D-chiro-inositol in clinical practice: A perspective from The Experts Group on Inositol in Basic and Clinical Research (EGOI).

BACKGROUND: D-chiro-inositol is a natural molecule that, in association with its well-studied isomer myo-inositol, may play a role in treating various metabolic and gynecological disorders. OBJECTIVES: This perspective seeks to explore the mechanisms and functions of D-chiro-inositol, laying the foundations to discuss its use in clinical practice, across dysmetabolism, obesity, and hormonal dysregulation. METHODS: A narrative review of all the relevant papers known to the authors was conducted. OUTCOME: D-chiro-inositol acts through a variety of mechanisms, acting as an insulin sensitizer, inhibiting the transcription of aromatase, in addition to modulating white adipose tissue/brown adipose tissue trans differentiation. These different modes of action have potential applications in a variety of therapeutic fields including: PCOS, dysmetabolism, obesity, hypoestrogenic/hyperandrogenic disorders, and bone health. CONCLUSIONS: D-chiro-inositol mode of action has been studied in detail in recent years, resulting in a clear differentiation between D-chiro-inositol and its isomer myo-inositol. The insulin sensitizing activities of D-chiro-inositol are well understood; however, its potential applications in other fields, in particular obesity and hyperestrogenic/hypoandrogenic disorders in men and women, represent promising avenues of research that require further clinical study.

Inositols: From Established Knowledge to Novel Approaches.

Myo-inositol (myo-Ins) and D-chiro-inositol (D-chiro-Ins) are natural compounds involved in many biological pathways. Since the discovery of their involvement in endocrine signal transduction, myo-Ins and D-chiro-Ins supplementation has contributed to clinical approaches in ameliorating many gynecological and endocrinological diseases. Currently both myo-Ins and D-chiro-Ins are well-tolerated, effective alternative candidates to the classical insulin sensitizers, and are useful treatments in preventing and treating metabolic and reproductive disorders such as polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), and male fertility disturbances, like sperm abnormalities. Moreover, besides metabolic activity, myo-Ins and D-chiro-Ins deeply influence steroidogenesis, regulating the pools of androgens and estrogens, likely in opposite ways. Given the complexity of inositol-related mechanisms of action, many of their beneficial effects are still under scrutiny. Therefore, continuing research aims to discover new emerging roles and mechanisms that can allow clinicians to tailor inositol therapy and to use it in other medical areas, hitherto unexplored. The present paper outlines the established evidence on inositols and updates on recent research, namely concerning D-chiro-Ins involvement into steroidogenesis. In particular, D-chiro-Ins mediates insulin-induced testosterone biosynthesis from ovarian thecal cells and directly affects synthesis of estrogens by modulating the expression of the aromatase enzyme. Ovaries, as well as other organs and tissues, are characterized by a specific ratio of myo-Ins to D-chiro-Ins, which ensures their healthy state and proper functionality. Altered inositol ratios may account for pathological conditions, causing an imbalance in sex hormones. Such situations usually occur in association with medical conditions, such as PCOS, or as a consequence of some pharmacological treatments. Based on the physiological role of inositols and the pathological implications of altered myo-Ins to D-chiro-Ins ratios, inositol therapy may be designed with two different aims: (1) restoring the inositol physiological ratio; (2) altering the ratio in a controlled way to achieve specific effects.

Inositol Treatment for PCOS Should Be Science-Based and Not Arbitrary.

The aim of this paper is to critically analyze the composition of many inositol-based products currently used to treat Polycystic Ovary Syndrome (PCOS). Several different combinations of myo-inositol and D-chiro-inositol, with and without additional compounds such as micro- and macroelements, vitamins, and alpha-lipoic acid, have been formulated over the years. Such therapeutic proposals do not take various features of inositol stereoisomers into consideration. As an example, it is important to know that D-chiro-inositol treatment may be beneficial when administered in low doses, yet the progressive increase of its dosage results in the loss of its advantageous effects on the reproductive performance of women and a deterioration in the quality of blastocysts created via in vitro fertilization (IVF). In addition, we have to consider that the intestinal absorption of myo-inositol is reduced by the simultaneous administration of D-chiro-inositol since the two stereoisomers compete with each other for the same transporter that has similar affinity for each of them. A decrease in myo-inositol absorption is also found when it is coadministered with inhibitors of sugar intestinal absorption and/or types of sugars such as sorbitol, maltodextrin, and sucralose. The combination of these may require higher amounts of myo-inositol in order to reach a therapeutic dosage compared to inositol administration alone, a particularly important fact when physicians strive to obtain a specific plasma level of the stereoisomer. Finally, we must point out that D-chiro-inositol was found to be an aromatase inhibitor which increases androgens and may have harmful consequences for women. Therefore, the inositol supplements used in PCOS treatment must be carefully defined. Clinical evidence has demonstrated that the 40 : 1 ratio between myo-inositol and D-chiro-inositol is the optimal combination to restore ovulation in PCOS women. Therefore, it is quite surprising to find that inositol-based treatments for PCOS seem to be randomly chosen and are often combined with useless or even counterproductive molecules, all of which can weaken myo-inositol's efficacy. Such treatments clearly lack therapeutic rationale.

Bye-bye chiro-inositol - myo-inositol: true progress in the treatment of polycystic ovary syndrome and ovulation induction.

Polycystic ovary syndrome (PCOS) is a multifactorial syndrome affecting 10% of women in reproductive age. Insulin sensitizer agents are the best therapeutic option for PCOS patients; among which there is Inositol. Inositol is a polyalcohol existing as nine different stereoisomers, two of which have been shown to be insulin mediators: myo-inositol (MI) and D-chiro-inositol (DCI). So far only MI have been show to be present in the follicular fluid and in a direct comparison between MI and DCI only MI was able to improve oocyte and embryo quality. Therefore, Could we say "bye-bye D-chiro-Inositol" in the practice of clinical gynecology and reproductive medicine?

The D-chiro-inositol paradox in the ovary.

The D-chiro-inositol-to-myo-inositol ratio is regulated by an insulin-dependent epimerase. Enzyme activity varies among tissues, likely owing to the specific needs of the two different molecules. We hypothesize that in the ovaries of polycystic ovary syndrome patients, epimerase activity is enhanced, leading to a local myo-inositol deficiency which in turn is responsible for the poor oocyte quality.

Improvement in sperm quality and function with French maritime pine tree bark extract.

OBJECTIVE: To determine the effects of Pycnogenol (French maritime pine tree bark extract) on sperm parameters and function in subfertile men. STUDY DESIGN: Prospective, nonrandomized, clinical study in a private infertility practice. Nineteen subfertile men were given 200 mg Pycnogenol daily orally for 90 days. Semen samples were analyzed before and after treatment for sperm count, motility score and strict morphology before and after capacitation, and mannose receptor binding. RESULTS: The mean sperm morphology following Ham's F-10 capacitation increased by 38% following Pycnogenol treatment, and the mannose receptor binding assay scores improved by 19%. CONCLUSION: Pycnogenol therapy resulted in improved capacitated sperm morphology and mannose receptor binding. The increase in morphologically and functionally normal sperm may allow couples diagnosed with teratozoospermia to forgo in vitro fertilization and either experience improved natural fertility or undergo less invasive and less expensive fertility-promoting procedures, such as intrauterine insemination.