Melatonin may help improve treatment of women with infertility

Hormone that regulates sleep plays a key role in ovarian follicle growth, researchers report.

By Diego Freire  |  Agência FAPESP – Researchers at the University of São Paulo’s Medical School (FM-USP) in Brazil have found that melatonin, a hormone whose main function in humans is sleep regulation, plays an important role in ovarian follicle growth. The discovery may help improve the treatment of women with infertility.

In addition to regulating several cellular functions, melatonin is responsible for conveying information about the duration of the daily photoperiod throughout the body. It transmits information on variations in the light during the day and night throughout the year and enables the organism to adapt to changes in the environment. The suspicion that melatonin could be linked to ovarian follicle maturation arose from the observation that the concentration of melatonin is three times higher in follicular fluid than in the bloodstream. In addition, follicular cells contain melatonin receptors.

“Angiogenesis is an essential process for the growth of gap junctions, channels of cylindrical particles that enable direct communication between cells to ensure that they function in a coordinated and harmonious manner. This process allows nutrients and growth factors to reach the follicular structures and trigger the secretion of sex steroids by follicular cells. So, follicular angiogenesis is important to the quality of follicles and oocytes. We discovered that melatonin’s participation in this process modulates the growth of ovarian follicles, the basic units of the female reproductive system,” said José Maria Soares Junior, Associate Professor of Gynecology and Vice Head of FM-USP’s Department of Obstetrics & Gynecology.

The research project “The effect of melatonin on the angiogenesis of granulosa cells in infertile women submitted to a program of in vitro fertilization”, supported by FAPESP with Soares Junior as the principal investigator, evaluated the pathways activated by melatonin in this process and concluded that, in high concentrations, melatonin also boosts expression of growth factors and cytokines, proteins that modulate the functioning of other cells or the cells from which they originate.

According to Soares Junior, there were already reports in the scientific literature that melatonin could contribute to the maturation of the oocyte, the female germ cell that becomes a mature ovum, by interfering with ovarian function. His PhD research at the Federal University of São Paulo (UNIFESP) focused on characterizing melatonin receptors in the ovaries of rats and their interaction with estrogen, a hormone that helps control ovulation.

The research carried out at FM-USP showed that certain concentrations of melatonin in the follicular cells of women who had been submitted to ovarian stimulation controlled estrogen metabolism and other substances related to VGS, a growth factor that is associated with cell proliferation and plays a key role in follicle and oocyte maturation.

To arrive at these results, between February 2014 and March 2016, the researchers cultured ovarian follicle granulosa cells and treated them with melatonin in the laboratory. For this experiment, they selected 20 patients aged 20-35 years who were being treated at FM-USP’s human reproduction unit. Granulosa cells due to be discarded during the fertilization process were removed for in vitro cultivation and divided into four groups, three of which were treated with different concentrations of melatonin. One group was left untreated.

Between March 2015 and April 2016, granulosa cells obtained from 68 other patients in the same age group were submitted to a new round of studies. The effect of melatonin was verified in all cells submitted to treatment in both rounds, with angiogenesis increasing between 30% and 80% in accordance with the melatonin concentration. In addition to proving the effect of melatonin, the researchers calculated the ideal concentration for treatment.

“The results show that melatonin plays an important role in the regulation of follicle growth, potentially leading to better oocyte quality, and suggest a possible treatment for women with infertility due to low levels of melatonin or problems in granulosa receptors,” Soares Junior said.

He added that more research is needed to determine whether increasing the melatonin concentration in the follicular fluid could result in better quality embryos.

The results of this research and a discussion of other effects of melatonin are described in the article, “Melatonin influence in ovary transplantation: systematic review”, published by the Journal of Ovarian Research and available at ovarianresearch.biomedcentral.com/articles/10.1186/s13048-016-0245-8. In addition to Soares Junior, the authors are Marcos Shiroma, a graduate student in FM-USP’s obstetrics and gynecology program; Luciana Lamarão Damous, a postdoctoral fellow at the same institution’s Structural & Molecular Gynecology Laboratory (LIM); Edmund Chada Baracat, a full professor of gynecology there; and Nara Macedo Botelho, a postdoctoral researcher in gynecology and a professor at the Federal University of Pará’s Medical School (FM-UFPA).

Other collaborators in the studies include Carla Cristina Maganhin, whose research project “Analysis of melatonin in women with infertility and submitted to program of in vitro fertilization: functional study in granulosa cells” is supported by FAPESP, and José Cipolla Neto, a full professor of physiology at the University of São Paulo’s Biomedical Science Institute (ICB-USP).