From ovarian rejuvenation to follicle activation, strategies for patients with low ovarian reserve

As a result of a number of different factors – essentially social and economic ones – including medical progress (availability and widespread use of contraception), there is a growing demographic trend in the Western world towards delaying when a woman tries for her first child. This translates into a number of different fertility issues that are caused mainly by age. This means numerous fertility problems caused mainly by age and leads professionals in this field to study new ways and techniques to manage ovarian aging and low reserve.

Advances in knowledge

A number of initiatives in the field of reproductive medicine have been studied over the last few years with a view to counteracting the impact of age on the reproduction process. One of these fields of research is linked to the concept of ’reactivating’ stem cells and residual follicles in the ovary that may contain ova.

Until quite recently, medical science believed that a woman’s reproductive lifespan was determined solely by a fixed reserve of available ova available at birth that depleted in its entirety during the menopause. However, this concept has recently been questioned in a number of studies. They suggest that so-called ovarian stem cells. This discovery, in addition to the compared and contrasted fact that the ovary contains approximately 1,000 residual follicles even after the menopause, are the bases for these so-called ‘ovarian rejuvenation techniques’.

Advances in knowledge Research pathways in an experimental state

Let us take a closer look at some of them.

Augment

A recent attempt (around 2013) to ‘rejuvenate’ the ovary (ovarian rejuvenation) is described in the protocol known as AUGMENT®. In short, the technique entailed an operation (a laparoscopy) to remove a section of the ovary (the surface or outer cortex). Following this, structures similar to ovarian stem cells were identified and mitochondria (the source of energy in cells) were removed from them. After this, the patient was given ovarian stimulation so that the mitochondria could be inserted into ova retrieved during ICSI and they could then be fertilised to generate ‘more healthy’ embryos that could be transferred to the mother’s uterus. Following some (rather questionable) medical publications about the efficiency of the AUGMENT® technique, during the most recent ESHRE Congress (European Society of Human Reproductive Medicine) which was held in July 2018, an appropriately-designed study was presented. It did not show any improvements when performing this technique on patients with poor ovarian reserve. In fact, the study had to be cancelled before it concluded precisely because the results were poor.

ASCOT

More recently, La Fé Hospital in Valencia (Spain) explored the concept known as ASCOT Autologous Stem Cell Ovarian Transplantation as performed on the patient. In this technique, the patient with poor ovarian reserve is given five subcutaneous injections of a type of medication that is used in haematology. It is called filgrastim or granulocyte-colony stimulating factor (G-CSF). The aim is to encourage bone marrow to produce different types of blood cells (including some adult stem cells called haematopoietic precursors) and release them into the blood stream where they are later extracted and filtered. Secondly, a ‘semi-invasive’ (according to the authors) intervention is performed. It consists of inserting a catheter into the patient’s inner thigh (through the femoral artery) and directing it from there towards one of the ovaries. Last of all, these haematopoietic adult stem cells are injected into the ovary in order to ‘stimulate oocyte production’. Some weeks later, the patient is prescribed medication for ovarian stimulation and IVF is performed. The conclusions of this pilot study on around 15 patients were recently published (August 2018) in Fertility and Sterility, an American journal. In my opinion, the results are not particularly encouraging. Following administration of ASCOT, 15 patients underwent 28 cycles of IVF. The resulting embryos were genetically analysed prior to transfer. Only one in every six were genetically healthy (16%) and, following embryo transfer, only one gestation evolved in a satisfactory manner. In addition, another patient got pregnant naturally and, interestingly, the only gestating patient following IVF got pregnant again but, on this occasion, she did so naturally. In total, there were three live births. The authors conclude that ‘Additional studies are needed in order to validate the results in a larger and more homogeneous population, and reproduction results must be monitored before ASCOT can be thought of as a real alternative when treating patients whose ovarian function has been compromised.”

Activation of sleeping follicles

Special mention should be made of the initiative that has been described by Dr Kawamura in Japan (2013). This author does not write about ‘ovarian rejuvenation’ but rather ‘activation of dormant follicles’ and the doctor focuses on a specific group of patients or patients with premature ovarian failure (menopause at a young age). Perhaps these patients represent the population of women who could benefit most from clinical use of the ovarian stem cell concept. Even so, the technique described by Kawamura is also invasive since it entails laparoscopic surgery to remove ovarian tissue, process it and then re-insert it into the ovary once it has been ‘activated’. The aim remains the same: to stimulate ‘activation’ of residual follicles in the ovary. The author describes recuperation of the menstrual cycle in these patients (or at least temporarily) and even cases of pregnancy.

Expectations

Clearly, the concept of ovarian rejuvenation is far from a reality. Initiatives in this area are still in the early experimental stage. Furthermore, they entail invasive procedures that are not risk-free. We might add that, whilst there is no current cure for ovarian insufficiency, recent progress in ovarian biology associated with stem cells from the ovary and populations of similar cells has meant that therapeutic strategies that are well worth exploring have been developed. However, it is likely that ovarian regeneration in human adults, even if it were possible, would only play a small role in terms of retaining fertility and endocrine function, particularly when decreases are caused by follicular depletion and ovarian function in general as a result of the unappeasable passage of time.

Learn more about our low ovarian reserve diagnosis and treatment unit.

Bibliographic references

1. Herraiz S, et al. Autologous stem cell ovarian transplantation to increase reproductive potential in patients who are poor responders. Fertil Steril. 2018 Aug;110(3):496-505.
2. O-210. E. Labarta Demur, et al. Autologous mitochondrial transfer as a complementary technique to ICSI to improve oocyte and embryo quality in IVF patients. A Randomized Pilot Study. Abstracts of the 34th Annual Meeting of the ESHRE 2018 , Barcelona, Spain 1 to 4 July 2018.
3. Kawamura K, et al. Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. Proc Natl Acad Sci USA. 2013 Oct 22;110(43):17474-9.
4. Sfakianoudis K, Simopoulou M, Grigoriadis S, Pantou A, Tsioulou P, Maziotis E, Rapani A, Giannelou P, Nitsos N, Kokkali G, Koutsilieris M, Pantos K. Reactivating Ovarian Function through Autologous Platelet-Rich Plasma Intraovarian Infusion: Pilot Data on Premature Ovarian Insufficiency, Perimenopausal, Menopausal, and Poor Responder Women. J Clin Med. 2020 Jun 10;9(6):1809. doi: 10.3390/jcm9061809. PMID: 32532000; PMCID: PMC7355907.

Dr Juan Carlos Castillo, a gynaecologist at Instituto Bernabeu.

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