Association of Hydroxy (Steroid) Dehydrogenase 11b1 Gene with Type 2 Diabetes Mellitus in Egyptian Population

Background Type 2 diabetes mellitus is a heterogeneous group of metabolic disorders caused by the interaction between genetic predisposition and environmental factors. The incidence of type 2 diabetes mellitus has increased over the last decades with more than 170 million individuals suffering from type 2 diabetes mellitus all over the world which imposes a greater economic impact on individuals, families and health systems. Though the genetic susceptibility to type 2 diabetes mellitus is polygenic, single nucleotide polymorphisms (SNP) at Hydroxy steroid dehydrogenase (HSD11B1) gene have been strongly associated with type 2 diabetes risk in various populations and ethnic groups. Objectives The aim of this study is to assess the association of Hydroxy-Steroid-Dehydrogenase-11B1 gene (rs846910) with type 2 diabetes mellitus in a sample of Egyptian population. Patients and Methods In the present study, we included 60 diabetic obese patients and 40 age and sex-matched controls. The mean age of the included patients was 50.26 ±9.1 year; while the majority of them were females (70%). All the participating patients were subjected to detailed history and the following investigations: fasting blood sugar, post prandial sugar,HbA1c, and lipid profile. Detection of gene polymorphism by real time PCR was performed for all subjects in the study. Results The study showed that homozygous GG genotype was more prelevant than GA genotype. No significant difference between GG and GA in terms of fasting and postprandial sugar and in terms of lipid profile: cholesterol (p = 0.642), TG (p = 0.808), LDL (p = 0.238), and HDL (p = 0.945).It showed no statistically significant difference between cases and controls in terms of HSD11B1 polymorphism (rs846910). The regression analysis showed that the HSD11B1 polymorphism did not significantly increase the risk of diabetes mellitus (OR 1.724, 95% CI [0.601 – 4.94]). Conclusion In conclusion, multiple further studies involving other single nucleotide polymorphism of 11 beta hydroxysteroid dehydrogenase gene as well as other genes involved in type 2 diabetes mellitus and obesity need to be done.

Progesterone Elevation and Preventive Strategies to Avoid Implantation Failure

Despite the wide utilization of gonadotropin-releasing hormone analogs, progesterone elevation (P4E) in the late follicular phase occurs in 5 to 30% of all ovarian stimulation (OS) cycles. Although the detrimental effect of P4E on pregnancy rates in fresh in vitro fertilization cycles is valid in all subsets of cases, higher levels of P4 and a longer duration of P4E may be needed in patients with a hyper-ovarian response in order for a negative impact on pregnancy rates to occur. Available preclinical and clinical data suggest that aggressive OS with high doses of follicle-stimulating hormone might increase 3β-hydroxy steroid dehydrogenase and 17β-hydroxy steroid dehydrogenase enzyme activity in human granulosa cells, which leads to high P4 production and hence a higher amount of leakage to the systemic circulation due to a lack of 17α-hydroxylase enzyme expression in human species. High P4 concentrations appear to alter gene expression in the endometrium; however, caution is necessary regarding its potential effect on oocyte/embryo quality with respect to the role of inherent follicular disruption in some women. In terms of the mechanism of overproduction in P4 synthesis, the main preventive strategy should be avoiding aggressive stimulation. Unfortunately, there is lack of large-scale randomized controlled trials for other approaches, including deferred embryo transfer in the thaw cycle. Since there is a significant inter-assay variability for P4 measurement, it may be wise to recommend that every center should define their own P4E and the level needed for harm to occur based on their own assays and datasets before deciding the best approach.

Antispermatogenic Effect of Piper betel Leaf Stalk Extract with Reference to Kinetic Studies of 17β-hydroxy Steroid Dehydrogenase Enzyme in Testes of Albino Rats

Background: In the development and maintenance of male reproductive function and fertility, steroidogenesis plays a key role. Aims: The aim of the present study was to investigate the effect of the betel leaf stalk extract on 17β- hydroxy steroid dehydrogenase activity levels. Methods: The observed elevation in testicular cholesterol levels may be due to decreased androgen production, which resulted in impaired spermatogenesis. The decreased steroidogenic enzyme 17β- HSD activity represents decreased androgen production by the extract administration. Reduction in enzyme active site density and Km value revealed that there was a reduction in enzyme-substrate affinities and rate of E-S complex breakdown in the administered rat testes. Results & Conclusion: The administration of betel leaf stalk extract resulted in decreased enzyme content probably through impaired synthesis.

Sex Steroid Metabolism in Benign and Malignant Intact Prostate Biopsies: Individual Profiling of Prostate Intracrinology

In vitrostudies reveal that androgens, oestrogens, and their metabolites play a crucial role in prostate homeostasis. Most of the studies evaluated intraprostatic hormone metabolism using cell lines or preprocessed specimens. Using anex vivomodel of intact tissue cultures with preserved architecture, we characterized the enzymatic profile of biopsies from patients with benign prostatic hyperplasia (BPH) or cancer (PC), focusing on 17β-hydroxy-steroid-dehydrogenases (17β-HSDs) and aromatase activities. Samples from 26 men who underwent prostate needle core biopsies (BPHn= 14; PCn= 12) were incubated with radiolabeled3H-testosterone or3H-androstenedione. Conversion was evaluated by TLC separation and beta-scanning of extracted supernatants. We identified three major patterns of conversion. The majority of BPHs revealed no active testosterone/oestradiol conversion as opposed to prostate cancer. Conversion correlated with histology and PSA, but not circulating hormones. Highest Gleason scores had a higher androstenedion-to-testosterone conversion and expression of 17β-HSD-isoenzymes-3/5.Conclusions. We developed an easy tool to profile individual intraprostatic enzymatic activity by characterizing conversion pathways in an intact tissue environment. In fresh biopsies we found that 17β-HSD-isoenzymes and aromatase activities correlate with biological behaviour allowing for morphofunctional phenotyping of pathology specimens and clinical monitoring of novel enzyme-targeting drugs.

Expression of LH receptor in nonpregnant mouse endometrium: LH induction of 3β-HSD and de novo synthesis of progesterone

In mouse uterus, at the late diestrus stage LH binding sites have previously been described. The aim of our study was to confirm the existence of LH receptor (Lhr (Lhcgr)) mRNA and its protein in mouse endometrium. Endometrium at all stages of the estrous cycle contained Lhr mRNA, essentially identical to that found in mouse ovary. Endometrium also contained a 72 kDa immunoreactive receptor protein that bound to mouse anti-LHR antibody in western blot. Both receptor mRNA and protein were maximally expressed in the endometrium at metestrus and LH caused a significant increase in their expression levels. Endometrium also contained 3β-hydroxy steroid dehydrogenase (3β-hsd) mRNA and 3β-HSD protein. LH addition elevated their expression and activity as evident from increased conversion of labeled pregnenolone to progesterone (P4) and de novo P4 synthesis. LH-induced endometrial P4 synthesis is mediated through expression of steroidogenic acute regulatory (Star) gene. Results demonstrated that LH-induced P4 synthesis in endometrium is possibly mediated through the cAMP pathway. Involvement of a MAPK pathway was also evident. Gonadotropin-stimulated endometrial P4 synthesis was markedly attenuated by an antagonist of MEK1/2, PD98059. LH-stimulated MEK1/2-dependent phosphorylation of ERK1/2 in a concentration- and time-dependant manner in cultured endometrial tissues. Moreover, involvement of cAMP in LH-stimulated activation of ERK1/2 was also evident. It is therefore possible that the major signaling pathways regulating endometrial steroidogenesis in mouse, including the adenylate cyclase and MAP kinase pathways, converge at a point distal to activation of protein kinase A and ERK1/2.