Poor Responder Needs To Know IVF Is Not All About Numbers: It 's About One Good Embryo

Question:

Hi Dr. Ramirez,

My name is A. and I am writing from Michigan. I am 33 years old and have DOR with an AMH of <.16, Hashimoto’s and positive ANA’s. I am on day 10 of stims for IVF #2 and responding poorly compared to our first attempt. I am hoping you could answer a few questions regarding the cause of the diminished response (compared to the first) and also give your opinion regarding canceling the cycle.

IVF #1 (March 2013):

BCP suppression 5 weeks

225 iu Bravelle, 150 iu Menopur, Ganirelix days 8-10. Stimmed for 10 days.

Day 5 of stims: 6 follies: 9-10 mm, E2 301

Day 10 of stims: 7 follies: 19-21 mm, E2 724

Retrieved 8 eggs, 6 mature, 4 fertilized with ICSI, 2 transferred (grade B’s, no frag), none to freeze.

IVF #2 (in progress):

BCP suppression 4 weeks

225 iu Bravelle, 225 iu Menopur, Ganirelix added day 8 of stims.

Day 7 of stims: 6 follies: 12, 12, 9, 9, 9, 9 mm, E2 243

Day 10 of stims: 4 follies: 15, 14, 11, 10 mm, E2 495

There are five factors that have changed since the first cycle. 1) Menopur was increased by 75 iu. 2) Ganirelix was introduced when follies were smaller at just 12 mm. 3) Slightly less time on BCP suppression; less one week 4) Added Methylprednisolone 16 mg. 5) Discontinued DHEA 50 mg and Myo-Inositol 2 g.

What could be causing the poorer response, loss of follicles and slow growth? Is there anything that can be done to speed up growth and/or catch up the 10 and 11? Does the slow growth speak to poor egg quality?

I am okay with going to retrieval with so few follicles as I realize I have DOR and cannot expect a normal response. However, with having had a better response previously, would you recommend canceling at this point? Why?

This is such a stressful time for us, so I greatly appreciate your attention and feedback.

A. from Michigan

Answer:

Hello A. from the U.S. (Michigan),

First, you should know that ovaries can and will respond differently with each cycle regardless of the protocol used.  That is to say that even poor responders will respond better or worst from one cycle to the next.

In your case, I can make several observations which may be helpful to you:

1.  Despite a low AMH, you have responded pretty well with each cycle.  You had 14 follicles and 10 in the second.  This is not a sign of a poor responder.  Poor responders tend to have less than 10 total follicles.  In addition, your stimulation was not that high, so I would say you are a pretty average (normal) responder.

2.  As mentioned, your stimulation protocol was in the mid-range (375 IU and 450 IU).  The max protocol that most clinics use is up to 600 IU (450 FSH + 150 FSH/LH (menopur).  So in terms of stimulation, you have lots of room to improve.

3.  You mentioned starting Ganerelix when the follicles were 12 mms.  That is way too soon in my opinion.  Based on European studies and over 10 years of use by myself, I do not start Ganerelix until the lead follicles are at least 16 mms and preferably when the 30% or more are between 16-18 mms.  The purpose of Ganerelix is to prevent premature ovulation so I hold it until the very latest that I can to allow the follicles to develop without suppression.  Starting too early will lead the smaller follicles to stop growing.

None of this implies low egg quality or poor outcome.  It is part of the "art" of assisted reproduction and what distinguishes one doctor or clinic from another.  Bottom line is that IVF is not all about numbers.  It is about getting at last one good embryo to attach and lead to a pregnancy.  For that reason, even if there are fewer follicles I recommend that you keep going just in case the perfect embryo is in this group.

Good Luck,

Edward J. Ramirez, M.D., F.A.C.O.G.
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
www.montereybayivf.com

Monterey, California, U.S.A.

 

"What FET Protocol Do You Use For Difficult PCOS Patients?" UK Patient Asks

Dear Dr Ramirez,

Firstly, thank you so much in advance for taking the time to read my question.

Brief History: Dx with PCOS at 17 y/o. HSG clear. My husband has severe m/f, so our only chance of conceiving is through IVF with ICSI. On my fresh cycle in 2008, I had 30 eggs retrieved and due to OHSS, couldn't have an Embryo Transfer. We had 13 embryos, all of which were frozen at the 2PN stage. I have gone through six FET cycles since, but only got to transfer three times, b/c the drugs used to suppress my ovaries (ProstapSR, Buserelin, Synarel) have actually stimulated my ovaries, leading to OHSS a further three times!

My treatment is in the UK and I cannot switch clinics b/c a) my treatment is free and b) since it's free I can't choose where to have my IVF/FET's. The Drs at my clinic have put their heads together to try to come up with an individualized protocol for me, since I keep suffering these rare responses to the suppression meds. I am naturally frightened and sceptical about this new protocol since it hasn't been tried and tested in the UK as yet (but apparently it has in other countries with good success for challenging PCOS patients).

The new protocol would not involve the usual suppression medications. On day 3 of my period, I would inject a long acting Cetrotide shot (sub-q) and also commence 6mg Progynova (estradiol valerate). On Day 5, I would commence daily Cetrotide shots, whilst continuing daily with the Progynova. All in all, this protocol should only take around 13days, then I would commence Progesterone, 3-4days before Embryo Transfer. I am terrified of hyperstimulating again. Is this likely to happen with the Cetrotide at all? Have you had any PCOS patients who have ever responded like I have to suppression medications?

If you were my Dr (I wish you were :D ), what protocol would you suggest for a FET? It may be helpful to add that I have always been a slim PCOSer (BMI 21) and have an AMH of 98.5. I also got pg on our first FET with twins, which I sadly miscarried at 8 weeks. My subsequent two transfers resulted in a negative beta. Thank you so much for reading and for any input you may be able to give! G. from the U.K.

Answer:

Hello G. from the U.K.,

I have never heard of such as thing as OHSS with an FET cycle. I'll have to do some research on that and see if that actually happens. If not, your docs might want to write your case up as an unusual case. Since you have been using GnRH "agonists (stimulators)" in your previous cycles, it sounds like maybe the dosages were not high enough to suppress the hypothalamus (which is what they are supposed to do and prevent ovarian function), but instead stimulated FSH production and ovarian stimulation leading to the OHSS.

I think the change to an "antagonist" is certainly the best way to go. I converted to using the antagonist, Cetrotide and now Ganerelix, over 5 years ago (mainly because it is less injections). I have not used it with an FET cycle (because it is more expensive), but it can work just as well with the protocol you have outlined. The antagonist will definitely suppress any ovarian function, so you should not be able to mount an OHSS response. This is definitely a good plan.

I thank you for the compliment :) and wish that you could be my patient as well. For many reasons, such as the fact that some like you can get IVF for free where they live, patients feel that they are stuck in the clinic near their home. This cannot be further from the truth. I have a patient from Serbia and South Korea in my IVF cycle this month. I have patients come from out-of-state, one from as far as Montana, which is like the difference between the UK and Poland. You can travel to the best center to do your IVF, thereby saving you years of frustration & grief. I had one patient who failed five times at a Los Angeles center only to succeed the first time with us. It is not that difficult to do or arrange IVF afar. There are additional costs involved, which is the biggest factor, but heck, you could plan a vacation at the same time. The IF community calls this "Reproductive Tourism" or "Cross-Border IVF", I believe.

An IVF cycle can be done so that you only have to come here for the minimum necessary time, which for an FET cycle would be 1 week or less or 10 days for a fresh cycle. Also, remember the old adage, "you get what you pay for." Free cycles are all well and good, but as you mentioned above, you are stuck with one center, one protocol, one embryology lab (and there quality can differ greatly), governmental restrictions and that is unfortunate. In the U.S., particularly in California, we have few restrictions and can do embryo donation, donor egg, donor sperm, frozen eggs, surrogacy, and are given leeway on the number of embryos we can implant. I wish that I could just outfit a 747 jet with an IVF clinic and jet all over the world where patients want to see me. I think that would be fun as well :D !!!

Good Luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

www.montereybayivf.com

Monterey, California, U.S.A.

Possible PCO Patient Adjusting IVF Antagonist Protocol For Fear Of OHSS: Decrease Gonal-F Dosage?

Question:

I am about to start my first IVF protocol (today is CD2). I am concerned about the recombinant FSH dosage prescribed and would like your opinion regarding appropriate dosage. I believe I am at higher risk for OHSS for several reasons (described below), however my recent ultrasounds are not showing definitive signs of PCO. Here is the protocol prescribed by my doc:

No pre-cycle BCPs (they make me very ill)
CD2: gonal-f 225
CD3: gonal-f 225
CD4: gonal-f 150
CD5: gonal-f 150
ultrasound on day 6
addition dosing determined following this ultrasound
Gonarilex to prevent premature ovulation

I called the doctor today because I was nervous about taking the first two days of 225IU gonal because of the risk of OHSS. After very little discussion, he switched me to 150IU for 4 days.

The difference between 225 and 150 is a big change. I wonder if I will get good results with a dosage that is this low. What is your opinion? I feel like there might be some sort of middle ground that is more appropriate? I would appreciate any thoughts. I would like to get the "best" results without complications of OHSS.

I believe I am at higher risk for OHSS than the normal woman for many reasons:

1) my ultrasound yesterday (on CD1) shows 9 follicles on right and 16 on left

2) I responded well to low doses of gonadotropins (6 IUI cycles some with letrozol/femera at 5mg/day?, others with clomid at 25mg/day all cycles gave 3-5 mature follicles on CD12),

3)I am petite (5'2", 100 lb.s)

4) in 2006 a doctor told me I had PCOS based on ultrasound results, a history of severe PMS, and moderate acne(two additional doctors I consulted with gave no diagnosis - I am not hairy or pear-shaped)

5) cancelled IUI due to elevated estrogen associated with a small complex cyst on cd2 (and another very uncomfotable IUI cycle when a different OBGYN proceeded with an IUI when I had a cyst at the start of my cycle).

6) grandma had type 2 diabetes

7)early male baldness runs in my family.

Answer:

Hello J. from the U.S.,

First of all, I have to caution you about trying to second guess your doctor. Sometimes that may not be good. I would presume that your doctor had a logical reason for selecting your protocol.

You were originally scheduled to be on a 3 down protocol (75IU x 3 for two days then decrease). That is a standard protocol and is on the low side. Because of your concern, your doc decreased you to 150IU and will make adjustments based on the response. The only down side to the lower protocol is that you may not recruit as many follicles as the higher dose, but there is no way to know this when it is the very first cycle. In most cases we determine the protocol based on an educated guess. The adjustment at CD#6 is still early enough to increase the dosage and recruit more follicles if necessary, and if you are indeed a PCO, then you will already have an increased number of follicles and the decreased dosage will be safer for you.

I am glad to see that your doc is using the "antagonist" protocol with ganerelix. I am a firm believer in this medication and its ability to decrease the risks of OHSS. With the antagonist, instead of using HCG to trigger ovulation, Lupron can be used to trigger and because of its shorter half-life, the risk of OHSS is dramatically reduced. This is the protocol I use with my PCOD patients to reduce their risk, in addition to careful monitoring, lowered FSH dosage, Drifting (if necessary) and Coasting (if necessary). My goal is to keep the Estradiol level less than 4000 at the time of trigger. With this protocol, I have had no incidence of OHSS in my center for the past 5 years. Most the reasons that you gave for being PCOD are not valid criteria, but my concern would be the same as yours based on the high number of antral follicles seen on ultrasound. I treat patients as a PCO patient if they have PCO-appearing ovaries even if they don't meet the strict criteria for PCO. And, I find that they do stimulate like a PCO ie have a high number of follicles (>25).

In your case, I think that being safe is better than being sorry and the lower dose is probably the way to go. I call your new protocol a 2up protocol and it is a standard protocol that I use with my PCO patients. I check estradiols at CD#5, however, and adjust from there.

Good Luck,

Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
www.montereybayivf.com

Monterey, California, U.S.A.

Follow Up Question From 30 Yr Old Austrian Who Failed 5 IVF Cycles & Is Trying Once Again

This is a follow-up question from a young woman with possible PCOS in Austria, who first wrote me in March. Please view the first two questions she posed in order to fully understand the problems she and her husband face. See the March 18th blog post: http://bit.ly/cqXqAp

QUESTION:

Dear Dr. Ramirez,

I had asked you a couple of questions two months ago, and thought of you now as we are preparing to do another IVF. I copy below what you suggested in terms of protocol for me (PCO-like stimulator), since I discussed it with my doctor and he is not sure that this kind of protocol can be done with the medicines available in Austria. You said:"Patients start at a low dose of Follistim 150IU for three days then the estradiol level is checked for response. If there is not a high response then I step up the dosage to Follistim 150IU + Menopur 75. We continue the same pattern of checking and adjusting the dosage as needed. I don't use Lupron agonist suppression (long protocol), but instead use the Antagonist Ganerelix. When the follicles are appropriate sized, I trigger with Lupron 0.5 mg instead of Ovidrel. These combination and protocol has been shown to be effective in preventing hyperstimulation syndrome"

The protocol he gave me last time (Dec. 2009) (starting on day 3 of cycle) was:Day 3-5 Gonal-f (150IU)Day 6 Gonal-f (112 IU)Day 7 Gonal-f (112 IU) + Cetrotide (one shot 0,25 mg)Day 8 Cetrotide (0,25mg) + Pergoveris shotDay 9 Cetrotide (0,25 mg) + Pergoveris shotDay 10 Cetrotide (0,25 mg) + Pergoveris shotDay 11 Cetrotide (0,25 mg) + Pergoveris shot Triggering with OvitrelleEven though this protocol was substantially reduced in quantity of medication, I still had 15 eggs and mild-hyperstimulation (enough for being 3-4 days uncomfortable to breathe and in pain and swollen all around).

The doctor is now proposing a similar protocol to this, but reducing from 150 IU to 112 IU to start and see what happens. I showed him your suggestion and he was receptive but I don't know if the medicines you suggested can't be found here or if what he is suggesting is similar to what you suggested. We are thinking of not having a treatment here anymore and moving onto a treatment in the States. In an ultrasound on day 19 of my cycle, he saw that I had ovulated recently and noted that I have/had around 15 follicles (or left overs of follicles) in my two ovaries. I was really shocked since I have been medication free for 6 months, so I didn't expect that's normal to have so many follicles on a natural cycle, he said that could mean I have a high ovarian reserve and could be a sign of why I hyperstimulate every time no matter what medicine they have given me.

My questions:

Is the protocol he proposes similar to what you wrote above?

What do you think about this empty follicles in my ovaries now?

Also, he has me taking Thyrex for my thyroid (one pill of 50 mg per day) since I started treatment with him over 10 months ago because my TSH level was over 4, and he wants to keep it at around 1, but am I supposed to take this pill forever? for Hypothyroidism? That's what he said, that until I achieve a pregnancy and give birth, I should be taking that pill.

Another question: What do you think about that? My TSH has been at around 1 since i started taking the pill. Regarding my husband's sperm (CF gene), they have been using his frozen samples for all treatments, saying that the freezing and thawing act as natural selection, whatever survives is better for ICSI than trying with fresh sperm. Do you think is better to use fresh sperm for ICSI? or frozen?

Finally, we are thinking of going to a US clinic because in Austria PGD is prohibited, and for us they have been doing polar biopsy of my eggs to only transfer the embryos which fertilized with the better eggs, but as you noted in your previous emails, the embryos should be checked as well to eliminate any effect by my husband's sperm...correct?

So thank you so much for your answers, we are about to cancel the cycle here which starts in one week and move on to make an appointment in the States with you or another clinic which can take us.

Receive my warm regards, L. from Austria

Answer:

Hello Again,

I am happy, yet surprised to hear that your doctor was receptive to my suggestions. I do not dispense recommendations with the expectation that patients will share it with their Physicians. It is mainly for patient knowledge. I do not mean to intrude on that doctor-patient relationship, nor your doctor's judgement, since they usually know you better, and many doctors will be offended.

The medications Gonal-f and Follistim are the same, but made by different companies. Cetrotide is the same as Ganerelix. Gonal-f and Cetrotide are made by Serono, whereas, Follistim and Ganerelix are made by Organon. They are interchangeable. Based on the protocol you showed me, you were already on a pretty low dose protocol. Since, despite this, you hyperstimulated, I would reduce the dose further to a starting dose of 75IU or 37IU Gonal-f. I would probably fight the inclination to increase the dose above this because you seem pretty sensitive and 75IU may be all that you need to get an adequate number of mature eggs.

The Pergoveris is the same as Menopur (FSH/LH). If it is added, as your doctor did previously, he might want to reduce the dose to 37.5 IU (half-dose), but it isn't absolutely necessary. Some studies have shown decreased hyperstimulation in PCO patients when the FSH/LH is left off because PCO patients tend to have an elevation in LH production.

Once your lead follicles reach 15 mms (at least 20% of the follicles), Cetrotide should be started at 0.25 mg per day and continued until the trigger shot. The Gonal-f may need to be increased because of this ovarian suppression, and you should expect a decrease/drop in the estradiol level initially because some of the smaller follicles will stop developing due to the suppression and stop producing estradiol. That is okay and the cycle should be continued (this is contradictory to current thought, where if the estradiol drops the cycle is usually cancelled).

The trigger should NOT be HCG or Ovidrel. Instead, Lupron 0.5mg (50 mcg) should be used subcutaneously as the trigger. This has been shown, in European studies, to be just as effective as HCG but because of a shorter 1/2 life (the amount of time the drug is in your system), there is a decreased incidence of hyperstimulation.

In addition, to the above, I will also sometimes use "drifting/coasting" if it looks like the estradiol level will go above 4000 before the lead follicles are at a mature size. This requires that the doctor predict the levels on a daily basis and the drift/coast is not started until the lead follicles are at least 16 mms. You doctor should understand what this technique is. But, just in case he is not familiar with it, it is where the stimulationn with Gonal-f and/or FSH/LH is stopped but the ultrasound surveillance continues until the lead follicles reach 18-24 mms, then the trigger is given.

Finally, your doctor is correct that the TSH (thyroid hormone) levels have to be in the normal range, otherwise this can have an adverse effect on your pregnancy chances. As I said previously, PGD is the only way to rule out your husband's CF gene from the embryo, as egg polar body biopsy only evaluates the egg (your genes), and frozen sperm is just as good as fresh sperm. I am flattered that you would consider us for a second opinion, thank you. If you do decide to come to the U.S. I would certainly enjoy meeting you and your husband and be assured that our center would do anything that it can to accommodate you and help you succeed.

In closing, tell you doctor that I have had patients where I even start the Gonal-f/Follistim at 37.5IU and step up to 75 or 150IU, so he might want to consider that in you since you are so sensitive.

The very best of luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

http://www.montereybayivf.com/

Monterey, California, U.S.A.

38 Year Old TTC'r With Factor V Lieden, MTHFR, High BMI, High FSH & Good Embryos Has Done 3 IVF Cycles: I'd Throw In The Kitchen Sink!

Question:

I am a 38 yo female in the Northeast US. I started menstruating when I was 10 yo and due to irregular (too frequent) and heavy periods, went on BCP's at age 15 thru 35 - after stopping BCP's, my periods are very regular. We started TTC 3 years ago, and after no success, initial tests showed my H had good sperm count but low motility. We started w/ an RE in Jan 09. For me, my problem areas are age, high BMI, hypothyroid (well controlled) and + for MTHFR (Methylenetetrahydrofolate reductase) & Factor 5 Leiden. No PCOS, no endometriosis, tubes are open, endometrial lining develops well, FSH 9.

We were advised to go right to IVF to increase our chances of conception. IVF#1 5/09 Lupron/Gonal F protocol - 13 retrieved, 7 fertilized, 3 day transfer of 3 embryos - all Grade 2 (8, 7, 6 cells), resulted in pregnancy that ended in m/c at 8 weeks due to triploidy. IVF#2 8/09 Lupron Flare protocol - 13 retrieved, 2 fertilized, 3 day transfer of 2 embryos - Grade 2 (6 & 5 cell) BFN. Dec 09 - had a d&c and a month of antibiotics & estrace to prepare for IVF. IVF #3 1/10 w/ acupuncture, Lupron/Gonal F/Menopur - 13 retrieved, 5 fertilized, 3 day transfer of 3 embryos - all Grade 1 (8 cells) another BFN. All IVF's had ISCI and last 2 w/Assisted Hatching and no embryos made it to freeze. My E2 levels were consistent for all 3 - always between 1900-2300. My meds are always prenatal vits, folgard, baby asa, and levoxyl (thyroid). Lovenox only during pregnancy. My RE says that my age is the problem & that although I respond well and fertilize well, my eggs are of poor quality and arrest several days after transfer. I have no more covered IVF's, but do have 6 IUI's. His recommendation was to try 4 IUI's and if I do not get pregnant, to move onto other options, like DE (donor eggs).

My questions:

1. Do you agree with this diagnosis? Would it be worth trying another IVF with another RE? I have been very happy w/ my experience w/ this group.

2. I've read about Natural Killer cells & antibodies & immunology treatments - my RE says the studies do not support this type of treatment and this will not help. Do you agree?

3. I've had my first IUI on 3/31 and am awaiting a beta on 4/13. Do you think trying several IUI's is worth it or are the chances of success so low that I am wasting my time?

4. Is moving onto Donor Eggs my best next step?

Thank you so much for taking the time to read and reply. I really enjoy reading your answers on this site. A. from the U.S.A.

Answer:

Hello Alyssa from the U.S.,

1. In reviewing your history, out of three IVF cycles, you were successful with one (the first one), but in each, you stimulated well, had a good number of eggs retrieved and, except for the second cycle, had decent embryos. So that means that your ovaries are functioning well and stimulating well despite your high FSH level, and you seem to make good embryos. Of course, since embryos are rated only based on how they look, we cannot know if they are normal or not. Your first pregnancy was genetically abnormal and that is the "age factor" i.e. poor quality eggs leading to abnormal embryos. It is possible that the embryos in cycles #2 and 3 were genetically abnormal as well and that is the reason they did not implant. So, I agree that egg quality might be the issue, leading to imperfect embryos. That is the hurdle that you need to overcome and is totally based on your age. You may not necessarily need to change doctors, but it just may take more tries to become pregnant, since the majority of your eggs are not good quality and the goal is to get a good one.

However, pregnancy rates do vary by physician and protocols, and that could possibly make a difference. For instance, I do not use the Long (lupron) protocol or flare protocol. I use a combination (Ganerelix (antagonist) + Follistim + Menopur) protocol. That could possibly make a difference in your stimulation and the number of eggs retrieved, thereby increasing the chances of finding a good egg. Also, a lot of it is just luck of the draw, so to speak. Each cycle is unique and has the potential to yield a different outcome.

2. You have a +MTHFR and Factor V Leidin. That puts you at increased risk immunologically. For that reason, low dose aspirin, Medrol, and possibly Heparin or Lovenox, might make a difference and would be a good idea. I automatically place my failed patients on this protocol. My reasoning is that, despite the studies showing no value to this regimen, it is like stress reduction, acupuncture or any number of other adjuncts that have not been clinically proven in that, it doesn't hurt and it might help. The American Society of Reproductive Medicine does not advocate the use of immunological therapies, so your RE is correct. However, if you keep failing multiple times and that is something you want to try, then go for it. Basically I throw the kitchen sink in to try to overcome the failures. So, what's the harm?

3. If your IUI is positive, great. If negative, then you need to understand that you are doing them because you have the benefit and not because it is a better treatment. It is not. It certainly has a chance of working that is better than trying naturally, but that chance is not that good. At 38 yo, the chances are about 7-10% per cycle, which is much less than the 60+% with IVF per cycle. But, that doesn't mean it can't work. The goal would be to make sure that you are ovulating as least three eggs with each cycle. It should preferably be 5. Use injectables if you have to. It is the ovulation of multiple eggs that increases the pregnancy rate with IUI.

4. Donor eggs is certainly an option and an option that you will have until you are 50 years old. It certainly gives you the best chances of success because it eliminates the egg factor and reduces the risk of miscarriage. It's your ace in the pocket. Whether or not to proceed with it at this time is your personal decision. Because your ovaries stimulate well, there is still the opportunity for you to get pregnant with your own eggs. There should still be some good ones left inside. It will just be a matter of time. But, if you would rather not keep trying until you find that good egg, and increase your chances of success in the shortest time, then donor eggs would be the logical option. There was a report in the NY Times about a patient who is now the oldest patient to get pregnant successfully with her own eggs at age 49. She was very persistent and dedicated to being successful, and it took her two years of doing IVF.

I hope this helps, you have the potential to get that one good embryo & it may only be a matter of time and changing up the treatment protocol a bit. I find it heartening that you are willing to stay open to all possibilities, so I know you will succeed!

Good Luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

www.montereybayivf.comMonterey, California, U.S.A.

IVF Poor Responder With Endometriosis And Nightsweats

Question:

Hello, Dr.

I am from New Jersey , USA. and I have 2 questions for you.

I was diagnosed with stage 4 endometriosis in January of 2009. The surgeon removed all my endo in the operating room. Since the surgery I've been having nightsweats in the morning. From what I read from the internet, it can be due to the high estrogen level in my blood. I have 1.5cm cyst on my left ovary). Somehow the doctors I have seen so far don't know what is causing this.

1)What is the cause of my nightsweats?(I have it almost every morning)

My hormone levels were taken several times.

FSH=3.84 E2=92.3? in JULY 2009

FSH=10.4 E2=52 in October 2009

AMH=1.4 in November 2009

I tried IVF in October 2009 and failed.

I had only 1 immatrue oocyte at the retrieval even though on the ultrasound there were at least big 6-7 follicles. The doctor who retrieved the egg said the others could be chocolate cysts not real eggs. My RE used an antagonist protocol for IVF in October 2009. I had to take estradiol tablets for a week in the luteal phase just before the actual cycle.

Now I changed my RE, and she said she'll try something "flare protocol". This will take 2 months and I will have to start with estradiol patch for a week before the cycle. Isn't this almost similar to the antagonist protocol I tried before? How come the RE'S give me extra estrogen when they know that I have endometriosis? Wouldn't it make my cyst( 1.5cm cyst on my left ovary) grow bigger when they do this?

2)Will this micro flare protocol work for me? Thank you!

ANSWER:

Hello J. from the New Jersey,

First of all, "night sweats" can be from multiple causes such as decreased estrogen (menopause or ovarian dysfunction) or thyroid problems or cardiac problems.

In terms of your subsequent questions, there is some confusion. You had two FSH levels drawn, one was 3.84 and the other 10.4. Were these done on cycle day# 2 or 3 because that is when they need to done to interpret them correctly. From a fertility perspective, we want the FSH level to be less than 7 on cycle day #2 or 3. When it is higher, that signifies that the ovaries are "resistant" which means that they will not respond well to stimulation because they are not going to pick up the hormone adequately. As a woman ages, her ovaries become more and more resistant, but this can occur in younger ages as well. That may explain why you did not have very many follicles. Endometriosis does not and will not affect your response to stimulation. The problem with increasing estrogen is that endometriosis thrives and grows from estrogen, so that it can cause a recurrence of the endometriosis. Your first FSH level was actually very good and would indicate good ovarian response. In fact, you would probably not need too much medication (low protocol). Without having all the details of your IVF cycle, I cannot answer questions to it specifically, but your yield was very low. There could be multiple reasons for this.

I presume your new RE is going to try the "flare" protocol because you are a poor responder, low ovarian response. The flare is only another technique that is used to try to increase the egg yield, and is something different to try but has not shown any additional benefit is current studies. The antagonist protocol just means that an antagonist is used to suppress the ovaries instead of an agonist. The ovaries are suppressed so that they don't spontaneously ovulate or function on their own, so that the cycle can be better programmed, the ovaries can respond to stimulation better and don't short-circuit the stimulation. In addition, we don't want the ovaries to ovulate before we have the chance to retrieve the eggs. There is no difference between using an antagonist or agonist, in general, except there are less injections with the antagonist (3-4 vs 21). Antagonists are medications such as Ganerelix or Cetrotide and Agonist is Lupron.

I would advise that you not worry so much about your endometriosis. IVF is the treatment of choice and bypasses the endometriosis. If you become pregnant, pregnancy is a GREAT treatment for endometriosis so that is the goal. Quite often, Endo pain decreases dramatically after a successful pregnancy.

Your first cycle did not do very well because of the poor stimulation (which could be due to not enough medications) and low retrieval number. The fact that the egg was immature could be because the egg was not given enough time to mature ie. you were triggered too soon. So, I would advise that you keep trying. Your RE will adjust your protocol to give you the best chance of success. Studies show good cumulative pregnancy rates if a patient keeps trying, even in older women.

Good Luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

www.montereybayivf.com

Poor Embryo Quality: Donor Eggs Vs. Change Protocol Vs. Change Centers

Question:

I have undergone 3 IVF cycles without success in Canada. First IVF using long protocol, failed to stim and the cycle was cancelled. Subsequent 2 IVF cycles were done in flare protocol.

Of the flare cycles, first one was using Gonal F (450IU) and Luveris, we got 18 eggs, 13 mature, all 13 fertilized, but on day 3 only 2 had divided to 6-8 cells. All others arrested at 2-4 cells. Transferred 2 back with assisted hatching, but failed.

Second flare cycle was using Menopur (375IU), 13 eggs retreived, 8 mature, all 8 fertilized, but on day 3 only 2 were good enough to transfer, one that had started compacting, another at 8 cell, both were transferred back with assisted hatching, but failed again. All others divided will odd cells (3-5) and arrested on day 3. After the 3rd cycle, doctors suspect the egg quality to be very poor and advice us to use donor eggs. All blood/hormone tests are normal, left fallopian tube is blocked at fimbral end. I'm now 33, never been pregnant. My husband's results are normal.

Is this indeed due to poor egg quality? Is there any treatment available to improve egg quality? Is there any other IVF protocol that we can try that might give better results?Any advice based on your extensive experience is greatly appreciated.

Answer:

Dear S. from Canada,

Based on the information you gave me, you certainly did stimulate well in your second and third cycles. One option is to use a combination protocol with Gonal-f and menopur, and the antogonist (ganerelix or cetrotide), instead of lupron flare protocol. That may help with egg development and quality. There have been several studies showing the benefit of the combination protocol. The antagonist allows the ovary to stimulate and develop the eggs without being suppressed, as occurs with lupron. You'll have to ask your docs if they feel comfortable using an antagonist protocol.

There is no direct way to improve egg quality after fertilization. However, eggs/embryos are very sensitive to their environment i.e. laboratory quality. Any airborne gas or contaminant can effect them.

For example, in 2007 I had terrible pregnancy rates. In review, we found that in this year, the building where I had previously had my offices & center had gotten several new tenants and was doing a lot of remodeling. The air flow system in that building was not isolated and the air shared throughout all the offices. We had a very good Hepa filter in the lab but it could not isolate the air effectively with the huge change in parameters. Luckily, in early 2008 we moved our center to a new building where we are the only tenants. I was able to build my lab using the latest technology and air flow recommendations. My under 35 pregnancy rate went from 27% in 2007 immediately to 74%. The only difference was the air quality and control. Our lab is now in an isolated part of the building and does not share airflow with any other part of the office. Environmental controls and air flow have been studied and written about extensively in the IVF literature.

Certainly, if you are consistently having poor embryos, then the only alternative would be donor eggs. But before I would draw that conclusion, you might want to try a different center. Another experience I had was a patient who moved from Washington D.C. to California. She had gone through two IVF cycles there and, like you, had poor embryo quality and also was recommended to undergo donor IVF. But because her husband's job location changed, they moved here and she presented to me. Like you, she was young and I counseled that she should continue trying with her own eggs, at least two more times. Well, in her first cycle with me, she had three excellent quality embryos and became pregnant with twins (all three were transferred). It just goes to show not only that a different center could have a different outcome, but because we know that each cycle is unique, the outcome could be different from just having a different set of eggs and embryos.

I hope this helps,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

http://www.montereybayivf.com/

Monterey, California, U.S.A.

OHSS: Ovarian Hyperstimulation Syndrome and the PCOS Patient

On Wednesday, February 24th, at 6pm EST, I will be interviewed by Sasha Ottey on her radio show. The subject: "The Real Deal about PCOS and Your Fertility" Join us at http://blogtalkradio.com/pcoschallenge.

Prior to my blog radio interview, I would like to publish a question from last year regarding OHSS, ovarian hyperstimulation syndrome, in a PCOS patient. In this year's January cycle I had a patient with PCOS at my clinic who had undergone IVF last year at another clinic in the Bay Area. There she developed severe, life-threatening OHSS, was admitted to the hospital and stayed there for seven days. Needless to say, that cycle failed. She returned to the same clinic to do a frozen embryo transfer, which also failed. She then came to me. I put her on my standard protocol for PCO patients, low dose stimulation (Lupron/Ganerelix) and carefully monitored her. I'm proud to report that this patient had no adverse reactions and is now pregnant after only her first cycle with us.

Typically, signs and symptoms of OHSS appear within the first 10 days after a gonadotropin injection, when the ovarian blood vessels have an abnormal reaction to the hormone and begin to leak fluid. This fluid fills the follicles, swells the ovaries and sometimes moves into the abdomen in large amounts. Fewer than 2% of women develop the most severe form of OHSS.

Here is a link to the Mayo Clinic's informative website regarding OHSS, definition and symptoms http://bit.ly/bYGk1R .

Question:

Dear Dr. Ramirez,

First I would like to give you some background information. I have PCOS and have been undergoing infertility treatment for apx. 2 years. First, I tried using drugs like Clomid and Follistem. After about 1 1/2 yrs of it not working, we decided to go the route of IVF.

On June 23 I had my egg retrieval. They retrieved 15. After the retrieval they recommended not doing the transfer due to the risk of over stimulation (OHSS). I ended up being admitted to the hospital on June 29 with severe OHSS and on July 1, they drained a little over a liter of fluid. I was sent home on July 2. I had my period on July 5. I went back on July 7 and still had a little fluid around my lungs and my left ovary was still swollen. They were able to freeze 7 fertilized eggs. How long should I wait to do the transfer and can I develop OHSS again with the transfer?

Thanks! I am from Missouri.

Answer:

Hello,

It is unfortunate that you developed OHSS with this cycle. It should have been expected and could have been prevented. There are measures/protocols an RE can take to reduce the chances of developing OHSS such as "coasting" using "antagonist + Lupron to trigger" and lowering the dosage of stimulation.

The Lupron trigger has been used extensively and written about extensively in Europe. It is better than HCG with hyperstimulation because it has a shorter duration, reducing the chances of developing OHSS. I use it with my PCO patients who have a tendency to hyperstimulate and are at higher risk of OHSS. I only given one injection, not two. Lupron used daily or in the higher doses can certainly suppress the ovary. It works indirectly but has the same effect as the Ganerelix. In low doses, it mimics HCG and triggers ovulation. I love the Ganerelix-Lupron protocol.

I have not had a case of OHSS in over 10 years by taking these precautions. In any case, you should not do the transfer until your ovaries have returned to normal. Pregnancy can exacerbate the OHSS. Once this resolves then you can go through the frozen embryo transfer cycle. You will not undergo ovarian stimulation with an FET. Only the uterine lining needs to be prepared. For that reason, you are not at risk of OHSS.

Good luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

www.montereybayivf.com

33 Yr. Old Low Responder Trying For A 5th IVF Cycle, One Stillbirth But Not Ready For Donor Eggs Yet

Question:

Dear Dr. Ramirez:

I've just recently gone through my 5th IVF Cycle. Yesterday at retrieval they got 11 eggs but said that 6 of them were empty. The embryologist called today to say that none of the eggs fertilized and they are not sure what is going on. To give you a brief synopsis of my history:I'm 33, my husband is 46. We have been together for 6+ years. I was first diagnosed with blocked tubes back in 2005. I had bilateral tubal repair which successfully opened both tubes. Since I did not get pregnant we moved to IUI, which most of those got cancelled due to relationship difficulties. In 2008 I had a chemical pregnancy using donor sperm. My RE didn't count it because my AF started the next day after the beta. We then found out that my husband had a low sperm count. He was not tested prior to this because he has a child from a previous relationship years ago.

We did our first IVF in May 2008 with the transfer of 3 day 3 embryos. I conceived on this first attempt. However, my son was stillborn when I was 25 weeks along. We don't know the reason why because an autopsy was not performed. All I know is that I had an amnio at about 19 weeks and things were never quite the same after that. After meeting with my RE a month later he said we could try again soon because I have a high FSH which normally measures around 10 or so. The last two cycles my FSH was 9.9 and 8.8. We have done 4 IVF cycles in 2009 and all have failed.

1/09--bcp for 1 week, lupron, follistim 450, and menopur 150. 5 Eggs retrieved, 3 fertilized only one made it to day 3 transfer. Result=BFN3/09--same protocal as above, retrieved around the same amount of eggs but none fertilized.

4/09--bcp, follistim 450, menopur 150, and ganirelix towards the end of stimulation. 7 eggs retrieved, 5 were mature, 4 fertilized, and 2 made it to day 5 transfer. My RE said the day 5 transfer was of morulas (by day 5 they should be blastocyst so they were lagging behind in thier development). Result=BFN. My RE did a hysterosonogram and indicated that my uterus looks fine.

6/09--At this point we've decided to go for a 5th try, although it is now out of pocket as I've maxed out on insurance benefits for IVF. This time around my RE starts me on stimulation day 2 of my cycle with 450 follistim, and 150 menopur. No suppression. I produced more follicles than in my previous cycles. What puzzles me is that as of last Friday I had 16 follicles measuring between 14mm - 18mm and a few that were below 12mm and a few that were less than 10mm. When they did the retrieval yesterday I was a bit surprised that they only got 11 and then more than half of those were empty. The trigger shot I take is two shots of Ovidrel, one on each side. The first cycle when I got pregnant the trigger I took was Novidrel in the butt.

During all of this, after I lost my son with the stillbirth last year, the only person that did any thorough testing on me was my hematologist to find a clue as to what happened. In May 2009 he did an entire work up and discovered I had a Protein S deficiency and something else that may cause my blood to clot along with a positive PPA which he indicated could cause congestive heart failure in a fetus. His recommendation to my RE was that I should be on 81mg of baby aspirin daily and once I conceive I should be placed on Lovenox. Of course this didn't seem like a big deal of concern to my RE. His take is lets get you pregnant first.

My question is, given what I've described above, is there any change in protocol that would be recommended? I'm 33 and not ready for donor eggs but can't afford the cost of more failed cycles. Are there questions I should be asking my RE that I'm not focusing on?

Answer:

Hello,

Boy, you have gone through quite an ordeal, and I'm sorry to hear it. At least you know that you can get pregnant. Despite the fact that you are a poor responder (high FSH), your chances should still be good at your age. I am very surprised that it has failed so many times.

The stimulation protocol that you used recently (Follistim 450/Menopur 150) is my highest protocol as well. I use ganerelix (GnRH antagonist) for 1-3 days prior to retrieval to prevent spontaneous ovulation. I also use Ovidrel to trigger (only 1 shot however). Your stimulation was very good. I am very shocked that there were "empty" eggs. I presumed that meant empty cumulus, not eggs. That is something that we usually only see in Older patients (over 40). That is highly suspicious.

My protocol for patients that fail two IVF cycle is to add the following:

1. Aspirin 81 mg daily beginning at the start of the cycle continue through the pregnancy.

2. Low Dose heparin 2000 units twice per day or Lovenox 30 mg per day starting at the beginning of the cycle. Continue until 10 weeks pregnancy.

3. Medrol 16 mg per day until embryo transfer then decrease to 8 mg per day until the pregnancy test then stop.

4. Both injectable progesterone 50 mg per day beginning after the retrieval and vaginal Endometrin 100 mg vaginally twice per day beginning after the transfer.

I NEVER take low responder patients to blastocyst. I do not believe the blastocyst culturing is perfected and there is still a high embryo loss rate. I only take high responder young patients to blastocyst to decrease the number of embryos to choose from. In most cases, I transfer at day 3.

I don't know if your RE will accept some of these things because they are not well established in studies. But when my patients fail, I pull out all the plugs. The medications are not harmful or dangerous and can only help. The aspirin, heparin and medrol help to decrease the immune response AND decrease the micro clot formation in the early blood vessels going to the implantation site.

Despite all the IVF cycles you have done, at your age I would still want you to continue to try, but certainly donor eggs would be the next option. If you have implantation failure, however, and don't use the above protocol, then even donor eggs might fail. One other option would be to consider trying a different clinic because success rates are highly variable among clinics and doctors within a clinic.

I hope this helps,

Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
www.montereybayivf.com

Lupron trigger instead of HCG

Question:
My RE gave me a lupron trigger instead of my usual HCG or ovidrel trigger. It concerns me because when I read about lupron it is a ovulation suppressor. Did I ovulate? I took two lupron shots 12 hrs a part. I am now on progesterone supp. and patch along with a estrogen pill 3 x daily.
　
I was on 150 gonal-f for 9 days and then 75 for day 10. I also used ganarelix starting day 5 of stim. My E2 was higher than my RE liked and he wsa worried about OHSS. It was an IUI cycle. I OHSS in 2004 when I got preg. with my twins.
　　
I love my RE, but I just can not find much info on lupron trigger so I am a little concerned.

Answer:
Hello Michelle from the U.S.,
　　
The Lupron trigger has been used extensively and written about extensively in Europe. It is better than HCG with hyperstimulation because it has a shorter duration, reducing the chances of developing OHSS. I use it with my PCO patients who have a tendency to hyperstimulate and are at higher risk of OHSS. As a result, I have not had a patient with OHSS in years. I only given one injection, not two. Lupron used daily or in the higher doses can certainly suppress the ovary. It works indirectly but has the same effect as the Ganerelix. In low doses, it mimics HCG and triggers ovulation. I love the Ganerelix-Lupron protocol.
　
My biggest concern with your story is why you are following an IVF protocol for an IUI cycle? You are getting stimulated way too much. With IUI, we only want up to 3 ovulatory sized follicles. If you ovulate more than that, you will be at high risk of a super-multiple pregnancy (not good). Also, if you stimulated so much that your RE would be worried about hyperstimulation then you should not be completing the cycle. It should be cancelled, again because of the high risk of a super-multiple. OHSS occurs when the Estradiol level is greater than 4000 and you have more than 20 follicles. that's way too much for an IUI cycle!!!　
　
I think you have good reason to be concerned.
　　
Sincerely,
　　
Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
http://www.montereybayivf.com/　
Monterey, California, U.S.A.

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