Felice Francavilla1 and Arcangelo Barbonetti2
(1)
Department of Life, Health and Environmental Sciences, University of L’Aquila, Coppito, 67100 L’Aquila, Italy
(2)
San Raffaele Sulmona Institute, Viale dell’Agricoltura, Sulmona, 67039, Italy
Felice Francavilla (Corresponding author)
Email: felice.francavilla@cc.univaq.it
Arcangelo Barbonetti
Email: arcangelobarbonetti@virgilio.it
Abstract
Naturally occurring antisperm-antibodies (ASA) exert an impairment to fertility, which is related to the extent of sperm autoimmunization. It determinates the degree of the interfering effect on sperm penetration through the cervical mucus independently from the antigenic specificity of ASA. Therefore, sperm-autoimmunization relevant to infertility can be diagnosed in the presence of a high proportion of ASA-covered spermatozoa, associated with a poor result of a carefully performed postcoital test. Whether or to what extent an ASA-interfering effect occurs, in each individual patient, downstream from the impairment of cervical mucus penetration, is still hard to establish. The main reason is the inability of current diagnostic tests to determine the antigenic specificity of ASA and to quantify the antibody density on the sperm surface, which are main determinants of ASA-impairment at the level of sperm/oocyte interaction. In any case, from a clinical point of view, to establish whether, or to what extent, this ASA-interfering effect occurs, in each individual patient, is not needed to diagnose ASA-related subfertility, because such impairment cannot occur in the absence of the interference at the level of mucus penetration. But, it would be relevant in choosing the more appropriate assisted reproductive treatment option.
12.1 Introduction: Does Antisperm-Antibodies-Related Infertility Really Exist?
An etiological link between naturally occurring antisperm-antibodies (ASA) and male infertility has been claimed since Rumke [45] and Wilson [53] reported the presence of serum sperm-agglutinating activity in some infertile men in 1954. However, although the clinical significance of ASA has been extensively investigated, it is still a debated matter. On one hand, the previous assertions that any link between sperm antibody presence and impaired conception has to be considered hypothetical [49] and the routine use of current ASA testing is not justified as an essential procedure in the fertility work-up [28] were more recently reasserted in a cohort study where no independent association was observed between the occurrence of ASA and reduced pregnancy rates in subfertile couples [32]. On the other hand, intracytoplasmatic sperm injection (ICSI) has been claimed as the primary choice of treatment in the presence of sperm autoimmunization [33], and a screening test for ASA has been reconfirmed as integral part of semen analysis in the last edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen [56].
Different approaches used for the recognition of the ASA-related infertility, paucity of prospective studies on the occurrence of spontaneous pregnancies, and lack of well-designed and controlled studies on treatments effectiveness have strongly contributed to generate confusion on the clinical significance of ASA.
This chapter critically reviews current understanding of the clinical relevance of naturally occurring ASA in men.
12.2 Prevalence of Antisperm Antibodies
A variable prevalence of ASA has been reported depending on the specificity and sensitivity of the test used for their detection and on the screened population. The first assays to be utilized were indirect tests detecting biological activities of ASA in serum and seminal plasma, i.e., sperm agglutination techniques and complement-dependent sperm immobilization/cytotoxicity techniques. Subsequently, widespread acceptance has been gained for antiglobulins-based tests used to detect antibodies coated to the surface of ejaculated spermatozoa, including the mixed antiglobulin reaction (MAR) test and the immunobead binding test (IBT). They reveal the percentage of antibody-coated spermatozoa, the Ig-isotype, and grossly the regional specificity of ASA. Old multicentric comparative studies [7, 54] showed that all these tests determine in large measure the same antibody specificities for surface antigens, but with different sensitivity, which is lower for complement-dependent sperm-immobilization/cytotoxicity techniques.
In epidemiologic studies, serum sperm-agglutinating activity ranged from 8.1 to 30.3 % in unselected men with infertile marriages [13, 21, 26, 40], but at low titers it was also reported up to 10 % of control sera [26]. When stricter criteria were used (i.e., the occurrence of sperm-immobilizing activity in addition to high titers of sperm-agglutinating activity in the serum and/or sperm-agglutinating activity in seminal plasma, indicating an excess of free antibodies in the semen), the prevalence of ASA in men with infertile marriages ranged from 4.6 to 5.7 % [21, 38]. Direct tests (MAR or IBT) gave positive results (>10 or >20 %) in 7.6–12.9 % of unselected infertile patients [11, 21, 38, 47], but highly positive results (≥50 %) were restricted to 5–6 % of patients [11, 21, 47]. In the most recent and largest multicentric survey, including 1794 consecutive subfertile couples, a positive IgG-MAR ≥10 % was detected in 7 % of men and a positive IgG-MAR ≥50 % was detected in 3 % of men [32].
Although a higher prevalence of ASA has been reported in some clinical conditions, including genital tract obstructions and infections, especially by Chlamydia trachomatis, testicular trauma, torsion, and surgery (see Chap. 8), only acquired genital tract obstructions represent a well-established risk factor: in vasectomized men the prevalence of ASA ranges from 33 to 74 % [5, 19, 29, 37], with their persistence in 38–60 % following successful vasovasostomy [5, 37].
12.3 Prognostic Studies
A causal link between ASA and fertility impairment, although suggested by epidemiologic studies, can only be proven by the association of the occurrence and the degree of sperm autoimmunization with a reduced pregnancy rate, independently from semen parameters and other clinical characteristics.
In retrospective studies, when the degree of sperm-autoimmunization was taken into account, it exhibited a significant inverse correlation with the incidence of spontaneous pregnancies. In an old report by Rumke et al. [46], during a 10-year follow-up of 254 infertile men with serum sperm-agglutinating activity (SAA), the titer of SAA was inversely correlated with the occurrence of spontaneous pregnancies. Notably, restricting the analysis to normozoospermic men, no pregnancy was observed with very high titer of serum SAA (≥1:1024), a low (15.8 %) pregnancy rate (PR) with titers ranging from 1:32 to 1:512, and a high PR (48.4 %) with titers <1:32. Ayvaliotis et al. [4] reported that in 108 infertile couples where the male exhibited a direct IBT >10 %, and the female was treated for other factors leading to impaired reproduction, PR was significantly higher when IBT was <50 % than when it was >50 % (43.4 % vs. 21.8 %) during a follow-up of at least 18 months. The difference in PR was ever of greater significance in a subgroup of 35 couples, where no other cause of infertility was found (15.3 % vs. 66.7 %). Abshagen et al. [1] reported that in 157 infertile couples with a direct IBT >10 %, cumulative spontaneous PR over 6 years was high (~50 %) when IBT was <50 %, lower (~30 %) when IBT was 50–90 %, and very low (~15 %) when IBT was >90 %, independently from the IgG-class (IgG and/or IgA). A significant inverse correlation between the degree of sperm autoimmunization and PR was also found in a follow-up study of 216 men after vasovasostomy by Meinertz et al. [39]. While no pregnancy was observed in a median period of ~4 years in men where all spermatozoa were antibody-coated at MAR test, in association with a high titer of serum SAA, pregnancy occurred in 64.3 % of couples with a less degree of sperm-autoimmunization. While in this study only a prevalent IgA autoimmunization was associated to a reduced fertility, a major role of IgA was not found in another study on vasovasostomized men by Matson et al. [37].
Altogether, these observations suggest that ASA represent a relative, rather than absolute, cause of infertility and the degree of fertility impairment appears to be related to the extent of sperm-autoimmunization. Accordingly, a threshold of 50 % positivity at MAR or IBT test has been established by WHO [56] for a degree of sperm-autoimmunization which might be clinically relevant.
However, the best evidence for a causal link between ASA and fertility impairment would be provided by prospective studies comparing the occurrence of natural pregnancies in men with and without ASA. Unfortunately this evidence is difficult to obtain: (1) the low incidence of sperm autoimmunization in unselected infertile couples requires multicentric studies including a large number of infertile couples (or, for the best evidence, couples without history of infertility) and a large number of observed cycles; (2) the inter-individual variability of semen parameters, not related to the presence of ASA, makes it very difficult to obtain a study- and a control-population, homogeneous for semen quality; and (3) the inter-couples variability in other clinical characteristics. Owing to these limitations, little information along with conflicting results has been produced by scanty prospective studies so far reported [13, 18, 55]. In the most recent and largest study [32], a positive IgG-MAR test ≥50 %, detected in 3 % of 1794 patients with infertile marriages, reduced, albeit not significantly, the probability of pregnancies during a 1-year follow-up. At the multivariate analysis, including semen parameters and other clinical characteristics, a positive MAR test ≥50 % did not contribute to the prediction of spontaneous pregnancy.
Therefore, the proof of a causal link between ASA and infertility has not yet been produced by the evidence-based medicine.
12.4 Mechanisms of Fertility Impairment by Antisperm-Antibodies: Clinical Relevance
Only ASA directed towards surface antigens have a physiopathological and clinical significance in the male immunological infertility, because subsuperficial antigens cannot be exposed to antibodies by living cells along the male genital tract.
12.4.1 Effect on Semen Quality
Sperm agglutination is the only well established semen alteration related to the presence of ASA [24]. However, sperm agglutination, which is a time-dependent phenomenon, only rarely involves a large proportion of motile spermatozoa soon after liquefaction, even when all ejaculated spermatozoa are antibody-coated. Therefore, sperm agglutination, although extremely suggestive of sperm-autoimmunization, does not represent either a sensitive marker of autoimmunization or an important mechanism of the antibody-interference with fertility in most cases. Apart from sperm-agglutination, there is little evidence that suggests a cause/effect relationship between ASA and abnormality of semen parameters [24]. Actually, an effect on sperm motility/vitality should involve a complement (C)-mediated sperm injury, but it is prevented by anticomplementary activity in human seminal plasma [15, 42].
12.4.2 Interference with Cervical Mucus Penetration
The impairment of sperm penetration through the cervical mucus represents the primary, well-documented mechanism of the ASA interference with fertility. Several studies have shown a significant association between a poor postcoital test (PCT) outcome and sperm autoimmunization [6, 25, 35]. Interestingly, in the above mentioned study by Leushuis et al. [32], although the evidence for an independent association between sperm-autoimmunization and reduced pregnancy rate was not provided, a negative PCT result was significantly associated with a positive MAR test result (relative risk 2.5, 95 % CI 1.4–4.3). The degree of the impairment of sperm penetration “in vivo” through the cervical mucus was found to correlate with the proportion of antibody-covered spermatozoa [6], as well as with the titer of circulating ASA [35]. The demonstration of the actual responsibility of ASA in impairing cervical mucus penetration was provided by matching donor sperm suspensions exposed to sera containing ASA against the same sperm suspensions exposed to control sera without ASA, using the in vitro cervical mucus penetration test [3]. Although a prominent role for IgA-ASA in impairing sperm penetration of cervical mucus was reported [10, 30, 52], other findings indicate that an abnormal interaction between the Fc portion of both IgA and IgG bound to the sperm surface and constituents of the cervical mucus is responsible for the impairment of mucus penetration and the shaking pattern of sperm motility observed in “in vitro” sperm-cervical mucus contact test (SCMC) [8]. Antibodies directed against the tail-tip do not impair sperm/cervical mucus interaction [52], and therefore have no role in infertility.
12.4.3 Complement-Mediated Cytotoxicity Through the Female Genital Tract
When spermatozoa coated with complement-fixing antibodies enter the female reproductive tract, they could undergo deleterious effects of complement activation, supposing that complement components are present in a sufficient amount through the female genital tract. In an old study by Price and Boettcher [43], although the level of complement activity in cervical mucus was only 11.5 % of the serum activity, this amount of complement was enough to cause complement-dependent immobilization of 50 % of ASA-coated spermatozoa in 1 h. Higher levels of complement activity were detected in human follicular fluid (one half of that in serum), and IgG-ASA were able to activate follicular fluid complement on human spermatozoa [16]. Due to the dilution of follicular fluid after ovulation, any sperm damage or dysfunction related “in vivo” to its complement activity is difficult to ascertain. Therefore, its clinical relevance is not proven.
12.4.4 Interference with Sperm/Egg Interaction
Although experimental “in vitro” studies have largely demonstrated that ASA can affect sperm functions involved in the sperm/egg interaction (see Chap. 3), the clinical relevance of these effects might be proven above all by the results of in vitro fertilization (IVF) as a model of study. In most reports, the overall fertilization rate was significantly lower in the presence of sperm-bound antibodies than in the case of other indications for IVF [2, 9, 12, 20, 36, 44, 50]. But, in some other reports no significant difference was found [14, 34, 48, 51]. In a meta-analysis by Zini et al. [57], including 10 studies (8 prospective and 2 retrospective), the presence of sperm-bound antibodies (with ASA cut-off value at direct tests ranging from 10 to 80 % as inclusion criterion) was not related to pregnancy rates after IVF: the combined OR for failure to achieve a pregnancy using IVF in the presence of ASA was 1.22 (95 % CI: 0.84, 1.77). However, the assessment of the actual interference of ASA on sperm fertilizing ability from the analysis of IFV results is hindered by the effect of concomitant nonimmunological sperm abnormalities and by the different degrees of sperm autoimmunization. Nevertheless, when the extent of sperm autoimmunization was taken into account, it was inversely correlated with the overall fertilization rate [17, 31, 41]. But, notably: (1) even when the percentage of fertilized oocytes was reduced in the presence of ASA, some oocytes were fertilized; (2) in some individual patients, a high fertilization rate was achieved even in the presence of a high extent of sperm autoimmunization.
This variable interfering effect emerging from the analysis of IVF results is also supported by experimental laboratory-based studies aimed to determine the level of the interference of ASA on sperm functions involved in gametes interaction [24]; see also Chap. 3]. Particularly illustrative is a study from our group where the occurrence of the ASA-interference with zona pellucida (ZP)-binding was tested in 22 patients exhibiting all ejaculated spermatozoa coated “in vivo” with antibodies against the sperm head [23]. Excluding patients with abnormal semen from the analysis, an impairment of the ZP-binding was observed in 50 % of cases, by matching patients and donor spermatozoa, labeled with different fluorochromes, for their binding ability to the same ZPs. It is worth noting that: (1) in no case the inhibition of ZP-binding was complete; and (2) a normal ZP-binding was observed even when all ejaculated spermatozoa were coated with both IgG- and IgA-ASA.
On the whole, human IVF results and experimental laboratory-based studies suggest that, at the level of the sperm/egg interaction, ASA exert a relative impairment, which, to some extent, is related to the degree of sperm autoimmunization. However, the degree of autoimmunization does not completely explain the variability of the antibody impairment. Apparently, at the level of gamete interaction, more than at other levels (i.e., cervical mucus penetration), the interference of ASA exhibits qualitative, apart from quantitative, differences among patients. Most likely, this interference also depends on the relevance of the specific antigens, targeted by natural ASA, to the fertilization process.
12.5 Clinical Implications
Given that the only ASA-related semen alteration is sperm-agglutination, which, however, is not a sensitive indicator, a direct screening test (MAR or IBT) should be performed on all semen samples examined in the couple-infertility work-up. As IgA-antibodies, whenever they occur, are always found in association with IgG [22, 27, 38], only IgG-ASA have to be screened. In all positive samples for IgG, even at a low degree, IgA-ASA should be screened, to determine whether and at what extent they are also bound to the sperm surface.
If ASA-direct tests are negative or with a low positive rating (<50 %), an ASA-related subfertility may be excluded. On the other hand, when ≥50 % of motile spermatozoa are coated by ASA, an immunological male subfertility can be diagnosed in the case of a poor PCT outcome, especially when a shaking pattern of sperm motility is observed in an in vitro sperm-cervical mucus contact test (SCMC).
Whether, or to what extent, an ASA-interfering effect occurs, in each individual patient, downstream from the impairment of cervical mucus penetration, when all or nearly all spermatozoa are antibody-coated, is still hard to establish. The main reason is the inability of current diagnostic tests in quantifying the antibody density on the sperm surface and in defining the antigenic specificities of ASA, main determinants of the ASA-impairment at level of sperm/oocyte interaction, which, however, seems to be less effective and certain than that at level of cervical mucus penetration.
In any case, from a clinical point of view, to establish whether, or to what extent, an ASA-interfering effect occurs, in each individual patient, downstream from the impairment of cervical mucus penetration is not needed to diagnose ASA-related subfertility, because such an impairment cannot occur in the absence of the more effective interference on mucus penetration. But, it would be relevant in choosing the more appropriate assisted reproductive treatment option. Although ICSI has been claimed as the primary choice of treatment for ASA-related subfertility, because it overcomes any potential interference of ASA with sperm fertilizing ability [33], it would be better to reserve it for patients for whom achieving a pregnancy with less invasive techniques would be most unlikely. In the light of preventing inappropriate aggressive intervention, the main question is whether/when intrauterine insemination (IUI) could represent an effective first-line ART treatment, as discussed elsewhere in the book.
References
1.
Abshagen K, Behre HM, Cooper TG et al (1998) Influence of sperm surface antibodies on spontaneous pregnancy rates. Fertil Steril 70:355–356CrossRefPubMed
2.
Acosta AA, van der Merwe JP, Doncel G et al (1994) Fertilization efficiency of morphologically abnormal spermatozoa in assisted reproduction is further impaired by antisperm antibodies on the male partner’s sperm. Fertil Steril 62:826–833CrossRefPubMed
3.
Aitken RJ, Parsow JM, Hargreave TB et al (1988) Influence of antisperm antibodies on human sperm function. Br J Urol 62:367–373CrossRefPubMed
4.
Ayvaliotis B, Bronson RA, Rosenfeld D et al (1985) Conception rates in couples where autoimmunity to sperm is detected. Fertil Steril 43:739–741CrossRefPubMed
5.
Broderick GA, Tom R, McClure RD (1989) Immunological status of patients before and after vasovasostomy as determined by the immunobead antisperm antibody test. J Urol 142:752–755PubMed
6.
Bronson RA, Cooper GW, Rosenfeld DL (1984) Autoimmunity to spermatozoa: effect on sperm penetration of cervical mucus as reflected by postcoital testing. Fertil Steril 41:609–614CrossRefPubMed
7.
Bronson RA, Cooper G, Hjort T et al (1985) Anti-sperm antibodies, detected by agglutination, immobilization, microcytotoxicity and immunobead-binding assays. J Reprod Immunol 8:279–299CrossRefPubMed
8.
Bronson RA, Cooper GW, Rosenfeld DL et al (1987) The effect of an IgA1 protease on immunoblobulins bound to the sperm surface and sperm cervical mucus penetrating ability. Fertil Steril 47:985–991CrossRefPubMed
9.
Chang TH, Jih MH, Wu TCJ (1993) Relationship of sperm antibodies in women and men to human in vitro fertilization, cleavage, and pregnancy rate. Am J Reprod Immunol 30:108–112CrossRefPubMed
10.
Clarke GN (1988) Immunoglobulin class and regional specificity of antispermatozoal autoantibodies blocking cervical mucus penetration by human spermatozoa. Am J Reprod Immunol Microbiol 16:135–138CrossRefPubMed
11.
Clarke GN, Elliott PJ, Smaila C (1985) Detection of sperm antibodies in semen using the immunobead test: a survey of 813 consecutive patients. Am J Reprod Immunol Microbiol 7:118–123CrossRefPubMed
12.
Clarke GN, Lopata A, McBain JC (1985) Effect of sperm antibodies in males on human in vitro fertilization (IVF). Am J Reprod Immunol Microbiol 8:62–66CrossRefPubMed
13.
Collins JA, Burrows EA, Yeo J et al (1993) Frequency and predictive value of antisperm antibodies among infertile couples. Hum Reprod 8:592–598PubMed
14.
Culligan PJ, Crane MM, Boone WR et al (1998) Validity and cost-effectiveness of antisperm antibody testing before in vitro fertilization. Fertil Steril 69:894–898CrossRefPubMed
15.
D’Cruz OJ, Haas GG (1990) Lack of complement activation in the seminal plasma of men with antisperm antibodies associated in vivo on their sperm. Am J Reprod Immunol 24:51–57CrossRefPubMed
16.
D’Cruz OJ, Haas GG, Lambert H (1990) Evaluation of antisperm complement-dependent immune mediators in human ovarian follicular fluid. J Immunol 144:3841–3848PubMed
17.
De Almeida M, Gazagne I, Jeulin C et al (1989) In-vitro processing of sperm with auto-antibodies and in-vitro fertilization results. Hum Reprod 4:49–53PubMed
18.
Eggert-Kruse W, Christmann WM, Gerhard I et al (1989) Circulating antisperm antibodies and fertility prognosis: a prospective study. Hum Reprod 4:513–520PubMed
19.
Fisch H, Laor E, BarChama N et al (1989) Detection of testicular endocrine abnormalities and their correlation with serum antisperm antibodies in men following vasectomy. J Urol 141:1129–1132PubMed
20.
Ford WCL, Williams KM, McLaughlin EA et al (1996) The indirect immunobead test for seminal antisperm antibodies and fertilization rates at in-vitro fertilization. Hum Reprod 11:1418–1422CrossRefPubMed
21.
Francavilla F, Catignani P, Romano R et al (1984) Immunological screening of a male population with infertile marriages. Andrologia 16:578–586CrossRefPubMed
22.
Francavilla F, Santucci R, Romano R et al (1988) A direct immunofluorescence test for the detection of sperm surface bound antibodies. Comparison with sperm agglutination test, indirect IF test and MAR test. Andrologia 20:477–483CrossRefPubMed
23.
Francavilla F, Romano R, Santucci R et al (1997) Occurrence of the interference of sperm-associated antibodies on sperm fertilizing ability as evaluated by the sperm-zona pellucida binding test and by the TEST-Yolk Buffer enhanced sperm penetration assay. Am J Reprod Immunol 37:267–274CrossRefPubMed
24.
Francavilla F, Santucci R, Barbonetti A et al (2007) Naturally-occurring antisperm antibodies in men: interference with fertility and clinical implications. An update. Front Biosci 12:2890–2911. ReviewCrossRefPubMed
25.
Haas GG (1986) The inhibitory effect of sperm-associated immunoglobulins on cervical mucus penetration. Fertil Steril 46:334–337CrossRefPubMed
26.
Hargreave TB, Haxton M, Whitelaw J et al (1980) The significance of serum sperm-agglutinating antibodies in men with infertile marriages. Br J Urol 52:566–570CrossRefPubMed
27.
Hellstrom WJG, Overstreet JW, Samuels SJ et al (1988) The relationship of circulating antisperm antibodies to sperm surface antibodies in infertile men. J Urol 140:1039–1044PubMed
28.
Helmerhorst FM, Finken MJJ, Erwich JJ (1999) Detection assays for antisperm antibodies: what do they test? Hum Reprod 14:1669–1671CrossRefPubMed
29.
Jarow JP, Goluboff ET, Chang TS et al (1994) Relationship between antisperm antibodies and testicular histologic changes in humans after vasectomy. Urology 43:521–524CrossRefPubMed
30.
Kremer J, Jager S (1980) Characteristics of anti-spermatozoal antibodies responsible for the shaking phenomenon with special regard to immunoglobulin class and antigen-reactive sites. Int J Androl 3:143–152CrossRefPubMed
31.
Lähteenmäki A (1993) In-vitro fertilization in the presence of antisperm antibodies detected by the mixed antiglobulin reaction (MAR) and the tray agglutination test (TAT). Hum Reprod 8:84–88PubMed
32.
Leushuis E, van der Steeg JW, Steures P et al (2009) Immunoglobulin G antisperm antibodies and prediction of spontaneous pregnancy. Fertil Steril 92:1659–1665CrossRefPubMed
33.
Lombardo F, Gandini L, Dondero F et al (2001) Antisperm immunity in natural and assisted reproduction. Hum Reprod Update 7:450–456CrossRefPubMed
34.
Mandelbaum SL, Diamond MP, DeCherney AH (1987) Relationship of antisperm antibodies to oocyte fertilization in in vitro fertilization-embryo transfer. Fertil Steril 47:644–651CrossRefPubMed
35.
Mathur S, Williamson HO, Baker ME et al (1984) Sperm motility on post coital testing correlates with male autoimmunity to sperm. Fertil Steril 41:81–87CrossRefPubMed
36.
Matson PL, Junk SM, Spittle JW et al (1988) Effect of antispermatozoal antibodies in seminal plasma upon spermatozoal function. Int J Androl 11:101–106CrossRefPubMed
37.
Matson PL, Junk SM, Masters JR et al (1989) The incidence and influence upon fertility of antisperm antibodies in seminal fluid following vasectomy reversal. Int J Androl 12:98–103CrossRefPubMed
38.
Meinertz H, Hjort T (1986) Detection of autoimmunity to sperm: mixed antiglobulin reaction (MAR) test or sperm agglutination? A study on 537 men from infertile couples. Fertil Steril 46:86–91CrossRefPubMed
39.
Meinertz H, Linnet L, Fogh-Andersen P et al (1990) Antisperm antibodies and fertility after vasovasostomy: a follow-up study of 216 men. Fertil Steril 54:315–321CrossRefPubMed
40.
Menge AC, Medley NE, Mangione CM et al (1982) The incidence and influence of antisperm antibodies in infertile human couples on sperm-cervical mucus interactions and subsequent fertility. Fertil Steril 38:439–446CrossRefPubMed
41.
Palermo G, Devroey P, Camus M et al (1989) Assisted procreation in the presence of a positive direct mixed antiglobulin reaction test. Fertil Steril 52:645–649CrossRefPubMed
42.
Petersen BH, Lammel CJ, Stites DP et al (1980) Human seminal plasma inhibition of complement. J Lab Clin Med 96:582–591PubMed
43.
Price RJ, Boettcher B (1979) The presence of complement in human cervical mucus and its possible relevance to infertility in women with complement-dependent sperm-immobilizing antibodies. Fertil Steril 32:61–66CrossRefPubMed
44.
Rajah SV, Parslow JM, Howell RJ et al (1993) The effects on in-vitro fertilization of autoantibodies to spermatozoa in subfertile men. Hum Reprod 8:1079–1082. autoimmune infertility. Fertil Steril 63:1260–1266PubMed
45.
Rumke PH (1954) The presence of sperm antibodies in the serum of two patients with oligospermia. Vox Sang 4:135–140
46.
Rumke PH, Van Amstel N, Messer EN et al (1974) Prognosis of fertility of men with sperm agglutinins in the serum. Fertil Steril 25:393–398CrossRefPubMed
47.
Sinisi AA, Di Finizio B, Pasquali D et al (1993) Prevalence of antisperm antibodies by SpermMAR test in subjects undergoing a routine sperm analysis for infertility. Int J Androl 16:311–314CrossRefPubMed
48.
Sukcharoen N, Keith J (1995) The effect of the antisperm auto-antibody-bound sperm on in vitro fertilization outcome. Andrologia 27:281–289CrossRefPubMed
49.
Taylor PJ, Collins JA (1992) Unexplained infertility. Oxford University Press, Oxford, pp 128–131
50.
Vazquez-Levin MH, Notrica JA, de Fried EP (1997) Male immunologic infertility: sperm performance on in vitro fertilization. Fertil Steril 68:675–681CrossRefPubMed
51.
Vujisic S, Lepej SZ, Jerkovic L et al (2005) Antisperm antibodies in sperm, sera and follicular fluids of infertile patients: relation to reproductive outcome after in vitro fertilization. Am J Reprod Immunol 54:13–20CrossRefPubMed
52.
Wang C, Baker HW, Jennings MG (1985) Interaction between human cervical mucus and sperm surface antibodies. Fertil Steril 44:484–488CrossRefPubMed
53.
Wilson L (1954) Sperm agglutinins in human semen and blood. Proc Soc Exp Biol Med 85:652–655CrossRefPubMed
54.
WHO Reference Bank for Reproductive Immunology (1977) Auto- and iso-antibodies to antigens of the human reproductive system. 1. Results of an international comparative study. Clin Exp Immunol 30:173–180
55.
Witkin SS, David SS (1988) Effect of sperm antibodies on pregnancy outcome in a subfertile population. Am J Obstet Gynecol 158:59–62CrossRefPubMed
56.
World Health Organization (2010) WHO laboratory manual for the examination and processing of human semen, 5th edn. WHO Press, Geneva
57.
Zini A, Fahmy N, Belzile E et al (2011) Antisperm antibodies are not associated with pregnancy rates after IVF and ICSI: systematic review and meta-analysis. Hum Reprod 26:1288–1295CrossRefPubMed