Thursday, October 31, 2013

PCOS Treatment: The Inositols

We've been discussing Polycystic Ovarian Syndrome (PCOS) and its impact on the health of women of size. Today, let's discuss the use of the inositols as insulin-sensitizing agents in the treatment of PCOS.

In previous posts, we've talked about PCOS's definition and symptoms, how it presents, its testing and diagnosis, and its possible causes. Now we are discussing common treatment protocols for PCOS (and the pros and cons of each) ─ from a size-friendly point of view.

We've already discussed metformin (Glucophage) and TZDs (Avandia, Actos) for treating insulin resistance and improving blood sugar.

Now, let's discuss the inositols, an intriguing emerging supplement that may provide another alternative, although more research is needed to confirm this and determine its efficacy and safety.
Disclaimer: I am not a medical health-care professional. While the following information is based on my best understanding of the research, always do your own research. This information is not a recommendation for nor a complete explanation of all the risks and benefits of a particular medication or treatment. Consult your healthcare provider before making any decisions about your care plan.
Trigger Warning: Passing mention of the possible weight loss effects of this medication. 

As previously mentioned, metformin is the first-line drug of choice for most doctors when treating the insulin resistance common to many women with PCOS. It has a long safety record, documented improvements in long-term outcomes in diabetics, relatively mild G.I. side effects (for most), and is very effective at both lowering blood sugar and improving insulin resistance.

For some women, though, metformin is not enough to control their insulin resistance/blood sugar, or they cannot tolerate its side effects. Although TZDs have significant safety concerns, some doctors do still use them in select cases, mostly in women with severe PCOS, those with very high blood sugar, those not responsive to metformin, or those who don't tolerate metformin well. Actos (pioglitazone) is the TZD of choice currently, as other TZDs have significant safety concerns.

But now there may be another insulin-sensitizing choice besides metformin and the TZDs.

Many women with PCOS are now exploring inositol, a carbohydrate commonly available as a nutritional supplement. 

Inositol used to be considered a B vitamin but is no longer considered an essential nutrient because the body can make its own in the kidneys. It is a lipotropic agent, meaning that it helps your body process and get rid of fats in the blood and organs.

Inositol is vital in the process of insulin signal transduction. In PCOS, this pathway does not seem to function properly, and supplementing with exogenous (outside the body) sources of inositol is thought to help restore proper signaling function.

One website summarizes inositol this way:
“Inositol” is a term used to refer to a group of naturally occurring carbohydrate compounds that exist in nine possible chemical orientations called stereoisomers... 
Inositol, particularly myo-inositol and another less common stereoisomer called D-chiro-inositol, plays a critical, but underappreciated, role in insulin signaling. Conditions such as hyperglycemia and diabetes are associated with disrupted inositol signaling, leading many researchers to suggest that this may be a key pathologic feature of insulin resistance. 
Research has shown that...inositol family members help to ameliorate conditions in which insulin resistance plays an important role, especially PCOS.
Inositol is a substance your body already makes. Your body uses bacteria from the gut to convert the phytic acid found in found in fruits, vegetables, legumes, whole grains, nuts, and other foods into d-chiro-inositol. This then helps with insulin-signaling in the body.

However, women with PCOS have abnormally high levels of d-chiro-inositol in their urine, suggesting that they are excreting it too efficiently.

While most people can get the inositol they need from foods, women with PCOS may have difficulty converting naturally-occurring inositols into d-chiro-inositol (DCI). Or they may convert it reasonably well but excrete it too quickly and therefore do not have enough in the body to help utilize its insulin properly.

D-chiro-inositol (DCI) is a naturally occurring compound that aids in metabolism. Usually called a member of the B-vitamin family, inositol is actually not a vitamin. Inositol is available in nine different forms, the most common of which is myo-inositol. Myo-inositol has been commercially sold as a nutritional supplement for years and is widely available, but the benefits of d-chiro-inositol are just being discovered. 
Without being too complicated, d-chiro-inositol is necessary for insulin metabolism. The human body naturally breaks down other forms of inositol, such as myo-inositol and pinitol, into d-chiro-inositol. The inositol we need to properly use insulin is found in our diets. However, women with PCOS have difficulty breaking other forms of inositol down into d-chiro-inositol, so insulin resistance develops. Her body cannot use the free-floating insulin because of the missing compound. Because of the insulin resistance, blood testosterone levels increase leading to a hormonal imbalance that causes the symptoms of PCOS including excess belly fat, facial and body hair, hair loss, acne and the absence of ovulation.
So, basically, the idea behind treatment with inositol is that women with PCOS are not able to break down natural forms of inositol in our diet into d-chiro-inositol ─ or perhaps, we break it down but then excrete it too easily instead ─ and this causes problems with efficient insulin metabolism. This leads to a build-up of insulin in the body, which leads to many of the other hormone imbalances of PCOS.

The hope is that supplementing with extra inositol in one of its various forms (myo-inositol, d-chiro-inositol) will improve insulin metabolism and lessen hormone issues.

Here is another long summary of how inositol may help with PCOS, from
Inositol may be important for PCOS women for at least three reasons:
  • It may aid insulin action and thus reduce insulin resistance.
  • It may help to relieve depression, which is common in polycystic ovary syndrome.
  • It helps your liver to metabolize fat.
Inositol is a compound that has nine different forms. The most well-known and nutritionally active form is "myo-inositol", which most people simply refer to as "inositol". It is a necessary component of the membranes of your cells and is vital to many biological processes in your body. It is a precursor to a number of essential "signaling molecules" that instruct cells how to behave. 
Some of inositol's signaling is related to activation of serotonin receptors, which could relieve depression and improve appetite balance. Serotonin is a brain chemical with several important functions in the body, including mood and appetite regulation. 
Inositol is also a fat-solublizing agent that helps to transport fat from the liver. For those overweight PCOS women who may have a problem with fatty liver congestion, inositol can be helpful...
Another naturally occurring form of inositol is d-chiro-inositol, which has been found to have activity against insulin resistance. It is found in legumes and especially in buckwheat. Consumption of buckwheat concentrate appears to reduce excessively high blood sugar levels and reduce the excretion of d-chiro-inositol in diabetic rats... 
Recent studies have suggested that women with PCOS may have insulin resistance and hyperinsulinemia due to a d-chiro inositol deficiency. D-chiro-inositol has been shown to influence the action of insulin. The amount of chiro-inositol in muscle has been shown to be lower in subjects with type 2 diabetes than in normal people...
Inositol supplementation is generally well tolerated. Gastrointestinal effects such as nausea or diarrhea are occasionally reported with high doses. No toxicity has been reported. 
Other good summary about the inositols can be found here and here.

In addition, here is a video (from a company that sells d-chiro-inositol, mind, so insert caveats) that gets into specifics of how myo-inositol and d-chiro-inositol bind to other molecules and are thought to work as "second messengers" in the body.

One early study summarizes this theory:
Evidence suggests that some actions of insulin are mediated by putative inositolphosphoglycan (IPG) mediators, also known as second messengers. We review studies indicating that the IPG signaling system transduces insulin's stimulation of human thecal androgen biosynthesis, thus offering a mechanism by which insulin can stimulate ovarian androgen production even in women with PCOS whose tissues are resistant to insulin's stimulation of glucose metabolism. Furthermore, a deficiency in a specific D-chiro-inositol-containing IPG may contribute to insulin resistance in women with PCOS. In support of this idea, administration of D-chiro-inositol has been demonstrated to improve glucose tolerance, decrease serum androgens and improve ovulation in PCOS. The hypothesis is advanced that PCOS may be characterized by a defect in the conversion of myo-inositol to D-chiro-inositol, and that such a defect would contribute to both insulin resistance and hyperandrogenism in the syndrome.
In fact, some researchers have suggested that improving insulin-mediated release of inositolphosphoglycan mediators is part of how metformin improves insulin resistance in women with PCOS.

However it works, research so far does seem to show that inositol supplements improve health markers and PCOS symptoms, at least in the short term. But studies are too short and are vastly underpowered to really establish its safety and efficacy at this time.

Possible Benefits of Inositols

Small trials of inositol use suggest that it helps restore regular cycles in many women with PCOS. It helps many ovulate and improves egg quality (which can improve the chances of getting pregnant naturally or with fertility treatment). Inositol seems to even have better results in restoring cycles and improving ovulation than metformin.

Some recent trials have suggested that myo-inositol may be more effective at improving egg quality than d-chiro-inositol, but this needs confirmation. Until recently, most research has focused more on d-chiro-inositol. Another possibility is that a combination of both myo-inositol (MI) and d-chiro-inositol (DCI) is most effective.

Some inositol trials also suggest less hyperinsulinemia, lower blood pressure, improved lipid profiles, and improved androgen levels with inositol use. In addition, it may also improve hirsutism (excess hair) and acne issues.

Although most research has been on restoring menstrual cycles and fertility, this other research shows that there is a role for inositols well beyond fertility treatment. It may help prevent or lessen some of the metabolic consequences of having PCOS (cardiovascular disease, diabetes, hypertension, hyperlipidemia). Therefore, it may be a particularly important treatment for PCOS as women age, and of course for those women with PCOS who do not want children.

Of course, with their usual hyper-focus on weight, many PCOS resources mention that inositol can result in a modest weight loss in some people. Like most weight loss information, this is usually based on very short-term research trials or on anecdotal consumer stories which are not controlled. Longer trials show little long-term effect on BMI. Therefore, take this possible side effect with a grain of salt and consider inositol instead for its many other potential benefits.

There is some evidence that larger doses of inositols can help lessen mild depression, obsessive-compulsive disorder, panic attacks, anxiety, insomnia, agoraphobia, and other mental health issues. However, research is small and mixed. Always consult your care provider before switching depression meds or trying something new.

Although there is little research on the safety of inositol in pregnancy and breastfeeding, a few trials have begun using them. One study found that myo-inositol helped significantly lower the rate of gestational diabetes in women with PCOS. On the other hand, several internet sources mention that inositol may stimulate uterine contractions and should be avoided in pregnancy. Yet many women with PCOS have continued DCI throughout pregnancy and anecdotally report no problems. Clearly, there is no consensus on this topic.

Incorporating Inositols

Because of these theories, many women with PCOS are taking MI and/or DCI directly. Whether this is a good idea of not is a matter of strong debate.

Although some reproductive endocrinologists are comfortable prescribing inositol to women with PCOS (and some even recommend it as a first-line treatment, like metformin), many others have never even heard of it, or feel that the research on it is too preliminary yet to recommend.

Some doctors have found that women start cycling on inositol, and so will try a trial of inositols alone before trying stronger drugs like metformin. Others have found that it can be used instead of clomiphene and/or metformin in those women who do not tolerate those drugs well. Some have used inositol (which is relatively inexpensive) as an alternative to In Vitro Fertilization in those who cannot afford another IVF treatment.

Although most care providers do not utilize inositol as a first-line treatment at this time, it is certainly an option you can pursue as long as you realize that we lack long-term information about its safety and efficacy.


The optimal dosage of inositols is unknown; at this time, most trials use 1-2 g of DCI per day. The most common dosage seems to be 600 mg (2x per day for 1200 mg total, or 1.2 g).

One source reports that when and how you take it may make a difference too:
It is apparently more effective to take both in divided doses, rather than once per day. It’s also better to take them on an empty stomach. Caffeine lessens the effectiveness of them too.
One source (who sells DCI, so insert caveats) suggests weight-based doses instead ─ 20 mg of DCI per kg (2.2 lbs.) of bodyweight.

Whether weight-based dosing is truly needed is unclear. Some medications clearly benefit from weight-based doses, while others do not. It all depends on how the medication works in the body. So whether a weight-based dose of DCI would be helpful is unknown. As a caution, it should be noted that some studies suggest that larger doses of DCI may actually not work as well as smaller doses.

Myo-inositol doses are generally higher than d-chiro-inositol doses, presumably because your body must convert the MI to DCI. The usual dosages seen in studies seem to be about 2-4 g.

It is unclear what the most optimal doses would be if a combined therapy of DCI and MI is used. Researchers are just beginning to examine combined therapy protocols now.

Doses of MI for mental health issues tend to be larger. Internet sources generally cite 12-18 g per day, divided into several doses.

Caffeine may suppress the effects of MI, so it's probably best to cut out or cut back strongly on caffeine if you are going to try a serious trial of inositol.

Side Effects

Very high doses of inositol can cause G.I. side effects like nausea, diarrhea, and gas. Some women tolerate inositols better than metformin and have fewer G.I. side effects with them.

Some women report anecdotally that taking inositol on an empty stomach may make G.I. side effects more likely. This seems to conflict with the advice on some sites to take them on an empty stomach for better efficacy.

Other reported side effects include headaches and dizziness, insomnia, and possible a worsening of bipolar manic symptoms in those with Bipolar Disorder, as reported here:
It's theoretically possible that inositol could worsen hypomanic or manic symptoms of bipolar disorder, so people with this condition should check with their doctor before using supplemental inositol. 
The same source recommends caution in using inositol supplements if you are taking an SSRI or SRNI for depression, or herbs such as St. John's Wort:
Theoretically, high-dose inositol may increase the effects of anti-depressant selective serotonin reuptake inhibitors (SSRI drugs) such as fluoxetine sertraline, paroxetine, fluvoxamine and citalopram, and with 5-hydroxytryptamine receptor agonists, such as sumatriptan. If you are taking anti-depressant drugs, consult with your doctor before taking supplemental inositol.
Other Possible Benefits

Several online sources mention that an inositol deficiency may be associated with hair loss. Although no study has been done to examine whether inositol supplementation might help with the alopecia that can sometimes accompany PCOS, it's an interesting possibility.

Inositol is sometimes also mentioned as a possible treatment for diabetic neuropathy, which happens when people who have had diabetes for a long time begin to experience nerve damage in their legs, feet, and hands. If inositol indeed improves insulin signaling and lowers blood sugar, it seems somewhat plausible it might help lessen some diabetes complications if caught early enough.

One intriguing finding has been that inositol use (especially d-chiro-inositol) has lowered the risk for neural tube defects (NTDs) in folate-resistant mouse models.

A defect in insulin-signaling pathways might be a plausible explanation for why "obese" women have a somewhat higher risk for neural tube defects than other women, and may offer hope for lowering this risk. Although no research on obese women has been done, preliminary research on inositol supplementation in women who are at high risk for a NTD (because of a prior NTD-affected fetus) has been promising.

However, because NTDs are a very rare occurrence (even in women at high risk), and because the inositols are not widely used at this point, it will probably be a very long time before we know for sure whether inositol use lowers the risk of NTDs in obese women.

Lingering Questions on Inositols

Assuming the theory of how inositol works is correct, some of the more important questions that still need answering are whether women get better results with myo-inositol or with d-chiro-inositol, the relative safety of each, whether they are effective/safe used together, whether they are safe used with metformin, and what dosage is most useful.

Because PCOS tends to come with a cluster of co-morbid conditions, it's also important to establish whether interactions occur between inositols and other medications (like blood pressure meds, statins, or diabetes meds). So far none seem to have been reported, but further study is needed.


Originally, d-chiro-inositol was manufactured as a drug through the company, Insmed, but they discontinued it in 2002 (see the next section for more details).

Currently you can find d-chiro-inositol or myo-inositol through several different sources in the U.S., including Chiral Balance and Cyvex. A number of PCOS-related websites offer it as well, such as this one. has it as well.

It is not cheap but is not so prohibitively expensive that it is impossible to afford. Myo-inositol is a little cheaper and easier to find, generally speaking. Many women find that ordering myo-inositol in a loose powder (stirring it into water and drinking it) is an easier and more affordable option than ordering it in capsules.

Currently, many U.S. women are getting myo-inositol through a supplement called "Pregnitude," which combines myo-inositol with folic acid. It has been on the market in Europe for some time under a different name, "INOFOLIC." However, it can also be found outside of these sources.

Women who want help getting inositols may find that "alternative" medicine practitioners (like naturopaths) may be more open to their use. On the other hand, those who live in Europe may find that traditional care providers are more open to their use than U.S. doctors, since much of the research on inositols has been done in Italy.

Some sources recommend taking inositol only with choline as well. Lecithin is a source of both inositol and choline, so some people take lecithin instead of inositol by itself.

As a side note, there is another inositol stereoisomer called d-pinitol (3-0-methyl d-chiro-inositol). Its main advantage is that it's much cheaper. It is popular in bodybuilding circles as a product called Inizitol. When used, about a third of the pinitol supposedly converts into d-chiro-inositol in the system. However, its utility for PCOS and IR is unproven. Given the questionable nature of many bodybuilding supplements, it might be better to skip this one until there is more data on it.

What about getting inositol naturally, via food sources? Some women with PCOS are choosing to try to get inositols directly from the diet instead of taking a supplement.

Supposedly, one of the best food sources for the inositols is buckwheat, though you must consume large amounts of it. One woman summarized her experience getting and using buckwheat here. Other possible food sources of inositols include chickpeas, soy lecithin, citrus fruits, certain melons, pumpkin, and pumpkin seeds.

On the other hand, some internet sources contend that the inositol found in grains, seeds, and brans is not bioavailable and that a better source may be organ meats.

At this point, it's not at all clear about the best way to take inositol, the best dosage for it, or the best source for getting inositol.


The use of inositols is an emerging field and long-term safety profiles are not available, so care should be taken. 

Nor is it clear yet that inositol is an effective treatment for PCOS. For example, one widely-publicized study in 1999 found that 6-8 weeks of treatment with d-chiro-inositol improved insulin sensitivity, lowered testosterone and triglycerides, and improved blood pressure modestly. Three times as many women on DCI in this trial ovulated, compared to those on the placebo. Some women with severe PCOS in this trial reported regular cycles for the first time in their lives, so the buzz in PCOS communities was considerable.

However, later researchers were unable to reproduce these results, which calls the validity of the 1999 findings into question. Insmed, the company that was making DCI, pulled it off the market in 2002 after Phase II trials, citing lack of efficacy.

Other concerns include the fact that some research suggests that very high dosages of DCI may have a negative effect on egg quality, and other research suggests that myo-inositol may result in better egg quality than DCI. Still other research suggests that a combined protocol of MI and DCI is more effective than either substance alone.

The best and most effective treatment protocols for the inositols are obviously still a work in progress, as is knowledge about its safety.

There are many questions about the inositols that have yet to be answered. For example, it is not clear which inositol is the best choice for treatment, nor what the best dosage is for differing purposes (i.e., fertility vs. anti-androgen effect on hirsutism).

Another problem is that the inositols are relatively unregulated nutritional supplements, and this means the quality of the product may vary significantly. One European study found that that amount of myo-inositol in the product available there varied significantly between 75%-95%. This could certainly affect efficacy. One has to wonder about the purity of some of these supplement sources too, or whether some might be contaminated with other substances.

One major limiting factor is that the research on DCI and the other inositols is relatively short-term, uses highly variable methodology, and typically has small sample sizes. Much of it has been done in Italy, and so many U.S. physicians are unaware of it or unwilling to accept it without reserve. One major review concluded that while some results were promising, the quality of the studies done thus far was too inconsistent to make recommendations.

The bottom line is that far more research is needed on the inositols before we can conclude anything about their safety, efficacy, or proper dosage. 

The good news is that research on these substances is beginning to expand significantly, so much more will be forthcoming on this possibility in the future.  Women with PCOS would do well to keep their eyes on this research to monitor its safety and efficacy before jumping on the bandwagon prematurely.


The inositols are an intriguing, plausible possible treatment for PCOS, and they deserve much more research.

It's important to remember, though, that at this point, we don't have a great deal of information on their long-term use or safety. Most of the studies on the inositols so far are very short-term, and not enough attention has been paid to safety issues.

It is clear at this point that inositol seems to be vital to normal body functions, but it is not clear that supplementing with inositol will help reverse or cure health problems.

Anecdotally, some women with PCOS have achieved good results with the inositols ─ but this is not the same as having quality, long-term research on its use. Apply caveats liberally.

Keep your eyes peeled for future developments, as research into the inositols is expanding rapidly. However, remember that many initially promising drugs do not turn out to be as promising or safe once larger and more in-depth trials are conducted.

The good news is that there are more choices than ever for dealing with the significant insulin resistance that seems to be an integral part of PCOS for most patients. The catch is that research into their safety is ongoing and the risks of newer drugs may not be fully known for some time. Careful vigilance when using them is mandatory.

*Do you have any experience with the inositols? Share it in the Comments Section.


*Trigger Warning: Many PCOS studies and links emphasize weight loss and weight control as a basic part of PCOS care. Use caution when reading these links if you find this triggering.

General Information on the Inositols
J Pediatr Endocrinol Metab. 2000;13 Suppl 5:1295-8. Role of inositolphosphoglycan mediators of insulin action in the polycystic ovary syndrome. Nestler JE, Jakubowicz DJ, Iuorno MJ. PMID: 11117673
Evidence suggests that some actions of insulin are mediated by putative inositolphosphoglycan (IPG) mediators, also known as second messengers. We review studies indicating that the IPG signaling system transduces insulin's stimulation of human thecal androgen biosynthesis, thus offering a mechanism by which insulin can stimulate ovarian androgen production even in women with PCOS whose tissues are resistant to insulin's stimulation of glucose metabolism. Furthermore, a deficiency in a specific D-chiro-inositol-containing IPG may contribute to insulin resistance in women with PCOS. In support of this idea, administration of D-chiro-inositol has been demonstrated to improve glucose tolerance, decrease serum androgens and improve ovulation in PCOS. The hypothesis is advanced that PCOS may be characterized by a defect in the conversion of myo-inositol to D-chiro-inositol, and that such a defect would contribute to both insulin resistance and hyperandrogenism in the syndrome.
Myo-Inositol and PCOS

Gynecol Endocrinol. 2008 Mar;24(3):139-44. Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome. Genazzani AD, et al.  PMID: 18335328
PATIENTS: ...20 overweight PCOS patients were enrolled after informed consent. INTERVENTIONS: All patients underwent hormonal evaluations and an oral glucose tolerance test (OGTT) before and after 12 weeks of therapy (Group A (n = 10): myo-inositol 2 gr. plus folic acid 200 mug every day; Group B (n = 10): folic acid 200 mug 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-inositol administration improves reproductive axis functioning in PCOS patients reducing the hyperinsulinemic state that affects LH secretion.
Eur Rev Med Pharmacol Sci. 2011 Aug;15(8):931-6. Inositol safety: clinical evidences. Carlomagno G, Unfer V. PMID: 21845803
Myo-inositol is a six carbon cyclitol that contains five equatorial and one axial hydroxyl groups. Myo-inositol has been classified as an insulin sensitizing agent and it is commonly used in the treatment of the Polycystic Ovary Syndrome (PCOS). However, despite its wide clinical use, there is still scarce information on the myo-inositol safety and/or side effects. The aim of the present review was to summarize and discuss available data on the myo-inositol safety both in non-clinical and clinical settings. The main outcome was that only the highest dose of myo-inositol (12 g/day) induced mild gastrointestinal side effects such as nausea, flatus and diarrhea. The severity of side effects did not increase with the dosage.
Eur Rev Med Pharmacol Sci. 2011 Apr;15(4):452-7. Myo-inositol rather than D-chiro-inositol is able to improve oocyte quality in intracytoplasmic sperm injection cycles. A prospective, controlled, randomized trial. Unfer V, et al.  PMID: 21608442
OBJECTIVE: ...we aimed to compare the effects myo-inositol and D-chiro-inositol on oocyte quality in euglycemic PCOS patients. MATERIALS AND METHODS: Eighty-four euglycemic PCOS patients, undergoing ovulation induction for ICSI, were recruited for this study. Forty-three participants received MyoInositol 2 g twice a day and forty-one patients received D-chiro inositol 0.6 g twice a day. RESULTS: The results of our study showed that the total number of oocytes retrieved did not differ in the two treatments groups. However, the number of mature oocytes was significantly increased in the myo-inositol group compared to D-chiro-inositol. Concurrently, the number of immature oocytes decreased in myo-inositol treated patients. Furthermore, the myo-inositol-treated group showed an increase in the mean number of top quality embryos and in the total number of pregnancies compared to the D-chiro-inositol-treated group. CONCLUSIONS: Our data show that, in PCOS patients having a normal insulin response, myo-inositol treatment rather than D-chiro-inositol is able to improve oocyte and embryo quality during ovarian stimulation protocols.
Gynecol Endocrinol. 2012 May 21. [Epub ahead of print]  Differential insulin response to myo-inositol administration in obese polycystic ovary syndrome patients. Genazzani AD, et al.  PMID: 22612517
...Attention has been given to the role of inositol-phosphoglycan (IPG) mediators of insulin action and growing evidences suggest that a deficiency of d-chiro-inositol (DCI) containing IPG might be at the basis of insulin resistance, frequent in PCOS patients. On such basis, we investigated the efficacy on insulin sensitivity and hormonal parameters of 8 weeks treatment with myo-inositol (MYO) (Inofert, ItalPharmaco, Milano, Italy) at the dosage of 2 g day in a group (n = 42) of obese PCOS patients,. After the treatment interval body mass index (BMI) and insulin resistance decreased together with luteinizing hormone (LH), LH/FSH and insulin. When subdividing the patients according to their fasting insulin levels, Group A (n = 15) insulin below 12 µU/ml and Group B (n = 27) insulin above 12 µU/ml, MYO treatment induced similar changes in both groups but only patients of Group B showed the significant decrease of both fasting insulin plasma levels (from 20.3 ± 1.8 to 12.9 ± 1.8 µU/ml, p < 0.00001) and of area under the curve (AUC) of insulin under oral glucose tolerance test (OGTT). In conclusion, our study supports the hypothesis that MYO administration is more effective in obese patients with high fasting insulin plasma levels.
Gynecol Endocrinol. 2013 Jan 22. [Epub ahead of print] Endocrine and clinical effects of myo-inositol administration in polycystic ovary syndrome. A randomized study. Artini PG, Di Berardino OM, Papini F, Genazzani AD, Simi G, Ruggiero M, Cela V. PMID: 23336594
...Design: Controlled clinical study...50 overweight PCOS patients were enrolled after informed consent. Interventions: All 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. Main outcome measures: Plasma LH, FSH, PRL, E2, 17OHP, A, T, glucose, insulin, C peptide concentrations, BMI, HOMA index and glucose-to-insulin ratio. 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.
Gynecol Endocrinol. 2011 Nov;27(11):920-4. doi: 10.3109/09513590.2011.564685. Epub 2011 Mar 21. The effect of a combination therapy with myo-inositol and a combined oral contraceptive pill versus a combined oral contraceptive pill alone on metabolic, endocrine, and clinical parameters in polycystic ovary syndrome. Minozzi M, Costantino D, Guaraldi C, Unfer V.  PMID: 21417594
AIM: Compare the effects of a combined contraceptive pill (OCP) in combination with myo-inositol (MI) on endocrine, metabolic, and clinical parameters in patients with polycystic ovary syndrome (PCOS). METHODS: One hundred fifty-five patients with PCOS were enrolled in this prospective, open-label clinical study. Patients were assigned to receive oral treatment with OCP alone (estradiol (EE) 30 μg/gestodene 75 μg) or in combination with myo-inositol 4 g/die, for 12 months. RESULTS: OCP plus MI therapy resulted in a higher reduction of FG score compared with OCP alone therapy. The combined therapy (OCP plus MI) significantly decreased hyperinsulinaemia, by positively affecting the fasting insulin and glucose levels and homeostasis model assessment-insulin resistance parameters, while no significant changes were observed in the OCP group. Androgens serum levels decreased in both groups, but significantly more in the combined therapy group. The lipid profile was improved in the combined therapy group, by reducing low-density lipoprotein cholesterol levels and enhancing high-density lipoprotein cholesterol levels. CONCLUSIONS: Our data show that a combination of combined contraceptive pill and MI may be more effective in controlling endocrine, metabolic, and clinical profile in patients with PCOS than OCP alone, and may reduce insulin levels and insulin resistance. Hence, combined treatment may become a more effective long-term therapeutic choice for controlling PCOS symptoms.
Gynecol Endocrinol. 2010 Apr;26(4):275-80. doi: 10.3109/09513590903366996. Insulin sensitiser agents alone and in co-treatment with r-FSH for ovulation induction in PCOS women. Raffone E, Rizzo P, Benedetto V. PMID: 20222840
OBJECTIVE: The aim of this study was to compare the effectiveness of myo-inositol (MYO) and metformin, in monotherapy or in association with recombinant follicle stimulating hormone (r-FSH), in the treatment of menstrual irregularities, chronic anovulation, and female infertility in patients with polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: One hundred twenty patients were randomly treated with metformin 1500 mg/day orally (n = 60), or 4 g MYO plus 400 microg folic acid daily (n = 60), continuously. If no pregnancy occurred, r-FSH (37.5 units/day) was added to the treatment for a maximum of three attempts. RESULTS: Fifty percent of the patients who assumed metformin restored spontaneous ovulation, 18.3% of these obtained pregnancy. The remaining 42 patients were treated with metformin plus r-FSH. Pregnancy occurred in a total of 11 women (26.1%). The total pregnancy rate was 36.6%. Sixty-five percent of the patients treated with MYO plus folic acid restored spontaneous ovulation activity, 30% of these obtained pregnancy. The remaining 38 patients were treated with MYO, folic acid plus r-FSH. Pregnancy occurred in a total of 11 women (28.9%). The total pregnancy rate was 48.4%. CONCLUSIONS: Both metformin and MYO, can be considered as first line treatment for restoring normal menstrual cycles in most patients with PCOS, even if MYO treatment seems to be more effective than metformin.
Climacteric. 2012 Oct;15(5):490-5. doi: 10.3109/13697137.2011.631063. Epub 2011 Dec 23. One-year effects of myo-inositol supplementation in postmenopausal women with metabolic syndrome. Santamaria A, Giordano D, Corrado F, Pintaudi B, Interdonato ML, Vieste GD, Benedetto AD, D'Anna R. PMID: 22192068
...METHODS: Eighty outpatient postmenopausal women, affected by metabolic syndrome, were enrolled in a 12-month study. All women were treated with a low-energy diet, and then they were randomly assigned to myo-inositol 2 g b.i.d. (n = 40) or placebo (n = 40). All the women were evaluated for serum glucose, insulin, HOMA-IR (Homeostasis Model Assessment-Insulin Resistance), triglycerides, total and high density lipoprotein cholesterol, body mass index (BMI), waist circumference and blood pressure at baseline and after 12 months of treatment. RESULTS: With the exception of BMI and waist circumference, after 12 months of treatment, all the parameters studied showed a significant improvement in the myo-inositol group compared to the control group. At the end of the study, in the myo-inositol group, the number of women without metabolic syndrome was eight (20%) whereas, in the control group, only one woman no longer had the metabolic syndrome after 12 months of diet. CONCLUSIONS: Myo-inositol might
be considered one of the insulin-sensitizing substances in the treatment of metabolic syndrome.
D-Chiro Inositol and PCOS

N Engl J Med. 1999 Apr 29;340(17):1314-20. Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. Nestler JE, et al. PMID: 10219066
Women with the polycystic ovary syndrome have insulin resistance and hyperinsulinemia, possibly because of a deficiency of a D-chiro-inositol-containing phosphoglycan that mediates the action of insulin. We hypothesized that the administration of D-chiro-inositol would replenish stores of the mediator and improve insulin sensitivity. METHODS: We measured steroids in serum and performed oral glucose-tolerance tests before and after the oral administration of 1200 mg of D-chiro-inositol or placebo once daily for six to eight weeks in 44 obese women with the polycystic ovary syndrome...Nineteen of the 22 women who received D-chiro-inositol ovulated, as compared with 6 of the 22 women in the placebo group (P<0.001). CONCLUSIONS: D-Chiro-inositol increases the action of insulin in patients with the polycystic ovary syndrome, thereby improving ovulatory function and decreasing serum androgen concentrations, blood pressure, and plasma triglyceride concentrations.
Metab Syndr Relat Disord. 2010 Apr;8(2):127-36. Uncoupling between insulin and release of a D-chiro-inositol-containing inositolphosphoglycan mediator of insulin action in obese women with polycystic ovary syndrome. Baillargeon JP, et al.  PMID: 20156067
Obese women with polycystic ovary syndrome (PCOS) manifest impaired insulin-stimulated release of a d-chiro-inositol-containing inositolphosphoglycan (DCI-IPG) insulin mediator during oral glucose tolerance testing (OGTT), which appears to be restored by the administration of metformin. This suggests that either obesity or PCOS is associated with a defect in the coupling of the stimulation of the insulin receptor by insulin to the release of the DCI-IPG mediator. The objective of this study was to compare the release of bioactive DCI-IPG between normal nonobese women and obese PCOS women during stimulation with two different concentrations of insulin when glucose levels are clamped...CONCLUSIONS: The coupling between insulin action and the release of the DCI-IPG mediator is selectively impaired in obese PCOS women, which may contribute to the insulin resistance in these women.
Diabetes Care. 2006 Feb;29(2):300-5. Altered D-chiro-inositol urinary clearance in women with polycystic ovary syndrome. Baillargeon JP,  et al. PMID: 16443877
...Evidence suggests that some actions of insulin are effected by inositolphosphoglycan (IPG) mediators. We hypothesize that a deficiency in D-chiro-inositol (DCI) and/or a DCI-containing IPG (DCI-IPG) may contribute to insulin resistance in humans...CONCLUSIONS: uCl(DCI) is inversely correlated with insulin sensitivity in women and is a strong independent predictor of insulin resistance in multivariate models. PCOS, which is characterized by insulin resistance, is associated with a selective increase in uCl(DCI) and impaired DCI-IPG release in response to insulin. These findings are consistent with a defect in tissue availability or utilization of DCI in PCOS that may contribute to the insulin resistance of the syndrome.
Gynecol Endocrinol. 2011 Apr;27(4):256-62. Epub 2010 Dec 10. D-Chiro-inositol and its significance in polycystic ovary syndrome: a systematic review. Galazis N, Galazi M, Atiomo W. PMID: 21142777
The objective of this study is to investigate the effects of insulin sensitising agents such as D-chiro-inositol (DCI) on ovulation and insulin resistance in women with PCOS. METHODS: This was a systematic review done in an Academic Department of Obstetrics and Gynaecology in the UK of all studies published on PCOS and DCI up till May 2010. Patients were women with PCOS receiving DCI or where the relationship between insulin resistance and DCI had been investigated. Ovulation rates and changes in insulin sensitivity were the main outcome measures. RESULTS: Less DCI-IPG was released in PCOS women compared to controls and this seems to correlate positively with insulin resistance and hyperinsulinemia evident in these patients. DCI administration had beneficial effects on ovulation, anthropometric and metabolic markers in PCOS women by enhancing insulin. The effects of metformin in improving insulin action in PCOS women was achieved though the release of DCI-IPG mediators. CONCLUSIONS: Heterogeneity observed in the methodologies of each study, the scarcity of relevant studies and the small sample sizes used prohibit reliable conclusions to be drawn. Therefore, more studies must be conducted in the future to evaluate accurately the effects of DCI in PCOS.
J Ovarian Res. 2012 May 15;5(1):14. [Epub ahead of print] Does ovary need D-chiro-inositol? Isabella R, Raffone E.  PMID: 22587479
BACKGROUND: ...While data on myo-inositol and restored ovulation were consistent, data on D-chiro- inositol were not once the dosage was increased. Recently, a comparative study, proposed a D-chiro-inositol paradox in the ovary of PCOS patients hypothesizing that only myo-inositol has a specific ovarian action. In the present study we aim to further study the role played by D-chiro-inositol at ovarian level. METHODS: A total of 54 women, aged <40 years and diagnosed with PCOS were enrolled in this study. Patients with insulin resistance and/or hyperglycaemia were excluded from the study. Patients were randomly divided into 5 groups (n=10-12): a placebo group, and 4 groups (A-D) that received 300-600-1200-2400 mg of DCI daily respectively. All treatments were carried out for 8 weeks before follicle stimulating hormone (rFSH) administration. RESULTS: Total r-FSH units increased significantly in the two groups that received the higher doses of DCI. The number of immature oocytes was significantly increased in the three groups that received the higher doses of DCI. Concurrently, the number of MII oocytes was significantly lower in the D group compared to placebo group. Noteworthy, the number of grade I embryos was significantly reduced by DCI supplementation. CONCLUSIONS: Indeed, increasing DCI dosage progressively worsens oocyte quality and ovarian response.
Inositol Combinations

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 M and Proietti E.  PMID: 22774396
BACKGROUND: ...Both myo-inositol (MI) and D-chiro inositol (DCI) glycans administration has been reported to exert beneficial effects at metabolic, hormonal and ovarian level. Beside these common features, MI and DCI are indeed different molecules: they belong to two different signal cascades and regulate different biological processes. AIM: In this study, we aim to verify whether the two molecules have a synergistic action by acting on their specific cellular pathways...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.
Support Groups for Women with PCOS Taking Inositol

Wednesday, October 23, 2013

PCOS Treatment: TZDs and Other Glucose-Lowering Medications

We've been discussing Polycystic Ovarian Syndrome (PCOS) and its impact on the health of women of size. It's time to discuss the use of non-metformin options in the treatment of PCOS.

If you've missed the last few posts, so far we've talked about the definition and symptoms of PCOS, how it presents, its testing and diagnosis, and its possible causes.

Currently, we are discussing common treatment protocols for PCOS, and the pros and cons of each. Unlike most resources, we are emphasizing a size-friendly, weight-neutral approach, rather than promoting weight loss for treatment.

We've already discussed metformin. Now, we discuss the TZDs, a.k.a. Actos, Avandia and related drugs, as other insulin-sensitizing agents often used in the treatment of PCOS.
Disclaimer: While the following information is based on my best understanding of the research, I am not a medical health-care professional and no medical advice should be inferred. Always do your own research and consult your healthcare provider.  
Trigger Warning: Passing mention of weight gain/weight loss side effects of some diabetes drugs.
Types of Insulin-Sensitizing Agents 

To summarize the information from previous posts, there are two main types of insulin-sensitizing agents ─ the group of drugs known as biguanides, and the group known as thiazolidinediones (which are also known as glitazones or TZDs). To repeat the summary from one website on insulin resistance:
  • Biguanides. Biguanides are drugs that improve the body's sensitivity to insulin by lowering the absorption of glucose in the small intestine, decreasing the liver's production of glucose, and increasing the uptake of glucose in muscle and fatty tissues...
  • Thiazolidinediones. These drugs stimulate glucose uptake in the muscles and fatty tissues by activating specific receptors in the cell nucleus. They also lower blood insulin levels in patients with hyperinsulinemia.
Of the biguanides, metformin hydrochloride (brand name: Glucophage) is the only drug still left in use. Metformin has been in use a long time, is very effective for many people, seems to prevent or reduce the risk of many poor outcomes, and has a longer safety profile than many other insulin-resistance (IR) drugs on the market. Because of this, it is the dominant insulin-sensitizing agent on the scene today, and deservedly so.

Thiazolidinediones (TZDs) were all the rage a few years ago because they seemed even more effective than metformin against IR and PCOS symptoms. However, safety concerns arose over the years and two TZDs (Rezulin and Avandia) were pulled from the market or limited in their use, while a third (Actos) remains under investigation.

In addition to metformin and TZDs, there are a few other insulin-sensitizing options for women with PCOS. Inositol (myo-inositol, d-chiro inositol, pinitol) is one option that received a lot of buzz at first and which is now experiencing a resurgence of interest. More on that in a separate post later on.

Limitations of the Data

A big limitation on our discussion here is that we do not have much information on the use of the TZDs for women with PCOS. Most of the information we have on insulin-sensitizing drugs has been done on the type 2 diabetes population only, so their effect on women with PCOS is somewhat speculative.

Furthermore, the studies we do have specifically on insulin-sensitizing drugs in a PCOS population are often short-term. And they place too much emphasis on surrogate outcomes like lower blood sugar or better insulin sensitivity, assuming that these will then translate to less morbidity and mortality down the line, but without actually examining whether or not they do.

As we shall see, drugs with short-term positive effects on risk factors don't always result in result in fewer heart attacks or deaths; sometimes they can actually worsen long-term outcomes. So it is key that we have long-term data on actual end-points, not just the effect on risk factors.

The bottom line is that data on the long-term efficacy and safety of these drugs in PCOS populations is urgently needed. Please keep that in mind as you read this post.

TZDs (glitazones)

The thiazolidinediones (known as glitazones or TZDs) include:
Basically, TZDs work mostly by improving sensitivity to insulin in muscle and fat tissue. As one resource explains:
The TZDs are a group of medicines that stimulate peroxisome proliferator-activated receptors (PPARs). There are many of these receptors, including PPAR-alpha, PPAR-gamma, and PPAR-delta...Once you stimulate the PPAR-gamma receptors, you improve insulin sensitivity not just in the liver, but everywhere in the body, especially in the adipose tissue and the skeletal muscles.
Like metformin, TZDs also inhibit hepatic (liver) glucose production. They are metabolized by the liver and excreted into the bile. They were introduced in the late 1990s.


TZDs have been shown to markedly improve blood sugar. Some research shows that TZDs may improve blood sugar in diabetics even better than metformin.

More importantly in PCOS, TZDs seem to improve insulin sensitivity. Many researchers feel that this is key in helping address the underlying metabolic disturbances of PCOS.

TZDs restores menstrual cycles and ovulation in many women with PCOS, both by itself and when used in combination with clomiphene. It also seems to improve ovulation and pregnancy rates in PCOS women who are clomiphene-resistant and those who don't respond to metformin.

TZDs may improve lipid and triglyceride levels as well. It also seems to lessen androgen levels, improve hormone balance, and improve hirsutism.

Recent research suggests that Actos may also be associated with an improvement in depressive severity in women with PCOS.

TZDs were thought to be the next class of wonder-drugs for insulin resistance. Many women with severe PCOS responded better to TZDs than to metformin, or responded well to a combination of both a TZD and metformin. Therefore, TZDs seemed to be a major step forward for women with PCOS.

But alas, as with many drugs, population-wide use soon found that TZDs came with drawbacks as well as benefits.

Safety Issues and Side Effects

Unfortunately, a number of safety issues have arisen with TZDs.
  • Troglitazone (Rezulin) was taken off the market in 2000 because it was associated with a increase in hepatotoxicity (liver problems)
  • Rosiglitazone (Avandia) was taken off the market in Europe in 2010 and subjected to restrictions in the US because of a purported increase in cardiovascular events (heart problems)
  • Pioglitazone (Actos) has a more favorable risk profile, but has recently been suspended in some European countries because some research suggested it might be associated with an increase in the risk for bladder cancer
At this time, TZDs are only approved for use with type 2 diabetics. Although commonly used for PCOS, this off-label use is still considered experimental.

As noted, most of the safety information we have is based on studies with diabetics and may not be the same for women with PCOS. In addition, it should be pointed out that many of the studies we do have on TZDs and PCOS are very small and short-term, and most do not meet the gold standard of randomized controlled trials.  

One of the risks of TZDs for diabetics is liver failure and/or hepatitis. Rezulin (troglitazone) was taken off the market because of its risk for liver toxicity, but all of the TZDs carry some degree of liver risk. Thus, many doctors recommend liver tests every few months when starting a TZD, and yearly thereafter. They should not be prescribed to anyone with existing liver disease.

A lesser-known risk associated with TZDs is a modestly increased risk of bone fractures and/or decreased bone density. This seems more associated with Actos than other TZDs, but data is still preliminary at this point and some research does not support an association. 

A common side effect of TZDs is edema (fluid retention). Although most who take a TZD don't experience it, edema from TZD use can lead to a significant worsening of undetected pre-existing heart failure. Therefore, weight gain and heart symptoms must be watched for closely in those on TZDs.

Although Avandia has been shown to lead to an increase in cardiovascular events and mortality in diabetic patients, there is still considerable debate over the validity of this finding. TZDs clearly increase the risk for congestive heart failure but the risk for myocardial infarction (heart attack) is less clear. Even if the risk is increased, the actual numerical risk is quite low, so many American doctors feel that the benefits of Avandia still outweigh the risks for some patients. European doctors, on the other hand, have basically discontinued its use.

Unlike Avandia, Actos has actually been shown to decrease some cardiovascular events, especially in those who have already had cardiac events. It can also decrease blood pressure and lipids. So the cardiovascular risk may depend on which TZD you take.

On the other hand, recent information also suggests that Actos could be associated with an increase in risk for bladder cancer in some users:
Although there was no increased risk of bladder cancer among Actos users overall, there was an increased risk of bladder cancer among those who had used the drug the longest. There was also a greater risk of bladder cancer among Actos users who had been exposed to the highest cumulative dose of the drug...FDA officials say in light of this new information, Actos should not be prescribed to people with bladder cancer or people with a history of bladder cancer.
Conversely, TZDs are associated with a lower risk for liver cancer and/or colorectal cancer in some studies. At this time, the relative benefit-risk ratio for each of these cancers is not available so it's difficult to weigh the pros and cons of their use.

Other side effects associated with TZDs may include upper respiratory tract infections, headaches, weight gain, anemia, muscle soreness, macular edema, and decreased effectiveness of oral contraceptives.

It should also be noted that TZDs are considered Pregnancy Class C drugs and, while effective for ovulation induction, should not be continued into pregnancy.

The bottom line is that the very significant benefits of TZDs may be balanced by significant risks.

Current Status and Future Use

While still used, TZDs have begun to fall from favor and many doctors do not consider them a first-line therapy for most people with diabetes. However, they are often still used to help lower blood sugar as diabetes progresses because they are very effective at lowering blood sugar, especially in combination with other drugs.

The use of TZDs as a mainstay treatment for PCOS is even less well-defined. Based on the evidence so far, most care providers feel that they are probably not the best first-line treatment for PCOS. However, they can be effective for those with more severe cases of PCOS, those with very high blood sugar, those with severe insulin resistance, or those who do not respond to/cannot tolerate metformin.

It should be pointed out that a recent review of the TZDs notes that the current TZD drugs comprise only the first generation of this drug class. Many times, the first generation of a drug class finds safety issues and results are improved upon in later generations of that drug class. Several recent reviews hint that the second generation of TZDs are on their way and may show significant improvements in both action and safety. However, only time will tell, since several other "next generation" TZD-related medications have been discontinued due to safety concerns.

For now, the benefits and risks of the current generation of TZDs (mostly Actos) must be weighed on an individual basis. For some, the possible risks may be offset by the considerable improvement in blood sugar and insulin sensitivity that may result. The trade-off would not be acceptable in someone with pre-existing heart disease or liver issues, however.

It is important to consult your healthcare provider carefully about the pros and cons of TZDs before incorporating them into your care, and to get frequent checks of your liver function if you decide to use them.

Combination Drugs

Metformin and a TZD are often used in conjunction for diabetes treatment. This combination seems particularly potent for lowering blood sugar in those with severe insulin resistance or those whose blood sugar does not normalize with metformin alone.

Rather than prescribing two different pills, the two medications are often combined into one pill. This makes it simpler and more convenient for the consumer, and the drug company is able to hold onto exclusive patent use longer for the drugs, thus prolonging the profit margins. As a result, these drug combinations are an increasingly popular way to prescribe diabetes medication.

Here are some common combination drugs:
  • Avandamet is a combination of metformin and Avandia (rosiglitazone). It was pulled from the market for a while because of manufacturing problems, but is available again. The controversy over Avandia's cardiovascular safety makes it less popular now, but there is a generic form coming soon
  • Actoplus Met is a combination of metformin with Actos (pioglitazone)
Again, the combination of metformin with either Avandia or Actos should probably be reserved for those with severe PCOS, or those whose diabetes does not respond adequately to metformin alone and who have contraindications to other diabetes medications.


Metformin is the first-line insulin-sensitizing treatment for diabetes
 because of its long history of usage and good safety profile, and deservedly so because it works well for many people with a relative minimum of side effects. It also seems quite effective for women with PCOS, although whether it should be used for normoglycemic women with PCOS is still debated.

However, metformin is not the only choice out there. In some people's opinion, TZDs also remain a viable choice for some women with PCOS. They are usually considered only when metformin fails to work well enough, has intolerable side effects, or when the patient has pre-existing kidney disease. They also are considered for women with severe hyperinsulinemia or hard-to-control diabetes.

There was much excitement when TZDs first came on the market, perhaps too much. Significant safety questions have arisen over the years, casting doubt on TZDs as a first-line treatment for either diabetes or PCOS. Because of restrictions, pioglitazone (Actos) remains the only real TZD available for most people these days, but it can be a powerful choice if monitored closely.

Newer-generation TZDs may be on their way, but users should remain vigilant about emerging safety research on these and other TZDs.

The potential for toxicity with these drugs is strong. Therefore, it is very important to have frequent blood monitoring before and during any trials of treatment with these drugs, including kidney tests, liver tests, blood sugar (fasting and HbA1c tests), and insulin levels.

The good news is that there are more choices than ever for dealing with the significant insulin resistance and blood sugar complications that seem to be an integral part of PCOS for most patients. The catch is that research into their safety is ongoing and the risks of newer drugs may not be fully known for some time.

Careful vigilance when using any of these drugs is obligatory.


General Information on Insulin-Sensitizing Agents
Overview of Various Diabetes Medications

Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Mar. Report No.: 11-EHC038-EF.
AHRQ Comparative Effectiveness Reviews.  PMID: 21735563
...The objective of this review was to summarize the benefits and harms of medications (metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 [DPP-4] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists), as monotherapy and in combination, for the treatment of adults with type 2 diabetes. RESULTS: The review included 140 randomized controlled trials and 26 observational studies..Most medications lowered HbA1c on average by 1 absolute percentage point, but metformin was more efficacious than the DPP-4 inhibitors. Two-drug combinations had similar HbA1c reduction. Compared with metformin, thiazolidinediones and sulfonylureas had a more unfavorable effect on weight (mean difference of +2.6 kg). Metformin decreased low density lipoprotein cholesterol relative to pioglitazone, sulfonylureas, and DPP-4 inhibitors. Sulfonylureas had a fourfold higher risk of mild/moderate hypoglycemia compared with metformin alone, and, in combination with metformin, had more than a fivefold increased risk compared with metformin plus thiazolidinediones. Thiazolidinediones had an increased risk of congestive heart failure relative to sulfonylureas and bone fractures relative to metformin. Diarrhea occurred more often for metformin compared with thiazolidinedione users...Although the long-term benefits and harms of diabetes medications remain unclear, the evidence supports use of metformin as a first-line agent. Comparisons of two-drug combinations showed little to no difference in HbA1c reduction, but some combinations increased risk for hypoglycemia and other adverse events.
Risks of TZDs
BMJ. 2011 Mar 17;342:d1309. doi: 10.1136/bmj.d1309. Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies. Loke YK, Kwok CS, Singh S. PMID: 21415101
...To determine the comparative effects of the thiazolidinediones (rosiglitazone and pioglitazone) on myocardial infarction, congestive heart failure, and mortality in patients with type 2 diabetes. DESIGN: Systematic review and meta-analysis of observational studies...RESULTS: Cardiovascular outcomes from 16 observational studies (4 case-control studies and 12 retrospective cohort studies), including 810,000 thiazolidinedione users, were evaluated after a detailed review of 189 citations...CONCLUSION: Among patients with type 2 diabetes, use of rosiglitazone is associated with significantly higher odds of congestive heart failure, myocardial infarction, and death relative to pioglitazone in real world settings.
JAMA. 2007 Sep 12;298(10):1189-95. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. Singh S, Loke YK, Furberg CD. PMID: 17848653 
...Recent reports of serious adverse events with rosiglitazone use have raised questions about whether the evidence of harm justifies its use for treatment of type 2 diabetes...Studies were selected for inclusion if they were randomized controlled trials of rosiglitazone for prevention or treatment of type 2 diabetes, had at least 12 months of follow-up, and monitored cardiovascular adverse events and provided numerical data on all adverse events. Four studies were included after detailed screening of 140 trials for cardiovascular events... CONCLUSION: Among patients with impaired glucose tolerance or type 2 diabetes, rosiglitazone use for at least 12 months is associated with a significantly increased risk of myocardial infarction and heart failure, without a significantly increased risk of cardiovascular mortality.
JAMA. 2007 Sep 12;298(10):1180-8. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. Lincoff AM, et al. PMID: 17848652
...Pioglitazone is widely used for glycemic control in patients with type 2 diabetes mellitus, but evidence is mixed regarding the influence of medications of this class on cardiovascular outcomes....A total of 19 trials enrolling 16 390 patients were analyzed. Study drug treatment duration ranged from 4 months to 3.5 years. Death, myocardial infarction, or stroke occurred in 375 of 8554 patients (4.4%) receiving pioglitazone and 450 of 7836 patients (5.7%) receiving control therapy (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.72-0.94; P = .005)...CONCLUSIONS: Pioglitazone is associated with a significantly lower risk of death, myocardial infarction, or stroke among a diverse population of patients with diabetes. Serious heart failure is increased by pioglitazone, although without an associated increase in mortality.
BMJ. 2009 Dec 3;339:b4731. doi: 10.1136/bmj.b4731. Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. Tzoulaki I, et al. PMID: 19959591
...To investigate the risk of incident myocardial infarction, congestive heart failure, and all cause mortality associated with prescription of oral antidiabetes drugs... CONCLUSIONS: Our findings suggest a relatively unfavourable risk profile of sulphonylureas compared with metformin for all outcomes examined. Pioglitazone was associated with reduced all cause mortality compared with metformin. Pioglitazone also had a favourable risk profile compared with rosiglitazone; although this requires replication in other studies, it may have implications for prescribing within this class of drugs.
BMJ. 2012 May 30;344:e3645. doi: 10.1136/bmj.e3645. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. Azoulay L, Yin H, Filion KB, Assayag J, Majdan A, Pollak MN, Suissa S. PMID: 22653981
OBJECTIVE: To determine if the use of pioglitazone is associated with an increased risk of incident bladder cancer in people with type 2 diabetes. DESIGN: Retrospective cohort study using a nested case-control analysis. SETTING: Over 600 general practices in the United Kingdom contributing to the general practice research database.PARTICIPANTS:
The cohort consisted of people with type 2 diabetes who were newly treated with oral hypoglycaemic agents between 1 January 1988 and 31 December 2009. All incident cases of bladder cancer occurring during follow-up were identified and matched to up to 20 controls on year of birth, year of cohort entry, sex, and duration of follow-up. Exposure was defined as ever use of pioglitazone, along with measures of duration and cumulative dosage...Overall, ever use of pioglitazone was associated with an increased rate of bladder cancer (rate ratio 1.83, 95% confidence interval 1.10 to 3.05). The rate increased as a function of duration of use, with the highest rate observed in patients exposed for more than 24 months (1.99, 1.14 to 3.45) and in those with a cumulative dosage greater than 28,000 mg (2.54, 1.05 to 6.14). CONCLUSION: The use of pioglitazone is associated with an increased risk of incident bladder cancer among people with type 2 diabetes.
Benefits of TZDs

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Hum Reprod. 2003 Aug;18(8):1618-25. Pioglitazone and metformin in obese women with polycystic ovary syndrome not optimally responsive to metformin. Glueck CJ, et al. PMID: 12871871
...In an observational study of 13 women with polycystic ovary syndrome (PCOS) not optimally responsive to metformin diet, we assessed the efficacy and safety of addition of pioglitazone. We also compared these 13 women to 26 women with PCOS, who were responsive to metformin diet, matched by age and by pre- treatment menstrual history and not different by obesity categories...In women with PCOS who failed to respond optimally to metformin, when pioglitazone was added, insulin, glucose, IR, insulin secretion, and DHEAS fell, HDL cholesterol and sex hormone-binding globulin rose, and menstrual regularity improved, without adverse side-effects.
J Affect Disord. 2011 Jul 20. Use of insulin sensitizers for the treatment of major depressive disorder: A pilot study of pioglitazone for major depression accompanied by abdominal obesity. Kemp DE, et al. PMID: 21782251
...This study was conducted to examine the safety and efficacy of pioglitazone, a thiazolidinedione insulin sensitizer, in adult outpatients with major depressive disorder. METHOD: In a 12-week, open-label, flexible-dose study, 23 patients with major depressive disorder received pioglitazone monotherapy or adjunctive therapy initiated at 15mg daily. Subjects were required to meet criteria for abdominal obesity (waist circumference greater than 35 in. in women and greater than 40 in. in men) or metabolic syndrome. The primary efficacy measure was the change from baseline to Week 12 on the Inventory of Depressive Symptomatology (IDS) total score. Partial responders (≥25% decrease in IDS total score) were eligible to participate in an optional extension phase for an additional three months...During the current episode, the majority of participants (74%, n=17), had already failed at least one antidepressant trial. The most common side effects were headache and dizziness; no patient discontinued due to side effects. CONCLUSION: Although preliminary, pioglitazone appears to reduce depression severity and improve several markers of cardiometabolic risk, including insulin resistance and inflammation. Larger, placebo-controlled studies are indicated.
Other TZD Studies