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.

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.

36 Year Old With 3 Miscarriages On Prometrim Using OPK : Continue With Calendar Method or Go For An Infertiity Consult?

Question:

Hi, My name is R. I am 36 years old living in Atlanta GA. My husband is 41 we do not have any kids and would like to have a baby.

In the past I have had 3 miscarriages. prior to my miscarriages, I had a hystersalpinogram(sp) when I was in my early 20's unblocking both of my tubes. Recently I had been diagnosed with Pcos and placed on Metformin 750mg 2x a day, although I have always had a regular period lasting only 3 days but it comes like clockwork every 28 days. So now let me bring you up to date. Today 08/15/2010 I had detected my LH surge via clearblue ovulation kit. But last month my doctor recommended the Clearblue ovulation test and prescribed me Prometrium.

I do not understand why I was prescribed the medication and 2 I am confused as to when to take it, the bottle says to take 3 days after ovulation, when is that? I just detected the LH surge so when should I begin taking it? In the meantime, shouldn't me and my husband be having intercourse to try and conceive? The Prometrium is a 30 count, so should I take the medication starting day 3 until its all gone? I am so confused and excited, I have never used the ovulation predictor and so I am surprised that I see this happy face, what should I do next? Beside sit and worry!

Thanks for your answer, I am anxiously awaiting to hear back from you.

Answer:

Dear R. from Georgia.,

I don't know why you have the diagnosis of PCO if you have very regular cycles, but there is a variant of PCO that you would fit into. You would not need to take Metformin, however. Did your doctor check an insulin level or how did he decide to put you on Metformin?

In terms of timing your ovulation, that is good but if you want to save yourself money, since you have such a regular cycle, the calendar method would work just as well. If using the OPK, when it turns positive, you begin intercourse (on that day#, once per day for four consecutive days #only one ejaculation per episode). With the calendar method, mark you calendar on the first day of your period then count each days in sequence. Stop having intercourse on cycle day #10 then on CD#13 begin having intercourse once per day for four consecutive days as explained above. In both cases, start the Prometrium on CD#16 and use it twice per day. Because this will suppress your menses, you will need to do a pregnancy test around CD#30.

You know, I need to emphasize that time is a critical factor in your case. I presume you have been trying for pregnancy for a while, so you & your husband really should see an infertility specialist. Your age, the miscarriages, previously blocked tubes and possible PCO diagnosis all indicate that it may be necessary. The specialist will lead you in the right direction, doing the tests that need to be done before starting an arbitrary treatment plan, and be the most efficient in helping you to get pregnant. Sometimes it may only take doing one Intra Uterine Insemination. With each year, your pregnancy rates are decreasing, even with the highest level of treatment, which is IVF, so don't waste time.

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.

Secondary Infertility, High Responder PCO Patient: Why Did I Fail Two IVF Cycles?

Question:

Hi, I am 28 years old and my husband and I have a naturally conceived 3 year old son. We are dealing with secondary infertility. We have gone through 2 IVF cycles.

1st IVF/ICSI cycle-21 eggs--11 fertilized (70% fert. rate)--transferred 2 great 8 cell embryos. None to freeze. Negative result

2nd IVF/ICSI cycle

19 eggs--(85% fert. rate)--8 embryos on day 3

1-8 cell grade 1 (best)

2-8 cell grade

21-8 cell grade

32-7 cell grade

22-5 cell grade 2

No transfer because of lining issues. Did one FET--ended in a chemical pregnancy.

My question--do I have poor egg quality? Lab results said some eggs were abnormal, with thicker zona. Any hope to go through IVF again?

I'm from Fargo, ND. Thanks in advance!

Answer:

Hello M. from North Dakota,

From the number of eggs retrieved, I presume you also had a high number of follicles (>20). That indicates that you are responding like a PCO patient, or have PCOD. Studies have shown that there is a decrease in pregnancy rates with PCO patients, probably due to a high number of immature eggs retrieved. It also seems to affect egg quality. That is not because you have abnormal eggs, it is probably because the PCO causes an inefficiency in egg maturation.I would not give up hope. In fact, I would encourage you to continue trying because you will be successful. It may take some more tries, and hopefully, your doctor will adjust your protocol to try to reduce your stimulation. It would be better to have fewer follicles with good eggs than lots of follicles with poor eggs.

By the way, I just had a patient from your end of the country, Montana, that previously went to a clinic in Washington state and had two failed IVF cycles. She was a secondary infertility patient as well. Well, the change in weather or location or clinic did the trick because she became pregnant with one attempt, and with twins. Infertility Physicians and clinics are not all equal. That may have a bearing on your success as well. I am worried about the fact that despite all the eggs, your embryo quality rate and number to freeze were so low. That might also indicate a laboratory issue.

In any case, don't give up hope. You will eventually be successful.

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.

Comment: Thank you for your insight! Very much appreciated! :)

Lupron trigger instead of HCG

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

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

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