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Melatonin is a promising reagent that can improve assisted reproductive technology (ART) outcomes in infertility patients. However, melatonin is not effective for all infertile patients, and it remains unclear for which patients melatonin would be effective. This study examined the effects of melatonin on ART outcomes and examined its mechanisms. Melatonin increased the fertilization rate in patients whose fertilization rates in the previous cycle were less than 50%, but not in patients whose fertilization rates were more than 50% in the previous cycle. Melatonin increased the blastocyst formation rate in patients whose embryo development rates in the previous cycle were less than 50%, but not in patients whose embryo development rates were more than 50% in the previous cycle. To clarify its mechanisms, transcriptome changes by melatonin treatment in granulosa cells (GCs) of the patients were examined by RNA-sequence. Melatonin treatment altered the transcriptomes of GCs of patients with poor ART outcomes so that they were similar to the transcriptomes of patients with good ART outcomes. The altered genes were associated with the inhibition of cell death and T-cell activity, and the activation of steroidogenesis and angiogenesis. Melatonin treatment was effective for patients with poor fertilization rates and poor embryo development rates in the previous ART cycle. Melatonin alters the GCs transcriptome and, thus, their functions, and this could improve the oocyte quality, leading to good ART outcomes.

Women usually experience body weight gain with aging, which can put them at risk for many chronic diseases. Previous studies indicated that melatonin treatment attenuates body weight gain and abdominal fat deposition in several male animals. However, it is unclear whether melatonin affects female animals in the same way. This study investigated whether long-term melatonin treatment can attenuate body weight gain with aging and, if it does, what the mechanism is. Ten-week-old female ICR mice were given melatonin-containing water (100 μg/mL) or only water until 43 weeks. Melatonin treatment significantly attenuated body weight gain at 23 weeks (control; 57.2 ± 2.0 g vs melatonin; 44.4 ± 3.1 g), 33 weeks (control; 65.4 ± 2.6 g vs melatonin; 52.2 ± 4.2 g) and 43 weeks (control; 66.1 ± 3.2 g vs melatonin; 54.4 ± 2.5 g) without decreasing the amount of food intake. Micro-CT analyses showed that melatonin significantly decreased the deposition of visceral and s.c. fat. These results suggested that melatonin attenuates body weight gain by inhibiting abdominal fat deposition. Metabolome analysis of the liver revealed that melatonin treatment induced a drastic change in the metabolome with the downregulation of 149 metabolites, including the metabolites of glucose and amino acids. Citrate, which serves as a source of de novo lipogenesis, was one of the downregulated metabolites. These results show that long-term melatonin treatment induces drastic changes in metabolism and attenuates body weight gain and fat deposition with aging in female mice.

Melatonin is probably produced in all cells but is only secreted by the pineal gland. The pineal secretion of melatonin is determined by the light-dark cycle, and it is only released at night. Melatonin regulates biological rhythms via its receptors located in the suprachiasmatic nuclei of the hypothalamus. Melatonin also has strong antioxidant activities to scavenge free radicals such as reactive oxygen species (ROS). The direct free radical scavenging actions are receptor independent. ROS play an important role in reproductive function including in the ovulatory process. However, excessive ROS can also have an adverse effect on oocytes because of oxidative stress, thereby causing infertility. It is becoming clear that melatonin is located in the ovarian follicular fluid and in the oocytes themselves, which protects these cells from oxidative damage as well as having other beneficial actions in oocyte maturation, fertilization, and embryo development. Trials on humans have investigated the improvement of outcomes of assisted reproductive technology (ART), such as in vitro fertilization and embryo transfer (IVF-ET), by way of administering melatonin to patients suffering from infertility. In addition, clinical research has examined melatonin as an anti-aging molecule via its antioxidative actions, and its relationship with the aging diseases, e.g., Alzheimer's and Parkinson's disease, is also underway. Melatonin may also reduce ovarian aging, which is a major issue in assisted reproductive technology. This review explains the relationship between melatonin and human reproductive function, as well as the clinical applications expected to improve the outcomes of assisted reproductive technology such as IVF, while also discussing possibilities for melatonin in preventing ovarian aging.