The Effects of Inositol on PCOS

Written By Laura Pollard

Polycystic ovary syndrome (PCOS) is an endocrine, metabolic and reproductive disorder that affects 4%-20% of women of childbearing age [1].In PCOS the eggs in the ovaries are unable to mature efficiently and cannot be released, resulting in small cyst formations and ovarian inflammation [2]. This condition is associated with such events as anovulation, insulin resistance, dyslipidemia, obesity, hormonal imbalances (elevated androgen levels, LH/FSH ratios, etc.), and ovulatory dysfunction [3]. In fact, the presence of PCOS puts an individual at a significantly higher risk of developing type 2 diabetes, gynecologic carcinomas, cardiovascular disease, and certain psychological conditions [1].  

     Inositol is a chemical compound and nutrient discovered in 1936 and is commonly found in such foods as legumes, meat, citrus fruit, and whole grains in the most common form of Myo-inositol (MI)[4] .In the body, Myo-inositol often undergoes epimerization to form D-chiro inositol (DCI) to create a healthy MI/DCI balance [5].Recently is has been a custom to treat PCOS with insulin-sensitizing drugs such as metformin; However, the use of drugs often exhibits unpleasant side effect[6]. Recently there have been many studies performed help us understand the association between PCOS and the inositol stereoisomers; this will help us develop a gentle yet effective treatment plan for PCOS individuals. 

 

Myo-inositol versus D-Chiro Inositol

     With so many pathophysiological factors associated with the manifestation and exacerbation of PCOS, there have been many theories and studies performed regarding the mechanism of action of MI and DCI. It is known that a healthy MI/DCI ratio varies in different tissues of the body. In women with PCOS the inositol ratio is reported to be higher than normal in peripheral tissues but lower than normal within the follicular fluid of the ovaries; in fact, it is expressed that the MI/DCI ratio of the follicular fluid of a healthy woman is approximately 100: 1 while the average ratio seen in PCOS women is 0.2:1[5]. Lower DCIlevels in the peripheral tissues lead to insulin resistance and promote high blood glucose levels, while and the higher DCI levels in the follicular fluid leads to insulin sensitivity of the thecal and granulosa cells, and thus impedes the proper maturation of oocyte[7].

     In the past, many studies have tried to prove either MI or DCI as the better agent for treating PCOS; however, more recent studies demonstrate that treatment consisting of a balanced ratio between the two is most effective. There is increasing evidence that both MI and DCI help to alleviate the pathologies of PCOS in very similar ways. MI and DCI have both shown the ability to regulate hormone levels and stabilize insulin response; however, MI demonstrates a greater ability to increase embryo and oocyte quality [8]. Alternatively, DCI is recognized to regulate menses and increase insulin sensitivity in peripheral tissues more efficiently [8]. Both forms of inositol have exhibited the ability to decrease the manifestation of certain conditions associated with PCOS.   

Effects relating to Cardiovascular disease and type 2 diabetes

    When the severity of PCOS is allowed to progress many complications can arise, such as type 2 diabetes; accordingly, it may be possible to prevent or manage the manifestation of such issues with the use of MI and DCI. A DCI deficiency in peripheral tissues may cause insulin resistance in PCOS women; controversially, it has also been observed that an increase in insulin resistance further exacerbates DCI deficiency by impeding the epimerization of MI to DCI [9]. Urinary clearance of DCI in women with PCOS is nearly six times greater than that of healthy women, indicative of a possible impairment of renal (kidney) clearance; this contributes to DCI deficiency [10]. A study conducted in 2014 found that DCI therapy of 500 mg daily for 3 months shows an improved insulin response during an oral glucose tolerance test, with greater improvement in women who have a family history of type 2 diabetes, similar to the effects of MI [11]. Additionally, taking 400 mg of DCI with folic acid and magnesium during pregnancy positively influences insulin response and significantly reduces the risk of gestational diabetes in women with PCOS[4]. In addition to type 2 diabetes, MI and DCI also contribute to preventing cardiovascular disease. 

     PCOS is also associated with cardiovascular diseases in which unhealthy lipid profiles and high-intensity C-reactive protein (hs-CRP) levels, common in women with PCOS, contribute to poor cardiovascular health.  Cardiovascular risk is associated with high levels of hs-CRP and dyslipidemia in women with PCOS. After 12 weeks of receiving 1.5g of MI twice a day, hs-CRP notably declined, resulting in a reduced occurrence of pro-inflammatory states and decreasing the risk for cardiovascular disease [11]. A combination of MI and DCI therapy also shows potential to reduce cardiovascular risk. After approximately six months of MI/DCI treatment, a significant decrease in LDL and triglycerides, and an increase in HDL levels can be seen; it is predicted that MI/DCI therapy reduces the risk of cardiovascular disease approximately 40:1[12]. Along with reducing the risk of developing diabetes and cardiovascular disease, MI and DCI treatment have been shown to improve reproductive health in women with PCOS. 

Effects on embryo oocytes and pregnancy

     There is strong that suggests MI signals for FSH and that DCI increases signaling for insulin sensitivity in the ovaries; therefore, the lower than normal MI/DCI ratio in the follicular fluid is linked to the high LH/FSH ratio and theca insulin sensitivity characteristic of PCOS women[5]. The reduction of epimerization of MI to DCI in ovarian tissue would decrease DCI concentration and, thus, d-chiro glycan (INS-2) mediated insulin sensitivity [7]. Positive results in ovarian function are seen in either MI or DCI treatment. Myo-inositol treatment consisting of 2g MI per day for 12 weeks can promote better oocyte quality with the same dimensions as oocytes from non-PCOS women [13]. DCI treatment displays antioxidant properties upon examining follicular proteins and is shown to act similarly, if not the same, to the anti-diabetic drug metformin: it increases oocyte number and quality by reducing oxidative stress, indicative of the higher levels of protein free-SH in follicular fluid, in addition to reducing BMI and increasing insulin sensitivity[6][14]. However, while the number of oocytes released during ovulation seems to be slightly higher with solely DCI treatment, the number of immature and degenerated oocytes is significantly lower with combination treatment; therefore, combined MI and DCI therapies hold the potential to increase further the quality of embryos and oocytes released by the ovaries;[9]. MI and DCI treatment have also shown to improve the ability to conceive and improve embryo development.

     As PCOS is the leading cause of infertility in women of child-bearing age, techniques in increasing fertility have been thoroughly examined; recently MI and DCI treatment have been examined as an option to alleviating infertility. An animal study involving the exposure of mice embryos to MI discovered that MI is particularity important in the early development of an embryo prior to implantation. Even in a subject without PCOS, a higher rate of cleavage was observed, and it was noted that blastocysts presented expansion and consisted of more blastomeres than those without treatment [15].Additionally, fertilization rate can be dramatically increased with the use of combination therapy [15]. After 60 days of combined treatment with added magnesium and folic acid, another study revealed that combination therapy could dramatically increase fertility in PCOS patients [4]. Even treatments consisting solely of MI show an increase in ovulation occurrence and a pregnancy rate increase up to 60% compared to 32%[13]. 

Future Research

     While currently, studies have revealed many important and useful properties of MI and DCI, there are some questions yet to be answered. Even people with PCOS tend to display different bodily requirements from each other; this provides an opportunity to research whether or not a “personal-dose” of MI and DCI is required for optimal results. Also, while some studies have been conducted to determine post-implantation embryo quality in humans and pre-implantation embryo health in mammals, little research has been done to determine how MI and DCI effect the quality of a pre-implanted embryo within a PCOS human environment.  Lastly, Due to the lack of agreed upon cell lines to study, epimerization has not been thoroughly examined in peripheral tissues; a thorough understanding of epimerization in ovarian and peripheral tissues would assist in determining the best delivery methods and doses of MI and DCI to give. Never-the-less the research encompassing the effects of inositol on PCOS suffers is very promising and a step forward in PCOS treatment advancements. 

 

References

  1. Teede H et al. Polycystic Ovary syndrome: a complex condition with psychological, reproductive, and metabolic manifestations that impacts health across the life span. BMC Medicine 2010; 8(41):1-10.
  2. Duleba AJ, Foyouzi N, Karaca M, Pehlivan T, Kwintkiewicz J, BehrmanHR. Proliferation of ovarian theca-interstitial cells is modulated byantioxidants and oxidative stress. Hum Reprod 2004; 19:1519–1524.
  3. Kuscu NK, Var A. Oxidative stress but not endothelial dysfunction exists in non-obese, young group of patients with polycystic ovary syndrome. Acta Obstet Gynecol Scand 2009;88:612–617.
  4. Malvasi A et al. Myo-inositol, D-chiroinositol, folic acid and manganese in second trimester pregnancy: a preliminary investigation. Eur Rev Med Pharmacol Sci 2014; 18:270-274. 
  5. Unfer V, Carlomagno G, Papaleo E, Vailati S, Candiani M, Baillargeon J. Hyperinsulinemia Alters Myoinositol to D-chiroinositol Ratio in the Follicular Fluid of Patients With PCOS. Repr Sci 2014; 21(7): 854-858. 
  6. Piomboni P, Focarelli R, Capaldo   A, Stendardi A, Cappelli V,  Cianci A, La Marca A, Luddi A, De Leo V. Protein modification as oxidative stress marker in follicular fluid from women with polycystic ovary syndrome: the effect of inositol and metformin. J Assist Reprod Genet 2014; 31:1269–1276 
  7. Heimark D, McAllister J,  Larner J. Decreased myo-inositol to chiro inositol (m/c) ratios and increased m/c epimerase activity in PCOS theca cells demonstrate increased insulin sensitivity compared to controls.Endocr J 2014; 61(6): 111-117. 
  8. Pizzo A, Lagana A S, Barbaro L. Comparison between effects of myo-inositol and D-chiro-inositol on ovarian function and metabolic factors in women with PCOS. Gynecol Endocrinol, 2014; 30(3): 205–208. 
  9. ColazingariS,  Mariangela Treglia M,  Najjar R, Bevilacqua A. The combined therapy myo-inositol plus D-chiro-inositol, rather than D-chiro-inositol, is able to improve IVF outcomes: results from a randomized controlled trial. Arch Gynecol Obstet 2013; 288:1405–1411.  
  10. Baillargeon J, Diamanti-Kandarakise E,  Ostlund R E, Apridonidze T, Iuorno M, Nestler J E. Altered D-Chiro-Inositol Urinary Clearance in Women With Polycystic Ovary Syndrome. Diabetes Care 2006; 29(2): 300-305.
  11. Genazzani A D, Santagni S, Rattighieri E,  Chierchia E, Despini G, Marini G, Prati A, Simoncini T. Modulatory role of D-chiro-inositol (DCI) on LH and insulin secretion in obese PCOS patients. Gynecol Endocrinol, 2014; 30(6): 438–443. 
  12. Minozzi M, Nordio M, Pajalich R. The combined therapy myo-inositol plus D-Chiro-inositol, in a physiological ratio, reduces the cardiovascular risk by improving the lipid profile in PCOS patients. Eur Rev Med Pharmacol Sci 2013; 17:537-540.  
  13. Artini P G, Di Berardino O M, Papini F, Genazzani A D, Simi G, Ruggiero M, Cela V. Endocrine and clinical effects of myo-inositol administration in polycystic ovary syndrome. A randomized study. Gynecol Endocrinol 2013; 29(4): 375–379. 
  14. Fruzzetti f, Perini D, Russo M, Bucci F, Gadducci A. Comparison of two insulin sensitizers, metformin and Myo-inositol, in women with polycyctic ovary syndrome(PCOS). Gynecol Endocrinol. 2017; 33(1): http://dx.doi.org/10.1080/09513590.2016.1236078
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