Thin Endometrium and FET Outcome - Is there a correlation?

It is boring in hotel room and it is drizzling outside. So I am sitting in the room doing nothing. As usual, I have no mood to watch television programme. I did a short search in pubmed regarding thin endometrium and pregnancy outcome in  FET or IVF cycle. I feel so happy when I learn something new and also to update my blog with some decent information. Am I obsessed? I think I am not. When I watch TV or sit without doing anything a kind of depression sets in. My thoughts waver too much in the negative direction. I feel happy and relaxed when my mind is working, especially regarding my FET stuff and my blog. My DH is not happy about it. His accusation is that I am stressing myself too much. How will I make him understand how I feel? :(

So here we go: As always, there are two different views on whether thin endometrium affects the outcome of FET or IVF cycle. A paper in Clin Exp Obstet Gynecol.states that a 47 year old woman with an endometrial thickness of 4 mm conceived twins using donor embryos (PMID: 22268266). I do understand exceptions cannot become the norm.  But this information does give me lots of hope. My belief that embryo competency is important than endometrium thickness might be true. But my RE who has extensive experience in the field of IVF does not agree with me :) Might be my view is flawed, who knows? There is one more publication which makes me happy. You can view it here (PMID: 1513611). I could just get the abstract which states that, the largest study to date on the association of endometrial thickness and subsequent pregnancy rates following frozen embryo transfer, with the endometrium prepared by estrogen and progesterone found no improved or adverse outcome if the endometrium is too thick or thin :) I am now on progynova for a longer time. I started progynova on May 31^st and I added progesterone only on June 23^rd. So I am on estrogen supplement (increased from 6mgs to 64mgs as of now) for 24 days. I am bit uncomfortable with this long-time stimulation to grow my endometrium to decent thickness. 'Will this have an adverse effect on my endometrial receptivity? Will my endometrium quality be compromised?' These are the questions which haunt me sometimes. But my fear seems to be unnecessary. This (PMID: 16983519) paper states that long-term estrogen administration to bring the lining to a decent thickness is beneficial and does have a positive effect on pregnancy rate (infact the pregnancy rate was higher when compared to the control group!).

Now, I will also cite papers which say endometrial thickness is important and thin endometrium compromises pregnancy outcome. This paper (PMID: 22346080) states that mean endometrial thickness is significantly higher in pregnant women compared to non-pregnant.  But they concluded that ‘the mean difference between two groups was <1 mm which may not be clinically meaningful. Although there may be a relationship between endometrial thickness and pregnancy, implantation potential is probably more complex than a single ultrasound measurement can determine.’ So, they did not find a sure correlation between endometrial thickness and pregnancy rate. Another study states that in donor embryo cycles thin endometrium is one among several factors which  can compromises the cycle outcome (PMID: 15482759). This study (PMID: 17681313) says that in medicated FET an endometrial thickness of 9-14mm on the day of progesterone administration is positively associated with pregnancy outcome than an endometrial thickness of 7-8 mm :( One more interesting publication states that, in ICSI cycles (that is ART cycles performed due to male factor infertility) the endometrial thickness has no effect on pregnancy outcome while in IVF cycle endometrial thickness (where female fertility problems are involved) is a factor which determines pregnancy outcome (PMID: 8671501).

In short, studies fail to show a strong negative correlation between Pregnancy Rate (PR) in IVF/FET cycles and thin endometrium. There are several other factors which play a role in embryo implantation. The most important of it all is the age of the woman or the embryo quality.

Now after reading all this I just wish that my two little blasties have a competent genome. No matter how much I obsess nothing is going to change. Whatever happens will happen and let me face the reality with a strong heart and calm mind :)

Thin Endometrium –a side-effect of calorie restriction and fat loss?

Vaginal ultrasound showing a thin endometrium

I always had great endometrial lining during all my IVF cycles (greater than 8mm, mostly between 10-12 mm). In FET cycle too there was no problem. So, what went wrong this time? Even though I can just speculate, I know deep within me that my speculation is right. I have lost lots of weight during the past 5 months. I was insulin resistant before. I had a HOMA IR (a measure of insulin resistance) of 4.1. There is no standard value for HOMA-IR. The current studies consider that HOMA-IR < 2 is normal, HOMA-IR ≥ 2 is pathological, with HOMA-IR > 4 reflecting the pre-diabetic stage. My fasting insulin was 17uUnits/ml (although a fasting insulin of 5-25uUnits/ml is considered normal, anything above 10uUnits/ml is not so good. People with fasting insulin of less than 5uUnits/ml are found to live longer). I have a family history of diabetes in my dad’s side. I was diagnosed with PCOD at the age of 25 and I am on metformin (1500mg) for a long time. I stopped metformin for the past year because of gastrointestinal problem. After stopping metformin my BMI was 26.2. I was overweight. Lack of implantation in my previous ART cycle made me to ponder what can be done to improve my chance of conceiving. The only sore point I had is my weight and perhaps insulin resistance because of it. My blood glucose was normal. I also became aware of the fact that calorie restriction has a positive impact on egg quality. This made me to think seriously about removing the excess weight. My boss is an endocrinologist. I used to discuss with him about the weight issue and ask him whether carbohydrate rich meals are the culprit. He used to say-eat anything, but eat less. I started a very strict calorie restriction diet and jogging. I limited my calories to 800-1000 for the first 2 weeks. I achieved this by intermittent fasting. To my surprise my fat deposits around my waist started to melt. After two weeks I upped my calories to 1200-1500 calories. I avoided sugar, sweets and carbohydrate rich foods. I avoided rice as much as I can. I took only 300 calories per meal. I started metformin 1000mg. I stopped non-vegetarian all together and I am not planning to eat it anymore during my lifetime :). Within 5 months my weight dropped from 68 kg to 61 kg. The best point is I lost all the excess fat. For the first time I had a flat stomach. My energy levels improved. I can skip a meal easily without any trouble. I attribute it to my lowered insulin levels. In short I felt great. Received mixed comments from friends. Some are worried. They said I have lost the charm. But my DH is happy. He said I looked better now. I am happy too :)

Everything sounds good, right? Then, where lays the problem? Calorie restriction is good. It was found to prevent aging in experimental animals. It also delayed egg cell aging and extended fertility in experimental mice. Metformin is a calorie restriction mimetic too. It can also improve egg quality (both by preventing egg cell aging and by decreasing insulin levels). I do not think short time calorie restriction will have any effect on egg quality in humans. If calorie restriction is started in 20s it might extend fertility into your 40s. The same is true with metformin usage. Long term metformin intake can preserve egg quality via preventing genetic defect accumulation, while short term intake can increase egg quality by decreasing insulin levels. It was found that exercise and weight loss is much effective than metformin in decreasing insulin levels. So bringing down your weight at any point of your lifetime will have positive effect on your overall health by decreasing insulin, glucose and harmful triglyceride levels. This will keep your hormones balanced which is necessary for optimal fertility. As a result egg quality (not genetic but physiological parameters) and  endometrial health improves. Consider calorie restriction if you are suffering with infertility due to overweight and PCOD (high insulin!).  Reduce your weight through calorie restriction and proper exercise. Continue exercise regimen and increase your calorie intake for maintaining the appropriate weight. BUT never do calorie restriction when you are on fertility medicines, if you are underwieght or when you are trying to conceive.  Never be on very restricted calories (less than 1500 calories) when you are trying to conceive. This is the mistake I did this cycle. Even after starting fertility medicines (progynova) I continued with fewer calories. Lesser calories actually signal your body to go into the survival mode (during which only minimal bodily functions are maintained). Reproduction is an extremely energy consuming process. Once your body senses that you do not have enough calorie supply (as in times of food scarcity) it switches on mechanisms which  prevents energy expenditure. It tries to switch off high energy demanding functions like reproduction. In short all the anabolic activities which require high energy are switched off and catabolic processes which produce energy are switched on. Since I took less calories my estrous cycle is severely affected leading to poor endometrial development. My body in short doesn’t want to get ready for performing reproductive function.

I got this information from a website:

Reproduction: Feeding the reproductive cycle

Energy metabolism is known to affect reproductive cycles, acting as an evolutionary oversight to ensure that reproduction occurs only in favorable nutritional conditions. A recent study characterizes a mechanism through which the liver integrates metabolic responses to control ovulation (Cell Metab. 13, 205–214).

Investigating the link between estrogen and food consumption in mice, Sara Della Torre and colleagues found that caloric restriction decreased hepatic estrogen receptor-α (ER-α) activation in the liver and arrested estrous cycle progression. Interestingly, amino acid supplementation was sufficient to rescue mice from this metabolic block of the estrous cycle.

The authors found that ER-α activation led to increased hepatic expression of insulin growth factor–like-1 (IGF-1) and increased the amount of circulating IGF-1. Increased IGF-1 expression was required for E2-induced proliferation of uterine lumen epithelial cells and for estrous cycle progression in vivo.

The findings highlight a crucial role of hepatic ER-α as an integrator of metabolic and reproductive functions. The exact mechanisms by which IGF-1 and E2 promote progression of the estrous cycle remain to be determined, but this study might provide insights into infertility conditions, especially those linked to metabolic dysfunction. 

On the other hand there must be a connection between fat reserve and estrogen function. It is known that estrogen is stored in fat reserves. I have read that people who are obese are prone to estrogen sensitive breast cancers. Overweight people are also more prone to endometrial cancer. You need healthy fat reserves for your estrogen to function properly. Dr.Malpani sent me the Frisch hypothesis paper which talks about the connection between body weight and onset of menarche.

In short I learned a lesson which is invaluable. Do not change your diet or exercise regimen extremely during IVF or FET cycles.  Do not loose weight especially fat reserves when undergoing fertility treatment. Increase your intake of healthy fats. Do not restrict calories. The above said are very important for proper functioning of your reproductive harmones which intrun is important for your treatment success.

Another interesting information to ponder : In certain regions of south India, daughter-in-law who enters husband's home for the first time, after marriage, is given cow's colostrum. Perhaps a nice way of preparing her to carry their generation :) Milk is know to increase IGF-1 levels. When I say this I do not want to make IGF-1 master of all reproductive functions, just a note because I am talking about IGF-1 in this post. Our ancestors do have lots of wisdom :)

Stupid me ! Dr said –don’t beat yourself up! He asked me to read ‘Shoulda, Woulda, Coulda’ :). I will try not to regret. Hopefully G-CSF works and perhaps everything happened for my good :) Otherwise I will not have had a chance to use G-CSF which is supposed to increase pregnancy rates atleast in a couple of studies :)

In Bombay for FET

We came to Mumbai two days back. A heavy downpour welcomed us! Every time I enter India, for a day or two, a kind of depression sets in instead of happiness. I feel as if I am waking up from a pleasant dream. The reality slaps me hard. I live outside India for 7 years. The country where I live now is clean, sparsely populated, rich and comfortable. The first thing that makes me vexatious when I reach India is the dirty environment. Mumbai is the financial capital of India, and no need to say how densely populated it is. The dust, unruly traffic, dirt and poverty made me wonder why there is so much discrepancy between two countries. I saw a family of three; husband with torn clothes, wife with the dirtiest saree you can ever imagine and a newborn lying nearby them - all three are resting inside a shed of tarpaulin, on an elevated mound, which is found in between two parallel roads! I could clearly read the worry on their faces. They must have been living in platform and the heavy rain made them to panic. When I saw it, how much I wished I could just go back to Germany and imagine that life is hunky-dory everywhere! If you accuse me of being selfish – I AM. I am selfish to the core. I need the comfort which Germany gives me. I need the clean environment. I need the calm working atmosphere and I badly need the money for our baby-making journey. I am helpless, truly helpless. Every time I come to India my conscience kills me. I feel guilty for being comfortable, for being self-sufficient moneywise, for living in a clean environment, for attempting to create a costly baby when many road-side children are living in the footpath. Wait; do not judge India by what you read just now. This is just one half of the story. When I see such extreme poverty on one side, I also see supreme richness too. Costly cars, branded clothes, dining in five star hotels and lavish spending-this is also the way of life for many in India. Why is Indian society too unbalanced? Are these the result of evil caste system which we created long back?  

Do not form an opinion about me from what you read in the previous paragraph. I am not trying to project myself as a simple person with great social responsibility. I am a very normal and self-cantered woman. All the above said guilty feelings usually vanish from me in 24 hours. I get used to the way of life in India. I do walk past the hungry, homeless road-side children and enter into a mega shopping area to satisfy my shopping spree. My guilty feeling vanes away day by day until it becomes negligible. I indulge myself in all normal worldly pleasures ignoring the sufferings around me! Sometimes I wish I was non-existent or I wish I had the power to change every misery around me. But at the age of 34 I have learned that life is not fair. If I have to remain sane and serene I should surrender to the fact that life is unfair. As a human, I am trying my best to be compassionate and kind to my fellow beings. I try to lend a helping hand to the needy whenever I can. I also try to keep in mind the serenity prayer which Dr.Malpani taught me:

God, grant me the serenity

To accept the things I cannot change,

Courage to change the things I can,

And wisdom to know the difference.

This serenity prayer was written by the theologian Reinhold Niebuhr.

So coming back to the original story - we are doing a FET. We have 7 embryos left from my last ICSI cycle (5 day 3 embies and 2 blasties). I am happy to see Dr.Malpani and his team. Dr, understood that I am the anonymous person who leaves crazy comments (sometimes good ones too!) in his blog. All his staffs are very friendly as usual. Dr.Anajli Malpani is  cute and pleasant as always.

I took 6 mg progynova for 12 days and had a vaginal ultrasound on 11.6.2012 to check my lining. Dr.Malpani was not so happy about my endometrial thickness. My lining was only 6 mm. He increased my progynova dosage to 16 mg. I am going for an ultrasound today. I wish my lining has grown at least a mm by now. I have no EWCM even after taking such a massive dose of progynova. Does it mean anything? I do not know. I am worried and I started to write this blog post to calm my anxiety. I will update after today's scan what actually is the next course of action, and I would also like to speculate in my next post why I ended up with a thin lining!