Magnesium
Magnesium amino acid chelate (Meta Mag^® - Magnesium bisglycinate)
Taurine
Inositol (Myo-inositol)
Vitamin C
Calcium ascorbate dihydrate
Tyrosine
Vitamin B5
Calcium pantothenate
Vitamin B6
Pyridoxal-5-phosphate
Zinc
Zinc amino acid chelate (Meta Zn® - Zinc bisglycinate)
5-Methyltetrahydrofolate
Levomefolate calcium
Vitamin B12
Mecobalamin
Chromium
Chromic hexahydrate chloride
Iodine
Potassium iodide
Selenium
Selenomethionine

• Alleviates the impact of stress
• Supports thyroid function
• Improves metabolic health
• Promotes oestrogen and xeno-oestrogen detoxification

• Premenstrual syndrome (PMS)
• Polycystic ovarian syndrome (PCOS)
• Primary dysmenorrhoea
• Perimenopause

Stress is a common and underappreciated cause of hormonal dysregulation in women. Elevated or prolonged stress, resulting in chronic activation of the stress response system known as the hypothalamic-pituitary-adrenal (HPA) axis, is linked with hormonal imbalances such as pre-menstrual syndrome (PMS), dysmenorrhoea, and the premature onset of menopause.[1-4] Further, overactivation of the HPA axis impacts thyroid function exacerbating climacteric symptoms during perimenopause, and promoting poor metabolic health in polycystic ovarian syndrome (PCOS). Women are often deficient in essential minerals, such as magnesium, chromium, selenium, iodine and zinc, integral to hormonal regulation, stress management, and cardiometabolic health.[5-8] To meet the needs of today’s dynamic and multitasking woman, it is paramount to utilise a comprehensive formula that harnesses the benefits of magnesium, along with other essential nutrients. This formula is designed to address all factors influencing women’s health (Figure 1).

Figure 1: Factors influencing women’s health.[9-17]

The menstrual cycle is governed by fluctuating gonadotropins (e.g. luteinizing hormone (LH) and follicle-stimulating hormone (FSH)) and sex steroid hormones (e.g., oestrogens and progesterone); key components of the hypothalamic-pituitary-ovarian (HPO) axis.[18] An overactive HPA axis has several direct effects on HPO axis functioning, including:

• Impeding or altering the release of FSH and LH, negatively impacting ovulation and progesterone synthesis.[9,10]
• Influencing prostaglandin synthesis associated with heightened pain perception at the myometrium, as seen with dysmenorrhoea.[9]
• Promoting an imbalance in neurotransmitters linked with alterations in mood, cognitive functioning, and pain processing, as seen in PMS, PCOS, during menopausal transition, and dysmenorrhoea.[11-13]

Chronic activation of the HPA axis further hampers thyroid function by hindering thyroid stimulating hormone (TSH) secretion and blocking the conversion of thyroxine (T4) to triiodothyronine (T3).[14] This interference in thyroid function holds significance, as thyroid hormones directly influence reproductive tissues and sex hormone availability through modulation of sex hormone binding globulin (SHBG) expression.[19] Notably, thyroid disorders such as hypothyroidism have been correlated with menstrual irregularities, fertility challenges and PCOS.[19,20]

Continued exposure to glucocorticoids, from a prolonged stress response, is linked with impairment of glucose uptake and metabolism, decreased insulin receptor affinity, hyperinsulinemia and insulin resistance, features of PCOS.[15] In return, hyperinsulinemia inhibits the “brakes” being applied to the HPA axis, allowing for its continued deleterious effects on hormonal health.[15,21]

Magnesium is a key nutrient which plays a role in numerous mechanisms that support female hormonal health and mediates the stress response (Figure 2).[22] Magnesium deficiency is commonly found in women with PCOS, PMS and climacteric symptoms during perimenopause.[5] Inadequate intake is prevalent amongst women, and the use of oral contraceptives have been associated with magnesium depletion.[23] Therefore, recommending a highly bioavailable magnesium supplement is a foundational step benefiting female hormonal health and well-being.

Figure 2: Role of magnesium in health.[22]

Magnesium is critical for protection against the stress response as it:

• Directly boosts 5-HT synthesis, receptor activity and transmission, found to be dysregulated in PMS/premenstrual dysphoric disorder (PMDD), thereby modulating HPA axis activity.[11,16]
• Acts as a GABA agonist and glutamate antagonist, regulating the activity of the N-methyl-d-aspartate (NMDA) receptor, which has been linked with improvements in PMS symptoms.[5]
• Suppresses oxidative stress and inflammation linked with mood disorders common in PMS, PMDD, PCOS and the transition to menopause.[5,11,12,16]

Vitamin B6 serves as a coenzyme in the biosynthesis of the neurotransmitters GABA, dopamine and 5-HT, whilst also participating in hormone detoxification processes. Deficiencies in vitamin B6 have been reported in women with PMS, and studies have shown that both stand-alone therapy and combination therapy with magnesium can bring about improvements in psychological and somatic symptoms in women with PMS and PMDD.[31,32]

Zinc, plays a pivotal role in supporting a women’s wellbeing, and women with PMS have been shown to exhibit lower serum zinc levels than healthy counterparts.[33] Consequently, zinc deficiency may elicit mood symptoms associated with PMS as this mineral modulates glutamate and GABA transmission, glucocorticoid synthesis and protects against oxidative stress and inflammation.[6,33,34] Studies have observed that zinc supplementation improves symptoms and quality of life (QOL) in women with PMS.[33,34]

Magnesium, vitamin B6 and zinc are imperative to protect the HPO axis against the detrimental effects of chronic stress, promoting healthy hormonal balance.

The hypothalamic-pituitary-thyroid (HPT) axis encompasses neurohormones thyrotropin-releasing hormone (TRH) and TSH, thyroid hormones T3 and T4, and several deiodinases, enzymes involved in thyroid hormone formation and catabolism.[19] Thyroid hormones are central to reproductive physiology, with a greater prevalence of menstrual irregularities, such as oligomenorrhea and menorrhagia, observed in women with thyroid abnormalities.[19] Whilst during perimenopause, alterations in thyroid function can manifest as anxiety, palpitations, sweating, sudden changes in weight and insomnia.[14]

Iodine is crucial for thyroid function and a rate-limiting factor for thyroid hormone synthesis. Statistics show iodine deficiency is common amongst women. In Australia, a staggering 18.3% of women aged 16-44 years exhibit iodine levels below 50 micrograms per litre (mcg/L), indicative of moderate to severe deficiency.[7] A study focusing on menstruating females demonstrated that iodine status was negatively correlated with menstrual irregularities. The correlation was further strengthened as many of the women with menstrual irregularities and iodine deficiency experienced improvements in cycle length, blood volume, and perceived pain during menstruation after receiving iodine supplementation for six months.[35]

Selenium is a cofactor for three of the four thyroid hormone deiodinases, which activate and deactivate thyroid hormones.[36] Further, selenium protects the thyroid gland against oxidative stress by its interactions as a cofactor for anti-oxidant enzymes glutathione peroxidase and reductase.[37]

Myo-inositol (MI) is commonly recognised for its insulin sensitising effects; however, this molecule plays an important role in the signalling of several hormones (insulin, FSH, LH, and TSH) thus an imbalance in inositol metabolism may impair thyroid hormone synthesis, storage and secretion.[36] In a prospective interventional multicentric study the combination of selenium and MI was administered to 148 women, aged 18-50 years, with subclinical hypothyroidism and menstrual irregularities for six months. Post trial participants experienced improvements in thyroid markers (TSH, thyroid volume, thyroid antibodies- anti-thyroglobulin and anti-thyroid peroxidase). After three months a significant improvement in recovering cycle regularity was observed (p<0.001), increasing from 71.8% to 84.6%. Meanwhile, the percentage of women with absent/irregular cycles decreased from 28.2% to 15.4%. What’s more, the significant improvement in menstrual cycle regularity continued beyond the 6 months of treatment (p<0.05).[38]

In females, poor metabolic health and increased body mass index (BMI) are linked with menstrual cycle irregularities and PCOS. Obesity and hyperinsulinemia contribute to an increase in free circulating androgens, testosterone and insulin, whilst concurrently lowering SHBG.[2,39]

Magnesium directly influences cellular glucose uptake and insulin receptor sensitivity, while also providing anti-inflammatory properties.[5,40] In women diagnosed with PCOS, lower serum magnesium levels have been linked to diminished insulin sensitivity and elevated testosterone levels.[40] A separate study demonstrated that PCOS women, upon receiving magnesium supplementation, exhibited substantial reductions in insulin resistance (p=0.032).[41]

MI plays a crucial role in metabolic health as it:

• Influences glucose availability by limiting absorption in the duodenum.
• Boosts glucose uptake by muscle cells through raising GLUT4 activity.[42,43]
• Facilitates insulin signalling through its role as a secondary messenger.[43,44]

However, elevated blood glucose levels decrease absorption, and bio-synthesis of MI, whilst promoting degradation and urinary excretion.[42] This becomes particularly relevant in conditions like PCOS, characterized by insulin resistance, as it inhibits the endogenous synthesis of MI. Further, insulin resistance and hyperinsulinemia contribute to hyperandrogenism and infrequent or failed ovulation, also a feature of PCOS.[44] Adding to its effects as an insulin sensitiser, MI acts as a FSH secondary messenger, playing a pivotal role in the proliferation, maturation, transportation and quality of oocytes.[42]

Selenium exhibits insulin-like actions in both in vitro and in vivo studies and supplementation in women with central obesity notably declined serum insulin levels. The effects of selenium on improved glucose homeostasis extend to lipid profiles. In women with PCOS, selenium supplementation over eight weeks significantly lowered serum insulin levels (p=0.013), serum triglycerides (p=0.025) and VLDL-C concentrations (p=0.025) compared with placebo group. Its beneficial effects on metabolic health may result from its inhibition of pro-inflammatory compounds, tumour necrosis factor-alpha (TNF-a), interleukin (IL)-1 and cyclooxygenase (COX)-2.[45]

Chromium is essential for carbohydrate and lipid metabolism. Chromium regulates glucose and amino acid transport into the cell via its actions on transporter GLUT 4, and influences cholesterol synthesis by modulating the activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase. Through these mechanisms, chromium is proposed to enhance insulin sensitivity and metabolic health. Two systematic reviews and meta-analysis showed chromium supplementation significantly improved fasting plasma glucose (p=0.03), insulin (p<0.001), haemoglobin A1C (HbA1C) (p=0.004), HOMA-IR (p<0.001), serum triglycerides (P=0.050) and total cholesterol (p<0.001).[46,47]

The modernisation of society has increased exposure to both exogenous and endogenous toxins, impacting hormonal health. Environmental toxins like bisphenol A (BPA), a known endocrine disruptor, can affect normal hormonal function.[48] Elevated systemic and/or tissue levels of oestrogen and/or environmental chemicals (xeno-oestrogens) are linked to various female reproductive conditions (Table 1). To address this, a strategic approach involves promoting the detoxification of oestrogen and xeno-oestrogens through liver detoxification pathways, thereby working to reduce their levels in the body.

Table 1: Conditions associated with oestrogen and/or xeno-oestrogen excess.[49-53]

Methylation, catalysed by the enzyme catechol-O-methyltransferase (COMT), is a key pathway for oestrogen conjugation in extrahepatic tissue. The activity of COMT and the availability of methyl groups depend on nutrients vitamin B6, mecobalamin and 5-methyltetrahydrofolate. These nutrients play a crucial role in supporting oestrogen and xeno-oestrogen detoxification.[54] Additionally, magnesium's influence on glucuronidation emphasises its importance in facilitating hormonal detoxification.[55]

PMS affects 80-90% of menstruating women, manifesting with cyclic affective and somatic symptoms during the late luteal phase of the menstrual cycle.[5] Chronic stress, poor dietary habits, and nutritional deficiencies are linked with PMS development.[5,56]

The effect of vitamin B6 on improving PMS symptoms has been highlighted in clinical trials.[32,57] A double-blind randomised-controlled trial administered 94 females with PMS either vitamin B6, at a dose of 80 mg/d or placebo over two menstrual cycles. Women receiving vitamin B6 experienced greater reductions in PMS symptoms compared to the placebo group.[57]

Women with PMS also exhibit lower intracellular blood cell concentrations of magnesium compared to their healthy counterparts. Interestingly, vitamin B6 is required for maintenance of healthy intracellular magnesium concentration.[5] In a randomised, controlled trial involving 150 women with PMS, participants were assigned to one of three groups: 250 mg/d of magnesium, 250 mg/d of magnesium combined with 40 mg/d of vitamin B6, or a placebo. Over two menstrual cycles participants recorded their PMS symptom scores for cravings, depression, fluid retention, anxiety, and somatic symptoms. Post trial, all groups showed a significant decrease in mean PMS scores, however the magnesium and vitamin B6 combination exhibited the most substantial improvement compared to the placebo group.[31] Evidence demonstrates the effects of magnesium at 250 mg/d, both as stand-alone treatment and in combination with 40 mg/d of vitamin B6, on PMS symptoms is achieved over two menstrual cycles.[5,31]

Additionally, zinc supplementation emerged as a promising intervention in a parallel double-blind randomised placebo-controlled trial. Sixty females aged 18-30 years with PMS received either 30 mg/d of zinc or placebo for 12 weeks. Zinc supplementation significantly reduced both somatic (p=0.03) and psychological symptoms (p=0.006).[33] These findings collectively highlight the potential of nutrients magnesium, vitamin B6 and zinc supplementation in enhancing the well-being of individuals enduring PMS symptoms.

PCOS is an endocrine disorder associated with hormonal and cardiometabolic complications, affecting 5-15% of reproductive-age women.[45,58] Insulin resistance and hyperinsulinemia are central to PCOS pathogenesis, contributing to inflammation, amenorrhea, hyperandrogenism and infertility.[42,59,60] PCOS is characterised by increased insulin-dependent epimerase activity in ovarian theca cells, resulting in higher D-chiro-inositol (DCI) concentrations at the expense of MI. An increased ratio of DCI:MI contributes to excess androgen synthesis, compounded by a surplus of LH and insulin, and a lack of FSH secretion which leads to ‘follicular arrest’.[42] This is a distinct phenomenon of PCOS where early follicular growth is excessive, but the maturation of a dominant follicle is reduced.[61] Simultaneously, ongoing MI depletion worsens FSH signalling and oocyte quality, whilst hyperinsulinemia inhibits SHBG synthesis.[42]

In a meta-analysis of 24 studies, MI supplementation in PCOS, compared to both placebo and metformin (the gold standard treatment), showed positive effects. Individuals taking MI at doses between 1000 mg/d and 4000 mg/d for 12 to 24 weeks were 1.79 times more likely to establish a regular menstrual cycle than the placebo group. Additionally, MI supplementation significantly increased SHBG levels compared to both placebo and metformin.[62] Combining MI with folate, known for reducing insulin levels in women with PCOS, has been shown to effectively improve PCOS symptoms (Table 2). Therefore, the combination of MI and folate supplementation should be a key consideration in PCOS treatment.[63]

Table 2: Efficacy of MI in PCOS[62,64,65]

Women with PCOS and insulin resistance exhibit considerably lower serum chromium levels compared to control subjects.[8] A prospective, randomised, double-blind, placebo-controlled trial of 64 women with PCOS found that 200 µg/d of chromium for eight weeks resulted in significant decreases in serum insulin levels (p<0.001), compared to placebo.

Epidemiological studies highlight the presence of hypomagnesemia in PCOS.[66] A triple-blind randomised placebo-controlled trial compared the effectiveness of magnesium supplementation on insulin sensitivity in women with PCOS. The 40 women were randomised to receive either 250 mg/d of magnesium or placebo for two months. The women receiving the magnesium experienced a significant reduction in serum insulin levels (p=0.036) and insulin resistance (p=0.032).[41]

Primary dysmenorrhoea (PD) is characterized by uterine cramping and pain without pelvic pathology, affecting up to 90% of menstruating females. Its aetiology is undefined, but prostaglandin F2 alpha and vasopressin hormones are implicated, causing abnormal uterine contractions and vasoconstriction, reducing uterine blood flow.[67,68] Modifiable factors, such as poor sleep, poor nutrition and high stress are associated with PD, and stress hormones adrenalin and cortisol have been observed to increase prostaglandin synthesis.[56,69]

In a Cochrane review on dysmenorrhoea management, magnesium provided greater pain relief than placebo, reducing the need for additional pain medication. Studies demonstrate significant pain reduction with 120 mg/d of elemental magnesium over six menstrual cycles (p<0.01).[70] Additional research using 200 mg/d during menstruation for three cycles showed significant reductions in pain compared with baseline (p<0.001).[67] While not fully understood, magnesium's mechanisms may involve acting as a calcium channel antagonist or attenuating prostaglandin synthesis.[71]

Evidence shows the presence of PD alongside iodine deficiency and thyroid dysfunction; hypothyroidism alters signalling pathways and concentrations of prostaglandins in uterine tissue.[35,72] Furthermore, in women with PD, improving iodine status led to reductions in uterine pain.[35] Research suggests that magnesium supplementation in conjunction with addressing iodine deficiency may provide relief for individuals experiencing PD.

The perimenopausal phase brings about menstrual irregularities and impactful symptoms, including vasomotor issues, sleep disturbances, mood swings, and urogenital tract atrophy, impacting QOL.[73] Recent findings highlight magnesium's crucial role in lessening the duration and intensity of perimenopausal symptoms.[5] Perimenopausal women are more susceptible to depression due to fluctuating hormones impacting the HPA-HPT-HPO axis, and low serum magnesium levels during perimenopause are linked to depressive symptoms.[5,74,75] Additionally, magnesium shows promise in reducing the severity and frequency of vasomotor symptoms, especially hot flushes. In a pilot trial with perimenopausal women previously treated for breast cancer, 240 mg/d of elemental magnesium, increasing to 480 mg/d if needed, resulted in a significant 41% reduction in hot flush frequency (p=0.02) and a 50% reduction in hot flush scores after four weeks. The study concluded that magnesium effectively diminishes the severity and frequency of hot flushes in women post-treatment for breast cancer, potentially through its modulation of neurotransmitter pathways involved in thermoregulation.[75]

Disclaimer: In the interest of supporting Healthcare Practitioners, all safety information provided at the time of publishing is in accordance with Natural Medicine Database (NATMED PRO), renowned for its professional monographs which include a thorough assessment of safety, warnings, and adverse effects.

For further information on specific interactions with medications, please contact Clinical Support on 1800 777 648, or via email, anz_clinicalsupport@metagenics.com

• Insufficient reliable information available; avoid using.[76]

• Contraindicated with Levodopa/Carbidopa (Sinemet); avoid this combination.[76]

[1]. Ansong E, Arhin SK, Cai Y, et al. Menstrual characteristics, disorders and associated risk factors among female international students in Zhejiang Province, China: a cross-sectional survey. BMC Women’s Heal. 2019;19(1):35. doi:10.1186/s12905-019-0730-5

[2]. Bae J, Park S, Kwon JW. Factors associated with menstrual cycle irregularity and menopause. BMC Women’s Heal. 2018;18(1):36. doi:10.1186/s12905-018-0528-x

[3]. Hantsoo L, Epperson CN. Allopregnanolone in premenstrual dysphoric disorder (PMDD): Evidence for dysregulated sensitivity to GABA-A receptor modulating neuroactive steroids across the menstrual cycle. Neurobiology Stress. 2020;12:100213. doi:10.1016/j.ynstr.2020.100213

[4]. Rafique N, Al-Sheikh MH. Prevalence of menstrual problems and their association with psychological stress in young female students studying health sciences. Saudi Med J. 2018;39(1):67-73. doi:10.15537/smj.2018.1.21438

[5]. Porri D, Biesalski HK, Limitone A, et al. Effect of magnesium supplementation on women’s health and well-being. NFS J. 2021;23:30-36. doi:10.1016/j.nfs.2021.03.003

[6]. Siahbazi S, Behboudi‐Gandevani S, Moghaddam‐Banaem L, et al. Effect of zinc sulfate supplementation on premenstrual syndrome and health‐related quality of life: Clinical randomized controlled trial. J Obstet Gynaecol Re. 2017;43(5):887-894. doi:10.1111/jog.13299

[7]. Australian Bureau of Statistics. Iodine. Published July 10, 2014. Accessed November 20, 2023. https://www.abs.gov.au/articles/iodine#:~:text=The%20NHMS%20showed%20that%20iodine,the%20national%20average%20of%2012.8%25.

[8]. Chakraborty P, Ghosh S, Goswami SK, et al. 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. doi:10.1007/s12011-012-9592-5

[9]. Gilbrech KI, Theses TEMS of NUH. The impact of stress on the menstrual cycle. Published online 2020. https://scholarworks.uark.edu/nursuht/102

[10]. Vigil P, Meléndez J, Soto H, et al. Chronic stress and ovulatory dysfunction: implications in times of COVID-19. Front Glob Women’s Heal. 2022;3:866104. doi:10.3389/fgwh.2022.866104

[11]. Tiranini L, Nappi RE. Recent advances in understanding/management of premenstrual dysphoric disorder/premenstrual syndrome. Fac Rev. 2022;11:11. doi:10.12703/r/11-11

[12]. Xing L, Xu J, Wei Y, et al. Depression in polycystic ovary syndrome: focusing on pathogenesis and treatment. Front Psychiatry. 2022;13:1001484. doi:10.3389/fpsyt.2022.1001484

[13]. Gilfarb RA, Leuner B. GABA system modifications during periods of hormonal flux across the female lifespan. Front Behav Neurosci. 2022;16:802530. doi:10.3389/fnbeh.2022.802530

[14]. Zhu Y, Wu X, Zhou R, et al. Hypothalamic-pituitary-end-organ axes: hormone function in female patients with major depressive disorder. Neurosci Bull. 2021;37(8):1176-1187. doi:10.1007/s12264-021-00689-6

[15]. Janssen JAMJL. New insights into the role of insulin and hypothalamic-pituitary-adrenal (HPA) axis in the metabolic syndrome. Int J Mol Sci. 2022;23(15):8178. doi:10.3390/ijms23158178

[16]. Pickering G, Mazur A, Trousselard M, et al. Magnesium status and stress: the vicious circle concept revisited. Nutrients. 2020;12(12):3672. doi:10.3390/nu12123672

[17]. Valsamakis G, Chrousos G, Mastorakos G. Stress, female reproduction and pregnancy. Psychoneuroendocrinology. 2019;100:48-57. doi:10.1016/j.psyneuen.2018.09.031

[18]. Jacobson MH, Howards PP, Darrow LA, et al. Thyroid hormones and menstrual cycle function in a longitudinal cohort of premenopausal women. Paediatr Perinat Ep. 2018;32(3):225-234. doi:10.1111/ppe.12462

[19]. Brown EDL, Obeng-Gyasi B, Hall JE, et al. The thyroid hormone axis and female reproduction. Int J Mol Sci. 2023;24(12):9815. doi:10.3390/ijms24129815

[20]. Jacobson MH, Howards PP, Darrow LA, et al. Thyroid hormones and menstrual cycle function in a longitudinal cohort of premenopausal women. Paediatr Périnat Epidemiology. 2018;32(3):225-234. doi:10.1111/ppe.12462

[21]. KR N, R N. Hormones of HPG-axis and their active role during chronic stress and PCOS induction: a review. Int J Sci Basic Appl Res. Published online 2022.

[22]. Kolanu BR, Vadakedath S, Boddula V, et al. Activities of serum magnesium and thyroid hormones in pre-, peri-, and post-menopausal women. Cureus. 2020;12(1):e6554. doi:10.7759/cureus.6554

[23]. Basciani S, Porcaro G. Counteracting side effects of combined oral contraceptives through the administration of specific micronutrients. Eur Rev Méd Pharmacol Sci. 2022;26(13):4846-4862. doi:10.26355/eurrev_202207_29210

[24]. Hartle JW, Morgan S, Poulsen T. Development of a model for in‐vitro comparative absorption of magnesium from five magnesium sources commonly used as dietary supplements. FASEB J. 2016;30(S1):128.6-128.6. doi:10.1096/fasebj.30.1_supplement.128.6

[25]. Schuette SA, Lashner BA, Janghorbani M. Bioavailability of magnesium diglycinate vs magnesium oxide in patients with ileal resection. Jpen-parenter Enter. 1994;18(5):430-435. doi:10.1177/0148607194018005430

[26]. Siebrecht S. Magnesium bisglycinate as safe form for mineral supplementation in human nutrition. Chemistry. Published online 2013.

[27]. Workinger JL, Doyle RobertP, Bortz J. Challenges in the diagnosis of magnesium status. Nutrients. 2018;10(9):1202. doi:10.3390/nu10091202

[28]. Vynckier AK, Canheule G, Vervaet C, et al. Types of magnesium salt and formulation solubility that determines bioavailability of magnesium food supplements. J Nutr Food Sci. 2020;10(5). doi:10.35248/2155-9600.20.10.781

[29]. Thongon N, Krishnamra N. Omeprazole decreases magnesium transport across Caco-2 monolayers. World J Gastroenterol. 2011;17(12):1574-1583. doi:10.3748/wjg.v17.i12.1574

[30]. Thongon N, Krishnamra N. Apical acidity decreases inhibitory effect of omeprazole on Mg2+ absorption and claudin-7 and -12 expression in Caco-2 monolayers. Exp Mol Med. 2012;44(11):684-693. doi:10.3858/emm.2012.44.11.077

[31]. Fathizadeh N, Ebrahimi E, Valiani M, et al. Evaluating the effect of magnesium and magnesium plus vitamin B6 supplement on the severity of premenstrual syndrome. Iran J Nurs midwifery Res. 2010;15(Suppl 1):401-405.

[32]. Retallick-Brown H, Blampied N, Rucklidge JJ. A pilot randomized treatment-controlled trial comparing vitamin B6 with broad-spectrum micronutrients for premenstrual syndrome. J Altern Complementary Medicine. 2020;26(2):88-97. doi:10.1089/acm.2019.0305

[33]. Jafari F, Amani R, Tarrahi MJ. Effect of zinc supplementation on physical and psychological symptoms, biomarkers of inflammation, oxidative stress, and brain-derived neurotrophic factor in young women with premenstrual syndrome: a randomized, double-blind, placebo-controlled trial. Biol Trace Elem Res. 2020;194(1):89-95. doi:10.1007/s12011-019-01757-9

[34]. Braun L, Cohen M. Herbs and Natural Supplements: An Evidence-Based Guide. Vol 2. 4th ed. Elsevier/Churchill Livingstone; 2014.

[35]. Gerasimova LI, Denisov MS, Samoilova AV, et al. Role of iodine deficiency in the development of menstrual disorders in young females. Sovrem Teh v Med. 2016;8(4):104-107. doi:10.17691/stm2016.8.4.14

[36]. Benvenga S, Vicchio T, Bari FD, et al. Favorable effects of myo-inositol, selenomethionine or their combination on the hydrogen peroxide-induced oxidative stress of peripheral mononuclear cells from patients with hashimoto’s thyroiditis: preliminary in vitro studies. Eur Rev Med Pharmaco. 2017;21(2 Suppl):89-101.

[37]. Talebi S, Ghaedi E, Sadeghi E, et al. Trace element status and hypothyroidism: a systematic review and meta-analysis. Biol Trace Elem Res. 2020;197(1):1-14. doi:10.1007/s12011-019-01963-5

[38]. Payer J, Jackuliak P, Kužma M, et al. Supplementation with myo-inositol and selenium improves the clinical conditions and biochemical features of women with or at risk for subclinical hypothyroidism. Front Endocrinol. 2022;13:1067029. doi:10.3389/fendo.2022.1067029

[39]. Itriyeva K. The effects of obesity on the menstrual cycle. Curr Probl Pediatr Adolesc Heal Care. 2022;52(8):101241. doi:10.1016/j.cppeds.2022.101241

[40]. Luo X, Cai WY, Ma HL, et al. Associations of serum magnesium with insulin resistance and testosterone in women with polycystic ovary syndrome. Front Endocrinol. 2021;12:683040. doi:10.3389/fendo.2021.683040

[41]. Shahmoradi S, Chiti H, Tavakolizadeh M, et al. The effect of magnesium supplementation on insulin resistance and metabolic profiles in women with polycystic ovary syndrome: a randomized clinical trial. Biol Trace Elem Res. Published online 2023:1-6. doi:10.1007/s12011-023-03744-7

[42]. Dinicola S, Unfer V, Facchinetti F, et al. Inositols: from established knowledge to novel approaches. Int J Mol Sci. 2021;22(19):10575. doi:10.3390/ijms221910575

[43]. DiNicolantonio JJ, O’Keefe JH. Myo-inositol for insulin resistance, metabolic syndrome, polycystic ovary syndrome and gestational diabetes. Open Hear. 2022;9(1):e001989. doi:10.1136/openhrt-2022-001989

[44]. Papaleo E, Unfer V, Baillargeon JP, Chiu TT. Contribution of myo-inositol to reproduction. Eur J Obstet Gyn R B. 2009;147(2):120-123. doi:10.1016/j.ejogrb.2009.09.008

[45]. Jamilian M, Farhat P, Foroozanfard F, et al. Comparison of myo‐inositol and metformin on clinical, metabolic and genetic parameters in polycystic ovary syndrome: A randomized controlled clinical trial. Clin Endocrinol. 2017;87(2):194-200. doi:10.1111/cen.13366

[46]. Asbaghi O, Fatemeh N, Mahnaz RK, et al. Effects of chromium supplementation on glycemic control in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Pharmacol Res. 2020;161:105098. doi:10.1016/j.phrs.2020.105098

[47]. Asbaghi O, Naeini F, Ashtary-Larky D, et al. Effects of chromium supplementation on lipid profile in patients with type 2 diabetes: A systematic review and dose-response meta-analysis of randomized controlled trials. J Trace Elem Med Bio. 2021;66:126741. doi:10.1016/j.jtemb.2021.126741

[48]. Hanioka N, Naito T, Narimatsu S. Human UDP-glucuronosyltransferase isoforms involved in bisphenol A glucuronidation. Chemosphere. 2008;74(1):33-36. doi:10.1016/j.chemosphere.2008.09.053

[49]. Cavalieri EL, Rogan EG. Unbalanced metabolism of endogenous estrogens in the etiology and prevention of human cancer. J Steroid Biochem Mol Biol. 2011;125(3-5):169-180. doi:10.1016/j.jsbmb.2011.03.008

[50]. Sasano H, Nagasaki S, Miki Y, Suzuki T. New developments in intracrinology of human breast cancer. Ann N York Acad Sci. 2009;1155(1):76-79. doi:10.1111/j.1749-6632.2008.03683.x

[51]. Wang M, Seippel L, Purdy Rhet al. Relationship between symptom severity and steroid variation in women with premenstrual syndrome: study on serum pregnenolone, pregnenolone sulfate, 5 alpha-pregnane-3,20-dione and 3 alpha-hydroxy-5 alpha-pregnan-20-one. J Clin Endocrinol Metab. 1996;81(3):1076-1082.

[52]. Stener-Victorin E, Holm G, Labrie F, et al. Are there any sensitive and specific sex steroid markers for polycystic ovary syndrome? J Clin Endocrinol Metab. 2010;95(2):810-819. doi:10.1210/jc.2009-1908

[53]. Rochester JR. Bisphenol A and human health: a review of the literature. Reprod Toxicol. 2013;42:132-155. doi:10.1016/j.reprotox.2013.08.008

[54]. Hall DC. Nutritional influences on estrogen metabolism. Applied Nutritional Science Reports. 2001;1:1-8.

[55]. Brown RC, Bidlack WR. Dietary magnesium depletion: p-nitroanisole metabolism and glucuronidation in rat hepatocytes and hepatic microsomal membranes. Proc Soc Exp Biol Med. 1991;197(1):85-90. doi:10.3181/00379727-197-43229

[56]. Mitsuhashi R, Sawai A, Kiyohara K, et al. Factors associated with the prevalence and severity of menstrual-related symptoms: a systematic review and meta-analysis. Int J Environ Res Public Heal. 2022;20(1):569. doi:10.3390/ijerph20010569

[57]. Kashanian M, Mazinani R, Jalalmanesh S, et al. Pyridoxine (vitamin B6) therapy for premenstrual syndrome. Int J Gynecol Obstet. 2007;96(1):43-44. doi:10.1016/j.ijgo.2006.09.014

[58]. Rosenfield RL, Ehrmann DA. The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev. 2016;37(5):467-520. doi:10.1210/er.2015-1104

[59]. Gao L, Gu Y, Yin X. High serum tumor necrosis factor-alpha levels in women with polycystic ovary syndrome: a meta-analysis. PLoS ONE. 2016;11(10):e0164021. doi:10.1371/journal.pone.0164021

[60]. González F. Nutrient-induced inflammation in polycystic ovary syndrome: role in the development of metabolic aberration and ovarian dysfunction. Semin Reprod Med. 2015;33(4):276-286. doi:10.1055/s-0035-1554918

[61]. Merviel P, James P, Bouée S, et al. Impact of myo-inositol treatment in women with polycystic ovary syndrome in assisted reproductive technologies. Reprod Health. 2021;18(1):13. doi:10.1186/s12978-021-01073-3

[62]. Greff D, Juhász AE, Váncsa S, et al. Inositol is an effective and safe treatment in polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials. Reprod Biol Endocrinol. 2023;21(1):10. doi:10.1186/s12958-023-01055-z

[63]. Asemi Z, Karamali M, Esmaillzadeh A. Metabolic response to folate supplementation in overweight women with polycystic ovary syndrome: A randomized double‐blind placebo‐controlled clinical trial. Mol Nutr Food Res. 2014;58(7):1465-1473. doi:10.1002/mnfr.201400033

[64]. Genazzani AD, Lanzoni C, Ricchieri Fet al. Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome. Gynecol Endocrinol. 2008;24(3):139-144. doi:10.1080/09513590801893232

[65]. Costantino D, Minozzi G, Minozzi E, et al. Metabolic and hormonal effects of myo-inositol in women with polycystic ovary syndrome: a double-blind trial. Eur Rev Med Pharmaco. 2009;13(2):105-110.

[66]. Hamilton KP, Zelig R, Parker AR, et al. Insulin resistance and serum magnesium levels among women with PCOS. Curr Dev Nutr. 2019;3(11):nzz108. doi:10.1093/cdn/nzz108

[67]. Gök S, Gök B, GÖK B. Investigation of laboratory and clinical features of primary dysmenorrhea: comparison of magnesium and oral contraceptives in treatment. Cureus. 2022;14(11):e32028. doi:10.7759/cureus.32028

[68]. Parazzini F, Martino MD, Pellegrino P. Magnesium in the gynecological practice: a literature review. Magnesium Res. 2017;30(1):1-7. doi:10.1684/mrh.2017.0419

[69]. Bavil DA, Dolatian M, Mahmoodi Z, Baghban AA. Comparison of lifestyles of young women with and without primary dysmenorrhea. Electron physician. 2016;8(3):2107-2114. doi:10.19082/2107

[70]. Proctor M, Murphy PA. Herbal and dietary therapies for primary and secondary dysmenorrhoea. Cochrane Db Syst Rev. 2001;(2):CD002124. doi:10.1002/14651858.cd002124

[71]. Shin HJ, Na HS, Do SH. Magnesium and pain. Nutrients. 2020;12(8):2184. doi:10.3390/nu12082184

[72]. Kowalczyk-Zieba I, Staszkiewicz-Chodor J, Boruszewska D, et al. Hypothyroidism affects uterine function via the modulation of prostaglandin signaling. Animals. 2021;11(9):2636. doi:10.3390/ani11092636

[73]. Franciscis PD, Colacurci N, Riemma G, et al. A nutraceutical approach to menopausal complaints. Medicina. 2019;55(9):544. doi:10.3390/medicina55090544

[74]. Bromberger JT, Epperson CN. Depression during and after the perimenopause. Obstet Gynecol Clin North Am. 2018;45(4):663-678. doi:10.1016/j.ogc.2018.07.007

[75]. Park H, Parker GL, Boardman CH, et al. A pilot phase II trial of magnesium supplements to reduce menopausal hot flashes in breast cancer patients. Support Care Cancer. 2011;19(6):859-863. doi:10.1007/s00520-011-1099-7

[76] Natural Medicines Database. AusDi; 2024. Accessed September 20, 2024. https://ausdi.hcn.com.au/