Abstract
Cyclophosphamide (CTX) has immunosuppressive effects and has been wildly used as one anti-cancer drug in clinical. Significant toxicity has been noticed particularly in the reproductive system. CTX promotes the maturation of ovarian follicles, decreases follicular reserve, and ultimately lead to ovarian failure or even premature ovarian failure (POF). The placental extract (HPE) has been shown to have some beneficial impact on reproductive system; however, little is known regarding to the effect of HPE on protecting CTX-induced ovarian injury and the mechanism involved. Whether human placental extracts (HPE) has a protective effect on CTX-induced toxicity on ovarian was studied by using a CTX-induced ovarian injury animal model. The effects of HEP on histopathology, the number of atretic follicles, the weight of the ovary, serum hormone levels, and apoptosis in granulosa cells were studied in mice with CTX or control vehicle. Our results have demonstrated that HPE inhibited p-Rictor, reduced the expression of Bad, Bax and PPAR, and activated Akt and Foxo3a (increased their phosphorylation). Mice treated with HPE showed higher ovarian weight, lower number of atretic follicles, higher serum levels of the hormones E2 and progesterone, and lower apoptosis and serum levels of LH and FSH in granulosa cells, than that in the control animal group. Our data show that ovarian injury can be attenuated by HPE. HPE likely protects follicular granulosa cells from undergoing significant apoptosis and reduce atresia follicle formation, therefore, alleviates CTX-induced ovarian injury.
Highlights
In premature ovarian failure (POF), the ovaries become dysfunctional or lost, and persistent amenorrhea and sexual atrophy are observed in some affected women before the age of 40[1]
The mechanisms involved in POF remain unclear, and clinical treatments, especially chemotherapy, play important roles as iatrogenic factors[3]
The results showed that the rate of apoptosis was significantly higher in ovarian granulosa cells in the POF group comparing to the control group
Summary
In premature ovarian failure (POF), the ovaries become dysfunctional or lost, and persistent amenorrhea and sexual atrophy are observed in some affected women before the age of 40[1]. CTX exerts a toxic effect by causing abnormal DNA base pairings, leading to misstructured and dysfunctional cells and irreversible injury in the ovary [4]. The proliferation, development and maturation of ovary germ cells are reported to be regulated by the mechanistic target of rapamycin (mTOR) pathway, in which Rictor, mTORC2, Akt, and Foxo3a play key roles. A mouse model of POF was constructed using 4-vinylcyclohexene diepoxide (VCD) [6,7] In these mice, molecular functions of Rictor and its downstream effector mTORC2 were affected and both of these apoptosis-related proteins were overexpressed. Molecular functions of Rictor and its downstream effector mTORC2 were affected and both of these apoptosis-related proteins were overexpressed These effects accelerated follicular atresia and apoptosis, leading to the loss of ovarian functions
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