Ovarian rejuvenation – myths and reality

Explained by: César Díaz García, MD PhD Assoc Prof, IVI Clinic London
Category:
From this video you will find out:
  • What ovarian rejuvenation techniques are aiming at?
  • Whether there are any pitfalls of the techniques – and if yes, what are they?
  • What Platelet Rich Plasma (PRP) is and how it activates dormant follicles?
  • If the transplantation of stem cells restores ovarian function?
  • If fragmenting ovarian tissue helps to avoid chromosomally abnormal embryos?
  • Who ovarian rejuvenation techniques should be used for?
 

Everything you need to know about ovarian rejuvenation

There are more and more techniques claiming to ‘rejuvenate’ ovaries and – as a result – reverse menopause. But are they really offering help or just false hope? Watch the webinar recording with dr César Díaz, MD PhD Assoc Prof, a Medical Director at IVI Clinic (London), who discusses ovarian rejuvenation for women of advanced maternal age and with a low ovarian reserve and the myths surrounding it.

In the general population, infertility is present in about 15% of the patients. This percentage varies a lot depending on the age – almost 30% of over 35-year olds are said to be affected by infertility. And this number increases as women get older. The process of ovarian ageing will have a tremendous impact on the results of IVF treatment. Thus, in order to increase the number of antral follicles stimulated during the IVF process, ovarian rejuvenation treatment was introduced.

Ovarian rejuvenation – the definition

Dr César Díaz introduces three different types of ovarian rejuvenation techniques that aim to boost and ‘wake up’ a pool of follicles that are dormant in woman’s ovaries. It basically refers to those patients in which the ovarian function has already stopped – so mainly to menopausal or perimenopausal women.

Waking up dormant follicles can be achieved by three different interventions:

  • by infusing growth factors – Platelet Rich Plasma (PRP)
  • by infusing cells that produce growth factors – autologous stem cell ovarian transplant (ASCOT)
  • by activating other molecular pathways – fragmenting ovarian tissue (chemical/mechanical)

How ovarian rejuvenation works

It has to be said from the very start that the process of ageing impacts infertility in two ways. Firstly, it decreases the number of follicles so disrupts the ovarian function. Secondly, it affects the quality of embryos (both genetic and non-genetic quality). It is well known that over the age of 40 , the embryos are going to be abnormal in more than 60% of patients. Dr César Díaz says that unfortunately, ovarian rejuvenation techniques will not impact in the genetic quality of the embryos and help to bypass the effect of chromosomal abnormalities related to ageing. Their goal is quite different. By using ovarian rejuvenation techniques, doctors are targeting microscopic primordial follicles and try to make them grow to the antral follicle stage, at which they can stimulated with gonadotropins. These follicles are sensitive to growth factors and other type of stimuli that could help them grow and make them activated.

Pitfalls of the techniques

Dr Díaz admits that as ovarian rejuvenation techniques are still experimental, there are a lot of pitfalls related to them. One of them is the way results are reported. Dr Díaz differentiates between two ways of reporting the results: bad and good ones. When we report results of any type of technique, we should show how many patients have undergone the technique and – obviously – how many of them didn’t succeed. This is what we probably lack the most nowadays when it comes to evaluating and assessing ovarian rejuvenation procedures.

Additionally, there are other effects of the treatment that could somehow mislead the patients: the placebo effect and detection bias. In order to control for all these types of potential confounding factors, it is important to use knowledge and experience from other clinical settings. By repeating the experiments that other people did and modifying certain aspects, it can be checked whether it is possible to improve the techniques or not. Enhancing the experimental designs can also be done by introducing control groups and randomising patients.

Types of ovarian rejuvenation

PRP

One of the techniques for doing ovarian rejuvenation is Platelet Rich Plasma (PRP). PRP is prepared from a fraction of autologous blood with high concentration of platelets. It is a source of many factors and substances, especially platelet derived growth factor and transforming growth factor-β (TGF-β). Platelets contain molecules that help to regenerate the tissue, they regulate cell migration, attachment, proliferation and differentiation as well as promote extracellular matrix accumulation. Dr Díaz stresses the fact that all these processes are also needed to activate dormant follicles.

Unfortunately, there is still very little done from the scientific point of view and the clinical evidence. There are mainly two groups who have reported the use of PRP in patients with low respond – the Greek group and the Iranian group. Unfortunately, the only available studies provided by them report on successful cases and they don’t tell us how many patients underwent the process. Thus, it is not possible to calculate the efficacy of the process accurately.

Apheresis

Another way of doing ovarian rejuvenation is by introducing the cells which will produce required growth factors. It is done by stimulating the stem cells in the bone marrow to go out from the bone marrow to the peripheral blood. Then the stem cells are taken out using an apheresis machine. Apheresis machines separate whole blood into cellular and plasma fractions and they are also used to collect blood products for transfusion and transplants. Once the stem cells are in an apheresis collection bag, they can be reintroduced into the ovary through interventional radiology by perfusing the ovarian and uterine arteries. The whole process is believed to promote the growth of follicles there.

When dr Díaz was working in Spain, he and his colleagues did a pilot study with 20 patients diagnosed with low ovarian reserve. They mobilised the stem cells, infused them again and looked at the effect in terms of serum anti-Müllerian hormone (AMH) and antral follicle count (AFC). They saw that, after doing the autologous stem cell ovarian transplant (ASCOT), AFC was enhanced and there was an increase in AMH levels as well. However, in terms of the whole population of patients included in the study, they we couldn’t see any increase in the number of mature metaphase-II oocytes retrieved. A statistically significant observation, on the other hand, was a slightly lower IVF cycle cancellation rate. Additionally, the procedure resulted in 6 pregnancies overall (three pregnancies after IVF and three spontaneous pregnancies) and 3 live births. Dr Díaz admits that such results were above what they could expect in terms of pregnancy rates in this group of patients with such characteristics.

Ovarian fragmentation for follicular activation (OFFA)

According to dr Díaz, the third technique used in ovarian rejuvenation is quite simple – although it requires a surgery. During the procedure, a biopsy of the posterior wall of the ovary is taken, the tissue is processed and then its fragments are introduced into the ovary again. If the follicles are activated, doctors grow antral follicles and after 1,5 – 4 months following the procedure, they perform IVF treatment.

In the original technique, in addition to fragmenting the tissue, the authors incubated it for two days with substances that promoted the growth of the follicles and helped to avoid a follicular death. According the the available study, the procedure done in patients with a proper ovarian failure, resulted in pregnancies and even live births. However, dr Díaz admits that such pregnancies can also happen naturally without doing anything. So in fact, it is difficult to determine whether the achieved results were the effect of the technique – or was it just the role of chance.

Dr Díaz and his colleagues at the IVI Group decided to repeat the original experiment but also add the modifications to improve the technique. They resigned from vitrifying the tissue in order to minimise cryodamage and looked for the best vascularised site to put the tissue back – in order to allow for a natural pregnancy as well. Avoiding the incubation of the tissue allowed them to avoid the lack of oxygen that could substantially and sequentially induce follicular apoptosis (programmed cell death). The recent findings show that the modified OFFA technique developed by dr Díaz’s team may result in a slight increase in follicles – however, there are no visible differences in terms of reproductive outcomes. A randomised controlled trial in patients with poor ovarian reserve showed that although there was an increase in the number of antral follicles, it didn’t result in any improvement in terms of pregnancy rates or live birth rates. What is more, the technique cannot modify the genetic chromosomal abnormality rates in embryos. Although it was possible to produce embryos from patients over the age of 40, unfortunately none of the generated embryos turned out to be genetically normal.

Take-home message

It is obvious that nowadays scientists are constantly trying to develop new tools to help patients overcome infertility problems. However, some of these research projects are still very preliminary. Dr Díaz admits that it is a doctors’ duty to properly counsel patients and not to create false expectations. That’s why ovarian rejuvenation procedures should be done within the context of control trials and not be offered as established techniques. There is still not enough data regarding the efficacy of the techniques – although the results seem to be promising. Based on the studies conducted at the IVI Group, it is necessary to establish the proper selection criteria in order to offer the technique to the patients who could really benefit from it. At this point of research, dr Díaz thinks that ovarian rejuvenation techniques should be aimed mainly at the patients who have already established ovarian insufficiency. However, doctors are still working on the molecular pathways that could help them select the best candidates to undergo ovarian rejuvenation techniques.

Everything you need to know about ovarian rejuvenation - Questions and Answers

Is ovarian rejuvenation suitable for cancer survivors? I have had a lot of chemotherapy over 15 years and now, at the age 36, I am postmenopausal.

The answer is: we don’t know. Strictly speaking, nobody has tried it yet. But it’s very unlikely that this will be a technique of choice in patients with these characteristics. What happens after chemotherapy is that the follicles – even the primordial ones that we are supposed to stimulate when we do the activation of the follicles – are not there. It depends a lot on the type of chemotherapy but when we give chemo, even the primordial follicles die. There is also another effect of chemo which is extensive fibrosis of the ovarian tissue and also of the outside of parenchyma. In my experience, when I was leading the Spanish fertility preservation program, we did this process in two patients, after passing the ethical committee, and in fact the results were not the most satisfactory. We didn’t see any increase. Doing other techniques, for example infusing growth factors or putting molecules that are used to wake up the follicles, such as P10/AKT, is not recommended in oncological patients either. I would never do them because those growth factors and molecules are also well-known to induce cancer so they could potentially induce a relapse. But as I told you, if we stick to the facts, the answer to your question is: we don’t know because nobody has tried it in oncologic patients yet.

Is there any point for a woman in her 50s, who has had multiple IVFs and multiple miscarriages, in going through ovarian rejuvenation? Or should she just go straight to an egg donor and a surrogate?

This is a question that is asked many times by patients. In fact, I have never seen a patient over the age of 38 being pregnant after doing ovarian rejuvenation techniques. This is why at the very beginning of the lecture, I explained to you that ovarian rejuvenation techniques do not
modify the genetics of the embryo. I’m not saying that it would not be possible, especially in younger patients between 38 and 40/41. But the problem is that these techniques only increase the number of follicles. And when you are, let’s say 40, in average you need nine eggs to generate one euploid embryo – we know it because we have a lot of statistics in our clinic and we do a lot of genetic testing.

Even if you can increase the number of eggs by one or maybe by two, it will take a lot to get to that point in which you can generate a genetically normal embryo. After the age of 43/44, the percentage of normal embryos is even lower. The amount of eggs that you need to generate a normal embryo at the age 45 is around 68 or 69. Therefore, if you are 50 and you have already undergone the process of IVF and you have been through probably very tough experiences in terms of results, going for egg donation would be doubtless the wiser option. Undergoing surrogacy or not depends a lot on the physical conditions of the mother and also on the uterine characteristics. I would not give you an opinion without knowing your case specifically. You also have to take into account the legal conditions of the different countries. Unfortunately, in many countries undergoing an embryo transfer after the age of 50 is something that you will not be allowed to do.

Did you say that for a 43-year-old, 68 eggs will be needed on average to find one good egg?

It’s not about finding one good egg – it is to get one normal euploid embryo with 46 chromosomes. I can give you statistics for that. Of course statistics can vary a little bit, depending on the technique that is used in the different labs and so on, but for a woman at the age of 43, it is up to 68 eggs. So what I told was not exactly correct – on average, it is 26 eggs but it can go up to 68.

How do you collect over 26 eggs? Do you do multiple IVF cycles or multiple retrievals and they are frozen until fertilisation?

When we need to get 26 eggs in a patient over the age of 40, what we will do most of the time is to do multiple ovarian stimulation. But not necessarily. For example, a week before we finished our egg collections – because of COVID-19 – I did an egg collection in a patient aged 45 years old and we retrieved 18 eggs. So such kind of things can happen. But generally, after the age of 40, we will have less eggs so the way of getting to that amount of eggs usually implies repeating the ovarian stimulation process. By doing so, we will get the mature eggs that we need. Then the decision about what to do with those eggs – freeze them or fertilise them directly – depends a lot on the plan that has been traced with that woman. In general, freezing the eggs could make the treatment cheaper. At the very end, when you have collected all the 26 eggs, you fertilise all of them together. But don’t forget that these are just statistics. Among these patients, there were the ones who needed an average of 26 eggs, those who needed up to 68 eggs and also the ones who already had a normal embryo with 13-14 eggs. How can you know if you are in the group of patients who need more, less or the average number of eggs? Well, before starting the process, you cannot know it. So what we would usually do, would be to assess with you your specific situation, balance the pros and cons and give you the information about the cost. Another option would be to fertilise the eggs when you get them straight away – it could happen that in the first stimulation we already have a good embryo. Therefore, why would you be spending your money in other cycles that you would not need? However, generally it’s not that you get such amount of eggs in one collection – you usually need more.

Is this procedure done in London?

The surgeries and also the infusion of growth factors are done in our central surgical facilities although the patients are initialised here with me in London. If you are very interested, I would recommend you to have a visit with me or – if you do not live here in London – we can organise a consultation the phone. As I told you, these techniques go under the umbrella of a research project, so the consultations are free of charge. What we usually do is that we assess first if you could benefit from this type of techniques, based on your specific characteristics. If you cannot, then we will explain to you why and you will not need to bother to come for a consultation if you don’t want to.

Before proceeding with PRP, the numbers were: AMH = 1.02 (ng/ml), FSH = 9.3 (IU/l), LH = 4.1 (mlU/ml) and estradiol = 36 (pg/ml). The first month after PRP the figures were: AMH = 1.2 (ng/ml), FSH = 7.8 (IU/l), LH = 6 (mlU/ml) and estradiol = 29 (pg/ml). Because my doctor believed that the numbers would be better the following month, we decided to proceed with ovarian stimulation. However, the following month the results were lower: AMH = 1.07 (ng/ml), FSH = 6.8 (IU/l), LH = 5.05 (mlU/ml) and estradiol = 28.57 (pg/ml). The outcome was 6 eggs. My questions are: 1) Should we proceed with the stimulation from the first month? 2) Do you believe it is worthy to repeat PRP process before the next simulation?

In fact, with AMH of 1 ng/ml, I will never do any type of ovarian rejuvenation technique. This kind of result, meaning 6 eggs, is above the average result that we usually have with this type of characteristics in our clinics in the daily practice. So probably you need to discuss it with your
consultant and he will need to explain to you why to do the procedure. But having 6 eggs with AMH of 1 or 1.02 after the first month is something that is completely feasible without any other intervention, just with an ovarian stimulation.

Is this technique currently available or is it still only experimental? If available, what is the cost and the availability for a single woman in her 40s?

Unfortunately, in our group we have decided not to offer this procedure in women above the age of 38. This is because of the reason that I previously explained: the efficacy of the technique is so low that we feel that is not ethical to do it. I think I mentioned it during the presentation: with more than 40 patients included in the prospective cohort of patients with premature ovarian insufficiency, we have not seen a single pregnancy in patients over the age of 38. Again, I’m not saying that is impossible but it’s very very unlikely.

My AMH is 1.07 and I’m 38. My doctor told me that ovarian rejuvenation will not help me as my AMH is still high. I thought it would help me to create more eggs than usual – was I wrong?

Yes, probably you were wrong and I think your doctor was right. This is kind of the same question as the previous patient asked. When you already have an established ovarian reserve – even if it’s low – the ovarian rejuvenation techniques will add very little. In our practice, the average amount of mature eggs that we get with patients with AMH of 1.07 is between 6 and 7. But it can differ a little bit between techniques or between clinics. So for that level of AMH, it’s a very good number of eggs. By doing things like infusion of PRPs or ovarian fragmentation or ASCOT, you are not going to increase significantly the number of eggs. You could increase potentially the number of follicles – but as I showed you in the result of our randomised control trial, it didn’t result in an increase in the number of eggs. And that was exactly the same population with characteristics similar to yours. So my advice would be as your doctor has told you: not to do it. The good news is that at your age, usually the amount of eggs that you need to generate a normal euploid embryo is about 5. So probably with just one round of IVF at a good clinic, you’ll have pregnancy rates over 60%.

How long before a proposed IVF cycle should ovarian rejuvenation be done for best results?

This is a very good question. A couple of years ago, I wouldn’t have answer to it. Nowadays I could tell you that we see the increase in terms of follicles between two and four months after the procedure. So in fact the rationale is not ‘how long before should I do the technique’ but ‘how long should I wait to get good results’. The key is also doing a proper monitoring session. Obviously 2-4 months is a minimum and most of the patients will be in that range but what if you are a patient in which that increase in follicles happens a little bit earlier or a little bit after? Obviously, we should not do it too early or too late in order not to lose that chance. So I think that a very important thing after doing any of these approaches is to do a proper follow-up, including ultrasound scans and sometimes even blood tests.

Who are the ideal candidates for ovarian rejuvenation (e.g. typically what age/ AMH level)?

I would say that with the data that we have nowadays, ideal candidates would be patients below the age of 38 with clinical symptomatology of premature ovarian sufficiency, which means menstruations space more than four months and FSH levels above 25. But this obviously can vary
within the different cycles. these patients usually have AMH levels that are undetectable or very low – below 5 picomolar which is the equivalent to 0.7 ng/ml.

Is this a good procedure for a 42-year old with no history of fertility treatment?

That’s a good question which I have no answer to. Talking about patients of a certain age, especially if they don’t have any previous history of infertility, is virtually impossible. Every day in our clinic we see patients, aged 42 or even older, getting pregnant with their own eggs without doing anything else. Yes, age usually correlates with a decrease in ovarian reserve – but not always. So if you are 42 and you have never had a fertility assessment, my advice is that you do a fertility assessment first and you discuss your options one-to-one with the doctor. Because you could be 40/42 and you could have an ovarian reserve with 15 follicles, which I see not so rarely. On the other hand, you could be 42 and have no follicles or maybe one or two follicles – in such a case my recommendation would be to go for egg donation. So just given your age, the prognosis for sure is going to be worse than in a younger patient. But having said that, there is still room for variability within different age groups. So my advice is that you look at other aspects such as your ovarian reserve – otherwise answering that question is impossible.

Do you have any experience in using Mesenchymal stem cells from Wharton’s Jelly of the umbilical cord? Or the use of exosomes for ovarian definition? How do you infuse the cells?

There are a couple of questions here. First, the use of Mesenchymal stem cells from Wharton’s Jelly – yes, there are some groups who have done it but mainly in mice models. So it’s still experimental but the principle could be the same as in fusing cells from peripheral blood. The question is what is cheaper, what is easier and how do we infuse the cells. What we do is that we get the cells out from the bone marrow by injecting something called GSF. It is a product that we use when we do bone marrow transplantations or, let’s say, peripheral blood cells transplantations. So we mobilise the cells from the bones to the peripheral blood and then we take them out with a machine. What we have done is that we have concentrated those cells and we have introduced them directly into the ovary by using a very fine catheter that goes into the blood vessels. This is a way of doing it. Nowadays in our group we are doing a randomised control trial in which we are experimenting another way of doing that. It is very simple – it is just injecting the growth factors that mobilise the cells out of the bone marrow (the GSF) and see if that can induce the same effect. Instead of taking all the cells out, concentrating them and putting them back, we just let them go to the peripheral blood and go to your whole body. And we are trying to see if that can cause the same effect as by doing the apheresis. That could be very interesting because then the process would be very simple – it would just be giving an injection during five days.

What do you mean by saying it is a simple procedure? Injection within five days of what?

Basically what we do in this study is that we are comparing two ways of doing the mobilisation of the stem cells. We are mobilising the stem cells as we have always done it by injecting five days of GSF and then doing the apheresis of those cells that are in the peripheral blood. We’re taking them out, concentrating them and putting them back into the ovary – that’s the classic way, so to speak. But there is also another way of trying to do it which means that we inject the GSF and – instead of taking the cells out, concentrating them and putting them back – we just let them be in your body. So we mobilise the cells out of the bone marrow and we let them be in your peripheral blood. That’s what I mean by doing a simpler procedure. But what we are doing now is to test if that’s really efficient or not – because we don’t know it yet. So that’s a study that is currently ongoing.

I’m 44, I’ve been postmenopausal for 3 years and I had a successful pregnancy last year with a baby boy (now four months old). Can I do the ovarian rejuvenation and still be possibly pregnant using my own eggs?

Again, my advice would be not to do it. At least in our experience, as I explained before, we didn’t see any pregnancy after the age of 38. Maybe case-by-case, we could consider going up to the age of 40, but not within the research protocols that we have nowadays. It would be an exceptional case but I think 44 is far too late for this type of techniques. The chromosomal abnormality is linked to age so even if we increase slightly the number of follicles, they will never bypass of the effect of age on the chromosomes.

Which technique for ovarian rejuvenation you consider to be the most promising?

In fact, there is no trial comparing the three different approaches. In terms of making things simple, probably the PRP would be the simplest. But unfortunately, despite the fact that it has been used for many years, there’s not a single control trial published yet – which makes me think that it is not as effective as they claim it is. In my own experience, I have worked a lot with the ASCOT (a stem cell infusion) and also with the ovarian fragmentation. I think that in a long term, we will see similar results but for the moment being, the ovarian fragmentation is the technique for which we have more data available so far. Therefore, that’s the one I’d recommend to you.

Does ovarian rejuvenation mean a better number follicles but not better quality of embryos?

Yes, essentially that’s what we know nowadays. That’s a very straight way of explaining it.

My female partner is 40 y/o (AMH = 0.7) and she had four egg retrievals. Each time she had 1 egg retrieved (one time two!). Altogether she had 5 eggs. 2 embryos of poor quality were created. I didn’t get pregnant (that was the ROPA method). Would this make sense with such outcome to do ovarian rejuvenation for her? Is she the right candidate?

Again, from our experience I would say: no. It could be tried but my advice would be not to do it. It’s basically because of the age which will imply a higher number of chromosomal abnormalities. Also, as we were responding to the previous question, we will now see any improvement in terms of embryo quality. So when it comes to the main problems that you had in your previous cycles, we are not going to bypass them.

Does PRP help to improve egg quality? I’ve had seven failed cycles, all down to poor embryo quality. There are no sperm issues so doctors are saying it’s about egg quality. I’m 35 years old.

The answer is: no – at least not with the data that we have nowadays. Surprisingly, there is very little data regarding the use of PRPs and reproductive outcomes. In fact, the only study that I could find with proper information was the the Iranian study. Even the Greek group, which claims to have done a lot of cases, never provided any data regarding reproductive outcomes or the embryo development. So if you are 35 years old, there are other things that could be evaluated in order to improve the quality of your eggs. Obviously, there are very difficult cases at that age but usually, in patients below the age of 40, the quality problems can be bypassed sooner or later. Probably the first thing that you have to discuss with your doctor is how the embryo was treated in the lab under conditions in the lab. It makes a big difference. Every day we have patients coming with backgrounds of many failed previous IVF cycles and they get pregnant easily – especially if they are that young. Obviously, there could also be conditions that motivate that quality problem – and if so, then you doctor should focus on treating the conditions motivating the quality problem. There are also some medical interventions that could be evaluated to improve egg quality and there are also stimulation protocols that could potentially improve egg quality. But as I’ve been mentioning from the very beginning of the talk, ovarian rejuvenation techniques are mainly aiming at increasing the number of eggs – and not the quality of eggs.

Is there is any training course for doctors to learn the procedure?

I have to say that I myself learned it already in 2013. In our group, we train doctors to do it but we try to keep it restricted because the experience is also very important. For example, we are a group of three people that deal with all these patients. We also have a strict protocol that our colleagues in different IVF clinics follow to do the follow-up of the patients. Obviously because those techniques are very new, the more cases you do, the more experience you have. So it’s not very productive to teach a lot of people to do it at the very beginning because then each of those doctors will have very little experience.

For a 42-year old with no history of fertility treatment as she just started TTC 6 months ago, will you suggest trying with own egg first or go to donor eggs straightaway?

This is the typical question that patients in this age group will always ask when they come for a first consultation – and it is a very legitimate question. The answer is: it depends on what you want and it depends on what you expect. But yes, you could try treatment with your own eggs. I would not give you a very strong recommendation until I know your ovarian reserve. Based on your ovarian reserve, I would calculate the probabilities of having a pregnancy with your own eggs versus the probabilities of having a pregnancy with the donated eggs. The latter probably are going to be higher but obviously do you already know that. So it’s more a matter of how much you want to risk or how much time you want to invest or how difficult it could be. I really respect the opinion of my patients and I believe in giving the information and helping a patient to take a shared decision. Just by knowing that you are 42 years old, I couldn’t tell you: do this or do that. I can only tell you that probably your chances they are higher with the donated eggs – but then there is also room for a lot of aspects to be taken into consideration. So when knowing a little bit more about your case, we could probably discuss it farther.

What are the parameters that determine if ovarian rejuvenation has worked? You mentioned monitoring and blood tests following the procedure. Would you basically periodically measure antral follicle count/AFC (during ultrasound scans) and serum AMH? Anything else?

To be honest, I think that these kinds of things are pretty much black or white. As a doctor, I would only tell you that the treatment has worked if you have a baby at home. Probably this is something that we should do in every single aspect of reproductive medicine. What you are aiming at for you at the end of the process is simply to have a baby. Obviously, we use AMH and antral follicle count mainly to monitor in-between if we can do the IVF treatment and of course this is what we call an interim marker of success. But it’s not the definitive marker of success. The only successful outcome of any fertility treatment is having a healthy baby at home.

Is there any proposed procedure to help patients over 40?

Again, it depends a lot on what it comes together with being 40. But let’s say that in a normal or a very usual scenario of a patient in her 40s and with low ovarian reserve, there are some things we can do. In fact, probably this is the type of patients that we see in the clinic most often. The average age of our patients is 39.2 years old. What I usually say to my patients is that if the main problem is low ovarian reserve, the simplest way of bypassing the lack of follicles is by repeating the treatment. Obviously, the main drawback of repeating the treatment is the cost. So by decreasing the cost of the treatment, we can make the treatment more affordable. Therefore, we can repeat it and eventually get to the number of follicles and the number of mature eggs that we need to generate a normal embryo. We can do that by doing ovarian stimulations that do not require a lot of medication – even no medication or very little medication. We can decrease costs by accumulating oocytes or by not putting the own embryo back. So there are many things that we can do. We can also try to do medical therapies together with a stimulation protocol (or before the stimulation protocol) to prepare the ovary better in terms of outcomes and when it comes to egg and embryo quality – although I’d say this is quite debatable. So yes, there are many things that we can do.

Will you suggest mini IVF or full IVF for a 43-year old with no history of fertility treatment? All tests say all is fine but AMH has not yet been done. When do you consider mini IVF to be better than full IVF for over 40-year olds?

In our practice, if you have enough follicles to do a full ovarian stimulation, I would always do a full ovarian stimulation. There is a misconception resulting from all the studies in which people tend to think that the more you stimulate the ovaries, the worse the outcome is going to be. And that’s not necessarily true. In fact, what we know nowadays is that in normal responders, the more eggs you have, the more chances of having embryos and a successful pregnancy there are. Obviously, this is not the case if your ovaries do not respond well to the medication. In those cases, doing what people call a mini IVF, or a mild stimulation or a modified natural cycle (because there are many variations of those protocols), could be a better option. Therefore, we would suggest you to do that. So basically, again it will depend a lot on your ovarian reserve. If your ovarian reserve is very low, then probably mini IVF would be a better option. If you have good ovarian reserve, the more eggs you have, the earlier you will get a normal embryo and the earlier you will get pregnant. Therefore, a full ovarian stimulation would be better.

What about a cytoplasmic transfer – using ovarian rejuvenation to get more follicles and then using younger woman’s cytoplasm?

This is a very good question. As far as I know, there are some groups who have licenses to do research in a mitochondria transfer. It is a very specific cytoplasmic transfer because you do not transfer all the cytoplasm, you only transfer small parts, small organelles called mitochondria, which are meant to produce energy. The cytoplasmic transfer is banned in most countries nowadays, especially given the outcomes that we saw in the United States of America. They did a couple of trials long time ago and there were babies born with reported abnormalities. So these types of treatments are not doable nowadays. Maybe what you are talking about is the transfer of mitochondria – but the test results from mitochondria are also very controversial. We have our own experience with a randomised control trial in our IVF clinic in Valencia and the results were not as good as we expected. It’s very frustrating because obviously patients want answers as soon as possible and we would like to provide them with those answers quicker. But unfortunately, conducting research in a proper way takes time and sometimes, especially when it comes to fertility treatment, patients don’t have that time. So that’s why it is frustrating. But we have to remember that what we are putting in danger here is the health of your future baby – and at the very end of the process, we are here to help you to have a healthy family.

Will ovarian rejuvenation help with the effects of menopause, such as headaches, high blood pressure and just feeling bad in general?

The Greek group has published some papers regarding the use of PRP in terms of menopausal symptoms. I can tell you that in our experience, most of the patients who underwent the ovarian fragmentation procedure resume menstruations again. But as a reproductive medicine consultant, I wouldn’t recommend you to do that just to treat the menopausal symptoms. Basically because sooner or later the effect will stop so you will do it and 3-6 months down the line you will be in the square one again. There is a simpler, safer and cheaper way of doing it which is Hormone Replacement Therapy (HRT). HRT nowadays has a very bad reputation but in fact there are very good ways – similar to the natural ones – of administration with not strong molecules that can mimic the natural cycle very well. They will have amazing effects when it comes to mitigating the most important menopausal symptoms – and besides, they’re very safe.

When I was beginning with IVF at the age of 39, my AMH was 1.1. After one year and several stimulation protocols, it dropped down to 0.3. Another year later, it was surprising surprisingly up to 1.43 – so even more than at the very beginning. The tests were done in the same laboratory and with the same measures. What do you think is the reason? The laboratory excluded an error.

AMH is an ovarian reserve marker that is much better than FSH – we know that for sure. And it is more reliable – but it does not mean that it is perfect. Nowadays we know that there are slight variations in the AMH levels that can be related e.g. to the weight of the patient. So if you have
gained or lost weight during this time, it could affect the AMH levels. It could also be affected by the fact of being under contraception – I don’t know if you were on the contraception before the first measurement or later. The ovarian stimulation process can sometimes also affect the AMH levels – there are some publications on that. Not a lot, I will say little, but it can have some impact. And also there is something what we call the coefficient of variation of AMH. Regardless of what your lab has told you and ruling out the presence of an error, there are also variations intra- and interassay. And if you put all of that together, it will explain why the results are different. It can also happen – but I don’t know if it’s the case or not – that in the lab that you are using for your AMH test, they have changed the assays that they are using – from the 2nd-generation assays to the 3rd-generation assays.

My weight has not changed, I have normal weight. I was doing several IVF cycles, mainly natural cycles. At this time I had an IVF stimulation and had 11 eggs collected – 1 reached the early blastocyst stage but there was no pregnancy.

In such a case, I would say that this is probably a measurement problem – it’s a problem with the lab. I’m not saying that they have done an error – however, if you had an ovarian stimulation with 11 eggs collected, that does not match your AMH levels at all. I mean, luckily for you.

Is there any suitable procedure with women who are PCOS and have OHSS (ovarian hyperstimulation syndrome) issues?

Yes, there are. To be honest, for me it is hard to talk about it because OHHS should not exist any longer. I remember exactly that the last time I saw a severe ovarian hyperstimulation syndrome was 15 years ago. I have not seen any ovarian hyperstimulation syndrome in my years as a consultant in my practice. Nowadays we have something called antagonists – and it should be the ovarian stimulation protocol of choice in patients at risk of ovarian hyperstimulation. It means that if we do an ovarian stimulation with an antagonist protocol, we can avoid the use of HCG – a pregnancy hormone – to do the trigger. I am sure that you are familiar with Ovitrelle or Gonasi. So if we avoid the use of those drugs, it is virtually impossible to have ovarian hyperstimulation syndrome. So having ovarian hyperstimulation syndrome is only the fault of the doctors. We should not see ovarian hyperstimulation syndrome even in patients with PCOS because we can avoid it by using an agonist (GnRH) trigger and by deferring the transfer. So we freeze the embryos and we put them back in the following cycle. I don’t like to say that we will avoid OHHS in 100% – because 100% does not exist in medicine. However, we can avoid it in almost 100% of cases.

What is GnRH trigger?

Basically, when we do an ovarian stimulation protocol, we give FSH to stimulate the ovary, plus/minus small amounts of LH. Those are the hormones that stimulate the ovary naturally. When the follicles are fully grown, we need to send a sign to your ovaries so they release the oocytes – although we will do the egg collection before the oocytes are released. But during that process of releasing the oocytes, the last steps of maturation will happen. In nature, that happens due to a huge increase in LH. Unfortunately, that increase in LH is very difficult to mimic by giving you external LH – we need a lot of it. Just to give you an idea: the doses of LH that we can use in a normal stimulation protocol are about 150 – 300 units. What we need at the day of the trigger is more than 10,000 units all of a sudden. So instead of doing that, what we classically do in IVF is to give a patient the pregnancy hormone called HCG. HCG is a combination of two proteins and one of those chains is exactly the same as LH. So this pregnancy hormone has an LH-like activity and it remains in the blood for a longer period of time. Therefore, we use HCG as a substitute of the LH trigger. But it can cause OHHS. So there is another way of doing the trigger which is by giving the analog of a molecule called GnRH. GnRH is the hormone that in your body will induce the trigger of LH. It’s a hormone that is produced by your brain and it will go to your pituitary gland. So instead of giving you huge amount of LH, what we will do is to give you small amount of the hormone that induces in your gland the huge release of LH. By doing that, we will avoid the use of the pregnancy hormone and therefore we will avoid the risk of OHHS.

What is the brand name of this GnRH trigger?

It’s Suprecur. It has been used for a lot for many other things in reproductive medicine so I’m sure your consultant will know it.

Do you use DHEA and/or CQ10 in patients with low ovarian reserve? If you do, for how long before IVF?

That’s a very good question and this is a question that we also face a lot in our daily consultations. In general, we do not recommend it because there is still not enough evidence behind the use of DHEA or coenzyme Q10. But having said that, I want to stress that the lack of evidence does not necessarily mean the lack of effect. It sometimes means that nobody has done the study proving that the intervention is a valid intervention. DHEA has to be used at least three months before ovarian stimulation. For CQ10, there is less data regarding the duration. Therefore, if you were my patient, I’d suggest that you have to balance the risks and the benefits. When it comes to DHEA, the side effects could be a little bit annoying, such as hirsutism, basically meaning hair on the face, and acne. Coenzyme Q10 is fairly inexpensive and has no side effects – so why not? What I cannot tell you is if it’s really going to make a difference or not – but probably it’s not going to harm you either.

What dose of DHEA and CQ10 do you give?

As I told you, I personally do not recommend DHEA. You know that it is not a registered drug in the UK. For CQ10, I usually use 200 milligrams every 12 hours.

What can we do to improve especially sperm motility and morphology?

There are a lot of vitamin complements that you can find in the market that will improve these parameters. But I will tell you something: the most important thing by far is to have a healthy lifestyle. It means that if you smoke, stop smoking. If you drink, stop drinking or – if you cannot stop because we all have a social life – at least decrease it a lot. Have a healthy diet: eat a little bit of everything, try to decrease the amount of processed carbohydrates, eat fruits, vegetables, cereals, but also meat, eggs and fish. And the most important thing of all – together with non-smoking – is practicing at least 30 to 40 minutes of aerobic activity 4 days a week. If you do all of that, you will probably get to an antioxidant endogenous activity that will bypass any of those supplements that you can find in the market. If you want to use supplements, there are a lot of supplements out there. They combine different products and most of them have antioxidant properties. Those are mainly directed at people with “bad” lifestyles or whose endogenes have high oxygen reactive species production. If you have a very healthy lifestyle, be careful when taking antioxidants because if you take a lot of them, instead of having oxidative stress, you could go to the other stream which is what we call ‘reductive’ stress.

Is there any sperm improvement with Voltaren and Viagra? What do you think?

If you have been recommended to use Voltaren, my advice would be that you discuss it with an andrologist. Sometimes the problems in morphology, motility or the concentration of the sperm are the result of an inflammatory process. Voltaren is what we call diclofenac and diclofenac is a very powerful anti-inflammatory drug that is not free of side effects. It will only be useful if you have an inflammatory process. And if you have an inflammatory process, then probably there is a cause. So my advice is that you discuss it with an andrologist or with your reproductive medicine doctor. Because if there is any inflammation in your testicles, that should be assessed and treated. I mean treating the cause – so not only the inflammation but also the cause behind the inflammation. Viagra, on the other hand, has properties that are related to the increase of vascularisation. It is a very powerful vasodilator. It has been used for many things in reproductive medicine but mainly for increasing the thickness of the endometrium. When it comes to sperm production, I have to be very honest with you: I never heard about the use of Viagra and sperm parameters. But what it will help for sure is to have a more satisfactory sex life and probably to perform better.

Is it possible to improve sperm with vitamin C and vitamin E as well?

Yes, probably it is. And this is again because of the antioxidant properties of vitamin C and also tocopherol. Both vitamin C and vitamin E are included in a lot of these supplement products that you can find in the market.

What about Clomid for improving sperm?

Yes, Clomid can be some treatment but only for a very specific group of patients and those are patients with very low FSH levels. FSH in women induce follicular growth while in men, FSH levels are involved in sperm production. There are men who don’t have enough good sperm because of the lack of FSH. Clomid increases the endogenous levels of FSH and therefore it can help to increase the sperm production. But I will not recommend you to take Clomid without having an assessment by a reproductive medicine doctor checking your FSH levels, etc. Otherwise, it could be counterproductive.

In the future, what technology/techniques show the most promise for women over 45? Have you heard of in vitro gametogenesis (IVG)?

Yes, this is a very interesting field. In fact, this is a field we are exploring in our group. Unfortunately, this is not going to be a solution in the close future. In vitro gametogenesis (IVG) is generating eggs and sperm in the lab and it has been done in animal models. Hopefully, maybe, that will be the future of reproductive medicine. I didn’t want to mention it in today’s lecture because that probably is too distant from this present moment. But I agree that everything points towards that direction.

Authors
César Díaz García, MD PhD Assoc Prof

César Díaz García, MD PhD Assoc Prof

César Díaz, MD PhD Assoc Prof, is a Medical Director at IVI Clinic, London, UK. He has completed his medical training in Spain and Sweden. Dr. Díaz is Board certified in Endoscopic Surgery (ESHRE). From 2009, he joined the Swedish program of uterus transplantation and was a part of the first team to obtain a live birth from uterus transplantation in 2012. In 2013, Dr. Diaz returned to Valencia and led the Valencian Program for Fertility Preservation, which is one of the most internationally recognised programs of fertility preservation for oncological patients. He was also part of La Fe University IVF program, the largest Spanish public IVF program, performing more than 2000 IVF cycles/year. He combined his medical duties in the field of fertility with his surgical activities at La Fe University Hospital within the fertility surgery unit and gynae-oncology units for national referral centres. His main research interests are ovarian rejuvenation, fertility preservation, with a special interest in ovarian cortex transplantation, uterus transplantation and poor response in IVF. Within his fields of interest, he obtained numerous awards, several grants from the Spanish Ministry of Health and the Valencian Health Agency as well as from different private institutions. He is a former Associate Editor of Human Reproduction (2013-2016), and he has published more than 100 peer-reviewed scientific papers and book chapters.
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Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is an International Patient Coordinator who has been supporting IVF patients for over 2 years. Always eager to help and provide comprehensive information based on her thorough knowledge and experience whether you are just starting or are in the middle of your IVF journey. She’s a customer care specialist with +10 years of experience, worked also in the tourism industry and dealt with international customers on a daily basis, including working abroad. When she’s not taking care of her customers and patients, you’ll find her travelling, biking, learning new things or spending time outdoors.

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