- Open Access
Metabolic and hormonal effects of melatonin and/or magnesium supplementation in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial
Nutrition & Metabolism volume 18, Article number: 57 (2021)
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders among women of reproductive age. This study was designed to investigate the effects of melatonin and/or magnesium supplementation on metabolic profile and levels of sex hormones in PCOS women.
In an 8-week randomized double-blind placebo-controlled trial, 84 subjects with PCOS aged 18–40 years were randomly assigned based on the random block procedure to take magnesium, melatonin, magnesium plus melatonin, and placebo. Fasting blood samples were obtained at the beginning and end of the study.
After intervention, the mean Pittsburg Sleep Quality Index score decreased significantly in both co-supplementation and melatonin groups (P < 0.001). Magnesium supplementation in combination with melatonin resulted in a significant greater decrease in testosterone concentrations compared with the placebo (P < 0.05). Co-supplementation of magnesium-melatonin had significantly reduced serum insulin levels (geometric means difference: − 1.11 (mIU/mL) (percent change: − 15.99)), homeostasis model of assessment-insulin resistance (HOMA-IR) (− 0.28 (− 18.66)), serum cholesterol (mean difference: − 16.08 (mg/dl) [95% CI − 24.24, − 7.92]), low-density lipoprotein cholesterol (LDL-C) − 18.96 (mg/dl) [− 28.73, − 9.20]) and testosterone levels (− 0.09 (ng/ml) (− 25.00)), as compared to the baseline values (P < 0.05). An increase in serum high-density lipoprotein cholesterol (HDL-C) levels was also observed following the administration of the melatonin alone (2.76 (mg/dl) [0.57, 4.95]) or in combination with magnesium (2.19 (mg/dl) [0.61, 3.77]) (P < 0.05).
Co-supplementation with magnesium and melatonin had beneficial effects on sleep quality and total testosterone. Additionally, melatonin supplementation alone was found to be associated with a significant reduction in PSQI score. Moreover, combined melatonin and magnesium supplementation was more effective in improving serum levels of cholesterol, LDL-C, HDL-C and insulin, and HOMA-IR.
Trial registration: Iranian Registry of Clinical Trial. http://www.irct.ir: IRCT20191130045556N1, January 2020.
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting about 7% to 10% of women of reproductive age and is a leading cause of infertility [1, 2]. The clinical expression of the syndrome is characterized by the manifestation of oligo/anovulation, clinical or biochemical hyperandrogenism and/or polycystic ovaries . PCOS is a heterogeneous gynecological syndrome, associated with a wide range of endocrine and metabolic abnormalities, including hyperinsulinemia, hyperglycemia, glucose intolerance, dyslipidemia, and obesity, which are regarded as the components of metabolic syndrome (MetS) . Insulin resistance (IR) with compensatory hyperinsulinemia plays a major role in the development of PCOS. Insulin excess stimulates androgen synthesis in the ovary and the adrenals [5,6,7]; besides, it can inhibit sex hormone-binding globulin (SHBG) synthesis in the liver  and increase the levels of free testosterone (T) [8, 9]. On the other hand, Adipokines such as leptin, as a product of the obesity gene, plays a crucial role in body weight homeostasis through possible neuroendocrine pathways [10,11,12] and has an impact on gonadal function and reproduction [13, 14]. It may contribute to the development of type 2 diabetes mellitus, and IR; therefore, leptin may be involved in the pathogenesis of PCOS . Lifestyle modifications are first-line treatment for PCOS, and small lifestyle changes (diet, exercise, and behavior) can improve metabolic dysfunction, ovulation, fertility, and mood [16, 17]. Nutritional supplements had received a great deal of attention in the management of PCOS .
Melatonin is the main hormone that is mainly secreted by the pineal gland to regulate circadian rhythms, reproduction, and the sleep cycle [19, 20]. High levels of melatonin in the follicular fluid are essential for folliculogenesis, ovulation, and oocyte quality, whereas reduced follicular melatonin concentrations may be responsible for anovulation and poor oocyte quality in PCOS . It had been suggested that melatonin has an antigonadal effect through the direct reduction of testosterone production . Also, beneficial effects of melatonin on the components of MetS, including hyperglycemia, dyslipidemia, and insulin resistance, have been shown in both animal and human studies [23, 24]. In a randomized controlled trial, Melatonin administration for 12 weeks in PCOS patients had beneficial effects on mental health parameters, insulin levels, homeostasis model of assessment-insulin resistance (HOMA-IR), the quantitative insulin sensitivity check index (QUICKI), total- and low-density lipoprotein cholesterol (LDL-C) levels .
On the other hand, the function of minerals, including magnesium (Mg), in the pathogenesis of PCOS due to its contribution to insulin sensitivity has been examined . It has been shown that hypomagnesemia increase PCOS risk by up to 19 times . There is evidence that Mg increases insulin sensitivity through its influence on tyrosine-kinase activity, and its deficiency is associated with IR . Beneficial effects on parameters of insulin metabolism and serum triglycerides, and total cholesterol in PCOS women have been shown in 12-week magnesium and vitamin E co-supplementation . Also, an 8-week Magnesium supplementation resulted in reduced body mass index (BMI) and testosterone levels as well as increased serum dehydroepiandrosterone (DHEA) and luteinizing hormone (LH) levels in women with PCOS, but it did not affect serum lipid profiles and glycemic indicators, follicle-stimulating hormone, 17OH progesterone, SHBG, and free androgen index (FAI) levels . Despite the relationships between Mg levels and PCOS status, few studies have evaluated magnesium supplementation in the management of PCOS.
We hypothesized that melatonin and magnesium co-supplementation might help improve metabolic profiles and clinical symptoms of PCOS and may work better than a single supplementation alone. The present study was carried out to investigate the effect of melatonin and magnesium supplementation, separately and together, on metabolic profiles and levels of sex hormones in women with PCOS.
This randomized double-blind placebo-controlled clinical trial was performed in Alzahra and 29 Bahman hospitals of Tabriz, Iran, from April 2020 through December 2020. The protocol of this study was approved by the Medical Ethics Committee of Ahvaz Jundishapur University of Medical Sciences which is in accordance with the Declaration of Helsinki (approval number IR.AJUMS.REC.1398.637). Also, this trial has been registered in the Iranian Registry of Clinical Trials (IRCT) with the number of IRCT20191130045556N1. Additionally, written informed consent was obtained from all participants.
Diagnosis of PCOS was performed according to the Rotterdam criteria . The participants were females with age ranges between 18 and 40 and body mass index (BMI) ≤ 35. The exclusion criteria were as follows: pregnancy, lactation, smoking, alcohol consumption, endocrine disorders, in particular any type of adrenal diseases, diabetes, hyperprolactinemia, receiving drugs affecting plasma androgen levels, lipid profile, or inflammatory factors during the last 3 months, weight loss of more than 5% in the last six months, supplementation with melatonin, magnesium, antioxidant and/or anti-inflammatory agents within the last three months and those with sleeping disorders and night shift working.
Participants were randomly assigned into four groups. Subjects in four groups were receiving: two melatonin tablets (each, 3 mg) plus a 250 mg magnesium oxide tablet (group one); two melatonin tablets (each, 3 mg) plus a magnesium placebo (group two); a 250 mg magnesium oxide tablet plus two melatonin placebos (group three), and two melatonin placebos plus a magnesium placebo (group four) for eight consecutive weeks. Melatonin and magnesium supplements were manufactured by Nature Made Pharmaceutical Company (California, USA) and Jalinous Pharmaceutical Company (Tehran, Iran), respectively. Placebos were provided by Pharmacy faculty, Tabriz University of Medical Science, Tabriz, Iran. The appearance of placebos, including color, shape, size, and packaging, was identical to that of melatonin and magnesium supplements. The participants were asked to take their melatonin tablets at night before sleeping and magnesium tablets in the evening for eight consecutive weeks.
At the onset of the study, the patients were asked to maintain their usual dietary pattern and physical activity level during the study. Additionally, patients were requested not to receive any antioxidant and/or anti-inflammatory, and other medications that could affect their reproductive physiology during the intervention. Compliance with the intake of supplements or placebos was checked by asking participants to bring the medication containers. Further, all participants were contacted two times per week by a dietitian. The participants were allowed to discontinue the trial if they were unwilling to complete the trial or if they experienced any adverse effects during the intervention. Consuming more than 90% of the supplements was considered compliant.
Dietary intakes and physical activity assessment
Dietary intakes were estimated from three 24 h dietary recalls (one weekend day and two weekdays). To obtain nutrient intakes of participants based on these three dietary recalls, we used Nutritionist IV software (First Databank, San Bruno, CA). Physical activity levels were determined by the short form of the International Physical Activity Questionnaire Short Form (IPAQ-S) at baseline and after eight weeks of intervention. Further, total physical activity is expressed as metabolic equivalents (METs) minutes/week .
Sleep quality assessment
Sleep quality was determined using the validated Iranian version of the Pittsburg Sleep Quality Index (PSQI) .
Assessment of anthropometric variables
At baseline and end-of-trial, all subjects underwent standard anthropometric measurements: height was measured using a non-stretched tape measure (Seca, Hamburg, Germany) to the nearest 0.1 cm. Body weight was measured in a minimal clothing state and no shoes using a digital scale (Seca, Hamburg, Germany) to the nearest 0.1 kg. BMI was calculated as weight in kg divided by height in meters squared. Waist circumference (WC) (the widest area between the lower rib and the superior iliac crest) was also measured to the nearest 0.1 cm.
Blood samples were collected after 12 h overnight fasting before and after the intervention, and serum was obtained by centrifugation at 3000 RPM for 10 min; the serum samples were frozen and stored at − 80 °C until biochemical analyses. Fasting blood sugar (FBS), TG, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and magnesium were measured using a colorimetric method (Parsazmoun, Tehran, Iran). The concentration of LDL-C was calculated using the Friedewald formula .
Serum insulin levels were measured by an enzyme-linked immune sorbent assay (ELISA) method using a laboratory kit (Monobind, USA). Serum testosterone and SHBG levels were measured by ELISA kit (DiaMetra, Italy). Free androgen index (FAI) was calculated as total testosterone divided by SHBG according to Azziz et al. Equation . Serum leptin values were also measured using an ELISA kit (LDN, Nordhorn, Germany). The HOMA-IR and homeostatic model assessment β cell function (HOMA-B) were determined according to the suggested formulas .
The sample size for the present study was calculated by PASS 15 (version 15, PASS; NCSS, LLC, US) . To determine the sample size, regression coefficient, and the confidence interval of the relationship between melatonin supplementation and serum insulin levels (reported by Shabani et al. ) were used (β: − 1.20 mIU/ml; 95% CI − 2.14, − 0.26). Considering a 95% confidence, a power of 95%, a two-tailed test, 1.2 unit change in slope, and a SD = 3 for insulin, the sample size was estimated to be 71 in total (18 per group). To consider the probable dropouts, 22 patients in the co-supplementation group, 21 patients in each melatonin and magnesium group and 20 patients in the placebo group were enrolled.
The patients were randomly assigned to intervention and placebo groups based on the random block procedure; for this, a third independent investigator who was not aware of the study clinical process created the randomization list assigning patients to the melatonin and magnesium co-supplementation, melatonin, magnesium, and placebo group. The random sequence was generated using random allocation software. Melatonin, magnesium, and placebo tablets were in the same form of a package. The study leader labeled these containers with patient numbers using the randomization list. All investigators and patients were blinded to the random assignments.
The analyses were done based on an intention-to-treat approach. For doing this, missing values were treated based on the linear interpolation method. The distribution of data was examined using the Kolmogorov–Smirnov test. Numeric and categorical variables were presented as mean ± SD or geometric mean (min, max) where appropriate and frequency (percentage), respectively. For non-normally distributed variables, a log transformation was conducted before the analysis. Percent change of variables was calculated using the following equation: ((after–before)/before) × 100. A 1-way ANOVA test and a χ2 test were used to compare the four groups for baseline measures of the quantitative and qualitative data, respectively. Comparison of the four groups at the end of the study was completed using analysis of covariance followed by Sidak’s test after adjusting for baseline values and energy intake. The comparison of mean values was done within groups after the intervention using paired sample t-tests. Statistical analysis was performed using IBM SPSS Statistics (Version 22.0; IBM SPSS Statistics Inc. Armonk, USA). P < 0.05 was considered as statistically significant.
In the current study, out of 84 participants who were selected for the intervention, seven subjects were excluded due to personal reasons [magnesium and melatonin co-supplementation (n = 2), melatonin (n = 3), placebo (n = 1), and magnesium (n = 1)]. Among participants in the magnesium plus melatonin supplements group, another woman did not complete the trial because of pregnancy. Finally, as the analyses were carried out according to the intention-to-treat approach, all 84 patients were included in the end analysis (Fig. 1). During the intervention, no adverse events or symptoms were reported by the patients.
There were no significant differences in terms of age, physical activity, family history of PCOS, irregular menstrual cycles, and height between different groups (Table 1). However, after eight weeks intervention, weight, BMI, and WC decreased significantly in the magnesium-melatonin co-supplementation (P < 0.05). Additionally, in comparison to baseline values, a significant reduction in WC was observed in the magnesium or melatonin supplementation alone (P < 0.05).
As summarized in Fig. 2, there was a significant increase in serum magnesium levels in magnesium or combined magnesium plus melatonin groups (P < 0.05), and a greater increase was found among those who took magnesium compared with the other groups (P = 0.022).
Based on Table 2, there were no significant differences in the dietary intakes between the four groups before the intervention (P > 0.05).
After two months of supplementation, the mean PSQI score decreased significantly (indicating sleep improvement) in both the magnesium-melatonin co-supplementation and melatonin groups (P < 0.001). When we controlled the analysis for baseline values and energy intake, patients who consumed melatonin alone or in combination with magnesium had a greater improvement in sleep quality than other categories (P < 0.001). The effects of magnesium, melatonin, and combined magnesium plus melatonin supplementation on the metabolic and hormonal parameters are presented in Table 3. Women who received magnesium- melatonin had significantly reduced glucose homeostasis parameters (insulin and HOMA-IR), serum cholesterol, LDL-C, and testosterone levels, as compared to the baseline values (P < 0.05). Although melatonin administration for eight weeks to women with PCOS decreased circulating levels of testosterone (P < 0.05), those who received the combination of magnesium plus melatonin experienced a greater decrease in testosterone concentrations compared with the placebo (P < 0.05). An increase in serum high-density lipoprotein cholesterol (HDL-C) levels was also observed following the administration of the melatonin alone or in combination with magnesium (P < 0.05). As well, within-group differences revealed a significant increase in FAI and circulating level of insulin in the placebo group (P < 0.05) (Table 3).
The present four-arm, parallel, double-blind randomized controlled trial was designed to evaluate the independent and additive effects of magnesium and melatonin on metabolic profiles and levels of sex hormones in women with PCOS. We found that combination therapy with magnesium and melatonin in patients with PCOS had beneficial effects on sleep quality and total testosterone. Additionally, melatonin supplementation alone was found to be associated with a significant reduction in PSQI score in PCOS subjects.
PCOS is one of the most common metabolic disorder which is characterized by hyperinsulinemic- and hyperandrogenic-related disorders . Since insulin resistance is an important etiological feature of PCOS, affected women are at higher risk of developing type 2 diabetes and related metabolic complications . On the other hand, it has been reported that sleep disturbances are common in PCOS, and some form of them, like obstructive sleep apnoea, in turn, exacerbates insulin resistance . In accordance with our results, there were studies that have shown treatment with exogenous melatonin had favorable effects on sleep quality, which was assessed by the PSQI, especially in the adults with metabolic disorders . As melatonin is known to be an effective regulator of circadian rhythm and promotes sleep , beneficial effects on sleep quality are not surprising. In several studies, it has been demonstrated that urinary excretion of 6-sulfatoxymelatonin, the main excretory metabolite of melatonin, along with the melatonin levels in blood and saliva was higher in patients with PCOS than women with normal fertility and the levels of these molecules (urinary 6-sulfatoxymelatonin and serum melatonin) were significantly correlated with the severity of sleep disturbances . Although the causal role of melatonin in the pathogenesis of PCOS and sleep disorders is still unclear, the production of higher amounts of melatonin in women with PCOS may be in an effort of eliminating extra free radicals as PCOS patient's high oxidative stress .
One of the main findings of the present study was the beneficial effects of melatonin (alone or in combination) on testosterone. In line with our finding, Jamilian and colleagues indicated that melatonin administration for three months to PCOS women significantly reduced total testosterone . In another study, long-term (6 months) melatonin administration to women with PCOS had beneficial effects on menstrual irregularities and biochemical hyperandrogenism . Prior studies have indicated hyperandrogenism is closely correlated with chronic inflammation and oxidative stress . There is promising evidence that shows melatonin is a powerful free radical scavenger and effective endogenous antioxidant which exerts protective effects, particularly in female reproductive organs . Additionally, the anti-inflammatory activity of magnesium and also its effects on improved insulin sensitivity have been previously shown [48, 49]. Although our study failed to find any significant effect of magnesium supplementation on glycemic indices (FBS, insulin, and HOMA-IR), taking magnesium plus melatonin supplements had protective effects on insulin and HOMA-IR in women with PCOS. This result agrees with some previous studies in which melatonin administration significantly improved glucose homeostasis and insulin resistance in women with PCOS . It seems that melatonin through melatonin receptors 1 and 2, suppresses hepatic gluconeogenesis and improves glucose uptake by peripheral tissues [50, 51]. In other words, melatonin administration exerts antihyperglycemic effects and improves glucose hemostasis .
Another key finding of the present study is that combined magnesium and melatonin supplementation was more effective in improving metabolic parameters, including cholesterol, LDL-C, and HDL-C. Moreover, supplementation with melatonin alone significantly increased serum HDL-C levels in PCOS women. These findings are consistent with growing evidence from both animal and human studies [23, 25]. For instance, Shabani and colleagues have shown that melatonin supplementation to patients with PCOS significantly decreased serum LDL-cholesterol levels . Another study designed by Raygan et al. demonstrated that supplementation with melatonin (10 mg/day) for 12 weeks to diabetic people with coronary artery disease had beneficial effects on HDL-C concentrations, glycemic control, and insulin sensitivity . Similarly, the results of a meta-analysis study showed noticeable effects of melatonin intake on the serum triglycerides and total cholesterol levels while did not influence HDL-C and LDL-C concentrations . These inconsistencies in results of these studies may be due to differences in dosage of melatonin intake, type of diseases, duration and design of the intervention, or ethnic background of the participants. Melatonin may exert protective impacts on lipid profile by increasing lecithin-cholesterol acyltransferase activity . The synergistic influence of co-administration of melatonin and magnesium in this study is also supported by some trials that indicated magnesium supplementation might help improve metabolic profiles in women with PCOS . In this regard, magnesium and vitamin E co-supplementation for 12 weeks to individuals with PCOS led to a significant reduction in serum triglycerides, VLDL, and total cholesterol . Magnesium seems to improve lipid concentrations through enhanced lipoprotein lipase activity  and increased excretion of fecal fat . Despite the fact that we failed to find any significant effect of melatonin and/or magnesium on serum levels of leptin, animal studies have previously shown that melatonin administration could attenuate the development of hyperinsulinemia . In fact, melatonin appears to regulate leptin synthesis, and lack of melatonin or knocking out the melatonin receptors can lead to leptin resistance .
One of the major concerns in PCOS patients is infertility which results mainly from follicular atresia, anovulation, and hyperandrogenemia [59, 60]. Thus, with regard to beneficial effects of both melatonin and magnesium on menstrual cycle improvement, administration of the two compounds, as therapeutic agents, to manage infertile patients in whom infertility occurs due to poor oocyte quality and anovualtion may create a new ray of hope for infertile patients [59,60,61]. However, the exact effect of long term melatonin and magnesium therapy on menstrual cyclicity and subsequently on the management of infertility needs to be evaluated in large scale prospective randomized studies.
It is worth noting that this is the first study, to our best knowledge, that has evaluated additive effects of melatonin and magnesium on the metabolic profile of patients with PCOS. Nevertheless, several limitations need to be addressed. Relatively short duration of supplementation should be considered in the interpretation of our findings, and long-term trials among various ethnic groups are needed to provide better effects. In addition, as the current research was conducted using relatively small number of eligible participants, the generalization of our findings is partly limited. Besides, 24-h dietary recall, as a memory dependent tool, is frequently associated with underestimation and represents only recent dietary patterns rather than a long term practice,. Thus, a valid and reliable food frequency questionnaire, (if available) may be much helpful in better estimating nutritional status of the participants and its potential effects on bio metabolic parameters of the patients.
Altogether, our study demonstrated that melatonin and magnesium co-supplementation, for eight weeks in women with PCOS had beneficial effects on sleep quality and total testosterone. Additionally, melatonin supplementation alone was found to be associated with a significant reduction in PSQI score. Moreover, combined magnesium and melatonin supplementation was more effective in improving metabolic parameters, including serum levels of cholesterol, LDL-C, HDL-C, insulin, and HOMA-IR. Further large-scale research with longer periods is needed to get stronger results.
Availability of data and materials
The data gathered and analyzed during the current study are available from the corresponding author on reasonable request.
body mass index
free androgen index
fasting blood sugar
high-density lipoprotein cholesterol
homeostasis model of assessment β cell function
homeostasis model of assessment-insulin resistance
low-density lipoprotein cholesterol
Pittsburg sleep quality index
quantitative insulin sensitivity check index
sex hormone-binding globulin
Glueck C, Papanna R, Wang P, Goldenberg N, Sieve-Smith L. Incidence and treatment of metabolic syndrome in newly referred women with confirmed polycystic ovarian syndrome. Metabolism. 2003;52(7):908–15.
Terzieva DD, Orbetzova MM, Mitkov MD, Mateva NG. Serum melatonin in women with polycystic ovary syndrome. Folia Med. 2013;55(2):10–5.
Goldenberg N, Glueck C. Medical therapy in women with polycystic ovarian syndrome before and during pregnancy and lactation. Minerva Ginecol. 2008;60(1):63–75.
Dokras A, Bochner M, Hollinrake E, Markham S, VanVoorhis B, Jagasia DH. Screening women with polycystic ovary syndrome for metabolic syndrome. Obstet Gynecol. 2005;106(1):131–7.
Nestler JE, Jakubowicz DJ, Falcon de Vargas A, Brik C, Quintero N, Medina F. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab. 1998;83(6):2001–5.
Tosi F, Negri C, Perrone F, Dorizzi R, Castello R, Bonora E, et al. Hyperinsulinemia amplifies GnRH agonist stimulated ovarian steroid secretion in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2012;97(5):1712–9.
Tosi F, Negri C, Brun E, Castello R, Faccini G, Bonora E, et al. Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women. Eur J Endocrinol. 2011;164(2):197.
Nestler JE, Powers LP, Matt DW, Steingold KA, Plymate SR, Rittmaster RS, et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab. 1991;72(1):83–9.
Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr Rev. 2015;36(5):487–525.
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425–32.
Chehab FF, Lim ME, Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet. 1996;12(3):318–20.
Jockenhövel F, Blum WF, Vogel E, Englaro P, Müller-Wieland D, Reinwein D, et al. Testosterone substitution normalizes elevated serum leptin levels in hypogonadal men. J Clin Endocrinol Metab. 1997;82(8):2510–3.
Moschos S, Chan JL, Mantzoros CS. Leptin and reproduction: a review. Fertil Steril. 2002;77(3):433–44.
Goumenou AG, Matalliotakis IM, Koumantakis GE, Panidis DK. The role of leptin in fertility. Eur J Obstet Gynecol Reprod Biol. 2003;106(2):118–24.
Mitchell M, Armstrong D, Robker R, Norman R. Adipokines: implications for female fertility and obesity. Reproduction. 2005;130(5):583–97.
Thomson RL, Buckley JD, Lim SS, Noakes M, Clifton PM, Norman RJ, et al. Lifestyle management improves quality of life and depression in overweight and obese women with polycystic ovary syndrome. Fertil Steril. 2010;94(5):1812–6.
Teede HJ, Misso ML, Deeks AA, Moran LJ, Stuckey BG, Wong JL, et al. Assessment and management of polycystic ovary syndrome: summary of an evidence-based guideline. Med J Aust. 2011;195(6):S65-112.
Farshchi H, Rane A, Love A, Kennedy R. Diet and nutrition in polycystic ovary syndrome (PCOS): pointers for nutritional management. J Obstet Gynaecol. 2007;27(8):762–73.
Cassone VM, Natesan AK. Time and time again: the phylogeny of melatonin as a transducer of biological time. J Biol Rhythms. 1997;12(6):489–97.
Reiter RJ, Tan D-X, Fuentes-Broto L. Melatonin: a multitasking molecule. Prog Brain Res. 2010;181:127–51.
Spinedi E, Cardinali DP. The polycystic ovary syndrome and the metabolic syndrome: a possible chronobiotic-cytoprotective adjuvant therapy. Int J Endocrinol. 2018;2018:1349868.
Sirotkin A, Schaeffer H. Direct regulation of mammalian reproductive organs by serotonin and melatonin. J Endocrinol. 1997;154(1):1–5.
Peschke E, Schucht H, Mühlbauer E. Long-term enteral administration of melatonin reduces plasma insulin and increases expression of pineal insulin receptors in both Wistar and type 2-diabetic Goto-Kakizaki rats. J Pineal Res. 2010;49(4):373–81.
Raygan F, Ostadmohammadi V, Bahmani F, Reiter RJ, Asemi Z. Melatonin administration lowers biomarkers of oxidative stress and cardio-metabolic risk in type 2 diabetic patients with coronary heart disease: a randomized, double-blind, placebo-controlled trial. Clin Nutr. 2019;38(1):191–6.
Shabani A, Foroozanfard F, Kavossian E, Aghadavod E, Ostadmohammadi V, Reiter RJ, et al. Effects of melatonin administration on mental health parameters, metabolic and genetic profiles in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. J Affect Disord. 2019;250:51–6.
Chakraborty P, Ghosh S, Goswami S, Kabir SN, Chakravarty B, Jana K. Altered trace mineral milieu might play an aetiological role in the pathogenesis of polycystic ovary syndrome. Biol Trace Elem Res. 2013;152(1):9–15.
Sharifi F, Mazloomi S, Hajihosseini R, Mazloomzadeh S. Serum magnesium concentrations in polycystic ovary syndrome and its association with insulin resistance. Gynecol Endocrinol. 2012;28(1):7–11.
Jamilian M, Sabzevar NK, Asemi Z. The effect of magnesium and vitamin E co-supplementation on glycemic control and markers of cardio-metabolic risk in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Horm Metab Res. 2019;51(02):100–5.
Babapour M, Mohammadi H, Kazemi M, Hadi A, Rezazadegan M, Askari G. Associations between serum magnesium concentrations and polycystic ovary syndrome status: a systematic review and meta-analysis. Biol Trace Elem Res. 2020;199:1297–305.
ESHRE TR, Group A-SPCW. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81(1):19–25.
Committee IR. Guidelines for data processing and analysis of the International Physical Activity Questionnaire (IPAQ)-short and long forms. 2005. http://www.ipaq.ki.se/scoring.pdf. Accessed 1 Dec 2019.
Naderi H, Dehghan H, Ghaderi M, Momeni F. Relationship of metacognitions with students’sleep quality. Shenakht J Psychol Psychiatry. 2017;2(4):12–23.
Ozkaya M, Cakal E, Ustun Y, Engin-Ustun Y. Effect of metformin on serum visfatin levels in patients with polycystic ovary syndrome. Fertil Steril. 2010;93(3):880–4.
Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. The androgen excess and PCOS society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril. 2009;91(2):456–88.
Pisprasert V, Ingram KH, Lopez-Davila MF, Munoz AJ, Garvey WT. Limitations in the use of indices using glucose and insulin levels to predict insulin sensitivity: impact of race and gender and superiority of the indices derived from oral glucose tolerance test in African Americans. Diabetes Care. 2013;36(4):845–53.
Neter J, Wasserman W, Kutner MH. Applied linear regression models. Homewood: Richard D. Irwin; 1989.
Baptiste CG, Battista M-C, Trottier A, Baillargeon J-P. Insulin and hyperandrogenism in women with polycystic ovary syndrome. J Steroid Biochem Mol Biol. 2010;122(1–3):42–52.
El Hayek S, Bitar L, Hamdar LH, Mirza FG, Daoud G. Poly cystic ovarian syndrome: an updated overview. Front Physiol. 2016;7:124.
Sam S, Ehrmann DA. Pathogenesis and consequences of disordered sleep in PCOS. Clin Med Insights Reprod Health. 2019;13:1179558119871269.
Fatemeh G, Sajjad M, Niloufar R, Neda S, Leila S, Khadijeh M. Effect of melatonin supplementation on sleep quality: a systematic review and meta-analysis of randomized controlled trials. J Neurol. 2021. https://doi.org/10.1007/s00415-020-10381-w.
Klerman H, Hilaire MAS, Kronauer RE, Gooley JJ, Gronfier C, Hull JT, et al. Analysis method and experimental conditions affect computed circadian phase from melatonin data. PLoS ONE. 2012;7(4):e33836.
Mojaverrostami S, Asghari N, Khamisabadi M, Khoei HH. The role of melatonin in polycystic ovary syndrome: a review. Int J Reprod Biomed. 2019;17(12):865.
Shreeve N, Cagampang F, Sadek K, Tolhurst M, Houldey A, Hill C, et al. Poor sleep in PCOS; is melatonin the culprit. Hum Reprod. 2013;28(5):1348–53.
Jamilian M, Foroozanfard F, Mirhosseini N, Kavossian E, Aghadavod E, Bahmani F, et al. Effects of melatonin supplementation on hormonal, inflammatory, genetic, and oxidative stress parameters in women with polycystic ovary syndrome. Front Endocrinol (Lausanne). 2019;10:273.
Tagliaferri V, Romualdi D, Scarinci E, De Cicco S, Di Florio C, Immediata V, et al. Melatonin treatment may be able to restore menstrual cyclicity in women with PCOS: a pilot study. Reprod Sci. 2018;25(2):269–75.
Su C, Chen M, Huang H, Lin J. Testosterone enhances lipopolysaccharide-induced interleukin-6 and macrophage chemotactic protein-1 expression by activating the extracellular signal-regulated kinase 1/2/nuclear factor-κB signalling pathways in 3T3-L1 adipocytes. Mol Med Rep. 2015;12(1):696–704.
Tan DX, Manchester LC, Hardeland R, Lopez-Burillo S, Mayo JC, Sainz RM, et al. Melatonin: a hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin. J Pineal Res. 2003;34(1):75–8.
Izadi A, Ebrahimi S, Shirazi S, Taghizadeh S, Parizad M, Farzadi L, et al. Hormonal and metabolic effects of coenzyme Q10 and/or vitamin E in patients with polycystic ovary syndrome. J Clin Endocrinol Metab. 2019;104(2):319–27.
Barbagallo M, Dominguez LJ, Galioto A, Ferlisi A, Cani C, Malfa L, et al. Role of magnesium in insulin action, diabetes and cardio-metabolic syndrome X. Mol Asp Med. 2003;24(1–3):39–52.
Faria JA, Kinote A, Ignacio-Souza LM, de Araújo TM, Razolli DS, Doneda DL, et al. Melatonin acts through MT1/MT2 receptors to activate hypothalamic Akt and suppress hepatic gluconeogenesis in rats. Am J Physiol Endocrinol Metab. 2013;305(2):E230–42.
Ha E, Yim SV, Chung JH, Yoon KS, Kang I, Cho YH, et al. Melatonin stimulates glucose transport via insulin receptor substrate-1/phosphatidylinositol 3-kinase pathway in C2C12 murine skeletal muscle cells. J Pineal Res. 2006;41(1):67–72.
Pai SA, Majumdar AS. Protective effects of melatonin against metabolic and reproductive disturbances in polycystic ovary syndrome in rats. J Pharm Pharmacol. 2014;66(12):1710–21.
Mohammadi-Sartang M, Ghorbani M, Mazloom Z. Effects of melatonin supplementation on blood lipid concentrations: a systematic review and meta-analysis of randomized controlled trials. Clin Nutr. 2018;37(6):1943–54.
Tamura H, Nakamura Y, Narimatsu A, Yamagata Y, Takasaki A, Reiter RJ, et al. Melatonin treatment in peri-and postmenopausal women elevates serum high-density lipoprotein cholesterol levels without influencing total cholesterol levels. J Pineal Res. 2008;45(1):101–5.
Rayssiguier Y, Gueux E. Magnesium and lipids in cardiovascular disease. J Am Coll Nutr. 1986;5(6):507–19.
Kishimoto Y, Tani M, Uto-Kondo H, Saita E, Iizuka M, Sone H, et al. Effects of magnesium on postprandial serum lipid responses in healthy human subjects. Br J Nutr. 2010;103(4):469–72.
Nishida S, Segawa T, Murai I, Nakagawa S. Long-term melatonin administration reduces hyperinsulinemia and improves the altered fatty-acid compositions in type 2 diabetic rats via the restoration of Δ-5 desaturase activity. J Pineal Res. 2002;32(1):26–33.
Buonfiglio D, Tchio C, Furigo I, Donato J Jr, Baba K, Cipolla-Neto J, et al. Removing melatonin receptor type 1 signaling leads to selective leptin resistance in the arcuate nucleus. J Pineal Res. 2019;67(2):e12580.
Tamura H, Nakamura Y, Korkmaz A, Manchester LC, Tan DX, Sugino N, et al. Melatonin and the ovary: physiological and pathophysiological implications. Fertil Steril. 2009;92:328–43.
Tamura H, Takasaki A, Taketani T, Tanabe M, Kizuka F, Lee L, et al. The role of melatonin as an antioxidant in the follicle. J Ovarian Res. 2012;5:5.
Howard JMC, Davies S, Hunnisett A. Red cell magnesium and glutathione peroxidase in infertile women: effects of oral supplementation with magnesium and selenium. Magnes Res. 1994;7(1):49–57.
The authors wish to thank Dr. Elaheh Foroumandi, Dr. Mehran Mesgari Abbasi and Mr. Kurosh Tabbakhi for their assistance. We thank all staff of Bist-o-noh (29) Bahman Hospital (Iranian Social Security Organization, Tabriz, Iran) for their cooperation and support through the study. We are grateful to Danesh Pathobiology and Genetic Centers (Tabriz, Iran) for their technical help. We also thank all of the study participants.
The present study was funded by the vice chancellor for research of Ahvaz Jundishapur University of Medical Science (Grant No.: NRC-9815) and Tabriz University of Medical science (Grant No.: 64999).
Ethics approval and consent to participate
The ethical committee of Ahvaz Jundishapur University of Medical Sciences confirmed the study and the approval of the Ethics Committee was obtained (IR.AJUMS.REC.1398.637).
Consent for publication
No personal data is noted herein.
The Author(s) declare(s) that they have no conflicts of interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Alizadeh, M., Karandish, M., Asghari Jafarabadi, M. 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) 18, 57 (2021). https://doi.org/10.1186/s12986-021-00586-9
- Polycystic ovary syndrome
- Metabolic profile