Etiological approach to infertility

As infertility specialists we assure you that we do not accept randomness in reproductive medicine. We investigate the underlining causes so that the problem can be corrected etiologically.

Dr. Tsilivakos Vassilis MD, PhD, Immunologist and Pathologist, Researcher of Reproductive Immunology


Dear Friends,

We would like to welcome you and to wish you a quick resolution of your problem. We would like to let you know of our work and findings by both our clinical practice as well as our laboratory research data in order to maximize the benefits of our collaboration. 

In our medical center, our mission is two-fold: On one hand we are investigating the underlining cause of infertility of couples that visit our center for diagnosis and treatment, which leads to either a natural conception and birth or a better outcome in an assisted reproduction attempt if needed (IVF, AI etc).

On the other hand, in our state-of-the-art laboratories we conduct clinical and basic research on male/female infertility, miscarriages and recurrent abortions in order to scientifically support our clinics with new information and data as well as novel diagnostic tests and treatments (i.e. patented diagnostic tests such as the Hidden-C test, the SPI test etc.). It is important that the two mutually beneficial branches of clinical medicine and laboratory research coexist, so that the former continuously provides material for study while the latter develops new diagnostic and therapeutic methodologies for clinical application.

20 years of self–funded research, have led us to strongly believe that chronic bacterial and (especially) viral infections of both partners are mainly responsible for endometrium toxicity (towards the zygote/embryo) that clinically presents itself as “infertility” or early miscarriages.


Regarding “unexplained” infertility and recurrent miscarriages of "unknown etiology", we can group their possible causes into 5 distinct categories or “factors” which can lead to infertility. Unfortunately, these factors are usually inadequately investigated by modern medical practice and are thus treated rather empirically. 

In addition to miscarriages, these factors may be also responsible for what is conceived as failure of conception if we consider the fact that for many couples infertility is a result of very early spontaneous abortions (miscarriages) which go undetected by the partners and are wrongly interpreted as inability to conceive.

In clinical practice, conventionally a pregnancy is taking polace when the human chorionic gonadotropin hormone (hCG) exceeds 10 units. However, as only embryonic tissue is able to produce any detectable amount of this hormone.  As a result, it is logical to assume that even minute amounts of hCG  in the bloodstream, must be considered an indication for implantation, even if it is less than 10 units which is conventionally accepted as the threshold for implantation.

It must be emphasized that many failed IVF attempts (in which low hCG levels below 10 units were considered negative for implantation) or many attempts for natural conception that were never tested for hCG and were considered failed, could in fact have been early miscarriages or fetus rejections. Therefore, a history of failed IVF attempts could be attributed to concurrent spontaneous abortions (miscarriages) the underlining causes of which should be treated in order for the couple to have any real chance of success either via natural conception or through IVF (or another assisted reproduction method).

The causes of infertility can be thus grouped into five main categories:

  1. Immunological and viral factors
  2. Genetic causes
  3. Thrombophilia
  4. Hormonal causes
  5. Microbial factors

Each of the above infertility factors which can by themselves alone or in combination with one or more of the others can negatively affect the reproductive outcome of a conception attempt are further analysed below.

1. Immunological and viral factors affecting fertility.

Immunological complications due to viral infection are implicated in more than 80% of cases of infertility. Infertility of immunological etiology should be addressed by specialized healthcare professionals.

The majority of cases of subfertility of immunological etiology can be attributed to viral infections of the female partner as we have shown in two scientific paper publications on the American Journal of Reproductive Immunology  on 2004 and 2005.

More specifically, the presence the Herpesviridae family of DNA viruses or herpesviruses (including Herpes Simplex Virus 1 and 2 which are responsible for most cold sores and most genital herpes cases respectively) has been identified as one of the main causes of Natural Killer Lymphocyte (NK cells) blood levels elevation. More than 50% of women with a history of infertility of unknown etiology are showing high NK blood concentration according to research (Michou (2003). Fertil Steril., 80 Suppl 2:691-7). It seems that in the majority of cases, NK increase was associated with the presence of herpesviruses in the blood of these women.

The problem of herpesvirus infection can be easily dealt with through the administration of proper anti-herpetic treatment. Indeed, when our research team identified the association of viral infections with infertility, a large number of couples overcame their problem after a simple antiviral treatment.

Up until recently, conventional methods for detecting viral infection exhibited low sensitivity. However, the development of highly sensitive PCR (polymerase chain reaction) -based detection methodology revealed a much higher prevalence of viral infection than originally thought.

2. Genetic causes: A large number of miscarriages are due to chromosomal (karyotypic) abnormalities.

It has been reported that more than 50% of first trimester miscarriages are caused by karyotypic abnormalities of the fetus. However, in most cases there is no histological examination or karyotypic analysis of the miscarriage material. In cases of karyotypic abnormalities the abnormal embryo is naturally rejected by the mother. These pregnancies cannot be saved. Usually, karyotypic abnormalities are more common in older women and there is no way of preventing them.

For male infertility, apart from chromosomal anomalies, other important genetic factors that can influence the reproductive outcome include chromosome Y microdeletions (especially frequent in cases of azoospermias/oligospermias) and mutations of the CFTR gene (cystic fibrosis) a “trademark” of obstructive azoospermia (CBAVD).

According to the instructions of the American Society for Reproductive Medicine, all three aforementioned genetic causes for male infertility (i.e. chromosomal abnormalities, chromosome Y microdeletions and cystic fibrosis mutations) should be investigated in cases of azoospermia, or severe oligo/asthenospermia. In these cases, assisted reproduction can be the solution, in conjunction with proper genetic counseling. Information regarding the risk of inheriting chromosome Y and cystic fibrosis mutations is very important, as for the former, male offspring born through IVF are almost certain of inheriting fertility problems from the father, while in the case of cystic fibrosis it is imperative that proper analytical procedure must be followed.

3. Thrombophilia: Mostly connected to miscarriages and to a lesser extent  to problems with conception.

In these cases, there is an increased risk of vascular thrombosis of the endometrium in the implantation area that can result in insufficient blood supply of the fetus. Histological examination of the implantation area in these cases, reveals endometrium blood vessel congestion, rupture of the endometrium wall and bleeding, followed by subsequent necrosis of the region that supplies the developing fetus with nutrients. Thrombophilia is commonly attributed to genetic mutations of coagulation factors that can be inherited from one or both parents of the mother. Treatment is possible through administration of anticoagulation drugs. It is interesting to note, that in most cases, the genetic predisposition leading to thrombophilia is not identified by the treating physicians.

4. Hormonal causes: Mainly concerns progesterone deficiency.

This hormone, normally produced in large quantities by the corpus luteum (the area in the ovary where ovulation occurs) seems to play an important role in preventing fetus rejection, mainly via the induction of inflammation inhibitors. All IVF and AI protocols, are supplemented by progesterone administration (Utrogestan, crinone etc). The problem is that the effect of progesterone is not directly measurable. Although it is a function of the concentration level of the hormone, it also depends on other factors such as the levels of prolactin, estrogen and progesterone receptors. Another known hormonal cause of infertility is the increased concentration of FSH above a certain level. This informs us that the ovaries do not produce good quality eggs, which normally happens when the woman is close to menopause. If this happens earlier than normal, (e.g. at 35), then a consultation with an endocrinologist is in order. Although nowdays there exist many options for both diagnosis and treatment of such cases, there is still room for basic research to further our knowledge in this field.

5. Infectious-non viral-factors may contribute to infertility and miscarriage.

Microorganisms such as Mycoplasma and Ureaplasma originating at the prostate can severely decrease sperm number and motility. Moreover, the endometrium is also susceptible to infections while Ureaplasma in particular has been associated with spontaneous abortion (miscarriage). We believe that the presence of Ureaplasma should be investigated in every case and that it should be treated in both male and female partners at the same time.

The determination of endometrial status by testing menstruation tissue (Hidden-C Test) apart from detection of Chlamydia can also be used for the detection of Mycoplasma hominis and Ureaplasma urealyticum or other pathogens in period tissue. State of the art Real Time PCR testing offers extreme sensitivity and specificity for the detection of these microorganisms compared to conventional testing such as cervical fluid cultures etc.

Other related factors.

Endometriosis is another cause of infertility, the nature of which still remains unclear. Endometriosis involves the ectopic (outside the womb) growth of endometrial tissue which follows the hormonal cycles of the body. At the moment, laparoscopy is the only method for the diagnosis of endometriosis, as there are no reliable laboratory tests available for this. Additionally, the clinical significance of endometriosis for each couple cannot be really evaluated in advance - we can only make an educated guess on the potential effect in each case. Finally, other factors of autoimmune nature, like thyroiditis and other thyroid disorders of the woman are often involved with cases of the so called “unexplained infertility”.

We are optimistic that research centers around the world such as our own will produce new evidence on how these factors are related to infertility. These new data will allow a progressively more etiological approach to the treatment of infertility. Much of the information above is considered new even for specialized laboratories such as our own. These data have been discovered after years of specialized research from scientific teams that will mostly remain unknown. We are using DNA technology and specialized immunology methods to uncover the underlying causes of infertility and aim at answering clinical questions so that we can eliminate “chance” as a factor during medical practice. We also strive to establish new methodology for diagnosis and treatment of infertility so that we can remove as much as possible the financial burden of the couple in their effort to have a child.

In conclusion our advice to couples with infertility problems is the following:

  • Be persistent in trying to understand (as much as possible) the causes (etiology) of your problem
  • Keep in mind that almost always, infertility is a multifactorial condition and try not to get frustrated if your doctor suggests a more spherical investigation of your problem. Even if one putative cause of the problem has been identified, it is likely that more will be discovered in the process. Infertility is a condition that requires patience, perseverance and common sense.
  • Try to be up to date with recent medical developments. It is likely that your doctor will have new interesting information regarding your problem on your next visit.
  • The best doctor for infertility is one that specializes in the area of your problem.
  • When IVF is necessary, keep in mind that it is a physically, mentally and financially costing process that will require of you great dedication and sacrifice. It is therefore extremely important that prior to the first IVF treatment, you should have completed a thorough infertility investigation and to have taken the necessary therapeutic steps to correct any pathological findings diagnosed in the process thus making sure that you are as good candidates for a successful IVF as possible.