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

Giovanni Monastra,Micaela Lucarelli,Jessica Dragotto,Carla Tatone,Giovanna Di Emidio,Arturo Bevilacqua

doi:10.3390/ijms22115691

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.

Highlights

Polycystic Ovary Syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is diagnosed by the presence of two of the following disorders: hyperandrogenism, oligo/anovulation and polycystic ovaries, with the exclusion of other related pathologies, according to the 2003 Rotterdam Criteria [1].The different features and pathophysiology of PCOS, which include genetic [2] and environmental/organic factors, such as endocrine disruptors [3], obesity and an imbalance in diet composition [4], have long been approached in experimentally modeled mammals [5,6]
A hyperandrogenism-dependent PCOS-like syndrome, with a failure in folliculogenesis, may be obtained by administration of androgens [9,10,11] or of the aromatase inhibitor letrozole [12], which prevents the physiological conversion of androgens to estradiol inside the ovarian follicle
Under the 5 mg/day DCIns dose employed, mice developed distinct morphological features of human PCOS, similar to those observed in mice that received 10 μg/day letrozole, an inducer of androgenic PCOS models [12,38]

Summary

Introduction

Polycystic Ovary Syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is diagnosed by the presence of two of the following disorders: hyperandrogenism, oligo/anovulation and polycystic ovaries, with the exclusion of other related pathologies, according to the 2003 Rotterdam Criteria [1].The different features and pathophysiology of PCOS, which include genetic [2] and environmental/organic factors, such as endocrine disruptors [3], obesity and an imbalance in diet composition [4], have long been approached in experimentally modeled mammals [5,6]. Polycystic Ovary Syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is diagnosed by the presence of two of the following disorders: hyperandrogenism, oligo/anovulation and polycystic ovaries, with the exclusion of other related pathologies, according to the 2003 Rotterdam Criteria [1]. Rodent models of PCOS are produced using various procedures [7,8]. A hyperandrogenism-dependent PCOS-like syndrome, with a failure in folliculogenesis, may be obtained by administration of androgens [9,10,11] or of the aromatase inhibitor letrozole [12], which prevents the physiological conversion of androgens to estradiol inside the ovarian follicle. Letrozole-conditioned mice are infertile and recapitulate most of reproductive and metabolic aspects of PCOS [13]. Rodents can be modeled by exposure to a regimen of continuous light, which disrupts the normal light–

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