Inositols and other supplements in the management of PCOS

Introduction

Polycystic ovary syndrome (PCOS) is associated with neuroendocrine dysfunctions, insulin resistance (IR), impaired ovarian steroidogenesis and hyperandrogenism .

Although the etiology of PCOS is still poorly known, androgens and insulin are thought to be two key factors in its pathogenesis. Thus, PCOS treatment needs to cure both hyperandrogenism as well as hyperinsulinemia.

Given the central role of insulin resistance in the onset of PCOS, insulin-sensitizing agents, such as metformin and pioglitazone have been proposed as first line approaches . However, pioglitazone though it positively modulates ovarian androgen synthesis via upregulation of progesterone biosynthesis, inhibition of testosterone, and production of E2, may be associated with relevant adverse effects , and metformin has only convincingly demonstrated the advantage of lowering IR, while women affected by PCOS present very often other metabolic and reproductive disorders .

Therefore, such a heterogeneity of clinical manifestations of PCOS suggests that the therapeutic strategy should consider the overall features of the patient and include pharmacological and/or nonpharmacological treatments.

This chapter will be focused on different supplements that may help to manage PCOS and its complications, starting with inositols.

Inositols

Physiological functions

In 1850, Johann Joseph Scherer isolated a hexahydroxycyclohexane from the muscle and he named this molecule “Inositol” .

In 1887, Maquenne established its cyclohexanol structure, purifying inositol from leaves . From the epimerization of the six –OH groups nine possible stereoisomers can be derived: cis-, epi, allo-, myo-, neo-, scyllo-, L-chiro-, D-chiro-, and muco-inositol . Among them, myo-inositol (MI) is quite ubiquitous in nature and is the most abundant form found .

In the human body, MI synthesis takes place in the kidneys, brain, liver, testes and mammary gland. In particular, kidneys produce daily approximately 4 g MI .

MI derives from the isomerization of glucose-6-phosphate (G6P) to inositol-3-phosphate (Ins3P) by D-3-myo-inositol-phosphate synthase enzyme (inositol synthase, Ino1, or MIPS1) . Then, through inositol monophosphatase-1 (IMPA-1 or IMPase), Ins3P is dephosphorylated to free MI .

Free inositol could also be obtained by the dephosphorylation of inositol-1,4,5-trisphosphate (InsP3) and inositol-1,4-bisphosphate (InsP2).

A specific Nicotinamide Adenine Dinucleotide (NAD)-NADH-dependent epimerase, under insulin stimulation, converts MI into D-chiro-inositol (DCI) .

Also, a normal diet provides inositols, mainly present in fruits, beans, grains, nuts cereals and legumes, as MI for the most part, phosphatidylinositol (PI) and inositol hexakisphosphate .

In order to exert its activity, insulin needs the presence of both MI and DCI. The two stereoisomers, as inositol-phosphoglycans (MI-IPG and DCI-IPG), are second messengers in the insulin signaling, mediating different effects . The activation of glucose transporters and glucose utilization are controlled by MI, whereas DCI regulates glycogen synthesis . Both molecules are therefore able to exert an insulin-sensitizing effect reducing the circulating insulin levels.

Furthermore, specifically, MI participates in the follicle-stimulating hormone (FSH) signaling, acting as second messenger. Through its receptor (FSHR), FSH regulates the proliferation and maturation of granulosa cells. MI-IPG also seems to regulate the cytoskeleton and the FSH-induced production of anti-Müllerian hormone (AMH), which modulates the sensitivity of follicles to FSH and, hence, their maturation .

On the other hand, DCI, in the phosphoglycan form, besides acting as a second messenger of insulin signal indirectly influences steroidogenesis. Nevertheless, DCI also exhibits an independent activity on androgen biosynthesis, as found by Nestler and co-workers . They demonstrated that DCI can reduce the activity of the enzyme aromatase (CYP19A1), that catalyzes the conversion of androgens to estrogens. These results are supported by the study of Sacchi and colleagues; they found that DCI affects the gene expression of aromatase, downregulating it in a dose-response manner .

Thus, DCI activity on steroidogenesis, may be twofold: on the one hand, an indirect effect as a result of insulin signal boosting; on the other hand, an independent direct effect on steroid biosynthesis through downregulation of the aromatase expression and enhancement of testosterone production .

Inositol's effects in PCOS

Over the years, the critical role of insulin resistance and/or compensatory hyperinsulinemia in the pathogenesis of PCOS have been consistently affirmed throughout the numerous in vitro and in vivo studies.

Approximately 35% of lean women and 80% of obese women with PCOS present the condition of insulin impairment .

Cheang and colleagues confirmed that an impairment of the inositol-phosphoglycan insulin second messenger pathway might cause a derangement in the insulin signaling in PCOS . Therefore, the rationale for the use of these two molecules as valuable therapeutic approach of PCOS is designated primarily for their “insulin mimetic” action.

Treatment with inositols proved to be side effect free, at the therapeutic dose, and effective in improving several clinical features of PCOS. Of note, FDA included MI in the list of specific substances defined “generally recognized as safe” (GRAS) .

Clinical evidence of MI effectiveness

As evidenced by Papaleo and co-workers, a 6-month treatment with 2 g MI twice a day, effectively restored spontaneous ovarian activity, and subsequent fertility in PCOS patients . In 72% of these patients, MI reactivated the normal ovulatory activity and achieved a pregnancy rate of 40% during the 6-month observation period.

Other researchers replicated these results investigating the metabolic and hormonal effects of MI in PCOS women. Patients underwent hormonal evaluations and OGTT before and after treatment; ultrasound examinations and Ferriman-Gallwey score were also performed. After MI administration, plasma LH, prolactin, testosterone, insulin levels and LH/FSH ratio were significantly reduced and insulin sensitivity, expressed as glucose-to-insulin ratio and HOMA index, resulted significantly improved. Menstrual cycle was restored in all subjects with amenorrhea or oligomenorrhea.

Thus, hormonal profile significantly improved, and the restoration of ovulation as well as regular menses in both obese and lean women was observed .

Up to date, several studies have been conducted on the effect of inositol on the biochemical and clinical parameters related to hyperandrogenism and metabolism in PCOS women .

Overall, these studies, even with many differences in trial design, sample size, treatment duration and dosage, share a common result: the beneficial effect of MI alone or combined with DCI in improving the metabolic profile of women with PCOS, and a concomitant reduction of hyperandrogenism .

Clinical evidence of DCI effectiveness

PCOS women have reduced serum level and increased urinary loss of DCI . This could be due to multiple causes, including a defective conversion of MI to DCI and/or to impairment of tubular transport by high glucose.

DCI administration re-stablishes an adequate tissue content of DCI derivatives, increasing insulin sensitivity and improving ovulatory frequency and serum androgens and/or levels of lipid biomarkers in women affected by PCOS .

The first study with DCI versus placebo in PCOS was published in 1999 by Nestler and colleagues. They orally supplemented 1200 mg of DCI once a day to 44 obese PCOS women; after 6–8 weeks an improved insulin sensitivity and a decreased circulating free testosterone level were observed. DCI administration also resulted in ovulation for 86% women, whereas only 27% ovulated in the placebo group .

In 2002, the same group performed a follow-up study in lean women with PCOS . Again, and in agreement with the earlier study , the administration of DCI was associated with improved insulin sensitivity, a reduction in circulating free testosterone, and increased frequency of ovulation.

Subsequently, Insmed Pharmaceuticals embarked on a large multicenter placebo-controlled trial supplementing PCOS woman with 2400 mg DCI, a dosage twice as high as ever previously used. However, the higher dose of DCI failed to reproduce the outcomes of the two previous studies in terms of improving ovulatory frequency; thus, the results were never published. Consequently, the company gave up proceeding with the use of DCI in clinical trials on PCOS.

The higher dose of DCI administered was identified as the main cause of the lack of efficacy in the latter trial.

Further evidence that DCI administration to PCOS women can improve insulin sensitivity and reduce serum free testosterone levels, leading to normal cycle and ovulation, is available from a retrospective study performed in PCOS patients with irregular cycles. In this case, 1–1.5 g DCI administered daily for a maximum of 15 months improved insulin levels along with an increase in the percentage of women reporting regular menstrual cycles, directly proportional to the duration of the treatment .

In another study, 1 g DCI plus 400 μg folic acid daily for 6 months significantly improved IR as measured by HOMA index and glycaemia/insulin resistance index (IRI) ratio. In the same study, an improvement of systolic blood pressure, Ferriman-Gallwey score, LH, LH/FSH ratio, total testosterone, free testosterone, 1-4-androstenedione, prolactin, and sex hormone binding globulin was observed .

Despite this evidence showing positive effects of DCI in the treatment of PCOS, Legro in 2016 reported that large, multicentred phase 2 clinical trials were suspended because of lack of efficacy .

Interestingly, in a comparative study of the effects of administration of MI versus DCI on oocyte quality in PCOS patients, Unfer and coworkers observed that in the MI group the number of mature oocytes was significantly higher, with a parallel diminution in the number of immature oocytes, in respect to the DCI group .

This phenomenon is likely to be related to the tissue-specific nature of insulin resistance in women with PCOS. Indeed, meanwhile, fat, muscle and liver are insulin resistant in women with PCOS, ovaries never become resistant. Unfer and coworkers refer to this phenomenon as “DCI paradox” in the ovary .

In fact, since in the ovary, under insulin stimulation, the epimerase converts MI to DCI, Unfer et al. proposed that in PCOS women hyperinsulinemia overstimulates ovarian epimerase activity, resulting in a harmful increased production of DCI and a concomitant depletion of MI. The authors postulated that the resulting deficiency of MI could be responsible for the poor oocyte quality and the impairment of the FSH signaling. Clearly, DCI supplementation would be ineffective, if not harmful, in such women as they already have high levels of this molecule in the ovary.

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