Immunologic infertility: types, causes and treatments

Immune system disorders and autoimmune diseases can cause infertility in both males and females.

Oftentimes, diagnosing immunological infertility is complicated. However, it is estimated that about 20 percent of the cases of unexplained infertility are due to immunological causes.

Infertility due to immunological causes can manifest in many different ways, including destroying the reproductive cells of the person affected, preventing embryo implantation, or even causing recurrent miscarriages.

What is the immune system?

The body's immune system is composed of a multitude of cells, molecules, and mechanisms that protect the body from foreign agents, such as viruses, bacteria, and other infectious agents that cause disease.

One of the most important immune cells is the lymphocytes or white blood cells, capable of recognizing their own structures and also of producing antibodies that recognize foreign substances.

What is the function of the immune system?

Occasionally, the immune system fails, cannot differentiate between self and foreign, and eventually acts against the body's own cells. This failure is what causes the appearance of the well known autoimmune diseases.

The immune system is also responsible for the rejections that occur with organ transplants, as it detects that cells from another individual have been introduced and attacks them.

Pregnancy

Pregnancy is a special, exceptional situation in a woman's body, as it is forced to be home for a "foreign body" for 9 months.

The immune system of embryos is different from that of the pregnant woman, as it contains genes from the father as well, which are unknown to the immune system of the mother.

For a pregnancy to be normal, the woman's immune system develops a mechanism of immune tolerance in order not to attack the embryo.

Immune system during pregnancy

In fact, it is the embryo itself that "warns" the pregnant woman through the expression of the HLA-G Antigen, which function is to erase the cells of the immune system in order for the embryo to continue growing in the womb.

Types of immunological infertility

There is a multitude of alterations of the immune system and many of them can affect male and/or female fertility, although the latter to a greater extent.

The woman's body may recognize the sperm and/or embryo as foreign, which will result in repeated implantation failures or miscarriages in the first trimester.

In the following, we will discuss some types of immunological sterility.

Antisperm antibodies (AEA)

This is the most common form of male immune infertility. Antisperm antibodies are a type of protein that binds to sperm, affecting their ability to move and fertilize the egg.

Female infertility due to antisperm antibodies

Moreover, when SAAs bind to spermatozoa, the body identifies them as foreign and directs its defenses towards them to destroy them.

This type of anti-sperm antibody can be formed in both male and female organisms. The causes in each case are as follows:

Male origin

rupture of the blood-testicular barrier due to varicocele, seminal infection, testicular torsion, etc. Antisperm antibodies appear in the blood and semen.

Female origin

sexually transmitted infections, genital endometriosis, cervicitis, etc. Anti-sperm antibodies are found in the cervical mucus and prevent sperm from advancing into the uterus.

Origin of antisperm antibodies or AEAs

If you want to get more detailed information about this, you can continue reading here: Antisperm antibodies in man.

Hereditary thrombophilias

Thrombophilia is an autoimmune disease that causes the body to develop abnormal blood clots in the vessels (veins and/or arteries). It is due to a dysfunction in the mechanism that prevents excessive blood clotting.

In particular, the cause of thrombophilia is due to the absence of natural anticoagulants, as well as the presence of mutations in anticoagulant systems or in fibrinolytic mechanisms.

Based on the cause, there exist various types of thrombophilias:

• Factor V G1691A (FV-Leiden) mutation
• Prothrombin G20210A mutation
• C677T mutation in the MTHFR gene
• Antithrombin deficiency
• Protein C deficiency
• Protein S deficiency
• Dysfibrinogenemia
• Homozygous homocystinuria

These genetic alterations may not have any serious impact on the health of the women who have them. However, during pregnancy, blood clots that form in the blood can reach the placenta and block the development of the fetus. To ensure that a pregnancy is evolutionary and that the baby can be born, patients suffering from thrombophilia must follow a treatment with acetylsalicylic acid (Aspirin, Adiro) and heparin during the entire gestation.

Antiphospholipid syndrome and recurrent miscarriage

If you are interested in the topic of thrombophilias, then we invite you to read the following article: Thrombophilias, a cause of implantation failure and repeat miscarriages?

Antiphospholipid syndrome (APS)

Antiphospholipid antibodies are a type of cells from the immune system that can be found in maternal blood and cause a state of hypercoagulability. It leads to the formation of thrombi in the placenta and subsequently to miscarriage.

There exist more than 20 types of antiphospholipid antibodies, being the lupus anticoagulant, anticardiolipin antibodies, and beta-2 Glycoprotein 1 Antibody the most important ones. All of them alter the function of phospholipids, a group of substances that are necessary for vital functions such as blood circulation and clotting.

APS is considered a type of acquired thrombophilia. In fact, it is the cause of approximately 15% of the cases of recurrent pregnancy loss.

For more information on this pathology, we recommend you read the following post: What is the Antiphospholipid Syndrome (APS)?

Alloimmune implantation dysfunction

The immune system of the pregnant woman recognizes the embryo as an invader and creates antibodies against the tissue that expresses proteins from the paternal origin as a response.

As a consequence, embryo implantation cannot take place or, if it happens, it typically ends up in miscarriage.

These patients have elevated levels of Natural Killer (NK) cells, a type of lymphocytes that can destroy those organisms detected as "invaders".

Alloimmune infertility due to elevated NK cells

Potential treatment options to fight this infertility cause are still being investigated.

Assisted reproduction

Amongst the different causes of immunological infertility described above, assisted reproduction will be necessary in all cases of anti-sperm antibodies.

Depending on the location of anti-sperm antibodies and the severity, we can use one of the following treatments:

Intrauterine Insemination (IUI)

If antibodies that stick to sperm are found in the cervical mucus, especially in the cervix. With IUI, the sperm sample is inserted directly into the uterine fundus using a catheter. By doing this, the sperms don't get in touch with the sperm antibodies, and the cells of the immune system won't attack them. In other words, they will be able to reach the egg.

In Vitro Fertilization (IVF)

If the amount of antisperm antibodies is greater or they are spread across the female reproductive system. If IVF/ICSI is the treatment of choice, a sperm cell is injected directly into the egg cell, thereby eliminating every chance of interaction between sperm and antisperm antibodies.

Thrombophilias, along with other alterations of the immune system, may require fertility treatment to achieve pregnancy. However, if there is no other fertility issue, you can get pregnant and carry the child until birth thanks to a treatment based on anticoagulant drugs.

FAQs from users

What is the best reproductive option for cases of immunological infertility?

When there is a suspicion that the implantation failure of a couple may have an immunological cause, the first thing to do (as in any branch of medicine) is to reach a good diagnosis. There are various tests that can be performed today: determination of the NK population, determination of NK activation, ideal interleukin balance, CD4/CD8 balance, Th1/Th2 balance, Treg/T17, complement, autoantibodies, lymphocytes...

It is now known that the alterations of these parameters in the blood do not always translate into the same alterations in the endometrium (which is where the embryo will be implanted). This means that the diagnosis of the alteration itself is not always accurate. Thus, the latest research recommends that these parameters should be determined directly in endometrial biopsy (in IVF-Spain this test is called Im Map).
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What fertility treatment should I follow if I have obtained a high number of Natural Killer cells in the analysis?

The prevalence of CD56+ NK cells in blood is approximately 10% of all peripheral blood lymphocytes. Some studies have reported that percentages as high as 12% may be related to poor reproductive outcomes.

For this reason, different treatments have been proposed over time, although there is still no clear scientific evidence of their efficacy. Among the different options, corticosteroids would be the most widespread treatment given their immunomodulatory role and a profile with fewer associated risks than the other treatments.

It is essential that this treatment be prescribed and controlled by a specialist in reproductive immunology.
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What does testing for immunological infertility involve?

On the one hand, it involves a series of tests for thrombophilia, including lupus anticoagulant, cardiolipin antibodies, testing for antiphospholipid antibodies, etc.

Then, performing a immunological study of antibodies, NK cells, cytokines, HLA-KIR compatibility, etc.

Does autoimmune thyroiditis cause infertility?

Yes, autoimmune thyroiditis, also known as Hashimoto's disease, is the most common cause of hypothyroidism. The woman's body makes antibodies that attack the thyroid gland. As a result, a decrease in the amount of thyroid hormones occurs, causing irregularities in the menstrual cycle, among others.

You may also enjoy some further information reading this: Impact of Thyroid Hormones on Female Fertility.

What effects can elevated D-dimer have on fertility?

D-Dimer is a substance that is produced after the degradation of a clot and its concentration can help diagnose thrombosis.

As we know, thrombophilias are a group of diseases that favour the formation of thrombi, both arterial and venous, and are associated with different complications before and during pregnancy such as: Implantation Failure, Repeated Miscarriage, Preeclampsia, Intrauterine Growth Restriction and Intrauterine Foetal Death.

It is important that, in the event of any of these manifestations, a doctor specialising in Assisted Reproduction should be consulted in order to carry out an exhaustive study and be able to determine the cause and administer the appropriate treatment in each case.

Can celiac disease affect fertility?

Although the causes why celiac disease affects fertility are still unknown, there exist many theories on why this may occur. In women affected by celiac disease who don't follow a gluten-free diet, it is more likely that they are deficient in folic acid, selenium, iron, zinc, etc.

In addition, women with coeliac disease may have difficulty in becoming mothers due to menstrual cycle disorders, implantation failures and repeated miscarriages.

Men with coeliac disease may have poor semen quality and a higher risk of impotence.

Is there a treatment for immunological infertility?

Actually, the answer to this question is that it will depend on what is causing the immunological infertility. For example, if the immune infertility is caused by autoimmune syndrome, then a possible therapeutic option would be the use of anti-thrombotic drugs.

On the other hand, if the autoimmune infertility is due to coeliac disease, then a gluten-free diet would be appropriate to try to increase the pregnancy rate.

Recommended readings

Oftentimes, unexplained infertility is the cause of miscarriage because the body recognizes the fetus as an invader. To learn more, read: What Is Recurrent Miscarriage? – Causes, Symptoms & Treatment.

There exist one more cause of infertility due to immunological causes. Although it is a rare condition, a woman may have an allergy to semen. This anomaly forces couples to have no choice but to use condoms and, for this reason, pregnancy won't be possible. Read more: Can You Be Allergic to Your Partner's Sperm? - Causes & Treatment.