الإينوزيتول ومُتلازمة المبيض المُتعدد الكيسات: هل يُعَدُّ الإينوزيتول فعالاً لعلاج مُتلازمة المبيض المُتعدد الكيسات؟

If you have PCOS there is a fairly good chance that you have heard of a success story about taking inositol. Making regular appearances on the various forums set up to aid women with the condition, inositol supplements are growing in popularity. Those women who take it are quick to highlight its benefits and virtues; claiming improvements in menstrual cycle regularity and relief from the symptoms of androgen excess.

Despite all of this positive press, questions remain over the effectiveness of inositol as a treatment option and it is highly improbable that your doctor will advocate its usage.

So, why the disconnect? Why has inositol not advanced beyond being a supplement? On paper, it certainly sounds like the ideal drug candidate, so what has hindered further work on its development? Why are women so keen to use it that they are prepared to invest in over-the-counter complementary therapies, rather than those prescribed by their doctor? Let’s not forget that these supplements are also likely to have undergone a substantial mark-up in price.

This review aims to explore some of these issues; deciphering the facts from the myths, and presenting a balanced argument so that you can make the decision that is right for you

What is Inositol?

Inositols (plural) are sugars; their chemical structure would suggest they belong to the vitamin B complex, however, as they can be synthesised by the body, they cannot be classed as essential nutrients. Endogenous biosynthesis of inositols from glucose primarily occurs in the kidneys. However, the body obtains most of its inositol supply from the diet; foods such as plants, beans and fruits are particularly rich in this beneficial carbohydrate. Inositols are involved in many normal physiological functions, including cell growth and survival, the development and function of nerve cells, bone remodeling (osteogenesis) and reproduction. As such, the different tissues throughout the body have varying requirements and inositol absorption differs accordingly.

There are nine stereoisomers of inositol and two of these appear to have a role in insulin regulation, myo-inositol (MI) and D-chiro-inositol (DCI). In fact, MI is converted into DCI in a non-reversible reaction and the two isomers usually work in synergy to regulate glucose metabolism.

Why is Inositol used to treat PCOS?

Polycystic Ovary Syndrome is a condition of hormonal dysregulation, thought to affect between 5 and 10% of women of reproductive age. Many women with the condition struggle to conceive and they are at increased risk of developing other metabolic conditions, including type 2 diabetes. With no definitive cure, the current emphasis is on providing symptomatic relief, but with such a range of clinical manifestations, the burden of PCOS, from both an economic and a social perspective, is high.

More research…

According to the 2003 Rotterdam criteria, a diagnosis of PCOS will be made if a female presents with two out of three of the following symptoms; anovulation, hyperandrogenism and/or polycystic ovaries. Despite not featuring as one of the defining characteristics of the condition, insulin resistance is strongly associated with PCOS. 80% of obese women with PCOS are insulin resistant, hardly surprising, as the two are intrinsically linked. However, even those women with a normal BMI are at increased risk of developing hyperinsulinaemia and peripheral insulin resistance.

Insulin resistance occurs when the cells and tissues of the body do not respond normally to insulin and require a greater amount to exert a biological effect. This results in a state of ‘compensatory hyperinsulinaemia’, whereby insulin secretions are increased to counteract the deficiency. Excess circulating insulin can further exacerbate the risk of type 2 diabetes. It is thought that the ovaries never become fully insulin resistant, however, they are sensitive to fluctuating levels of the hormone. Insulin stimulates the ovarian theca cells to produce androgens and this can be one of the triggers for the hyperandrogenism seen in women with PCOS.

Inositol as an insulin sensitiser

Insulin sensitisers clearly have a role in the management of PCOS and its associated symptoms, particularly for those women looking to restore (or maintain) their normal ovulatory cycle with a view to falling pregnant.

The two most widely utilised options to date have been metformin and thiazolidinediones, which have been shown to improve ovulation and reduce metabolic symptoms. However, both exhibit significant side effects, including gastrointestinal complaints in the case of metformin and weight gain in the case of the thiazolidinediones and therefore, patient compliance can be low. An association between the thiazolidinediones and liver toxicity, led to this class of drugs being removed from the market.

Interestingly, it has been proposed that the beneficial effects of metformin are secondary to an increase in inositol availability. Furthermore, alternative research has suggested that the metabolism of inositol (MI to DCI conversion) is severely disrupted in obese PCOS patients who are insulin resistant. Currently, this data has not been replicated in lean women; however, the information to date is sufficient to suggest a possible therapeutic role for the inositols in alleviating insulin resistance.

What does the science suggest?

With the ongoing drive to find a treatment approach that will simultaneously rectify multiple PCOS symptoms and the growing interest in the inositols, clinically relevant research was essential. So, what was investigated and what did it show?

As mentioned previously, the predominant forms of inositols are MI and DCI. Within the ovaries, MI is the more highly expressed of the two, and acts to regulate glucose uptake and FSH (follicle stimulating hormone) signaling. DCI, expressed at lower levels, modulates insulin-induced androgen synthesis.

Despite the lower expression of DCI, preliminary work was performed using this form of inositol. Partly because of the specific link between androgen synthesis and DCI, but also because women with PCOS were found to have reduced serum levels and increased urinary loss of that isoform. Initial results were encouraging; women who had PCOS, diagnosed using the Rotterdam criteria, who were treated with DCI, had improved insulin sensitivity and 86% saw a restoration in ovulation. However, the sample size was only 22 so conclusions were speculative at best  and larger, more well-designed studies are imperative for further validation.

Subsequent Studies

Subsequent studies, using higher doses of DCI, found that oocyte quality was deteriorating with high concentrations of the compound. In contrast, women with PCOS who took a MI supplement had improved ovarian function and enhanced oocyte and embryo quality. This, in turn, led to studies looking at the effectiveness of just giving MI as a supplement and, encouragingly, some women did see an improvement in their symptoms. However, it soon became apparent that an excess of MI could have a paradoxical effect, exacerbating the imbalance between MI and DCI.

More recent studies have used a combination of MI and DCI for maximal benefit, although the optimal proportion of each remains controversial. The rationale behind using a combination of the two comes from the suggestion that PCOS-induced insulin resistance is caused by an imbalance between MI and DCI and that the ratio of the two might be insulin dependent. The normal ratio of MI:DCI in the ovary is estimated to be 100:1, based on measurements taken from the follicular fluid. However, the normal physiological ratio of MI:DCI in the plasma is 40:1 and this is the combination used in most commercially available inositol supplements.

MI and DCI

Certainly, some studies show that this combination of MI and DCI can be effective at improving ovulation and increasing menstrual cycle regularity, but there is scant reliable evidence that it is the optimal dose. The ovary is not metabolically active, thus what is happening in the plasma is unlikely to be indicative of what is happening in the ovary and there is no data on the ovarian uptake of free MI/DCI following exogenous delivery. Meaning that dietary supplements, given in the proportions currently accepted as standard, may not even be reaching the target organ (the ovary) in the case of PCOS.

MI and DCI given in combination prior to in vitro fertilisation (IVF) has been shown to improve pregnancy rates, when compared to DCI given in isolation; but only in younger women. As this data came from a single study, further validation is necessary.

Using Inositols for weight loss

There have been a number of meta-analyses, attempting to compare the efficacy of MI, DCI and/or MI+DCI across studies. The majority of studies do show an improvement in insulin resistance with treatment, however most are considered to be poorly designed and of low quality. Significant increases in ovulation rates and improved menstrual cycle frequencies are often reported, but improved experimental design would show whether these positive effects were scientifically robust. Using inositols for weight loss is something heavily advocated by those who manufacture the commercially available supplements. However, the truth is, most of the data in terms of BMI reduction is inconclusive. At best, minimal weight loss with treatment is seen, but as the majority of studies to date have utilised obese patients, a small reduction in BMI is unsatisfactory. 

To understand more

Theoretically, correcting any hyperinsulinaemia should reduce the production of ovarian androgens, which will have been contributing to the symptoms of hyperandrogenism, including hirsutism, acne and hair loss.

Studies have indicated a trend towards reduced androgen levels with inositol treatment and there is limited data that suggests improvements in hirsutism and acne. However, longer-term studies may be necessary to confirm the effectiveness of MI and DCI in improving PCOS-induced hyperandrogenism. It should also be considered that metformin, which is an alternative insulin sensitiser, has never been as effective as other treatment options at improving hyperandrogenism.

Why don’t doctors routinely recommend Inositols?

Up to this point, everything has looked encouraging; the data published to date suggests that inositols are a viable treatment option, providing symptomatic relief for women with PCOS, with minimal to no adverse side effects.  However, doctors do not routinely prescribe them and women who wish to use them are reliant on sourcing and purchasing these supplements themselves.

Why?

As positive as the data initially appears, it is preliminary in nature and most of the studies have employed very small sample sizes. This may not be such a problem if the methodology was consistent across the different studies, enabling cross-study comparisons and detailed meta-analyses. However, the study designs are inherently variable, with different dosages, treatment regimes and controls. There is a distinct lack of quantifiable data on reproductive end points, such as live birth and miscarriage rates.

As discussed above, there is a fundamental lack of understanding with regards to the normal physiological levels of MI and DCI in the ovary. If, as has been suggested, PCOS is causing an imbalance in the ratio of the two, the exact magnitude of this disruption remains unclear. Thus, the current 40:1 ratio that is most often cited seems slightly arbitrary.

Multicenter phase II clinical trials on DCI as a treatment for PCOS were initiated. However, they were suspended as the beneficial effects seen in smaller studies could not be replicated. Unfortunately, the results were never published.

Cochrane Review

Cochrane reviews are widely regarded as providing amongst the highest standards of evidence-based healthcare. They undertake systematic reviews of primary research to provide unbiased answers to pertinent questions. In the case of using inositols for PCOS, a cochrane review was established, looking at 13 inositol trials, involving 1472 women. The published conclusion was that the evidence across the trials was low, to very low. There was poor reporting of methods, inconsistencies and a lack of clinically relevant information, such as live birth rates and adverse events. Likewise, the guidelines from the American Society for Reproductive Medicine state that inositols are “currently considered an ‘experimental’ therapy with very low quality evidence for their use”.

What’s next for Inositols?

So where do we go from here? It is a challenging question.

More clinical trials

Inositol therapy, in its current guise as a dietary supplement, does provide symptomatic relief to some women with PCOS. Look hard enough and there is scientific evidence to support this, as well as biological justification for their use. However, the data available is weak and there is an urgent need for well designed, multicenter trials before inositol can be routinely recommended by healthcare professionals.

Testing effects on ovarian function

There remain extensive gaps in our knowledge; for example, it is still not known how inositols improve insulin sensitivity at the molecular level. The role of inositols in the ovaries in unclear and the data on whether there is dysregulation in MI and DCI metabolism within the reproductive system is conflicting. Whether inositols have an effect on other ovarian functions, such as steroidogenesis also remains to be elucidated.

Targeting insulin resistance

What we do know is that improving insulin resistance is a key therapeutic target for those investigating PCOS. Although insulin resistance is not one of the main diagnostic criterium for PCOS; it is a feature in many women who are diagnosed with PCOS and triggers many of the phenotypic features of the disease, including hyperandrogenism and menstrual cycle irregularities. It also increases the risk of type 2 diabetes. Inositol supplementation is still a potentially valuable tool to explore for combating some of these symptoms and risks.

Personalising treatment options

As our understanding of the specifics of the inositol stereoisomers grows, there is scope for a more personalised treatment approach. Those with a familial history of hyperinsulinaemia seem to respond well to DCI treatment, particularly if they are also obese. Women whose ovarian function is compromised may respond better to MI treatment. Although interest in a combination approach has grown, perhaps this is not the best option for all patients.

It should be remembered that PCOS is a multi-faceted condition, presenting with a range of symptoms, differing in severity between patients. Thus, a simple therapeutic approach that works for all patients is highly unlikely. Supplements are less regulated than medicines, therefore, the safety data for inositols is limited and the specific formulations available are restricted. A highly individualised treatment plan for each patient may be what is required.

Understanding inositol resistance

A further area that requires additional investigation is with regards to inositol resistance. Across the different studies, MI has been shown to be relatively successful at inducing ovulation; however, up to 40% of women still do not ovulate. Resistance to MI has been proposed to occur as a result of insufficient absorption of inositols. Indeed, it has already been shown that the gut microbiota is altered in women with PCOS and hypothesised that this could affect nutrient absorption.

Preliminary work suggests that alpha-lactalbumin milk protein improves the uptake of MI and induces ovulation. As with all work on the inositols, sample sizes in this study were small and further work is essential before conclusions can be drawn; however, this study does highlight the value in considering combination therapy for the treatment of PCOS.

In conclusion

As far as the inositols go, currently it appears we have more questions than answers. Until inositols become a regulated supplement recommended by clinicians, is likely that women will continue to take dietary supplements. Women struggling with the symptoms of PCOS should also be encouraged to adopt lifestyle changes, as even small changes in weight have been shown to alleviate some of the negative effects of the condition.

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