Immunological Testing and Treatment for Infertility

Immunological Testing and Treatment for Infertility

A new ELISA-based hormonal test, measuring the levels of Inhibin B in serum on day 3 of the menstrual cycle. Since only the Follicular Granulosa cells secrete this hormone, its level reflects on the potential of the ovary to grow follicles, which physicians refer to as 'ovarian reserve'. Women with low levels of the hormone were found to have more impaired ovulation in the course of the IVF cycle, lower pregnancy rates, higher cancellation rates and higher abortion rates. Inhibin B is secreted by the granulosa cells while estradiol is secreted by several other cell types in the ovary. Thus the Day 3 Inhibin B test provides the physician with a more direct and appropriate measure of 'ovarian reserve', compared to the currently used indirect FSH measurement (FSH is secreted by the pituitary gland). It may provide the couple some qualitative estimate of success in future cycles of artificial reproductive techniques. This information may also be used by couples to decide whether to try IUI, ART or to resort to another solution such as donor egg or adoption.

Treatments - If Day 3 Inhibin B is abnormally low with a positive Anti-Ovarian Antibody test; then treat for Anti-Ovarian Antibodies with Dexamethasone or Prednisone. Consult a reproductive immunologist before treatment for Premature Ovarian Failure. Treatment should start on day one of the cycle. For low responders to induction of ovulation, treatment is also to start on day one of the cycle. If Day 3 Inhibin B is abnormally low with a negative Anti-Ovarian Antibody test; then increase Hmg dosage. If this is not successful, an egg donor is indicated.

Anti Phospholipid Antibody (APA)

An ELISA-based test to evaluate and quantify the presence of any one of 9 different species of antibodies to 3 different phospholipids in the woman. Elevated concentrations of these antibodies are thought to interfere with feto-maternal blood flow due to enhanced blood clotting-related functions. Anti Phospholipid Antibody may also interfere with the formation of the syncithiotrophoblast formation which is an important function of implantation. These impairments may lead to retardation of fetal development, first trimester abortions or in extreme cases interference with the embryo implantation in the uterus. The test is usually ordered for women with failed IVF cycles, recurrent pregnancy loss (natural or following ART procedures). Positive tests results necessitate treatment which counteract the enhanced clotting functions associated with the antibodies and allow normal blood flow to the fetus.

Treatments - (APA) & (ACA) - If any one or more of the 12 tests is moderately positive or high, the recommended treatment is a low dose of aspirin taken orally daily, starting 10 days prior to ovulation. Heparin may be given in addition to the baby aspirin at the end of menses. IVIG has recently been written up as a recommended treatment.

Anti Cardiolipin Antibody (ACA)

An ELISA test measuring three different species of antibodies to the phospholipid cardiolipin. This test is essentially an anti phospholipid antibody test, with all features similar to those of the APA. Its 'stand alone' status is solely due to historical reasons. It is clear today that the phospholipid testing must cover as many as possible different phospholipids since serum samples found negative for ACA may be positive for other phospholipids. Such samples would be diagnosed falsely negative if ACA was performed without APA.

Treatments - see APA (above)

NK Cell Test

A new white blood cell typing analysis, using fluorescence-tagged (flow cytometry) antibodies to specific markers on the surface of those cells. When activated, NK cells function to fight, kill and destroy their targets and their excessive numbers in blood, and very likely in the uterine tissue, was correlated with pregnancy loss and reduced success in IVF cycle outcome. The test is recommended within the first trimester of pregnancy but elevated levels may be detectable earlier. Positive test results may indicate a few types of therapeutic treatments all aimed at suppressing the immune response for the early parts of the pregnancy, thus alleviating the woman of this fetus-rejecting activity and allowing a successful implantation and normal development of the pregnancy.

Treatments - If positive; IVIG (intravenous immunoglobulin) or lymphocyte immunotherapy have been successful. Also, consult a reproductive immunologist before treatment. Treatment to start during the follicular phase of the cycle. Treatments should continue on a monthly basis.

Anti Ovarian Antibody (AOA)

A novel ELISA-based test to assess the presence and concentration of antibodies against ovarian targets. Such antibodies would bind to important functional sites in the ovary and granulosa cells and impair the normal response. Women with elevated AOA were shown to have reduced and impaired response to ovulation induction in the course of IVF treatment. Women with severe AOA were found to have all the symptoms of premature ovarian failure (early menopause). Positive test results would indicate any of a few therapeutic (drug) treatments which have been shown to open a window for pregnancy, essentially by removing the antibody inhibition within a short period of time, allowing a normal ovarian functioning to take place.

Treatments - If positive, treat with 4mg of Dexamethasone or Prednisone. Consult a reproductive immunologist before treatment for Premature Ovarian Failure. Treatment to start on day one of the cycle. One paper documented success with two patients by treating with Medrol (methyl prednisolone)- 96mg/day for ten days, followed by 48mg/day for two days; then 16 mg/day for two days, and finally 8 mg/day for two days. For low responders to induction of ovulation, treatment is to also start on day one of the cycle.

Embryo Toxic Factor (ETF)

A combination of two procedures. The first involves maternal cell (lymphocyte) culture which is aimed to stimulate the lymphocytes using components of the human embryo (trophoblast) cell line, and the second is an embryo culture. These procedures are set in order to measure if the patient's lymphocytes secrete anything that may be toxic to the embryo (test utilizes two-cell stage mouse embryos) Women who have been sensitized in the course of their earlier pregnancies or in any other mode, could amass an immune response against their own fetus in the following pregnancy, and end up losing it (in the implantation process or later in the first trimester). The toxicity, if established by this test, my result from multiple factors. It may exist in the cells prior to stimulation in the culture or be induced by the exposure to the trophoblast components.

Treatments - High dosage Progesterone suppositories taken vaginally twice daily from fertilization until 16 weeks 200mg - 400mg. Increase dosage and add other immunosuppressive treatments if more SAb's occur. It has been shown that Progesterone in high dosages is immunosuppressive. Other treatments to suppress the immune response might be effective. Ref. Textbook (Reproductive Immunology) 1996; Blackstone Scientific. Call Repromedix for copies of articles.

Sperm Penetration Assay (SPA)

This test examines the ability of the sperm to perform the functions involved in fertilization, namely the attachment to the egg, and the actual penetration into the egg. The test is performed on the male partner's sperm using a Chinese hamster egg, which is as generally suitable for this test and emulates a human egg. Reduced penetration reflects on the quality of the sperm and its ability to fertilize, assuming other parameters such as sperm motility and sperm morphology are normal.

Treatments - There is no real therapy for positive tests. If the test is abnormal, patients may be referred to an infertility specialist at an IVF center. A sperm donor with IUI is also suggested.

Anti Sperm Antibodies (ASA) - male

This immuno-bead- based test checks the presence of auto-antibodies directed to the male partner's sperm (IgG, IgM). If excessive amounts of antibodies are bound to the surface of the sperm cell, they may mask receptors or other functionally important proteins, interfere with the sperm-egg interaction and thereby reduce the potential for successful fertilization. A positive test may be indicative of past exposure of the male reproductive system to his own immune system in the course of injury or inflammation.

Treatments - Sperm washing (with or without a preceding immunosuppressive therapy) may reduce the anti-sperm antibodies to an insignificant level prior to IUI or IVF. Otherwise, ICSI would always circumvent motility and penetration dysfunctions.

Anti Sperm Antibodies (ASA) - female

This immuno-bead-based test will detect antibodies to the sperm cells in the woman's serum (IgG, IgM, IgA) or cervical mucus. Such antibodies would interfere with the ability of normal sperm to move up the female reproductive tract and fertilize.

Treatments - Use immunosuppressive therapy such as low dosage of 10mg/day of Prednisone or 4mg/day Dexamethasone. Consult with a Reproductive Immunologist.

Lupus Anti Coagulant (LAC)

Is a clotting time test (Dilute Russel's Viper Venom Test) to detect the women's antibodies against components of the blood clotting system, such as negatively charged phospholipids or prothrombin. These antibodies cause a prolongation in the clotting time, a disorder that was correlated with recurrent pregnancy loss (First trimester spontaneous abortion). Positive patients are usually put on anti-coagulant therapy.

Treatments - Injected Heparin anticoagulant. Please consult an immunologist or a hematologist for appropriate dosages.

Acrosome Reaction (MCP, CD46)

This is an immuno-bead-based assay for testing sperm function. In the process of fertilization, just prior to penetration into the egg, the sperm is activated to go through a phenomenon called the Acrosome Reaction, in which the membranes of the front portion of the cell ruptures, releasing various enzymes. This function exposes various surface antigens which were hidden inside the cell prior to this stage. The test examines the ability of the sperm to "perform" the Acrosome Reaction by testing the exposure of a known antigen following artificial induction of this reaction.

Treatments - Positive test results may indicate the need for intra cytoplasmic sperm injection (ICSI) or sperm donor with IUI is recommended.

Anti Nuclear Antibodies (ANA Screen)

This is a component of one's autoimmune response (woman's immune system attacking her own cell nucleus). ANA are antibodies against one or more elements within a biological cell, involved in the machinery of translating gnomic message into proteins. These antibodies can destroy cells, and their effect usually leads to the disease Lupus (SLE). Women with Lupus or ANA are at a higher risk of miscarriage and IVF implantation failure due to inflammatory effects on the placenta and or the fetus. The first test is usually a 'screen' which identifies up to 100 of this type of antibodies as a group. If positive, the ANA panel is ordered to determine if any of the 10 most clinically important antigens in the group is involved. Positive ANA can often be treated with immunosuppressive agents.

Treatments - If positive Anti-Histone or Anti-Double Stranded DNA (dsDNA); then immunosuppressive therapy is the recommended course. 10mg/day Prednisone or 4mg/day Dexamethasone should be considered. For exact appropriate dosages, consult a Reproductive Immunologist. Treatments should start ten days prior to ovulation.

Chromosome Analysis

It is widely known that the majority of recurrent first trimester spontaneous abortions (Recurrent Pregnancy Loss) are caused by an abnormal karyotype (abnormal number and shape of chromosomes in the cell nucleus). In many cases this is due to one of the parents being a carrier of an abnormal chromosome, and the incidence of this increases with the maternal age. The test involves a 3 day stimulation of the peripheral blood cells, spreading of the chromosomes on a microscope slide and karyotyping (analysis of chromosome number and shape). If any abnormality is detected, further attempts may be made to identify a potential disease. Several solutions exit, depending on the nature of the abnormality, but consultation with a geneticist is recommended. Because chromosomal translocations have a 25% chance of reaching the embryo, repeated attempts at pregnancy would be recommended, but other solutions that would reduce the risk, (e.g.: gamete donation) might also be discussed.

Treatments - (Male and Female; both partners tested) If an abnormality is detected, it is recommended that further testing be done at a cytogenetic laboratory. In the case of a severe genetic abnormality, either sperm or egg donor is the indicated course of action. If however the abnormality is recessive, prenatal genetic diagnosis should be performed on the embryo.

Anti Thyroglobulin (ATA)& Anti Microsomal Antibodies (AMA)

These are ELISA-based tests to identify high levels of these auto antibodies. Women with elevated levels were found to have higher risk of RPL (Recurrent Pregnancy Loss) and associated with IVF failures. These auto antibodies interfere with Thyroid functions, and thus with normal metabolism. They are also indicators for a predisposition of the patient to auto immunity which may involve additional auto antibodies that interfere with the reproductive process (e.g., AOA, APA, ACA, ASA.).

Treatments - Patients with positive tests may be treated with immunosuppressive steroids, 10mg/day Prednisone or 4mg/day Dexamethasone. Consult with a Reproductive Immunologist for proper dosage.

Fibronectin (Capacitation)

Is a test for sperm function. Every sperm cell becomes capacitated before it can interact with the egg. Fibronectin is a protein which is expressed on the surface of capacitated cells. The test examines the number of capacitated cells in the semen sample. Low percentage may indicate functional impairment.

Treatments - All problems with sperm access to the egg and penetration can be circumvented by Intra Cytoplasmic Sperm Injection (ICSI) or sperm donor.

Leukocyte Antibody Detection (LAD)

LAD is another measure of immuno-compatibility between husband and wife. In order for the maternal immune system to down regulate during pregnancy, and in order for her to produce "blocking antibodies" that would prevent her system from attacking the embryo/fetus, she must respond to her husband alloantigens. LAD tests the presence of blocking (allo-)antibodies in her blood. A positive test is desired; a positive test is also an indication for an efficient Lymphocyte Immunotherapy (LI) treatment.

Treatments - If LAD is negative, immunization with paternal or third party lymphocytes has been shown to be helpful by stimulating the production of blocking antibodies.

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Comments

I would like to ask for advice. My partner has primary male infertility: oligozoospermia, cytogenetic factor.

I got pregnant and had a missed miscarriage. Foetus stopped developing at 8.5 weeks because of chromosomal abnormalities.

We have high probabilities that any future pregnancies will end prematurely because of abnormal DNA brought by the sperm. We may have no chance for future foetus to reach birth. Is there a way to select sperm based on their DNA?

May I also ask you for guidance on using a sperm bank. Would you have any advice for the use of donor sperm?

Many thanks for your help.

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