Ovarian Follicle Depletion Induced by Chemotherapy and the Investigational Stages of Potential Fertility-Protective Treatments—A Review

Abstract

Ovarian follicle pool depletion, infertility, and premature menopause are all known sequelae of cancer treatment that negatively impact the quality of life of young cancer survivors. The mechanisms involved in this undesired iatrogenic ovarian damage have been intensively studied, but many of them remain unclear. Several chemotherapeutic drugs have been shown to induce direct and indirect DNA-damage and/or cellular stress, which are often followed by apoptosis and/or autophagy. Damage to the ovarian micro-vessel network induced by chemotherapeutic agents also seems to contribute to ovarian dysfunction. Another proposed mechanism behind ovarian follicle pool depletion is the overactivation of primordial follicles from the quiescent pool; however, current experimental data are inconsistent regarding these effects. There is great interest in characterizing the mechanisms involved in ovarian damage because this might lead to the identification of potentially protective substances as possible future therapeutics. Research in this field is still at an experimental stage, and further investigations are needed to develop effective and individualized treatments for clinical application. This review provides an overview of the current knowledge and the proposed hypothesis behind chemotherapy-induced ovarian damage, as well as current knowledge on possible co-treatments that might protect the ovary and the follicles from such damages.

Hot Topics on Fertility Preservation for Women and Girls—Current Research, Knowledge Gaps, and Future Possibilities

“…There are numerous experimental studies currently ongoing aiming at developing possible pharmaceutical fertility preservative substances, which can be administrated prior to or during ovarian-toxic treatment to prevent its damage to ovaries [ 87 ]. Published studies in this field have been mainly designed according to the proposed mechanisms of how the ovaries are damaged by gonadotoxic treatment, especially chemotherapy.…”

“…The involved mechanisms proposed include induction of primordial follicle apoptosis triggered by DNA damage and/or oxidative stress [ 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 ]. Additional proposed mechanisms to explain primordial follicle depletion include the overactivation effect of the gonadotoxic chemotherapy on the dormant primordial follicles through the activation of the PI3K/PTEN/Akt signaling pathway, which results in a premature “burnout” of the ovarian reserve [ 87 , 96 , 97 , 98 , 99 , 100 ]. Chemotherapy has also been suggested to damage the ovarian blood vessels [ 101 , 102 , 103 ].…”

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

“…Both direct acute and indirect delayed mechanisms have been reported for the effects of anticancer agents that cause a decrease in ovarian reserve. The main mechanism is that anticancer drugs directly induce DNA double-strand breaks (DSBs), which activate apoptosis and/or autophagy-related pathways [ 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. The second mechanism is that anticancer drugs can indirectly cause primordial follicle depletion by microvascular and stromal injury through ischemia, necrosis, or inflammation [ 38 , 42 , 43 , 44 , 45 ].…”

Isoform-Specific Roles of Mutant p63 in Human Diseases

“…This activation is irreversible [ 40 , 43 ] and de-phosphorylation does not convert the protein back to its inactive dimeric state. Oocyte death resulting in Premature Ovarian Insufficiency (POI) can be triggered, for example, by chemotherapy and irradiation [ 44 , 45 , 46 , 47 , 48 , 49 ] as used for the treatment of cancer patients or by mutations in p63 [ 50 ] that abrogate the function of the C-terminal Transactivation inhibitory domain (TID) [ 51 ] (see also Section 5 below).…”