PCOS and inositols: controversial results and necessary clarifications. Basic differences between D-chiro and myo-inositol

Myo-Inositol (myo-Ins) and its phosphate derivatives—including inositol phosphates (InsPs), inositol pyrophosphates (IPPs) and phosphatidyl-inositol phosphate (PtdIns)—are credited to act as second messengers, which accumulate rapidly and transiently in response to external or endocrine signals, a phenomenon that allows signaling to be discrete and regulated (1, 2). Noticeably, inositol is involved in the transduction of several endocrine signals, including insulin (3, 4), thyroid hormones (5), gonadotropins (6), lipids with hormone-like activity (as prostaglandins) (7), and many other endocrine systems (8). Namely, in the last decade, a growing body of clinical and experimental research provided robust evidence about the efficiency of inositol in reversing a few clinical, metabolic, and endocrine features of the Polycystic Ovary Syndrome (PCOS). Myo-inositol, alone or in combination with its isomer D-Chiro-Inositol (D-Chiro-Ins), showed to exert a variable—albeit significant—effect in improving both symptoms and outcome in PCOS patients (9). Experimental and pilot clinical studies pointed out that a combination of both isomers could provide a reliable rationale for establishing a proper treatment strategy, as first suggested by Beemster’s seminal study (10, 11). However, the proper formula—i.e., the respective percentage of myo-Ins and D-Chiro-Ins—is still a matter of debate. In several cases, no conclusive insights can be obtained from clinical trials based on unclear rational design, limited number of recruited patients and variable formula composition and dosage(s). First, it is improper to compare clinical results from studies in which commercial nutraceutical formulas involve a wide range of concentrations (Table 1), with the myo-Ins/D-Chiro-Ins ratio varying implausibly from 0.4:1 to 104:1. Current commercial preparations also contain D-Chiro-Ins alone at concentrations reaching 600 mg that can be administered once or twice a day. Therefore, the daily dose of D-chiro-Ins, alone or with myo-Ins, ranges from low (less than 300 mg/die), medium (300–600 mg/die) and high (600–1,200 mg/die).