High Doses of D-Chiro-Inositol Alone Induce a PCO-Like Syndrome and Other Alterations in Mouse Ovaries

Abstract

Administration of 1000–1500 mg/day D-Chiro-Inositol (DCIns) or a combination of Myo-Inositol (MyoIns) and DCIns in their plasma molar ratio (40:1) for three or more months are among recommended treatments for metabolic syndrome and/or Polycystic Ovary Syndrome (PCOS). We previously confirmed the efficacy of this formulation (8.2 mg/day MyoIns and 0.2 mg/day DCIns for 10 days) in a mouse PCOS model, but also observed negative effects on ovarian histology and function of formulations containing 0.4–1.6 mg/day DCIns. We therefore analyzed effects of higher doses of DCIns, 5, 10 and 20 mg/day, administered to young adult female mice for 21 days, on ovarian histology, serum testosterone levels and expression of the ovarian enzyme aromatase. Five mg/day DCIns (human correspondence: 1200 mg/day) altered ovarian histology, increased serum testosterone levels and reduced the amount of aromatase of negative controls, suggesting the induction of an androgenic PCOS model. In contrast, 10–20 mg/day DCIns (human correspondence: 2400–4800 mg/day) produced ovarian lesions resembling those typical of aged mice, and reduced serum testosterone levels without affecting aromatase amounts, suggesting a failure in steroidogenic gonadal activity. Notwithstanding physiological/biochemical differences between mice and humans, the observed pictures of toxicity for ovarian histology and function recommend caution when administering DCIns to PCOS patients at high doses and/or for periods spanning several ovulatory cycles.

Inositols: From Established Knowledge to Novel Approaches

“…On the other hand, one study [ 55 ] considers the amount of DCI in the 40:1 ratio very low and proposes combining the two inositols using D-chiro-Ins at high doses. However, some concerns arise when D-chiro-Ins is used at high doses and for prolonged time, as demonstrated in a recent paper by Bevilacqua et al [ 56 ] and discussed below.…”

“…Accordingly, Bevilacqua and coworkers hypothesized that, like the aromatase inhibitor Letrozole, high doses of D-chiro-Ins administered to normal female mice would generate an androgenic PCOS-like model or other ovarian lesions [ 56 ].…”

d-chiro-Inositol facilitates adiponectin biosynthesis and activates the AMPKα/PPARs pathway to inhibit high-fat diet-induced obesity and liver lipid deposition

“…44 Although no side effects of administration or injection of DCI in the range of 1–500 mg per kg body weight have been reported in animal studies, treatment with 500–100 mg per kg body weight of DCI (human correspondence: 2400–4800 mg day −1 ) worsens the ovarian function. 45 Strangely enough, 250 mg kg −1 day −1 DCI significantly reduced weight gain, while 500–1000 mg kg −1 DCI promoted weight gain. 45 As found in Fig.…”

“…45 Strangely enough, 250 mg kg −1 day −1 DCI significantly reduced weight gain, while 500–1000 mg kg −1 DCI promoted weight gain. 45 As found in Fig. 5B and in the study of Larner, 20 not only DCI has different preferences and sensitivities for different organs, but its optimal physiological concentration also varies.…”

New Insights into the Activities of D-Chiro-Inositol: A Narrative Review

“…However, at the ovarian level, high DCI quantities would exacerbate the impaired steroidogenesis, increasing the conversion of progestogens into androgens and impairing androgens catabolism. In fact, its administration in high content for a prolonged time seems to induce a PCO-like phenotype [61].…”