Authors: Shiva Siahbazi1,3, Samira Behboudi-Gandevani2, Lida Moghaddam-Banaem3 and Ali Montazeri4
1School of Nursing and Midwifery, Tehran University of Medical Sciences, 2 Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, and 3Department of Midwifery and Reproductive Health, Faculty of Medical Sciences, Tarbiat Modares University; and 4Mental Health Research Group, Health Metrics Research Center, Iranian Institute for Health Sciences Research, ACECR, Tehran, Iran
Summary
This double-blind, randomized, and placebo-controlled study evaluated a total of 142 women from 20 to 35 years of age in order to assess the effect of zinc sulfate supplementation on premenstrual syndrome. Researchers also evaluated the health-related quality of life the women experienced. The participants experienced moderate to severe premenstrual syndrome symptoms and were split into two groups, those who took the zinc sulfate supplement and those who took a placebo. Women who were given zinc took 220mg capsules containing 50mg of zinc from the 16th day of the menstrual cycle to the second day of the next cycle.
Researchers found a significant decrease of premenstrual syndrome symptoms in the intervention group throughout the study. As well, quality of life improved for many participants, although this was only statistically significant for the first three months.
Abstract
Aim: The purpose of study was to assess the effect of zinc sulfate (ZS) supplementation on premenstrual syndrome (PMS) and health-related quality of life (QoL).
Methods: This was a double-blind randomized and placebo-controlled trial using the parallel technique conducted between June 2013 and May 2014. A total of 142 women (aged, 20–35 years) with PMS were allocated to either the ZS or placebo group. The women in the intervention group received ZS 220-mg capsules (containing 50mg elemental zinc) from the 16th day of the menstrual cycle to the second day of the next cycle. Data were collected using the Premenstrual Symptoms Screening Tool (PSST) and 12-item Short-Form Health Survey Questionnaire.
Result: The prevalence of moderate to severe PMS in the ZS group significantly decreased throughout the study period (9.5% in the first, 6% in the second and 2.6% in the third month of the study, P < 0.001), but in the control placebo group this reduction was seen only in the first month of the study (14.2% in the first, 13.7% in the second and 13.5% in the third month, P = 0.08). Also, ZS improved the PSST component scores throughout the study period. The mean scores of QoL in physical and mental components were significantly improved in the ZS intervention group. However, the differences were statistically significant only three months after the intervention.
Conclusion: Zinc sulfate, as a simple and inexpensive treatment, was associated with improvement of PMS symptoms and health-related QoL. Additional studies are warranted to confirm these findings.
” Low dietary intake of zinc has been identified as a possible risk factor for the development of PMS.” -Chicano-Bodoya et al., 2013
Introduction
Premenstrual syndrome (PMS) is one of the most prevalent disorders among premenopausal women, and is characterized by a combination of physical and emotional/mental symptoms appearing both prior to and during menses, of varying severity.1 The prevalence of PMS is approximately 20–48% in reproductive age women.2 The most severe type of PMS, known as premenstrual dysphoric disorder (PMDD), is observed in 3–5% of women.3 It substantially impairs physical functioning, psychological health and leads to severe dysfunction in social, familial and occupational realms. Previous studies have suggested that women with PMS have poor health-related quality of life (QoL).4,5 The underlying mechanisms mediating the pathogenesis of the disorder, however, are complicated and multifactorial, and are not fully understood. It has been hypothesized that physical manifestations of PMS may be associated with increased inflammatory and oxidative stress, as well as with overactivation of the renin-angiotensin-aldosterone system, possibly associated with abnormal sex hormone fluctuations.6 Also, the psychological feature of this syndrome may further augment surges of inflammatory load7 or abnormalities in neurotransmitters such as serotonin, opioids, catecholamines, or gamma-Aminobutyric acid (GABA).
Some minerals deficiencies may play an important role in PMS/PMDD,8,9 although the role of this mineral has not been thoroughly explored. Das and Chowdhury reported that the serum concentration of some metallic ions changes during normal menstruation: the concentration of zinc was the highest during menses and lowest in the ovulatory phase. Also, a reduction was observed in zinc level during the luteal phase.10 Although the role of this mineral has not been thoroughly explored, some studies report that the serum zinc level in PMS is significantly lower than that in healthy controls.11, 12, 13
Zinc is an essential trace mineral that is involved in many biological processes, including enzyme function, nucleic acid metabolism, cell signaling and apoptosis; it is necessary for growth and development, lipid metabolism, brain and immune function.14, 15, 16 Inherited deficiency and dietary factors that decrease the zinc bioavailability play an important role in zinc deficiency.17,18 Zinc deficiency might decrease zinc concentrations in the hippocampus, induce irregular glucocorticoid production, and elicit neuropsychological symptoms such as emotional instability, isolation, irritability and depression.19,20
Zinc supplementation is supported by case–control data,11,12, 13, 21 but no systematic, double-blind placebo-controlled clinical trials have been carried out on the effect of zinc in the treatment of PMS. Therefore, the aim of this study was to determine whether zinc sulfate (ZS) supplement can improve PMS symptoms and health-related QoL using a double-blind, randomized controlled trial.
“If a patient is taking zinc routinely, they should choose a product that also contains copper-—zinc supplements can reduce the body’s copper levels. What’s more, taking zinc can cause a metallic taste in the mouth as well as nausea, so it is important to take it after meals.” -Sherry Torkos, pharmacist and author of The Canadian Encyclopedia of Natural Medicine
Methods
This double-blind randomized and placebo-controlled trial using the parallel technique was conducted at five health centers in Tehran between June 2013 and May 2014. The patients consisted of women who sought treatment for premenstrual symptoms in a gynecology clinic. The patients were referred by their general practitioner, or were self-referred. In this study, PMS was defined as the recurrence of somatic, psychologic, or behavioral symptoms in the premenstrual phase of the menstrual cycle in at least four of the previous six menstrual cycles, including the most recent.
The women were aged between 20 and 35 years, had regular menstrual cycles, normal body mass index (range, 19.8–26 kg/m2) and had PMS. Regular menstrual cycle was defined as occurring regularly at 21–35 days, and lasting <7 days without heavy blood flow.
Women were excluded if they had any psychiatric or chronic disease or suffered from severe form of PMS, as were those receiving any psychiatric, hormonal or supplementation treatment at the time of the study or within the six months before the study, and those who were cigarette smokers or vegetarians. Women were also excluded if there was a suspicion of pregnancy, if they were currently lactating, or if they wished to conceive before the end of the study.
One hundred and forty-two women with PMS were recruited into the study and allocated into the ZS intervention or control placebo groups. Subject selection followed the CONSORT design (Fig. 1).
Premenstrual syndrome is a common condition amongst women lasting anywhere from seven to 14 days before menstruation. Symptoms can range from various emotional, behavioural, and physical signs, including fatigue, altered mood, headaches, breast pain, and bloating, to name a few.
The Mayo Clinic states it is estimated that three of every four menstruating women have experienced some form of PMS. Primary causes of PMS remain unknown, although there are several factors which seem to play a role.
The Mayo Clinic points out that contributing factors can include cyclic changes in hormones, chemical changes in the brain, and depression. As well, some women with PMS show elevated signs of prolactin, the hormone which regulates the menstrual cycle and produces breast milk. Is a woman does not produce enough prostaglandin E, she will be unable to balance the effects of prolactin. Prostaglandin E1 comes from gamma-linolenic acid, a type of omega-6 essential fatty acid.
“Excessive and incorrect prostaglandin (PG) synthesis has been implicated in the cause of PMS, and a deficiency of prostaglandin E1(PgE1) at the central nervous system has been proposed to be involved in PMS. There are many nutrients important for the synthesis of PgE1. These include magnesium, linoleic acid, vitamin B6, zinc, vitamin C, and vitamin B3. This theory is carried through as a basis for some of the nutritional therapies in the treatment of PMS,” explains Tori Hudson, ND.
For many, PMS can affect day-to-day quality of life, and those who suffer from the symptoms are often put on antidepressants, NSAIDs, diuretics, and hormonal contraceptives. It is important to discuss alternative methods for those who would like more natural options. Modifying the diet can also play a major role in limiting or controlling some symptoms. As well, exercise and stress reduction can alleviate certain symptoms.
“It has been identified that women with PMS symptoms have a poorer diet—they tend to consume more refined carbohydrates, sugar, dairy and sodium and also seem to be deficient in iron, manganese and zinc,” says Michelle Peris, ND.
Zinc has been shown to increase gamma-linolenic acid into prostaglandin E1, ultimately decreasing the severity of PMS symptoms. It is also necessary for the sex hormones, and zinc’s role in controlling the secretion of these hormones is very significant.
Study protocol
After confirmation of eligibility, sociodemographic and obstetric subject characteristics were noted. Also, each participant provided information on weekly dietary zinc intake.
Patients were then randomly allocated to receive three cycles of treatment with either ZS 220mg capsules containing 50mg elemental zinc or placebo once daily (ZS dose was determined according to lower effective dose used in a previous study22), starting in the mid-luteal phase at the 16th day of the menstrual cycle to the second day of the next cycle or placebo. Placebo was completely similar to the ZS capsule in shape, taste and smell, containing sucrose, 220mg.
The patient was then assessed for one cycle before treatment commenced (consisting of three cycles during treatment). The subjects were specifically asked about PMS signs and symptoms at every visit, using the Iranian version of the Premenstrual Symptoms Screening Tool (PSST),23 a validated simple user-friendly screening tool to identify women with PMS and the severity of it. The PSST reflects and translates categorical DSM-IV criteria into a rating scale involving degrees of severity. This tool has two domains: (i) premenstrual symptoms with 14 questions; and (ii) interference of those symptoms with some activities as well familial and social relationships (five questions). All questions were rated on a 4-point Likert scale (not at all; mild; moderate; and severe).
In the first domain, moderate to severe PMS was defined as follows:
1. At least one of the symptoms including “anger/irritability, anxiety/tension, tearful, and depressed mood” was rated moderate to severe.
2. At least four of the symptoms including “decreased interest in work activities, decreased interest in work, home and social activities, difficult concentrations, fatigue/lack of energy, overeating/food cravings, insomnia, hypersomnia, feeling overwhelmed and physical symptoms” were rated moderate to severe.
3. In the second domain, at least one of the symptoms including “work efficiency or productivity, relationships with coworkers and family, social life activities, home responsibilities interfered with activities and relationships and were rated moderate to severe.
In addition, QoL was assessed using the Iranian version of the 12-item Short Form Health Survey (SF-12) Questionnaire,24 a shorter version of the SF-36 general health questionnaire. It was used to measure the physical and mental components of health-related QoL from baseline to after the completion of treatment.
During the study process, the participants recorded symptoms, symptom severity, medication compliance, unwanted side-effects and medications other than treatment medication. The women were asked to complete the PSST and SF-12 on days 7–10 of the menstrual cycle.
Treatment compliance was evaluated during regular monitoring through monthly follow-up visits at the end of menstruation. PSST and SF-12 questionnaires were collected and reviewed and new medications dispensed.
There are several common types of zinc that consumers may find:
❯ Chelated Zinc
❯ Zinc Orotate
❯ Zinc Picolinate
❯ Zinc Gluconate
❯ Zinc Acetate
❯ Zinc Oxide
❯Zinc Sulphate
Zinc has commonly been used to boost the immune system, treat common colds, skin conditions, and a number of other issues. It is needed to maintain an optimal level of health and proper immune function. It also plays a key role in healthy vision and protecting against viruses.
“It acts as a cofactor with more than 300 different enzymes, boosting the functioning of many of the body’s most basic chemical processes,” shares Dr. Edward Group DC, NP, DACBN, DCBCN, DABFM.
Zinc is believed to be safe; however, it is possible to overdose. This can cause fever, coughing, stomach pain, fatigue, and it can also be possibly fatal.
There are several moderate interactions with several medications, including penicillamine, cisplatin, quinolone antibiotics, and tetracycline antibiotics.
Sample size calculations
A study of independent cases and controls with one control per case was devised. Sample size requirements were determined according to a pilot study with 15 women in each group for primary estimation of the effect size of treatment on PMS. Setting type I error to 0.05 (two-tailed) and type II error to 0.10, including the loss of 10%, a sample size of 71 participants per treatment group was determined to be required in this trial to make the rejection of the null hypothesis (PMS improvement in women receiving ZS) possible.
Outcome measure
The primary outcome measure was the mean rank of symptoms and intensity of complaints according to the PSST for the ZS versus placebo groups before and during the first, second and third month of treatment. The secondary outcome measure was the physical and mental component summary of QoL scores in both groups at baseline and over the follow-up period.
Ethics
Ethics approval was obtained from the Institutional Review Board of the Tarbiat Modares University. The purpose of the study was explained to all women prior to enrollment and all participants signed written informed consent. This study was registered at the participating university (clinical trials registry: ID no., 138 809 212 843 N22).
Statistical analysis
Data are described as mean ± SD, or frequencies and percentages when appropriate. Comparison of variables was performed using chi-squared test, and Fisher’s exact test when the expected frequency was t-test. Statistical significance was determined on the basis of two-tailed tests at P < 0.05. All statistical analysis was performed using SPSS version 15.0 for Windows (SPSS, Chicago, IL, USA).
The Selling Point
Speaking face-to-face with your customers about their menstrual cycles may be a little daunting—never mind taboo. Yet, many of your customers will experience PMS on a regular basis, and a number of them might feel that it affects their quality of life. So, how can you reach them without scaring them off?
It’s all about how you present the information. Think about hosting a short information session, if you have the room, with a local nutritionist or naturopath. You can combine efforts to market the event, and it’s a win-win for both parties. If you are a clinic with a storefront, then you already have the resources. You can also have a zinc supplement on display during the discussion. Ensure not to overload the participants with information, and allow time for a Q&A. This will encourage people to participate. If you don’t have the space for this, you can also do live talk sessions on your social media platforms.
If you aren’t very confident in your on-screen presence, you can post punchy facts about the relationship between zinc and PMS, while promoting your store and/or a specific product. This could be anywhere from a “myth vs. fact” style to a “reasons why” that encourages consumers to come in and ask more questions. You might even consider using these posts to offer a promotional code on a specific day.
Chances are, you already have a zinc supplement in-store—not to mention several products containing zinc. It is found in multivitamins, children’s health products, beauty products, and meal replacements, to name a few. U.S. zinc sales grew over 75 per cent in 2015, according to SPINS natural products specialist Kimberly Kawa. Canada equally has the same room for growth, with Health Canada reporting that between 10 and 35 per cent of Canadians consume inadequate levels of zinc. Even if you aren’t ready to discuss PMS with your customers, you can definitely approach them from another angle and mention its overall benefits.
Results
During the first month of the study, six participants from the ZS intervention group and six from the control placebo group dropped out (Fig. 1). The study was completed and the analysis carried out with 65 patients in each group. Both ZS and placebo supplementation were well tolerated, and no serious event was observed during the study period. In addition, the prevalence of moderate to severe PMS in the intervention and control groups was 16.9% and 18.3%, respectively.
Sociodemographic subject characteristics are listed in Table 1, and there were no significant differences between the groups. Mean age, and age at menarche in women competing the trial, in the intervention versus control group were 22.4 ± 3 versus 22.6 ± 2.2 years, and 13.3 ± 1.7 versus 13.5 ± 1.2 years, respectively (P = n.s.). The percentage of qualitative symptoms and their interference with daily activities on the PSST are listed in Table 2.
Zinc sulfate improved the mean PSST component scores throughout the study period. The PSST component scores in the study period were significantly lower than those before treatment with ZS. Also, in the placebo group the mean rank of “decreased interest in social activities” after the intervention significantly decreased from 76.06 to 63.98 (P = 0.031), whereas the mean rank of other components after the intervention was not significantly different to that before the intervention. Statistical significance was observed between all components of the PSST, including symptoms and interference with various activities, between the intervention and placebo groups (Table 2).
The prevalence of moderate to severe PMS in the ZS intervention group significantly decreased throughout the study period (9.5% in the first, 6% in the second and 2.6% in the third month of the study, P < 0.001), but in the control placebo group this reduction was seen only in the first month (14.2% in the first, 13.7% in the second and 13.5% in the third month of the study, P = 0.08; Fig. 2).
The mean scores of QoL in physical and mental components were significantly improved in the ZS intervention group (Table 3). However, the differences were statistically significant only three months after the intervention.
Discussion
Premenstrual syndrome has been described as one of the most common disorders among premenopausal women, but few therapeutic modalities have proved consistently effective. This study found that ZS effectively alleviates the symptoms of PMS superior to placebo, and improves health-related QoL.
The control placebo group also had lower PSST scores after intervention, but only in the first month of the study. The positive role of placebo has been reported by others,25, 26, 27 suggesting that the response to placebo in published trials on psychological aspects of disorders or treatment of pain is highly effective.28
Despite the overwhelming prevalence of PMS, the underlying mechanisms are not fully understood. Some investigations of basal levels of gonadal steroid hormones, gonadotropins, thyroid, and other hormones have not detected differences between women with symptoms and those who do not.29
The mineral, zinc, may be involved in the pathophysiology of PMS. Blood zinc levels fluctuate across the menstrual cycle.10 Also, Posaci et al. observed that the blood zinc level in women with PMS is lower than in healthy controls.11 In agreement with the present study, however, Chocano-Bedoya et al., in a nested case-control study, observed that high intake of zinc from supplements was marginally associated with lower risk of PMS (intake ≥25 mg/day vs none: relative risk, 0.69; 95%CI: 0.46–1.02; P for trend = 0.05).21
In addition, some somatic complaints of PMS, including breast tenderness and bloating, also can prove disruptive to overall functioning and QoL. In the present study, ZS enhanced health-related QoL outcomes, which may reduce the complications associated with this disorder, or at least make it more tolerable.
Zinc, however, is highly localized in the brain and might be involved in neuropsychological function.30 Although the blood–brain barrier controls zinc transportation between plasma and brain, chronic zinc deficiency might reduce zinc concentration in the hippocampus, induce abnormal glucocorticoid secretion, and produce neuropsychological symptoms such as isolation and depression.31 Furthermore, zinc is also required for the production and modulation of melatonin and GABA,32,33 which helps regulate dopamine function, an important factor in PMS and its treatment.34 Zinc supplementation increases melatonin and serotonin synthesis and consequently improves aggressive behaviors and impulsivity.35
The limitations of the study include the short study duration, which might have not been sufficiently long to detect ZS side-effects. Also, some PMS confounders were not studied, such as relationship status, lifestyle and physical activity. In addition, we did not measure blood zinc concentration to monitor alterations in zinc levels before and during treatment.
In conclusion, ZS, as a simple and inexpensive treatment, was associated with improvement of PMS symptoms and health-related QoL. Given that this is among the first studies to evaluate the effect of ZS supplementation on PMS, additional studies are warranted to confirm these findings.
“Premenstrual syndrome (PMS), affects 75-90 per cent of women at some point, making it very common, but it is certainly not healthy… PMS is caused by nutrient deficencies, blood sugar instability, and hormonal fluctuation throughout a woman’s menstrual cycle.” -Dr.Pamela Franc, BSc (Hons), ND
Acknowledgments
This article is derived from the thesis of Shiva Siahbazi for fulfillment of a Master degree in Midwifery at Tarbiat Modares University (Faculty of Sciences), Tehran, Iran. The authors would like to sincerely thank all the participants for their cooperation in the study.
Disclosure
The authors declare no conflict of interest
