The Effects of Myo-Inositol and D-Chiro-Inositol in a Ratio 40:1 on Hormonal and Metabolic Profile in Women with Polycystic Ovary Syndrome Classified as Phenotype A by the Rotterdam Criteria and EMS-Type 1 by the EGOI Criteria.

SETTING: Insulin resistance (IR) and compensatory hyperinsulinemia are considered contributing factors toward polycystic ovary syndrome (PCOS). OBJECTIVES: This study evaluates the frequency of metabolic abnormalities in PCOS patients and the effects of myo-inositol (MI) and D-chiro-inositol (DCI), in a 40:1 ratio on hormonal and metabolic parameters. PARTICIPANTS: Thirty-four women with PCOS phenotype A (endocrine-metabolic syndrome [EMS-type 1]) between the ages of 20-40. DESIGN: Open prospective study with phenotype A (EMS-type I, n = 34) supplemented with 2,255 mg/day of inositol (MI and DCI in a 40:1 ratio) for 3 months. METHODS: The following were measured before and after treatment: serum levels of follicular stimulating hormone, luteinizing hormone (LH), estradiol, total and free testosterone, sex hormone-binding globulin (SHBG), free androgen index (FAI), anti-Müllerian hormone, glucose, insulin, HOMA-IR, and body mass index (BMI). RESULTS: 55.9% of the enrolled patients were overweight or obese, 50% affected by IR, 17.6% with a history of gestational diabetes mellitus, and 61.8% had familial diabetes mellitus. At the conclusion of the study, BMI (p = 0.0029), HOMA-IR (p < 0.001) significantly decreased, along with decreased numbers of patients with elevated insulin levels. The supplementation resulted in decreased total testosterone (p < 0.001), free testosterone (p < 0.001), FAI (p < 0.001), and LH (p < 0.001); increased SHBG (p < 0.001) and estradiol (p < 0.001). LIMITATIONS: The present analysis was limited to a 12-week follow-up, which precluded a long-term evaluation of the effects of MI and DCI combination. Also, this period was insufficient to achieve and analyze clinical changes such as restoration of the menstrual cycle, restoration of reproductive function, and clinical manifestations of hyperandrogenism. CONCLUSIONS: Supplementation improved metabolic and hormonal profile in PCOS phenotype A (EMS-type I) patients. This builds upon previous work that demonstrated that combined inositol treatment may be effective in PCOS. The study presented herein, used a reduced concentration than in prior literature; however, a significant change in hormonal and metabolic parameters was still observed.

Effects of Low Luteinizing Hormone Serum Levels on Oocyte Retrieval, Fertilization Rate, and Embryo Quality during Controlled Ovarian Stimulation: Results from a Prospective Cohort Analysis.

OBJECTIVES: Luteinizing hormone (LH) plays a key role in normal follicular development and oocyte maturation in controlled ovarian stimulation. LH stimulates the proliferation and differentiation of theca cells for the secretion of androgens, synergistically increasing estrogen production. This study aimed to investigate the effects of low LH concentrations on oocyte retrieval, fertilization, and embryo development in patients undergoing in vitro fertilization/intracytoplasmic sperm injection. DESIGN: We prospectively (ClinicalTrials ID: NCT05755529) analyzed patients undergoing in vitro fertilization/intracytoplasmic sperm injection, subdividing them into three groups according to their age. Serum LH levels were evaluated on day 3, during stimulation (day 10) and before ovulation induction (day 12). PARTICIPANTS/MATERIALS, SETTING, METHODS: Forty-three consecutive women were scheduled for IVF and received ovarian stimulation with follitropin alfa (Gonal F, Merck Serono, Germany) and ganirelix (Fyremaldel, Sun Pharma, Italy). Statistical analysis was performed with InStat 3.10, GraphPad software, San Diego, CA, USA. Normal distribution was tested by the Shapiro-Wilk test. Continuous variables were expressed as the mean and standard deviation. Categorical variables are expressed as frequencies and percentages. RESULTS: Our data analysis suggests that serum LH levels progressively decrease during controlled ovarian stimulation, and this effect is more evident in the early phase of this procedure. From this perspective, circulating LH levels may significantly decrease during the late follicular phase due to the negative feedback of ovarian hormones from multiple follicular developments or after the suppressive effects of gonadotropin-releasing hormone antagonists. LIMITATIONS: Although our study confirms that exogenous LH can be considered a strategy in women with reduced LH levels during ovarian stimulation to improve oocyte quality and reproductive outcome, the generalizability of the results is limited by the low number of participants enrolled. CONCLUSIONS: Exogenous LH may be considered a strategy in women with a decrease in LH levels during ovarian stimulation to improve oocyte quality and reproductive outcome.

D-chiro-inositol in clinical practice: A perspective from The Experts Group on Inositol in Basic and Clinical Research (EGOI).

BACKGROUND: D-chiro-inositol is a natural molecule that, in association with its well-studied isomer myo-inositol, may play a role in treating various metabolic and gynecological disorders. OBJECTIVES: This perspective seeks to explore the mechanisms and functions of D-chiro-inositol, laying the foundations to discuss its use in clinical practice, across dysmetabolism, obesity, and hormonal dysregulation. METHODS: A narrative review of all the relevant papers known to the authors was conducted. OUTCOME: D-chiro-inositol acts through a variety of mechanisms, acting as an insulin sensitizer, inhibiting the transcription of aromatase, in addition to modulating white adipose tissue/brown adipose tissue trans differentiation. These different modes of action have potential applications in a variety of therapeutic fields including: PCOS, dysmetabolism, obesity, hypoestrogenic/hyperandrogenic disorders, and bone health. CONCLUSIONS: D-chiro-inositol mode of action has been studied in detail in recent years, resulting in a clear differentiation between D-chiro-inositol and its isomer myo-inositol. The insulin sensitizing activities of D-chiro-inositol are well understood; however, its potential applications in other fields, in particular obesity and hyperestrogenic/hypoandrogenic disorders in men and women, represent promising avenues of research that require further clinical study.

PCOS phenotype focus: phenotype D under the magnifying glass.

Polycystic ovary syndrome (PCOS) is defined as the combination of polycystic morphology, hyperandrogenism, and ovulatory disruption; this heterogeneity presents a conundrum for the medical community. The Rotterdam criteria have governed the diagnosis of PCOS, separating the patient cohort into four distinct phenotypes. It has been suggested that the lone normoandrogenic phenotype, so-called phenotype D, should not be classified as a PCOS subtype, with phenotypes A, B, and C displaying a hyperandrogenic biochemical and clinical profile thought to be characteristic of PCOS. To understand how to treat phenotype D patients, this review shines a spotlight on the phenotype, gathering various reports of how phenotype D is differentiated from the other PCOS phenotypes.

A PCOS Paradox: Does Inositol Therapy Find a Rationale in All the Different Phenotypes?

A recent evaluation of the published data regarding the PCOS topic has highlighted a paradox in the definition of this condition. Even though the name of the syndrome refers to ovarian dysfunction, it seems that patients diagnosed with PCOS are more likely affected by an endocrine and metabolic issue. The term PCOS might not be appropriate to indicate the phenotypes described by the Rotterdam criteria, since the only phenotype with a gynecological issue alone is PCOS phenotype D. This novel perspective regarding how PCOS is currently defined leads the way to a reinterpretation of the entire pathological context and the treatment prescribed, such as inositols. A new point of view on the etiopathogenesis of the disease completely changes the current meaning of PCOS and consequently the therapeutic rationale evaluated to date.

D-Chiro-Inositol and Myo-Inositol Induce WAT/BAT Trans-Differentiation in Two Different Human Adipocyte Models (SGBS and LiSa-2).

White adipose tissue/brown adipose tissue trans-differentiation is one of the main study targets for therapies against obesity and metabolic diseases. In recent years, numerous molecules able to induce such trans-differentiation have been identified; however, their effect in obesity therapies has not been as expected. In the present study, we investigated whether myo-inositol and its stereoisomer D-chiro-inositol could be involved in the browning of white adipose tissue. Our preliminary results clearly indicate that both, at 60 µM concentration, induce the upregulation of uncoupling protein 1 mRNA expression, the main brown adipose tissue marker, and increase mitochondrial copy number as well as oxygen consumption ratio. These changes demonstrate an activation of cell metabolism. Therefore, our results show that human differentiated adipocytes (SGBS and LiSa-2), assume the features typical of brown adipose tissue after both treatments. Furthermore, in the cell lines examined, we proved that D-chiro-inositol and myo-Inositol induce an increase in the expression of estrogen receptor mRNAs, suggesting a possible modulation by these isomers. We also found an increase in the mRNA of peroxisome proliferator-activated receptor gamma, a very important target in lipid metabolism and metabolic diseases. Our results open new opportunities for the use of inositols in therapeutic strategies to counteract obesity and its metabolic complications.

The Role of Inositols in the Hyperandrogenic Phenotypes of PCOS: A Re-Reading of Larner's Results.

Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder in women, in which, besides chronic anovulation/oligomenorrhea and ovarian cysts, hyperandrogenism plays a critical role in a large fraction of subjects. Inositol isomers-myo-Inositol and D-Chiro-Inositol-have recently been pharmacologically effective in managing many PCOS symptoms while rescuing ovarian fertility. However, some disappointing clinical results prompted the reconsideration of their specific biological functions. Surprisingly, D-Chiro-Ins stimulates androgen synthesis and decreases the ovarian estrogen pathway; on the contrary, myo-Ins activates FSH response and aromatase activity, finally mitigating ovarian hyperandrogenism. However, when the two isomers are given in association-according to the physiological ratio of 40:1-patients could benefit from myo-Ins enhanced FSH and estrogen responsiveness, while taking advantage of the insulin-sensitizing effects displayed mostly by D-Chiro-Ins. We need not postulate insulin resistance to explain PCOS pathogenesis, given that insulin hypersensitivity is likely a shared feature of PCOS ovaries. Indeed, even in the presence of physiological insulin stimulation, the PCOS ovary synthesizes D-Chiro-Ins four times more than that measured in control theca cells. The increased D-Chiro-Ins within the ovary is detrimental in preserving steroidogenic control, and this failure can easily explain why treatment strategies based upon high D-Chiro-Ins have been recognized as poorly effective. Within this perspective, two factors emerge as major determinants in PCOS: hyperandrogenism and reduced aromatase expression. Therefore, PCOS could no longer be considered a disease only due to increased androgen synthesis without considering the contemporary downregulation of aromatase and FSH receptors. Furthermore, these findings suggest that inositols can be specifically effective only for those PCOS phenotypes featured by hyperandrogenism.

The "Asthma-Polycystic Ovary Overlap Syndrome" and the Therapeutic Role of Myo-Inositol.

Asthma is a heterogeneous inflammatory disease characterized by abnormalities in immune response. Due to the inherent complexity of the disease and the presence of comorbidities, asthma control is often difficult to obtain. In asthmatic patients, an increased prevalence of irregular menstrual cycles, infertility, obesity, and insulin resistance has been reported. Given that these conditions are also common in patients with polycystic ovary syndrome (PCOS), we propose the definition of "asthma-PCOS overlap syndrome" to indicate a medical condition which shares characteristics of both diseases. The aim of this review is to analyze the links between asthma and PCOS and evaluate the therapeutic role of myo-inositol, a natural compound currently utilized in patients with PCOS, in the management of asthma patients.

The role of vitamin D in metabolic and reproductive disturbances of polycystic ovary syndrome: A narrative mini-review.

Vitamin D is a secosteroid hormone that plays a pivotal role in several metabolic and reproductive pathways in humans. Increasing evidence supports the role of vitamin D deficiency in metabolic disturbances and infertility in women with polycystic ovary syndrome (PCOS). Indeed, supplementation with vitamin D seems to have a beneficial role on insulin resistance (IR) and endometrial receptivity. On the other hand, exceedingly high levels of vitamin D appear to play a detrimental role on oocytes development and embryo quality. In the current review, we summarize the available evidence about the topic, aiming to suggest the best supplementation strategy in women with PCOS or, more generally, in those with metabolic disturbances and infertility. Based on the retrieved data, vitamin D seems to have a beneficial role on IR, insulin sensitivity and endometrial receptivity, but high levels and incorrect timing of administration seem to have a detrimental role on oocytes development and embryo quality. Therefore, we encourage a low dose supplementation (400-800 IU/day) particularly in vitamin D deficient women that present metabolic disturbances like PCOS. As far as the reproductive health, we advise vitamin D supplementation in selected populations, only during specific moments of the ovarian cycle, to support the luteal phase. However, ambiguities about dosage and timing of the supplementation still emerge from the clinical studies published to date and further studies are required.

A Deeper Assessment of ω3-Poly-Unsaturated Fatty Acids in Polycystic Ovary Syndrome Management. Comment on Regidor et al. Chronic Inflammation in PCOS: The Potential Benefits of Specialized Pro-Resolving Lipid Mediators (SPMs) in the Improvement of the Resolutive Response. Int. J. Mol. Sci. 2021, 22, 384.

I have read with great interest the article recently published by Regidor et al. [...].

Melatonin and Myo-Inositol: Supporting Reproduction from the Oocyte to Birth.

Human pregnancy is a sequence of events finely tuned by several molecular interactions that come with a new birth. The precise interlocking of these events affecting the reproductive system guarantees safe embryo formation and fetal development. In this scenario, melatonin and myo-inositol seem to be pivotal not only in the physiology of the reproduction process, but also in the promotion of positive gestational outcomes. Evidence demonstrates that melatonin, beyond the role of circadian rhythm management, is a key controller of human reproductive functions. Similarly, as the most representative member of the inositol's family, myo-inositol is essential in ensuring correct advancing of reproductive cellular events. The molecular crosstalk mediated by these two species is directly regulated by their availability in the human body. To date, biological implications of unbalanced amounts of melatonin and myo-inositol in each pregnancy step are growing the idea that these molecules actively contribute to reduce negative outcomes and improve the fertilization rate. Clinical data suggest that melatonin and myo-inositol may constitute an optimal dietary supplementation to sustain safe human gestation and a new potential way to prevent pregnancy-associated pathologies.

Inositols Depletion and Resistance: Principal Mechanisms and Therapeutic Strategies.

Inositols are natural molecules involved in several biochemical and metabolic functions in different organs and tissues. The term "inositols" refers to five natural stereoisomers, among which myo-Inositol (myo-Ins) is the most abundant one. Several mechanisms contribute to regulate cellular and tissue homeostasis of myo-Ins levels, including its endogenous synthesis and catabolism, transmembrane transport, intestinal adsorption and renal excretion. Alterations in these mechanisms can lead to a reduction of inositols levels, exposing patient to several pathological conditions, such as Polycystic Ovary Syndrome (PCOS), hypothyroidism, hormonal and metabolic imbalances, like weight gain, hyperinsulinemia, dyslipidemia, and metabolic syndrome. Indeed, myo-Ins is involved in different physiological processes as a key player in signal pathways, including reproductive, hormonal, and metabolic modulation. Genetic mutations in genes codifying for proteins of myo-Ins synthesis and transport, competitive processes with structurally similar molecules, and the administration of specific drugs that cause a central depletion of myo-Ins as a therapeutic outcome, can lead to a reduction of inositols levels. A deeper knowledge of the main mechanisms involved in cellular inositols depletion may add new insights for developing tailored therapeutic approaches and shaping the dosages and the route of administration, with the aim to develop efficacious and safe approaches counteracting inositols depletion-induced pathological events.

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.

Altered Ovarian Inositol Ratios May Account for Pathological Steroidogenesis in PCOS.

The presence of abnormal ovarian ratios of myo-inositol (MI) to D-chiro-inositol (DCI) is a recurrent feature in PCOS. Available evidence suggests that MI and DCI may modulate steroid biosynthesis, likely in an opposite manner. Specifically, MI seems to induce estrogen production, while DCI has a role in the synthesis of androgens. Elevated insulin levels, generally associated with PCOS, alter the physiological MI/DCI ratio, increasing MI-to-DCI conversion through activation of a specific epimerase enzyme. DCI directly increases testosterone biosynthesis in thecal cells and reduces its conversion to estradiol by downregulating aromatase enzyme in granulosa cells. This manuscript reviews the literature that supports the connection between altered MI/DCI ratios and pathological steroidogenesis observed in PCOS women. Furthermore, it discusses the application of inositol-based treatment protocols in managing PCOS symptoms and improving the quality of patients' life.

The Key Role of IP6K: A Novel Target for Anticancer Treatments?

Inositol and its phosphate metabolites play a pivotal role in several biochemical pathways and gene expression regulation: inositol pyrophosphates (PP-IPs) have been increasingly appreciated as key signaling modulators. Fluctuations in their intracellular levels hugely impact the transfer of phosphates and the phosphorylation status of several target proteins. Pharmacological modulation of the proteins associated with PP-IP activities has proved to be beneficial in various pathological settings. IP7 has been extensively studied and found to play a key role in pathways associated with PP-IP activities. Three inositol hexakisphosphate kinase (IP6K) isoforms regulate IP7 synthesis in mammals. Genomic deletion or enzymic inhibition of IP6K1 has been shown to reduce cell invasiveness and migration capacity, protecting against chemical-induced carcinogenesis. IP6K1 could therefore be a useful target in anticancer treatment. Here, we summarize the current understanding that established IP6K1 and the other IP6K isoforms as possible targets for cancer therapy. However, it will be necessary to determine whether pharmacological inhibition of IP6K is safe enough to begin clinical study. The development of safe and selective inhibitors of IP6K isoforms is required to minimize undesirable effects.

Short-term effects of metformin and myo-inositol in women with polycystic ovarian syndrome (PCOS): a meta-analysis of randomized clinical trials.

Metformin (MET), the most commonly used insulin sensitizer, is the reference off-label drug for the treatment of polycystic ovary syndrome (PCOS), worldwide. However, its use may be limited mainly by gastrointestinal adverse effects. Myo-inositol (MI), a well-recognized food supplement, also represents an evidence-based treatment for PCOS women, popular in many countries. Our aim is to provide a systematic review of the literature and a meta-analysis which compares these two treatments, for their short-term efficacy and safety in PCOS patients. Systematic review and meta-analysis of randomized clinical trials (RCTs). RCTs were identified from 1994 through 2017 using MEDLINE, Cochrane Library, PubMed, and ResearchGate. Included studies were limited to those one directly comparing MET to MI on several hormones changes. Standardized mean difference (SMD) or risk ratios (RRs) with 95% CIs were calculated. Changes in fasting insulin was the main outcome of measure. Six trials with a total of 355 patients were included. At the end of treatment, no difference between MET and MI was found on fasting insulin (SMD=0.08 µU/ml, 95% CI: -0.31-0.46, p=.697), HOMA index (SMD =0.17, 95% CI: -0.53-0.88, p=.635), testosterone (SMD= -0.01, 95% CI: -0.24-0.21, p=.922), SHBG levels (SMD= -0.50 nmol/l, 95% CI: -1.39-0.38, p=.263) and body mass index (BMI) (SMD= -0.22, 95% CI: -0.60-0.16, p=.265). There was strong evidence of an increased risk of adverse events among women receiving MET compared to those receiving MI (RR =5.17, 95% CI: 2.91-9.17, p<.001). No differences were found in the effect of MET and MI on short-term hormone changes. The better tolerability of MI makes it more acceptable for the recovery of androgenic and metabolic profile in PCOS women.

The use of inositol(s) isomers in the management of polycystic ovary syndrome: a comprehensive review.

The aim of this review is to present the current data about the role of inositols in the management of polycystic ovary syndrome (PCOS) women and in the prevention and treatment of gestational diabetes mellitus (GDM). We analyzed the available literature with key words PCOS, Myo-inositol, D-chiro-inositol, assisted reproductive technologies and GDM. The most recent literature would suggest that Myo-inositol, D-chiro-inositol and their combination in physiological ratio 40:1 could represent an important therapeutic strategy for the improvement of metabolic, hormonal and reproductive aspects of PCOS. In assisted reproductive technologies, however, myo-inositol and the combined treatment, despite D-chiro-inositol monotherapy, are able to improve clinical outcomes. Myo-inositol monotherapy results more effective in preventing and treating GDM even if a larger cohort of studies is needed to better clarify these results.

From Implantation to Birth: Insight into Molecular Melatonin Functions.

Melatonin is a lipophilic hormone synthesized and secreted mainly in the pineal gland, acting as a neuroendocrine transducer of photoperiodic information during the night. In addition to this activity, melatonin has shown an antioxidant function and a key role as regulator of physiological processes related to human reproduction. Melatonin is involved in the normal outcome of pregnancy, beginning with the oocyte quality, continuing with embryo implantation, and finishing with fetal development and parturition. Melatonin has been shown to act directly on several reproductive events, including folliculogenesis, oocyte maturation, and corpus luteum (CL) formation. The molecular mechanism of action has been investigated through several studies which provide solid evidence on the connections between maternal melatonin secretion and embryonic and fetal development. Melatonin administration, reducing oxidative stress and directly acting on its membrane receptors, melatonin thyroid hormone receptors (MT1 and MT2), displays effects on the earliest phases of pregnancy and during the whole gestational period. In addition, considering the reported positive effects on the outcomes of compromised pregnancies, melatonin supplementation should be considered as an important tool for supporting fetal development, opening new opportunities for the management of several reproductive and gestational pathologies.