A rousing game of ‘Guess Dr. Schoolcraft’s Answer’ [updated with results]

Thanks to all of you for your help compiling questions to ask Dr. Schoolcraft during our upcoming CCRM consultation. Per your suggestions, I added some questions and prioritized them to make sure we get to my most pressing questions first. Then, during my run this morning, I got a little cocky and found myself thinking that I probably can guess Dr. Schoolcraft’s answer to most of my questions. Next I thought, why not make it interesting?

So I’m putting my educated guesses in writing, here on the interweb for all to see. [Gulp!] If you have guesses of your own, please share them in the comments! After our phone consultation on Monday, I’ll update I updated this post with Dr. Schoolcraft’s answers – so don’t forget to check back and see how well (or poorly) we all did!

[Insert cheesy game show music]

Deep announcer voice, building: And now it’s time. Let’s play…

Audience shouting in unison: GUESS! DOCTOR! SCHOOLCRAFT’S! ANSWER!

[Applause]

* My answers are shown in black. Dr. Schoolcraft’s answers (as best I can remember them) are in blue.

1. What do you estimate our chances of success with my eggs to be?

Actually, I have no idea what his answer to this one will be, which is why I want to ask it first. My fear is that he “won’t be able to say without the information from my one-day-workup.” (The one-day workup is the full set of tests that CCRM conducts – in one day – for all new out-of-state patients. If he defers to the one-day-workup as an answer to each question, then I’m going to wonder why I went to all the trouble of sending my medical records and completing the detailed medical history. I’ll also be bummed to have spent $250 for what amounts to an elaborate advertisement…)

<<DING!>>

I won’t have enough information to say until we have your results from the one day workup. I can say that between the options of 1) doing IVF again with your eggs, 2) doing nothing, and 3) doing IVF with donor eggs, your best chance of success would be from IVF with donor eggs.

2. If you think it’s worth trying with our eggs, what new information would change your mind? At what point should we seriously consider donor eggs?

Aside from perhaps deferring to the one-day-workup, I imagine that he would recommend trying at least one cycle at CCRM with my own eggs before moving on to donor eggs. Seeing how I respond to a new protocol, after 3 months of supplements, would provide additional data to inform our next steps.

<<DING!>>

I would recommend trying IVF at least once with a conventional [i.e. high-stim] protocol. That would give you the greatest chance of recruiting the maximum possible number of eggs. And then we’d know how many eggs/embryos each subsequent cycle is likely to yield.  Your response to the stimulation, as well as the results of genetic testing on any embryos retrieved, will help us to know whether your problem is with egg quality [in which case egg donation might be a good option] or if there is another issue.

3. What do you think accounts for CCRM’s remarkable success rates?/What can CCRM do to improve my prognosis relative to my local clinic?

I’m guessing he’ll say some combination of the following three things: (a) world-class embryologists (In general, I’m told the embryology lab is the biggest factor in determining IVF success rates.); (b) genetic testing (A procedure called Comprehensive Chromosomal Screening or CCS – which permits selection of only embryos with the correct number of chromosomes – was developed at CCRM. Transfer of selected embryos dramatically increases success rates, as can be seen here.); and/or (c) experience (CCRM did 2464 ART cycles in 2011, about 5 times as many as my local clinic. Such a large number of cycles per year means that the embryologists are constantly honing their skills, while the doctors have more data to draw from in choosing appropriate protocols, etc.)

<<DING!>>

The lab. The embryology lab makes the biggest difference for IVF outcomes, and we have the best lab. This is especially true in your case, where you can only afford a low margin of error. For example, if you had 17 eggs retrieved, and six make it to blast, and you get pregnant, it looks like a success, even though more than half of the eggs didn’t make it. But you’re not going to have that many; you may only have one or two eggs. You want the best embryology lab to maximize the odds that those eggs make it to blast. At CCRM, we’ve also developed several specific techniques that improve outcomes, like embryo glue [and others that I didn’t hear because C was whispering that my typing was too loud…]

4. What other kinds of tests will CCRM do? Do you recommend genetic testing in our case?

I’m not sure what all the tests they do are, but I’m pretty confident that it is more than I’ve had so far (namely Day 3 FSH, AMH, and E2 testing; antral follicle count; HSG; and saline sonogram). I’m guessing that he will recommend CCS (since I turn 35 in November), but probably not PGD/PGS (since C and I are different races and have no family history of genetic disorders).

<<DING!>>

I would definitely recommend that you do chromosomal screening [CCS]. If the cycle doesn’t work, you want to know whether it’s because of a genetic issue [which would be resolved by using a donor] or if there is some other factor – a lining issue, etc. [which would not be]. The goal is to “get a baby or get an answer.”

5. How would we go about scheduling a cycle with CCRM, given my & C’s work schedules? (I can’t exactly take off for 10 consecutive days in the middle of the semester!)

I’m not sure what he’ll say about this. Assuming he recommends a fresh cycle, I’m guessing that he’ll say I should schedule retrieval & transfer between semesters (in December/January). Alternatively, if he recommends a freeze-all cycle (as would be the case if we do CCS), maybe it wouldn’t require so much time off and I might be able to time something around Fall Break?

<<DING!>>

C would only need to be here for one day, and assuming you did most of your monitoring appointments at home, you would only need to be here for 4-5 days [since I recommend freezing all for CCS]. One possibility is that we might time it so you could come over Thanksgiving break.

6. If, due to scheduling constraints, we opt to do another cycle locally before cycling with CCRM, do you have any recommendations for our local cycle? (With regard to stims? freeze day? other?)

No idea what he’ll say to this… I’m guessing he’ll push for going straight to CCRM, but I’d love to be surprised here.

<<<BUZZ!!!>>>

Not really. Our lab is here. There’s no way to take it with you.

7. How much variability do you expect from cycle to cycle? In other words, is it worth trying a particular protocol again if the first cycle yielded nothing?

I think he’ll say that there can be variability from cycle to cycle even with the same protocol, although I’m guessing that he will also suggest a protocol change…

<<<BUZZ!!!>>>

The outcome is not likely to change much if you use the same protocol. But I would recommend changing the protocol.

8. Do you recommend trying low stim (like last time) vs. high stim? What do you think about ‘natural cycle IVF’?

Based on what I’ve heard from other CCRM patients, I think he’ll say, “There are no scientific studies to suggest that high levels of stimulation drugs damage eggs, nor any that show better outcomes for low-stim or natural cycle IVF (whether for DOR sufferers or others).” He might also add that IVF is a numbers game, and that the goal is to get as many mature eggs as we can, and that high doses of stims are our best bet to get them.

<<DING!>>

Natural cycle IVF is “a total waste of time.” You’re not taking anything to prevent ovulation, and there’s a 40% chance of ovulating prematurely. With mini-IVF [low-stim], you’ve basically decided, “I’m gonna be happy with 2 or 3 eggs.” I suggest that you give this “one really good try” [meaning with high-stims]. If you try the “Bazooka” protocol and only get 2 or 3 eggs anyway, then you’ll know that mini-IVF is just as good in your case…plus it’s a lot cheaper.

9. What particular stims would you recommend in my case? What sort of suppression drugs would you use? (Ganirelix? microdose Lupron (agonist)? Other?)

I have no idea what he’ll say. Since my cycle with Clomid/Menopur + Ganirelix yielded just three eggs and no embryos, I might expect that he would suggest trying something different, but who knows.

<<<BUZZ!!!>>>

Your particular protocol will be determined using the results of your one-day-workup.

10. Should I be avoiding alcohol? Caffeine? Exercise? For three months prior to cycling? During my cycle? During stims?

I’m guessing – okay, I’m hoping – that he’ll say something along the lines of, “As long as you’re practicing moderation (defined as 1 alcoholic beverage, 1 cup of coffee, and 1 hour of exercise per day), and assuming that you’re at a healthy weight, there’s no reason to believe that these things would hurt fertility. However, to be safe, we recommend abstaining from all three during your IVF cycle, starting at Day 1 of stims.”

<<DING! DING! Hallelujah! DINGGG!!!>>

Moderate consumption of caffeine and alcohol (up to 1 cup per day of a caffeinated beverage, and up to 3 glasses per week of wine) shouldn’t be a problem. [I volunteered that I would stop when we start stims, so he didn’t say anything about that.]

11. Is limited exposure to organic solvents (in the context of teaching lab courses) a problem?

Again, here’s what I desperately hope he will say: “In the spectrum of organic solvent exposure, working as a lab chemist or chemistry teacher (where you are educated about safety and working in rooms designed with appropriate ventilation and fume hoods) is actually quite safe. Workers at hair and nail salons, dry cleaners, janitors, exterminators, and (non-organic) farmers all have much more dangerous levels of chemical exposure, yet no link has been discovered between these professions and infertility.” I don’t actually think he’ll say this, but I’m confident that it’s true, and it would be so nice to hear (and have C hear) it coming from a world-renowned infertility expert… Sigh!

<<DING!>>

I don’t think that your exposure to chemicals caused your diminished ovarian reserve. [Boo ya!] It’s mainly a concern when we get to the point of embryo transfer. At that point, you will want to avoid chemical exposure, as you would when you’re pregnant.

12. Am I taking the right set & doses of supplements?

I think he’ll say ‘yes’, since my list is essentially the same as the CCRM-recommended list. (The exceptions are that I’m taking a higher dose of CoQ10, along with aspirin, and a high antioxidant drink powder called Nanogreens.)

<<DING!>>

Probably. When you schedule your one-day workup, we’ll give you our list of recommended supplements.

13. Should I be taking PQQ (recommended by my acupuncturist) to promote mitochondria generation?

I’m guessing he’ll say something along the lines of, “There is no evidence to suggest that PQQ improves pregnancy outcomes for patients undergoing IVF.”

<<DING!>>

There are no human studies on PQQ.

14. In your experience, does taking the aforementioned supplements actually make a difference? In AMH and/or FSH levels? In number of eggs retrieved? In embryos that make it to blast? In ultimate pregnancy outcomes?

I’m not sure what he’ll say. I haven’t found any good scientific studies that say these supplements help, but the fact that CCRM recommends them suggests that they at least believe it may help. Dr. Schoolcraft has seen enough patients that he may have an opinion about what the supplements do, even if he hasn’t gotten around to conducting and publishing a study to that effect.

<<DING!>>

Nobody knows. There isn’t good data to support it, but it probably won’t hurt. The groups of common supplements including the antioxidants (of which you have many choices, including pycnogenol, vitamin C, vitamin, E, melatonin, etc.) These decrease reactive oxygen species, which are thought to cause a deterioration in egg quality. Another supplement is CoQ10, which is thought to affect mitochondrial function. However, this has not been shown in human studies, only in a mouse study. Based on the results of the mouse study, the corresponding effective dose in humans would be 600 mg/day.

In the case of DHEA, there is retrospective data, but no good prospective data. There is good prospective data showing that testosterone priming (for at least 21 days) improves outcomes, so we will likely put you on testosterone for 21 days prior to starting stims. Based on the results with testosterone, it looks like androgens are good; it may be that DHEA is just too weak an androgen to show the same result…

15. What do you think about estrogen- and/or testosterone-priming?

Again, no idea.

<<<BUZZ!!!>>>

[See answer to #14, above.]

16. Assuming we were able to get any embryos, would you go for a fresh vs. frozen transfer?

I’m guessing that he’ll suggest we do CCS (see #s 3 and 4, above). In that case, they have to freeze the embryos while performing the testing.

<<DING!>>

I recommend doing CCS, which requires that you freeze all embryos for testing.

17. Do you recommend trying to do multiple retrievals to try and ‘bank’ embryos? How many embryos is ‘enough’?

Given my poor response on my first cycle, I think he will recommend banking embryos. Also, since the cost for CCS is ‘per test’ rather than ‘per embryo’, the most economical option is to bank a bunch of embryos and then test them all at once. The question of ‘how many is enough’ is tough to know up front. If all my embryos test normal, then I may not need that many. On the other hand, odds are good that half or more might not be. The limiting factors for determining ‘how many embryos are enough’ will probably be time and money…

<<<BUZZ!!!>>>

It depends how your first cycle goes. If you only get 1 or 2 embryos, I would probably suggest banking them to have more for CCS; if you get more, it may be worth testing them immediately.

18. What causes DOR? In other words, what could I have done differently (besides have babies in my twenties…)? Could my career choice (organic chemistry) have contributed?

I think he’ll say that he has no idea. It may be a combination of genetic and/or environmental factors, but the only environmental factor that is known to cause a decrease in egg quantity and quality is smoking (which I don’t). On the topic of chemistry and DOR, see my wishful answer to #11.

[I didn’t technically ask this question, but see his answer to #11…]

19. What would be the cost per cycle with CCRM?

I don’t need to ask this one anymore, as I found the answer here.

————————————————————————————————————-

Deep announcer voice: Well done, knalani! You correctly guessed 12 answers out of 17! Bambi, show her what her prize is…

Sultry assistant voice: It’s…a no-expense-paid trip to the lovely city of Denver!

Audience: Ooh! Aah!

Deep announcer voice: Thank you for playing, and we’ll see you next time on…

Audience shouting in unison: GUESS! DOCTOR! SCHOOLCRAFT’S! ANSWER!

[Cheesy game show music]

Antagonistic

The ultrasound today seemed to go fine. Lefty is at 17 mm, with Righty lagging behind… still measuring 11 mm. (Dr. Y also measured a third at 8 mm, but didn’t say anything about it.) C and I think that Dr. Y was disappointed with Righty’s slow growth, but felt sorry for us and refrained from saying anything… He recommended continuing stims + Antagon for a couple more days to give them more time to grow. He’d like Lefty to be at 20 mm for retrieval.

The next ultrasound will be Wednesday, with tentative retrieval on Friday – possibly later. Back when we started the cycle, Dr. Y said that it will be good if we can get a couple extra stim days prior to retrieval, so I’m going to stick with that and say this is a good thing…

*****

So, Antagon

I’m on day 3 of Antagon (aka ganirelix), which I inject into my belly every morning by way of a prefilled syringe with an annoyingly dull needle. (It doesn’t hurt that much, but it actually bounces off of my skin if I don’t shove it hard enough!) Aside from looking like a human pincushion, I haven’t observed any side-effects.

Despite my disappointing Saturday, I didn’t want to put off writing about Antagon for too much longer, since it is actually the drug that I find the most interesting, but first:

I am NOT an endocrinologist, or any kind of medical professional! This blog does NOT purport to offer medical advice, medical opinions, or recommendations. Please take this for what it is – the ramblings of an infertile woman trying to make sense of her complicated treatment protocol!

*****

Before explaining what Antagon does, it’s probably worth reviewing how this whole sex hormone signaling cascade is supposed to go normally.

Image

First, my brain sends a signal to my pituitary, which in turn sends a signal to my ovaries, which in turn make estrogen, grow eggs, and ovulate.

The ‘signal’ that my brain sends to my pituitary is carried by a peptide hormone called gonadotropin-releasing hormone (GnRH; also known as luteinizing hormone-releasing hormone or LHRH).

The ‘signal’ that my pituitary sends to my ovaries is carried by two proteins – our old friends FSH and LH. Normally, FSH stimulates one or two of the follicles to grow and develop into a single mature egg. LH (released in a surge) signals the ovaries to ‘drop’ the mature egg.

Of course, in the case of IVF, we don’t want to just have one mature egg, and we don’t want to have it get released before we are good and ready for it.

Here’s where Antagon comes in.

Image

As its name suggests, Antagon (aka ganirelix) is a GnRH antagonist, which means that it looks a lot like GnRH, but it doesn’t act like GnRH. You can see this if you look at the chemical structures of the two (below). Antagon is about the same size and shape as GnRH; it has similar atoms and functional groups (I highlighted the differences in red for your convenience). As a result, it can fit into the same tight spaces that GnRH can fit into – like the inside of the receptor protein ‘switch’ that GnRH normally turns on to make the pituitary send its signal…

Image

While Antagon looks like GnRH, it doesn’t act like GnRH. So when Antagon fits into the GnRH receptor protein, it doesn’t actually flip the switch ‘on’.

To pick another analogy, GnRH is the key that opens a lock on the pituitary gland. Antagon is like another key that fits into the same keyhole…but doesn’t open the lock. Having lots of Antagon around filling up keyholes makes it really hard for GnRH to actually turn any locks. (In biochemistry-speak, Antagon is a competitive inhibitor.) The effect is the same as if we had somehow removed all the GnRH from the system.

Without GnRH stimulating the pituitary gland, the pituitary gland doesn’t produce LH (or FSH, but we’re more concerned with LH at the moment), and we don’t get the surge, and ovulation is prevented (left panel, below).

Image

What about Lupron?

Interestingly, using a GnRH antagonist isn’t the only (or even the most popular) option for preventing ovulation.

The other, more common, method involves using a GnRH agonist (such as Lupron, aka leuprolide). A GnRH agonist both looks and acts like GnRH.

Lupron has a chemical structure that is even closer to that of GnRH. In fact, they differ by only one amino acid (in blue on the previous chemical structure drawing). Lupron also flips the GnRH receptor protein ‘on’…and keeps it on for longer than GnRH does.

But I thought we were trying to prevent GnRH from sending its signal?

The initial response of the agonist is to increase the GnRH signal – the opposite of what we want. But we’re counting on what happens next. All this signaling is very carefully regulated, so after a few days of having its GnRH switch frozen in the ‘on’ position, the pituitary figures out that something is wrong. It absorbs the GnRH receptors (the keyholes) from the cell surface, and all further signaling in the pathway gets shut down (above right).

It’s like the sirens go off, red lights start flashing, and the pituitary says “TERMINAL ERROR DETECTED. COMMENCE SYSTEM SHUTDOWN.

With the signal shut down, the pituitary doesn’t continue to make LH, and ovulation can be prevented until we’re ready for it.

What does DOR have to do with it?

Despite sounding more complicated, the agonist protocol is the more commonly-used option, or ‘plain Vanilla IVF’ if you prefer, and works well for the majority of IVF patients. However, some recent studies seem to suggest that using an antagonist might be better for poor responders (like people with diminished ovarian reserve). I think this is still pretty controversial, though.

I think the theory is that for DOR patients, the traditional agonist long protocol suppresses signaling for too long and gets in the way of recruiting the already-poorly-responsive eggs. For the agonist protocol to work, the agonist has to begin to be administered relatively early – before there are any follicles ready to drop (otherwise the initial burst of LH & FSH might trigger ovulation before the desired ‘System Shutdown’), so things are shut down for a relatively long period. By contrast, the antagonist can be administered later in the cycle, for just a few days.

*****

Whatever the reason, I’m gambling on the short, antagonist protocol. Odds are that I’m going to lose this poker hand, but dammit, I am not folding!