The impact of chemotherapy on the ovaries depends not only on the dosage and chemical properties of each drug but also on the patient's age at the time of treatment, with a higher risk of ovarian damage in patients with advanced reproductive age [[1], [2], [3]]. The effects of antitumoral treatments on ovarian function can be analyzed through different markers, including levels of serum early phase FSH, estradiol, and anti-Mullerian hormone (AMH), as well as oligo- or amenorrhoea and antral follicle count. Doxorubicin (Doxo) is a widely used anthracycline to manage leukemia, breast cancer, sarcomas, and lymphomas [4,5]. Doxo intercalates with DNA and prevents its replication and transcription. Numerous studies have demonstrated Doxo toxicity in the mouse ovary in vivo, most of which have been supported by in vitro studies reporting increased apoptosis in granulosa cells and oocytes [6,7]. Doxo causes not only an increase in the number of double-strand DNA breaks in oocyte and granulosa cells in the ovary, but stromal and vascular damage have also been reported, suggesting that premature ovarian failure is associated with injury to the oocyte, follicular cells and endothelial cells [8].

GnRH agonists have been administered to decrease chemotherapy-induced gonadotoxicity by downregulation of gonadotropin secretion from the pituitary gland and its consequent modulation of folliculogenesis [9]. Nonetheless, several studies have demonstrated contradictory results regarding the use of GnRH agonists to avoid gonadotoxic damage in the ovary [10,11]. Accordingly, more studies are needed to identify novel candidates to protect ovaries from chemotherapy. A suitable ovarian protective agent should be easy to administer, noninvasive, and effective. Thus, such a compound administered at the time of chemotherapy may preserve ovarian function and fertility in children, adolescents, and adult female cancer survivors.

Resveratrol (Res) is a stilbene-type aromatic phytoalexin mainly present in peanuts, grapes, berries, and red wine [12]. Res is found in nature as cis-resveratrol and trans-resveratrol. Studies have focused on the trans-resveratrol isomer because it is thought to be more abundant and more biologically active than the cis-resveratrol form [13]. In plants, Res contributes to resistance against bacterial and fungal infections as well as ultraviolet and mechanical damage.

Res possess anti-microbial, anti-aging, anti-inflammatory, cardio-protective, and antioxidant effects [[14], [15], [16], [17]]. In cancer cells, Res causes apoptosis, and therefore acts as a chemotherapeutic agent [18]. In contrast, Res also decreases apoptotic cell death in non-cancerous cells [19].

In the female reproductive system, many studies have shown that Res alone regulates folliculogenesis, decreases ovarian apoptosis, and protects against age-related infertility in mice [20,21].

So far, no in vivo studies have evaluated the effect of Res on ovarian function in a doxorubicin-induced POF model. Hence, the main objective of this study was to analyze the in vivo effects of Res administration on folliculogenesis, ovarian reserve, apoptosis, vascular development and stability in ovaries from a doxorubicin-induced mice model. Additionally, we analyzed the expression of antioxidant enzymes, catalase (CAT) and superoxide dismutase 1 (SOD-1) and uterine morphology in this model.