Is IMSI better than ICSI ?

Sperms attached to egg coat

Myth :  IMSI is better than ICSI

Fact :  This is another unproven claim in the field of ART , another logical fallacy ! 

A sperm is the smallest cell in a human body and an egg the largest. The union of the sperm and the egg brings the genetic material from the male and female together , to allow the creation of a new life.  A normal human semen sample consists of anywhere between 20 – 150 million sperms and not all sperms look alike ! Human sperms are very heterogeneous in their appearance and they have many different shapes. This is in sharp contrast to animals, most of whom have perfect looking sperm.  When we test a sperm sample in the lab, we check the shape ( morphology) of the sperm by staining them and examining them under high magnification. When studying male fertility , researchers were very interested to understand whether the shape of the sperm is in any way connected to the man’s fertility potential. This led to lots of studies aimed at determining what normal human sperm morphology is !

What does a normal (fertile men’s sperm) sperm look like ? – Actually, no one knows the answer !

This is a question which still doesn’t have a good, solid answer. A human semen sample consists of sperms which exhibit significant intra (within a single ejaculate) and inter variability (when ejaculates from different fertile men; and even ejaculates from the same fertile man at different times, are compared) in their morphology. Hence , determining the criteria to say whether a sperm is normal in its morphology is very difficult.  In the animal world, fertile animals have sperm which look identical , and this  makes it easy to determine what an abnormally shaped sperm looks like . Infertile animals have sperm which are abnormally shaped. On the other hand , when you compare the ejaculates of two fertile human males , their semen sample contains sperm of widely varying shapes, even though they are both fertile. As a result of this , it is hard to find a benchmark as to whether a particular sperm shape is normal or abnormal ! Hence characterizing the fertility potential of men based on sperm morphology became a hard task. 

In earlier times , researchers observed human sperms under the microscope carefully. When they felt that a particular sperm looked very different from the rest,  they considered such a sperm as being abnormally shaped  and recorded such sperm shapes in the form of schematic representation and drawings (which lacked accurate details). By using such an approach , sperms which are not considered to be abnormal are considered as normal ; and normal sperms are thus identified as being normal by default , because of the absence of any gross defect. This method , which is used to classify sperms as being morphologically normal, is called the liberal approach.

Then came the method of identifying sperm morphology using strict criteria or Tygerberg criteria (Kruger’s strict criteria). According to this approach , the morphology of sperms which are found at the internal cervical os (the part of the cervix closest to the uterus) and the sperms which are found attached to the zona pellucida (egg coat) of the human egg are considered to be the gold standards for labeling a sperm as normal. The sperm present in the above places are found to be homogenous in their morphology , although they still exhibited differences in their head shapes. This method of sperm morphology evaluation also included the functional capability of the sperm , because sperms which are able to reach the egg are used as a benchmark for determining what normal sperm morphology is. This means that studying sperm morphology is still not perfect , and there are still several arguments as to the right approach!

Ref :PMID: 20111081

What is the cut-off value for evaluating normal sperm morphology in a semen sample?

The standard textbook for evaluating sperm is the WHO laboratory manual for the examination and processing of human semen. In the first World Health Organization (WHO) manual published in 1980 , the cut-off value for mean normal sperm morphology was 80.5%, with a range of 48.0%–98.0%. In the second WHO manual published in 1987 the cut-off was lowered to 50%. Both the cut-off values were determined based on the liberal approach for sperm morphology evaluation. In the third edition, the value for normal sperm morphology was changed to ≥ 30% morphologically normal spermatozoa , based on strict criteria for sperm morphology evaluation.  In the fourth  edition of the WHO manual , no cut-off value was provided but it stated that 'Multicentre population-based studies utilising the methods of morphology assessment in this manual are now in progress. Data from assisted reproductive technology programmes suggest that, as sperm morphology falls below 15% normal forms using the methods and definitions described in this manual, the fertilisation rate in vitro decreases.' And in the newest ( fifth ) edition the proposed cut-off value for normal sperm morphology is just 4% based on strict criteria for sperm evaluation!

This means a man needs only 4% of normal shaped sperms in his semen to achieve a pregnancy (PMID: 1550422).This evolution of cut-off value for evaluating normal sperm morphology clearly shows the confusion which exists in determining what a normal looking sperm is ; and with the strict criteria which are used now for sperm evaluation , more and more sperms are classified as being abnormal. Actually the decline in the cut-off value for morphologically normal sperm doesn’t mean that the semen quality is declining, it just means that the sperm morphology evaluation criteria have changed ! Sperms which were considered normal in the 1980s are considered abnormal now ( the field of sperm morphology evaluation is very confusing !)

Can a sperm shape predict the quality of DNA it is carrying?

It is tempting to assume that an ugly sperm (morphologically abnormal sperm) carries defective DNA , which is not competent enough to create a beautiful baby. But looks can be deceiving as always. A high amount of morphologically abnormal sperm might indicate poor sperm function but it doesn’t automatically mean that a morphologically normal sperm  is functionally competent , or that the DNA it carries is normal. It also doesn’t mean that sperms with abnormal morphology carry chromosomal defects.

With this background in mind, let’s see what IMSI is !

What is IMSI ?

Magnified sperms (7000X)

 

Intracytoplasmic morphologically selected sperm injection (IMSI) is a new technique which is also called as ‘super ICSI’.  In IMSI technique,  the sperms are magnified 7000X (whereas in ICSI the sperms are magnified only 400X).  Evaluation of sperm morphology at this high magnification enables the embryologist to select sperms which are devoid of any obvious morphological defects. For example any defect in (DNA compaction) is visible in the form of vacuoles in the sperm’s head , and the IMSI technique identifies such ‘defective’ sperm (those are the sperms which are supposed to carry a defect in their DNA !) . Such sperms are excluded from being used for fertilizing the egg. Selecting a sperm which is morphologically perfect from a semen sample high contains a high number of abnormal sperms is thought to help in achieving and maintaining pregnancy via ART technique. This is what the IMSI technique promises us.

Isn’t it logical to use IMSI in place of ICSI ?

Theoretically , it appears logical to use IMSI , but this is not true in real life for a variety of reasons :

1. Just because a sperm is morphologically normal doesn’t guarantee that its DNA is normal. Similarly, just because the sperm is morphologically abnormal doesn’t mean that its DNA integrity is compromised and that it will fail to give rise to a healthy baby. You can’t judge a book by its cover !
2. Sperm DNA integrity is not as important as we think. It is a well-established fact that sperm contribute only 10% to embryo aneuploidy ( abnormal chromosomal content) ; and that 90% of aneuploidy defects in embryos arise as a result of abnormal eggs. It has also been proven that the sperm’s DNA is extensively repaired (any defects in sperm DNA integrity is set right) and remodeled by the egg’s ‘error correction’ machinery after fertilization(PMID: 21546611)(PMID: 22541549)(PMID: 17978187). Although it is surprising to know that such a mechanism exists , it is very logical from nature’s point of view. Nature provide an egg with much more power to control the embryo’s development ! A woman is the one who is going to carry the baby to term and take care of the baby until it becomes independent. This is perhaps why nature has given the egg an upper hand in deciding a baby’s developmental fate ! An egg from a young woman can efficiently repair damaged DNA of a sperm ! So when the egg is young , even poor sperms can give rise to healthy babies.
3. There is no solid scientific proof to say IMSI is better than ICSI! There are no well-controlled randomized studies to prove this claim.

IMSI is not a magical solution for couples with multiple IVF failures, with poor sperm morphology or with recurrent pregnancy loss. In fact, abnormal sperm morphology cannot even be the only indication for performing ICSI because men labeled as having abnormal sperm morphology are able to father a child without any medical help many a time ! Today, a man who has 96% abnormal sperms and only 4% normal sperms is still considered to be fertile . If your husband has only 2% normal sperm morphology ,then should he be labeled as infertile ? My logical answer will be a ‘NO’. Can 96% abnormal sperm and 98% abnormal sperm really make a difference ?

What does scientific research say about improving oocyte/egg quality?

Oocyte quality is the most important determinant of IVF success. As a result of aging more chromosomal and spindle abnormalities accumulate in oocytes leading to increased incidence of infertility, foetal loss and birth defects like trisomy 21 or Down syndrome. Eggs obtained from younger women carry less genetic abnormalities and hence have higher chance of implanting and becoming a healthy baby. This is evident by the fact that women even after their menopause are able to get pregnant and carry the baby to term using donor eggs obtained from younger women.

When a woman undergoing IVF faces repeated failure, naturally the issue of egg quality crops up in the mind of infertility specialist and the patient. Unfortunately even after dramatic improvement in ART techniques, there is no sure way of saying whether an egg is competent enough (without genetic abnormalities) to produce an embryo which will subsequently implant and produce a baby. Although embryologists are able to select good embryos by observing their morphology under the microscope it doesn’t guarantee that the embryos are without abnormalities. A beautiful looking embryo of an older woman has more chance of being genetically defective than that of a younger woman. 

As a result older women as well as younger women who undergo repeated IVF failures are desperately searching for ways which would increase their egg quality and give them their most wanted wish-a baby! Infertility bulletin boards are filled with women who are determined to find a cure for their bad quality eggs. DHEA, metformin, melatonin, myo-inositol, wheat grass, anti-oxidants, fish oil, co-enzyme Q10, vitamins, especially vitamin D and other nutritional supplements are now-a-days extensively used by women to improve egg quality. Some of these substances used have scientific proof but some not. Selling supplements to improve egg quality is growing into a huge market as many businessmen are trying to make cash of our desperate situation. This led me to screen the scientific literature to find out what does science say really! Most of the experiments concerning oocyte quality are conducted in mice as it is difficult to do such experiments in humans for a number of reasons. 

Anti-oxidants

Oxidative stress contributes to somatic aging and it is also implicated in reproductive aging. So experiments were done to see whether using anti-oxidants improve egg quality and reproductive parameters. The researchers supplemented mice with pharmacological doses of vitamin C and E (both are well-known antioxidants) during their early or late life. They found that administration of oral anti-oxidants counteracted the negative effects of female aging on oocyte number and quality (PMID: 11835584). Good news right! Please do not rush to the pharmacy. Their research finding is not yet complete! Even though they found a positive effect of these supplements on the oocyte level they also found that oral administration of pharmacological doses of vitamin C and E reduced reproductive fitness and impaired ovarian and uterine function of female mice. They also said that the antioxidant diet decreased the frequency of litters, litter size, total number of offspring born and survival of male pups to weaning (PMID:12054212). Shocking or? A very recent publication suggested that, when mice are given low concentration of N-acetyl-L-cysteine the quality of fertilized oocytes and early embryo development improved. It also improved the quality of oocytes in older mice (PMID: 22357770). 

Now the question is how seriously we should take these experiments? First we should keep in mind that these experiments are performed in mice. The next thing to remember is ‘nothing equals a good diet’. Do you feel that you are not able to eat enough vegetables and fruits a day? Is your medical condition preventing you from getting appropriate amounts of nutrition from your diet? Supplementing with a good vitamin pill is a nice thing to do. Otherwise the best way is to add colour to your life by eating different coloured vegetables and fruits. Remember darker their colour more is the anti-oxidant content in them. 

DHEA

I am sure most of you will be aware of DHEA. If you google you will find lots of information about DHEA. Please visit CHR (Center for Human Reproduction) website for further details. DHEA was found to increase oocyte production (PMID: 16169414). The mechanism behind it is not so clear. DHEA is used in mice to induce PCOS phenotype in previously normal ovaries (PMID: 16514202). DHEA supplementation was also shown to decrease embryo aneuploidy (genetic defects) (PMID: 21067609). 

I have seen women who swear on DHEA for their IVF success. Many women even achieved natural pregnancies after taking DHEA. Will DHEA work for me? It might work. It worked for many but we should not also forget that it didn’t work for so many others. I am not trying to be negative, just trying to be cautiously optimistic. Try to monitor your thyroid levels and insulin levels when on DHEA (as it is found to affect both either in a positive or negative manner). Please remember that it is a steroid hormone and it is wise to be safe than sorry! 

Melatonin and Myo-inositol

Melatonin is a hormone produced in our body and it regulates circadiac rhythm. It has very powerful anti-oxidant properties and is found to protect nuclear and mitochondrial DNA (hence less genetic abnormalities) (PMID: 16217125). A recent publication concluded that melatonin is likely to improve oocyte and embryo quality in women undergoing IVF or ICSI but they found no statistical significance between the treated and non-treated group (PMID: 21770829). Melatonin was found to significantly improve thyroid function, reduce gonodotrophin levels, and in some women it helped in the re-acquisition of normal menstrual cycle. Furthermore, an abrogation of menopause-related depression, amelioration of hot-flashes and improvement of quality and duration of sleep has been reported. Myo-inositol is involved in several aspects of human reproduction. Elevated concentrations of myo-inositol in human follicular fluids appear to play a positive role in follicular maturity and also act as a marker for good quality oocytes. (I got this information from clinical trials.gov identifier: NCT01115127)

Should I try it?

Why not? Both melatonin and myo-inositol are naturally synthesized in our body and supplementing them won’t be a bad idea (but please read about the side-effects of melatonin supplementation). But better way is to optimize your health and get sound sleep.

Vitamin D

A search for vitamin D and oocyte quality did not give any appropriate pubmed result. I am sure many publications will come in the future on this topic. But searching for vitamin D and fertility gave some interesting information. Human sperms express vitamin D. Serum concentration of vitamin D is positively associated with sperm motility (PMID: 21427118). It is also found to regulate a large number of genes in reproductive tissue (PMID: 22047005). Animal data show that low vitamin D status is connected with impaired fertility, endometriosis and polycystic ovary syndrome (PMID: 10232622). 

Are you living in a country where winter is harsh and there is very less sunlight? It is advisable to take vitamin D supplements. There is lot of contradictions regarding safe vitamin D dosage. According to the new guidelines the tolerable upper limit is 4000 IU for ages 9 and above. Vitamin D at very high doses is found to cause calcification of soft tissues including brain tissue and several other complications. Published cases of toxicity, for which serum levels and dose are known, all involve intake of ≥ 40000 IU (1000 mcg) per day (search in google for Vitamin D Council for further information).

In summary are you living in a country where you get ample sunlight? Then just roam around with no sunscreen and expose your skin to sun’s rays. Exposure to sun rays for 10 minutes will help your body synthesize 10,000 IU of vitamin D. You can do this without the fear of vitamin D toxicity because your skin has a built in mechanism to prevent vitamin D toxicity. Take vitamin D supplements if you live in a country where there are very less sunny days and monitor your serum vitamin D levels at appropriate intervals. 

Diet or calorie restriction

This section is the most interesting part of this article. I found a very high quality publication on this topic and this is means it is more reliable. Calorie restriction in the absence of malnutrition is found to slow down the aging process and extend lifespan. If calorie restriction can slow down the aging process of somatic cells does it has the ability to slow down oocyte aging too? The research says YES. Recently a publication in PNAS, which is a reputed, high-ranked journal, showed that calorie restriction showed striking beneficial effects on chromosomal, spindle and mitochondrial dynamics in mature oocytes of adult female mice at ages normally associated with poor reproductive parameters. The study said that calorie restriction vastly improved fertility in aged animals. When initiated during adulthood calorie restriction significantly extended reproductive lifespan and increased the survival rate of offsprings conceived by aging females. This study clearly states that old age induced oocyte aneuploidy and spindle defects can be safely circumvented using calorie restriction (PMID:21730149). The study is well-designed and very promising. Rhesus monkey maintained on calorie restriction diet into advanced age showed the same health benefits as in mice.

Should I start a calorie restricted diet?

Why not? But you should also remember that this study is done in mice. Sometimes animal studies cannot be translated to humans. Please remember to take a good nutritional supplement (especially folic acid) when you are on a calorie restricted diet. Our ancestors are wise enough to starve themselves (do a fast) atleast once a week. Calorie restriction comes with an added benefit, who wouldn’t love to look younger than their real age!!!

Metformin

Metformin is a calorie restriction mimetic. It induces a dietary restriction like state (PMID: 20090912). It extends life span and is considered to be an anti-aging drug. It possesses anti-tumour properties. It activates genes which are induced during calorie restriction. So if calorie restriction preserves oocyte quality metformin can also do it! Hyperinsulinemic conditions are detrimental for oocyte quality. Metformin reduces insulin levels by decreasing insulin resistance and hence increases the egg quality of women suffering with PCOD.

Should I start metformin?

Are you diagnosed with PCOD? Do you have insulin resistance? Are you having poor egg quality because of PCOD? Metformin is for you. Do you have diminished ovarian reserve? Are you struggling to produce enough eggs? Then metformin is not for you. Metformin is known to reduce antral follicle count and when you are undergoing IVF number of eggs collected matters too!

Does lowering FSH and increasing AMH help me if I have poor egg quality?

FSH and AMH help to determine our ovarian reserve (egg quantity) and not egg quality (

PMID:

 21133869), (

PMID:

2073613). But as you age both egg quantity and egg quality starts to decrease simultaneously. This does not mean that egg quantity and quality are related. I think egg quantity and quality are two different events which has no connection to each other. This can be substantiated by the fact that younger women with diminished ovarian reserve are more likely to get pregnant and carry the baby to term even though they produce less amount of eggs during IVF stimulation (

PMID:

21602123). On the other hand older women with low ovarian reserve are less likely to conceive. So both FSH and AMH should be just looked as markers for poor ovarian reserve and nothing more. This can be understood if the actual modes of action of these two hormones are studied in detail. Egg quality is something to do with our genetic machinery which has no connection to these two hormones. Decreasing FSH or increasing AMH is also less likely to increase follicle numbers. Actually increasing AMH artificially can bring down your antral follicle count. 

These are some of the important scientific information which every woman undergoing multiple IVFs should understand. I wish this will reduce their tension about what supplements to take and what not to take, what is realistic and what is not. But at the end if you think taking certain supplements (because your friend took a supplement and fell pregnant miraculously!) increases your confidence level go ahead and take it, provided it should be from a reliable pharmaceutical company. You should also know for sure that the particular supplement does not have any negative side-effects that will compromise your health. Good luck for every woman who is searching frantically for that single good egg which will make their dream come true!

Reason for the genesis of this blog!

Why I wanted to write this blog? There are several reasons. I love writing. I can express my emotions in a better way when I write. After going through infertility for five long years, I am tired. I just need a change. My life has become too routine. All these five years I am foccused on only one thing- MY BABY. Not even a single day passes by without thinking about him/her. The beauty is, my baby doesn't have a LIFE still. But before it can acquire a life the little one has everything it needs- wonderful parents, a beautiful name and more than anything else lots and lots of LOVE. Sometimes I think what kind of insanity is this? You can live by thinking about someone who is alive or dead but can you live by thinking about someone who is not yet born. I am a living example and there are many women like me. I just want to reach out to them. I want to share my infertility experiences and the knowledge I gained during this journey. Only a person going through infertility can understand how painful it is! Getting in touch with women who are in  similar situation like me will give me immense support and strength. This will help me to remain sane and confident. I do not know what I can contribute through this blog, but I am sure it will bring about a positive change in my life.

I always wanted to write this blog. But I had many inhibitions in my mind. Will I be able to spend time for this? Am I efficient enough to write about my infertility in a rational way? Won't it be more nicer if I win this infertility battle first, and then write about it? With all these questions in mind, I postponed my urge to write. But all these changed because of another blog (blogger!) which I read more often. To tell the truth, that blog gave me lots of confidence. When I suffer emotionally, I open that blog and read some posts written by the infertility specialist. Yes, it's a doctor's blog and it's my doctor's blog! You may think, because he is the infertility specialist I am getting treatment from I am giving undue importance to it, or I am attempting to please him in order to get better care. Definitely not! If you are a woman suffering with infertility there are lots of possibility that you know him already. I am taking about Dr. Aniruddha Malpani and his blog. I think every woman undergoing infertility should read his blog posts. You can get immense intellectual and emotional support from it. The best thing about his writing is, he really puts himself in his patient's shoes. I always wonder how could a doctor empathize so much with his patients!  It just shows the passion he has for the work he does. I did my last IVF with him. I met him perhaps thrice during my treatment. Had very few things to talk with him because I am a graduate  in IVF treatment, (I have already done 5 IVFs, great or ;) ) so didn't have much to talk about the treatment as such, and I am very afraid to talk anything else which is beyond the scope of the treatment (Will I spoil his valuable time?). I mail him whenever I have some doubts, and he replies very promptly. I have many things to say about him which I will talk later. Now, I just wanted to say that he is one of the most important person for the genesis of my blog. He wrote 'I do wish you'd keep a blog - this will help you let out your bottled emotions in a constructive fashion. Keeping a journal has been proven to help patients cope better - and helping others is the best way of helping yourself !' Thank you Doctor! The interesting part is, he did not know to whom he said this ( I donno whether he guessed that it is me !) since I used to comment in his blog as an anonymous! But he did know that the anonymous commenter is one of his patient :)

Whatelse I have to say, hmmm perhaps a bit about me : I am emotional, loving, intuitive, imaginative, shrewd, cautious, protective and sympathetic.  My darker side : Constantly changing, moody, over-emotional, touchy, clingy, and unable to let go. This is what they say about cancerian traits and it applies 100% to me!  I want to write a lot about many other things apart from my (in)fertility journey. Wish me good luck and with this note I start my blogging journey. Happy blogging! :)