Behavioral Ecology Advance Access originally published online on November 3, 2004
Behavioral Ecology 2005 16(2):410-416; doi:10.1093/beheco/ari004
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Does immunity regulate ejaculate quality and fertility in humans?
Department of Evolution and Ecology, IB, University of Tromsø, 9037 Tromsø, Norway
Address correspondence to P.A. Skau. E-mail: philip.skau{at}ib.uit.no.
Received 16 February 2004; revised 19 September 2004; accepted 28 September 2004.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The production of high-quality ejaculates may represent significant costs during male reproduction. Spermatozoa are perceived as nonself by the immune system and are exposed to immunological attacks in the male reproductive tract. Autoimmunity to spermatozoa results in the production of antisperm antibodies that reduce sperm quality and hence fertility. Thus, males are dependent on the testis being an immunoprivileged site to reduce immunological reactions against their own sperm, and immunoprivilege is obtained by the blood-testis barrier and by hormonal immunosuppression. A meta-analysis on the effects of immunosuppressive corticosteroid treatment of male infertility revealed that treatment reduced the level of antisperm antibodies, improved sperm motility and sperm count, and increased conception rate. These results emphasize the importance of immunosuppression and the associated pathogenicity from infectious organisms as important costs for the production of high-quality ejaculates.
Key words: antisperm antibodies, corticosteroid treatment, ejaculate quality, immunosuppression, male infertility, meta-analysis, parasite resistance, sperm.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The conventional view that the cost of producing sperm is trivial compared to that of producing eggs has recently been seriously challenged, and it is now clear that the production of high-quality ejaculates may represent significant costs of male reproduction (Dewsbury, 1982
; Folstad and Skarstein, 1997; Nakatsuru and Kramer, 1982; Olsson et al., 1997; Pitnick et al., 1995; Wedell et al., 2002). For example, sperm number in ejaculates is an important determinant of fertilization success (Bonde et al., 1998; Marconato and Shapiro, 1996; Pizzari et al., 2003; Warner et al., 1995; Wedell et al., 2002), and males generally show reduced sperm numbers in successive ejaculations (Freund, 1963; Levin et al., 1986), indicating that sperm production or sperm maturation may be limited, at least in some species (Marson et al., 1989; Synnot et al., 1981).
High costs to sperm production are in particular the case in species that experience sperm competition (Hosken and Ward, 2001; Møller, 1988, 1989; Møller and Briskie, 1995). In humans, the current frequency of sperm competition is uncertain. Yet, human males show traits indicative of a history of sperm competition. First, testes size and sperm numbers in ejaculates of humans are close to those expected from body mass compared to other primates (Harcourt et al., 1995). Second, the frequency of extrapair paternity is approximately 10% in humans, indicating at least some extent of polyandry (Birkhead, 1999). Third, there exists a gel component of high viscosity in late-ejaculate fractions of human males, which is otherwise only found in polygamous mammals. This gel may function as a copulatory plug and prevent sperms of competing males from reaching the egg (Dott and Glover, 1999). These findings suggest that sperm competition has been important in the evolution of human reproductive physiology.
Previously unrecognized costs to sperm production may come from concomitant immunosuppression. Immunosuppression is important because sperm cells express surface antigens that occur neither on somatic nor on premeiotic germ cells (Diekman and Goldberg, 1995). Developing germ cells possess foreign antigens because spermatogenesis begins at puberty, long after the immune system has acquired tolerance to self-antigens (Diekman and Goldberg, 1995; Turek, 1999). During contact with immunocompetent cells, antigens on sperm cells are recognized as foreign, and an autoimmune reaction may be initiated (Bronson, 1999; Shulman, 1995). Normally, the blood-testis barrier, which forms at puberty, prevents this reaction, that is, tight cell junctions that construct the barrier effectively isolate the germ cell compartment from lymphocytes, antibodies, and other blood-borne immune components (Johnson and Setchell, 1968; Turek, 1999). However, although tight cell junctions protect the autoantigenic germ cells behind this blood-testis barrier; there are autoantigens on the surface of germ cells just about to enter meiosis (Saari et al., 1996; Yule et al., 1988). Furthermore, lymphocytes and macrophages have been observed within the epithelial layer of the rete testes and epididymis (El-Demiry et al., 1985; Wang and Holstein, 1983). This indicates that the barrier does not completely protect the sperm against immune attack. Additional protection of sperm cells may come from down-regulation of cellular immunity (Turek et al., 1996). Such immune suppression may be caused by cytokines and other humoral mediators, for example, testosterone. Testosterone levels are inversely correlated with serum levels of antisperm antibodies (Kelly, 1995; Lehmann and Emmons, 1989), and testosterone may also induce T suppressor cells (Lehmann et al., 1988). Thus, local immunosuppression may prevent autoimmune reaction against germ cells.
Antisperm antibodies, which occur naturally from puberty (Flickinger et al., 1997), have since long been considered a factor of male infertility (Marshburn and Kutteh, 1994; Rumke and Hellinga, 1959). It is estimated that approximately 3–12% of all infertile men have antisperm antibodies in serum or semen (Turek, 1999). Yet, the incidence of antisperm antibodies is still subject to controversy (Zeyneloglu and Yarali, 2002). A heightened level of antisperm antibodies does not, however, necessarily imply infertility, only that the quality of the ejaculate is reduced (e.g., lower sperm count and motility). This condition of immunological subfertility may be due to a reduced ability to conduct immunosuppression (Folstad and Skarstein, 1997; Liljedal et al., 1999; Skau and Folstad, 2003).
The suppression of immune responses is costly, in particular for nonresistant individuals with high levels of somatic infections (Folstad and Karter, 1992; Folstad and Skarstein, 1997; Hillgarth et al., 1997). Consequently, the production of high-quality ejaculates involving immunosuppression is costly not only because it drains resources from other activities but also because it increases the pathology from infectious organisms. Folstad and Skarstein (1997) suggested that development of secondary sex traits by sex hormones might be an evolutionarily derived characteristic of the testicular immunosuppression conducted by sex hormones. As a consequence of such association, females could evaluate both the ejaculate qualities of a male and his resistance toward infectious organisms from his sex trait development. Males with high intensities of parasites should display an increased level of systemic immune activity and consequently have a heightened level of testicular immunity. Thus, high parasite intensities could result in a reduction of ejaculate quality and, in turn, reduced fertility (Folstad and Skarstein, 1997). Accordingly, antibiotic treatment of men with a heightened level of leukocytes in semen but without symptoms of urogenital infections results in improvement of ejaculate quality. This implies that a reduction in the level of pathogens may be necessary for allowing reduced immunological activity and thereby increased ejaculate quality (Skau and Folstad, 2003).
Drugs having an immunosuppressive effect, such as glucocorticosteroids, have been used in an attempt to reduce the antisperm antibody concentrations in both humans and other mammals (Bandopadhyay et al., 1994; Behre et al., 2000). Yet, there is no consensus to the effect of such treatment (Bronson, 1999). The purpose of this study was to examine the hypothesis that treatment with immunosuppressives will reduce the level of circulating antisperm antibodies and the presence of antisperm antibodies in the ejaculate. This will subsequently lead to an improved ejaculate quality and increased pregnancy rates. This hypothesis was addressed using a meta-analysis of studies conducted to examine the effect of corticosteroid treatment of males with heightened level of antisperm antibodies.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Locating studies
In order to identify clinical trials, we searched, at the end of 2003, the following databases: Cochrane Controlled Trials Register, MEDLINE, EMBASE, CINAHL, and Biological Abstracts. The following keywords were used in the search: "male infertility," "autoimmune infertility," "immunological infertility," "antisperm-antibodies," "sperm autoantibodies," and "antispermatozoal antibodies." Additionally, male infertility was used in combination with "steroid therapy" and "corticosteroid therapy." In order to reduce the risk of missing studies, a search in the Science Citation Index was performed using the names of the first authors of papers obtained from the other databases. Additionally, the reference list of all included articles, selected reviews, and books on male infertility was read systematically for citations of potentially eligible trials. Such a search should provide a near-complete coverage of published data on the subject. No attempt was made to locate unpublished studies. The most commonly used drugs in the treatment of antisperm antibody were prednisolone and prednisone, which are analogs of the natural corticosteroid cortisol and belong to the glucocorticoids (Butler and Rossen, 1973
). A total of 36 clinical studies of corticosteroid treatment of male infertility were identified. Four of the studies located were case studies (i.e., De Almeida and Soufir, 1977; Kremer et al., 1978; Shulman, 1976; Tsatsoulis and Shalet, 1991) and could therefore not be included in the meta-analysis.
Coding
To be included in the meta-analysis, each study had to report original data, a quantitative measure of effect size, or data that could be transformed into effect sizes. In addition to sample sizes and effect sizes, the following variables were coded for each study: (1) type and dosage of drugs used in the treatment, (2) duration of treatment, (3) method for diagnosing antisperm antibodies, (4) study design, (5) side effects, and (6) year of publication.
The best design to investigate a cause-effect relationship is a randomized and controlled experiment. This is not always feasible, and it should be pointed out that also quasi experiments may reveal useful information about the effect of a treatment (Cook and Campbell, 1979). Some authors have reported that studies with a small sample size and poor study design tend to exaggerate the overall estimate of treatment effects and thus lead to incorrect conclusions (Khan et al., 1996; Moher et al., 1998), while others have failed to find that including the so-called poor studies affect the overall estimate in a meta-analysis (e.g., Balk et al., 2002; Greenwald and Russell, 1991). It may also be difficult to find exact criteria for excluding studies in a meta-analysis as the judgment of methodological quality is to some extent subjective (Greenwald and Russell, 1991). Because the total number of available studies is rather low on the present topic, no attempt was made to exclude studies because of poor methodological quality.
Sperm count is the total number of spermatozoa per ejaculate and is classified as normal at more than 40 million sperms per ejaculate. A semen sample has normal motility if more than 50% of the spermatozoa show forward progression (WHO, 1999). The evaluation of sperm motility is often subjective, and various methods are in use (WHO, 1999). Consequently, more variation is also expected between studies for this semen parameter. Moreover, a wide range of assays is available to detect and quantify antisperm antibodies, but there is no method that has achieved universal acceptance. Ideally, a testing methodology should be able to detect the presence, localization, and isotype of the antisperm antibody (IgG, IgA) with high sensitivity and specificity. Commonly used methods include the mixed agglutination reaction test, which detects sperm-surface–bound antisperm antibodies; the tray agglutination test, which detects antisperm antibodies in serum or semen; and flow cytometry, in which immunolabeled spermatozoa are evaluated and sorted. Heterogeneity is consequently expected for the levels of antisperm antibodies between studies.
Meta-analysis calculations
The meta-analysis calculations on pregnancy rates were performed using the program METADOS (Martinussen and Fjukstad, 1997), which is based on the Hunter and Schmidt (1990) method. The method was used because it can be applied to proportions, like the proportion of successful pregnancies, not only to correlations or effect sizes. The meta-analysis calculations of sperm and immunological parameters were performed using the computer program "Comprehensive meta-analysis" (Borenstein and Rothstein, 1999), using effect sizes calculated based on data from the primary studies. In studies using a control group, the effect size was calculated as the standardized difference between means using a pooled standard deviation. Correspondingly, in studies using a pretest-posttest design, the standardized difference between the pretest and posttest means was calculated.
An important component of meta-analysis is the investigation of the consistency of treatment effects across studies (Lipsey and Wilson, 2001). Because the trials have been conducted according to different protocols, there will necessarily be variations in patient groups, clinical settings, concomitant care, and methods for administering the interventions. An important issue that may be addressed by meta-analysis is whether sampling error or other artifacts actually explain all the observed variance between effect sizes or whether true moderators are present. If the results of the studies differ greatly, it may not be appropriate to combine the results into one overall measure of effect. One approach is to statistically examine the degree of similarity between the studies' outcomes, that is, to test for heterogeneity across studies. Such tests examine whether the results of a study reflect a single underlying effect rather than a distribution of effects. Statistically significant heterogeneity may be caused by methodological variation between trials, for example, study designs, method of randomization, and methods of measuring sperm quality or quantity. If the test shows homogenous results, then the differences between studies are assumed to be a result of sampling error alone. The heterogeneity test provides information about the dispersion of individual study outcomes vis-à-vis the combined effect. It is calculated by using the squared distance of each study from the combined effect and weights each value, assigning a greater weight to more precise studies (Borenstein and Rothstein, 1999). However, the possibilities for studying variation between studies are limited by the number of studies available. Heterogeneity tests were calculated for the parameters sperm motility, sperm count, total reduction of antisperm antibodies and reduction in IgG and IgA in ejaculate, total reduction of antisperm antibodies and reduction in IgG in serum.
Hunter and Schmidt (1990) have suggested use of the 75% rule when using their method: if 75% or more of the observed variance can be accounted for by sampling error or other artifacts, then the rest can be ascribed to reporting or transcription errors. Possible moderators in this meta-analysis were (1) year of publication; (2) the difference in effect size between patients treated with low-dose (
20 mg), medium-dose (21–96 mg), and high-dose (
96 mg) medication; and (3) duration of treatment, which was divided into two categories: short-term (6 months) and long-term (6–9 months) treatments.
The "file-drawer problem" is one aspect of publication bias (Rosenthal, 1979). There are findings suggesting that the set of available studies does not reflect the total set of studies ever conducted because some reports are not published due to the lack of statistically significant results (Begg and Berlin, 1988; Møller and Jennions, 2001; Rosenthal, 1991). Publication bias clearly is a major threat to the validity of meta-analysis, and including data from unpublished trials may help solve the problem. However, inclusion of data from unpublished studies can itself introduce a bias (Sterne et al., 2000). There are no objective criteria on how unpublished studies should be located, for example, the use of scientific databases, and the trials that can be located may in itself be an unrepresentative sample of all unpublished studies. One approach to the problem of publication bias is to determine the number of additional studies with an effect size of zero needed to reduce the mean effect size to a specified level. The specified level used here is an effect size of 0.10, which is considered as a small effect according to Cohen (1988). This procedure was conducted using the equation provided by Orwin (1983).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Identified trials
A total of 32 clinical studies were included in this meta-analysis. The studies were published between 1970 and 1998 in 14 different journals, and they had been conducted in 13 different countries. In all studies, the patients had a history of minimum 1 year of diagnosed immunological infertility with the presence of heightened levels of antisperm antibodies in semen, serum, or both. Of the studies, 27 reported pregnancy as an outcome variable. Moreover, 14 of these studies had a design that included a control group, while 13 had no control group but used a pre-post design instead. The majority of studies used the mixed agglutination reaction test alone or in combination with the tray agglutination test. Only two studies used flow cytometry, which is considered to be the most appropriate method in the analysis of antisperm antibodies (Haas and Cunningham, 1984
). The rest of the studies used different immunological or agglutination tests. Information about observed side effects of the treatment was not systematically reported.
Effect of treatment and moderator variables
The analysis revealed a positive effect of corticosteroid treatment on the pregnancy rate (Table 1). In the groups treated with corticosteroids, the treatment resulted in an average pregnancy rate of 32%. In the control groups, the average pregnancy rate was 17%. The mean effect size for studies with a control group was the same as that for the studies without any control group (32%, n = 445 and 415, respectively), indicating that study design did not have an effect on the overall effect size. Moreover, the percentage of explained variance for pregnancy rate did not reach 75 for either the treatment or control group, which indicates that moderators are present. The percentage of variance accounted for in the treatment group did reach 42, and for the control group, it reached only 32, which is generally considered as rather low (Hunter and Schmidt, 1990).
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The first moderator examined was the possible effect of the year of publication. There was no correlation between the year of publication and proportions of pregnancy rate (r = .003, n = 27). Due to limited number of studies available in the present study, the examination of other moderators was not possible. Other possible moderators would have been treatment dosage and duration of treatment. The treatment also resulted in a significant reduction in seminal and plasma levels of both IgA and IgG antisperm antibodies. It was also a positive effect for the sperm parameters: sperm count and sperm motility (Table 2). The only parameter that showed a statistically significant heterogeneity between effect sizes was sperm motility (p = .041, df = 12). This may be caused by differences in methods used for assessment, but as the number of studies available in our meta-analysis is limited, it was not possible to test this hypothesis.
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Fail-safe number
The fail-safe number for the different parameters ranged from 17 to 62 (see Table 2). No firm guidelines could be given as to what constitutes an unlikely number of unretrieved and unpublished studies, but a robust result has been suggested to be five times the number of studies included in an analysis plus 10 (Rosenthal, 1991
: 106). Consequently, none of the present results had a fail-safe number higher than that suggested by this rule of thumb. Yet, because corticosteroid treatment of infertility has been a controversial issue and studies reporting no treatment effect are published, the problem of publication bias may therefore be of less importance for our meta-analysis. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Treatment of male infertility with corticosteroids resulted in a reduced level of plasma and seminal antisperm antibodies, an improved sperm count and sperm motility, and an increased pregnancy rate.
The purpose of the use of corticosteroids in the treatment of male infertility is to induce an immunosuppressive effect and thereby reduce the level of antisperm antibodies (Behre et al., 2000; Kamischke and Nieschlag, 1999). Accordingly, the level of antisperm antibodies IgA and IgG, both in the serum and in the ejaculate, was significantly reduced after steroid treatment, and, as expected, the effect on serum antibodies was among the strongest after treatment. The blood-testis barrier separates two distinct anatomical compartments (Yule et al., 1988): the soma outside the blood-testis barrier, which is accessible to circulating immune cells and their humoral products, and the soma inside, where the antigenic spermatozoa to some extent are sheltered from circulating immune cells (Weienbauer et al., 2000). However, autoantigenic germ cells migrate through the blood-testis barrier, and are, in the outside soma, are constantly exposed to circulating immune cells producing antisperm antibodies (Saari et al., 1996; Tung et al., 1987; Yule et al., 1988). Consequently, the concentration of antisperm antibodies in blood is also found to be higher than that in seminal plasma (Shulman, 1995). Circulating antisperm antibodies can gain access to the male genital tract through the seminiferous tubules, epididymis, or prostate (Turek, 1999) and have been shown to diffuse passively into the genital tract. Thus, antisperm antibodies in seminal plasma consist of antibodies from the circulation, but there are also locally produced antibodies (Shulman, 1995). Behind the blood-testis barrier, antisperm antibodies may reduce sperm quality (e.g., Matson et al., 1988; Mazumdar and Levine, 1998; Zeyneloglu and Yarali, 2002), but which antisperm antibodies are responsible for the reduced fertility remain unclear (Behre et al., 2000; Shulman, 1995). Recent studies suggest that sperm-bound IgA are considered to be of particular clinical relevance. Sperm-bound IgA are associated with poor cervical mucus penetration (Clarke, 1988), and conception rates after vasovasostomy are significantly reduced with the presence of IgA but not with the presence of IgG. However, presence of IgG class antibodies in the ejaculate is also associated with reduced fertility as there is a negative correlation between IgG levels on the tail of the spermatozoa and cervical mucus penetration (Zeyneloglu and Yarali, 2002). Consequently, levels of both IgG and IgA behind the blood-testis barrier may be of importance for sperm quality (Bronson, 1999).
Corticosteroid treatment resulted in a significant improvement of sperm motility, which is considered to be an important factor in male fertility (Drobnis and Overstreet, 1992; WHO, 1999; for an alternative view, see BenChetrit et al., 1995, and Bonde et al., 1998). Antisperm antibodies present in semen may bind to the surface of spermatozoa (Bronson, 1999), and such binding is shown to considerably reduce sperm motility (Barratt et al., 1990; Purvis and Christiansen, 1995; Turek and Lipshultz, 1994). A heightened level of antisperm antibodies may also lead to sperm agglutination, which may impair motility (McLachlan, 2002; Parslow et al., 1985). In mice, it is shown that subordinate individuals produce sperm cells with lower motility compared to dominant individuals (Koyama and Kamimura, 1999), which may be caused by low levels of androgens in subordinate mice (Bronson and Desjardins, 1971; Gandelman, 1980). Immunosuppressive androgens could influence the level of antisperm antibodies in semen in a similar way as glucocorticoids, and reduced levels of antisperm antibodies and improved motility may be a consequence of increasing these hormonal levels.
Treatment with corticosteroids led to an increased sperm count. The numbers of sperms surviving during the passage through the female tract appear to be related to sperm numbers in the ejaculate (Gomendio et al., 1998), and sperm concentration in ejaculates is also strongly associated with the probability of pregnancy (Bonde et al., 1998). Macrophages are known to scavenge sperm cells (Hughes et al., 1981). Thus, as glucocorticoids reduce production, density, and activity of macrophages (Fauci et al., 1976), treatment may have caused a reduction in the rate of sperm cells scavenged by macrophages, and, in turn, higher sperm cell numbers.
The group treated with corticosteroids had a significant higher pregnancy rate compared to the control group. This is unlikely to result from an increased sexual activity among treated men as corticosteroid levels rather are associated with reduced sexual performance (Ückert et al., 2003). Whether this, in turn, has increased the risk of extrapair copulations among females is uncertain. Yet, it seems unlikely that this chain of hypothetical events should increase the pregnancy rate from 17% to 32%. The increased pregnancy rate in the treated group is, however, in accordance with the finding that presence of antisperm antibodies in seminal plasma and in circulation is associated with reduced fertility (Ayvaliotis et al., 1985; Bates, 1997; Eggert-Kruse et al., 1991; Lucas et al., 1998; Mazumdar and Levin, 1998). However, a previous meta-analysis examining the effect of corticosteroids on the treatment of antisperm antibodies reported no significant effect on pregnancy rates (Kamischke and Nieschlag, 1999). The analysis was based on only five clinical studies with a total of 190 patients, which is a considerably smaller sample compared to our 27 studies and 867 patients. Thus, our results are both more reliable and also in line with the recent theoretical developments.
We believe that there is a causal sequence from immunosuppression to increased ejaculate quality to higher conception probability. The possibility for unconstrained immunosuppression during spermatogenesis will, however, be decreased by infectious organisms, which thus can interfere with ejaculate quality. In accordance with this, parasite intensities are negatively related to qualities of the ejaculate in nonhuman animals (Liljedal et al., 1999; Masvaer et al., 2004; Meagher and Dudek, 2002). Additionally, antibiotic treatment of leukocytospermic men, without genital tract infections, increases ejaculate quality (Skau and Folstad, 2003). Males with genetic resistance against infectious organisms will have a higher potential for elevated levels of immunosuppressive hormones compared to nonresistant males (Folstad and Skarstein, 1997). Therefore, males resistant toward infectious organisms may be at an advantage during spermatogenesis and consequently have high-quality ejaculates (Skau and Folstad, 2003). This logic, suggesting that infectious organisms may impose costs on sperm production, has implications both for sperm competition theory and for the current understanding of the evolution of sexually selected characters under androgen control (Folstad and Skarstein, 1997). Females may thus obtain heritable parasite resistance for their offspring by exploiting a male trade-off, evolutionarily rooted in male need for germ line control. Theories of sperm competition and the evolution of secondary sexual characters may thus have a common denominator in a male trade-off between immune activity and ejaculate quality.
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ACKNOWLEDGEMENTS |
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We thank Bård-Jørgen Bårdsen, Henning Ø. Klausen, Monica Martinussen, Birgit Rautenberg, Geir Rudolfsen, and two anonymous referees for helpful comments on the manuscript.
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