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

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

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

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

Serine/arginine-rich protein 30c activates human papillomavirus type 16 L1 mRNA expression via a bimodal mechanism.

Two splice sites on the human papillomavirus type 16 (HPV-16) genome are used exclusively by the late capsid protein L1 mRNAs: SD3632 and SA5639. These splice sites are suppressed in mitotic cells. This study showed that serine/arginine-rich protein 30c (SRp30c), also named SFRS9, activated both SD3632 and SA5639 and induced production of L1 mRNA. Activation of HPV-16 L1 mRNA splicing by SRp30c required an intact arginine/serine-repeat (RS) domain of SRp30c. In addition to this effect, SRp30c could enhance L1 mRNA production indirectly by inhibiting the early 3'-splice site SA3358, which competed with the late 3'-splice site SA5639. SRp30c bound directly to sequences downstream of SA3358, suggesting that SRp30c inhibited the enhancer at SA3358 and caused a redirection of splicing to the late 3'-splice site SA5639. This inhibitory effect of SRp30c was independent of its RS domain. These results suggest that SRp30c can activate HPV-16 L1 mRNA expression via a bimodal mechanism: directly by stimulating splicing to late splice sites and indirectly by inhibiting competing early splice sites.

Iodine and Myo-Inositol: A Novel Promising Combination for Iodine Deficiency.

Despite universal salt iodization programmes implemented over the last decades, iodine deficiency remains a major public health problem in many countries worldwide. Endeavors are still required to ensure sufficient iodine intake in the populations at risk in order to eliminate deficiency. Iodine is crucial for the synthesis of thyroid hormones triiodothyronine (T3) and thyroxine (T4), as well as for the thyroid health. When iodine levels are insufficient, T4 attests toward the lower limit of the physiological range, causing subtle fluctuations in the T3:T4 ratio. Monitoring these variations may be an accurate way to assess patient's iodine status. Recently, a number of published clinical studies documented a growing interest toward the use of myo-inositol in thyroid diseases. Myo-inositol, a carbocyclic polyol, regulates the generation of hydrogen peroxide (H2O2) in thyrocytes, crucial for iodine organification and thyroid hormone biosynthesis. Thus, combined supplementation of iodine and myo-inositol may promote higher iodine availability in thyrocytes improving thyroid functionality. This review presents novel strategies for the diagnosis and the management of iodine deficiency, focusing on the potential role of myo-inositol combined with iodine.

Myo-inositol effects in women with PCOS: a meta-analysis of randomized controlled trials.

Myo-inositol (MI) supplementation in women with polycystic ovary syndrome (PCOS) has been evaluated over the last years. Many hormonal and reproductive impairments associated with this disorder seem relieved by the supplement. The objective of the meta-analysis was to assess the effects of MI alone or combined with d-chiro-inositol (DCI) on the endocrine and metabolic abnormalities of women with PCOS. Literature was retrieved from selected databases, MEDLINE, EMBASE, PubMed and Research Gate (up to November 2016). Only randomized controlled trials (RCTs) investigating the effects of MI alone or combined with DCI were reviewed. Nine RCTs involving 247 cases and 249 controls were included. Significant decreases in fasting insulin (SMD = -1.021 µU/mL, 95% CI: -1.791 to -0.251, P = 0.009) and homeostasis model assessment (HOMA) index (SMD = -0.585, 95% CI: -1.145 to -0.025, P = 0.041) were identified after MI supplementation. The trial sequential analysis of insulin meta-analysis illustrates that the cumulative z-curve crossed the monitoring boundary, providing firm evidence of the intervention effect. A slight trend toward a reduction of testosterone concentration by MI with respect to controls was found (SMD = -0.49, 95% CI: -1.072 to 0.092, P = 0.099), whereas androstenedione levels remained unaffected. Throughout a subgroup's meta-analysis, a significant increase in serum SHBG was observed only in those studies where MI was administered for at least 24 weeks (SMD = 0.425 nmol/L, 95% CI: 0.050-0.801, P = 0.026). These results highlight the beneficial effect of MI in improving the metabolic profile of women with PCOS, concomitantly reducing their hyperandrogenism.

Development and validation of a novel reporter assay for human papillomavirus type 16 late gene expression.

To facilitate the investigations of HPV-16 late gene expression HPV-16 reporter plasmids were generated using previously described sub-genomic HPV-16 plasmids, named pBEL and pBELM, that, similar to the full viral genome, produce primarily HPV-16 early mRNAs and very little, if any, late mRNAs in cervical cancer cells. The HPV-16 late L1 gene was replaced by the chloramphenicol acetyltransferase (CAT) reporter gene, or green fluorescent protein (GFP), preceded by the poliovirus internal ribosome entry site (IRES). Results show that the reporter genes mimic the expression of L1 from these plasmids. For example, overexpression of adenovirus E4orf4 protein (E4orf4), polypyrimidine tract binding protein (PTB), arginine/serine-rich SRp30c protein (SRp30c) or alternative splicing factor/splicing factor 2 (ASF/SF2) induced an increased expression of CAT or GFP. Stable cell lines with reporter plasmids pBELCAT and pBELMCAT were also generated. An induction of CAT was observed in HPV-16 reporter cell lines in the presence of the small molecule phorbol 12-myristate 13-acetate (TPA). Further experiments identified the TPA-inducible, hnRNP A2/B1 protein as a regulator of HPV-16 late gene expression. In conclusion, the HPV-16 reporter plasmids and reporter cell lines described herein can be used to identify small molecules and cellular factors that regulate HPV-16 gene expression.