Testicular descent occurs in two consecutive stages: the transabdominal stage and the inguinoscrotal stage. Androgens play a crucial role in the second stage by influencing the development of the gubernaculum, a structure that pulls the testis into the scrotum. However, the mechanisms of androgen actions underlying many of the processes associated with gubernaculum development have not been fully elucidated. To identify the androgen-regulated genes, we conducted large-scale gene expression analyses on the gubernaculum harvested from luteinizing hormone/choriogonadotropin receptor knockout ( Lhcgr KO) mice, an animal model of inguinoscrotal testis maldescent resulting from androgen deficiency. We found that the expression of secreted protein acidic and rich in cysteine (SPARC)-related modular calcium binding 1 ( Smoc1 ) was the most severely suppressed at both the transcript and protein levels, while its expression was the most dramatically induced by testosterone administration in the gubernacula of Lhcgr KO mice. The upregulation of Smoc1 expression by testosterone was curtailed by the addition of an androgen receptor antagonist, flutamide. In addition, in vitro studies demonstrated that SMOC1 modestly but significantly promoted the proliferation of gubernacular cells. In the cultures of myogenic differentiation medium, both testosterone and SMOC1 enhanced the expression of myogenic regulatory factors such as paired box 7 ( Pax7 ) and myogenic factor 5 ( Myf5 ). After short-interfering RNA-mediated knocking down of Smoc1 , the expression of Pax7 and Myf5 diminished, and testosterone alone did not recover, but additional SMOC1 did. These observations indicate that SMOC1 is pivotal in mediating androgen action to regulate gubernaculum development during inguinoscrotal testicular descent.
Animals ; Male ; Mice ; Testis/growth & development* ; Mice, Knockout ; Androgens/pharmacology* ; Testosterone/pharmacology* ; Receptors, LH/metabolism* ; Calcium-Binding Proteins/metabolism*

Most prostate cancers initially respond to androgen deprivation therapy (ADT). With the long-term application of ADT, localized prostate cancer will progress to castration-resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), and neuroendocrine prostate cancer (NEPC), and the transcriptional network shifted. Forkhead box protein A1 (FOXA1) may play a key role in this process through multiple mechanisms. To better understand the role of FOXA1 in prostate cancer, we review the interplay among FOXA1-targeted genes, modulators of FOXA1, and FOXA1 with a particular emphasis on androgen receptor (AR) function. Furthermore, we discuss the distinct role of FOXA1 mutations in prostate cancer and clinical significance of FOXA1. We summarize possible regulation pathways of FOXA1 in different stages of prostate cancer. We focus on links between FOXA1 and AR, which may play different roles in various types of prostate cancer. Finally, we discuss FOXA1 mutation and its clinical significance in prostate cancer. FOXA1 regulates the development of prostate cancer through various pathways, and it could be a biomarker for mCRPC and NEPC. Future efforts need to focus on mechanisms underlying mutation of FOXA1 in advanced prostate cancer. We believe that FOXA1 would be a prognostic marker and therapeutic target in prostate cancer.
Humans ; Male ; Androgen Antagonists/therapeutic use* ; Androgens/metabolism* ; Hepatocyte Nuclear Factor 3-alpha/metabolism* ; Mutation ; Prostatic Neoplasms, Castration-Resistant/drug therapy* ; Receptors, Androgen/metabolism*

ObjectiveTo investigate the relationship of the levels of serum androgens with lipid metabolism in middle-aged and elderly men in Zunyi, Guizhou.

METHODSUsing the stratified cluster sampling method, we conducted a questionnaire investigation and physical examinations among 437 men in Zunyi City. We divided the subjects into a middle-aged (40－64 ［53.20 ± 7.41］ years, n = 269) and an elderly group (=≥65 ［70.63 ± 4.66］ years, n = 168) and collected fasting elbow venous blood samples from them for measuring the levels of total testosterone (TT), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), total cholesterol (TCH), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), calculated free testosterone (cFT), free testosterone index (FTI), and testosterone secretion index (TSI).

RESULTSCompared with the elderly group, the middle-aged males showed significantly lower SHBG, LH, HDL and LDL, and higher cFT, FTI, TSI, TG and TCH (all P < 0.05). TT and SHBG were negatively correlated with TG, TCH, HDL and LDL, while cFT was positively correlated with TCH, and so was FTI with TG, TCH with LDL, and TSI with TCH, HDL and LDL (all P < 0.05), but LH was negatively correlated with TG, TCH and LDL (all P < 0.05). Multivariate linear regression analysis showed that TT and SHBG were negatively correlated with TG, TCH, HDL and LDL, and so was LH with TCH, HDL and LDL (all P < 0.05).

CONCLUSIONSIn the middle-aged and elderly men in Zunyi, low concentrations of TT, SHBG and LH were associated with the increased risk of high-TCH and -LDL dyslipidemia, low concentrations of TT and SHBG with that of high-TG dyslipidemia, while high concentrations of TT, SHBG and LH with that of low-HDL dyslipidemia.

Adult ; Aged ; Androgens ; blood ; China ; Cholesterol ; blood ; Dyslipidemias ; etiology ; Humans ; Lipid Metabolism ; Lipoproteins, HDL ; blood ; Lipoproteins, LDL ; blood ; Luteinizing Hormone ; Male ; Middle Aged ; Multivariate Analysis ; Sex Hormone-Binding Globulin ; Testosterone ; blood ; Triglycerides ; blood

Androgen receptor (AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding of ligands to AR triggers the conformational changes in AR that may affect the recruitment of coactivators and downstream response of AR signaling pathway. Therefore, AR ligands have great potential to treat these diseases. In this study, we searched for novel AR ligands by performing a docking-based virtual screening (VS) on the basis of the crystal structure of the AR ligand binding domain (LBD) in complex with its agonist. A total of 58 structurally diverse compounds were selected and subjected to LBD affinity assay, with five of them (HBP1-3, HBP1-17, HBP1-38, HBP1-51, and HBP1-58) exhibiting strong binding to AR-LBD. The IC values of HBP1-51 and HBP1-58 are 3.96 µM and 4.92 µM, respectively, which are even lower than that of enzalutamide (Enz, IC = 13.87 µM), a marketed second-generation AR antagonist. Further bioactivity assays suggest that HBP1-51 is an AR agonist, whereas HBP1-58 is an AR antagonist. In addition, molecular dynamics (MD) simulations and principal components analysis (PCA) were carried out to reveal the binding principle of the newly-identified AR ligands toward AR. Our modeling results indicate that the conformational changes of helix 12 induced by the bindings of antagonist and agonist are visibly different. In summary, the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases.
Androgen Receptor Antagonists ; pharmacology ; Androgens ; metabolism ; pharmacology ; Biological Assay ; Cell Line, Tumor ; Drug Discovery ; methods ; Humans ; Ligands ; Male ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Phenylthiohydantoin ; analogs & derivatives ; pharmacology ; Principal Component Analysis ; Prostatic Neoplasms ; drug therapy ; Protein Binding ; physiology ; Protein Conformation ; drug effects ; Receptors, Androgen ; metabolism

The aim of hormonal male contraception is to prevent unintended pregnancies by suppressing spermatogenesis. Hormonal male contraception is based on the principle that exogenous administration of androgens and other hormones such as progestins suppress circulating gonadotropin concentrations, decreasing testicular Leydig cell and Sertoli cell activity and spermatogenesis. In order to achieve more complete suppression of circulating gonadotropins and spermatogenesis, a progestin has been added testosterone to the most recent efficacy trials of hormonal male contraceptives. This review focusses on the potential effects of male hormonal contraceptives on cardiovascular risk factors, lipids and body composition, mainly in the target group of younger to middle-aged men. Present data suggest that hormonal male contraception can be reasonably regarded as safe in terms of cardiovascular risk. However, as all trials have been relatively short (< 3 years), a final statement regarding the cardiovascular safety of hormonal male contraception, especially in long-term use, cannot be made. Older men with at high risk of cardiovascular event might not be good candidates for hormonal male contraception. The potential adverse effects of hormonal contraceptives on cardiovascular risk appear to depend greatly on the choice of the progestin in regimens for hormonal male contraceptives. In the development of prospective hormonal male contraception, data on longer-term cardiovascular safety will be essential.
Age Factors ; Androgens/therapeutic use* ; Antispermatogenic Agents ; Cardiovascular Diseases/epidemiology* ; Contraceptive Agents, Male/therapeutic use* ; Gonadotropins/metabolism* ; Humans ; Male ; Progestins/therapeutic use* ; Testosterone/therapeutic use*

Epidemiological studies hint at a beneficial influence of endogenous circulating testosterone (T), or its metabolite dihydrotestosterone (DHT), such that men with lower concentrations of T or DHT appear to have poorer health outcomes including frailty, diabetes, cardiovascular disease, and mortality. Small interventional studies of T have shown favorable effects on surrogate outcome measures, but a large randomized controlled trial (RCT) with the prespecified outcome of cardiovascular events has not been performed and would be logistically demanding. In the absence of such a definitive RCT, there is a controversy about the cardiovascular risks of T-therapy fuelled by contradictory findings from retrospective analyses of insurance databases of men prescribed T. The US Testosterone Trials (T-Trials) are the largest published RCTs of T-therapy in older men with symptoms or signs of hypogonadism and circulating T <9.54 nmol l⁻¹ at baseline. The T-Trials showed a modest benefit of T-therapy over a 12-month period on sexual function, a significant benefit in bone density and for anemia and neutral effect on cognition. The T-Trials cardiovascular sub-study was designed to determine the effects of T in these older men, and there was a statistically significant difference in the increase in noncalcified plaque volume in the T-treated group compared to placebo, but it is difficult to interpret these results due to differences in baseline coronary plaque burden (>50% difference) between the treatment and placebo arms of the subset involved. Therefore, there continues to be ongoing uncertainty over the effect of T-therapy on the cardiovascular system in men.
Age Factors ; Androgens/therapeutic use* ; Cardiovascular Diseases/metabolism* ; Dihydrotestosterone/metabolism* ; Hormone Replacement Therapy ; Humans ; Hypogonadism/metabolism* ; Male ; Protective Factors ; Risk Factors ; Testosterone/therapeutic use*

Testosterone deficiency is common in men with cardiovascular disease (CVD), and randomized placebo-controlled trials (RCTs) have reported beneficial effects of testosterone therapy on exercise-induced cardiac ischemia in chronic stable angina, functional exercise capacity, maximum oxygen consumption during exercise (VO_2max) and muscle strength in chronic heart failure (CHF), shortening of the Q-T interval, and improvement of some cardiovascular risk factors. Testosterone deficiency is associated with an adverse CV risk profile and mortality. Clinical and scientific studies have provided mechanistic evidence to support and explain the findings of the RCTs. Testosterone is a rapid-onset arterial vasodilator within the coronary circulation and other vascular beds including the pulmonary vasculature and can reduce the overall peripheral systemic vascular resistance. Evidence has demonstrated that testosterone mediates this effect on vascular reactivity through calcium channel blockade (L-calcium channel) and stimulates potassium channel opening by direct nongenomic mechanisms. Testosterone also stimulates repolarization of cardiac myocytes by stimulating the ultra-rapid potassium channel-operated current. Testosterone improves cardiac output, functional exercise capacity, VO_2maxand vagally mediated arterial baroreceptor cardiac reflex sensitivity in CHF, and other mechanisms. Independent of the benefit of testosterone on cardiac function, testosterone substitution may also increase skeletal muscle glucose metabolism and enhance muscular strength, both factors that could contribute to the improvement in functional exercise capacity may include improved glucose metabolism and muscle strength. Testosterone improves metabolic CV risk factors including body composition, insulin resistance, and hypercholesterolemia by improving both glucose utilization and lipid metabolism by a combination of genomic and nongenomic actions of glucose uptake and utilization expression of the insulin receptor, glucose transporters, and expression on regulatory enzymes of key metabolic pathways. The effect on high-density lipoprotein-cholesterol (HDL-C) differs between studies in that it has been found to fall, rise, or have no change in levels. Testosterone replacement can suppress the levels of circulating pro-inflammatory cytokines and stimulate the production of interleukin-10 (IL-10) which has anti-inflammatory and anti-atherogenic actions in men with CVD. No effect on C-reactive protein has been detected. No adverse effects on clotting factors have been detected. RCTs have not clearly demonstrated any significant evidence that testosterone improves or adversely affects the surrogate markers of atherosclerosis such as reduction in carotid intima thickness or coronary calcium deposition. Any effect of testosterone on prevention or amelioration of atherosclerosis is likely to occur over years as shown in statin therapy trials and not months as used in testosterone RCTs. The weight of evidence from long-term epidemiological studies supports a protective effect as evidenced by a reduction in major adverse CV events (MACEs) and mortality in studies which have treated men with testosterone deficiency. No RCT where testosterone has been replaced to the normal healthy range has reported a significant benefit or adverse effect on MACE nor has any recent meta-analysis.
Androgens/therapeutic use* ; Angina, Stable/drug therapy* ; Body Composition ; C-Reactive Protein ; Calcium Channel Blockers/therapeutic use* ; Cardiovascular Diseases/prevention & control* ; Chronic Disease ; Coronary Circulation ; Cytokines ; Exercise Tolerance ; Glucose/metabolism* ; Heart Failure/drug therapy* ; Humans ; Insulin Resistance ; Lipid Metabolism ; Male ; Muscle Strength ; Oxygen Consumption ; Pulmonary Circulation ; Randomized Controlled Trials as Topic ; Testosterone/therapeutic use* ; Vascular Resistance ; Vasodilation

We sought to investigate the underlying mechanism of action of the long noncoding RNA (lncRNA) LOC283070 in the development of androgen independence in prostate cancer. The interactions between LOC283070 and target proteins were investigated by RNA pull-down and RNA-binding protein immunoprecipitation (RIP) assays. Subcellular fractionation and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were used to detect the subcellular localization of LOC283070. Western blotting was performed to detect the expression of prohibitin 2 (PHB2). Luciferase activity assays were performed to evaluate the effects of LOC283070 and PHB2 on the androgen receptor (AR) signaling pathway. A methyl thiazolyl tetrazolium (MTT) assay and a growth curve assay were used to test cell viability. Flow cytometry was performed to analyze cell cycles. A transwell assay was employed to test cell migration. We identified PHB2 as an interaction partner of LOC283070 in the pull-down and RIP experiments. Furthermore, we confirmed that the enrichment of LOC283070 with PHB2 in androgen-independent LNCaP (LNCaP-AI) cells was much greater than that in LNCaP cells. Moreover, the expression of PHB2 was not significantly different between the two cell lines, and the expression of LOC283070 in the nuclei of the LNCaP-AI cells was significantly greater than that in the LNCaP cells. In vitro data revealed that PHB2 overexpression significantly inhibited AR activity and cell proliferation and migration and induced accumulation of prostate cancer cells in G0/G1 phase. Moreover, the overexpression of LOC283070 fully abrogated the effects of PHB2 overexpression. In conclusion, we found that LOC283070 can bind to PHB2 located in the nucleus and inhibit its effect, and this is one of the mechanisms by which LOC283070 is involved in the transition of LNCaP cells into androgen-independent cells.
Androgens/metabolism* ; Cell Line, Tumor ; Cell Proliferation/physiology* ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Prohibitins ; Prostatic Neoplasms/metabolism* ; RNA, Long Noncoding/metabolism* ; Receptors, Androgen/metabolism* ; Repressor Proteins/metabolism* ; Signal Transduction/physiology*

The epithelium of the human epididymis maintains an appropriate luminal environment for sperm maturation that is essential for male fertility. Regional expression of small noncoding RNAs such as microRNAs contributes to segment-specific gene expression and differentiated functions. MicroRNA profiles were reported in human epididymal tissues but not specifically in the epithelial cells derived from those regions. Here, we reveal miRNA signatures of primary cultures of caput, corpus, and cauda epididymis epithelial cells and of the tissues from which they were derived. We identify 324 epithelial cell-derived microRNAs and 259 tissue-derived microRNAs in the epididymis, some of which displayed regionalized expression patterns in cells and/or tissues. Caput cell-enriched miRNAs included miR-573 and miR-155. Cauda cell-enriched miRNAs included miR-1204 and miR-770. Next, we determined the gene ontology pathways associated with in silico predicted target genes of the differentially expressed miRNAs. The effect of androgen receptor stimulation on miRNA expression was also investigated. These data show novel epithelial cell-derived miRNAs that may regulate the expression of important gene networks that are responsible for the regionalized gene expression and function of the epididymis.
Adult ; Androgens/pharmacology* ; Computer Simulation ; Epididymis/metabolism* ; Epithelial Cells/metabolism* ; Epithelium/metabolism* ; Gene Expression Profiling ; Gene Regulatory Networks/drug effects* ; Humans ; Male ; MicroRNAs/genetics* ; Primary Cell Culture ; Receptors, Androgen/metabolism* ; Sequence Analysis, RNA

Glycogen synthase kinase3 (GSK3α and GSK3β) are serine/threonine protein kinases acting on numerous substrates and involved in the regulation of various cellular functions such as their proliferation, survival, glycogen metabolism, and autophagy. Accumulating evidence indicates that the expression of GSK3α is increased mainly in androgendependent while that of GSK3β in androgenindependent prostate cancer, and that GSK3β is also involved in the regulation of the transactivation of the androgen receptor (AR) and growth of prostate cancer. Animal experiments have proved that some GSK3 inhibitors, such as lithium, can significantly suppress tumor growth in different animal models of prostate cancer. The GSK3 inhibitor is promising to be an important agent for the clinical management of prostate cancer.
Androgens ; Animals ; Cell Line, Tumor ; Glycogen Synthase Kinase 3 ; antagonists & inhibitors ; metabolism ; Glycogen Synthase Kinase 3 beta ; antagonists & inhibitors ; metabolism ; Humans ; Male ; Neoplasm Proteins ; metabolism ; Neoplasms, Hormone-Dependent ; enzymology ; metabolism ; Prostatic Neoplasms ; drug therapy ; enzymology ; pathology ; Receptors, Androgen ; metabolism