Resveratrol ameliorates mitochondrial biogenesis and reproductive outcomes in women with polycystic ovary syndrome undergoing assisted reproduction: a randomized, triple-blind, placebo-controlled clinical trial

Abstract

Background: This study was designed to examine the effect of resveratrol on mitochondrial biogenesis, oxidative stress (OS), and assisted reproductive technology (ART) outcomes in individuals with polycystic ovary syndrome (PCOS).

Methods: Fifty-six patients with PCOS were randomly assigned to receive 800 mg/day of resveratrol or placebo for 60 days. The primary outcome was OS in follicular fluid (FF). The secondary outcome involved assessing gene and protein expression related to mitochondrial biogenesis, mitochondrial DNA (mtDNA) copy number, and adenosine triphosphate (ATP) content in granulosa cells (GCs). ART outcomes were evaluated at the end of the trial.

Results: Resveratrol significantly reduced the total oxidant status (TOS) and oxidative stress index (OSI) in FF (P = 0.0142 and P = 0.0039, respectively) while increasing the total antioxidant capacity (TAC) (P < 0.0009). Resveratrol consumption also led to significant increases in the expression of critical genes involved in mitochondrial biogenesis, including peroxisome proliferator-activated receptor gamma coactivator (PGC-1α) and mitochondrial transcription factor A (TFAM) (P = 0.0032 and P = 0.0003, respectively). However, the effect on nuclear respiratory factor 1 (Nrf-1) expression was not statistically significant (P = 0.0611). Resveratrol significantly affected sirtuin1 (SIRT1) and PGC-1α protein levels (P < 0.0001 and P = 0.0036, respectively). Resveratrol treatment improved the mtDNA copy number (P < 0.0001) and ATP content in GCs (P = 0.0014). Clinically, the resveratrol group exhibited higher rates of oocyte maturity (P = 0.0012) and high-quality embryos (P = 0.0013) than did the placebo group. There were no significant differences between the groups in terms of chemical or clinical pregnancy rates (P > 0.05).

Conclusions: These findings indicate that resveratrol may be a promising therapeutic agent for patients with PCOS undergoing assisted reproduction.

Trial registration number: http://www.irct.ir ; IRCT20221106056417N1; 2023 February 09.

Keywords: Antioxidants; Assisted reproductive technique; Granulosa cells; Mitochondrial biogenesis; Polycystic ovary syndrome; Resveratrol.

Fig. 1

Enrollment, allocation, and follow-up of participants and the CONSORT diagram of the clinical trial

Fig. 2

The expression of PGC-1α (A), Nrf-1 (B), and TFAM (C) in GCs from the resveratrol and placebo groups. (A, C) The results revealed that the expression of PGC-1α and TFAM was significantly greater in the resveratrol group (P < 0.05). (B) The increase in Nrf-1 levels did not reach statistical significance between the two groups (P > 0.05). The treatment group received a daily dose of 800 mg/day of resveratrol. The data are presented as the means ± SDs. ***P < 0.001, **P < 0.01. (Mann‒Whitney test). PGC-1α, peroxisome proliferator-activated receptor gamma coactivator; Nrf-1, nuclear respiratory factor 1; TFAM, mitochondrial transcription factor A

Fig. 3

The protein expression levels of SIRT1 and PGC-1α in GCs from the placebo and resveratrol groups. (A, B) Western blot analysis was performed to assess the protein expression of SIRT1 and PGC-1α, which was subsequently normalized to that of β-actin. The protein expression of SIRT1 and PGC-1α was significantly greater in the treatment group than in the control group (P < 0.05). (C) Blots of SIRT1, PGC-1α, and β-actin. The treatment group received a daily dose of 800 mg/day of resveratrol. The data are presented as the means ± SDs. ****P < 0.0001, **P < 0.01 (Unpaired t test). SIRT1, Sirtuin 1; PGC-1α, Peroxisome proliferator-activated receptor gamma coactivator

Fig. 4

Comparison of mtDNA copy number and intracellular ATP content between the two groups. (A) The relative mtDNA copy numbers were significantly greater in the treatment group than in the control group (P < 0.05). (B) A comparison of the intracellular ATP content in GCs between the resveratrol and placebo groups revealed a significant increase in the resveratrol group (P < 0.05). The treatment group received a daily dose of 800 mg/day of resveratrol. The data are presented as the means ± SDs. ****P < 0.0001, **P < 0.01 (Unpaired t test). ND1, NADH-dehydrogenase subunit; ATP, adenosine triphosphate

Fig. 5

Comparison of the chemical and clinical pregnancy rates between the resveratrol and placebo groups. In the resveratrol group, the chemical pregnancy rate was 45.83% (11/24), while it was 33.33% (8/24) in the placebo group (Fisher’s test; two-tailed P = 0.5556). Furthermore, the clinical pregnancy rate was 37.50% (9/24) in the resveratrol group and 29.17% (7/24) in the placebo group (Fisher’s test; two-tailed P = 0.7601). Placebo: n = 24, Treatment: n = 24