Oocytes are the key factor in fertility. As the rarest cells of the human body and yet the most rapidly ageing they are decisive in the outcome of IVF treatment. During this webinar Dr Łukasz Sroka from InviMed answers the question how a woman’s age influences oocyte quality.
Oocytes, just like sperm, contain only half of human genetic material. While sperm is produced every day and almost all the time, oocytes, are formed very early on in the human development. During the meiotic maturation division process, through which immature oocytes become eggs, oocytes go into the so-called primary arrest. In other words, they are stopped during the division for a very long time, even decades. This special feature of oocytes is very important when we compare oocyte quality versus a woman’s age.
Dr Sroka starts with describing Oocyte quantity. He bases his explanation on the well-known publication by Wallace and Kelsey who analysed a lot of human tissue from different sources as well as what happens to oocytes during the whole of a woman’s life – from seven weeks after conception up to 51 years old. According to it, NGF (non-growing follicle) is the base for ovarian reserve, the number of oocytes in the ovaries. Human ovaries do not produce eggs every day all the time. The production happens when a woman is still in her mother’s womb and then the number is constant. It just decreases with the age.
Dr Sroka says that the number of oocytes in the ovaries is fixed on the day of birth. The average number we come across most often is about 300,000-400,000 of NGF on the day of a woman’s birth. This is very important information because it means that a woman can be born with different number of non-growing follicles and this number will decrease with age.
We cannot assume that the speed at which the number of oocytes is decreasing is similar across the female population. Usually we think that a woman aged 25 is quite capable of being pregnant and at this time the average number of remaining non-growing follicle population is about 20%. Nowadays, the most typical age for getting pregnant in Western countries is about 30 years plus. And currently there is only 10-12 % of NGF population. On the average, the non-growing follicle population decreases up to the age of 50 when their number is exceptionally low. Of course there is also a small group of women for whom this number starts from much lower values and decreases much faster. They can achieve a kind of premature menopause at 40 or below. Conversely, some women with ‘hyper fertility’ can get pregnant at a much older age.
Dr Sroka makes another significant point here. There is no way that IVF stimulation will deplete a woman’s own ovarian reserve faster than it happens normally. A woman loses her eggs every month at an exceedingly high speed. The maximum is about 900 follicles per month on average. This number of course decreases also with the age. What is interesting is that probably the more NGF you have, the faster you lose them.
When it comes to oocyte quality, there is this already mentioned moment of arrest when the oocyte is kept in the middle of division. The doctor recalls another publication where the authors examined a very large number of oocytes acquired from women at different age and checked the normality of chromosomes in these oocytes. It was found out that as a woman’s maternal age increases so do the number of aneuploid (impaired) oocytes. At the age of 45 it is difficult to find any healthy oocytes. You might still have a plenty of oocytes in your ovaries but their quality is rather poor.
There are a few clinical implications related to the quantity and quality of oocytes. Dr Sroka presents the information from the Centers for Disease Control and Prevention (CDC). They collect data from almost all IVF clinics in the United States. There is a sharp decline in pregnancy rate and live birth after the age of 36 or 37. Around this time, human oocytes become much worse in quality. That is why most IVF clinics in the world do not perform IVF on women after 43/44 years old. The pregnancy rate and the live birth rate for women at 40-42 is about 10-12%. We must bear in mind that the quality of oocytes affects the results of IVF procedure. Additionally, after 40 there is a sharp increase in the miscarriage rate.
However, even at the age of 44-45 it is possible to achieve 75% of positive results of oocytes pick-up procedure. But despite that the pregnancy rate is as low as 4% and the live birth rate is about 3% (including babies with genetic disorders). Additionally, embryos received from unhealthy oocytes will not implant. Of course, in case of egg donors, we get a constant number of pregnancies regardless of woman age. This all points to the fact that a woman’s fertility is related to the age of her oocytes. That is the reason women have to think about getting pregnant faster.
That’s a very interesting question. Of course we have to remember that all slides I showed to you were just statistical presentation. So when we discuss single cases, we have to remember that there are always some exceptions to the rule. From my personal experience as an IVF doctor, I personally never faced the situation when we got a viable pregnancy from patient’s own eggs at age 48, which would then end in delivery of a healthy child. Of course I had some situations when we were able to have embryos, as in your case, and even achieved a clinical pregnancy with some kind of implantation. But when we talk about a final result such as delivery of a healthy child, I personally never faced such situation. However, in my gynecological career I’ve met few women who conceived naturally after 48 or 49. But then there are different subpopulations of women. There is a small group of women with the so-called hyper-fertility. If you are in the group of hyper fertility women, you can be pregnant even at age 46, 47 or 48. Usually at the age of 40 such a woman has already a small group of children and grandchildren. So if you need to go to IVF to be pregnant, probably your ovaries are not in that group and your chances of a viable and well-developing pregnancy ending with delivery of a healthy child are unfortunately very close to zero. Of course if there were no embryos produced with donor eggs, the procedure of egg donation could have failed because of many reasons. These are often: bad quality eggs, bad stimulation of the donor, some laboratory errors and so on. We also have to remember about sperm quality as it can also affect the results. Even at your situation, when you produce embryos with your own eggs and there were no embryos with the donor eggs, I will advise you to try one more time with donor eggs rather than try to undergo the next IVF procedure.
I think you’re asking about one of my slides. You know it’s the so-called raw data presentation from the publication which is based on some group of tested oocytes. Usually these oocytes are coming from the very common source. They are coming from IVF procedures, they’re so-called left-over oocytes or oocytes donated for some some kind of tests. We have to smooth this curve somehow, to make some average, to calculate the tendency or a trend. There are some changes which can be hard to explain. The general trend is increasing and that’s the main final result from the publication. So sometimes when we present the raw data, there are some discrepancies, some things which had to be mathematically and statistically corrected.
This is a very good question. We still think how what we can do it. As I presented to you, there is very little we can do about improving oocytes quality because ovaries are like a warehouse. The testicles are like a factory, they are producing sperm. So when we do some things, we can either improve or decrease the quality of sperm production. It’s like in a factory: when you do some changes to the machines or to the production process, you can produce better or worse products. Ovaries are more a warehouse so when we already have something lying on the shelves, there is very little we can do about improving its quality. The best option is to use oocytes as early as possible and think about pregnancy before you are 30 years old. And after 30, you shouldn’t hesitate about the IVF procedure because when the quality goes down, you can repair it by increasing quantity. When we do IVF procedure and when we stimulate ovaries, as a result we get not 1 or 2 but 10 or 12 eggs. And even in the situation when the quality of these oocytes is worse than a few years ago, we still have 10 or 12 oocytes and then statistics just helps us. Sometimes the number can beat the quality. So when talking about the improvement of oocytes quality, we shouldn’t hesitate about doing IVF. We shouldn’t wait until late 40s. You should remember one thing: if you’re trying to get pregnant for more than 2-3 years, the chances that you will get pregnant without IVF are much lower. Sometimes I meet patients with history of 8 or 10 years of trying to conceive naturally. When they decide to do the IVF procedure, sometimes it’s just too late and we have to go for donor eggs. So to answer this question: there are some, but very limited options, to improve oocytes quality. They’re mainly based on changing the hormonal status of ovaries, for example with the use of testosterone or prasterone, like DHEA. Sometimes for a woman with a low ovarian reserve, we use such protocols to improve oocytes quality with very different results. I use a protocol with DHEA adapted from Professor Norbert Glacier from New York clinic and I had almost 100 patients on this protocol. One or two of them conceived naturally on this protocol and some small group achieved much better results regarding IVF procedure. But these protocols have very limited scientific support and from different sources we get non-conclusive results. So if your ovarian reserve is really low and there are no other options, sometimes it’s worth to try to improve the quality using testosterone protocol or DHEA protocol. Of course there are other tested options in some clinics, like IVA method or some injections of your own serum into ovaries but the data is still very limited. Some centres also do the tests with growth hormone but it’s very costly and the data is also limited.
It’s what I said just a second before. It’s the procedure in which we are injecting ovaries with some extract from your own blood and there is some scientific support saying it should help. In your blood, there are cells that are responsible for reactivating some process which, in theory, helps in reactivating oogenesis – the production of newer oocytes. But as I said, the data is still very limited and there is no big scientific support for this procedure. There are some clinics in Poland doing it. It’s not available at our clinic, we don’t have any experience with this method so I cannot tell you if this method really works. I think that we should wait for some reliable scientific results published in some scientific papers. Talking about side effects: I think that if it’s done properly, there’s no risk of some serious side effects. But does it really work? I don’t know, I don’t have any experience with this method. But I know that there are some clinics trying to do this for women with a very low ovarian reserve.
As I said, I don’t have any personal experience with this technique so we have to wait for some scientific publications.
As you know, the mitochondria are a very special part of each cell. We believe that in the past there were bacteria that just stayed in our cells and now they play a very important role in many metabolic processes. Mitochondria also contain their own DNA which goes down from a mother to a daughter. Because of its special role in cell metabolism, this part of the cell can be very important for the so-called cytoplasmic oocyte maturity. When talking about oocyte maturity, we can talk about nuclear maturity. It means that the DNA of oocyte is in the right phase for being fertilised and connected with sperm. We can also talk about cytoplasmic maturity. It means that the oocyte is properly equipped with all the machinery for a new embryo development. Sometimes, when for example the stimulation for IVF is too short, we can see that the eggs are ready for fertilisation from nuclear maturity point of view but the embryos are very weak, they’re not good quality embryos and we don’t get implantation from such embryos. Then we can say that maybe the cytoplasmic maturity of such oocytes was not good. Talking about coenzyme Q10: it’s a very special substance, it’s also used in the DHEA protocol. We believe that it may somehow improve quality of oocytes but the scientific background for it is still not very strong. But probably it will not harm you anyway. High doses of coenzyme Q10 may in some cases, for example when combined with high doses of prasterone, substantially improve the quality of oocytes, especially in cases of low ovarian reserve.
I have to say that fresh eggs are better because when we freeze eggs, we lose part of them when we warm them up. So when we use frozen eggs, we usually try to freeze more eggs than we need because after warming them up, we end up with a lower number of eggs. But when eggs are properly frozen and then warmed up according to the special procedure, the quality is not very much reduced. The number can be reduced of course. So in case when we need 6 fresh eggs, we should freeze at least 10 or 12 eggs because after warming them up, we can end with 10, 8 or 6 eggs. But I don’t think that with a proper vitrification technique the quality is much reduced. A lot depends on the quality of eggs before freezing. When we have good quality eggs and freeze them and then warm them up, we still have a lot of good quality eggs. Of course the number is usually reduced, but not the quality.
I think I would use the frozen younger eggs now. Of course the question is how many eggs you you have frozen. This 4-year difference is quite relevant. A four-year difference between the age 26 and 30 is not very big but between 41 and 37 – it’s a really huge difference in quality. By the way, social freezing should be done a bit earlier. I think that the best age for social freezing is up to 35. But if you have eggs from age 37 and five unsuccessful IVFs, I would rather use these frozen younger eggs. Of course the question is also at what age these five unsuccessful IVF procedures were performed, but I would recommend to use the frozen eggs anyway.
You have to know that when we do research on the group of women with low AMH and low ovarian reserve, there is some point (usually 0.4) below which the results for IVF procedure are really poor. We almost don’t get any pregnancies when the AMH is below 0.4. Of course age also matters. There is a difference if this AMH level is at 30 or 40 years old. Of course it’s always okay to try DHEA protocol. I use professor Glacier protocol when I apply DHEA at a dose of 75 milligrams per day: 25 milligrams of the DHEA three times daily. This protocol with DHEA should last at least three months because this is the time when the small follicles are developing in ovaries. The two most common pitfalls with DHEA protocol are too short time and too low dose. The dose should be at least 75 milligrams and the time of the treatment should be at least three to four months. After that time, you can try to check your AMH level. Even in cases when this AMH level is not increasing, it’s worth to try to stimulate the ovaries. Sometimes the response from ovaries after the DHEA protocol is better, even in spite of not growing AMH level. However, you should keep in mind that this is extremely low AMH level and the results are not a very good prognosis.
I’m afraid I will not attend this event. In fact, I wasn’t aware of that event and I even don’t know when it is. Probably I will not be able to leave the clinic in October. There were a lot of holidays during June, July and August and it’s time to work it off.
I think I would recommend it. When we have the transportation done in a proper way, with all the medical requirements for medical transport, it doesn’t harm frozen eggs anyway. If it’s possible and it’s legal and you can’t find the matching donor in your home country because of some missing phenotype, I think it’s ok. But you have to discuss the costs of such procedure. Sometimes it can be cheaper to go to another country and to do all the procedure in the local clinic where you can find the match, instead of doing oocyte transportation. Of course it depends how much you can trust the staff in the clinic in another country and how well you can communicate with them. I think that sometimes it’s easier to do the IVF with donor eggs just on-site rather than to transport oocytes. But it’s mainly because of costs and not because of any medical risk.
I don’t know if you got pregnant third time at the age of 40 with the help of IVF or just naturally. But if you achieved the success and you delivered a baby at 41 and now the baby is 5 months old and in perfect health, maybe, assuming that you are not breastfeeding, it’d be good to try natural pregnancy. But if you want to try natural pregnancy, you should do it as soon as possible. Sometimes after a successful pregnancy we see the effect of temporary ovarian rejuvenation. Personally I had one patient who’d had three unsuccessful IVFs, then two unsuccessful donor eggs procedures and then she conceived naturally and delivered a healthy baby. And half a year later she conceived naturally for the second time and delivered a second healthy baby and now she came for contraception. Of course pregnancy at 41 is somehow connected with a bit higher risk of some genetic diseases, like for example Down syndrome. But if you are ready to try a natural pregnancy now or in the next few months, I think it’s worth to try. There’s no need for speedy decisions because there is a lot of time for donor eggs. You can still do the donor eggs in the next year or two or three or even five years.