Endogel to clear endometriosis tissue in uterus !

Questions # 3

Hope you and your baby are fine,I have been reading your postings on IVF so encouraging,I have had three fa

iled cycles,am now preparing for the forth one,my doctor told me I have endometriosis tissues in my uterus,that has been made it impossible for my babies to implant,so I was given Endogel to have them cleared,can this increase the chances of becoming pregnant,am so depressed I surely don't know what to expect next.....               

both my tubes are blocked that's why I opted for IVF am turning 37 years this year, first cycle I had 15 eggs13 fertilized, en two were put back, my lining was 12mm, the second cycle were frozen embryo 2, en the third one was the the fresh one, I only had 4 embryos due to some problems with the last injection that helps the the eggs to mature, it was given very late after the due time, so only one develop en it was a grade A, so I have decided to change the doctor...so I did hysteroscopy with him and he found that I had some tissus in the uterus, so they had to cut them, then the following day I went in for Endogel, in the night I developed serious running stomach just for few minutes, there after I started my periods, they were so heavy for 8 days same flow, after periods I had some creamish discharge for almost  one month,en now everything has become normal and my vaginal discharge is 100% normal, now I have even started ovulating before I never used to........  I actually paid $1000 for the Endogel

Answer :

I have come across this Endo Gel query many a time now ( especially from many African women ! ) I don't understand how Endo Gel can dissolve endometriosis tissue in the uterus ! I feel so sorry for women who are taken for a ride by their IVF doctor. An IVF doctor is a person whom patients trust and handover the responsibility of making their most desired baby dream come true. I feel disgusted when such doctors use their patients' ignorance to make money. It is the utmost responsibility of every IVF patient to read and keep themselves well -informed about infertility treatments , if not , they are in danger of losing their money , health and eventually their baby dream , too.

Let me explain : Endometrium is the tissue that grows in your uterine cavity -  it is the lining of the uterus where your embryo implants. Imagine it as a bedding for your embryo. Endometriosis is a disease where your uterus lining ( endometrium ) grows in places where it is not meant to grow. For example , it can grow in your pelvic cavity , in the organs present in  pelvic cavity , and even in the brain ( very rarely ) . Endometriosis of uterus , that is , when endometrium that lines the uterine cavity grows into the muscular wall of the uterus it is called adenomyosis. Adenomyosis may or may not cause infertility.

Endo Gel is a derivative of hyaluronic acid In surgical medicine , it is used to prevent  adhesion from forming between different tissues or organs.  For example , if you are having a surgery to remove emdometriosis tissue grown in your pelvic region , there is a possibility that the surgery can itself lead to the formation of new adhesions between your pelvic organs during wound healing.  In order to prevent them from adhering to each other ( to stick to each other ) , Endo Gel is applied immediately after surgery.

Endo Gel cannot dissolve endometriosis tissue - it is used to prevent de novo adhesions from forming after abdomino - pelvic surgeries.

As per the above email , the doctor has performed hysteroscopy and done some surgical procedure on her uterus. The next day , he had applied endogel and informed her that the gel will dissolve endometriosis tissue in her uterus. Because of the rhyming between the words endometriosis and endogel , the poor patient believes that endogel will dissolve her endometriosis and all will be well soon ,  so that she can conceive. She had paid a hefty fee for the same - how sad !

This is exactly why  patients must stay well - informed about their treatment. Please stop believing all that your doctor says , blindly !  Seek second opinion ( or multiple opinions ) whenever you are asked to do costly tests , or before undergoing any invasive surgical therapy. Hysteroscopy can actually do much harm when done without any proper indication - it can even damage your uterus , permanently !

If you want to win over infertility , the first thing one had to do is to seek knowledge. Knowledge is power !

Please read the disclaimer at the top right corner of this blog !

If you need to talk to me , you can write to manjupadmasekar@yahoo.com

My embryos fail to implant repeatedly – Recurrent Implantation Failure in IVF !

“My doctor said that my embryos looked picture-perfect, yet they failed to implant – why did this happen? “

This is the question in the minds of women who undergo IVF failure and this becomes a particularly nagging doubt when they face multiple IVF failures. Many women naturally think that their uterus is defective or their body is not good enough to accept the embryo and hence the transferred embryo is getting rejected by their uterus , or it is being killed by their own body. After all, fertilization happened in the lab , the embryo grew well in vitro , and they even saw their embryo (remember, you must always see your embryos and ask for photos  before embryo transfer !) The embryologist assured them that they looked perfect, , and they’ve read lots of IVF success stories of women who got pregnant with such good embryos. As a result, they naturally come to the conclusion that good embryos  are meant to implant – and if they didn’t, this clearly means there’s a problem with their uterus or their body. Because they have low self-esteem because of their infertility, it’s easy for them to jump to this conclusion and beat up on themselves. A bad situation is often made worse by relatives telling them that their embryo must have “fallen out” because they did not rest sufficiently; or that the cycle failed because they are too stressed out or have too much “body heat”. This is why many women who undergo repeated implantation failure opt for surrogacy. This article has been written to help you understand what causes repeated implantation failure (is the cause really known ? and which is the culprit – the seed (embryo) or the soil (uterus) ?

What is implantation failure?

When an egg and sperm unite together an embryo is formed (this event takes place in the fallopian tube in your body and in the IVF lab it takes place in a “ test tube” ( actually a petri dish ) which contains nourishing culture medium). The embryo thus formed divides rapidly and reaches the uterus in the blastocyst stage (or is transferred to the uterus on day 3 or day 5 during an IVF cycle). When in the uterus, the blastocyst starts to communicate (initiates a molecular conversation) with the endometrium ( the uterine lining) by secreting protein molecules which results in implantation, if the embryo is competent enough and if the endometrium is receptive. Implantation is the attachment of the blastocyst stage embryo to the endometrial lining of the uterus , so that it further develops into a baby (imagine planting a seed in the soil).

When a woman undergoes three or more failed IVF attempts (with good quality embryos) or if implantation doesn’t happen even after transferring more than 10 ‘good-looking’ embryos over many cycle, then the woman is said to have “ implantation failure” . When an embryo fails to implant , there can only be two logical reasons: the embryo is not good enough (genetically abnormal), the endometrium is not “receptive” (doesn’t allow the embryo to implant) enough.  So, what really causes implantation failure? Please keep reading!

Which is the culprit – the seed or the soil?

Imagine a farmer who owns a piece of land and wants to cultivate rice. He ploughs and tills the land , making it ready for sowing, finds the right season (a season which provides good water, air and temperature so that the environment is conducive enough for the sprouting and growth of saplings) and he carefully selects the seeds. This is analogous to how an IVF doctor prepares a woman for undergoing an IVF cycle. He gives hormone injections so that the eggs are collected and fertilized with her partner’s sperms to form embryos (seeds), hormones (estrogen and progesterone) are also used make the uterus ready for accepting the embryo (just like ploughing the land, adding fertilizers and so on) . The woman needs to be in good health (analogous to waiting for the right season to sow the seeds).

When a farmer takes care of all these things and sows the seeds, he expects the seeds to germinate and grow. But what happens when the seeds fail to sprout? There are three plausible reasons for this happening:

• Poor seed quality (embryo)
• Soil which is not fertile (uterus)
• The environment is not conducive enough (physical health of the mother-to-be)

There are also other minor factors which can prevent seed germination like, improper seeding (improper embryo transfer), the seed getting eaten by insects and so on!

In the same way, there can be three logical reasons for implantation failure:

·         Poor quality embryo (genetically abnormal embryos)

·         Non-receptive endometrium (due to defects in the uterus)

·         The body is unhealthy

Other minor factors which play a role in failed implantation are: difficult or traumatic embryo transfers, infections present in the uterus and so on!

How does embryo quality impact successful implantation?

It is a well-known fact that young women fall pregnant quickly when compared to their older counterparts. This is because eggs from older women are more prone to genetic defects , such as aneuploidies (presence of the wrong number of chromosomes ), and contain incorrect or insufficient genetic information necessary to build a healthy baby).When such eggs are fertilized by a sperm , it leads to the generation of embryos which are genetically incompetent (either such embryos do not implant and even if they do , the pregnancy ends in early miscarriage . In rare instances , they can also lead to a full-term birth , where the new born has genetic defects). With the advent of comprehensive chromosome screening, it is now possible to screen all “24-chromosomes” (22 autosomes and 2 sex chromosomes) for the presence of aneuploidy (even though the effectiveness of such a technique to increase live birth via ART in clinical practise is still not provem ). One such study using CGH showed that 96% of aneuploid embryos failed to implant (http://www.ncbi.nlm.nih.gov/pubmed/?term=22305103). This clearly shows that embryo competency plays a major role in implantation. This is why older women find it difficult to find success with IVF , or require more attempts than their younger counterparts.  When an older woman uses donor eggs her chance of achieving IVF success goes up dramatically! This is irrefutable proof that it is embryo quality which plays a major role in implantation and IVF success.

Role of endometrium in embryo implantation

The old scripture, Manu Smriti says “Subeejam Sukshetre Jayate Sampadyathe” i.e., Good seed in good soil yields abundantly. The importance of soil quality in agriculture is well-known.  Does endometrium play such a crucial role in embryo implantation? What happens when a fertile seed (genetically competent embryo) is seeded on defective soil (non-receptive endometrium)?

The period during which the uterus is able to receive the embryo (blastocyst) is called the “window of implantation.” Human uterus is receptive only during a short period of time and this period is also called as the period of “uterine receptivity”. In humans, the receptivity period is between day 20 to day 24 of regular menstrual cycle i.e, 7-11 days after the LH surge that triggers ovulation. During IVF, embryos are transferred to the uterus either day 3 (embryo transfer) or day 5 (blastocyst transfer) after egg collection (the day of ovulation) which coincides with the “window of implantation” of natural menstrual cycle. During FET transfer, the day of starting progesterone is taken as the first day of ovulation and embryo transfer is done accordingly.

Human embryo implantation is an enigmatic biological phenomenon – after all, in-vivo experiments are impractical and unethical to conduct; and studies with animal models do not translate well to humans. But it is well-known fact that embryo and endometrium exhibit cross-talk with each other (talk to each other) using molecular signals and such cross-talk is necessary for successful implantation. However, no reliable molecular markers for endometrial receptivity have been identified. This makes it difficult to find out whether an endometrium is receptive or not during an IVF cycle.

During IVF, endometrial receptivity is assessed crudely with the help of ultrasound images. Endometrial thickness is measured using ultrasound images and an endometrium of greater than 8mm which is trilaminar is said to be optimum for embryo transfer.

It is a well-known fact that the endometrium becomes receptive only after progesterone exposure. Progesterone brings about necessary changes in endometrium (converts the endometrium from proliferative to secretory phase) so that it becomes ready to accept the embryo. Recently, frozen embryo transfers are becoming much more successful than fresh embryo transfers in the field of IVF. It is hypothesized that high estrogen concentration in the body during the fresh IVF cycle compromises endometrial receptivity.

What are the possible reasons for “non-receptive” uterus during an IVF cycle?

• If the uterus contain adhesions, polyps or fibroids in the cavity, then its receptivity will be impaired
• If there is premature increase in progesterone levels (that is, rise in progesterone levels before egg collection due to premature luteinisation of follicles) during an IVF cycle, then the receptivity of the uterus doesn’t synchronize well with the time of embryo transfer and this can lead to failed implantation. This problem can be solved by careful monitoring of the IVF cycle.
• It is believed that thin endometrial lining (a lining which is less than 8mm) is not receptive enough.
• An infection of the uterus has also been hypothesized to prevent implantation, by making the uterine environment less optimal.

There are also so many unproved reasons cited for lack of uterine receptivity, which include: immunological theories like the presence of high number of uterine NK cells, excessive HLA matching between partners ; and blood clotting issues.

What factors other than the embryo and uterus might contribute to implantation failure?

The ease with which the uterus can be negotiated for the embryo transfer also plays a pivotal role in achieving successful implantation. If the uterus is hard to access via the cervix ( for example, in patients with cervical stenosis) , then other embryo transfer methods like ZIFT should be used in order to enhance implantation.

Can implantation failure be successfully treated? What kinds of evidence based therapies are available?

Yes, it can be treated , but only if the reason is known. The one and only well-known, scientifically proven reason for implantation failure is genetically incompetent embryos. If you are a women of advanced maternal age or if you have premature ovarian aging, even if you get some embryos to transfer during an IVF cycle, many a time they can be genetically abnormal and will not implant successfully. The irony is many women do not want to accept this fact ( after all, it is very difficult to accept the fact that they can’t have their genetic baby) and try to blame their uterus for the failed implantation. As a result they believe that surrogacy can help them conceive, which is not true! Doctors make use of their ignorance and “treat” them with many different therapies which are not evidence based. I have seen so many women of advanced maternal age subjecting themselves to many useless therapies and ultimately finding success when they finally use donor eggs. So if advanced maternal age or poor ovarian reserve is the cause of failed implantation, the only reasonable solution is to use donor eggs.

If your uterine cavity contains adhesions, fibroids or polyps which interfere with implantation, removing them will help in achieving embryo implantation.

The role of endometrial thickness in successful implantation is still a question. Many women with thin endometrium do have successful implantation, but the scientific literature shows that an endometrium thickness of more than 8mm is optimum for achieving implantation.

What kinds of “non-evidence” based therapies are available to treat implantation failure?

The following therapies do not have solid proof for their efficacy and are very speculative:

• Use of blood thinners like aspirin and heparin.
• Causing local injury to endometrium before embryo transfer, to improve local uterine blood flow
• Therapies like use of steroids, IVIG, intralipids etc which claim to reduce NK cell levels in the uterus.
• Paternal lymphocyte immunotherapy to “ treat “ HLA matching between partners.
• Use of G-CSF (Granulocyte-Colony Stimulating Factor) which is commercially known as neupogen.
• Use of embryo glue (a substance which is claimed to enhance the attachment of embryo to the uterus).
• Routinely making a hole in the zona pellucida of the embryo (outer coat of the embryo) with the aim of helping the embryo to hatch out of the shell successfully. This is known as laser assisted embryo hatching.
• Co-culturing embryos with endometrial epithelial cells.
• Intrauterine administration of PBMCs ( Peripheral Blood Mononuclear Cell)

Doctors must actually resist offering such treatments that are not evidence based or at least they must share information honestly with their patients. They must make sure that the patient understands that the above mentioned therapies are not a panacea for their problem.

What can I do if I have repeated implantation failure?

• Test your AMH ; day 3 FSH and E2 value ; and your antral follicle count – are they normal? Do you have good ovarian reserve? If you have poor ovarian reserve or are older than 40 years of age and have suffered repeated implantation failure, you should consider using donor eggs.
• If you are young and have good ovarian reserve, ask the embryologist how your embryos look – are they of good quality? If they are of good quality (dividing well according to their age) , then the chances are that the embryos which were transferred may have been genetically normal ( sadly, we still do not have the technology to test for all possible genetic defects before the transfer)
• Do you have PCOD? Did they retrieve lots of eggs (more than 25 eggs) from your ovaries? PCOD could be a reason for the lack of embryo implantation. Taking insulin sensitizers like metformin and myoinositol might solve your problem.
• If your doctor has used the same ovarian stimulation protocol for retrieving eggs from your ovaries, you can try other ovarian stimulation protocols too. Mild ovarian stimulation protocols are found to be superior in producing better quality eggs and embryos in a selected subset of IVF patients (mostly patients with poor ovarian reserve).
• If you have failed IVF several times by using a day 3 embryo transfer, try having a day 5 embryo transfer. The fact that embryos are developing to blastocyst stage is a good indication (not an ultimate proof though) that your embryos are good enough.
• You can try doing a frozen embryo transfer instead of a fresh transfer. High levels of estrogen in the body during a fresh cycle can damage uterine receptivity.
• If you have cervical stenosis and embryo transfer through cervical route becomes difficult you can try other modes of embryo transfer (like ZIFT )
• You can try changing the clinic – sometimes this works!
• Another option available is to use donor embryos!
• If your uterine cavity contains adhesions, polyps or fibroids, you need to remove these. If there are lots of adhesions or if you suffer from a thin endometrial lining because of Asherman’s syndrome (and if it is untreatable!) you can opt for surrogacy.

So following are the options in front of you:

• Change the ovarian stimulation protocol
• Use frozen embryo transfer instead of fresh transfer
• Change the mode of embryo transfer ( do a ZIFT ) if cervical embryo transfer is difficult
• Change the clinic
• Change the egg
• Change the sperm
• Use donor embryos
• Consider surrogacy

What is the take home message?

When an embryo enters the uterus in the blastocyst stage, it initiates a molecular cross-talk with the endometrium. Perhaps it says, “Hey I am here and I want to establish connection with you, attach and grow, are you ready to accept me ? ” The endometrium senses the signal sent by the embryo and responds accordingly. All this cross-talk happens by releasing appropriate protein molecules. It is believed that if there is some problem with this cross-talk, embryo implantation fails.  

It is hypothesized that the endometrium acts as a biosensor of embryo quality. This means, if a genetically abnormal blastocyst enters the uterine cavity, the endometrium senses this by the signals sent by the embryo and prevents the implantation of the embryo. So if this biosensor mechanism is defective in some women, they paradoxically become “ superfertile” . That is, such women fall pregnant very easily because even genetically abnormal embryos are allowed to attach to the endometrium and establish a pregnancy. On the other hand, they suffer from recurrent biochemical pregnancies or miscarriages because even if the genetically abnormal embryo implants , it can’t develop into a healthy baby and gets aborted eventually.

There are also studies which show that even if the endometrium is not optimally receptive,  a genetically competent embryo can modify the endometrial environment to make it favourable,  so that successful implantation is achieved.

When you talk to a well-experienced IVF specialist, he will say from his practical experience that when women suffer from recurrent implantation failure, most of the time changing the egg can bring about successful implantation and pregnancy!

The endometrium seems to act as a passive recipient. After all a seed , can sprout even in the absence of soil ( for example, in women who have ectopic pregnancies, where the embryo implants in the fallopian tube, where there is no endometrium at all ! ) If you are suffering from recurrent implantation failure, please do not blame your uterus , if it doesn’t have any obvious defects.

‘Tests’ for NK cells and ‘cures’ for infertility and miscarriage – yet another way to exploit the desperate, vulnerable patient!

 

I get mails from patients saying that their NK cell number or NK cell activity is high and hence their doctor has asked  them to undergo  immunotherapy , using either IVIG infusion ; or intralipid therapy; Lymphocyte Immunotherapy (LIT) ; or tumour necrosis factor alpha blocking agents and steroids , or a combination of these, in order to 'treat' this abnormality.  They are advised that, by doing this, they can improve their chance of having a baby. Is this claim justified ? What are NK cells ? What are their functions in human body ? How are they connected to fertility ?  Do women who undergo this therapy improve their odds of having a baby  ? Does your doctor who asked you to undergo this test and therapy have  proof for its efficacy ? Is it wise to invest so much emotional, physical and financial energy in it ? There are so many unanswered questions and this article might help in answering them.

What are NK cells ?

Our body is attacked by bacteria and viruses constantly. Some cells in our body can become cancerous if errors occur in their DNA during cell division. In order to protect our body from microbes and from tumour causing cells, our body has developed a surveillance mechanism called the immune system  which consists of cells called white blood cells. These cells constantly scrutinize our body and remove the infected or abnormal cells.  Natural Killer (abbreviated as NK cells) cells are part of our immune system and are involved in early defense.  As the name suggests, their main function is to
kill ! They have the ability to remove the microbe infected cells and genetically abnormal cells which might cause cancer. They do this by secreting a protein called perforin which makes hole in the infected cells. Then a lethal dose of enzymes are used to destroy the deleterious cells. In short, these NK cells function to protect our body against infections and cancer.  The name natural 'killer' cells comes from the invitro assay used to identify them (identifying NK cells by its ability to kill target cells). Please do not imagine NK cells as something which is waiting in the uterus to devour your much loved embryos !

Where are natural killer cells present in our body ?

NK cells are mainly found in the blood stream.  They are also found in liver, skin, lungs, thymus and uterus. They are the predominant type of maternal immune cells found in the uterine mucosa during the formation of placenta. They are also present in the endometrium of non-pregnant woman and accumulate at large numbers in the implantation site. Uterine natural killer cells are present in high numbers in early gestation.

Are peripheral NK cells and uterine NK cells similar ?

No they are not ! Both these cells are functionally as well as phenotypically different. NK cells are identified by the receptor they are carrying. The receptor used to identify NK cells are called as CD 56. NK cells which express less CD 56 are called CD 56 dim cells. These kind of NK cells are predominant in peripheral blood and show extensive cytolytic (killing deleterious cells) activity. The NK cells present in uterine mucosa carry more CD 56 receptors on them and are called CD 56 bright cells. Their cytolytic potential is comparatively less than the CD 56 dim cells.

If so, is studying peripheral blood cells in order to assess the number and activity of uterine NK cells justified ?

 

Definitely not !  It is analogous to counting  the number of people and studying their behavior in Africa in an attempt to study the same in Asia. Both are humans but neither the place they inhabit nor their behaviour is similar !

What functions do NK cells have in uterus ?

The truth is, the function of NK cells in uterus is not yet clearly defined. The NK cells in the uterus are thought to produce several angiogenic factors and thereby help in regulating the menstraul cycle. There is evidence that they play a beneficial role by helping the proper invasion of placental trophoblast cells into uterine decidua by secreting essential cytokines and thus helping to establish a normal blood supply to the fetus and placenta throughout pregnancy. NK cells do not kill trophoplast cells !

How are natural killer cells linked to infertility and why it is not a scientifically valid observation ?

It was shown that women with recurrent miscarriage had increased amount of NK cells in their peripheral blood circulation or in their endometrium and/or their NK cells showed increased cytotoxic property . It was hypothesized that, in infertile women, overactive (malfunctional) uterine NK cells destroyed the trophoblast of the developing embryo preventing implantation or leading to miscarriage.  But this observation had many flaws to it :

1. The method used to measure the number of NK cells varied in different studies. The results can vary a lot , depending on the technique used to measure NK cells.

2. NK cells in the blood of normal healthy individual can vary from 5% to 29% depending on the sex of the individual, ethnicity, stress and age. Inspite of this, infertile women who had more than 12% NK cells in their circulation are defined as having “ abnormally elevated “ NK cells and are ‘treated’ in the studies conducted. Moreover peripheral blood NK cells are different from uterine NK cells. Studying peripheral blood NK cells cannot throw light on the number and function of uterine NK cells.

3. When NK cells are collected from the uterus, they must be isolated from the same depth in all women because their density varies widely along the uterine mucosa. If not, the results can vary widely.

4. Well designed, sufficiently powered clinical trials with appropriate population selection and using the same NK cell testing methodology are lacking.

5. The cytolytic potential of NK cells are tested using cancer cells (K562 cells). It was shown that NK cells can kill cancer cells and not normal human trophoblastic cells invitro.

So there is no scientific rationale for these tests !

Why is it unlikely that uterine NK cells will attack the embryo ?

Progesterone is considered as one of nature's best immunosuppresant. It was shown that progesterone at the concentration present at the materno-fetal interface inhibits NK cell activity. The placenta also secretes several factors which act as immunosuppressants. Even the human embryo has been shown to produce certain chemicals which stimulate the maternal system to produce Early Pregnancy Factor ( EPF) which acts as an immunosuppressant too. Trophoblast cells also express certain receptors which prevent NK cells from attacking them. Hence it is highly unlikely that uterine NK cells attack your embryo in vivo.

What is the NK cell activity assay and how useful is this assay ?

In order to find out whether NK cells show abnormal cytotoxic activity, the NK cells (mostly from peripheral blood) are removed from our body's natural environment where progesterone, placental factors and other natural immunosuppressants are present in plenty. Then an in vitro assay is carried out using k562 cells as a target . k562 is a myelogenous leukemia cell line. The percentage of k562 cells lysed or killed by NK cells gives an idea about how active your NK cells are. Using the result of this NK cell cytotoxicity assay , some doctors decide whether a particular woman should undergo immune therapy or not.

There are certain important points to be noted here: K562 are cancerous cells and such cancerous cells are readily recognized by healthy NK cells. It is the normal function of NK cells to kill cancer causing cells. The use of the K562 lysis assay to determine whether your NK cells have the capability to attack your embryo is a very crude, vague and controversial method. Even if a particular woman’s NK cells are active against cancer cells (K562) , this doesn’t necessarily mean that her cells will behave the same way against her embryo's trophoblast cells. So why don’t labs test NK cells activity against trophoblast cells in vitro ? This is because NK cells in such invitro assays do not kill human trophoblast cells !

It must be kept in mind that the in vitro environment is extremely different from in vivo conditions. Uterus environment (in vivo environment) is extremely rich in natural immunosuppressant (like progesterone) and when a competent embryo enters the uterus , it signals the maternal system to secrete immunosuppressants. How can an assay conducted without simulating a natural in vivo environment be used to predict NK cell cytotoxicity against human embryos ? How could one correlate activity against a cancer cell line with activity against human trophoblast cells? How many studies were done to determine the cut-off value for determining NK cell cytotoxicity?  Very few studies have been done , and most of them were published in low-ranking journals , which means they lack enough power !

What are the ‘therapies’ available to ‘treat’ malfunctional NK cells and how useful they are?

It is believed that by using intravenous immunoglobulins , intralipids, lymphocyte immunotherapy or by using tumour necrosis factor - alpha blocking agents and steroids the ‘raised’ or ‘malfunctional’ NK cells can be ‘ treated’ by dampening the immune response. Such therapies have no scientific validity and can pose significant health risks to the patients. Intravenous immunoglobulin is a pooled blood product and can result in anaphylactic response, fever, flushing, nausea, and headache and pose an increased risk for the transmission of infectious diseases. Intralipid therapy and IVIG, can dampen the immune response and make one prone to infectious diseases.

If this is true; why do many REs offer NK cell testing and therapy?

There are many reasons for this :

1.            Money – many doctors are not ashamed to make money out of your desperation and vulnerability.

2.            Doctors are humans too and are prone to cognitive biases. They conveniently forget the 9 patients who failed IVF after undergoing such scientifically invalid therapy , but they remember that one patient who had 8 failed IVFs and who achieved success after being treated for malfunctional NK cells! They remember their sensational success stories and crave credit for it. As a result many become vocal advocates for pseudo science!  Many REs do not maintain proper records of the treatment they offer and hence have no chance to make a valid statistical analysis of the treatment they offer. They value their personal experience much more than the knowledge accumulated by several scientists after careful research over a period of time.  As a result they forget that evidence based medicine is the golden standard of good medical practice.

3.            Patients, out of desperation, believe all the sensational media news which is based on anecdotal evidence (for example read this: http://www.dailymail.co.uk/femail/article-2361112/Mayonnaise-miracle-babies-150-IVF-attempts-controversial-egg-yolk-oil-jabs-theyre-mums-last.html - very impressive, beautiful pictures, right). Extensive coverage of anecdotal success stories by the media creates a bandwagon effect. Because of their lack of scientific knowledge , patients are unable separate the wheat from the chaff.  As a result, they believe that by using the therapy they read about on a website or in an article in the newspaper ( which may actually just be a press release) they can get their much desired baby. This kind of blind expectation of patients in the efficacy of new, unproven treatments pushes many REs to offer them these treatment, irrespective of their scientific validity. Patient pressure forces doctors to do stuff they may not believe I because they are scared they might lose their patient to some other doctor who offers them !

5.            Many doctors find it difficult to understand the rationale behind these tests. They get duped by the diagnostic and pharmaceutical companies who promote these tests and therapies.

How do you explain all the success stories of women who have failed 5 IVF cycles and then got pregnant after treating their high NK cell activity?

Let me ask you another question: how will you explain all the failure stories , even after the high NK cell activity was “treated” ? Just because your friend or a blogger says that they achieved success after taking treatment for their high NK cell activity  doesn’t mean that the observation is scientifically valid . Anecdotes are not proof of efficacy! We humans are social storytelling animals and we learn by the experience of others  -  this is how we are hardwired. That is why our mind gives undue importance to such stories , instead of looking for valid scientific proof. Another important thing we must realize is that patients who benefit from a particular treatment are more likely to boast about it than the patients who didn’t get success, who are resigned to their fate. So for every five women who succeed, there might be another fifty who failed , but you do not get a chance to know about them. This is why anecdotal evidence is not reliable. In order to test the effectiveness of a particular treatment, a randomized clinical trial with sufficient power must be conducted. At present , there are not enough RCTs to prove that NK cell testing and therapy really benefits infertile patients.

My RE says experience is as important as knowledge and assures that he has seen it work in his practice!

Just because your RE has seen it work in his practice doesn’t mean it really works ! Again your RE is telling you a story , and this can only be considered as his individual view about the treatment – just more anecdotal “ evidence” . As I have already mentioned, your RE is a human too with cognitive biases , and hence his judgments can be flawed too.

I read a RE’s blog where he defends his approach of providing treatment based on anecdotal evidence , by giving an elephant trail adage. He quotes this:

Elephants in Africa migrate hundreds of miles each year to reach their ancestral feeding grounds. The journey requires that they cross mountains, ravines, jungles, turbulent rivers and unforgiving desert terrains. They always follow the same path, one that over time has proven to be the least challenging and the most productive.  Indeed, in the beginning they must have made many costly directional and topographic errors, but over time they eventually defined the best way to reach their destination safely. This is how I learn too – from my experience, over years of trial and error.

Humans are rational animals! They need not have to subject themselves to risks which animals have to go through. As humans , we can form a hypothesis and test its validity by conducting proper research - we don’t have to believe anecdotal evidence alone.  The  RE equates his patients to experimental rats , and claims that everyone learns by mistakes , and that errors do happen. If someone wants to experiment on their patients, it has to be done with informed consent , and not by exploiting their vulnerability. If an experimental procedure is tried on you, why should you pay them a huge fee for the treatment? Is it even ethical? He claims that he has no scientific evidence to prove intralipid therapy is effective but he knows that it works by his experience! If doctors can judge correctly by their experience alone, then there is no need for pharmaceutical companies to spend millions on performing  RCTs and extensive research !

What should I do now ? Why shouldn’t I take a chance and try the therapy (I am desperate to have a baby!) Who know, it might work for me!

After hearing all the rational arguments , if your heart still says that you must give it a try, then you can go ahead.  But please understand the following :

Try to see whether you can enroll yourself in clinical trials which are conducted to assess the therapy’s validity. If not , ask your RE whether he could provide the treatment free of charge, since it is not a proven treatment and is based on anecdotal evidence. This way, you get the treatment and he gains knowledge – a ‘win-win situation’ (I bet no RE will agree to this unless and until they themselves are involved in conducting a clinical trial for the same)

Please educate yourself about the risks involved in such treatments and be aware of the emotional risks such treatments carry! There is also the opportunity cost to consider.   By barking up the wrong tree ,you may waste a lot of time and tons of money.

If you are a woman of advanced maternal age , please understand that it is your oocyte competence which is the most important factor in influencing implantation – not your NK cell activity ! Please do not subject yourself to such unproven therapies – they are very unlikely to help !

Take home messages

1.            NK cells are not proven to kill your embryo by attacking the trophoblast. They do not kill trophoblast even in the invitro assay used to assess its activity !

2.            The tests available for measuring NK cell number and assaying its activity are highly variable and do not yield consistent results.

3.            Your NK cell number in peripheral blood can vary a lot,  depending on stress, age, ethnicity etc

4.            Peripheral blood NK cells are very different than that of uterine ( uNK) NK  cells; studying them will not shed light on uNK cells.

5.            The therapies offered for NK cell malfunction have many side-effects, please be well-informed about these.

6.            Your RE’s personal experience and observation (plural of anecdote is not data !) cannot replace good clinical research data.

7.            In your quest for a baby , do not get desperate and allow the idiosyncratic personal practices of some physicians to exploit you !