Grape is an economically important and one of the most grown fruits worldwide (1). Most of the production (about 80% of the yield) is used for wine making (2). An important by-product of grape processing – grape pomace is the most important residual after juice extraction or wine making and consists of peel, seed, stem, and pulp (3). Grape pomace is considered a rich source for the extraction of a wide range of valuable phytonutrients, which exhibit a variety of bioactivities, such as antioxidant, anti-inflammatory, cardioprotective, anti-aging, antimicrobial and anti-cancer properties (4–9). Bioactive substances including proanthocyanidins, anthocyanins, phenolic acids, stilbenes, and flavonols are abundant in grape by-products (10) that can help in prevention or management of several conditions such as inflammatory conditions characterized by bowel disruption and the involvement of the immune system and colorectal cancer. Grape by-products can promote remarkable effects in reducing pro-inflammatory, pro-oxidative, and proliferative actions in inflammatory bowel diseases and colorectal cancer both in vivo and in vitro (10). Moreover, bioactive substances, such as resveratrol (11), anthocyanidins like delphinidin (12) and procyanidin such as procyanidin B2 (13) are valuable in multiple industries, including pharmaceuticals, agri-food, or cosmetics (13–15). Another abundant by-product of winemaking is grapeseed oil, which is processed from grapeseeds and presents an excellent source of γ-tocotrienol, and α-tocopherol. It also contains fatty acids mainly linoleic, oleic, palmitic, and stearic acids, as well as polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs) and saturated fatty acids (SFAs) (16). Furthermore. secondary plant metabolites such as polyphenols are produced by the grape berries during the growth in reaction to environmental stressors. They form significant components of red wines that enhance the sensory qualities and antioxidant capacity (17). Red wine polyphenols comprise newly generated ones during the winemaking process (such as highly polymerized polyphenols) in addition to those found in grapes as mentioned earlier many of which are recognized to possess beneficial impacts on health (17). Although several studies have summarized the most known physiological and therapeutic effects of grapes and their by-products (12, 15, 18–20), the action of grape extract and grape polyphenols on reproductive processes has not been sufficiently elucidated yet. The present evidence-based study summarizes the current knowledge concerning the provenance, properties, as well as physiological and therapeutic actions of grape extract and grape polyphenols on various cellular processes with a focus on female reproduction.

Grapes (Vitis vinifera L.) present an important source of phenolic compounds including phenolic acids, tannins, coumarins, flavonoids, flavones, and stilbenes (7). Grape pomace also contains neutral polysaccharides (30%), pectic substances (20%), and insoluble proanthocyanidins (15%) (21).

Among grape pomace compounds with high nutraceutical value, polyphenols (phenolic acids, flavanols, flavonols, anthocyanins, proanthocyanidins, and stilbenes) are the most interesting due to their bioactive properties (22–24). One of the most efficient bioactive compounds found in grape skin, seeds, and wine is stilbenoid resveratrol (25, 26), widely known primarily for its phytoestrogenic and antioxidant activities (27). Additionally, polyphenolic pigments anthocyanidins, including delphinidin, mainly extracted from grape skins, are responsible for many of the red-orange to blue-violet colors (28). Grapeseeds contain proanthocyanidins, which are composed of epicatechin and monomeric catechin, gallic acid, and polymeric and oligomeric proanthocyanidins (29). Interestingly, proanthocyanidins present more powerful free radical scavengers than vitamins C, E, or β-carotene (30). Monomeric and dimeric flavanols, as well as mono- and diglycosides have been identified in grapeseed extracts. Diglycosylated flavanol dimers have been detected in grape skin extracts, too. The concentration of the mono- and diglycosides depends largely on the grape variety and grape source (31). Major bioactive compounds present in different parts of grape and grape products are given in Table 1 .

Grape polyphenols are effective inhibitors of enzymes linked with various ailments. Findings indicate an inverse relationship between the consumption of grapes or grape products and the development of age-related complications including cardiovascular disorders with an estimated 6–7% reduction in deaths from cardiovascular disorders (7). Studies demonstrated biological activities including antioxidant, cardioprotective, anti-cancer, anti-inflammatory, anti-aging, and antimicrobial properties exerted by grape polyphenols such as anthocyanins, flavanols, flavonols, and resveratrol. Chromatographic analysis confirmed the presence of 19 phytochemicals. The prominent compound was catechin followed by gallic acid, caftaric acid, and epicatechin (4–6, 48). Moreover, skin protection, antidiabetic, immunomodulatory and anti-neurodegenerative activities as well as hepatoprotective and neuroprotective effects using phenolic compounds gathered form grape ethanol extract have been reported (11, 15, 18, 48).

Oxidative stress has been associated with the pathogenesis of several chronic diseases and inflammatory processes. Polyphenols are strong antioxidants that act as a defense barrier against free radicals, as well as non-radical oxidants (49). Phenolic acids, stilbenoids, tannins, quinones, coumarins and flavonoids from grapes have the potential to enhance the oxidant capacity of cells stimulating enzymatic expression and reducing the reactive oxygen species (ROS) by either inhibiting their production or by directly scavenging them or via xenobiotic detoxification. For example, administration of Bordo grape juice to human test subjects, led to elevation of antioxidant activities and lowering of blood glucose (50). Grape polyphenols, particularly flavanols can maintain cellular protein homeostasis (proteostasis). Since impaired proteostasis is closely involved in all amyloid diseases, grapeseed extracts may be a valuable therapeutic agent for the prevention and/or management of neurodegenerative diseases (51). The antimicrobial activity against Gram-positive bacteria and antioxidant properties could be associated with phenolic compounds found in grape stems (52). Resveratrol isolated from grape stems was applied on hepatocellular carcinoma Hep-G2 (hepatoma G2) cells, breast adenocarcinoma MCF-7 cells, colon carcinoma HCT116 cells, and lymphoblastic leukemia cells (1301). After treatment, it was shown that resveratrol possesses anti-proliferative and apoptotic effects (53). Anthocyanidins have been found to possess anti-aging and anti- inflammatory properties (28). Lim and Song (12) described the possible use of delphinidin according to its effect on different types of cancers and various chronic diseases. For the study, they used ovarian adenocarcinoma cells (SKOV3) which were then treated with delphinidin alone or with various inhibitors of cell signaling proteins.

Grape pomace contains a high level of antioxidants with the ability to counteract chronic inflammatory symptoms which was demonstrated on colorectal adenocarcinoma-derived intestinal epithelial cell line Caco-2 after grape pomace ethanolic extract treatment (54). Additionally, grapeseeds contain several flavonoids and non-flavonoids which can exert antioxidant and anti-inflammatory activities. Beneficial effects of grapeseed extract in relation to oxidative stress and metabolic disorders such as insulin resistance have been associated with the modulation of plasma adipokines in mammals (55, 56). Grapeseed supplementation has the potential to scavenge oxygen free radicals in the egg yolk in mammals and chicken, as well as it can reduce oxidative damage in the liver in rats (57, 58). It has been reported that grapeseed proanthocyanidin extract possess anti-inflammatory and antioxidant activities (13, 59, 60), and can reduce cytotoxicity as well as genotoxicity (49), including decreasing oxidative damage induced by aflatoxins (61). Proanthocyanidin B2 found in grapeseed present one of the most valuable components of grapeseed extract and can be used due to its protective action against oxidative stress and development of cardiovascular diseases demonstrated on human umbilical vein endothelial cells (HUVEC) (62, 63). In this regard, grape extracts and their polyphenols exhibit protective effects against different toxins and a variety of mechanisms of their action, disturbing physiological homeostasis through increase in superoxide dismutase (SOD) levels and glutathione peroxidase activities, as well as decrease in malondialdehyde (MDA) levels or activation of the nuclear erythroid 2-related factor 2/ARE pathway demonstrated on PC12 rat cells (26). Possible physiological and therapeutic actions of grape polyphenols depending on their bioactive substances are presented in Table 2 .

Reproductive dysfunctions can be indicated by a negative correlation between muscle growth and reproductive effectiveness (76, 77). Exposure to oxidative stress can lead to the inflammation initiation which is the trigger of multiple reproductive disorders, including ovarian cancer or multiple reproductive defects, such as oocyte mutation, polycystic ovary syndrome (PCOS), endometriosis, as well as can affect ovarian folliculogenesis, oocyte maturation and the release of sex hormones (78–80). Bioactive phytonutrients are known to impart several properties such as anti-inflammatory and antioxidant activities that may have a beneficial impact on reproductive functions (81, 82). Polyphenols can pass through various protective barriers in reproductive organs, which can possibly affect their physiological functions (11, 83, 84). Moreover, grape seed extract had positive impact on improving fertility in golden laying hens (85). Although few studies have been carried out on reproductive cells we have summarized the available information related to the effects of grape polyphenols on female reproductive organs and their (dys)functions in a nutshell. The action on female reproductive processes is presented in Figure 1 .

Grape, grape extract and their bioactive polyphenols can affect female reproductive processes via extracellular regulators and multiple intracellular signaling pathways. Their mechanism(s) of actions on female reproductive processes have been studied insufficiently, however, there are some studies describing the possible mechanism(s) of effect on female reproduction (11).

Utilization of grape by-products has attracted increasing attention for the availability of grape skins, their health benefits and pharmacological use. Grape polyphenols can play an important role in the prevention of reproductive disorders due to their ability to mitigate the negative impact of oxidative stress and inflammation on the reproductive processes. Moreover, the beneficial impact on oocyte maturation, cell viability, cell proliferation, as well as steroidogenesis has been reported. Resveratrol from grape stems may have a potential to prevent endometriosis and could serve as a novel dietary supplement. Furthermore, available data suggest the possible use of grapeseed extract to improve oocyte quality, as well as healthy gravidity, embryogenesis, and labour due to its beneficial effect on the endometrium. Moreover, the applicability of grapeseed extract including proanthocyanidin B2 in the prevention and/or management of endometriosis, age-related menopausal reproductive insufficiency and ovarian or cervical cancers has been mentioned. Therefore, grape extract and polyphenols present a promising biostimulator, which can be used as dietary supplement in the improvement of reproduction in the field of animal production, biotechnology, or assisted reproduction. Similarly, phytoestrogenic activity of grape might be used as a potential alternative tool to the hormonal treatment of disorders related to estrogen deficiency, such as menopausal syndrome, and osteoporosis. However, to our knowledge, such potential of grape extract or grape polyphenols has not been examined in depth yet.

The present review sheds light on the potential health benefits of grape polyphenols while also emphasizing the need for further research and a more cautious interpretation of the findings. It is evident thatconfirmatory claims about the therapeutic effects of grape polyphenols cannot be made at this stage, given the intricacies of human physiology and the many variables at play. Grape polyphenols exert a wide range of health benefits posing grape extract as an interesting and valuable dietary supplement for natural complementary therapy. This evidence-based study focuses on the actions of grapeseed extract and grape polyphenols on female reproductive processes at various regulatory levels and multiple signalling pathways by regulating reproductive hormones (GnRH, gonadotropins, prolactin, steroid hormones, IGFBP), steroid receptors, markers of proliferation and apoptosis. Moreover, the role of grapes in various reproductive disorders, including reproductive insufficiency, PCOS, menopausal syndrome, ovarian cancer or ovarian ischemia has been indicated. Studies also demonstrate the impact of grapeseed extracts or their bioactive constituents (proanthocyanidin B2, resveratrol, delphinidin) on steroidogenesis, oocyte quality and maturation, and developmental capacity. However, lack of knowledge of standardized dosage limits the clinical applications of grapeseed extract despite the wide range of biological and therapeutic potential.

On the other hand, it should be remembered that in vitro and in vivo studies have been performed with far greater quantities of polyphenols than those frequently found in human diets. Hence, the extent of grape polyphenols consumed on a regular basis is an open question and needs to be addressed in future studies. Determining suitable doses for therapeutic applications remains a critical challenge, as highlighted in the previous sections. The appropriate dosage of grape polyphenols is a key factor in achieving the desired health outcomes, and future research should focus on defining these optimal dosage ranges and accounting for potential variations in individual responses. Moreover, the studies have mainly been performed in vitro or in vivo, whilst clinical studies are lacking and the efficacy of all grape phytosubstances on reproductive processes has not been tested properly yet.

Conceptualization: SR, AK; writing – original draft preparation: LK, AK; writing – review and editing: SB, MM, LB, AS, SR; supervision: AK. All authors contributed to the article and approved the submitted version.