The importance of myo-inositol and D-chiro-inositol to support fertility and reproduction

This review details the physiologic roles of two insulin sensitizers, myo-inositol (MI) and D-chiro-inositol (DCI). In the human ovary, MI is a second messenger of follicle stimulating hormone (FSH) and DCI is an aromatase inhibitor. These activities allow a treatment for polycystic ovary syndrome (PCOS) to be defined based on the combined administration of MI and DCI, where the best MI:DCI ratio is 40:1. In addition, MI plays a pivotal role in the physiology of reproduction, and has beneficial effects on the development of oocytes, spermatozoa, and embryos. By contrast, DCI has little effect on spermatozoa, but high concentrations in the ovary can negatively affect the quality of oocytes and the blastocyst. Overall, the evidence in the literature supports the beneficial effects of MI in both female and male reproduction, warranting clinical use of MI in assisted reproductive treatment (ART).Cette revue détaille les rôles physiologiques de deux sensibilisateurs à l'insuline, le myo-inositol (MI) et le D-chiro-inositol (DCI). Dans l'ovaire humain, le MI est un second messager de l'hormone folliculostimulante (FSH) et le DCI est un inhibiteur de l'aromatase. Ces activités permettent de définir un traitement du syndrome des ovaires polykystiques (SOPK) basé sur l'administration combinée de MI et de DCI, où le meilleur rapport MI:DCI est de 40:1. En outre, le MI joue un rôle essentiel dans la physiologie de la reproduction et a des effets bénéfiques sur le développement des ovocytes, des spermatozoïdes et des embryons. En revanche, le DCI a peu d'effet sur les spermatozoïdes, mais des concentrations élevées dans l'ovaire peuvent avoir un effet négatif sur la qualité des ovocytes et du blastocyste. Dans l'ensemble, les données de la littérature confirment les effets bénéfiques du MI dans la reproduction féminine et masculine, ce qui justifie l'utilisation clinique du MI dans l'assistance médicale à la procréation

Inositols: From established knowledge to novel approaches

Myo-inositol (myo-Ins) and D-chiro-inositol (D-chiro-Ins) are natural compounds involved in many biological pathways. Since the discovery of their involvement in endocrine signal transduction, myo-Ins and D-chiro-Ins supplementation has contributed to clinical approaches in ameliorating many gynecological and endocrinological diseases. Currently both myo-Ins and D-chiro-Ins are well-tolerated, effective alternative candidates to the classical insulin sensitizers, and are useful treatments in preventing and treating metabolic and reproductive disorders such as polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), and male fertility disturbances, like sperm abnormalities. Moreover, besides metabolic activity, myo-Ins and D-chiro-Ins deeply influence steroidogenesis, regulating the pools of androgens and estrogens, likely in opposite ways. Given the complexity of inositol-related mechanisms of action, many of their beneficial effects are still under scrutiny. Therefore, continuing research aims to discover new emerging roles and mechanisms that can allow clinicians to tailor inositol therapy and to use it in other medical areas, hitherto unexplored. The present paper outlines the established evidence on inositols and updates on recent research, namely concerning D-chiro-Ins involvement into steroidogenesis. In particular, D-chiro-Ins mediates insulin-induced testosterone biosynthesis from ovarian thecal cells and directly affects synthesis of estrogens by modulating the expression of the aromatase enzyme. Ovaries, as well as other organs and tissues, are characterized by a specific ratio of myo-Ins to D-chiro-Ins, which ensures their healthy state and proper functionality. Altered inositol ratios may account for pathological conditions, causing an imbalance in sex hormones. Such situations usually occur in association with medical conditions, such as PCOS, or as a consequence of some pharmacological treatments. Based on the physiological role of inositols and the pathological implications of altered myo-Ins to D-chiro-Ins ratios, inositol therapy may be designed with two different aims: (1) restoring the inositol physiological ratio; (2) altering the ratio in a controlled way to achieve specific effects

When one size does not fit all: Reconsidering PCOS etiology, diagnosis, clinical subgroups, and subgroup-specific treatments

Polycystic Ovary Syndrome (PCOS) is a complex endocrine disorder that affects a large proportion of women. Due to its heterogeneity, the best diagnostic strategy has been a matter of contention. Since 1990 scientific societies in the field of human reproduction have tried to define the pivotal criteria for the diagnosis of PCOS. The consensus Rotterdam diagnostic criteria included the presence of hyperandrogenism, oligo/anovulation, and polycystic ovarian morphology (PCOM), and have now been updated to evidence based diagnostic criteria in the 2018 and 2023 International Guideline diagnostic criteria endorsed by 39 societies internationally. Within the Rotterdam Criteria, at least two out of three of the above-mentioned features are required to be present to diagnose PCOS, resulting in four phenotypes being identified: phenotype A, characterized by the presence of all the features, phenotype B, exhibiting hyperandrogenism and oligo-anovulation, phenotype C, presenting as hyperandrogenism and PCOM and finally the phenotype D that is characterized by oligo-anovulation and PCOM, lacking the hyperandrogenic component. However, it is the hypothesis of the EGOI group that the Rotterdam phenotypes A, B, and C have a different underlying causality to phenotype D. Recent studies have highlighted the strong correlation between insulin resistance and hyperandrogenism, and the pivotal role of these factors in driving ovarian alterations, such as oligo-anovulation and follicular functional cyst formation. This new understanding of PCOS pathogenesis has led the authors to hypothesis that phenotypes A, B, and C are endocrine-metabolic syndromes with a metabolic clinical onset. Conversely, the absence of hyperandrogenism and metabolic disturbances in phenotype D suggests a different origin of this condition, and point towards novel pathophysiological mechanisms; however, these are still not fully understood. Further questions have been raised regarding the suitability of the “phenotypes” described by the Rotterdam Criteria by the publication by recent GWAS studies, which demonstrated that these phenotypes should be considered clinical subtypes as they are not reflected in the genetic picture. Hence, by capturing the heterogeneity of this complex disorder, current diagnostic criteria may benefit from a reassessment and the evaluation of additional parameters such as insulin resistance and endometrial thickness, with the purpose of not only improving their diagnostic accuracy but also of assigning an appropriate and personalized treatment. In this framework, the present overview aims to analyze the diagnostic criteria currently recognized by the scientific community and assess the suitability of their application in clinical practice in light of the newly emerging evidence

Acute and chronic exposure to hypoxia alters ventilatory pattern but not minute ventilation of mice overexpressing erythropoietin

Apart from enhancing red blood cell production, erythropoietin (Epo) has been shown to modulate the ventilatory response to reduced oxygen supply. Both functions are crucial for the organism to cope with increased oxygen demand. In the present work, we analyzed the impact of Epo and the resulting excessive erythrocytosis in the neural control of normoxic and hypoxic ventilation. To this end, we used our transgenic mouse line (Tg6) that shows high levels of human Epo in brain and plasma, the latter leading to a hematocrit of approximately 80%. Interestingly, while normoxic and hypoxic ventilation in Tg6 mice was similar to WT mice, Tg6 mice showed an increased respiratory frequency but a decreased tidal volume. Knowing that Epo modulates catecholaminergic activity, the altered catecholaminergic metabolism measured in brain stem suggested that the increased respiratory frequency in Tg6 mice was related to the overexpression of Epo in brain. In the periphery, higher response to hyperoxia (Dejours test), as well as reduced tyrosine hydroxylase activity in carotid bodies, revealed a higher chemosensitivity to oxygen in transgenic mice. Moreover, in line with the decreased activity of the rate-limiting enzyme for dopamine synthesis, the intraperitoneal injection of a highly specific peripheral ventilatory stimulant, domperidone, did not stimulate hypoxic ventilatory response in Tg6 mice. These results suggest that high Epo plasma levels modulate the carotid body's chemotransduction. All together, these findings are relevant for understanding the cross-talk between the ventilatory and erythropoietic systems exposed to hypoxia

The very last dance of unconjugated p-cresol... historical artifact of uremic research

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Protein-bound uremic toxins: putative modulators of calcineurin inhibitors exposure

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Preservation of residual kidney function to reduce non-urea solutes toxicity in haemodialysis

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Exposition to glucose-based peritoneal dialysis fluids exacerbates adipocyte lipolysis and glycogen storage in rat adipose cells

International audienceGlucose absorption during peritoneal dialysis (PD) is suspected to promote visceral fat accretion and weight gain in PD patients. The current study was designed to test the impact of glucose-based PD fluids on adipose cell lipolysis and glycogen content. Rat adipose cells, isolated from epididymal fat pad, were exposed to a 30 vol./70 vol. mixture of glucose-based dialysis solutions (containing 1.36% and 3.86% glucose, Physioneal 35®; Baxter) or Krebs-Henseleit buffer for 4 h. Adipose cells were further incubated with laboratory-made solutions containing 1.36% and 3.86% glucose or mannitol as an osmotic control. Baseline and noradrenaline-stimulated lipolysis was measured, and glycogen content assayed. The glucose-based commercial PD fluids as well as the laboratory-manufactured high glucose solutions exacerbated lipolysis in baseline and noradrenaline conditions and increased glycogen stores in adipose cells. Mannitol solutions (1.36% and 3.86%) used as an osmotic control did not produce such effects. This study provides the first evidence that glucose-based dialysis solutions increase basal as well as stimulated lipolysis in adipocytes, an effect that is directly attributable to high concentrations of glucose per se

Breathing pattern and hypoxic sensitivity during ageing in a new model of obesity-resistant rat

The Lou/C rat, an inbred strain of Wistar origin, is presented both as an obesity-resistant rat and as a relevant model of successful ageing. In the present study, we examined throughout ageing the breathing pattern and the ventilatory response to hypoxia in Lou/C and age-matched Wistar rats. Ventilation was assessed by whole body plethysmography in resting condition and during a hypoxic challenge (10% 02) at 2, 6, 12 and 24 months of age. Lou/C rats maintained constant their resting ventilation rate throughout ageing while Wistar rats tended to decrease their ventilation with advancing age. Elderly Lou/C as well as Wistar rats increased their frequency rather than their tidal volume in response to hypoxia. As Lou/C rats did not develop obesity, ageing per se surpasses the effect of fat accumulation and prevents old rats to mobilise their tidal volume in response to hypoxia

Should we integrate the gut microbiota composition to manage idiopathic nephrotic syndrome?

Editorial MaterialInternational audienceNo abstract availabl