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.

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/

Young Canadian With Hydrosalpinx And Endometriosis Complicating IVF Cycle

Question:
Hello Dr. Ramirez,

I am 27 years old and last year stage 4 endometriosis was discovered and I had 2 large cysts removed from both my ovaries, one was 12cm and and the other was 5cm. My left ovary is almost completely gone and both my tubes are not functional. My hormones as far as I know it are normal and my antral follicle count is 8.

My first IVF with ICSI (my husband has blood in his semen due to unknown reasons) was last November with an antagonist estrogen priming protocol. I had 10 eggs retrieved, 5 mature, 3 fertilized, and ended up with 1 good quality day 3 embryo to put back. The cycle ended with a chemical pregnancy. I was on 400 puregon and 75 repronex.

I did my second IVF cycle with ICSI this month on the exact same protocol. They saw 11 follicles before my retrieval and 6 was retrieved, but none fertilized at all. My RE said that egg quality was very poor and may not suggest another cycle for me.

My questions are:
1. Is my endo the cause of bad eggs?

2. Will changing the protocol help better egg quality?

3. They noticed 2 small cysts on a recent ultrasound, and also a hydrosalphinx on the left. Would it help to have another surgery?

4. Do I have any hope in becoming pregnant with my own eggs?
Thank you so much for your information!

Thanks... A. from Canada

Answer:

Hello A. from Canada (Ontario),

I don't think that endometriosis is causing the egg problem, but that is certainly debatable. There are some studies showing better results if the IVF cycle is preceded by 3 months of Lupron depot in stage 3 and 4 endometriosis. There is definitely an effect if there are endometriomas that are penetrated at the time of egg retrieval. These endometriosis debris has been found to be detrimental to egg quality. Because of that, I am very careful to avoid the endometrioma at the time of retrieval, or if it is penetrated, I replace the needle and tubing before continuing.

In terms of protocol, you certainly seem to be stimulating well, which is the goal of the protocol and there are many variations that can be used. Each doctor has their own preferences. There is not one protocol that is better than another. However, I would probably use a stronger protocol if you were my patient (you are currently using a 475 combination protocol# such as a 600 IU combination protocol #450 FSH + 150 FSH/LH (Menopur)). Changing the protocol will not improve egg quality, but having more eggs may help with getting more embryos to work with.

If you have a hydrosalpinx, you definitely need to have that surgically removed or excised from the uterus. Numerous studies have shown a reduction in pregnancy rates with IVF by 50% if a hydrosalpinx is present. In the U.S. it is now considered the standard of care. The cysts are not an issue.

I am always hopeful for my patients, in terms of your last question, even those that have a minimal chance because they are way too old. I see exceptions all the time and believe in miracles.You are only 27 years old. Your chances should be much much better and I am leery of the results you have had thus far. Frankly, it doesn't make sense to me, but I would have to review your medical records to see what might be going on. At your age, you should not have an egg quality issue and fertilization should be at least 60%. In my clinic, your age group has a 76% chance of pregnancy per attempt. That makes me worried about the quality of the clinic you are going to. You may want to seek a second opinion.

Good luck and don't hesitate to keep me updated,

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.

IVF Protocol For High FSH

Question:

Dear Dr. Ramirez,
I am 39 years old in 2 weeks and about to undergo my first ivf (in vitro fertilization). I have only one fallopian tube, which an hsg has shown to be blocked, probably by adhesions (my other tube was removed due to damage from extensive adhesions - a reaction to previous surgery to remove a dermoid cyst on my left ovary).


My FSH level was 14 in March. Two weeks ago my FSH dropped to 8 and my AMH level was 7.42. An ultrasound scan and follicle count showed 9 follicles on my right ovary and 3 on my left (the ovary which the cyst was removed from).

My consultant has suggested the long protocol, as he thinks I will respond ok. I have read much about the short protocol being better for my age group, and if fsh has been high. I am anxious to get the correct protocol from the outset. What do you think my response might be, based on my levels? Do you think a short protocol would be better in my case? Many thanks, R. from the U.K.

Answer:

Hello R. from the U.K.,

The worst thing you can do is try to second guess your doctor, especially with information that you read on the internet. You are not an expert and don't have sufficient knowledge to make a proper decision. However, it is good to be educated regarding what you will be going through, and certainly, I have the knowledge to answer questions, so you can trust my input. But, given that you are not my patient, I don't have all your medical information and am not doing the procedure, the answers I give you have to be generalities and cannot be specific.

I personally don't criticize "protocol" questions because there is not one way or best way to do IVF. There are many different protocols and usually the specific protocol is based on the training and experience of your doctor. They all have the possibility to work. Some doctors stimulate less, some more, some use only pure FSh, some use mixed protocols, some use the long Lupron protocol, some use the antagonist protocol and some use the micro-dose flare protocol. There is not way to predict how any one will respond to any given protocol. But studies have shown no benefit to the micro-dose flare protocol (short protocol) in comparison to any other protocol, just as there is no study that shows that the long protocol is better than the antagonist protocol. I prefer the antagonist protocol because there are less injections in comparison to the long protocol.

Because you have had an elevated FSh level, despite it being lower more recently, you would still be considered a poor responder (or at least have the potential of being a low responder). For that reason, my preference would be to NOT inhibit your ovaries with Lupron in the stimulation phase, and only begin ovarian suppression once the lead follicles are at least 16 mms. This is the technique used in the antagonist protocol. With the long protocol, your ovaries are suppressed by the lupron starting from the previous cycles and may not respond as well. Before the antagonist protocol was developed, the micro-dose protocol was developed to reduce that suppression phase. Without criticizing your doctor's choice of protocols, my personal choice would have been different. But that is what makes Infertility doctors and clinics different and gives them different pregnancy rates.

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/

Woman Wonders: Natural FET Cycle Vs. Controlled FET Cycle?

Question:

Dr. Ramirez, I have some embryos frozen. I have adenomyois and endo and chronic endometritis diagnosed.

Have done antibiotic treatment with uterine lavages and IVs.

After depot lupron treatment, is it better to do a natural FET (frozen embryo transfer) or medicated FET. Since it takes about 2-3 months to wait for period to arrive is it better to do a medicated FET? I am concerned about medicated FET as the last time I did a medicated FET I had fluid in the uterus although nearer to transfer it disappeared and I did go on to transfer although BFN (big fat negative).

My RE seems to want to wait for a period before transfer but would not that waste 2-3 months since you said the endo can return in 6 months? Will the cycle be regular and as in ovulation or will it be not regular when I do FET. At the moment my cycles are regular. I have also heard of high dose progesteone treatments treating endo and adeno. Can you explain how this works?

I am confused what to do as we have limited embryos and want to do everything as possible as once the embryos are used up we are done.

Thank you. R. from Rhode Island

Answer:

Hello R. from the U.S. (Rhode Island),

Your RE should have explained that one of the critical steps in getting pregnant, natural or with IVF, is the state of the uterine lining at the time the embryo reaches it for implantation. We know that there is a very limited time that the embryo can implant and the endometrial lining has to be in a very specific and correct microscopic state for implantation to occur. This is where timing is absolutely essential. If you miss this "implantation window", then it will fail.

Conceivably you could do this with a natural cycle, but then there is a wider margin of error because we don't know exactly what the timing is or what is going on microscopically in the uterus. For this reason, we do not do this in FET cycles. FET cycles are always done as a controlled and programmed cycle. With this protocol, you can have a period induced artificially with medication and then start the cycle, but most clinics will want their patients to be on the birth control pill for at least two weeks period to the FET cycle in order to suppress the ovaries, which then allow complete control of the FET cycle.

If this is in fact gong to be your last attempts at getting pregnant, then I would make absolutely certain that you are in the best clinic that you can be in and that it will give you the highest chances of success. A good clinic would be able to answer these questions and make sure everything is clearly laid out.

Finally, in terms of progesterone treatment with endometriosis and adenomyosis, progesterone has suppressive action or counteracts estrogen in estrogen receptors. AS you probably know, endometriosis/adenomyosis are stimulated by estrogen and therefore, will be somewhat suppressed by progesterone. However, there is still some small amount of stimulation so progesterone is not the perfect treatment. Estrogen receptor blockers such as Lupron are better at suppressing endometriosis. Progesterone is used mainly to slow down the recurrence of the endometriosis after they have been treated with surgery or Lupron.

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.

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.

Young Canadian With Endometriosis: Will Have Six Month Window For TTC Post Surgery

Question:

Hi, I’m from Calgary, Alberta in Canada. I am 33 and my husband is 30, we are both healthy and we’ve been TTC unsuccessfully for 19 cycles. I have never been pregnant. We have been tested at the fertility clinic and told that there is no obvious reason why we shouldn't’t be able to conceive. I had blood work to check my hormone levels, an ultrasound to check my follicles and an HSG to make sure my tubes were open, my husband had a SA done and it showed good numbers and motility. He does have some antibodies, but less than 50%.

All that being said, I contracted chlamydia about 14 years ago, but it was treated quickly (I believe within 1-2 months). I have also been experiencing some symptoms of endo since going off the BC pill so I am a candidate for the laparoscopic surgery. The doctor said I could also try clomid or clomid with assisted insemination. I’m looking for additional guidance on how to proceed. Given that I have symptoms of endo, would you recommend that I proceed with the surgery before trying clomid or even IVF?

Thanks. J. from Canada

Answer:

Hello J from Canada,

You pose an interesting question and the answer will be based on personal desires.

Given that your infertility evaluation has been negative thus far, and you are only 33 years old, if you want to attempt pregnancy by natural means (intercourse or IUI), then you should proceed with the laparoscopy. This is the only method that can diagnose endometriosis. It can be treated at the time surgically and then followed with a 3 month course of medication (Lupron depot) to eradicate any microscopic endometriosis. You will then be free to try on your own or with IUI for the next six months. That is the window of opportunity. If the laparoscopy shows that the endometriosis is stage 3 or 4, then IVF would be indicated.

Certainly if you decide to proceed with trying by natural mean after the laparoscopy, I would recommend an aggressive treatment plan because you need to try to get pregnant within six months. After six months there is a high chance that the endometriosis will return and you will be back to square one. By aggressive natural means, I mean ovulation induction with Clomid, Femara or injectables and either timed intercourse or IUI.

If you don't want to do the laparoscopy, then the best option would be to proceed with IVF. That is the decision that my wife and I made when we faced a similar point in our infertility evaluation and treatment. This is because IVF will bypass any endometriosis and you won't have to undertake the pain or risks of surgery. But, it is the most expensive way to go.

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.

Indian Woman TTC For 3 Years, Has Endo: Danazole Or Lupron Therapy?

Question:

I am tryiong to concieve last 3 years. I did on 6 January 2011 report as follows:

H-Lap, D&C/ PT(HPE) done

Hysteroscopy--Ut cavity regular canal narmal B/L ostia seen.

Laproscopy-- Ut normal size. retroverted congestion, Small Seedling fibroid, both ovaries are normal size and healthy.

Both Tubes Patents and healthy.

B/L adhesions, Endometriotic patches seen on both sides.

Now i completed 2 months course with DANAZOLE (200) which i am taking daily twice, only one month left. after laparascopy on 6 jan my period come after 21 days i.e. on 27 of Jany and i started Danazole Therapy on 17 of Jan. but still my periods not come almost 18 days left.

I asked the doctor she said some women concieve with Danazole also and some may not, so first complete the course of one month then try to concieve with Letrofil and all medicine.

But now i am thinking i dont want to waste time so instead of continue with Danazole i want to take LUPRON Depo Injection. Please guide me is it right ? Or good for me altough its expensive,. Please tell me should i take only one injection of Lupron or more than one becoze already i completed 2 months course with Danazole. Also, when my period expected and when should i try to concieve doctor, i m very much crazy about child.

Thank you. S. From India

Answer:

Hello S. from India,

Danazol is a medication that is given for the treatment of endometriosis. It inhibits estrogen production and therefore ovarian function. Because of this ovulation will usually be inhibited and pregnancy is not possible. It will also cause you to not have periods. Sometimes you will get breakthrough (irregular) bleeding in the first cycle but by the second and third cycle, the periods will stop.

Lupron is another similar medication. It is slightly chemically different but does the same thing. I like the Lupron because it has less side effects than Danazol. Danazol is really an older treatment. We rarely use that anymore in the U.S. Instead, Lupron depot can be given as a 3.75 mg monthly dose for three months or an 11.25 mg single dose that lasts for three months.

Once you finish the three month therapy of either of these medications, you can begin trying for pregnancy. I would recommend aggressive treatment with either ovulation induction and IUI or IVF. You will have about a 6 month window before the endometriosis will return again. Endometriosis is usually given a stage from 1-4. If you have stage 3 or 4 endometriosis, you should go directly to IVF as the treatment of choice. If it is stage 1or 2, then IUI would be appropriate.

Good luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

www.montereybayivf.com

After Failing IVF Three Times 45 Yr Old Wonders, Higher Stim or Lower Stim? Use BCP?: I Recommend A High Stim Mixed Protocol & BCP

Question:

Hi Dr. Ramirez,

I am 44 turning 45 this June. I have had 3 failed IVFs - 1 didn't go beyond retrieval because I pre-ovulated so no eggs to retrieve. My recent failed ivf cycle I had 3 follicles 19mm, 18mm and 16.5mm. The biggest follicle had no egg, the second largest had a degenerative cell and the third an immature egg. I took 300 iu's of follistim and 1 vial of menopur increased to two mid cycle.

Can taking too little or too much meds (follistim/menopur) cause this outcome?

We are trying a gentler dose and using follistim instead of gonal f. My first few cycles I was taking 600 iu's of gonal f and 150 iu;s of menopur. They had me doing this protocol for months and I started to respond poorly to it. I insisted on changing the meds or trying a gentler dose.

We interviewed with a new doctor here and his approach is less is more, less meds and get better quality vs. quantity eggs. And is it true that the smaller follicles esp. women my age will have bad eggs? My last cycle debunked that whole theory because the dominant follicle or the two largest didn't have any eggs. The smallest follicle did have an egg but it was immature.

I know that on the average I produce 5-8 follicles per cycle. I think it's important to save as many of the follicles we can, we can't afford not to even if they have bad eggs in them. I am not young and producing 20 follicles. How much do you recommend women my age take in meds (follistim/menopur)? The new doctor wanted to put me on 150iu's of follistim every other day or maybe everyday? That did not seem enough? He only wants to stimulate the dominant follicle or larger follicles. I don't want to take so little that it doesn't stimulate enough or take too much that I can get overstimulated and not respond well. I know my body and I am very sensitive to the drugs. I have also used micro-dose lupron and I responded poorly to it.

What protocol do you at your clinic use on women my age? My recent baseline fsh is 8.6, E2 is 30 and my AMH 0.27. It started low and increased up to 0.7 taking dhea and in the last few months started to decrease. I have no other issues other than my age and thyroid disease but it's under control. Do you change dosage depending on blood levels, number and size of follicles? The doctors I went to never did that.

Do you use clomid or birth control pills? I am not fond of either of them but I have heard and read that if you are on clomid you third ivf cycle will be successful? I prefer to use estrace or patches over the birth control pill to suppress. Why do clinics use birth control pills? I have read clomid was found to give cancer to lab rats?

Your help is greatly appreciated. I don't have time to waste anymore.

Thank you, C. from New York

Answer:

Hello C. from New York,

In general I don't comment on specific protocols because each doctor has their personal preferences and there are none that are perfect or better than others. However, I don't think I like your new doctor's recommendations or protocols and I'll explain why.

The biggest hurdle that you are facing is an age related decline in egg quality AND a decreased ovarian reserve. There is nothing that can be done about the egg quality but the goal with IVF is to increase the number of eggs recruited and available in the hope that a good egg is still present and we can find it. So, the protocol is always to try to stimulate an increased number of follicles and hopefully eggs.

I have read studies where the argument is if you use a natural cycle (no stimulation or decreased stim cycle), the egg quality will be better, but I believe that to be nonsense. Why would decreasing the number of follicles or relying on a natural cycle (only one follicle) produce better eggs? That is illogical. The quality of the eggs are already predetermined. Stimulation or lack thereof does not influence its quality. Again, I believe that the only way to overcome the age factor is to try to get the maximum number of eggs out at a time. For this I use a high protocol or mixed protocol that is 450IU of follistim and 150IU of Menopur. I also Do Not Use Lupron (called the long protocol) because I think it is inhibiting the ovaries too much at the time of follicle recruitment. Instead I use an antagonist protocol where the antagonist is given for only 1-3 days.

The only time I will decrease the amount of medication is if the patient has gone through one or two IVF cycles and still the number of follicles encountered or eggs retrieved are few. I decrease the protocol because I don't want her to spend lots of money on medications if the increased amount is really not doing too much. The ovaries do get to a point where they won't stimulate much despite increased dosage of medications. Unfortunately, your ovaries sound like they are there already. Again, the reason for doing this is to reduce the cost of medications.

I do alter my dosages as the cycle goes on, but only if I am starting from a lower dose and the patient is not stimulating, in which case I increase the dosage, or if I start on a higher dosage protocol and she is stimulating too strongly, in which case I decrease the dosage. Other than that, the dosage stays the same for most of the cycle without alterations.

I would not even consider Clomid for an IVF cycle. Some clinics do again to decrease the cost of medications but multiple studies show that the injectables are superior to Clomid.

Finally, in terms of the birth control pill, I do use it. Several studies have shown a better response if preceded by birth control pills. It suppresses the ovaries in the cycle preceding the IVF cycle and there may be a rebound effect so that the ovaries stimulate better. Estrogen does not suppress the ovaries unless given in very high amounts such as with the birth control pill. I have read of clinics trying to do IVF after a natural "unsuppressed" cycle, but I don't think it makes much difference. The other reason to use the birth control pill is that it allows us to take control of your cycle so that we can be sure that timing is correct. Timing is absolutely critical with IVF. There is a very small window of opportunity for the embryo to implant and if you miss it, then the cycle will fail. Also, using the birth control pill helps with scheduling if you batch patients (put them in the same group).

I think it is meritorious that you are trying to achieve pregnancy with your own eggs at 45 years old, but you have to understand that pregnancies rarely occur after 43 even with IVF unless donor eggs are used. However, I always remind my patient that the oldest woman to achieve pregnancy through IVF using her own eggs was 49 years old. It did take her two years of doing IVF, so persistence can count if you can afford it and want to wait that long to have a child. But you also have to be realistic and not let your expectations be too high. I hope that your journey will go well nonetheless, and that you achieve your goal of having a child.

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.

Infertility Patient Worried About Side-Effects From Lupron Trigger Shot

Question:

Hello. I am about to undergo a cycle in which we will use Lupron as a trigger. I recently have read frightening stories of women who have had long-term, debilitating physical and cognitive side effects after using Lupron even once (usually to treat medical conditions). I am wondering if using Lupron as trigger shot could subject me to the same permanent, debilitating side effects. (I do have endometriosis, and I don't know if that makes one more susceptible to the dangerous effects of this drug)?

Thank You. L. From the U.S.

Answer:

Hello L. from the U.S.,

The lupron you are reading about is for the treatment of endometriosis and not the same dose that is used for the trigger. The endometriosis dosage is 3.75 mg or 11.25 mg, whereas the trigger dose is 0.5 mg. There are no known serious side effects from the Lupron trigger. Some mild side-effects might include: hot flashes, vaginal dryness, and headaches. If these side effects occur they will usually resolve after you start taking gonadotropins. After ovulation is triggered, there is no further need to continue on Lupron.

Besides, I and many other docs use full-dose Lupron for the treatment of endometriosis all the time and I have yet to have a patient with the horror stories that are published on the internet. Keep in mind that internet stories are not edited or filtered so you have to believe them carefully and with a little reservation.

Good Luck and don't worry,

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.

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.

Stage 2 Endometriosis Patient: Life & Fertility After Lupron?

Question:

Hi. My name is B. I am 26 and I live in Mississippi. I was diagnosed with Stage 2 Endo in June of 2009. Within 4 months of the lap (performed in June) I was already experiencing high levels of pain during urination, bowel movements and intercourse. My doctor had previously recommended Lupron, but I had declined so I went on continuous birth control. I still had high amounts of pain on a regular basis. I decided to do the treatment after the pain returned so quickly.

While on the shots, I didn't experience nearly as many hot flashes as I had expected and I only gained about 12 -15 lbs. I had my last shot about 27 days ago (3.75mg) and I want to know what I can expect.

When should I start having a cycle again? Also, I have had some mild-moderate pain during the last 3 months of my treatment and occasionally what felt like menstrual cramps. My doctor said he thought it was probably scar tissue.

Any thoughts on the pain I experienced during the second half of my treatment? Any thoughts on my statistical time frame for the possibility of having a family vs. infertility. My boyfriend is very cynical and doesn't believe my best chance at a family is within the next two years. How adamant should I be about going for it considering my circumstances? Thank you!

Answer:

Hello B. from Mississippi, let me answer your questions in sequence:

1. In general, the normal cycle will resume within 3 months of the last month of Lupron injections. That means, give yourself three months after the one month from the injection.

2. I can't explain the pain that you had in the last 3 months of treatment. Scar tissue is a possibility but the symptom is so nonspecific that I can't give a more definite answer.

3. In general, I advise patients to begin trying for pregnancy immediately after completing a Lupron treatment because there is a 6 month window before the endometriosis will return and inhibit fertility. If you are not in the position to try for pregnancy right away, then you should follow the Lupron with some type of prophylactic treatment to prevent the immediate return of the endometriosis. I recommend Depo provera but if you don't want to take this, then a low estrogen dose, high progesterone birth control pill is second best. Do not use a high dose estrogen pill (30mcg or greater) because the estrogen feeds the endometriosis. Again, Depo provera is my preference.

4. Lastly, I hope you don't mind this piece of advice: You should never insist on having a child with a partner. It needs to be a mutually acceptable proposition. Having a child is a life-changing event. You want your situation to be stable before then.

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.

Twitter with me at @montereybayivf and follow me on Facebook at http://bit.ly/9Iw9oV

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

Question:

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

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

My questions:

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

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

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

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

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

Answer:

Hello Alyssa from the U.S.,

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

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

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

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

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

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

Good Luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

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

IVF Poor Responder With Endometriosis And Nightsweats

Question:

Hello, Dr.

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

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

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

My hormone levels were taken several times.

FSH=3.84 E2=92.3? in JULY 2009

FSH=10.4 E2=52 in October 2009

AMH=1.4 in November 2009

I tried IVF in October 2009 and failed.

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

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

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

ANSWER:

Hello J. from the New Jersey,

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

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

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

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

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

Good Luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

www.montereybayivf.com

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

Question:

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

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

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

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

Answer:

Dear S. from Canada,

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

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

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

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

I hope this helps,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

http://www.montereybayivf.com/

Monterey, California, U.S.A.

South African Had Surgery for Stage 4 Endometriosis - Now What?

Question:

Hi, doc, I'm 30yrs old and recently had laparascopic surgery. I was diagnosed with stage iv endometriosis, most of it was removed. My fiance also has fertility issues. He was diagnosed with anti sperm antibodies. We are desperate to conceive and will meet our doctor next week to discuss our options. I would love your opinion on this matter?

Thank you, Regards from South Africa.

Answer:

Dear M. from South Africa,

Stage IV endometriosis is the worst stage that you can have. This has definitely been shown to impair fertility via natural means. The problem is that the endometriosis has now impaired the pelvis and this is the path that the egg must take in order to reach the tube. Both the scar tissue formed from the endometriosis and surgery, and the inflammation caused by the endometriosis will interfere with the egg.

Most women with stage III or IV will not get pregnant naturally and will need to go directly to IVF. To these women I first recommend trying naturally after surgery for a 6 month period. You can either try on your own or with IUI, it doesn't really make that much of a difference. Most RE's would treat with Lupron or Letrozole after the laparoscopy for three months to remove any residual endometriosis prior to starting with a treatment.

Since your problem is combined with your partner's problem, then you have two major strikes against you. That would definitely make me strongly recommend IVF as the treatment of choice. That is not to say that you could not get pregnant without IVF. I have had a patient with stage four endometriosis that became pregnant spontaneously. However, the statistical chances of pregnancy is 1% or less.

Thank you for your question and good luck!

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

www.montereybayivf.com

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