Polycystic Ovarian Syndrome
Polycystic Ovarian Syndrome (PCOS) is a gynecological, endocrine disorder affecting 5–10% of women. It is a multifactorial disease with increased androgens, hirsutism, acne, insulin resistance, central obesity, amenorrhea or oligomenorrhea, poor sleep, anovulation, and decreased fertility (1). Melatonin is relevant for PCOS given that not only are there melatonin receptors on the cells as in other tissues, but melatonin is synthesized in the oocytes, ovarian follicular cells, and cytotrophoblasts of the placenta (2). As discussed above, melatonin and its metabolites are powerful antioxidants that can preserve oocyte quality.
Both the circadian pattern and levels of melatonin are altered in PCOS. In adolescents with PCOS compared to control participants, melatonin offset is later in terms of both clock time and their wake time, while melatonin duration is longer. In adolescents with and without PCOS, later melatonin offset is associated with increased serum-free testosterone levels and worse insulin sensitivity. This finding suggests that morning circadian misalignment may be part of the pathophysiology of PCOS (3). Other studies have found that melatonin patterns are altered in PCOS with higher serum levels but decreased follicular fluid levels, typically higher than serum levels (4). A meta-analysis including 2553 women with PCOS and 3152 control women found that two nucleotide polymorphisms in the melatonin receptor 1A and 1B genes are significantly associated with PCOS (5). A pilot study of university women with PCOS demonstrated that the level of urinary melatonin concentration was dependent on PCOS status. Further, women with PCOS had lower weekend sleep efficiency compared to the control group (6).
Six months of melatonin treatment in forty normal-weight women with PCOS causes meaningful hormone changes. Androgens, free testosterone, hydroxyprogesterone, anti-Mullerian hormone, and low-density lipoprotein all significantly decreased, while there was no change in other lipid parameters or glucoinsulinemic measures. Menstrual irregularities decreased in 95% of the women (7). This result is due to a direct effect of melatonin on the ovaries that is independent of insulin. In an eight-week trial, eighty-four participants with PCOS received either melatonin, magnesium, melatonin plus magnesium, or a placebo. Melatonin alone significantly improved subjective sleep as measured by the Pittsburgh Sleep Quality Index (PSQI) and serum high-density lipoprotein cholesterol. When melatonin and magnesium were taken together, it resulted in a significant decrease in insulin, cholesterol, low-density lipoprotein cholesterol, and testosterone levels (8). In a randomized, double-blind, placebo-controlled study of fifty-eight women (ages 18–40 years old) they took either 10 mg of melatonin or a placebo an hour before bed for twelve weeks. Results at the end of the intervention found improvements in the melatonin group compared to placebo for mental health on the Beck Depression and Beck Anxiety Inventories. Subjective sleep quality improved on the PSQI. Lab analysis showed improvements for the melatonin group, including decreased homeostasis model of assessment-insulin resistance (HOMA-IR), serum insulin, total and LDL-cholesterol, and increased quantitative insulin sensitivity check index. Additionally, those who took melatonin had upregulation of genes for the low-density lipoprotein receptor and peroxisome proliferator-activated receptor gamma (7).
Authors: Deanna Minich, Ph.D., Melanie Henning, ND, Catherine Darley, ND, Mona Fahoum, ND, Corey B. Schuler, DC, James Frame
Reviewer: Peer-review in Nutrients Journal
Last updated: October 31, 2023
References
1. Khan MJ, Ullah A, Basit S. Genetic basis of polycystic ovary syndrome (PCOS): Current perspectives. Vol. 12, Application of Clinical Genetics. 2019.
2. Reiter RJ, Tan DX, Tamura H, Cruz MHC, Fuentes-Broto L. Clinical relevance of melatonin in ovarian and placental physiology: A review. Gynecological Endocrinology. 2014;30(2).
3. Simon SL, McWhirter L, Diniz Behn C, Bubar KM, Kaar JL, Pyle L, et al. Morning Circadian Misalignment Is Associated with Insulin Resistance in Girls with Obesity and Polycystic Ovarian Syndrome. Journal of Clinical Endocrinology and Metabolism. 2019;104(8).
4. Li H, Liu M, Zhang C. Women with polycystic ovary syndrome (PCOS) have reduced melatonin concentrations in their follicles and have mild sleep disturbances. BMC Womens Health. 2022;22(1).
5. Yi S, Xu J, Shi H, Li W, Li Q, Sun YP. Association between melatonin receptor gene polymorphisms and polycystic ovarian syndrome: A systematic review and meta-analysis. Vol. 40, Bioscience Reports. 2020.
6.Evans AT, Brink H Vanden, Lim JS, Jarrett BY, Lujan ME, Hoeger KM. Overnight Melatonin Concentration and Sleep Quality Are Associated With Clinical Features of Polycystic Ovary Syndrome. J Endocr Soc. 2021;5(Supplement_1).
7. Tagliaferri V, Romualdi D, Scarinci E, Cicco S de, Florio C di, Immediata V, et al. Melatonin Treatment May Be Able to Restore Menstrual Cyclicity in Women With PCOS: A Pilot Study. Reproductive Sciences. 2018;25(2).
8. Alizadeh M, Karandish M, Asghari Jafarabadi M, Heidari L, Nikbakht R, Babaahmadi Rezaei H, et al. Metabolic and hormonal effects of melatonin and/or magnesium supplementation in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Nutr Metab (Lond). 2021;18(1).