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.

Keywords: animal studies; anti-inflammatory; clinical trials; endometriosis; in vitro studies; inflammatory disease; melatonin.

Figure 2

Forest plots of effectiveness of melatonin treatment compared with control in endometriosis. Forest plot of included studies comparing the effect of exogenous melatonin (10 mg/kg) in a rat model of endometriosis. (A) Lesion size at 2 weeks [50,51,61]. (B) Lesion size at 4 weeks [50,58,61,62]. (C) Histopathological score after 2 weeks [50,51,61]. (D) Histopathological score after 4 weeks [50,58,61,62]. (E) Level of superoxide dismutase (SOD) after 2 weeks [50,58,62].

Figure 1

Therapeutic targets of melatonin toward inhibiting the development and progression of endometriosis. The effect of melatonin with respect to various molecular targets involved in the processes of endometriosis, including adhesion, invasion, EMT, oxidative stress, angiogenesis, and chronic pelvic pain. Abbreviations: MMP, Matrix metalloproteinase; TIMP, Tissue inhibitors of metalloprotease; EMT, Epithelial–mesenchymal transition; MDA, Malondialdehyde; COX-2, Cyclooxygenase 2; SOD, Superoxide dismutase; CAT, Catalase; VEGF, Vascular endothelial growth factor; BDNF, Brain-derived neurotrophic factor.