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The Rationale of the Myo-Inositol and D-Chiro-Inositol Combined Treatment for Polycystic Ovary Syndrome
Abstract
PCOS is one of the most common endocrine disorders affecting women and it is characterized by a combination of hyper-androgenism, chronic anovulation, and insulin resistance.Whilst a significant progress has recently been made in the diagnosis for PCOS, the optimal infertility treatment remains to be determined. Two inositol isomers, Myo-inositol (MI) and Dchiro-inositol (DCI) have been proven to be effective in PCOS treatment, by improving insulin resistance, serum androgen levels and many features of the metabolic syndrome. However, DCI alone, mostly when it is administered at high dosage, negatively affects oocyte quality, whereas the association MI/DCI, in a combination reproducing the plasma physiological ratio (40:1), represents a promising alternative in achieving better clinical results, by counteracting PCOS at both systemic and ovary level.
... Throughout the whole body, each tissue or cellular type displays a peculiar ratio of MI to DCI. Actually, high MI/DCI ratios are present in almost every tissue, except for those deputed to storage, which display higher contents of DCI at the expense of MI [5]. ...
... However, in pathological clinical pictures such as diabetes and insulin resistance, an altered DCI signal would impair steroidogenesis, in addition to euglycemia. Particularly, women suffering from Poly-Cystic Ovary Syndrome (PCOS) usually display insulin resistance [5] and show increased DCI content in the ovary, coupled with a lack of DCI in non-germinal tissues [58]. Moreover, PCOS women display increased presence of steroidogenic enzymes in thecal and granulosa cells, including 17α-hydroxylase [59]. ...
D-chiro-inositol (DCI) is a natural compound detectable in cell membranes, which is highly conserved as a biological signaling molecule. In mammals, its function is primarily characterized in the intracellular transduction cascade of insulin. In particular, insulin signal promotes the release of pivotal DCI-containing molecules. In fact, impaired release of DCI is a common feature of insulin-resistant tissues, and insulin-sensitizing pharmaceuticals induce higher concentrations of free DCI. Moreover, it also plays important roles in several other processes. DCI is involved in the regulation of steroidogenesis, due to its regulatory effects on steroidogenic enzymes, including 17α-hydroxylase, 3β-hydroxysteroid dehydrogenase, and aromatase. Such regulation of various enzymes indicates a mechanism by which the body regulates different processes via a single molecule, depending on its concentration. DCI also reduces the expression of integrin β3, which is an adhesion molecule involved in embryo implantation and cellular phenomena such as survival, stemness, and invasiveness. In addition, DCI seems to have important anti-inflammatory activities, like its 3-O-methyl-ether, called pinitol. In vitro evidence demonstrates that treatment with both compounds induces a reduction in pro-inflammatory factors—such as Nf-κB—and cytokines—such as TNF-α. DCI then plays important roles in several fundamental processes in physiology. Therefore, research on such molecule is of primary importance.
... To evaluate the tumor cell invasion and metastatic ability, we Dil-red-labeled these cells. We then treated them with a pharmacological dose of myo-Ins (4 mM) similar to that used in the inositol-based treatment of polycystic ovary syndrome [15]. Approximately 100 triple-negative and hormone-responsive breast cancer cells were injected into the perivitelline space of each zebrafish embryo. ...
... We scored an average of only three metastases after 24 and 48 h in MDA-MB-231 cells of the zebrafish tail region, whereas the metastases were five times more (ca. [15][16][17] in MCF-7 cells. A statistically significant effect was already recognizable in triple-negative breast cancer after the first 24 h of treatment. ...
The deregulation of PI3K/Akt signaling is among the most causes in inducing the acquisition of a metastatic phenotype in breast cancer cells, leading to Epithelial-Mesenchymal Transition (EMT). Inhibition of the PI3K/Akt pathway is known to be beneficial in the clinical setting. However, the activation of secondary pathways and toxicity profiles of available inhibitors, hindering optimal therapeutic results. Preliminary studies showed that myo-Inositol inhibits the PI3K/Akt pathway by exerting a pleiotropic anti-tumor action. Herein, we demonstrate that myo-Inositol triggers a prompt and profound remodeling of delineated expression pattern in triple-negative breast cancer cells (MDA-MB-231). Consequently, it inhibits metastasis and tumor progression through miR-125a-5p transcription and the subsequent inhibition of IP6K1. In contrast, hormone-responsive breast cancer cells (MCF-7) are insensitive to myo-Inositol. This is due to the persistence of MDM2 synthesis promoted by estrogen-dependent pathways. Conversely, the counteraction of estrogen effects recovered the sensitivity to myo-Inositol in the hormone-responsive model. Overall, these results identify a novel axis primed by miR-125a-5p to downregulate IP6K1 gene that inhibits metastasis. Thus, administration of myo-Inositol can activate this axis as a molecular target therapy in breast cancer.
... However, the combined administration of myo-Ins and a small dosage of D-chiro-Ins enhances the therapeutic effect, since D-chiro-Ins is immediately functionable. Therefore, a therapeutic combination of myo-Ins and D-chiro-Ins should reflect the physiological ratios in plasma and follicular fluid ranging from 40:1 and 100:1 [113]. Notably, myo-Ins: D-chiro-Ins 40:1 ratio is considered the first-line approach to the integrative treatment with inositols for hyperinsulinaemic PCOS patients [19], defined as the most appropriate strategy to correct metabolic aspects in PCOS patients [114]. ...
... These patients tend to exhibit insulin resistance, resulting in reduced intracellular conversion of myo-Ins to D-chiro-Ins [16,18,151]. An opposite situation occurs in the ovaries of PCOS patients, which maintain normal sensitivity to insulin [113,152,153], becoming enriched in D-chiro-Ins and depleted in myo-Ins. This depletion promotes hyperandrogenism and the related features (hirsutism, acne) due to the physiological roles played in the ovaries by myo-Ins as a second messenger of the follicle-stimulating hormone (FSH), and by D-chiro-Ins, which is responsible for insulin-mediated androgens synthesis [80,154]. ...
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.
... D-chiro-ins is the second most represented isomer, as it is commonly detectable as a minor constituent in almost all the tissues containing myo-ins [1]. Researchers found a higher myo-ins/D-chiro-ins ratio in tissues requiring high energy, and lower ratios in tissues where glucose is mainly stored as glycogen [2,3]. In the form of inositol phosphates, both isomers are primarily involved in cellular signaling cascades [3], transmitting extracellular stimuli to cellular organelles [4]. ...
... Researchers found a higher myo-ins/D-chiro-ins ratio in tissues requiring high energy, and lower ratios in tissues where glucose is mainly stored as glycogen [2,3]. In the form of inositol phosphates, both isomers are primarily involved in cellular signaling cascades [3], transmitting extracellular stimuli to cellular organelles [4]. ...
Pregnancy is a complex process, featuring several necessary changes in women’s physiology. Most women undergo healthy pregnancies; even so, several women experience reduced fertility or pathologies related to the pregnancy. In the last years, researchers investigated several molecules as promoters of fertility. Among all, myo-inositol (myo-ins) represents a safe compound that proved useful in issues related to fertility and pregnancy. In fact, myo-ins participates in several signaling processes, including the pathways of insulin and gonadotropins, and, therefore, it is likely to positively affect fertility. In particular, several clinical trials demonstrate that its administration can have therapeutic effects in infertile women, and that it can also be useful as a preventive treatment during pregnancy. Particularly, myo-ins could prevent the onset of neural tube defects and the occurrence of gestational diabetes mellitus, promoting a trouble-free gestation. Due to the safety and efficiency of myo-ins, such a treatment may also substitute several pharmaceuticals, which are contraindicated in pregnancy.
... Inositols exist either in their free form or as phosphate derivatives. Inositol-phosphates are the active molecules that participate to intracellular signaling pathways 4 , being either components of cell membranes as phosphatidyl-inositol-phosphates (PIP) or water-soluble molecules (IP). Myo-Ins is involved in the Follicle-Stimulating-Hormone (FSH) and the Thyroid-Stimulating-Hormone (TSH) pathways, while both myo-Ins and dchiro-Ins are insulin second messengers 1,5 . ...
... Myo-Ins participates in more processes than dchiro-Ins, and it is also its precursor. Myo-Ins is synthesized through multiple steps, starting from glucose-6-phosphate 4 . Eventually, an enzyme of the epimerase family catalyzes the direct transformation of myo-Ins to dchiro-Ins according to specific tissue requirements 8 . ...
Objective:
D-chiro-Inositol has been widely used in clinical practice to induce ovulation in women with polycystic ovary syndrome. Only recent evidence established that this molecule acts through two different mechanisms, with potentially different outcomes. On the one hand, under a metabolic perspective, D-chiro-Inositol improves insulin signaling, thus restoring physiological insulin levels in resistant subjects. On the other hand, at a cellular level, it downregulates the expression of steroidogenic enzyme aromatase, which is responsible for the conversion of androgens to estrogens.
Materials and methods:
We reviewed current literature in different databases, searching for D-chiro-Inositol in relation with one of the following keywords: myo-inositol, PCOS, infertility, insulin resistance, aromatase, androgen and inositol, testosterone, estrogen and inositol, estradiol, hypogonadotropic hypogonadism, fat tissue, estrogens and cancer, anovulation, uterine myoma, endometriosis, endometrial hyperplasia.
Results:
D-Chiro-Inositol treatment may be helpful in restoring physiological hormonal levels in various clinical disorders. However, D-Chiro-Inositol intervention should be carefully designed to avoid possible undesired side effects stemming from its multiple mechanisms of action.
Conclusions:
We evaluated the optimal D Chiro-Inositol administration for different pathologies, defining dosages and timing. Even though further studies are required to validate our preliminary results, this paper is primarily intended to guide researchers through some of the pathways of D-Chiro-Inositol.
... A plenty of evidence [9][10][11] reported that high MI concentrations in the follicular fluids are strongly correlated with higher oocytes quality, meanwhile low concentration of MI correlates with poor oocyte quality. In this regard, MI involvement in oocyte maturation is clear and it could be considered as oocyte quality marker [9][10][11] . ...
... A plenty of evidence [9][10][11] reported that high MI concentrations in the follicular fluids are strongly correlated with higher oocytes quality, meanwhile low concentration of MI correlates with poor oocyte quality. In this regard, MI involvement in oocyte maturation is clear and it could be considered as oocyte quality marker [9][10][11] . Further evidence showed that MI enhances the quality of the blastocysts, whereas its stereoisomer, D-chiro-inositol (DCI), above a certain level, exerts a negative effect 12 . ...
Objective:
To evaluate the efficacy of a treatment with Myo-inositol (MI) plus melatonin and vitamin D3 in women underwent intra cytoplasmatic sperm injection (ICSI).
Patients and methods:
100 women undergoing ICSI procedure were enrolled and randomly divided 1:1 in two groups. The study group was treated with 2 g MI, 50 mg Alpha-Lactalbumin (alpha-LA) and 200 µg folic acid in powder every morning for 6 months (3 months before oocyte pick up and 3 months after ICSI); the same patients underwent treatment with 600 mg MI, 1 mg melatonin plus 200 µg folic acid during the evening for 3 months before oocyte pick up; subsequently the pick up these patients were treated with 600 mg MI, 200 µg folic acid, 1 mg melatonin, 50 µg vitamin D3 as cholecalciferol until the 12th week of gestation. The control group was treated with 200 µg folic acid twice a day. Clinical pregnancy rate was evaluated as primary outcome, followed by blastocyst and oocyte quality, as well as gestational period as secondary outcomes.
Results:
Treatment significantly improved blastocyst and oocyte quality in the study group, achieving the 42% of clinical pregnancies vs. 24% in the control group, even though the course of pregnancy did not significantly differ between the groups. However, the mean gestational period was shorter in the control group.
Conclusions:
The supplementation of MI in combination with melatonin in the first 3 months before oocyte pick up and with vitamin D3 in the further 3 months could represent an innovative support for all those women undergoing ICSI.
... Fruits Grapefruit juice 120 g of grapefruit juice provides about 468.8 mg of the compound [18] Fresh mandarin orange 3.07 mg/g [18] Dates, palms, prunes 46 mg/g [19] Vegetables Lettuce 1.07 mg/g [20] White onion 0.6642 mg/g [20] Carrots 2.2-9.8 mg/g [21] Milk-derived products Bovine milk 5.3-8.7 mg/100 mL [22] Sweetened condensed milk 0.26 mg/g [23] Meat Beef liver 0.64 mg/g [18] Legumes Soybean 1.22 mg/g in pod, 8 mg/g in seed [12] Dried fruit Pine nuts 0.7 mg/g [24] Peanut butter 3.04 mg/g [18] Almond 2.78 mg/g [18] Both MYO and DCI isomers are precursors of membrane phosphoglycans (PG), MYO-PG, and DCI-PG, which are primarily involved in cellular signaling cascades [16], transmitting extracellular stimuli to cellular organelles [25]. The main functions of the inositol cascades are in the signaling of insulin [26], gonadotropins [16,27], and cytoskeletal rearrangement processes [28]. ...
Myo-inositol (MYO) and D-chiro-inositol (DCI) are the two most significant isomeric forms of inositol, playing a critical role in intracellular signaling. MYO is the most abundant form of inositol in nature; DCI is produced from MYO through epimerization by an insulin-dependent enzyme. Recently, it has been demonstrated that inositol may influence oocyte maturation and improve intracellular Ca2+ oscillation in the oocytes, and it has been proposed as a potential intervention for restoring spontaneous ovulation. The MYO concentration in human follicular fluid is considered a bioindicator of oocyte quality. In the ovary, DCI modulates the activity of aromatase, thus regulating androgen synthesis. Under physiological conditions, the MYO/DCI ratio is maintained at 40:1 in plasma. In women with PCOS, the MYO/DCI ratio is lowered to 0:2:1, contributing to elevated androgen production. By regulating FSH signaling, MYO administration increases the number of high-quality embryos available for transfer in poor responder patients. Finally, by acting downstream to insulin signaling, inositol administration during pregnancy may represent a novel strategy for counteracting gestational diabetes. These findings show that diet supplementation with inositol may be a promising strategy to address female infertility and sustain a healthy pregnancy.
... Peanut butter 3.04 mg/g [17] Almond 2.78 mg/g [17] Both MYO and DCI inositol isomers are precursors of membrane phosphoglycans (PG), MYO-PG and DCI-PG, which are primarily involved in cellular signaling cascades [15], transmitting extracellular stimuli to cellular organelles [24]. The main functions of the inositol cascades are in the signaling of insulin [25], gonadotropins [15,26], and cytoskeletal rearrangement processes [27]. ...
Myo-inositol (MYO) and D-chiro-inositol (DCI) are the two most significant isomeric forms of inositol, playing a critical role in intracellular signaling. MYO is the most abundant form of inositol in nature; DCI is produced from MYO through epimerization by an insulin-dependent enzyme. Recently, it has been demonstrated that inositols may influence oocyte maturation, improve intracellular Ca2+ oscillation in the oocytes and have been proposed as potential interventions for restoring spontaneous ovulation. MYO concentration in human follicular fluid is considered a bioindicator of oocyte quality. In the ovary, DCI modulates the activity of aromatase thus regulating androgen synthesis. Under physiological conditions, MYO/DCI ratio is maintained at 40:1 in the plasma. In women with PCOS, MYO/DCI ratio lowers to 0:2:1, contributing to elevated androgen production. By regulating FSH signaling, MYO administration increases the number of high-quality embryos available for transfer in poor responder patients. Finally, by acting downstream to insulin signaling inositol administration during pregnancy may represent a novel strategy for counteracting gestational diabetes. These findings show that diet supplementation with inositols may be a promising strategy to address female infertility and sustain healthy pregnancy.
... MI is converted in d-chiro-inositol (DCI) by an insulindependent epimerase, whose activity varies according to the tissue profile [10]. The physiological plasma ratio between MI and DCI is 40:1 [11]. ...
Pregnancy is a critical period marked by intricate physiological changes and maintaining maternal and fetal well-being is paramount. Inositols, a group of naturally occurring sugar alcohols, have gained attention for their potential benefits during pregnancy. This abstract provides a comprehensive review of the current literature on using inositols, primarily myo-inositol (MI) and D-chiro-inositol (DCI) in pregnancy. Inositols are crucial in cellular signal transduction and insulin sensitivity, making them integral to various physiological processes. Several studies suggest that inositols may contribute to preventing and managing gestational diabetes mellitus (GDM). MI, in particular, has shown promise in improving insulin sensitivity and mitigating insulin resistance, thereby influencing glucose metabolism. As our understanding of inositol’s role in pregnancy deepens, it may emerge as a valuable supplement to enhance maternal and fetal health outcomes.
... Mioinositol como alternativa para el tratamiento de SOP Los mecanismos de acción del MI se fundamentan en la mejora de la sensibilidad a la insulina en los tejidos, lo cual tiene un impacto positivo en el sistema reproductivo (restableciendo la ovulación y mejorando la calidad de los ovocitos) y las funciones hormonales (reduciendo el exceso de andrógenos y la dislipidemia), así como disminuyendo los niveles de insulina en la sangre [30]. Por ejemplo, el MI reduce la cantidad de hormona foliculoestimulante (FSH) necesaria durante la estimulación ovárica, lo que aumenta las posibilidades de embarazo [31]. ...
Los inositoles son hexahidroxiciclohexanos conformados por nueve estereoisómeros, la mayoría biológicamente activos. La presente revisión pretende recapitular los principales efectos del mioinositol (MI) sobre las características patológicas del síndrome de ovario poliquístico (SOP) y su papel como regulador en la respuesta hormonal y bioquímica femenina. Las pacientes con SOP presentan trastornos clínicos, hormonales, metabólicos y fisiológicos que requieren tratamiento especializado a largo plazo. Por su parte, el inositol ha demostrado ser efectivo para reducir la severidad de los síntomas, regular la función menstrual y mejorar el perfil hormonal controlando parámetros metabólicos, por lo que su administración representa una opción efectiva para el manejo de los síntomas del SOP. A pesar de esto, existen limitaciones para los estudios como el hecho de que, al tratarse de un síndrome, el SOP es una condición heterogénea con una amplia variedad de síntomas y manifestaciones clínicas, por lo que también implica variedad de respuesta en las pacientes al MI. En los últimos años, su investigación ha generado evidencia terapéutica prometedora, pero aún falta abarcar más estudios controlados y doble ciego para definir su efecto según los fenotipos del SOP, así como investigaciones a largo plazo que evalúen la seguridad y eficacia del tratamiento en períodos prolongados. De manera general, el MI representa una alternativa efectiva y segura para el tratamiento del SOP, mostrando resultados similares a los presentados por otros tratamientos sin la presencia de los efectos secundarios conocidos.
... Additionally, it functions as a secondary messenger in cellular signal transduction pathways, influencing a range of physiological processes (Gillaspy 2011). In the context of metabolic health, MI is implicated in insulin signalling and may enhance insulin sensitivity, offering potential benefits for conditions such as polycystic ovary syndrome (PCOS) and diabetes (Bevilacqua and Bizzarri 2018;Dinicola et al. 2014). Its role as an intracellular secondary messenger underscores its importance in regulating various hormonal processes, including the modulation of thyroid-stimulating hormone, follicle-stimulating hormone (FSH), and insulin levels (Papaleo et al. 2007). ...
Inositols, regarded as a sugar-alcohol isomeric group, is a class of polyol compounds with six-carbon ring structure and each carbon being hydroxylated. Among different biologically active isomers of the group, myo-inositol (MI), is regarded one of the most widespread and versatile metabolite with occurrence in plants, animals, yeasts, and microorganisms. With respect to mammals, MI is particularly abundant in the brain and other organs such as kidneys, ovaries, heart, liver, and muscle tissues. Additionally, MI represents an important constituent of membrane phospholipids and mediating osmoregulation with its phosphorylated derivatives participating in several intracellular signalling pathways and other physiological processes. Of late, significance of MI has been also observed in medical research wherein altered levels of MI in the brains are associated with Alzheimer’s disease (AD), epilepsy, and psychiatric disorders. Moreover, MI supplements do help in preventing insulin resistance, decreasing hyperandrogenism, preventing polycystic ovarian syndrome, etc. Keeping in view the diverse roles of MI, the present chapter summarizes the current understanding on the role of MI as an osmolyte in response to hyperosmolarity, a cellular metabolite in the human brain and a biomarker for both healthy and disease conditions and an effective supplementation for treatment of wide variety of diseases such as polycystic ovary syndrome, cardiovascular diseases, respiratory distress syndrome, and neurological disorders. Future insights in this direction are also highlighted at the end of the chapter.
... As a result, MI monotherapy has greatly impacted the quantity of follicular fluid in a fertilised egg or the number of normal mature follicles in a patient with PCOS, as well as the quality of the oocyte and embryo [41,39]. The concurrent use of MI and DCI throughout therapy had the greatest clinical outcomes [77]. Data collected after mice were exposed to continuous light revealed developed ovaries with morphological characteristics common to PCOS in humans as well as decreased gonad activity. ...
Introduction: Background: Women of reproductive age are often affected by Polycystic Ovary Syndrome (PCOS), a condition that can cause infertility and metabolic problems. Hormonal changes contribute to PCOS's mechanism. It involves three interrelated symptoms, namely ovulation disorders, androgen excesses, and Polycystic Ovarian Morphology (PCOM), which should all be treated appropriately. Inositol therapy has been shown to play a significant role in PCOS in several studies. Despite this, there is no comprehensive discussion of Myo-Inositol (MI) and D-Chiro-Inositol (DCI) in relation to particular symptoms. Aim: The purpose of this review is to demonstrate how well Myo-inositol treats PCOS symptoms. Additionally, the study emphasises on evaluating inositol consumption while considering their physiological characteristics and the process by which certain PCOS symptoms arise. Methods: Using the databases PubMed and Google Scholar, a review of the literature was carried out using one of the following keywords: PCOS, myo-inositol, and insulin resistance. Results: Multiple research studies have shown that the treatment of MI improved the function of ovaries and fertility in patients with Polycystic Ovarian Syndrome (PCOS), reduced symptoms of hyperandrogenism, including acne and hirsutism, beneficially affected metabolic aspects, and regulated a number of hormonal factors that are deeply connected to the function of the reproductive system and ovulation. Thus, using MI as a treatment has become a breakthrough approach to enhance spontaneous ovulation, stimulate ovulation, or minimise PCOS symptoms. Conclusion: A physiological ratio of 40:1 between MI and DCI could prove to be advantageous for addressing the metabolic, hormonal, and reproductive components of PCOS, according to the existing clinical evidence.
... Myo-Ins is a cyclic alcohol, which plays a central role in modulating inflammation, metabolic-endocrine processes, and oxidative damage in several human diseases, including polycystic ovary syndrome (PCOS), metabolic syndrome, and cancer [24][25][26][27]. Previous studies also revealed positive effects of the oral administration of myo-Ins in improving mastalgia in women suffering from PCOS or premenstrual dysphoric syndrome [28,29]. In addition, in vitro experiments revealed the anti-inflammatory and anti-fibrotic activity of myo-Ins by reducing levels of Transforming Growth Factor-β (TGF-β), fibronectin and type I collagen [27]. ...
Background:
The management of mastodynia plays a central role in improving women quality of life. Despite its high occurrence, specific therapeutic guidelines for mastalgia are still lacking. Available therapies include unspecific anti-inflammatories, even though they may often expose to undesirable effects and low compliance.
Objective:
The aim of this study was to highlight the efficacy of the topical application of combined natural molecules including Boswellia serrata, Betaine and myo-Inositol in improving cyclic mastalgia.
Methods:
In this retrospective pilot clinical study, patients with cyclic mastalgia applied a specific breast gel for three months. The severity of the pain was measured through the Visual Analogue Score (VAS) in the treated group compared to untreated one. Treated patients also filled in a questionnaire evaluating acceptance and safety of the breast gel.
Results:
This pilot clinical study demonstrated for the first time the efficacy of the topical application of a breast gel based on Betaine, Boswellia serrata, and myo-Inositol in improving cyclic mastodynia. The completed questionnaires also revealed high levels of acceptance, as both safety and compliance.
Conclusions:
Besides confirming the positive effects of these natural molecules in the management of conditions affecting breast physiology - so far evaluated as oral supplementation - the obtained results pave the way for further studies supporting the use of such molecules as a tailored medical device in the management of breast pain, thus also opening toward a combined oral and topical approach.
... While some studies have not found significant effects of MI on LH levels in women with PCOS [30,31], other studies have suggested that MI may have a beneficial effect on LH levels [19,32]. One study found that MI supplementation led to a significant reduction in LH levels in women with PCOS [42], and a randomized controlled trial reported a significant decrease in LH:FSH ratio in women with PCOS after 12 weeks of MI supplementation [24]. MI has also been found to improve HOMA-IR in women with PCOS [23,25]. ...
Introduction: Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by ovulatory dysfunction, hyperandrogenism, and metabolic dysregulation. Insulin resistance (IR) is a common hallmark of PCOS and contributes to metabolic dysfunction. A combination of lifestyle changes and symptom management treatments can help manage the condition. Metformin and myo-inositol (MI) have been shown to improve insulin sensitivity and reduce excess androgen levels in women with PCOS, but there is a lack of research on the effects of combinatory therapy of MI and metformin. This study aims to investigate the hypothesis that a combination of MI and metformin will result in improved insulin sensitivity and clinical outcomes of PCOS. Methods: The study is a double-blinded, randomized controlled trial examining 60 women diagnosed with PCOS that demonstrate the presence of IR. Participants are randomized to one of the following treatments over a six-month period: metformin (MET), inositol (INO), combined metformin and inositol (MET-INO) or placebo-control (CON). BMI, LH:FSH ratio, and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) were assessed at day 0, day 84 and day 168. Anticipated Results: It is anticipated that the MET-INO group will have the most profound effects following intervention, with a decrease in BMI by 3-4%, a decrease in LH:FSH ratio by 30-40%, and a decrease in HOMA-IR by 1-1.5. MET group is expected to have a significant decrease in BMI by 2-3%, a decrease in LH:FSH ratio by 20-30%, and a decrease in HOMA-IR by 0.5-1.5. The INO group is anticipated to experience a significant decrease in BMI by 1-2%, a decrease in LH:FSH ratio by 10-20%, and a decrease in HOMA-IR by 0.2-0.4. Conclusion: The findings of this study suggest that a combination therapy of metformin and MI may offer a more effective treatment option for improving insulin sensitivity in women with PCOS, compared to metformin or inositol treatment alone. These results have important implications for patients with PCOS and clinicians managing their care. Future studies should further investigate the effectiveness and long-term effects of these treatments.
... Based on the present study and previously published literature, we suggest that the use of metformin and MI would be beneficial in women with PCOS with insulin resistance. As clinical improvements especially menstrual cycle regularity improvement was considerably improved by adding MI, it could be possible that the local action of MI at the level of ovarian follicles may exert a synergistic effect to the insulin sensitivity of metformin, though not reflected biochemically by greater improvement in fasting insulin and HOMA-IR.22,23 In both groups reduction in total testosterone and increase in SHBG at the end of 6 months. ...
Objective:
Insulin resistance and hyperinsulinemia plays an important role in pathogenesis of polycystic ovary syndrome (PCOS). Metformin, Myoinositol and d-chiro-inositol acts as insulin sensitizers and exerts a beneficial effects in PCOS. The objective is to compare the effect of metformin monotherapy versus a combination of metformin with Myoinositol and d-chiro-inositol in PCOS.
Design:
This study is a randomized controlled trial conducted over a period of 6 months. All overweight and obese women with PCOS with the age group between 18 and 35 were included and randomized into two groups, 27 in the metformin monotherapy arm and 26 in the myoinositol combination arm.
Patients and measurements:
The variables assessed were duration of menstrual cycle, anthropometric parameters, modified Ferriman Gallwey score, global acne score, Fasting insulin, HOMA-IR, fasting lipid profile, serum testosterone, sex hormone binding globulin, luteinizing hormone, follicle stimulating hormone, anti-Mullerian hormone, and pelvic ultrasound to assess ovarian volume, PCOS Questionnaire score. Changes in the parameters from baseline at the end of 6 months of treatment were assessed and compared between the groups.
Results:
Menstrual cycle regularity improved in both groups with significantly greater improvement in the group receiving myoinositol-based therapy (p < .001). Pregnancy rate was equal in both the arms. There was a significant improvement in PCOSQ score in myoinositol-based therapy group (p < .001). However, there was no statistically significant difference in other hormonal, metabolic parameters between two groups in spite of symptomatic benefits.
Conclusions:
The addition of myoinositol to metformin exerts additional benefits in improving menstrual cycle regularity, and quality of life in women with PCOS.
... Nonetheless, these assumptions have been challenged for a while by controversial clinical results obtained in PCOS patients treated with inositol formulations, in which both myo-Ins and D-Chiro-Ins have been associated according to different ratios [40]. ...
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.
... In particular, MI concentration in ovaries is usually 70-100 times higher than DCI concentration and it acts as second messengers not only of insulin but also of FSH with a possible role in oocyte maturation [2] and in ovulation induction [12]. MI also seems to regulate the production of anti-mullerian hormone induced by the FSH [13], which modulates the sensitivity of follicles to the FSH. Culturing embryos [14] in media enriched with MI ameliorates embryo quality and MI has been suggested to play a key role in oocyte fertilization [15,16]. ...
In the last decades, inositols attracted a growing interest since the acknowledgement of their role in insulin-activated signalling pathways. Myo-inositol (MI) and D-Chiro Inositol (DCI) are the most important isoforms and their use as insulin-sensitizer in treatment of polycystic ovarian syndrome is well known. New discoveries have paved the way for a wide range of new applications. For this reason, we collected the most interesting ideas and updates regarding inositols therapy to reason on innovative uses, with a particular focus in the field of infertility. We reviewed recent literature on inositol with a particular focus in the field of ovarian function and infertility. Recent researches on inositols are focusing on different signalling pathways other than the insulin-sensitizing one, such as inflammation signalling or androgens modulation. Furthermore, MI and DCI act in different ways and dosage and ratio seem to have different effects in different organs. Indeed, the use of inositols is developing promisingly in situations other than the treatment of insulin resistance and this is opening up new perspectives for increasingly personalized and effective therapies.
... MI also seems to regulate the production of anti-mullerian hormone induced by the FSH [13], which modulates the sensitivity of follicles to the FSH. ...
... In the first pathway, MYO, synthesized from glucose 6-phosphate, carried into the cell from plasma or obtained by a recycling of intracellular inositol 1,4,5-triphosphate, is incorporated into activated phosphatidic acid to constitute membrane phosphatidylinositols. In the second pathway, either MYO or its epimeraseconverted (Artini et al. 2020;Genazzani 2016) chiro-isoform DCI (Dinicola et al. 2014;Morley et al. 2017) constitutes IPGs, which are released from cell membrane glycosylphosphatidylinositols in response to insulin. Once released, IPGs can affect any tissues and cells implicated in insulin action (Ravanos et al. 2017;Unfer et al. 2017;Sortino 2017;Zacchè et al. 2009), thus potentiating insulin effects. ...
d-chiro-Inositol (DCI), an isomer of inositol, possesses antioxidative and endothelial protective properties. Possibly due to a deficiency of insulin mediators, polycystic ovary syndrome (PCOS) is often associated with insulin resistance (IR) and hyperinsulinemia, likely responsible for an elevated production of reactive oxygen species. We investigated oxidative-related alterations of inositol in the blood of women with PCOS before and after treatment with DCI. A total of 38 normal-weight PCOS women were investigated before and after DCI administration (500 mg/day for 12 weeks; n = 38) by evaluating serum testosterone, serum androstenedione, fasting serum insulin, fasting serum glucose, and parameters of IR. From the blood, we determined biomarkers of oxidative stress: superoxide anion radicals, hydrogen peroxide, nitric oxide, and the index of lipid peroxidation. The activity of catalase and superoxide dismutase and the reduced glutathione (GSH) content in the hemolysate were also assessed. Data showed that PCOS patients' plasma underwent oxidative stress, as indicated by the higher level of prooxidants and reduced cytosolic GSH content. DCI treatment significantly improved the metabolic parameters. Also, serum values of testosterone were reduced. In conclusion, PCOS patients suffer from a systemic oxidative stress that induces endothelial dysfunction. Treatment with DCI is effective in reducing hormonal, metabolic, and oxidative abnormalities in PCOS patients by improving IR.
... The higher DCI treatment formula with a ratio of 5:1 was found to be ineffective with negative pathological outcomes [52]. Thus MI/ DCI (40:1) represents a promising alternative by counteracting PCOS at both systemic and ovary level [53]. ...
Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women is characterized by polycystic ovaries, chronic anovulation and hyperandrogenism. The treatment in PCOS is mainly symptomatic and involves lifestyle interventions and medications such as Metformin, Oral contraceptives and Antiandrogens. However, the management of PCOS is challenging and current interventions are not able to deal with outcomes of this syndrome. This review encompasses latest pharmacotherapeutic and non-pharmacotherapeutic interventions currently in use to tackle various symptomatic contentions in PCOS. Our focus has been mainly on novel therapeutic modalities for treatment/management of PCOS, like use of newer insulin sensitizers viz., Inositols, Glucagon-like peptide-1(GLP-1) agonists, Dipeptidyl pepdidase-4 (DPP-4) inhibitors, and sodium-glucose transport protein 2 (SGLT2) inhibitors. Also, evidence suggesting the use of vitamin D, statins, and Letrozole as emerging therapies in PCOS have been summarized in this review. Additionally, novel cosmetic techniques like electrolysis, laser and use of topically applied eflornithine to tackle the most distressing feature of facial hirsutism associated with PCOS, non-pharmacological therapy like acupuncture and the role of herbal medicine in PCOS management have also been discussed.
... Indeed, the physiologic ratio appeared to optimize the improvement of fertility [13]. In addition, literature data indicate that MI signaling may regulate the AMH production induced by FSH in the granulosa cells [66]. AMH decreases oocyte sensitivity to FSH and participates in regulating follicle maturation. ...
... Considering that drug-induced depletion of myo-ins also influences d-chiro-ins levels, a combined administration is therapeutically more advantageous than myo-ins alone. The 40:1 combined ratio, in favour of myo-ins, is effective in recovering endogenous conditions including metabolic impairments and endocrine alterations both in PCOS women and in diabetic or overweight patients 27,35,46,47 . However, higher amounts of myo-ins are required to recover iatrogenic depletion of inositols. ...
Objective:
Patients with bipolar disorder (BD) experience a poor quality of life (QoL) and a weak adherence to the therapy due to the various side effects occurring during the pharmacological therapy. To date clinicians have no tools to intervene on such effects, considering them as an unavoidable part of the therapy. This review paves the way for a step forward in the management of patients with BD bridging the therapeutic gap in clinical practice.
Materials and methods:
We reviewed the literature, searching through different databases (MEDLINE, Scopus, Google Scholar). We used different keywords, including bipolar disorder, lithium and valproic acid, inositol role in bipolar disorder, side effects, inositol depletion, supplementation of inositols under lithium treatment, inositol role in metabolism, hypothyroidism, renal and cardiac functionality. In particular, we narrowed the search down to English literature, excluding works before 1980s. Regarding clinical studies, we included case reports and both preclinical and clinical studies, especially only those exhibiting a control group. The outcome of the database search was to highlight the threat of side effects and the relationship with inositol lower levels, paving the way for a step forward in the management of patients with BD.
Results:
Based on the collected evidence, the combined administration of myo-inositol (myo-ins) and d-chiro-inositol (d-chiro-ins) is strongly recommended in order to restore levels and metabolism of inositols. Previous studies pointed out the beneficial effects of inositols in recovering pathological conditions, like polycystic ovary syndrome (PCOS), hypothyroidism, weight gain, cardiac functionality, being all these conditions related to the depletion of inositols. Furthermore, a controlled dosage of inositols, up to 6 grams/daily, may reduce the side effects caused by lithium therapy, without hindering its central therapeutic role on patients' mood.
Conclusions:
Considering the iatrogenic depletion of inositols, the tailored ratio 80:1 in favour of myo-ins, may become a safe and effective strategy to counteract side effects, by providing a large amount of myo-ins and an adequate one of d-chiro-ins. The clinical dosage of inositols used as dietary supplementation is 4 grams/daily, and it may allow the recovery of the side effects and improve patients' QoL, without reducing the central therapeutic effect of the pharmacological therapy.
... After treatment, the GQOLI-74 scores of the two groups were significantly improved (p<0.01), and the observation group was significantly better than the control group in improving the quality of life scores, the differences were statistically significant (p<0.01). The etiology and mechanism of breast fibroma are not clear, and some studies believe that hormone level disorder is one of the causes of breast fibroma [9] . In recent years, the incidence rate of breast fibroma has been increasing. ...
... The aim was defining, in the most reliable way, the correct dosage of MI and DCI to administer orally in PCOS (and not only), in harmony with the woman's physiology. In 2016, Facchinetti and co-workers, based on unpublished data obtained by some Unfer's collaborators, had established that the MI/DCI plasma ratio is around 40:1 (Facchinetti and Neri 2016), confirming some Unfer's ideas based on previous studies (Dinicola et al. 2014;Unfer and Porcaro 2014). Translated at therapeutic level, it means that PCOS women, under inositol treatment aimed at restoring a physiological condition, should take 4 g MI and 0.1 g DCI in powder, but the use of innovative technologies for the improvement of drug absorption have led to the administration of 550 mg of MI and 13.8 mg of DCI in a pharmaceutical form of soft gel capsule, patented by the company of Unfer, corresponding to the plasma ratio 40:1 of MI and DCI De Grazia et al. 2012). ...
Myo-inositol and D-chiro-inositol are insulin sensitising agents. In the ovary, myo-inositol acts as second messenger of Follicle Stimulating Hormone (FSH). Both molecules were administered to Polycystic Ovary Syndrome (PCOS) women. The gynaecologist Vittorio Unfer was the first to give specific value to myo-inositol for the treatment of PCOS: this important innovation opened new ways of research to identify efficient therapies based on myo-inositol alone or with low doses of D-chiro-inositol. Significant successes were also gained using myo-inositol in treating male and female infertility. Unfer’s researches allowed to identify “the D-Chiro-Inositol Paradox in the Ovary” and the best myo-inositol/D-chiro-inositol ratio (40:1) for the treatment of PCOS. Furthermore, his studies allowed to improve the inositol’s efficacy using alpha-lactalbumin. As shown in this review, the main stages of Unfer’s scientific career have been closely intertwined with important phases of the recent pharmacological research about the topic.
... Производные МИ способствуют мейотической прогрессии ооцитов в зрелые яйцеклетки мышей, а истощение внутриклеточных запасов МИ в яичнике нарушает развитие доминантного фолликула [29] . Кроме того, МИ, по-видимому, участвует в регуляции цитоскелета и необходим для ускорения транспорта ооцитов по маточным трубам [30] . Наконец, в исследованиях выявлено, что сигнальный путь МИ может регулировать уровень продукции АМГ в клетках гранулёзы . ...
For many years, the use of combined oral contraceptives (COC) with antiandrogenic effects was the main treatment of clinical and biochemical hyperandrogenism in patients with polycystic ovary syndrome (PCOS). At the same time, the creation of an alternative therapy regimen for patients who have contraindications to taking hormonal drugs, as well as planning pregnancy, is obvious. Various combinations of inositol stereoisomers (myoinositol ― MI, and D-chiro-inositol ― DCI) are being actively studied. The review reflects the current understanding of the etiology, pathogenesis of hyperinsulinemia and androgen-dependent dermatological manifestations of polycystic ovary syndrome. The mechanisms of action of inositols at the molecular level are normalization of carbohydrate metabolism in the body and the reduction of hyperinsulinemia, as well as the levels of male sex hormones in PCOS. A comparative analysis of studies with various combinations of inositols was conducted on the effectiveness of treatment of clinical manifestations of hyperandrogenism, such as hirsutism and acne. The use of MI in conjunction with DCI reduces the risk of developing metabolic syndrome and improves the endocrine profile and manifestations of insulin resistance, but further multicenter studies on this problem are required.
... The two main inositol isomers, myo-inositol (MyoIns) and D-chiroinositol (DCIns), are precursors of inositol phosphoglycans (MyoIns-IPG and DCIns-IPG) that act as second messengers of insulin [20][21][22]. A growing body of research has shown that MyoIns and DCIns can be synergistically integrated in the clinical management of PCOS, exerting therapeutic effects and representing a reliable alternative to conventional treatments for insulin resistance [23][24][25][26], if combined in amounts corresponding to their physiological plasma molar ratio of 40:1 [27,28] at doses of approximately 2g twice a day [27]. ...
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.
... Myo-inositol (MI) and d-chiro inositol (DCI) are isomerical types of insulin-like inositol that act as the second messenger in the intracellular pathway of insulin and both molecules contribute to the increased insulin sensitivity of various tissues to improve metabolic and ovulatory functions [50]. Inositols are found freely in the cells, as well as in phosphatidylinositols in the plasma membrane, and phosphorylated PIP and PIP2 [51]. MI turns into DCI under insulin stimulation by a NAD-NADH-dependent epimerase [52]. ...
Since the lack of certainty in identifying polycystic ovary syndrome (PCOS) demonstrates confusion regarding the disorder’s pathophysiology and its therapeutic approaches, systematic screening of women under diagnostic guidelines of the NIH reported that about 4–10 percent of reproductive women aged 20–44 years suffer from PCOS. Not all females with PCOS-defining biochemical and clinical characteristics and about 22% of PCOS women have no symptoms. PCOS is a heterogeneous phenotypic and clinical condition, combined with metabolic implications. The root cause of PCOS is the major issue of IR or irregular androgen secretion and constant effort is being made in identifying the dynamic pathogenic network underlying the syndrome. Regardless of PCOS initiating cause, IR therapy and hyperinsulinemia can restore metabolic and hormonal homeostasis, and minimize ovarian dysfunction. Thus, the impact of insulin on ovaries in hyperinsulinemic individuals can account for many of the PCOS characteristics and is important for developing treatment strategies. Therefore, our primary aim is to investigate the proper understanding of endocrine disruption during PCOS and secondary to the therapeutic potential of inositol in reestablishing the equilibrium of ovarian dysfunction, anovulation, and eventually infertility.
... Выраженный дефицит МИ вызывает снижение ФСГ-сигнализации в клетках гранулезы яичников, по-давление фолликулогенеза и созревания яйцеклеток [15,56]. Еще больше резистентность фолликулов к ФСГ усиливает возрастающая продукция АМГ [57]. Как известно, АМГ в большом количестве вырабатывается в преантральных и небольших антральных (до 8 мм) фолликулах, их преждевременное созревание блокируется за счет подавления чувствительности к ФСГ. ...
The article presents key data on the physiology of inositols in the body, their pathogenetic role in the development of polycystic ovary syndrome, and the possibilities of myo-inositol and D-chiro-inositol in the restoration of ovarian function, metabolic parameters, and overcoming of infertility.
... In the past few decades, several therapies for human PCOS based on the administration of myoinositol (MI) and/or DCI [13] have been proposed. Inositol is a sugar represented by nine stereoisomers, of which MI (more than 99%) and DCI are the most widely distributed in the human body. ...
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.
... The major finding in this work is that COC treatment in PCOS patients modified the hormonal profile and worsened lipid parameters, and insulin resistance, while inositol therapies improved significantly insulin resistance and glycosylated hemoglobin, reducing cholesterol and triglyceride serum levels as compared to PCOS patients treated with COC. These beneficial effects of inositol therapies are in accordance with those reported by other authors [29][30][31][32][33][34][35][36][37][38][39], some of whom even advise the co-administration of myoinositol and D-chiro-inositol (40:1) to increase the effectiveness in restoring ovary function and metabolic parameters in PCOS [40,41]. Thus, inositol therapies could be considered an easy, beneficial and integrative treatment for PCOS patients, due to their better tolerability and their diminished risk of adverse effects, compared to metformin treatments for PCOS patients [42]. ...
PurposeTo investigate the metabolic impact of currently used therapies in polycystic ovary syndrome (PCOS).Methods
This is an observational, retrospective and transversal protocol. A small cohort of 133 patients, aged 14–48 years, diagnosed with PCOS was divided into four experimental groups: 1) untreated PCOS patients (n = 51); 2) PCOS patients treated with one of the following therapies (n = 82): a) combined oral contraceptives (COC, n = 35); b) metformin (n = 11); and c) inositols (n = 36).ResultsAlthough only < 10% of patients included in this cohort can be strictly encompassed in the development of metabolic syndrome, approximately 20% had insulin resistance. In PCOS patients, COC treatment modified the hormonal profile and worsened lipid parameters (increasing cholesterol and triglyceride levels) and insulin resistance, whereas inositol therapies improved significantly insulin resistance and glycosylated hemoglobin, reducing cholesterol and triglyceride levels. In these women, obesity was associated with greater alterations in lipid and glycemic metabolism and with higher blood pressure levels. PCOS patients with phenotype A presented vaster alterations in lipid metabolism and higher values of glycosylated hemoglobin as well as blood pressure compared to other PCOS phenotypes.Conclusions
Results in this paper suggest that inositol therapies (alone or combined with COC) are the most useful therapies with the best benefits against PCOS symptoms. Thus, integrative treatment may become a more efficient long-term choice to control PCOS symptoms. Furthermore, obesity can be considered as an adverse symptom and calorie restriction a key element of combined treatment in PCOS, not only for fertility management but also in long-term metabolic sequelae.
... Such plasma ratio was determined to be about 40:1 and, according to this evidence, a treatment based on the same ratio was used. This choice is supported by several studies [15][16][17][18][19][20] and by a recent animal research where an experimental animal model of PCOS was obtained exposing mice to continuous light for 10 weeks 21 . Interestingly, such research, demonstrated that the 40:1 ratio between MI and DCI is the most effective treatment, in comparison with other different ratios (5:1, 20:1 and 80:1). ...
Objective:
The aim of this clinical trial was to evaluate the efficacy of seven different ratios between two inositols stereoisomers, myo-inositol (MI) and D-chiro-inositol (DCI), in the therapy of polycystic ovary syndrome (PCOS).
Patients and methods:
fifty-six PCOS patients (8 for each group) were treated by oral route using the following formulations: DCI alone, and 1:3.5; 2.5:1; 5:1; 20:1; 40:1, 80:1 MI/DCI ratio. They received 2 g of inositols twice a day for 3 months. The primary outcome was ovulation, the secondary outcome included the improvement of FSH, LH, Sex Hormone Binding Globulin (SHBG), 17-beta-Estradiol (E2), free testosterone, basal and postprandial insulin levels, as well as HOMA index, BMI and menses.
Results:
We found that the 40:1 MI/DCI ratio is the best for PCOS therapy aimed at restoring ovulation and normalizing important parameters in these patients. The other formulations were less effective. In particular, a decreased activity was observed when the 40:1 ratio was modified in favour of DCI.
Conclusions:
Our data demonstrated that DCI activity is beneficial mainly at a specific ratio with MI, whereas the increase of DCI causes the loss of the beneficial effects at reproductive level. These results in humans validate a previous preclinical study with different MI/DCI ratios carried out in an experimental model of PCOS mice.
Background:
We sought to conduct a systematic review and meta-analysis of randomized clinical trials to evaluate the impact of Myo-inositol on oocyte and embryo quality in women undergoing assisted reproduction.
Methods:
The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)2020 checklist.
Registration number:
CRD42023433328. Studies were identified by searching PubMed, Cochrane Library, Google Scholar, Scopus, Embase and ClinicalTrials databases.
Results:
8 randomized clinical trials (RCTs) were included for qualitative analysis reporting on 820 participants. 4 meta-analyses were performed. Numbers of retrieved oocytes in comparison of intervention and control group were higher in inositol group (mean difference (MD) = 0.41, 95% CI: 0.05-0.77, p=0.02). Meta-analysis of two studies compared numbers of oocytes among poor ovarian responder patients showed no significant difference between intervention and control group (MD=0.50, 95% CI: 0.57-1.58, p=0.36). Miscarriage rate was no statistically significant difference between the treatment and control groups (risk ratios (RR)=0.81, 95% CI: 0.20- 3.32, p=0.77). Inositol played no role in improving clinical pregnancy rates, there was no significant difference between the intervention group and the control group (RR=1.41, 95% CI: 0.88-2.25, p=0.15).
Conclusion:
Thus, we did not find any benefits of using myo-inositol on oocyte and embryo quality in women undergoing reproductive technologies. Further studies are needed to assess efficacy, safety and high compliance by female patients.
To provide the latest scientific knowledge on the efficacy of inositols for improving reproductive disorders in women with and without polycystic ovary syndrome (PCOS) and to reach a consensus on their potential use through a Delphi-like process.
A panel of 17 endocrinologists and 1 gynecologist discussed 4 key domains: menses irregularity and anovulation, fertility, pregnancy outcomes, and neonatal outcomes.
A total of eight consensus statements were drafted. Myo-inositol (Myo) supplementation can be used to improve menses irregularities and anovulation in PCOS. Myo supplementation can be used in subfertile women with or without PCOS to reduce the dose of r-FSH for ovarian stimulation during IVF, but it should not be used to increase the clinical pregnancy rate or live birth rate. Myo supplementation can be used in the primary prevention of gestational diabetes mellitus (GDM), but should not be used to improve pregnancy outcomes in women with GDM. Myo can be preconceptionally added to folic acid in women with a previous neural tube defects (NTD)-complicated pregnancy to reduce the risk of NTDs in newborns. Myo can be used during pregnancy to reduce the risk of macrosomia and neonatal hypoglycemia in mothers at risk of GDM.
This consensus statement provides recommendations aimed at guiding healthcare practitioners in the use of inositols for the treatment or prevention of female reproductive disorders. More evidence-based data are needed to definitively establish the usefulness of Myo, the appropriate dosage, and to support the use of D-chiro-inositol (DCI) or a definitive Myo/DCI ratio.
Context
Insulin resistance is common in women with Polycystic Ovary Syndrome (PCOS). Inositol may have insulin sensitising effects; however, its efficacy in the management of PCOS remains indeterminate.
Objective
To inform the 2023 International Evidence-based Guidelines in PCOS, this systematic review and meta-analysis evaluated the efficacy of inositol, alone or in combination with other therapies, in the management of PCOS.
Data Sources
Medline, PsycInfo, EMBASE, All EBM, and CINAHL from inception until August 2022.
Study Selection
Thirty trials (n=2230; 1093 intervention, 1137 control), with 19 pooled in meta-analyses were included.
Data Extraction
Data were extracted for hormonal, metabolic, lipids, psychological, anthropometric, reproductive outcomes and adverse effects by one reviewer, independently verified by a second.
Data Synthesis
Thirteen comparisons were assessed, with three in meta-analyses. Evidence suggests benefits for myo-inositol or D-chiro-inositol (DCI) for some metabolic measures and potential benefits from DCI for ovulation but inositol may have no effect on other outcomes. Metformin may improve waist-hip ratio and hirsutism compared to inositol but there is likely no difference for reproductive outcomes, and the evidence is very uncertain for BMI. Myo-inositol likely causes fewer gastrointestinal adverse events compared with metformin; however, these are typically mild and self-limited.
Conclusions
The evidence supporting the use of inositol in the management of PCOS is limited and inconclusive. Clinicians and their patients should consider the uncertainty of the evidence together with individual values and preferences when engaging in shared decision-making regarding the use of inositol for PCOS.
Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder affecting women worldwide. It refers to a condition that often has 'poly' liquid containing sacks around ovaries. It affects reproductive-aged females, giving rise to menstrual and related reproductive issues. PCOS is marked by hormonal imbalance, often resulting in hyperandrogenism. Women with PCOS might experience abnormal insulin activity and complications such as acne, mood swings, hirsutism, obesity, and infertility. The disease is linked with severe clinical ailments such as type 2 diabetes (T2DM), cardiovascular diseases (CVDs), and cancer. A faulty lifestyle, neu-roendocrine factors, genetic causes, and androgen exposures often cause PCOS. The approach of society towards physiological problems such as PCOS in women is that it must be under the veil that is the ultimate barrier to the early diagnosis of PCOS. Thus, this review summarizes the causes , symptoms, pathophysiology, diagnosis, and possible treatment (medical, herbal, and lifestyle improvement, acupuncture, and bariatric surgery) related to PCOS.
The Polycystic Ovary Syndrome (PCOS) disease was one of the most crucial endocrinological diseases (ED) of infertile females in generative age, affecting around) 4-8% (of this populace. Nearby (seventy-four%) of polycystic ovarian infertile women will have an ovulatory Cycles (OC), also (forty-two%) of them may have (forty-eight%) have Hyperandrogenism (HA) and insulin resistance (IR). In a review the syndrome disease (SD) of (PCOS) possibly will be measured as well as the consequence of simultaneous Endocrinological alterations (EA), that each other effect of hyper-androgenism (HA) necessity remain owing toward the native inflammatory response (IR) of the ovarian by chemokines, specific Cytokines (SC) and Reactive Oxygen Species-(ROS secreted via. the Fatty-Tissue (FT). Moreover, the fatness may delay by inhibiting the Hypothalamus-Hypophisis-Gonads Regulation System (HHGRS) and the physiological process of ovarian follicular maturation.
Polycystic ovary syndrome (PCOS) is a very frequent disease that affects reproductive ability and menstrual regularity. Other than the criteria established at the Rotterdam consensus, in these last few years a new issue, insulin resistance, has been found frequently, and at a very high grade, in patients with PCOS. Insulin resistance occurs for several factors, such as overweight and obesity, but it is now clear that it occurs in patients with PCOS with normal weight, thus supporting the hypothesis that insulin resistance is independent of body weight. Evidence shows that a complex pathophysiological situation occurs that impairs post-receptor insulin signalling, especially in patients with PCOS and familial diabetes. In addition, patients with PCOS have a high incidence of non-alcoholic fatty liver disease related to the hyperinsulinaemia. This narrative review focuses on the recent new insights about insulin resistance in patients with PCOS, to better understand the metabolic impairment accounting for most of the clinical signs/symptoms of PCOS.
d-chiro-Inositol (DCI) is a promising drug candidate for treating insulin resistance and associated diseases such as type 2 diabetes or polycystic ovary syndrome. In this study, we developed two production processes for DCI using Corynebacterium glutamicum as host. In the first process, myo-inositol (MI) is oxidized to 2-keto-myo-inositol (2KMI) by the inositol dehydrogenase (IDH) IolG and then isomerized to 1-keto-d-chiro-inositol (1KDCI) by the isomerases Cg0212 or Cg2312, both of which were identified in this work. 1KDCI is then reduced to DCI by IolG. Overproduction of IolG and Cg0212 in a chassis strain unable to degrade inositols allowed the production of 1.1 g/L DCI from 10 g/L MI. As both reactions involved are reversible, only a partial conversion of MI to DCI can be achieved. To enable higher conversion ratios, a novel route towards DCI was established by utilizing the promiscuous activity of two plant-derived enzymes, the NAD+-dependent d-ononitol dehydrogenase MtOEPa and the NADPH-dependent d-pinitol dehydrogenase MtOEPb from Medicago truncatula (barrelclover). Heterologous production of these enzymes in the chassis strain led to the production of 1.6 g/L DCI from 10 g/L MI. For replacing the substrate MI by glucose, the two plant genes were co-expressed with the endogenous myo-inositol-1-phosphate synthase gene ino1 either as a synthetic operon or using a novel, bicistronic T7-based expression vector. With the single operon construct, 0.75 g/L DCI was formed from 20 g/L glucose, whereas with the bicistronic construct 1.2 g/L DCI was obtained, disclosing C. glutamicum as an attractive host for of d-chiro-inositol production.
Background
Myo-inositol (MI) is incorporated into numerous biomolecules, including phosphoinositides and inositol phosphates. Disturbance of inositol availability or metabolism is associated with various disorders, including neurological conditions and cancers, while supplemental MI has therapeutic potential in conditions such as depression, polycystic ovary syndrome and congenital anomalies. Inositol status may be influenced by diet, synthesis, transport, utilisation and catabolism.
Objectives
We aimed to investigate potential genetic regulation of circulating MI status and to evaluate correlation of MI concentration with other metabolites.
Methods
Gas chromatography mass spectrometry was used to determine plasma MI concentration of more than 2,000 healthy, young adults (aged 18–28 years) from the Trinity Student Study. Genotyping data was used to test association of plasma MI with SNPs in candidate genes, encoding inositol transporters and synthesising enzymes, and test for genome-wide association. We evaluated potential correlation of plasma MI with D-chiro inositol, glucose and other metabolites by Spearman's rank correlation.
Results
Mean plasma MI showed a small but significant difference between males and females (28.5 and 26.9 µM, respectively). Candidate gene analysis revealed several nominally significant associations with plasma MI, most notably for SLC5A11, encoding a sodium-coupled inositol transporter, also known as SMIT2 (sodium-dependent myo-inositol transporter 2). However, these did not survive correction for multiple testing. Subsequent testing for genome-wide association with plasma MI did not identify associations of genome-wide significance (p < 5 × 10–8). However, 8 SNPs exceeded the threshold for suggestive significant association with plasma MI concentration (p < 1 × 10–5), 3 of which were located within or close to genes: MTDH, LAPTM4B and ZP2. We found significant positive correlation of plasma MI concentration with concentration of D-chiro-inositol and several other biochemicals including glucose, methionine, betaine, sarcosine and tryptophan.
Conclusion
Our findings suggest potential for modulation of plasma MI in young adults by variation in SLC5A11 which is worthy of further investigation.
Objective:
PCOS is a syndrome is characterized by 2 out of 3 of the criteria established during the Rotterdam Consensus Conference. Recently the issue of insulin resistance (IR) has caught attention.
Subjects:
A group of overweight/obese PCOS patients (n = 30) have been evaluated before and after 3 months of daily integrative administration of d-chiro inositol (DCI) (500 mg) and alpha lipoic acid (ALA) (300 mg).
Methods:
Hormonal and metabolic profiles, oral glucose tolerance test (OGTT) for glucose, insulin and C-peptide response were performed in baseline conditions and after DCI plus ALA treatment. Hepatic Insulin Extraction (HIE) index was computed along the OGTT to evaluate the liver ability in degrading insulin.
Results:
The treatment decreased LH, Androstenedione (A), insulin plasma levels, BMI, HOMA index, AST and ALT. Considering patients for the presence (n = 17) or absence of familial diabetes (n = 13), the greatest improvements occurred in the former patients. Insulin response to OGTT was greatly reduced after the treatment interval in PCOS with familial diabetes. HIE computation disclosed that in presence of familial diabetes liver degradation of insulin is reduced thus leaving a higher amount of circulating insulin. DCI plus ALA administration decreased AST and ALT and restored hepatic insulin clearance since HIE profile was improved.
Conclusion:
Our study demonstrates that in overweight/obese PCOS the predisposition to familial diabetes triggers IR not only through the endogenous impaired DCI and ALA synthesis but also through a reduced hepatic clearance of insulin. DCI plus ALA administration positively improved hormonal, metabolic profiles as well as liver function.
Introduction:
Several antioxidants are available for the treatment of male infertility. Although the benefit of myo-inositol (MYO) and D-chiro-inositol (DCI) for female infertility is recognized, their role in male infertility is a matter of debate.
Areas covered:
The authors review the impact that treatment with MYO and/or DCI may have on conventional and bio-functional sperm parameters [mitochondrial membrane potential (MMP), sperm chromatin compactness, and sperm DNA fragmentation (SDF)], seminal oxidative stress (OS) and pregnancy, miscarriage, and live birth rates, and the possible mechanisms involved. Furthermore, the authors gather evidence on the effects of MYO and/or DCI on sperm function in vitro.
Expert opinion:
MYO can improve sperm count, motility, capacitation, acrosome reaction, and MMP. No data are currently available on the effects of DCI in vivo. Both MYO and DCI ameliorate sperm motility and MMP in vitro. Therefore, the use of inositols should be preferred in patients with idiopathic asthenozoospermia, especially in case of impaired sperm mitochondrial function. Due to their insulin-sensitizing action, a role for these molecules may be envisaged for the treatment of infertility caused by carbohydrate metabolism derangement.
Polycystic ovary syndrome (PCOS) is one of the most common disorders among women of reproductive age and can be diagnosed when at least two of the following criteria are present: chronic ovulatory disorder, clinical and/or biochemical hyperandrogenism, and polycystic ovaries. Diet and lifestyle modifications are the main therapeutic intervention and they can fully restore ovary function and avoid PCOS consequences in a certain number of patients. However, prescription of medications or dietary supplements is often needed. The literature has confirmed the significant role of inositol therapy in PCOS, with particular reference to Myo-inositol and D-chiro-Inositol. The aim of this review is to clarify the use of inositols for the treatment of PCOS and the recent scientific theories about D-Chiro-Inositol properties as an ovarian aromatase inhibitor.
Polycystic ovary syndrome (PCOS) is a heterogenous disorder characterized by chronic ovulation dysfunction and hyperandrogenism. It is considered the most common endocrinological disorder, affecting up to 25% of women of reproductive age, and associated with long-term metabolic abnormalities predisposing to cardiovascular risk, such as insulin resistance (IR), dyslipidemia, endothelial dysfunction, and systemic inflammation. PCOS is also characterized by elevated serum levels of luteinizing hormone (LH), causing a condition of hyperandrogenism and a consequent altered ratio between LH and the follicle stimulating hormone (FSH). Over the years, several different approaches have been proposed to alleviate PCOS symptoms. Supplementation with natural molecules such as inositols, resveratrol, flavonoids and flavones, vitamin C, vitamin E and vitamin D, and omega-3 fatty acids may contribute to overcoming PCOS pathological features, including the presence of immature oocyte, IR, hyperandrogenism, oxidative stress and inflammation. This review provides a comprehensive overview of the current knowledge about the efficacy of natural molecule supplementation in the management of PCOS.
We report here the in vivo conversion of [3H]myoinositol to [3H]chiroinositol. After labeling intraperitoneally with [3H]myoinositol for 3 days to reach radioisotope equilibrium in urine, [3H]chiroinositol was isolated from tissues and purified after 6 N HCl hydrolysis by two sequential paper chromatographies and high performance liquid chromatography (HPLC). Percent conversion of [3H]myoinositol to [3H]chiroinositol was highest in urine (36%), liver (8.8%), muscle (8.8%), and blood (7.6%) with intestine, brain, kidney, spleen, and heart decreasing in percentage from 2.8 to 0.7%. Labeling of other inositol isomers including scyllo-, neo-, and epi-, and mucoinositol was minimal, approximately 0.06% of [3H]myoinositol. Glucose was unlabeled, but glucuronate, the product of myoinositol oxidation, was labeled up to 1.5% of the [3H] myoinositol. Acid hydrolysates of combined inositol-containing phospholipids contain significant labeled chiroinositol. [3H]Phosphatidylinositols and [3H]glycosylphosphatidylinositols were extracted from liver, muscle, and blood, isolated by thin layer chromatography, and inositols purified by HPLC after acid hydrolysis. Percent conversion of [3H]myoinositol to [3H] chiroinositol was highest in blood (60.4%) followed by muscle (7.7%) and liver (2.2%).
Since the 1990 NIH‐sponsored conference on polycystic ovary syndrome (PCOS), it has become appreciated that the syndrome encompasses
a broader spectrum of signs and symptoms of ovarian dysfunction than those defined by the original diagnostic criteria. The
2003 Rotterdam consensus workshop concluded that PCOS is a syndrome of ovarian dysfunction along with the cardinal features
hyperandrogenism and polycystic ovary (PCO) morphology. PCOS remains a syndrome and, as such, no single diagnostic criterion
(such as hyperandrogenism or PCO) is sufficient for clinical diagnosis. Its clinical manifestations may include: menstrual
irregularities, signs of androgen excess, and obesity. Insulin resistance and elevated serum LH levels are also common features
in PCOS. PCOS is associated with an increased risk of type 2 diabetes and cardiovascular events.
Myo-inositol (myoIns) has a positive role in mammalian development and human reproduction. Since experiments on farming species suggest a similar role in preimplantation development, we evaluated the hypothesis that the inclusion of myoIns in human embryo culture media would produce an increase in embryo quality in IVF cycles, using the mouse embryo assay.
To determine the effect of myoIns on completion of preimplantation development in vitro, one-cell embryos of the inbred C57BL/6N mouse strain were produced by ICSI, cultured in human fertilization media in the presence of myoIns (myoIns+) or in its absence (myoIns-) and evaluated morphologically. Daily progression through cleavage stages, blastocyst production and expansion and blastomere number at 96 hours post fertilization were assessed.
Compared to myoIns- embryos, myoIns+ embryos displayed a faster cleavage rate and by the end of preimplantation development, the majority of myoIns+ blastocysts was expanded and formed by a higher number of blastomeres.
The presence of myoIns resulted in both an increase in proliferation activity and developmental rate of in vitro cultured early mouse embryos, representing a substantial improvement of culture conditions. These data may identify myoIns as an important supplement for human embryo preimplantation culture.
Myoinositol (MI) and d-chiroinositol (DCI) are 2 stereoisomers and insulin sensitizers. Their physiological ratio differs from tissue to tissue, and they are regulated by an insulin-dependent epimerase whose activity is drastically reduced in conditions of insulin resistance. Based on literature data and on the fact that MI phospholipids are follicle-stimulating hormone (FSH) second messengers, we speculated that patients with polycystic ovary syndrome (PCOS) having hyperinsulinemia, present an enhanced MI to DCI epimerization in the ovary, leading to MI deficiency that impairs FSH signaling, resulting in reduced oocyte quality. In the present study, 20 patients with PCOS and 20 healthy women were enrolled for measurement of MI and DCI levels in their follicular fluid. Follicular fluid samples were taken using a vaginal probe and both MI and DCI were quantified analytically. Results showed that the ratio of MI-DCI dropped from 100:1 in healthy participants to 0.2:1 in patients with PCOS who additionally displayed significantly higher levels of insulin resistance, hyperinsulinemia, and luteinizing hormone. This study is the first one to analyze the misbalance in the MI-DCI ratio in the ovary of patients with PCOS, supporting the concept that maintaining the physiological levels of the 2 stereoisomers is crucial, in restoring the ovarian functionality.
Previous studies from our and other labs have shown that insulin resistance is associated with an inositol imbalance of excess myo-inositol and deficient chiro-inositol together with a deficiency of myo-inositol to chiro-inositol epimerase in vivo and in vitro. In this report, we utilized well characterized theca cells from normal cycling women, with normal insulin sensitivity, and theca cells from women with polycystic ovary syndrome (PCOS), with increased insulin sensitivity to examine the myo-inositol to chiro-inositol ratio (M/C) and the myo-inositol to chiro-inositol epimerase activity. PCOS theca cells with increased insulin sensitivity were specifically used to investigate whether the inositol imbalance and myo-inositol to chiro-inositol epimerase are regulated in a similar or the opposite direction than that observed in insulin resistant cells. The results of these studies are the first to demonstrate that in insulin sensitive PCOS theca cells the inositol imbalance goes in the opposite direction to that observed in insulin resistant cells, and there is a decreased M/C ratio and an increased myo-inositol to chiro-inositol epimerase activity. Further biochemical and genetic studies will probe the mechanisms involved.
Aim of this pilot study is to examine the effects of myo-inositol administration on ovarian response and oocytes and embryos quality in non PolyCystic Ovary Syndrome (PCOS) patients undergoing multiple follicular stimulation and in vitro insemination by conventional in vitro fertilization or by intracytoplasmic sperm injection.
One hundred non-PCOS women aged <40 years and with basal FSH <10 mUI/ml were down-regulated with triptorelin acetate from the mid-luteal phase for 2 weeks, before starting the stimulation protocol for oocytes recovery. All patients received rFSH, at a starting dose of 150 IU for 6 days. The dose was subsequently adjusted according to individual response. Group B (n=50) received myo-inositol and folic acid for 3 months before the stimulation period and then during the stimulation itself. Group A (n-50) received only folic acid as additional treatment in the 3 months before and through treatment.
Total length of the stimulation was similar between the two groups. Nevertheless, total amount of gonadotropins used to reach follicular maturation was found significantly lower in group B. In addition, the number of oocytes retrieved was significantly reduced in the group pretreated with myo-inositol. Clinical pregnancy and implantation rate were not significantly different in the two groups.
Our findings suggest that the addition of myo-inositol to folic acid in non PCOS-patients undergoing multiple follicular stimulation for in-vitro fertilization may reduce the numbers of mature oocytes and the dosage of rFSH whilst maintaining clinical pregnancy rate. Further, a trend in favor of increased incidence of implantation in the group pretreated with myo-inositol was apparent in this study. Further investigations are warranted to clarify this pharmacological approach, and the benefit it may hold for patients.
We report here the in vivo conversion of [3H]myoinositol to [3H]chiroinositol. After labeling intraperitoneally with [3H]myoinositol for 3 days to reach radioisotope equilibrium in urine, [3H]chiroinositol was isolated from tissues and purified after 6 N HCl hydrolysis by two sequential paper chromatographies and high performance liquid chromatography (HPLC). Percent conversion of [3H]myoinositol to [3H]chiroinositol was highest in urine (36%), liver (8.8%), muscle (8.8%), and blood (7.6%) with intestine, brain, kidney, spleen, and heart decreasing in percentage from 2.8 to 0.7%. Labeling of other inositol isomers including scyllo-, neo-, and epi-, and mucoinositol was minimal, approximately 0.06% of [3H]myoinositol. Glucose was unlabeled, but glucuronate, the product of myoinositol oxidation, was labeled up to 1.5% of the [3H] myoinositol. Acid hydrolysates of combined inositol-containing phospholipids contain significant labeled chiroinositol. [3H]Phosphatidylinositols and [3H]glycosylphosphatidylinositols were extracted from liver, muscle, and blood, isolated by thin layer chromatography, and inositols purified by HPLC after acid hydrolysis. Percent conversion of [3H]myoinositol to [3H] chiroinositol was highest in blood (60.4%) followed by muscle (7.7%) and liver (2.2%).
PCOS is the main cause of infertility due to metabolic, hormonal and ovarian dysfunctions. Women affected by PCOS often suffer of insulin resistance and of a compensatory hyperinsulinemia. These conditions put the patients at risk of developing several metabolic disorders. Both myo-inositol (MI) and D-chiro inositol (DCI) glycans administration has been reported to exert beneficial effects at metabolic, hormonal and ovarian level. Beside these common features, MI and DCI are indeed different molecules: they belong to two different signal cascades and regulate different biological processes.
In this study, we aim to verify whether the two molecules have a synergistic action by acting on their specific cellular pathways. The effectiveness in reducing the risk of metabolic syndrome as well as in enhancing the ovarian functions of a combined therapy with MI and DCI was compared to a mono therapy in a randomized controlled trial.
Fifty overweight women with PCOS were enrolled and divided in two groups to receive MI and DCL (MI+DCI group) or MI alone (MI group) for a period of six months. Baseline measurements were repeated at three months (T1) and at the end of the treatment (T2).
At the end of the treatment, both MI and MI+DCI groups showed an improvement of the metabolic parameters and no significant differences were found. As expected, the combined supplementation with MI and DCI resulted to be more effective, compared to the MI group, after three months of treatment.
The combined administration of MI and DCI in physiological plasma ratio (40:1) should be considered as the first line approach in PCOS overweight patients, being able to reduce the metabolic and clinical alteration of PCOS and, therefore, reduce the risk of metabolic syndrome.
A total of 54 women, aged <40 years and diagnosed with PCOS were enrolled in this study. Patients with insulin resistance and/or hyperglycaemia were excluded from the study. Patients were randomly divided into 5 groups (n=10-12): a placebo group, and 4 groups (A-D) that received 300-600-1200-2400 mg of DCI daily respectively. All treatments were carried out for 8 weeks before follicle stimulating hormone (rFSH) administration.
Total r-FSH units increased significantly in the two groups that received the higher doses of DCI. The number of immature oocytes was significantly increased in the three groups that received the higher doses of DCI. Concurrently, the number of MII oocytes was significantly lower in the D group compared to placebo group. Noteworthy, the number of grade I embryos was significantly reduced by DCI supplementation.
Indeed, increasing DCI dosage progressively worsens oocyte quality and ovarian response.
Polycystic ovary syndrome (PCOS) affects 5%-10% of women in reproductive age, and it is the most common cause of infertility due to ovarian dysfunction and menstrual irregularity. Several studies have reported that insulin resistance is common in PCOS women, regardless of the body mass index. The importance of insulin resistance in PCOS is also suggested by the fact that insulin-sensitizing compounds have been proposed as putative treatments to solve the hyperinsulinemia-induced dysfunction of ovarian response to endogenous gonadotropins. Rescuing the ovarian response to endogenous gonadotropins reduces hyperandrogenemia and re-establishes menstrual cyclicity and ovulation, increasing the chance of a spontaneous pregnancy. Among the insulin-sensitizing compounds, there is myo-inosiol (MYO). Previous studies have demonstrated that MYO is capable of restoring spontaneous ovarian activity, and consequently fertility, in most patients with PCOS. With the present review, we aim to provide an overview on the clinical outcomes of the MYO use as a treatment to improve ovarian function and metabolic and hormonal parameters in women with PCOS.
To evaluate the effects of metformin on the ovarian response to gonadotropins given for in vitro fertilization (IVF) programs in patients with polycystic ovary syndrome (PCOS) and reduced ovarian reserve.
Prospective, parallel, randomized, double-blind, placebo-controlled clinical trial.
Academic departments of obstetrics and gynecology, and a private IVF center.
Primary infertile patients with PCOS older than 35 years and/or with a basal follicle-stimulating hormone (FSH) level higher than 10 IU/L who were scheduled for IVF cycles.
Gonadotropin-releasing hormone agonist flare-up protocol and high starting doses of recombinant FSH plus metformin or placebo tablets.
Primary end point: cancellation rate for low ovarian response. Secondary end-points: other clinical, biochemical, and reproductive data.
Enrollment was stopped after 88 participants had been randomized and analyzed due to an unacceptable increased risk of poor ovarian response in the metformin arm. Statistically significant differences between the metformin and placebo groups were observed in the dose of gonadotropins used, peak estradiol levels, and the number of dominant follicles, retrieved oocytes, and metaphase II oocytes.
In patients with PCOS and reduced ovarian reserve, metformin worsened the response to gonadotropins, and its administration should be stopped before the start of controlled ovarian hyperstimulation for IVF programs. CLINICAL TRIALS IDENTIFICATION NUMBER: NCT01208740.
Myo-inositol is a six carbon cyclitol that contains five equatorial and one axial hydroxyl groups. Myo-inositol has been classified as an insulin sensitizing agent and it is commonly used in the treatment of the Polycystic Ovary Syndrome (PCOS). However, despite its wide clinical use, there is still scarce information on the myo-inositol safety and/or side effects. The aim of the present review was to summarize and discuss available data on the myo-inositol safety both in non-clinical and clinical settings. The main outcome was that only the highest dose of myo-inositol (12 g/day) induced mild gastrointestinal side effects such as nausea, flatus and diarrhea. The severity of side effects did not increase with the dosage.
The D-chiro-inositol-to-myo-inositol ratio is regulated by an insulin-dependent epimerase. Enzyme activity varies among tissues, likely owing to the specific needs of the two different molecules. We hypothesize that in the ovaries of polycystic ovary syndrome patients, epimerase activity is enhanced, leading to a local myo-inositol deficiency which in turn is responsible for the poor oocyte quality.
Polycystic ovary syndrome (PCOS) is the most common cause of infertility due to menstrual dysfunction, and the most promising treatments for this disease are insulin sensitising agents. Myo-inositol and D-chiro-inositol are insulin sensitizing agents used in PCOS treatment. In the present paper, we aimed to compare the effects myo-inositol and D-chiro-inositol on oocyte quality in euglycemic PCOS patients.
Eighty-four euglycemic PCOS patients, undergoing ovulation induction for ICSI, were recruited for this study. Forty-three participants received MyoInositol 2 g twice a day and forty-one patients received D-chiro inositol 0.6 g twice a day.
The results of our study showed that the total number of oocytes retrieved did not differ in the two treatments groups. However, the number of mature oocytes was significantly increased in the myo-inositol group compared to D-chiro-inositol. Concurrently, the number of immature oocytes decreased in myo-inositol treated patients. Furthermore, the myo-inositol-treated group showed an increase in the mean number of top quality embryos and in the total number of pregnancies compared to the D-chiro-inositol-treated group.
Our data show that, in PCOS patients having a normal insulin response, myo-inositol treatment rather than D-chiro-inositol is able to improve oocyte and embryo quality during ovarian stimulation protocols.
Compare the effects of a combined contraceptive pill (OCP) in combination with myo-inositol (MI) on endocrine, metabolic, and clinical parameters in patients with polycystic ovary syndrome (PCOS).
One hundred fifty-five patients with PCOS were enrolled in this prospective, open-label clinical study. Patients were assigned to receive oral treatment with OCP alone (estradiol (EE) 30 μg/gestodene 75 μg) or in combination with myo-inositol 4 g/die, for 12 months.
OCP plus MI therapy resulted in a higher reduction of FG score compared with OCP alone therapy. The combined therapy (OCP plus MI) significantly decreased hyperinsulinaemia, by positively affecting the fasting insulin and glucose levels and homeostasis model assessment-insulin resistance parameters, while no significant changes were observed in the OCP group. Androgens serum levels decreased in both groups, but significantly more in the combined therapy group. The lipid profile was improved in the combined therapy group, by reducing low-density lipoprotein cholesterol levels and enhancing high-density lipoprotein cholesterol levels.
Our data show that a combination of combined contraceptive pill and MI may be more effective in controlling endocrine, metabolic, and clinical profile in patients with PCOS than OCP alone, and may reduce insulin levels and insulin resistance. Hence, combined treatment may become a more effective long-term therapeutic choice for controlling PCOS symptoms.
To investigate the effects of treatment with Myo-inositol (an insulin sensitizing drug), on circulating insulin, glucose tolerance, ovulation and serum androgens concentrations in women with the Polycystic Ovary Syndrome (PCOS). Forty-two women with PCOS were treated in a double-blind trial with Myo-inositol plus folic acid or folic acid alone as placebo. In the group treated with Myo-inositol the serum total testosterone decreased from 99.5 +/- 7 to 34.8 +/- 4.3 ng/dl (placebo group: from 116.8 +/- 15 to 109 +/- 7.5 ng/dl; P = 0.003), and serum free testosterone from 0.85 +/- 0.1 to 0.24 +/- 0.33 ng/dl (placebo group: from 0.89 +/- 0.12 to 0.85 +/- 0.13 ng/dl; P = 0.01). Plasma triglycerides decreased from 195 +/- 20 to 95 +/- 17 mg/dl (placebo group: from 166 +/- 21 to 148 +/- 19 mg/dl; P = 0.001). Systolic blood pressure decreased from 131 +/- 2 to 127 +/- 2 mmHg (placebo group: from 128 +/- 1 to 130 +/-1 mmHg; P = 0.002). Diastolic blood pressure decreased from 88 +/- 1 to 82 +/- 3 mmHg (placebo group: from 86 +/- 1 to 90 +/- 1 mmHg; P = 0.001). The area under the plasma insulin curve after oral administration of glucose decreased from 8.54 +/- 1.149 to 5.535 +/- 1.792 microU/ml/min (placebo group: from 8.903 +/- 1.276 to 9.1 +/- 1.162 microU/ml/min; P = 0.03). The index of composite whole body insulin sensitivity (ISI comp) increased from 2.80 +/- 0.35 to 5.05 +/- 0.59 mg(-2)/dl(-2) (placebo group: from 3.23 +/- 0.48 to 2.81 +/- 0.54 mg(-2)/dl(-2); P < 0.002). 16 out of 23 women of Myo-inositol group ovulated (4 out of 19 in placebo group). Treatment of PCOS patients with Myo-inositol provided a decreasing of circulating insulin and serum total testosterone as well as an improvement in metabolic factors.
The addition to intact cells of an inositol phospho-oligosaccharide (POS), which is the polar head-group of an insulin-sensitive glycosylphosphatidylinositol, mimics and may mediate some of the biological effects of this hormone. Here we report the existence of a POS transport system in hepatocytes. This POS transport system is specific and time- and dose-dependent. Insulin-resistance caused by dexamethasone administration to rats was accompanied by a decrease in the hepatocyte POS transport system. In contrast, bilateral adrenalectomy provoked a significant increase in the transport of POS. Both the temporal uptake of POS and the regulation of this process by conditions known to modify the sensitivity to insulin suggest that this novel transport system might be involved in the insulin signalling mechanism.
We have studied the mechanism of generation of insulin mediators by using specific antibodies raised against the oligosaccharide anchor of membrane proteins. These antibodies (i) block the in vitro effects of purified insulin mediators and (ii) block the insulin-induced stimulation of pyruvate dehydrogenase in intact BC3H1 myocytes but not insulin-stimulated glucose uptake, generation of diacylglycerol, or generation of insulin mediators. When added to intact cells in the presence of insulin, these antibodies induce the accumulation of insulin mediator activity in the extracellular medium. We therefore conclude that these anti-inositolglycan antibodies block some of the effects of insulin by inhibiting the uptake of specific insulin mediators generated outside the cell.
Two insulin mediators, inositol phosphoglycans, were isolated from bovine liver by methods previously developed for rat liver, i.e. chromatography on an AG 1 x 8 ion exchange column and selective elution with HCl at pH 2.0 and 1.3. The pH 2.0 mediator containing D-chiroinositol stimulated pyruvate dehydrogenase phosphatase, whereas the pH 1.3 mediator containing myo-inositol inhibited cAMP-dependent protein kinase. Each mediator was further purified by thin layer and Bio-Gel P4 column chromatography and injected ip into normal fed rats together with [U-14C]glucose. After 2.5 h, diaphragms were removed, and glycogen isolated. Insulin mediators, like insulin, stimulated [U-14C]glucose incorporation into glycogen by 150-160% in a dose-dependent manner in the nanomolar range. Mediators injected iv in the nanomolar range into low dose streptozotocin-diabetic rats decreased plasma glucose 30-45% in 30-60 min, with a return to basal concentrations after 150-180 min. These in vivo insulin-like effects of mediator were observed without changes in serum insulin concentrations. The pH 2.0 mediator was 50-100 times more active (per nmol organic phosphate) than the pH 1.3 mediator in the ip diaphragm glycogenesis assay. Mediator effects on diaphragm were completely blocked by preincubation with an immunopurified inositol phosphoglycan antibody. Both mediators were equally active iv in lowering plasma glucose (per nmol inositol) at concentrations comparable to those of insulin.
Myo-inositol is involved in several aspects of human reproduction. Elevated concentrations of myo-inositol in human follicular fluids appear to play a positive function in follicular maturity and provide a marker of good quality oocytes. Nevertheless its positive role in PCOS women is a consequence of a defect in the insulin signaling pathway (inositol-containing phosphoglycan mediators) that seems to be primarily implicated in the pathogenesis of insulin resistance. This article will review the involvement of inositol in female reproduction. After describing the biologic function of inositol and its derivatives, studies are quoted in which the role of inositol in fertility, oogenesis, and polycystic ovary syndrome are examined.
Germinal vesicle (GV)-intact fully grown mouse oocytes do not undergo cortical granule (CG) exocytosis in response to A23187 treatment, whereas metaphase II (MII)-arrested eggs do. This differential response may reflect the development of the ability of the egg to undergo CG exocytosis, which is responsible for the biochemical modification of the glycoprotein ZP2 in the zona pellucida. Accordingly, we compared in these two stages the ability of 12-O-tetradecanoyl phorbol 13-acetate (TPA) or inositol 1,4,5-trisphosphate (IP3) to promote CG exocytosis and/or the ZP2 to ZP2f conversion; these agents are known to stimulate early events of mouse egg activation. TPA (10 ng/ml) treatment for 60 and 120 min resulted in a 25% and 52% CG loss in GV-intact oocytes and a 38% and 76% loss in MII eggs, respectively; fertilization resulted in a CG loss of approximately 70-80%. Although a similar extent of ZP2 to ZP2f conversion was observed in oocytes and eggs after a 120-min TPA treatment (approximately 70-80%), a greater extent of conversion was observed in oocytes after a 60-min treatment (80% for oocytes, 50% for eggs). Microinjection of IP3 (final concentration 1 microM) into MII eggs resulted in an extent of ZP2 conversion similar to that observed following fertilization, whereas little conversion occurred in GV-intact oocytes similarly injected. These results indicate that a protein kinase C sensitivity develops prior to meiotic maturation, whereas responsiveness to IP3 develops after maturation has resumed. We propose that the regulatory mechanism involving an IP3-mediated calcium release is deficient in GV-stage oocytes.
We studied the presence and distribution of the intracellular calcium channel regulating type I inositol 1,4,5-trisphosphate receptors (IP3R) in human immature and mature oocytes, pronuclear zygotes and cleaved embryos using a specific antibody. Two approaches were used: (i) fluorescence immunocytochemistry using a confocal laser scanning microscope (CLSM) and (ii) Western blotting. With confocal microscopy, the receptors were found in the oocytes, fertilized zygotes as well as cleaved embryos at all stages studied. The pattern and distribution of the receptor staining in the oocytes changed gradually from a diffuse granular patchy one at the germinal vesicle (GV) stage to a reticular and predominantly peripheral one through the metaphase and metaphase II (MII) stages. After fertilization, the distribution changed gradually to both, peripheral and central in the zygotes and early 2-4-cell embryos and predominantly perinuclear in the 6-8-cell embryos. Furthermore, an overall increase in the staining intensity was observed from GV to MII stage oocytes and from zygotes to 6-8-cell embryos. We also studied the spatial distribution of the receptor in detail by constructing three-dimensional images from the serial optical sections obtained on the CLSM. Peculiar peripheral aggregates of receptor clusters were noted in the MII stage oocytes, zygotes and some blastomeres from early cleaved embryos. Finally, Western blots performed on the extracts of 72 in-vitro matured oocytes and 50 spare cleavage stage embryos showed positive bands at similar to 260 kDa. These findings coincide with and thus possibly represent the dynamic changes occurring in the cellular Ca2+ release systems through oocyte maturation, fertilization and early embryogenesis. Thus, type I IP3R are likely to play a role during these stages of early development in the human.
The polycystic ovary syndrome is a prevalent disorder characterized by chronic anovulation and hyperandrogenism. It has recently been appreciated that insulin resistance with a compensatory hyperinsulinemia is also a prominent feature of the disorder and plays a key role in its development in many affected women. The purpose of this review is to highlight clinical studies in this area that were published during the past year. Areas discussed include the use of insulin-sensitizing drugs for treatment, D-chiro-inositol and insulin resistance, syndrome X (ie, the dysmetabolic syndrome), genetics of polycystic ovary syndrome, precocious puberty and adrenarche as early manifestations of polycystic ovary syndrome, and early pregnancy loss in polycystic ovary syndrome.
Purpose:
The present study aims to investigate the effects of the combined therapy myo-inositol (MI) plus D-chiro-inositol (DCI) or D-chiro-inositol treatment in oocyte quality.
Methods:
Polycystic ovary syndrome (PCOS) women undergoing IVF-ET were treated with myo-inositol combined with D-chiro-inositol in the physiological ratio (1.1 g myo-inositol plus 27.6 mg of D-chiro-inositol; INOFOLIC combi Lo.Li.pharma) or D-chiro-inositol alone (500 mg; Interquim, s.a., Barcelona, Spain) to evaluate the umber of morphological mature oocytes, total International Units (IU) of recombinant FSH administered and the number of grade 1 embryos.
Results:
The data clearly showed that only the combined therapy was able to improve oocyte and embryo quality, as well as pregnancy rates, in PCOS women undergoing IVF-ET.
Conclusion:
The present paper further supports the hypothesis that MI plays a crucial role in the ovary in PCOS women. In particular, due to the physiological role played by MI and DCI, the combined therapy should represent a better choice.
The discovery of the second-messenger functions of inositol 1,4,5-trisphosphate and diacylglycerol, the products of hormone-stimulated inositol phospholipid hydrolysis, marked a turning point in studies of hormone function. This review focusses on the myo-inositol moiety which is involved in an increasingly complex network of metabolic interconversions. myo-Inositol metabolites identified in eukaryotic cells include at least six glycerophospholipid isomers and some 25 distinct inositol phosphates which differ in the number and distribution of phosphate groups around the inositol ring. This apparent complexity can be simplified by assigning groups of myo-inositol metabolites to distinct functional compartments. For example, the phosphatidylinositol 4-kinase pathway functions to generate inositol phospholipids that are substrates for hormone-sensitive forms of inositol-phospholipid phospholipase C, whilst the newly discovered phosphatidylinositol 3-kinase pathway generates lipids that are resistant to such enzymes and may function directly as novel mitogenic signals. Inositol phosphate metabolism functions to terminate the second-messenger activity of inositol 1,4,5-trisphosphate, to recycle the latter's myo-inositol moiety and, perhaps, to generate additional signal molecules such as inositol 1,3,4,5-tetrakisphosphate, inositol pentakisphosphate and inositol hexakisphosphate. In addition to providing a more complete picture of the pathways of myo-inositol metabolism, recent studies have made rapid progress in understanding the molecular basis underlying hormonal stimulation of inositol-phospholipid-specific phospholipase C and inositol 1,4,5-trisphosphate-mediated Ca2+ mobilisation.
There is no clear acceptance of specific follicular fluid biomarker and its correlation with oocyte quality or related embryo variable till now. Most of the studies analyze correlation between certain biomolecules and the oocyte quality using single variable, instead of multivariate analysis algorithms. Our hypothesis is not based on single biomarker discovery, but attempts to explain oocyte quality in terms of energy metabolic pathways by considering its various intermediates. Reduced availability of glucose in the oocytes and follicular cells caused by defective transportation of glucose is expected in polycystic ovary syndrome (PCOS). This initiates alternative pathways to utilize fatty acid, amino acids etc. for energy as a compensatory mechanism to deal with the energy requirement. These compensations can be reflected by altered levels of various biomolecules in follicular fluid (e.g. ketone bodies, lipids, amino acids, lactate, pyruvate etc.). The amount of compensation, in order to meet the energy requirement can be directly correlated to quality of oocytes and better outcome after in vitro fertilization (IVF) in PCOS cases. This can be predicted with fair accuracy by doing a multivariate analysis of altered levels of various biomolecules in follicular fluid. Various supervised and unsupervised classification techniques based on spectroscopic data, obtained from follicular fluid samples may certainly prove to be an important tool to predict oocytes quality and IVF outcome with better accuracy in women with PCOS.
In an attempt to evaluate the role of inositol supplementation in insulin-resistant patients with polycystic ovary syndrome (PCOS), undergoing gonadotropin ovulation induction using the low-dose step-down regimen, we conducted a prospective longitudinal study comparing the stimulation characteristics of 15 patients treated with inositol, to a cohort, matched by age and body mass index (BMI), without inositol. Inositol nutritional supplementation produced very good clinical results with a significant reduction in cancellation rate (0 vs. 40%) and the consequent improvement in clinical pregnancy rate (PR) (33.3% vs. 13.3%).
The aim of this study was to evaluate whether myo-inositol, an insulin-sensitizing substance, may improve some features of metabolic syndrome in postmenopausal women.
Eighty postmenopausal women affected by the metabolic syndrome were enrolled prospectively in the study and treated with diet plus supplementation of myo-inositol (2 g BID plus diet: intervention group) or with diet plus placebo (control group) for 6 months. They were evaluated at baseline and after 6 months for insulin resistance (homeostasis model assessment ratio [HOMA] insulin resistance), lipid profile, and blood pressure.
Myo-inositol plus diet improved systolic and diastolic blood pressure, HOMA index, cholesterol, and triglyceride serum levels with highly significant differences, compared with the groups treated only with diet and placebo. In the group treated with myo-inositol, a decrease in diastolic blood pressure (-11%), HOMA index (-75%), and serum triglycerides (-20%) and an improvement in high-density lipoprotein cholesterol (22%) were shown.
Supplementation with myo-inositol may be considered a reliable option in the treatment of metabolic syndrome in postmenopausal women.