Immunological causes of infertility

The communication mechanisms between the embryo that starts from the penetration to the endometrium (in order to successfully complete the process of implantation) and the uterus, as the receptive organ accepting the evolving embryo, are complex and largely unknown.

When this communication fails, the process of implantation is stopped early as in biochemical pregnancies. Also, a pregnancy may stop later after the growth or existence of embryo sac with fetal pulse.

Many argue that during this communication, the uterus considers the fetus as a "foreign" material since half of the genetic material comes from the sperm, and discards it. In this pathogenetic mechanism, several factors have been occasionally implicated, such as antiphospholipid syndrome, non istosyvatotita of HLL antigens and elevated levels of toxic lymphocytes (natural killer cells = NK).

What are the toxic lymphocytes (NK cells)?

Lymphocytes are blood cells (white blood cells) which are involved into immune responses, and NK is a subtype of these cells that plays an important reason to the reaction of the body so as to destroy or inactivate infectious and malignant cells.

NK cells are large granular lymphocytes which are activated and proliferated when they receive messages from other immunological stimuli, such as interferone receptor activation of cells of the immune system. The granules in the cytoplasm of NK cells contain toxic proteins.

NK cells are present in the bloodstream and after receiving the appropriate messages, they are displayed in different organs.

NK cells are present in the endometrium of non-pregnant women and help, in conjunction with the various hormonal stimuli, in the normal process of ovulation and reproduction.

The levels of endometrial NK cells are increased dramatically after ovulation. Many studies have shown that therapies designed to reduce the levels of NK cells are beneficial in patients with reproductive problems that are related to immunology.

During an early pregnancy, NK cells in the endometrium have greater toxicity and produce large quantities of TNF, a protein which is able to kill the placental and fetal cells.

NK cells are identified by protein CD 56 + with or without 16 + which function as surface markers. The CD 56 + NK cells are those that are normally in the endometrium during the creation of the placenta and remain with high numbers throughout the implantation surface. The normal range of CD 56 + NK cells in the blood ranges from 5-12% of total lymphocytes.

Rates over 18% have been associated with a very poor reproductive outcome. Normally, the NK cells present in the endometrium assist in vascular changes that occur at the site of implantation in order to support the growth of cells of fetal trophoblast leading to proper development of the placenta.

However, when the growth or activation of NK cells is abnormal, it can lead to inhibition of the process of implantation or early pregnancy loss.

To amend-reduce the number of NK cells, the following has been used:

  • Steroids (eg cortisone).
  • Intravenous immunoglobulin (IVIg).
  • TNF neutralizing drugs like embler.
  • Vaccination with lymphocytes of the husband to develop Antipater antibodies (APCA) and through them reduce the number of NK cells
  • Infusion of intralipid (concentrated soy oil).

Although cortisone has been widely used, the opinions differ on its effectiveness and modify the immunological causes the level of the endometrium that could affect the evolution of implantation-pregnancy.

Vaccination with lymphocytes of spouse-partner can have negative long-term impact on a woman's immune response to various stimuli, typically repeated about every 21-28 days and continues until the first trimester of pregnancy.

The treatment with intravenous immunoglobulin (antibodies given intravenously in order to strengthen the immune system) is a biological product and must undergo extensive testing before using it, such as on the risk of transmission of infectious diseases. It has a short reaction and must be repeated every month. In addition, it is accompanied by allergic reactions, such as anaphylactic shock, renal failure, thrombosis, pulmonary edema, dermatitis, headaches, meningitis, Alzheimer GFD (Transmission of pathogenic prions).

There is no scientific acceptance for inoculation lymphocytes or the immunoglobulins in terms of efficiency. However, it is used non-specifically, during recurrent miscarriages, when the use of intravenous immunoglobulin appeared to improve the percentage of viable pregnancies in contrast with the selection based on immunological causes that appeared to be more effective.

In addition, intravenous immunoglobulin was found to be more effective in women who had a successful pregnancy the first time and then had recurrent miscarriages throughout.

However, for women who have not had previous successful pregnancies, it did not appear to be effective.

Bearing in mind all of the above, it is obvious to consider the scientists’ attempts to find a treatment that affects the immune system locally, in the uterus, in such a manner so as to assist embryo implantation and the maintenance of good growth, that is easy to handle having few side effects and low cost.

This seems to be represented on the face of intralipid (soyal oil) with only negative effect –an allergy which one may have to eggs or soybeans, and can result in anaphylactic reaction in these patients.

However, the most common side effect is fever, which occurs in 1 in every 100 women, very rarely it may cause chills, nausea, abdominal pain, headache and fatigue.

The treatment is given intravenously 4-7 days prior to egg collection under the medical supervision and repeated pregnancy tests.

Some scientists support the continued delivery of monthly in the first quarter but the value of this approach has been questioned.

The cost is very low and acceptable to most patients. At AKESO center, it is applied in the manner described above with a very low overhead cost infertility treatment.

M. TSIRIGOTIS MD FRCOG Gynecologists, Reproductive Medicine Specialist