In this session, Dr. Ashim Kumar, Board Certified Endocrinologist and Infertility Specialist at Western Fertility Institute, Los Angeles, USA has explained options for IVF patients with poor prognosis as well as with previous failed IVF attempts.
Dr Kumar started his presentation by explaining that whenever we look at fertility, we need to always start by having a look at the oocytes, sperm, uterus, and tubes.
Those tests are not initial evaluations for the uterus. Provided that a regular sonohysterogram has abnormal results, then those tests will be considered. In that case, an endometrial biopsy (EMB) will be first recommended, which entails the removal of cells that are sent for later testing and diagnosis. In cases of repeat failure, medical resonance imaging (MRI) will also be considered. In this way, a high-resolution magnet that provides detail-oriented results will be fundamental to identifying if the lining of the uterus is invading the surrounding muscle (endometriosis). If there is inflammation caused by endometriosis lesions, it is a fact that there might be cell factors that can negatively affect the opportunities for implantation. That being the case, a hysteroscopy would be recommended. Additionally, an endometrial receptivity assay, a test that measures what should be the duration of exposure to progesterone before embryo transfer, consists of going through a frozen embryo transfer cycle to analyze if the transfer timing should be changed specifically for the individual characteristics. Ultimately, a thrombophilia evaluation should also be considered as its main focus is on clotting disorders and these have long been associated with recurrent pregnancy loss.
According to Dr Kumar, ovarian reserve encompasses these two following ideas.
First of all, from a biological perspective, a female-gender fetus will produce an average of 6 to 8 million eggs at 20 weeks of gestation and that specific amount decreases as the individual grows. Most of the eggs are lost at birth with just a million remaining. Most women will only release 400 hundred eggs over their reproductive years. Consequently, there are 1000 eggs left by menopause but of inferior quality that are unresponsive to the stimulatory hormones.
Ways to assess the quantity (Number of eggs that can be obtained):
Looking at the woman’s age, we need to keep in mind that a 31-year-old woman with a high number of eggs is going to have a bit higher quality than one with a low number of eggs. However, in a 31-year-old with fewer eggs, the egg quality will still be far better than a 45-year-old with a lot of eggs. It is crucial to remember that age depends more on egg quality than the number of eggs, but the number of eggs plays a small role.
“Euploid” means the true number of chromosomes present, while the prefix “aneu” in medicine means not. What we want are euploid embryos, meaning the correct number of chromosomes in the embryo, which would be 46 – 23 from the egg and 23 from the sperm. Aneuploid embryos, on the other hand, would have an abnormal number of chromosomes or missing or extra pieces of chromosomes.
The egg starts with 92 chromosomes. All the cells in our body except for red cells have 46 chromosomes; the red cells don’t have a nucleus or chromosomes. These 23 chromosomes are from the egg that created us, and 23 are from the sperm that created us. When 1 mother cell is going to make 2 daughter cells, the DNA replicates in the cell, the DNA goes to each side of the cell, the cell pinches itself into 2, and you have 2 identical daughter cells from 1 mother cell. With ovulation, the chromosomes line up, and then they’re pulled aside, 46 to one side, 46 to the other. One set of chromosomes is thrown out, that’s called the first polar body. The 46 are lined up again, 23 pulled out on one side, 23 on the other. Another 23 are thrown out, and that’s the second polar body. The sperm comes in with another 23, and we have the 46 to make a new embryo.
This depicts the even distribution of the chromosomes so that the resulting eggs have the correct number. This kind of issue can also happen in the sperm, but it’s much less frequent. Up until age 33-34, the number of eggs is relatively stable, then it goes down rapidly. The egg quality is the inverse of that. This is the likelihood of finding an abnormal embryo. It’s relatively stable, and after age 34, it starts to increase. Aneuploid embryos are the most common cause of miscarriages.
It is quite acknowledged that male hormones (androgens) increase follicular recruitment. However, having high testosterone levels or high androgen levels throughout the cycle will eventually result in retrieved poor-quality eggs and subsequently poor-quality embryos.
What is used most often for these cases?
According to Dr Kumar, quality is related to the propensity of the egg to generate a euploid versus aneuploid embryo. Furthermore, it is important to note that age is of the utmost importance for egg quality as the number of eggs has a small role.
In the first place, it is known that with poor prognosis patients, a much gentler approach is much more efficient rather than an aggressive type of stimulation. Nowadays, the focus on medication has slowly shifted from high doses for a low number of eggs to individualization of both the particular characteristics of the patient and the cycle based on the antral follicle count.
Even though opting for donor eggs can essentially be an emotionally exhausting decision to make, it is strongly suggested to consider it seriously as it might ultimately lead to the expected outcome. Deciding to opt for egg donation treatment requires thinking about all factors that need to be addressed, including the financial and medical aspects as well.
Related reading:
When your AMH is probably 19 (pmol/L), and we use ng, so it’s about 2.6 if I’m doing some decent math off the top of my head, which is pretty favorable and appropriate with your AFC. My recommendation would be to do an antagonist protocol, and I think that you’d do better with a mixed dose with maybe, let’s say 300 units of FSH, 150 units of HMG and I would consider maybe 50 milligrams of clomiphene for about the first seven days. A little bit lower dose and this is one of those cases where the adverse outcome may be due to a few problems in the sperm itself and frequent ejaculation. This is where your lifestyle changes play a role, so a handful of nuts and berries you should be eating every day. Get those antioxidants on board, not through pills but dietary changes, exercise every day, it’s a huge benefit in decreasing the inflammation in our body, improving our body, and much more so than any pill could ever do. The third thing daily ejaculation for even a week leading up to the egg retrieval again, you only need 20 sperm, you don’t need 20 000, we don’t need 20 million, so frequent ejaculation, I think would help. So, a little bit lower dose and frequent ejaculation.
We commonly use Doxycycline, and we start with a two-week course, we re-biopsy, and if we still have it, we do a four-week course.
The key here seems to be looking at the embryos because the ERA test is also used for implantation failure, and this might not be implantation failure in your mind. But in the physician’s mind, this is implantation failure, so a biochemical pregnancy, we consider implantation failure even a very early miscarriage falls into that realm of implantation failure/RPL, so recurrent pregnancy loss. It’s all kind of viewed as one continuum
I don’t use the flare protocol at all, I think it’s a crummy protocol, it’s very aggressive, and I think it most often results in poor quality eggs. Over other protocols, I’m a strong believer in antagonists or a mini, I don’t use the flare protocol. I think the mini is going to be better in terms of equality than a flare. I use a dual trigger, I use a low dose HCG, and I use buserelin acetate, but there’s decent evidence that suggests you’re going to get maximum yield of eggs from each follicle if you use a dual trigger.
It is an MII. The MI eggs can fertilize, we do the IVM in vitro maturation, there is the success with that but it’s not the same as MII.
They do grow, but it’s irrelevant. There’s no reference range for the follicles on retrieval days, so this could be 20 millimeters, could be 22 millimeters, but it’s irrelevant. Remember that we’re worrying either we do the long estimation, or we’re doing mean diameter, and it’s a gross estimate, it’s not exact, and people talk about the lining on the day of transfer versus the day you start progesterone, so the reference range meaning in our mind, are they mature, immature those kinds of things. It is for the day of trigger beyond that, it’s irrelevant.
Yes, slightly more likely, but I think they’re still almost as good. We’ve looked at the results meaning what percent is normal versus abnormal on day-5 versus day-6, there is a small difference, but it’s pretty small. I wouldn’t worry about that issue there, but all 4 of those embryos are good.
We did estrogen priming for a prolonged period. This is about maybe 12 years ago. I had this idea that if we did estrogen priming, you would upregulate the FSH and LH receptors on the granulosa and theca cells. You get a better response, and what I noticed is that I was getting much more dominant follicles and dysfunctional stimulations.
I think that again it sounds wonderful theoretically. Practically, speaking it’s better to get a fully synchronized good stimulation than to think that we’re going to get an extra egg or 2 or to do this miraculous supple regulation of FSH receptor by giving estrogen priming. The only time I think about this is when there’s hypothalamic hypogonadism where the woman hasn’t been exposed to estrogen for a long period, and those stimulations can take a long, long time unless you give a month or two of estrogen beforehand but during a normal IVF cycle. I think that this is hypothetically interesting, but practically it doesn’t work.
I think Cabergoline would be indicated to lower prolactin for IVF stimulation, and it shouldn’t affect either high or low prolactin. It should not affect the overall stimulation. If you think about prolactin, the way that it causes infertility is that it suppresses FSH and LH production, so potentially if you didn’t want to take cabergoline, you could let your prolactin be very high, and you wouldn’t need an antagonist or an antagonist stimulation, but in terms of it negatively affecting the stimulation, there’s no physiologic basis in that.
Testosterone would be before the ovarian stimulation. The HGH would be during the ovarian stimulation, we do sometimes retreat for 2 or 3 weeks, but that’s less common.
In this situation, this is where the cycle difference is a very great deal, so this type of thing you have to look at the size of the follicles if there are 3 or 4 that are a little bit like 8-9 millimeters and 2 or 3 that are 4 millimeters, then I would do a mini dose stem with just Clomid and human growth hormone. If there are 7 and all look good and uniform then I would do a moderate dose and maybe as a good high amount of Clomid with maybe 300 units of HMG rather than FSH.
I think the vast majority of us would treat with or without symptoms. I would recommend the MRI, again the reference range is not there, and there are different units used all over the world, but it seems like it’s a pretty high prolactin level. I would get an MRI to make sure there’s not a microadenoma in the pituitary. With high levels like that again, I would incline to treat. I think the majority of the issues are related to the ovarian reserve issues and not prolactin. Even emotionally speaking, having high prolactin levels you being concerned about it makes so much more sense to treat it haven’t come down to normal, and at least that’s one less worry that you have.
I think 1 or 2 is fine. If these are untested embryos. This is one area where I would take a timeout and maybe do an HSG or even a laparoscopy and look at your fallopian tubes because the most common reason for an ectopic is that something is going on with the tubes. Given how young you are, how many embryos you’ve had transferred, and either the biochemical I would just want to check on your tubes. I’m fine with the natural cycle or programmed, but the main thing is to check your tubes before you do anything else.
That’s a very difficult situation because it’s a last resort type of thing. Where once we can’t figure out anything else and why it’s not happening, you can try it, but I’ve read about this again recently because we had a patient that was referred to us and the patient was having poor fertilization in the past. We’ve tried this, we’ve even tried electrocuting, shocking the egg to get it to fertilize, it’s the last resort, it’s not something that’s routinely used, and it’s not something that routinely works.
I wouldn’t worry about the Hashimoto. Let’s get the easy one out of the way. As long as your TSH is between point 5 and 2.5. The semen fragmentation again that’s only going to tell you if you need to do ICSI or not, and it seems like that part’s okay. The most important thing, I would go to day-5 and see if you can get PGT-A done because then you know the truth. When it comes to day-3, I know some people are doing it thinking that the embryos can be better in the uterus than in the IVF lab, but if you think that, then you need to switch IVF labs because the IVF lab should be good enough to take it out to day-5. If you’re barely getting into a blastocyst, then I would stop, let them go to day-6, do the biopsy, find out what you have.
If you’re putting in embryos that are not viable, then you could go down this whole path of implantation failure workup, etc. and it’s just the embryos. If you are putting in genetically viable embryos and it’s not working, then you need to take a pause, time out, do this whole implantation failure work up, figure out what’s going on. We need to know, is it A or B? You can only do that with the PGT-A.
I would use testosterone, maybe a high dose of Clomid, a low dose of Menopur and Growth Hormone.
Most of the time, I recommend a mixed dose protocol. Mixed doses, those being FSH in the combination of HMG. In the very low dose protocols, I do use HMG in place of mixed dose, or pure FSH, and you have to drive the system meaning too low of LH, you’re not going to get anything done. Too high like the Lupron flare is going to adversely affect the outcome, but you need some decent amount of LH there to make the precursor for the FSH to work on. Remember that FSH binds to granulosa cells and converts testosterone to estradiol. Where does the testosterone come from? LH, so HMG is a combination of FSH and LH, so LH binds to theca cells and converts cholesterol to testosterone, and that testosterone is a precursor for the granulosa cells driven by FSH to work on. Without testosterone as a precursor, how do you get estradiol? You don’t. That’s why you need both FSH and LH.
