Intraovarian Injection of Platelet-rich Plasma in Assisted Reproduction: Too Much too Soon?

Lloyd Atkinson; Francesca Martin; Roger G. Sturmey

Disclosures

Hum Reprod. 2021;36(7):1737-1750. 

In This Article

PRP: A Note of Caution

A primary consideration of the effect of PRP in any aspect of regenerative medicine is the 'activation status' of the platelet (Figure 1). As previously discussed, platelets have the capacity to respond to agonists and release a range of molecules, creating a 'releasate' (Piersma et al., 2009; Parsons et al., 2018). Indeed, PRP from resting platelets differs markedly to that containing activated platelets, and the mode of activation will influence the composition of the releasate. Despite this, there is considerable variation in the activation status of platelets used in studies of ovarian rejuvenation; some studies describe using calcium (Sills et al., 2018; Hsu et al., 2020; Melo et al., 2020) or thrombin (Hosseini et al., 2017), while others inject quiescent platelets or simply do not state their activation status (Callejo et al., 2013; Farimani et al., 2019; Pantos et al., 2019). The importance of reporting the activation status and the methods therein, paired with the use of appropriate controls, is critical, given reported effects of thrombin or calcium alone in the regulation of ovarian function. For example, thrombin has been shown to regulate progesterone synthesis in the preovulatory ovary homogenates, with multiple cell types within the ovary readily expressing PAR1 and PAR4 receptors (Cheng et al., 2012) through which thrombin elicits biological function directly. In addition, there is good evidence of an interaction between calcium signalling and ovarian steroidogenesis (reviewed in Kouba et al., 2019).

To date, it appears that efforts to investigate the role of platelet activation in the context of ovarian rejuvenation remain limited. For example, platelets possess CD40 and αIIbβ3 on their surface in a resting state (Inwald et al., 2003; Li et al., 2010). Thus, it is conceivable that these adhesive receptors and ligands are sufficient to elicit folliculogenesis or to recruit immune cells to the ovary without the need for platelets within the PRP to have become activated prior to injection. By contrast, activation and subsequent degranulation may be the critical function required for PRP to elicit an effect and quiescent PRP may become activated through exposure to platelet-activating matrices within the ovarian stroma. Differentiating the effects of stimulated versus unstimulated PRP should be a focus of future investigations and may help isolate the most effective agents that cause the reported regenerative effect in the ovary, paving the way for more defined interventions.

The contents of platelet granules may not all be beneficial for re-establishing female fertility among all disease settings. As a theoretical example, thrombospondin-1 has been implicated in follicle development (Kõks et al., 2010; Bender et al., 2019), yet it inhibits the proangiogenic action of VEGF (Greenaway et al., 2007) which may be undesirable where perfusion of the ovaries is limited. In addition, increased intraovarian VEGF and blood flow is thought to play a role in the pathogenesis of PCOS (Chan et al., 2003; Carmina et al., 2005; Peitsidis and Agrawal, 2010). Conversely, Anvari et al. (2019) recently reported that PRP therapy partially re-established hormonal balance in a rat model of PCOS. Here, PRP treatment increased the expression of oestrogen receptors α and β and of superoxide dismutase and glutathione peroxidase in ovarian homogenates. PRP-treated ovaries had significantly more pre-antral and antral follicles up to 30 days after treatment, suggesting that PRP may be a viable option for driving folliculogenesis in females with PCOS. In addition, platelets also release significant quantities of IL-15 when activated (de Miguel-Gómez et al., 2020). Increased IL-15 concentrations in follicular fluid have been negatively correlated with pregnancy outcomes via IVF, indicating that this cytokine may be detrimental to follicle maturation (Spanou et al., 2018). Interestingly, it is highly expressed in immature follicles, and falls during their maturation, which raises the potential importance of IL-15 in the activation of germline stem cells, as IL-15 is a potent regulator of other stem cell types (Huntington et al., 2009; Gómez-Nicola et al., 2011). This interplay and opposing effects of PRP constituents in different contexts serve to illustrate the importance of detailed studies of the mechanisms of how PRP might act on the ovary, and much additional work is required before any conclusions can safely be drawn.

processing....