Introduction

Premenstrual syndrome or PMS includes series of recurrent physical and psychological symptoms that affect a large number of women in their reproductive ages. These symptoms including mood swing, fatigue, irritability, depression, food craving and tender breast occur during the last days of luteal phase and persist for 2–4 days after starting the menses [1, 2]. The onset of PMS is usually during late adolescence, but the symptoms remain unrecognized and untreated so they can negatively affect the quality of life, work and social functions [3, 4]. Premenstrual dysphoric disorder (PMDD) is a more severe form of PMS, that impairs the patients’ normal functions and cause disruption of personal relationships [5]. It is believed that about 85% of women go through at least one of mild PMS symptoms in their lives, 20–25% experience moderate to severe symptoms and about 5% suffer from PMDD [6]. Based on a systematic review and meta-analysis, it is estimated that worldwide prevalence of PMS is about 48% [1]. Some studies report that the prevalence of women suffering from PMS in Egypt [7], northern Ethiopia [8] and Poland [9] are: 65, 37 and 76.39%, respectively. It has been reported that PMS prevalence in Iran varies between 30 and 99.5% [10]. The etiology of PMS is unknown, but several studies suggested that cyclical changes in ovarian hormones levels initiate the symptoms [11,12,13].

Abnormal sex hormones fluctuations probably associated with increased inflammatory and oxidative stress and over activation of the renin–angiotensin–aldosterone system that results in physical symptoms of PMS [14]. It has been stated that PMS symptoms negatively affect quality of life (QOL) of these women [3]. WHO defined QOL as “an individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns” [15]. Health-related quality of life (HRQOL) determines how a chronic illness interfere one’s life. HRQOL is significantly lower in women with PMS than non-affected women [16]. In a study by Borenstein et al. health-related burden of PMS was estimated to be comparable to major depression and cyclothymia disorder [17]. It has been reported that PMS symptoms not only impairs quality of life of the women, but can also negatively affect their interpersonal relationships, social activities, sexual function and job performances [18]. Based on an epidemiologic survey conducted in Sao Paulo (EPISONO), the PMS group had poorer sleep quality than the control group [19]. Women with PMS complain about insomnia, fatigue, nightmares and poor sleep quality [20,21,22]. Usual sleep problems related to PMDD are repeated night time awakenings, sleep onset insomnia and non-restoration of sleep; these sleep difficulties can lead to daytime sleepiness, poor concentration, declined alertness and weak performance at work and study [23].

Although it is suggested that some minerals deficiency may partially play a role in pathogenesis of PMS and PMDD, this role has not been fully explored [24, 25]. Serum concentration of some metallic ions such as zinc changes during menstrual cycle. Zinc is an essential mineral that is involved in numerous physiological pathways [26]. Women who suffer from PMS have significantly lower serum zinc than normal women [27,28,29]. Zinc deficiency leads to abnormal glucocorticoid’s production that can result in some neuropsychological symptoms such as irritability, depression and emotional instability, similar to some of PMS symptoms [30, 31]. Several studies showed that supplementation with zinc may have a positive effect on sleep disorders in children, childhood hyperactivity, attention and mental disorders such as depression [32,33,34]. To our knowledge, except for case–control studies that support the idea of supplementation with zinc in PMS [27, 29, 35], there is only one clinical trial published on the effect of zinc on quality of life of women with PMS and their symptoms, showing positive effect of zinc supplementation in PMS [36]. Previously, we observed that zinc supplementation can alleviate PMS symptoms, improve total antioxidant capacity and BDNF levels in these patients [37]. Accordingly, we aimed to examine the effects of 12 weeks of supplementation with 30 mg/day elemental zinc in the form of zinc gluconate on sleep quality in addition to quality of life in women with PMS.

Methods

Participants

This double-blind randomized and placebo-controlled trial was conducted at the Isfahan University of Medical Sciences girls’ dormitories between June 2017 and June 2018 using a parallel design. Inclusion criteria included healthy single young women with regular menstrual cycle of 21–35 days, aged 18–30 years old, BMI between 18.5–24.9, not taking any oral contraceptives or any medications, not exercising professionally, not taking zinc supplement in the last 3 months, not being depressed or having anxiety. Exclusion criteria were: not filling out the daily record questionnaire, taking less than 80% of the zinc or placebo pills, getting married and not willing to continue the study. Students who met the inclusion criteria were initially diagnosed using a 30 item questionnaire consisted of physical and psychological symptoms of PMS [38].

Study design

We conducted this study in 2 phases. In the first phase, 200 young women who met the inclusion criteria were asked to fill out a questionnaire consisting of 30 symptoms of PMS. Girls who experienced 5 or more PMS symptoms with at least one psychological symptom, 7 days prior to 4 days after onset of menses, were initially diagnosed with PMS. These young women were asked to fill out the Beck’s anxiety and depression questionnaires. Those with scores of depression and anxiety lower than 4 and 15, respectively, were eligible to participate in the study.

In the second phase, after explaining the study, participants gave their written consent and completed food frequency questioner (FFQ) with the help of a trained nutritionist. To obtain participants’ zinc intakes, we used customized Nutritionist IV software (N-Squared Inc., San Bruno, CA, USA). Women who were temporarily diagnosed with PMS, recorded their symptoms for 2 consecutive months pre-intervention, using Daily Symptoms Record form. The form included 30 most prevalent psychological and physical symptoms of PMS based on DSM-V [38, 39] that was validated by Pakgohar et al. using content validity. They also stated a Pearson’s correlation coefficient of r = 0.92 for the reliability of this questionnaire [40]. Participants with definite diagnosis of PMS, were randomly allocated into 2 groups of 30; one group took zinc gluconate tablets (contained 30 mg of elemental zinc) and the other group consumed the placebo tablets that contained starch. Both zinc gluconate and placebo tablets were provided by Dine Iran Pharmaceutical Company (Tehran, Iran) in identical appearance. Women were asked not to change their physical activity and diet and not to take any supplements during the trial. All participants nor had specific diets neither followed special regimens before and during the study. In the second and third months, along with the packages of tablets, same daily record questionnaires were given to them to fill out.

Sample size calculations

To calculate the sample size, we used the standard equation for parallel clinical trials considering the type one error (α) of 0.05 and type two error (β) of 0.10 (power of 90%). Based on previous study [41], we used 2.71 and 2.32 as SD and 2.66 as the difference in mean (d) of sleep quality score as the key variable. Based on this study and considering the dropouts, we recruited 30 women in each group.

Outcome measure

Participants that were eligible for the trial completed the Pittsburgh sleep quality questionnaire (PSQI) and the Persian version of WHO quality of life questioner (WHOQOL-BREF) in luteal phase of their menstrual cycle pre- and post-intervention. Pittsburgh sleep questionnaire (PSQI) is one of the most applicable questionnaires about quality of sleep used in studies that investigates subject’s attitude about their sleep in the past 4 weeks. PSQI includes 19 self-rated questions containing seven components: subjective quality of sleep, sleep latency, duration, efficiency, disturbance, use of sleep medication and daytime dysfunction. Each component is scored from 0 to 3 and total score would be between 0 and 21 [42]. Scores above 5 indicate poor quality of sleep. Sensitivity and specificity of PSQI are 90 and 87%, respectively [43]. Another questionnaire was the Persian version of (WHOQOL-BREF) that has been validated in Iranian population [44]. The (WHOQOL-BREF) questionnaire contains 26 questions based on 4 domains including: physical health, psychological health, social and personal relationships and environmental aspect of life [44]. Participants recorded their symptoms severity on the scale of (0 = not having the symptoms) to (3 = sever symptom prevents the person from taking part in normal daily activities). PMS was diagnosed according to diagnostic criteria of American Psychiatry Association [40]. To avoid diurnal variations, blood samples were collected after an overnight fasting from individual’s cubital vein. The samples were then centrifuged at 5000 rpm for 15 min and serums were removed and then stored at − 80 °C until further measurements. Serum zinc levels were measured by a colorimeter using 5-BR-PAPS method. Biochemical kits (Biosystems S.A., Barcelona, Spain) were applied to determine serum zinc. Results obtained from this technique are correlated well with those by atomic absorption spectrophotometry [45, 46].

Statistical analysis

We applied Kolmogorov–Smirnov test to verify the normal distribution of variables. To detect differences in basic variables between the two groups, we used independent t test and to determine the effects of zinc supplementation on sleep quality and health-related quality of life score, multivariate analysis of covariance (MANCOVA) test was applied with adjustment for the baseline confounders. P value below 0.05 was considered statistically significant. We used Statistical Package for Social Science version 16 (SPSS Inc., Chicago, IL, USA) to perform statistical analysis (Fig. 1).

Fig. 1
figure 1

Summary of patient flow diagram

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Results

In this study, out of 200 students who met the inclusion criteria and were initially diagnosed with PMS, 60 women whose Beck’s scores for depression and anxiety were respectively less than 4 and 15 and recorded their symptoms for 2 consecutive menstrual cycles were allocated into 2 groups of 30. In the second phase of the study, 3 participants in the intervention group dropped out due to personal reasons. The participants took 87 and 90% of the tablets in placebo and intervention groups, respectively. Both zinc and placebo pills were well tolerated and no sensible side effects were reported following the intervention. No significant differences were seen in the baseline parameters (Table 1). As shown in the Table 1, there was no significant difference in dietary zinc intake between the two groups. After 12-week intervention, zinc supplementation significantly increased the serum zinc levels (P < 0.001). Moreover, this group demonstrated increased score of the first domain of quality of life indicating improved physical aspects (P  < 0.001). Based on independent t test, quality of life total score of intervention group significantly increased, however, after comparing with those of placebo group using MANCOVA test, no significant changes were observed. Moreover, no significant changes were seen in social and personal relationships, environment aspect of life and psychological aspects of quality of life of the groups pre- and post-supplementation. Sleep quality of the intervention group improved marginally (− 1.48 ± 4.12, P = 0.07) after supplementation, however, scores were not different between the groups (Table 2).

Table 1 Basic characteristics of study participants
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Table 2 Metabolic profiles at baseline and after the 12-week intervention in subjects with premenstrual syndrome
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Discussion

PMS is one of the most prevalent disorders among premenopausal women. In the present study, after 12 weeks of treatment with zinc, total score of quality of life and sleep quality increased in the intervention group, yet these changes were not significantly different from those of placebo group. In addition, first domain of quality of life indicating the physical aspects of quality of life in PMS woman was improved. There are limited therapies to relieve PMS symptoms [47]. Therapies suggested for this disorder include psychiatric, anovulatory, supplements, herbal and non-pharmacological treatments [48]. Selective serotonin reuptake inhibitors, in spite of their side effects such as weight gain, sexual dysfunction and sleep disturbances, are the first-line medicine being used to alleviate the symptoms of PMS and PMDD [48]. Despite overwhelming prevalence of PMS, its underlying mechanisms are yet to understand. It is suggested that some minerals such as zinc might have a role in the etiology of PMS. Serum zinc level fluctuates across the menstrual cycle [49] and is lower in women with PMS [27, 29]. There have been some case–control studies that support supplementation with zinc in PMS. Zinc is concentrated in hippocampus and in PMS patients its level is lower than normal women; this can lead to isolation and depression [50]. Chocano-Bedoya et al., in a nested case–control study, showed that high intake of zinc from supplements was marginally associated with lower risk of PMS [35]. There is scarce evidence on the effect of zinc supplementation on PMS symptoms and patients’ quality of lives. In a study conducted by Siahbazi et al., supplementation with 50 mg/day elemental zinc improved the PMS symptoms and physical and psychological aspects of health related quality of life in these patients [36]. Previously, we found that supplementation with zinc could alleviate physical symptoms of PMS [37] as well as the fact that improved zinc status could enhance the psychological aspects of this syndrome, serum levels of BDNF and TAC in subjects with PMS [37]. In another study by Ribeiro et al. oral zinc supplementation 45 days prior and up to 12 weeks post-chemotherapy for colorectal cancer prevented worsening of fatigue symptoms and preserved quality of life [51]. It has been proposed that irregular response to normal hormonal fluctuations might be responsible for this syndrome. Fluctuating gonadal hormones negatively affect certain neurotransmitters [48]. Estrogen has excitability effect on neurotransmitters whereas progesterone exhibits inhibitory effect on neurotransmitters through increasing monoamine oxidase activity, decreasing serotonin and stimulation of GABA receptors [13]. Allopregnanolone, major metabolite of progesterone, is a positive modulator of GABA-A receptors [6]. As GABA system is one of the strongest inhibitory systems in the CNS, allopregnanolone has anxiolytic, anesthetic, and sedative effect in response to the stressors [6, 13]. Women with PMS have lower alopregnanolone levels than women who are not affected by the syndrome [52]. These affected women after stimulation with gonadotropin releasing hormone (GnRH) in luteal phase, seem to have decreased production of progesterone and allopregnanolone, resulting in PMS [53]. SSRIs enhance allopregnanolone’s production and GABA-A receptors function [54]. It has been documented that zinc functions as an agonist on GABA system, so that it can relieve PMS symptoms and increases quality of life [55].

It is well documented that sleep quality and hormonal changes are related, therefore, PMS can affect women’s quality of life and sleep [22]. Poor sleep quality is a common feature of sever PMS [56]. Ji and Liu reported that sufficient zinc concentration is associated with good sleep quality in children [57]. In our study, we did not detect any significant change in sleep quality post-supplementation, in spite of these results, the scores in intervention group improved from 8.00 ± 3.32 indicating low sleep quality to 6.14 ± 3.58 being marginally better sleep quality. Gholipour Baradari et al. demonstrated that supplementation with 220 mg/day zinc sulfate, improves sleep quality in ICU nurses [41]. Rondanelli et al. observed that administration of nightly melatonin, magnesium and zinc improved the sleep quality and quality of life in long-term care facility residents with primary insomnia [58]. This discrepancy might be due to different study designs, dosage and form of zinc administration as well as duration of the study and combination of zinc with other supplements. Zinc, as an important micronutrient, exerts important role in more than 300 enzymes in human body [59] and it is concentrated in hippocampus in the brain. Low zinc concentration in hippocampus results in dysregulation of glucocorticoid secretion that can cause some neuropsychological dysfunctions such as isolation and depression that are known as common symptoms of PMS [50]. The possible role and mechanisms in which zinc regulates sleep is still unclear. It is hypothesized that zinc’s inhibitory effect on glycinergic neurons excitation projecting to orexin neurons in lateral hypothalamus involved in maintenance of wakefulness, might be the possible pathway in which zinc involves in sleep regulation [60]. In addition, zinc is required for production and inflection of melatonin and GABA that help regulating dopamine function [61]. Zinc also increases melatonin and serotonin synthesis, therefore, it can improve violent behavior and impulsivity [62].

PMS is a prevalent disorder among women in their reproductive ages that interferes with women’s personal relationships, studies or work. One of the most significant concerns about PMDD, sever form of PMS, is potential development of suicidal thoughts, so treatments are needed [63]. Further studies with longer duration could be helpful to improve women’s lives affected by PMS.

Our study had some limitations such as lack of measurement of sex hormones to confirm the menstrual cycle phases and also relatively short duration to detect any possible side effects of zinc supplementation in long-term course.

As the final point, our findings revealed that zinc supplementation in PMS women for 12 weeks positively influenced the physical aspect of quality of life but did not affect sleep quality of women with PMS.