36 Yr. Old Has Repeated Implantation Failure With Great Embryos...What's Wrong?

Question:

Dear Dr,

We have just had our 4th failed IVF (in vitro fertilization).

Our history.  I am 36, my husband is 39. 1st pregnancy was in 2009 after 3 IuI's (intra uterine insemination) and clomid, but had to terminate at 15 weeks due to large enphaloceale (was a random genetic mutation)and my 2nd pregnancy with IUI was a success with a full term healthy baby boy.

Started with IuI's for 2nd child in 2011! We had 10 IuI's and now 4 IVF's.  Each IVF has been with icsi (intracytoplasmic sperm injection) and this time we had Embryo hatching. Last 3 transfers were 3 top grade 8 cell embryos each time on day 3.  I am not a great responder and only ever have 5-7 eggs, of which usually 4 fertilise.

I have had all the immunity checks done, my husbands sperm dna damage is within normal, fertilisation rate is good.  My ovarian reserve was also checked and the level was 1.0- My specialist said that he wasn't overly worried about the reserve for my age.  I have had a hysteroscopy and all normal.  I have been on various drug protocols and this last one was the long Lupron cycle with menapur.

We are just not sure what to do next?  Do we keep going, as my doctors are very positive and we have the finances. Are my doctors missing something?  Is there anything else we can do to improve our chances.  I am on DHEA and Royal Jelly, and my hubby is also on supplements.

I am writing from CapeTown, South Africa.

Thank you for your consideration, R.

Answer:

Hello R. from South Africa,

The exact cause of your failure cannot be known as there are still four steps your embryo has to go through in order to produce a pregnancy: embryo has to develop to blastocyst, the blastocyst has to hatch our of its shell, it then has to attach to the uterine lining and the lining has to grow around it.  As of now, there is no technology that can make this happen.  "Assisted hatching" is just making a defect in the shell so that the embryo can exit (hatch) more easily.

Something I always worry about when I have patients tell me they have failed multiple cycles despite good embryos, is the quality of the final step of the IVF process, which is the transfer.  You can have the absolute best and perfect embryos but if the transfer technique is not done well, then it will fail.  This has been shown by numerous studies.  Since you have been going to the same clinic, I wonder if that is not the problem, in which case, I would recommend that you seek out a different clinic.

One thing that I do with my patients that is not universally accepted but done by many of us, is to use a recurrent miscarriage protocol to reduce the immune system, thinking that a heightened immune system might be at fault.  For this regimen I add low dose heparin or lovenox, medrol, low dose aspirin, extra estrogen and extra progesterone (both injectable and vaginal).  I don't think that DHEA does anything so I don't use it.

At 36 years old, I have a 66% pregnancy rate in my clinic.  By two to three attempts with good 8 cell embryos, you should already be pregnant.  Your rate should especially be increased over other 36 year olds since you have been pregnant before.  For these reasons, I think the fault may lie in your clinic and not in you or your husband. 

Good luck in your journey to have a second child,

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

 

Monterey, California, U.S.A.

A Step By Step Guide To The IVF Process: Steps Three And Four--Egg Retrieval

Dear Readers:

This is the fourth 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 continue to be posted over the next few weeks in installments.

STEPS THREE AND FOUR: EGG RETRIEVAL

Thus far, we have covered the first two steps in the reproductive process. In the natural process, the brain has sent signals to the ovaries to recruit and grow the follicle and mature an egg within. The same process has been done in IVF through stimulation by the fertility medications. The follicles have grown and the eggs within have gone through their maturation process. In a natural cycle, one follicle will rupture and the fluid will rush out, taking the egg with it, and empty into the cul-de-sac. The egg will then have to find its way to the fimbriated end of one of the fallopian tubes. Follicular aspiration is the way that IVF accomplishes the ovulation step so that the egg can be retrieved. It is also the method that the egg and sperm are brought together, and therefore, a substitute for finding and being picked up by the tube.

Egg retrieval is technically known as "transvaginal ultrasound guided oocyte (egg) or follicular aspiration". It is a relatively safe procedure and simply put, just a needle poke, like drawing blood. There are some potential risks to this procedure, as with all medical procedures, such as causing bleeding, infection, organ injury or pain but these risks are very minimal and rarely occur. As with all surgeries or procedures, the experience of the physician directly influences the risks. The more experience a physician has doing the procedure, the lower the risks. In many centers, some form of conscious sedation is used so that the patient does not move or feel pain. Despite the quick duration of the procedure, the ovaries are very sensitive and can elicit a large amount of pain. There are some clinics that do not use any sedation, however, and a few that still use general anesthesia where the patient is intubated.

Some clinics will use an Anesthesiologist or Nurse anesthetist to give the conscious sedation and monitor the patient during the procedure. The safety of this set-up is that the physician doing the procedure does not have to be distracted by constantly thinking about the patient’s vital signs, and thus will be able to concentrate fully on just the aspiration part of the procedure. Also if the patient has any difficulties, such as difficulty breathing, bronchospasm, inadequate sedation or increased movement, the Anesthesiologist can attend to it without the fertility physician having to stop the aspiration procedure. The procedure takes 5-20 minutes to perform depending on the skill of the physician, the number of follicles to be aspirated and whether or not the physician uses a technique of follicular flushing (rinsing out the follicle with culture media after the initial aspiration).

The procedure proceeds as follows:

The patient is placed into an operating suite or procedure room, vital sign monitors are placed, the patient is put into the lithotomy (or pap smear type) position and the sedation medication given. In some cases, sterile drapes are put in place, but this is not absolutely necessary. In most clinics, a vaginal speculum is placed and the vagina irrigated with sterile water. Betadine or similar antiseptics are NOT used because they could be lethal to the egg if the solution contaminates the aspiration needle. Local anesthesia is not used in this procedure. Once the vagina has been thoroughly irrigated, the speculum is removed. Just as was done with a vaginal probe to view and monitor the follicular growth, a vaginal probe is used to visualize each ovary, but in this case, a needle guide has been mounted to the probe. This needle guide is so that a needle can be directed to where the probe is pointing. The vaginal ultrasound probe, with the needle guide mounted, is then placed into the vagina once the patient is sedated, and a quick inspection of the ovaries are carried out to verify position and confirm that the follicles are intact. If ovulation had occurred prematurely, the follicles would be absent. The probe is placed toward one side so that it can clearly see one ovary.

With IVF, the ovaries usually fall into the cul-de-sac, a space behind the uterus, which is located just on the other side of the vaginal wall, so the probe is actually millimeters away from the ovary and the ovary can be seen clearly. In addition, the probe is almost in direct contact with the ovary. There is only a small amount of vaginal wall between the probe and the ovary. The needle can then be easily passed through the vaginal wall, into the ovary and into the first follicle to be aspirated. Once within the ovary, it can then be moved from follicle to follicle to aspirate (or vacuum extract) the fluid within the follicle. It does not need to be removed and reinserted for each follicle. Basically the physician will move from follicle to follicle aspirating each follicle until all the fluid is removed. If the physician uses a flushing technique, the fluid will first be aspirated then culture media is injected back into the follicle and aspirated. This is done several times. Some physicians use this technique because that is how they were trained. There is no advantage of using flushing over not using flushing on pregnancy rates, but flushing may help to make sure that an egg is either retrieved or not present, especially if there are only few follicles as occurs with poor responders. The downside of this techniques is that is lengthens the retrieval procedure and so more sedation medication is required.

If the egg within the follicle has matured, and assuming that there was an egg within the follicle because not all follicles have eggs, the egg releases from the follicle wall and is floating within the follicular fluid. The exact physiologic process is more detailed than can be explained here, but suffice it to say that the egg is surrounded by a layer that is congruent with the wall of the follicle. As it matures that connection slowly gets pinched off and the egg is released from the wall. If the egg does not reach maturity, it will usually stay attached to the wall. That is why it is important for the physician to determine when is the appropriate time to trigger the follicle with HCG and schedule the aspiration/retrieval. This is another place where the “art” of IVF comes into play and experience plays an important role. Usually once the appropriate follicle size has been reached, the trigger is scheduled so that it is 34-39 hours prior to the time of the retrieval. Most clinics will schedule the retrieval to be at 36-37 hrs.

So by aspirating the follicular fluid, the egg is retrieved from that follicle. The physician will work on one ovary at a time and aspirate each follicle on that side. Once that is completed, then he or she will move to the second ovary and aspirate all the follicles on that side. The follicular fluid with the egg is aspirated, using a specialized aspiration machine with a low aspiration pressure, into a tube that has been prepared with a special culture media. A special 16 or 17 gauge aspiration needle is also used. As the needle is placed into the follicle, the end of the needle can be seen via the ultrasound as a bright echo. This allows the physician to know where the needle tip is at all times to prevent injury to other structures.

The aspirated fluid, collected in a test tube (hence the name “test tube baby” ) is then passed to the embryologist. The embryologist empties the fluid into a small plastic dish and looks for the egg using a high powered microscope. Some of the tubes will not have an egg within because either the egg did not mature and release from the follicle wall, or there was no egg within the follicle i.e. the follicle was empty. Once an egg is identified, the embryologist will move it into a special petri dish or other prepared dish with culture media. This is the dish that the eggs will stay in as it develops into an embryo. The eggs will then be placed into an incubator that has a set temperature, humidity and gas content within so that there is a stable and idealized environment for embryo growth. Fertilization is then the next step in the process.

In the meantime, the patient is awakened, most don’t remember anything that has occurred and enjoyed a short sleep, and moved to a recovery bed or returned to her recovery area. My clinic has individual rooms where the patient is prepared for the procedure and then returned to for her post-procedure care. Many clinics have an open recovery room area, and each patient is separated by a curtain. She is then closely watched by a nurse for 30 minutes to 1 hour to make sure that the sedation has cleared her system, that she remains stable and that there are no signs of any complications. She can take fluids orally at this point (we don’t allow food or drink prior to the procedure).

Once she has met criteria for discharge, she is allowed to go home. My criteria for discharge is that she will need to be able to take and keep down oral fluids, that her vital signs, especially the pulse, remain stable and within normal limits, that she is able to sit upright without getting dizzy and that she can urinate prior to leaving the recovery area. Because we place an intravenous catheter and run IV fluids in our patients, she will receive sufficient fluid to have an urge to urinate by the end of her stay. Most patients will be able to walk out of the clinic on her own after this procedure. From a pain perspective, there is some cramping that occurs immediately after the procedure, but by 30 minutes it is mostly gone. It usually does not need anything more than a warm pad on the stomach or mild nonsteroidal pain medication to relieve the pain. Most patients will not need a pain medication prescribed when they go home. Patients are directed to remain at very light activity, what I call “couch potato rest”, for the duration of the day. They do not need to remain in bed, and I do not encourage it. They should not engage in any strenuous activities, even long walks, or intercourse for 24-48 hours. I usually will prescribe antibiotics for a short course to reduce the chances of pelvic infection, but not all clinics do this. It is also at this point that patients will start their progesterone supplementation which starts the luteal phase of the endometrium in preparation for implantation.

We will continue this discussion soon with the next installment, "Step Five: "Fertilization". 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/

Recurrent Pregnancy Loss (RPL) Workup Shows MTHFR: What Next?

Question:

Dear Dr. Ramirez,

I am 31 years old and have had 3 chemical pregnancies in the past 12 months. They have run a slew of genetic testing and a RPL (recurrent pregnancy loss) workup and all has come back normal with exception to the MTHFR test. I have tested positive for 1 copy of the MTHFR mutation. The nurse told me that because I was considered heterozygous that this was not a big deal. They prescribed me with a high dosage of Folic Acid. She said that it was likely not contributing to the repeat losses. I have been reading online and while the homozygous mutations seem to be more serious, there seem to be mixed reviews on whether this can contribute to early miscarriage.

Do you prescribe Lovenox or Heparin in this type of situation (only 1 copy?) Should I be concerned about this and demand that they treat it somehow? It doesn't seem like they are planning on doing anything besides the folic acid.

Also, given that this test has come back as it did, is there any other testing that you would reccommend that may be related to this? I am a little frustrated because this test was not originaly included in the work up and I had heard about it from online research and specifically requested it.

I just want to make sure that I am not missing anything.

Thank you,

D. from Boston

Answer:

Hello D. from the U.S. (Massachusetts),

The treatment for MTHFR (Methylenetetrahydrofolate reductase), is increased Folic acid (for more information MTHFR.net). But with your history of recurrent pregnancy loss or RPL, I usually will add the following to my patients, although there is not clear research backing it up if you are immunologically negative:

1. Low dose aspirin 81 mg starting with the start of the cycle

2. Low dose heparin 2000 units bid starting with the start of the cycle (you can substitute lovenox but it is more expensive).

3. Medrol 16 mg starting with the beginning of the cycle until ovulation then decrease to 8 mg

4. Increase progesterone supplementation of either Crinone 8% per day or Endometrin 100 mg three times per day starting after ovulation.

This cocktail has been shown to be effective in recurrent miscarriages (see Reproductive Immunology Associates for further information regarding immunological causes of miscarriage). My presumption is that you have had immunological testing, specifically antiphospholipid antibodies?

I hope this helps!

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

Implantation Problems & Causes Of Chemical Pregnancy

Question:

Hi again, it's K. in NY. I have written to you in the past about my difficulties staying pregnant. I have had 7 chemical pregnancies in the past 18 months and one miscarriage at 9 weeks after using femara (you felt it was probably due to a respiratory virus I contrated around 6 weeks). I tested positive for MTHFR mutation heterozygous but also this didn't appear to be the issue.

I guess I have a 2 part question for you. The first would be related to causes of chemical pregnancies. My progesterone levels have been on the low side of normal (even during the pregnancy that ended in miscarrige) and I really thought that was the cause. I was placed on 50 mg suppositories 2 months ago and I did get a positive result this month (8 DPO Hcg 12, progesterone 18.8, took femara and progesterone) but my HCG level was back to <5 on 10 DPO.

Are there other implantation issues that could be my problem besides chromosomal abnormalities and low progesterone that lead to a pregnancy not progressing? I know I shouldn't test early, but I was trying to establish if low progesterone levels were the cause of my losses.

Part 2: is it possible to just have an underlying HCG level that elevates above 5 regularly, and if so, what would that signify? As you may remember, my old RE wrote off the HCG values as me eating too much cereal and developing an antibody to HCG that triggers pregnancy tests. I will be visiting a new RE soon and want to be sure to ask the right questions and supply the best information.Thank you very much for all of your insight and for volunteering your services. Merry Christmas!

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

Let me take the second question first since it is the easier of the two to answer. The answer is NO, you can't have an underlying HCG level from cereal or any other source other than pregnancy. Serum pregnancy tests are very sensitive and testing for the beta subtype (bHCG), so there is no cross reaction even if the cows you were using the milk from were given hormones for some reason (I presume that is what your old RE was thinking as a source. A little far fetched if you ask me).

In terms of your chemical pregnancies, that is a difficult problem to answer. If you have already undergone a complete recurrent miscarriage evaluation (hormones, infectious diseases, anatomical, genetic, immunologic) then we may not have the technology to find the exact cause. However, the hormonal is easy to check through blood tests, and I automatically place my patients on progesterone supplementation just in case; anatomical testing would take an ultrasound and hysteroscopy, again an easy test; and infectious diseases and genetic are also easy to test. The only one that is difficult and not completely understood is the immunologic component. Many authorities have looked into many different immune factors.

If you look at a website by Reproductive Immunology Associates, who have made a practice of the immunologic causes of miscarriage, you will see lots of different test that they recommend. Because this component is so difficult to define, experts have conflicting opinions.

If you were my patient, I would put you on a protocol that I use and, for the most part, have been successful with. It involves taking aspirin 81 mg per day starting at the beginning of the cycle, medrol (prednisone) 16 mg per day taken from the beginning of the cycle then decreasing to 8 mg after ovulation, progesterone vaginal suppositories beginning after ovulation and, finally, heparin 2000 units twice per day subcutaneously beginning at the start of the cycle. The aspirin, medrol and heparin treat for subclinical immunologic problems and the aspirin and heparin also help to increase blood flow at the microvascular level at the implantation.

Good Luck & Merry Christmas to you too :) ,

Dr. Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
http://www.montereybayivf.com/
Monterey, California, U.S.A.

Comment: Thank you SO much for your opinion. I will definitely have to look into these additional things. Glad to hear that I am doing all that I can do on my own and that I am advocating for the right things. It makes a HUGE difference when you have an idea what direction you should be headed so that you can work with a doctor to get there. Merry Christmas!

Progesterone After IVF

Question:

My wife had IVF (in vitro fertilization) in Canada. She was prescribed Gonal-F, Repronex and Orgalutran for the stimulation phase. Two blastocysts were transferred at day 5 and yesterday our day-14 serum HCG pregnancy test was positive.

We were told by the nurses at the fertility center to stop taking the Prometrium pessaries now that the pregnancy test is positive. From reading, Progesterone seems to have many beneficial effect to the fetus, with minimal adverse effects. I think continuing progesterone supplements until the 10-12th wk is important. I am not sure why they want my wife to stop this!

Can you advise? A. from Canada

Answer:

Hello A. from Canada,

Your research is correct. Most IVF programs, if not all, will continue the progesterone until at least 8 weeks. I continue until 10 weeks and some programs will continue until 12 weeks.

I see that your center had your wife on progesterone pessaries (suppositories). For those others reading this post, there are different forms of progesterone to choose from:
• Daily oral progesterone
• Daily intramuscular injections (IM)
• Daily vaginal pessaries. These are mounted in wax, which melts as progesterone is absorbed causing discharge. It may be necessary to wear a panty liner.
• Daily vaginal tablets
• Daily vaginal gel

There are several formulations of vaginal progesterone: Crinone 8%, Prochieve 8%, Endometrin 100mg and pharmacy formulated versions. Several very good studies have shown equal efficacy to IM injectable progesterone. However, most RE's are trained on IM Prog and so don't want to make any drastic changes. I happen to use both. If a patient cannot tolerate the IM Prog or has an allergic reaction to it, then they can switch to the vaginal version.

Bottom line: There is no harm in continuing the progesterone, but if removed prematurely, it could jeopardize the pregnancy.

Good Luck and Congratulations,

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

IVF Patient Has False Negative On Pregnancy Test: Late Implantation? What Went Wrong?

Question:

Dr.Ramirez,

I have written to you in the past and you have always been such a great sounding board. I need help and closure and I am hoping that you can help.

In September I went through IVF (in vitro fertilization). On 9/7 I transferred 2 embryos- 1 7cell grade AF and a 4cell grade BF. On 9/16 I had some light spotting and cramping. My beta was on 9/19 (12dp3dt)was negative & my RE instructed me to stop taking the PIO & Estrace. A few days later, what I thought was my period arrived. It was a medium flow w/some small clotting & lasted about 4 days & stopped. A couple of days later, I started bleeding very heavily & passing large clots. I went in to see my RE. She conducted an Ultrasound & some blood work to make sure I wasn't anemic. At that time I asked her to run a pregnancy test. She said that there was no way that I could have been pregnant but did it anyway. The next day she called to tell me my beta was 512!

I am absolutely devastated. I can't believe that I was pregnant the whole time. My RE is calling it a biochemical pregnancy and is saying that it probably wasn’t a healthy pregnancy but I am getting the feeling that they are trying to place blame elsewhere. I feel like I need some questions answered by a neutral party. I am having a hard time moving on so maybe you may be able to offer me some closure.

1.Should something have shown up on the beta 12dp3dt? If not, do you think it was a lab error?

2.Could it have shown as negative because of late implantation? If the cramping/spotting on the evening of the 16th was implantation, would HCG have shown up on the morning of the 19th?

3.I have a luteal phase defect. What effect/impact would stopping the PIO and Estrace have on the pregnancy? Do you think that stopping meds was the reason for the miscarriage?

4.My beta was 512 after bleeding for over a week (heavily). I would think it was much higher to start. Do you think that this would have been a healthy pregnancy?

5.Should the clinic have done a 2nd beta?

6.Any suggestions on where to go from here? Any help would be greatly appreciated.

D. from Boston, MA

Answer:

Hello D. from the U.S. (Boston),

Certainly what you have gone through is very unusual and unfortunate. It shows that late implantation exists. I usually do my first bHCG at 8-9 days post embryo transfer. I do two bHCG's, one at that time and another 48 hrs after. I have had a successful pregnancy case where the first bHCG was negative (<1) and the second positive (14) that went on to deliver a beautiful baby. Keep in mind, however, that there are no specific protocols regarding how many bHCG's to do and it is totally up to the medical director of your clinic.
I cannot answer the question about the cramping and spotting on the 16th. If you have a luteal phase defect, then yes, stopping the supplemental hormones can lead to a miscarriage. There is no way to know if this was the reason for your loss because there are many other possibilities as well, such as an abnormal embryo. I cannot answer your question about whether or not this pregnancy would have been healthy. The number was certainly a good and high number.

What is important to keep in mind at this point: This experience showed that you can achieve pregnancy. IVF only has the capability of giving you the opportunity to become pregnant. It cannot force a pregnancy on you. Keep in mind that the last two steps required to achieve pregnancy, embryo hatching and exiting the shell and implantation are natural steps. We don't have the technology to make these happen. That is why I say that IVF can only give you the opportunity. The last steps are in God's hands. The fact that implantation occurred (positive bHCG) shows that the last two steps took place and you can do it again.

Now you just have to maintain your hope, diligence and savvy. You've gotten this close. After all that you have been through, why would you not keep trying? Hopefully, the next one will be a "home run" or "touchdown" depending on which sport you prefer. If you don't try, you certainly won't be any closer to success, so don't give up!

Good Luck,
Dr. Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
http://www.montereybayivf.com/
Monterey, California, U.S.A.

Progesterone Supplementation During An IUI Cycle

Question:

Hello Doctor,

I have been TTC since the past 15 months, I have irregular menstrual cycles. My husband has no fertility issues. I have been undergoing treatment - clomid, ovidrel followed by IUI (intra uterine insemination) since the past 3 months.

My luteal phase is 14 days long. I get a .8/1 degree increase in temperature the day after ovulation.This time ( 3rd IUI ), my RE asked me to take a vaginal progesterone supplement 2 days after the IUI.

There have been no tests performed to find if there is Luteal phase defect. I am scared/apprehensive about taking the progesterone supplements and I think my hormonal levels should be okay as my LP is 14 days long. Can you advise ? Your advise/suggestion on this matter will be much appreciated. Thanks in advance ! S. from California

Answer:

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

I prescribe progesterone to ALL my infertility patients undergoing treatment. It is an easy medication to use, will cover any possible deficits in progesterone level that could impair implantation or continuation of the pregnancy and has no side effects. I think you should have been doing this from the first IUI treatment. I usually start it the day after the IUI.

You are correct that you don't have a luteal phase defect because your luteal phase is 14 days, but the additional progesterone won't hurt and it will make sure that you have adequate b-Integrin development, which is what is needed for implantation at the cellular level.

Good Luck,
Dr. Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
http://www.montereybayivf.com/
Monterey, California, U.S.A.

Secondary Infertility Patient With Seven Miscarriages: Cannot Afford IVF

Question:

Hello-I am 33 and have a healthy 3 1/2 year old daughter who was conceived naturally. I have had 7 miscarriages (1 before my daughter and 6 consecutive since her birth). I have had 4 chemicals, 2 confirmed blighted ovums and 1 xxx69..this one had a heartbeat and all hormones were great, heart stopped at 8 weeks and did a karyotype on fetal tissue.

I've been to an RE and have had the following tests: Karyotype, HSG, Day 3 Hormone Panel, Clotting Disorder Panel, ultrasound to measure lining of uterus and to check for any abnormalities...all results are "normal". I have also supplemented with progesterone after a positive pregnancy test as well, my LP is usually 11-12 days. My hubby has only had a karyotype and he is "normal" as well. The RE said that our XXX69 was more than likely due to a mutated sperm containing an entire extra set of chromosomes. He has recommended we do IVF (in vitro fertilization) with PGD (pre genetic determination).

Our insurance doesn't cover ANY fertility, so that is really not an option for us.The RE wanted to me to try a monitored clomid cycle as a plan "B". In doing some research, I just don't think clomid will help with unknown recurrent pregnancy loss...what is your opinion? I "O" just fine without any meds. What else would you recommend? I am in excellent shape, eat organic whole foods, don't consume any alcohol or caffeine..

I take prenatals and fish oil daily. Do you think that all my miscarriages could be a sperm issue? I'm really at a loss....what do you think our chances are of having another healthy child without doing IVF/PGD? Thanks, S. from Maryland.

Answer:

Hello S. from Maryland,

I am sorry for your losses. You certainly have recurrent abortion as a diagnosis, but the exact cause is unknown. Granted that the fetal tissue from the last miscarriage showed a genetic abnormality, but if your husband's genetic testing was normal, then I would not expect that all the miscarriages were for the same reason. I would think that it is more likely to be a spontaneous genetic abnormality occurring with division of the embryo. Hopefully that is the case because that means that there is still a good chance of having a normal pregnancy. If the problem is a sperm abnormality causing a genetic problem, then there is very little that can be done to change that other than using donor sperm.

One alternative would be to try IUI (intra uterine insemination), since the sperm will be washed and the best sperm will be made available for fertilization. There is no guarantee with this but it is an option. Your RE is correct in that the only way to make sure that a normal embryo is available for implantation is to do preimplantation genetic screening with IVF. Since you cannot do IVF, then the only option is to continue to try and hope/pray for the best. I do not think you need to do Clomid either. It doesn't help with this problem. The good thing is that you are still young and have time to keep trying. Hopefully with continued trying, you will be successful.

If you were my patient, I think I would add low dose aspirin 81mg per day, PNV with folic acid, Medrol 16 mg per day, progesterone supplementation in the luteal phase (Crinone or Endometrin) and low dose heparin 2000 unit injections twice per day with each cycle. These are more to cover the immunologic causes of miscarriage, but have been shown in numerous studies to help. Since we cannot be sure exactly why the previous miscarriages occurred and can't conclude that it is ONLY a genetic problem, I would favor covering those bases.

Good Luck,

Dr. Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
http://www.montereybayivf.com/
Monterey, California, U.S.A.

40 Yr Old German Woman With Great Ovarian Stim Fails IVF: Likely Abnormal Embryos, Try Again!

Question:

Dear Dr. Ramirez,

My name is A. from Germany, 40 years old, never pregnant before. I had 2 failed IVF this year (1 in March, 1 in June). My FSH=10.6, AMH=0.8. progesterone level is normal.

The 1.IVF had 6 eggs (2 embryos were transferred: 1 grade 1 and 1 grade 2) and 2.IVF had 7 eggs (3 embryos with grade 1 were transferred in July).

The 2.IVF was done in North Cyprus. Do you think the failure was caused by taking airplane back home on the 2.day after transfer? It was just about 3.5 hours flight.I will try the 3.IVF this year.

How long should I take a break before trying the 3.IVF? Because I heard that the hormone level, uterus lining and ovary need time to get back to normal. Are these correct? I have also read an answer of yours regarding implantation failure.

You wrote in March this year:

"My approach to patients with implantation failure is to add the following medications:
1. Aspirin 81 mg per day beginning at the start of the cycle.
2. Heparin 2000 units twice per day beginning at the start of the cycle.
3. Medrol 16 mg daily until transfer then 8 mg from that point until positive pregnancy, then stop.
4. Increase progesterone to 50 mg injection plus Endometrin 100 mg twice per day vaginally. The injections starts on the day of the retrieval and the suppositories start the day after the transfer. "

My questions are:

1.what for an effect is the heparin in the case of repeated failure? I did not have this in the last 2 IVF. Do I need this, even I do not have thrombosis problem?

2. Do I need to increase my progesterone level even I have a normal level?

3. I will do an autoimmune test next month. Which tests should I do in addition?Thank you very much for your time. Best Wishes. A.

Answer:

Hello A. from Germany,

I was impressed to see that your ovary stimulated well and gave you an adequate number of embryos despite your age and elevated FSH levels. One thing to keep in mind is that despite having a good IVF cycle with reasonable embryos, IVF is not a perfect technology. The last two steps, embryo hatching and attaching to the endometrium and implantation, must occur naturally. This does not always happen. Also the embryos have to be completely genetically and otherwise normal. There is a higher chance of abnormal embryos with increasing age. That is what is called the "Age factor."

What that means for older women (35 years and older) is that it may take a lot more attempts to achieve a pregnancy, but as long as the ovaries still respond and put out eggs and embryos, then you have a good chance. Also keep in mind that pregnancy rates are highly variable among clinics so the clinic you go to is very important.

With multiple failed attempts, I add the protocol that you cited. There is a saying in the U.S. called "throwing in the kitchen sink" which basically means doing everything you can possibly do. That is the reason for this protocol. These medications are mainly used in patients that have recurrent miscarriages. But in IVF failure patients, it seems to work as well.

The Heparin and aspirin are at low doses so they are mainly targeting very small clots that occur in the micro-vessels that feed the implantation site. It is not enough to prevent a large clot in your vasculature. At that level they also have an anti-immune action to prevent failure due to an increased immune response from your body. That is also the reason for the Medrol or prednisone. It is an anti-immune drug. Some women are found to have an increased immune system when an antiphospholipid antibody screen in done (21 points). Finally, the increased progesterone is to insure that adequate progesterone is reaching the endometrium because this hormone is vital to implantation and survival of the pregnancy.

Travel is not an issue. I have many patients that come to me from far away places, yet they have been successful. Studies have shown that travel has no impact on pregnancy rates. What is more important is finding a good IVF center that uses state of the art techniques and has good pregnancy rates in your age group. I have many patients that come from Europe so that is always an option as well.

Good Luck,

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

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

Question:

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

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


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


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


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


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


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


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


Thank you! K. from New York

Answer:

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

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

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

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

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

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

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

Good Luck,

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

Secondary Infertility With Miscarriage And Possible Luteal Phase Defect: Is Clomid OK?

QUESTION:

Hi Dr. Ramirez. Here I am writing again. I previously emailed you, I had a miscarriage in Feb 2010, at about 7 weeks. I have a 4 year old and a 3 year old, conceived the first month I tried with both. I also got pregnant the first time with the miscarried pregnancy. Since March I have been trying to get pregnant and nothing has happened. I have been getting my period every 25-27 days, and the last 2 months I have been doing BBT charting so I am pretty sure I am ovulating. I had hormonal blood work done in June and another estrodial draw in July and all were within normal range, Although the estrodial was a little low.

I had an HSG procedure last month; normal tubes and uterus. Now we have to have my husband's sperm checked. It has been 8 months now and for the last 6 weeks I have been having acupuncture/taking chinese herbs, to strengthen my uterus and help me relax. I have told you before that my periods are shorter and lighter since the loss, the tend to start and stop and the flow is very limited. My obgyn has now suggested that I start a low dose clomid to see if that will help me.

I have read your blog and I understand that you do not agree with clomid for people that already ovulate on their own. I am wondering if you think I should see a specialist. Also, since I have started charting I have noted that my cycle last month was just 25 days, and from the temp drop indicating ovulation to the start of my next period was only 9 days (luteal phase). This month the luteal phase was 11 days. My obgyn said that the way they would help that would also be through clomid. I thought, from reading your blog that progestorone is only suggested. If I start the clomid, do you think I should also ask for estrogen since my period is so short.

I am trying to relax doctor, but I am worried that I won't be able to get pregnant again. I am 31 years old. My husband is 38. Thanks in advance for your time and advice. J. from the U.S.

ANSWER: Hello Again,

Thank you for following my blog.

I think you misunderstood a little. I don't disagree with ovulating patients using Clomid, I just don't like docs who turn to that immediately in ovulating patients without having done a full infertility evaluation. There certainly is a place and time to use Clomid in ovulating patients, and we call that "super-ovulation". I use this especially is older patients to help them ovulate more than one egg at a time to increase there chances because as a woman ages, more and more of her eggs are debilitated and poor quality. By increasing the number ovulated, you increase the chances of getting a good egg.

In your case, even though you are ovulating, your luteal phase is too short. It is likely that you have a luteal phase defect. Your doctor is correct that Clomid can correct a luteal phase defect, although not always. What it does is correct the ovulatory-hormonal problem that is leading to the LPD. In addition, by getting you to ovulate more than one egg, it increases your chances for a pregnancy with each cycle. But, because it doesn't always correct the LPD, the treatment of choice would be supplemental progesterone such as Crinone, Procheive, Prometrium or Endometrin. You would start that after ovulation.

If you continue to fail to conceive, my recommendation would be to see a fertility specialist, instead of undergoing treatment that is more of a "shotgun" treatment. That way you don't waste too much time. But if you want to try some low dose Clomid with your current doc, that would be okay too. The advantage you have is that you are still young. If the low dose Clomid does not work, or your doc is not doing the cycles correctly, then definitely go see a fertility specialist.

I don't think you need supplemental estrogen.

Follow Up Question (Sometimes Great Things Happen When You Least Expect!):

Hi Dr. Ramirez,

I just wanted to repost and thank you so much for all your help and advice in taking the time to answer my questions over the last several months.Your answers to my questions and that of many others have always been honest, reassuring and optimistic. I never got to take the clomid, I was supposed to start January 2011, but with prescription in hand, I instead bought a HPT and I am now 10 weeks pregnant! So yes, a bit more patience and relaxation helped...9 months after my miscarriage I am pregnant. I saw the heartbeat at 6 weeks 7 days and again at 9 weeks 3 days, so I know we are not in the clear yet but we are headed to 12 weeks!

My OBGYN said that once you see the heartbeat, there's a low chance of loss. I am also taking prometrium (spelling) progesterone by mouth. My levels were good in the beginning, but my doc is just being safe with me. Is around 10 weeks gestation the time you have your patients stop taking them? Just wondering what your protocol was.

Thanks again! Keeping my fingers crossed that everything will go smoothly this time around!

J. from the U.S.

Follow Up Answer:

Hello Again,

Thank you for the kind words and CONGRATULATIONS! Once the pregnancy reaches 8 weeks and the size is appropriate for dates and the heart rate at 120 or higher, the chances of a miscarriage drop to 5% (from 40%). So, you are in a very good position for this pregnancy to keep going.

One thought: Studies have shown that progesterone (prometrium) orally does not help with luteal support. Too much of the chemical is lost in the liver. For that reason it is usually used vaginally. I usually will stop it at exactly 10 weeks gestational age, but some clinics will keep going until 12 weeks. By 10 weeks, the placenta has taken over so it doesn't do much. I think the extra time is for peace of mind.

Good luck with the pregnancy and congratulations again.

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: Excellent source of information from Dr. Ramirez. Highly value his thoughts and advice!

HCG Trigger Shot Must Be Timed With Ultrasound Surveillance NOT With Calendar Dating When Doing IUI

Question:

I am writing from Hawaii with several questions. We will be undergoing our first IUI soon. The background is the following: I am 36 years old with no fertility factors. We decided to seek out fertility help because my husband, also 36, has an ejaculatory issue. I have been using Follistim AQ for the past 10 days and have two more days to go. My doctor instructed me to use my hCg shot at 11pm the night before my IUI. My first question is this, with only a 13 hour window between my hCg shot and IUI is this optimal? I have read that 36 hours is best.

Also, my normal cycle length is 26-27 days, I will be inseminated on day 16, will I still follow my normal cycle and expect to see my period on day 26? Should I ask my specialist for Progesterone supplements? I had 5 decent sized follicles 5 days ago, all between 10 and 12mm. Today during my ultrasound only 2 follicles were visible, one at 14mm and one at 15mm. I have been using a ClearBlue Easy fertility monitor, which said 3 days ago I was reaching peak fertility. Is it possible I already ovulated one or more egg? Thank you so much for your time. My doctor is a good doctor, but very busy and I often don't formulate my questions until after I have left the office. Mahalo! H. from Hawaii

Answer:

Hello H. from Hawaii,

First, let me say that I am a little skeptical of your doctor, based on your questions.

The optimal size for a follicle at ovulation is 18-20 mms. Using Follistim, your cycle should not be timed based on a calendar, but on the growth and size of your folllicles. In addition, at your age, the maximum number of ovulatory follicles should be no more than 3 because of the significant increased risk of a super-multiple if there is more than 3. So, the proper way to do this is daily ultrasound, if necessary, as your follicles reach closer to the 18 mm point. Once the follicle is 18 mm (my personal preference is 20mms), then the HCG shot is given and the IUI is done at 36 hours if only one IUI is done or at 24 and 48 hrs if two are done (My preference is the two IUI protocol).

The times don't have to be exact. The sperm just needs to be there reasonably close to ovulation and precede ovulation. Since it cannot be known exactly when ovulation occurs and it is know that it can take up to 12 hours for the egg to find and enter the tube, exact timing cannot be done. In general, follicles grow at 2mms per day but this can vary as well. That is why close ultrasound surveillance needs to be done as you get closer. If your doctor solely uses a calendar date, such as cycle day #16, there is a possibility of missing ovulation, which essentially dooms this cycle. In any case, based on a 27 day cycle (and counting backwards), you would ovulate at around cycle day #13 not #16.

I ALWAYS supplement with progesterone. It is an easy thing to do and there is no downside risks. If you have inadequate stimulation of progesterone in the luteal phase, you risk non-implantation and/or early miscarriage. I hate to take that chance when I can cover the risk by adding a little progesterone. I have written extensively regarding timing and doing IUI's in my blog. I would recommend you review that material and discuss your concerns with your physician.

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.

Alaskan Worried After First Miscarriage: Was The Cause Low Progesterone? No!

Question:

Hello, I am writing to you from a remote community in Alaska,

We have a clinic and Doctors here but, no hospital or specialists, so I am glad to have found your site and hope to receive an answer to my concern. I suffered a miscarriage on Jan 10th at 8 weeks. For the year leading up to my pregnancy I had mid cycle bleeding starting around 7 DPO. I now believe that I bled and lost my pregnancy due to low progesterone.

My MD here in town tested my levels on days 10-12-14 post ovulation and the results were 7.8 - 17.9 - 20. She says these are all normal and I can try again, but everything I see online says the numbers are in fact low and supplements should be started after I ovulate next. I also have been BBT charting and my temp drops to pre ov levels within 2 days of the ovulation spike and stays low. Do you see a low progesterone issue here and would you recommend suppositories? Please respond as I am so confused and somewhat upset that the info I am getting from my Doc. does not match the info on the web. Thank you so very much for taking the time to consider this.

I appreciate it more than you know. S. From Alaska, USA

Answer:

Hello S. from Alaska,

Thank you for writing me with your concerns. Progesterone levels measured at the mid-luteal phase do not make the diagnosis of luteal phase defect. They are mainly used to confirm ovulation. Any level above 10 confirms ovulation if the test is done in the mid-luteal phase (CD#20-22). In order to make a diagnosis of luteal phase defect, an endometrial biopsy would need to be taken at the end of the cycle to check for endometrial dating. This is usually done around CD#26-28 (before your period starts).

Progesterone is such a simple treatment with no side effects and much benefit that I do not see any harm from using it after ovulation. We certainly use it with every type of fertility treatment that we give. There are two that are made specifically for infertility treatment called Crinone and Endometrin. Another one that is used is called Prometrium but is not specifically for infertility use. You would start the supplementation on cycle day #16 and continue until a pregnancy test is done at the end of the month. Do not stop the medication until a pregnancy test is done and do not wait for a period because the progesterone will likely prevent that from occurring. If you are pregnant then you would continue it until you are 10 weeks gestational age.

Now with all that being said, a lack of progesterone is NOT the reason why you miscarried. The placenta takes over progesterone production at the 6th week so a luteal phase defect or lack of progesterone would not cause a miscarriage at that point. It is usually earlier. The most common reason for a miscarriage in the first trimester is a spontaneous chromosomal defect that occurred at the time of embryo division. This led to an abnormal embryo, which the body detected and stopped. It is most likely that you will have a successful pregnancy subsequently.

You have to take the information you find on the web with a very large grain of salt, and don't try to micro-interpret what may or may not have happened or is happening. Since you were able to get pregnant naturally before, you chances of a successful pregnancy are high. We don't worry about recurrent miscarriages until there have been at least three consecutive miscarriages. Keep trying!

Good Luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

www.montereybayivf.com

Can Progesterone Be Given With Clomid Induction? PCO Patient With 3 Failed Cycles Wants To Know...

Question:
I'm 31, never pregnant. Dx PCOS, receiving metformin 1500 mg a day. Three cycles with clomid with no ovulation. HSG normal, husband semen analysis OK. Now going through second cycle of IUI (intra uterine insemination), ovulation stimulated with Gonal F and triggered with ovidrel.

First cycle progesterone level on day 3 after second IUI was low (2.3), so I asked the doctors why they can not prescribe progesterone to improve luteal phase and make implantation more possible, and they told me they do it only with IVF. Is this Ok? What I mean is, why don't give progesterone if the level is low, and it is know than low progesterone impairs implantation and also increases risk of miscarriage in first trimester? Please give me some advice, or some reference articles where to read about this (scientific articles to support my request) Thank you! S. from Arkansas

Answer:

Hello S. from the U.S.,

You have a very valid question and you should ask your doctor why they don't give progesterone after intra-uterine insemination. I'm sure there are many articles on the web that you could find that advise this technique. There is absolutely no reason not to give progesterone after IUI or even after simple ovulation induction.

However, I think that your thinking may be incorrect, however. If the ovulation induction were proceeding correctly, and ovulation occurs, then the hormones should be corrected and there should be a normal luteal phase. Usually a mid-luteal progesterone is not to see if there is adequate progesterone for implantation, but to see if ovulation in fact took place because if it did not, the progesterone would be low. So you see, rising progesterone levels occur from ovulation. If the progesterone is low, that is an indication that ovulation did not take place and replacing progesterone would not have anything to help i.e. no implantation would occur any way.

I have to wonder about the protocol that your doctor is using, and I would suggest that you look at my blog under how I do clomid induction cycles. One specific technique that I use is to follow the follicle(s) with the ultrasound to determine when ovulation is going to occur. That way, I can better time the insemination. I also give an HCG trigger. Then I start progesterone the day after the second IUI (I do two IUI's per cycle) for luteal phase support. This is mainly because progesterone is an easy medication to use, is not expensive and has no adverse reactions/side effects/harm to the pregnancy. It can only help and increased progesterone is one of the main stays for the treatment of implantation failure due to inadequate b-integrin levels.

Maybe you should ask your doctor why he uses it for IVF and not for IUI? The reason to use it should be the same.

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.

Marathon Runner Has Amenorrhea And Is Trying To Conceive: May Need Gonadotropins

Question:

Hi, I am a 25 year old, PhD student and I am a competitive marathoner. My husband and I would like to get pregnant over the next 8 months. I was on the pill until last April, when I went off the pill. I had been on the pill for nine years and my cycle was regular before I went on the pill. During the years I was taking the pill my cycle was fairly regular, light and short in duration, but still regular. I have not had a period since I went off the pill 6 months ago. I am 5 7' and about 108lbs.

I have met with my Dr and she suggested that I go on the pill for a month so I can at least have my period to shed my uterine wall. Then she said if my period does not stick around I may need to gain a bit of body fat. I have also done blood work to make sure there are no other issues. Do you think that I will have to gain weight before I can get pregnant? Or can I just cut back on my training and lose some muscle mass and avoid gaining weight? Also can I get pregnant with my period being absent? Thanks! A. from Canada

Answer:

Hello A. from Canada,

The problem with competitive runners is that they lose a tremendous amount of body fat and so cannot produce hormones. They develop a disorder called hypogonadotropin hypogonadism. For this reason, they do not cycle normally. The birth control pill artificially takes over ovarian function and so you have an artificial period, but it is not because the ovaries are working. Having stopped the BCP (birth control pill), you are now at your normal state and your ovaries are not working. This is the reason your doctor recommended that you gain fat weight. Hormones are made from cholesterol. It is the chemical basis for all hormones. Unless you gain fat weight, you will not ovulate naturally and so will be unable to get pregnant.

I would not recommend another course of BCP's at this time, however. You can wait and see if you get a period, which you only need to have every three months at a minimum, and if it does not occur by itself, then you can take progesterone for 5 days to start the period. That way you will have the opportunity to become pregnant should ovulation occur.

The only other option for getting you pregnant would be to give you the hormones that your brain is not making to stimulate the ovaries. This is a medication called a gonadotropin. We would use a medicine called Menopur that is FSH and LH hormone. These hormones stimulate the ovaries to ovulate. You cannot use Clomid or Femara because the hypothalamus needs to be working for these to work and yours is not working.

Although there are many reasons for primary & secondary amenorrhea (absence of menstruation), I believe yours is due to your pattern of exercise and has a good chance of being corrected. See the Mayo Clinic website for more information: "Amenorrhea: Causes".

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.

Canadian Wonders If Progesterone Is Needed for Clomid & IUI Cycles: YES!

QUESTION:

I am trying to conceive and I have had 3 rounds of Clomid (100mg) by itself with no success. I have also now done round 4 with IUI. With the IUI cycle, my doctor told me to take 100mg Progesterone 2xday, intervaginally, and 2mg of estrace 2xday. My question is this...should I have been given Progesterone with the first 3x of Clomid?

I have heard Clomid lowers the progesterone levels and mine was only 7 to start with. I have also had a history of lots of ovarian cysts which has been explained to me as one of the possible reasons I haven't conceived again...because cysts indicate being estrogen dominant.

With this in mind, I have looked up estrace and it is contraindicated in pregnancy...so now I am confused. Why am I being prescribed a med that is contraindicated in pregnancy, when that is what I am trying to achieve, and why if I am already high in estrogen?

I am confused and wonder if I should only be taking the Progesterone....Help! A. from Canada

ANSWER:

Hello A. from Canada,

Practically ALL medications state that they are contraindicated in pregnancy (for legal issues). In actuality, if you read all the fine print, it says to consult your doctor. Both estrogen and progesterone are required for pregnancy to occur. The estrogen is required to prime the endometrium for implantation and the progesterone both converts the endometrium for implantation and supports the pregnancy. They are both used in fertility treatments, and have been for many many years. No problems so far! So, you don't need to worry about using them.

However, I am not sure that you need the estrogen supplementation, especially in the luteal phase (after ovulation). It is usually required in the proliferative (endometrial proliferation in preparation for implantation) phase. The progesterone is required in the luteal phase (after ovulation).

I use progesterone, but not necessarily estrogen, in ALL my Clomid cycles. Clomid is an estrogen receptor blocker and so extra estrogen might be require in the first half of the cycle to make sure that a proper endometrial lining is developed, but that is not always the case. On the other hand, often Clomid with cause a lack of progesterone production, and progesterone is such a benign and easy supplement to use that I don't risk not having enough.

From what you have briefly described, I am not sure that you are in the best hands for this treatment. I know Canada limits the availability of specialists, but you might want to see a fertility specialist. I would recommend that you look up my blog, under "how I do Clomid cycles" and it will describe my recommendations for a proper Clomid induction cycle with or without insemination.

Good Luck and stay informed!

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.

Woman With Hypogonadotropic Hypogonadism Needs FSH, LH and Hormones To Get Pregnant With IUI

Question:

Dear Sir, I have hypogonadotropic hypogonadism. I am trying to get pregnant and did IUI twice, but did not succeed. I was injected with GMH 150. I had to take around 26 injection to develop my follicles and then had to be injected with HCG for ovulation. My E2 level was 2250 and 4 big follicle. After IUI my doctor gave me only progestrone support. My question is that " is there no need of any other hormone medication as my body don't produce any hormone"? After fertilization can egg produce enough hormone which need for proper implantation. Can taking so many injections for stimulating the ovary affect the ovary or uterus in future? M. from India

Answer:

Hello M. from India,

In order to get you pregnant, you need to take supplemental FSH and LH (such a Menopur) and then when the follicle is appropriate size (18-22 mms), HCG is given to trigger ovulation. Progesterone supplementation is then started 3-4 days after the HCG to support implantation. You also have to consider that since this is a "natural" treatment, and most normal women don't get pregnant immediately when they begin trying for pregnancy (it usually takes 8-12 months of trying), this treatment is just making you into a normal ovulatory woman and so it may take several tries as well.

Finally, you have to make sure that you are taking thyroid hormone and adrenal hormone (cortisol), as well so that all your hormones are normal. If you don't, that could affect your ability to become pregnant. It sounds like your doc is doing the proper thing so you should trust in him/her, and ask him/her the same question.

Follow-Up Question:

Hello Dr., Good news. After HMG therapy and IUI, now I'm pregnant. 3rd month is going on, right now I am taking progestrone support only. I want to know in future will breast milk produce naturally or I have to take any hormone replacement for that. Will my baby affect because of my diseases? Thank you!

Follow-Up Answer:

Hello Again,

The pregnancy takes over hormone production, so you should not have problems producing breast milk. Your disease should not affect your baby unless it is due to some sort of congenital/genetic disease that is passed to your child.

Congratulations!

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.

Positive Beta But I Missed Dose Of Prometrium, Now Spotting: Am I Miscarrying?

Hello Dr. Ramirez,

I am on prometrium 200mg/1morning and 2evening. I forgot evening dose on my 12th dpo. Experienced spotting and pencil line blood in mucus next 3 days. Since I forgot to take the prometruim could I be miscarrying? Today it's 16dpo and my beta came back + but at 77. Thanks! M. from the U.S.A.

Answer:

Hello M. from the U.S.,

It is unlikely that this missed dose would cause you to miscarry. Remember, the progesterone you are taking (prometrium) is a supplement and not the only source of progesterone. Your ovary, or follicle that you ovulated from, becomes a corpus luteum cyst and is the natural source of progesterone to support implantation and an early pregnancy. Once the placental develops, it takes over the production of progesterone.

The number for your first bHCG is fine. It should double approximately every other day (48 hrs) and the trend gives a good indication of how the pregnancy is progressing until an ultrasound can be done at 6 weeks gestational age. The actual amount of rise of the bHCG is at least 80% so if it doesn't double completely, don't be worried as long as it is going up.

Good Luck and don't worry too much,

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 so much for the information! I appreciate the advice. I am actually moving to santa clara county and will see if it is feasible to use Dr. Ramirez as my physician!

American In The UK Taking Clomid & Has Thin Uterine Lining: Needs A Specialist

Question:

Hi Dr. Ramirez,

I will try to keep this as concise as possible. I am very healthy, slim and 29 years old, and have never had issues with my periods. My husband (29 years also) and I conceived on our first try last year, but unfortunately had a missed M/C at 12 wks (fetus stopped growing at 8 wks). Tests confirmed non-recurring genetic abnormality. After the D&C I had only spotting, until 5 days after when I had a very heavy bleed with large clots lasting only one day. Then I got my first period 6 weeks later. The 3 subsequent cycles were 42-45 days.

Pelvic ultrasound revealed PCOS, hormone levels were all normal, including thyroid. Lining on this ultrasound was only 5.5 on day 40, just before I started my period. I have just completed one round of 50 mg Clomid unmonitored due to travel, and BBT shows clear ovulation on day 18 with 12 day luteal phase. This cycle I have had my first follicle tracking on day 11 which showed dominant follicle at 15 mm, but lining of only 4 mm. My questions are:

1. Could the thin lining be due to problems from the D&C?

2. My gyn prescribed Progesterone pessaries for the second half of this cycle to help thicken the lining- is this the appropriate treatment?

3. When should I consider seeing a fertility specialist?

Thank you for your time- I am writing from London. M.

Answer:

Hello M. from the U.K.,

A thin lining could certainly be due to an over-vigorous D&C, leading to scarring in the uterus. This is called Asherman's syndrome. A procedure called hysteroscopy can be done to evaluate the uterus cavity for this. However, that being said, it is not very common to develop this with D&Cs. The more common possibility is a thin lining due to the use of Clomid.

Clomid is an estrogen receptor blocker and so blocks estrogen receptors at the endometrium (uterine lining). For that reason, many patients have to use extra estrogen given vaginally in order to overcome the blockage from the Clomid, or they use a different medication such as Femara or injectables.

Progesterone is NOT the hormone that thickens the uterine lining. Endometrial thickening and priming is dependent on ESTROGEN in the first half of the cycle. The fact that your doc told you the wrong info makes me skeptical that he/she clearly understands the physiology of this treatment. So, I think you should go see a fertility specialist instead. Without proper estrogen priming, the uterine lining will not be ready for implantation. The progesterone, which is given after ovulation, is to convert the endometrial lining to develop the "pinopodes" that are necessary for implantation. (See diagram up above, the "pinopodes" are small finger-like protrusions in the endometrium) Without the proper priming, the pinopodes will not develop.

Good Luck and keep trying, you should succeed with the right treatment path,

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 Dr. Ramirez! I am very grateful to have your opinion, which confirmed to me that I need to see a specialist. As an American living abroad, it can be daunting to find the same quality of health care that we take for granted in the US. Again, I really appreciate your help.

Prometrium Vs. Endometrim For Luteal Phase Support In IVF

Question:

Dear Dr. Ramirez,

I've written to you before about luteal phase bleeding. We've tried 3 IUI's, but my husband's morphology has been consistently 0%, so we are moving on to IVF with ICSI.

My RE has me on a long protocol (BCP, Synarel, Puregon, Repronex). My main concern is luteal phase support. My RE plans to have me on 200mg of Prometrium PV TID starting the evening of retrieval... During my last natural cycle I tried this dose of Prometrium and I still had some breakthrough bleeding (but not everyday). Do you think that this is sufficient luteal phase support for someone with a history of luteal bleeding? My RE is doing a hysteroscopy next week to rule out other causes.

Thank-you for your time, L. from Canada

29yo, secondary infertility

Answer:

Hello L. from Canada,

The dosage of prometrium that your doctor has prescribed is certainly adequate for luteal phase support but is not the mainstay with IVF treatments. The gold standard is injectable progesterone 50 mg per day starting on the day of the retrieval. The alternatives that have been studied with IVF are Endometrin 100 mg vaginally three times per day or Crinone 8%/Prochieve 8% vaginally each morning. I double up and use the progesterone injection and the Endometrin or Crinone together to make sure that I have adequate progesterone coverage. So, prometrium can be used but is not the medication of choice with IVF. It is the cheapest alternative however.

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 Dr. Ramirez! My RE has given me the option of using Endometrin (just recently approved in Canada) so I will use your advice.