Immunological Factors & Infertility

by Dan Gehlbach, M.D. & Gilbert G. Hass, Jr., M.D.

Center for Reproductive Health, PC
1000 N. Lincoln Blvd, Suite 300
Oklahoma City, OK 73104
(405) 271-9200

Introduction

The immune system provides us with a multilayer defense against invading microbes and foreign intruders. It can recognize the difference between normal (self) and alien (non-self) cells, trigger a local or widespread inflammatory response, and retain the memory of the offending organism to repel it again if it should ever return. Like any finely-tuned machine, however, the system can break down and leave us open to the threat of infection, or, conversely, turn against our own healthy tissues, as occurs in such diseases as rheumatoid arthritis or lupus.

The immune system also plays an important role in human reproduction. Inflammatory cells and their secretory products are involved in the processes of ovulation and preparation of the endometrium for implantation of a fertilized egg. Dysfunction of the immune system can interfere with the normal reproductive processes and result in infertility. It has been estimated that an immune factor may be involved in up to 20% of couples with otherwise unexplained infertility. Although many of these associations with infertility remain unproven, there is solid scientific evidence to implicate the formation of antibodies against sperm as an important infertility factor.

Antisperm Antibodies: How common are they?

Sperm are relatively protected from the immune system by a natural protective mechanism called the blood-testes barrier. Tight connections between the cells lining the male reproductive tract keep immune cells from gaining entry to the sperm within. If an injury breaches this barrier, then the immune system has access to sperm and antibodies are formed.

Antisperm antibodies have been reported in approximately 10% of infertile men, compared to less than 1% of fertile men. The prevalence of antibodies jumps dramatically in men who have had surgery on their reproductive tract: nearly 70% of men who have undergone a vasectomy reversal will have antibodies present on their sperm. Women have a much lower chance for developing antibodies to sperm: less than 5% of infertile women can be shown to have antisperm antibodies, and it is unclear who is at risk for their formation.

Who is at risk for antisperm antibodies?

Anything that disrupts the normal blood-testes barrier can result in the formation of antisperm antibodies. This may include any of the following conditions:
Vasectomy reversal
Varicocele (dilation of the veins surrounding the spermatic cord)
Testicular torsion (twisting of the testicle)
Congenital absence of the vas deferens
Testicular biopsy
Cryptorchidism (failure of testicular descent)
Testicular cancer
Infection (orchitis, prostatitis)
Inguinal hernia repair prior to puberty

Fortunately, intrauterine insemination (the placement of washed sperm into the uterine cavity - a common fertility treatment) has not been shown to cause antisperm antibody formation.

Despite the long list of risk factors, most men with antisperm antibodies have not had any of the conditions listed above. Therefore all infertile men are potentially at risk, and consideration should be given to testing infertile men for antisperm antibodies, especially if no other reasons for the infertility have been detected by the diagnostic workup.

How do antisperm antibodies cause infertility?

Antibodies that attach to the sperm may impair motility and make it harder for them to penetrate the cervical mucus and gain entrance to the egg; they may also cause the sperm to clump together, which is occasionally noted on a routine semen analysis. Antibodies may also interfere with the ability of the sperm to fertilize the egg.

What is the best way to detect antisperm antibodies?

Over the years, many tests have been developed to detect antisperm antibodies. In women, blood tests for antisperm antibodies in women may be more practical than trying to measure antibodies in the cervical mucus, which is the primary site where her immune system interacts with sperm. The postcoital test, which has been a standard part of the infertility evaluation, may suggest the presence of antisperm antibodies. By examining the cervical mucus following intercourse near the time of ovulation, antisperm antibodies may result in either a lack of sperm or in the presence of sperm, which are shaking in place rather than actively swimming through the mucus.

In men, a direct examination of their sperm for attached antibodies is more reliable than testing blood for the presence of antibodies. Two commonly used tests are the immunobead assay and the mixed agglutination reaction (MAR). Both tests use antibodies bound to a small marker, such as plastic beads or red blood cells, which will attach to sperm that have antibodies on their surface. The results are read as a percentage of sperm bound by antibodies.

What treatments are available for antisperm antibodies?

Suppressing the immune system with corticosteroids may decrease the production of antibodies but can result in serious side effects, including severe damage to the hipbone. Intrauterine insemination, with or without the use of fertility medications, has been used for the treatment of antisperm antibodies. It is believed to work by delivering the sperm directly into the uterus and fallopian tubes, thus bypassing the cervical mucus.

In vitro fertilization appears to be the most effective treatment for antisperm antibodies, especially when there are very high levels of antibodies (near 100% of sperm are bound by antibodies). There is no clear guidance on whether intracytoplasmic sperm injection (ICSI), the direct fertilization of an egg with a single sperm, is required for the treatment of antisperm antibodies, unless there had been a complete absence of fertilization on a prior attempt at in vitro fertilization


Are there other antibodies that affect fertility?

For women with recurrent miscarriage, there are a group of antibodies that appear to attack an early developing pregnancy, resulting in either a miscarriage or severe preeclampsia with risk of intrauterine growth retardation or even fetal death. Collectively these belong to a class of antibodies known as antiphospholipid antibodies, which include the lupus anticoagulant and the anticardiolipin antibody. Testing for these antibodies are an integral part of the workup for recurrent pregnancy loss. However, it is unclear whether these antibodies play any role in the ability to conceive. Some physicians believe that the presence of antiphospholipid antibodies may decrease the chance for pregnancy through in vitro fertilization. Although this is a controversial subject, one of the largest studies that looked for these antibodies in women undergoing in vitro fertilization found that these antibodies were no more likely to be detected in those who did not become pregnant as in women who did conceive.