Inositols: From Established Knowledge to Novel Approaches.

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

Improv to improve medical student communication.

BACKGROUND: Effective patient provider communication skills can be difficult and time-consuming to teach. Deliberate practice of communication skills through improvisational theatre exercises, with structured debriefing, can provide a solution for teaching patient-centred communication skills in time-limited settings. The objective of this study was to determine if improvisational theatre exercises improved the ratings of patient satisfaction and empathetic communication by standardised patients. METHODS: This was a randomised controlled trial looking at the effect of improvisational theatre exercises on ratings of patient satisfaction and empathetic communication. Third-year medical students (n = 188) participated in a formative team-based standardised patient (SP) experience. Prior to the SP experience, teams of students were randomly assigned to receive a 45-minute communication-focused improvisation intervention (immediately before the SP experience) or to a control arm without intervention. All teams then participated in the SP experience; the SPs (blinded to team randomisation assignment) then assessed each team's empathetic communication and completed patient satisfaction questions focused on physician behaviours derived from Press GaneyTM and the Hospital Consumer Assessment of Healthcare Providers and System SurveysTM . Fifty teams of three or four students participated; 20 teams in the intervention arm and 30 teams in the control arm. RESULTS: Student teams in the improvisation intervention group had increased measures of empathetic communication (p = 0.04) compared to the control group. The intervention group had increased patient satisfaction survey ratings of 'ability to listen carefully' (p = 0.001) and of 'physician skills' compared to control groups (p = 0.03). DISCUSSION: Improv exercises with students increased students' empathetic communication and patient satisfaction as assessed by standardised patients.

Inositols in Polycystic Ovary Syndrome: An Overview on the Advances.

This review details the physiologic roles of two insulin sensitizers, myo-inositol (MI) and d-chiro-inositol (DCI). In the human ovary, MI is a second messenger of follicle-stimulating hormone (FSH) and DCI is an aromatase inhibitor. These activities allow a treatment for polycystic ovary syndrome (PCOS) to be defined based on the combined administration of MI and DCI, where the best MI:DCI ratio is 40:1. Moreover, MI enhances the effect of metformin and clomiphene on the fertility of PCOS women seeking pregnancy. As impaired intestinal transport may lead to unsuccessful inositol treatment, we also discuss new data on the use of alpha-lactalbumin to boost inositol absorption. Overall, the physiological activities of MI and DCI dictate the dosages and timing of inositol supplementation in the treatment of PCOS.

Experts' opinion on inositols in treating polycystic ovary syndrome and non-insulin dependent diabetes mellitus: a further help for human reproduction and beyond.

Introduction: This Experts' opinion provides an updated scientific support to gynecologists, obstetricians, endocrinologists, nutritionists, neurologists and general practitioners on the use of Inositols in the therapy of Polycystic Ovary Syndrome (PCOS) and non-insulin dependent (type 2) diabetes mellitus (NIDDM).Areas covered: This paper summarizes the physiology of Myo-Inositol (MI) and D-Chiro-Inositol (DCI), two important molecules present in human organisms, and their therapeutic role, also for treating infertility. Some deep differences between the physiological functions of MI and DCI, as well as their safety and intestinal absorption are discussed. Updates include new evidence on the efficacy exerted in PCOS by the 40:1 MI/DCI ratio, and the innovative approach based on alpha-lactalbumin to overcome the decreased therapeutic efficacy of Inositols in some patients.Expert opinion: The evidence suggests that MI, alone or with DCI in the 40:1 ratio, offers a promising treatment for PCOS and NIDDM. However, additional studies need to evaluate some still unresolved issues, such as the best MI/DCI ratio for treating NIDDM, the potential cost-effectiveness of reduced gonadotropins administration in IVF due to MI treatment, or the benefit of MI supplementation in ovulation induction with clomiphene citrate in PCOS patients.

Insulin sensitizers in adolescents with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common disorder of androgen excess in women of reproductive age. The diagnosis of PCOS can be more challenging in adolescents than in adult women given significant overlap between normal puberty and the signs of PCOS, including acne, menstrual irregularity, and polycystic ovarian morphology. Optimal treatments for adult women with PCOS vary depending on patient risk factors and reproductive goals, but mainly include hormonal contraception and insulin sensitizers. There is continued interest in targeting the intrinsic insulin resistance that contributes to metabolic and hormonal derangements associated with PCOS. The vast majority of published data on insulin sensitizing PCOS treatments are reported in adult women; these have included weight loss, metformin, thiazolidinediones, and the inositols. Furthermore, there is also a small but growing body of evidence in support of the use of insulin sensitizers in adolescents, with or without oral contraceptives. Discussion of the available treatments, including benefits, potential side effects, and incorporation of patient and family preferences is critical in developing a plan of care aimed at achieving patient-important improvements in PCOS signs and symptoms while addressing the longer-term cardiometabolic risks associated with the syndrome.

Corrigendum to "Inositol(s) from Bench to Bedside in Endocrinology and Gynecology".

[This corrects the article DOI: 10.1155/2017/8515703.].

Effects of Inositol(s) in Women with PCOS: A Systematic Review of Randomized Controlled Trials.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder, with complex etiology and pathophysiology, which remains poorly understood. It affects about 5-10% of women of reproductive age who typically suffer from obesity, hyperandrogenism, ovarian dysfunction, and menstrual irregularity. Indeed, PCOS is the most common cause of anovulatory infertility in industrialized nations, and it is associated with insulin resistance, type 2 diabetes mellitus, and increased cardiovascular risk. Although insulin resistance is not included as a criterion for diagnosis, it is a critical pathological condition of PCOS. The purpose of this systematic review is the analysis of recent randomized clinical trials of inositol(s) in PCOS, in particular myo- and D-chiro-inositol, in order to better elucidate their physiological involvement in PCOS and potential therapeutic use, alone and in conjunction with assisted reproductive technologies, in the clinical treatment of women with PCOS.

The role of variants regulating metformin transport and action in women with polycystic ovary syndrome.

AIMS: Variants in genes encoding metformin transport proteins and the ATM gene are associated with metformin response. We hypothesized that these gene variants contribute to variable metformin treatment response in polycystic ovary syndrome. MATERIALS & METHODS: The discovery cohort (n = 38) was studied in an open-label study. Results were replicated in two additional cohorts (n = 26 and n = 131). Response was assessed after 3-6 months of treatment with metformin extended-release 1500-2000 mg/day. RESULTS: The rs683369 variant was associated with less weight loss in the discovery cohort (p = 0.003), but these results were not replicated (p = 0.8). There were no differences in glucose parameters, testosterone levels or ovulatory frequency as a function of genotype. CONCLUSION: Variants in organic ion transporters do not explain the variable metformin response in polycystic ovary syndrome.

Effect on Insulin-Stimulated Release of D-Chiro-Inositol-Containing Inositolphosphoglycan Mediator during Weight Loss in Obese Women with and without Polycystic Ovary Syndrome.

Background. A deficiency of D-chiro-inositol-inositolphosphoglycan mediator (DCI-IPG) may contribute to insulin resistance in polycystic ovary syndrome (PCOS). Whether the relationship between impaired DCI-IPG release and insulin resistance is specific to PCOS rather than obesity is unknown. We assessed insulin-released DCI-IPG and its relationship to insulin sensitivity at baseline and after weight loss in obese women with and without PCOS. Methods. Obese PCOS (n = 16) and normal (n = 15) women underwent 8 weeks of a hypocaloric diet. The Matsuda index, area under the curve DCI-IPG (AUCDCI-IPG), AUCinsulin, and AUCDCI-IPG/AUCinsulin were measured during a 2 hr OGTT at baseline and 8 weeks. Results. PCOS women had lower AUCDCI-IPG/AUCinsulin at baseline and a significant relationship between AUCDCI-IPG/AUCinsulin and Matsuda index (p = 0.0003), which was not present in controls. Weight loss was similar between PCOS (-4.08 kg) and normal women (-4.29 kg, p = 0.6281). Weight loss in PCOS women did not change the relationship between AUCDCI-IPG/AUCinsulin and Matsuda index (p = 0.0100), and this relationship remained absent in control women. Conclusion. The association between AUCDCI-IPG/AUCinsulin and insulin sensitivity was only found in PCOS but not in normal women, and this relationship was unaffected by weight loss. DCI and its messenger may contribute to insulin resistance in PCOS independent of obesity.

Vitamin D Status Relates to Reproductive Outcome in Women With Polycystic Ovary Syndrome: Secondary Analysis of a Multicenter Randomized Controlled Trial.

CONTEXT: Experimental evidence supports a relevance of vitamin D (VitD) for reproduction; however, data in humans are sparse and inconsistent. OBJECTIVE: To assess the relationship of VitD status with ovulation induction (OI) outcomes in women with polycystic ovary syndrome (PCOS). DESIGN: A retrospective cohort. SETTING: Secondary analysis of randomized controlled trial data. PARTICIPANTS: Participants in the Pregnancy in PCOS I (PPCOS I) randomized controlled trial (n = 540) met the National Institutes of Health diagnostic criteria for PCOS. INTERVENTIONS: Serum 25OHD levels were measured in stored sera. MAIN OUTCOME MEASURES: Primary, live birth (LB); secondary, ovulation and pregnancy loss after OI. RESULTS: Likelihood for LB was reduced by 44% for women if the 25OHD level was < 30 ng/mL (<75 nmol/L; odds ratio [OR], 0.58 [0.35-0.92]). Progressive improvement in the odds for LB was noted at thresholds of ≥38 ng/mL (≥95 nmol/L; OR, 1.42 [1.08-1.8]), ≥40 ng/mL (≥100 nmol/L; OR, 1.51 [1.05-2.17]), and ≥45 ng/mL (≥112.5 nmol/L; OR, 4.46 [1.27-15.72]). On adjusted analyses, VitD status was an independent predictor of LB and ovulation after OI. CONCLUSIONS: In women with PCOS, serum 25OHD was an independent predictor of measures of reproductive success after OI. Our data identify reproductive thresholds for serum 25OHD that are higher than recommended for the nonpregnant population.

Pioglitazone Therapy Increases Insulin-Stimulated Release of d-Chiro-Inositol-Containing Inositolphosphoglycan Mediator in Women with Polycystic Ovary Syndrome.

BACKGROUND: Insulin resistance in women with polycystic ovary syndrome (PCOS) may be mediated, in part, by a deficiency in the insulin-stimulated release of a d-chiro-inositol-inositolphosphoglycan (DCI-IPG) mediator of insulin action. Supporting this idea, several studies have reported improved insulin sensitivity in both lean and obese women with PCOS after oral administration of DCI. Pioglitazone improves insulin sensitivity in women with PCOS, but it is unknown whether this may be contributed by enhanced insulin-stimulated release of the DCI-IPG second messenger. The study aimed to determine if pioglitazone increases release of biologically active DCI-IPG per unit insulin released during an oral glucose tolerance test (OGTT). METHODS: A randomized, double-blind placebo-controlled trial was conducted in 32 women with PCOS at a tertiary referral center in Venezuela. The intervention comprised administration of pioglitazone 45 mg daily or matched placebo for 6 months. Outcome measures included area under curves (AUC) of DCI-IPG (AUCDCI-IPG), insulin (AUCinsulin), and the ratio of AUCDCI-IPG to AUCinsulin during a 2-hr OGTT. RESULTS: After treatment with pioglitazone, AUCinsulin during the OGTT decreased and whole body insulin sensitivity, as determined by the Matsuda index, increased significantly only in the pioglitazone group. The ratio of AUCDCI-IPG/AUCinsulin increased in the pioglitazone group by 1.85-fold (P < 0.0001) with no significant change in the placebo group. Change in Matsuda index correlated with change in DCI-IPG released per unit of insulin during OGTT (r = 0.47, P < 0.01). CONCLUSION: In women with PCOS, pioglitazone increased insulin-stimulated release of the DCI-IPG second messenger of insulin action, which may contribute to its insulin-sensitizing effect in these women.

Metabolic Effects of a Commonly Used Combined Hormonal Oral Contraceptive in Women With and Without Polycystic Ovary Syndrome.

BACKGROUND: Data on combined hormonal oral contraceptives' (OCs) effects on metabolic changes in women with polycystic ovary syndrome (PCOS) have been conflicting and were predominantly based on OCs with cyproterone acetate (unavailable in the United States) Most studies did not include normal women as controls. We compared metabolic changes before and after an OC commonly used in the United States between women with and without PCOS. METHODS: Ten PCOS and 20 control women took ethinyl estradiol 35 µg and norgestimate 0.18/0.215/0.25 mg. Fasting glucose and insulin, area-under-the-curve (AUC) glucose and insulin, insulin sensitivity (homeostatic model assessment of insulin sensitivity index [HOMA-ISI] and Matsuda index), insulinogenic index (Δinsulin0-30 minutes/Δglucose0-30 minutes), blood pressure, and lipids were evaluated at baseline and after three cycles of OC. RESULTS: At baseline, PCOS women had lower insulin sensitivity (Matsuda index p = 0.0093, HOMA-ISI p = 0.0397), higher fasting insulin (p = 0.0495), fasting glucose (p = 0.0393), AUC insulin (p = 0.0023), and triglycerides (p = 0.0044) versus controls. Baseline AUC glucose did not differ between PCOS women and controls. After 3 months of OC use, glucose tolerance worsened in PCOS women versus controls (p = 0.0468). Higher baseline androgens were predictive of worsened glucose tolerance, and a reduction of AUC insulin during OC use. The insulinogenic index significantly decreased in PCOS women (p < 0.01), while fasting insulin and insulin resistance significantly worsened in control women. CONCLUSION: Women with PCOS exhibited worsened glucose tolerance (demonstrated by AUC glucose) after 3 months of a commonly used OC compared with control women. Larger studies with longer follow-up should confirm these findings.

Reflections on inositol(s) for PCOS therapy: steps toward success.

In polycystic ovary syndrome (PCOS) pathogenesis, both the insulin resistance and the related compensatory hyperinsulinemia are involved. Despite their similarities, Myo-inositol (MI) and d-chiro-inositol (DCI) play different roles in PCOS etiology and therapy. Indeed, in tissue such as the liver both molecules are involved in the insulin signaling, i.e. MI promotes glucose uptake and DCI glycogen synthesis. In reproductive tissue such as the ovary, MI regulates glucose uptake and follicle stimulating hormone (FSH) signaling, whereas DCI is devoted to the insulin-mediated androgen production. The new hypothesis on "DCI paradox" in the ovary has provided the key for a better understanding. Unlike other tissues, ovary is not insulin resistant, indeed because the epimerase enzyme, which converts MI to DCI, is insulin dependent, the "DCI paradox" hypothesis suggests that in the ovary of PCOS women, an increased epimerase activity leads to a DCI overproduction and MI depletion. This imbalance could be the cause of the poor oocyte quality and the impairment in the FSH signaling. Owing to this situation, the focal point is the administration of both MI and DCI in a proper ratio for treating PCOS. This topic, with several other "hot" issues, was the driving thread in the discussion between the two scientists.

Polycystic ovary syndrome and insulin: our understanding in the past, present and future.

Insulin resistance is prevalent in women with polycystic ovary syndrome (PCOS), and plays a critical pathophysiologic role in both the metabolic and reproductive complications of PCOS. This review focuses on the contribution of insulin resistance to anovulation in PCOS and to the high risk for Type 2 diabetes, metabolic syndrome and early cardiovasular disease. Key points for clinicians emphasized by this review are the following: PCOS is a clinical diagnosis and alternative diagnoses must be excluded; PCOS carries an inherent risk of insulin resistance and, hence, metabolic consequences for which women with PCOS should be screened regardless of BMI or degree of obesity; and PCOS is associated with infertility and this should be discussed early on in care of women diagnosed with PCOS, recognizing that there are several possible strategies to address infertility in women with PCOS, each with its own risks and benefits.

Smoking in infertile women with polycystic ovary syndrome: baseline validation of self-report and effects on phenotype.

STUDY QUESTION: Do women with polycystic ovary syndrome (PCOS) seeking fertility treatment report smoking accurately and does participation in infertility treatment alter smoking? SUMMARY ANSWER: Self-report of smoking in infertile women with PCOS is accurate (based on serum cotinine levels) and smoking is unlikely to change over time with infertility treatment. WHAT IS KNOWN ALREADY: Women with PCOS have high rates of smoking and it is associated with worse insulin resistance and metabolic dysfunction. STUDY DESIGN, SIZE, DURATION: Secondary study of smoking history from a large randomized controlled trial of infertility treatments in women with PCOS (N = 626) including a nested case-control study (N = 148) of serum cotinine levels within this cohort to validate self-report of smoking. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with PCOS, age 18-40, seeking fertility who participated in a multi-center clinical trial testing first-line ovulation induction agents conducted at academic health centers in the USA. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, self-report of smoking in the nested case-control study agreed well with smoking status as determined by measure of serum cotinine levels, at 90% or better for each of the groups at baseline (98% of never smokers had cotinine levels <15 ng/ml compared with 90% of past smokers and 6% of current smokers). There were minor changes in smoking status as determined by serum cotinine levels over time, with the greatest change found in the smoking groups (past or current smokers). In the larger cohort, hirsutism scores at baseline were lower in the never smokers compared with past smokers. Total testosterone levels at baseline were also lower in the never smokers compared with current smokers. At end of study follow-up insulin levels and homeostatic index of insulin resistance increased in the current smokers (P < 0.01 for both) compared with baseline and with non-smokers. The chance for ovulation was not associated with smoking status, but live birth rates were increased (non-significantly) in never or past smokers. LIMITATIONS, REASONS FOR CAUTION: The limitations include the selection bias involved in our nested case-control study, the possibility of misclassifying exposure to second hand smoke as smoking and our failure to capture self-reported changes in smoking status after enrollment in the trial. WIDER IMPLICATIONS OF THE FINDINGS: Because self-report of smoking is accurate, further testing of smoking status is not necessary in women with PCOS. Because smoking status is unlikely to change during infertility treatment, extra attention should be focused on smoking cessation in current or recent smokers who seek or who are receiving infertility treatment. STUDY FUNDING/COMPETING INTERESTS: Sponsored by the Eugene Kennedy Shriver National Institute of Child Health and Human Development of the U.S. National Institutes of Health. CLINICAL TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov numbers, NCT00068861 and NCT00719186.

Activation of the LH receptor up regulates the type 2 adiponectin receptor in human granulosa cells.

PURPOSE: Adiponectin is a predominantly adipocyte-derived hormone which influences insulin sensitivity and energy homeostasis through at least two receptors, AdipoR1 and AdipoR2. In animal models, adiponectin may regulate ovarian steroidogenesis, folliculogenesis, and ovulation. The receptors AdipoR1 and AdipoR2 are present in the human ovary, but their regulation is unknown. In these studies, we determined the effects of LH receptor activation on the expression and function of the two adiponectin receptors in human granulosa cells. METHODS: Granulosa cells were obtained at the time of oocyte retrieval in women undergoing in vitro fertilization (IVF). Cells were isolated and cultured for 48 h in DMEM/F12 medium with 5 % FBS and 50 ug/ml gentamicin. Medium was changed to low serum for 12 h and cells were treated with hCG (100 ng/ml), forskolin (30 µMol/L), or FSH (1 IU/ml) for 24 h for mRNA experiments. mRNA was isolated and RT PCR was performed using Taqman assays and quantification with the delta delta CT method. For immunocytochemistry, cells were grown on chamber slides and treated with hCG for 1 to 24 h and fixed with acetone. ICC was performed with polyclonal rabbit primary antibodies followed by alexa fluor goat anti-rabbit antibody and imaging with a fluorescence microscope and Zeiss software analysis. 3ß-hydroxysteroid dehydrogenase (3ßHSD) enzyme activity was determined by measuring the progesterone produced when cells were provided with an excess of 22-hydroxy-cholesterol as substrate following an incubation with hCG (1 IU/ml) and/or adiponectin (10 ng/ml). Progesterone content in the media was determined by ELISA. RESULTS: Messenger RNA for the two Adiponectin receptors is differentially regulated by activation of LHR with hCG treatment. AdipoR2 was increased nearly 4-fold (p < 0.05), whereas AdipoR1 expression was not changed by hCG treatment. Treatment with either FSH or forskolin (an activator of cAMP) had similar effects. Basal AdipoR2 protein was fairly low in granulosa cells in culture however treatment of cells with hCG resulted in a discernible increase in immunodetectable cytoplasmic protein as early as 6 h after treatment and was maintained for at least 24 h. The number of cells positive for AdipoR2 at 6 h increased from a basal of 20 % to almost 60 % (p < 0.05). Adiponectin treatment of hCG-primed cells resulted in increased 3ßHSD activity by approximately 60 % over hCG alone and more than 3-fold over basal levels. CONCLUSIONS: AdipoR2 is regulated by the LH receptor function via a cAMP dependant mechanism. Increased expression of adipoR2 prior to and following ovulation may contribute to enhanced 3ßHSD activity and increased progesterone secretion by the corpus luteum of the ovary. Dysregulation of adiponectin that may occur with PCOS may impair normal progesterone production.

Cardiometabolic aspects of the polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder amongst women of reproductive age and is associated with various metabolic perturbations, in addition to chronic anovulation and factors related to androgen excess. In general, women live longer than men and develop cardiovascular disease at an older age. However, women with PCOS, as compared with age- and body mass index-matched women without the syndrome, appear to have a higher risk of insulin resistance, hyperinsulinemia, glucose intolerance, dyslipidemia, and an increased prothrombotic state, possibly resulting in a higher rate of type 2 diabetes mellitus, fatty liver disease, subclinical atherosclerosis, vascular dysfunction, and finally cardiovascular disease and mortality. Further alterations in PCOS include an increased prevalence of sleep apnea, as well as various changes in the secretion and/or function of adipokines, adipose tissue-derived proinflammatory factors and gut hormones, all of them with direct or indirect influences on the complex signaling network that regulates metabolism, insulin sensitivity, and energy homeostasis. Reviews on the cardiometabolic aspects of PCOS are rare, and our knowledge from recent studies is expanding rapidly. Therefore, it is the aim of the present review to discuss and to summarize the current knowledge, focusing on the alterations of cardiometabolic factors in women with PCOS. Further insight into this network of factors may facilitate finding therapeutic targets that should ameliorate not only ovarian dysfunction but also the various cardiometabolic alterations related to the syndrome.