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Patients with low ovarian reserve – is egg donation an option regardless of patient’s age? Case study #IVFWEBINARS

Ovarian reserve is the quantity and quality of woman’s eggs. Diminished ovarian reserve occurs with age when ovaries lose their reproductive potential. This, in turn, can cause infertility. It is completely normal for your ovarian reserves to decrease with age. However, it may happen that even young women may suffer from a diminished number of eggs.

Watch the webinar recording and learn more from our expert, one of the best Reproductive Medicine Specialists, Papanikolaou Evagelos, MD, Ph.D., the Co-Founder of Assisting Nature, Greece. Prof. Papanikolaou is a world class recognized specialist infertility treatment. He is ESHRE and EBCOG accredited as Reproductive Specialist. He has Ph.D. diplomas and one Master in Reproductive Endocrinology. His first Ph.D. degree thesis was written on “Premature ovarian failure and endothelial dysfunction”. Prof. Papanikolaou discusses low ovarian reserve on the basis of a few patient case studies from his clinic.

Low ovarian reserve – Questions & Answers

Question:

I have failed IVF, diagnosed with PCOS. I am 42 years old. AMH level is 16. I started on metformin 1500 mg 3 months ago and added victor 1.2 mg last week. I have been on Clomid 50 mg for 2 months not, still awaiting success. Should I try IVF with my own eggs again or should I go for an egg donor?

Answer:

I think that, as I showed you in real case scenario no. 4, at 42 and having a PCOS genetic condition, actually could be positive for becoming a mother after 40. So, taking metformin is the right thing to do. You should stop taking Clomid. You should try again with IVF—I would suggest with your own eggs. If the PGS result is positive, [inaudible] there is a 50% chance of becoming pregnant with your own embryo. If you would like to go for a 4th attempt—if you’ve already done the 3rd one—the maximum you can do is 4 cycles. You’ve already done 2 IVFs. I would totally suggest that you should do it with pre-implantation genetic diagnosis and if you still believe that you’re capable of having a baby with your own eggs, a 4th IVF trial should be the final attempt. Then you might opt for oocyte donation.

Question:

A few years ago, a doctor saw something on my right ovary while performing a USG scan and said that it could be a symptom of endometriosis. He checked the Ca 125 marker on day 3 of the cycle, and the level of this marker was too high. Later in the cycle the marker level was ok. The conclusion was that I have endometriosis. Last year I had IVF and 4 ET. Because of the endometriosis diagnosis I was taking metyloprednizolon before the IVF and ET. Although I had 11 good embryos, none of the ETs were successful. Recently, I have repeated the Ca 125 marker test on day 3 of the cycle and it is ok now. Can metyloprednizolon be the reason for the failure? Are there any recommendations for taking metyloprednizolon? Or does it do more harm than good?

Answer:

What is the age? Ok, 37. Although we used to say that endometriosis does not affect the quality of the eggs, there are studies on donors who were diagnosed with endometriosis after donation and tend to have fewer pregnancy outcomes when compared with eggs from normal healthy ladies. Probably there is only a tiny effect on the quality of the eggs in cases of endometriosis. Only 1 unsuccessful IVF with 4 ET does not really mean anything. Definitely, metyloprednizolon does not influence the success or failure of a cycle. Before you undergo a new IVF trial, you should have your endometrial cavity screened and you and your husband should have a karyotype analysis and check thrombophilia. If you try next time, only do it in the freeze-all strategy and only with blastocysts.

Question:

I have an AMH of 1.4 and I’m 40. Is there any point going for IVF with my own eggs (one failed before) because when I look at the average success rates for my age, it is less than 8% with my own eggs compared to 50-60%, depending on the clinic, with donor eggs?

Answer:

At the age of 40, the success rate is not 8% but around 20% with your own eggs. So, an AMH of 1.4—if this means nanograms—is normal for the age of 40. If it’s nanomoles—i.e. 0.3—then it’s a bit low, meaning that you have a low ovarian reserve but if it’s nanograms, then you’re completely normal. Definitely try two more cycles with your own eggs and only if this fails should you try egg donation. That is the easy choice, of course.

Question:

According to the research about oocyte aneuploidies that we saw in the presentation, I just wanted to ask what technique was used to test the oocytes. Were all the chromosomes tested or just a group of them?

Answer:

The research was performed with polar body biopsies, which is an expensive technique first of all, and all the chromosomes were tested, not only a group of them. Also, studies have been performed on real eggs but they couldn’t be used afterward. You can test the egg but, unfortunately, the egg dies after the test and you cannot use it. This is the problem. We hope that this will be the next big evolution in IVF—how to test the eggs non-invasively and know straight away how many of the eggs are euploid, which means with 23 chromosomes. So, this will be the future and one day it will definitely come.

Question:

I am 34 with low ovarian reserve, undergoing IVF with egg donation but have difficulties in getting a thick enough endometrium (more than 7 mm). During my last try, I took 4 mg of estrofem 3 times per day over 17 days but I got an endometrium of only 5.8 mm. Here are my questions:

1. Does a low ovarian reserve influence the thickness of the endometrium?
2. Is the medication (estrofem and utrogestan) less efficient for a patient with a low ovarian reserve?
3. If estrofem and utrogestan do not help enough to get a thick endometrium, are there any other medications that can help?
4. What are the chances of getting a healthy child when we get a blastocyst that is at an early stage of development at day 6?
5. What are the side-effects of taking estrofem and utrogestan during several IVF treatments?

Answer:

So, to answer the first question, low ovarian reserve is not connected with the thickness of the endometrium. Actually, what we see in virtually the majority of patients is that if they have a low ovarian reserve, they have an excellent endometrium, which means more than 7 mm. So, 7 is the limit, not 8 or 9 as it used to be in the past. So, if it’s 7, this is perfect and I would like to answer here that if it’s not 7 but above 6 and trilaminar—you can see 3 lines in the endometrium—this is also a very positive indicator for the quality of the endometrium. So, the answer to the first question is definitely no.

As for the second, estrogen and progesterone supplementation is not affected by the ovarian reserve.

In answer to the third question, if the estrogen [55:47 inaudible] endometrium of 7 mm, then we can try other routes. For example, in our clinic we use 8 mg—4 in the morning and 4 in the evening—and 2 mg vaginally. So, we give 5 tablets of estrogen—4 tablets of perox and 1 vaginally—and this helps sometimes. We have also developed a very good protocol that was published in the Journal of Assisted Reproduction and Genetics, where for 7 days at the beginning of estrogen supplementation, in the second week of it, we also supplement with a minimal dose of acid Z that sometimes helps the endometrium to reach 7 mm, but this is a protocol that we follow in our clinic and it seems that it works.

The fourth question: what are the chances of getting a healthy child with a blastocyst on day 6? Definitely, becoming a blastocyst on day 6 means less chance of getting pregnant. So, if you’re below 35 and have an excellent blastocyst on day 5, the chances of getting pregnant are 33%. If you have 1 blastocyst on day 6, the chances of becoming pregnant are less than 20%.

Answering the fifth question, about the side-effects of taking estrogen and progesterone during several IVF treatments, actually, progesterone is protective against cancer, so don’t worry. Taking estrogen, the only possible side-effect is that you might develop thrombosis in the lower extremities. This is mainly superficial thrombosis, not deep vein thrombosis which is very rare unless you have a thrombophilic predisposition. If you’ve taken estrogen and progesterone over 3–4 trials and you’re not pregnant but will continue with future IVF treatment, then it will be wise to check for thrombophilia. Also take aspirin treatment together with estrogen.

Question:

I’m using donor eggs. I’m 42. We got 6 eggs with 2 going to blastocyst. I was prescribed fematab 4 times daily and cyclogest. My scan showed that the lining was 7 mm. Then, 3 days later, it shrunk to below 6 mm so implantation was cancelled. Have you heard of this happening? I’m starting again tomorrow with the same meds plus estradot—1 tablet every 72 hours. Previously aspirin got my lining to 9 mm but this was with follicle stimulation and timed intercourse. Any advice, please?

Answer:

Most of the time it’s not that it shrinks, but that it was measured incorrectly on one of the two occasions. Even if the same doctor did the measurement, sometimes a doctor can make a mistake so maybe the first time was 6 or the second time was 7 but it was measured as 6. As I said before, 7 mm is perfect. Sometimes there are cycle variabilities. During some cycles, the endometrium may never reach 7, either with medication or with a natural cycle. You took the right decision to try again and if it’s 7 mm, that’s perfect for performing the embryo transfer. As for whether aspirin might assist the endometrium thickness, the answer is no. Aspirin has nothing to do with endometrium thickness. It’s just a coincidence.

Question:

What is the maximum dose of progesterone and estrofem/progynova that you prescribe for your patients?

Answer:

In our on-site donation program, if that’s what the question refers to, we start with 4 mg of estrogen and we go up to 8 mg, i.e. 4 tablets. Then, if the endometrium does not reach 7 mm, we prescribe a fifth tablet to be taken vaginally [inaudible] we use up to 600 mg of micronised progesterone like Utrogestan or 3 tablets of micronised progesterone like Lutinus or 2 vaginal creams Crinone or a maximum of 2 subcutaneous injections of Prolutex. We don’t go for high doses because if you know physiology, you know that the progesterone and estrogen receptors have thresholds beyond which whatever you give, the receptor gives the same response. So, there is a ceiling effect and once this is reached, it doesn’t matter how large the dose is; the result is the same.

Question:

After 5 failed ETs, I checked the receptivity (biopsy) of the endometrium. On day 5 of taking progesterone, the number of CD56 marker was 19 in the large field of view. On day 7 of progesterone, the CD56 marker was 29. Are those numbers ok?

Answer:

If we measure natural killers in the blood rather than on the endometrium, this is a mistake. I guess that this CD56 marker refers to endometrial cells, although I’m not 100% sure. The natural killer cell marker CD56 normally decreases during the implantation window, but these results of 19 and 29 are so weak that clinically it means nothing since we never test the maximum percentage of CD56 for naturally conceived babies at the moment the woman got pregnant because this would be unrealistic. So, actually, we don’t have normal values and the normal values that this test provides are completely arbitrary and, in my opinion, of no meaning. I can’t really answer this question, but we should not focus on 5 embryo transfers without pre-implantation genetic diagnosis. It would be a pity to blame the endometrium if we don’t know which of the embryos of the 5 embryo transfers—I don’t know if there were 10 embryos, for example—were normal or not. So, how can we blame our endometrium receptivity when we have no clue whether we transferred normal blastocysts?

Question:

Which tests check endometrium receptivity? Which are the most reliable?

Answer:

None of the tests are reliable. They can only assist 1 in 1000 patients with repeated implantation failures of a maximum of 10 blastocysts or biopsied euploid blastocysts. Then you can test the endometrium receptivity with any of the tests available on the market and try to find an answer, but for the time being, they are less informative than we would like.

Question:

If the number of NK cells is too low, is scratching a good way to make this number higher? What is the optimum level of NK cells? How can we know if scratching won’t increase the number of NK cells too much?

Answer:

As I mentioned before, the concept of uterine scratching started by reading many years ago published literature on monkeys and baboons. They did endometrium biopsies and after 1 month removed the uterus of the monkey. We found out that they were pregnant when they were sacrificed and the uterus was tested. Some of the baboons were pregnant and the implantation site was on the incision of the endometrium because of the biopsy. This led to the notion to start thinking that maybe scratching induced an aseptic inflammation that with the chemokines, not really with downregulating the natural killer cells, actually more of a chemotactic effect, so the chemokines or interleukins may attract the blastocysts to invade the place where the upper layer of the endometrium has been set off .

Question:

I have had 4 egg retrievals and the first 2 resulted in 10 eggs, 0 fertilised. With a new specialist, I ended up with a few more eggs and slow growing embryos. Morula day 5, no pregnancy. During my last cycle, I had endometriosis removed and ended up with 2 blastocysts on day 5, no pregnancy. We are having one more try this month. If I don’t get pregnant, do you think we should try egg donation? I am 34.

Answer:

I think the best person to reply to this question is the embryologist who treated your eggs So, really, if the impression is that your eggs were of bad quality during all of those 4 egg retrievals at the beginning—from day 0, I mean, from the day of fertilisation—maybe there is an oocyte quality problem. As I mentioned, there is no way to look into the quality of the eggs. However, if the third or final attempted ended up with 2 blastocysts, that’s not a bad result. Maybe the first 2 IVF trials were not performed under optimal conditions. If you have blastocysts with your next try, I would suggest that you have them biopsied and do preimplantation genetic diagnosis (PGD) to find out if there is a problem with the genetic quality of the embryos. Still, it won’t be possible to blame the eggs for the genetic quality of the embryos. However, we know that 80% of abnormal embryos is due to egg quality and 20% is down to sperm quality. So, I think before you jump into egg donation, you should definitely do pre-implantation genetic diagnosis.

Question:

Is it possible to do a successful donor egg transfer after menopause (I have an early low ovarian reserve)? I’m 34.

Answer:

Definitely. The only caveat that you should be aware of is that when we have really premature menopause, we should use estrogen replacement therapy. The reason is that if you don’t take any pills in a cyclic way, the uterus becomes atrophic, as does the endometrium. So, if you, or anyone else, are not on cyclic HRT (hormone replacement therapy), I advise you to start the hormones for 3 months to make the uterine environment start rolling up and then there will be no problem at all trying egg donation.

Question:

I am 42 and had several of my own IVF cycles with 1 pregnancy lost in week 7. Afterward we had one egg donation program and we got 2 good blastocysts out of 16 oocytes, but both transfers failed. What would you suggest? My endometrium was also ok.

Answer:

My worst moment is when I have a lady who has the same scenario as yours—with several of your own IVF cycles and having made the difficult decision to move into oocyte donation, you then experience another failure. My answer is that 95% of women will have a baby either with the first, second or third egg donation. Some patients really do need a third egg donation—by that I mean a third donor trial and not a third embryo transfer. This does happen. I would definitely check the genetic quality of your partner’s sperm and perform PGS the next time.

If you think that egg donation treatment is something you are willing to consider, your next step would be to choose between fresh or frozen donor eggs. Before you make a decision, you may want to watch another webinar organized with Assisting Nature“Fresh donor eggs or frozen eggs for IVF – what’s better?” We also recommend another webinar on Donor eggs – it’s all about quality, no. of eggs & qualification process.

#IVFWebinars are brought to you with the help of our Partners:
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Donor Conception Network UK

About the Author

Evagelos Papanikolaou

Evagelos Papanikolaou

Prof. Evagelos Papanikolaou, MD, Ph.D., is a Reproductive Medicine Specialist as well as a world-class recognized Specialist in Fertility treatment. Dr. Papanikolaou is the author of dozens of medical publications and has been at the forefront of several innovations and improvements in IVF treatment and is the main visionary and founder of Assisting Nature IVF Unit. He is ESHRE and EBCOG accredited as a Reproductive Specialist.

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