Homepage The best IVF protocol
Category: Fertility TreatmentsTo find the best IVF protocol for you, we look to your personal medical history, we decide upon the medication dose, and then finally we individualize your care against one of several standardized protocols.
Medical History
We need to know your ovarian reserve (FSH and antral follicle counts…for more, look here). For example, if you have a good ovarian reserve, you won’t need very much stimulating medication. Conversely, if you have few eggs, you might need a higher dose.
In addition to ovarian reserve, we also need to estimate your personal ovarian sensitivity to hormones. This part is more art than science. It is very helpful if you have used stimulating medications in the past (eg through insemination cycles) as a guide. We also use your age, your BMI, and knowledge of pelvic compromise (eg from surgery or endometriosis).
Medication Dose
Through a combination of ovarian reserve and your ovarian sensitivity, we should have an idea of the ideal starting dose of stimulating medication. The dosing can be as little as 75IU, to a theoretical maximum of about 300-450IU. (You can probably take higher doses safely, but your kidneys will just excrete the excess). In Canada, the main two medications used are Gonal F and Puregon, though we will also use Menopur, Repronex, Bravelle, and Luveris, usually in supporting roles. Less commonly, some doctors will add clomiphene (Clomid, Serophene) or letrozole (Femara) into the mix.
Standardized Protocols
natural start, long, OCP-antagonist, estrogen primed, and flare…
You can run a natural start cycle, which simply means that you come in at the beginning of your menstrual cycle, say on day 3, and if there are no cysts, you start the agreed-upon dose of stimulating medication. This simple approach is appealing because it is, well, simple. But there is a catch: it is quite likely that egg growth will be scattered across a variety of maturity levels. ”Scattered” maturation makes the ideal timing of egg retrieval difficult, and the cycle might suffer as a result.
More commonly, we like to suppress the ovaries before stimulation. The idea is that none of the eggs will develop too quickly…so that all the eggs will be ready at the same time. Suppression also allows us to schedule treatments. Too many retrievals on the same day would compromise pregnancy rates for everyone.
The longest, deepest suppression is done with the long protocol. It is, as the name suggests, the longest of the protocols: several weeks on the birth control pill in most cases, overlapping with a GnRH Agonist (Lupron, Suprefact, or Synarel) which is even more suppressive. By the time you are done with this pre-treatment, your ovaries should be well-and-truly suppressed. As you can imagine, there is the risk of going too far. When your ovaries are over-suppressed, the stimulating medications simply will not work. You will know this is happening to you when your estrogen starts off low –sometimes less than 50 pmol/l– and never climbs above 200 despite day after day of stimulation. This happens to my patients about 5% of the time.
So why use the long protocol? Because when the long protocol works, most clinics find that we get the best pregnancy rates.
Nonetheless, the long protocol isn’t for everyone. Particularly for women with a low BMI (less than 21) or other reasons to suspect sensitivity to suppression, we usually opt for an OCP-antagonist protocol. In this case, we use the birth control pill (aka oral contraceptive pill or OCP) for a bit of suppression, then once the cycle starts, use a GnRH Antagonist (like Orgalutran or Cetrotide) to prevent ovulation. I like OCP-antagonist cycles, and have had a lot of success with them recently. It is a more pleasant protocol for patients, with fewer injections and side effects. It is a bit more fiddly to run, however, and (in my opinion) greater attention to detail is required by the clinical team.
The challenge with using a birth control pill, for some women, is that even a low dose pill (Alesse, Yasmin) for a short period (2 weeks) is too suppressive. Natural start is one solution, but if the woman’s natural estrogen levels are not very high in the luteal phase, her FSH levels will drift up and…the ovaries will start to stimulate too early and egg growth scattering results. In these select cases, we can use estrogen-priming, in which an estrogen patch (0.1 q2d) or Estrace tablets (8mg daily) are used starting about day 21 in the cycle before stimulation. Estrogen priming is very successful in bringing down FSH levels, of real benefit to women of borderline ovarian reserve, and we have seen successful stimulations where none were possible before. The catch (there is always a catch) is that estrogen primed cycles take a long time before we can see if they are going to work…..when we have to cancel them, it is usually quite late into a stimulation.
Estrogen priming is usually matched with an antagonist to prevent ovulation. But there is one more protocol to consider: a flare cycle. A flare cycle may involve OCP or estrogen-only pretreatment, but the key is that a GnRH agonist (Lupron, Suprefact, or Synarel) will be started at exactly the same time as the stimulating medication. The result is invariably rapid egg development. A flare protocol is the most “raw” of the protocols, sometime yielding difficult-to-interpret results. But we do use it in select circumstances.
Tying it all together
There is no universal “best” protocol. However, there may be a best one for you. It is appropriate to discuss protocols and medication dosing with your doctor before your cycle starts, so that you feel comfortable that the path chosen should maximize your chances for a good cycle.
Low-dose stimulations are coming in vogue at present, and I can write to that topic if enough people are interested. But, in the main, we get the best ongoing pregnancy rates when we aim for a healthy number of mature eggs. For most cycles, that means 7-12 mature eggs at retrieval. I hope you find your cycle sets you up for success. Please let us know; happy stories are always a pleasure to read.
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Shirley
Dear Dr. Hannam,
I am currently under an IVF treatment (I am 41 years old) and using an E2 patch protocol. Could you please tell me which day (day2 or day 3) of my menstrual cycle I should start shots of FSH? Is there any difference? I have two failed cycles using same protocol. Both cycles I had 14 eggs and all matured. 12 fertilized but no good development after that. After two failed cycles, would you change protocol for your patient? Does protocol make some difference? Thanks!
Sincerely,
Shirley from Toronto
TGH replies,
Day 2 or Day 3 won’t make a difference; it actually takes most women a few days for their ovaries to recover from the estrogen suppression so…even day 4 would probably work. The key is for the estrogen patch to be in place for long enough before your menses arrive…ideally about 7 days.
To know if a new protocol would be more likely to work, I would have to see the previous stimulation sheets and subsequent embryo reports. But twelve fertilized eggs is a good number.
Each of the five elements to an IVF cycle (pre-treatment investigations; protocol; how the cycle is actually run; IVF lab; embryo transfer) matter.
Good luck Shirley, I hope you find success.
Shirley
Thank you very much for your reply, Dr. Hannam. Shirley.
Cathy
Hi Dr. Hannam,
I just stumbled on your blog today and - wow! So much interesting information that I haven’t heard presented in the manner you present it in; very, very helpful. Thank you!
I am preparing to undergo my first IVF cycle in August. In reading this post on the best protocol (and after doing some additional reading elsewhere), I would like your input on what protocol you might recommend. Initially, I was thinking the long lupron would be best because of my high LH & resting antral follicle count, however, based on your information regarding too much suppression, I’m not entirely sure. I have a low BMI and just one ovary, so now I’m concerned maybe that wouldn’t be the way to go. With the PCOS, I’m not sure I’d want to use an antagonist though.
Any thoughts you have would be greatly appreciated. I’ve outlined the info I thought you’d need below. Please let me know if you desire anything additional.
Thank you very much for your time!
Cathy
- - - - -
AGE: 27
* One Ovary (& One tube)
* PCOS
* Pelvic Scarring from surgery when I was 13 (ovary is adhered to uterus)
* History of very long, irregular cycles. Often no ovulation, but when I do ovulate, it is always much later in a long cycle.
* Have done 2 cycles of clomid. First, 50mg ovulated on CD25. Second, 100mg didn’t ovulate at all and had bad reaction (vision issues). Then I went to see an RE. I’ve never done injectables at all; the recommendation was to go straight to IVF due to the pelvic scarring.
BMI: 18
FSH: 5.5 (day 3)
LH: 27.3 (day 3)
Resting antral follicle count: 15+ on the one ovary
TGH replies:
Hi Cathy
I think that with the high resting LH level, most REs would recommend trying the long protocol first.
As you know, you will be at risk for over-suppression.
There are risks and tradeoffs with every approach. Your worst-case scenario –cancellation– would be annoying and expensive and you’d have to start again. But the next-best alternative, OCP-controlled antagonist, could be tricky in its own way. The long protocol is likely the best place to start.
Good luck. From what you have written, you should have very good prognosis.
Cathy
Thank you for such a quick, thorough response! So glad to hear that your initial outlook for our situation is a positive one. Have a wonderful day!
Cathy
Jacqui
I wanted to take the opportunity to thank you so much for this very helpful post. I have been looking high and low for a readable and understandable explanation of EPP and am so glad to have found it.
I recently turned 40 and am about to start IVF#2; this time with EPP and antagonist. Although my FSH was “fine” at 5, and my AFC was “okay” at 13, during my first IVF in February 2009 on the flare protocol with a natural start I had scattered egg growth which created real problems with the timing of my trigger. I ended up with 11 eggs, but only 7 mature (and some of those over-mature), and only 3 fertilized with ICSI. Although I did get a BFP from one of those three embryos, I m/c at 7.5 weeks and later learned that the embryo was non-viable due to trisomy 13. We are hoping that we will have better luck this time.
This site is extremely helpful and I greatly appreciate your efforts to post useful information in a readable format. I will visit often.
Thanks again.
Mama
Hi Dr. Hannam,
does this protocol make sense?
-birth control pill started on day 3 for 2 weeks(last one on day 16)
-Suprefact.2 cc started on day 14, undefinetelly (3 days overlaping of BCP and Suprefact)
- Puregon 200 u.i started on day 22, for 5 days
Not to have an ultrasound/blood appt until day 27, with the Puregon and Suprefact overlaping for at least 5 days.
Was instructed to take suprefact until advised by clinic staff to stop it, but there is no other encounter with clinic staff until day 27.Is it ok to take Puregon 200 u.i. for 5 days with no monitoring?
Is it ok to take Suprefact for that long, and have it overlapped with Puregon?
Thank you.
TGH replies
Yes, that is a fairly standard “long” protocol. The suprefact will continue as long as you take the Puregon; it will prevent you from ovulating.
Deanne
Dr. Hannam,
I completed my first IVF cycle a couple of months ago and it was unsuccessful(Agonist protocol, ICSI). Nine eggs were retrieved, 8 mature, but only 1 fertilized (4 cell, grade 3.5). At my follow-up appointment, the RE said there was an issue with “egg elasticity” and that trying another protocol(antagonist) might help, but it might be that my eggs are always poor quality. I can’t find any information on elasticity and whether trying the antagonist protocol could work.
Any information you can provide would be appreciated.
thanks.
(Age: 36)
Dear Deanne,
‘Egg elasticity’ is not a medical term, it is a descriptor that your doctor used in conversation with you. So it will be difficult to google this topic…
One embryo from eight mature eggs is concerning. I agree: trying a second time makes sense, and with a different protocol. As you follow the cycle with your clinical team, know that estrogen should generally be rising, and end up at the point where the level is about 1000 per mature egg. In this fashion, you’ll know you maximized your opportunity for success.
I have seen cycles not go well the first time, but much better on a second. I hope that will be the case for you.
Tom Hannam
Naomi
I am horribly confused at the moment.
I was about to start a treatment cycle at one clinic (clinic A). On the day I should have started injections they discovered a cyst and said I need to go back on birth control and come back in 3 weeks. In that time I went back to my original doctor (clinic B).
Now I have had two conflicting protocols recommended by two different Doctors. Both Dr’s were adamant that their protocol was in my best interest and that the other protocol is not the best for my situation.
Some background: Clinic B - 1st cycle Oct 08 – Synaral and Gonal f at 225- 12 mature eggs, only 2 embryos left by day 3, both transferred – resulted in blighted ovum. AMH was 9.99.
I have a regular 28 – 30 day cycle.
Current levels:
AMH 6.89
E2 120
FSH 10.5
Progesterone 3.5
Age 30
Clinic A suggested that I now do Clomid, Gonal-f, and Cetrotide. They suggested that the nasal spray will suppress my ovaries too much and will result in less eggs.
Clinic B said Clomid should not be used as I have an ovarian cyst and have a history of lutual cysts. They suggest the nasal spray and Menopur at 375.
I don’t understand how two doctors in the same field can be adamant that their suggestion is correct and that the other protocol is wrong. Please can you shed some light on which protocol is best for me. I am in tears every day about this and next week I need to start on the nasal spray or start the antagonist protocol. If I ask to see the Doctors again they will only tell me again that their decision is the correct one. Please help me.
TGH replies
Dear Naomi,
I would need to see you in person and look at all the records in detail to be able to truly help you.
But I understand your dilemma. The two clinics disagree. Now what?
This is why your doctors are disagreeing:
1. Your AMH levels are low, even though you are young and have regular cycles. This would suggest that you have a low ovarian reserve. The bordeline FSH level at 10.5 is consistent with the diagnosis.
2. A low ovarian reserve often is associated with limited egg quality….consistent with the results of your first IVF attempt (a reasonable number of eggs to start with, but very few embryos and an early pregnancy loss.)
The doctors disagree because we really don’t know what the best way is to help when ovarian reserve/egg quality is a concern. The two most common protocols suggested under such circumstances are the antagonist protocol (as Clinic A said) and a flare protocol (as Clinic B may be suggesting).
My advice: go with whichever clinic is treating you better and seems more organized. I know that sounds like a strange, non-medical thing to say, but here is the truth about running a fertility programme: good “customer service” is extremely difficult to deliver…it doesn’t happen accidentally, only when great attention to paid to every detail.
You should be at the clinic that pays attention to every detail: it means they are more likely to be paying attention to the other important details too, like when to modify your protocol, or what is happening in the lab, or what the latest research says.
Naomi, I cannot tell you if A or B is giving the best protocol. I’m sure if you saw me I’d suggest something slightly different again. At this point, I think the key is to follow your instinct, as to who seems to be looking out for you the most.
Hope that helps,
Tom Hannam
Liz
Dear Dr. Hannam,
I wanted to see if you could point my in the right direction…..Recently we decided to move on to IVF. My doctor put me on a lupron protocol. I took bcp and then begin lupron about a week before I started my gonal f. At my first ultrasound I had 13 noted follicles. After six days of taking gonal F, my doctor called me to cancel, as no follicles were over the size of 10mm and he noted that my estrogen levels did not increase. He said my ovaries were not responding and even questioned whether or not I was taking the medicine, as I was not reacting to triple the gonal f I was taking in my iuis. He said my ovaries were acting as I was much older; I am 31 years of age. He mentioned I was a poor responder and that we would try a different protocal (flare protocol) and I would have to come see him to discuss it. Upon doing a little research, it sounds as though maybe the antagonist protocol might be better for me. Would you have any advice for me or sites for me to further research before going in to discuss this? Any information is greatly appreciated.
Regards,
Liz
Liz, when you review the stimulation sheet, look to see if your estrogen levels started -and stayed-well below 200 for an extended period. Sometimes (especially for young women, or women with BMI <<22) the Lupron will over-suppress…and it doesn’t matter how high the Gonal F dose is, a stimulation won’t work.
We often see Lupron over-suppression in women who go on to have excellent cycles (and ongoing pregnancies) when the protocol is changed. My preference is to consider antagonist cycles in such circumstances, but many doctors will suggest flare protocols. This may have only been a response to the medication, and not a reflection of your ovarian potential at all. Your age alone would suggest this is the most likely explanation.
Best,
Tom Hannam
Shannon
Hi Dr Hannam,
I am 37 years old. My husband and I have been trying to conceive for 4 years - 2 of those with the help of a fertility clinic.
I have high fsh (average around 20-24) and we were told stimulated iui cycles would be the best route for us. My protocol has been ocp for 21 days, wait for menstruation, on day 3 start 150 of puregon and add orgalutran when the follicles reach 10mm. I stimulate fairly well with 4 - 5 follicles each time but on occasion I have ovulated through the orgalutran. We did achieve a pregnancy last year even with an fsh level of 21 on that cycle but sadly it was short-lived and I miscarried early.
This past cycle we tried something different. I took 8mg of estrace for 30 days then on day day 31 I took my baseline bloodwork and ultrasound and started my stims. My fsh level was incredible - 5.8 - but I didn’t produce any follicles and my estrogen never rose above 50. My cycle was canceled.
At my most recent appointment with my RE she talked to me about donor eggs and said that it is not worth it to continue on stimulated iui cycles.
Considering my good response to stimulation and my previous pregnancy do you think there is hope with my own eggs using the estrogen priming protocol you describe above or is it truly time to consider donor eggs?
Thank you in advance for your help.
Shannon
TGH responds:
Dear Shannon:
Such high levels of FSH suggest a primary ovarian insufficiency.
POI does not necessarily mean that egg quality is affected, but egg quantity is low. When the quantity is low, it means that response to stimulating drugs is limited. You have been on some nonstandard protocols, clearly in an effort to generate multiple numbers of eggs. However, when fewer than five mature eggs are present, it is true that IUI will often have similar outcomes to IVF, and when fewer than three lead follicles are present, it may even be more reasonable to step back and look at intercourse alone. This is because pregnancy rates start to fall to levels lower than 5 percent, even lower than 2 percent and going through multiple cycles through fertility clinics with such low odds becomes unsustainable.
I understand such numbers are harsh, but they are not zero percent. Just this week I was able to discharge a patient from my practice pregnant and happy. Her highest FSH level had been 28. So, yes, there can always be hope, but that hope should be balanced with the reality that donor egg cycles will provide much higher success rates, for many clinics in the 50 to 60 percent range, and in some clinics, even higher.
The choice then becomes highly personal for you, as you weigh the relative odds of success against personal desires for a biological child. Your final answer will of course be highly personal, and I would strongly recommend counselling as you consider your options.
Maxine
Dear Dr. Hannam,
I just finished my first ivf cycle. I had the long protocol, with two vials of Bravelle and two vials of Menopur nightly. Within a few days my e2 started to skyrocket. My RE gradually and dramatically lowered my stimulation dose, but by the time of hcg trigger I had over 25 follicles of different sizes and e2 was close to 6000. They were able to retrieve 28 eggs, 23 were mature, but only 11 fertilized with ICSI. They ended up freezing 5 embryos and foregoing a fresh transfer because I started to have some OHSS symptoms before the transfer was scheduled.
My question is–does the high response to the stimulation adversely affect egg and embryo quality? And also, for the future, what protocol do you usually use or recommend for a person who has this kind response to the gonadotropins?
Thanks so much.
TGH responds:
1. Dear Maxine:
The first IVF cycle we run, we are estimating the best protocol and estimating the best gonadotropin dose. This means that some patients will understimulate and others will overstimulate (as happened to you), and it also explains why second attempts at IVF are often more successful than the first—because we can start to personalize the protocols to the individual patient.
Ideally, estrogen will be approximately 1000 pmol/liter per mature follicle at the time of the ovulation trigger. An estrogen level of 6000 might therefore suggest six mature follicles, or the presence of many more immature ones.
With 28 eggs retrieved, it is clear that there are big discrepancies, as can so often happen when in the midst of a hyperstimulated cycle. Had your doctor decided to delay ovulation, estrogen could well have been expected to rise higher, well over 20,000. Given that, in retrospect, the starting doses were too high. The decision to retrieve early was the right call.
You ended up with about the right number of embryos – 5 – that the estrogen level had predicted.
I am sorry that you are unable to go through the fresh transfer. But, I would strongly recommend a frozen embryo transfer as the next step, for it may well be successful. Yes, there are concerns that high dose gonadotropins yielding great numbers of eggs can effectively reduce the quality per egg, as if there is a natural “maximum” number of eggs above which we start to see lower pregnancy rates. The ideal number of eggs to retrieve is based on many factors, but most clinics aim for between 8 to 15.
I would have to see a detailed analysis of your last cycle to provide good advice as to how a new protocol might be best run. I hope that the frozen embryo transfer cycle will work, but if not, simply lowering the doses of stimulating drugs should be the basis of a remarkably better cycle and quite possibly a higher chance for success.