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.

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

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.

After 11 IUI's, Canadian Fails 1st IVF cycle: Poor Embryos, Bleeding Or Implantation Failure?

Question:

Dear Dr. Ramirez,

I'm writing to you from Toronto, Canada. Thank you in advance for your answer!

My husband and I are both 37 years old. I was diagnosed with mild PCOS due to the shape of my ovary (pearl-like follicles) and irregular cycle (28-36 days), and as result was prescribed Metformin. My husband has low sperm count and motility. Last year I was pregnant after 5 attempts of IUI (intra uterine insemination), but unfortunately ended up in miscarriage due to chromosome abnormality. The protocols include Letrozole Femara on its own, Letrozole Femara in combination with Gonal-f and Hcg Ovidrel, and one unstimulated cycle. In all cycles, we only worked with 1 follicle. My husband's sperm ranged from 1-5 million after washed during those cycles. During our pregnant cycle, Letrozole Femara in combination with Gonal-f and Hcg Ovidrel were used, his sperm was 1.6 million after washed.

Three months after the miscarriage we tried again, with 6 rounds of IUI with similar protocols as before, but also include doubling Letrozole Femara with Gonal-f and Orgalutron, as well as Gonal-f injection only but none resulted in pregnancy. With the exception of 1 cycle where we worked with 2 follicles, the rest we only worked with 1 follicle. My husband's sperm ranged from 1-7 million after washed during those cycles.

Recently we went through an unsuccessful round of IVF-ICSI (in vitro fertilization with intra cytoplasmic sperm injection), with 5 days transfer. Protocols include Gonal-f, Repronex, Orgalutron, and Hcg Ovidrel. I was also put on a birth control pill the cycle prior to IVF cycle, and had an endometrium biopsy during the luteal phase of the birth control cycle. Post retrieval include antibiotics and vaginal natural progesterone 100mg in the morning and 200mg in the evening. Post transfer include vaginal natural progesterone 200mg in the morning and 200mg in the evening, and 81 mg aspirin daily.15 eggs were retrieved with 11 matured. 3 were IVF and 8 were ICSI. 1 out of the 3 IVF fertilized, and 4 out of the 8 ICSI fertilized. Since more than 3 eggs fertilized, the clinic's policy is to do 5 days transfer. By day 3 the quality of the 5 embryos were as follows: 10-12 cells grade 2 (good), 8 cells grade 1 (excellent), 8 cells grade 1 (excellent), 8 cells grade 2 (good), and 6 cells grade 2 (good).Unfortunately only 1 of the 8 cells (ICSI) turned into a blastocyst (with quality "not bad" according to my doctor).

The day 5 transfer include the only blastocyst we have and the 10-12 cells embryo. We ended up having no embryos to freeze. I started bleeding 7 days after the transfer.

Sorry for the long background story, my questions are as follows:

What should we do to ensure successful IVF next time? Failing the IVF, do I have an implantation problem?

What could have been done to prevent the early bleeding, could the progesterone injection prevent it? I didn't seem to have luteal phase defect in the past since my period normally come 14-16 days after ovulation.

What would have caused the poor embryo development after day 3? My doctor mentioned about possible sperm DNA fragmentation issue although this still need to be tested. Are there any other tests we should do?

What could have caused sperm DNA fragmentation, my husband doesn't smoke or drink, or exposed to any chemical environment in his day to day.

What protocol would you suggest for an IUI? Just want to mention that I didn't respond well to clomid and therefore my doctor prescribed letrozole. Why did IUI work for us last year and the last 6 attempts didn't? Also, I started taking Chinese herbs subsequent to miscarriage, therefore for the first 5 attempts out of the 6 IUI attempts I was also taking Chinese herbs at the same time, would that be why the IUI's failed?

I very much appreciate your time and help.Yours sincerely, E. from Canada

Answer:

Hello E. from Canada,

Thank you for all the information, it helps a great deal. Let me get to your questions directly.

1. Unfortunately, I don't comment on specific protocols because each doctor, clinic and country use different protocols. There is no right one or wrong one. These variations will often determine pregnancy success, however, and is the reason why some clinics are more successful than others. So, despite what I might advise you as to protocols, inevitably it will be your doctor's opinion, based on his training, knowledge and experience, that determines what protocols you use. Given that, it looks like you stimulated well, had a good number of eggs and embryos formed. The only changes I might suggest, which you have control over is (1) ICSI ALL eggs to allow for maximum fertilization and embryo number, (2) DO NOT PROGRESS TO BLASTOCYST CULTURE without at least 5 8-cell grade 1 or 2 embryos.There is an inherent attrition rate from day#3 embryos to blastocyst that may have nothing to do with inherent embryo quality. Based on preimplantation genetic testing data, sometimes even genetically normal and healthy embryos may not make it to blastocyst. Keep in mind that blastocyst culturing is still in its early development stages and not perfect. If you don't have enough embryos to lose, don't do it.

2. The bleeding after embryo transfer is very very common. I would refer you to my blog where that particular topic is the most often viewed. There is more information to this than I can give in this forum. Basically, however, it is not clear why or where this bleeding is from and how to prevent it. The good thing is that in many, if not most cases, it is of no consequence.

3. As mentioned above, the lack of embryo development does not necessarily have to be due to poor embryo quality. But, embryo quality can certainly affect the ability of an embryo to develop to blastocyst. The sperm fragmentation part . . . I'm not sure I would agree with that. Your age affects egg quality and therefore embryo quality more significantly.

4. Unknown what causes sperm fragmentation.

5. If you were going to return to IUI (which is an option but you have to consider that you will be lowering your chances of pregnancy) I would probably go to injectables only stimulation and not a combination protocol. The goal would be for you to have three to four ovulatory sized follicles (n0t one like you have been having), which will increase your chances of a successful pregnancy. The fact that you have gotten pregnant in the past is an indication that your reproductive system works but you have to overcome the sperm factors and the age factor. For these two, I would probably recommend IVF.

I would caution against adding herbal regimens. These are just un-purified pharmaceuticals. They could certainly have adverse affects.

Follow-Up Question:

Thank you so much for your reply.

In reading your blog on early bleeding, I mentioned to my doctor about using injectable progesterone. She wasn't on board and she still recommends vaginal progesterone. She explained that based on numerous researches, the vaginal progesterone is as effective as injectable, and the injectable create much discomfort. Instead for the next IVF, she will add estrogen patch. Should I insist on the injectable, I'm worried that I won't have enough progesterone support for implantation. Is it possible that's what might have caused the early period bleeding in my last IVF (7 days post 5 days transfer)?

Lastly, could the miscarriage that happened last year after IUI was also caused by lack of progesterone? That cycle I was only prescribed 100mg vaginal progesterone daily. However there was no bleeding whatsoever and after the fetal heartbeat stopped at 2.5 months pregnancy, I had a D&C done.

We will be doing another IVF 2 months later, in these 2 months, 1st month will be natural cycle and the 2nd month will be birth control cycle. Will doing the next IVF this early affect the eggs quality (the quality will be worse) and therefore reduce the pregnancy chance? Best regards, E.

Follow Up Answer:

Hello Again, Your doctor is correct in that studies have shown that vaginal progesterone is just as effective as injectable, and doesn't have the discomfort of the injection (Injectable progesterone has to be given intramuscularly). Injectable progesterone is still the gold standard, however, and if that is the form that you want, I don't see why your doctor can't change. But these kinds of things are what make each doctor different. Extra progesterone does not hurt, so why not? You could continue to argue with her but it sounds like she has her preferred way and will stand by it. The estrogen is a different hormone. I don't see any benefit to that for the bleeding but I certainly supplement with estrogen in my protocols.

Remember, I said that you cannot compare protocols because there is no one way, right way or wrong way. Protocols differ between doctors and clinics and that is okay.In the IUI pregnancy, which found a heart beat, progesterone was definitely not the cause. The lack of progesterone will result in very early pregnancy loss. Way before the placenta develops to produce its own progesterone. After that point, losses are usually due to abnormal pregnancies or fetal development.

The answer to your last question is NO. One can do an IVF cycle as quickly as every other month. Each cycle is different and unique and the eggs retrieved are unique. They can be good eggs or bad eggs, which is already predetermined prior to the IVF cycle depending on the state that the egg is in prior to stimulation.

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.