Causes of Infertility
We, as expert scientists-researchers, assure you that the phrase “it happenes” is not an adequate explanation for us. We look for the causes, so that the problems are treated causally.
Introduction
In the infertility investigation department, on the one hand we investigate the causes of the problem of the couples who visit us, and on the other hand we conduct clinical and fundamental research around male and female infertility and failed pregnancies / miscarriages. It is important that in LOCUS- MEDICUS SA the two mutually supportive branches coexist (routine laboratory and research laboratory), since the routine supports the research financially and provides material for study to it, while the research constantly feeds the routine with new diagnostic and therapeutic possibilities.
So, after self-financed research since 1999, in conjunction with constant monitoring of the literature and conferences, we have concluded that chronic infections of the couple (microbial and viral) are particularly responsible in specific ways for endometrial toxicity, clinically manifested as infertility or miscarriage. For unknown etiology miscarriages, but also for couple infertility, five causes are considered prevalent and which will be analyzed below. In modern practice they are usually treated beforehand rather empirically, and unfortunately, they are either not researched at all or bypassed with very fast manipulations, which unfortunately do not lead to good results.
Common causes determine both couple infertility and miscarriages.
In this briefing we will avoid mentioning the term recurrent miscarriages. We believe that all causes may have been established before the first failed pregnancy / miscarriage. Regarding the question of many interested parties about the common causes of failed pregnancies / miscarriages on the one hand and infertility on the other, our answer is that all five causes can be involved in both problems, and we remind the greatly increased possibility of failed pregnancy on the ground of a difficult conception.
In addition, many unsuccessful IVF attempts with virtually negative — but not zero — control hormone (which is chorionic gonadotropin), or many physical attempts that were never controlled in time, could actually be very early failed pregnancies or fetus rejections that occurred before detectable hormone levels. So, many couples with a history of long-term infertility may have had miscarriages without knowing it and resort to assisted reproduction methods with unsuccessful results in their pregnancies, because they have not faced the real problem by investigating the causes. From now on we have to emphasize the important role of male factors in failed pregnancies / miscarriages.
Causes of infertility and failed pregnancies – miscarriages
The causes of miscarriage and infertility are generally classified into five main categories:
(a) immune and viral
(b) genetic
(c) thrombophilic
(d) hormonal and
(e) infectious non-viral.
Each of them can create the problem on its own, or in combination with the others. From the detailed description we will see that the boundaries between these causes are not clear since many of them may be involved in the pathophysiology of others. In particular:
1. Immune and Viral causes.
At LOCUS-MEDICUS we believe that the immune etiology consists of two parts: One concerns the aggression of the woman against fetal antigens (most likely viral) and is investigated by the immunophenotype, whereas the second concerns the antigens content in sperm (mainly viral), that is mainly determined with the SPI immunological examination and contributes to the formation of antigenic embryos.
According to the researchers, these causes affect a significant percentage (more than 40%) of infertile couples and are the main reason that needs to be addressed by specialized scientists.
The majority of immunological causes of infertility appear to be attributed to predominantly viral infections of women, just as we indicated years ago in two publications in the American Journal of Reproductive Immunology (Thomas et al. (2005). Am J Reprod Immunol. 54 (2 ), 101-11 and Thomas et al. (2004). Am J Reprod Immunol., 51 (3), 248-255).
More specifically, the presence of a group of viruses (herpesviruses, including the herpes simplex virus) was found to be the main cause of the growth of some toxic cells in the blood known as NK cells (Natural Killer cells or Natural Killers). These are known cells, whose concentration is increased in the blood of women with a history of infertility of unknown etiology and whose quantitative assessment is the first priority in the investigation of the infertile couple by determination of the Peripheral Blood Lymphocyte Immunophenotype. A very large percentage (~ 35%) of women with conception problems show an increase in NK cells in the blood (see a study by our Locus Medicus Center published in the scientific journal Fertility and Sterility, September 2003).
It seems that the vast majority of the increase is due to a subclinical response to herpes viruses in these women. When our research team noticed the involvement of viruses in infertility, a great many couples with this type of problem achieved their goal after a very simple antiviral treatment. The success was mainly in cases where the NKs in the peripheral blood were at abnormal levels but in a relatively small deviation from the upper normal limits. On the contrary, when the deviation from the normal was greater, then the Lymphocyte Vaccine that we apply since 1998, is — according to our experience — undoubtedly the most reliable treatment.
To date, the methods used to detect the presence of viruses do not appear to have been sensitive at all. However, with the use of molecular (DNA) techniques, it is revealed that viruses exist in us at a much higher frequency than scientists have estimated.
In cases of first trimester miscarriages, in the histological picture of the scraping material (carrietage), the presence of NK lymphocytes (CD16 +) in a diffuse configuration and with tropism to embryonic cells is characteristic. More specifically, these cells surround necrotic areas of the pregnant endometrium (perishable), which also contain abundant, normal, scattered embryonic cells. We see no other reason than the fact that the necrosis occurred exactly where the NK lymphocytes met and exerted toxicity on the fetal cells, which — according to the rules of immunology — are ideal targets for the action of NK.
Immune etiology has also a male aspect. Interestingly, such images, i.e., the coexistence of toxic NK cells with embryonic cells and necrosis can also be observed in cases where the concentration of NK in the blood of women is normal. This was the main motivation to blame the fetus, that it could carry viral antigens inside it.
Over time, our research team is concerned about the possible presence of similar viruses in sperm. The predicted result of such a presence after a vertical transmission of viruses to the fetus, would be:
a) the inability of the fetus to multiply properly,
b) the rejection of the infected fetus by the female defense mechanisms and, why not:
c) the creation of functional problems of the fetus that can appear in the late stages of pregnancy.
The content of sperm in microorganisms has not been of concern to the medical sector worldwide. In our view, the purity of the genetic material of the first cell of the fetus is of paramount importance.
The presence of intracellular pathogens and viruses such as HSV1/2 and CMV in the sperm can lead to their vertical transmission from the sperm to the first cell of the embryo during fertilization. The presence of viral DNA between the embryonic genome can lead to the expression of viral antigens by the embryonic cells. This causes the NK lymphocytes to exert tropism against them, resulting in the immune rejection of the fetus. We remind you that the target cells are those whose function is to develop mechanisms of stealing oxygen from the vessels of the endometrium. These cells, called interstitial trophoblast cells, are the ones that produce chorionic (β-hCG).
This can result in premature miscarriages which are misinterpreted as inability to conceive when they occur before the confirmation of pregnancy by hormonal chorionic sampling, or it can even manifest with recurrent miscarriages of immunological etiology.
Even if the fetus survives a vertical transmission of viruses, there is a possibility that the viruses will be considered as “self” by the new organism and will not be treated for the rest of their lives. As a result, the fetus will be tolerant of these pathogens and will therefore coexist with them in the future.
To prevent and avoid the above, we recommend the SPI™ TEST (sperm pathogen immunophenotyping test), a new, patented, award-winning diagnostic test that allows for the first time the detection of intracellular pathogens such as viruses (eg CMV, HSV 1/2) and Chlamydia inside the sperm, by flow cytometry.
The SPI ™ test allows the etiological investigation of male infertility as it may be involved in immune causes, premature pregnancy failure and recurrent miscarriages due to sperm-derived pathogens, even in cases of chronic, subclinical infections where conventional methods, such as cultures, immunofluorescence, and PCR, fail to detect them. It is the most sensitive, commercially available test (more sensitive than standard PCR-based detection methods), while providing excellent specificity, allowing the correlation between infection and infected cell type.
In conclusion, we consider that the immunological etiology consists of two parts: One concerns the aggression of the woman against fetal antigens (most likely viral) and is investigated with the immunophenotype, while the second concerns the antigens content of sperm — and therefore of the fetus — which is mainly identified with the SPI immunological examination.
2. Genetic Causes.
These include causes that result from the accumulation of DNA damage in the sperm, that has not been adequately corrected by the egg enzymes on the zygotic cell immediately after fertilization and over the next few cell generations. Additionally, cases of inherited pathological karyotypes are included.
A large percentage of cases with miscarriages or failed pregnancies are due to karyotypic (chromosomal) causes which are approached by karyotypic analysis of peripheral blood of parents or fetal cells. It is reported that karyotypic abnormalities of the fetus exceed the 50% of first trimester spontaneous miscarriages. However, most of the time no diagnostic abrasion is performed and thus no material is obtained for examination of Karyotypic Analysis of Miscarriage Products. In any case, in these cases nature acts properly, rejecting the embryos and effectively protecting the population from the birth of problematic organisms. These pregnancies are not saved. They usually affect older women and there is no way to prevent them from recurring.
But apart from the age of the woman, the male factor plays an equally important role in the cases of karyotypically abnormal fetuses. In everyday practice we encounter cases even with normal parameters of sperm diagram, where the DNA of the sperm has damage which — in the literature — is related to a large extent with the creation of genetically aberrant embryos.
Sperm genetic integrity is assessed by DFI analysis of sperm with Flow Cytometry / TUNNEL and is necessary for the development of the normal fetus, while the fragmentation of genetic material in the sperm significantly undermines the chance of a successful pregnancy and increases the risk of miscarriage, regardless of the way of conception (i.e., naturally or through assisted reproduction), thus causing male infertility. In addition, due to limited levels of antioxidant defense and a unique, limited mechanism for detecting and repairing DNA damage, sperm is particularly vulnerable to oxidative stress. 8-OHdG test in sperm allows the measurement of the levels of 8-OHdG (8-hydroxy-deoxyguanosine) which is a byproduct of DNA degeneration due to oxidative stress and is detected by flow cytometry inside the sperm. Oxidative stress is a major cause of defective sperm function causing DNA damage in addition to fragmentation, thus associated with male infertility or even failed pregnancies.
However, our way of presenting the DNA changes of the sperm might give the impression that we cited these two types of damage as causes of infertility and failed pregnancies. It is more practical to consider these lesions as the result of more central causes, such as chronic inflammation of the male genital tract, or habits such as smoking or substance use, or conditions such as obesity, varicose veins or various endocrine or metabolic diseases. After all, in many cases, these DNA lesions pass by, either permanently or temporarily. Thus, by measuring them, it can be assessed whether it is a suitable time for assisted reproduction or whether they should be corrected beforehand.
The age of the woman must always be considered here. After all, we all need to be reminded that the interested party is a couple and not a man alone or a woman alone. It should be noted that the role of eggs, in addition to the structural involvement in the first cell of the fetus, is to correct the alterations of male DNA. We therefore emphasize that the corrective capacity of the eggs decreases with the age of the woman. So, because we cannot increase it, we must offer the woman the best possible sperm quality, which would not need her reduced corrective abilities. We know that if DNA damage to the first cells of the fetus is not corrected, then the cell divisions are not promoted; and this is another dimension in genetic causes, apart from the karyotype pathology.
In addition to the acquired reasons that are presently timidly beginning to be implied and presented mainly behind the fragmentation of sperm DNA, the inherited reasons that lead to infertility must also be mentioned.
Karyotypic abnormalities of prospective parents with chromosomal permutations or other related lesions are an important part of the couple’s investigation into both a history of infertility and failed pregnancies. Usually in these couples, pre-implantation control of the embryos with a process of assisted reproduction is recommended, in order to exclude abnormal embryos.
