Chemotherapy-induced ovarian damage and fertility preservation in young patients with cancer are emerging disciplines. The mechanism of treatment-related gonadal damage provides important information for targeting prevention methods.
It is estimated that 9.2 million women were newly diagnosed with malignancy worldwide in 2020 . Among adolescents and young adults aged 15–39 years, 89,500 patients were newly diagnosed with cancer, and 9270 mortalities were reported in the United States . In these patients, oncologic therapies can harm normal ovarian function and result in ovarian damage . Fertility preservation is now an emerging discipline that plays a critical role in preventing infertility in the care of young cancer patients .
Chemotherapy could harm gonadal function in young cancer patients and cause loss of the ovarian reserve . The molecular mechanism of chemotherapy-induced ovarian damage has been investigated to understand and prevent gonadotoxicity in cancer treatment . However, the genetic aspects of chemotherapy-induced ovarian damage are still not fully understood. This article reviews the genetics of chemotherapy-induced ovarian dysfunction and explores the gene-targeted prevention of ovarian damage.
|Type of Chemotherapy||Agents||Target Disease||Mechanisms of Action|
|Interference with cell division via cross-linking of DNA;
Mitochondrial transmembrane potential reduction;
Inhibition of the accumulation of cytochrome c in the cytosol;
Induction of DSBs in oocytes
germ cell tumors,
|Inhibition of tubulin forming into microtubules;
Low gonadotoxic risk
ovarian cancer, gastrointestinal cancer
|Inhibition of purine, pyrimidine becoming incorporated into DNA; Inhibition of RNA synthesis;
Low gonadotoxic risk
head and neck cancer,
|DNA damage by the formation of DNA adducts, which interfere with cellular transcription and replication, leading to oocyte death.|
|Intercalation with DNA and prevention of its replication and transcription via the inhibition of topoisomerase II;
Upregulation of P53 protein which induces apoptosis;
DNA DSBs leading to activation of ATM, which initiates apoptosis
|Inhibition of DNA methylation and RNA and protein synthesis|
DSB, double-strand breaks.
Fertility preservation options can be personalized in terms of patient age, desire for conception, treatment regimen, and socioeconomic status . Such options include hormonal medications for ovarian suppression, cryopreservation, in vitro oocyte maturation, artificial ovaries, and stem cell technologies. Additionally, the potential ovarian protective effects of several genetic variants could be considered. Several established options including embryo cryopreservation and oocyte cryopreservation are already in clinical use. However, there are also experimental options including ovarian tissue cryopreservation, oocyte in vitro maturation, artificial ovary, and stem cell technologies .
A protective effect of reduced allele frequency of the Inha gene promoter was observed in patients with premature ovarian insufficiency . In a study involving ovarian insufficiency, increased expression levels of Mvh , Oct4 , Sod2 , Gpx , and Cat were detected after resveratrol treatment , implying that genes related to ovarian stem cell proliferation or anti-oxidative processes may help protect the ovary against chemotherapy-induced damage. An association between microRNA polymorphisms and the risk of premature ovarian insufficiency was also reported previously. Further investigations are warranted to identify significant protective genes against chemotherapy-induced ovarian damage.
Traditional biochemical markers for ovarian reserve include AMH level, follicle-stimulating hormone concentrations, inhibin-B level, and antral follicle count on ultrasound . However, due to the development of genetic testing, several candidate genes for ovarian insufficiency are being investigated . Fmr1 and Brca testing can be performed easily in genetic clinics. Patients with mutations in these genes are at a higher genetic risk at baseline . Evaluation of other frequent genetic variants, including Nobox , Figla , Bnc1 , Sohlh1 , Sohlh2 , Foxo3 , and Hfm1 , could help identify individuals with increased genetic risk of ovarian damage due to chemotherapy. Next-generation sequencing could be considered in ovarian reserve testing by using targeted gene panels, whole-exome sequencing, or whole-genome sequencing . The application of this technique is the future of genetic evaluation of patients who are at high risk of ovarian dysfunction after chemotherapy.
Ovarian tissue cryopreservation could be considered for fertility preservation in children or young patients with cancer who need immediate treatment and do not have enough time for ovarian stimulation. Using this technique, a large number of oocytes can be preserved, and the hormonal functions of the ovary can be protected . Slow freezing has been established as the preferred method for ovarian tissue cryopreservation rather than vitrification . Ovarian activity was restored in 92.9% of the cases after transplantation of cryopreserved ovarian tissue by using the slow-freezing method . Owing to the possible contamination of the ovarian tissue with malignant cells, this procedure is not utilized for patients with ovarian or hematologic malignancies .