Antisperm antibodies

Antisperm antibodies (ASA) are antibodies produced against sperm antigens.

Types

Antisperm antibodies are immunoglobulins of IgG, IgA, and/or IgM, which are directed against sperm antigens. ASA can be detected in ejaculate, cervical mucus, follicular fluid, and blood serum of both males and females.^[1] While IgG and IgA might be present in blood serum and/or genital tract fluids, IgM is only present in blood serum. IgG occurring in genital tract fluids is either produced locally or transuded from blood serum, whereas IgA (secretory type) is always produced locally.^[2]

Causes

Traditionally, the breakdown of the blood-testis barrier had been established as the cause of ASA production. This mechanism had been advocated in testicular trauma and surgery, orchitis (mumps), varicocele, bacterial infections (epididymitis, prostatitis), testicular cancer, and unprotected anal intercourse. However, the association between aforementioned conditions and ASA production is controversial.^[2] Only chronic obstruction, most typically represented by vasectomy followed by vasectomy reversal, is the only one condition leading constantly to high and permanent ASA titers.^[3] Apart from breaching of blood-testis barrier, epididymal distension, raised intraluminal pressure, and sperm granuloma formation leading spermatozoal phagocytosis seem to be contributing factors.^[4]

As of 2017, it is unclear how or why women generally do not develop ASA, and why some women do develop them; the clearest correlations are that women whose male partners have ASA in their semen are more likely to have ASA, and women with ASA tend to react only to their partner's sperm and not to other men's sperm.^{[5]: 161 [6]} The hypotheses for how women form ASA, as of 2017, includes cross-reactivity with microbial antigens, antibodies raised against ASA in their partner's semen, and a cytokine-driven immune response to ASA in their partner's semen.^{[5]: 165–169} In women, spermatozoa in the genital tract after intercourse are not a factor in the production of antisperm antibodies. But this is possible with a trauma to the vaginal mucosa during the intercourse or the deposition of sperm in the gastrointestinal tract by oral or anal intercourse.^[7][8]

Influence on reproductive processes

In both men and women, ASA production are directed against surface antigens on sperm, which can interfere with sperm motility and transport through the female reproductive tract, inhibiting capacitation and acrosome reaction, impaired fertilization, influence on the implantation process, and impaired growth and development of the embryo.^[1][9]

Diagnosis

Different tests have been developed to identify ASA in various biological substrates. However, only Mixed Antiglobulin Reaction (MAR) test and Immunobead Test (IBT) are currently being recommended by the WHO for the assessment of human sperm antibodies.^[10]

MAR test in its original version is based on the classical Coombs test; sperm is mixed with human red blood cells coated with human IgG. A rabbit or goat monospecific anti-human IgG antibody is added. Agglutination (slow “shaky” movements) can be observed if sperm are coated with ASA. Instead of human red blood cells, commercial version of MAR test uses latex particles coated with human IgG ASA. Since the test is performed with fresh semen and the incubation requires only 10 minutes, it renders MAR test a quick and simple screening tool for ASA in human ejaculate. However, samples with very low sperm count (i.e. severe oligoastheno-, or even azoospermia) cannot be evaluated using this method. Also presence of debris or high viscosity of semen can preclude its use.^{[citation needed]}

IBT is based on polyacrylamide spheres coated with rabbit anti-human immunoglobulins antibody. These particles are used either to identify ASA bound to sperm (direct IBT), or ASA present in various biological fluids – seminal plasma, cervical mucus, uterine, oviduct or follicular fluid (indirect IBT); the latter one requires addition of donor ASA-free sperm.

ASA might be present also in the cervical mucus of the female. These antibodies might be proved by the postcoital test (PCT). Although the test has been declared obsolete by some authors, it has still been widely used by many gynecologists.^[11] The test is performed 8–12 hours after an unprotected sexual intercourse at the estimated time of ovulation, when the cervical mucus is least viscous and thus most permeable for the sperm. The result is considered poor in case of less than 10 sperm per high power field are apparent.

Generally, the main drawback of all tests used for the diagnosis of ASA is a heterogeneity of data presented in available studies, caused by lack of method standardisation, various semen preparations, and inconsistent cut-off values. These facts compromise precise comparison between various methods.^[2]

Treatment

Since the precise etiology of ASA production is mostly unknown, causative treatment of ASA-mediated infertility is rarely possible.

Immunosuppressive therapy comprising corticosteroids or ciclosporin has been proposed by several authors with promising results, nevertheless large randomized controlled trials failed to show a clear benefit. Owing to sometimes severe adverse effects, many clinicians are reluctant to treat immune infertile patients with above mentioned drugs.

In the clinical practice, assisted reproductive techniques are being considered as a golden standard for the immune-mediated infertility.

Albeit intrauterine insemination (IUI) might circumvent ASA present in the cervical mucus, in a study comprising 119 IUI, no live pregnancy was reported, suggesting involvement of other mechanisms of ASA.^[12] Since ASA are usually bound to sperm surface antigens with high affinity, ordinary wash-up used before ICSI is not effective.^[2] Thus, some authors recommend treatment of sperm with chymotrypsin/galactose to cleave ASA molecules.^[13] However, this method has not been adopted by clinicians as some concerns exist regarding a possible negative impact of this digestive enzyme on sperm surface receptors involved in fertilization.^[14]

In vitro fertilization (IVF) reaches lower pregnancy rates in ASA-positive individuals – basically, the higher ASA titers, the more negative outcome. This inverse association is more pronounced in ASA-positive males.^[15] It has been reported ASA binding to the sperm head have more negative impact on fertilization than those binding to the sperm midpiece or tail.

If intracytoplasmic sperm injection (ICSI) is added to IVF, similar outcome has been observed in both ASA-positive and ASA-negative couples. Nevertheless, one study showed significantly higher spontaneous pregnancy loss in the ASA-positives.^[16]

Prevalence

ASA can arise whenever sperm encounter the immune system.^[6] ASA occur in women and men, including women or men who receive anal sex from men or who perform oral sex on men.^{[17]: 210 [7]}

ASA have been considered as infertility cause in around 10–30% of infertile couples, and in males, about 12–13% (20,4% in meta-analysis)^[9] of all diagnosed infertility is related to an immunological reason. The incidence can well be higher as the contribution to idiopathic infertility (31% of all cases) still remains elusive. However, these antibodies are also present in approximately 1–2.5 % of fertile men and in 4% of fertile women; the presence of ASA in the fertile population suggests that not all ASA cause infertility.^[18]: 27 Only those antibodies directed against antigens involved in the fertilization process impair fertility.^[2]

While around 75% of vasectomized men who have the process reversed by vasovasostomy have high levels of ASA in their blood,^[19]: v these circulating antibodies do not affect fertility in men; only ASA in the male reproductive tract appears to do so.^[20]: 134

About 40-45% of sex workers test positive for antisperm antibodies, compared to just 5% in the control group.^[21] Research has shown that these numbers increase for those who do not use contraceptive methods.^[7]

Research

There is a general effort to identify concrete sperm surface antigens which serve as a target for ASA. As sperm undergoes biological changes including capacitation, acrosome reaction, zona binding, and sperm-egg fusion, the set of sperm surface antigens is highly dynamic in time. Additionally, some of the sperm surface antigens might be incorporated into the plasma membrane of the embryo resulting in postfertilization negative impact of ASA.^{[citation needed]}

Research has been conducted, but not clinically tested, to use sperm antigens or recombinant ASAs as contraceptive vaccines for humans,^[22] as well as captive and wild animals.^[23]

The mechanisms through which both women and men develop ASA is also poorly understood and a subject of research.^{[5]: 161 [20]: 133}

References

1. Restrepo, B; Cardona-Maya, W (October 2013). "Antisperm antibodies and fertility association". Actas Urologicas Espanolas. 37 (9): 571–8. doi:10.1016/j.acuro.2012.11.003. PMID 23428233.
2. Krause, Walter K.H. (2017). Immune infertility: impact of immune reactions on human fertility (2 ed.). Springer Verlag. ISBN 978-3-319-40786-9.
3. Lee, Richard; Goldstein, Marc; Ullery, Brant W.; Ehrlich, Joshua; Soares, Marc; Razzano, Renee A.; Herman, Michael P.; Callahan, Mark A.; Li, Philip S.; Schlegel, Peter N.; Witkin, Steven S. (January 2009). "Value of Serum Antisperm Antibodies in Diagnosing Obstructive Azoospermia". Journal of Urology. 181 (1): 264–269. doi:10.1016/j.juro.2008.09.004. ISSN 0022-5347. PMID 19013620.
4. BOORJIAN, STEPHEN; LIPKIN, MICHAEL; GOLDSTEIN, MARC (January 2004). "The Impact of Obstructive Interval and Sperm Granuloma on Outcome of Vasectomy Reversal". Journal of Urology. 171 (1): 304–306. doi:10.1097/01.ju.0000098652.35575.85. ISSN 0022-5347. PMID 14665900.
5. Clarke, Gary N. (2017). "Chapter 10: ASA in the Female". In Krause, Walter K.H.; Naz, Rajesh K. (eds.). Immune Infertility: Impact of Immune Reactions on Human Fertility (2nd ed.). Springer. ISBN 978-3-319-40788-3.
6. Kokcu, A; Yavuz, E; Celik, H; Bildircin, D (November 2012). "A panoramic view to relationships between reproductive failure and immunological factors". Archives of Gynecology and Obstetrics. 286 (5): 1283–9. doi:10.1007/s00404-012-2480-6. PMID 22843034. S2CID 9909636.
7. Selvaraj, Kamala; Selvaraj, Priya (2014). "Chapter 24: Immunology in Infertility". In Rao, Kamini; Carp, Howard; Fischer, Robert (eds.). Principles & Practice of Assisted Reproductive Technology, Volume 1. JP Medical Ltd. p. 311. ISBN 9789350907368. OCLC 865062991.
8. Bronson, Richard; Fleit, Howard B. (2015-01-01). "Immunologically Mediated Male and Female Reproductive Failure". Mucosal Immunology: 2157–2181. doi:10.1016/B978-0-12-415847-4.00111-7. ISBN 9780124158474.
9. Cui, D; Han, G; Shang, Y; Liu, C; Xia, L; Li, L; Yi, S (15 April 2015). "Antisperm antibodies in infertile men and their effect on semen parameters: a systematic review and meta-analysis". Clinica Chimica Acta. 444: 29–36. doi:10.1016/j.cca.2015.01.033. PMID 25659295.
10. World Health Organization (2010) WHO laboratory manual for the examination and processing of human semen,5th edn. WHO Press, Geneva, Switzerland
11. Practice Committee of the American Society for Reproductive Medicine (June 2015). "Diagnostic evaluation of the infertile female: a committee opinion". Fertility and Sterility. 103 (6): e44–e50. doi:10.1016/j.fertnstert.2015.03.019. ISSN 0015-0282. PMID 25936238.
12. França villa, Felice; Romano, Rossella; Santucci, Riccardo; Marrone, Virginia; Corrado, Giovanni (September 1992). "Failure of intrauterine insemination in male immunological infertility in cases in which all spermatozoa are antibody-coated*†*Supported by the Ministero della Pubblica Istruzione, Rome, Italy.†Presented in part at the 2nd International Congress on Therapy in Andrology, Pisa, Italy, June 13 to 15, 1991". Fertility and Sterility. 58 (3): 587–592. doi:10.1016/s0015-0282(16)55268-6. ISSN 0015-0282.
13. Bollendorf, A.; Check, J.H.; Katsoff, D.; Fedele, A. (March 1994). "The use of chymotrypsin/galactose to treat spermatozoa bound with anti-sperm antibodies prior to intra-uterine insemination". Human Reproduction. 9 (3): 484–488. doi:10.1093/oxfordjournals.humrep.a138532. ISSN 1460-2350. PMID 8006139.
14. Inoue, Naokazu; Ikawa, Masahito; Isotani, Ayako; Okabe, Masaru (March 2005). "The immunoglobulin superfamily protein Izumo is required for sperm to fuse with eggs". Nature. 434 (7030): 234–238. Bibcode:2005Natur.434..234I. doi:10.1038/nature03362. ISSN 0028-0836. PMID 15759005. S2CID 4402928.
15. Zouari, Raoudha; De Almeida, Marta; Rodrigues, Daniel; Jouannet, Pierre (March 1993). "Localization of antibodies on spermatozoa and sperm movement characteristics are good predictors of in vitro fertilization success in cases of male autoimmune infertility". Fertility and Sterility. 59 (3): 606–612. doi:10.1016/s0015-0282(16)55808-7. ISSN 0015-0282. PMID 8458465.
16. Nagy, Z.P.; Verheyen, G.; Liu, J.; Joris, H.; Janssenswillen, C.; Wisanto, A.; Devroey, P.; Van Steirteghem, A.C. (July 1995). "Andrology: Results of 55 intracytoplasmic sperm injection cycles in the treatment of male-immunological infertility". Human Reproduction. 10 (7): 1775–1780. doi:10.1093/oxfordjournals.humrep.a136172. ISSN 1460-2350. PMID 8582978.
17. Ulcova-Gallova, Zdenka; Losan, Petr (2017). "Chapter 14: Impact on Fertility Outcome". In Krause, Walter K.H.; Naz, Rajesh K. (eds.). Immune Infertility: Impact of Immune Reactions on Human Fertility (2nd ed.). Springer. ISBN 978-3-319-40788-3.
18. Shetty, Jagathpala; Sherman, Nicholas E.; Herr, John C. (2017). "Chapter 2: Methods of Analysis of Sperm Antigens Related to Fertility". In Krause, Walter K.H.; Naz, Rajesh K. (eds.). Immune Infertility: Impact of Immune Reactions on Human Fertility (2nd ed.). Springer. ISBN 978-3-319-40788-3.
19. Krause, Walter K.H.; Naz, Rajesh K. (2017). "Preface". In Krause, Walter K.H.; Naz, Rajesh K. (eds.). Immune Infertility: Impact of Immune Reactions on Human Fertility (2nd ed.). Springer. ISBN 978-3-319-40788-3.
20. Marconi, Marcelo; Shetty, Wolfgang Weidner (2017). "Chapter 8: M Site and Risk Factors of Antisperm Antibodies Production in the Male Population". In Krause, Walter K.H.; Naz, Rajesh K. (eds.). Immune Infertility: Impact of Immune Reactions on Human Fertility (2nd ed.). Springer. ISBN 978-3-319-40788-3.
21. Beer, Alan E. (2006). Is your body baby-friendly?: "unexplained" infertility, miscarriage and IVF failure explained. Kantecki, Julia., Reed, Jane. Houston, TX: AJR Pub. ISBN 0-9785078-0-0. OCLC 72438534.
22. Naz, Rajesh K. (2017). "Chapter 17: Antisperm Contraceptive Vaccine". In Krause, Walter K.H.; Naz, Rajesh K. (eds.). Immune Infertility: Impact of Immune Reactions on Human Fertility (2nd ed.). Springer. ISBN 978-3-319-40788-3.
23. Jewgenow, Katarina (2017). "Chapter 18: Immune Contraception in Wildlife Animals". In Krause, Walter K.H.; Naz, Rajesh K. (eds.). Immune Infertility: Impact of Immune Reactions on Human Fertility (2nd ed.). Springer. ISBN 978-3-319-40788-3.