Clinical Strategies for Counteracting Human Ovarian Aging: Molecular Background, Update, Outlook

Ovarian aging (OA) results from senescence of different cell types present in the ovary, decreases female fertility and quality of life and augments the risk of a variety of fertility-unrelated pathological conditions. The changes observed in the ovarian cells are accompanied by those oc-curring in various elements of the hypothalamic-pituitary-ovarian (HPO) axis, the complex endo-crine system that regulates the female reproductive cycle. Issues of the HPO axis were addressed in animal models by hormonal treatments with preparations inhibiting ovarian follicular recruitment at the level of receptors of gonadotropin-releasing hormone (GnRH)-secreting neurons, mainly acting on glutamate- and gamma-aminobutyric acid (GABA)-driven signalling. GnRH agonists and antagonists were also used in women exposed to chemotherapeutics. HPO-independent OA can be delayed by the administration of different antioxidants and mitochondria-protecting agents, among which melatonin was shown to be particularly useful. Other therapeutic approaches used with success in women include hormonal and growth factor (GF) modulators, such as growth hormone (GH), insulin-like growth factor 1 (IGF-1), vascular endothelial growth factors (VEGF) and dehydroepiandrosterone (DHEA), and the development of patient-tailored combination-based therapies (IGF-1 + VEGF + DHEA) was suggested. Intraovarian injection of autologous platelet-rich plasma (PRP), mitochondrial donation through pronuclear transfer, and ovarian tissue cryopre-servation and autotransplantation also gave promising results in women, and their use can protect not only fertility but also the ovarian endocrine function. Personalized mixtures of specific agents (desatinib, quercetin, rapamycin, metformin, resveratrol, melatonin, and coenzyme Q10) targeting different cell types of the ovary are currently under investigation.