Treating PCOS with inositols: Choosing the most appropriate myo- to d-chiro-inositol ratio

Myo-inositol and d-chiro-inositol are natural compounds involved in many biological pathways. Since the discovery of their involvement in endocrine signal transduction, inositol-based supplementation has contributed to the management of several gynecological and endocrinological diseases. Inositols are well-tolerated and effective alternative to the classical insulin sensitizers and are increasingly used in the treatment of reproductive disorders such as polycystic ovary syndrome (PCOS). Inositols enhance insulin activity and are proven to exert beneficial effects in several metabolic conditions, including insulin resistance, metabolic syndrome, and gestational diabetes mellitus. Notably, besides their metabolic activity, inositols deeply influence steroidogenesis in the ovary, regulating the pools of androgens and estrogens, likely in opposite ways. Specifically, d-chiro-inositol mediates insulin-induced testosterone biosynthesis in ovarian theca cells and directly affects the synthesis of estrogens by inhibiting the expression of the enzyme aromatase. Studies performed on experimental models of PCOS strongly suggest that high d-chiro-inositol doses are detrimental to ovarian steroidogenesis, shifting their endocrine activity toward an androgenic phenotype. Indeed, in PCOS rodents, the theca layer—in which androgens are synthetized—undergoes a functional hyperplasia that can be successfully reverted by the treatment with a proper myo-inositol/d-chiro-inositol formula in a 40:1 ratio. Conversely, altered inositol ratios may account for pathological conditions, causing an imbalance in sex hormones. Such situations are usually associated with medical conditions, such as PCOS, or in consequence of pharmacological treatments. Facing this evidence, the inositol-based approach vs. PCOS should be designed with the aim of restoring the appropriate inositol physiological ratio to reverse the androgenic pattern and counteract the features of the syndrome.