Inositols in the ovaries: activities and potential therapeutic applications.

INTRODUCTION: Myo-inositol (MI) and d-chiro-inositol (DCI) play a key role in ovarian physiology, as they are second messengers of insulin and gonadotropins. Ex-vivo and in-vitro experiments demonstrate that both isomers are deeply involved in steroid biosynthesis, and that reduced MI-to-DCI ratios are associated with pathological imbalance of sex hormones. AREAS COVERED: This expert opinion provides an overview of the physiological distribution of MI and DCI in the ovarian tissues, and a thorough insight of their involvement into ovarian steroidogenesis. Insulin resistance and compensatory hyperinsulinemia dramatically reduce the MI-to-DCI ratio in the ovaries, leading to gynecological disorders characterized by hyperandrogenism, altered menstrual cycle and infertility. EXPERT OPINION: Available evidence indicates that MI and DCI have very specific physiological roles and, seemingly, physiological MI-to-DCI ratios in the ovaries are crucial to maintain the correct homeostasis of steroids. Inositol treatments should be evaluated on the patients' specific conditions and needs, as long-term supplementation of high doses of DCI may cause detrimental effects on the ovarian functionality. In addition, the effects of inositol therapy on the different PCOS phenotypes should be further investigated in order to better tailor the supplementation.

Graves' disease: pathophysiological aspects and considerations about using the chemometric analysis in the study of the disease.

Graves' disease is an immune system disorder that results in the overproduction of thyroid hormones (hyperthyroidism). Thyroid disorders are a societal problem of great public concern because of their high prevalence. This problem can affect the well-being and quality of life of patients. The predisposing factors leading to this disease are not yet fully established and are likely to be interconnected in a complex way. Chemometric analysis allows for the detection of specific relationships between the medical parameter measurements obtained from the patients in an observation group, and the identification of patterns of similarity between these patients. It is not commonly used in clinical trials; however, it can provide reliable information which may help in creating more successful, individualised treatment strategies for established groups (patterns) of patients.The aim of this review is to summarize the latest knowledge about the risk factors for Graves' disease and considerations about using the chemometric analysis in the study of the disease.

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.

Serum AGEs and sRAGE levels are not related to vascular complications in patients with prediabetes.

BACKGROUND: While hyperglycemia has a key role in the pathogenesis of microvascular complications of diabetes, it is just one of the many factors contributing to macrovascular damage. The aim of the present study is to investigate the link between serum pentosidine and sRAGE levels and vascular complications in patients with prediabetes compared to normal glucose tolerance controls with obesity. METHODS: In this study were included 76 patients with mean age 50.7 ±â€¯10.7 years, divided into two age and BMI-matched groups - group 1 with obesity without glycemic disturbances (n = 38) and group 2 with obesity and prediabetes (n = 38). RESULTS: There was no significant difference in pentosidine and sRAGE levels between patients with obesity and prediabetes. Patients with hypertension had lower levels of sRAGE compared to nonhypertensive subjects. sRAGE showed a weak negative correlation to blood glucose on 60th min of OGTT and HOMA index. There was no correlation between sRAGE and pentosidine levels and the markers of micro- and macrovascular complications. There was no difference in sRAGE and pentosidine levels between patients with and without endothelial dysfunction. CONCLUSIONS: sRAGE and pentosidine levels are similar in patients with obesity with and without prediabetes and do not correlate to the markers of micro- and macrovascular complications.

Peroxiredoxin 4 levels in patients with PCOS and/or obesity.

BACKGROUND: Peroxiredoxin 4 is a part of endogen antioxidant system and its levels are elevated in increased oxidative stress conditions. It is found to be positively associated with cardiovascular risk. The aim of the study was to investigate peroxiredoxin 4 levels in women with polycystic ovarian syndrome (PCOS) and/or obesity. METHODS: In this cros-sesctional study were included 80 patients. Anthropometric measurements and biochemical tests, including peroxiredoxin 4 measurement, were performed. RESULTS: There was a tendency towards lower peroxiredoxin 4 levels in non-obese PCOS subjects (5674.8 ± 3822.4 pg/ml), higher in obese PCOS (6588.9 ± 3731.0 pg/ml) and even higher in obese patients without PCOS (7724.6 ± 4840.4 pg/ml). Patients with abdominal obesity according to waist circumference and waist-to-hip ratio had significantly higher levels of peroxiredoxin compared to those without (7108.2 ± 4568.0 vs. 5079.8 ± 2555.4 pg/ml; p = 0.015 and 7310.6 ± 2646.2 vs. 4785.0 ± 2646.2 pg/ml; p = 0.013). There was no difference in peroxiredoxin 4 levels in patients with and without insulin resistance, hypertension, dislipidemia, hyperandrogenemia, metabolic syndrome. Peroxiredoxin 4 showed weak positive correlation to weight (r = 0.228; p = 0.044) and visceral adiposity index (r = 0.278; p = 0.031) and higher to erythrocyte sedimentation rate (r = 0.4; p < 0.01), but not to hormonal parameters and insulin sensitivity indexes. CONCLUSIONS: Non-obese patients with PCOS have a tendency towards lower peroxiredoxin 4 levels compared to obese patients with and without PCOS. Patients with abdominal obesity have significantly higher peroxiredoxin 4 levels than those without. We were not able to prove correlation between peroxiredoxin 4 levels and hormonal and carbohydrate status of the PCOS patients.

Higher levels of thioredoxin interacting protein (TXNIP) in patients with prediabetes compared to obese normoglycemic subjects.

BACKGROUND: Thioredoxin interacting protein (TXNIP) is one of the mediators of oxidative stress induced beta-cell glucotoxisity. TXNIP might play a key role in impaired glucose homeostasis preceding overt T2DM. The aim of the present study was to compare TXNIP levels between patients with prediabetes and obese normoglycemic controls and to evaluate the link between TXNIP and metabolic risk factors. PATIENTS AND METHODS: In the present study we included 79 patients with mean age 50.3 ±â€¯10.6 years, divided into two age and BMI matched groups -control group with obesity without glycemic disturbances (NGT) (n = 40) and prediabetes (n = 39). RESULTS: We found significantly higher levels of TXNIP in patients with prediabetes compared to normoglycemic obese controls (54.2 ± 69.9 vs. 23.9 ± 47.1 pg/ml; p = 0.03). The levels of TXNIP gradually increased from normal glucose tolerance trough IFG/IGT only to IFG + IGT (27,1; 44.0; 49.9 and 95.7 pg/ml respectively; p = 0.025 between NGT and IFG + IGT). TXNIP levels correlated weakly only with fasting blood glucose (r = 0.235; p = 0.04) but not with glucose during OGTT or the markers of insulin resistance. CONCLUSIONS: The levels of TXNIP are higher in patients with prediabetes compared to normoglycemic controls as they increase gradually from NGT trough IFG/IGT only to IFG + IGT.

Myostatin and carbohydrate disturbances.

Purpose/aim of the study: Myostatin is a myokine that has been shown to inhibit muscle growth and to have potentially deleterious effects on metabolism. The aim of the current study was to compare its circulating serum levels in subjects from the whole spectrum of carbohydrate disturbances leading to diabetes. MATERIALS AND METHODS: A total of 159 age-, sex-, and BMI-matched subjects participated in the study - 50 had normal glucose tolerance (NGT), 60 had prediabetes (PreDM), and 49 had type 2 diabetes mellitus (T2D). Oral glucose tolerance testing was used to determine glucose tolerance. Serum myostatin was quantified by means of ELISA. RESULTS: Circulating serum myostatin levels were highest in patients with T2D, lower in subjects with prediabetes, and lowest in subjects with normoglycemia (all p < 0.05). Myostatin was shown to be positively associated with fasting plasma glucose, HOMA-IR, hepatic enzymes, uric acid, and FINDRISC questionnaire scores in both sexes. ROC analyses determined circulating myostatin levels to be of value for differentiating subjects with T2D (AUC = 0.72, p = 0.002 in men; AUC = 0.70, p = 0.004 in women) in the study population. After adjustment for potential confounders, in a multiple binary logistic regression model, serum myostatin added further information to traditional risk estimates in distinguishing subjects with T2D. CONCLUSIONS: Serum myostatin levels are higher with deterioration of carbohydrate tolerance. Furthermore, circulating myostatin is positively associated with traditional biochemical estimates of poor metabolic health. These data add to evidence of the involvement of this myokine in the pathogenesis of T2D.

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.

Results from the International Consensus Conference on Myo-inositol and d-chiro-inositol in Obstetrics and Gynecology: the link between metabolic syndrome and PCOS.

In recent years, interest has been focused to the study of the two major inositol stereoisomers: myo-inositol (MI) and d-chiro-inositol (DCI), because of their involvement, as second messengers of insulin, in several insulin-dependent processes, such as metabolic syndrome and polycystic ovary syndrome. Although these molecules have different functions, very often their roles have been confused, while the meaning of several observations still needs to be interpreted under a more rigorous physiological framework. With the aim of clarifying this issue, the 2013 International Consensus Conference on MI and DCI in Obstetrics and Gynecology identified opinion leaders in all fields related to this area of research. They examined seminal experimental papers and randomized clinical trials reporting the role and the use of inositol(s) in clinical practice. The main topics were the relation between inositol(s) and metabolic syndrome, polycystic ovary syndrome (with a focus on both metabolic and reproductive aspects), congenital anomalies, gestational diabetes. Clinical trials demonstrated that inositol(s) supplementation could fruitfully affect different pathophysiological aspects of disorders pertaining Obstetrics and Gynecology. The treatment of PCOS women as well as the prevention of GDM seem those clinical conditions which take more advantages from MI supplementation, when used at a dose of 2g twice/day. The clinical experience with MI is largely superior to the one with DCI. However, the existence of tissue-specific ratios, namely in the ovary, has prompted researchers to recently develop a treatment based on both molecules in the proportion of 40 (MI) to 1 (DCI).

Results from the International Consensus Conference on myo-inositol and D-chiro-inositol in Obstetrics and Gynecology--assisted reproduction technology.

A substantial body of research on mammalian gametogenesis and human reproduction has recently investigated the effect of myo-inositol (MyoIns) on oocyte and sperm cell quality, due to its possible application to medically assisted reproduction. With a growing number of both clinical and basic research papers, the meaning of several observations now needs to be interpreted under a solid and rigorous physiological framework. The 2013 Florence International Consensus Conference on Myo- and D-chiro-inositol in obstetrics and gynecology has answered a number of research questions concerning the use of the two stereoisomers in assisted reproductive technologies. Available clinical trials and studies on the physiological and pharmacological effects of these molecules have been surveyed. Specifically, the physiological involvement of MyoIns in oocyte maturation and sperm cell functions has been discussed, providing an answer to the following questions: (1) Are inositols physiologically involved in oocyte maturation? (2) Are inositols involved in the physiology of spermatozoa function? (3) Is treatment with inositols helpful within assisted reproduction technology cycles? (4) Are there any differences in clinical efficacy between MyoIns and D-chiro-inositol? The conclusions of this Conference, drawn depending on expert panel opinions and shared with all the participants, are summarized in this review paper.

Diabetic somatic neuropathy.

Diabetic neuropathy (DN) is the most common, most neglected and difficult to treat diabetic complication. It affects the whole body, and presents with diverse clinical pictures. The most important outcome of somatic and autonomic DN are the development of diabetic foot followed by diabetic ulceration and possible amputation. In this chapter the definition, epidemiology, pathophysiology and classification of somatic DN will be discussed. Attention will be given to various practical aspects of somatic DN of different types with their specific clinical presentation, diagnostic approaches and treatment options, including the usually rarely discussed gender differences. DN remains a problem in diabetology, compared to other micro- and macrovascular complications. The disease is rarely investigated, although simple testing devices for somatic nerve impairment exist, and remains difficult to treat because ofthe complex pathogenetic mechanisms. The main prevention/progression delaying measure for the progression of DN is the tight glycaemic control. Painful DN is common and need appropriate symptomatic relieving drugs. Future investigations must be targeted on new treatment options.

Diabetic autonomic neuropathy.

Diabetic autonomic neuropathy (DAN) affects each tissue, organ, system and the whole body, and presents with a diverse clinical picture. Originating from endocrine factors, this neurological disease may cause symptoms, whose differential diagnosis needs a good knowledge of the whole internal medicine. DAN is strongly involved in the development of diabetic foot, ulceration and amputation. The life threatening consequences of cardiac and patient-frustrating sequels of other types of DAN is more difficult to estimate. In this chapter the different clinical aspects of DAN will be discussed, according to the involved system--cardiovascular, gastrointestinal, genitourinary, sudomotor and pupillary dysfunctions and the unawareness and unresponsiveness to hypoglycaemia. The diagnostic tests for DAN are more complicated and time consuming, compared with the somatic tools. There is a need for simple devices and methods for evaluation of autonomic functions in the everyday clinical practice. Tight glycaemic control is the cornerstone of the prevention, progression and retardation of DAN. An effective broad-spectrum pathogenetic treatment of neural deterioration remains to be established. In most cases symptomatic drugs are the treatment of choice.

25(OH) vitamin D levels in premenopausal women with polycystic ovary syndrome and/or obesity.

BACKGROUND: Insulin resistance, hyperinsulinemia, and obesity play an important role in development of polycystic ovary syndrome (PCOS). Current evidence suggests that vitamin D (VitD) deficiency may contribute to the disturbance in insulin metabolism and the development of the metabolic syndrome. The aim of this study was to investigate VitD levels, measured as 25(OH)D, in Bulgarian women with PCOS and/or obesity. MATERIALS AND METHODS: The study included 103 women, divided into three groups - group 1 Obese (n = 33); group 2 Nonobese PCOS (n = 50), and group 3 Obese PCOS (n = 20). 25(OH)D levels were measured by electrochemiluminescence immunoassay. RESULTS: Almost 2/3 of the women with PCOS and/or obesity appeared to be VitD-deficient. Women with obesity, especially visceral (with or without PCOS), had significantly lower levels of 25(OH)D compared to lean PCOS subjects. Women with and without metabolic syndrome however did not differ significantly in 25(OH)D levels. Women with normal body mass index (BMI) had higher 25(OH)D levels compared to overweight and obese (p = 0.028). There was no correlation between 25(OH)D levels and indices of glucose metabolism - fasting blood glucose and immunoreactive insulin (IRI) and after OGTT and HOMA index.

Effect of short-term standard therapeutic regimens on neuropeptide Y and adipose tissue hormones in overweight insulin-resistant women with polycystic ovary syndrome.

AIM: The study was aimed at elucidating the influence of a 3-month treatment with routine therapeutic regimens--oral hormonal contraceptives (OHC) with antiandrogenic activity (a standard combination of ethynil estradiol 35 microg plus cyproterone acetate 2 mg) in combination with insulin sensitizing agents--metformin (Group I) and rosiglitazone (Group II) on adipose tissue hormones and hypothalamic neuropeptide Y (NPY) in women with polycystic ovary syndrome. PATIENTS AND METHODS: The study included 66 overweight insulin resistant women with PCOS according to the recent ESHRE-ASRM criteria randomized into 2 age-matched therapeutic groups. RESULTS: Significant decrease of leptin (P < 0.01; P = 0.001, resp.), resistin (P < 0.01; P < 0.01, resp.), tumour necrosis factor alpha (TNF alpha) (P = 0.001; P < 0.001, resp.), and NPY (P < 0.05; P < 0.001, resp.) was observed in both groups after treatment. These findings were in parallel with a significant decrease in the anthropometric parameters of body weight in the metformin group only. No significant changes in hormonal characteristics of the groups were found except for a significant decrease in androstenedione and DHEA-S (P < 0.05) in the metformin group and in 17-OH-progesterone (P < 0.05) in the rosiglitazone group. HDL-cholesterol rose and diastolic blood pressure fell significantly (P < 0.05) in the metformin group. CONCLUSION: Our data suggest beneficial effects of the treatment on potential cardiovascular risk in insulin resistant PCOS women.

Ultrasound-guided fine-needle aspiration biopsy in unselected consecutive patients with thyroid nodules.

The objective was to analyze the results of UG-FNAB, performed in unselected consecutive patients with thyroid nodules. Methods. The UG-FNAB records were analyzed in this retrospective study. Indication for biopsy was the presence of at least one nodule detected by ultrasound. Results. 330 patients at mean age ± SD 48.4 ± 11.2 years; women/men = 12.8/1 were analyzed. From the total 596 nodules found 546 (91.6%) were investigated with 1231 punctures (2.3 per nodule and 3.7 per patient). Benign solitary nodules had 42.7%, multinodular goiter (MNG) 44.8%, inconclusive 4.8%, and others 2.1% and malignant nodules 5.5% of the patients (6.6% of solitary and 5.1% of MNG patients). The risk for a separate nodule in MNG to be malignant was 2.7%. Conclusions. UG-FNAB is a safe and reliable diagnostic approach for thyroid nodules. It is the method of choice for hypo- and isoechoic not purely cystic solitary nodules, regardless of the nodule size. In MNG, its positive predictive value and diagnostic accuracy are lower. The final decision for regular US monitoring, UG-FNAB of the dominant nodule, multipuncture UG-FNAB or surgical exploration is one of complex appraisal. We consider UG-FNAB appropriate for most nodules in MNG, according to the above mentioned criteria.

Effect of tibolone on sexual function in late postmenopausal women.

BACKGROUND: Sexual dysfunction may significantly affect quality of life and marital relations in the postmenopausal period. The aim of the study was to assess the effect of tibolone on climacteric symptoms and sexuality in late postmenopausal but still symptomatic women. PATIENTS AND METHODS: A six-month prospective study was conducted of two groups of clinically healthy postmenopausal women: a control group (n = 18; mean age 57.8 +/- 4.1 yrs; menopause at 49.7 +/- 2.5; years of amenorrhea 8.1 +/- 4.0 yrs) and a tibolone group (n = 22; mean age 57 +/- 4.5 yrs; menopause at 47.7 +/- 3.9; years of amenorrhea 9.2 +/- 4.6 yrs), who received 2.5 mg tibolone daily for six months. The Kupperman menopausal index (KI) was calculated for both groups at baseline and at six months. Sexual function was assessed by the Female Sexual Function Index (FSFI) questionnaire at the beginning and at the end of the study. The FSFI comprised five main domains: desire, arousal, lubrication, orgasm and pain. Satisfaction and a total score were also recorded. RESULTS: The results showed that during the observation period KI decreased significantly in the tibolone group (15.7 +/- 9.2 vs 11.3 +/- 6.8, p < 0.001), while in the control group no difference was observed. There was a significant improvement of sexual function in the tibolone group in all domains: desire -- from 2.6 +/- 1.0 to 3.1 +/- 1.0 (p < 0.001); arousal -- from 2.3 +/- 1.8 to 3.4 +/- 1.1 (p < 0.001); lubrication - 2.6 +/- 2.1 and 3.5 +/- 1.4 (p < 0.05). The ability to reach orgasm increased (p < 0.001) and pain and discomfort during and after sexual intercourse significantly decreased (p < 0.01). The overall satisfaction and the total score in the treated group changed favourably in a statistically significant manner, while these parameters did not change in the control group. CONCLUSIONS: Treatment with tibolone had a beneficial effect on the climacteric symptoms and sexual function of late postmenopausal women. Moreover, tibolone seems to have an advantage over conventional hormone replacement therapy (HRT) in improving desire and arousal.