Similar IVF Protocol But Different Results: Why?

Question:

Hi Dr. Ramirez,

I'm back again with a question about my recent IVF (second one). This IVF (in vitro fertilization) cycle we did the same protocol as last time (antagonist) but started off at a higher dose of Gonal-f based on my response last cycle. This cycle we started off at 300iu gonal-f and 75iu menopur whereas last cycle we started with 225iu gonal f and 75 IU menopur but had to increase to 300 IU gonal f after day 4 showed an E2 of only 90. Both cycles I started out with similar AFCs of 10 and 12 at suppression check. My usual AFC is between 16-20. Last cycle it seemed that I recruited more follies along the way and ended up with an E2 of 3030 and 23 eggs retrieved (17 of which were mature based on icsi and conventional fert rates as we did 50/50 split fertilization). This cycle my E2 was 2100 at trigger and they retrieved 12 eggs (still waiting on fert report today but we are doing all conventional fertilization).

My question is why did I have such a different response this cycle given that we started off at a higher dose this cycle compared to last? Last cycle we went up from 225iu gonal to 300 IU gonal at day 4 and stayed there until trigger. this cycle we started at 300iu gonal and stayed there until we added ganirelex on day 7. At that point my E2 stalled and do they increased my gonal f to 375iu gonal f and kept me there until trigger.

As always thanks for your advice/insight. S. from the U.S.A.

Answer:

Hello S. from the U.S. (Virginia).

The human body is not a consistent nor predictable structure so I can't explain why your response is different.  I have always explained to patients that have low response to stims that the ovaries can react differently each cycle and your experience is a case in point.  That being said, I would not have increased your dosage since your stimulation was so good the previous time and you bordered on entering OHSS territory.  In any case, IVF is not a contest where the person with the highest number of follicles or eggs wins the prize.  The goal is to find 1 or 2 perfect eggs that will lead to perfect embryos and a successful pregnancy.  So despite the fact that you stimulated less, that might be a better thing.  Bottom line is you only need one good one.  Also, there have been some studies showing that when a patient stimulates hard with lots of follicles, sometimes the egg quality suffers and the pregnancy rate drops.  This is especially true in PCO patients.  In those patients, our preference is to stimulate less and get fewer follicles.

So, in any case, as the saying goes: "I don't think you should sweat the nitty gritty" i.e the fine details.  Hope for the one perfect one.  That is the goal.

Good Luck!

Dr. 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.

How To Reduce The Risk Of OHSS

Question:

Hello,

I have been able to get pregnant naturally, but due to my kidney disease was not able to carry to term.  I have about 50 percent kidney function due to mild segmental mesangial sclerorsis.  I'm planning on pursuing surrogacy and would like to know what you would recommend for cycling treatment to reduce to the risk of OHSS (ovarian hyperstimulation syndrome) during the stimulation process?

Thank you, R. from California

Answer:

Hello R. from the U.S. (California),

First, I would choose a good IVF clinic.  OHSS is mostly due to overstimulation.  You'll want a doctor that is cautious, has a protocol to reduce the chances of developing OHSS and watches his patients carefully.

Second, OHSS tends to be most common in patients with PCOS where the ovaries are very sensitive to the stimulation.  If you don't have PCOS, then the chances of developing this problem are lower.

Third, patients at risk for OHSS get less medication than patients not at risk.  That is because their ovaries are so sensitive that they don't need much stimulation, and in fact, you don't want to stimulate them too strongly.  So a low dose FSH only or FSH/LH protocol is used.  I also don't use the "long protocol" in patients at risk for OHSS.  The long protocol is using Lupron injections starting from the luteal phase of the preceding cycle.  I use the antagonist protocol (the antagonist is to prevent spontaneous ovulation by suppressing the ovaries) which then allows me to trigger with Lupron instead of HCG (such as Ovidrel).

Finally, the estradiol levels and close monitoring of follicular growth are required so find a physician/clinic that works closely with their patients.  A large "factory" type of clinic is probably not a good choice. See this article regarding an American egg donor who underwent an IVF cycle through a Canadian clinic in 2011 to get an idea of the worst case scenario:  http://news.nationalpost.com/2013/03/28/kylee-gilman-sues-toronto-fertility-doctor/

Good Luck!

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

Monterey, California, U.S.A.

High Responder Fails Two IVM and Two IVF Cycles: PCOD & Follicle Maturation Issues

QUESTION: Hello,

During the last year we did two IVM (in vitro maturation) and two IVF (in vitro fertilization) cycles at different clinics at Montreal, Canada. All failed. I'm 39 years old and my husband is 40. My FSH was 11.1 and AMH 2.2 two years ago. The first IVM was without stimulation, I was triggered when the lead follicle was 13mm, 11 eggs were collected, 7 managed to mature in the lab and 4 fertilized. By the day 3 we had transferred 2 embryos 6 and 8 cells (they did not give us their grade). Endometrium was 6.8mm by the day of collection. No pregnancy...

The second IVM I had 3 days light stimulation (about 150UI Puregon days 3-5 + Estrace from day 6). I was not aware of my hormone test that shown the E2 level fell on day 6. We had collected only 8 immature eggs from 17 follicles, the only egg fertilized and on the second day the weak embryo was transferred. Endometrium was 7.3mm. Of cause, no pregnancy.

We moved to another clinic and did there two IVFs. The first one I had stimulation from the second day: 225 Gonal-F + 75 Luveris. After 4 days dosage was increased up to 300 Gonal-F + 150 Luveris. On the day 13 I was triggered when I had one follicle about 22mm, 2 about 18mm, and many smaller ones. We collected 16 eggs, 12 were mature, 9 fertilized. My doctor decided to wait till day 5 for the transfer. We had one blast, the other embryos stopped developing. The lining was 8.2mm at the day of transfer. No pregnancy.

As the clinic doesn't work during weekends, the stimulation for our second IVF started on day 4 and lasted 9 days. It was more aggressive: 300 Gonal-F + 150 Luveris from the start and about 200 Gonal-F + 150 Luveris at the end as I had developed mild OHSS. I was triggered when my follicles were 1-19mm, 1-18mm, 3-16mm, and many 15mm and less. As I said the clinic doesn't work weekends. My collection was Friday. I asked to wait for follicle growing bigger and the answer was: no, they are big enough. We collected 25 eggs, only 13 were mature, and only 5 fertilized. They were stopping developing one after another. The last one stopped at day 6 on the morulae stage. The lining was perfect: 13.5mm. It was an epic failure: nothing to transfer... I was told that the issue is my egg quality (my husband has no issues with his sperm).

I see that I had the only follicle bigger 20mm at the collection and we had the only blast. So I really would like to understand whether it's not a coincidence? If there is a way to have more equal size of follicles by changing the protocol? If I'm a good responder and have many eggs and they usually fertilize good (if they are mature) but they stop developing - does it mean they are poor quality? Or they were not fully mature at the day of collection? As I'm getting older and we have no time to experiment with different protocols I would like to maximize our chances by using more effective protocol for our next attempt. It would be great to hear your opinion on it. Could the change in protocol give us better chance for success?

Thank you in advance! O. from Canada.

ANSWER: Hello O. from Canada,

I can't give you specific protocol recommendations because each doctor and each clinic do different things. There is no one way to do IVF as you have found out.

The latter stimulation cycles show that you are NOT a poor responder but a high responder with PCOD tendencies. That means your ovaries are very sensitive to stimulation and that is a good thing. Yes, your age and therefore your egg quality are issues. However, hope is not lost because there is a chance that you still have a few good eggs left. As long as your ovaries respond well to stimulation, your chances of finding the good eggs are high. However, it also means that you need to find the right clinic because pregnancy rates will vary highly depending on the skill of the clinic and factors such as when to retrieve. I think it is a mistake to go to a clinic that only does egg maturation, and a clinic that doesn't work weekends. Both clinics are short changing you. It's time to find a better clinic.

It is also known that when OHSS develops, the pregnancy rates also drops. Probably because the majority of the eggs are not adequately matured. So one goal would be to decrease the stimulation and try for fewer eggs and a longer stimulation to get higher quality eggs. That is my goal with patients that are high responders. One method I use to try to even out the stimulation is to use the "sandwich protocol" which is to use 2-3 days of antagonist prior to starting the stimulation (I don't use the long Lupron protocol)to suppress the ovaries so that the follicles all start at the same point. Not all doctors use this protcol.

One final note: I let my follicles reach 20 mms before trigger. In some cases, I'll go up to 24 mms on the lead follicles if there is some unevenness, the goal of which is to try to get as many mature eggs as possible. Again, these things/variations are what make clinics and doctors different. You need to find a clinic that has a respectable pregnancy rate for your age group (and that will stay open on the weekends) so that you don't waste any more IVF cycles.

FOLLOW-UP QUESTION:

Dr. Ramirez,

At first, thank you very much for your fast and detailed response.

I've forgot to mention that our infertility is unexplained and I always have a lot of follicles at any given cycle (the first time we asked medical help for infertility 4 years ago).

Today I've got some new details about my IVFs: first time the E2 was about 8000 at the day of trigger and progesterone was about 4. The second time E2 was more than 22000 and progesterone was 6.4 so that my doctor didn't wait anymore and triggered me when the lead follicle was still 19mm (and not because they do not work weekends, as he explained). Is it possible that the E2 level could compromise egg quality the second time?

My doctor told me that assisted hatching is not possible for a blast as it can be easily damaged. Do you agree with that? Is assisted hatching used for day 3 embryos only?

Also my doctor is tended to wait for a blast and do 5-day transfer as he believes it would give stronger embryo and higher chances of implantation. As I see we had many good-looking embryos on day 3 and 1 or no blast at day 5. Would it better to transfer at day 3 instead?

Thanks again for sharing your knowledge

Regards, O. from Canada.

FOLLOW-UP ANSWER:

Hello again,

You have to understand that my advice is my personal opinion and not necessarily the gold standard or generally accepted standard because there are many many variations in the stimulation portion of the IVF cycle. But let me give you my opinion.

Both cycles led to overstimulated cycles. If the peak E2's are correct, you went very very high and in the U.S., in general, we don't like the E2 to go above 4000. Yes, it has been shown that when hyperstimulation occurs, i.e. the E2 goes above 4000, there seems to be a decline in egg quality and pregnancy rates.

You don't necessarily have a diagnosis of "unknown" infertility. You have the "age factor" which means that your egg quality could be compromised based on your age. That is a diagnosis. My approach to transfer is to use D#3 transfers unless I have so many good D#3 embryos that it is harder to determine which ones to transfer. In that case I will proceed to D#5. I am not a big D#5 person because I don't think that it is an absolutely perfect technology and we probably lose some good embryos because of it (that has been shown by genetic testing of the embryos on D#3). Not all blastocysts are genetically good embryos. Because of your age, I don't think it makes any difference which day you transfer, but I would prefer to put back more and let nature decide that the lab. YES, assisted hatching can be done on blastocysts.

The only other option that might help you, is to consider preimplantation genetic screening so that only normal embryos are replaced. I would also recommend tranferring at least 4 embryos because of your age. PGS might decrease your pregnancy chances a little, depending on the expertise of the clinic, but can help you to distinguish the genetically normal from the abnormal. PGS can be done on D#3 or D#5.

Good Luck,

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

Comment: Dr. Ramirez gives detailed and clear answers. He is extremely helpful and very knowledgeable.

A Step By Step Guide To The IVF Process: Step Two -- Follicle Growth And Egg Maturation

Dear Readers:

This is the third part in the series I have begun to help answer what In Vitro Fertilization (IVF) is and how it works with my world-wide Blog audience. What you read here is what I also provide my patients with on a daily basis. I plan on going into some detail but in a way that is understandable to the normal (lay) audience, and not the medical or scientific one. I also hope that this will not only clarify what you will go through, but explain why things are done a certain way and what the goals of each step are. I also want to convey that IVF is actually a replacement for some of the “natural” steps required to get pregnant and not some miraculous high tech fertility treatment that gets patients pregnant artificially, as many think it is. It is somewhat of a miracle that we can do as much as we can, but there are still lots of things/steps that we cannot do or influence. I hope this discussion will benefit you. This series will be posted over the next few weeks in installments.

STEP TWO: FOLLICLE GROWTH AND EGG MATURATION

Under the influence of FSH (follicle stimulating hormone), dormant follicles within the ovary start to grow. Measurement of the dormant follicle number is called the “antral follicle count (AFC)” and also measured by the “Anti-Mullerian Hormone (AMH)”. Both these measurements are used to give one an idea of the ovarian capacity to be stimulated, also known as ovarian reserve, similar to the FSH level. They are additional indirect measurements. Many physicians and patients believe that these two measurements actually tell them how many eggs are left within the ovaries, but that is too broad an interpretation. We do not have the technology to know how many eggs are present without doing a careful dissection of the ovaries. So these are indirect measurements that serve to give warning about your fertility. Their only use is to help predict, as much as possible, whether the ovaries will yield many follicles upon the hyperstimulation that occurs with giving increased amounts of FSH.

So the real interpretation of a low AFC or AMH is that there might be a lower number of follicles produced, and consequently less eggs retrieved. As explained previously, these are additional measurements of “ovarian reserve.” They only predict success from a statistical point of view because part of how IVF enhances your chances of fertility is by increasing the number of eggs that are available for fertilization and hence the number of embryos and hence the increased chance of finding the perfect embryo that will lead to a pregnancy as explained in the previous segment. It is a total misunderstanding or misinterpretation to say that a low AFC or low AMH indicates that you are infertile, that your ovaries won’t stimulate or that you won’t have good eggs! Taken together with an elevated FSH, these measurements serve as red flags from a time point of view. It means that you may not have as much time to get pregnant using your own eggs as you might have thought. Since we cannot predict when you will run out of time, time becomes a critical consideration.

Currently, transvaginal ultrasound is used to monitor the follicular growth by simply measuring the follicles. This measurement is usually an average diameter taken from a horizontal and vertical measurement of the follicle and reported in millimeters (mms). As the ovary is stimulated with FSH, some of the follicles will grow. Follicles grow approximately 2 mms per day so there is some predictability of when the follicles will reach the appropriate size for ovulation or retrieval. As the follicle expands, Estradiol hormone is produced in increasing amounts by the growing follicle and so estradiol levels can be monitored to also help determine progress as well. With IVF, the goal is to have 15-20 total follicles and estradiol levels between 2000-4000. Each mature follicle will produce approximately 150-250 of estradiol. In IVF, we want to keep the estradiol level at less than 4000 because if there are more than 20 growing follicles and the estradiol level goes above 4000, there is an increased risk for an illness called “ovarian hyperstimulation syndrome”. That is a whole other topic so it won’t be explained here. Suffice it to say that OHSS has the potential to cause death in its worst form. A competent physician with experience doing IVF will take appropriate precautions to prevent this from occurring.

It is known that the follicle has to reach an average diameter of a minimum of 15 mms for the egg within to be mature. We cannot see the egg because it is microscopic size. Therefore, maturation is assumed by the size of the follicle, as has been shown in early IVF studies. With most IVF clinics, a follicle is deemed to be mature size and appropriate to trigger once it has reached at least 18 mms, but it can be as low as 15 mms based on previous studies. Because the follicles will grow unevenly, meaning there will be some that grow faster and some that grow slower, most physicians will trigger with HCG when the largest 2-4 follicles reach maturity size, or when the highest number are between 15-24 mms. My preference is for the larger follicles to be 20-24 mms which I have decided to use based on my long term experience. I don’t necessarily trigger when the largest ones reach that size but, rather, I want to get as many follicles into the mature stage as I can without losing the larger ones or have too many smaller ones. The problem with smaller sized follicles is the eggs within them will not have had adequate time to mature and so will be unusable. Also, follicles that grow to over 24 mms tend to have eggs that are over-mature and therefore not viable. Once the majority of the follicles reach a size of 20-24 mms, then you are ready for the “trigger” shot. The decision of when to give this shot is determined by the experience of the doctor part of the art of IVF. If given too soon, you may lose eggs because they will not be mature. Too late and you may lose them because they will be over-mature. The goal is to try to get the majority number of mature eggs as possible because only mature eggs will fertilize.

Until the trigger shot is given (or the body goes through an LH surge if allowed to occur naturally) the egg within the follicle does not go through its final phase of maturation, meiosis stage 2. Eggs within the follicle are usually in the “germinal vesicle (GV)” stage. Once stimulation occurs, they then go through meiosis phase 1 (M1) and then are mature at meiosis phase 2 (M2). In the natural reproductive process, the “trigger” occurs under the influence of a hormone called LH (luteinizing hormone) and is known as the LH surge. This is what is being checked when you use an ovulation detector kit. There is a sudden rise in the LH hormone which then signals the ovary to begin the ovulation event.

In IVF, HCG (human chorionic gonadotropin) hormone, which is chemically similar to LH, is substituted for the LH to make the eggs go through their final maturation phase and begin the process of ovulation. There are three sources for this medication:

(1) Urinary HCG extracted from human urine,
(2) Recombitant HCG (synthesized HCG) and
(3) Lupron, another drug that has a similar chemical structure to LH.

Lupron can only be used if you are on an antagonist protocol, with Ganerelix or Cetrotide, and not in a long Lupron protocol. This trigger shot will also cause the ovary to begin the ovulation process but because we don’t want the ovulation to occur, and thereby lose the eggs into the pelvis, the egg retrieval procedure is timed to occur before ovulation will take place. This is usually scheduled for 35-36 hours from the trigger shot.

We will continue this discussion soon with the next installment, "Step Three And Four: Egg Retrieval". Thank you for joining me today!

Edward J. Ramirez, M.D. F.A.C.O.G.
Medical Director, Monterey Bay IVF
Monterey, CA
http://www.montereybayivf.com/

Failed IVF Cycle With Drop in Estrogen & Progesterone Levels & PCO Type Response: Might Benefit From Adjustment In Protocol

Question:

HI, I have a question regarding spotting 5 days post transfer with full period bleed on 6 days post transfer. Here is our history:-I am 32 and my husband is 41. He has a daughter from a previous relationship.-I was diagnosed with diminished ovarian reserve in January, and also stage III endometriosis in June with a laparoscopy. They were able to clean out almost all of the endometriosis except for some on the colon because I did have some bowel in my colon and they didn't wan to rip it. They also found a polyp in my uterus that they removed. Also, I have a luteal phase defect as I always would spot around 9dpo and would have an 11 day luteal phase with 24-26 day cycles.

- January/February 2011 - First treatment cycle. Letrozol with monitoring and intercourse and prometrium 50mg 1x a day. Luteal phase increased to 14 days with 29 day cycle. Negative.


-February/March - An ovulatory cycle - went in on day 3 and never came down to baseline. Ovulated day 8 (which has never happened) so couldn't do meds. Prometrium again, but only 11 day luteal phase, obviously negative.


-March/April. Anther cycle on Letrozol and prometrium - same as first cycle but negative.


-April/May - Moved to injections. Follistim 150mg and then decreased to 75 due to good response and high estrogen. Ganirelex 3-4 days prior to IUI. HCG trigger with 6 follicles developed and 1 mature. IUI with crinone (prometrium was causing depression). Luteal phase 14 days with 28 day cycle - negative.-Laproscopy in June.


-IVF June/July - Long protocol - BCP, 10mg Lupron for 10 days, Follistim 150mg day's 3-6, increase to 175 day 7-9 (estrogen at 840 after this). Decrease to 150mg days 10-11(estrogen shot up to 3400) Decrease Follistim to 75mg day 11-12 (estrogen 6000). All along with 5mg Lupron. HCG shotday 13(only half dose b/c estrogen so high. Retrieval on day 15. Starteg Crinone that day. 15 eggs retrieved with 14 fertilizing without assistance (husbands sper is great quality). Day 5 transfer, 1 blastocyst very good quality. All other embryo's taken to day 6 to freeze, but all but 1 poor quality so couldn't freeze. The 1 completely hatched so couldn't freeze and they didn't want to disrupt other embryo by transferring it. I had a follow up on day 5 post transfer to just check me for OHSS and they took my levels and my progesterone was 3 and estrogen 60 (at baseline they have never seen it below 72).


I knew something was wrong b/c I started spotting that day and a full period started that night. It is very heavy bleed which I usually don't have, but not nearly as much pain as I have had int he past, most likley from the endo surgery. I am taking a little while off, but it sounds like they think I have a true luteal phase as they never see this response to IVF. I want to be as edcuated as possible when I meet with my doctor.


What would your suggestion be for a luteal phase protocol to address this? I am nervous about the shots. The nurse said possibly estrogen patch, prometrium, and crinone or something along those lines with 2 progeteron meds. I have also asked to have my levels monitored during the next luteal phase. I am taking a cycle or two off before jumping into the next cycle. I am lucky to have the flexibility b/c my insurance covers this. I appreciate your feedback on this.


Thank you! K. from New York

Answer:

Hello K. from the U.S. (New York),

You had an awkward IVF cycle to say the least, was my first impression. There were several interesting moments in your cycle. First, your response was very characteristic of a PCO-type response, very sensitive ovaries. I don't know if your doctor was expecting this or not, but hitting an estrogen level of 6000 put you at very high risk of OHSS. Despite this, your doctor continued the cycle and triggered with HCG, which further increases the risk. I think you are lucky to not have developed full blown OHSS.

Second, I found the up and down of your meds to be unusual.

Third, a PCO type response would explain the decrease in embryo quality. When the ovaries are hyperstimulated they often lead to a deficit in embryo development or quality. That would explain why there were so few embryos to freeze. If they had to culture to day#6 that means that the embryos had not reached blastocyst stage by day#5, which is not necessarily a good sign. For the one that did, I was surprised it wasn't just frozen at day#5 so there would not have been a hatching problem. Why did they wait an extra day?

Finally, the abrupt drop in estrogen and progesterone levels was sure curious. I have never seen such a precipitous drop in a patient that is receiving supplementation. Surely, the problem with serum (blood) hormone levels is that they don't accurately reflect the levels within the endometrium, but there will be some levels and there are minimum levels in the blood that we know usually mean there is adequate levels in the endometrium. Neither of your levels met these minimum levels, but there should have been hormone in the blood because of the medications you were taking. You were taking medications weren't you? I would be very surprised if they didn't supplement you. Basically the bleeding that you had was the onset of your period because the hormone levels had dropped so precipitously. That is how it works in a natural cycle.

Certainly in the next cycle, I would recommend that you take progesterone injections (50mg) per day beginning with the retrieval, then add vaginal progesterone (Crinone or Endometrin) after the embryo transfer (because it is messy and interferes with the transfer), I also would add estrogen supplementation by patch starting with the transfer as well, but in your case, your levels should have been high from the hyperstimulation. I'm still thinking of possible causes for the drop. . . did you not stop the lupron?

Protocols are highly different between centers and there is not one protocol that is necessarily better than another. These are just suggestions. Your doctor may want to do something entirely different. Also, because you had a PCO-type response, I would recommend that you not use the long protocol and instead use an antagonist protocol with Lupron 0.5 mg as the trigger instead of HCG. This will reduce your chances of developing OHSS.

Good Luck,

Dr. 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.

Jamaican Woman Doing 1st IVF Confused About Meds: Possible PCOS Misdiagnosis

Question:

I am about to do my first ivf with a clinic and I got a lsit of medications that I will have to use/purchase. I am a litte uncertain about one of them - menopur. The list has over 40 vials of 75iu. I am certain that this is a mistake.

I will of course be asking the clinic but I wanted to be certain. I have had two iui - failed previously. one on clomid with three follicles gretaer than 10mm and one with menopur 150 with about 4 or 5 follicles. This is why I am uncertain about the quantity of menopur on the list.This medication represents the most expensive item on the list and I wouldn't want to order this many at once.

Again, I will be clarifying but I needed additional research/opinion. I have pcos and was diagnosed with endo, had a laporoscopy, ovarian drilling, suppression after lap etc etc

Thank you. KL from Jamaica

Answer:

Hello KL from Jamaica,

I cannot tell you if this is the right dose or not because it depends on the protocol your doctor has you on. But I can make the following comments:

1. PCOS patients tend to be very sensitive to medication and therefore require less medication to stimulate. For that reason alone, I would be skeptical, as you are, of the amount of medication ordered.

2. Menopur is NOT a good medication for PCO patients (if that is a correct diagnosis) because PCO patients already tend to have an increase LH level and the additional LH in Menopur is not needed and will lead to the risk of ovarian hyperstimulation syndrome (OHSS). I will usually either use only Follistim or will use a very low dose of Menopur less than or equal to 75IU. However, given that you only had 4-5 follicles with Menopur 150IU before, I wonder if maybe the PCO diagnosis is not correct?

You definitely need to ask your doctor regarding these concerns.

Good Luck,

Dr. 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.

39 Year Old IVF Patient, DH Severe Male Factor, Surprised By Treatment Protocol: May Also Have PCOS & Will Need Med Adjustment

Question:

Can you help figure out what the next step should be? I'm 39 but have day 3 tests of 6.4 FSH, 53 estradiol and 25 antral follicles. Also great uterine ultrasound. We're doing IVF due to severe male factor. Just finished our first cycle, during which I somewhat overstimmed (16 eggs, sky-high E2 levels) but we got 3 good embryos, froze 1 and implanted 2 (my lining was 10.2 if I recall correctly), but they didn't take. I feel like I got a bit of a "cookie cutter" treatment from current RE and am wondering what changes you might recommend.

What felt "cookie cutter" was that despite my great day 3 tests, RE put me on microdose Lupron flare protocol with 300 units of Follistim (150 twice a day). Isn't that kind of an aggressive protocol for someone with day 3 numbers like that? Couldn't that risk sacrificing egg quality to quantity? I just feel like all they saw was my birthday (almost 40), not the day 3 numbers, good health and family history (women in my family stay fertile pretty late).

Anyway, after 4 days of 300 units of Follistim I had tons of follicles and my E2 was too high--almost 900--so that day and the next they had me skip the PM dose of Follistim (in other words on days 4 and 5 I had 150 of Follistim once a day). The E2 kept climbing, to 1100+ on day 5 and 1900+ on day 6. So on day 6 they had me go back to two 150 unit doses of Follistim. The next day (day 7) my E2 shot up to 4300+ so they had me coast. By day 8 E2 had spiked to over 7300, but it fell to 5300+ on day 9.

In order not to lose the cycle they had me do HcG on day 9, even though apparently a lot of clinics won't do the HcG shot unless the E2 is under 4000 due to the OHSS risk. (To prevent OHSS they had me use a half-dose of HcG and also gave me albumin.) Out of 16 follicles we got 16 eggs, of which 14 were mature, and 7 fertilized. On day 3 after retrieval, we had 4 embryos. Two looked great--we transferred them, both 7 or 8-cell--and two didn't look so great. They let those continue growing; one made it to blastocyst and is frozen now.

My RE said, of my response to the protocol, that I "reacted WAAAY more than any of our testing led us to expect." I don't understand what part of my testing suggested that I would have any problem producing enough eggs. Do you see anything that suggests that? I am just trying to figure out if I can trust my RE... I don't know if they actually are less worthy of trust or if I'm just feeling that way because I'm upset at the failed cycle.

More importantly, do you think these estrogen spikes and/or the overly aggressive protocol damaged my egg quality? I've seen some things on the web saying that excess E2 can kind of "toast" the eggs. What would you do now, if I were your patient? My RE wants to switch me to a more standard Lupron downregulation cycle with 225 units of Follistim a day. She said it's up to me whether to precede the Lupron with birth control pills. I don't want to take the pills--it just seems like going from one extreme to another, IVF protocol-wise, and I don't want to risk being over-suppressed. What do you think? Also, is this a situation where you would lean towards antagonists instead of Lupron to avoid over-suppression?

Sorry for the long post. I just wanted you to know enough to comment. And thanks in advance for your help. M. from the United States.

Answer:

Hello M. from the U.S.,

Before I answer the specifics of your questions, let me precede with the disclaimer that (1) there are lots of variations of protocols and opinions in the world regarding stimulation and none are absolute (meaning apply to all people) and none are better than others, and (2) the opinions I give are my own opinions based on my knowledge and experience and (3) the first IVF cycle is hard to predict with everyone because there are too many unknowns as to how a person will respond until you do it the first time and (4) pregnancy does not occur every time a woman does IVF for many reasons.

In answer to your questions, the protocol you were on (300IU per day) is actually a low dose protocol. Medication can be given up to 600IU per day. However, based on your response, it seems that your ovaries have a tendancy toward PCO-type response even if you are not a classic PCO. That is to say, your ovaries were very sensitive to the stimulation and hyperstimulated. For that reason you had to coast. I don't use the microdose flare protocol, which is indicated for "poor responder" patients or patients with "decreased ovarian reserve", neither of which you fit. Your FSH level was fine and your antral follicle count was more like a PCO. If I see ovaries with PCO-type characteristics in the pre-IVF ultrasound, I will usually defer to a PCO protocol because I don't want to put the patient at risk for hyperstimulation syndrome.I think that the adjustment of the medications was appropriate.

One thing to keep in mind, which I think you already know and have read, is that PCO patients that hyperstimulate have a reduced pregnancy rate because many of the eggs within don't mature. In addition, there does seem to be a reduction in egg quality, and that is further enhanced when coasting is required. That is part of the reason why we try to avoid coasting, but the risk of hyperstimulation is much greater so we sacrifice the egg quality for preventing OHSS.

I also will differ with your doc in that I prefer to use a "mixed protocol" (using both FSH + FSH/LH) because there have been some studies that show that LH is required for egg development and quality. In addition, I ALWAYS precede my patients with the birth control pill to help with quieting the ovaries (putting them at rest) prior to the IVF stimulation, to assist me with stimulation (studies have shown better stimulation) and to help with scheduling/controlling the cycle. Also, I strongly differ with your doc in the number of embryos I would have transferred. I would have transferred or recommended transferring all four of the embryos on day#3 just based on your age (that is totally based on whether or not you would be willing to take the risk of a twin pregnancy). We know that just based on your age, even with the family history of retained fertility at an older age, your chances of quality eggs are reduced, so the goal is to have a lot of eggs and embryos to work with in the hope of getting a good embryo in the end (keep in mind that "good looking embryos" does not necessarily mean that the embryo has good internal quality. We have no technology to access that at this time.) In my 39 year olds, I will transfer 4-6 embryos in order to get one implantation.

Finally, since we now know that you respond like a PCO patient, I would use a PCO protocol. In my practice, I exclusively use the antagonist protocol rather than the long protocol (Lupron), so that I can trigger with Lupron instead of HCG (which has been shown to reduce the chances of OHSS), and decreases the number of injections required. I call my PCO protocol the "low slow protocol", where I start with a low dose of medication and slowly increase it based on response.

Thank you for providing detailed information, it helps a great deal in formulating my response! I hope this answers your questions and that any subsequent cycles go better than the first.

Good 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.

"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.

Confused Canadian IVF Patient Told She Is PCOS & Ovarian Resistant: Not Possible! What Is The Right Approach?

Question:

Hello Dr. Ramirez,

I am a 36 year old woman who has just attempted my first IVF cycle after 5 unsuccessful IUI's. I have been diagnosed with PCOS and ovarian resistance even thought my FSH has always been low on my day 3 blood work. I do not have a regular period and have needed clomid and Puregon injections in order to ovulate for the IUI's.

This past IVF cycle my numbers were as follows: Day 3 - FSH 5.7, Estrogen 112, Progesterone 3.5 and LH 7.6. I commenced 150 of Puregon on Day 3 and continued on Day 4 and 5. On Day 6 my blood work results were: Estrogen 334, Progesterone 3 and LH 4 and I had many follicles at 1.0. I upped my Puregon to 200 for Day 6 and 7. On Day 8 my blood work was Estrogen 717, Progesterone 2.7 and LH 2.7 and none of the follicles were progressing. I went back in on Day 9 for a follow-up ultra sound and there was no change in follicle size. My IVF cycle was cancelled.

My question is what would the IVF protocol be for someone who has a history of ovarian resistance? Would my dosage need to be increased or combined with other medication? I have had a egg reserve blood test done and I apparently have a very high number of eggs for someone my age. I would assume that would be because I do not ovulate on a regular basis. The question then comes down to egg quality. If I do not ovulate, does that compromise egg quality? Any advice or light you can shine on my situation would be very helpful.

B. from Canada

Answer:

Hello B. from Canada,

First of all, having BOTH PCOS and Ovarian resistance does not compute. Ovarian resistance is when the ovaries do not respond well to stimulation. PCOS patients tend to over-respond to stimulation. Somehow, I'm not sure your doctors have it right. You should be one or the other.

You do not have ovarian resistance based on your description of having "many follicles". You were also on a low protocol, probably in anticipation of being a high responder due to PCOS. Based on your estradiol levels, you were progressing well, but your follicles were small as is characteristic of PCOS patients. They tend to stimulate and grow a lot of follicles, which progress more slowly, instead of selecting a few and growing them more rapidly. Keep in mind that 200IU or Puregon is a low dose. My highest protocol is 600IU. I don't know why your doctor canceled your cycle. Maybe he/she felt uncomfortable with number of follicles you had and did not want to risk hyper-stimulation syndrome. Obviously, your doctor is not used to treating PCOS patients. Also, you were only cycle day #8 which is still early in the cycle. Most patients will go to cycle day #12 or 14 before the follicles are ready. Since your estradiol was only 717, you were not at risk for hyper-stimulation syndrome as yet. Patients that develop hyper-stimulation syndrome tend to have estradiol levels over 2000 by cycle day # 9.

Also, you should keep in mind that at 36, you are still young and most of your eggs should still be at good quality. You have a good FSH. Age is not an issue for you yet.

In terms of protocols, I cannot give you a standard protocol because every program and doctor has different protocols and combination of protocols. I prefer to use a "mixed" protocol which combines both FSH and FSH/LH (I use Follistim for FSH and Menopur for FSH/LH). In your case, you just were not stimulated enough, and the doc should have kept going and increasing the dosage, whether you use the single agent protocol like you did or use a mixed protocol.

I hate to say this, but I might suggest that you consider seeking out a different clinic or doctor, because I am leery about how your first cycle went. Again, I don't think you are a "low responder" so you might want to discard that label for yourself. Low responders barely respond to 600IU or more of medication and often the estradiol doesn't get much above 300-400.

Keep trying and good 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.

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

PCOS Patient Beginning IVF Treatment, What Questions Should She Ask Her Doctor?

Question:

I have PCOS and I've started IVF (in vitro fertilization). I have concerns because I don't really understand what is going on. They say they want my estrogen level up and that it is going in the right direction but they keep increasing my medication. Why? How can I tell if it is working?

I have started since January 22nd. Is it normal to continue and what questions do I ask my doctor to see if my chances remain good?

Answer:

Thank you for your question, it's always good to know exactly what is going on so don't hesitate to ask your doctor as many questions as you can. Take a pad of paper with you and write down the answers if you need to.

Let me begin with our protocol at our clinic for patients such as yourself. With PCOS patients we have to be very careful because if you over-respond, you could develop and illness called ovarian hyperstimulation syndrome (OHSS). Many IVF programs use a protocol called a "step-up" protocol whereby you start on a lower dose and it is slowly increased based on your estradiol levels and ovarian response. They should be doing ultrasounds at the same time to see how many follicles are growing and what size the are. Once it looks like you are stimulating, the dose is usually kept constant until the follicles reach the appropriate size for retrieval (18-24 mms).

If you started on the 22nd of January, your cycle is definitely going kind of slow. Most patients will respond within 10-16 days. I would presume you are getting closer.

If your doctor is not explaining these things, then you need to be more insistant that you want an explanation at each visit. Most doctors, or their respective nurses, will then explain how things are going and what the goal and timeline is. We can usually predict, within a day or two, when you will be ready to retrieve.

What you should ask is:

1. How am I doing?

2. Am I responding to this dose or protocol? Are my follicles increasing?

3. How many growing follicles do I have?

4. When are you expecting me to be ready to retrieve? Transfer? Explain that you need to plan the date.

5. What if I have too many follicles? Will you cancel me? Do you Coast? Will you trigger with HCG or Lupron? (Lupron is what I use because it has a shorter duration of action and has been shown to decrease the incidence of OHSS if there are too many follicles and the estradiol is too high (over 4000).

6. What is my estradiol level? (the goal is to have a level of 2000-4000 at the point that the follicles are ready for retrieval. If the estradiol level is over 4000, then the risk for OHSS is higher).

I hope this gives you enough questions to ask for now. Keep informed and stay in touch! Good luck!

Sincerely,

Edward J. Ramirez, M.D.

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF program

http://www.montereybayivf.com/

Monterey, California, U.S.A.

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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