© Springer International Publishing Switzerland 2017
Walter K.H. Krause and Rajesh K. Naz (eds.)Immune Infertility10.1007/978-3-319-40788-3_1616. Treatment Modalities for Antisperm Antibodies-Mediated Immune Infertility
(1)
Department of Obstetrics and Gynecology, West Virginia University, School of Medicine, 2085 Robert C. Byrd Health Sciences Center North, Morgantown, WV 26506, USA
Abstract
Immune infertility due to antisperm antibodies is an important cause of infertility in humans. The incidence of ASA in infertile couples is 9–36 % depending on the reporting center. ASA directed against the fertilization-related antigens are more relevant to infertility than the immunoglobulin binding to sperm antigens that do not play a role in fertility. Several methods have been reported for treatment of immune infertility. These include immunosuppressive therapies using corticosteroids or cyclosporine; assisted reproductive technologies such as intrauterine insemination, gamete intrafallopian transfer, in vitro fertilization, and intracytoplasmic sperm injection; and laboratory techniques such as sperm washing, immunomagnetic sperm separation, proteolytic enzyme treatment, and use of immunobeads. Some of these available techniques have side effects, and others are invasive and expensive, with low efficacy, and provide conflicting results. Presently, antisperm antibodies-mediated immune infertility is primarily treated in the clinics using the assisted reproductive technologies. Recent findings on delineating sperm antigens that have a role in fertilization/fertility may provide novel modalities for treatment which will be less invasive and expensive.
16.1 Introduction
Antisperm antibodies (ASA) can cause infertility. Incidents of antisperm immunity in infertile couples are 9–36 %, depending on the reporting center [7, 15, 40, 54]. ASA reactive with sperm antigens that are involved in fertilization and expressed on the surface for antibody binding are more relevant to infertility. Also, these antibodies have to be present in the genital tract secretions of a female partner or bound on the sperm surface in a male partner in sufficient amount to cause infertility effects. The kinetics, valency, and class/subclass of antibodies play an important role in defining the significance of ASA in infertility.
Although there are several articles written on various aspects of immune infertility, there are only a few covering the therapeutic treatment modalities for male and female immune infertility. The aim of this chapter is to review the conventional treatment methods for immune infertility, discuss their relative merits and limitations, and describe the recent novel perspectives that are being investigated. The focus of the chapter is on antisperm antibodies-mediated immune infertility and not on pregnancy loss due to immune dysfunction. A PubMed search (1971–2015) was performed using keywords: “immune infertility,” “antisperm antibodies,” and “treatment of immune infertility.” All of the articles were read, and also the articles referenced in these publications were thoroughly examined.
16.2 Discussion
Although the understanding of etiology of ASA has increased, the therapeutic measures have not made the same strides [46]. Various treatment methods available at present can be divided broadly into four categories: immunosuppressive therapies, assisted reproductive technologies (ART), laboratory techniques, and novel recent perspectives using defined sperm antigens.
16.2.1 Immunosuppressive Therapies
The method of immunosuppression that has been most commonly used is corticosteroid therapy. Pregnancy rates of 6–50 % have been reported after corticosteroid therapy [56]. However, almost all studies reported in the literature for the effect of steroid treatment on immunosuppression of ASA titers lack appropriate placebo controls, have employed different doses and regimens of various immunosuppressive drugs, and have used different laboratory techniques to monitor the ASA titers to examine the effect of drug treatment. These factors make it difficult to compare and conclude whether or not immunosuppression is indeed effective in the treatment of immune infertility.
Two of the clinical trials had appropriate placebo controls and are worth describing here. One study conducted a 6-month randomized trial using high dose of prednisolone given through cycle days 1–10 of the female partner, which was then tapered rapidly for the next 2 days [27]. The steroid treatment group resulted in a pregnancy rate of 31 % compared with 9 % in the placebo group. Another prospective, double-blind, placebo-controlled study included 43 men that had ASA bound to sperm [25]. Of these, 24 were given methylprednisolone and 19 received placebo for three cycles. There was a statistically significant decrease in sperm-associated IgG, but not IgA, in the steroid treatment group and not in the placebo group. However, in spite of decrease in the antibody titer, there was no statistically significant difference in pregnancy outcome between the two groups.
The efficacy of steroid treatment, if any, must be judged against the potential adverse side effects. The steroid therapy could cause several side effects [55]. The potential adverse effects and lack of effectiveness in many cases have decreased the enthusiasm for use of steroids for treatment of immunologic infertility. As an alternative, cyclosporine was tested in a cohort of men with ASA. After treatment, a pregnancy rate of 33 % was observed [9]. Since this study did not have placebo controls, no definite conclusions can be drawn.
16.2.2 Assisted Reproductive Technologies (ART)
Recently ART have been used to treat ASA. Several studies have examined the use of intrauterine insemination (IUI), gamete intrafallopian transfer (GIFT), in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI) procedures for the treatment of immune infertility in men and women as discussed below.
16.2.2.1 IUI Procedure
IUI has been found to be useful for treatment of ASA-positive infertile men and women. Theoretically, it should circumvent problems related to sperm transport in the female genital tract especially sperm passage through the cervical canal/mucus. However, in women having ASA in the cervical mucus, pregnancy rates after IUI were identical to women who did not have ASA, if the male partner did not have ASA or male factor infertility [13]. In two other studies of female sperm immunity, IUI treatment did not increase the pregnancy rates per couple or per cycle [23, 37]. However, the pregnancy outcome significantly improved after including the ovarian hyperstimulation treatment along with IUI.
IUI also has been found to enhance pregnancy rates in some cases of ASA-positive infertile men. A 56 % pregnancy rate has been reported after IUI procedure in ASA-positive infertile men, who had a poor postcoital test, compared with an 83 % pregnancy rate in ASA-negative infertile men, who also had a poor postcoital test [12]. In another study, after IUI, the pregnancy outcomes in 19 couples having male immune infertility were compared with 86 couples having other diagnoses. No pregnancy was seen in 110 IUIs in the ASA-positive group (0 %) versus a 26 % pregnancy rate per couple and 5.6 % cycle fecundity in the control group [21]. From the Cleveland Clinic Foundation, Agarwal compared 42 ASA-positive couples with 117 ASA-negative infertile couples who were treated with sperm washing and IUI over a 2-year period [5]. There were 15 pregnancies in the ASA-positive group compared with 37 for the entire group.
Another study compared IUI with oral steroid therapy [34]. This study included 46 couples in which the male partner had ASA. The immune infertile men either received 20 mg/day of prednisolone for days 1–10 followed by 5 mg/day for days 11 and 12 of the cycle and timed intercourse or underwent IUI with no steroid treatment for three cycles. The couple was switched to the other group if not pregnant. The pregnancy rate before switching for the IUI group was 16.7 % and for the steroid group was 0 %. After switching, one more pregnancy occurred in the IUI group and one in the steroid group. This study concluded that IUI is better than low-dose steroid therapy for treating male immune infertility.
It is not clear, theoretically speaking, how IUI can circumvent male immune infertility. Washing the sperm in the incubation medium should not elute the antibodies bound to the sperm surface proteins, unless: (a) these antibodies are directed against the adsorbed seminal plasma proteins that are shed off during capacitation/acrosome reaction, (b) the antibodies are of low binding affinity, which does not seem to be the case in immune infertility, and/or (c) the swim-up sperm used for IUI are not coated with antibodies like non-swim-up sperm, which also seems highly unlikely.
There are mixed reports on simple sperm washing on ASA elution from various laboratories. Adeghe [2] found that washing decreased IgG bound on the sperm surface. Another group [58] did not find the similar positive effects, nor did Haas and associates [26], even after subjecting the sperm to multiple washings. Antibodies were also not reduced by passing sperm through percoll gradient [6].
16.2.2.2 GIFT Procedure
In GIFT procedure, sperm and eggs are mixed in vitro and then transferred to the fallopian tubes for fertilization. Theoretically speaking, there is not a strong rationale to how it will help either the ASA-positive infertile men or women. Nevertheless, in one study, GIFT was performed in 16 immune infertile couples. This group achieved pregnancy rates of 43 % per couple and 24 % per cycle [57]. This study did not include any control group, and the pregnancy rates are comparable to those that are reported after GIFT in patients having other etiologies.
16.2.2.3 IVF Procedure
Several studies have shown decreased rates of oocyte fertilization in IVF in immune infertile patients [30]. An inverse relationship between ASA titers and fertilization rates has been reported [19]. In a study, 33 ASA-positive infertile couples were subjected to 47 IVF cycles [32]. The couples with high ASA titers had lower fertilization rates than those with lower ASA titers. In contrast, there are also studies that found fertilization to be identical in ASA-positive and ASA-negative population [17]. Interestingly, there are also studies reporting increased rates of IVF outcome including implantation and pregnancy rates in ASA-positive infertile women compared to women with tubal factor infertility [16]. In IVF procedure, generally albumin instead of female partner’s serum is used as a protein source in the insemination medium that circumvents the antibodies if present in the female partner. Thus, theoretically speaking, IVF can take care of female but not male immune infertility. Indeed, fertilization and pregnancies have been achieved using oocytes from ASA-positive infertile women where the men had normal semen analysis and were free of ASA [1, 62]. In ASA-positive infertile men, both the class/subclass specificity and subcellular localization of the antibodies on sperm have been correlated with various degrees of fertilization failure rates in IVF [54]. ASA that bind to the sperm head may decrease fertilization more than ASA bound to midpiece or tail regions of the sperm cell. In the IVF procedures involving 21 immune infertile couples, it was found that the couples that had ASA bound to the head region of the sperm cell showed more fertilization failure than those having ASA bound to the tail region [62]. Yeh and associates [59] reported that IgA significantly reduces fertilization rates in IVF procedure only when it was associated with IgM and was present on the sperm head. Equality of embryo obtained after IVF using sperm from ASA-positive men is generally poor compared to sperm from ASA-negative men [33, 36].
16.2.2.4 ICSI Procedure
IVF with ICSI have become a routine and widely acceptable procedure in the clinics. In ICSI procedure, a single sperm is injected into the cytoplasm of the oocyte. ICSI has been tried using sperm of ASA-positive infertile men. Two of these studies are worth mentioning here. One study subjected 29 infertile ASA-positive couples to ICSI; 22 of them were tested before in IVF procedure and had poor fertilization rate (6 %) [33]. After ICSI, the fertilization (79 %) and cleavage (89 %) rates in the ASA-positive group were similar to those (68 % and 93 %, respectively) in the ASA-negative group. Surprisingly, 46 % of the pregnancies in the ASA-positive group ended in spontaneous pregnancy loss compared with none in the ASA-negative group. In contrast, another study did not demonstrate any difference in pregnancy rates (30 %) between the ASA-positive and ASA-negative group undergoing ICSI procedure [42].
Recently, meta-analysis was performed to obtain an odds ratio (OR) for the effect of ASA on pregnancy rates using IVF or ICSI [61]. This study analyzed 16 studies (10 IVF and 6 ICSI). The meta-analysis revealed that the combined OR for failure to achieve a pregnancy using IVF or ICSI in the presence of positive semen ASA was 1.22 (95 % Cl: 0.84, 1.77) and 1.00 (95 % Cl: 0.72, 1.38), respectively. The overall (IVF and ICSI) combined OR was 1.08 (95 % Cl: 0.85, 1.38). The meta-analysis indicated that semen ASA are not related to pregnancy rates after IVF or ICSI. However, all these studies ASA were sperm-reactive immunoglobulins, rather than fertility antigens-related antibodies [14, 53].
16.2.2.5 Postfertilization Effects of ASA
Some antisperm antibodies can have deleterious postfertilization effects on developing preimplantation embryos [3, 4, 38, 44]. ASA can affect early embryonic development if: (a) an oocyte is fertilized with a sperm cell, which carries these specific antibodies into the ooplasm, and/or (b) these antibodies are cross-reactive with the antigens present on the developing embryos. Some of these antigens and antibodies have been characterized, and the cDNA encoding for a few of these antigens has also been cloned and sequenced [29]. Using the ICSI procedure in immunoinfertile men, one can achieve higher fertilization rates than using the IVF procedure; however, the fertilized zygotes show higher degeneration and mortality and decreased embryonic development.
16.2.3 Laboratory Techniques
Several innovative laboratory techniques have been investigated and can broadly be classified into two categories: (1) methods that prevent binding of ASA to sperm or elute the bound ASA from sperm surface and (2) methods that separate ASA-free sperm from ASA-coated sperm. Although these methods have been explored extensively, due to conflicting findings, these techniques have not been accepted as the methods for treatment in the clinics. Some of these reports and their findings are discussed below.
It was erroneously thought that ASA bind to sperm during and/or just after ejaculation and the antibodies are mostly present in the secretions of prostate and seminal vesicles. Based upon this notion, the antibodies and the sperm are present and ejaculated in different fractions of the semen. To avoid binding of antibodies to sperm, splitting the semen into various fractions during ejaculation was attempted in various laboratories. However, it has been proven ineffective in decreasing ASA binding to sperm [35]. Collection of semen into insemination medium containing high concentrations of fetal cord/maternal serum has also been investigated to examine if it would decrease the antibody binding to sperm. Two studies [11, 18] observed that semen collection into serum-supplemented medium results in increased fertilization rates in IVF procedure, and one of these studies also showed an increase in pregnancy rates. We conducted a study to investigate at which site of the male genital tract the antibodies percolate from serum to bind to sperm [49]. I125 labeled antibodies to sperm-specific FA-1 antigen were injected intravenously into male mice. The results indicate that the antibodies preferentially transude into epididymis (especially corpus or caudal regions) and vas deferens to bind to sperm cells and not into testes. These findings indicate that in men ASA bind to sperm before ejaculation via transudation through epididymis, vas deferens, and probably rete-testis.
The immunomagnetic separation technique has been tried to separate the antibodies bound on the sperm surface [20]. The sperm with antibodies are tagged with anti-immunoglobulin antibodies coupled to magnetic microspheres, and then magnetic field is applied. However, limited success in isolating sufficient number of ASA-free sperm of good motility makes this procedure theoretically interesting but clinically an unacceptable procedure.
Bronson suggested that protease treatment may be utilized to destroy antibodies on the sperm surface [10]. Kutteh and associates reported that IgA1 protease treatment was effective in reducing IgA on sperm [31]. In another study, incubation of sperm with chymotrypsin before IUI resulted in a 25 % cycle fecundity versus 3 % in controls [8]. However, this needs to be examined whether or not the treatment with proteolytic enzymes affect proteins especially the oocyte binding receptors present on the sperm surface [28].
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