Premature ovarian failure (POF), the premature aging of the ovaries, manifests itself by secondary amenorrhea before the age of 40, with follicle-stimulating hormone levels >40 u/L (1), estradiol levels <20 pg/mL, and low anti-Mullerian hormone values close to 0 ng/mL (2). In addition, ultrasound examinations show no follicles in the ovary and often an atrophic shrunken uterus with a thin endometrium. The etiology of POF is complex and unclear in most patients, but may be related to autoimmune factors, infections, or drugs. Common treatment drugs causing POF include platinum compounds, antimetabolic drugs, and antibiotics. The widely used platinum drugs bind covalently to ovarian DNA, form cross-links between DNA chains, and lead to follicle DNA cleavage during replication, thereby inhibiting follicle DNA transcription and synthesis; however, these toxic effects are not specific to primordial follicles (3). Researchers have suggested that high cisplatin doses can induce hyperactivation of primordial follicles during quiescent states, resulting in loss of ovarian reserve function (4). 2 Cytotoxic mechanisms of cisplatin.

Cisplatin is a common tumor therapeutic agent available only with a medical prescription due to its toxicity and side effects. Studies have suggested that platinum compounds can be used in cancer therapy, and that these drugs have cytotoxic effects (5). Cisplatin has strong cytotoxic effects that can destroy cancer cells, through its effects on DNA metabolism ( Figure 1 ). The drug hydrolyzes in the cell mainly according to the concentration state and the carrier protein channel on the surface of the cell membrane, and then produces binding reaction with other substances. For example, adenosine triphosphate is transported through the endoplasmic reticulum along with cisplatin, glutathione (GSH), and L-cysteine. The fusion of cisplatin with GSH, cysteine (L(+)-Cysteine), and other proteins leads to the depletion of antioxidant reserves in the cytoplasm and causes cellular oxidative stress, which is the major mode of action of cisplatin toxicity. Oxidative stress affects antioxidant enzymes and other molecules, reduces GSH, and increases cisplatin toxicity (6). When cisplatin enters cancer cells, it activates reactive oxygen species pathways, resulting in apoptosis. Cisplatin hydrolysates fuse with DNA bases in the nucleus, and these complexes get identified by the nucleotide excision repair protein (NER), and the mismatch repair (MMR) and Pt-DNA complexes. HMG1 (High Mobility Group 1) and HMG2 (High Mobility Group 2) are two highly conserved nuclear proteins, which play an important role in a variety of biological processes such as DNA repair and apoptosis, and can improve the effect of cisplatin therapy, which includes the following aspects (7): First, the differentiation of in-strand DNA complexes between similar guanines can change the cell cycle activity and induce death. Second, these proteins accelerate the binding of p53 and DNA to induce trans-activation of target genes involved in cell cycle development, DNA repair, and cell apoptosis. Third, they inhibit Pt-DNA complex repair enhancing cisplatin efficacy. NER is an effective enzyme clearing Pt-DNA complexes. If NER is defective, cells become hypersensitive to cisplatin. MMR protein complexes repair DNA damage, but not cisplatin–DNA complexes, and unsuccessful repair initiates cell death. In summary, DNA damage activates multiple cellular signaling pathways that cause cell death. Recent studies have elucidated potential mechanisms of chemotherapy-induced ovarian damage, including DNA damage, oxidative stress, mitochondrial dysfunction, and apoptotic signalling abnormalities induced by cisplatin and other chemotherapeutic agents (8, 9).

Cisplatin produces toxicity and side effects, which affect the clinical outcome of patients. Researchers administering cisplatin (5 mg/kg) to rats found marked toxic effects related to the dosage and timing in relation to their sexual cycle (23). The concentration of the medication, the administration route, and the age of patients also affect the actions of cisplatin. During treatment, cisplatin kills many rapidly dividing cells, the endocrine system is greatly affected, and the resulting ovarian dysfunction may be irreversible. Cisplatin combines with DNA to form complexes between and within the chain, affecting cell transcription and causing DNA damage. If left untreated, the drug activates cell-death signaling pathways. Studies have confirmed that the drug can induce ovarian cell death and tissue necrosis (24). In addition, cisplatin activates the non-receptor tyrosine kinase (Abl) and downstream p53 homologous protein in mouse ovarian blast cells, which continuously aggregate to cause oocyte death. Oocyte apoptosis can be reduced by treatment with an Abl activity blocker (18). Cisplatin also activates mitochondrial pathways that release cytochrome C into the cytoplasm leading to caspase pathway activation, which causes a stress response and cell death (25).

Due to the significant renal toxicity of cisplatin therapy, pre-treatment hydration therapy must be initiated before the treatment (26): A large infusion needs to be given 2–16 hours before and at least 6 hours after the cisplatin administration. In addition, patients need to drink plenty water and undergo diuretic treatments to ensure a daily urine volume within 2000–3000 mL. Changes in blood potassium and magnesium concentrations also need monitoring to avoid kidney function injury and cardiac burden. The discussion on side effects mitigation strategies was removed to align with the focus on POF.

For gastrointestinal toxicity causing nausea and vomiting, antiemesis drugs can be used before the medication, a four-drug combination regimen consisting of NK1 receptor antagonist, 5-HT3 receptor antagonist, dexamethasone, and olanzapine has been recommended by the American Society of Clinical Oncology guidelines (27).

For hematological toxicity, granulocyte colony stimulating factor (G-CSF), recombinant human platelet growth factor, erythropoietin (EPO) and other drugs can be used to treat the symptoms, the chemotherapy doses can be adjusted, or blood transfusions may be required (28).

The neurotoxicity caused by cisplatin treatment cannot be avoided. Some neuroprotectants may be effective, such as α-lipoic acid (29), but their value needs to be validated by clinical studies.

Platinum anticancer drugs such of cisplatin are cell cycle non-specific drugs that act on the cellular DNA. During clinical treatments, these drugs affect ovarian function and cause ovarian impairment that can lead to POF. POF is the main factor affecting female infertility. However, POF can progress without clear manifestations, and clinical diagnoses are mostly made during later stages of the disease. POF diversity and the genetic heterogeneity in women may contribute to the regulation of ovarian function. Therefore, understanding the genetic mechanisms of POF may lead to early detection and improvements in treatments for the condition. Knowledge of the chemotherapy-related effects can be used to prevent disease occurrences and provide a reliable basis for clinical treatments.

ZL: Writing – original draft, Writing – review & editing. HQ: Writing – original draft. ZL: Writing – original draft. YB: Writing – review & editing. KY: Writing – review & editing. QM: Supervision, Writing – review & editing.