By fertility experts from Spain.
Primary ovarian insufficiency (POI) — also called premature ovarian failure — is a condition in women where the ovaries stop functioning normally before the age of 40. In such case, egg donation seems to be the only effective infertility treatment. But is it the only one? In this webinar, Dr Mara Simopoulou (Associate Professor of Experimental Physiology and Embryology at the Medical School of NKUA and Deputy Laboratory Manager of the Assisted Conception Unit at Aretaieio University Hospital) discussed novel medical approaches to addressing low ovarian reserve in assisted reproduction and answered patients’ questions.
Infertility is everyday reality for 1 out of 8 couples worldwide. According to Dr Mara Simopoulou, a considerable percentage of these couples are actually undergoing IVF treatment because of ovarian insufficiency. Undoubtedly, ovarian sufficiency is really challenging to manage. Dr Simopoulou says that one of the reasons for it is the lack of consensus and gold standard for doing it. Generally, the most common treatment to use is egg donation.
The ovaries are the primary female reproductive organs and they have an endocrine function and an exocrine function: they secrete hormones (such as estradiol) and are the ‘house’ of oocytes . Being the latter, they should support oocyte development and release mature oocytes in every menstrual cycle. However, the picture is not always so ideal.
Ovarian insufficiency is a term describing a wide range of pathopsychological conditions where ovarian function is compromised. And the reasons for it are really various. They can include maternal age, pathologies, surgeries and infections in the reproductive system, autoimmune diseases, mutations in genes implicated in the regulation of ovarian function and development (such as chromosomal and developmental abnormalities) or gonadoxic treatments (chemotherapy or radiotherapy). Dr Simopoulou admits that, apart from all that has been mentioned, there is also some data on ethnicity and how it affects ovarian insufficiency, e.g. Chinese, Latin and African women are of high risk for poor ovarian reserve. Last but not least – there is a woman’s lifestyle that can influence the functioning of her ovaries.
In the context of assisted reproductive technology (ART), women with ovarian insufficiency tend to produce oocytes of compromised quality and, as a result, they don’t have a high fertilisation rate in the IVF laboratory. POI patients may also be unable to ovulate normally and they not respond to ovarian stimulation protocols.
Dr Mara Simopoulou differentiates between two categories of ovarian insufficiency. The first one is when oocytes are being produced in low numbers and in most of cases, they are also of low quality. This category describes patients of poor ovarian response (the so-called ‘poor responders’) and perimenopausal women. The second category, on the other hand, refers to no folliculogenesis (meaning no oocyte production) and includes POI patients as well as the ones already in menopause.
According to Dr Simopoulou, there’s an ongoing debate in the scientific community on how to categorise the poor responders properly. On the basis of the 2011 Bologna-ESHRE criteria, at least two of the following features must be present to qualify a patient as a poor responder:
Despite that kind of clear distinction, one has to remember that poor responders are a very heterogeneous group of population. Luckily, in 2016 Poseidon criteria came along and helped scientists to subgroup these patients. Premature ovarian insufficiency, on the contrary, has a very strict definition – it is a cessation of menstruation in women under the age of 40. However, Dr Simopoulou reminds at this point that POI patients always have to be seen as a whole. In their case, it is not only infertility but there are also other issues involved. The latter refers to both menopausal symptoms (e.g. psycho-affective changes, vasomotor symptoms and urogynaecology and sexual changes) and long-term sequelae (auto-immune diseases, osteoporosis or accelerated cardiovascular disease).
There are two physiological processes that lead to ovarian insufficiency and that’s why POI patients can be divided into the pre-menopausal and menopausal ones. Perimenopause is the period preceding menopause and it can last for 5 to 7 years prior to menopause. During that time, there is a progressive reduction of ovarian function being observed and that manifests itself in menstrual cycle irregularities and mild vasomotor symptoms. The latter leads to the final stage – menopause. It is classified as least 12 months of calendar year of amenorrhea (not having periods) and cessation of folliculogenesis – the production of oocytes.
It is well-known that when women age, their fertility rate drops. In Dr Simopoulou’s opinion, it is one of the reasons why ovarian insufficiency is so challenging to deal with. One of the way of managing it is prevention – and it means oocyte cryopreservation. It is especially beneficial if a woman is below the age of 35.
However, the majority of women treated in IVF labs are between 35 and 45 years old. The most common method of dealing with such patients seems to be compensating for the average efficiency that is coming up. Up to recently, the approach was to maximise the ovarian response to the stimulation. The problem is that in case of ovarian insufficient patients, the response is generally poor – irrespectively of how much of a hard conventional stimulation protocol has been used. Dr Simopoulou says that nowadays there’s been a shift to rescuing oocyte competence and rejuvenating the ovary rather than trying to treat the symptoms. And this is where the novel approaches to ovarian insufficiency come into play: mitochondrial, spindle-chromosomal complex or pronuclear transfer, chromosome therapy, etc. They may be an alternative to the solution that is in common use today – meaning oocyte donation. It is not a surprise that the donation route is not an easy choice to make for many patients. In fact, what drives all these novel approaches is the patients’ will to explore all possible options for a genetically linked offspring.
Dr Simopoulou divides novel approaches to ovarian insufficiency into two categories. In the first one, we find those with the aim to restore the jeopardised ovarian micro-environment – and it means ovarian rejuvenation or ovarian function reactivation. This approach includes Platelet Rich Plasma (PRP) and stem cells. The other approach focuses on the oocytes rather than on ovaries and its aim is to restore oocyte quality and competence. This second scenario is all about Mitochondrial Replacement Therapy (MRT).
PRP is an autologous treatment, during which 30-60 ml of peripheral blood is drained from vein in a patient’s arm. Then this blood is centrifuged in order to end up with a concentrated version of plasma enriched with the patient’s own platelets. PRP consists of numerous proteins, such as cytokines, growth factors and hormones. The proteins serve as chemo-attractants for stem cells, macrophages and neutrophils which all contribute greatly to tissue regeneration. All the growth factors are considered responsible for cell migration and differentiation, as well as for proliferation, activation of angiogenesis and tissue regeneration. Because of all of that, PRP has emerged among the most innovative autologous blood products used to enhance tissue healing and regeneration. It has been used, among others, for tendonitis, nerve injuries, osteoarthritis skin rejuvenation and wound healing and fat grafting.
Dr Mara Simopoulou admits that it didn’t take long for certain fertility experts to start thinking how to turn all of the latter to their advantage and use PRP in the reproductive system. The pioneers behind the development of the intra-ovarian infusion of PRP treatment were Dr Konstantinos Pantos and Dr Konstantinos Sfakianoudis of Genesis Athens Clinic. They investigated the efficiency of the treatment in regards to the reactivation of dysfunctional ovarian tissue .
Dr Simopoulou describes the technique of PRP injection as an empirical approach, resembling the oocyte pick-up procedure. While the patient is under inhaled minimal sedation, her ovaries are visualised via transvaginal ultrasound monitoring and they are intramedullary injected on multiple sites. It is followed by the infusion of 4 ml of the prepared PRP mixture.
When it comes to the results, Dr Simopoulou says there are four randomised control trials run with the Genesis Athens Clinic at the moment and this is where the hard data and the proof are going to come from. But there are already some reports available and there are indications that PRP may effectively restore ovarian function in patients undergoing peri-menopause and menopause. It may also lead to cycle restoration, promote folliculogenesis and improve patients’ hormonal profile in the first 2-5 months following the treatment. But according to Dr Simopoulou, it is not just infertility that scientists are looking into in case of PRP.
As ovarian insufficiency leads to menopause-like symptoms that are jeopardising a woman’s well-being, addressing patients’ attitudes is crucial. Taking all of the latter into account, it has to be noted that PRP implementation certainly requires serious consideration regarding its biological efficiency and there is still more research data needed to come in. Dr Simopoulou’s conclusion is that PRP seems to work – but it does not work for every patient. That’s why the scientists’ main task today is to find out what is the profile of the patient that PRP works for.
Mesenchymal stem cells (MSCs) are known to migrate to damaged tissues and organs and differentiate to tissue-specific cells, promoting healing processes. They secrete a wide spectrum of growth factors, chemokines and mitogenic proteins and via these, they are able to promote proliferation and vascularisation. Besides, MSCs modulate immune response, present anti-inflammatory properties and exert anti-apoptotic properties limiting tissue degeneration. That’s why – like with PRP – it didn’t take long for fertility specialists to wonder if stem cell ovarian transplantation could restore the jeopardised ovarian micro-environment.
Dr Mara Simopoulou says there are a few studies available on autologous stem cell ovarian transplantation to increase reproductive potential in patients who are poor responders. They bring a lot of conclusions but there are also questions that emerge, like whether it should be heterologous or autologous transplantation, if the treatment is safe and free of malignant transformation or what the best administration method is. The primary results from the studies indicate the stem cells are a promising approach. They may effectively restore ovarian function in patients with POI, POR and peri-menopause as well as promote folliculogenesis and improve patients’ hormonal profile. And all of this – in result – may enhance the reproductive outcome. But just like with PRP, the experimental status of the stem cell treatment is retained until there is further data from well-designed clinical trials available.
It is known that in order to achieve fertilisation and development, huge amounts of energy are required. And these are produced by the oocytes’ mitochondria. There is a proven association between mitochondrial DNA and poor oocyte quality and ovarian reserve. Dr Simopoulou highlights that the embryonic development up to day 5 heavily relies on mitochondria energy and the advancement of age corresponds to the reduction of functionality and number of oocytes’ mitochondria. That’s why the scientific community started to analyse whether replacing an older oocyte’s mitochondria with mitochondria from a younger oocyte would improve oocyte’s function. There are various techniques of performing the procedure being considered, such as heterologous/autologous germinal vesicle and spindle or pronuclear transfer. The latter is about moving the nuclear DNA from the patient’s oocyte right into the cytoplasm of the donor’s oocyte – after the removal of nuclear DNA from both oocytes. As a result, the donor egg is left with nuclear DNA from the mother and DNA from the donor.
Unfortunately, there is still a lack of robust or even adequate data indicating safety and effectiveness of the method. The European Society of Human Reproduction and Embryology (ESHRE) recommends extreme caution on the use of spindle transfer in human oocytes as a clinical application to address fertility problems. That is why Mitochondrial Replacement Therapy currently maintains its experimental status. Long-term follow-up of MRT is required in order to report on the safety and efficacy of the procedure.
Dr Mara Simopoulou is aware of the fact that the novel approaches to ovarian insufficiency that are under research nowadays used to sound like science-fiction 20 or even 10 years ago. That’s why the scientific community needs to be very careful with respect to where they’re heading with their work and, what is more, they have to consider what is it that drives the advances in assisted reproductive technologies. Although they perfectly realise there are extreme idiopathic cases in ART (that have no other alternative), they need to acknowledge the biological debate and experimental stages that some of the novel techniques are facing. The only way to make patients feel safe is to move forward with proper research methodologies and provide the randomised control trial data prior to the possible application of any of these techniques in large number of patients.
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Let me just preface my response by saying that I’m a clinical embryologist and a researcher so probably you would need a physician to try answer this question about a very complicated reproductive history that you have been facing. I cannot really suggest something at this point in time. I think it is a good idea that you’d take a look into what’s been happening all this time and why you didn’t get pregnant – also with respect to the uterine environment. I don’t know how much you have researched it other than your own oversight and whether these attempts were competent or not – apparently they weren’t all that much. I don’t have a lot of data on your IVF and your average cycles and, also, I’m guessing all these efforts have been done throughout a couple of years – and things can be changing after a couple of years. I can see you’ve had to attend with an oocyte donor and I’m sure you’ve done PGD. It’s really difficult to actually answer this question. I would suggest you need to make sure that you trust your doctor and you have a very good relationship with your doctor before you move any further. I’m not sure about stem cells though. If we’re talking about restoration therapy, maybe you should give PRP a go? But I’m really not the right person to actually be suggesting any of that. I would definitely suggest though to research further what’s been happening on the uterus. So that’s as far as I can go with this question.
Again, I’m not the right person to be discussing it. All the work on PRP that we’ve been doing is with Genesis Athens Clinic so, in my eyes, these are the experts with regards to PRP. One of the disadvantages would be the fact that PRP is not working in everybody. Basing on the studies that we’ve done so far, it doesn’t look that there are any side effects or anything that actually raises any red flags. We don’t have any long-term follow-up data because it’s so novel that you cannot have any long-term follow-up data – but it doesn’t look like there is anything to raise any suspicion. With regards to whether it causes cancer later on: every time there is regenerative medicine being mentioned, cancer and malignancies are being stirred up and notions of that come up. But on the basis of the work that we’ve done so far – and there are a lot of pregnancies from PRP at Genesis Athens Clinic – we haven’t seen anything that has been troubling us so far, other than the fact it’s not working for everybody. So our job next is to find out who is the patient that this is working for.
With regards to MRT, there is still a very long way to go. The recommendation from ESHRE now is “NO” so that would also be a recommendation from me. So it leaves us with the choice between PRP and stem cells transplantation. With stem cells, there are a lot of questions with regards to which protocol is more optimal. At the moment, the data that I’ve seen from PRP is the most interesting. Again, the issue here is that there’s no guarantee. This is always what happens with novel approaches. If there was a guarantee that it would work, then my talk would not be 30 minutes long but it would be 3 minutes – but we’re not there yet. However, we’re doing a lot of work on PRP and we have seen it working on some patients so this is where I would probably go to. Also, just on the grounds of the fact that it’s less invasive than stem cells. PRP is a really straightforward procedure to actually obtain and prepare so it’s much more ‘user-friendly’.
I’m sorry but personally I am not aware whether the Augment technique is being done somewhere in the world right at this point in time. But I do know that the large starting study by Labarta was very hopeful and that the same group discontinued the study because it didn’t look like conveying promising results. I cannot answer your question but I would suggest just looking into ClinicalTrials.gov and see if there’s anything registered there. But the fact that the group from IVI Valencia discontinued it, is an indication for me with regards to the Augment technique and its efficiency.
Like I said, I am not a physician so it’s probably not the best idea that I provide advice with regards to treatment as such. But we would definitely suggest to try with your own eggs once again. We do not know at the moment if you have been trying anything else or what could be the next thing. Despite your AMH, you got 7 eggs and you got a very good blastocyst in your first attempt so that looks good. When we don’t get a positive outcome, we don’t know what has gone wrong. It could be something uterine, it could be the embryo, it could be a combination of many factors. It could be like an overall thing so it’s not so easy to point your finger to something and say this is what has been wrong. From an IVF lab perspective, your first cycle looked went really well. Then, in your second cycle when you were 38, you had six oocytes which is fine – that’s a perfectly compatible number of oocytes for your age and especially for your AMH. But they didn’t reach the blastocyst stage – again, it can have to do with various reasons . I do not have a lot of data on your cycle with respect to how those embryos actually developed in the IVF lab. Not reaching the blastocyst stage is one piece of information but it doesn’t say it all. So I would definitely suggest to try again. The fact that you’ve had a blastocyst and your first attempt is definitely hopeful. With regards to the protocol: because of your age, I would probably suggest mild simulation protocol but nothing too high. And again, I would suggest that you need to trust your physician and the doctor that’s treating you at the moment. You should feel that you’re in safe hands and then you move ahead with the protocol that they suggest. With regards to improving oocytes’ quality: there are some supplements that you can perhaps use that might help with the oocyte metabolism. But that’s as far as I would go with regards to the question.
The U.S. also offers PRP so if you’re closer to the States, then that might be of help. If you’re looking for alternatives, I would suggest you go to ClinicalTrials.gov or any other registry and look for studies that are actually being run on PRP or stem cells. That will help you and will guide you with regards to the geographical position and where these groups are being based.
I do want to stress again that I am not a physician. But if I had to choose out of the three procedures, I would go for PRP because I do a lot of work on PRP. What I know is that it’s rather straightforward to prepare, it’s minimally invasive with respect to the procedure. With regards to its efficiency, again we need to have the hard data. We know that it is working – it’s important – but it’s not working for everybody. But then the same stands for stem cells. I wouldn’t go for MRT. Like I said, the ESHRE standpoint is very precise: namely, MRT should not be viewed as an alternative right now, also for the reasons that have been stated according to ESHRE. But when choosing between PRP and stem cells, I would be more inclined to do PRP. But I would like to stress at this point – like I did at the end of my talk – that novel approaches require some
patience. This is why we call them ‘novel’ approaches. We need some time to see the data so that we can actually answer these questions with conviction rather than with inclination towards doing this or doing that. And we have to look at research groups that are actually running this kind of data and find out more from them. For example, PRP is a procedure that can be done nowadays but the centres that offer it rely only on their practice. So we need to be careful – that’s all I’m saying.
Again, I would suggest to discuss it with a physician. There are some contraindications with regards to PRP treatment. If, for example, there is a blood disorder of the blood system, then that would not be a very good indication. There are other things as well but it’s not a good idea for me to provide advice on that matter. I think that you should take advice from the experts on PRP – the ones that actually practice it clinically. Like I said before, I’m on the research side so I can give you the data with regards to where we are now and what it looks like.
When you have an impaired ovarian function below the age of 40 and there is a cessation of menstrual cycles, it means this is premature ovarian sufficiency. We do have tools to have an idea of whether that is coming up – these are levels of FSH, LH and anti-Müllerian hormone (AMH) along with antral follicle count (AFC) and the ultrasound that gives us the impression from the ovaries. And then there are tests to be done just to make sure the diagnosis is correct.