Abstract and Introduction
The prospect of ovarian rejuvenation offers the tantalising prospect of treating age-related declines in fertility or in pathological conditions such as premature ovarian failure. The concept of ovarian rejuvenation was invigorated by the indication of the existence of oogonial stem cells (OSCs), which have been shown experimentally to have the ability to differentiate into functional follicles and generate oocytes; however, their clinical potential remains unknown. Furthermore, there is now growing interest in performing ovarian rejuvenation in situ. One proposed approach involves injecting the ovary with platelet rich plasma (PRP).
PRP is a component of blood that remains after the in vitro removal of red and white blood cells. It contains blood platelets, tiny anucleate cells of the blood, which are responsible for forming athrombus to prevent bleeding. In addition, PRP contains an array of cytokines and growth factors, as well as a number of small molecules. The utility ofPRP has been investigatedin a range of regenerative medicine approaches and has been shown to induce differentiation of a range of cell types, presumably through the action of cytokines.
A handful ofcasereports have described the use of PRP injections into the ovaryin the human, and while these clinical data report promising results, knowledge on the mechanisms and safety of PRP injections into the ovary remain limited. In this article, we summarise some of the physiological detail of platelets and PRP, before reviewing the existing emerging literature in this area. We then propose potential mechanisms by which PRP may be eliciting any effects before reflecting on some considerations for future studies in the area. Importantly, on the basis of our existing knowledge, we suggest that immediate use of PRP in clinical applications is perhaps premature and further fundamental and clinical research on the nature of ovarian insufficiency, as well as the mechanism by which PRP may act on the ovary, is needed to fully understand this promising development.
Female infertility is recognised by the World Health Organisation (WHO) as a global public health issue (Macaluso et al., 2010), with more than one million cycles of IVF being performed globally each year since 2005 (Zegers-Hochschild et al., 2014; Adamson et al., 2016). Female infertility can arise from a range of conditions, including endocrine dysfunction, implantation failure, endometriosis and uterine fibroids, as well as pathologies related directly to the ovary, including polycystic ovary syndrome (PCOS), primary ovarian insufficiency (POI), environmental factors and inflammatory disease. However, 'ovarian exhaustion' is a natural part of the ageing process. In the past 50 years, the mean age at which women have their first child in the UK has increased from 23.8 to 30.7 years (Office for National Statistics, 2020), suggesting that women are delaying childbearing. The impact of delayed childbearing means that women are moving closer to the period of climacteric for conception, and, in many cases, women are choosing not to reproduce until much later. One consequence of this has been a rise in fertility treatment and a rise in the age of women attending for medical investigation. Indeed, in the UK alone, the mean age of women attending for IVF treatment has hovered around 35 for the past 20 years (Human Fertilisation and Embryology Authority, 2020). Since the advent of clinical IVF in 1978 (Steptoe and Edwards, 1978) and associated Assisted Reproductive Techniques (ARTs), it has been possible to treat infertility in a number of cases. However, such approaches are reliant on a healthy oocyte for fertilisation and so have limited success in treating peri- or post-menopausal women without the use of donor eggs. Moreover, ARTs do little to tackle fundamental dysfunction within the ovary and in the oocytes that lead to female infertility and associated physiological adaptations.
The prospect of rejuvenating the exhausted ovary has been enticing ever since the description of oogonial stem cells (OSCs) in the ovarian cortex (White et al., 2012), hinting at a possibility of therapeutic stimulation of post-natal folliculogenesis in subfertile women. In a study by Niikura et al. (2009), transplantation of ovarian stem cells from atrophic ovaries from aged mice into young, healthy counterparts resulted in their resumption of spontaneous oogenesis, suggesting that ovarian aging or insufficiency could be reversed if OSCs are provided a healthy environment. Further work has implicated a role for mitochondria in loss of oocyte quality associated with the aged ovary (Cozzolino et al., 2019); indeed, methods to replenish mitochondria within aged oocytes are currently being explored as a means to rejuvenate them (Labarta et al., 2019). However, as with IVF, efforts to improve egg quality do not address the wider aspects of age-related ovarian dysfunction.
One recently proposed option for ovarian rejuvenation is the intraovarian injection of platelet-rich plasma (PRP) which is being used increasingly in clinical settings for a number of soft tissues, including to support wound healing and ligament and muscle repair (Suthar et al., 2017; Hurley et al., 2019; Verma et al., 2019; Zhang et al., 2020). PRP was first described for ovarian rejuvenation by Pantos et al. (2016). Their work described how PRP, which is a component of blood, could, when in injected directly into the ovary, trigger the resumption of menstrual cycles in women exhibiting signs of the climacteric. In this review, we will briefly consider the concept of ovarian rejuvenation before describing what PRP is and how it is generated and finally reflecting on the current state of knowledge of ovarian rejuvenation with PRP.
Hum Reprod. 2021;36(7):1737-1750. © 2021 Oxford University Press