Posts Tagged ‘IVF protocols’

What seems to work best for which poor responders and women over 40?

Thursday, June 3rd, 2010

This is one of those areas where we’d hope the empirical literature would be able to tell us what works for whom and under what conditions. But unfortunately poor responders and women over 40 – and particularly poor responders over 40 – are a relatively small group and rather neglected in the research (JMHO). So, what can we draw on instead?

This isn’t particularly scientific, but if you look at some of the research that’s been conducted over the years and combine this with informal sources such as the Over 40 High FSH Board‘s Timeline post (click here or search for “timeline” to find the latest) and also the high FSH google stats page, and also based on what I observed (IVF successes and failures) over many years on those high FSH boards, here’s what I concluded:

  1. There didn’t seem to be any pattern about whether the flare protocol, the antagonist protocol, or Mini IVF worked best – it’s basically a crap shoot. You just have to try them and see.
  2. The high stim success cases (live births) were generally women under 40 with a lot of antral follicles. The few over 40 exceptions tended to have higher AFCs (>5).
  3. The VAST majority of over 40 IVF success cases were low stim. [Lots of natural conceptions too, but of course there are many more people ttc naturally than with IVF, so it’s hard to infer whether, say, low stim IVF is more or less effective per cycle than ttc naturally – High FSH specialist Dr. Jerome Check thinks IVF gives high FSHers 2.5 times better odds for that cycle cf ttc naturally in your late 30s and early 40s.]
  4. Often on high stims you can get more follicles and sometimes more eggs retrieved, but the number of embryos generally seemed to be the same from either high or low stim (I’m excluding natural and boost protocols from low stim here). In other words, on high stims you often get more empty follies and/or lower fert rates.
  5. Those of us over 40 gals who’ve tried both high and low stim have quite often seen a difference in eyeballable embryo quality – just one example, but check out my high and low stim embie pics and see for yourself

So … based on what I’ve seen, my conclusions for poor responders/high FSHers/low AMHers were:

  • Under 40 and with OK AFC –> give medium-high stims a try first (say, 450-600IU)
  • Over 40 but a pretty decent AFC (say, consistently >5) OR under 40 with a low AFC –> try medium stims first (225-375IU)
  • Over 40 with a low AFC and FSH not through the roof –> try low stim (75-150IU)
  • Really excessively high FSH or a system that goes wacky with drugs –> go natural (BD or IVF) or try a ‘boost’ cycle (start natural, add tiny 75IU boost IF needed based on monitoring)

Not very scientific, but FWIW, that’s what I concluded in the end (after starting medium/high stim at age 40 and eventually listening to my wise board buddies and Jerome Check – and trying low stim).

Please note that this post is directed at couples and women who do NOT at this point want to consider donor eggs, but want to try and get a handle on what might be the best approach to try with their own eggs.

Other posts of potential interest:

What are the main IVF options for poor responders?

Tuesday, June 1st, 2010

In an earlier post I covered what a high FSH/low AMH reading means, what else to ask for in the way of diagnostic investigation, and the basics about whether this is a ‘no hope’ diagnosis or not.

I’ll talk in this post about the main IVF protocol options for women with high FSH/low AMH/DOR and poor responders, but will be back sometime soon with a post about other lower-cost options for those not willing or able to do [more] IVF.

IVF Protocol Options

OK, first let’s talk about protocols. As I mentioned in the post about the main about IVF protocols used in New Zealand, there are basically three possible protocols that are used for poor responders, and 1. The “long protocol” is NOT one of them. The main options for poor responders are:

2. The microdose flare – usual starting protocol for high FSHers and women over 40. It’s less likely to oversuppress poor responders than the long protocol.

Usually but not always starts with a course of BCPs (birth control pills) for about three weeks, then you stop for a couple of days, then start your microdose course of Buserelin (this gives your ovaries a kickstart or ‘flare’), then a day or two later you start your stims (Gonal F injections). As with the long protocol, you stim for about 10 days with scans and blood tests every 2-3 days. When your follies are ready, you are instructed to take a trigger injection and turn up for egg collection about 36 hours later.

3. The antagonist protocol another option for high FSHers, poor responders and older women. Often the first choice protocol for these women, but in NZ it’s typically tried only after the flare protocol has given a weak response because the drugs are cheaper for the flare.

Usually starts with a mild pre-cycle suppression course of estradiol valerate (E2V) from CD21 or 7dpo the previous cycle (you can ttc on your own the previous cycle; this won’t affect a pregnancy); when AF (your period) arrives this is counted as Day 1 and you may be asked to go in for a baseline scan to check that you have no cysts, your antral follicles are ready to go and no big dominant follicles; on CD2 you start stimming, having bloods and scans every 2-3 days. When your lead follicle reaches 14mm, you start Cetrotide (the antagonist that stops you ovulating too soon). When your follies are ready, you are instructed to take a trigger injection and turn up for egg collection about 36 hours later.

4. The Modified Colorado protocol (a.k.a. The “Wellington”)

“As an adjunct to standard IVF or TER for patients with recurrent implantation failure who have had no problems identified following a recurrent implantation failure screen. The Wellington is a treatment that in theory will improve the lining of the uterus to aid implantation of the embryo.”

Stim Options

OK, having discussed with your specialist which protocol to try first – and don’t forget to ask what he/she would try next if the first one works very poorly! – the next question to discuss is what to use to stimulate your ovaries. The usual default is to start with straight Gonal F; if that doesn’t work well, you might raise the possibility of adding something else as well. The options are:

  1. Straight Gonal F (or Puregon) – this is pure FSH
  2. Combination of Gonal F (or Puregon) and Luveris (pure LH)
  3. Combination of clomiphene (Clomid) and Gonal F or Puregon

Dose Options

There are two diametrically opposed schools of thought among specialists when it comes to how to treat poor responders. They are basically:

1. SHOUTING: High FSH means your ovaries do not respond well to IVF stim drugs. It’s like having ovaries that are hard of hearing when it comes to stim drugs’ message, so the best strategy is to shout at them very loudly (i.e. give you a high dose of stims). This might just get you an extra egg or two. IVF is a numbers game, so more eggs improve your odds.

2. Coaxing: Women with high FSH often have eggs that are more fragile, especially if they are ‘older’ as well. High doses of stims simply ‘fry’ those eggs. If you have high FSH/low AMH, you are going to be a poor responder, so it’s a waste of time going after quantity; the best strategy is to go for quality. You can’t actually improve egg quality per se, but you can avoid damaging eggs with high doses of stims by using very low stim protocols. ‘Low stim’ usually means 75-150IU/day. [I’ll write more sometime about the details of some interesting low-stim protocols used overseas.]

Which of these makes more sense for you? Well, the body of research is building but still hasn’t yielded a definitive answer. My own observations over several years (talking to high FSH women and watching who achieved success and who didn’t, plus reading the empirical research) have been that the only high FSH successes on high stim IVF seem to be women under the age of 40. The vast majority of high FSH IVF successes over age 40 seem to be low stim (with a few exceptions). Younger women with high FSH can also do well on low stims. This isn’t scientific research; just my own observations based on a lot of cases I have known about internationally.

Having said that, the New Zealand definition of ‘max stims’ (usually 300IU) is actually more like ‘medium stims’ internationally. In the States, ‘high stim’ generally means 600IU or more, and there are (believe it or not) some total egg-frying protocols that crank it all the way up to 900IU.

My own hunch is that if you are under 40 OR if you have a reasonably decent antral follicle count, consider giving 300IU (or 450IU) a shot. But if that doesn’t get you decent numbers or,  if embryo quality looks poor, consider a switch to low stim for your next try.

If you’re self-pay, there’s a cost advantage to low stims as well.

Conflicting expert opinions – how do I know who’s right?

Saturday, April 10th, 2010

So, you finally plucked up the courage to go for a second opinion (see also When and how should I seek a second opinion?) and guess what – now you have two or more well-qualified and plausible experts with compelling arguments telling you to do the exact opposite. Maybe one cites empirical research and another doesn’t; maybe they all cite different research. Maybe one sides with the ‘mainstream’ while the others are mavericks – who’s more credible? Who should you trust?

Here’s a classic example encountered by women in their late 30s and 40s with elevated FSH or low AMH (which means they have diminished ovarian reserve – very few eggs left, on the fast track to early menopause). [This example may not relate to your case specifically, but the reflections about how to deal with it are definitely generalisable.]

Specialist A: Once your Day 2/3 FSH is over [insert cut-off; some say 10, some say 12, some say 15, some say 20] the odds of pregnancy through IVF are so incredibly low that IVF is a waste of time altogether, so we would actually not treat you unless you plan to use donor eggs. Just move on already!

Specialist B: Your FSH is elevated, which means you will be a poor responder to stims (Gonal F, etc) and your odds will be lower than other patients your age. It’s like your ovaries are old and going deaf, so we have to give you a very high dose of stims (i.e. ‘shout’ at your ovaries) to get them to wake up and produce any eggs at all. So, I would recommend we put you on maximum dose stims and see what happens. If that doesn’t work we will try mega mega doses.

Specialist C: Your FSH is elevated, you will be a poor responder, but actually, large doses of stims for women like you will often cause your ovaries to shut down and not respond at all. If they do respond, the dose is so high that you will end up with fried eggs that are unlikely to result in a live birth anyway. No, your ovaries are like an old squeaky violin that has to be coaxed gently into life so that it sings the sweetest tune  it possibly can. I recommend a very low-stim IVF, IUI or TI (timed intercourse) cycle with either very low stims right from the start, or just starting with no stims and letting your own [already elevated] FSH drive follicle growth before adding a ‘tiny boost’ to help things on their way.

Yes, intelligent people do hold different views. The field is still growing and not everything is cut-and-dried (and  actually, never will be). They all have theory and evidence to back their explanations …

Specialist A will cite a ton of empirical research showing the inverse correlation between FSH levels and IVF response (number of eggs produced) and success rates. No argument with that.

Specialist B will cite studies showing that the higher the dose, the more eggs patients produce, and the more eggs you retrieve the higher the success rates. It’s a numbers game.

Specialist C will say ah yes, but what those studies don’t show (but mine do) is that, although you get more eggs from higher stims, in older women and those with high FSH, those eggs are of lower quality, less likely to fertilise, and most importantly, less likely to result in live births.

They are all speaking the truth based on what they have seen and read; they all have evidence and experience to back their claims. So, how do we weigh up conflicting arguments and figure out what makes the most sense for us?

First, let’s talk about the big studies (either randomised experimental trials or retrospective studies) showing that Protocol X works (or, helps) better than protocol Y. These are very important to understand, but what YOU need to consider is not “does it help” on AVERAGE across a large study of all sorts of different women; the real question to have in mind when you read (or, discuss with your dr) such research is WHOM does it help (what age, dx, individual characteristics), and under what conditions? And, will it help ME with my unique constellation of age, treatment history, diagnosis and other characteristics?

There are some aspects of fertility treatment that are so nuanced, unpredictable and idiosyncratic that the reality is NO-ONE is ever going to get “the” answer through large study research. Once you’re past the relatively well-established big picture stuff and trying to individualise protocols based on what you see and what you’ve seen in the past, it’s less about big picture science and hypothesis testing and more about human judgement and pattern recognition.

When we’re in this territory, fertility treatment is less a “science” and more of an “art” or a “craft”. You’re having to trust pattern recognition, judgement, intuition and instincts because the research just isn’t there to the level of detail you’d need to be able to make a call. Also, many of the cutting-edge treatments have no more than a plausible theory and a few success cases; the research needed to fully test them is still in progress or may be years away or may never be done because they help such a small segment of the ttc population – but they may still help (see also New and “untested” treatments). Just about all of my ttc journey was in that murky domain -  I was too specific a mix of age, diagnosis and treatment history for enough large studies to have been conducted to clearly indicate what would work in my case. There were no easy answers – there wasn’t a clear right or wrong because the research out there could only predict what would happen across a large group (that included many women NOT like me), not what would happen in MY case (or cases very similar to mine).

When you’re in instinct and judgement and pattern-recognition territory, the only things you can do are arm yourself with as much knowledge as you can muster, listen to the instincts and judgement of the people who have had more experience with cases specifically like your own, and listen to your own instincts and debate these back and forth with your specialist(s). It’s a crap-shoot, but some people have a knack for this stuff …

Or, the simple version for the example above (please just insert your own dilemma and the answer is likely the same): high stims work for some people; low stims work better for others. Which are you? Well, you won’t know until you try because the studies have been done on a huge range of women, only a fraction of whom are like you in various ways – and none of them are exactly like you. So, research like crazy to try and figure out what seems promising for women and couples most like you, and when it’s still not clear how to choose among various plausible options on your shortlist, go with your gut.

See also: New and “untested” treatments for some thoughts about which new-fangled ideas to consider seriously.

We did IVF but had heaps of empty follicles – help!

Monday, April 5th, 2010

Some of us do IVF, go for those scans and see hardly any follicles after all those injections. Others are relieved to see a healthy crop developing as they go through their cycles. Unfortunately, the number of follicles (or “follies”) doesn’t necessarily equate to the number of eggs collected. And for some women, a huge proportion of the follies are ’empty’. This is sooo frustrating after seeing all those follies on the screen and usually having a fantastic E2 (estrogen level) to match.

There is such a thing as “empty follicle syndrome”, but unfortunately it’s still not all that well understood, and there are various theories …

  1. The most common explanation given by the specialists is that egg maturity and quality are related to how easy they are to get out. Those that are flushed out are lower quality than those that came out easily. ‘Empty’ follicles may not actually be empty; they may just contain very poor quality eggs. OK, there’s obviously a heavy element of truth to this (i.e. it’s a known fact about eggs in general), but the big question, of course, is whether (and how much) it applies in YOUR case. It probably does, to some extent, in just about all cases of empty follicle syndrome. But that’s actually a “There’s nothing we can do about it” diagnosis, and not much use unless you are looking for  a reason to switch to donor eggs or give up altogether. So, the following are some other plausible theories that may or may not apply, but many of which CAN be addressed.
  2. One theory is that you got a dud trigger shot. It’s rare, but it can happen. And it’s unlikely to happen again. But if you want to be absolutely sure, some women use a double trigger shot the next time. This is when you inject not one but TWO vials of Ovidrel (the usual trigger used in NZ), one after the other. Very important: The vials should come from two different batches (check the batch numbers on the packet before signing them out and taking them home – you can’t return injectable drugs for exchange or refund). I’ve not seen any mention that this could have any adverse effect on the egg quality – it’ll cost you some $$ for one more vial of trigger (but this is cheaper than one more IVF cycle and a lot cheaper than the baby once he/she arrives!), but apart from that, it’s a “won’t hurt, might help” measure as far as I can tell. But ask your dr.
  3. Another theory floated a lot is that you may have ovulated just before retrieval, but not so long before that they would have seen collapsed follies. The remedy for this, if true (and it’s very hard to tell) is to schedule your egg collection just a bit earlier – say, 34 to 35 hours after trigger, instead of the usual 36. Reasons to hesitate about doing this might be if several of the eggs that were retrieved were immature – collecting early could exacerbate this problem.
  4. A rather delicate theory to probably NOT raise with your specialist is that the person doing the retrieval wasn’t very skilled. Yes, well, obviously a possibility, but hard to tell as a patient, and there’s no way you’ll get an admission about this one!! If you’ve had several cycles with ’empty’ follies, was it the same person doing the procedure each time?
  5. OK, time to start thinking outside the very simple boxes outlined above. One possibility is that the protocol disagrees with you – gets you follies but most of them are ‘decoys’. Now, you won’t get far on this one if you are under one of NZ’s one-size-fits-all specialists. Obviously, there are some cases where a change in protocol might be risky (e.g. greater risk of overstimulation, OHSS), but personally, I couldn’t bear to go into a new cycle on the exact same protocol as a failed one, so ask lots of questions about alternatives – and see also the post: What are the main IVF protocols used in NZ? The other protocol-related thing to ask about is what stims are being used. In NZ, just about everyone gets put on straight FSH (Gonal F or Puregon), but some specialists will add some LH (e.g. Luveris) into the mix. This seems to help some women with egg quantity or quality or both; others seem to do better on straight FSH.
  6. Some fertility specialists say that if your eggs are overcooked, i.e. if you stim too long before triggering and the egg over-ripens, then the resulting egg will stick to the follicle lining and not come out easily. The same is said about eggs that are ‘undercooked’ (i.e. if you triggered too early and the egg is not yet mature). Although there is some empirical research on the best time to trigger based on follicle size, it’s become quite clear to me (after listening to others’ experiences) that one size does not fit all, and some women need to trigger earlier than the norm, some a bit later.
  7. The other possibility is that maybe your ovaries are of the “less is more” variety, so that if you halve your dose you may get fewer follies but the eggs in them are likely to be (a) really there and (b) better quality. I haven’t seen a lot of research on the latter, but I have talked to a low-stim specialist about this in some depth, and also to several women who swear they get far fewer empty follies when they are on a much lower dose. [And, I suppose my experience was similar numbers but better embryo quality, so I’m a fan of the low-dose option in general.] Internationally there is a fast-growing interest in the reproductive endocrinology (fertility specialists) community about low-stim and natural approaches to IVF.One of the more interesting recent innovations in IVF is in vitro maturation (IVM), where the eggs are removed from the follicles while immature and then matured in the lab. This is nil to near-nil stims technology. Last I heard – in a Nov 2007 National Radio interview with Dr. Simon Kelly (Fertility Associates Auckland) it hadn’t been approved by the ethics people, but it may be by now, or that  may be coming soon. If it sounds interesting, get yourself a consultation with Simon – he did a post-doc fellowship at McGill in Montreal, where IVM was pioneered.

OK, there’s a big laundry list of possibilities here. My own experience grappling with infertility has taught me to push back quite hard if only the “we can’t do anything about it – you just have bad eggs” explanation is being offered. OK, the bad eggs thing may be true (and in my case it certainly was, since I was IVFing over 40 and with high FSH!), but that doesn’t mean there aren’t some other treatable explanations that are also in play. There are quite a few non-drastic options here to tinker with the protocol, and IMHO they are well worth discussing seriously with your dr. If he or she is reluctant, make sure you ask whether your specialist thinks this is likely to be risky or harmful in some way, or whether they think it’s relatively harmless but just unlikely to be effective. If it’s the latter, and if your instincts are telling you it makes sense, then ask to try it.