Melatonin: its triple actions with antioxidative, anti-inflammatory and immunoregulatory potentials can help reduce Endometriosis

Posted By Braverman IVF & Reproductive Immunology || 13-April-2018

A recent study published in the American journal of Reproductive Immunology showed the beneficial role of Melatonin for women with Endometriosis.

The article is a systematic review summarizing the beneficial and pleiotropic impact that melatonin has on obstetrical and gynecological disorders including Endometriosis. Endometriosis is a benign gynecologic disorder, described as chronic, inflammatory and estrogen-dependent (1). It affects 11% of women of reproductive age worldwide (2) and is characterized by the presence of endometrial cells outside the endometrium (3). It is the most common gynecological disorder that may be present in up to 44% of asymptomatic women (4). A large proportion of women with endometriosis (up to 50%) experiences some degree of infertility (5) that can be trigger by:

  • anatomic distortion
  • diminished ovarian reserve
  • alteration of oocyte quality by inflammatory factors or disruption of the oocyte mitochondrial activity (for more information, read our blog on the topic)
  • peritoneal inflammation that can disrupt the endometrial receptivity

    Endometriosisis an inflammatory disease where high levels of pro-inflammatory cytokines such as Il-6, IL-8 or TNFa and high level oxidative stress as seen by levels of myeloperoxidase, an enzyme involved in the production of pro-oxidative molecules have been reported (6). Oxidative stress in the peritoneal cavity of endometriosis women is one of the main causes of infertility inducing:

  • lipid peroxidation
  • protein oxidation
  • DNA damage, greatly impacting oocyte quality Therefore, targeting oxidative stress may be a valid line of treatment for endometriosis (7).

    Melatonin is a hormone secreted by the pineal gland that controls the wake/sleep cycles, circadian rhythms and reproduction (8). Melatonin is by nature an agent able to pass through any cellular membranes. It is a potent anti-oxidant that prevents oxidative stress induced by reactive oxygen species. While melatonin has a direct effect on oxidative stress by scavenging ROS and RNS (9), its metabolites (product of its degradation) are also active and act indirectly by inducing the production of anti-oxidative enzymes and lowering the synthesis of pro-oxidative molecules (10) leading to an overall reduction of oxidative stress thus inducing a significant decrease in inflammation. Further, melatonin has immunostimulatory properties through its action on T helper (Th) lymphocytes and can also inhibit the secretion of the pro-inflammatory cytokine tumor necrosis factor α (TNFα) by monocytes (11).

    Many animal studies have shown the dramatic and positive effect of melatonin on Endometriosis as reported in the recent review. In a rat model for endometriosis where endometriotic implants were introduced by surgery (12), melatonin injection for 4 weeks causes a significant regression of lesions by decreasing angiogenesis, increasing tissue levels of antioxidants and reducing matrix metalloproteinases activity (enzyme enabling lesions invasiveness and adhesion).

    These results were confirmed in many independent studies (13-14) and further showed the melatonin dose-response effect (15) as well as its ability to decrease the endometriotic lesions recurrence rate (16). In a same way, in a rat model for endometriosis, a pinealectomy (ablation of the pineal gland) was associated with significant growth of endometrial explants and decreased antioxidant activity while melatonin supplementation reverses the progression of endometriosis implants (17).

    The effects of melatonin may directly impact the apoptosis process leading to the cell death in these growing lesions (18) and preventing peritoneal adhesion (19) in a rat model. Lastly, the only study in human (double-blind, placebo-controlled trial) showed that melatonin at a dose of 10mg/day is a proven medication in the treatment of pain associated with endometriosis and dysmenorrhea (20).

    Melatonin use is safe and did not show any teratogenic effects in both human and animal (21-22) as well as no toxicity (23) even at very high dose (5-20mg/day). Given the potential clinical benefits of melatonin and its safety, it is a target of choice to counteract oxidative stress, reduce inflammation and limit endometriotic lesions progression and recurrence.

    As world leader in the field of Reproductive Immunology, we have, at Braverman Reproductive Immunology, developed a dietary supplement “The Endo-Optimize” containing many ingredients including melatonin, with beneficial actions on reducing ROS and free-radicals’ production, reducing endometriotic lesions and their recurrence and enhancing oocyte maturation and quality. In addition, this “all in one” pill contains many other ingredients enhancing mitochondrial activity (a key component in oocyte development) and reducing inflammation thus allowing optimal microenvironment for the oocyte to develop and mature into a fertilizable egg (for more information read our blog “ENDO-optimize: an "all in one" dietary supplement with beneficial effects on egg quality, endometriosis and PCOS”).

    Our diet supplements are available for purchase.
    For more information about our supplements range, please consult our website. 

    Questions? Call 516.584.8710 We would be happy to help you take control of your fertility journey and answer any questions you may have. 


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    2- Giudice, L.C., Kao, L.C., 2004. Endometriosis. Lancet 364, 1789–1799.

    3- Buck Louis, G.M., Hediger, M.L., Peterson, C.M., Croughan, M., Sundaram, R., Stanford, J., Chen, Z., Fujimoto, V.Y., Varner, M.W., Trumble, A., Giudice, L.C., 2011. Incidence of endometriosis by study population and diagnostic method: the ENDO study. Fertil. Steril. 96, 360–365.

    4- Rawson JM. Prevalence of endometriosis in asymptomatic women. JRM 1991; 36:513–5.

    5- Pritts EA, Taylor RN. An evidence-based evaluation of endometriosis associated infertility. Endocrinol Metab Clin North Am 2003;32: 653–67.

    6- Riley CF, Moen MH, Videm V. Inflammatory markers in endometriosis: reduced peritoneal neutrophil response in minimal endometriosis. Acta Obstet Gynecol Scand. 2007; 86:877‐881.

    7- Harlev A, Gupta S, Agarwal A. Targeting oxidative stress to treat endometriosis. Expert Opin Ther Targets. 2015;19(11):1447-64.

    8- Cipolla-Neto J, Amaral FG, Afeche SC, Tan DX, Reiter RJ. Melatonin, energy metabolism, and obesity: a review. J Pineal Res. 2014;56(4):371-381.

    9- Tan DX, Chen LD, Poeggeler B, Manchester LC, Reiter RJ. Melatonin: a potent endogenous hydroxyl radical scavenger. Endocr J 1993; 1:57– 60.

    10- Reiter RJ, Tan DX, Manchester LC, El-Sawi MR. Melatonin reduces oxidant damage and promotes mitochondrial respiration implications for aging. Ann N Y Acad Sci 2002; 959:238–50.

    11- Calvo JR, Gonzalez-Yanes C, Maldonado MD. The role of melatonin in the cells of the innate immunity: a review. J Pineal Res. 2013; 55:103‐120.

    12- Güney M, Oral B, Karahan N, Mungan T. Regression of endometrial explants in a rat model of endometriosis treated with melatonin. Fertil Steril. 2008 Apr;89(4):934-42.

    13- Yilmaz B, Kilic S, Aksakal O, Ertas IE, Tanrisever GG, Aksoy Y, Lortlar N, Kelekci S, Gungor T. Melatonin causes regression of endometriotic implants in rats by modulating angiogenesis, tissue levels of antioxidants and matrix metalloproteinases. Arch Gynecol Obstet. 2015 Jul;292(1):209-16.

    14- Yesildaglar N, Yildirim G, Yildirim OK, Attar R, Ozkan F, Akkaya H, Yilmaz B. The effects of melatonin on endometriotic lesions induced by implanting human endometriotic cells in the first SCID-mouse endometriosis-model developed in Turkey. Clin Exp Obstet Gynecol. 2016;43(1):25-30.

    15- Cetinkaya N, Attar R, Yildirim G, et al. The effects of different doses of melatonin treatment on endometrial implants in an oophorectomized rat endometriosis model. Arch Gynecol Obstet. 2015; 291:591‐598.

    16- Yildirim G, Attar R, Ozkan F, Kumbak B, Ficicioglu C, Yesildaglar N. The effects of letrozole and melatonin on surgically induced endometriosis in a rat model: a preliminary study. Fertil Steril. 2010 Apr;93(6):1787-92.

    17- Koc O, Gunduz B, Topcuoglu A, Bugdayci G, Yilmaz F, Duran B. Effects of pinealectomy and melatonin supplementation onendometrial explants in a rat model. Eur J Obstet Gynecol Reprod Biol. 2010; 153:72‐76.

    18- Paul S, Bhattacharya P. Das Mahapatra P, Swarnakar S. Melatonin protects against endometriosis via regulation of matrix metalloproteinase-3 and an apoptotic pathway. J Pineal Res. 2010;49: 156‐168.

    19- Ozcelik B, Serin IS, Basbug M, Uludag S, Narin F, Tayyar M. Effect of melatonin in the prevention of post-operative adhesion formation in a rat uterine horn adhesion model. Hum Reprod. 2003; 18:1703‐1706.

    20- Schwertner A, Conceição Dos Santos CC, Costa GD, Deitos A, de Souza A, de Souza IC, Torres IL, da Cunha Filho JS, Caumo W. Efficacy of melatonin in the treatment of endometriosis: a phase II, randomized, double-blind, placebo-controlled trial. Pain. 2013 Jun;154(6):874-81.

    21- Staikou C, Kyrozis A, Moschovos C, Fassoulaki A: Effects of morning melatonin administration on electroencephalographic theta to alpha power ratio in reproductive versus postmenopausal healthy female volunteers. Neurosci Lett 2012, 507:90–93.

    22- Eryilmaz O, Devran A, Sarikaya E, Aksakal F, Mollamahmutoğlu L, Cicek N: Melatonin improves the oocyte and the embryo in IVF patients with sleep disturbances, but does not improve the sleeping problems. J Assist Reprod Genet 2011, 28:815–820.

    23- Batıoğlu A, Şahin U, Gürlek B, Öztürk N, Ünsal E: The efficacy of melatonin administration on oocyte quality. Gynecol Endocrinol 2012, 28:91–93.

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