Update on the combination of myo-inositol/d-chiro-inositol for the treatment of polycystic ovary syndrome

Abstract

In this article, we present a narrative review on the use of inositol in the treatment of polycystic ovary syndrome (PCOS). Of the different inositols that exist, only myo-inositol (MYO) and D-chiro inositol (DCI) have been studied in the treatment of PCOS. The results of the studies show that there is insufficient or controversial evidence to recommend the use of DCI alone, while MYO alone shows positive results and, above all, the MYO/DCI combination is effective when used at a ratio of at least 40:1, but there is enough rationale to further study ratios such as 66:1 to 100:1 as other possible effective combinations.

Keywords:

• Polycystic ovary syndrome
• inositol
• MYO/DCI ratio

Introduction

Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine-metabolic disorders and is estimated to affect 5%–10% of women of childbearing age [1]. Its most frequent clinical features are the occurrence of menstrual disturbances, hyperandrogenism and infertility due to anovulation, recruitment of immature follicles, altered oocyte quality and even an increase in first trimester miscarriages [2]. In addition, insulin resistance occurs in PCOS patients, leading to hyperinsulinemia. These high levels of insulin resistance lead to increased plasma levels of luteinising hormone (LH), plasma androgens, and decreased circulating levels of sex hormone binding globulin (SHBG) as well as some degree of metabolic compromise with an increased tendency to develop diabetes or metabolic syndrome [3].

Patients with PCOS have higher rates of infertility, phenotypic androgen disorders, obesity, metabolic syndrome and increased risk of endometrial cancer and should be treated in a comprehensive manner to reduce the risks associated with their disease [4].

For years, PCOS has been treated with combined hormonal contraceptives (CHCs), with generally satisfactory results [5]. The limitations to the use of CHCs lie in their safety profile, which involves an increased risk of venous thromboembolism (VTE) in this type of patient [6]. Another drug commonly used in the treatment of PCOS has been and continues to be metformin [7], which has a high rate of gastrointestinal side effects [8], which leads to low compliance and adherence. Therefore, to avoid hormonal treatments and improve the safety profile of PCOS therapies, one of the proposed treatments for PCOS, apart from lifestyle changes and weight loss, is the use of agents that increase insulin sensitivity, leading to improved ovulatory function and a reduction in circulating levels of androgens [9]. This group of drugs that increase insulin sensitization includes inositols. In this review, we conducted an analysis of the efficacy of inositols, especially the combination of myo-inositol (MYO) and D-chiro-inositol (DCI) in the treatment of PCOS patients.

Inositols

Inositol is an organic compound of the polyol or polyalcohol family found in plasma membranes and other natural product structures. Inositol is considered a member of the vitamin Bcomplex [10]. There are nine possible stereoisomers, of which the most common and widespread in nature is cis-1,2,3,5-trans-4,6-cyclohexanehexol, or myo-inositol (MYO). Other natural isomers, although present in much smaller proportions, are scyllo-, muco-, D-chiro- (DCI) and neo-inositol. Other possible isomers are L-chiro-, allo-, epi- and cis-inositol [11].

Inositol is present in all animal tissues, with the highest levels observed in the heart and brain. It is part of all cell membranes and has the function of helping the liver to process fats as well as contributing to muscle and nerve function [12]. Inositol is necessary for nerve cell health and lipid metabolism as, together with choline (also related to the B vitamins), it is responsible for the creation of neurotransmitters and for preventing lipids from being deposited in the liver and promoting their transport and penetration into cells [13].

The most abundant stereoisomer in nature is MYO, which is considered a member of the vitamin B complex. It is synthesized by the human body from glucose [14]. MYO can be transformed into DCI through the action of the enzyme epimerase, which is stimulated by insulin [15]. In healthy women, the plasma MYO/DCI ratio is 40:1 [16], while in ovarian follicular fluid, the ratio is 100:1 [17]. In women with PCOS, this ratio between MYO and DCI becomes inverted and can go as low as 0.2:1 [17]. Altered inositol ratios may account for pathological conditions, causing an imbalance in sex hormones [18]. Therefore, the therapeutic goal when treating a patient with PCOS is to reverse the MYO/DCI ratio and make it as similar as possible to the follicular and plasma rates of healthy women.

Clinical applications of inositols

Inositol and some of its mono- and polyphosphates are involved in several biological processes, including signal transduction (insulin), cytoskeleton assembly, nerve guidance, and control of intracellular calcium (Ca²⁺) concentration, breakdown of fats and reduction of blood cholesterol [19]. In addition, MYO phospholipids are messengers of Follicle Stimulating Hormone (FSH) activity and some studies have shown that patients with PCOS and hyperinsulinemia present enhanced MYO to DCI epimerisation in the ovary, leading to MYO deficiency that impairs FSH signaling, resulting in reduced oocyte quality [17].

Some but not all studies suggest that high doses of inositol may be useful in treating psychological or psychiatric illnesses [20–24]. In addition, a small double-blind study designed to assess whether inositol is useful for the treatment of severe premenstrual dysphoric disorder failed to obtain conclusive results, so this line of work was stopped [25]. Consequently, research with inositol as a therapeutic agent focused on other areas.

The therapeutic area in which inositol has shown the greatest effectiveness is in PCOS, especially in helping to induce ovulation. Several studies have shown that taking 2 grams of Inositol daily helps restore ovarian function [26] with a success rate equal to or higher than that of clomiphene citrate, but with a better safety profile due to fewer side effects [27]. This effect in PCOS patients is because inositols in general, and MYO and DCI in particular, have insulin-sensitising activity and beneficial effects on metabolism [28] as well as PCOS-related infertility [29]. Insulin regulates glucose metabolism, and the concept of insulin resistance refers to the reduced ability of insulin to act effectively on peripheral target tissues (especially muscle and liver). In PCOS patients, there is insulin resistance, which generates hyperinsulinemia that, in turn, acts as a secondary messenger leading to an increase in LH and an increase in granulosa cell sensitivity to LH, which ultimately leads to hyperandrogenism and alterations in ovulation and decreased plasma levels of SHBG, a decrease that, in turn, leads to increased plasma levels of free androgens [30].

Several studies have shown insulin resistance and compensatory hyperinsulinemia in approximately 80% of obese women with PCOS and in 305–40% of lean women [31, 32]. The presence of insulin receptors on ovarian cells in both healthy women and women with PCOS supports the suggestion that excess insulin may have a high endocrine impact on the ovary [33, 34].In studies in isolated ovarian thecal tissue, insulin has shown an ability to directly stimulate androgen secretion and a greater LH-mediated response than in tissue isolated from healthy ovaries. In vivo, the frequent coexistence of elevated LH levels and increased insulin concentrations leads to a more severe expression of this syndrome [35].

Increasing insulin sensitization is accompanied by an improvement in ovulatory function, a decrease in the number of immature oocytes recruited and a reduction in both plasma and intrafollicular androgen levels and thus improved fertilization rates [5].

The role of insulin resistance in PCOS has supported multiple studies evaluating treatment with hypoglycemic agents such as metformin in women with PCOS, especially in situations of anovulation [7, 36, 37].Insulin resistance has been observed only in a fraction (50%–70%) of PCOS patients. Consequently, beneficial effects of inositols observed in lean patients, not resistant to insulin, cannot be explained only by advocating the hypothesis first suggested by Larner who postulated a defect in insulin transduction. Independently from insulin, PCOS subjects show a significant downregulation in both FSH-receptor and aromatase expression in the ovaries. These findings have prompted to reconsider old hypothesis and to formulate new ones [38].A study conducted on primary cultures of human granulosa cells, reported that D-Chiro inhibits aromatase synthesis, and it could help explaining why, despite the beneficial effects induced on insulin activity, D-Chiro-Ins finally worsen the clinical response in PCOS women [39].

However, the safety profile, especially in a situation of chronicity and long-term treatment, affects patients’ quality of life and adherence. A meta-analysis established that no difference in efficacy on endocrine changes was found between metformin and myo-inositol, emphasizing that the better tolerability of MYO makes it more acceptable for the recovery of androgen and metabolic profiles in women with PCOS [8].

The first controlled clinical trial on the use of inositols in PCOS was published in 1999. In that study, the use of 1200 mg DCI versus placebo, administered orally once daily for 6–8 weeks, was compared in 44 obese women with PCOS. An improvement in insulin sensitivity and a decrease in circulating free testosterone levels were observed in the group of women taking DCI, while there was no effect in the placebo group. In addition, ovulation occurred in 19 out of 22 women (86%) in the DCI group, while only 6 out of 22 women (27%) ovulated in the placebo group [40]. This trial was continued with a follow-up study of the same group of women, and the results were similar in terms of efficacy in inducing ovulation in the DCI-treated group [41]. Based on these previous good results, a large multicenter placebo-controlled trial was launched in women with PCOS using twice the dose of DCI (2400 mg). However, the results were never published and were both surprising and disappointing [42]. The higher dose of DCI failed to reproduce the results of the two previous studies in terms of improved ovulatory frequency. The lack of efficacy in the latter trial was attributed to the higher dosage of DCI administered, and the development of high-dose DCI products was halted [42]. The interpretation of these results was that increasing the doses of DCI not only does not improve ovulation outcomes, but it actually worsens them, so the use of only DCI in the treatment of PCOS was abandoned [42].It is known that follicular fluid volume and MYO content were significantly higher in follicles containing mature oocytes and subsequently in fertilized oocytes compared to follicles with recovered but unfertilized oocytes. The ratio of MYO to DCI in the follicular fluid of mature oocytes in women without PCOS is 100:1¹⁷, clearly above the 40:1 ratio found in plasma. Furthermore, the levels of MYO in follicular fluid were positively correlated with embryo quality, and subsequently with fertility in women [43]. Accordingly, a randomized clinical trial was conducted in 30 PCOS patients undergoing intracytoplasmic sperm injection (ICSI) for infertility and treated with 4 g of MYO daily from the time they started taking gonadotropin-releasing hormone (GnRH) [44]. The study showed that an increase in the frequency of spontaneous menstrual cycles was observed in the group of women treated with MYO, and the findings suggested that MYO might be useful in the treatment of infertility in PCOS. Another study also found that administration of MYO to women with PCOS undergoing in vitro fertilization (IVF) was associated with a reduction in the total amount of recombinant FSH (rFSH) administered and the number of days required for ovarian stimulation [45]. The evidence shows that MYO improves FSH sensitivity, and its use beneficially affects the ovary and oocyte function and development when used alone. In 2011, Unfer et al. conducted a comparative study of the effects of MYO versus DCI administration on oocyte quality in PCOS patients [46]. The study concluded that the number of mature oocytes was significantly increased, with a parallel decrease in the number of immature oocytes, in the MYO group compared to the DCI group, although the total number of oocytes retrieved did not differ between the two treatment groups. A potential explanation for this phenomenon of better response to MYO could be related to the different and specific tissue-dependent response to insulin resistance in PCOS patients. In these patients, while the muscle and liver show resistance to the action of insulin, the ovaries maintain normal insulin sensitivity, highlighting this different insulin resistance, which has come to be known as the DCI paradox [47]. The paradox is because the enzyme epimerase, responsible for converting MYO to DCI, is stimulated by insulin, and in PCOS patient’s insulin resistance leads to hyperinsulinemia, which stimulates epimerase activity leading to increased production of DCI and depletion of MYO. Therefore, if epimerase activity increases, some of the MYO is converted into DCI, so the amount of MYO does not increase and, in fact, in PCOS the ratio of MYO vs DCI can reach 0.2:1.¹⁵ What explains the paradox is that the MYO/DCI ratio in women without PCOS is 100: 1, whereas in PCOS patients it can be as low as 0.2:1.

The combination of myo-inositol and D-chiro-inositol

It has previously been mentioned that the plasma MYO/DCI ratio is 40:1, which is why many of the pharmacological formulations for the treatment of PCOS use this ratio, although this is the plasma ratio and not the follicular ratio, which it should be remembered is 100:1. This is also due to the fact that, although MYO shows satisfactory results, its combination with DCI improves the results due to the reduction of circulating insulin levels and the restoration of MYO levels in the ovary, which enables an improvement in oocyte quality [47]. In addition, MYO increases cellular glucose uptake and DCI increases glycogen synthesis, leading to a decrease in insulin resistance [48].

A meta-analysis evaluated the efficacy of treatment with MYO alone or MYO combined with DCI in a 40:1 ratio in nine clinical trials that included 247 PCOS patients and 249 controls [49]. The authors concluded that both MYO alone and MYO in combination with DCI are effective for the treatment of PCOS and induce higher ovulation rates and a better metabolic profile.

Another meta-analysis involving 10 clinical trials and 573 patients also confirmed the efficacy of the two forms of inositols in the treatment of PCOS and showed that low doses of DCI in combination with MYO decrease insulin resistance, correct hyperinsulinemia and consequently improve ovulation rates [50]. Since the efficacy of the MYO/DCI combination first became known, different doses of the two compounds have been investigated and experimented with to try to find the most effective ratio.

A study conducted in an animal model of PCOS-induced rats compared the efficacy of different MYO/DCI combinations (5;1, 20;1, 40;1 and 80;1) in reversing PCOS symptoms, concluding that the 40;1 combination was the most effective and the fastest in reversing the disease [52]. The conclusions of this study should be viewed with caution as they reflect what happens in an animal model, which cannot always be extrapolated to the human model. For this reason, to determine the impact on humans and with the aim of evaluating the different doses of DCI alone, MYO alone or the MYO/DCI combination available on the market at that time, in 2019, a clinical trial was published in which a total of seven different formulations of MYO/DCI (DCI alone, and 1:3.5; 2.5:1; 5:1; 20:1; 40:1, 80:1) were used to treat 56 women with PCOS (eight patients per group) and the efficacy of each formulation in inducing ovulation was evaluated as the primary endpoint [51]. The trial found that the administration of DCI alone, especially if high doses are used, does not give good results and should be avoided; that MYO alone can be effective in the treatment of PCOS, but that the MYO/DCI combination is effective when DCI is administered at a low ratio to MYO and that increased doses of DCI lead to a worsening of reproductive outcomes. Given the results of the above-mentioned studies, there is a consensus that the MYO/DCI ratio should favor MYO and provide low doses of DCI, which could be explained by the ovarian paradox effect discussed above.

Dysregulation of epimerase activity affects the MYO/DCI ratio and may impair signaling of hormones such as insulin and FSH. The findings published in the scientific literature are consistent in demonstrating a defect in the availability and/or utilization of the MYO/DCI combination in ovarian tissue in women with PCOS [52]. At the ovarian level, DCI is responsible for insulin-mediated overproduction of testosterone [53] while MYO is involved in FSH signalling [46]

Based on the fact that epimerase activity, regulating the MYO/DCI ratio, is insulin-dependent while the ovaries never become insulin-resistant, several studies have shown that PCOS patients are likely to have increased epimerisation of MYO to DCI in the ovary. This would result in an overproduction of DCI and deficiency of MYO, which is accompanied by poorer reproductive outcomes [53]. In PCOS patients, the MYO/DCI ratio is much lower than in patients without PCOS (0.2:1 versus 100:1) and the depletion of MYO levels affects the oocyte quality of these patients [53]. Therefore, it seems advisable to increase the MYO/DCI ratio to improve the results. In this regard, it is worth noting the wide variety of combinations that can be found in existing formulations, with MYO/DCI ratios ranging from 0.4:1 to 104:1, although the rationale for these ratios is based on the 40:1 plasma ratio rather than the 100:1 plasma ratio.

Despite the above, there are studies that have shown satisfactory results with higher concentrations of DCI. A multicenter comparative clinical trial in Spain, which recruited 60 women with PCOS who were undergoing ICSI assisted reproduction and compared the MYO/DCI combination at 3.6:1 versus 40:1, concluded that higher DCI concentrations are associated with better pregnancy rates [54]. Similar results were obtained by the same authors, although in a small sample of 11 patients in whom high doses of DCI were also associated with better reproductive outcomes [55]. The results of these latter studies should be analyzed with due caution because of the small number of patients included.

Therefore, in PCOS as well as in other pathologies, the correct posology of MI and DCI administered in therapy plays a pivotal role to provide the correct supplementation and the expected results, avoiding unwanted effects (currently, the administration of the 40:1 ratio between MI and DCI proved effective in PCOS). This important issue has to be managed considering the two stereoisomers use the same transporter. Therefore, when MI and DCI are administered together, their absorption can be decreased in an unequal way as consequence of this competition. MI and DCI have higher affinity for their transporter as compared to glucose; nonetheless, compounds that reduce glucose absorption at intestinal level may interfere with MI absorption if administered together. This causes an inadequate supplementation [56].

Conclusions

Research on inositols has taught us that a proper myo-Ins to D-chiro-Ins ratio governs the healthy state of organs and tissues, while an imbalance in inositol levels or their peripheral tissue depletion may account for pathological conditions. Therefore, restoring the inositol physiological ratio or altering this ratio in a controlled manner are proving to be two reasonable aims to achieve specific effects [18].

The effect of inositols in the treatment of PCOS is well established, as is their excellent safety profile. There is also good quality supporting evidence that the MYO/DCI ratio in PCOS preparations should be as low as possible favoring the MYO dose. The choice of the 40:1 ratio appears to be based on plasma levels, with studies having fixed this ratio, although this may not be supported by adequate levels of evidence. The data seem to indicate that favoring the DCI in this ratio by decreasing this proportion (e.g. 20:1, 10:1 or others) is not effective and may even compromise the effect of treatment, whereas increasing the MYO ratio may be more effective. Since we know that follicular ratios are 100:1, we know the effect of epimerase on the rapid depletion of MYO to DCI in women with PCOS and good results have been obtained with low doses, it seems appropriate to suggest that further studies should be carried out to evaluate the impact of ratios greater than 40:1 (up to 100:1) in the treatment of PCOS.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article.

Additional information

Funding

This article was written with a grant from Sakura, Italy