Melatonin in Endometriosis: Mechanistic Understanding and Clinical Insight

Abstract

Endometriosis is defined as the development of endometrial glands and stroma outside the uterine cavity. Pathophysiology of this disease includes abnormal hormone profiles, cell survival, migration, invasion, angiogenesis, oxidative stress, immunology, and inflammation. Melatonin is a neuroendocrine hormone that is synthesized and released primarily at night from the mammalian pineal gland. Increasing evidence has revealed that melatonin can be synthesized and secreted from multiple extra-pineal tissues where it regulates immune response, inflammation, and angiogenesis locally. Melatonin receptors are expressed in the uterus, and the therapeutic effects of melatonin on endometriosis and other reproductive disorders have been reported. In this review, key information related to the metabolism of melatonin and its biological effects is summarized. Furthermore, the latest in vitro and in vivo findings are highlighted to evaluate the pleiotropic functions of melatonin, as well as to summarize its physiological and pathological effects and treatment potential in endometriosis. Moreover, the pharmacological and therapeutic benefits derived from the administration of exogenous melatonin on reproductive system-related disease are discussed to support the potential of melatonin supplements toward the development of endometriosis. More clinical trials are needed to confirm its therapeutic effects and safety.

The Importance of Natural Antioxidants in Female Reproduction

“…Melatonin (N-acetyl-5-methoxytryptamine) is a naturally occurring peptide hormone secreted by the pineal gland and multiple extra-pineal tissues (e.g., uterus, ovaries, and placenta) involved in the regulation of response to darkness, immune responses, inflammation, and microenvironmental angiogenesis [ 108 ]. Therefore, it is involved in the regulation of the sleep cycle and in multiple biological functions such as the metabolism of lipids, saccharides and the immune response [ 109 ].…”

“…Therefore, it is involved in the regulation of the sleep cycle and in multiple biological functions such as the metabolism of lipids, saccharides and the immune response [ 109 ]. Melatonin was shown to decrease OS, inflammation processes, and apoptosis [ 108 ]. It is directly involved in the detoxification of ROS and NOS, and is indirectly involved in the stimulation of enzymatic antioxidants and the suppression of pro-oxidants [ 110 ].…”

“…It is directly involved in the detoxification of ROS and NOS, and is indirectly involved in the stimulation of enzymatic antioxidants and the suppression of pro-oxidants [ 110 ]. Melatonin was shown to downregulate COX-2 protein levels and upregulate SOD, GPx, CAT, and Bcl-2 activity, possibly via upregulating the Nrf2 signaling pathway [ 108 ]. Melatonin has an important role in female reproduction during childhood and puberty when it controls women’s reproductive endocrinological system [ 111 ] and affects the ovulation process [ 108 ].…”

“…Melatonin was shown to downregulate COX-2 protein levels and upregulate SOD, GPx, CAT, and Bcl-2 activity, possibly via upregulating the Nrf2 signaling pathway [ 108 ]. Melatonin has an important role in female reproduction during childhood and puberty when it controls women’s reproductive endocrinological system [ 111 ] and affects the ovulation process [ 108 ]. Melatonin levels and fertility both decrease with age, [ 111 ] and these two processes could be linked.…”

Perspective Chapter: Ovarian Reproductive Aging and Rejuvenation Strategies

“…Melatonin is a chemical that functions as both a direct antioxidant and a modulator of the mechanisms defending cells against oxidative stress. It was initially utilized in reproductive medicine to treat endometriosis and adenomyosis-related infertility [33,34,127,128]. Since then, fresh research has shown how melatonin may delay the aging of the ovary [36].…”