
the development of TGCTs (e.g., human papillomavirus (HPV), Epstein–Barr virus (EBV),
cytomegalovirus (CMV), Parvovirus B-19, and human immunodeficiency virus (HIV))
have been studied, but with contrasting results [
27
]. The immune system plays a key
role in the prevention of the occurrence of clinical malignancy; therefore, HIV may create
a favorable environment for the development of tumors, including those of TC [
28
]. In
Western countries, the majority of HIV-infected people are men, thus explaining why the
incidence of testicular cancer is also increased in men with HIV [
75
]. In a 2017 review,
Hentrich showed that seminoma and extragonadal germ cell cancer are more frequent in
HIV-infected patients, whereas the risk for nonseminoma was marginally increased [
76
].
In the same way, HPV is closely linked with infertility in males and the role of this virus
in testicular carcinogenesis cannot be excluded [
66
]. Recently, Kao et al. focused on epi-
didymoorchitis, an inflammatory disease that affects the epididymis and the testis, caused
by a wide range of microbes, including sexually transmitted and urinary germs. The
authors found that patients with TC had a higher prevalence of prior epididymoorchitis
than subjects without TC (11.0% vs. 0.3%, p< 0.001) and prior epididymoorchitis was
significantly associated with TC even after adjustment for other variables (OR 47.17, 95%
CI 23.83–93.40) [
73
]. However, a meta-analysis conducted by Traber et al. reported that
mumps orchitis or orchitis infection were not associated with TGCT (pooled OR: 1.80, 95%
CI 0.74–4.42) [
30
]. Testicular inflammation can also be the consequence of a traumatic
event; more specifically, traumatic injuries to the testicle may result from either blunt or
penetrating trauma. Sexual intercourse, in addition to sport activities, may represent a
cause of this trauma. Testicular trauma can lead to various consequences, such as hydrocele,
hematocele, hematoma, testicular rupture, alterations in perfusion, and dislocation of the
testis [
77
]. No relationship between testicular trauma and cancer has been described in the
literature; however, instrumental examinations indicated in these situations may enable
the identification of pre-existing lesions [78].
4. Prevention
Although the relationship between sexual activity and male cancer is not yet fully
understood, and strong evidence has not yet been provided, there are some behaviors
that could be adopted to reduce risk. First, prevention of STIs can play a crucial role in
decreasing cancer incidence [
79
]. Several measures can be adopted to prevent or reduce
STI transmission:vaccination coverage; reduction in the efficacy of transmission (condoms,
microbicides, etc.); treatment of the infection to reduce the duration of infectivity; changes in
Int. J. Environ. Res. Public Health 2021,18, 8500 11 of 16
sexual behaviors; avoidance of oral, anal, and vaginal sex; having a mutually monogamous
relationship with someone who is not infected; decreasing the number of sexual partners;
and avoiding or limiting the use of alcohol and drugs before and during sex [
79
] (Table 2).
Table 2. Role of SA in development of male genital cancers.
Protective Factors Risk Factors
Penile cancer Circumcision *
Transmission of HPV 16 and HPV 18;
transmission of HIV;
phimosis
Prostate cancer High ejaculatory frequency High number of sexual partners; homosexuality;
STDs (e.g., gonorrhea)
Testicular cancer Trauma ** Viral infection and epididymoorchitis ***
SA: sexual activity; HPV: human papillomavirus; STD: sexually transmitted disease; NA: not available. * Conflicting data, ** Allows
incidental diagnosis, *** Very low evidence.
The use of male condoms is the most effective method of reducing STI transmission.
Condoms provide an impervious barrier to pathogens in genital fluids. Their correct and
consistent use is highly effective in reducing the risk of transmission of different STIs,
including HIV/AIDS. Nonetheless, condoms may fail due to either method failure or user
failure. Examples of the former include rupture or breakage, slippage, incomplete coverage
of infected areas, and rare manufacturing defects. Types of user failure include inconsistent
use, genital contact prior to use, incorrect application and positioning, use of oil-based
lubricants, and incorrect withdrawal. Several studies have shown that the consistent and
correct use of condoms reduces the risk of acquiring HIV infection by 87%. In addition,
the importance of the correct and consistent use of condoms has been confirmed by data
that show about 80% of new HIV transmissions result from individuals who do not know
they are infected [
80
]. The most important health problems relate to adolescents that have
a misconception of the correct and consistent use of condoms. One of the most important
topics in public health is the introduction of an appropriate and accurate educational course.
Vaccines against STIs, and particularly those against HPV, are another important topic in
public health. At present, guidelines indicate that there are three vaccines approved in
Europe for females and males [
81
], namely: Gardasil (Merck & Co., Kenilworth, NJ, USA),
a quadrivalent HPV vaccine and the first commercially available HPV vaccine licensed by
the United States Food and Drug Administration (FDA), in 2006; Cervivax, (GSK, Brentford,
UK) a bivalent HPV vaccine, approved by the European Medicines Agency (EMA) in 2007
and by the FDA in 2009; and the World Health Organization’s human papillomavirus
vaccines [
82
], which protects against the most common oncogenic genotypes of HPV (types
16 and 18), responsible for around 70% of cervical cancers [
83
]. Gardasil was developed
against HPV 16, 18, and 11. In particular, HPV 6 and HPV 11 cause around 90% of genital
warts. In 2014, a nine-valent vaccine, Gardasil 9 (Merck & Co., Kenilworth, NJ, USA), was
licensed by the FDA, and offers protection against HPV 6, 11, 16, 18, 31, 33, 45, 53, and
58 [
84
]. According to the World Health Organization, HPV vaccination is recommended at
the age of 9–14 in girls and, in some countries, boys aged 11–13 years [
85
,
86
]. Vaccination at
a young age is preferred because several studies have shown that vaccines are less effective
after the onset of sexual activity and exposure to HPV. Thus, it is strongly recommended
that immunization takes place before initiation of sexual activity and subsequent exposure
to HPV [
87
]. Although there is a lower risk of HPV-related cancers in heterosexual men,
it is very important to vaccinate men because this offers protection for both individuals,
thus leading to a faster achievement of “herd immunity” by reducing the size of the
overall HPV reservoir [
87
]. Several studies have shown the positive effects of vaccines
in men. The quadrivalent vaccine in HPV-naïve men has been shown to reduce the risk
of a persistent anal HPV 16/18 infection by 96% [
88
]. Hillman et al. showed that the
immunogenicity of the quadrivalent human papillomavirus vaccine is highly effective in
men aged from 16 to 26 years, with seroconversion within 7 months and antibody detection
Int. J. Environ. Res. Public Health 2021,18, 8500 12 of 16
even at 36 months [
89
]. Giuliano et al. showed similar outcomes regarding the effect of the
quadrivalent HPV vaccine against infection in male patients [
90
]. In a recent systematic
review of 5196 articles and seven studies (four randomized controlled trials (RCTs) and
three non-randomized studies) involving 5294 participants, on the effectiveness and safety
of vaccination against the human papillomavirus in male patients,
Harder et al.
showed
that vaccine effectiveness was low in individuals who were previously infected with the
corresponding HPV type, but high when compared with groups of HPV-negative males [
91
].
Thus, early vaccination of boys is appropriate, with the goal of vaccine-induced protection
before the onset of sexual activity. Another important topic regarding the prevention of
HPV infection is circumcision. Although data are still unclear, many studies have shown a
positive effect of circumcision to prevent HPV infection. In a study involving 4033 healthy
men, Albero et al. showed that circumcision is not associated with the incidence and
clearance of genital HPV detection, with the exception of certain HPV types. The clearance
incidence was significantly lower among circumcised versus uncircumcised men for HPV
types 58 (p= 0.01), 68 (p< 0.001), 42 (p= 0.01), 61 (p< 0.001), 71 (p< 0.001), 81 (p= 0.04), and
IS39 (p= 0.01), and higher for HPV types 39 (p= 0.01) and 51 (p= 0.02). Despite the lack of
an overall association between the risk of HPV clearance and circumcision (for any HPV,
aHR 0.95, 95% CI 0.88–1.02) [
92
]. Tobian et al. showed that the prevalence of high-risk
HPV genotypes was 18.0% in the circumcised group and 27.9% in the uncircumcised group
(adjusted risk ratio, 0.65; 95% CI, 0.46 to 0.90; p= 0.009) [
93
]. In another randomized
controlled study involving 1264 men aged 18–24 years, Auvert et al. showed that the
prevalence of urethral HR-HPV infection after circumcision was reduced (95% CI 1.5–3.3)
and 2.2 (95% CI 1.5–3.2) [
94
]. Circumcision has various health benefits, not only related to
HPV prevention, namely, making it easier to wash the penis, decreasing the risk of urinary
tract infections in males, and decreasing the risk of penile cancer [
95
]. Circumcision is
highly important in phimosis prevention and treatment. Phimosis or lichen sclerosus can
cause chronic preputial inflammation, which, in several cases, is associated with penile
cancer. Circumcision lowers the risk of penile cancer (hazard ratio: 0.33) [96].
5. Strengths and Limitations
To the best of our knowledge, this is the first systematic review describing the impact
of SA on male genital cancers. This paper should be interpreted in the context of several
limitations. The main limitation is the lack of data synthesis. Other weaknesses are the
relative paucity of relevant studies (particularly for TC), and the studies’ heterogeneity,
contradictory results, and overall moderate-to-low quality. In addition, several mechanisms
by which SA may be implicated in the development of male genital tumors are only
hypothesized or inferred indirectly. Finally, the lack of detail in the descriptions of the
characteristics of SA (e.g., type, duration, frequency, and partner) in the original studies
makes it difficult to interpret the data.
6. Conclusions
The association between SA and male genital tumors may be based on several sex-
related risk factors. SA is closely associated with the development of PC through the
high-risk HPV transmission; in this context, phimosis appears to be a favoring factor.
Sexual behaviors appear to play a significant role in PCa pathogenesis, probably through
inflammatory mechanisms; however, protective sexual habits have also been described. A
direct correlation between SA and TC has not yet been proven, although infections remain
the most studied sex-related factor. The limited evidence available in the literature prevents
clear conclusions from being drawn. Further primary studies with appropriate designs are
needed to elucidate the association between SA and male genital tumors.
Author Contributions:
Conceptualization: F.C., C.M. and D.A.; methodology L.N. and F.P.C.; soft-
ware: R.L.R., M.C.; validation: C.I. and M.D.S.; formal analysis: B.B. and V.F.C.; investigation: F.C.
and L.N.; resources: D.A.; data curation: F.P.C. and V.F.C.; writing—original draft preparation: R.L.R.
Int. J. Environ. Res. Public Health 2021,18, 8500 13 of 16
and M.C.; writing—review and editing: C.I. and M.D.S.; visualization: L.N. and B.B.; supervision:
D.A. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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