Antisperm Immunity and Infertility

Jin-Chun Lu; Yu-Feng Huang; Nian-Qing Lu


Expert Rev Clin Immunol. 2008;4(1):113-126. 

In This Article

Treatment of ASA-mediated Human Infertility

The identification of functionally relevant ASA antigens is a prerequisite for treatment options. Currently, no antibody-specific treatment of autoimmune diseases is possible, but the treatment is based on the suppression of antibody production in general.

Several methods have been attempted for the treatment of ASA-mediated infertility,[2] including immunosuppressive therapies, assisted reproductive technologies, laboratory techniques and integrative Chinese and Western medicine (ICWM) treatment.[78] However, currently used therapy for ASA-associated infertility is empiric and largely unproven. The results are usually disappointing. It justifies a therapeutical approach in the presence of high levels of antibodies.

Reduction of antigenic load is advised for infertile women. From an immunologic point of view, condom therapy, although it may work, is illogical. Although the antibody activity declined from 1:256 to 1:8 after 7 months of condom therapy, antibody titer will rise when no condom is used. In fact, results of condom therapy were disappointing. Therefore, condom therapy is now less used.

Steroids, such as corticosteroids, hydrocortisone, prednisolone or ciclosporin, have been used to treat those patients with ASAs. Corticosteroids suppress antibody levels and thus improve certain spermatozoan parameters and enhance fertility in such patients. Hydrocortisone may inhibit the production of ASA, in cervical mucus. However, the overall results of all the steroid-treated patients showed significant differences in performance. The results of the patients who were treated with prednisolone for three cycles showed a clear reduction of sperm-bound IgG antibody levels in three out of 11 (27%) patients, while only IgA was reduced in two out of 11 (18%) patients, and in one patient the level of sperm antibody even increased.[79] Also, high-dose corticosteroid therapy was ineffective in achieving pregnancies induced by infertile men positive for ASAs.[80] Moreover, there was no relationship between the decline of antibody titer and the occurrence of pregnancy. The data suggested that steroid therapy may be ineffective for immune infertility. The fluctuations of antibody levels in some individuals may be the result of drug administration.

Most importantly, side effects of corticosteroids should not be underestimated in healthy men.[80] A total of 63% of patients complained of weight gain, dyspepsia, irritability, acne or tingling sensations. Several reports showed that the side effects were less marked with β-methasone than with methylprednisolone.

Assisted reproductive technologies include intrauterine insemination (IUI), gamete intrafallopian transfer, IVF, and intracytoplasmic sperm injection (ICSI). Each patient who will undergo the various techniques of insemination or IVF should have the ASA assay performed as a preliminary screening.[33] While IUI can diminish the level of sperm-bound immunoglobulins and can improve the chance of conception in a selected group of couples with a diagnosis of immunological infertility, insemination can induce the production of ASAs and increase the ASA titer in other groups. With intraperitoneal insemination, the immediate and intense effect of direct microtraumatic contact of the pool of sperm with peritoneum could cause ASA production, which can block sperm passage through the female genital tract and interfere with the fertilization process, and this can reduce the chance of a successful assisted reproductive treatment. In this case, only ICSI seems able to overcome the problem,[33,81,82] for fertilization and pregnancy rates of ASA-positive patients undergoing ICSI maintains in the same range as ASA-negative patients.[83] Moreover, in assisted reproduction, when there are several oocytes to be inseminated, the chance of fertilization rises. These data indicate that ASAs did not hamper embryonal development and implantation, but further investigations on the development of fetuses are necessary.

In cases of male immune infertility, the use of various techniques for semen manipulation, such as sperm washing, swim-up, dilution, cryopreservation, immunomagnetic sperm separation and proteolytic enzyme treatment, has been proposed in order to elute the ASAs bound to sperm and obtain ASA-free sperm pools.

Sperm washing can diminish the level of sperm-bound immunoglobulins and thus improve the chance of conception in a selected group of couples with a diagnosis of immunological infertility. The percentage of spermatozoa bound to IgG decreased significantly by rapid dilution and washing of the semen containing ASAs. Cumulus/oocyte complex washing and/or enzymatic cumulus removal are also considered as selective interventions in the case of antisperm immunity. However, because of the difficulty to elute the antibodies from the sperm surface by any method, these techniques are discouraging. Moreover, the rate of fertilization was not improved.[84] Treatment of ASA-positive seminal fluid using Percoll gradient separation is ineffective for removing ASAs bound on sperm.[33] Another approach was reported to elute ASAs bound to sperm, that is, modifications of sperm membrane taking place during capacitation of sperm.[33] Indeed, this approach changed the nature of antigens, declining their reactivity with ASAs. If so, the detection of ASAs is unnecessary. Moreover, whether there was new ASAs or not remains unclear.

FA-1 can remove autoantibodies from the surface of sperm cells of immunoinfertile men by immune adsorption and permit an increased AR.[85] Moreover, the IUI of FA-1 antigen-adsorbed antibody-free sperm caused normal pregnancies and healthy babies, indicating that the antigen treatment does not have deleterious effects on implantation or on embryonic and fetal development. Similarly, can other sperm antigens that are involved in immunoinfertility be applied in the therapy of immunoinfertility? If the antigen has a real effect on fertility, it can be applied not only to the specific diagnosis of immunoinfertility but also to the treatment. More research is needed to confirm this approach.

It was reported that soluble complement receptor (sCR)1 can treat complement-mediated sperm injury, for sCR1 abrogated the binding of C3 fragments to human sperm and fully protected sperm from C5b-9-mediated sperm immobilization. Moreover, CR1 inhibited ASA- and complement-mediated neutrophil aggregation by 46% and sperm phagocytosis by 57%.[51] These findings suggested the therapeutic potential of sCR1 to prevent complement-dependent sperm dysfunction.

in vitro treatment of sperm with antisperm Fab fragments had a protective effect from isoimmune attack in vivo. Successful use of Fab fragments for reversal of ASA-mediated infertility observed in the isoimmune rabbit model offers the prospect of a new means of restoring fertility in some isoimmune women.[86]

It was shown, by immunobead binding, that immediate exposure of spermatozoa to d-galactose in the presence of chymotrypsin resulted in a considerable decrease or total loss of bound ASAs in males who had previously had a high titer of antibodies.[55] This pretreatment regimen for the ejaculate is suggested as a form of therapy for infertility related to the presence of ASAs.

The effects of plasmapheresis and hemosorption on the efficacy of the treatment of autoimmune male infertility (AMI) were studied in 289 AMI males with oligoasthenozoospermia aged 19-37 years.[87] Patients of group 1 with high ASA levels in the blood but low in ejaculate received a course of plasmapheresis. Patients of group 2 with high ASA levels, both in the blood and ejaculate were subjected to hemosorption and plasmapheresis in one contour. Group 3 patients with high levels of ASAs in ejaculate but low in blood received efferent therapy only after medication and photomodification of blood. The treatment reduced elevated levels of ASAs in blood and ejaculate, normalized free-radical oxidation, cellular and humoral immunity and antioxidant defense. This resulted in improvement of spermogram parameters, efficacy of assisted reproductive technologies, and a higher probability of natural pregnancy in the patients' wives. However, similar reports are few.

Although it remains a mystery, the combined therapy of acupuncture with herbal drugs has reportedly definite therapeutic effects on male immune infertility.[88] Chinese medicine Yiqihuoxuetang (YQHXT) could inhibit ASAs by maintaining the balance of T-lymphocyte subpopulations in immunoinfertile men.[89] Herb medicine could treat immune infertility accompanied by chronic seminal vesiculitis. The results showed that ASA tests became negative in 85.6% of the patients after treatment, and the pregnancy rate of their wives was 49.1%.[90] In addition, ICWM therapy could effectively regulate autoimmunity and endocrine function.[2] Since most of the available techniques, such as the aforementioned methods, have side effects, are invasive and expensive and have low efficacy, or have conflicting results, Chinese medicine treatment may be a relatively adequate choice, although their action mechanisms remain unclear.

Except the aforementioned methods, monoclonal antibodies were used in the treatment of autoimmune diseases[4] and may be adapted for the treatment of autoimmune infertility. In addition, zinc therapy (250 mg twice daily for 3 months) has a role in reducing the levels of ASAs and TNF-α and increasing that of IL-4.[91]


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