D-Chiro-Inositol Treatment Affects Oocyte and Embryo Quality and Improves Glucose Intolerance in Both Aged Mice and Mouse Models of Polycystic Ovarian Syndrome.

Eva Pericuesta,Juan A Navarro,Ricardo Laguna-Barraza,Fernando Rodríguez De Fonseca,Priscila Ramos-Ibeas,Elena Baixeras,Julia L Gutierrez-Arroyo,Alfonso Gutierrez-Adan,Katia Vera,Carlos Sanjuan

doi:10.3390/ijms21176049

Abstract

Polycystic ovarian syndrome (PCOS) is the main cause of female infertility. It is a multifactorial disorder with varying clinical manifestations including metabolic/endocrine abnormalities, hyperandrogenism, and ovarian cysts, among other conditions. D-Chiro-inositol (DCI) is the main treatment available for PCOS in humans. To address some of the mechanisms of this complex disorder and its treatment, this study examines the effect of DCI on reproduction during the development of different PCOS-associated phenotypes in aged females and two mouse models of PCOS. Aged females (8 months old) were treated or not (control) with DCI for 2 months. PCOS models were generated by treatment with dihydrotestosterone (DHT) on Days 16, 17, and 18 of gestation, or by testosterone propionate (TP) treatment on the first day of life. At two months of age, PCOS mice were treated with DCI for 2 months and their reproductive parameters analyzed. No effects of DCI treatment were produced on body weight or ovary/body weight ratio. However, treatment reduced the number of follicles with an atretic cyst-like appearance and improved embryo development in the PCOS models, and also increased implantation rates in both aged and PCOS mice. DCI modified the expression of genes related to oocyte quality, oxidative stress, and luteal sufficiency in cumulus-oocyte complexes (COCs) obtained from the aged and PCOS models. Further, the phosphorylation of AKT, a main metabolic sensor activated by insulin in the liver, was enhanced only in the DHT group, which was the only PCOS model showing glucose intolerance and AKT dephosphorylation. The effect of DCI in the TP model seemed mediated by its influence on oxidative stress and follicle insufficiency. Our results indicate that DCI works in preclinical models of PCOS and offer insight into its mechanism of action when used to treat this infertility-associated syndrome.

Highlights

Polycystic ovarian syndrome (PCOS) is a multisystem reproductive-metabolic disorder that affects 5–25% of women of reproductive age causing ovulation and menstruation problems, hyperandrogenism, polycystic appearance of ovaries and, in most cases, infertility [1,2,3]
We checked for the presence of DCI in the diets used to feed the mice (Teklad Global Rodent Diets #2014 and #2018; Teklad Diets, Madison WI) by gas chromatography coupled to mass spectrometry (GC-MS) and gas chromatography coupled to a flame ionization detection (GC-flame ionization detector (FID))
Our study reveals the effects of two months of treatment with DCI on ovary histology, superovulation, embryo production, implantation rate, and oocyte and blastocyst gene expression levels in aging female mice, and two models of PCOS created in mice

Summary

Introduction

PCOS is a multisystem reproductive-metabolic disorder that affects 5–25% of women of reproductive age causing ovulation and menstruation problems, hyperandrogenism, polycystic appearance of ovaries and, in most cases, infertility [1,2,3]. Prenatal androgenization of female mice with dihydrotestosterone (DHT) causes irregular estrous cycles in adulthood [7,8] and affects metabolism by impairing glucose tolerance and pancreatic islet function but without causing obesity or peripheral insulin resistance [8] As these DHT-induced PCOS mice show a modified reproductive biology but are not insulin resistant or hyperinsulinemic [8], they are a good model to assess the reproductive effects of D-chiro-inositol (DCI) that are independent of its insulin-lowering effect. This model reflects several features of women with a milder PCOS phenotype including glucose tolerance and an increased number of small antral follicles, but lacks cyst-like follicles and shows only mild adiposity with no change in adipokine levels [5]. Another model of PCOS can be produced by treating female mice with testosterone propionate (TP) during the first days of life, which leads to anovulation and poly-follicular ovaries [9], cyst-like follicles [10], and changes in follicular function later in life causing premature luteinization of follicles [11]

Methods

Results

Conclusion