The objective of the study was to investigate the effects of 6 months of melatonin administration on clinical, endocrine, and metabolic features of women affected by polycystic ovary syndrome (PCOS). This is a prospective cohort study including 40 normal-weight women with PCOS between January and September 2016, enrolled in an academic research environment. Ultrasonographic pelvic examinations, hirsutism score evaluation, hormonal profile assays, oral glucose tolerance test, and lipid profile at baseline and after 6 months of melatonin administration were performed. Melatonin treatment significantly decreased androgens levels (free androgen index: P < .05; testosterone: P < .01; 17 hydroxyprogesterone: P < .01). Follicle-stimulating hormone levels significantly raised (P < .01), and anti-Mullerian hormone serum levels significantly dropped after 6 months of melatonin treatment (P < .01). No significant changes occurred in glucoinsulinemic and lipid parameters after treatment except a significant decrease of low-density lipoprotein cholesterol. Almost 95% of participants experienced an amelioration of menstrual cycles. Until now, only few data have been published about the role of melatonin in women with PCOS. This is the first study focused on the effects of exogenous oral melatonin administration on the clinical, endocrine, and metabolic characteristics of patients with PCOS. After 6 months of treatment, melatonin seems to improve menstrual irregularities and biochemical hyperandrogenism in women with PCOS through a direct, insulin-independent effect on the ovary. Based on our results, melatonin could be considered a potential future therapeutic agent for women affected by PCOS.
GlueckCJPapannaRWangPGoldenbergNSieve-SmithL. Incidence and treatment of metabolic syndrome in newly referred women with confirmed polycystic ovarian syndrome. Metabolism. 2003;52(7):908–915.
2.
PasqualiRStener-VictorinEYildizBO. PCOS Forum: research in polycystic ovary syndrome today and tomorrow. Clin Endocrinol. 2011;74(4):424–433.
3.
GonzálezFRoteNSMiniumJKirwanJP. Reactive oxygen species-induced oxidative stress in the development of insulin resistance and hyperandrogenism in polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91(1):336–340.
4.
TamuraHTakasakiATakeaniT. Melatonin as a free radical scavenger in the ovarian follicle. Endocr J. 2013;60(1):1–13.
5.
GonzalezFRoteNSMiniumJKirwanJP. Reactive oxygen species induced oxidative stress in the development of insulin resistance and hyperandrogenism in polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91(1):336–340.
6.
SabuncuTVuralHHarmaMHarmaM. Oxidative stress in polycystic ovary syndrome and its contribution to the risk of cardiovascular disease. Clin Biochem. 2001;34(5):407–413.
7.
Cipolla-NetoJAmaralFGAfecheSCTanDXReiterRJ. Melatonin, energy metabolism, and obesity: a review. J Pineal Res. 2014;56(4):371–381.
8.
CassoneVMNatesanAK. Time and time again: the phylogeny of melatonin as a transducer of biological time. J Biol Rhythms. 1997;12(6):489–497.
9.
BrzezinskiASeibelMMLynchHJDengMHWurtmanRJ. Melatonin in human preovulatory follicular fluid. J Clin Endocrinol Metab. 1987;64(4):865–867.
10.
RonnbergLKauppilaALeppäluotoJMartikainenHVakkuriO. Circadian and seasonal variation in human preovulatory follicular fluid melatonin concentration. J Clin Endocrinol Metab. 1990;71(2):492–496.
11.
NakamuraYTamuraHTakayamaHKatoH. Increased endogenous level of melatonin in preovulatory human follicles does not directly influence progesterone production. Fertil Steril. 2003;80(4):1012–1016.
12.
ItohMTIshizukaBKuribayashiYAmemiyaASumiY. Melatonin, its precursors, and synthesizing enzyme activities in the human ovary. Mol Hum Reprod. 1999;5(5):402–408.
13.
TanavdeVSMaitraA. In vitro modulation of steroidogenesis and gene expression by melatonin: a study with porcine antral follicles. Endocr Res. 2003;29(4):399–410.
14.
JainPJainMHaldarCSinghTBJainS. Melatonin and its correlation with testosterone in polycystic ovarian syndrome. J Hum Reprod Sci. 2013;6(4):253–258.
15.
Prata LimaMFBaracatECSimoesMJ. Effects of melatonin on the ovarian response to pinealectomy or continuous light in female rats: similarity with polycystic ovary syndrome. Braz J Med Biol Res. 2004;37(7):987–995.
16.
TamuraHNakamuraYKorkmazA. Melatonin and the ovary: physiological and pathophysiological implications. Fertil Steril. 2009;92(1):328–343.
17.
AdriaensIJacquetPCortvrindtRJanssenKSmitzJ. Melatonin has dose-dependent effects on folliculogenesis, oocyte maturation capacity and steroidogenesis. Toxicology. 2006;228(2-3):333–343.
Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2003;19(1):41–47.
20.
PeterkinBB. Dietary Guidelines for Americans, 1990 edition. J Am Diet Assoc. 1990;90(12):1725–1727.
21.
TaylorRWKeilDGoldEJWilliamsSMGouldingA. Body mass index, waist girth, and waist to hip ratio as indexes of total and regional adiposity in women: evaluation using receiver operating characteristic curves. Am J Clin Nutr. 1998;67(1):44–49.
22.
FerrimanDGallweyJD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab. 1961;21:1440–1447.
23.
National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes. 1979;28(12):1039–1057.
24.
MatthewsDRHoskerJPRudenskiASNaylorBATreacherDFTurnerRC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–419.
25.
CiampelliMLeoniFCucinelliF. Assessment of insulin sensitivity from measurements in the fasting state and during an oral glucose tolerance test in polycystic ovary syndrome and menopausal patients. J Clin Endocrinol Metab. 2005;90(3):1398–1406.
26.
LaaksoM. How good a marker is insulin level for insulin resistance?Am J Epidemiol. 1993;137(9):959–965.
27.
OrsiniLFVenturoliSLorussoRPluchinottaVParadisiRBovicelliL. Ultrasonic findings in polycystic ovarian disease. Fertil Steril. 1985;43(5):709–714.
28.
CiampelliMFulghesuAMCucinelliF. Impact of insulin and body mass index on metabolic and endocrine variables in polycystic ovary syndrome. Metabolism. 1999;48(2):167–172.
29.
LuboshitzkyRQuptiGIshayAShen-OrrZFutermanBLinnS. Increased 6-sulfatoxymelatonin excretion in women with polycystic ovary syndrome. Fertil Steril. 2001;76(3):506–510.
30.
TerzievaDDOrbetzvaMMMitkovMDMatevaNG. Serum melatonin in women with polycystic ovary syndrome. Folia Med (Plovdiv). 2013;55(3):10–15.
31.
WuCSLeuSFYangHYHuangBM. Melatonin inhibits the expression of steroidogenic acute regulatory protein and steroidogenesis in MA-10 cells. J Androl. 2001;22(2):245–254.
32.
VaneckJ. Cellular mechanisms of melatonin action. Physiol Rev. 1998;78(3):687–721.
33.
TanDXManchesterLCSainzRM. Interaction between melatonin and nicotinamide nucleotide: NADH preservation in cells and in cell-free systems by melatonin. J Pineal Res. 2005;39(2):185–194.
34.
ReiterRJTanDXMaldonadoMD. Melatonin as an antioxidant: physiology versus pharmacology. J Pineal Res. 2005;39(2):215–216.
35.
PasqualottoEBAgarwalASharmaRK. Effect of oxidative stress in follicular fluid on the outcome of assisted reproductive procedures. Fertil Steril. 2004;81(4):973–976.
36.
DewaillyDAndersenCYBalenA. The physiology and clinical utility of anti-Mullerian hormone in women. Hum Reprod Update. 2014;20(3):370–385.
37.
BroekmansFJVisserJALavenJSBroerSLThemmenAPFauserBC. Anti-Müllerian hormone and ovarian dysfunction. Trends Endocrinol Metab. 2008;19(9):340–347.
38.
RomualdiDDe CiccoSTagliaferriVProtoCLanzoneAGuidoM. The metabolic status modulates the effect of metformin on the antimullerian hormone-androgens-insulin interplay in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2011;96(5):E821–E824.
39.
HirshfieldAN. Development of follicles in the mammalian ovary. Int Rev Cytol. 1991;124:43–101.
40.
McCartneyCREaglesonCAMarshallJC. Regulation of gonadotropin secretion: implications for polycystic ovary syndrome. Semin Reprod Med. 2002;20(4):317–326.
41.
FranksS. Polycystic ovary syndrome. N Engl J Med. 1995;333(13):853–861.
42.
HillierSG. Current concepts of the roles of follicle stimulating hormone and luteinizing hormone in folliculogenesis. Hum Reprod. 1994;9(2):188–191.
43.
ChuffaLGSeivaFRFavaroWJ. Melatonin reduces LH, 17 beta-estradiol and induces differential regulation of sex steroid receptors in reproductive tissues during rat ovulation. Reprod Biol Endocrinol. 2011;9:108.
44.
LuboshitzkyRLavieP. Melatonin and sex hormone interrelationships—a review. J Pediatr Endocrinol Metab. 1999;12(3):355–362.
45.
TanDXManchesterLCFuentes-BrotoLParedesSDReiterRJ. Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity. Obes Rev. 2011;12(3):167–188.
46.
ZanutoRSiqueira-FilhoMACaperutoLC. Melatonin improves insulin sensitivity independently of weight loss in old obese rats. J Pineal Res. 2013;55(2):156–165.
47.
NishidaSSegawaTMuraiINakagawaS. Long-term melatonin administration reduces hyperinsulinemia and improves the altered fatty-acid compositions in type 2 diabetic rats via the restoration of Delta-5 esaturase activity. J Pineal Res. 2002;32(1):26–33.
48.
PeschkeEFreseTChankiewitzE. Diabetic Goto Kakizaki rats as well as type 2 diabetic patients show a decreased diurnal serum melatonin level and an increased pancreatic melatonin-receptor status. J Pineal Res. 2006;40(2):135–143.
49.
CagnacciAAranginoSRenziA. Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women. Clin Endocrinol (Oxf). 2001;54(3):339–346.
