Our study showed that resveratrol pretreatment for 3 months before IVF could increase ovarian sensitivity. Indeed, a significantly increased FORT and FOI was observed in study versus control group. Consistently an increased, despite not significant, OSI was observed in the study group compared with control group.
To the best of our knowledge, this is the first study that have described an effect resveratrol on ovarian sensitivity. The mechanism by which the resveratrol could increase ovarian sensitivity should be still elucidated, despite several hypothesis could be proposed. The main one might be related to the positive effect exerted by resveratrol on mitochondrial activity. Resveratrol can increase mitochondrial mass in human granulosa cells (GC) through a mechanism involving reduction of voltage-dependent potassium currents, intracellular calcium homeostasis, and regulation of mitomiRNAs (28, 29). Women with reduced ovarian responsiveness exhibit reduced mitochondrial mass, cholesterol uptake capacity and expression of enzymes involved in steroidogenesis, such as StAR (Steroidogenic Acute Regulatory), 3-beta-hydroxysteroid dehydrogenase (3-beta-HSD) and aromatase, compared with normal responders (30). Low expression of these enzymes leads to a reduced estrogen and progesterone production even after OS. Since low responsiveness to FSH may correlate with reduced mitochondrial mass, we propose that the enhanced ovarian responsiveness observed in the present study is related to the ability of resveratrol to stimulate mitochondrial biogenesis in GC.
Another mechanism of action could be related to the anti-inflammatory and antioxidant properties of resveratrol. Indeed, resveratrol might contrast the negative effect exerted by pro-inflammatory environmental factors related to the hypo-response physiopathology (31, 32). The possibility of improving the sensitivity of the ovary to gonadotropins could be useful in reducing the number of patients with an unpredictable hypo-response to OS, as in the case of POSEIDON groups 1 and 2 patients (11). POSEIDON’s groups 1 and 2 encompass women who had poor (< 4) or suboptimal (4–9) number of oocytes retrieved after a conventional OS despite the presence of an adequate ovarian reserve, defined by an AFC of ≥ 5 and/or an AMH ≥ 1.2 ng/mL. Indeed, retrieval of fewer than 10 oocytes is associated with decreased cumulative live birth rates (CLBR) (33). Thus, given a patient who fits POSEIDON’s groups 1 or 2, the final goal would be to find ways to maximize oocyte yield aiming at obtaining more than 9 oocytes at the end of stimulation (33, 34).
Other studies have investigated the role of resveratrol in IVF. Consistently with a recently published randomized trial (35), we observed an increased, despite not significant, number of oocytes retrieved and MII oocytes and no effect in terms of BPR, CPR and LBR. This mild discrepancy could be related to the fact that we involved only women with advanced reproductive age that are associated per se with a reduced prognosis to IVF and poor ovarian response (36). In contrast with a retrospective analysis of Ochiai et al. we do not observe a detrimental effect of resveratrol on pregnancy outcome (37). This could be probably due to the retrospective design, heterogenous population and different IVF protocol adopted in Ochiai study comparing with our trial (mild versus conventional stimulation). Furthermore, the amount of resveratrol prescribed in Ochiai et al. study (200 mg daily) was higher comparing with our trial (150 mg daily). Finally, it should be considered that the age at the oocyte retrieval in Ochiai et al. study was significantly higher in women who were supplemented with resveratrol comparing with control group (37).
The strengths of our study reside in the design, the prospective nature and the selective inclusion criteria involving specifically women with the worst IVF prognosis namely those with advanced reproductive age (38, 39).
The limitation of our study lies in the low sample size. This makes it impossible to speculate on the comparison between the groups in terms of oocytes parameters (es. retrieved and blastocytes) and pregnancy outcomes. Should we have reached a higher enrollment number the positive trend might have been significant in accordance to a previous study Gerli. et al (35). Difficulties in achieving the planned sample size were mainly related to the COVID-19 pandemic. At the time of enrollment, there was no published study on IVF outcomes in patients treated with resveratrol, so a sample size calculation could not be performed. Nonetheless, a post hoc analysis revealed that the number of women recruited were adequate to detect a difference in terms of FOI and FORT with a power over 90%.
In conclusion, preliminary results from this study indicate that pre-treatment with resveratrol may improve ovarian sensitivity to exogenous FSH, which in turn may decrease the risk of unexpected hypo-response to OS in advanced reproductive age women.