## 1 Introduction  
Chemotherapy is still the most common treatment against cancer, both for humans and animals [1; 2]. Even if chemotherapeutic drugs have so many side effects that affect healthy cells, such therapies are the most effective. Chemotherapy-induced ovarian damage is the foremost cause of ovarian dysfunction, early menopause, primary ovarian insufficiency, or even loss of fertility. Therefore, scientists are still searching for alternatives that could be used for alleviating the inherent side effects [3; 4; 5].  
Cyclophosphamide (CPA) is an alkylating agent, well-known for its gonadotoxic activity, that induces cross-links into DNA structure leading the follicular cells into apoptotic pathways [6]. In addition, reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced, which are harmful for the ovarian cells [7]. In addition, CPA activates the P13K/ PTEN/Akt/mTOR pathway that leads to \"the burnout effect\", which means an overactivation of the primordial follicles associated with their massive recruitment into the growing pool of follicles [8; 9].  
Phytotherapy has been employed multiple times during chemotherapy, with the aim of preventing or reducing the expected side effects [10; 11]. From thousands of plants and numerous phytochemicals that have been investigated over the years, a particularly attractive approach in this field is to find a proper chemical formulation that could preserve fertility. The ovarian protective effect of _Plantago_ species has not been previously investigated. According to previous studies, _Plantago_ extracts, taken from leaves, exhibit various properties, including anticarcinogenic, anti-inflammatory, anti-hypertensive, weakly antibiotic, wound healing and other pharmacological activities [12; 13; 14]. Our previous studies suggest that _Plantago species_, such as _P. major, P. lanccolata, P. cornuti, P. media, and _P. sempervirens_, follow a common chemical composition, rich in luteolin, apigenin, and rutin, but each of the extracts has a particular chemical pattern. With respect to their antioxidant activity, _P. sempervirens_ stands out as being an antioxidant six times stronger than its _Plantago_ counterparts [15; 16].  
Hence, this paper was designed to further evaluate the effects of _P. sempervirens_ extract in a model of ovarian failure due to chemotherapy. The main hypothesis is based on the potential of _P. sempervirens_ to maintain the ovarian follicles at resting stages, which are known to be more resistant to chemotherapy drugs [9]. Taking into consideration the chemical composition rich in phenolic compounds with estrogen-like activity, we aimed to investigate the protective effects of _P. sempervirens_ at different doses on nitro-oxidative stress, oestus cycles, FSH levels, and cell structural changes in the rat ovaries.  
Our study highlights the potential protective effect of _P. sempervirens_ alcoholic extract on the ovary oestus cycle, histology (ultrastructure), hormones, and stress markers after the induced cytotoxic effects of CPA, in a rat model. This protective effect of _P. sempervirens_ has not been previously demonstrated. The study covers three increasing concentrations (25/50/100 mg/kg BW) of the _P. sempervirens_ extract and it highlights the fact that dose-dependent studies are important. This calls for more in depth studies regarding the investigation of active compounds and synergistic effects of the extract and requires more data from rat groups, larger mammals, or volunteering patients.