Choosing the correct IVF protocol

My response to the IVF protocol, the agonist flare protocol, where I got a microdose of lupron from day 2 continuously followed by stims (with a mix of follistim and menagon, which contains equal amounts of both FSH and LH), was truly awful- we got a lot of eggs (11 eggs from 13 follicles), but most of them were immature and failed to mature and fertilize and even though we produced one 'good' Day 5 embryo, that failed to implant.


Why was this? I've always thought that maybe my protocol was not best suited for me, but never thought I'd be able to find a good (or any) explanation as to why and how.

However, I just found a recent opinion by Geoffrey Sher, which gave a plausible explanation of what may have been the issue:

Some background- there are two ways to shut down the pituitary gland, which is the master remote controller of ovulation:

1. The first method developed is through agonists- these work by a weird method- they first stimulate the pituitary gland, but such a strong stimulation however later shuts it down completely.
2. The second developed method is antagonists, which directly shut down pituitary activity (or is it just LH secretion?)

Dr. Sher makes that the point that if you start the agonist at day 2 or 3, it first produces a spike of LH at this point,  and THEN shuts it completely. His theory is that this increase in LH, on CD2/3  (which is, importantly, also out of time with this natural process, though he does not put it this way), may be bad, especially in vulnerable populations like PCOS patients or older women.

I really think this point makes sense for one reason, and here it is: What is associated with annovulatory PCOS? A really high ratio of LH to FSH, on CD3. This is a hallmark of this syndrome and if his interpretation that agonist use first causes that LH spike is right, it may actually mimic the natural situation that produces annovulation in PCOS, if first given on CD2/3.

He makes several other less important, and less strong, nonetheless plausible points:

Ideal curve of LH in a healthy ovulatory cycle, courtesy Wikipedia.

• Menagon (which is equal doses of FSH and LH) may be less than idea- This may be true- it deviates the natural bell shaped curve of LH found in nature in health, but nonetheless, it clearly works for many.
• Femara may also increase LH at the wrong point

Dr Sher's opinion really makes for interesting reading- I'm very glad I came across it. See above the bell shaped curve of LH in the natural cycle- maybe protocols that deviate from this may not serve optimally. Maybe too much LH at the spike or any other point may be bad too- its difficult to say

All i know is, if I'm doing IVF, I need to go away from what was done the last time. Based on what he said, I've also decided to avoid Femara and Clomid.

I may go straight to low dose FSH from an early point. I'm going to figure out if I want to use antagonists or not. The reason I'm vacillating on this point is that LH IS important- the gradual increase of this as ovulation nears, resulting in that spike, may be a good thing. But too much LH may be a problem too, and the reason pituitary shutdown was introduced was that 51 % of women had a premature LH surge which resulted in cycle cancellation.

Trying natural cycle IVF is so very alluring- except I have 2 IUI and 1 IVF vial of swimmers, and the really steep costs of IVF come in during the pickup and fertilization. Finances are not a problem, yet nor can I act like money grows on trees.

There are many choices to be made, but the good news is, right now, I'm pursuing the next option without the angst and hand-wringing and feeling that time crunch. Other people are always telling me my attitude is awesome, and I have to say, I'm impressing myself at this point.

Making a case for not messing too badly with nature

This is a hopelessly  technical post- its mostly a prelude for the discussion with my RE.

I'm somebody in whom, the natural process, at a surface glace, works beautifully.

• My ovulation are extremely predictable. 
• My estradiol levels per mature follicles are bang on target(around 250/ single mature follicle) .
• My LH surge is huge, regular and easy to identify. My levels are super low on CD 3 (around 2.5 in one test) and go up to around 40 on day of surge. 
• The appearance of the uterine lining elicits extravagant praise from doctors. 
• My natural progesterone levels  (only during pregnancy) are usually perfect, over 40 ng/ml.
•  And since I've corrected my vitamin D levels , my luteal phases have been perfect in length, usually around 15 days (Note: In my days of vitamin D deficiency, they were much shorter, around 10-11 in a particular cycle pattern)
• Most importantly, all of this usually results in a pregnancy rate/cycle far above the population average.

On the other hand, when I did IVF, everything went to hell. Basically, shutting down my pituitary and hitting me with monster doses of FSH had a shitty outcome.

• While my E2 levels were even higher than normal (3521 pg/ml, with 11 eggs being extracted, translating to around 320 pg/ml per follicle), only 3 of these eggs managed to fertilize, even with ICSI.
• As my estrogen levels got higher and higher, my cervical mucus disappeared- it was abundant during the first 4-5 days of FSH injections and then as my E2 climbed, it just vanished. It actually makes sense- whatever stimulates a process at one concentration can inhibit the same process at a much higher concentration.
• My luteal phase was a short 10 days- very striking. 

My RE blames my weird response to the drugs on the fact that my AFC, which was 30 in 2010, had dropped in half. Few issues with this line of thought---

• My AFC has maintained around 16 for an entire year before the IVF and its drop correlates to the time when my Vitamin D levels tripled. Its hard to correlate a drop in AFC to a bad response to  FSH- After all I managed to get pregnant  naturally in response to the FSH my pituitary manufactured, well after the drop.
• I think MY RE is stuck on this theory because it is natural for an RE to connect a poor response to IVF protocol to ovarian aging because these 2 normally do go hand in hand, a 40 year old woman would have had a large decrease in AFC in the past few years of her life and she may be a poor responder as well by this age . However, mine is not the typical scenario: I believe my drop in AFC was the end result of the reactions caused by the increase in my vitamin D levels and is conclusively NOT due to ovarian aging, so trying to link the two is trying to compare apples to oranges- there is no logical connection.  

I think that my protocol really did not suit me. Why that is hard to say. How to fix it is even harder.

What we all forget- the natural process has about a 1000 intricate layers, and is beautifully controlled- in comparison the IVF protocol, which often shuts down the pituitary and all feedback mechanisms, is like a caveman with a club- I'm not disputing that it works, only noting that in me, the natural process appears to be superior to IVF.

So what I'm trying to do with my next IVF cycle:

• Keep my stimulation to a minimum, using a mini-IVF
• I really want to keep my pituitary gland in play for as long as possible. During IVF, this is shut down with agonists/antagonists. I want my body to tell me when the the follicles it is making are mature, through all the feedback mechanisms it possesses- In other words, I want to trigger when my body decides to go with its LH surge.  I don;t want the doctor to decide this just through just looking at follicle size/E2 levels- this worked really badly the last time, but maybe it was also because of asychronization of follicles- I believe that the first 6 follicles that grew first yielded the 4 M2 and 2 M1 eggs and these were kept waiting for about 3-4 days while we tried to get other follicles to grow.
• Option 1: I'm debating trying to get my doctor to agree to avoid pituitary suppression using antagonists and allow a natural surge. I recognize that this is entirely antithetical to the nature of IVF itself and most people may say I'm nuts to risk 'premature luteinization' of follicles  and  yes, there is a good chance it may end badly, in cycle cancellation. However, in the indian system you don't end up loosing too much--- meds cost very little, and anyway I'm going with low doses.The real investment is in the pickup of follicles and subsequent in vitro fertilization steps. However, I need to understand the role of LH and how it rises in me. I know that In normal cycles my baseline LH is super low and rises gradually to a full surge. How will it be in an IVF cycle? Will such a natural rise make better eggs compared than suppressing it entirely? What causes the LH surge? Is it only the rising Estrogen or is it other factors as well, which 'tell' the pituitary when the egg is ready? 
• Option 2: Alternate to avoiding antagonist use completely, as a compromise, can one delay its administration as far as possible?Here is an interesting article about women who showed a premature surge (which was then suppressed through antagonist admistration), who actually ended up making decent eggs..so it brings in to question the benefit of LH in a cycle. I think this is really multifaceted issue...

All my worldly belongings for a crystal ball..

I honestly was not expecting a BFN, given that the embryo had gotten to day 5, and the embryos I make naturally show an excellent capacity to implant. Statistically, I thought implantation was likely, with a strong probability of pregnancy loss.

So now, I'm asking the questions-

• Was it an embryo issue? How did the embryo I made during superovulation compared to the ones I make during a natural cycle? 

• Is it that the surrogates womb is less receptive than mine?

To discuss the embryo quality in my natural vs superovulatory cycles, lets look at the following percentages:

20 %  : The probability of anybody's getting pregnant, say, while being in their late 20s, in any particular cycle (correct me if needed, I'm citing from dim memory)

50-60 % : The probability of a high quality Day 5 blastocyst implanting in any given cycle. I've asked my RE to provide the stats from his clinic as well.

75% : Probability of my getting pregnant, naturally. Calculated using an average of 4 cycles, where I've gotten to clinical pregnancy stage through a natural cycle, 3 out of the 4 times.

So going just by this, the odds were really in favor of the embryo implanting, unless it was different from those I make in a natural cycle.

It is always possible that mine is one of those high fertility wombs that just allows all embryos to survive and implant, not just the best quality ones, making me a candidate for recurrent pregnancy loss. This possibility is derived from this study.

But there is the other possibility- that the superovulation produced poorer quality embryos than what I make naturally. I clearly respond badly to higher doses of FSH- In the start, I was on 300 IU follistim and 6 eggs were on the route to responding, and in the end, possibly gave my 4 M2 and 2 M1 eggs. On increasing that dose (to 450) and using a mix of menagon and follistim, we got up to 11 eggs, but I believe those later growing  follicles yielded the immature eggs, even though my estradiol levels rose appropriately.

I beleive, no matter what I do next, that if I go for another round of IVF, stimulating me very gently would be a more sensible option. I'm also going to elaborate on the role on myo-inositol, that I've started taking, in a later post/ Please, anybody who is an armchair RE or a real one, fee free to weigh in here. I'm thinking about 2 things

-Agonist/Antagonist (with or without conversion) with a low dose of FSH.
-Natural cycle, or very close to it, with mimimum stimulation, with a transfer to the surrogate.

I've also started thinking about donor eggs. I went and looked at this website, and I was pretty aghast- although it says Indian egg donors, the majority are caucasian and well, though a lot of them are very pretty, they don't appear to have done too much with their lives.Ditto the few indians there- a few of them look and sound like those girls that pop up on the websites where you download torrents. Plus the website does not seem very well run- one girl listed her height as 5.2 cm. What is she, Thumbelina?

 A really good friend talked about offering her eggs yesterday, and she is like my dream donor, smart, good looking, accomplished, determined and I think I would really be able to identify with her genetic babies, because god, we think alike. But she is a really good friend I'd want to keep always, and I've always believed that if you do these things, its best to use people who will not be in your life afterwards. Sigh- I just wish the strangers I am finding were more like her, but that is a really tall order.

If I go the donor egg route, I'd probably have to place an ad in the papers and pray I get lucky. Then there is that million dollar question- do I carry the baby or use a surrogate?  Honestly, when people talk about the joy and intimacy of a pregnancy, I no longer feel it. To me, pregnancy is terror, stress and the possibility of losing my figure, my baby, and my even keel, which has managed to hold through through all this, at 24 weeks. I can get past this, and god knows, things may even go well, but I don't at all feel like I want to do it.

What do I do?!

Negative

R is not pregnant. I'm mystified as to why that is, because if anything, my embryos formed naturally showed a higher than average ability to implant in a fertile uterus, and R had no issues there. Plus, going by embryo quality, it did not get much better than 3AA.

But biology presents too many variables to predict what was different and its impossible to say where the mojo went here. Regrouping, reassessing, will be back with options later.

Awaiting the verdict

The beta is tomorrow. In the plus side, this has been the easiest 2ww I’ve been through. There have been moments of the kind of fear that sucks your breath away, but they have definitely been less frequent compared to the 4 others I’ve lived through.

My friend asked me if I’d be ok if the surrogate was not pregnant. I replied, I would be, because I had to be. That just about sums up everything. A BFN would definitely not be the hardest thing I’ve had to face yet. The only way it is horrible is that it would create the necessity of another IVF, and that I don’t look forward to.

I’m mystified at my fear again, because the IVF was, in truth, not that difficult. Things were a bit more painful because I was taking menagon IM and follistim and Lupron SC ----each day I had to take 3 injections instead of 2.  When you are taking these injections on a daily basis for a fortnight, at some point, 3 vs 2 starts mattering.  But I have no lasting souvenirs from that IVF- no weight gain, no debt, nothing other than a zit the size of mount Everest whose scar still lingers and that awful traumatic  memory of finding my cat had died when I was woozy from the retrieval.  So if I have to do it again, hopefully, it should not be so bad, definately sans any violent loss of something/body that I love.

Hopefully, we wont have to have the IVF conversation for a long time because the surrogate is knocked up and that baby will stick. But if not, I’ll be ok. In happy news, I got a real job, as opposed to the one I was doing for shits and giggles. Right now, I’m jumping ship from science to scientific writing- It’s a job in a really good company with a decent starting pay. I pick up the offer letter tomorrow, and after 5 pm IST, I get to know if the surrogate is knocked up. Pray for me- not for a BFP in particular, but that overall, the universe will be good to me in this next period of my life.

Another rolling of the dice (updated)

Yesterday was a big day. My sole 3AA embryo was thawed, and transferred to my surrogate. Things went well.

Its so surreal that this is happening again, and I have no part in it.  The one overwhelming emotion I felt was gratitude that it was not me going through this again- that 2ww, the waking up 3 times a night, the changes in your body, the sheer terror of waiting to see how things will go. I LOVED everything the first time I was pregnant. I used to walk around with this foolish smile, savoring it all, even the crummy bits. The second time, I was also excited, yet scared. By the 3rd time, I didn't even know what I was feeling anymore, stress was the one thing that stood out.

Now, all of this pregnancy-related noise, instead of being a roar in my head, is a dull noise in the background. I'm still scared, but yet, I feel protected by distance. That is a good thing.  

BUT-There is always a pro and a con- I cannot find out in 5-6 days if my embryo got to win the first battle and invade that uterine wall- I have to wait 12 days for the beta. That is positively cruel. But its all relative- I heard that in England, they do not even bother with a beta during surrogacy, they go straight to the  6(?) week U/S. 

I have not told anybody at home the transfer happened yesterday- They know the surrogate's(lets call her R) cycle is underway, but they did not ask, and I did not tell, because I don't want them to have to play this waiting game with me.  Its all so very surreal- how can your baby/embryo be alive and not within you? How can something so utterly momentous have nothing to do with you? How can you be ok with such a situation?

This is a very strange world we live in, where very strange things are possible.  And I thank god for it.

Update: A couple of you have asked if the surrogate would be doing HPTs. This is definitely an available option, I could meet the handler, give her the sticks, and the instructions, but it would also complicate stuff. I'm fairly sure R has never even heard of a home pregnancy test, much less taken one. Nor probably has the handler, who has been a surrogate herself.  I find myself overall, reluctant to do something like this, because it is complicated and decreases that distance I want to maintain to protect myself from the terrifying reality of all this. But that is me talking right now. I may *totally* cave in 5 days. But I know this from experience- testing early always makes for unnecessary drama. It will be nice If I can find the inner discipline to avoid it this time around.