Superoxide dismutases: marker in predicting reduced left ventricular ejection fraction in patients with type 2 diabetes and acute coronary syndrome.

AIM: To examine the prognostic value of superoxide dismutase (SOD) activity for monitoring reduced left ventricular ejection fraction(LVEF)in the patients with type 2 diabetes and acute coronary syndrome (ACS). METHODS: The population of this cross-sectional study included 2377 inpatients with type 2 diabetes who had an ACS admitted to the Shandong Provincial Hospital Affiliated to Shandong First Medical University from January 2016 to January 2021. RESULTS: Diabetic patients with ACS were divided into 2 subgroups based on LVEF. The mean SOD activity was significantly lower in patients with an LVEF ≤ 45% than in those with an LVEF > 45% (149.1 (146.4, 151.9) versus 161.9 (160.8, 163.0)). Using ROC statistic, a cut-off value of 148.8 U/ml indicated an LVEF ≤ 45% with a sensitivity of 51.6% and a specificity of 73.7%. SODs activity were found to be correlated with the levels of NT-proBNP, hs-cTnT, the inflammatory marker CRP and fibrinogen. Despite taking the lowest quartile as a reference (OR 0.368, 95% CI 0.493-0.825, P = 0.001) or examining 1 normalized unit increase (OR 0.651, 95% CI 0.482-0.880, P = 0.005), SOD activity was found to be a stronger predictor of reduced LVEF than CRP and fibrinogen, independent of confounding factors. CONCLUSIONS: Our cross-sectional study suggests that SOD activity might be a valuable and easily accessible tool for assessing and monitoring reduced LVEF in the diabetic patients with ACS.

Power Equipment Fault Diagnosis Method Based on Energy Spectrogram and Deep Learning.

With the development of industrial manufacturing intelligence, the role of rotating machinery in industrial production and life is more and more important. Aiming at the problems of the complex and changeable working environment of rolling bearings and limited computing ability, fault feature information cannot be effectively extracted, and the current deep learning model is difficult to be compatible with lightweight and high efficiency. Therefore, this paper proposes a fault detection method for power equipment based on an energy spectrum diagram and deep learning. Firstly, a novel two-dimensional time-frequency feature representation method and energy spectrum feature map based on wavelet packet transform is proposed, and an energy spectrum feature map dataset is made for subsequent diagnosis. This method can realize multi-resolution analysis, fully extract the feature information contained in the fault signal, and accelerate the convergence of the subsequent diagnosis model. Secondly, a lightweight residual dense convolutional neural network model (LR-DenseNet) is proposed. This model combines the advantages of residual learning and a dense connection, and can not only extract deep features more easily, but can also effectively use shallow features. Then, based on the lightweight residual dense convolutional neural network model, an LR-DenseSENet model is proposed. By introducing the transfer learning strategy and adding the channel domain, an attention mechanism is added to the channel feature fusion layer, with the accuracy of detection up to 99.4%, and the amount of parameter calculation greatly reduced to one-fifth of that of VGG. Finally, through an experimental analysis, it is verified that the fault detection model designed in this paper based on the combination of an energy spectrum feature map and LR-DenseSENet achieves a satisfactory detection effect.

Efficacy and safety of PEGylated exenatide injection (PB-119) in treatment-naive type 2 diabetes mellitus patients: a Phase II randomised, double-blind, parallel, placebo-controlled study.

AIMS/HYPOTHESIS: Glucagon-like peptide 1 receptor agonists (GLP-1 RA) such as exenatide are used as monotherapy and add-on therapy for maintaining glycaemic control in patients with type 2 diabetes mellitus. The current study investigated the safety and efficacy of once-weekly PB-119, a PEGylated exenatide injection, in treatment-naive patients with type 2 diabetes. METHODS: In this Phase II, randomised, placebo-controlled, double-blind study, we randomly assigned treatment-naive Chinese patients with type 2 diabetes in a 1:1:1:1 ratio to receive subcutaneous placebo or one of three subcutaneous doses of PB-119 (75, 150, and 200 µg) for 12 weeks. The primary endpoint was the change in HbA1c from baseline to week 12, and other endpoints were fasting plasma glucose, 2 h postprandial glucose (PPG), and proportion of patients with HbA1c < 53 mmol/mol (<7.0%) and ≤48 mmol/mol (≤6.5%) at 2, 4, 8 and 12 weeks of treatment. Safety was assessed in all patients who received at least one dose of study drug. RESULTS: We randomly assigned 251 patients to one of the four treatment groups (n = 62 in placebo and 63 each in PB-119 75 µg, 150 µg and 200 µg groups). At the end of 12 weeks, mean differences in HbA1c in the treatment groups were -7.76 mmol/mol (95% CI -9.23, -4.63, p < 0.001) (-0.72%, 95% CI -1.01, -0.43), -12.89 mmol/mol (95% CI -16.05, -9.72, p < 0.001) (-1.18%, 95% CI -1.47, -0.89) and -11.14 mmol/mol (95% CI -14.19, -7.97, p <0 .001) (-1.02%, 95% CI -1.30, -0.73) in the 75 µg, 150 µg and 200 µg PB-119 groups, respectively, compared with that in the placebo group after adjusting for baseline HbA1c. Similar results were also observed for other efficacy endpoints across different time points. There was no incidence of treatment-emergent serious adverse event, severe hypoglycaemia or death. CONCLUSIONS/INTERPRETATION: All tested PB-119 doses had superior efficacy compared with placebo and were safe and well tolerated over 12 weeks in treatment-naive Chinese patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03520972 FUNDING: The study was funded by National Major Scientific and Technological Special Project for Significant New Drugs Development and PegBio.

Genetic and Epigenetic Characteristics of Autosomal Dominant Pseudohypoparathyroidism Type 1B: Case Reports and Literature Review.

Autosomal dominant pseudohypoparathyroidism 1B (AD-PHP1B) is a rare endocrine and imprinted disorder. The objective of this study is to clarify the imprinted regulation of the guanine nucleotide binding-protein α-stimulating activity polypeptide 1 (GNAS) cluster in the occurrence and development of AD-PHP1B based on animal and clinical patient studies. The methylation-specific multiples ligation-dependent probe amplification (MS-MLPA) was conducted to detect the copy number variation in syntaxin-16 (STX16) gene and methylation status of the GNAS differentially methylated regions (DMRs). Long-range PCR was used to confirm deletion at STX16 gene. In the first family, DNA analysis of the proband and proband's mother revealed an isolated loss of methylation (LOM) at exon A/B and a 3.0 kb STX16 deletion. The patient's healthy grandmother had the 3.0 kb STX16 deletion but no epigenetic abnormality. The patient's healthy maternal aunt showed no genetic or epigenetic abnormality. In the second family, the analysis of long-range PCR revealed the 3.0 kb STX16 deletion for the proband but not her children. In this study, 3.0 kb STX16 deletion causes isolated LOM at exon A/B in two families, which is the most common genetic mutation of AD-PHP1B. The deletion involving NESP55 or AS or genomic rearrangements of GNAS can also result in AD-PHP1B, but it's rare. LOM at exon A/B DMR is prerequisite methylation defect of AD-PHP1B. STX16 and NESP55 directly control the imprinting at exon A/B, while AS controls the imprinting at exon A/B by regulating the transcriptional level of NESP55.

NR4A1 counteracts JNK activation incurred by ER stress or ROS in pancreatic ß-cells for protection.

Sustained hyperglycaemia and hyperlipidaemia incur endoplasmic reticulum stress (ER stress) and reactive oxygen species (ROS) overproduction in pancreatic ß-cells. ER stress or ROS causes c-Jun N-terminal kinase (JNK) activation, and the activated JNK triggers apoptosis in different cells. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an inducible multi-stress response factor. The aim of this study was to explore the role of NR4A1 in counteracting JNK activation induced by ER stress or ROS and the related mechanism. qPCR, Western blotting, dual-luciferase reporter and ChIP assays were applied to detect gene expression or regulation by NR4A1. Immunofluorescence was used to detect a specific protein expression in ß-cells. Our data showed that NR4A1 reduced the phosphorylated JNK (p-JNK) in MIN6 cells encountering ER stress or ROS and reduced MKK4 protein in a proteasome-dependent manner. We found that NR4A1 increased the expression of cbl-b (an E3 ligase); knocking down cbl-b expression increased MKK4 and p-JNK levels under ER stress or ROS conditions. We elucidated that NR4A1 enhanced the transactivation of cbl-b promoter by physical association. We further confirmed that cbl-b expression in ß-cells was reduced in NR4A1-knockout mice compared with WT mice. NR4A1 down-regulates JNK activation by ER stress or ROS in ß-cells via enhancing cbl-b expression.

Successful Management of Recurrent Subacute Thyroiditis by Adding Colchicine to Glucocorticoid Treatment: A Case Series Study.

Although subacute thyroiditis (SAT) is thought to be a self-limited inflammatory thyroid disease, the recurrence rate of SAT is approximately 10-20%. It is difficult for these patients to stop glucocorticoid treatment, and they are usually bothered with recurrent pain and the side effects of glucocorticoids for more than several months. We describe three cases who were diagnosed with recurrent subacute thyroiditis after a reduction in prednisolone (PSL) dose, either immediately upon the cessation of PSL or shortly thereafter. Their symptoms, including the adverse effects of PSL, severely impacted their quality of life. After a complete assessment, we administered colchicine at 1 mg per day for 1-2 months to control the recurrence of SAT and monitored their routine blood parameters every two weeks. All 3 patients were successfully tapered off of PSL treatment and were free of frequently recurrent SAT. Colchicine may be therapeutic in patients with prednisolone-refractory, recurrent SAT. However, a large-scale, double-blind, controlled, prospective multicenter study is required to provide a solid body of evidence.

HC diet inhibited testosterone synthesis by activating endoplasmic reticulum stress in testicular Leydig cells.

Emerging epidemiological studies indicate that hypercholesterolaemia is a risk factor for testosterone deficiency. However, the underlying mechanism is unclear. Testicular Leydig cells are the primary source of testosterone in males. To identify the effect and mechanism of cholesterol overload on Leydig cell function, rats were fed with a HC (HC) diet to induce hypercholesterolaemia. During the 16-week feeding period, serum testosterone levels were reduced in a time-dependent manner in rats fed the HC diet. Accordingly, these steroidogenic enzymes within the Leydig cells, including steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage cytochrome P450 (P450scc) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD), were down-regulated. Notably, the HC-fed rats showed evident endoplasmic reticulum (ER) stress in the testis, including a dilated ER as an evident pathological change in the Leydig cell ultrastructure, up-regulated ER stress biomarker (binding immunoglobulin protein) levels and activation of the activating transcription factor 6 (ATF6)-related unfolded protein response pathway. Further analysis showed that when 4-phenyl butyric acid (4-PBA) was used to block ER stress in HC-fed rats for 8 weeks, the testosterone deficiency was significantly alleviated. Our findings suggested that high dietary cholesterol intake affected serum testosterone levels by down-regulating steroidogenic enzymes and that activated ER stress might serve as the underlying mechanism.

Cyclophilin D participates in the inhibitory effect of high-fat diet on the expression of steroidogenic acute regulatory protein.

OBJECTIVE: The high-fat diet (HFD)-induced obesity is responsible for the testosterone deficiency (TD). However, the mechanism remains unknown. Mitochondrial homeostasis is proved to be important for maintaining the function of steroidogenic acute regulatory protein (StAR), the first rate-limiting enzyme in testosterone synthesis. As the key regulator of mitochondrial membrane permeability, cyclophilin D (CypD) plays a crucial role in maintaining mitochondrial function. In this study, we sought to elucidate the role of CypD in the expression of StAR affected by HFD. METHODS: To analyse the influence of CypD on StAR in vivo and in vitro, mouse models of HFD, CypD overexpression and CypD knockout (Ppif-/- ) as well as Leydig cells treated with palmitic acid (PA) and CypD overexpression plasmids were examined with an array of metabolic, mitochondrial function and molecular assays. RESULTS: Compared with the normal diet mice, consistent with reduced testosterone in testes, the expressions of StAR in both mRNA and protein levels in HFD mice were down-regulated, while expressions of CypD were up-regulated. High-fat intake impaired mitochondrial function with the decrease in StAR in Leydig cells. Overexpression of CypD inhibited StAR expressions in vivo and in vitro. Compared with C57BL/6 mice with HFD, expressions of StAR were improved in Ppif-/- mice with HFD. CONCLUSIONS: Mitochondrial CypD involved in the inhibitory effect of HFD on StAR expression in testes.

The Effect of Statins on Levels of Dehydroepiandrosterone (DHEA) in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND Currently, statins are used to treat polycystic ovary syndrome (PCOS). This systematic review and meta-analysis aimed to investigate the effect of statins on serum or plasma levels of dehydroepiandrosterone (DHEA) in women with PCOS. MATERIAL AND METHODS Databases that were searched included PubMed, Embase, and the Cochrane Library from their inception to August of 2018. Published randomized controlled trials (RCTs) were identified that evaluated the impact of statins on plasma DHEA levels in women with PCOS. The Cochrane risk of bias tool was used to assess the quality of the included RCTs. A random-effects model was used to analyze the pooled results. RESULTS Meta-analysis was performed on data from ten published studies that included 735 patients and showed that statin treatment could significantly reduce plasma DHEA levels when compared with controls (SMD, -0.43; 95% CI, -0.81-0.06; p=0.02; I²=82%). Statins were significantly more effective than placebo in reducing the levels of DHEAs. Subgroup analysis based on statin type showed that atorvastatin significantly reduced DHEA levels (SMD, -0.63; 95% CI, -1.20 - -0.05; p=0.03; I²=38%) but simvastatin did not significantly reduce DHEA levels (SMD: -0.14; 95% CI, -0.49-0.28; p=0.43; I²=77%). Subgroup analysis based on duration of treatment showed no significant difference between 12 weeks of statin treatment (SMD, -0.61; 95% CI, -1.23-0.02; p=0.06; I²=85%) and 24 weeks (SMD, -0.34; 95% CI -0.95-0.28; p=0.29; I²=83%). CONCLUSIONS Meta-analysis showed that statins significantly reduced the levels of DHEA when compared with placebo in patients with PCOS.

Expression of FSHR in chondrocytes and the effect of FSH on chondrocytes.

OBJECTIVE: Chondrocytes express many kinds of hormone receptors. The function of Follicle stimulating hormone (FSH) in the ovary is mediated by FSH receptor (FSHR). FSH receptor (FSHR) is found in many non-ovarian tissues, however it has been unclear if chondrocytes express FSHR. The purpose of this study is to determine it. METHODS: Mouse primary chondrocytes and human articular cartilage tissues were examined. The expression and sequence of FSHR mRNA by reverse transcription polymerase chain reaction (RT-PCR) and sequenced, respectively, and its protein expression was tested using western blotting and location was observed under immunofluorescence microscopy. Ovarian tissue was as a positive control. After FSH stimulated mouse chondrocytes, intracellular cAMP levels were assessed by ELISA, and gene expression relative to Mouse WNT Signaling Pathway was tested by RT2 Profiler PCR Arrays. RESULTS: FSHR was detected at the transcriptional level and confirmed to have the same sequence as that of ovary-derived mRNA of FSHR. FSHR proteins presented at the same line as the positive proteins of ovary, in mouse chondrocytes and human cartilage tissue, respectively. FSHR proteins were located at the cell membrane. Intracellular cAMP contents were significantly elevated up to 7-fold in mouse chondrocytes by forskolin (100 mM) (P < 0.001); however, different doses of FSH did not change the cAMP contents in mouse primary chondrocytes. RT2 Profiler PCR Arrays demonstrated that FSH could cause changes in gene expression among the 84 preordained genes, such as Fosl1, Rhou, and Dkk1, in mouse chondrocytes relative to the control. CONCLUSION: Mouse chondrocytes and human articular cartilage express functional FSHR. Moreover, FSH can act on chondrocytes and cause genetic changes.

Impaired secretion of active GLP-1 in patients with hypertriglyceridaemia: A novel lipotoxicity paradigm?

BACKGROUND: Lipotoxicity plays an important role in the pathogenesis of ß-cell dysfunction. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that exerts beneficial effects on the number and function of islet ß cells. However, the effect of lipotoxicity on GLP-1 secretion is still unknown. METHODS: Twenty-five patients who were newly diagnosed with diabetes were recruited from 400 subjects based on 75-g Oral Glucose Tolerance Test. Patients were divided into diabetes (DM) and DM combined with hypertriglyceridaemia (DM + HTG) groups according to their serum triglyceride (TG) levels. Seventy-one normal controls and 17 patients with isolated hypertriglyceridaemia were matched by age and gender. RESULTS: Total and active fasting GLP-1 and 2-hour GLP-1 levels were not significantly altered among the 4 groups. However, total and active ΔGLP-1 levels (the difference between 2-hour GLP-1 and fasting GLP-1 levels) were significantly reduced in the isolated HTG, DM, and DM + HTG groups, particularly the DM + HTG group. The ratio of serum active GLP-1 (AGLP-1) to total GLP-1 (TGLP-1) levels was also decreased in patients with isolated HTG, suggesting that active GLP-1 secretion may be more seriously impaired. Both ΔTGLP-1 and ΔAGLP-1 levels were negatively correlated with serum TG levels, body mass index and fasting plasma glucose (FPG) levels and positively correlated with HDL-C levels. According to the multivariate linear regression analysis, only TG and FPG levels were independently associated with ΔTGLP-1 and ΔAGLP-1 levels. CONCLUSION: Impaired GLP-1 secretion was associated with hypertriglyceridaemia and diabetes, and a more obvious association was noted in hypertriglyceridaemic patients with diabetes.

Effect of Testosterone Synthesis and Conversion on Serum Testosterone Levels in Obese Men.

Obesity is associated with decreased testosterone levels in males. Testosterone is synthesized by testosterone synthetic enzymes, which are stimulated by luteinizing hormone (LH). Testosterone can also be converted to estradiol via the aromatase. The objective of this study was to examine the factors related to testosterone synthesis and conversion, and to systematically evaluate the key processes that influence testosterone levels in male obesity. Three hundred and two male subjects (aged 25-45 years old) were divided according to BMI into normal weight (18.5-23.9 kg/m2), overweight (24-27.9 kg/m2), and obese (≥28 kg/m2) groups; or divided following WHR into non-abdominal obesity and abdominal obesity groups (WHR: ≥0.9). Male C57BL/6 mice were divided into normal diet (ND) and high-fat diet (HFD)-induced obesity group. Serum sex hormones and aromatase levels were measured using ELISAs. Testosterone synthetic enzymes in the testes were measured by qRT-PCR. The testosterone levels in obese men and abdominal obesity men were lower than normal men. In abdominal obesity men serum LH levels were decreased and associated with testosterone levels after multivariate regression analysis. Serum aromatase levels were increased in abdominal obesity males. In mice, compared to the ND group, the HFD group had decreased steroidogenic acute regulatory protein (StAR). However, aromatase levels in subcutaneous adipose tissue were higher in the ND group than HFD group. In conclusion, according to this study decreased testicular synthesis function and the conversion of testosterone may explain the reduction in testosterone levels in male obesity, and the decrease of testicular synthesis may change first.

Association of maternal serum lipids at late gestation with the risk of neonatal macrosomia in women without diabetes mellitus.

BACKGROUND: Macrosomia is a serious public health problem worldwide due to its increasing prevalence and adverse influences on maternal and neonatal outcomes. Maternal dyslipidemia exerts potential and adverse impacts on pregnant women and newborns. However, the association between maternal serum lipids and the risk of macrosomia has not yet been clearly elucidated. We explored the association between the maternal lipids profile at late gestation and the risk of having macrosomia among women without diabetes mellitus (DM). METHODS: The medical records of 5407 pregnant women giving birth to single live babies at term were retrospectively analyzed. Subjects with DM, hypertension, thyroid disorders and fetal malformation were excluded. Maternal fasting serum lipids were measured during late pregnancy. Logistic regression analysis was used to analyze the variables associated with the risk of macrosomia. RESULTS: Maternal serum triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels were related to macrosomia; each 1 mmol/L increase in TG resulted in a 27% increase in macrosomia risk, while each 1 mmol/L increase in HDL-C level resulted in a 37% decrease in macrosomia risk, even after adjusting for potential confounders. Notably, the risk of macrosomia increased progressively with increased maternal serum TG levels and decreased HDL-C levels. Compared with women with serum TG levels < 2.5 mmol/L, women with TG levels greater than 3.92 mmol/L had an approximately 2.8-fold increased risk of macrosomia. Compared with women with serum HDL-C levels above 2.23 mmol/L, women with HDL-C levels of less than 1.62 mmol/L had a 1.9-fold increased risk of giving birth to an infan with macrosomia. In addition, a higher risk of macrosomia was observed in women with simultaneous hypertriglyceridemia and low serum HDL-C levels (odds ratio [OR] 2.400, 95% confidence interval [CI]: 1.760-3.274) compared to those with hypertriglyceridemia or low serum HDL-C alone (OR 2.074, 95% CI: 1.609-2.673 and OR 1.363, 95% CI: 1.028-1.809, respectively). CONCLUSIONS: Maternal serum TG levels and HDL-C levels at late gestation are independent predictors of macrosomia in women without DM.

Clinical and molecular characterization of 5α-reductase type 2 deficiency due to mutations (p.Q6X, p.R246Q) in SRD5A2 gene.

Early diagnosis and optimal management for steroid 5α-reductase type 2 deficiency (5α-RD2) patients are major challenges for clinicians and mutation analysis for the 5α-reductase type 2 (SRD5A2) gene is the golden standard for the diagnosis of the disease. In silico analysis of this enzyme has not been reported due to the lack of appropriate model. Moreover, the histological and pathological changes of the gonads are largely unknown. In the present study, a 5α-RD2 patient born with abnormal external genitalia was studied and mutation analysis for SRD5A2 gene was conducted. Moreover, we constructed the homology modeling of 5α-reductase using SWISS-MODEL, followed by the molecular docking study. Furthermore, immunohistochemical staining of Ki67 for the testes tissue was conducted to investigate the potential pathological characteristics. The patient had male (46, XY) chromosomes but presented female characteristics, and the mutation analysis identified a heterozygotes mutation (p.Q6X, p.R246Q) in SRD5A2 gene. In silico analysis elucidated the potential effect of the mutation on enzyme activity. Immunohistochemical staining for the excised testes showed that 30%-50% of the germ cells were Ki67 positive, which indicated the early neoplastic potential. In conclusion, we analyzed the genotype-phenotype correlations of 5α-RD2 caused by a heterozygotes mutation (p.Q6X, p.R246Q). Importantly, we conducted the homology modeling and molecular docking for the first time, which provided a homology model for further investigations. Immunohistochemical results suggested gonadectomy or testis descent should be performed early for 5α-RD2 patient, as delayed treatment would have maintained the testes in a tumorigenic condition.

Cytochrome P450 (CYP) epoxygenases as potential targets in the management of impaired diabetic wound healing.

Epoxyeicosatrienoic acids (EETs) are the epoxidation products of arachidonic acid catalyzed by cytochrome P450 (CYP) epoxygenases, which possess multiple biological activities. In the present study, we aimed to explore the role and effects of CYP epoxygenases/EETs in wound healing in ob/ob mice. Full-thickness skin dorsal wounds were made on ob/ob mice and C57BL/6 control mice. The mRNA and protein expression of CYP epoxygenases were determined in granulation tissues of wounds. Effects of EETs on wound healing were evaluated. Inflammation and angiogenesis in wounds were also observed. Compared with C57BL/6 mice, the mRNA and protein expression of CYP2C65 and CYP2J6 in the granulation tissues in ob/ob mice were significantly reduced. 11,12-EET treatment significantly improved wound healing in ob/ob mice, whereas 14,15-EEZE, an EET antagonist, showed the opposite effect. 11,12-EET treatment decreased neutrophil and macrophage infiltration to the wound sites, resulting in reduced production of inflammatory cytokines, decreased MMP-9 expression, and increased collagen accumulation in the granulation tissues of ob/ob mice. In addition, 11,12-EET increased angiogenesis in the granulation tissues of wounds in ob/ob mice. These findings indicate that reduced expression of CYP epoxygenases may contribute to impaired diabetic wound healing, and exogenous EETs may improve diabetic wound healing by modulating inflammation and angiogenesis.

The lipid-lowering effect of levothyroxine in patients with subclinical hypothyroidism: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: Dyslipidaemia is common in patients with subclinical hypothyroidism (SCH). To date, there is no universal agreement regarding the lipid-lowering effect of substitution treatment with L-T4 in patients with SCH. We aimed to clarify the effect by conducting this systematic review and meta-analysis of randomized controlled trials (RCTs). DESIGN: We systematically searched PubMed, the Cochrane Library, ClinicalTrials.gov and EMBASE for RCTs comparing substitution treatment to placebo treatment or observation. We focused on the primary outcomes of changes from baseline of total, low-density lipoprotein and high-density lipoprotein cholesterol (TC, LDL-C and HLD-C) and triglycerides. Subgroup analyses were performed, assessing the effect of treatment duration, disease severity and ethnicity on the occurrence of discrepancy. RESULTS: Twelve trials, with 940 participants, were eligible for analysis. Compared with the control group, levothyroxine substitution yielded a mean reduction in TC (-0.29 mmol/L, [-0.42 to -0.16]) and LDL-C (-0.22 mmol/L, [-0.36 to -0.09]), with no significant effects on HDL-C (-0.04 mmol/L, [-0.08 to 0.01]) or triglycerides (-0.04 mmol/L, [-0.08 to 0.00]). Trials in which only patients with mild SCH (thyrotropin <10 mIU/L) were enrolled showed equivalent effects. The lowering effects were weaker, but still significant, in long-term treatment (>6 months) compared with short-term treatment (≤6 months) for TC (-0.19 mmol/L [-0.35, -0.03] vs -0.50 mmol/L [-0.68, -0.31], P=.047) and LDL-C (-0.09 mmol/L [-0.16, -0.02] vs -0.46 mmol/L [-0.68, -0.25], P=.006). CONCLUSIONS: Levothyroxine treatment has clear benefits on TC and LDL-C in SCH patients, including those with mild SCH.

The Effect of Aromatase on the Reproductive Function of Obese Males.

Obesity has increased dramatically worldwide, which is associated with male infertility. Androgen deficiency, impaired spermatogenesis, and erectile dysfunction are characteristics of male infertility. The balance of androgens and estrogens is essential for maintaining normal reproductive function in males. Aromatase, the rate-limiting enzyme in the conversion of androgens into estrogens, is present in various tissues. The expression of aromatase is proportional to body fat mass and causes more fat accumulation, thus forming a vicious cycle. Excessive aromatase activity in adipose tissue leads to increased conversion of androgens into estrogens, eventually results in a reduction of testosterone levels and is the underlying reason for obesity-related infertility. In the male reproductive system, all testicular somatic cells and germ cells express aromatase, except for peritubular myoid cells. The results of studies regarding the effect of aromatase in testicular somatic cells and germ cells have been contradictory. The effect of estrogens in testicular somatic cells is inhibitory, leading to reduced testosterone levels and sperm production; however, it has been observed that aromatase participates in the acquisition of sperm motility. The overall effect of estrogen modulation is an inhibition of spermatogenesis. Aromatase inhibitors are an effective therapy for obesity-associated hypogonadism because they restore normal sex hormone levels and improve semen parameters. This article systematically introduces the basic knowledge of aromatase and provides information of the current advances relating to aromatase in male reproductive function. Increasing our knowledge on the role of aromatase in male obesity could help in proposing new approaches to treat infertile men.

SIMVASTATIN DECREASES SEX HORMONE LEVELS IN MALE RATS.

OBJECTIVE: Statins can inhibit therate-limiting enzyme hydroxymethyl glutaric acid-coenzyme A reductase to reduce cholesterol biosynthesis, and they are used frequently in the clinic. Cholesterol is also a precursor for sex hormones. However, it is not clear whether statins can affect sex hormone levels. The aim of this study was to investigate the effect of long-term use of statins on sex hormone levels in vivo. METHODS: Forty male Sprague-Dawley rats were randomly divided into four groups. Three simvastatin groups were administered different doses of simvastatin intragastrically daily (4, 8, or 16 mg/kg/day, n = 10). The control group was administered vehicle intragastrically daily (n = 10). The serum lipid spectrum and testosterone, estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels were measured before (0 weeks) and after 20 and 40 weeks of simvastatin administration. RESULTS: In the control group, there were no statistically significant differences between lipid levels, liver function, or sex hormone levels before and after intragastric administration. Compared with the previous intragastric administration group, there was no obvious change in liver function with different doses of simvastatin. However, serum levels of total cholesterol, low-density-lipoprotein cholesterol, triglycerides, testosterone, estradiol, and progesterone were markedly decreased in a dose- and time-dependent manner. By contrast, the levels of FSH and LH were significantly higher, showing feedback regulation. CONCLUSION: Long-term simvastatin intake reduces serum testosterone, estradiol, and progesterone levels in male rats. ABBREVIATIONS: HMG-CoA = hydroxymethyl glutaric acid CoA LDL = low-density lipoprotein LDL-C = low-density-lipoprotein cholesterol FSH = follicle-stimulating hormone LH = luteinizing hormone.

Natural history of mild subclinical hypothyroidism in a middle-aged and elderly Chinese population: a prospective study.

Subclinical hypothyroidism (SCH) has a high global prevalence. Most SCH patients have mild cases (thyrotropin ≤10 mIU/L). Treatment recommendations for mild SCH are controversial, which raises concerns about the natural history of mild SCH. We aimed to clarify the natural history of mild SCH. This is a prospective population-based study. We measured thyroid function in 11,000 participants in the REACTION study and followed 505 newly diagnosed mild SCH patients aged 40-years or older between 2011 and 2014. Logistic regression analysis was used to seek baseline parameters associated with the natural outcomes of mild SCH. Among 505 mild SCH patients, 221 (43.8%) had persistent SCH, 251 (49.7%) reverted to euthyroidism, and 17 (3.4%) progressed to overt hypothyroidism (OH). Patients with higher baseline total cholesterol (TC, between 201.0-240.0 mg/dL or >240.0 mg/dL vs. <201.0 mg/dL, p = 0.048 and 0.006, respectively) or positive thyroid peroxidase antibodies (TPOAb, p = 0.009) had higher risks of progression to OH, while those with higher baseline creatinine (CR, between 0.71-0.80 mg/dL or >0.80 mg/dL vs. ≤0.65 mg/dL, p = 0.031 and 0.004, respectively), higher baseline thyrotropin (≥7 mIU/L, p < 0.001) or older (>60 years vs. ≤50 years, p = 0.012) had lower odds of reverting to euthyroidism. In conclusion, TPOAb and TC seem to be more important predictors of progression to OH than initial thyrotropin, whereas high baseline thyrotropin or CR were negative correlated with reversion to euthyroidism. The prognostic value of TC and CR in mild SCH should be considered.