Table 1.

In vitro and in vivo studies about antioxidants and vitamins in in vitro fertilization.

Component	Authors	Animal Model	Study Design	Dose	Results
	Lee et al., 2010 [36]	Bovine	In vitro	0.5 µM	-Resveratrol increased the percentage of parthenogenically-activated and IVF-produced embryos reaching the blastocyst stage and the total cells number of blastocysts ($\uparrow )$
	Abdel-Wahab et al., 2012 [37]	Bovine	In vitro	0.5 µM	-Resveratrol increased survival and hatching rates of embryos cryopreserved $(\uparrow )$
	Salzano et al., 2014 [38]	Bovine	In vitro	0.5 µM	-Resveratrol increased development and hatching rates of embryos cryopreserved ($\uparrow$)
	Gaviria et al., 2019 [39]	Bovine	In vitro	0.5 µM	-Resveratrol attenuated the increasing in active mitochondria in embryos cryopreserved ($\uparrow )$
	Kwak et al., 2012 [40]	Porcine	In vitro	0.1, 0.5, 2.0, 10.0 µM	-Lower levels of intracellular ROS in oocytes matured in vitro (2.0 µM) ($\uparrow )$ -Higher blastocyst formation rates and total cells number after parthenogenic activation and IVF (2.0 µM) ($\uparrow )$ -Lower expression of apoptosis-related genes in COC treated with 2.0 µM resveratrol ($\uparrow )$
	Liu et al., 2013 [41]	Mouse (C57BL6)	In vivo (aged 2–3 months) In vitro	Resveratrol added to drinking water at 30 mg/L for 6 or 12 months (in vivo) 0.1, 0.5, 1.0 µM (in vitro)	-Aged mice that received resveratrol delivered pups albeit with a reduced litter size ($\uparrow )$ -Increased number of primary and growing follicles (6 months of resveratrol intake) and prevention of telomere shortening together with an increase in telomerase activity (12 months) ($\uparrow )$ -Higher frequency of normal oocytes than age-matched untreated control (6 months of treatment) ($\uparrow )$ -Increased rate of development to blastocysts and increased total cells number in blastocysts (0.1 µM resveratrol in culture medium) ($\uparrow )$
	Wang et al., 2014 [42]	Bovine	In vitro	0.1, 0.5, 1.0 µM	-Improved cumulus expansion, polar body formation, hatched blastocyst rate and mean number of cells in blastocysts (1.0 µM) ($\uparrow )$ -Resveratrol induced progesterone secretion and had antioxidants effects ($\uparrow )$
	Li et al., 2018 [43]	Bovine	In vitro	0, 10−3, 10−4, 10−5, 10−6 M	-Resveratrol decreased ROS, phosphatidylserine externalization and malonialdehyde and protected mitochondrial function in sperm and acrosome integrity (10−4 M) ($\uparrow )$ -Increased blastocysts number and quality following IVF (10−4 M) ($\uparrow )$
	Piras et al., 2020 [44]	Cat	In vitro	5 µM	-The rate of blastocyst formation, after IVM of oocytes incubated with resveratrol, was higher than that of oocytes matured without resveratrol $(\uparrow )$
Melatonin	Dai et al., 2017 [45]	Mouse (ICR)	In vitro	10−9, 10−7, 10−5,10−3 M	-Increased fertilization potential and elevated sperm binding ability in post-ovulatory aged oocytes (10−3 M) ($\uparrow )$ -Decreased ROS and early apoptosis with melatonin supplementation $(\uparrow )$
	R. Osorio et al., 2007 [46]	Porcine	In vitro	10−12, 10−9, 10−6,10−3 M	-Positive effects on cleavage rates and blastocysts cells number (10−9 M) ($\uparrow )$ -Decreased cleavage rates (10−3 M) $(\downarrow )$ -Melatonin (10−9 M) protection of embryos against heat stress (40 °C for three hours) $(\uparrow )$
	He et al., 2016 [47]	Mouse (CD1)	In vitro	10−5, 10−7, 10−9 M	-Melatonin improved mitochondrial function (10−5 M and 10−7 M) together with mitochondrial distribution and ATP production in oocytes (10−7 M) ($\uparrow )$ -Role in reducing ROS formation (10−7 M) and in enhancing meiotic spindle assembly (10−7 M) ($\uparrow )$ -Melatonin improved IVF embryo development: higher blastocysts rate with 10−5 and 10−7 M melatonin and higher number of blastocysts cells with 10−7 M melatonin supplementation $(\uparrow )$
	Serrano et al., 2013 [48]	Bovine	In vitro	10−12, 10−9, 10−4; 10−3 M	-10−4 M melatonin alleviated bovine oocytes from the harmful effects of heat stress $(\uparrow )$
	Zhao et al., 2018 [49]	Mice (ICR)	In vivo (aged 7 weeks)	Melatonin added to drinking water at 0,3, 30, and 300 µg/mL for 21 days	-Litter size increased (3 µg/mL) ($\uparrow )$ -Higher antral follicles count and hatched blastocysts rate in 30 µg/mL group than control group $(\uparrow )$
CoenzymeQ10	Zhang et al., 2019 [50]	Mice (ICR)	In vitro	25, 50, or 100 μM	-Role of CoQ10 supplementation in preventing aging damages ($\uparrow )$ -Number of sperm binding to the zona pellucida significantly restored in the CoQ10 supplemented group ($\uparrow )$ -Localization of Juno on the membrane in aged oocytes rescued with CoQ10 supplement ($\uparrow )$ -Levels of superoxide and DNA damage reduced with CoQ10 administration $(\uparrow )$
	Ben-Meir et al., 2015 [51]	Mouse (ICR)	In vivo (For aging experiments, only retired breeders were used. Young controls were virgin females aged 7–8 weeks old)	Subcutaneous doses of ALA (33 mg/kg), resveratrol (10 mg/kg), CoQ10 (22 mg/kg), or placebo (sesame oil) three times a week for a period of at least 12 weeks. For experiments in the Pdss2 model, mothers during pregnancy and their offspring after weaning received CoQ10 in drinking water (0.4 mg/mL).	-Age-related decline in oocyte quality and quantity reversed by the administration of CoQ10 ($\uparrow )$ -Prevention of premature ovarian failure in the oocyte-specific Pdss2-deficient animals by maternal dietary administration of CoQ10 ($\uparrow )$
	Boots et al., 2016 [52]	Mouse (C57BL6)	In vivo (aged 4 weeks)	22 mg/kg CoQ10 3 times/week dissolved in sesame oil, subcutaneously.	-Reduced levels of intracellular ROS in oocytes of mice treated with normal diet but not in those in high fat-high glucose diet -Higher percentage of normal spindles and chromosome alignment in oocytes of mice supplemented with CoQ10 $(\uparrow )$ -No differences in the number of mature oocytes, fertilization rate, blastocyst formation rates, implantation rates, resorptions rates, or litter size between obese mice receiving CoQ10 or vehicle $(\to )$
	Maside et al., 2019 [53]	Porcine	In vitro	10, 25, 50, and 100 μM	-No effects on the percentage of MII oocytes, fertilization, and on the parameters of subsequent embryonic development (10–50 μM CoQ10 to the IVM medium) $(\to )$ -The highest concentration of CoQ10 (100 μM) in the maturation medium negatively affected blastocyst rates $(\downarrow )$
B-Vitamins	Huang et al., 2013 [54]	Mouse (Kumming), Xenopus	In vitro	500 μM	-The deleterious effects of hypoxantine counteracted by folic acid (500 μM) ($\uparrow )$ -In folic acid-treated Xenopus eggs, extracellular signal-regulated kinase 1 was phosphorylated, cyclin B2 and Mos up-regulated and the frequency of GVBD accelerated ($\uparrow )$
	Tsuji et al., 2017 [55]	Mouse (ICR)	In vivo (aged 5–6 weeks)	Female mice were fed a 20% casein diet (control group) or a vitamin B1–free diet (test group)	-Frequency of abnormal oocyte was increased by vitamin B1 deficiency when deficiency was accompanied by body weight loss -The frequency of abnormal oocytes decreased by refeeding of a vitamin B1–containing diet $(\uparrow )$
Vitamin C	C. Martin et al., 2014 [56]	Porcine	In vitro	50 µM β-mercaptoethanol or 100 µM l-ascorbic acid	-ROS levels and survival rates after vitrification–warming significantly improved in embryos cultured with ascorbic acid ($\uparrow )$ -l-ascorbic acid into vitrification–warming media enhanced embryo survival and embryo quality after warming $(\uparrow )$
	C. Martin et al., 2015 [57]	Porcine	In vitro	100 µM	-l-ascorbic-acid enhanced survival rates of blastocysts and reduced peroxide levels ($\uparrow )$ -No significant differences in total cells number, DNA fragmentation, and BAX, BCL2L1 and POU5F1 expression levels in vitrified blastocysts among experimental groups ($\to )$ -Vitrification procedures increased HSPA1A transcript abundance, but this increase was lowered with l-ascorbic acid supplementation $(\uparrow )$
	Nohalez et al., 2018 [58]	Porcine	In vitro	50 µM	-No significant effects of l-ascorbic acid in any of the maturation, fertilization, or embryo development parameters assessed $(\to )$ -Blastocyst survival rate after vitrification increased with l-ascorbic acid addition to vitrification/warming media $(\uparrow )$ -Blastocysts intracellular ROS decreased with addition of l-ascorbic acid to vitrification/warming media but did not affect GSH $(\uparrow )$
Vitamin E	Wang et al., 2002 [59]	Mouse	In vitro	Vitamin C (0 to 400 µM), and vitamin E (0 to 800 µM) (3–6 h)	-Increased blastocyst development rate co-incubating embryos with vitamin C (50 µM–3 h) and PMA-activated supernatant -Increased blastocyst development rate with vitamin E supplementation (400 µM) at 6 h $(\uparrow )$
	Olson et al., 2000 [60]	Bovine	In vitro	100 mM vitamin E; 100 mM vitamin E + 100 mM vitamin C 100 mM vitamin E + 100 mM vitamin C + 3 mM EDTA	-More zygotes developed to expanded blastocysts (culture medium contained 100 mM vitamin E) $(\uparrow )$ -Combined vitamins E and C resulted in lower development to early, expanded, and hatched blastocysts than with vitamin E alone, as was the mean number of cells per blastocyst $(\to )$ -Addition of EDTA (3 mM) failed to improve development over that in culture with vitamin E + vitamin C ($\to )$ -Larger surface area of embryos cultured with vitamin E $(\uparrow )$