Subfertility/Reproductive Medicine

Chapter 1. How to gain maximum benefit with minimum consumption of physical and mental health, time and money.

  1. The first objective: Definition of factors contributing to the couple’s infertility
  2. The second objective: Taking the appropriate therapeutic measures aimed specificaly at each cause contributing to the problem
  3. The third objective: Reach week 12 of pregnancy without any problems

Chapter 2. Etiological approach to infertility.

  1. Immunological and viral factors
  2. Genetic damage
  3. Thrombophilia
  4. Hormonal causes
  5. Microbial factors
  6. Other related factors
  7. Conclusion: Our advice to couples with infertility problems
 

Chapter 1. How to gain maximum benefit with minimum consumption of physical and mental health, time and money.

Dr. Tsilivakos Vassilis M.D., Ph.D.

After 15 years of dealing exclusively with the treatment of infertility I would like to share my findings on the subject.

From a scientific point of view, I hope that my findings communicated through publications and conferences, contributed to a better understanding of the complex nature of the problem. I also hope that from a social perspective, the information provided here will help couples to achieve the desired result in a way that will allow them to save not only money, but also spare them from both physical and emotional grief.



The objective of this effort is clear: To gain maximum benefit possible with minimum consumption of physical and mental health, time and money.


During the last 15 years in the fields of reproductive healthcare and assisted reproduction, two areas demonstrated considerable progress. The first, concerns the improvement of IVF. In this area, progress was achieved through continuous improvement of stimulation protocols and stricter regulations of standardized work in the embryology laboratory. The competition brought about by the increase of IVF center numbers played a key role to that effect. Also important was the improvement of embryos, sperm and ova freezing methods. The second area that significantly evolved over the last 15 years, was the development of an etiological approach to the diagnosis and treatment of infertility.

Admittedly, the likelihood a successful IVF attempt in later years has been increased due to the gradually applied causal (etiological) approach of infertility and to the individualized assessment of reproductive health problems of couples undergoing treatment. This is a highly complicated medical field, where the sum effect of the interaction of a large number of factors can ultimately lead to infertility. In spite of the great heterogeneity of infertility-contributing factors, we can now target each one in a more precise and effective way compared to previous years. These recent developments in the field have lead to successful new pregnancies even by means of natural conception rather than IVF.

Natural conception should be the primary goal of every couple. At the same time however the continuation of a pregnancy all the way through the later stages must be ensured in advance, especially since miscarriages are more likely to occur in couples with a history of infertility.


Therefore, I propose that the couple during the course of their attempt to conceive, should set clearly defined objectives and even set deadlines for their achievement if possible.


The first objective should be the definition of factors contributing to the couple’s infertility.

Simply put, the couple should learn the reason why it is difficult for them to conceive. Under no circumstances should any kind of treatment and/or assisted reproduction attempt be started before an assessment of all factors which contribute to infertility has been made. The only exception to this rule is the treatment of infection (microbial, fungal or viral), which is also a matter of good healthcare in general. It is needless to say that consideration of IVF options, before the above investigation has been completed is considered premature.

In most cases however, the procedure described above is not followed. Unfortunately, after one spermiogram and one salpingography most couples are directed towards a series of assisted reproduction attempts. What's more, if in spite multiple IVF attempts, conception is still elusive, these cases are classified as “infertility of unknown cause”! To avoid this eventuality one must persist in the first question of "what are the reasons that prevent conception?". The answer to this question should be convincing to the couple according to their common sense and logic. If not, this should be clarified by more questions (In my opinion a doctor’s ability to clearly explain an answer to the couple reflects his expertise on the subject).

Apart from discovering the primary causes for their infertility, the couple should also ask themselves "when conception occurs how can we be sure that we have done everything possible to avoid a miscarriage?”. In this case too, the doctor should provide the couple with a convincing answer. Keep in mind, however, that infertility is a highly complex medical chapter that spans through many clinical, laboratory and research disciplines of medicine. Even for a doctor very well-versed in reproductive medicine it is sometimes difficult to assess a case. It is my opinion that specialization, experience and investigative thinking are essential qualities a medical reproductive health specialist must possess. Unfortunately, a large number of physicians that are not experts on the subject of infertility, in order to live up to their patient’s expectations, rather than referring them to a specialist, they resort to prescribing extended lists of diagnostic tests which are not aiming at answering specific questions. To make things worse, the results of these tests are often misinterpreted.

The field of gynecology and obstetrics is very extended. A gynecologist is not obligated to have a deep understanding  of all the required details from the fields of to andrology, immunology, hematology, endocrinology, genetics and medical laboratory technology which are needed for handling  complex and highly specialized infertility cases.

At this point one must consider the financial implications of infertility testing. The prescribed tests should be personalized, few in number and extremely focused. If the financial costs are very high, this will eventually impact the couples psychology resulting in aggravation of the problem. Patients should always perform a market research beforehand and when the couple is referred to a specific laboratory or medical center for diagnostic testing, the doctor should be able to explain that choice. Higher prices should always be justified by higher quality of information made available by the tests’ results.

With a high morale, the couple should be both good natured as well as suspicious. The patients must ask questions and should expect convincing answers. They must always be able to understand where their money is spent. Keep in mind of course, that the problems of each couple are different. Some face more complicated problems than others. However, a good specialist can inform the couple in such way that the patients understand the complexity of their problem which will explain the costs of the prescribed tests and therapies.


The second objective for the couple should is taking the appropriate therapeutic measures aimed specificaly at each cause contributing to the problem.

The couple should be able to understand the correspondence between treatment and each individual factor that contributes to their infertility. In this way, the couple will be able to clarify any questions regarding their treatment in order to minimize the chance of making a mistake (unfortunately this happens frequently and is almost always the couple’s fault due to misunderstanding of the doctor’s instructions).

As I mentioned earlier, etiological therapies begin by treatment of microbial infections. Treatment of the rest of the factors then follows according to the way that the couple wants to attempt a conception. After achieving the first goal, (diagnosing the cause(s) of the problem) the couple should think about the way of conception that they want to try. In cases of tubal occlusion, or serious sperm problems, or advanced age or in cases where for some reason is imperative for the couple to achieve conception as soon as possible, the answer is simple: Completion of the second objective (completion of etiological treatment) should be followed be an IVF attempt. In fact many of the etiological therapies are temporally adapted to the expected date for oocyte- or embryo-transfer.

On the other hand, when the conditions are less severe, that is when even a single doctor can suggest that conception is possible with ways other than IVF, then the couple should set their deadlines. According to their age, psychological condition, financial status, jobs, relationship and the advice of their family doctor, the couple should allow a number of months (cycles) for natural conception to occur in which case they will have avoided a lot of expense and drugs.  During the stage of waiting for a natural conception to occur, etiological therapies should continioue correctly during every cycle (except from antibiotics). One should be extremely careful to maintain a continuous and accurate treatment regime since, with the exception of antibiotics administered early during treatment to remove infection, all other treatments have temporary effects and must be repeated in order to remain effective.

During this period via assisted reproduction or through natural conception most couples would have achieved pregnancy. The treatment received not only helped achieve a conception, but will also help to maintain the pregnancy provided the doctor’s instructions are followed correctly during 1st trimester. If during this time the couple did not achieve a conception then a consultation with their doctor must take place in order to decide whether a more strict regime of diagnostic testing should be performed or whether the couple should proceed with some method of assisted reproduction, intrauterine insemination (IUI) or IVF.


The third objective. Reach week 12 of pregnancy without any problems.

At this point the couple should refrain from excessive excitement and preparations. Keep in mind that, unfortunately, spontaneous abortions mainly occur during the first trimester and are more frequent in couples with a history of difficult conceptions.

This period requires much patience, optimism and understanding of the situation of pregnancy in order to control sudden movements as much as possible. During the first trimester, blood is congested in the blood vessels of the endometrium and at the slightest a detachment of the embryo may occur, which can pose a serious threat to the pregnancy.

In the first trimester, particularly women that had a hard time trying to conceive should not ignore the possibility of a bad outcome for the pregnancy. Chromosomal abnormalities are not easily detectable and can occur even if both partners have normal karyotypes.

My suggestion to women at this stage is that they should look at their pregnancy not only as the protagonist of the play but also as an outside observer. The reason I suggest this, is to minimize the later psychological repercussions of a miscarriage. The attempt that will follow will require the woman to be in a and good psychological condition. A new attempt cannot begin if the woman has already resigned psychologically.

I also suggest that the couple should not commit to their friend, family and working environment through impulsive disclosure of pregnancy. Depending on their temperament and character, the couple may feel badly when a widely known pregnancy does not end successfully. The correct way to go about this, is for the couple to disclose the news of the pregnancy in a controlled manner keeping in mind all possible outcomes, both good and bad.

At the end of the 1st trimester, if all fetal measurements are normal, then we can say we have a good indication that we are well on the road of achieving the final objective.

My field of expertise however, extends up to this point.


Chapter 2. 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 M.D., Ph.D.

Dear Friends,

On behalf of the reproductive health clinic of Locus Medicus, 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.

11 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.


As far as the so–called “unexplained” (of unknown etiology) miscarriages  are concerned, 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 damage
  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 information on Locus Medicus research can be found here).

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 our research (Michou V.I.et.al. (2003). Fertil Steril., 80 Suppl 2:691-7 , Locus Medicus Laboratory, Athens, Greece). 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.

Using state-of-the-art techniques, detection of virtually any microorganism is possible (bacteria, viruses or fungi) through our tests. The question is, which pathogens are of clinical significance in any given medical case such as subfertility, STD screening, endometritis etc. Our new “17 in 1” test that can detect 17 sexually transmitted microorganisms in the same sample, including Chlamydia, Mycoplasma, Ureaplasma and Herpesviruses 1/2 can be used for diagnosis of all three of the above clinical questions.


2. Genetic damage: 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. Thrombophilic causes: 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 subfertility 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.

Furthermore, as the sample can be self-collected at home, it is not necessary to visit a clinical facility or employ the help of a medical professional for specimen collection (of course your clinician should be advised for result interpretation and therapy).


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. Due to the fact that our medical center specializes in other areas we do not have an in depth opinion on the subject. However, we have seen several cases in which conception was attained after treatment for endometriosis.  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.

"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 etiologically corrected."

 

For more information on recent developments in the field of reproductive medicine please don’t hesitate to contact us. We hope that in our next update of our website we will have more interesting news to communicate.

On behalf of the Department of Infertility of Locus Medicus,

 

Tsilivakos Vassilis M.D., Ph.D.

Immunologist and Pathologoanatomist

Researcher of Reproductive Immunology