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Research on the benefits of potential new therapies, particularly therapies that interest us as naturopathic doctors, rarely advances in a straight line. While one study looks good, the next study doesn't. Sometimes we can blame this on study size and magnitude of change; the number of participants is too few and the amount of change brought on by the intervention is too small and together this prevents statistical significance. Yet sometimes even big studies in which we think things are pretty well proven take a turn. The recent Holmes aspirin for breast cancer paper comes to mind.
In 2010 Michelle Holmes et al. reported in the Journal of Clinical Oncology that regular aspirin use reduced the risk of breast cancer recurrence. Using observational data from 4164 women diagnosed with breast cancer who were part of the Nurses' Health Study, they reported that taking aspirin 2 to 5 times per week was associated with a 71% decrease in risk of recurrence ( RR: 0.29: 95% CI, 0.16 to 0.52).1 These are clinically significant numbers, and while many of our patients were reluctant to use aspirin, we have been obligated to encourage breast cancer patients to do so.
In a second and quite similar study, Holmes reported in June 2014 that in a cohort of 27,426 Swedish women there was no association between aspirin use and BC recurrence.2 Many of us are accustomed to research going back and forth, first it's good, now it's bad; this is how science usually works.
With this in mind, we noticed and want to tell you about something that seems to be an exception to the typical faltering pattern, an idea that so far has advanced in a straight line. As we have watched the growing body of research on the use of inositol for treating polycystic ovarian syndrome (PCOS), it seems to be moving forward steadily. The evidence supporting use of inositol in PCOS just gets better and better with each new publication.
Inositol was first isolated and identified by Johanes Joseph Scherer, who isolated it from muscle tissue in 1850. The name itself comes from a Greek word that means "sinew sugar." In the body, inositol is found as a component of phospholipids. In 1903, Theodor Hartig reported that phytates were high in inositol, and the terms phytic acid and inositol are still sometimes interchanged.3 We sometimes worry about foods high in phytic acids, as these compounds block mineral absorption, in particular iron. Interestingly, phytic acids increase insulin sensitivity.4 Up until the mid part of the last century, it was believed that inositol was a vitamin. Though this has been disproved, we often find it mentioned or listed in association with B vitamins.
Two stereoisomers of inositol found in the body are important in this discussion. The first, myo-inositol (MI), was identified in 1914 by Anderson. MI regulates both follicule stimulating hormone (FSH) and thyroid stimulating hormone (TSH). It also contributes to regulation of glucose uptake. MI may be converted into a second stereoisomer called D-chiro-inositol (DCI) by an insulin-dependent enzyme. DCI regulates glucose uptake and glycogen synthesis.
Larner et al. reported in 1988 that both stereoisomers, MI and DCI, mediate insulin action. Over the next two decades, Larner continued to investigate the role of these two inositol forms in type 2 diabetes (DM-2). People with DM-2 have altered ratios of MI to DCI. Their DCI urine levels are lower than in healthy people, and their MI levels are elevated. Lerner theorized that the fault was in the epimerization process, the conversion of MI to DCI.5
The time period when Larner's research was published overlaps the years in which PCOS became clearly defined as a disease.
While some practitioners blame PCOS on modern lifestyle, diet, and resultant obesity and insulin insensitivity, such a view is likely in error. Reports of women with symptoms that sound suspiciously like PCOS are noted throughout medical history.
Hippocrates describes "those women whose menstruation is less than three days or is meager, are robust, with a healthy complexion and a masculine appearance; yet they are not concerned about bearing children nor do they become pregnant."6
Moses Maimonides (1135–1204 AD) noted, "There are women whose skin is dry and hard, and whose nature resembles the nature of a man. However, if any woman's nature tends to be transformed to the nature of a man, this does not arise from medications, but is caused by heavy menstrual activity."7
PCOS is theorized to have originated in Paleolithic hunter-gatherer communities, a time at which PCOS provided survival advantage. Individuals with the greatest capacity for energy storage necessary to endure episodes of hunger, the "thrifty genotypes," have an advantage in societies that lack grocery stores or food stamps. PCOS, because it is a "thrifty genotype," would have enhanced survival during times of food shortage, as insulin resistance would have lowered energy expenditure and been an evolutionary advantage.
While modern PCOS women are able to conceive, though at a lower than normal rate, it is possible that in earlier times when caloric intake was lower and energy expenditures greater, the pregnancy rates of PCOS women may have been significantly higher than at present.8
PCOS is characterized by the presence of ovarian cysts, elevated androgen levels, and abnormal ovulatory function. According to the current National Institute of Health (NIH) definition, two of the three criteria must be met in order to make a diagnosis.9 Key features include obesity, acne, and hirsutism. However, PCOS presents in a variety of ways, so diagnosis is often difficult. While the stereotypical PCOS patient has a high body mass index (BMI), hirsutism, and hyperinsulinemia, this image is not the rule. Only about half of women with PCOS are obese; the other half have a normal body mass; this later group is referred to as "lean" PCOS. The other classic symptom, hyperinsulinemia, may or may not be present.
While the symptom picture of PCOS is ancient, actual criteria for diagnosing PCOS were not established by NIH until 2003. That same year saw the publication of the first of several studies demonstrating the benefit of inositol in the treatment of PCOS.
Gerli et al. reported a positive impact from inositol on ovarian function. In their randomized controlled trial, 136 of 281 women took just 100 mg of 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 with the placebo group, who gained weight.10 A 2007 study by Papaleo et al. described the effect of MI combined with folic acid. Twenty-five infertile PCOS women took 2 grams of MI per day combined with folate. After 6 months of treatment, 22 of the participants experienced restoration of one cycle with 18 maintaining their results at the time of follow-up. Additionally, nine pregnancies resulted.11 In a second study by Gerli's team, also published in 2007, 92 PCOS patients were randomized and 45 women received 4 g/day of MI plus 400 mcg of folic acid; the remainder received just folic acid and a placebo. The treatment group had a significantly higher ovulation frequency rate (25%) compared with the placebo (15%), and the time to first ovulation was significantly shorter: 24.5 days compared with 40.5 days.12 Constantino's 2009 trial reported that women receiving MI plus folic acid combination had other improvements beyond ovulatory function. Women in the treatment group experienced significant decreases in serum total testosterone, serum free testosterone, plasma triglycerides, systolic and diastolic blood pressure, and circulating insulin levels.13
Raffone et al. reported in 2010 the results of a trial in which 42 women with PCOS were randomized in a double-blind fashion to receive either 1500 mg of metformin/day or 4 grams of myo-inositol in combination with 400 mcg of 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.14 Le Donne et al. reported in 2012 results from a comparison 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.15 These findings suggest that both MI and metformin are helpful in restoring normal ovulatory function, and that 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 myo-inositol and d-chiro-inositol.
Colazingari's December 2013 paper reported outcomes of 100 women undergoing in vitro fertilization who received either a combined MI + DCI supplement (1.1 g MI and 27.6 mg DCI) or just DCI (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 amount of mature oocytes and therefore a higher embryo quality as well as fertilization rate.16
Pizzo in a March 2014 study reported on 50 women with PCOS, who were treated with either 4 grams of MI plus 400 mcg of folic acid or 1 gram of DCI plus 400 mcg of folic acid each day for 6 months.
"Both the forms of inositol were effective in improving ovarian function and metabolism in patients with PCOS, although myo-inositol showed the most marked effect on the metabolic profile, whereas D-chiro-inositol reduced hyperandrogenism better."17
Studies suggest that despite 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 with BMIs greater than 25.5, improvements due to MI (2 g/day) and folic acid (200 mcg/d) were found to be more significant in the group that had baseline fasting insulin levels greater than 12 µU/mL; however, the women who had insulin levels less than 12 µU/mL still benefited in endocrine parameters and insulin sensitivity.18 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) 2 times per day, and after 12 weeks of treatment hormonal parameters improved; however, there was no change in BMI.19
As can be seen, research on PCOS is progressing not just rapidly but steadily; there doesn't seem to be the common phenomenon of a step backward for every few steps forward. With new studies' being published so frequently, it is likely that the information we have just presented will not remain current for long. Of course we worry that, having described this information in the manner we have, negative studies will now come to light. Still, for the time being, things look straightforward.
For now, research suggests that both myo-inositol and D-chiro-inositol are therapeutic for individuals with PCOS regardless of type. It's a bit fuzzy whether or how the ratio between isomers should be adjusted depending on symptoms, but we suspect that this will become clearer in the future. It may be that one ratio is more appropriate for women with higher BMIs, as this presentation is associated with more metabolic alterations.20
Positive outcomes have been reported with dosing usually ranging from 2 to 4 g per day; however, additional benefit is suggested when various other supplements and modalities are used in combination with the inositol. Specifically, incorporating some amount of folic acid into a treatment plan may lead to better results, particularly in regard to ability to conceive. Both forms of inositol appear to offer benefit, with the MI having more impact on metabolic symptoms (blood sugar) and the DCI on hyperandrogenism (hirsutism and acne). In cases where metformin is used, inositol supplementation, along with diet and exercise, may produce greater results in symptom reduction.
We spend so much of our time trying to make sense of the discrepancies in research findings, it is a pleasant change to feel as if the studies are making sense, or at least moving in a consistent direction.
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