Gonadotropins as pharmacological agents in assisted reproductive technology and polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complex endocrinopathy associated with subfertility/infertility and pregnancy complications. Most PCOS women opt for assisted reproductive technologies (ART) for successful conception; however, optimization of the relative doses of the gonadotropins [follicle-stimulating hormone (FSH), luteinizing hormone (LH)/human chorionic gonadotropin (hCG)] for appropriate steroidogenesis, without causing ovarian hyperstimulatory syndrome (OHSS), is challenging. Embryonic factors probably do not contribute to pregnancy loss in PCOS women, albeit hormonal imbalance impairs the metabolic microenvironment critical for oocyte maturation and endometrial receptivity. Certain clinical studies have confirmed the role of metabolic corrections in increasing the rate of pregnancy in PCOS women. This review focuses on the impact of untimely high LHCGR and/or LH levels on oocyte/embryo quality, pregnancy outcomes in ART, and exploring LHCGR as a potential drug target in PCOS women.

Is #SDG13 Trending Online? Insights from Climate Change Discussions on Twitter.

Anthropogenic activities over the past few decades have led to increased vulnerability of environmental and ecological stability on this planet. Accelerated climate change is one such subset of the environmental problems that threatens the very existence of humankind in twenty first century. Governments, United Nations (UN) and other humanitarian agencies across the globe have developed and devised strategies for climate action that requires grater public awareness and actions. Social media has played a vital role in information dissemination and raising public awareness of climate change in the digital era. To this aid, an upsurge has been documented in recent times regarding discussions over climate change with #SDG13 (Sustainable Development Goals) at its epicenter. Following the principles of Actor Network Theory (ANT) we analyzed a large volume of Twitter data to understand general citizens' perception and attitude towards climate change. Our findings unveil people's opinion on causes and concerns related to barriers of adopting a more sustainable consumption and lifestyle practice. There is also a growing apathy towards sluggish government actions that makes little difference. People were also found to exchange innovative concepts and measures towards mitigating the effects of climate change.

Direct impact of gonadotropins on glucose uptake and storage in preovulatory granulosa cells: Implications in the pathogenesis of polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is often associated with higher levels of LH, and arrested ovarian follicular growth. The direct impact of high LH on FSH mediated metabolic responses in PCOS patients is not clearly understood. METHOD: In order to investigate the impact of FSH and LH on glucose metabolism in preovulatory granulosa cells (GCs), we used [U14C]-2 deoxyglucose, D-[U14C]-glucose or 2-NBD glucose to analyse glucose uptake and its incorporation into glycogen. To reproduce the high androgenic potential in PCOS patients, we administered hCG both in vitro and in vivo. The role of IRS-2/PI3K/Akt2 pathway was studied after knockdown with specific siRNA. Immunoprecipitation and specific assays were used for the assessment of IRS-2, glycogen synthase and protein phosphatase 1. Furthermore, we examined the in vivo effects of hCG on FSH mediated glycogen increase in normal and PCOS rat model. HEK293 cells co-expressing FSHR and LHR were used to demonstrate glucose uptake and BRET change by FSH and hCG. RESULTS: In normal human and rat granulosa cells, FSH is more potent than hCG in stimulating glucose uptake, however glycogen synthesis was significantly upregulated only by FSH through increase in activity of glycogen synthase via IRS-2/PI3K/Akt2 pathway. On the contrary, an impaired FSH-stimulated glucose uptake and glycogen synthesis in granulosa cells of PCOS-patients indicated a selective defect in FSHR activation. Further, in normal human granulosa cells, and in immature rat model, the impact of hCG on FSH responses was such that it inhibited the FSH-mediated glucose uptake as well as glycogen synthesis through inhibition of FSH-stimulated IRS-2 expression. These findings were further validated in HEK293 cells overexpressing Flag-LHR and HA-FSHR, where high hCG inhibited the FSH-stimulated glucose uptake. Notably, an increased BRET change was observed in HEK293 cells expressing FSHR-Rluc8 and LHR-Venus possibly suggesting increased heteromerization of LHR and FSHR in the presence of both hCG and FSH in comparison to FSH or hCG alone. CONCLUSION: Our findings confirm a selective attenuation of metabolic responses to FSH such as glucose uptake and glycogen synthesis by high activation level of LHR leading to the inhibition of IRS-2 pathway, resulting in depleted glycogen stores and follicular growth arrest in PCOS patients.

The role of Indian gynecologists in oncofertility care and counselling.

Oncofertility is gaining importance because of increasing cancer incidence, high survivorship, the need to provide a good quality of life to survivors and the desire of patients to preserve their fertility. Disseminating information about the effect of cancer and cancer treatment on fertility and the availability and effectiveness of fertility preservation techniques is critical. Gynaecologists in India act as family physicians and are in a unique position to guide cancer patients on issues of fertility and fertility preservation. Their contribution in oncofertility is vital to improve the quality of life of many young survivors. This paper presents the result of a survey done with Indian gynaecologists. The aim of this survey was to ascertain awareness and knowledge of reproductive damage by cancer therapy, knowledge of fertility preservation techniques and an understanding of the barriers to fertility preservation. This information would assist in planning programs to improve oncofertility care and counselling.

Data in support of FSH induction of IRS-2 in human granulosa cells: Mapping the transcription factor binding sites in human IRS-2 promoter.

Insulin receptor substrate-2 (IRS-2) plays critical role in the regulation of various metabolic processes by insulin and IGF-1. The defects in its expression and/or function are linked to diseases like polycystic ovary syndrome (PCOS), insulin resistance and cancer. To predict the transcription factors (TFs) responsible for the regulation of human IRS-2 gene expression, the transcription factor binding sites (TFBS) and the corresponding TFs were investigated by analysis of IRS-2 promoter sequence using MatInspector Genomatix software (Cartharius et al., 2005 [1]). The ibid data is part of author׳s publication (Anjali et al., 2015 [2]) that explains Follicle stimulating hormone (FSH) mediated IRS-2 promoter activation in human granulosa cells and its importance in the pathophysiology of PCOS. Further analysis was carried out for binary interactions of TF regulatory genes in IRS-2 network using Cytoscape software tool and R-code. In this manuscript, we describe the methodology used for the identification of TFBSs in human IRS-2 promoter region and provide details on experimental procedures, analysis method, validation of data and also the raw files. The purpose of this article is to provide the data on all TFBSs in the promoter region of human IRS-2 gene as it has the potential for prediction of the regulation of IRS-2 gene in normal or diseased cells from patients with metabolic disorders and cancer.

FSH stimulates IRS-2 expression in human granulosa cells through cAMP/SP1, an inoperative FSH action in PCOS patients.

Follicle stimulating hormone (FSH) plays a central role in growth and differentiation of ovarian follicles. A plethora of information exists on molecular aspects of FSH responses but little is known about the mechanisms involved in its cross-talk with insulin/IGF-1 pathways implicated in the coordination of energy homeostasis in preovulatory granulosa cells (GCs). In this study, we hypothesized that FSH may regulate IRS-2 expression and thereby maintain the energy balance in GCs. We demonstrate here that FSH specifically increases IRS-2 expression in human and rat GCs. FSH-stimulated IRS-2 expression was inhibited by actinomycin D or cycloheximide. Furthermore, FSH decreases IRS-2 mRNA degradation indicating post-transcriptional stabilization. Herein, we demonstrate a role of cAMP pathway in the activation of IRS-2 expression by FSH. Scan and activity analysis of IRS-2 promoter demonstrated that FSH regulates IRS-2 expression through SP1 binding sites. FSH stimulates SP1 translocation into nucleus and its binding to IRS-2 promoter. These results are corroborated by the fact that siRNA mediated knockdown of IRS-2 decreased the FSH-stimulated PI3K activity, p-Akt levels, GLUT4 translocation and glucose uptake. However, FSH was not able to increase IRS-2 expression in GCs from PCOS women undergoing IVF. Interestingly, IRS-2 mRNA expression was downregulated in GCs from the PCOS rat model. Taken together, our findings establish that FSH induces IRS-2 expression and thereby activates PI3K, Akt and glucose uptake. Crucially, our data confirms a molecular defect in FSH action in PCOS GCs which may cause deceleration of metabolism and follicular growth leading to infertility. These results lend support for a therapeutic potential of IRS-2 in the management of PCOS.

Differential gene expression in granulosa cells from polycystic ovary syndrome patients with and without insulin resistance: identification of susceptibility gene sets through network analysis.

CONTEXT: Polycystic ovary syndrome (PCOS) is a heterogeneous, genetically complex, endocrine disorder of uncertain etiology in women. OBJECTIVE: Our aim was to compare the gene expression profiles in stimulated granulosa cells of PCOS women with and without insulin resistance vs. matched controls. RESEARCH DESIGN AND METHODS: This study included 12 normal ovulatory women (controls), 12 women with PCOS without evidence for insulin resistance (PCOS non-IR), and 16 women with insulin resistance (PCOS-IR) undergoing in vitro fertilization. Granulosa cell gene expression profiling was accomplished using Affymetrix Human Genome-U133 arrays. Differentially expressed genes were classified according to gene ontology using ingenuity pathway analysis tools. Microarray results for selected genes were confirmed by real-time quantitative PCR. RESULTS: A total of 211 genes were differentially expressed in PCOS non-IR and PCOS-IR granulosa cells (fold change≥1.5; P≤0.001) vs. matched controls. Diabetes mellitus and inflammation genes were significantly increased in PCOS-IR patients. Real-time quantitative PCR confirmed higher expression of NCF2 (2.13-fold), TCF7L2 (1.92-fold), and SERPINA1 (5.35-fold). Increased expression of inflammation genes ITGAX (3.68-fold) and TAB2 (1.86-fold) was confirmed in PCOS non-IR. Different cardiometabolic disease genes were differentially expressed in the two groups. Decreased expression of CAV1 (-3.58-fold) in PCOS non-IR and SPARC (-1.88-fold) in PCOS-IR was confirmed. Differential expression of genes involved in TGF-ß signaling (IGF2R, increased; and HAS2, decreased), and oxidative stress (TXNIP, increased) was confirmed in both groups. CONCLUSIONS: Microarray analysis demonstrated differential expression of genes linked to diabetes mellitus, inflammation, cardiovascular diseases, and infertility in the granulosa cells of PCOS women with and without insulin resistance. Because these dysregulated genes are also involved in oxidative stress, lipid metabolism, and insulin signaling, we hypothesize that these genes may be involved in follicular growth arrest and metabolic disorders associated with the different phenotypes of PCOS.