Consequences of chemotherapeutic agents on primordial follicles and future clinical applications

Abstract

The ovarian reserve is necessary for female fertility and endocrine health. Commonly used cancer therapies diminish the ovarian reserve, thus, resulting in primary ovarian insufficiency, which clinically presents as infertility and endocrine dysfunction. Prepubertal children who have undergone cancer therapies often experience delayed puberty or cannot initiate puberty and require endocrine support to maintain a normal life. Thus, developing an effective intervention to prevent loss of the ovarian reserve is an unmet need for these cancer patients. The selection of adjuvant therapies to protect the ovarian reserve against cancer therapies underlies the mechanism of loss of primordial follicles (PFs). Several theories have been proposed to explain the loss of PFs. The "burn out" theory postulates that chemotherapeutic agents activate dormant PFs through an activation pathway. Another theory posits that chemotherapeutic agents destroy PFs through an "apoptotic pathway" due to high sensitivity to DNA damage. However, the mechanisms causing loss of the ovarian reserve remains largely speculative. Here, we review current literature in this area and consider the mechanisms of how gonadotoxic therapies deplete PFs in the ovarian reserve.

Female fertility preservation: Impact of cancer on ovarian function and oocyte quality

“…2 Thus, it is important to propose measures for fertility preservation of patients who desire future pregnancies. [3][4][5][6][7] In 2013, the American Society for Reproductive Medicine determined that mature oocyte cryopreservation should no longer be considered an experimental procedure. 8…”

Continuous treatment with cisplatin induces the oocyte death of primordial follicles without activation

“…It has been proposed that certain intervention agents may have efficacy to protect ovarian reserves against cancer therapies. 6 However, there have been no clinical guidelines for the strategic selection of fertoprotective agents due to a lack of thorough knowledge for the exact mechanisms of follicle loss in response to each chemotherapeutic drug. Most of the human data are from ovaries of patients who have been exposed to chemotherapies months or years before collection.…”

Extended adverse effects of cyclophosphamide on mouse ovarian function

“…There is limited information regarding the effects of Cy in the ovaries. Cy is thought to act as a direct ovotoxin that destroys dormant primordial follicles and activates quiescent primordial follicles by inducing apoptosis in pregranulosa cells and oocytes [ 27 ]. Cy exposure also generates increased reactive oxygen species in oocytes, resulting in mitochondrial dysfunction and disrupting the meiotic spindle [ 23 , 28 ].…”