Antisperm antibodies and varicocele.

A male factor alone is responsible for greater than 20% of infertile couples and contributes to another 30 to 40% of cases. (1) The aim of the male infertility evaluation is to identify correctable causes, note irreversible conditions that are amenable to assisted reproductive techniques (ARTs) using the sperm of the male partner, and to act upon life-threatening conditions that may underlie infertility. (2) The minimum evaluation of the infertile male includes a complete medical and reproductive history, physical examination, and at least two consecutive semen analyses. Specialized tests, including screening for antisperm antibodies (ASAB), are reserved only for cases in which identification of the cause of male infertility would direct a different form of treatment. (2)

ASAB have been identified in 9% to 12.8% of infertile couples, (3) in 1% to 2.5% of fertile men, (4) and in 4% of fertile women. (5) The occurrence of ASAB in the fertile population suggests that not all ASAB cause infertility. ASAB have been identified in male and female serum, semen, follicular fluid, and vaginal or cervical secretions,

or as antigenic epitopes bound directly to the outer sperm plasma membrane. Different isotypes of ASAB have been identified, specifically immunoglobulin (Ig)A, IgG, and IgM.

Commercially available ASAB assays either directly measure ASAB bound to sperm or indirectly measure ASAB in solution (serum, seminal fluid, vaginal or cervical secretions, or follicular fluid). Methods for assessment of ASAB can be categorized into: 1) direct methods to detect the presence of ASAB on sperm (sperm mixed agglutination reaction [sMAR], immunobead test [IBT]) or; 2) agglutination tests using donor sperm (gelatin agglutination test, tray agglutination test [TAT], radiolabeled agglutinin assay). (6) ELISA and flow cytometry detect ASAB quantitatively. All tests have advantages and disadvantages. It is generally accepted that the IBT is the gold-standard method for measuring ASAB. The direct IBT characterizes ASAB quantitatively and qualitatively and provides the most clinically relevant data. Furthermore, the specificity of the direct IBT is extremely high as evidenced by the low incidence of nonspecific binding. (7,8) A number of laboratories have demonstrated that sperm function in vitro and fertility in vivo are not significantly impaired unless [greater than or equal to] 50% of the motile spermatozoa are coated with antibodies. It is generally accepted that direct IBT results be reported as < 20% as negative, 20 to 49% as positive, and [greater than or equal to] 50% as highly clinically positive. (9)

Each type of ASAB may interfere directly or indirectly with a different step in the fertilization process, including sperm motility, sperm penetration of the cervical mucus, sperm capacitation and the acrosome reaction, sperm binding and penetration of the zona pellucida, zona reaction, gamete fusion, cleavage, and embryo development. (10) An inverse correlation between the proportion of sperm bound ASAB and fertilizing capability of sperm has been shown. (11) All three isotypes of ASAB are capable of binding to sperm (IgA, IgG, and IgM). IgG and IgA ASAB are found in 21% of infertile men. (12) IgG ASAB on sperm and IgM ASAB in female serum has been reported to be correlated with a reduction in fertilization, while the presence of IgA ASAB in female sera is associated with a decrease in pregnancy rate. (13) Some studies have suggested that the combination of IgG and IgA ASAB has a synergistic negative impact on fertilization and pregnancy rates. (14,15)

There are several hypotheses for ASAB formation in men. Theoretically, the blood-testis barrier may be breached by a variety of mechanisms resulting in exposure of immunogenic sperm antigens to the body's immune system. Ultimately, this exposure initiates an immune response. Numerous pathologies causing mechanical obstruction of the reproductive tract and extravasation of sperm, including congenital abnormalities (cystic fibrosis, congenital absence of vas deferens), vasectomy, trauma, testicular torsion, surgery, inflammation, childhood inguinal herniorrhaphy, sexually transmitted disease, leukocytospermia, varicocele, and immunosuppression, can in theory lead to ASAB formation. Similarly, the production of ASAB in women may occur as a result of mechanical or chemical disruption of the mucosal layer of the female genital tract, sperm exposure within the peritoneal cavity after transtubal passage, or by local inflammation after genital tract infection.

Whether or not a varicocele leads to ASAB remains controversial. In an animal model of unilateral varicocele, researchers reported that significant titers of ASAB were present in animals with varicoceles but not in controls. (16) There are few clinical studies suggesting an association between ASAB and varicocele. Using ELISA, Gilbert et al found sperm-bound immunoglobulins in 32% of infertile men with varicocele, linking ASAB formation and varicocele-associated infertility. (17) Another revealed a significantly increased rate of immunobead-positive ASAB in infertile men with varicocele (28%) compared with fertile controls (0%). (18) In a relatively recent controlled and comparative study, 50% of men with clinically palpable varicoceles were documented to have positive ASAB, whereas no ASAB was detected in the fertile control using sMAR and the peroxidase-labeled protein A methods. (19) However, a number of investigators have found no association between ASAB formation and the presence of varicocele. (20,21)

Another recent observation was a 16% rate of ASAB-positive conversion after varicocele repair in ASAB-negative men. (22) Because surgical correction of varicocele did not show any significant differences in semen parameters in men with or without ASAB, some authorities postulate that the presence of ASAB is of little relevance in varicocele-associated infertility. (18)

The prospective study in this issue of the Southern Medical Journal investigated the relationship between varicocele/varicocelectomy and ASAB formation. Djaladat et al (23) assessed the presence of ASAB before and six months after varicocelectomy and compared those patients to an idiopathic infertile population without varicocele. This study examines whether varicocele is associated with ASAB formation and further impairs fertility, and if varicoeelectomy may reduce the ASAB level.

Needless to say, the debate over ASAB and varicocele will continue as a number of issues remain to be answered, such as the exact role of ASAB in infertility; which method of ASAB testing is optimal for screening and final determination; which isotopes (IgG, IgA, IgM) are relevant to infertility; what threshold levels of ASAB are significant; if ASAB binding locations on spermatozoa have an effect; and what is the best method to circumvent or treat ASAB-related subfertility.

References

1. Thonneau P, Marchand S, Tallec A, et al. Incidence and main causes of infertility in a resident population (1,850,000) of three French regions (1988-1989). Hum Reprod 1991;6:811-816.

2. Jarow JP, Sharlip ID, Belker AM, et al. Male Infertility Best Practice Policy Committee of the American Urological Association Inc. Best practice policies for male infertility. J Urol 2002;167:2138-2144.

3. Collins JA, Burrows EA, Yeo J, et al. Frequency and predictive value of antisperm antibodies among infertile couples. Hum Reprod 1993 Apr; 8:592-598.

4. Heidenreich A, Bonfig R, Wilbert DM, et al. Risk factors for antisperm antibodies in infertile men. Am J Reprod Immunol 1994 Mar-Apr;31:69-76.

5. Omu AE, Makhseed M, Mohammed AT, et al. Characteristics of men and women with circulating antisperm antibodies in a combined infertility clinic in Kuwait. Arch Androl 1997;39:55-64.

6. Helmerhorst FM, Finken MJ, Erwich JJ. Antisperm antibodies: detection assays for antisperm antibodies: what do they test? Hum Reprod 1999 Jul;14 (7):1669-1671.

7. Bronson R, Cooper G, Rosenfeld D. Sperm antibodies: their role in infertility. Fertil Steril 1984;42:171-183.

8. Hellstrom WJ, Samuels SJ, Waits AB, Overstreet JW. A comparison of the usefulness of SpermMar and immunobead tests for the detection of antisperm antibodies. Fertil Steril 1989;52:1027-31.

9. WHO Laboratory Manual for the examination of human semen and semen cervical-mucus nteraction. WHO. Cambridge, Cambridge Unversity Press, 3rd ed, 1992.

10. Kutteh WH. Antisperm antibodies. Do antisperm antibodies bound to spermatozoa alter normal reproductive function? Hum Reprod 1999;14:2426-2429.

11. Chiu WW, Chamley LW. Clinical associations and mechanisms of action of antisperm antibodies. Fertil Steril 2004;82:529-35.

12. Witkin SS, David SS. Effect of sperm antibodies on pregnancy outcome in a subfertile population. Am J Obstet Gynecol 1988;158:59-62.

13. Chang TH, Jih MH, Wu TC. Relationship of sperm antibodies in women and men to human in vitro fertilization, cleavage, and pregnancy rate. Am J Reprod Immunol 1993;30:108-112.

14. Matson PL, Junk SM, Spittle JW, Yovich JL. Effect of antispermatozoal antibodies in seminal plasma upon spermatozoal function. Int J Androl 1988;11:101-106.

15. Meinertz H, Linnet L, Fogh-Andersen P, et al. Antisperm antibodies and fertility after vasovasostomy: a follow-up study of 216 men. Fertil Steril 1990;54:315-321.

16. Shook TE, Nyberg LM, Collins BS, et al. Pathological and immunological effects of surgically induced varicocele in juvenile and adult rats. Am J Reprod Immunol Microbiol 1988;17:141-144.

17. Gilbert BR, Witkin SS, Goldstein M. Correlation of sperm-bound immunoglobulins with impaired semen analysis in infertile men with varicoceles. Fertil Steril 1989;52:469-73.

18. Knudson G, Ross L, Stuhldreher D, et al. Prevalence of sperm bound antibodies in infertile men with varicocele: the effect of varicocele ligation on antibody levels and semen response. J Urol 1994;151:1260-1262.

19. Isitmangil G, Yildirim S, Orhan I, et al. A comparison of the sperm mixed-agglutination reaction test with the peroxidase-labelled protein A test for detecting antisperm antibodies in infertile men with varicocele. BJU Int 1999;84:835-8.

20. Verajankorva E, Laato M, Pollanen P. Analysis of 508 infertile male patients in south-western Finland in 1980-2000; hormonal status and factors predisposing to immunological infertility. Eur J Obstet Gynecol Reprod Biol 2003;111:173-8.

21. Oshinsky GS, Rodriguez MV, Mellinger BC. Varicocele-related infertility is not associated with increased sperm-bound antibody. J Urol 1993;150:871-873.

22. Cetinkaya M, Memis A, Adsan O, et al. Antispermatozoal antibody values after varicocelectomy. Int Urol Nephrol 1994;26:89-92.

23. Djaladat H, Mehrsai A, Rezazade M, et al. Varicocele and antisperm antibody: Fact or fiction? South Med J 2006;99:44-47.

Muammer Kendirci, MD, and Wayne J. G. Hellstrom, MD, FACS 

From Tulane University Health Sciences Center, Department of Urology, New Orleans, LA.

Reprint requests to Muammer Kendirei, MD, Tulane University Health Sciences Center, 1430 Tulane Avenue, S1-42. New Orleans, LA 70112. Email: [e-mail]

Accepted September 22, 2005.