Severe Allergy To Progesterone During IVF Cycles

QUESTION:

Dr. Ramirez, I have a problem with progesterone but my symptoms are not typical of an allergic reaction. My husband and I have done 3 IVF cycles, all failed. They were all chemical pregnancies

1st cycle: The day after the first progesterone in ethyl oleate injection, I developed chills, a high fever, blood pressure drop and an elevated heart rate. The doctor thought it was an infection but the lab results were negative. I was then switched to Endometrin which caused intense vaginal itching and burning. So the RE put me on Crinone which also resulted in intense burning and terrible headaches.

2nd cycle: I was put on compounded progesterone capsules. After 5 days, I developed severe redness, swelling and pain. So I was then put on compounded suppositories which looked like white bullets. These caused burning and bleeding. The RE then had me try progesterone in sesame oil injection. About an hour after the shot, I became flushed and felt like I was going to pass out. I also developed a fever, drop in blood pressure and an increase in my heart rate.

We then did a mock cycle with the compounded progesterone capsules along with Zyrtec and Singulair. When the vaginal redness, swelling and pain returned, I was put on Benadryl. Unfortunately, that didn't work either.

3rd cycle: The RE had me do daily HCG injections along with oral Prometrium 200 mg three times daily. I had no problems with that protocol but it was not successful in achieving a pregnancy.

Prior to my mock cycle, an allergist tested the various progesterones to which I had an adverse reaction. The prick test was negative for all but the intra-dermal shots induced a wheal (9 & 10) and flare (both 12).

Is there a way to either prevent symptoms from developing or are there other progesterones which will not induce a reaction in the first place? Thank you! S. from Michigan

ANSWER: Hello S. from Michigan,

I think that you should avoid compounded progesterone. Instead, you could try an injectable progesterone made with an oil other than sesame oil so that would be one option, or a pharmaceutical formulated progesterone such as Crinone 8% or Endometrin would be alternatives. I use a pharmacy called MDR who makes an progesterone in a different oil that is less viscous and more easy to inject. I presume that the injectable that was tested by your allergist was with sesame oil. It is most likely that the allergen was the "oil" and not the progesterone itself, since the oil is a protein. You might want to have him check that.

Crinone and Endometrin are both used vaginally which has been shown to be the optimal method for delivering progesterone to the endometrium. Oral progesterones have been shown to be ineffective because most of the drug is lost in the first pass through the liver. Only injectable, vaginal or dermal have been shown to be effective.

Although there are no pharmaceutical companies that sell transdermal progesterone products on the market, there are a lot available through health stores and the internet, and also can be compounded. I don't use them so can't attest to their effectiveness or dosage but have seen some studies looking at them. It is possible that MDR can compound one for you.

The alternative for luteal phase support would be low dose HCG injections, like your RE has done. That has been shown to be effective. As a last resort, a surrogate could be used. Although expensive, it is an alternative that some of my patients have used with success when they could not carry the pregnancy for whatever reason.

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.

Why Do I Need HCG Injections After Ovulation During IUI Cycle?

Question:

Dr. Ramirez,

My husband and I have been trying to start our family for a few years. I have been pregnant and miscarried 3 times, but is has been over a year and a half since my last miscarriage. I am seeing a Reproductive Endocrinologist and their diagnosis for not getting pregnant again is unexplained infertility. We have are trying the IUI process now using Letrozole and I have also been given a prescription to do HCG injections on days 3, 6, and 9 past my LH surge. I am not finding very much information about using HCG after ovulation. I know their reasoning is to supplement my progesterone... but not sure why then, they don't just use progesterone? Please help!

Thank you! G. from Colorado

Answer:

Hello G. from the U.S. (Colorado),

HCG (human chorionic gonadotropin) injections can be used to support the luteal phase in place of progesterone and there is nothing wrong with that protocol. Most don't use that method because you have to take it as injections and the medication is considerably more expensive. There are many progesterone alternatives such as Crinone, Endometrin, Prometrium that can be used vaginally as a supplement. You should ask your doctor why they don't just use a progesterone supplement.

The other question to ask is "what are they treating or trying to achieve"? Do they suspect that your miscarriages are due to a luteal phase defect i.e. decreased progesterone? In that case testing by an end of cycle endometrial biopsy for dating and/or b-integrin would have diagnosed luteal phase defect and your diagnosis would not be "unexplained infertility." I am not a strong believer in "unexplained infertility" as a real entity. I think it is more like undiagnosed infertility. The cause just has not been found because either a test has not been done to find it or doesn't exist. Often we find that many of these cases of fertilization failures or defects with the sperm (found at the time of IVF) or endometriosis found on laparoscopy. Sometimes age is the problem as well leading to poor embryo quality.

Your question is a good one and you should ask your doctor. Be sure they explain everything to you!

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.

Comment: Thank you so much... for all of your information and quick response! I will follow up with my doctor.

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

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.

Spotting In First Trimester Not Placenta Previa

Question:

Hi Dr. Ramirez,

I am a 35 yo with no children. I found out I am 7 weeks pregnant and went for blood work and a sonogram since I have been spotting and had sporadic cramps for a few days. My doctor discovered I have low implantation of the embryo and placenta previa from the sono, and low progesterone levels from my blood work.

My doctor said my progesterone levels are 13.5 and should be higher (around 15) so he prescribed Prochieve Vaginal Gel. Is Procheive a good thing and is it needed? Will it produce side effects in the baby?

For the placenta previa, I have read so much negative information which speaks of hemorrhaging to hysterectomy and C-section. While I am okay with the thought of a C-section as it may save my life and the baby's, is there any statistical information available which discusses the probabilities of fatalities and hysterectomies?

With that being said, I am pro-choice and would like to make an educated decision on if I should carry this pregnancy to full term. With all the obstacles in front of me, in your experience and opinion, what are the chances of having a healthy child?

Answer:

First of all, I don't think you need to consider terminating this pregnancy because there is nothing seriously wrong at this point.I think that your doctor is over-calling things. To be frank, the recommendations and diagnosis he/she has given you is inappropriate at this gestational age.

Placenta previa CANNOT be made at 7 weeks gestation. That is a third trimester (after 28 weeks) diagnosis. At your gestational age, the entire amniotic sac is filled with the placenta. The mature placenta has not even developed yet. Placenta previa is when the placenta blocks the cervical opening, which then requires a c-section. As the uterus grows, the placenta will move and 99% of the time, the placenta moves out of the way. So you don't need to worry about it.

In terms of the progesterone, he/she is mistaken about that as well, however, we use progesterone all the time with infertility patients to help support the pregnancy. It is usually started before implantation, however. It would not hurt and Endometrin is the prescription that I use. It will not harm you or the baby. The alternatives to Endometrin, which are just as good, are Crinone and Procheive.

Spotting is very common in the first trimester. We see it all the time with our IVF patients. It does not necessarily mean that anything bad is occurring. However, you are still in the miscarriage risk stage so sometimes, spotting or bleeding could mean that the pregnancy is not doing well and will eventually end in miscarriage. There is no way to know this unless the ultrasound does not show a viable fetus i.e. no heart beat or not growing.

I hope this helps. Don't worry too much.

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

Monterey, California, U.S.A.

www.montereybayivf.com

Progesterone Injections & Travel After IVF

Question:

Dear Sir,

Our first IVF (during June 2008) failed and so, we are going for the second IVF which is FET (frozen embryo transfer). I have the following questions:

a) Progesterone-in-oil shots: During the last IVF it was very difficult and stressful to have the intra-muscular shots every day. After a week, the muscle became very rigid and at some point could not even poke the needle into the muscle. Will it be okay if I do a hot water massage after every shot? I am concerned because some nurses are saying it may raise the body temperature and could cause problems.

Are there any alternatives for intra muscular injections (for progesterone)? One of the nurses is suggesting to apply directly into the vaginal area. Since we haven't done that before we are not sure how tedious is that and the possibilities it could go wrong.

b) Will it be okay to travel long distance (approx. 3 hours) in a car - three days after the transfer?

Thanks so much in advance for your valuable suggestions.

Roger

Answer:

Dear Roger,

The progesterone injections are probably the worst of all the injections because it requires a bigger needle and the fluid is thick. I have changed from a prgesterone in sesame oil to a progesterone in canola oil that my pharmacy make us (MDR). Because it flows easier, we can use a smaller bore needle to reduce the pain and it doesn't harden up. You might want to check into that formulation. MDR Pharmacy is an infertility specialty pharmacy and you can get your meds via mail. It is also less expensive.

In terms of hot packs at the injection site, that would be fine. I don't expect that will change anything at all if it stays local.

Also, make sure you are rotating the sites i.e. one buttock then the other. You can also change the specific sites in the buttocks as long as you are in the upper outer quadrant. Make sure your nurse shows you all the areas that you can use.

As an alternative to IM progesterone, you can also use vaginal progesterone. There are several formulations: Crinon 8%, Prochieve 8%, Endometrin 100mg and pharmacy formulated versions. Several very good studies have shown equal efficacy to IM 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. Some programs, such as USC, have switched to vaginal completely. If your wife cannot tolerate the IM Prog or has an allergic reaction to it, then you can switch to the vaginal version. Crinone and Procheive are twice per day, and Endometrin is three times a day. They are messy but they don't hurt.

In terms of travel, yes it is okay to take a three hour trip after the transfer. As long as your wife is in a resting position, such as sitting, then you can travel. I only don't recommend strenuous activities such as exercise, karate, horse back riding, running and the like.

I hope this helps!

Edward J. Ramirez, MD

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

Monterey, California, U.S.A.

Check me out on Facebook http://www.facebook.com/ejramirez and Twitter with me at @montereybayivf

Trying for Pregnancy. . . Thank You! Success at last!

QUESTION: I have been trying to get pregnant for 7months. My period is regular every 26 days. Ultrasound and sperm tests indicate normalcy. I was given Clostilbegyt 50mg to take on day 2-6 and Provera for 10 days fron day 16. Does this sound correct? Won't Provera induce a period and stop me from getting pregnent. Oh I'm 33.

ANSWER: Hello,　
　
I hate to see these type of questions because it shows that the doctor you are seeing is not treating you appropriately. Have you had all the infertility testing done? Hysterosalpingogram, Hormone testing, Hysteroscopy, Laparaoscopy, Midluteal phase progesterone level. If not, then you shouldn't be jumping to Clomiphene. For one, if you have regular periods, ovulation is not the problem, although you may have a hormone problem as manifest by a short menstrual cycle. The only other reason is to try "something" since there doesn't seem to be a reason for your infertility. Many general docs give Clomid because they can, and not for any good reason, thinking that because it is a "fertility drug" it will help you to get pregnant. That is incorrect thinking. It should only be used for a specific reason i.e. it is treating a specific disorder.　
　
Technically, if you are under 35 years old, you would not be considered to have an infertility problem yet, because you have only been trying for 7 months. We don't consider a person to have an infertility problem until they have not been able to become pregnant for over one year. If you are over 35 then we shorten that time line. In women under 35 years old, it takes 8-12 months for the majority to achieve pregnancy naturally. So you may just need to keep trying on your own for a while longer. If your cycles are 26 days, then you are ovulating around day # 12, so you should start having intercourse on day # 10 for 5 consecutive days.　
　
Provera is not used with fertility because it is a "synthetic" progeterone. We only use natural progesterones like Prometrium, Endometrin, Progesterone in oil, when augmenting the luteal phase for fertility treatments. That is what me suspect that your doc doesn't have all the knowledge required for your treatment.
　
Sincerely,
　
Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
http://www.montereybayivf.com/
　　
---------- FOLLOW-UP ----------
QUESTION: Great news, I am now 6 weeks pregnant after following your advice. However, before I got pregnant I had a yeast infection for almost three months. My doctor gave me Canesten tablets and inserts and that did not work.It eased the symptoms for two days and then they returned. She then gave me Flagyl tablets for both my husband and I for ten and five days respectively ( 3 tabs per day). I was also given Klion to insert every night for ten days. That last dose of medication was a nightmare as it caused severe pain and irritation, I stopped after five days. Now I'm still having some irrtiation and itching and extremely painful sex on penetration and afterwards. My new doc gave me Travogen cream and it has helped a little with the itching but sex is still painful. Is this normal? Is it that I may have something more serious? Can this affect my pregnancy? I'm really worried.... please advise me!

Answer:
Hello Rhonda from Trinidad-Tobago,
　
Congratulations!!! :) :)
　
If you have symptoms, then you need to be checked and have cultures done. It may be a simple yeast infection that can be treated easily, or something else. Don't go the trial and error route like your doctor did previously. Have the cultures done so that he/she knows exactly what to treat, especially since you are pregnant. There are some medications that you don't want to take at this time. Sex should not be painful, but since you are newly pregnant, you might want to avoid sex until you are further along (12 weeks gestational age).
　　
Sincerely,
　　
Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
http://www.montereybayivf.com/

IVF implantation failure

Questioner: Sophie
Subject: IVF implantation failure; luteal phase brown spotting, even with high progesterone levels Date

Question:
Dear Dr. Ramirez,

I have found your responses to others extremely helpful!

I am 35 years old and am writing from Hungary. My husband
and I've just finished our second, unsuccessful round of IVF
with ICSI; both were 5th-day transfers with a good quality
pair of embryos in each. My husband had had two samples
frozen before his BMT several yrs ago, which is what we used
for the IVFs--it looks like now he occasionally has a
nonmotile cell or two, but not much else.

I would very much appreciate your thoughts and advice on
luteal phase issues, including luteal phase support during
IVF, given a potentially short luteal phase and pre-cycle
brown spotting.

The first round of IVF, I got progesterone suppositories,
but my prog. level was fluctuating with that (was as low as
18.85 9 days post-transfer, and was up to 43 3 days later).
As a result, bleeding started 7 days post-transfer.

For the second IVF (with frozen embryos), I got progesterone
injections instead, which kept my prog. level up (56, 65).
Nonetheless, I still had definite brown spotting starting 4
days post transfer, gradually turning rust-colored. Both
transfers, I had mild cramps on days 2 and 3 after the
transfer.

As we were making preparations for the IVF, my fertility
doctor determined that I have a relatively short luteal
phase despite the fact that my cycles are 28-31 days long: I
ovulate on the 17th-21st day (20th is typical). In addition,
for the past three years, my period has always been preceded
by 1-4 days of brown spotting. And *including* those
spotting days, my luteal phase has been 9-12 days long
throughout 2009 (13 days when I was on Suprefact for the
ovarian stimulation).

A further detail that could be relevant: I have an
autoimmune thyrod disorder that is being monitored, no
medications for it. My anti-TPO level is 1516 and I have a
thyroid cyst about 3x2x3 cms in size, the biopsy was
negative. My thyroid levels have been normal: TSH 0.65-1.2,
T4 15.6.

Any thoughts on what might be behind the persistent pre-
cycle spotting, despite the high prog. levels with the
injections, and what can be done about it?

I would like to do all I can to exclude the possibility that
the embryos did not implant because of a luteal-phase-
related issue, especially because the number of chances
we've got are limited. Do you have any suggestions what
might be worth asking about, any variations on the protocol,
any further tests? Right now, the plan is to do the 3rd IVF
round--with potentially the last batch of frozen sperm--with
the same luteal phase support as before: ovitrelle for the
ovulation and prog injections, following a stimulation phase
consisting of suprefact and gonal-f 150. I am told that
based on my low HCG level ( 0.1) measured at 12 days post
transfer, the embryos did not even begin to implant in
either of the previous rounds. So the spotting in this
second round wasn't due to implantation then.

Also, I have read about taking vitamin B6 for luteal phase
defect, my doctor here says he doesn't know about that
helping with the short luteal phase and the spotting. What
are your thoughts on the matter?

I very much appreciate your time and help.
Yours sincerely,
Sophie

Answer:
Hello,

Thank you for all the information and the very well written letter. I can't even tell that you are from Hungary. Your English is perfect!

First of all, despite the fact that you may have had a luteal phase defect in the past, the purpose of the progesterone after retrieval is to treat for possible luteal phase defect. Therefore, you don't have a luteal phase defect with your IVF cycles, and this is NOT the reason for the implantation failure. Something else must be going on. You don't mention the quality of the embryos, but that would be one question. Also, you don't mention how many were retrieved, how many fertilized, how many did not make it to blastocyst and how many were frozen. I presume there were none to freeze since you don't mention it.

Implantation failure is a difficult problem because we are not able to distinguish all the processes required for implantation, and there are not tests to help. The only current test available, b-Integrins, don't help because the treatment is to use more progesterone. I would do that any way. Please read more on implantation failure and recurrent miscarriage here: "Recurrent Pregnancy Loss".

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.

This regimen covers most immune responses that might prevent implantation, as well as, any micro-clots that form at the site of implantation. It is used mainly in patients that have recurrent miscarriages, but has proved useful in IVF as well. You might want to suggest this to your doctors. This regimen is unproven and controversial, however. Another suggestion would be to transfer at day # 3 instead of going to blastocyst. Blastocyst culturing is not perfected, and I still believe that the uterus is a much better culture media and incubator that the lab.

Also keep in mind that pregnancy rates are very clinic dependent. There is a wide variety of pregnancy rates between clinic, and the rates can very much be influenced by the laboratory environment, the physician skill doing the transfer and the stimulation and culture protocols. One option might be to try a different clinic. I recently changed my clinic location and our pregnancy rates are much better than before because we were able to build a better facility.

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