Antisperm antibodies

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

Contents

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

As of 2017 research was ongoing in several areas related to ASA.

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.

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 

Related Research Articles

<span class="mw-page-title-main">Spermatozoon</span> Motile sperm cell

A spermatozoon is a motile sperm cell, or moving form of the haploid cell that is the male gamete. A spermatozoon joins an ovum to form a zygote.

<span class="mw-page-title-main">Intracytoplasmic sperm injection</span> In vitro fertilization procedure

Intracytoplasmic sperm injection is an in vitro fertilization (IVF) procedure in which a single sperm cell is injected directly into the cytoplasm of an egg. This technique is used in order to prepare the gametes for the obtention of embryos that may be transferred to a maternal uterus. With this method, the acrosome reaction is skipped.

Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species. It is the normal state of a human child or other young offspring, because they have not undergone puberty, which is the body's start of reproductive capacity.

<span class="mw-page-title-main">Artificial insemination</span> Pregnancy through in vivo fertilization

Artificial insemination is the deliberate introduction of sperm into a female's cervix or uterine cavity for the purpose of achieving a pregnancy through in vivo fertilization by means other than sexual intercourse. It is a fertility treatment for humans, and is a common practice in animal breeding, including dairy cattle and pigs.

Insemination is the introduction of sperm into a female’s reproductive system for the purpose of impregnating, also called fertilizing, the female for sexual reproduction. The sperm is introduced into the uterus of a mammal or the oviduct of an oviparous (egg-laying) animal. In mammals, insemination normally occurs during sexual intercourse or copulation, but insemination can take place in other ways, such as by artificial insemination.

<span class="mw-page-title-main">Acrosin</span>

Acrosin is a digestive enzyme that acts as a protease. In humans, acrosin is encoded by the ACR gene. Acrosin is released from the acrosome of spermatozoa as a consequence of the acrosome reaction. It aids in the penetration of the Zona Pellucida.

Hypospermia is a condition in which a man has an unusually low ejaculate volume, less than 1.5 mL. It is the opposite of hyperspermia, which is a semen volume of more than 5.5 mL. It should not be confused with oligospermia, which means low sperm count. Normal ejaculate when a man is not drained from prior sex and is suitably aroused is around 1.5–6 mL, although this varies greatly with mood, physical condition, and sexual activity. Of this, around 1% by volume is sperm cells. The U.S.-based National Institutes of Health defines hypospermia as a semen volume lower than 2 mL on at least two semen analyses.

Male infertility refers to a sexually mature male's inability to impregnate a fertile female. In humans it accounts for 40–50% of infertility. It affects approximately 7% of all men. Male infertility is commonly due to deficiencies in the semen, and semen quality is used as a surrogate measure of male fecundity. More recently, advance sperm analyses that examine intracellular sperm components are being developed.

<span class="mw-page-title-main">Female infertility</span> Diminished or absent ability of a female to achieve conception

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The hamster zona-free ovum test, or hamster egg-penetration test, or sometimes just hamster test, is an in-vitro test used to study physiological profile of spermatozoa. The primary application of the test is to diagnose male infertility caused by sperm unable to penetrate the ova. The test has limited value, due to expense and a high false negative rate.

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Pregnancy rate is the success rate for getting pregnant. It is the percentage of all attempts that leads to pregnancy, with attempts generally referring to menstrual cycles where insemination or any artificial equivalent is used, which may be simple artificial insemination (AI) or AI with additional in vitro fertilization (IVF).

Reproductive immunology refers to a field of medicine that studies interactions between the immune system and components related to the reproductive system, such as maternal immune tolerance towards the fetus, or immunological interactions across the blood-testis barrier. The concept has been used by fertility clinics to explain fertility problems, recurrent miscarriages and pregnancy complications observed when this state of immunological tolerance is not successfully achieved. Immunological therapy is a method for treating many cases of previously "unexplained infertility" or recurrent miscarriage.

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<span class="mw-page-title-main">Fertility testing</span>

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<span class="mw-page-title-main">Ashok Agarwal</span> Medical Scientist

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The sperm–cervical mucus contact test is an in-vitro slide test used for detecting antispermal antibodies. It is one of the investigations done for infertility. It should not be confused with Kurzrock–Miller test, where there is interface between the two materials; whereas in this test the materials are thoroughly mixed.

<span class="mw-page-title-main">Male infertility crisis</span> Observed decline in male fertility and sperm quality

The male infertility crisis is an increase in male infertility since the mid-1970s. The issue attracted media attention after a 2017 meta-analysis found that sperm counts had declined by 52.4 percent between 1973 and 2011. The decline is particularly prevalent in Western countries such as New Zealand and Australia, Europe and North America. A 2022 meta-analysis reported that this decline extends to non-Western countries, namely those in Asia, Africa, Central America, and South America. This meta-analysis also suggests that the decline in sperm counts may be accelerating.

References

  1. 1 2 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. 1 2 3 4 5 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. 1 2 3 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. 1 2 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. 1 2 3 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. 1 2 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. 1 2 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.
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