Sexual Factors and the Risk of Prostate Cancer

Karin A. Rosenblatt1, Kristine G. Wicklund2 and Janet L. Stanford2,3

1 Department of Community Health, University of Illinois at Urbana-Champaign, Champaign, IL.
2 Division of Public Health Sciences, Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA.
3 Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A population-based case-control study of prostate cancer was performed in King County, Washington, in White men and Black men aged 40–64 years, between 1993 and 1996. Incident prostate cancer cases (n = 753) were identified from the Seattle-Puget Sound Surveillance, Epidemiology, and End Results (SEER) cancer registry. Controls (n = 703) were identified through random digit dialing and were frequency matched to cases on age. Sexual behavior, medical history, and other potential prostate cancer risk factors were ascertained through an in-person interview. There was no relation between sexual orientation and prostate cancer, although the number of men who had sex with men was small. Risk estimates increased directly with the lifetime number of female sexual partners (trend p < 0.001) but not with male partners (trend p = 0.62). Risk also increased with decreasing age at first intercourse, but this effect disappeared after adjusting for the number of female partners. Prior infection with gonorrhea was positively associated with risk (odds ratio = 1.50; 95% confidence interval: 1.0, 2.2), but no effect was seen among men with other sexually transmitted diseases. No relation between lifetime frequency of sexual intercourse and risk of prostate cancer was apparent. These findings are consistent with previous studies that support an infectious etiology for prostate cancer.

prostatic neoplasms; sex behavior; sexually transmitted diseases

Abbreviations: CI, confidence interval; HPV, human papillomavirus; OR, odds ratio; SEER, Surveillance, Epidemiology, and End Results


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Prostate cancer is the most frequently diagnosed cancer among men in the United States (1Go). Although age, family history, and race/ethnicity strongly contribute to the etiology of prostate cancer, the role of other factors is less certain. A role for sexual behavior and associated infectious agents has been supported by some previous studies. In 1995, Key (2Go) summarized epidemiologic studies assessing sexual factors and reported modest positive associations with early age at first intercourse (odds ratio (OR) = 1.31; 95 percent confidence interval (CI): 1.1, 1.6), large number of sexual partners (OR = 1.24; 95 percent CI: 1.0, 1.5), history of any sexually acquired infection (OR = 1.86; 95 percent CI: 1.4, 2.4), and a history of gonorrhea (OR = 1.22; 95 percent CI: 0.9, 1.6). No association was seen for a history of syphilis (OR = 0.77; 95 percent CI: 0.5, 1.1). A subsequent paper (3Go) reported a significant increase in risk among men with eight or more sexual partners (OR = 2.24; 95 percent CI: 1.1, 4.4). Another study (4Go) observed a nonsignificant elevation in risk among men with a history of any sexually transmitted disease (OR = 2.06; 95 percent CI: 0.4, 11.2).

More recent evidence also supports an infectious hypothesis for prostate cancer. Based on data from a large population-based case-control study, Hayes et al. (5Go) found a significant 60 percent elevation in risk among men who reported a history of any sexually acquired infection (OR = 1.6; 95 percent CI: 1.2, 2.1). Compared with men who had no history of sexually transmitted diseases, men with a history of both syphilis and gonorrhea or those with three or more episodes of gonorrhea had over threefold significant elevations in risk. Serologic evidence of past syphilis infection was linked to an excess risk (OR = 1.8; 95 percent CI: 1.0, 3.5) and was correlated with the reported number of sexual partners. However, there was no association with serologic evidence of antibodies against human papillomavirus (HPV) type 16 (5Go). Most, but not all (6Go), recent studies found a positive association between HPV and prostate cancer (7GoGo–9Go).

Previous studies have been unable to separate out the effects of sexual behaviors and associated infectious exposures from sexual drive and activity, perhaps associated with the hormonal milieu. In an attempt to address some of these issues, we examined medical and sexual activity factors, over a subject's lifetime, in a large population-based case-control study of middle-aged men.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study subjects
Caucasian and African-American men residing in King County in northwestern Washington State, aged 40–64 years, who were diagnosed with histologically confirmed prostate cancer between January 1, 1993, and December 31, 1996, were eligible. Cases were identified from the Seattle-Puget Sound cancer registry, which is part of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. We included as eligible 100 percent of cases aged less than 60 years at diagnosis and a 75 percent random sample of those aged 60–64 years at diagnosis. Only cases with a residential telephone at the time of the cancer diagnosis were eligible because random digit dialing was the method used to select controls. During the ascertainment period, we identified 1,055 eligible patients and excluded 138 on the basis of the sampling protocol. We interviewed 753 (82.1 percent) of the 917 eligible, selected cases. Reasons for nonresponse included physician refusal to allow patient contact (2.6 percent), patient refusal (12.5 percent), inability to locate the patient (1.5 percent), patient inability to participate because of illness (0.4 percent), and death (0.2 percent).

Male residents of King County, Washington, aged 40–64 years, were identified as a control group using random digit telephone dialing (10Go, 11Go). Controls were frequency matched to cases by age (same 5-year group) and recruited evenly throughout the ascertainment period of cases. During the first step of random digit dialing, complete household census information was obtained for 94 percent of the residential numbers contacted. A total of 941 men who met the study eligibility criteria were identified and agreed to receive information about the study. Of these, 703 (74.7 percent) were interviewed, 228 (24.2 percent) refused, six were lost to follow-up, and four were too ill to participate.

Data collection
Prior to interview, all subjects signed informed consent for participation, and all study forms and procedures were approved by the Fred Hutchinson Cancer Research Center Institutional Review Board. Study subjects completed in-person interviews conducted by trained male interviewers using a standardized questionnaire. Information on the following topics was elicited: social and demographic factors; physical development, height, weight, and physical activity; reproductive history; detailed medical history including genitourinary diseases, symptoms, and procedures and screening for prostate cancer; vasectomy status; family structure and cancer history; smoking and lifetime alcohol consumption; lifetime sexual history, including sexual orientation, lifetime number of male and female sexual partners, frequency of sexual intercourse, and condom use during specified age intervals; and number and type of episodes of sexually transmitted diseases. Following the interview, subjects were asked to complete a self-administered food frequency questionnaire.

Clinical information on prostate cancer cases was available from the Seattle-Puget Sound SEER cancer registry. Tumor histologic grade was coded according to the Gleason system, with 2–4 being low grade (well differentiated), 5–7 being moderate grade, and 8–10 being high grade (poorly differentiated) (12Go). The stage at diagnosis was based on SEER summary stage and incorporated the best available clinical and pathologic information obtained within 4 months of diagnosis. For men not undergoing radical prostatectomy, stage was based solely on clinical information. Surgical and pathologic data were incorporated into the staging for men who had radical prostatectomy. For this analysis, stage was defined as 1) localized disease confined to the prostate, 2) regional disease spread beyond the prostate, and 3) metastatic disease. We classified "aggressive" tumors as those with high histologic grade (Gleason score 8–10) or regional or distant stage.

Statistical analysis
Odds ratios were calculated as estimates of the relative risk of prostate cancer associated with various parameters of medical history and sexual history (age at first intercourse, number of partners, history of sexually transmitted diseases). Logistic regression models were used to compute odds ratios and estimate 95 percent confidence intervals around the point estimates of risk (13Go). In order to evaluate whether risk related to sexual activity factors varied by tumor aggressiveness, case strata were compared with controls using polytomous logistic regression (14Go). For this analysis, tumor aggressiveness was modeled as a categorical outcome. Differences in means between cases and controls were assessed by t test, and all p values were two sided. Tests for linear trends in risk estimates were performed by constructing scored variables that were entered into logistic models as continuous covariates. Multiplicative effect modification was evaluated by comparing the significance of the difference between models including and excluding the interaction term.

Established and suspected prostate cancer risk factors were examined for potential confounding effects on the sexual history-prostate cancer association, including the following: age at reference date; race; family history of prostate cancer (none, first-degree relative, second-degree relative); marital status; income; education; religious preference; smoking history; alcohol consumption; weight, height, and body mass index; history of benign prostatic hyperplasia (diagnosed by a physician >2 years before reference date); ever and frequency of prostate cancer screening (prostate-specific antigen blood tests and digital rectal examinations); and dietary intake (total fat and total saturated fat adjusted for total energy). Each of these variables was added one at a time to a model containing age and sexual history status to assess confounding, which was considered if the factor changed the odds ratio by more than 5 percent. Final logistic regression models controlled for the confounding effects of age (continuous), race, family history of prostate cancer, and the number of prostate-specific antigen tests within the 5 years before the reference date. The potential variation in odds ratios was also examined according to strata of age, race, and family history of prostate cancer to assess whether any subgroups experienced alterations in the odds ratio associated with the number of sexual partners and age at first sexual intercourse.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Table 1 illustrates case-control comparisons, with a higher proportion of cases being African American, having a family history of prostate cancer, and having a history of benign prostatic hyperplasia. Cases reported more frequent digital rectal examinations and prostate-specific antigen tests within the 5 years before the reference date. There was no relation with religion, marital status, income, or education.


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TABLE 1. Distribution of potential confounders by prostate cancer status, Health Interview Study of Men, 1993–1996

 
There was a nonsignificant pattern of increasing risk with increasing number of sexually transmitted diseases reported (table 2). A borderline significant increase in risk was observed for prior infection with gonorrhea (OR = 1.50; 95 percent CI: 1.02, 2.18). Slightly elevated risks were also observed for syphilis and genital herpes, but these were not significant. No associations were observed for urethritis, genital warts, chlamydia, testicular infection, epididymitis, or prostatitis. A nonsignificant decrease in risk was observed among men who had undergone circumcision (OR = 0.86; 95 percent CI: 0.67, 1.10). An increased risk was also observed with infertility due to a male cause (OR = 2.60; 95 percent CI: 1.28, 5.29), but no association was observed with the number of fathered pregnancies. The infertility association was not explained by previous infection with gonorrhea (not shown).


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TABLE 2. Odds ratios for prostate cancer according to selected medical history variables, Health Interview Study of Men, 1993–1996

 
There was no relation between sexual orientation and prostate cancer risk (table 3), although the number of men who had sexual intercourse with men was small. As shown in table 4, there was a significant trend of increasing risk with increasing number of female sexual partners (p < 0.001) but not with the number of male sexual partners (p = 0.28). The risk declined with increasing age at first intercourse (table 4), but this trend became weaker after controlling for the lifetime number of female sexual partners (p = 0.62).


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TABLE 3. Odds ratios for prostate cancer according to sexual orientation, Health Interview Study of Men, 1993–1996

 

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TABLE 4. Odds ratios for prostate cancer according to age at first intercourse and number of sexual partners, Health Interview Study of Men, 1993–1996

 
Having had two or more female sexual partners during the teens (OR = 1.60; 95 percent CI: 1.17, 2.18), the twenties (OR = 1.24; 95 percent CI: 0.98, 1.56), the forties (OR = 1.32; 95 percent CI: 1.02, 1.72), and ages 50–64 (OR = 1.73; 95 percent CI: 1.25, 2.41) increased the risk of prostate cancer (table 5), compared with men who had one partner during each specified period. No association was observed with age-specific frequency of sexual intercourse after adjusting for the number of sexual partners.


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TABLE 5. Odds ratios for prostate cancer according to age-specific number of sexual partners and sexual frequency, Health Interview Study of Men, 1993–1996

 
We also examined whether tumor aggressiveness was associated with the number of sexual partners. The relation with total lifetime number of female sexual partners appeared to be stronger for men with less aggressive tumors (trend p < 0.001), although men with 30 or more sexual partners had an odds ratio of 1.76 for aggressive disease (table 6). The reduction in risk associated with later age at first intercourse did not differ with respect to tumor aggressiveness (data not shown).


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TABLE 6. Odds ratios for nonaggressive and aggressive prostate cancer by number of female sexual partners, Health Interview Study of Men, 1993–1996

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Our findings suggest that there is a direct positive relation between the number of lifetime female sexual partners and the risk of prostate cancer in middle-aged men. The increased risk associated with having more than one female sexual partner was observed during most age periods evaluated. These findings are consistent with those of other studies (2Go, 5Go), and they suggest that sexual behavior and associated exposure to sexually transmitted agents enhance the risk of prostate cancer.

A previous study suggested that an early age at first intercourse increased the risk of prostate cancer (15Go), but the investigators did not control for the potential confounding effect of the number of sexual partners. When we controlled for the number of sexual partners, the effect of early age at first intercourse disappeared.

In addition, some older studies theorized that "sexual frustration" had an etiologic role in the development of prostate cancer and observed that cases had less frequent sexual intercourse than did controls (15GoGo–17Go). Although we did not observe a negative association with sexual frequency, we also did not observe a positive one after adjustment for the number of sexual partners. This argues against a "sexual frustration" hypothesis and indirectly against a hormonal etiology, assuming that there is a relation between sexual activity and androgen levels. To further examine the potential effect of hormonal exposures, we estimated the risk according to the age at which a man started shaving and the age at which full height was attained. No association was found with either of these indirect measures of hormonal status. A positive relation between circulating testosterone levels and prostate cancer incidence has been observed (18Go), and serum dihydrotestosterone levels have been related to sexual activity (19Go). Thus, it is possible that associations with sexual behavior may be confounded by androgen levels. This possibility, however, has not been directly evaluated.

Our findings do not implicate a specific sexually transmitted disease agent (with the exception of gonorrhea) in the development of prostate cancer. Some sexually transmitted diseases may have been asymptomatic and therefore underreported. Previous studies also found an association with a history of gonorrhea and other sexually transmitted diseases (2Go, 5Go, 20Go).

Recent studies that assessed serologic evidence of exposure to sexually transmitted diseases provide further evidence for an infectious hypothesis. Hayes et al. (5Go) found an 80 percent elevation in risk among men with a positive serologic test for syphilis (95 percent CI: 1.0, 3.5). In a nested case-control study, serologic evidence of HPV type 18 (OR = 2.88; 95 percent CI: 1.27, 6.56) and HPV type 16 (OR = 2.58; 95 percent CI: 0.77, 8.56) was more frequent in prostate cancer cases than in controls (8Go). Three other studies showed nonsignificant elevations in risk after exposure to HPV type 16 (5Go, 6Go, 9Go), while a fourth small study showed no association between HPV type 16 and prostate cancer (7Go). Studies of oncogenic HPV types in prostate cancer tissue specimens have largely been positive for evidence of HPV type 16 and negative for HPV type 18 (21Go). The findings of these studies are interesting but await confirmation.

We observed an increased risk in men who reported infertility due to a male cause. This was not explained by stratifying on whether there was a history of gonorrhea. We did not collect information on the specific cause of the infertility and therefore are not able to provide an explanation for this finding.

Our study has several limitations that should be considered. We were able to interview 82 percent of cases and 75 percent of controls. Although a sample of nonrespondents (who were interviewed by telephone) showed modest differences in the distributions of age, race, and education compared with respondents, these differences were not substantial enough to cause a major bias in risk estimates for the association between the number of sexual partners and prostate cancer. We did not ask nonrespondents about sexual behaviors on the brief telephone interview. One possible reason for our findings may be recall bias, that is, cases reporting more sexual partners than controls. However, recall bias seems unlikely because sexual frequency was not found to be associated with prostate cancer, although there was an association with the number of sexual partners.

We did not observe as strong a relation with the number of sexual partners as has been reported for other anogenital tumors such as anal cancer (22Go) and penile cancer (23Go) in men from the western Washington area (ORs = 6.8 and 3.4, respectively, for highest vs. lowest lifetime number of sexual partners). These anogenital tumors have been associated with serologic evidence of HPV infection and with a previous history of genital warts. This suggests that exposure to HPV or some, as yet undetected, sexually transmitted agent may increase the risk of prostate cancer, but the association is not as strong as for other cancers known to have an infectious etiology.

One advantage of this study is that various aspects of lifetime sexual behavior could be controlled for other sexually related variables and demographic and screening variables that may be associated with prostate cancer risk and detection. In summary, our results support a role for sexual behavior and associated exposure to infectious agents in the etiology of prostate cancer. Additional research will be required to identify specific exposures that may explain the observed link between the number of sexual partners and prostate cancer risk.


    ACKNOWLEDGMENTS
 
This research was supported by grant CA56678 and contract NO1-CN-05230 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.

The authors thank the men who participated in the study and the interviewers for their help with data collection.


    NOTES
 
Correspondence to Dr. Janet Stanford, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, MW-814, Seattle, WA 98109-1024 (e-mail: jstanfor{at}fhcrc.org).


    REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication March 27, 2000. Accepted for publication November 15, 2000.