The Impact of Chemotherapy on the Ovaries: Molecular Aspects and the Prevention of Ovarian Damage

Abstract

Cancer treatment, such as chemotherapy, induces early ovarian follicular depletion and subsequent infertility. In order to protect gametes from the gonadotoxic effects of chemotherapy, several fertility preservation techniques—such as oocyte or embryo cryopreservation with or without ovarian stimulation, or cryopreservation of the ovarian cortex—should be considered. However, these methods may be difficult to perform, and the future use of cryopreserved germ cells remains uncertain. Therefore, improving the methods currently available and developing new strategies to preserve fertility represent major challenges in the area of oncofertility. Animal and ovarian culture models have been used to decipher the effects of different cytotoxic agents on ovarian function and several theories regarding chemotherapy gonadotoxicity have been raised. For example, cytotoxic agents might (i) have a direct detrimental effect on the DNA of primordial follicles constituting the ovarian reserve and induce apoptosis; (ii) induce a massive growth of dormant follicles, which are then destroyed; or (ii) induce vascular ovarian damage. Thanks to improvements in the understanding of the mechanisms involved, a large number of studies have been carried out to develop molecules limiting the negative impact of chemotherapy on the ovaries.

Fertility‐sparing treatment for early‐stage epithelial ovarian cancer: Contemporary oncologic, reproductive and endocrinologic perspectives

“…Most notably, these include sphingosine-1-phosphate(S1P) and ceramide-1-phosphate(C1P), both membrane sphingolipids that may decrease chemotherapy-induced apoptosis, as well as imatinib, a tyrosine kinase inhibitor that blocks p63 activation in the apoptotic pathway and holds promise specifically when used with cisplatin. 94,95 Anti-mullerian hormone is also under study given its physiologic function in inhibiting recruitment of primordial follicles but has yet to be studied in humans. 80…”

Advances in the Treatment and Prevention of Chemotherapy-Induced Ovarian Toxicity

“…There is third hypothesis called the “burnout” effect. A few studies have shown that anticancer drugs induce activation of the phosphoinositide 3-kinase/protein kinase B/forkhead box protein O3a (PI3K/AKT/FOXO3a) pathway, which leads to follicle reduction by massive activation of primordial follicles in mice and cultured human ovarian tissue [ 36 , 46 , 47 , 48 , 49 ]. However, there is some question of methodology and biological mechanism of follicle loss based on studies supporting “burnout theory”.…”

“…It has not been proven that primordial follicle growth is the main cause of chemotherapy-induced primordial follicle loss. Thus, the “burnout” theory of chemotherapy-induced follicle depletion is still lacking evidence and is under debate [ 36 , 46 ]. The main cause of the follicle depletion induced by chemotherapy seems to be DNA double-strand breaks and apoptosis.…”

Knowledge of iatrogenic premature ovarian insufficiency among Chinese obstetricians and gynaecologists: a national questionnaire survey

“…This process makes PGCs extremely sensitive to the effects of CT and RT. Chemotherapeutic agents might i) have a detrimental effect on the DNA of primordial follicles; ii) induce overactivation, apoptosis, or atresia of follicles; or iii) cause stromal fibrosis as well as vascular damage in ovaries [23,24]. Whereas RT induces rapid prolonged primordial follicle loss mostly via ionisation and oxidative stress [25,26], which can be more damaging to ovarian reserve than CT due to its inevitable off-target effects.…”