Figure 1.

Melatonin, which is nocturnally produced in and secreted by the pineal gland and in a non-circadian manner by the mitochondria of other cells, including those that are components of the ovary, is proposed as a critical factor in protecting against premature infertility and reproductive cessation. Moreover, published evidence indicates that supplementation with melatonin delays ovarian aging in animals and lowers the frequency of infertility in humans. In reference to melatonin’s protective actions against reproductive collapse, the figure summarizes the multiple receptor-independent and receptor-dependent processes that interfere with especially oxidative stress-mediated ovarian deterioration with the critical cells undergoing apoptosis. In addition to directly scavenging ROS/RNS and indirectly lowering oxidative damage by upregulating antioxidative enzymes and downregulating pro-oxidant enzymes, melatonin binds redox reactive metal ions to limit the Fenton and Haber–Weiss reactions thereby reducing the production of the highly toxic hydroxyl radical. Red arrows indicate inhibition; green arrows indicate stimulation. The bottom panel illustrates what has come to be known as melatonin’s antioxidant cascade as a radical scavenger. Thus, not only is melatonin a direct radical scavenger, but so are its metabolites, cyclic 3-hydroxymelatonin (c3OHM), N-acetyl-N-formyl-5-methoxykynuramine (AFMK), N-acetyl-5-methoxykynuramine (AMK) and possibly others. Moreover, relative to some reactive species (ROS, reactive oxygen species: RNS, reactive nitrogen species), the metabolites are more effective scavengers than melatonin itself. ¹O₂ superoxide anion radical; H₂O₂, hydrogen peroxide; ^•OH, hydroxyl radical; NO^•, nitric oxide; ONOO⁻, peroxynitrite anion; ¹O₂, singlet oxygen; LOO^•, lipid peroxyl radical. MnSOD, manganese superoxide dismutase; CuSOD, copper superoxide dismutase; GPx, glutathione peroxidase; GR, glutathione reductase; CAT, catalase; γ-GC, gamma-glutamylcysteine synthase.