Sunday, January 4, 2015

Recent Studies on Inositol for PCOS

Here are the abstracts of some new studies on the use of inositol (d-chiro-inositol or myo-inositol) in women with Polycystic Ovarian Syndrome (PCOS).

Inositol is a naturally-occurring substance in our foods that helps us process insulin properly. Normally, our bodies convert substances in plants and animals into several different forms of inositol. Two of these inositols are used in insulin-signaling pathways. However, some research suggests that women with PCOS do not use inositol properly, leading to insulin-signaling problems. 

These defects in insulin signaling means that the body has to over-produce insulin to compensate. The insulin that is produced does not get used properly, causing excess amounts to stay in the body.

This in turns stimulates the production of androgens ("male" hormones), leading to an imbalance in hormones in the body and many of the distressing symptoms of PCOS (including hirsutism, alopecia, acne, and difficulty ovulating).

And because the body struggles to use its insulin properly, this can lead to increased blood sugar issues over time. This is why many women with PCOS become diabetic at some point in their lives.

Now, however, emerging research suggests that supplementing the body with these inositols may help insulin signaling, thus lowering insulin resistance and improving blood sugar. It may even help lessen PCOS symptoms.

We've discussed inositols before in detail, here, which can be read for a good start on the subject. But right now let's take a look at some of the latest thinking on inositols, as well as on studies that have been released since that original post or were not cited in it.

How Inositols Work in Insulin Signaling

First, a little background for those new to the topic.

Inositols act as "second messengers" in insulin signaling. They play a very important role in how we use insulin.

Insulin produced by the body binds to insulin receptors on the cell walls. From there, the receptor generates second messengers (inositolphosphoglycans, or IPGs) to relay and amplify the signal to help the body use the insulin effectively.

But women with PCOS seem to have a defect in their second messenger pathway. This could explain why they have such strong insulin resistance. One PCOS resource simplifies it this way:
When we eat foods (mostly carbohydrates), they get converted into glucose in our blood stream. We need the glucose to enter our cells to be used for energy. When blood glucose levels rise, a signal (imagine a doorbell is rung) is sent from the cell door to the nucleus telling it to open up. However, with PCOS, the doorbell on the cell door may be defective. This means that it takes longer for the cells to open its doors to glucose resulting in higher amounts of insulin needing to be secreted. Secondary messengers acts to repair the doorbell so that the cell doors open in response to glucose, resulting in less insulin needing to be secreted. 
Improving this second messenger pathway could also become a radical new way of treating PCOS. As one review noted:
The discovery that the impairment in the insulin signalling could be due to a defect in the inositolphosphoglycans (IPGs) second messenger pathway opened a new horizon in the clinical management of PCOS. IPGs are known to have a role in activating enzymes that control glucose metabolism. In PCOS women, a defect in tissue availability or altered metabolism of inositol or IPGs mediators may contribute to insulin resistance
So the problem in PCOS may simply be errors in the second messenger insulin signaling pathway, and treating women with some form of inositol may help bridge the errors in this pathway.

The question is, which is the most effective form of inositol and should the type/dosage used depend on its purpose?

Which Form of Inositol Works Best?

Two forms of inositol get the most attention in PCOS research:
  • myo-inositol (MI or MYO)
  • d-chiro-inositol (DCI)
Both are forms of inositol, just slightly different stereoisomers. Both play important roles in insulin signaling; their roles are different but complementary.

MI is usually seen as a precursor to DCI; evidence suggests that the body converts myo-inositol to d-chiro inositol. Another inositol stereoisomer, d-pinitol, is also thought to convert into DCI in the body, but MI is thought to be the more important source.

However, many women with PCOS seem to have difficulty with the conversion from MI to DCI, suggesting that PCOS may be caused (or at least influenced) by errors in inositol metabolism. 

So, the theory goes, if we supplement the body directly with inositol, that might help help replace what's missing or make it work more efficiently.

As a result, people have been experimenting with inositol supplements, either myo-inositol or d-chiro-inositol. And the results of these experiments have been promising so far, both in research and anecdotally.

One of the most important questions that has yet to be answered is whether myo-inositol or d-chiro inositol (or some combination of the two) is the best treatment for women with PCOS and what the best dosage/treatment regimen would be.

MI is the form of inositol that is cheapest and easiest to use. It can be bought in capsules over the counter in many health food stores or in bulk powder over the internet. The thought is that if you take enough of it, then the body will convert more of it into DCI and improve insulin signaling, thus decreasing PCOS symptoms and health issues.

On the other hand, DCI is the form that seems to work best on improving hyperandrogenism and possibly insulin resistance. If some women have difficulties converting MI to DCI, why not skip to the chase and supplement directly with DCI?

Early studies on DCI had excellent results and so DCI was the focus of most research at first. However, subsequent studies were not able to replicate these results, so the drug companies largely abandoned DCI as a line of inquiry in 2002. DCI seemed discredited at that point.

What the research since then has suggested is that the initial follow-up studies didn't replicate the studies exactly ─ they increased the dosage in hopes of even better effect. But it seems that they increased the DCI dosage too much ─ apparently, there is a point of diminishing returns with DCI, beyond which it ceases to be helpful, particularly with fertility concerns. So the reason the follow-up studies didn't validate the original studies was because they used a too-high dosage, not because DCI was not potentially useful.

After the supposed "discrediting" of DCI, research on inositols was minimal and mostly focused on MI. Once researchers realized that a too-high DCI dosage was counter-productive and that MI also had benefits, research began to increase on both inositols.

Since myo-inositol is much cheaper and easier to produce, research still often focuses on MI. But some providers still feel that a moderate dose of DCI is a better choice. Still others feel that a combination of MI and DCI should work better, since both work on insulin signaling in different ways.

So what we do know is that there is no clear consensus on inositols yet but that data is emerging and it's important to keep up on the latest research.

Current research seems to suggest that MI is the inositol of choice for PCOS women with fertility issues (it especially seems to improve egg quality) and that MI works better than DCI for fertility treatment.

On the other hand, DCI may be better for those PCOS women with major hyperandrogenism issues and for whom fertility is not a major concern.

The jury is still out on which form is better for significant blood sugar/insulin resistance issues; there is research to support either MI and DCI (or both) for this purpose.

The very latest trend seems to be having women with PCOS take both MI and DCI in a 40:1 ratio (MI to DCI). This usually translates to MI (2-4 grams) and DCI (50-100 mg), but exact dosages will vary from person to person.

Recent research suggests this combination seems to be more effective than either MI or DCI alone. This is logical if they do indeed work on insulin signaling in different ways.

But it may be that the best treatment regimen may differ from woman to woman because the degree of impaired conversion may differ from person to person.

Remember, PCOS tends to have a spectrum of severity. Some have only mild symptoms while others have very severe symptoms. This may reflect a spectrum of efficiency in conversion of MI to DCI. As one resource speculates:
Considering the spectrum of human genetic diversity (take height for example), why should this trait be black/white, yes/no, or on/off? With a little imagination, we can see this impaired conversion of myo-inositol to D-chiro-inositol as a spectrum. Some women make the conversion efficiently, and they have no symptoms of PCOS. Others may make the conversion with some degree of efficiency, but not quite enough to have an optimal MYO/DCI ratio. Their symptoms may be mild. At the other end of the spectrum some people would be completely unable to make this conversion, and they would consequently present with the most severe symptoms. And, as part of the human tapestry, there would be everything in between as well.

Which brings us to the question of which inositol is right for me? Along this spectrum, people who are completely unable to convert myo-inositol to D-chiro-inositol are only going to benefit from supplementation with D-chiro-inositol. Other people who make the conversion, but with less than optimal efficiency, may benefit from large doses of myo-inositol. And, folks in between, might see the best results from a blend of the two.
In other words, some women with PCOS seem to convert MI to DCI pretty well, in which case they probably don't need to take supplemental DCI, just MI. However, others probably do not convert MI to DCI very well and may benefit more from just DCI. Still others may do best with a combination of both.

How are we to know which treatment regimen to try? As always, we need bigger and more qualitative studies to guide our choices.

But in the end, it may also be that each woman (in concert with her care provider) has to experiment and find the right regimen and dosage for her unique needs. 


More and more research is being done on the use of the inositols for PCOS, and most of this research so far is very encouraging. Some researchers are even suggesting that:
...the combined administration of MI and DCI in physiological plasma ratio (40:1) should be considered as the first line approach in PCOS overweight patients.
As we have seen, the most important benefit of inositols may be in improving insulin signaling, thus reducing insulin resistance and lessening PCOS symptoms. If insulin resistance is the major issue with PCOS and research continues to be promising, then inositols may become the key element to treating it. They may be especially useful for those who cannot tolerate metformin.

But there may be other benefits beyond improving the insulin-signaling pathway. For example, inositols are thought to also help the liver to metabolize fat, which may be helpful to those PCOS women with NAFLD (Non-Alcoholic Fatty Liver Disease).

In addition, inositols act as "signal transduction systems" in ways beyond insulin signaling pathways. They may also be related to the activation of serotonin receptors. Some research suggests that high doses of MI may reduce the risk of depression, which may be more common in people with PCOS.

There is only limited data on the use of inositols during pregnancy but some research suggests that use of myo-inositol may significantly lower the risk for the development of gestational diabetes in women with PCOS, in women with diabetic relatives, or in those who are at otherwise high risk for gestational diabetes.

However, keep in mind that most of the research trials on inositols have been very small, quite short-term, and are highly variable in methodological quality. Most are done in Italy and are not taken very seriously by many care providers in the U.S. or U.K. As a result, some researchers don't feel that any of the inositols have been adequately proven yet. And some care providers haven't even heard of inositols, so it can be difficult to find a provider supportive of trying this therapy.

Bottom line, we need more and better trials to know if long-term use of the inositols is safe and effective and to help care providers feel more comfortable with their use.

In particular, there are a few pressing safety questions that need to be addressed:

  • Some sources suggest that women who are on anti-depressants or medications for bipolar disorder may need to avoid inositols or use them only with great care since inositols may affect serotonin receptors
  • Some resources recommend that DCI not be used in conjunction with anti-androgen medications like spironolactone because the two together may be too effective against androgens and a certain amount of androgens are actually needed by the body
  • We need more data proving conclusively that inositols are safe in pregnancy
  • We need more data examining potential interactions with other drugs since many women with PCOS take other medications as well

In short, research on the use of inositols for PCOS is emerging and it behooves us to keep a close watch on emerging research to keep up with the latest developments.

The good news is that the results so far are promising. Below are the abstracts from some of the more important recent studies on inositol use.

*You can read more about the use of the inositols for treatment of PCOS herehere, here, and here. My original blog post about the use of inositols for PCOS can be found here



Eur Rev Med Pharmacol Sci. 2014 Jul;18(13):1896-903. Inositol: history of an effective therapy for Polycystic Ovary Syndrome. Bizzarri M1, Carlomagno G. PMID: 25010620 Free full text here.
Inositol is a physiological compound belonging to the sugar family. The two inositol stereoisomers, myo-inositol and D-chiro inositol are the two main stereoisomers present in our body. Myo-inositol is the precursor of inositol triphosphate, a second messenger regulating many hormones such as TSH, FSH and insulin. D-chiro inositol is synthetized by an insulin dependent epimerase that converts myo-inositol into D-chiro-inositol...In [PCOS] patients myo and/or D-chiro-inositol administration improves insulin sensitivity while only myo-inositol is a quality marker for oocytes evaluation. Myo-inositol produces second messengers for FSH and glucose uptake, while D-chiro inositol provides second messengers promoting glucose uptake and glycogen synthesis. The physiological ratio of these two isomers is 40:1 (MI/DCI) and seems to be an optimal approach for the treatment of PCOS disorders.
d-chiro inositol

Gynecol Endocrinol. 2014 Jun;30(6):438-43. doi: 10.3109/09513590.2014.897321. Epub 2014 Mar 7. Modulatory role of D-chiro-inositol (DCI) on LH and insulin secretion in obese PCOS patients. Genazzani AD1, Santagni S, Rattighieri E, Chierchia E, Despini G, Marini G, Prati A, Simoncini T. PMID: 24601829
...Since it has been demonstrated a high incidence of insulin resistance in PCOS patients, our study aimed to evaluate the efficacy of the integrative treatment with D-chiro-inositol (DCI) (500 mg die, per os, for 12 weeks) on hormonal parameters and insulin sensitivity in a group of overweight/obese PCOS patients (body mass index; BMI > 26). After the treatment, interval several endocrine parameters improved (luteinizing hormone [LH], LH/follicle stimulating hormone [FSH], androstenedione and insulin), insulin response to oral glucose tolerance test reported the significant improvement of insulin sensitivity as well as the gonadotropin-releasing hormone (GnRH)-induced (10 µg, in bolus) LH response. BMI decreased, though no lifestyle modification was requested. When data were analyzed according to the presence or absence of first-grade diabetic relatives, PCOS patients with diabetic relatives showed greater improvement after DCI administration. In conclusion DCI administration is effective in restoring better insulin sensitivity and an improved hormonal pattern in obese hyperinsulinemic PCOS patients, in particular, in hyperinsulinemic PCOS patients who have diabetic relatives.
Arch Gynecol Obstet. 2014 Nov 22. [Epub ahead of print] Evaluation of ovarian function and metabolic factors in women affected by polycystic ovary syndrome after treatment with D-Chiro-Inositol. Laganà AS1, Barbaro L, Pizzo A. PMID: 25416201
...We enrolled 48 patients, with homogeneous bio-physical characteristics, affected by PCOS and menstrual irregularities. These patients underwent treatment with 1 gr of D-Chiro-Inositol/die plus 400 mcg of Folic Acid/die orally for 6 months...We evidenced a statistically significant reduction of systolic blood pressure, Ferriman-Gallwey score, LH, LH/FSH ratio, total Testosterone, free Testosterone, ∆-4-Androstenedione, Prolactin, and HOMA Index; in the same patients, we noticed a statistically significant increase of SHBG and Glycemia/IRI ratio. Moreover, we observed statistically significant (62.5 %; p < 0.05) post-treatment menstrual cycle regularization. CONCLUSIONS: D-Chiro-Inositol is effective in improving ovarian function and metabolism of patients affected by PCOS.
Gynecol Endocrinol. 2015 Jan;31(1):52-6. doi: 10.3109/09513590.2014.964201. Epub 2014 Sep 30. The menstrual cycle regularization following d-chiro-inositol treatment in PCOS women: a retrospective study. La Marca A1, Grisendi V, Dondi G, Sighinolfi G, Cianci A. PMID: 25268566
...The objective of this study was to retrospectively analyze the effect of DCI on menstrual cycle regularity in PCOS women. This was a retrospective study of patients with irregular cycles who were treated with DCI. Of all PCOS women admitted to our centre, 47 were treated with DCI and had complete medical charts. The percentage of women reporting regular menstrual cycles significantly increased with increasing duration of DCI treatment (24% and 51.6% at a mean of 6 and 15 months of treatment, respectively). Serum AMH levels and indexes of insulin resistance significantly decreased during the treatment. Low AMH levels, high HOMA index, and the presence of oligomenorrhea at the first visit were the independent predictors of obtaining regular menstrual cycle with DCI. In conclusion, the use of DCI is associated to clinical benefits for many women affected by PCOS including the improvement in insulin resistance and menstrual cycle regularity. Responders to the treatment may be identified on the basis of menstrual irregularity and hormonal or metabolic markers.

Gynecol Endocrinol. 2014 Sep 26:1-5. [Epub ahead of print] Ovulation induction with myo-inositol alone and in combination with clomiphene citrate in polycystic ovarian syndrome patients with insulin resistance. Kamenov Z1, Kolarov G, Gateva A, Carlomagno G, Genazzani AD. PMID: 25259724
...The aim of the present study is to evaluate the effectiveness of myo-inositol alone or in combination with clomiphene citrate for (1) induction of ovulation and (2) pregnancy rate in anovulatory women with PCOS and proven insulin resistance. Patients and methods: This study included 50 anovulatory PCOS patients with insulin resistance. All of them received myo-inositol during three spontaneous cycles. If patients remained anovulatory and/or no pregnancy was achieved, combination of myo-inositol and clomiphene citrate was used in the next three cycles. Ovulation and pregnancy rate, changes in body mass index (BMI) and homeostatic model assessment (HOMA) index and the rate of adverse events were assessed. Results: After myo-inositol treatment, ovulation was present in 29 women (61.7%) and 18 (38.3%) were resistant. Of the ovulatory women, 11 became pregnant (37.9%). Of the 18 myo-inositol resistant patients after clomiphene treatment, 13 (72.2%) ovulated. Of the 13 ovulatory women, 6 (42.6%) became pregnant. During follow-up, a reduction of body mass index and HOMA index was also observed. Conclusion: Myo-inositol treatment ameliorates insulin resistance and body weight, and improves ovarian activity in PCOS patients.
Gynecol Endocrinol. 2013 Apr;29(4):375-9. doi: 10.3109/09513590.2012.743020. Epub 2013 Jan 22. Endocrine and clinical effects of myo-inositol administration in polycystic ovary syndrome. A randomized study. Artini PG1, Di Berardino OM, Papini F, Genazzani AD, Simi G, Ruggiero M, Cela V. PMID: 23336594
...50 overweight PCOS patients...underwent hormonal evaluations and an oral glucose tolerance test (OGTT) before and after 12 weeks of therapy (Group A (n¼10): MYO 2 g plus folic acid 200 mg every day; Group B (n¼10): folic acid 200 mg every day). Ultrasound examinations and Ferriman-Gallwey score were also performed... RESULTS: After 12 weeks of MYO administration plasma LH, PRL, T, insulin levels and LH/FSH resulted significantly reduced. Insulin sensitivity, expressed as glucose-to-insulin ratio and HOMA index resulted significantly improved after 12 weeks of treatment. Menstrual cyclicity was restored in all amenorrheic and oligomenorrheic subjects. No changes occurred in the patients treated with folic acid. CONCLUSIONS: MYO administration improves reproductive axis functioning in PCOS patients reducing the hyperinsulinemic state that affects LH secretion.
Combined Therapy (MI plus DCI)

J Clin Pharmacol. 2014 Oct;54(10):1079-92. doi: 10.1002/jcph.362. Epub 2014 Jul 18. The rationale of the myo-inositol and D-chiro-inositol combined treatment for polycystic ovary syndrome. Dinicola S1, Chiu TT, Unfer V, Carlomagno G, Bizzarri M. PMID: 25042908
...Two inositol isomers, myo-inositol (MI) and D-chiro-inositol (DCI) have been proven to be effective in PCOS treatment, by improving insulin resistance, serum androgen levels and many features of the metabolic syndrome. However, DCI alone, mostly when it is administered at high dosage, negatively affects oocyte quality, whereas the association MI/DCI, in a combination reproducing the plasma physiological ratio (40:1), represents a promising alternative in achieving better clinical results, by counteracting PCOS at both systemic and ovary level.
Eur Rev Med Pharmacol Sci. 2013 Feb;17(4):537-40. 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. Minozzi M1, Nordio M, Pajalich R. PMID: 23467955
BACKGROUND: ...The aim of the present study was to evaluate whether the combined therapy myo-inositol plus D-chiro-inositol (in a in a physiological ratio of 40:1) improve the metabolic profile, therefore, reducing cardiovascular risk in PCOS patients. PATIENTS AND METHODS: Twenty obese PCOS patients [BMI 33.7 ± 6 kg/m2 (mean ± SD)] were recruited. The lipid profile was assessed by measuring total cholesterol, LDL, HDL and triglycerides before and after 6 months treatment with the combined therapy. Secondary end points included changes in BMI, waist-hip ratio, percentage of body fat, HOMA-IR and blood pressure. RESULTS: The combined therapy myo-inositol and D-chiro-inositol improved LDL levels (3.50 ± 0.8 mmol/L versus, 3 ± 1.2 mmol/L p < 0.05), HDL (1.1 mmol/L ± 0.3 versus 1.6 mmol/L ± 0.4 p < 0.05) and triglycerides (2.3 ± 1.5 mmol/L versus 1.75 ± 1.9 mmol/L p < 0.05). Furthermore, significant improvements in HOMA-IR were also observed. CONCLUSIONS: The combined therapy myo-inositol plus D-chiro-inositol is able to improve the metabolic profile of PCOS women, therefore, reducing the cardiovascular risk.
Monotherapy vs. Combined Therapy

Eur Rev Med Pharmacol Sci. 2012 May;16(5):575-81. The combined therapy with myo-inositol and D-chiro-inositol reduces the risk of metabolic disease in PCOS overweight patients compared to myo-inositol supplementation alone. Nordio M1, Proietti E. PMID: 22774396
...In this study, we aim to verify whether the two molecules have a synergistic action by acting on their specific cellular pathways. The effectiveness in reducing the risk of metabolic syndrome as well as in enhancing the ovarian functions of a combined therapy with MI and DCI was compared to a mono therapy in a randomized controlled trial. METHODS: Fifty overweight women with PCOS were enrolled and divided in two groups to receive MI and DCL (MI+DCI group) or MI alone (MI group) for a period of six months. Baseline measurements were repeated at three months (T1) and at the end of the treatment (T2). RESULTS: At the end of the treatment, both MI and MI+DCI groups showed an improvement of the metabolic parameters and no significant differences were found. As expected, the combined supplementation with MI and DCI resulted to be more effective, compared to the MI group, after three months of treatment. CONCLUSIONS: The combined administration of MI and DCI in physiological plasma ratio (40:1) should be considered as the first line approach in PCOS overweight patients, being able to reduce the metabolic and clinical alteration of PCOS and, therefore, reduce the risk of metabolic syndrome.
Arch Gynecol Obstet. 2013 Dec;288(6):1405-11. doi: 10.1007/s00404-013-2855-3. Epub 2013 May 25. 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. Colazingari S1, Treglia M, Najjar R, Bevilacqua A. PMID: 23708322
PURPOSE: The present study aims to investigate the effects of the combined therapy myo-inositol (MI) plus D-chiro-inositol (DCI) or D-chiro-inositol treatment in oocyte quality. METHODS: Polycystic ovary syndrome (PCOS) women undergoing IVF-ET were treated with myo-inositol combined with D-chiro-inositol in the physiological ratio (1.1 g myo-inositol plus 27.6 mg of D-chiro-inositol; INOFOLIC combi Lo.Li.pharma) or D-chiro-inositol alone (500 mg; Interquim, s.a., Barcelona, Spain) to evaluate the umber of morphological mature oocytes, total International Units (IU) of recombinant FSH administered and the number of grade 1 embryos. RESULTS: The data clearly showed that only the combined therapy was able to improve oocyte and embryo quality, as well as pregnancy rates, in PCOS women undergoing IVF-ET. CONCLUSION: The present paper further supports the hypothesis that MI plays a crucial role in the ovary in PCOS women. In particular, due to the physiological role played by MI and DCI, the combined therapy should represent a better choice.


Mich said...

Thank you for more information. I have looked at Amazon for products and found a bunch, plus I read their reviews. I am wondering though how you determine if a woman is not producing enough of one inositol: blood test? urine? hair?

Is there any known benefit or harm in taking them if you are not out of balance, or just don't know? I'm excessively hairy, and if I grow my hair long enough I will have mutton chops that could rival any man's, and even twirl my moustache. I'd sure like to not have to shave anymore.

Well-Rounded Mama said...

Mich, you ask some excellent questions and I don't know the answers to them. I too would like to know if there is a way to tell if someone is deficient in inositol conversion and needs supplementation. Right now, I think a trial of meds is the only way to know if it helps.

As far as I know there is no known harm in taking them; I haven't seen anything in the research so far, outside of the possible reactions outlined above (SSRIs, bipolar etc.). I think some people get better results with them than others, but which would be best for hirsutism I don't know. Many care providers seem to favor the combined approach, 40:1 ratio, these days.