What are the main IVF options for poor responders?

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.

22 comments to What are the main IVF options for poor responders?

  • Pauline

    Hi, this is very helpful. I’ve just been sent an article about a ‘softly softly’ approach to IVF in the UK, in particular with regard to older women. The article talks about ‘soft’ or ‘mild’ IVF, and ‘natural cycle’ ivf. Soft IVF uses lower doses of drugs, so I presume is similar to the antagonist cycle that I’ve been on. Natural cycle IVF doesn’t use any drugs, with the egg being collected just before ovulation, and an embryo (hopefully) being replaced a few days later. While there is only one egg per cycle, the procedure can be done each cycle without the need for a break. I wondered if you’d heard of anyone trying this natural cycle ivf here and if there is any support for it at the clinics? Thanks Pauline

  • Eve

    Thanks, Pauline, for your comment and question.

    Yes, natural cycle IVF is gaining more traction internationally, particularly in the UK, where there was a conference on it a few years ago. Also of interest is the ‘Mini IVF’ approach pioneered by the Kato Clinic on Tokyo – this uses just a small amount of clomiphene and the aim is to gather 1-2 eggs every month. The other protocol of note is Dr. Jerome Check’s ‘tiny boost’ protocol for high FSHers, which I’ll post more about sometime.

    I have an American friend who lives in Tokyo who (in her 40s) banked about a dozen frozen embryos via Mini IVF, then did one last low-stim (injectable) cycle as a fresh one, got pregnant with that at age nearly 44, and now is looking to do TERs (FETs) with the Mini IVF frosties to see if she can have a sibling. She’s now 45 or 46, so IVF would be hopeless at this point, but frosties made when she was 43-44 may have a chance.

    I have not heard of anyone doing natural IVF in NZ, but I know Dr. Simon Kelly at FAA will do low stim and I am pretty sure he mentioned he had one or two patients doing natural IVF. Also of interest as a low-stim approach is IVM, which was pioneered by McGill in Canada (where SK worked) and which he’s been trying to get approval for here. Check out Simon’s 2007 interview on Radio NZ on this topic.

    HTH!
    Eve

  • tamlyn

    hi
    i was interested to know why you said that IVF would be hopeless in a 45 or 46 year old?

    I thought it was about egg quality which surely differs according to the person?

  • Eve

    hi tamlyn,

    It’s very true that egg quality varies from person to person, but the reality is that even in women who are at the lucky end of the egg quality spectrum, egg quality is way down for all of us by then and the stats for IVF at age 45+ are really abysmal. There are some excceptions, but very few.

    It’s thought that at that age the eggs are just too fragile to handle the effects of the drugs and the manipulation that comes with IVF.

    By far the best odds at that age are ttc naturally … unless of course you have no tubes or MFI, in which case the best option (assuming you don’t want to or can’t use donor eggs) is very low stim IVF that will be gentle on the eggs. The odds are still lowat age 45+, but, well, in theory it’s doable.

    A good place to have a look at the stats are: (1) whatever clinic you are working through (just ask the lab for the stats for over 40s by age), (2) the CDC’s annual stats by age (just google this), and (3) the stats for older women from the few clinics that specialise in AMA (advanced maternal age), particularly those that use low stims. [Cooper Clinic in NJ, USA; and search for anywhere that does Mini IVF – the Kato Clinic in Tokyo pioneered this, and there’s a clinic in New York that does it too (New Hope).

    Hope this helps – and good luck! 🙂
    Eve

  • Suparna Tyers

    Hi Eve,
    I was interested to read about your American friend who lives in Tokyo who has mini IVF and then one last low-stim cycle where she used the fresh egg from to get pregnant. I was interested to find out what her exact protocal was for this last low-stim cycle as usually with these sort of cyles you need to use Clomid for an extended period of time and this stops the endometrium from growing, making it necessary to ‘freeze’ the collected egg until such time as when the woman is no longer on the CLomid before transfer takes place.
    I just wondered how she managed to use a ‘fresh’ egg with a low-stim cycle as I am interested in this procedure.
    Suparna

  • Eve

    Hi Suparna,

    My friend’s last low-stim cycle was with injectables only, not Clomid. She has a bunch of frozen embryos from Mini IVF (Clomid) cycles. Her injectable protocol was very similar to mine (see my story, top menu), but I think she did 1 amp (75IU) more of stims than I did since she was an ok responder.

    Hope this helps clarify! 🙂
    Eve

  • Kim

    So happy to see you post Eve! I read your story over and over to give me hope! I just turned 43 a couple of weeks ago and have gone through several rounds of IVF attempts with only one retrieval. Oddly enough, my 2nd, new and will be last RE is at Cornell has tried lower doses of meds. This last cycle I almost made it to retrieval with 2 eggs using 75iu menopur days 2-4 then step up to 150iu menopur days 5-10 with ganerilix when the lead was 12.5mm. My RE thought I had more follicles as my estrogen popped up to 557. We should have triggered on day 11 b/c I surged on my own that night given my day 12 bloodwork showed I had surge and broken through the ganerilix. We are supposed to try again this month if we are not lucky with the IUI this cycle, but I am second guessing going ahead one more time b/c of just turning 43. You think there is a chance at 43 with only 2-3 eggs? My highest FSH was 19.7 almost a year ago, so I have to do estrogen priming the cycle before – which I already started yesterday. My doctor will not allow me to start if my FSH is above 12 I think. This cycle the estrogen priming brought my FSH down to 5.6 on day 2 – which is great and so my follicles can line up better to get at least 2 follicles on low doses. Also, been taking 75mg of DHEA except the LP of this cycle since my doctor said to hold off and pick it up again at the next cycle. Any encouragement would help -oh also, have one 3-year old daughter conceived naturally and two miscarriages with the the last one in 9/09 – which seems so long ago!

    Kim

  • Eve

    Hey Kim, good on you for persisting with the dream! Are you with Dr. Davis @ Cornell? They have a good rep in general BUT the one serious issue is not letting women in their 40s cycle unless FSH is low/normal. Sure, odds are better if your FSH clocks in low (so this helps their stats), but being benched cycle after cycle is a real problem when you’re close to or over 42.

    Have you considered a consult with Check? He’ll cycle you even if your FSH is high; he just uses a different strategy. I consulted with him before my last few cycles and he said the odds for age 42 and 43 are about the same, but there’s a real drop off once you turn 44. So, in your shoes (and i was close to them) I would definitely go for gold until your next birthday anyway. If you can, and if the costs/toll on your life etc don’t outweigh the hope of success and the need to get through all this with no regrets. [Think I have a post on “when to stop” somewhere …]

    Good luck!!
    Eve

  • Kim

    Thanks Eve! I am with Dr. Davis and just really am so pleased with him and his staff! This last cycle, I think he felt really bad about holding off one more day to trigger b/c he was not sure both follicles measuring 17.2 and 16.4mm on day 11 in the am were ready – but apparently they were – and I surged during that night possibly – and they had grown to 19 and 20mm by the next am. I did have a consult scheduled with Dr. Check but he does not do phone consults so I would have to travel. I decided to cancel the appt. with Dr. Check, since he is older and does not go to retrievals but he works with his staff. Although I need to travel with Dr. Davis, my husband and I were happy with him after our consult. Also, Dr. Davis offered high doses with estrogen priming first, which I tried at my local doctor’s office and shut me down with only one folicle developing. Then I called back, and he suggested low doses (actually after I had a few tries at high and moderate doses at my local doctor’s office). Given Cornell’s co-culture program, that he was offering lower doses (which I had asked my doctor to do for months based on what you had written about – quality over quantity!) and fact that it is an academic/research atmosphere, my husband and I decided to switch to Dr. Davis. Thanks for letting me know on the 43-year old eggs not being too bad off just yet. I feel that you were lucky on your own too with so many in between chemical pregnancies! I feel now that it has been over 1.5 years that I have generated any pregnancy hormones on my own and wondering if my body has forgotten! Take care and thanks again for giving us all hope with high FSH. By the way, the estrogen priming with the Climara patches is great (think you used EV?) because this current cycle I had a high AFC for me -like 10<10mm (the estrogen patches or the DHEA helped). Just wish all those follicles would soak up the FSH they are getting!

    Take care,
    Kim

  • Kim

    Hi Eve! I sent you an email but wondering if you could respond today or soon! I did estrogen priming with 2mg estrace from 2dpo to the day before my cycle start, but my day 2 FSH is 15.7 still. The day 2 ultrasound shows 5 follicles, with one on the right a 7.8mm. So the one has just a slight head start but not by much. My RE planned and wants to do 225iu FSH starting out and throughout my cycle. I’m worried about stimming fast. What are your thoughts on starting meds with starting FSH a little higher? I know your successful protocol, you were to have FSH less than 11. Any thoughts on whether to go with this cycle or cancel now and wait until next month to see what my FSH day 2 is? I’m 43.75, so time is wasting away and feel I have one last shot at IVF/ZIFT since that is what my husband and I agreed to. My doctor is thinking we could do another round if this one is not good. I want to do just one more round and end this journey. Any advice would be appreciated as I should make my decision today on day 3, and I did take my meds last night to give myself options. Thanks! Kim

  • Diane

    Hello,
    I am 42 and have so many mixed feelings about having Mini Ivf or traditional IVF. I became pregnant with first IVF 5 years ago and miscarried at 8 weeks.We have been trying for 9 yrs. When I went through IVF I did not produce eggs with Bravelle and only 4 with Gonal 5. I am confused which route to go thid will be last try my hubby has low motility.Thanks.

  • Eve

    It’s an incredibly hard choice at any time, but especially if it’s your last shot. And of course, I can’t offer medical advice, just maybe a few ideas that could be useful as you speak with your specialist about this.

    There’s high stim, moderate stim, low stim, and no stim approaches – and mini IVF is one very specific low-stim approach that uses Clomid instead of injectables. Other low stim options involve low-dose injectables, or a mix of Clomid and injectables (again, low dose).

    Diane, all I can say is that the women I have talked to over the years who were getting small numbers of eggs with traditional IVF never really did any better if they upped the dose or kept it high. I was also a 3-4 egg gal, and was amazed that I got the same number on low stim. But on Clomid I’d only get 2-3. I guess everyone is different.

    Have you posted your question on the Over 40 High FSH board? (see the list of Support BBs on the left) Several opinions may be better than just my limited experience.

    What does your dr say, and how much do you trust his/her judgement? Would either option give you more “what if” regrets? These are the things I’d grapple with …

    Good luck, and hugs!
    Eve

  • Diane

    Hi Eve,
    Sorry for the late response. I know a few months have gone by and I am getting ready for IVF. I will be speaking to my specialist who of course has been encouraging me to do IVF for the longest time. But as you imagine it is so expensive. Now my FSH is high and I am going to acupuncture hoping it will reduce it. I don’t know if I could proceed with IVF with my own eggs. I do have a sister who is willing to be my donor if needed but of course that is another option. My RE is agressive with meds and does not want me to do Mini IVF. I also found IVF to be cheaper in Mexico but would need to do more research.

  • Eve

    Hi Diane,

    It’s incredibly hard to decide when it’s your last shot, or close to it.

    If you decide to go with your own eggs, then the high stim/low stim question you just need to think hard about, research it, then go with your gut. Your RE is big on high stim; others are big on low, and they each have plausible arguments. You need to work out which set of arguments makes the most sense in your case.

    See also the post called Conflicting expert opinions – how do I know who’s right? http://infertilityinfo.co.nz/conflicting-expert-opinions-how-do-i-know-whos-right/

    It’s fantastic your sister is prepared to be a donor (how old is she?), so that leaves you with another option, and one that is presumably less urgent if she’s young.

    Good luck with it all! Are you hooked into a good support site or two? There are some links here under Support BBs that are great places to start.

  • LouD

    Hi Eve,

    I am at Fertility Associated, Richard Fisher. I have high FSH (14) and low AMH (0.8). I concieved my first child at 35, from a 2nd IVF cycle, with FET. I am 38 and on my second round of IVF, TTC our second child. My IVF potocol is, micro dose flare, BCP for 3 weeks, Gonal F (300) and Buserilen (5) for 2 weeks. First IVF (I was 37) produced 5 eggs, all fertilised (ICSI) and 1 x 8 cell transfered Day 3 – BFN. My second IVF (I was 38, Jan 2014), we added a testosterone patch prior to the cycle, and herbs from my accupuncturist, produced 8 eggs, 5 fertilised, and 3 grew to 8 cells. 1 transfered on Day 3, 1 grew to blastocyclst but not good quality to freeze and 1 didnt grow. BFN from this cycle.

    I am keen to try again, I was looking at mini IVF, as I wonder at my age if we go for fewer but higher quality eggs. And looking at your experience, I wonder if we try for lower dose to focus on quality eggs. I know my number of eggs are not bad at between 5 and 8, so perhaps we just keep trying the conventional approach.

    Any thoughts?

    Thanks,
    Lou

  • Lou, have you discussed alternative protocols with Richard? Always a good first step.

    In my experience, each specialist has a few protocols they tend to use, so it’s always good to ask what they’d recommend as a Plan B approach (and why) and also thinking ahead to a Plan C. Some seem to draw on a wider range of “outside the box” protocols, while others often stick with a smaller set of more standard approaches.

    I always found it important to satisfy myself that the rationale/reasoning my specialist used really made sense to me. In those cases where they were reluctant to discuss it with me, or where I just didn’t think the reasoning made sense, I switched specialists until I found someone who spoke my own language, as it were. It wasn’t that he’d let me try anything I asked about, but he’d discuss it with me as an intelligent equal and we’d decide together.

    Hope this helps, and do tell us how you go! 🙂

  • Jess

    Hello Eve,

    I am Aussie but now in US. Your story inspire me and I wish I will have the luck one day. I am turning 41in one month, did 5 ivf already, the past three are back to back Clomid with injectable, I was able to bring down FSH after cycling, my normal FSH is between 6-8, but this cycle spike to 24, the highest ever, did you ever hear that Clomid will cause increase in FSH,
    Also I wish I found you earlier, New hope push the embryo to blasts but my only at cavitated stage and morula by day 5 and never grow after, I wish I transfer those or freeze at day 3. I was too sad that my embryo didn’t make to day five and FSH spike up the following cycle.

  • Hi Jess,

    Clomid is designed to push FSH up within the cycle you use it; that’s how it works. And I have heard a few stories of women who believe it pushed their FSH higher in general. Hard to say though because FSH does jump around anyway when you are a high FSHer.

    So sorry to hear of your embryo not making it to blast. That is so hard to take. Hugs!

  • Hi Eve,
    I am a 36year old TTC#3. I had my first son at 32 conceived easily. TTC #2 was difficult, I had a polyp removed then had the dreaded low AMH diagnosis. My AMH was 0.05, in October 2011. We did IVF in December 2011, got four eggs, two fertilised normally, did a day 3 transfer, bfn. The other embryo didn’t make it to freeze. I fell pregnant naturally in feb 2012. We have been TTC #3 for 10 months, have done 4 cycles of 2.5mg femara with a lot of supplements including DHEA. My AMH has increased to 0.8, not had FSH tested. My husband is loathe to do IVF again, given the fact it didn’t work and we are completely out of pocket. I’m more pragmatic about it, and will do whatever it takes. I am thinking of doing an femara injectable IUI in July. But then I wonder if we should go straight to IVF. I’ve been reading a lot about estrogen priming, lower stims and assisted hatching. What do you think?

  • Diana Gorates

    I am curious, is there a ivf protocol where birth control pills is used to put the ovaries to sleep for 21 day and begin stim on day 22, the specialist did this protocol as a part of my treatment, I bled on the birth control pills from the first pill to day 21, they ignored my complains and say its normal, they started stim on day 22, the ovaries wouldn’t wake up ( age 38, ovarian reserve 8 on the left 9 on the right, amh 25.4, although my blood work didn’t show signs of pcos, I had pcos in the past but it disappeared after I changed my diet). After the 3rd scan they said the follicles are still asleep however they want me to use the trigger medication to trigger ovulation then return to see the doctor for a new protocol.

  • Megan, what does your fertility specialist say? Is he/she willing to let you give it another shot? And, do his/her ideas strike you as thoughtful, innovative, definitely worth a shot?

    Obviously I can’t advise what you should do, but I can give you a few thoughts from my own perspective as a former fertility patient.

    When I was struggling the same kinds of decisions as you are, my logic went like this: I need to get to age 50, look back, and not have any regrets about those decisions.

    Would I regret throwing us into financial strife by doing another few IVF cycles? The circumstances are completely different for everyone, but for me I figured I could make money after menopause but not eggs.

    Would I regret NOT trying more IVFs? For me, I needed to feel that I’d left no potentially promising stone unturned. So, when I was at the point where we’d tried IVF a few times but only the standard protocols, somehow I didn’t feel like we’d given it our best shot. If we’d tried something innovative and it’d been no better response or embryo quality than the standard protocol, I might have considered we were done at that point. But we did see some improvement, so it spurred me to try that again.

    I knew I also needed to be OK with a negative outcome even after spending all that money on more IVFs, putting the family into financial difficulty, plus the emotional and psychological stress that comes along with that.

    It’s a very very personal decision for each couple. I’d suggest painting each scenario – we do more IVFs, we don’t, we get the outcome we want, and we don’t. That’s a 2×2, four possibilities, all with their own costs and dramas. Now fast forward to 50 years of age and consider how you’ll feel looking back.

    I wrote some more about this under “How do we know when to move on?”

  • Diana, yes, I have done the protocol that uses birth control pills (BCPs) for 21 days as precycle suppression, and it is true that bleeding is normal and doesn’t affect its effectiveness.

    I did find that the BCPs oversuppressed me. I had zero response to stims and my cycle was cancelled. Sounds very similar to your case, actually.

    You are still relatively young (being under 40) and with a decent antral follicle count, so I would be optimistic that a different protocol might work for you.

    Go in there armed with some good questions. For me, I wanted to hear the specialist’s reasoning about why they thought the suggested new protocol would work better than the last one.

    Good luck, and let us know how you go!

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