Abstract
BACKGROUND: Premature ovarian failure (POF) and ovarian reserve loss are common problems associated with cancer therapies. Carvacrol (Carva) showed significant efficacies in ameliorating several toxicological impacts and complications associated with chemotherapeutic agents. Thus, this study was established to speculate on the efficacy of Carva against cyclophosphamide (Cyclo)-provoked POF. METHODS: A twenty-four mature female rats were randomly and equally allocated into four groups; normal group, Carva (15 mg/kg/day/orally/3 weeks) group, Cyclo (75 mg/kg/i.p/once weekly/3 weeks) group, and Carva + Cyclo group. Assessments of serum sex hormones, as well as ovarian oxidative stress-related pathways, along with histopathological alterations in ovary and uterine tissues, have been investigated. In addition, monitoring the rats' estrous cycle was performed via vaginal cytology. RESULTS: Our findings revealed that Carva ameliorated the disturbance of rats' estrous cycle, as well as loss of rats' body weight, and reproductive tract weight brought on by Cyclo. In addition, Carva administration modulated the disturbances in serum Anti-Mullerian hormone, estradiol, total estrogen, progesterone, follicle-stimulating hormone, and luteinizing hormone that resulted from Cyclo toxicity. The incidence of oxidative stress following Cyclo was significantly corrected by Carva, as indicated by a decline in ovarian malondialdehyde content and an increase in glutathione level. Carva effectively abrogated the increase in phosphorylated forms of protein kinase B (AKT), forkhead box protein O3a (FOXO3a), phosphoinositide 3-kinases (PI3K), and phosphatase and tensin homolog protein content in the ovarian tissue following Cyclo. Moreover, Carva ameliorated the structural changes of Cyclo in the ovarian and uterus tissues, and collagen condensation in the uterus. A marked preservation in the follicle count was recorded in the Cyclo + Carva group. The immunohistochemical findings revealed the hyper-expression of p-AKT along with activation of caspase 3 in the ovarian regions of Cyclo group, which is down-regulated by Carva. CONCLUSION: Hence, it could be concluded that Carva could preserve rat ovarian function from the degenerative impacts of Cyclo treatment by lessening the oxidative and apoptotic insult via regulating the PI3K/AKT/FOXO3a pathways in the ovarian tissues, along with successful attenuation of uterine fibrosis.