Three IVF Cycles With Immature Eggs: PCOS and HCG Trigger?

QUESTION:

Dear Dr. Ramirez,

I'm 39 years old and have done 3 IVFs (in vitro fertilization cycles). During the first two IVFs, half of my eggs were immature. I had 25 retrieved (age 37) the first time, and 16 retrieved (age 38) the next time with 50 percent maturity in both cases. However, I just had an egg retrieval where 15 were retrieved and only 2 eggs were mature. They used generic HCG in this case, and the doc seems to want me to try the transfer the pretty crappy embryos that resulted from this retrieval. He is offering no answers as to why just 2 eggs were mature upon retrieval and the embryo quality was my worst yet.

Does the kind of HCG trigger make a difference? For the second retrieval, I didn't use generic HCG but Novarel. I think I used Ovidrel for the first trigger. Do you think I have a genetic defect and should be tested? I also think I have some of the signs of PCOS (acne and some sideburn hair that I remove), but doctors don't think I have PCOS because I have regular periods and am not overweight. Yet, I've heard many PCOS (polycystic ovarian syndrome) women produce immature eggs. Also think I may be insulin resistant and have heard a connection between this and immature eggs as well.

Would appreciate your insight.  Emma from California

ANSWER:

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

Egg maturity at the time of retrieval is based on two things: (1) the size of the follicle when triggered and (2) adequate HCG stimulation. 

First, let me answer the HCG question.  If the HCG is an inadequate dosage or not a quality product, then it is possible that the follicle and consequently the egg within, will not get adequate hormonal stimulation to go through the final maturation phase.  Sometimes the egg will not release from the wall and so no egg will be retrieved but otherwise, it would not be mature.  In terms of follicle size, it is usually a requirement that the follicle reach a minimum of 16 mm to insure that the egg within has matured.  Physiologically, as the follicle grows from FSH stimulation, the egg grows toward maturity.  When it reached mature size, the final act is for the HCG or LH which is the physiologic trigger, causes the egg to go through the final phase of maturation and release from the wall.  If the follicle is less than 16 mm, an egg could still be retrieved but it would not be mature.  This is where the "art" and experience of the physician comes into play.  It is his/her decision as to when the optimal time to trigger is.  The goal, or what should be the goal, is to trigger when the majority of follicles are of mature size but not let it go on so long that you begin losing the larger follicles.  That balance is the key.  In my case, I use 50% maturity as my baseline measure, since follicles tend to grow at different rates.  That is to say, that I strive to have at least 50% of the retrieved eggs to be mature.  In most cases it is much more than that.

You are correct that PCOD patients tend to have a lot of immature eggs but that is because they have so many follicles that result from stimulation.  Where a normal woman might produce 15-20 follicles, a PCOD patient will often produce 30-40 follicles.  Since they develop at different rates, that leads to different maturity levels.  In terms of medication, I favor Ovidrel.  In my experience (22 years), I have had cases where the eggs don't mature as a result of Novarel or Generic HCG, so I abandoned them.  In addition, Ovidrel is a subcutaneous injection whereas the HCG is intramuscular so, it hurts more. 

Good Luck,

Dr. Edward J. Ramirez, M.D., FACOG

---------- FOLLOW-UP QUESTION ----------

QUESTION:

Thank you, Dr. Ramirez. There was one more piece of information I forgot to include. Before I started this last cycle, I had been on a three-month dose of lupron. I began stimming exactly three months to the day of my lupron injection, even though I still had hot flashes and only had six follicles to start. Follicles grew from 6 to 8 to 12 the day of the trigger. Normally my number of follicles are in the teens at the beginning of the cycle. I even mentioned this to the doctor and told him that I was still having hot flashes as well. Is it possible that my ovaries were over-suppressed, which resulted in just two immature eggs out of 15?

Thank You,

Emma

Answer:

Hello Again,

Usually the stimulation, if given in adequate dosage, is enough to overcome the Lupton suppression, but I think that your thinking may be right, and that your ovaries may have been suppressed enough so as to not perform as well in the last cycle and the stimulation was not enough to overcome that suppression.

Good Luck,

Dr. Edward J. Ramirez, M.D., FACOG

Monterey, California, U.S.A.

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

www.montereybayivf.com 

Monterey, California, U.S.A.

Follicles Too Big In Clomid Ovulation Induction Cycle

Hello,
I am writing from San Diego, CA.  I was on 100mg Clomid on Cycle Day 3-7, then 2mg estradiol on cd 8-12. I went in for an ultrasound to check follicles on cycle day 13.  My RE said that this was most likely a lost cycle because I had 2 dominant follicles at 26 and 31 mm.  He gave me an HCG trigger because he did not want the follicles to get bigger and become cysts.  My uterine lining was 14 mm, and my RE was happy with that.  My husband and I had intercourse the day of the trigger and the day after, then skipped a day and had intercourse one more time.  

Were the follicles too big?  Do we have any chance of conceiving this cycle?  I have also been feeling cramps since yesterday at 7 days after the trigger.  Is this normal?  

Thanks for your input. L. from San Diego

Answer:

Hello L. from the U.S. (San Diego),

I don't have the ability to foresee the future, and certainly exceptions can occur, however, the follicle sizes were too big.  Usually once the follicle is greater than 24 mms, the egg within is overmature and therefore no longer viable.  Ovulation may occur but that is the main problem.  Also, it is highly likely that these follicles will turn cystic (persist) and have to be suppressed with birth control pills. You need to make sure a baseline ultrasound is done to evaluate for this at the start of your next cycle.

So, statistically and physiologically speaking, this cycle is probably a bust.  Unfortunately, your doctor missed the appropriate point by not doing the ultrasound early enough.  Next cycle he should begin looking at cycle day #9 or 10, which is what I do.  If I'm too early that's okay because nothing is lost and gives me a better idea of follicular development.  If you're too late, as in your cycle, then then cycle is lost; a big price to pay.

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.

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/

35 Year Old Responds Well To Low Dose Clomid IUI Cycle: NOT A Low Responder!

Question:

Dr. Ramirez,

My husband and I have been infertile for more than 2 years now. We have gone through a wide variety of tests. I have had a polyp removed through operative hysteroscopy and we were asked to try on our own for 3 months afterwards (unsuccessfully). I am 35 years with borderline bad FSH (around 10 on day 3). I have a low antral follicle count (usually around 7 if they can see both ovaries during the ultrasound). We have tried 1 IUI (negative for pregnancy) and I was prescribed 50 mg Clomid on days 3 - 7 for the IUI. I ovulated 3 eggs with this dose and was triggered with an HCG shot when the 3 follicles were between 1.7 - 2.0 and IUI took place approximately 24 and 48 hours after this injection.

I have 2 questions:

1. Is the fact that I developed 3 eggs on Clomid a good or bad sign? My doctor says I will likely be what he calls a poor responder to medications because of my low antral follicle count and IVF may not be more worthwhile than IUI because of this. Does the fact that I got 3 with Clomid mean I might do better with injections then he thinks or are the 2 medications so different that my response to Clomid doesn't indicate anything?

2. What is the purpose of a blood test the day of my second IUI? I have a lot of problems with all the blood work that is required for monitoring due to bad veins (day 3 plus 4 more days of blood tests/ultrasounds before my IUI). I thought when I was triggered that would be my last blood test, but I was told I needed another blood test/ultrasound the day of my second IUI (48 hours post trigger). I asked the nurse if the blood test was essential and she said yes and it is part of the cycle monitoring that all fertility clinics require it so I forced another blood test through my already bruised veins. I understand the ultrasound was to show if the follicles released, but what would the purpose of this blood test be and is it really as essential as they say it is? (I was also on progesterone suppositories 200 mg twice a day following the IUI so I don't think it was to measure progesterone since those were prescribed regardless of the blood results).

I really appreciate you providing this service and if we do decide to travel for treatment, California will be our choice. Thanks again, A. from British Columbia

Answer:

Hello A. from Canada (British Columbia),

The fact that you responded well to low dose Clomid is very, very reassuring and I completely disagree with your doctor's opinion. FSH levels and Antral counts are indirect measures of ovarian response but not absolute. In other words, studies have shown that these numbers can vary from cycle to cycle and so the response can vary from cycle to cycle. Besides, an FSH level of 10 is not necessarily that bad. Sure, we prefer the level to be 7 or less, but it is much better than a level of 12 or greater, which I often see. Even these patients do respond to stimulation albeit only a few follicles.

So, considering that you responded well to Clomid, low dose Clomid no less, is more of an indication that you are NOT a low responder. A low responder would have only one follicle despite high dose (250mg) of Clomid. One thing these two levels do tell you, however, is that you may not have as much time to work with as you would have thought. You will need to use your time wisely and strongly consider a more aggressive approach (such as IVF). I would not recommend more than 4 IUI attempts. If that does no work (which is the number where most patients will be pregnant), then you have to go to IVF.

In terms of your second question regarding the blood test, I have absolutely no idea why it is being done. It must be something specific to your doctor. You will have to ask him. Now, I do an ultrasound after each IUI so that I can see if ovulation has occurred. That way I know that the timing was good. Since I don't know what test they did or what it could be, I can't try to explain why they would do it. It can't or shouldn't be a progesterone level, which is what we often use to determine if ovulation occurred, but that test is not valid if progesterone supplementation is given.

Thank you for your question and consideration...Good Luck,

Dr. 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.

Young IVF Patient Fails Two IVF Cycles: Empty Follicles

Question:

Dear Dr. Ramirez, I am 31 years old, have never been pregnant. My husband and I haver been trying to conceive for about 3 years, tried 5-6 cylces of Femara.

I had three failed IUI's and two failed IVF cycles. The first IVF cycle there was one egg but it disintergrated before it could fertilize. The second IVF cycle there were no eggs. Each cycle had 14-16 follicles 8-10 of them being mature. My AMH level is 2.19. My husband has been tested and is fine. I have a left blocked tube, which they say could be a spasm reaction from the dye. During the IVF I was on Bravelle, Menopur and Ganerelix injections, along with the trigger shot. It is emotionally and financially draining. Any thoughts? Thanks, H. from New York

Answer:

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

There is a finding called "empty follicle syndrome" where no eggs are within the follicles. But this occurs in a single cycle and those patients generally have eggs when retrieved in subsequent cycles. I have had young patients, and many older ones, with no eggs retrieved. In older patients, many of the follicles don't have eggs i.e. they have run out of eggs, so it is fairly common. But, this is not common in young women.

In most cases when eggs are not retrieved in a young woman, it is often because either (1) the HCG trigger was not adequate, or (2) the follicles sizes were not mature enough and therefore the eggs were not mature. I am suspicious that you fit into the latter category based on your first cycle. It is possible that you are being triggered too soon. In terms of the HCG not being adequate, when I previously encountered empty follicles in my young patients, I came to the conclusion that either the HCG had a manufacturing defect, was not stored properly or not given properly. I used to use generic HCG. I have now switched to the brand HCG, Ovidrel, and have not had a repeat of that problem.

I also worried that in more obese patients, the depth of the injection was not adequate to get the HCG into the tissues so I have my obese patients given the HCG injection into the back of there arm where the fatty tissue is less, rather in the abdomen where the fatty tissue is thicker.

Finally, if it is that the follicles were not allowed to grow sufficiently, that is a procedural problem. So you either can ask your doctor to wait a little longer to trigger you (I have found in my experience that I have to wait until the lead follicles are 21-22 mms rather than the 18 mms that most doctors will trigger at) or you can try a different clinic/center because each doctor and clinic are different and the outcome can be different.The bottom line is not to give up.

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.

Wondering About Follicle Size And Ovidrel Shot

Question:

Hi, I am on Gonal-f and my US (ultra-sound) yesterday showed I had 2 follicles measuring at 17mm and 14mm, my doctor told me to take one more shot of 75ui Gonal-f last night and to trigger with ovidrel tonight.

Do you think my eggs will be mature enough to ovulate???
Thanks! N. from the U.S.

Answer:

Hello N. from the U.S.,

If the follicles grow normally, they should increase by 2 mms each day. That means that they will be 19 and 16 mms the next day. I NEVER trigger without knowing the follicle size for sure. That is sloppy care. In addition, I would want you to be able to ovulate both follicles so I would probably wait one extra day and use the gonal-f another day. That way the follicle sizes should be 21 and 18 mms, so that both would be ovulatory size. Since follicles don't always follow the expected growth rate, I feel you have to look each day to know for sure.

In terms of your question, if the follicles grow to 19 mms and 16 mms the next day, then the 19 mm follicle definitely should ovulate and the 16 mm follicle may or may not.

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.

Ovulation Induction With Follistim Keeps Failing & Estradiol Remains Low

Question:

We are currently TTC our 2nd baby. My daughter who is 2 was conceived on our second cycle of follistim75iu. We are currently on our 4th cycle of Follistim 75iu. Each cycle I'm told my estradiol is low and they end up increasing my dose of Follistim to 150 iu and even by the time I trigger it's still on the low side.

I understand that ideally estradiol should be 200-250per mature follicle. But this cycle it is 110 with follicle sizes of a 14 and a11. So at this point of my cycle what should it be since they are not mature follicles? Also last cycle they had me do hcg booster shots after ovulation because I had a low estradiol (it was 80) 7 days after ovulation the cycle prior. The boosters helped increase my estradiol to 354. My concern is do the boosters really help achieve pregnancy or are they just masking a bigger problem?? Thanks in advance, S. from Pennsylvania, U.S.A.

Answer:

Hello S. from the U.S. (Pennsylvania),

There is no fixed protocol when using gonadotropins such as Follistim. Basically, these medications are the hormone FSH which is the hormone that your brain produces to stimulate the ovary to produce a mature follicle for ovulation. If the amount of hormone is insufficient to do this, then it has to be increased and this is usually done on an incremental basis. Please see how I do ovulation inductions here: "Ovulation Induction".

For example, it may be started at 75IU but every three to four days, and estradiol level can be drawn and checked to see if it is increasing. If it is increasing then starting on cycle day #9, an ultrasound is done to evaluate the ovaries and see how many follicles are present, what their sizes are and when to trigger. In your case it sounds like that is not being done. For some reason, your doctor is fixated on keeping the same dosage. I'm not sure I understand why.

You are correct about the estradiol level of a mature follicle. If your follicle does not reach the mature size18-20 mms, then the estradiol level will not reach the appropriate size either. Basically the follicle increases in size by increasing the number of cells. Think of it as a chain of cells in a circle. These cells to increase in size, rather, more cells are added to the chain and each cell produces some estradiol. That is why as the follicle increases, more estradiol is emitted. In order for the follicles to grow more cells, increasing amounts of FSH is required. So, if your doctor stops the dosage at 150IU and it is not enough FSH to stimulate follicular growth, then nothing will happen. He needs to keep increasing the dosage until the follicle grows appropriately. Once the follicle reaches the ovulatory size of 18-24 mms, then ovulation can be triggered with HCG (a substitute for the LH surge you would produce in a natural cycle).

The "HCG booster shots" do nothing to help the estradiol rise. Rather, this was merely a coincidence. The growing follicle causes the increased estradiol. The HCG can be used after ovulation to help prime the enodmetrial lining for ovulation. Some clinics use this instead of progesterone. It is also used to trigger ovulation, as I've mentioned previously.

Based on the information you have given me, I'm wondering if you are seeing the right doctor. Your doctor may be comfortable with using Follistim, but is he really an infertility specialist i.e. have a thorough knowledge of the gonadotropins to use them for IVF (in vitro fertilization) if he has to? There are many Ob/Gyn docs that feel comfortable with ovulation induction and use gonadotropins like Follistim on a protocol basis, but in reality, don't know what they are doing. Could you be in that type of situation? Maybe it is time for a second opinion. The best way to find an infertility specialist is to simply ask the clinic or doctor, "Do you do IVF?".

Good Luck,
Dr. 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.

Cancelled IVF Cycle: Australian Wonders If She Can Risk Conceiving Naturally

Dear Doctor,

I found out today that my IVF (in vitro fertilization) cycle was cancelled due to not enough follicles stimulated. I was day 11 of my cycle and had 6 follicles in total but only 3 measuring over 10 - at 16, 14 and 11. Another was 9. This is my first cycle - I have an AMH level of 3 and DH has a low sperm count and motility. I have been taking 400iu of FSH (puregon) and an antagonist. What are the risks if we were to have intercourse? Would I need to take my HCG injection prior to intercourse?

Given our history, I don't see why we couldn't try to conceive naturally? Thank you! C. From Australia

Answer:

Hello C. from Australia,

I don't understand why your cycle was cancelled because it only takes 1-2 good embryos to get pregnant. Although you did not have a large response, you did have a sufficient one. Also, your doctor could have increased your medication up to 600IU of FSH or have added Menopur (FSH/LH).

In any case, you could convert your cycle to an IUI (intrauterine insemination) cycle or intercourse at this point. IUI would probably be the better choice. You would continue on the medication until the lead follicle is at least 18-20 mms, visible with ultrasound. The goal would be to have 3 ovulatory sized follicles (greater than 16 mms) at the trigger, then you would take the HCG and have the IUI's at 24 and 48 hrs after the trigger or have intercourse for the next four consecutive days.

I am in agreement with you that you should not give up this cycle so easily.

Good Luck,

Edward J. Ramirez, M.D., FACOG
Executive Medical DirectorThe Fertility and Gynecology Center
Monterey Bay IVF Program
www.montereybayivf.com
Monterey, California, U.S.A.

Was My IUI Triggered Prematurely?

Question:

Hello, I just had my first IUI (intra uterine insemination) this past Tuesday and although the doctor was not happy with my follicles after Gonal f, he decided that I should trigger anyway with Ovidrel. The ultrasound the day of the trigger showed follicles 16.5mm, 16mm, 15.5mm and also some 13's, 12's and 10's. Were my follicles sufficient enough in size to produce a viable egg or two? :(( also do they continue to grow after Ovidrel? I had my IUI 34 hours after the Ovidrel injection.

I so desperately want a child and am not sure whether I even have a chance with this IUI! Please help. V. From the U.S.A.

Answer:

Hello V. from the U.S., I have to admit I don't understand at all why your doctor triggered you at this point? Why not wait for the follicles to grow bigger? Were they not responding to max stimulation? If you weren't on max stimulation then why not increase the dosage and wait?

In general, in order to achieve maturity, we will wait until the leading follicles are at least 18 mms. It is known, however, that if the follicles reach 16 mms then there is a chance that they will be mature at aspiration (retrieval) during IVF. But, I do think that the trigger was premature with your IUI. Yes, you might get three mature eggs, but all the follicles that are less than 16 mms will be immature. With an intra uterine insemination as opposed to in vitro fertilization, the picture is different. If the follicle does not reach 18-20 mms, it is unlikely that the follicle will ovulate despite HCG (Ovidrel). They do continue to grow a little, but the follicle has not reached ovulatory size.

I hate to burst your hopes, there is always a chance that a pregnancy can occur, but in general, I would not expect you to achieve pregnancy with this cycle because the trigger was premature thereby lessening the chance that ovulation will occur. I think you need to have a serious talk with your doctor and ask why he triggered so early! Was it a scheduling issue i.e. you would have reached maturity on the weekend and he would not have been able to do the IUI? Real infertility doctors work the weekends as necessary. I know that one of the local Ob/Gyn's in my area does not work the weekends. He cancels the cycle or turns it into a timed intercourse cycle if it falls on the weekend. If this is the case, I think you need to consider whether you want to continue to expend time and money on this doctor.

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.

Ovarian Follicle Size Is Key When Planning For Trigger Shot

Question:

Dear Doctor Ramirez,

I had 3 follicles when I received the trigger shot. 30mm 24mm and not sure what size the 3rd one was. Is the 30mm follicle a good size to have a mature egg to be released?

Thanks, G. from the U.S.

Answer:

Hello G. from the U.S.,

I'm sorry to say but those follicle sizes are way too big. The trigger should be given when the follicle is between 18-23 mms. Once larger than that, the egg becomes over mature and non-viable. In some cases the follicle will not ovulate and be retained as a retained physiologic cyst. This type of situation generally occurs when patients are seeing the wrong type of doctor. I would advise that you consider seeking out a specialist in infertility or at least an ob/gyn who knows how to monitor your cycle properly so that you trigger at the correct time.

Good Luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

www.montereybayivf.com

Empty Follicle Syndrome In 40 Year Old Attributed To Age Factor

Question:

Hello Doctor,

I am from Cuba but I live in Miami. I am 40 y/o now. I had my first IVF cycle at 39 that failed, back in July. I started 2nd round in Sept.- Oct. but it was just cancelled due to empty follies. It is possible that I have no more eggs in my ovaries?

I have another theory but I am not an expert and I don't know if it is possible to be true. The first step was taking birth control pill. I took them for 21 days. After that I had NO PERIOD. I did have symptoms "as if" my period was there (cramping, pain) but no bleeding. I did an ultrasound but the endometrium was not big enough to shed. At day 7 after the last pill, my Dr. told me to start the stimulation for IVF anyways. There were 6 follies formed but empty. What do you think? Could this (bcp) be the cause for no eggs retrieved? Thank you very much. I am very frustrated. T. from Florida

Answer:

Hello T. from Florida,

We tend to see a higher incidence of "empty follicle syndrome" with increasing age. This is indeed because there are fewer and fewer eggs left. However, no eggs at the time of retrieval is not related to having used the birth control pill and not having a period. There are other reasons, besides age, where no follicles are retrieved as well.

I have had several cases of EFS in my career (16 years) of doing IVF and in some cases they were in younger women, so the age factor did not apply. Those younger cases I attributed to a lack of adequate HCG triggering. I used to use a generic HCG, and it is possible that either the medication was not stored correctly and lost its efficacy, or it was not injected properly, or it was a bad batch of medicine. For that reason, I switched to Ovidrel, which is what I still use. I have not had a case of EFS in a young woman since. I still do see older women that have no eggs retrieved, however, and that is the age factor. Nothing can be done about the age factor except continuing to try in the hopes that (1) the next cycle will yield some eggs and (2) there will be a good one in the group.

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.

Kuwaiti Woman Asks: How To Thicken My Endometrium Lining?

Question:

Hi Dr. Ramirez,

I feel am really blessed to find someone very expert and caring like you :)

This is N. from Kuwait, I am very concerned about my endo thickness (was between 6.5 to 7.9 on CD14). On the other hand, I don’t want to take medicine that may harm me. The dr. is giving me Duphaston and Progyluton. The Norgestrel is combined with Estradiol valerate in one pill that comes in medicine call Progyluton (I don’t know if you know it). 11 white tablets each containing Estradiol valerate and 10 light brown tablets to be taken from CD16, each containing Estradiol valerate and Norgestrel). You have said previously that the Norgestrel is not used in the USA to treat endos.

What about the Duphaston which is Dydrogesterone 10 mg- Orally – 2 times a day from CD14? Should I take it Vaginally? Does it hurt? What do you suggest? Should I take natural Progesterone instead of the Duphaston? If yes, would you please give me name of the medicine?

Unfortunately it seems there are not that good doctors over here, they are RE and Gyno. This is the 3rd doc. The 2nd doc believes that clomid will increase the endo because it produces eggs; and she sees endo thickness 7 or 8 mm is not bad!!! Dr. Ramirez, If you don’t mind to give me Online Consultancy and I will PAY for it (I can call). Write me a prescription with what should I take and when and how? For example estrace from CDx to CDx, and then XXX medicine from CDxx. (I can order them online)

I know that it sounds weird, but with the globalization and the existence of internet the behaviors and habits are changing. I will go to the doctor on CD14 (or whenever you think is the best) to do the ultrasound and then will let you know about the size of eggs, endo and so on :)

Thank you!

Answer:

Hello N. from Kuwait,

The Duphaston can be used vaginally. Progesterone is important to help with implantation. I would NOT recommend the Progyluton. It is used from hormone replacement therapy and cycle control. It is not used in infertility because of the Norgestrel. Although the Estradiol component is okay, and necessary to increase the uterine lining, the Norgestrel (progesterone) will compete with the estrogen and keep the lining thin. With this combination women don't usually have periods, which is the reason why it is used for menopausal hormone replacement therapy. In fertility cycles, the first half of the cycle needs to have unopposed estrogen stimulation so that the lining will grow. Then once ovulation occurs, the progesterone is introduced to help the lining convert to a luteal phase lining so that implantation can occur.

Your proposal for an internet consultancy is interesting, I will send you an email. I'll have to think about that one. In terms of your supplementation, I use the following protocol:

1. I use the estrogen patch for estrogen supplementation such as the Climara patch. I use two 0.1 mg Climara patches beginning at the start of the cycle and continuing until the pregnancy test. If it is positive, then I continue it until you are 10 weeks pregnant.

2. For progesterone, I use a product called Endometrin 100 mg vaginal tablets. You place 1 vaginally twice per day beginning on cycle day # 16, or beginning with the HCG injection if you use an HCG trigger for ovulation. You would then continue this until the pregnancy test or 10 weeks gestational age if you get pregnant. Other forms of progesterone that you can use in the same way are Prometrium 100 mg or Crinone/Procheive 8% cream.

If you look up my blog regarding how I do Clomid ovulation inductions, it will give you directions on how I recommend doing Clomid cycles. Normally, as the follicles are stimulated and grow, they produce increasing amounts of estrogen. This then goes to the uterine lining and increases it. The problem with Clomid, however, is the way it works. It blocks estrogen receptors in the reproductive system and tricks the brain into thinking that it is not producing enough estrogen. So the brain responds by increasing the amount of stimulation of the ovary, hence ovulation is stimulated or multiple eggs are stimulated. By blocking the receptors, however, it can cause the uterine lining (endometrium) to no grow sufficiently.

Don't stress too much over all this, please take your time and copy these instructions. Take the time to discuss this thoroughly with your physician and good luck!

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.