Context Sexual activity has been hypothesized to play a role in the development
of prostate cancer, but epidemiological data are virtually limited to case-control
studies, which may be prone to bias because recall among individuals with
prostate cancer could be distorted as a consequence of prostate malignancy
or ongoing therapy.
Objective To examine the association between ejaculation frequency, which includes
sexual intercourse, nocturnal emission, and masturbation and risk of prostate
cancer.
Design, Setting, and Participants Prospective study using follow-up data from the Health Professionals
Follow-up Study (February 1, 1992, through January 31, 2000) of 29 342
US men aged 46 to 81 years, who provided information on history of ejaculation
frequency on a self-administered questionnaire in 1992 and responded to follow-up
questionnaires every 2 years to 2000. Ejaculation frequency was assessed by
asking participants to report the average number of ejaculations they had
per month during the ages of 20 to 29 years, 40 to 49 years, and during the
past year (1991).
Main Outcome Measure Incidence of total prostate cancer.
Results During 222 426 person-years of follow-up, there were 1449 new cases
of total prostate cancer, 953 organ-confined cases, and 147 advanced cases
of prostate cancer. Most categories of ejaculation frequency were unrelated
to risk of prostate cancer. However, high ejaculation frequency was related
to decreased risk of total prostate cancer. The multivariate relative risks
for men reporting 21 or more ejaculations per month compared with men reporting
4 to 7 ejaculations per month at ages 20 to 29 years were 0.89 (95% confidence
interval [CI], 0.73-1.10); ages 40 to 49 years, 0.68 (95% CI, 0.53-0.86);
previous year, 0.49 (95% CI, 0.27-0.88); and averaged across a lifetime, 0.67
(95% CI, 0.51-0.89). Similar associations were observed for organ-confined
prostate cancer. Ejaculation frequency was not statistically significantly
associated with risk of advanced prostate cancer.
Conclusions Our results suggest that ejaculation frequency is not related to increased
risk of prostate cancer.
Sexual activity is hypothesized to affect prostate carcinogenesis through
numerous etiologic pathways. One of the most commonly postulated mechanisms
implicates increased sexual activity as an indicator of higher androgenic
activity and thus a marker for a high-risk population.1 Another
mechanism proposes that sexual activity represents a marker for opportunity
for exposure to infectious agents, although no sexually transmitted infection
has been consistently implicated in prostate cancer development.2
An alternative hypothesis suggests that a reduced ejaculatory output
in otherwise normal men is an etiologic risk factor for prostate cancer. That
proposition is based on the theory that infrequent ejaculation increases the
risk of prostate cancer because of retained carcinogenic secretions in the
prostatic acini.3 A further hypothesis implicates
repression of sexuality as a risk factor for prostate cancer and is derived
from reports of greater sexual drive coupled with deprived sexual activity4 and greater interest in more sexual intercourse than
experienced5 among prostate cancer cases compared
with controls.
In the United States, 38% of married persons aged 60 years or older
reportedly engage in sexual activity between 1 and 4 times per month, and
14% indicate being sexually active at least 5 times per month.6 Although
the libido declines with age, sexual activity is common among 70-, 80-, and
even 90-year-old men.7 Given that sexual activity
is common, including in older men,6,7 and
that prostate cancer risk is high,8 any association
between these factors would have clinical and public health relevance. A recent
meta-analysis9 reported an increased risk of
prostate cancer with greater sexual activity (odds ratio, 1.2; 95% confidence
interval [CI], 1.1-1.3 for an increase in sexual activity of 3 times per week).
Epidemiological data on sexual activity and prostate cancer are almost
entirely limited to case-control studies,2,9,10 which
may be particularly prone to methodological bias because information on prediagnosis
sexual activity is collected after the diagnosis of cancer. Sexual function
may diminish after the diagnosis of prostate cancer and its treatment,11 and recall of past levels of sexual activity among
individuals with prostate cancer could be distorted as a consequence of prostate
malignancy or ongoing therapy.
Prospective data on self-reported sexual activity and prostate cancer
are restricted to 2 investigations. These studies12,13 considered
age at first marriage, marital status, and number of children as measures
of sexual activity and found no association between these factors and prostate
cancer. Thus, the relationship between sexual activity and risk of prostate
cancer is not clear.
To help resolve this issue, we prospectively examined the association
between ejaculation frequency and risk of prostate cancer in the Health Professionals
Follow-up Study, a large cohort of middle-aged US men. We focused on ejaculation
frequency, capturing sexual intercourse, nocturnal emission, and masturbation.
Thus, our exposure definition encompasses a wide range of variability in exposure
to sexual activity. In addition, we reasoned that by examining ejaculation
frequency, the effects of sexual function per se would be more readily distinguishable
from effects related to exposure to sexually transmitted agents, which we
do not consider in this article.
The Health Professionals Follow-up Study was initiated in 1986 when
51 529 US predominantly white male health professionals aged 40 to 75
years responded to a questionnaire concerning their medical history and known
or suspected risk factors for cancer and other chronic diseases. Subsequently,
follow-up questionnaires were mailed every 2 years to the entire cohort to
update information on potential risk factors and to identify newly diagnosed
illnesses. In 1992, the questionnaire included an assessment of frequency
of ejaculation. Men were included if they did not have a diagnosis of cancer
(6098 excluded); answered the 1992 questionnaire (8478 excluded); answered
the question on ejaculation frequency (6862 excluded); and provided adequate
dietary data (749 excluded). Men who had nonmelanoma skin cancer were allowed
in the study. The analytic cohort consisted of 29 342 men, who were followed
up to 2000. Participants provided informed consent. The Health Professionals
Follow-up Study was approved by the human subjects committee of the Harvard
School of Public Health, Boston, Mass.
Assessment of Ejaculation Frequency
Ejaculation frequency was assessed in 1992 by asking participants to
report the average number of ejaculations they had per month during the ages
of 20 to 29 years, 40 to 49 years, and during the past year (1991). There
were 6 possible response categories for each age period (none, 1-3, 4-7, 8-12,
13-20, and ≥21 ejaculations per month). We collapsed the none and 1 to
3 ejaculation categories because of insufficient numbers of participants in
the none category.
On each follow-up questionnaire, we asked participants whether they
had received a diagnosis of prostate cancer during the prior 2 years. For
men who reported a diagnosis of prostate cancer (or next of kin for decedents),
we requested permission to obtain medical records and pathological reports
to confirm the diagnosis and obtain further details. Most deaths in the cohort
were ascertained through reports from family members and searches of the National
Death Index. A study investigator who was unaware of questionnaire data used
the information received from any procedures or tests conducted during the
initial diagnosis, including staging prostatectomy and bone scans, to stage
prostate cancer. The major end point was total prostate cancer incidence.
We also considered organ-confined prostate cancer and advanced cancer as separate
groups. The latter was defined as cancer extending regionally to the seminal
vesicle or other adjacent organs, metastasis to pelvic lymph nodes or distant
organs (usually bone) at the time of diagnosis, or that was fatal by the end
of follow-up (C2 or D or fatal; T3b or T4 or N1 or M1, or fatal). Because
stage T1a lesions are typically indolent and are especially prone to detection
bias, we excluded these (3% of the total) from our primary analyses.
Person-time of follow-up for each participant was calculated from the
date of return of the 1992 questionnaire to the date of prostate cancer, death,
or the end of the study period in 2000. The relative risk (RR) was calculated
as the incidence rate of prostate cancer among men in a specific category
of ejaculation frequency divided by the rate among a common reference group
with adjustment for age. We used the category of 4 to 7 ejaculations per month
as the common reference group to achieve meaningful comparisons between increasingly
extreme ejaculation frequencies and to ensure stability of the RR estimates.
Multivariate RRs were computed using the Cox proportional hazards model.14 The basic multivariate model included covariates
that were previously observed to be associated with risk of total or advanced
prostate cancer or that have been associated with risk in the literature.
Covariates were racial group; family history of prostate cancer; history of
vasectomy; body mass index at age 21 years, which was calculated as weight
in kilograms divided by square height in meters; height; pack-years of smoking
in the previous decade; history of type 2 diabetes; vigorous physical activity;
and intake of total energy, calcium, fructose, supplemental vitamin E, supplemental
zinc, red meat, tomato-based foods, fish, α-linolenic acid, and alcohol.
To account for lack of proportionality in the hazards across follow-up, we
fit separate baseline hazards for groups defined by age and calendar period.
Because the relationships between age-specific ejaculation frequencies and
prostate cancer could potentially confound each other, we entered terms representing
ejaculation frequency at ages 20 to 29 years, 40 to 49 years, and during the
year prior to the 1992 questionnaire simultaneously in our models. We also
considered ejaculation frequency across a lifetime, which was calculated as
the average of the ejaculation frequencies at ages 20 to 29 years, 40 to 49
years, and during the prior year. All reported P values
are 2-tailed and P<.05 was considered significant.
All analyses were performed using SAS statistical software (release 8.02,
SAS Institute Inc, Cary, NC).
During 222 426 person-years of follow-up between 1992 and 2000,
there were 1449 cases of total prostate cancer, 953 cases of organ-confined
prostate cancer, and 147 cases of advanced prostate cancer. The mean (SD)
ejaculations per month at ages 20 to 29 years were 15.1 [6.9]; 40 to 49 years,
11.3 [6.1]; 50 to 59 years, 9.4 [6.1]; and 60 years or older, 5.0 [4.5]. Fifty-eight
percent of men reported an ejaculation frequency of more than 3 times per
week at ages 20 to 29 years, whereas the proportion of men having more than
3 ejaculations per week decreased to 32% at ages 40 to 49 years, and further
declined to 22% at ages 50 to 59 years and to 5% at ages 60 years or older.
Ejaculation frequency at ages 20 to 29 years showed positive correlations
with ejaculation frequency at ages 40 to 49 years (r =
0.70); 50 to 59 years (r = 0.54); and 60 years or
older (r = 0.39); all P<.001.
The number of ejaculations at ages 40 to 49 years was positively correlated
with those at ages 50 to 59 years (r = 0.81) and
60 years or older (r = 0.53); all P<.001.
Age-standardized lifetime ejaculation frequency was evaluated in relation
to various risk factors for prostate cancer to assess the potential for confounding
(Table 1). Men with greater lifetime
ejaculation frequency tended to be physically more active and were more likely
to have a history of syphilis or gonorrhea, prostatitis, and vasectomy than
men with lower ejaculation frequency. In addition, men with greater ejaculation
frequency were more likely to be currently divorced or separated and consumed
more total energy, lycopene, fish, alcohol, supplemental vitamin E, and supplemental
zinc. Men in the highest category of average lifetime ejaculation frequency
were less likely to have a family history of prostate cancer and a history
of surgery for enlarged prostate than men in the lower categories of ejaculation
frequency. Men in the highest and lowest categories had a lower prevalence
of prostate-specific antigen (PSA) screening relative to men in the intermediate
categories of ejaculation frequency.
Ejaculation frequency was examined in relation to risk of total prostate
cancer (Table 2). In age- and
multivariate-adjusted analyses, most categories of ejaculation frequency were
unrelated to risk of total prostate cancer. However, a lower risk was observed
in the highest category of ejaculation frequency. The multivariate RR for
men reporting 21 or more ejaculations per month compared with men reporting
between 4 and 7 ejaculations per month at ages 20 to 29 years was 0.89 (95%
CI, 0.73-1.10); 40 to 49 years, 0.68 (95% CI, 0.53-0.86); in the prior year,
0.49 (95% CI, 0.27-0.88); and across a lifetime, 0.67 (95% CI, 0.51-0.89).
When the entire range of ejaculation frequency was analyzed as a continuous
variable in the multivariate model, each increment of 3 ejaculations per week
across a lifetime was associated with a 15% (95% CI, 4%-24%) decrease in risk
of total prostate cancer. However, there was a suggestive decreased risk of
total prostate cancer observed among men in the lowest category of ejaculation
frequency at ages 40 to 49 years and across a lifetime. The multivariate RR
for men reporting 3 or less ejaculations per month compared with men reporting
between 4 and 7 ejaculations per month across a lifetime was 0.89 (95% CI,
0.69-1.15).
Restricting the outcomes to organ-confined prostate cancer, the relationships
were similar to those for total prostate cancer, albeit somewhat stronger
(Table 3). Each increment of 3
ejaculations per week across a lifetime was associated with a 19% (95% CI,
7%-30%) decrease in risk of organ-confined prostate cancer. Again, a suggestive
decreased risk of organ-confined prostate cancer was observed among men in
the lowest category of ejaculation frequency at ages 20 to 29 years, 40 to
49 years, and across a lifetime. The multivariate RR for men reporting 3 or
fewer ejaculations per month compared with men reporting between 4 and 7 ejaculations
per month across a lifetime was 0.72 (95% CI, 0.51-1.01).
In contrast to the results for total and organ-confined prostate cancer,
the intermediate categories of ejaculation frequency at ages 40 to 49 years
were associated with a lower risk of advanced prostate cancer (Table 4). High ejaculation frequencies during the previous year
and across a lifetime were associated with a suggestive increase in risk of
advanced prostate cancer. The multivariate RR for men reporting 21 or more
ejaculations per month compared with men reporting between 4 and 7 ejaculations
per month across a lifetime was 1.76 (95% CI, 0.81-3.80).
The consistency among ejaculation frequencies at ages 20 to 29 years,
40 to 49 years, and during the previous year was examined. Compared with men
who were consistently in the lowest 4 categories of ejaculation frequency,
men who were consistently in the highest category of frequency of ejaculations
showed a markedly reduced risk of total prostate cancer (RR, 0.25; 95% CI,
0.12-0.54) and organ-confined prostate cancer (RR, 0.15; 95% CI, 0.05-0.47).
There was not a sufficient number of cases to examine patterns of ejaculation
frequency over time in relation to advanced prostate cancer risk.
The results regarding the relationship of ejaculation frequency with
prostate cancer were not materially altered after controlling for history
of syphilis or gonorrhea or limiting the study population to men (1) younger
than 60 years; (2) 60 years or older; (3) married; (4) without a history of
prostatitis, a previous diagnosis of enlarged prostate, or surgery for enlarged
prostate; (5) with a PSA test by 2000. The results also were not altered when
either the first 2 or 4 years of follow-up were excluded and the 1992 reporting
of ejaculation frequency was related to incidence of prostate cancer from
1994 to 2000 or 1996 to 2000, respectively (Table 5).
The associations between ejaculation frequency and risk of prostate
cancer were not modified by subgroups defined by current body mass index,
family history of prostate cancer, history of smoking, history of prostatitis,
history of syphilis or gonorrhea, or marital status (all P for interaction >.05).
In this prospective cohort study among predominantly white men, higher
ejaculation frequency was not related to increased risk of prostate cancer.
Our results suggest that high ejaculation frequency possibly may be associated
with a lower risk of total and organ-confined prostate cancer. These associations
were not explained by potential risk factors for prostate cancer, such as
age, family history of prostate cancer, history of syphilis or gonorrhea,
smoking, and diet. Although we cannot exclude a possibly greater risk of advanced
prostate cancer with higher recent ejaculation frequency, we did not observe
a higher risk of advanced prostate cancer for high ejaculation frequency earlier
in life.
Although each of several analytic approaches indicated that high ejaculation
frequency was related to decreased risk of total and organ-confined prostate
cancer, there are several plausible alternative explanations for our results.
We were concerned about the possibility that the observed inverse relationships
were due to avoidance of ejaculation among men with early symptoms related
to prostate cancer. However, diminished ejaculation frequency as a preclinical
consequence of prostate cancer would be expected to be more pronounced among
men with advanced prostate cancer than among men with organ-confined prostate
cancer, a circumstance that was not supported by our data. In addition, our
findings were essentially unaltered when we excluded cases diagnosed in the
early years of follow-up. Hence, our results suggest that reverse causation
may have accounted for very little, if any of the observed inverse association
between high ejaculation frequency and total and organ-confined prostate cancer
risk.
A further potential explanation for our results is that men with high
ejaculation frequency may wish to preserve their sexual function and, thus,
undergo less screening tests for prostate cancer, leading to less diagnosis
of organ-confined prostate cancer among these men. The fact that men in the
highest category of ejaculation frequency underwent slightly fewer PSA screening
tests and less prostate biopsies than most men with lower ejaculation frequencies
suggests the possibility of modest detection bias. In contrast to this possible
explanation, the inverse relationship with total and organ-confined prostate
cancer persisted when the analysis was restricted to men with the opportunity
to have prostate cancer detected by PSA. Thus, decreased prostate cancer detection
among men with greater ejaculation frequency is unlikely to entirely account
for our results.
Because factors such as diet, smoking, physical activity, and the quality
of personal relationships are strong determinants of sexual function,15-18 a
further potential concern was the possibility that the apparent beneficial
effect of greater ejaculation frequency on risk for total and organ-confined
prostate cancer was due to the existence of a healthy lifestyle related both
to ejaculation frequency and to prostate cancer. We observed similar results
before and after controlling for a broad range of lifestyle and dietary factors
potentially related to prostate cancer risk. In addition, the fact that the
age-adjusted and multivariate-adjusted RRs were almost identical makes it
unlikely that an unconsidered factor that correlates with these lifestyle
and dietary factors could produce such strong confounding. Thus, our results
are probably not due to confounding by purported lifestyle or dietary risk
factors for prostate cancer.
Our results are not likely to be explained by differential measurement
error in our assessment of ejaculation frequency between cases and noncases.
Notwithstanding, self-reported ejaculation frequency may have contained some
inaccuracy because of its sensitive nature and the need for individuals to
recall ejaculation frequency in the distant past. It is possible that the
oldest men in our cohort (men aged 81 years in 1992) may not have accurately
recalled their average monthly ejaculation frequency from ages 20 to 29 years.
Moreover, recall of past levels of ejaculation frequency may have been more
accurate among men who had the highest ejaculation frequencies than among
those with lower ejaculation frequencies. Reported ejaculation frequency rates
among men in our study are largely consistent with survey data on sexual activity
among US adults.6,19 Furthermore,
our mailed questionnaire on ejaculation frequency was identifiable only by
study identification number and not by name, which may have resulted in a
more accurate report than in-person interviews. Because these data were collected
prior to the occurrence of prostate cancer, the accuracy of reported ejaculation
frequency should not differ between men with and without subsequent prostate
cancer. Thus, error in the measurement of ejaculation frequency would tend
to dampen the results, but would not produce an inverse association. In addition,
reporting of other lifestyle factors in this cohort of health professionals
has been found to be reasonably accurate.20,21
We noted a suggestive decrease in risk of total and organ-confined prostate
cancer among men in the lowest category of ejaculation frequency across a
lifetime. Whether that finding was due to lower androgenicity among these
men remains unknown. The apparent decrease in risk of total and organ-confined
prostate cancer among men with a low ejaculation frequency was not due to
low prevalence of sexually transmitted infections among these men because
adjustment for history of syphilis or gonorrhea did not alter the results.
We only evaluated ejaculation frequency during adulthood, but not during
adolescence. The peripubertal period may be of etiologic significance with
respect to prostate carcinogenesis because prostate epithelial cell differentiation
occurs at this critical period.22 If ejaculation
frequency during puberty was most important for prostate carcinogenesis, measuring
adult ejaculation frequency would fail to capture the relevant period of exposure.
However, our findings suggest that ejaculation frequency during mid and late
adulthood rather than in early adulthood are etiologically relevant periods
for influencing prostate tumors. Because the inverse relation was observed
for organ-confined cases but not advanced cases, sexual activity may be hypothesized
only to affect slow-growing, early stage prostate cancers. Our results are
generalizable to white US men aged 46 years or older.
Previous investigations on reported ejaculation frequencies or sexual
intercourse and prostate cancer are limited to studies of retrospective design
and results are mixed. Nine studies observed a statistically significant1,23-27 or
nonsignificant28-30 positive
association; 3 studies27,31,32 reported
no association; 7 studies found a statistically significant4,5,10,33 or
nonsignificant34-36 inverse
relationship; and 1 study37 found a U-shaped
relationship.
Nine4,24,25,27,30-32,35,36 of
the aforementioned studies found little or no variation in prostate cancer
risk according to sexual activity during different ages. However, 1 study35 observed a nonsignificant inverse association between
sexual activity before the age of 30 years and prostate cancer, and no relationship
with sexual activity in later life. In contrast, 2 other studies38,39 reported
a positive association between frequency of sexual intercourse before ages
50 to 60 years and prostate cancer and an inverse relationship for frequency
of sexual intercourse after age 60 years. A recent meta-analysis9 of
these studies1,4,5,23-39 reported
RRs for sexual activity at 3 times per week of 1.14 (95% CI, 0.98-1.31) during
the third decade of life, 1.24 (95% CI, 1.05-1.46) during the fifth decade,
and 0.68 (95% CI, 0.51-0.91) during the seventh decade. That meta-analysis9 noted the somewhat inconsistent association between
frequency of sexual activity and risk of prostate cancer in previous studies.
Several features distinguish our analysis from previous reports on sexual
activity and prostate cancer. First, the prospective study design precluded
bias attributable to differential recall of sexual activity by men with and
without prostate cancer. Second, we focused on ejaculation frequency rather
than on frequency of sexual intercourse, which enhanced exposure variability
and allowed us to explore the physiological effects of sexual function per
se. Third, our analysis included nearly 50% more cases than the number of
cases included in any of the previous studies reporting on sexual activity
and prostate cancer. Fourth, our study had data on PSA tests, which allowed
us to address the possibility of detection bias. Finally, because we controlled
for a wide range of medical, lifestyle, and dietary factors, potential confounding
by these factors was likely minimized.
Our finding of no association or a possibly inverse association between
high ejaculation frequency and prostate cancer is difficult to reconcile with
the commonly proposed concept that androgenic stimulation is related both
to enhanced libido and to increased risk of prostate cancer. In some studies,
circulating testosterone levels are positively associated with prostate cancer
risk.40 Limited evidence shows that circulating
levels of testosterone or its major metabolite dihydrotestosterone correlate
positively with sexual desire,41 erectile function,42 and frequency of orgasms.43
However, sexual activity is a complex physiological function, which
may relate to prostate cancer risk through several nonandrogenic pathways.
For example, frequency of ejaculations may modulate prostate carcinogenesis
by altering the composition of prostatic fluid. Frequent ejaculations may
decrease the intraprostatic concentration of xenobiotic compounds and chemical
carcinogens, which readily accumulate in prostatic fluid.44,45 Frequent
ejaculations may also reduce the development of intraluminal prostatic crystalloids,46 which have been associated with prostate cancer in
some,47,48 but not all pathology
studies.49 Because seminal plasma locally reduces
host responsiveness50-52 (possibly
by factors produced by the prostate gland53),
retained prostatic fluid may diminish intraprostatic immune surveillance against
tumor cells.
A more speculative possibility linking increased ejaculation frequency
with decreased prostate cancer risk is that ejaculation is accompanied by
a release of psychological tension during the emission phase,54 which
may lower central sympathetic nervous activity when repeated frequently. Prostate
epithelial cell division is stimulated by the release of growth factors from
adjacent stromal cells that are heavily innervated with α1 adrenergic
receptors.55,56
In summary, our results among predominantly white men suggest that ejaculation
frequency is not related to increased risk of prostate cancer. High ejaculation
frequency may possibly be associated with a lower risk of total and organ-confined
prostate cancer. It is unlikely that reverse causation, differences in prostate
cancer screening behavior, or confounding are entirely responsible for the
observed results. Mechanisms other than the link between androgenicity and
ejaculation frequency should be evaluated as potential etiological factors
underlying the inverse association between ejaculation frequency and prostate
cancer.
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