Melatonin and Fertoprotective Adjuvants: Prevention against Premature Ovarian Failure during Chemotherapy

Abstract

Premature ovarian failure is one of the side effects of chemotherapy in pre-menopausal cancer patients. Preservation of fertility has become increasingly important in improving the quality of life of completely recovered cancer patients. Among the possible strategies for preserving fertility such as ovarian tissue cryopreservation, co-treatment with a pharmacological adjuvant is highly effective and poses less of a burden on the human body. Melatonin is generally produced in various tissues and acts as a universally acting antioxidant in cells. Melatonin is now more widely used in various biological processes including treating insomnia and an adjuvant during chemotherapy. In this review, we summarize the information indicating that melatonin may be useful for reducing and preventing premature ovarian failure in chemotherapy-treated female patients. We also mention that many adjuvants other than melatonin are developed and used to inhibit chemotherapy-induced infertility. This information will give us novel insights on the clinical use of melatonin and other agents as fertoprotective adjuvants for female cancer patients.

Keywords: chemotherapy; fertoprotective adjuvant; melatonin; premature ovarian failure.

Figure 1

Schematic model for chemotherapy-induced oocyte death via the TAp63 signaling pathway. Cisplatin treatment causes DNA damage in oocytes and induces a surveillance factor, Chk2, followed by activation of NOXA, PUMA, and TAp73. Therefore, DNA-damaged oocytes undergo programmed cell death. However, imatinib and S1P rescue these DNA-damaged oocytes via inactivation of the TAp63 signaling pathway. Black arrow: activation; red T bar: suppression.

Figure 2

Schematic model for regulation of primordial follicle activation via the PI3K signaling pathway. Cisplatin induces activation of the PI3K/AKT/GSK/FOXO3a pathway via a phosphorylation cascade leading to activation of dormant primordial follicles. However, melatonin suppresses cisplatin-induced activation by inducing PTEN activity and inhibiting FOXO3a phosphorylation, thereby resulting in the expression of p27^Kip1, CDK inhibitor, during chemotherapy. Black arrow: activation; red T bar: suppression; dotted line T bar: possible inhibition; red arrow: inactivation; blue arrow: transcription.