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.

Calcium and Vitamin D Supplementation. Myths and Realities with Regard to Cardiovascular Risk.

Vitamin D and calcium are considered crucial for the treatment of bone diseases. Both vitamin D and calcium contribute to bone homeostasis but also preserve muscle health by reducing the risk of falls and fractures. Low vitamin D concentrations result in secondary hyperparathyroidism and contribute to bone loss, although the development of secondary hyperparathyroidism varies, even in patients with severe vitamin D deficiency. Findings from observational studies have shown controversial results regarding the association between bone mineral density and vitamin D/calcium status, thus sparking a debate regarding optimum concentrations of 25-hydroxyvitamin D and calcium for the best possible skeletal health. Although most of the intervention studies reported a positive effect of supplementation with calcium and vitamin D on bone in patients with osteoporosis, this therapeutic approach has been a matter of debate regarding potential side effects on the cardiovascular (CV) system. Thus, the aim of this review is to consider the current evidence on the physiological role of vitamin D and calcium on bone and muscle health. Moreover, we provide an overview on observational and interventional studies that investigate the effect of vitamin D and calcium supplementation on bone health, also taking into account the possible CV side-effects. We also provide molecular insights on the effect of calcium plus vitamin D on the CV system.

Current evidence on vitamin D deficiency and kidney transplant: What's new?

Kidney transplant is the treatment of choice for end-stage chronic kidney disease. Kidneys generate 1,25-dihydroxyvitamin D (calcitriol) from 25-hydroxyvitamin D (calcidiol) for circulation in the blood to regulate calcium levels. Transplant patients with low calcidiol levels have an increased risk of metabolic and endocrine problems, cardiovascular disease, type 2 diabetes mellitus, poor graft survival, bone disorders, cancer, and mortality rate. The recommended calcidiol level after transplant is at least 30 ng/mL (75 nmol/L), which could require 1000-3000 IU/d vitamin D3 to achieve. Vitamin D3 supplementation studies have found improved endothelial function and acute rejection episodes. However, since kidney function may still be impaired, raising calcidiol levels may not lead to normal calcitriol levels. Thus, supplementation with calcitriol or an analog, alfacalcidiol, is often employed. Some beneficial effects found include possible improved bone health and reduced risk of chronic allograft nephropathy and cancer.

Low vitamin D status and obesity: Role of nutritionist.

Low vitamin D status and obesity have concomitantly reached epidemic levels worldwide. Up to now the direction of the association between low vitamin D status and obesity, the exact mechanisms responsible for this association and the clinical usefulness to increase vitamin D status for reducing adiposity still warrant further evaluation. The aim of the present review was to examine the current evidence linking low vitamin D status and obesity in relation to the role of the nutritionist. On the one side, considering obesity as a causal factor, low sun exposure in obese individuals due to their sedentary lifestyle and less outdoor activity, vitamin D sequestration in adipose tissue, and volumetric dilution of ingested or cutaneously synthesized vitamin D3 in the large fat mass of obese patients, might represent some of the factors playing a major role in the pathogenesis of the low vitamin D status. On the other side, the expression of both vitamin D3 receptors and enzymes responsible for vitamin D3 metabolism in adipocytes depicted a role for the low vitamin D status per se in the development of obesity by modulating adipocyte differentiation and lipid metabolism. Nutritionists need to accurately address the aspects influencing the low vitamin D status in obesity and the vitamin D supplementation in obese individuals.

Shedding new light on female fertility: The role of vitamin D.

In the last decades several studies suggested that vitamin D is involved in the modulation of the reproductive process in women due to the expression of VDR and 1α-hydroxylase in reproductive tissues such as ovary, uterus, placenta, pituitary and hypothalamus. Vitamin D has also a role in the regulation of sex hormone steroidogenesis. Increasing evidence suggests that vitamin D might have a regulatory role in polycystic ovary syndrome (PCOS)-associated symptoms, including ovulatory dysfunction, insulin resistance and hyperandrogenism. Vitamin D deficiency also has been reported to contribute to the pathogenesis of endometriosis due to its immunomodulatory and anti-inflammatory properties. Although most of the studies supported a role of vitamin D in the onset of these diseases, randomized controlled trials to assess the efficacy of vitamin D supplementation have never been performed. In this review we critically discuss the role of vitamin D in female fertility, starting from in vitro and in vivo studies, focusing our attention on the two most frequent causes of female infertility: PCOS and endometriosis.

Vitamin D and chronic diseases: the current state of the art.

The objective was to provide the current state of the art regarding the role of vitamin D in chronic diseases (osteoporosis, cancer, cardiovascular diseases, dementia, autism, type 1 and type 2 diabetes mellitus, male and female fertility). The document was drawn up by panelists that provided their contribution according to their own scientific expertise. Each scientific expert supplied a first draft manuscript on a specific aspect of the document's topic that was subjected to voting by all experts as "yes" (agreement with the content and/or wording) or "no" (disagreement). The adopted rule was that statements supported by ≥75 % of votes would be immediately accepted, while those with <25 % would be rejected outright. Others would be subjected to further discussion and subsequent voting, where ≥67 % support or, in an eventual third round, a majority of ≥50 % would be needed. This document finds that the current evidence support a role for vitamin D in bone health but not in other health conditions. However, subjects with vitamin D deficiency have been found to be at high risk of developing chronic diseases. Therefore, although at the present time there is not sufficient evidence to recommend vitamin D supplementation as treatment of chronic diseases, the treatment of vitamin D deficiency should be desiderable in order to reduce the risk of developing chronic diseases.

Low serum vitamin D-status, air pollution and obesity: A dangerous liaison.

The aim of this review is to provide a general overview of the possible associations among the vitamin D status, air pollution and obesity. Sunlight exposure accounts in humans for more than 90 % of the production of vitamin D. Among emerging factors influencing sunlight-induced synthesis of vitamin D, prospective and observational studies proved that air pollution constitutes an independent risk factor in the pathogenesis of vitamin D hypovitaminosis. In addition, environmental pollutants can affect risk of obesity when inhaled, in combination with unhealthy diet and lifestyle. In turn, obesity is closely associated with a low vitamin D status and many possible mechanisms have been proposed to explain this association. The associations of air pollution with low vitamin D status on the hand and with obesity on the other hand, could provide a rationale for considering obesity as a further link between air pollution and low vitamin D status. In this respect, a vicious cycle could operate among low vitamin D status, air pollution, and obesity, with additive detrimental effects on cardio-metabolic risk in obese individuals. Besides vitamin D supplementation, nutrient combination, used to maximize the protective effects against air pollution, might also contribute to improve the vitamin D status by attenuating the "obesogen" effects of air pollution.

Mechanisms in endocrinology: vitamin D as a potential contributor in endocrine health and disease.

OBJECTIVE: It has been suggested that vitamin D may play a role in the pathogenesis of several endocrine diseases, such as hyperparathyroidism, type 1 diabetes (T1DM), type 2 diabetes (T2DM), autoimmune thyroid diseases, Addison's disease and polycystic ovary syndrome (PCOS). In this review, we debate the role of vitamin D in the pathogenesis of endocrine diseases. METHODS: Narrative overview of the literature synthesizing the current evidence retrieved from searches of computerized databases, hand searches and authoritative texts. RESULTS: Evidence from basic science supports a role for vitamin D in many endocrine conditions. In humans, inverse relationships have been reported not only between blood 25-hydroxyvitamin D and parathyroid hormone concentrations but also with risk of T1DM, T2DM, and PCOS. There is less evidence for an association with Addison's disease or autoimmune thyroid disease. Vitamin D supplementation may have a role for prevention of T2DM, but the available evidence is not consistent. CONCLUSIONS: Although observational studies support a potential role of vitamin D in endocrine disease, high quality evidence from clinical trials does not exist to establish a place for vitamin D supplementation in optimizing endocrine health. Ongoing randomized controlled trials are expected to provide insights into the efficacy and safety of vitamin D in the management of endocrine disease.

Effects of metformin with or without supplementation with folate on homocysteine levels and vascular endothelium of women with polycystic ovary syndrome.

OBJECTIVE: To evaluate whether the administration of metformin exerts any effects on serum homocysteine (Hcy) levels in patients with polycystic ovary syndrome (PCOS) and whether supplementation with folate enhances the positive effects of metformin on the structure and function of the vascular endothelium. RESEARCH DESIGN AND METHODS: A total of 50 patients affected by PCOS, without additional metabolic or cardiovascular diseases, were enrolled in a prospective nonrandomized placebo-controlled double-blind clinical study. They were grouped into two treatment arms that were matched for age and BMI. Patients were treated with a 6-month course of metformin (1,700 mg daily) plus folic acid (400 microg daily; experimental group, n = 25) or placebo (control group, n = 25). Complete hormonal and metabolic patterns, serum Hcy, folate, vitamin B12, endothelin-1 levels, brachial artery diameter at the baseline (BAD-B) and after reactive hyperemia (BAD-RH), flow-mediated dilation, and intima-media thickness in both common carotid arteries were evaluated. RESULTS: After treatment, a significant increase in serum Hcy levels was observed in the control group compared with the baseline values and the experimental group. A beneficial effect was observed in the concentrations of BAD-B, BAD-RH, flow-mediated dilation, intima-media thickness, and serum endothelin-1 in both groups. However, the results were improved more significantly in the experimental group than in the control subjects. CONCLUSIONS: Metformin exerts a slight but significant deleterious effect on serum Hcy levels in patients with PCOS, and supplementation with folate is useful to increase the beneficial effect of metformin on the vascular endothelium.

Low doses of dexamethasone constantly delivered by autologous erythrocytes slow the progression of lung disease in cystic fibrosis patients.

OBJECTIVE: To evaluate the safety and efficacy of the administration of low doses of glucocorticoids in patients with cystic fibrosis (CF) by using autologous erythrocytes loaded with dexamethasone 21-phosphate. STUDY DESIGN: Nine consecutive CF patients (patients nos. 1-9) received autologous erythrocytes loaded with increasing amounts of dexamethasone 21-phosphate to obtain a slow delivery of dexamethasone in circulation. The appearance of possible adverse effects, the reproducibility of the procedure, and the dexamethasone pharmacokinetics were evaluated. Subsequently, patient no. 9 and eight additional patients (patient nos. 10-17) received dexamethasone 21-phosphate-loaded erythrocytes at 1-month intervals to evaluate the efficacy of continuous release in circulation of low doses of dexamethasone. RESULTS: Erythrocytes from CF patients can be processed to be loaded with increasing dexamethasone 21-P concentrations. Once reinfused in respective donors, a slow and prolonged delivery of dexamethasone in the blood stream was measured up to 28 days. Repeated administrations of drug-loaded erythrocytes at 4-week intervals for 15 months showed that very low doses of glucocorticoids provide significant improvement in FEV1 values and significant reduction of infective relapses due to Pseudomonas aeruginosa without adverse effects. CONCLUSIONS: The administration of very low doses of glucocorticoids using autologous erythrocytes is possible, with benefits for patients and without side effects. This method is likely to be extended to other chronic diseases.

Raloxifene administration in women treated with gonadotropin-releasing hormone agonist for uterine leiomyomas: effects on bone metabolism.

This prospective randomized, single-blind, placebo-controlled clinical trial was performed to evaluate the efficacy of raloxifene in preventing the bone loss associated with GnRH agonist (GnRH-a) administration. One hundred premenopausal women with uterine leiomyomas were treated with leuprolide acetate depot at a dosage of 3.75 mg/d for 28 d and then randomized into two groups to receive raloxifene hydrochloride at 60 mg/d (group A) or placebo (1 tablet/d; group B). Bone mineral density (BMD) and serum bone metabolism markers were evaluated at admission and after six treatment cycles. Posttreatment BMD differed significantly from baseline BMD in group B but not in group A. BMD was significantly higher in group A than in group B. In group A, serum osteocalcin and bone alkaline phosphatase levels and urinary deoxypyridinoline and pyrilinks-D excretion were unchanged vs. baseline. Differently, posttreatment concentrations of these bone turnover markers were significantly lower in group B compared with baseline and group A values. In conclusion, raloxifene prevents GnRH-a related bone loss in premenopausal women with uterine leiomyomas.