- Email: [email protected]
Semen quality in fertile men in relation to psychosocial stress
Semen quality in fertile men in relation to psychosocial stress Audra L. Gollenberg, Ph.D.,a Fan Liu, M.S.,b Charlene Brazil, B.S.,c Erma Z. Drobnis, Ph.D.,d David Guzick, M.D., Ph.D.,b James W. Overstreet, M.D., Ph.D.,c James B. Redmon, M.D.,e Amy Sparks, Ph.D.,f Christina Wang, M.D.,g and Shanna H. Swan, Ph.D.b a Division of Biostatistics and Epidemiology, Department of Public Health, School of Public Health and Health Sciences, University of Massachusetts-Amherst, Amherst, Massachusetts; b Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, Rochester, New York; c Center for Health and the Environment, University of California, Davis, California; d Department of Obstetrics, Gynecology and Women’s Health, School of Medicine, University of Missouri, Columbia, Missouri; e Departments of Medicine and Urologic Surgery, University of Minnesota Medical School, Minneapolis, Minnesota; f Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa; and g Division of Endocrinology, Department of Medicine, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, California
Objective: To examine the association between stressful life events and semen parameters. Design: Cross-sectional analysis in a pregnancy cohort study. Setting: Prenatal clinics in five U.S. cities. Patient(s): Fertile men (n ¼ 744) in the Study for Future Families, a cohort study of pregnant women and their partners. Intervention(s): None. Main Outcome Measure(s): Sperm concentration, percent motile, and percent normal morphology and classification above/below World Health Organization (WHO) cutoffs for semen quality. Result(s): After adjusting for confounders, men reporting 2þ recent stressful life events had an increased risk of being classified below WHO thresholds for ‘‘normal’’ defined by concentration, motility, and morphology criteria compared with men reporting <2 stressful life events (odds ratio [OR] ¼ 2.06; 95% confidence interval [CI], 1.18, 3.61; OR ¼ 1.54; 95% CI, 1.04, 2.29; OR ¼ 1.93; 95% CI, 1.02, 3.66 for concentration, motility and morphology, respectively). Men experiencing 2þ stressful life events had lower sperm concentration (log scale, b ¼ 0.25; 95% CI, 0.38, 0.11) and lower percent motile sperm (b ¼ 1.95; 95% CI, 3.98, 0.07), but percent normal morphology was less affected. Conclusion(s): These results suggest that stressful life events may be associated with decreased semen quality in fertile men. The experience of psychosocial stress may be a modifiable factor in the development of idiopathic infertility. (Fertil Steril 2010;93:1104–11. 2010 by American Society for Reproductive Medicine.) Key Words: Sperm concentration, sperm motility, sperm morphology, semen quality, psychosocial stress, life events
Approximately 10%–15% of U.S. couples experience infertility (at least 12 months of unprotected intercourse without pregnancy), while another 10% have fewer children than they desire (1). Male reproductive factors are thought to be the cause in about one-third of cases and a contributing factor Received September 30, 2008; revised December 5, 2008; accepted December 8, 2008; published online February 24, 2009. A.L.G. has nothing to disclose. F.L. has nothing to disclose. C.B. has nothing to disclose. E.Z.D. has nothing to disclose. D.G. has nothing to disclose. J.W.O. has nothing to disclose. J.B.R. has nothing to disclose. A.S. has nothing to disclose. C.W. has nothing to disclose. S.H.S. has nothing to disclose. This work was supported by the National Institute of Health grant nos. R01-ES09916 to the University of Missouri from the National Institute of Environmental Health Sciences (NIEHS); MO1-RR00400 to the University of Minnesota General Clinical Research Center; and MO1RR0425 to the Research and Education Institute at Harbor-UCLA Medical Center and the Cedars-Sinai Research Institute from the National Center for Research Resources. Reprint requests: Dr. Shanna H. Swan, University of Rochester School of Medicine and Dentistry, Department of Obstetrics and Gynecology, 601 Elmwood Avenue, Box 668, Rochester, New York 14642 (FAX: 585-276-2151; E-mail: [email protected]).
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in another 20% of cases (1, 2). Psychological stress has been implicated as a cause of idiopathic infertility in both men and women (3–8), with the majority of studies conducted among women. Numerous studies have investigated psychological causes of male factor infertility (6, 9–15), but because of the many potential confounders, it remains difficult to tease out stress as a cause or consequence of infertility. The majority of existing studies that examined this question used populations from assisted reproduction technology (ART) clinics or other nonrepresentative populations, making it difficult to differentiate between stress as a cause or a consequence of infertility. In addition, the availability of a wide range of different tools to assess stress and other psychological conditions makes comparison across studies difficult. Some studies examined the relationships between different types of stress and/or anxiety and semen quality (9, 12, 14, 16–21), while others have looked at semen quality in relation to psychosocial personality factors and stress coping styles (10, 13, 15, 22). Several studies reported an association between higher stress levels and decreased semen
Fertility and Sterility Vol. 93, No. 4, March 1, 2010 Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc.
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quality (6, 9, 13, 14, 16–23), although one study reported no association between stress and semen quality but did observe a decreased pregnancy rate in high-stress cycles (12). The high variability in semen parameters makes it difficult to obtain sufficient power in studies of semen quality. The aim of this study is to examine the association between one measure of psychological stress (number of stressful life events) and semen quality in a population-based sample of fertile men using strict quality-control methods. Our objectives were to [1] examine semen parameters in relation to a six-value measure (total life events) as well as to a dichotomized measure of (two or more vs. fewer) life events in the 3 months before semen collection and [2] the relation between these measures of life events and the risk of being classified below World Health Organization (WHO) thresholds for ‘‘normal’’ using three clinical criteria (24). MATERIALS AND METHODS Study Population Men in these analyses were participants in the Study for Future Families (SFF), a multicenter pregnancy cohort study. Methods for SFF have been described elsewhere (25). Briefly, women were recruited from September 1999 to December 2005 at prenatal clinics affiliated with university hospitals in five U.S. cities: Los Angeles, California (Harbor-UCLA Medical Center and Cedars-Sinai Medical Center); Minneapolis, Minnesota (University of Minnesota Health Center); Columbia, Missouri (University Physicians); New York, New York (Mt. Sinai School of Medicine); and Iowa City, Iowa (University of Iowa). Only pregnancies that were conceived without medical intervention were eligible. The male partner was recruited if the woman agreed, and all men were asked to give at least one semen sample, complete a brief questionnaire, and undergo a physical exam. In addition, a sample of men (about 15% of all participants) was recruited, even though they refused to give a semen sample to assess potential selection bias associated with semen collection.
movement, whether twitching or progressive. Motility was also analyzed using the WHO 1999 a, b, c, and d method with forward motile sperm classified as a þ b (24). Seminal smears were prepared at the clinical centers and shipped to the Andrology Coordinating Center at the University of California, Davis, for Papanicalou staining, analysis, and storage, where a single technician assessed sperm morphology using the strict morphology method, as recommended by WHO (24, 28). In addition to the primary measures of semen quality (sperm concentration, volume, percent morphologically normal sperm, and percent motile sperm), we analyzed the total count (sperm concentration volume, or TC). Institutional Review Board human subject committees at all participating institutions approved the SFF, and all subjects signed informed consents. None of the authors have declared a conflict of interest. Psychosocial Stress Assessment The men’s questionnaire asked about stressful life events in the 3 months before semen sample collection, the approximate length of the spermatogenic cycle, and final maturation (29). These life event questions were derived from two standardized questionnaires (30, 31) and assess the occurrence of five major life events, plus an open-ended question to capture other major life events. The selection of life events was based on principles outlined by Dohrenwend and colleagues (30, 32). Life events included in the questionnaire represent major psychological traumas known to adversely affect health outcomes (17, 30, 33). Participants were asked to indicate whether or not they had experienced any of the following stressful life events in the recent 3 months: job loss or unemployment (self or wife/partner); serious illness or injury (self or wife/partner); death of a close family member (i.e., parent, child, sibling); divorce, separation, or serious difficulties with wife/partner; legal, or financial problems (self or wife/partner); and other major life events (write-in option).
Semen Collection and Analysis Men were requested to observe a 2- to 5-day abstinence period before providing each semen sample, but the importance of accurately reporting the actual abstinence period was stressed. At the study visit, men collected semen samples by masturbation at the clinic, and these were analyzed, on average, within 27 minutes of collection (range, 10–105 minutes). Nine subjects were excluded because the analysis was started less than 10 minutes after sample collection.
Covariate Assessment Study participants completed questionnaires requesting information on sociodemographics, race, age, current and prior job information, cigarette smoking, alcohol use, illicit drug use, diet, and reproductive health history. Participants also underwent a physical examination including height and weight, blood pressure, and reproductive abnormalities as well as a blood draw on the day of semen collection.
Methods used for semen evaluation have been described elsewhere (26). Briefly, concentration assessments were evaluated by hemacytometer (Improved Neubauer; Hauser Scientific Inc., Horsham, PA). Ejaculate volumes were estimated by specimen weight, assuming a semen density of 1.0 g/mL. In this analysis the percent motile sperm was counted in a MicroCell chamber (Conception Technologies, San Diego, CA) (27) and refers to the percentage of sperm with any flagellar
Statistical Analyses The primary outcomes of interest in this study were sperm concentration, TC, percent motility, and percent normal morphology. Because sperm concentration, semen volume, and TC (but not percent normal morphology or percent motile) were skewed, we transformed these using the natural logarithm, as recommended (34). We also examined the risk of
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being classified below WHO thresholds (24) based on sperm concentration (<20 million/mL) and forward motility (<50% motile sperm of class a þ b). These criteria are based on forward motion, unlike the total percent motile sperm (any flagellar movement) used in the linear regression analyses. While WHO has no comparable cutoff for morphology, we used normal forms <4% by strict criteria as suggested by WHO laboratory standards and used in other studies of semen quality (35, 36). Exposure variables were [1] total number of stressful life events from 0 to 6; and [2] the categorical variable R2 stressful life events versus fewer. Covariates considered in the analysis were age, race, educational attainment, study center, cigarette use, alcohol use, illicit drug use, body mass index (BMI), self-rated health status, history of sexually transmitted disease (STD), genital infection, testicular conditions, recent fever, ejaculation abstinence time, and time to analysis (only for analysis of percent motility). Variables were entered into the model if they were shown to be associated with life events in bivariate analyses or have been associated with decreased semen quality in previous literature. We also evaluated the association between number of life events and the number of semen samples the man provided (0, 1, or 2) using the c2-test. We evaluated the bivariate relationships between potential confounders and life events using c2-tests for categorical variables and Student’s t-test for continuous variables. We then used multiple linear regression analyses to model the associations between stressful life events and each semen parameter. We also calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression to estimate the likelihood of classification below WHO thresholds by the number of life events while adjusting for potential confounders. For both the linear regression and logistic regression analyses, multiplicative interactions were assessed for stressful life events and race, education, and age by adding an interaction term to the final models for each semen param-
eter. Statistical analyses were performed using SAS, version 9.1 (SAS Institute, Inc., Cary, NC). RESULTS Of the total SFF population (N ¼ 950), 145 men did not provide a semen sample, 32 men had incomplete information for relevant covariates on the men’s questionnaire, and 29 men did not complete the stressful life event scale, with n ¼ 744 remaining for the current analysis. Mean sperm concentration was 80.3 106/mL and ranged from 2.8 to 420.5 106/mL (Table 1). The mean percent motile sperm and percent morphologically normal were 51% (range, 5%–78.0%) and 11% (range, 0.5%–26.0%), respectively. The distribution of life events according to sociodemographic and lifestyle characteristics is displayed in Table 2. Twenty-two percent (n ¼ 166) of participants reported two or more life events in the recent 3 months (Table 2). Nonwhite race, lower educational attainment, study center, younger age, cigarette use, BMI, and a history of STD were significantly associated with two or more stressful life events (P<.05). In contrast, recent fever and ejaculation abstinence time, alcohol use, illicit drug use, self-rated health status, history of genital infection, or testicular conditions (undescended testicles, varicocele, or hydrocele) did not vary significantly by number of stressful life events (P>.05). Most men (74%) provided two samples, while 10% provided only one sample, and 16% provided none. The mean numbers of life events for these three groups did not differ appreciably (0.80, 1.01, and 0.86 for two, one, and zero samples; P¼.38). A recent analysis of our population showed that semen parameters did not vary significantly by the number of samples provided (37). We examined life events both as a dichotomous variable (R2 vs. <2) and as a discrete variable (total events reported). In unadjusted analyses, the total number of stressful life events was significantly associated with decreased sperm
TABLE 1 Distribution of semen parameters: The Study for Future Families, 1999–2005. Semen parameter a
6
Concentration , 10 /mL TCb, 106 Total percent motility Strict percent normal morphology Specimen volume, g/mL Abstinence time, hoursc
Mean
SD
Median
Minimum
Maximum
80.3 304.4 50.7 10.7 3.9 82.1
59.9 251.2 11.9 5.1 1.7 38.5
67.7 243.0 52.0 10.5 3.7 73.5
2.8 4.2 5.0 0.5 0.5 9.3
420.5 2456.1 78.0 26.0 11.5 240.0
Note: n ¼ 744; SD ¼ standard deviation. a Hemocytometer. b TC ¼ concentration specimen volume. c Abstinence time truncated at a maximum of 240 hours. Gollenberg. Psychosocial stress and semen quality. Fertil Steril 2010.
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TABLE 2 Distribution of characteristics by number of recent stressful life events. The Study for Future Families, 1999-2005. No. of stressful life events, n (%) Characteristics Race White Nonwhite Educational attainment Less than college College graduate or higher Study center CA MN MO NY IA Mean age, y (SD) Cigarettes smoked/d 0 1–<10 10 or more Alcohol use in the last wk 0 drinks 1–3 drinks 4+ drinks Illicit drug use in the last wk No Yes Mean body mass index (SD) Self-rated health status Excellent Good Fair/poor Ever diagnosed with an STD No Yes Ever diagnosed with a genital infectiona No Yes Ever diagnosed with a testicular conditionb No Yes Recent fever No Yes Mean abstinence time, h (SD)
<2
2+
Total
P
434 (75.1) 144 (24.9)
107 (64.5) 59 (35.5)
541 (72.7) 203 (27.3)
.007
204 (35.3) 374 (64.7)
104 (62.7) 62 (37.4)
308 (41.4) 436 (58.6)
< .0001
128 (22.2) 159 (27.5) 139 (24.1) 34 (5.9) 118 (20.4) 31.9 (5.9)
54 (32.5) 36 (21.7) 46 (27.7) 3 (1.8) 27 (16.3) 30.5 (6.8)
182 (24.5) 195 (26.2) 185 (24.9) 37 (5.0) 145 (19.5) 31.6 (6.1)
.009
473 (82.3) 25 (4.4) 77 (13.4)
112 (67.9) 8 (4.9) 45 (27.3)
585 (79.1) 33 (4.5) 122 (16.5)
.0001
244 (42.2) 122 (21.1) 198 (36.8)
73 (44.0) 40 (24.1) 53 (31.9)
317 (42.6) 162 (21.8) 265 (35.6)
.5
524 (90.7) 54 (9.3) 28.2 (5.1)
145 (87.4) 21 (12.7) 29.3 (6.2)
669 (89.9) 75 (10.1) 28.4 (5.4)
.2
211 (36.5) 319 (55.2) 48 (8.3)
54 (32.5) 93 (56.0) 19 (11.5)
265 (35.6) 412 (55.4) 67 (9.0)
.4
518 (89.6) 60 (10.4)
134 (80.7) 32 (19.3)
652 (87.6) 92 (12.4)
.002
523 (90.5) 55 (9.5)
148 (89.2) 18 (10.8)
671 (90.2) 73 (9.8)
.6
535 (92.6) 43 (7.4)
152 (91.6) 14 (8.4)
687 (92.3) 57 (7.7)
.7
562 (97.2) 16 (2.8) 83.5 (39.4)
160 (96.4) 6 (3.6) 77.2 (34.8)
722 (97.0) 22 (3.0) 82.1 (38.5)
.6
.01
.02
.06
Note: n ¼ 744. P-values are derived from the c2-test for categorical variables and from the t-test for continuous variables comparing <2 life events and 2+ life events; STD ¼ sexually transmitted disease. a Genital infection includes epididymitis, orchitis, prostatitis, or cystitis. b Testicular conditions include undescended testicles, varicocele, or hydrocele. Gollenberg. Psychosocial stress and semen quality. Fertil Steril 2010.
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TABLE 3 Linear regression estimates and 95% CIs for stressful life events in relation to sperm concentration, TC, percent motile, and percent normal morphology: The Study for Future Families, 1999–2005. Semen parameter Log hemocytometer Log TC Percent motile sperm Percent normal morphology
Unadjusted: total life events, beta (95% CI)
Adjusted: total life events, beta (95% CI)
Unadjusted 2D vs. Adjusted: 2Dvs. <2 life events, beta <2 life events, beta (95% CI) (95% CI)
0.12 (0.17, 0.07) 0.10 (0.15, 0.05) 0.32 (0.45,0.18) 0.25 (0.38, 0.11) 0.16 (0.22, 0.11) 0.11 (0.17, 0.05) 0.43 (0.59, 0.28) 0.30 (0.45, 0.15) 0.60 (1.3, 0.16) 0.74 (1.5, 0.02) 1.8 (3.8, 0.29) 1.95 (3.98, 0.07) 0.03 (0.35, 0.29)
0.08 (0.42, 0.25)
0.44 (1.3, 0.43)
0.59 (1.48, 0.30)
Note: n ¼ 744. Estimates adjusted for center, age, age squared, race, education, recent fever, abstinence time, and abstinence time squared. Motility was also adjusted for time to analysis. TC ¼ (concentration volume). Concentration and TC were natural log transformed. Gollenberg. Psychosocial stress and semen quality. Fertil Steril 2010.
concentration and TC but not with percent motile sperm or percent normal forms (Table 3). Reporting two or more life events was also associated with a significant reduction in concentration and TC before adjustment. These associations remained significant in multivariable analyses, although associations were somewhat attenuated. For example, men experiencing two or more stressful life events had significantly lower sperm concentration (log scale, b ¼ 0.25; 95% CI 0.38, 0.11) and TC (log scale, b¼ 0.30; 95% CI, 0.45, 0.15) compared with men who reported less than two life events after adjusting for center, age, age squared, race, education, recent fever, ejaculation abstinence time, and ejaculation abstinence time squared. We
also observed an inverse association between 2þ life events and percent motile sperm after adjustment, although it was borderline statistically significant (P¼.06; Table 3). Furthermore, consistent with a threshold effect at 2þ stressful life events, the semen parameters of men reporting only one life event did not differ significantly from that of men reporting zero life events (P>.05 for all semen parameters). Next we examined the likelihood of classification below WHO normal thresholds (24) by the number of stressful life events (Table 4). In unadjusted analyses, an increased number of life events was significantly associated with an increased likelihood of classification below the WHO concentration cutoff. This association remained significant after adjustment
TABLE 4 ORs and 95% CIs for risk of classification below WHO thresholds for semen concentration, motility, and morphology: The Study for Future Families, 1999–2005. Semen parameter below WHO cutoffs
Unadjusted: total life events,a OR (95% CI)
Adjusted: total life events,a,b OR (95% CI)
Unadjusted 2D vs. <2 life events, OR (95% CI)
Adjusted: 2Dvs. <2 life events,b OR (95% CI)
Concentrationc Forward motilityd Normal morphologye
1.35 (1.11, 1.63) 1.03 (0.90, 1.18) 1.10 (0.88, 1.39)
1.30 (1.05, 1.60) 1.11 (0.95, 1.28) 1.19 (0.93, 1.53)
2.26 (1.33, 3.84) 1.27 (0.89, 1.83) 1.58 (0.87, 2.87)
2.06 (1.18, 3.61) 1.54 (1.04, 2.29) 1.93 (1.02, 3.66)
Note: n ¼ 744. a OR for 1-unit increase in no. of life events. b Estimates adjusted for center, age, age squared, race, education, recent fever, abstinence time, and abstinence time squared. Motility was also adjusted for time to analysis. c Hemacytometer concentration <20 million/mL. d Percent motile sperm <50%. e Kruger’s strict morphology <4% normal forms. Gollenberg. Psychosocial stress and semen quality. Fertil Steril 2010.
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for center, age, age squared, race, recent fever, education, abstinence time, and ejaculation abstinence time squared (2þ life events vs. <2; OR ¼ 2.06; 95% CI, 1.18, 3.61). In contrast, number of life events was not significantly associated with classification below motility and morphology cutoffs before adjustment. However, in multivariable analyses, men reporting two or more life events were also more likely to be classified below the WHO threshold for forward motility (OR ¼ 1.54; 95% CI, 1.04, 2.29) and strict morphology (OR ¼ 1.93; 95% CI, 1.02, 3.66). Moreover, men reporting only one life event did not differ in risk of classification below any WHO cutoff compared with men reporting zero life events (P¼.35 for concentration, P¼.55 for motility, and P¼.50 for morphology), which is consistent with the threshold effect observed for the semen parameters in continuous form. Finally, we did not observe statistically significant interactions between stressful life events and race, age, or education. DISCUSSION In this population-based study of fertile men, we observed decreased semen quality among men who reported recent stressful life events. Specifically, the experience of two or more life events was associated with decreased sperm concentration, TC, and percent motile sperm and an increased likelihood of classification below WHO thresholds for ‘‘normal’’ for concentration, motility, and morphology. These findings are consistent with previous studies conducted among varying populations that demonstrated that psychosocial stress, as measured by a wide range of assessment tools, including the Zung’s Anxiety Scale Inventory (21), State Anxiety Inventory (16), WHO Well-Being Index (21), physiologic stress symptoms (18), stressful life events (17, 18), the Infertility Distress Scale (14), the Coping Inventory for Stressful Situations (13), undergoing stressful examinations (38), and other methods (9, 19, 20, 23), is associated with decreased semen quality. To our knowledge, previous studies have not examined psychosocial stress in relation to WHO semen quality thresholds. Such results have important implications for men attempting to achieve pregnancy given that men with semen parameters below the WHO cutoffs have decreased odds of pregnancy compared with men with semen parameters above such cutoffs (24, 39). The majority of previous studies on this association were small, cross-sectional studies. Most found associations between various forms of psychosocial stress and semen quality, although one prospective study did not (12). Hjollund et al. prospectively assessed psychological distress using the General Health Questionnaire (GHQ) among over 400 couples planning to conceive (12). Although the study authors found no association between GHQ scores and semen quality, they did observe reduced fecundity in high-stress cycles. It should be noted that the GHQ measures a different construct than the stressful life event scale used in our study as it was originally developed to assess the severity of symptoms consistent with mental illness (40–42). Validation studies of the GHQ have most often compared GHQ scores with other scales for diagnosing mental illness, including the Fertility and Sterility
Composite International Diagnostic Interview and the Present State Examination (40, 42, 43), further underscoring the construct of the GHQ. While persons experiencing mental illness may also be under psychosocial stress, the physiological effect of mental illness alone on semen production may in fact be different than that of life event stress, and this may account, in part, for the conflicting findings. The association between psychosocial stress and decreased semen quality has biologic plausibility supported by numerous studies. Most hypothesized pathways by which stress may impact semen quality operate under endocrine factors. Men undergoing stressful situations are shown to have lower T and LH levels and an interference with spermatogenesis (44–48). Klimek et al. demonstrated that a rise in stress hormones, cortisol and adrenocorticotropic hormone (ACTH), can cause a disruption of the conversion of androstenedione into T in Leydig cells (45). This disruption results in the rise of the precursor androgen, androstenedione, a drop of the product T, and lower average values of semen volume, sperm concentration, and sperm cell motility (45). Eskiocak et al. has shown other stress-related changes in seminal plasma, specifically, a marked rise in nitric oxide and a decrease in arginase activity resulting in poorer semen quality under stress (16). Moreover, in animals, induced psychological stress negatively affects T and LH levels, sexual behavior, and semen parameters (1, 49). In a secondary analysis, we examined several hormonal measures (total T and two measures of free T), but none were related to the recalled stressful life events, perhaps because the events might not have been sufficiently proximal to blood sampling. We observed several associations between the number of stressful life events and demographic and lifestyle characteristics that generally agree with prior literature. The finding that nonwhite ethnicity, lower education, and younger age were associated with an increased number of life events is in accord with a recent review of life events in relation to sociodemographics (50). Similarly, in prior research, those experiencing stressful events are more likely to smoke and have higher BMI, consistent with our findings (51–53). The positive association between life events and STD diagnosis may suggest a group with a history of high-risk behaviors (i.e., unprotected intercourse), although we did not observe an association between alcohol intake and illicit drug use in the last week. In addition, there was a suggestion that the number of life events was associated with a shorter ejaculation abstinence time before semen collection (P¼.06). Our study has several limitations. While our method of stress assessment, stressful life events, has been associated with multiple health endpoints (17, 32), we cannot eliminate potential misclassification due to inaccurate reporting of life events or the differential perceived severity of life events. Other misclassification of exposure may occur as a result of measuring stress solely by reported major life events. While stressful life events are thought to exert a chronic effect on bodily functioning (32), acute stress associated with other daily hassles and lifestyle will not be detected using this 1109
life event scale. Moreover, we did not collect information on potential modifiers of stress such as social support or coping style, which could modify the effect of stress on semen quality. If these types of misclassification occurred, it would most likely be nondifferential and thus could lead to an underestimate of associations between stress and semen quality. This study has several strengths. First, since we recruited men with proven fertility, it is unlikely that these men were experiencing additional distress due to failed attempts at conceiving. Unlike the current study, previous studies were not able to distinguish stress as a cause of infertility or a consequence of infertility when ART clinic populations were used. In addition, it is unlikely that men would differentially report life events based on perceived differences in semen quality. We used extensive quality control techniques to ensure that semen parameters were measured accurately by highly qualified technicians (25). Finally, we examined a variety of factors that may be associated with both psychosocial stress and semen quality, including substance use (alcohol, cigarettes, and illicit drugs), although adjustment for these factors did not alter the findings and were not included in the final model. Results of this study have important implications for families attempting pregnancy. Stress as a result of life events may have an impact on semen quality and thus affect the likelihood of conceiving. Future studies should prospectively assess whether semen quality improves after the effect of the stress is mediated or removed. That is, future studies should seek to determine whether the negative effect of stress on semen quality is a temporary or persistent problem. Future studies should also prospectively evaluate different types of stress on the quality of semen and the likelihood of future conception. Finally, these results are based on a population of fertile men and may not be generalizable to all reproductive-age men, including those without demonstrated fertility. Acknowledgments: We acknowledge the Study for Future Families Research Group; the physicians, midwives, and staff of University Physicians Clinic, Columbia, Missouri; Fairview Riverside Women’s Clinic, Minneapolis, Minneapolis; Harbor-UCLA Medical Center, Torrance, California; Cedars-Sinai Medical Center, Los Angeles, California; and Mt. Sinai Medical Center, New York, New York; and the study participants.
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7. Wasser SK, Sewall G, Soules MR. Psychosocial stress as a cause of infertility. Fertil Steril 1993;59:685–9. 8. Wright J, Duchesne C, Sabourin S, Bissonnette F, Benoit J, Girard Y. Psychosocial distress and infertility: men and women respond differently. Fertil Steril 1991;55:100–8. 9. Clarke RN, Klock SC, Geoghegan A, Travassos DE. Relationship between psychological stress and semen quality among in-vitro fertilization patients. Hum Reprod 1999;14:753–8. 10. Hellhammer DH, Hubert W, Phil C, Freischem CW, Nieschlag E. Male infertility: relationships among gonadotropins, sex steroids, seminal parameters, and personality attitudes. Psychosom Med 1985;47:58–66. 11. Hjollund NH, Bonde JP, Henriksen TB, Giwercman A, Olsen J. Job strain and male fertility. Epidemiology 2004;15:114–7. 12. Hjollund NH, Bonde JP, Henriksen TB, Giwercman A, Olsen J. Reproductive effects of male psychologic stress. Epidemiology 2004;15: 21–7. 13. Morelli G, De Gennaro L, Ferrara M, Dondero F, Lenzi A, Lombardo F, et al. Psychosocial factors and male seminal parameters. Biol Psychol 2000;53:1–11. 14. Pook M, Krause W, Rohrle B. Coping with infertility: distress and changes in sperm quality. Hum Reprod 1999;14:1487–92. 15. Pook M, Tuschen-Caffier B, Kubek J, Schill WB, Krause W. Personality, coping and sperm count. Andrologia 2005;37:29–35. 16. Eskiocak S, Gozen AS, Taskiran A, Kilic AS, Eskiocak M, Gulen S. Effect of psychological stress on the L-arginine-nitric oxide pathway and semen quality. Braz J Med Biol Res 2006;39:581–8. 17. Fenster L, Katz DF, Wyrobek AJ, Pieper C, Rempel DM, Oman D, et al. Effects of psychological stress on human semen quality. J Androl 1997;18:194–202. 18. Giblin PT, Poland ML, Moghissi KS, Ager JW, Olson JM. Effects of stress and characteristic adaptability on semen quality in healthy men. Fertil Steril 1988;49:127–32. 19. Harrison KL, Callan VJ, Hennessey JF. Stress and semen quality in an in vitro fertilization program. Fertil Steril 1987;48:633–6. 20. Ragni G, Caccamo A. Negative effect of stress of in vitro fertilization program on quality of semen. Acta Eur Fertil 1992;23:21–3. 21. Zorn B, Auger J, Velikonja V, Kolbezen M, Meden-Vrtovec H. Psychological factors in male partners of infertile couples: relationship with semen quality and early miscarriage. Int J Androl 2008;31:557–64. 22. De Gennaro L, Balistreri S, Lenzi A, Lombardo F, Ferrara M, Gandini L. Psychosocial factors discriminate oligozoospermic from normozoospermic men. Fertil Steril 2003;79(Suppl 3):1571–6. 23. Fukuda M, Fukuda K, Shimizu T, Yomura W, Shimizu S. Kobe earthquake and reduced sperm motility. Hum Reprod 1996;11:1244–6. 24. World Health Organization. WHO laboratory manual for the examination of human semen and semen-cervical mucus interactions. 4th ed. Cambridge, UK/New York: Cambridge University Press; 1999. 25. Swan SH, Brazil C, Drobnis EZ, Liu F, Kruse RL, Hatch M, et al. Geographic differences in semen quality of fertile U.S. males. Environ Health Perspect 2003;111:414–20. 26. Brazil C, Swan SH, Drobnis EZ, Liu F, Wang C, Redmon JB, et al. Standardized methods for semen evaluation in a multicenter research study. J Androl 2004;25:635–44. 27. Overstreet JW, Brazil C. Semen analysis. In: Lipshultz LI, Howards SS, eds. Infertility in the male. 3d ed. St. Louis, MO: Mosby, 1997:487–90. 28. Guzick DS, Overstreet JW, Factor-Litvak P, Brazil CK, Nakajima ST, Coutifaris C, et al. Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med 2001;345:1388–93. 29. Dym M. The male reproductive system. In: Weiss L, ed. Histology, cell and tissue biology. 5th ed. New York, Amsterdam, Oxford: Elsevier Biomedical, 1983:1000–53. 30. Dohrenwend BS, Krasnoff L, Askenasy AR, Dohrenwend BP. Exemplification of a method for scaling life events: the Peri Life Events Scale. J Health Soc Behav 1978;19:205–29. 31. Holmes TH, Rahe RH. Social readjustment rating scale. J Psychosom Res 1967;11:213–8. 32. Dohrenwend BS, Dohrenwend BP. Some issues in research on stressful life events. J Nerv Ment Dis 1978;166:7–15.
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33. Carmichael SL, Shaw GM. Maternal life event stress and congenital anomalies. Epidemiology 2000;11:30–5. 34. Berman NG, Wang C, Paulsen CA. Methodological issues in the analysis of human sperm concentration data. J Androl 1996;17:68–73. 35. Hauser R, Meeker JD, Duty S, Silva MJ, Calafat AM. Altered semen quality in relation to urinary concentrations of phthalate monoester and oxidative metabolites. Epidemiology 2006;17:682–91. 36. Menkveld R, Wong WY, Lombard CJ, Wetzels AM, Thomas CM, Merkus HM, et al. Semen parameters, including WHO and strict criteria morphology, in a fertile and subfertile population: an effort towards standardization of in-vivo thresholds. Hum Reprod 2001;16: 1165–71. 37. Stokes-Riner A, Thurston SW, Brazil C, Guzick D, Liu F, Overstreet JW, et al. One semen sample or 2? Insights from a study of fertile men. J Androl 2007;28:638–43. 38. Eskiocak S, Gozen AS, Kilic AS, Molla S. Association between mental stress and some antioxidant enzymes of seminal plasma. Indian J Med Res 2005;122:491–6. 39. Bonde JP, Ernst E, Jensen TK, Hjollund NH, Kolstad H, Henriksen TB, et al. Relation between semen quality and fertility: a population-based study of 430 first-pregnancy planners. Lancet 1998;352:1172–7. 40. Donath S. The validity of the 12-item General Health Questionnaire in Australia: a comparison between three scoring methods. Aust N Z J Psychiatry 2001;35:231–5. 41. Goldberg D, Williams P. A user’s guide to the General Health Questionnaire. Windsor: NFER-Nelson 1991. 42. Goldberg DP, Gater R, Sartorius N, Ustun TB, Piccinelli M, Gureje O, et al. The validity of two versions of the GHQ in the WHO study of mental illness in general health care. Psychol Med 1997;27:191–7.
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43. Banks MH. Validation of the General Health Questionnaire in a young community sample. Psychol Med 1983;13:349–53. 44. King JA, Rosal MC, Ma Y, Reed GW. Association of stress, hostility and plasma testosterone levels. Neuro Endocrinol Lett 2005;26:355–60. 45. Klimek M, Pabian W, Tomaszewska B, Kolodziejczyk J. Levels of plasma ACTH in men from infertile couples. Neuro Endocrinol Lett 2005;26:347–50. 46. Kreuz LE, Rose RM, Jennings JR. Suppression of plasma testosterone levels and psychological stress. A longitudinal study of young men in Officer Candidate School. Arch Gen Psychiatry 1972;26:479–82. 47. Rose RM, Kreuz LE, Holaday JW, Sulak KJ, Johnson CE. Diurnal variation of plasma testosterone and cortisol. J Endocrinol 1972;54:177–8. 48. Theorell T, Karasek RA, Eneroth P. Job strain variations in relation to plasma testosterone fluctuations in working men—a longitudinal study. J Intern Med 1990;227:31–6. 49. Cui KH. The effect of stress on semen reduction in the marmoset monkey (Callithrix jacchus). Hum Reprod 1996;11:568–73. 50. Hatch SL, Dohrenwend BP. Distribution of traumatic and other stressful life events by race/ethnicity, gender, SES and age: a review of the research. Am J Comm Psychol 2007;40:313–32. 51. Barry D, Petry N. Gender differences in associations between stressful life events and body mass index. Prev Med 2008;47:498–503. 52. Booker CL, Unger JB, Azen SP, Baezconde-Garbanati L, Lickel B, Johnson CA. A longitudinal analysis of stressful life events, smoking behaviors, and gender differences in a multicultural sample of adolescents. Subst Use Misuse 2008;43:1521–43. 53. Roberts ME, Fuemmeler BF, McClernon FJ, Beckham JC. Association between trauma exposure and smoking in a population-based sample of young adults. J Adolesc Health 2008;42:266–74.
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Objective: To examine the association between stressful life events and semen parameters. Design: Cross-sectional analysis in a pregnancy cohort study. Setting: Prenatal clinics in five U.S. cities. Patient(s): Fertile men (n ¼ 744) in the Study for Future Families, a cohort study of pregnant women and their partners. Intervention(s): None. Main Outcome Measure(s): Sperm concentration, percent motile, and percent normal morphology and classification above/below World Health Organization (WHO) cutoffs for semen quality. Result(s): After adjusting for confounders, men reporting 2þ recent stressful life events had an increased risk of being classified below WHO thresholds for ‘‘normal’’ defined by concentration, motility, and morphology criteria compared with men reporting <2 stressful life events (odds ratio [OR] ¼ 2.06; 95% confidence interval [CI], 1.18, 3.61; OR ¼ 1.54; 95% CI, 1.04, 2.29; OR ¼ 1.93; 95% CI, 1.02, 3.66 for concentration, motility and morphology, respectively). Men experiencing 2þ stressful life events had lower sperm concentration (log scale, b ¼ 0.25; 95% CI, 0.38, 0.11) and lower percent motile sperm (b ¼ 1.95; 95% CI, 3.98, 0.07), but percent normal morphology was less affected. Conclusion(s): These results suggest that stressful life events may be associated with decreased semen quality in fertile men. The experience of psychosocial stress may be a modifiable factor in the development of idiopathic infertility. (Fertil Steril 2010;93:1104–11. 2010 by American Society for Reproductive Medicine.) Key Words: Sperm concentration, sperm motility, sperm morphology, semen quality, psychosocial stress, life events
Approximately 10%–15% of U.S. couples experience infertility (at least 12 months of unprotected intercourse without pregnancy), while another 10% have fewer children than they desire (1). Male reproductive factors are thought to be the cause in about one-third of cases and a contributing factor Received September 30, 2008; revised December 5, 2008; accepted December 8, 2008; published online February 24, 2009. A.L.G. has nothing to disclose. F.L. has nothing to disclose. C.B. has nothing to disclose. E.Z.D. has nothing to disclose. D.G. has nothing to disclose. J.W.O. has nothing to disclose. J.B.R. has nothing to disclose. A.S. has nothing to disclose. C.W. has nothing to disclose. S.H.S. has nothing to disclose. This work was supported by the National Institute of Health grant nos. R01-ES09916 to the University of Missouri from the National Institute of Environmental Health Sciences (NIEHS); MO1-RR00400 to the University of Minnesota General Clinical Research Center; and MO1RR0425 to the Research and Education Institute at Harbor-UCLA Medical Center and the Cedars-Sinai Research Institute from the National Center for Research Resources. Reprint requests: Dr. Shanna H. Swan, University of Rochester School of Medicine and Dentistry, Department of Obstetrics and Gynecology, 601 Elmwood Avenue, Box 668, Rochester, New York 14642 (FAX: 585-276-2151; E-mail: [email protected]).
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in another 20% of cases (1, 2). Psychological stress has been implicated as a cause of idiopathic infertility in both men and women (3–8), with the majority of studies conducted among women. Numerous studies have investigated psychological causes of male factor infertility (6, 9–15), but because of the many potential confounders, it remains difficult to tease out stress as a cause or consequence of infertility. The majority of existing studies that examined this question used populations from assisted reproduction technology (ART) clinics or other nonrepresentative populations, making it difficult to differentiate between stress as a cause or a consequence of infertility. In addition, the availability of a wide range of different tools to assess stress and other psychological conditions makes comparison across studies difficult. Some studies examined the relationships between different types of stress and/or anxiety and semen quality (9, 12, 14, 16–21), while others have looked at semen quality in relation to psychosocial personality factors and stress coping styles (10, 13, 15, 22). Several studies reported an association between higher stress levels and decreased semen
Fertility and Sterility Vol. 93, No. 4, March 1, 2010 Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc.
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quality (6, 9, 13, 14, 16–23), although one study reported no association between stress and semen quality but did observe a decreased pregnancy rate in high-stress cycles (12). The high variability in semen parameters makes it difficult to obtain sufficient power in studies of semen quality. The aim of this study is to examine the association between one measure of psychological stress (number of stressful life events) and semen quality in a population-based sample of fertile men using strict quality-control methods. Our objectives were to [1] examine semen parameters in relation to a six-value measure (total life events) as well as to a dichotomized measure of (two or more vs. fewer) life events in the 3 months before semen collection and [2] the relation between these measures of life events and the risk of being classified below World Health Organization (WHO) thresholds for ‘‘normal’’ using three clinical criteria (24). MATERIALS AND METHODS Study Population Men in these analyses were participants in the Study for Future Families (SFF), a multicenter pregnancy cohort study. Methods for SFF have been described elsewhere (25). Briefly, women were recruited from September 1999 to December 2005 at prenatal clinics affiliated with university hospitals in five U.S. cities: Los Angeles, California (Harbor-UCLA Medical Center and Cedars-Sinai Medical Center); Minneapolis, Minnesota (University of Minnesota Health Center); Columbia, Missouri (University Physicians); New York, New York (Mt. Sinai School of Medicine); and Iowa City, Iowa (University of Iowa). Only pregnancies that were conceived without medical intervention were eligible. The male partner was recruited if the woman agreed, and all men were asked to give at least one semen sample, complete a brief questionnaire, and undergo a physical exam. In addition, a sample of men (about 15% of all participants) was recruited, even though they refused to give a semen sample to assess potential selection bias associated with semen collection.
movement, whether twitching or progressive. Motility was also analyzed using the WHO 1999 a, b, c, and d method with forward motile sperm classified as a þ b (24). Seminal smears were prepared at the clinical centers and shipped to the Andrology Coordinating Center at the University of California, Davis, for Papanicalou staining, analysis, and storage, where a single technician assessed sperm morphology using the strict morphology method, as recommended by WHO (24, 28). In addition to the primary measures of semen quality (sperm concentration, volume, percent morphologically normal sperm, and percent motile sperm), we analyzed the total count (sperm concentration volume, or TC). Institutional Review Board human subject committees at all participating institutions approved the SFF, and all subjects signed informed consents. None of the authors have declared a conflict of interest. Psychosocial Stress Assessment The men’s questionnaire asked about stressful life events in the 3 months before semen sample collection, the approximate length of the spermatogenic cycle, and final maturation (29). These life event questions were derived from two standardized questionnaires (30, 31) and assess the occurrence of five major life events, plus an open-ended question to capture other major life events. The selection of life events was based on principles outlined by Dohrenwend and colleagues (30, 32). Life events included in the questionnaire represent major psychological traumas known to adversely affect health outcomes (17, 30, 33). Participants were asked to indicate whether or not they had experienced any of the following stressful life events in the recent 3 months: job loss or unemployment (self or wife/partner); serious illness or injury (self or wife/partner); death of a close family member (i.e., parent, child, sibling); divorce, separation, or serious difficulties with wife/partner; legal, or financial problems (self or wife/partner); and other major life events (write-in option).
Semen Collection and Analysis Men were requested to observe a 2- to 5-day abstinence period before providing each semen sample, but the importance of accurately reporting the actual abstinence period was stressed. At the study visit, men collected semen samples by masturbation at the clinic, and these were analyzed, on average, within 27 minutes of collection (range, 10–105 minutes). Nine subjects were excluded because the analysis was started less than 10 minutes after sample collection.
Covariate Assessment Study participants completed questionnaires requesting information on sociodemographics, race, age, current and prior job information, cigarette smoking, alcohol use, illicit drug use, diet, and reproductive health history. Participants also underwent a physical examination including height and weight, blood pressure, and reproductive abnormalities as well as a blood draw on the day of semen collection.
Methods used for semen evaluation have been described elsewhere (26). Briefly, concentration assessments were evaluated by hemacytometer (Improved Neubauer; Hauser Scientific Inc., Horsham, PA). Ejaculate volumes were estimated by specimen weight, assuming a semen density of 1.0 g/mL. In this analysis the percent motile sperm was counted in a MicroCell chamber (Conception Technologies, San Diego, CA) (27) and refers to the percentage of sperm with any flagellar
Statistical Analyses The primary outcomes of interest in this study were sperm concentration, TC, percent motility, and percent normal morphology. Because sperm concentration, semen volume, and TC (but not percent normal morphology or percent motile) were skewed, we transformed these using the natural logarithm, as recommended (34). We also examined the risk of
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being classified below WHO thresholds (24) based on sperm concentration (<20 million/mL) and forward motility (<50% motile sperm of class a þ b). These criteria are based on forward motion, unlike the total percent motile sperm (any flagellar movement) used in the linear regression analyses. While WHO has no comparable cutoff for morphology, we used normal forms <4% by strict criteria as suggested by WHO laboratory standards and used in other studies of semen quality (35, 36). Exposure variables were [1] total number of stressful life events from 0 to 6; and [2] the categorical variable R2 stressful life events versus fewer. Covariates considered in the analysis were age, race, educational attainment, study center, cigarette use, alcohol use, illicit drug use, body mass index (BMI), self-rated health status, history of sexually transmitted disease (STD), genital infection, testicular conditions, recent fever, ejaculation abstinence time, and time to analysis (only for analysis of percent motility). Variables were entered into the model if they were shown to be associated with life events in bivariate analyses or have been associated with decreased semen quality in previous literature. We also evaluated the association between number of life events and the number of semen samples the man provided (0, 1, or 2) using the c2-test. We evaluated the bivariate relationships between potential confounders and life events using c2-tests for categorical variables and Student’s t-test for continuous variables. We then used multiple linear regression analyses to model the associations between stressful life events and each semen parameter. We also calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression to estimate the likelihood of classification below WHO thresholds by the number of life events while adjusting for potential confounders. For both the linear regression and logistic regression analyses, multiplicative interactions were assessed for stressful life events and race, education, and age by adding an interaction term to the final models for each semen param-
eter. Statistical analyses were performed using SAS, version 9.1 (SAS Institute, Inc., Cary, NC). RESULTS Of the total SFF population (N ¼ 950), 145 men did not provide a semen sample, 32 men had incomplete information for relevant covariates on the men’s questionnaire, and 29 men did not complete the stressful life event scale, with n ¼ 744 remaining for the current analysis. Mean sperm concentration was 80.3 106/mL and ranged from 2.8 to 420.5 106/mL (Table 1). The mean percent motile sperm and percent morphologically normal were 51% (range, 5%–78.0%) and 11% (range, 0.5%–26.0%), respectively. The distribution of life events according to sociodemographic and lifestyle characteristics is displayed in Table 2. Twenty-two percent (n ¼ 166) of participants reported two or more life events in the recent 3 months (Table 2). Nonwhite race, lower educational attainment, study center, younger age, cigarette use, BMI, and a history of STD were significantly associated with two or more stressful life events (P<.05). In contrast, recent fever and ejaculation abstinence time, alcohol use, illicit drug use, self-rated health status, history of genital infection, or testicular conditions (undescended testicles, varicocele, or hydrocele) did not vary significantly by number of stressful life events (P>.05). Most men (74%) provided two samples, while 10% provided only one sample, and 16% provided none. The mean numbers of life events for these three groups did not differ appreciably (0.80, 1.01, and 0.86 for two, one, and zero samples; P¼.38). A recent analysis of our population showed that semen parameters did not vary significantly by the number of samples provided (37). We examined life events both as a dichotomous variable (R2 vs. <2) and as a discrete variable (total events reported). In unadjusted analyses, the total number of stressful life events was significantly associated with decreased sperm
TABLE 1 Distribution of semen parameters: The Study for Future Families, 1999–2005. Semen parameter a
6
Concentration , 10 /mL TCb, 106 Total percent motility Strict percent normal morphology Specimen volume, g/mL Abstinence time, hoursc
Mean
SD
Median
Minimum
Maximum
80.3 304.4 50.7 10.7 3.9 82.1
59.9 251.2 11.9 5.1 1.7 38.5
67.7 243.0 52.0 10.5 3.7 73.5
2.8 4.2 5.0 0.5 0.5 9.3
420.5 2456.1 78.0 26.0 11.5 240.0
Note: n ¼ 744; SD ¼ standard deviation. a Hemocytometer. b TC ¼ concentration specimen volume. c Abstinence time truncated at a maximum of 240 hours. Gollenberg. Psychosocial stress and semen quality. Fertil Steril 2010.
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TABLE 2 Distribution of characteristics by number of recent stressful life events. The Study for Future Families, 1999-2005. No. of stressful life events, n (%) Characteristics Race White Nonwhite Educational attainment Less than college College graduate or higher Study center CA MN MO NY IA Mean age, y (SD) Cigarettes smoked/d 0 1–<10 10 or more Alcohol use in the last wk 0 drinks 1–3 drinks 4+ drinks Illicit drug use in the last wk No Yes Mean body mass index (SD) Self-rated health status Excellent Good Fair/poor Ever diagnosed with an STD No Yes Ever diagnosed with a genital infectiona No Yes Ever diagnosed with a testicular conditionb No Yes Recent fever No Yes Mean abstinence time, h (SD)
<2
2+
Total
P
434 (75.1) 144 (24.9)
107 (64.5) 59 (35.5)
541 (72.7) 203 (27.3)
.007
204 (35.3) 374 (64.7)
104 (62.7) 62 (37.4)
308 (41.4) 436 (58.6)
< .0001
128 (22.2) 159 (27.5) 139 (24.1) 34 (5.9) 118 (20.4) 31.9 (5.9)
54 (32.5) 36 (21.7) 46 (27.7) 3 (1.8) 27 (16.3) 30.5 (6.8)
182 (24.5) 195 (26.2) 185 (24.9) 37 (5.0) 145 (19.5) 31.6 (6.1)
.009
473 (82.3) 25 (4.4) 77 (13.4)
112 (67.9) 8 (4.9) 45 (27.3)
585 (79.1) 33 (4.5) 122 (16.5)
.0001
244 (42.2) 122 (21.1) 198 (36.8)
73 (44.0) 40 (24.1) 53 (31.9)
317 (42.6) 162 (21.8) 265 (35.6)
.5
524 (90.7) 54 (9.3) 28.2 (5.1)
145 (87.4) 21 (12.7) 29.3 (6.2)
669 (89.9) 75 (10.1) 28.4 (5.4)
.2
211 (36.5) 319 (55.2) 48 (8.3)
54 (32.5) 93 (56.0) 19 (11.5)
265 (35.6) 412 (55.4) 67 (9.0)
.4
518 (89.6) 60 (10.4)
134 (80.7) 32 (19.3)
652 (87.6) 92 (12.4)
.002
523 (90.5) 55 (9.5)
148 (89.2) 18 (10.8)
671 (90.2) 73 (9.8)
.6
535 (92.6) 43 (7.4)
152 (91.6) 14 (8.4)
687 (92.3) 57 (7.7)
.7
562 (97.2) 16 (2.8) 83.5 (39.4)
160 (96.4) 6 (3.6) 77.2 (34.8)
722 (97.0) 22 (3.0) 82.1 (38.5)
.6
.01
.02
.06
Note: n ¼ 744. P-values are derived from the c2-test for categorical variables and from the t-test for continuous variables comparing <2 life events and 2+ life events; STD ¼ sexually transmitted disease. a Genital infection includes epididymitis, orchitis, prostatitis, or cystitis. b Testicular conditions include undescended testicles, varicocele, or hydrocele. Gollenberg. Psychosocial stress and semen quality. Fertil Steril 2010.
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TABLE 3 Linear regression estimates and 95% CIs for stressful life events in relation to sperm concentration, TC, percent motile, and percent normal morphology: The Study for Future Families, 1999–2005. Semen parameter Log hemocytometer Log TC Percent motile sperm Percent normal morphology
Unadjusted: total life events, beta (95% CI)
Adjusted: total life events, beta (95% CI)
Unadjusted 2D vs. Adjusted: 2Dvs. <2 life events, beta <2 life events, beta (95% CI) (95% CI)
0.12 (0.17, 0.07) 0.10 (0.15, 0.05) 0.32 (0.45,0.18) 0.25 (0.38, 0.11) 0.16 (0.22, 0.11) 0.11 (0.17, 0.05) 0.43 (0.59, 0.28) 0.30 (0.45, 0.15) 0.60 (1.3, 0.16) 0.74 (1.5, 0.02) 1.8 (3.8, 0.29) 1.95 (3.98, 0.07) 0.03 (0.35, 0.29)
0.08 (0.42, 0.25)
0.44 (1.3, 0.43)
0.59 (1.48, 0.30)
Note: n ¼ 744. Estimates adjusted for center, age, age squared, race, education, recent fever, abstinence time, and abstinence time squared. Motility was also adjusted for time to analysis. TC ¼ (concentration volume). Concentration and TC were natural log transformed. Gollenberg. Psychosocial stress and semen quality. Fertil Steril 2010.
concentration and TC but not with percent motile sperm or percent normal forms (Table 3). Reporting two or more life events was also associated with a significant reduction in concentration and TC before adjustment. These associations remained significant in multivariable analyses, although associations were somewhat attenuated. For example, men experiencing two or more stressful life events had significantly lower sperm concentration (log scale, b ¼ 0.25; 95% CI 0.38, 0.11) and TC (log scale, b¼ 0.30; 95% CI, 0.45, 0.15) compared with men who reported less than two life events after adjusting for center, age, age squared, race, education, recent fever, ejaculation abstinence time, and ejaculation abstinence time squared. We
also observed an inverse association between 2þ life events and percent motile sperm after adjustment, although it was borderline statistically significant (P¼.06; Table 3). Furthermore, consistent with a threshold effect at 2þ stressful life events, the semen parameters of men reporting only one life event did not differ significantly from that of men reporting zero life events (P>.05 for all semen parameters). Next we examined the likelihood of classification below WHO normal thresholds (24) by the number of stressful life events (Table 4). In unadjusted analyses, an increased number of life events was significantly associated with an increased likelihood of classification below the WHO concentration cutoff. This association remained significant after adjustment
TABLE 4 ORs and 95% CIs for risk of classification below WHO thresholds for semen concentration, motility, and morphology: The Study for Future Families, 1999–2005. Semen parameter below WHO cutoffs
Unadjusted: total life events,a OR (95% CI)
Adjusted: total life events,a,b OR (95% CI)
Unadjusted 2D vs. <2 life events, OR (95% CI)
Adjusted: 2Dvs. <2 life events,b OR (95% CI)
Concentrationc Forward motilityd Normal morphologye
1.35 (1.11, 1.63) 1.03 (0.90, 1.18) 1.10 (0.88, 1.39)
1.30 (1.05, 1.60) 1.11 (0.95, 1.28) 1.19 (0.93, 1.53)
2.26 (1.33, 3.84) 1.27 (0.89, 1.83) 1.58 (0.87, 2.87)
2.06 (1.18, 3.61) 1.54 (1.04, 2.29) 1.93 (1.02, 3.66)
Note: n ¼ 744. a OR for 1-unit increase in no. of life events. b Estimates adjusted for center, age, age squared, race, education, recent fever, abstinence time, and abstinence time squared. Motility was also adjusted for time to analysis. c Hemacytometer concentration <20 million/mL. d Percent motile sperm <50%. e Kruger’s strict morphology <4% normal forms. Gollenberg. Psychosocial stress and semen quality. Fertil Steril 2010.
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for center, age, age squared, race, recent fever, education, abstinence time, and ejaculation abstinence time squared (2þ life events vs. <2; OR ¼ 2.06; 95% CI, 1.18, 3.61). In contrast, number of life events was not significantly associated with classification below motility and morphology cutoffs before adjustment. However, in multivariable analyses, men reporting two or more life events were also more likely to be classified below the WHO threshold for forward motility (OR ¼ 1.54; 95% CI, 1.04, 2.29) and strict morphology (OR ¼ 1.93; 95% CI, 1.02, 3.66). Moreover, men reporting only one life event did not differ in risk of classification below any WHO cutoff compared with men reporting zero life events (P¼.35 for concentration, P¼.55 for motility, and P¼.50 for morphology), which is consistent with the threshold effect observed for the semen parameters in continuous form. Finally, we did not observe statistically significant interactions between stressful life events and race, age, or education. DISCUSSION In this population-based study of fertile men, we observed decreased semen quality among men who reported recent stressful life events. Specifically, the experience of two or more life events was associated with decreased sperm concentration, TC, and percent motile sperm and an increased likelihood of classification below WHO thresholds for ‘‘normal’’ for concentration, motility, and morphology. These findings are consistent with previous studies conducted among varying populations that demonstrated that psychosocial stress, as measured by a wide range of assessment tools, including the Zung’s Anxiety Scale Inventory (21), State Anxiety Inventory (16), WHO Well-Being Index (21), physiologic stress symptoms (18), stressful life events (17, 18), the Infertility Distress Scale (14), the Coping Inventory for Stressful Situations (13), undergoing stressful examinations (38), and other methods (9, 19, 20, 23), is associated with decreased semen quality. To our knowledge, previous studies have not examined psychosocial stress in relation to WHO semen quality thresholds. Such results have important implications for men attempting to achieve pregnancy given that men with semen parameters below the WHO cutoffs have decreased odds of pregnancy compared with men with semen parameters above such cutoffs (24, 39). The majority of previous studies on this association were small, cross-sectional studies. Most found associations between various forms of psychosocial stress and semen quality, although one prospective study did not (12). Hjollund et al. prospectively assessed psychological distress using the General Health Questionnaire (GHQ) among over 400 couples planning to conceive (12). Although the study authors found no association between GHQ scores and semen quality, they did observe reduced fecundity in high-stress cycles. It should be noted that the GHQ measures a different construct than the stressful life event scale used in our study as it was originally developed to assess the severity of symptoms consistent with mental illness (40–42). Validation studies of the GHQ have most often compared GHQ scores with other scales for diagnosing mental illness, including the Fertility and Sterility
Composite International Diagnostic Interview and the Present State Examination (40, 42, 43), further underscoring the construct of the GHQ. While persons experiencing mental illness may also be under psychosocial stress, the physiological effect of mental illness alone on semen production may in fact be different than that of life event stress, and this may account, in part, for the conflicting findings. The association between psychosocial stress and decreased semen quality has biologic plausibility supported by numerous studies. Most hypothesized pathways by which stress may impact semen quality operate under endocrine factors. Men undergoing stressful situations are shown to have lower T and LH levels and an interference with spermatogenesis (44–48). Klimek et al. demonstrated that a rise in stress hormones, cortisol and adrenocorticotropic hormone (ACTH), can cause a disruption of the conversion of androstenedione into T in Leydig cells (45). This disruption results in the rise of the precursor androgen, androstenedione, a drop of the product T, and lower average values of semen volume, sperm concentration, and sperm cell motility (45). Eskiocak et al. has shown other stress-related changes in seminal plasma, specifically, a marked rise in nitric oxide and a decrease in arginase activity resulting in poorer semen quality under stress (16). Moreover, in animals, induced psychological stress negatively affects T and LH levels, sexual behavior, and semen parameters (1, 49). In a secondary analysis, we examined several hormonal measures (total T and two measures of free T), but none were related to the recalled stressful life events, perhaps because the events might not have been sufficiently proximal to blood sampling. We observed several associations between the number of stressful life events and demographic and lifestyle characteristics that generally agree with prior literature. The finding that nonwhite ethnicity, lower education, and younger age were associated with an increased number of life events is in accord with a recent review of life events in relation to sociodemographics (50). Similarly, in prior research, those experiencing stressful events are more likely to smoke and have higher BMI, consistent with our findings (51–53). The positive association between life events and STD diagnosis may suggest a group with a history of high-risk behaviors (i.e., unprotected intercourse), although we did not observe an association between alcohol intake and illicit drug use in the last week. In addition, there was a suggestion that the number of life events was associated with a shorter ejaculation abstinence time before semen collection (P¼.06). Our study has several limitations. While our method of stress assessment, stressful life events, has been associated with multiple health endpoints (17, 32), we cannot eliminate potential misclassification due to inaccurate reporting of life events or the differential perceived severity of life events. Other misclassification of exposure may occur as a result of measuring stress solely by reported major life events. While stressful life events are thought to exert a chronic effect on bodily functioning (32), acute stress associated with other daily hassles and lifestyle will not be detected using this 1109
life event scale. Moreover, we did not collect information on potential modifiers of stress such as social support or coping style, which could modify the effect of stress on semen quality. If these types of misclassification occurred, it would most likely be nondifferential and thus could lead to an underestimate of associations between stress and semen quality. This study has several strengths. First, since we recruited men with proven fertility, it is unlikely that these men were experiencing additional distress due to failed attempts at conceiving. Unlike the current study, previous studies were not able to distinguish stress as a cause of infertility or a consequence of infertility when ART clinic populations were used. In addition, it is unlikely that men would differentially report life events based on perceived differences in semen quality. We used extensive quality control techniques to ensure that semen parameters were measured accurately by highly qualified technicians (25). Finally, we examined a variety of factors that may be associated with both psychosocial stress and semen quality, including substance use (alcohol, cigarettes, and illicit drugs), although adjustment for these factors did not alter the findings and were not included in the final model. Results of this study have important implications for families attempting pregnancy. Stress as a result of life events may have an impact on semen quality and thus affect the likelihood of conceiving. Future studies should prospectively assess whether semen quality improves after the effect of the stress is mediated or removed. That is, future studies should seek to determine whether the negative effect of stress on semen quality is a temporary or persistent problem. Future studies should also prospectively evaluate different types of stress on the quality of semen and the likelihood of future conception. Finally, these results are based on a population of fertile men and may not be generalizable to all reproductive-age men, including those without demonstrated fertility. Acknowledgments: We acknowledge the Study for Future Families Research Group; the physicians, midwives, and staff of University Physicians Clinic, Columbia, Missouri; Fairview Riverside Women’s Clinic, Minneapolis, Minneapolis; Harbor-UCLA Medical Center, Torrance, California; Cedars-Sinai Medical Center, Los Angeles, California; and Mt. Sinai Medical Center, New York, New York; and the study participants.
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