Abstract
Polycystic ovarian syndrome (PCOS) affects approximately 4% to 12% of reproductive age women. It is a leading cause of infertility and is also associated with increased risk of metabolic syndrome, diabetes mellitus type-2, cardiovascular disease, and endometrial cancer. In order to decrease the likelihood of patients' developing these comorbidities, it is imperative that practitioners implement adequate treatment. Standard treatment for PCOS includes the use of oral contraceptives, insulin sensitizing medications, and fertility drugs. Several dietary supplements are of interest in the management of PCOS, including inositol, n-acetyl-cysteine, L-arginine, green tea, and saw palmetto among others. This review highlights inositol in order to provide current information that can be applied to a clinical setting for the naturopathic treatment of PCOS.
Introduction
Presence of ovarian cysts, elevated androgen levels, and abnormal ovulatory function along with obesity, acne, hirsutism, and hyperinsulinemia make up the stereotypical symptoms of a PCOS patient. While all are strong indicators of the syndrome, it is now known that there are exceptions to this rule. In fact, there are numerous ways in which PCOS may manifest, making diagnosis difficult. Reports suggest only about half of women with PCOS are overweight or obese; the other half have normal body mass and are referred to as “lean” PCOS cases. Furthermore, not all women have cystic ovaries. According to the National Institutes of Health (NIH), current diagnostic criteria for PCOS include chronic anovulation plus measured hyperandrogenism in women for whom secondary causes, such as hyperprolactinemia and congenital adrenal hyperplasia, have been excluded.1
While the syndrome presents very differently in each individual, recent research has focused primarily on 2 of the most common concerns experienced by some, but not all, women with PCOS: insulin resistance and infertility. Several recent studies suggest that in combination with lifestyle modifications, dietary supplementation with inositol may help to reduce symptoms as well as risk factors associated with PCOS.
History of Inositol
German physician Johanes Joseph Scherer first identified inositol in muscle tissue in 1850. Inositol is widely distributed in food and is structurally very similar to glucose. It is a cyclic 6-carbon compound saturated with 6 hydroxy groups. Inositol’s structure allows the formation of 9 different stereoisomers. Of these, myo-inositol (MI) is the most common in the body.2 As Scherer first isolated it from muscle, it was initially called muscle sugar and later named inositol from the Greek word in-, meaning “sinew,” and -ose, meaning “sugar.”
Experiments conducted in the 1940s suggested that inositol was an essential nutrient, so it was initially classified as a B vitamin. There is no longer any evidence that this early finding is true because it is assumed that the human body can synthesize adequate amounts of inositol for its needs, which is not the case with B vitamins. Although inositol is not technically a vitamin, it is still often listed as a B vitamin in many sources.
MI is present in relatively large amounts in most animals and plants. In animal cells, it is a component of phospholipids. In plants, it is found as phytic acid,2 an organic acid that binds calcium iron and zinc and interferes with their absorption.3 Phytic acid increases insulin sensitivity, improves glucose uptake, and inhibits lipolysis.4
In 1914, R. J. Anderson first identified the structure of MI, 1 of the 2 stereoisomers of inositol found in the body.2 MI, the precursor of inositol triphosphate, regulates both follicular stimulating hormone (FSH) and thyroid-stimulating hormone (TSH) and also plays a role in regulating glucose uptake. Both MI and d-chiro inositol (DCI) mediate insulin action.5 An insulin-dependent epimerase regulates the conversion of MI into DCI.
Discussion
In 1988, Larner et al demonstrated that both forms of inositol are chemical mediators of insulin. Over the next 20 years, Larner explored the relationship between the 2 stereoisomers and suggested that individuals with diabetes mellitus type 2 have an altered MI-to-DCI ratio. Additionally, he found that DCI levels in these patients’ urine were depressed while their MI levels were elevated. Larner proposed that the imbalance was due to a defect in the conversion of MI to DCI.2 At the time that these findings were published, awareness and knowledge of PCOS was also developing, so standards for diagnosis were still undefined.
Inositol phosphoglycans (IPGs) act as a signaling pathway that mediates glucose uptake in a manner different from the insulin signaling cascade. IPGs from DCI have been shown in vitro to stimulate pyruvate dehydrogenase and activate glycogen synthase in muscle and adipose tissue in a manner similar to insulin.
IPG release is triggered by insulin when it binds to insulin receptors—or at least it should be. Understanding that IPGs were important to insulin function provided an understanding of the mechanisms of PCOS.2,6
Criteria for diagnosing PCOS were not formally established until 2003. That same year, several studies demonstrating the benefit of inositol in the treatment of PCOS were published. Although unspecified as to which form of inositol was used, a 2003 clinical trial demonstrated the positive impact of the supplement on ovarian function. In this randomized controlled trial, 136 of 281 women took 100 mg inositol twice a day. Within weeks of the start of treatment, the group receiving inositol experienced rapid follicular maturation as well as a significant reduction in weight compared to the placebo group who gained weight.7 A 2007 study highlighted the role of MI in combination with folic acid. Twenty-five women who were infertile due to PCOS took 2 g per day MI combined with folate. After 6 months of treatment, 22 of the participants experienced restoration of 1 cycle, with 18 maintaining their results at the time of follow-up. Additionally, 9 pregnancies resulted.8 In a similar study also published in 2007, 92 PCOS patients were randomized, and 45 women received either 4 g per day MI plus 400 µg folic acid, and the remainder received just folic acid and a placebo. The treatment group had a significantly higher ovulation frequency rate (25%) compared with the placebo group (15%), and the time to first ovulation was significantly shorter, 24.5 days compared with 40.5 days.9 A 2009 trial demonstrated that women receiving an MI–folic acid combination treatment had other improvements beyond ovulatory function. Women in the treatment group experienced a significant decrease in serum total testosterone, serum free testosterone, plasma triglycerides, systolic and diastolic blood pressure, and circulating insulin levels.10
In just the past 2 years, several important clinical trials have been published that help us better understand the benefits of inositol for patients with polycystic ovarian syndrome, including several studies that highlight the different roles of myo-inositol and d-chiro inositol.
In 2010, Raffone and colleagues reported the results of a trial in which 42 women with PCOS were randomized in double-blind fashion to receive either 1500 mg metformin (generally prescribed to treat diabetes) per day or 4 g MI in combination with 400 µg folic acid. Spontaneous ovulation was achieved in 65% of the patients receiving MI with 30% obtaining pregnancy. In comparison, of the women receiving metformin, only 50% ovulated spontaneously, resulting in 18.3% becoming pregnant.11 A 2012 study compared the effect of diet alone, diet combined with metformin, or diet plus metformin and MI. Weight loss was linked to use of metformin, while menstrual cycle regulation was primarily dependent on the use of MI.12 These findings suggest that both MI and metformin are helpful in restoring normal ovulatory function, although MI may be slightly more effective than metformin.
In just the past 2 years, several important clinical trials have been published that help us better understand the benefits of inositol for patients with PCOS, including several studies that highlight the different roles of MI and DCI. A 2013 article reported the outcomes of 100 women undergoing in vitro fertilization who received either a combined MI and DCI supplement (1.1 g MI and 27.6 mg DCI) or DCI only (500 mg) daily. Primary outcomes measured included quantity of mature oocytes, FSH levels, and number of grade-1 embryos. Upon completion of treatment, the women taking the MI-DCI combination produced fewer degenerated oocytes and had a greater number of mature oocytes and therefore had higher embryo quality as well as fertilization rate compared to patients taking DCI only.13
A study published in 2014 reported on 50 women with PCOS who were treated with either 4 g MI plus 400 µg folic acid or 1 g DCI plus 400 µg folic acid each day for 6 months. The authors concluded, “Both forms of inositol were effective in improving ovarian function and metabolism in patients with PCOS, although MI showed the most marked effect on the metabolic profile, whereas D-chiro-inositol reduced hyperandrogenism better.”14
A 2014 review article investigated the role of MI and DCI in the treatment of PCOS. The authors support the idea that MI improves ovarian function. Specifically, the review suggested that greater amounts of MI in follicular fluids indicate better quality oocytes. It is theorized that oocyte energy status and quality are improved due to increased glucose uptake. On the other hand, DCI may negatively impact ovary function when taken alone in high doses (more than 600 mg/d). The authors suggest a 40:1 MI-to-DCI ratio for maximized benefit.15
Studies suggest that despite patient type (lean, obese, insulin resistant, or non-insulin resistant), incorporation of MI into a treatment plan for PCOS is beneficial. In a study involving 42 overweight women, each with a body mass index (BMI) greater than 25.5, daily administration of 2 g MI and 200 µg folic acid more significantly reduced fasting insulin levels in the women with baseline insulin greater than 12 µU/mL; however, those who had insulin levels less than 12 µU/mL still benefited in endocrine parameters and insulin sensitivity.16 On the other hand, 24 women of normal weight and no presence of hyperinsulinemia received a combination of MI (1500 mg), lactoferrin (100 mg), and bromelain (20 mg) twice a day, and after 12 weeks of treatment, hormonal parameters improved, although there was no change in BMI.17
As evidenced by this review, there is support for inositol in the treatment of PCOS. With new studies being published so frequently, it is likely that the information presented here will not remain current for long. For now, it is known that, in general, both MI and DCI are therapeutic for individuals with PCOS regardless of type; however, it remains unclear whether or not dosing is dependent on the way in which the syndrome manifests. Women who present classically with PCOS have a BMI falling in the overweight-to-obese range with a noticeable accumulation of abdominal fat. For these individuals, exacerbation of symptoms usually occurs in relation to weight. On the other hand, being lean does not correlate to specific PCOS symptoms. These individuals generally do not experience proportional changes in weight with the progression of the syndrome, and there is a lower occurrence of metabolic issues, thus suggesting a correlation between increased weight and metabolic alteration.18
Conclusion
Positive outcomes were reported with MI dosing ranging from 2 g to 4 g per day. A number of studies have investigated folate in combination with the MI, but no studies appear to compare this combination with MI alone. Both forms of inositol appear to offer benefit, with MI having more impact on metabolic symptoms (blood sugar) and DCI on symptoms of hyperandrogenism (hirsutism and acne). The recent suggestion that a 40:1 MI-to-DCI ratio may be most effective is worth consideration. In cases where metformin is used, inositol supplementation, along with diet and exercise, may produce greater results in symptom reduction.
