Sperm autoimmunity is an important cause of male infertility. It is present in 4% to 10% of men seen for the treatment of infertility. In some surveys of infertile men, very high proportions of positive results have been reported. The condition is important to recognize as a cause of asthenozoospermia, idiopathic infertility, or the unexpected failure of standard in vitro fertilization (in vitro fertilization (IVF). Yet, the significance of sperm autoimmunity is disputed because early tests for the detection of sperm antibodies were not very accurate, and even recent tests, such as those based on immunofluorescence, can still be misleading. It has also been suggested that screening for anti-sperm antibodies before in vitro fertilization is not cost-effective, as a positive test has a low predictive value for the failure of fertilization and the need for intracytoplasmic sperm injection (ICSI). This is an unfortunate attitude that, if extended, would result in minimal evaluation of patients and a consequent inability to counsel patients regarding their prognosis for conception without treatment, the evaluation of assisted reproductive technology results for different conditions, or the prompt consideration of alternative approaches to couples management.

Despite considerable research effort, the pathogenesis of sperm autoimmunity remains unclear. In particular, the antigens involved in sperm autoimmunity are poorly understood. Experimental models such as autoimmune orchitis and immunization with testis- or sperm-specific proteins has yet to expose the causes and mechanisms of human sperm autoimmunity. More is known about the effects of sperm antibodies, however. In the male, these antibodies can impair sperm output and function, reducing penetration of the cervical mucus and oocyte vestments and causing severe infertility. Sperm isoimmunity is an equivalent condition in females that can also produce severe infertility, although this is difficult to predict from the currently used antibody tests. The severity of the infertility associated with sperm autoimmunity and isoimmunity combined with the lack of other resultant effects elsewhere in the body both suggest that, if these conditions could be induced in a controlled manner, it is possible that they could be used to develop a method of long-term contraception. As with other organ-specific autoimmune conditions in which the autoanribody tests are positive in a considerable number of healthy people, however, sperm antibodies may also be present without an impairment of fertility. Therefore, the clinician must be careful not to over-interpret test results.

While acquired immune deficiency syndrome (AIDS) and other autoimmune diseases such as systemic lupus erythematosus, polyarteritis nodosa, and immunological hypopituitarism may also affect testicular function, these diseases will not be discussed in this post.

Definition

Sperm autoimmunity is an organ-specific autoimmune disease in which antibodies bind to sperm and impair their function, causing severe infertility. Therefore it is necessary for clinical diagnosis that there is both a positive antibody test and a test result demonstrating a detrimental effect on sperm function, typically that of impaired sperm-cervical mucus penetration. Historically, a positive Isojima sperm immobilization test in blood serum combined with impaired sperm mucus penetration tests provided a useful algorithm for the provisional diagnosis. The results were confirmed by a second set of tests before making a conclusive diagnosis of sperm autoimmunity. The criteria for impaired mucus penetration consisted of either the absence of progressively motile sperm in a mid-cycle, post-coital test (PCT), or an in vitro sperm cervical mucus contact test, or alternatively, no sperm penetration beyond 2 cm in the Kremer capillary tube cervical mucus penetration test. Since the introduction of the immunobead test in the 1980s, a positive immunobead test is used (greater than 50% of motile sperm with anti-IgA and / or anti-IgG beads bound), and a blocked Kremer test on two separate occasions. The indirect immunobead test on blood serum is used if there are no motile sperm in the semen. Positive sperm antibody tests without evidence of severe impairment of sperm function are termed “low-level sperm antibodies,” and patients with such results should not be regarded as having sperm autoimmunity. In these patients, other causes for infertility should be sought. Failure to appreciate this important distinction between clinically insignificant positive sperm antibody tests and sperm autoimmunity is probably a major cause of the confusion in the literature about the significance of the condition.

Types of Sperm Autoimmunity

Pathophysiology of Sperm Autoimmunity

Prognosis For Natural Fertility And Standard In Vitro Fertilization

Poor prognosis for fertility in men with high levels of sperm antibody activity in serum was found in early follow-up studies (Table Pregnancy Rates in Subfertile Couples with and without Sperm Autoimmunity). It must be emphasized that these data were obtained with high-titer antibody positivity only (particularly sperm immobilization test), or when blocked sperm mucus penetration was also present. Under these conditions, sperm auto-immunity causes persistent severe infertility. The authors studied 101 men with positive sperm immobilization test who were not azoospermic. Of the 14 men not tested for sperm mucus penetration, four individuals achieved pregnancies within six months without medical treatment. Eight of 15 men who had sperm mucus penetration tests showing progressively motile sperm produced pregnancies within seven months. As summarized in Table Pregnancy Rates in Subfertile Couples with and without Sperm Autoimmunity, six pregnancies occurred during follow-up review of the 72 men with positive sperm immobilization test and blocked sperm mucus penetration, and three of these pregnancies occurred with the use of glucocorticoid therapy. The pregnancy rate for these men with sperm autoimmunity (positive sperm antibody test and blocked sperm mucus penetration) was 0.67 / 100 months, compared with 2.6 / 100 months in 753 control infertile men not known to have sperm autoimmunity.

Table Pregnancy Rates in Subfertile Couples with and without Sperm Autoimmunity

Group Numberof

couples

Pregnant(%) Pregnancy rate (pregnancies/ 100 cycles)
Control (sperm antibody test negative or not done) 753 30 2.6
Sperm autoimmunity (sperm antibody test positive and blocked sperm-mucus penetration) 72 8.3 0.67
Treated by AIH (1-6 cycles) 17 5.9 1.3
Treated with testosterone esters (250 mg 2 weekly for 3 months) 15 13 2.6
Treated with prednisolone (0.5-0.75mg/kg/day, 4-6 months) 14 21 4.6
No treatment 35 2.8 0.3

Similarly low pregnancy rates with sperm autoimmunity are apparent in the literature. If the definition of sperm autoimmunity is loosened to include all sperm antibody positive patients, the spontaneous pregnancy rates are higher, approaching 1.7% per cycle.

Occasionally, sperm autoimmunity may fluctuate in severity. The rare patients who produce pregnancies without treatment appear to have spontaneous improvements in semen quality, with a fall in antibody levels and increased sperm-mucus penetration. Sperm antibodies may also decrease after relief of genital tract obstruction, but this may take many months or years to occur. As explained in the following, glucocorticoid treatment typically produces only a transient benefit.

Clinical Features

Diagnosis

Surveys comparing infertile men with and without sperm antibodies indicate that the former have longer durations of infertility and fewer previous pregnancies despite higher average sperm concentrations and less ovulatory disorders in the female partners. Sperm morility tends to be low, and sperm agglutination is common. Interestingly, however, there is no characteristic semen pattern with sperm autoimmunity. Sperm agglutination and low motility are not invariable; the semen analysis may vary from normal to azoospermic. Thus, all infertile men must be screened. The WHO laboratory manual for the examination of human semen and semen-cervical mucus interaction includes testing for sperm antibodies as a standard procedure. Either the immunobead test or the mixed antiglobulin reaction (MAR) test is recommended, although the immunobead test may be preferable, as it is a more robust test. It should be noted that the various agglutination tests and sperm immobilization test are now obsolete for clinical purposes. A positive result must be evaluated further by a sperm mucus penetration test. An alternative to screening for antibodies would be to perform a sperm mucus penetration test. If there are no motile sperm in the semen, an indirect immunobead test may be performed on blood or seminal plasma.

Differential Diagnosis

Men with sperm autoimmunity must be distinguished from those with low-level sperm autoantibodies that are not relevant to the infertility. Previous suggestions that 20% immunobead test binding should be regarded as positive were misleading. Patients with positive bead binding to less than 50% of motile sperm do not have additional impairment of fertility. Such patients have mucus penetration tests that are normal or only marginally impaired. Treatment for the antibodies is not warranted, and other causes of the couple’s infertility should be sought. Many patients with low-level sperm antibodies have immunobead binding only to the tail tips, or immunobead test results with less than 70% binding to the sperm heads.

If there are few or no sperm present in the semen, the main problem to be determined is whether the sperm antibodies are the only source of the pathology or whether there is also an obstruction or a spermatogenic disorder. Clinical features such as previous genital tract trauma, surgery, or palpable abnormalities in the epididymides or vasa may suggest obstruction, while testicular atrophy and elevated serum follicle-srimulatiing hormone (FSH) levels typically indicate a spermatogenic defect. Because the presence of sperm antibodies indicates that sperm are being produced; thus, a positive immunobead test in an azoospermic man suggests an obstructive element. A trial of glucocorticoid therapy may be useful to differentiate those patients with combined mechanical obstruction and sperm antibodies from those with azoospermia or very severe oligospermia as the result of sperm autoimmunity alone. In the latter case, there may be a dramatic increase in sperm output.

Treatment of Sperm Autoimmunity

Glucocorticoid Treatment of Sperm Autoimmunity

Other Possible Treatments

Testosterone suppression of spermatogenesis, artificial insemination (AI), washing sperm to remove sperm antibodies, antibiotic therapy, and in vitro fertilization or gamete intra-fallopian transfer (GIFT) without prior prednisolone therapy are ineffective for sperm autoimmunity. Reports in the literature claiming success for these procedures do not separate patients with low-level sperm antibodies. Lahteenmaki et al. performed a trial in 31 men with positive anti-sperm antibodies in order to compare inrrauterine insemination (IUI) with low-dose prednisolone and timed intercourse. The latter course of treatment had a poorer outcome than the IUI without glucocorticoid therapy. Similarly, IUI was compared with in vitro fertilization for patients with a positive MAR of greater than 50%, with no difference in results.

Also worthy of consideration are surgeries to relieve obstructions, such as repeat vasovasostomy and vasoepididymostomy, or the removal of an orchiric tesris. Some experts suggest that partial obstruction is a more important cause of the development of sperm antibodies. In one open study, sperm antibody titers were reportedly decreased after the treatment of prostatitis.

Separation of sperm with less antibodies on the surface from those that are more heavily coated is possible in patients with low-level antibodies. This fact is not helpful for treatment, however, since the antibodies in such patients are not present in sufficient quantity to cause severe infertility. Removal of sperm-bound antibodies by washing cannot be successful due to the seven-day half-life of antibody-antigen dissociation interactions. It is possible that enzyme methods may be more successful, such as in the example of IgA protease. The use of pure antigen to block binding has also been considered. In the future, immunomodulatory approaches may be available. Preliminary results with Levamisol and Cyclosporin have been reported. Other approaches using Fab fragments and anti-idiotypic antibodies have been postulated.

Conclusion

Sperm autoimmunity is an important cause of male infertility and it should be screened for routinely. Diagnosis should be made only after repeated tests demonstrate positive immunobead test and failure of sperm cervical mucus penetration. Patients with these characteristics are severely infertile and are unlikely to produce pregnancies without treatment with intracytoplasmic sperm injection or glucocorricoids. These treatments have limited success rates and severe side effects are possible. Donor insemination or adoption may be a suitable alternative for some couples.

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