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
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.
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.
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.