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Supplementation of Myo & D-Chiro Inositol + MTHF Folate + Vitamin D3 and its Added Benefits for Fertility and PCOS

Polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disorder in women of reproductive age. [1] Characterized by ovulatory dysfunction, hyperandrogenism, and polycystic ovaries, PCOS is a complex condition in which the cause remains largely unknown. [1] Current treatment is generally individualized and targets the presentation of the patient’s clinical symptoms: metformin, hormonal contraceptives, and clomiphene. [1]

The supplementation of Myo Inositol (MI) + D-Chiro Inositol (DCI), MTHF folate and/or vitamin D have shown promise as alternative treatment options to alleviate symptoms of PCOS. The following briefly describes each supplement’s specific function(s) that may help improve certain PCOS symptoms – and thus, how the combination of these supplements may benefit those struggling with PCOS.

Remember to talk with your primary care doctor before starting any supplements, especially if taking other medications.

Myo & D-Chiro Inositol (MI and DCI)

MI and DCI are organic compounds that act as insulin mediators and work synergistically in the processes that increase insulin sensitivity in tissues [2] and in glucose metabolism. [3]

Increasing research evidence has shown that insulin resistance (IR), commonly observed in women with PCOS, as the link between the cardiometabolic and reproductive disorders of PCOS. [4]

Also observed in women with PCOS: the imbalance of MI/DCI ratio in tissues. This altered ratio occurs in “diseased states,” such as with IR. [5]

Thus, it’s hypothesized that the supplementation of MI and DCI can restore that balance and thus, may help alleviate insulin resistance. [3] Correcting insulin resistance then reduces circulating insulin and androgen, [2] preventing the domino-style effects that ultimately manifest as symptoms of PCOS. Numerous research and clinical studies have shown therapeutic benefits and improvement of symptoms in women with PCOS. [6]

MTHF

Although folate is the umbrella term used to describe the different forms of vitamin B9, there is a difference between folic acid and folate. [7]

Folic acid is the synthetic form that is often used in fortified foods and supplements, while natural folate can be found in whole foods (leafy green vegetables, beans, and citrus fruit). [7]

Both forms need to be converted in our body by the enzyme MTHFR to the final form called L-methylfolate (also known as 5-MTHF). [8, 9]

5-MTHF is the predominant, natural and bioactive form of folate that is transported to tissues for metabolism. [9, 8] There is no difference between MTHF and 5-MTHF. These terms are used interchangeably and are both folate in the monoglutamyl form. [10]

5-MTHF may be more well absorbed, have higher bioavailability, and reduce the potential for masking vitamin B12 deficiency compared to folic acid. [11, 12] For individuals with the MTHFR gene mutation (inability to convert synthetic folic acid into active methylfolate), 5-MTHF supplementation may be more beneficial than folic acid. [9, 13] In a 2014 meta-analysis study, researchers found that specific MTHFR gene mutations may increase susceptibility to PCOS. [14]

In the body, folate functions as a coenzyme in the metabolism of amino acids and in the synthesis of DNA and RNA. [9] One of the most important chemical reactions that depend on folate (particularly methylfolate) is the conversion of homocysteine to methionine. [9] Thus, a lack of 5-MTHF (commonly caused by the MTHFR gene mutation) may lead to increased homocysteine levels. [9]

Women with PCOS typically have higher homocysteine levels compared to women who don’t have PCOS. [8] Several studies have found a strong association between insulin resistance and elevated homocysteine levels in women with PCOS. [15, 16, 17]

5-MTHF has been shown to increase insulin sensitivity and maintain stable folate levels, thus potentially restoring normal homocysteine levels. [11] A 2018 study showed that there was a negative correlation between homocysteine levels and 5-MTHF levels, suggesting that the supplementation of 5-MTHF may lower homocysteine levels. [18]

Vitamin D3

Vitamin D3 (cholecalciferol) is naturally produced in the body when the skin is exposed to UVB rays from sunlight which triggers its synthesis. [19] Vitamin D3 can also be obtained from the diet in animal foods (fatty fish, egg yolk, etc.) [20] (Wholesome Story's Vitamin D3 is derived from lichen, which is a vegan source of cholecalciferol). Vitamin D2 (ergocalciferol) is an analog that is photosynthesized in mushrooms and yeast, and generally used in fortifying foods. [19]

Both these forms are inactive precursors of vitamin D and need to be converted in the liver and kidneys to the biologically active form, calcitriol. [19]

The difference?

A meta-analysis study found that the vitamin D3 supplements tended to raise the serum concentrations more and sustained the levels for a longer period of time than vitamin D2. [20]

Generally, some prefer the vitamin D3 form as it’s organically produced in the body and naturally found in most foods that are rich in the vitamin. [20]

Adequate vitamin D levels are associated with insulin sensitivity and normal functioning of the pancreatic β-cells, while deficiency may cause impaired insulin resistance and glucose tolerance. [19]

It’s been hypothesized that vitamin D deficiency may be the link between insulin resistance and PCOS. [21] The active vitamin D receptor (VDR) complex regulates genes that are essential for the metabolism for glucose and lipids, and has been identified in numerous tissues including pancreatic β-cells and reproductive organs. [21, 22]

A 2013 systematic review and 2015 meta-analysis have showed an association between low vitamin D status and the metabolic and hormonal abnormalities in PCOS. [21, 23]

A 2018 cross-sectional study suggested that: [22]

  1. Women with PCOS have significantly lower serum vitamin D levels compared to fertile control subjects, and
  2. That low serum vitamin D status is “significantly associated with a higher insulin resistance in women with PCOS – independent of major confounders such as BMI, season and ethnicity.”

    Although with inconsistent overall research results, a few studies have indicated that vitamin D supplementation may have a beneficial effect on insulin resistance [24, 25, 26] – including a meta-analysis study which suggested that vitamin D supplementation of PCOS individuals may improve insulin sensitivity. [27]

     

    Article References:

    [1] Williams, T., Mortada, R., & Porter, S. (2016). Diagnosis and treatment of polycystic ovary syndrome. American Family Physician, 94(2), 106-113. Retrieved from: https://www.aafp.org/afp/2016/0715/p106.html#sec-5

    [2] Benelli, E., Del Ghianda, S., Di Cosmo, C., & Tonacchera, M. (2016). A combined therapy with myo-inositol and d-chiro-inositol improves endocrine parameters and insulin resistance in PCOS young overweight women. International Journal of Endocrinology. DOI: http://dx.doi.org/10.1155/2016/3204083

    [3] Sortino, M. A., Salomone, S., Carruba, M. O., & Drago, F. (2017). Polycystic ovary syndrome: insights into the therapeutic approach with inositols. Journal Frontiers in Pharmacology, 8(341), 1-13. DOI: 10.3389/fphar.2017.00341

    [4] Troisi, J., Cinque, C., Giugliano, L., Symes, S., Richards, S., Adair, D., Cavallo, P., Sarno, L., Scala, G., Caiazza, M., & Guida, M. (2019). Metabolomic change due to combined treatment with myo-inositol, d-chiro-inositol and glucomannan in polycystic ovarian syndrome patients: a pilot study. Journal of Ovarian Research, 12(25). DOI: https://doi.org/10.1186/s13048-019-0500-x

    [5] Kalra, B., Kalra, S., & Sharma, J. (2016). The inositols and polycystic ovary syndrome. Indian Journal of Ednocrinology and Metabolism, 20(5), 720-724. DOI: 10.4103/2230-8210.189231

    [6] Unfer, V., Facchinetti, F., Orru, B., Giordani, B., & Nestler, J. (2017). Myo-inositol effects in women with PCOS: a meta-analysis of randomized controlled trials. Endocrine Connections, 6(8), 647-658. DOI: 10.1530/EC-17-0243

    [7] Centers of Disease Control and Prevention. (2018, April 11). Folic acid. https://www.cdc.gov/ncbddd/folicacid/faqs/faqs-general-info.html 

    [8] Melitis, C. Folate vs. folic acid – facts about vitamin B. American Pregnancy Association.   https://americanpregnancy.org/infertility/folate-vs-folic-acid-what-you-need-to-know/

    [9] National Institutes of Health. (2020, March 11). Folate. https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/

    [10] Lynch, B. L-methylfolate, methylfolate, 5-MTHF, L-5-MTHF. What is the difference?! http://mthfr.net/l-methylfolate-methylfolate-5-mthf/2012/04/05/

    [11] Stracquadanio, M., Ciotta, L., & Palumbo, M. A. (2018). Effects of myo-inositol, gymnemic acid, and L-methylfolate in polycystic ovary syndrome patients. Gynecological Endocrinology, 34(6), 495-501. DOI: 10.1080/09513590.2017.1418852

    [12] Scaglione, F., & Panzavolta, G. (2014). Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica, 44(5), 480-488. DOI: 10.3109/00498254.2013.845705

    [13] Obeid, R., Holzgreve, W., & Pietrzik, K. (2013). IS 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects? Journal of Perinatal Medicine, 41(5), 469-483. DOI: 10.1515/jpm-2012-0256

    [14] Fu, L., Dai, L., Li, X., Zhang, K., & Bai, Y. (2014). Association of methylenetetrahydrofolate reductase gene C677T polymorphism with polycystic ovary syndrome risk: a systematic review and meta-analysis update. European Journal of Obstetrics, Gynecology, and Reproductive Biology, 172, 56-61. DOI: 10.1016/j.ejogrb.2013.10.001

    [15] Diwaker, A., & Kishore, D. (2018). Evaluation of plasma homocysteine levels in patients of PCOS. The Journal of the Association of Physicians of India, 66(10), 17-20. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/31317701/?from_term=pcos+homocysteine&from_pos=1

    [16] Schachter, M., Raziel, A., Friedler, S., Strassburger, D., Bern, O., & Ron-El, R. (2003). Insulin resistance in patients with polycystic ovary syndrome is associated with elevated plasma homocysteine. Human Reproduction, 18(4), 721-727. DOI: 10.1093/humrep/deg190

    [17] Badawy, A., State, O., Sh Abd El Gawad, S., & Abd El Aziz, O. (2007). Plasma homocysteine and polycystic ovary syndrome: the missed link. European Journal of Obstetrics, Gynecology, and Reproductive Biology, 131(1), 68-72. DOI: 10.1016/j.ejogrb.2006.10.015

    [18] Saadeh, N., Alfaqih, M. A., Mansour, H., Khader, Y. S., Saadeh, R., Al-Dwairi, A., & Nusier, M. (2018). Serum homocysteine is associated with polycystic ovary syndrome in Jordan. Biomedical Reports, 9(5), 439-445. DOI: 10.3892/br.2018.1149

    [19] Linus Pauling Institute. (2017, October). Vitamin D. https://lpi.oregonstate.edu/mic/vitamins/vitamin-D

    [20] Harvard T.H. Chan School of Public Health. (2020, March). Vitamin D. https://www.hsph.harvard.edu/nutritionsource/vitamin-d/

    [21] Krul-Poel, Y. H. M., Snackey, C., Louwers, Y., Lips, P., Lambalk, C. B., Laven, J. S. E., & Simsek, S. (2013). The role of vitamin D in metabolic disturbances in polycystic ovary syndrome: a systematic review. European Journal of Endocrinology, 169(6), 853-865. DOI: 10.1530/EJE-13-0617

    [22] Krul-Poel, Y. H. M., Koenders, P. P., Steegers-Theunissen, R. P., Ten Boekel, E., Ter Wee, M. M., Louwers, Y., Lips, P., Laven, J. S. E., & Simsek, S. (2018). Vitamin D and metabolic disturbances in polycystic ovary syndrome (PCOS): a cross-sectional study. PLoS One, 13(12). DOI: 10.1371/journal.pone.0204748

    [23] He, C., Lin, Z., Robb, S. W., & Ezeamama, A. E. (2015). Serum vitamin D levels and polycystic ovary syndrome: a systematic review and meta-analysis. Nutrients, 7(6), 4555-4577. DOI: 10.3390/nu7064555

    [24] Thomson, R. L., Spedding, S., Buckley, J. D. (2012). Vitamin D in the aetiology and management of polycystic ovary syndrome. Clinical Endocrinology, 77(3), 343-350. DOI: 10.1111/j.1365-2265.2012.04434.x

    [25] Dastorani, M., Aghadavod, E., Mirhosseini, N., Foroozanfard, F., Modarres, S. Z., Siavashani, M. A., & Asemi, Z. (2018). The effects of vitamin D supplementation on metabolic profiles and gene expression of insulin and lipid metabolism in infertile polycystic ovary syndrome candidates for in vitro fertilization. Reproductive Biology and Endocrinology, 16(1), 94. DOI: 10.1186/s12958-018-0413-3

    [26] Javed, Z., Papageorgiou, M., Deshmukh, H., Kilpatrick, E. S., Mann, V., Corless, L., Abouda, G., Rigby, A. S., Atkin, S. L., & Sathyapalan, T. (2019). Nutrients, 11(1), 188. DOI: 10.3390/nu11010188

    [27] Kagowska, K., Bajerska, J., & Jamka, M. (2018). The role of vitamin D oral supplementation in insulin resistance in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials. Nutrients, 10(11), 1637. DOI: 10.3390/nu10111637

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