© Springer International Publishing Switzerland 2017
Walter K.H. Krause and Rajesh K. Naz (eds.)Immune Infertility10.1007/978-3-319-40788-3_1515. Sperm Antibodies and Assisted Reproduction
(1)
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Cooper Medical School of Rowan University, Camden, NJ, USA
(2)
Cooper Institute for Reproductive Hormone Disorders, P.C., Mt. Laurel, NJ, USA
Abstract
The presence of antisperm antibodies (ASA) coating sperm can be a cause of infertility. However, their presence is not an invariable cause of infertility. This lack of consistency may be related to the percentage of sperm that are coated with the ASA or the concentration of ASA on each sperm. Also sometimes the explanation for achieving a pregnancy despite the presence of ASA may be related to the ASA directed against inert antigens. Based on studies showing very poor pregnancy rates following intrauterine insemination (IUI) of sperm where 100 % are coated with ASA, one can make a reasonable assumption that the majority of males with a high percentage of their sperm coated with ASA will be a factor causing a couple’s infertility. Another reasonable assumption is that the majority of ASA must effect the fertilization process as the negative effects of immobilizing ASA would be circumvented by IUI. One of the best treatment options for overcoming ASA is to perform in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI). Though conventional insemination of oocytes may be more effective than IUI, the ASA can sometimes lead to failure of sperm to bind to the zona pellucida leading to low fertilization rates. Unfortunately, IVF with ICSI is very expensive. A less expensive option is to try to neutralize the adverse effects of the ASA before IUI. There is evidence that this can be accomplished by treatment of the sperm prior to IUI with a protein digestive enzyme, e.g., chymotrypsin.
15.1 Introduction
A very recent manuscript was published by a group well known to the andrology field entitled “Functional defect of sperm and fertility impairment in men with antisperm antibodies” by Bozbedomov et al. [4]. In their introduction, they mention that “antisperm antibodies (ASA) have been detected in 8–21 % of infertile men; however the presence of ASA has also been detected in 12–19 % of fertile men” [4]. They quote references from Krause et al., Francavilla and Barbonetti, Vasquez-Leven et al. [4, 24, 30, 46].
The study by Bozbedomov et al. discusses the results of the largest study to date, which evaluated 1794 infertile couples by Leushuis et al. [4, 33]. The conclusion from this study states “that the MAR test is not able to predict spontaneous pregnancy chances.” Their conclusion from Leushuis et al. about measuring ASA was that “It’s routine use in the basic fertility workup for identification of couples with low spontaneous pregnancy chances is not justified when a threshold of >50 % is used” [33].
The results of these studies suggested no higher frequency of significant ASA levels (>50 %) in fertile vs. subfertile males and no evidence of a significant impairment of fertility even when ASA are present. This has led to the majority of present day infertility specialists abolishing the measuring of ASA in their routine practice.
The objective of this manuscript is to explore whether it is useful to measure ASA routinely or in certain specific circumstances. In addition, this manuscript will also examine if their presence should influence treatment by assisted reproductive technology, i.e., intrauterine insemination (IUI) or in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI). If routine measurement of ASA is not recommended, an objective of this article is to carefully review the literature to determine if there are any specific circumstances that would warrant ASA testing. Another objective is to consider whether the seemingly lack of correlation between ASA and fertility outcome or lack of increased frequency of ASA in infertile couples may actually be related to the parameters set for a positive ASA level. This study will address if the cutoff of >50 % is too low, i.e., will levels >80 % or levels restricted to 100 % show better correlation. Finally, the intent of this manuscript is to explore the relative value of treatment options in infertile cases that seem to be related in part, or in whole, to ASA, i.e., is IVF with ICSI the best option? How do other treatment options, e.g., intrauterine insemination (IUI) compare? Are there other methods to improve the success of IUI when ASA are present?
15.1.1 Mechanism by Which ASA May Impair Fecundity
- 1.
Interference with sperm progression through cervical mucus and thus preventing sperm access into the uterine cavity.
It has been known for over two decades that when sperm are laden with ASA, this can impair sperm progression through the cervical mucus, even if there does not appear to be any detriment to sperm motility upon evaluating the semen analysis or not finding sperm agglutination [19, 22, 36].
Probably the best way to detect if there is the presence of immobilizing antibodies is to find the absence of sperm progressing through the cervical mucus on postcoital testing [9]. However, recently the Practice Committee from the American Society of Reproductive Medicine considered the postcoital test to be an archaic test and recommended against its routine use [42]. Nevertheless, they did state that in the hands of some clinicians the test has value [42]. Part of the problem with interpreting the value of the postcoital test is the lack of standardization, e.g., how long after intercourse to perform the test, how many sperm should be present per high powered field to consider the test normal, and the need for precision of the timing of the test. The author’s preference is to perform the postcoital test in natural cycles, 8–12 h after intercourse when the serum estradiol exceeds 200 pg/mL with the serum progesterone level <1.5 ng/mL but preferably <1 ng/mL, and before the luteinizing hormone (LH) surge [7].
The reason why antisperm antibodies do not immobilize the sperm in the ejaculate is because of the absence of complement in the seminal plasma [19]. The cervical mucus, however, does contain complement, and thus the ASA-complement reaction causes sperm immobilization, thus impairing sperm penetration through the cervical mucus [19]. However, a certain amount of time is needed for this ASA-complement reaction to occur and that is why one should wait perhaps 8 h from intercourse to perform the postcoital test when screening for ASA immobilization antibodies.
If ASA causing immobilization is the main type of problem, theoretically simple IUI should overcome the problem. There has been a tendency for most infertility specialists to give the infertile couple the option of an IUI or an IVF cycle no matter what seems to be the etiologic factor. Thus, based on performing IUI as a routine, if indeed the majority of those with ASA have exclusive immobilizing antibodies, and IUI overcomes the problems, the tendency for routinely performing IUI could justify not measuring for ASA when performing semen analysis and also not doing a postcoital test. In contrast, if a postcoital test is performed correctly, and the results showed a poor postcoital test despite the presence of normal appearing cervical mucus quality and normal standard semen parameters, this would otherwise alert the physician to measure ASA [9]. This would be especially important for physicians who do not routinely treat every woman with IUI.
The peak quality cervical mucus may be 36–40 h before ovulation. The theoretical advantage of performing an IUI is to allow sperm to enter the uterine cavity at the time of ovulation when the cervical mucus quality generally wanes, and thus prohibits sperm movement [7]. However, IUI can considerably increase the cost of conceiving (either to the patient or to the insurance company). There are data suggesting that IUI does not improve pregnancy rates in infertile couples where semen parameters are normal and postcoital tests are adequate [16]. Related to a tendency for infertility specialists to favor expensive IVF procedures, for economical reasons there has become a trend for the obstetrician gynecologist (OB/GYN) to initially investigate and treat infertility before referring to an infertility specialist. Because the OB/GYN’s are generally not equipped to perform IUI, they must rely on the postcoital test. The OB/GYN generalist may be the most likely physician to order sperm ASA if faced with normal sperm and a poor postcoital test despite normal mucus quality and a normal semen analysis [8].
- 2.
Evidence that ASA may impair conception in other ways than inhibiting cervical mucus penetration:
There are various sites of potential ASA action. There is evidence that ASA can affect sperm-zona binding and/or zona-induced acrosome reaction [2, 23, 34, 45, 48]. Antibodies to the sperm antigen FA-1, which is found in the sperm membrane, can interfere with zona binding [28, 38, 39]. Another protein, IZUMO, is found in the acrosomal region of intact sperm and the equatorial segment of reacted sperm [26]. This protein is involved in sperm-oolemma fusion. The YLP-12 antigen is located in the acrosome and is functional in both the acrosome reaction and zona pellucida binding [40]. Of course there is the possibility that ASA can sometimes be directed to inert proteins not involved in the conception process.
Is there any evidence that ASA other than immobilizing antibodies when present play a significant role in infertility? Suggestive evidence that ASA effecting zona binding, acrosome reaction, or other negative effects on fecundity was provided by Francavilla et al., who found no live pregnancies following 119 IUI cycles when ASA was present in 100 % of the sperm [25]. If immobilizing ASA was the only immunoglobulin involved, IUI should have been successful. The study by Francavilla et al. suggests that if ASA may be directed against inert sperm proteins, exclusive ASA related to antigens not impairing fertility are not common [25].
If ASA other than immobilizing antibodies, e.g., ones that interfere with sperm binding to the zona pellucida, play a significant role in causing infertility, one would expect reduced fertilization rates and lower pregnancy rates following conventional oocyte insemination. Indeed the first publication exploring the effect of ASA claimed that ASA adversely affected fertilization rates [27]. However, subsequently, other studies did not support these findings [44, 47]. These studies failing to support ASA as a negative factor for conventional insemination suffered from inadequate power and a generous range of what they considered positive for ASA [44, 47]. For example, the study by Vujisic et al. only evaluated 14 patients, they used a cutoff of only 20 % for positive ASA, and there were only four men with ASA over 75 % [47]. However, more studies, supporting the original premise of ASA reducing fertilization, were published [1, 5, 21, 31, 35, 43]. Again the percentage of couples used whose male partner had 100 % of the sperm coated by ASA vs. 50 % (some even call positive ASA at 20 %) could explain the differences in outcome.
Some of the studies finding no significant differences in frequency of sperm with ASA present in fertile vs. nonfertile couples may be related to too low of a threshold for a positive test. Perhaps to be able to ensure a likelihood of an adverse effect of ASA, one should consider a positive test as >80 %. Using an 80 % cutoff, we found the presence of ASA in 3.54 % of 6551 male partners of couples with infertility and it was 4.22 % using a 50 % cutoff and 1.8 with a 100 % cutoff (unpublished data).
15.1.2 Treating Sperm Bound with ASA with Chymotrypsin Galactose Prior to IUI
A study was performed involving 16 couples where all infertility factors were corrected except a poor properly timed postcoital test (no sperm with progressive linear motion) despite what appeared to be appropriate quality cervical mucus [3]. Furthermore, the male partner was found by immunobead testing to have >50 % of sperm with ASA. Intrauterine insemination was performed with all the males ejaculating into 5 ml of equal parts of modified human tubal fluid buffered with HEPES solution and 7.5 % bovine serum albumin in an attempt to dilute the sperm to theoretically negate the attachment of antibodies at the time of ejaculation. Another group ejaculated into media with the protein digestive enzyme chymotrypsin with galactose in order to cleave part of the ASA immunoglobulin molecule to neutralize its function prior to sperm washing. The 16 couples were randomly assigned one of the two sperm preparations, and if no pregnancy was achieved, the other preparation was used for the second cycle of treatment [3]. With each failure, they were switched to the other protocol for the next treatment [3]. There were 65 treatment cycles – 32 with chymotrypsin/galactose and 33 with albumin. Pregnancies were achieved in 8 of 32 (25 %) cycles following IUI with chymotrypsin/galactose vs. only one of 33 (3 %) performed with sperm ejaculated into albumin fortified media [3]. When 100 % of sperm was found to be coated by ASA, Francavilla et al. found no live pregnancies following 119 IUI cycles [25]. In contrast, a pregnancy rate of 25 % per cycle was found following IUI with chymotrypsin-treated sperm when evaluating the subset of couples whose male partner had 100 % of the sperm coated with ASA [3].
Interestingly the pregnancy rate for female partners of males with 100 % ASA was 75 % with three treatment cycles when treated with chymotrypsin/galactose. This suggests that the antibodies that may inhibit the fertilization process rather than the antibodies that impede sperm from reaching the oocyte play a significant role in infertility and they need to be neutralized prior to insemination. Though IUI is less expensive than IVF, nevertheless, it still adds expense and missed time at work. Though significant levels may only be present in <5 % of the couples, theoretically, it makes sense to measure this potential infertility factor prior to initiating any therapy. There do not appear to be any subsequent studies refuting or corroborating the beneficial effects of treating sperm with chymotrypsin/galactose prior to IUI.
15.1.3 The Use of In Vitro Fertilization (IVF) with Intracytoplasmic Sperm Injection (ICSI) for Treating ASA Related Infertility
The patient’s choice of IUI or IVF with ICSI is frequently determined by economics and rules of the insurance companies. Most insurances that cover IVF-ET and ICSI will approve this procedure if a high percentage of the sperm are laden with ASA. Nevertheless those without sufficient funds or insurance coverage may elect to try IUI first. Based on the poor pregnancy rates demonstrated by Francavilla et al., and the good success rates demonstrated by Bollendorf et al. with sperm first pretreated with chymotrypsin/galactose, if IUI is planned, it makes more sense to first treat with the aforementioned protein digestive enzyme [3, 25].
However, experience dictates that most treating physicians are not aware that enzymatic pretreatment before IUI is an option. Even if they read about the procedure, they may be reluctant to use it because of lack of experience. Thus, if ASA is detected on the sperm, and if the decision is made to try IUI first, many infertility specialists will perform the procedure without any pretreatment of the sperm hoping that either the antibodies are directed to inert antigens or merely to immobilizing antibodies, and therefore, in theory, by bypassing the cervical mucus, IUI would overcome the problem.
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