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- Differential Effects of Dehydroepiandrosterone and Testosterone in Prostate and Colon Cancer Cell Apoptosis: The Role of Nerve Growth Factor (NGF) Receptors. [JOURNAL ARTICLE]
- Endocrinology 2013 May 21.
Tumor growth is fostered by inhibition of cell death, which involves the receptiveness of tumor to growth factors and hormones. We have recently shown that testosterone exerts proapoptotic effects in prostate and colon cancer cells through a membrane-initiated mechanism. In addition, we have recently reported that dehydroepiandrosterone (DHEA) can control cell fate, activating nerve growth factor (NGF) receptors, namely tropomyosin-related kinase (Trk)A and p75(NTR), in primary neurons and in PC12 tumoral cells. NGF was recently involved in cancer cell proliferation and apoptosis. In the present study, we explored the cross talk between androgens (testosterone and DHEA) and NGF in regulating apoptosis of prostate and colon cancer cells. DHEA and NGF strongly blunted serum deprivation-induced apoptosis, whereas testosterone induced apoptosis of both cancer cell lines. The antiapoptotic effect of both DHEA and NGF was completely reversed by testosterone. In line with this, DHEA or NGF up-regulated, whereas testosterone down-regulated, the expression of TrkA receptor. The effects of androgens were abolished in both cell lines in the presence of TrkA inhibitor. DHEA induced the phosphorylation of TrkA and the interaction of p75(NTR) receptor with its effectors, RhoGDI and RIP2. Conversely, testosterone was unable to activate both receptors. Testosterone acted as a DHEA and NGF antagonist, by blocking the activation of both receptors by DHEA or NGF. Our findings suggest that androgens may influence hormone-sensitive tumor cells via their cross talk with NGF receptors. The interplay between steroid hormone and neurotrophins signaling in hormone-dependent tumors offers new insights in the pathophysiology of these neoplasias.
- Ketamine attenuates cytochrome p450 aromatase gene expression and estradiol-17β levels in zebrafish early life stages. [JOURNAL ARTICLE]
- J Appl Toxicol 2013 May 20.
Ketamine, a dissociative anesthetic, is a noncompetitive antagonist of N-methyl-D-aspartate-type glutamate receptors. In rodents and non-human primates as well as in zebrafish embryos, ketamine has been shown to be neurotoxic. In cyclic female rats, ketamine has been shown to decrease serum estradiol-17β (E2) levels. E2 plays critical roles in neurodevelopment and neuroprotection. Cytochrome p450 (CYP) aromatase catalyzes E2 synthesis from androgens. Although ketamine down-regulates a number of CYP enzymes in rodents, its effect on the CYP aromatase (CYP19) is not known. Zebrafish have been used as a model system for examining mechanisms underlying drug effects. Here, using wild-type (WT) zebrafish (Danio rerio) embryos, we demonstrate that ketamine significantly reduced E2 levels compared with the control. However, the testosterone level was elevated in ketamine-treated embryos. These results are concordant with data from mammalian studies. Ketamine also attenuated the expression of the ovary form of CYP aromatase (cyp19a1a) at the transcriptional level but not the brain form of aromatase, cyp19a1b. Exogenous E2 potently induced the expression of cyp19a1b and vtg 1, both validated biomarkers of estrogenicity and endocrine disruption, but not cyp19a1a expression. Attenuation of activated ERK/MAPK levels, reportedly responsible for reduced human cyp19 transcription, was also observed in ketamine-treated embryos. These results suggest that reduced E2 levels in ketamine-treated embryos may have resulted from the suppression of cyp19a1a transcription. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.
- Osteocalcin is not a strong determinant of serum testosterone and sperm count in men from infertile couples. [JOURNAL ARTICLE]
- Andrology 2013 May 22.
Osteocalcin (OC) - released by osteoblasts and known as a marker of bone turnover - has been suggested to influence male fertility in murine models by enhancing testosterone production and sperm count. Results from clinical studies are scarce, however. The aim of this cross-sectional study was to investigate the proposed association of OC, undercarboxylated osteocalcin (ucOC) or carboxylated osteocalcin (cOC) with testosterone and sperm count in a cohort of 159 young male adults from infertile couples. Semen analysis was performed. Testosterone, free testosterone, LH, OC and ucOC were measured in serum samples after an overnight fast. cOC and OC correlated weakly but significantly with testosterone (OC: r = 0.165, p = 0.040, cOC: r = 0.193, p = 0.017), but not after adjusting for age and body mass index (BMI) or waist-hip ratio (WHR). %ucOC (ucOC levels expressed as percentage of total OC) correlated inversely with LH (r = -0.184, p = 0.023) and remained significant after the same adjustment. No significant correlations were observed between OC, cOC, ucOC, %ucOC and sperm count, semen volume and number of vital spermatozoa. In binary logistic regression analyses, none of the parameters of OC were predictors of oligozoospermia after adjusting for age and BMI or WHR. The weak association between %ucOC and LH has marginal clinical importance because of the lack of associations of parameters of OC with testosterone and sperm count. The current data thus cannot support the notion that OC is associated with male fertility in young men from infertile couples.
- Sustained in vivo blockade of alpha1-adrenergic receptors prevented some of stress-triggered effects on steroidogenic machinery in Leydig cells. [JOURNAL ARTICLE]
- Am J Physiol Endocrinol Metab 2013 May 21.
This study was designed to systematically analyze and evaluate the effects of in vivo blockade of α1-adrenergic receptors (α1-ADRs) on the stress-induced disturbance of steroidogenic machinery in Leydig cells. Parameters followed: (1) steroidogenic enzymes/proteins, transcription factors and cAMP/testosterone production; (2) the main hallmarks of stress (adrenaline, glucocorticoids); transcription profiles ADRs and oxydases with high affinity to inactivate glucocorticoids. Results showed that sustained blockade of α1-ADRs prevented stress-induced: (1) decrease of the transcripts/proteins for main steroidogenic CYPs (CYP11A1, CYP17A1); (2) decrease of Scarb1 & Hsd3b1 transcripts; (3) decrease of transcript for Nur77, one of the main activator of the steroidogenic expression; (4) increase of Dax1 and Arr19, the main steroidogenic repressors in Leydig cells. In the same cells, the expression of steroidogenic stimulatory factor Creb1, StAR and androgen receptor increased. In this signaling scenario, stress-induced stimulation of Adra1a/Adra1b/Adrbk1 and Hsd11b2 (the unidirectional oxydase with high affinity to inactivate glucocorticoids) was not changed. Blockade additionally stimulated stress-increased transcription of most abundantly expressed ADRs Adra1d/Adrb1/Adrb2 in Leydig cells. In the same cells, stress-decreased testosterone production, the main marker of Leydig cells functionality was completely prevented, while reduction of cAMP, the main regulator of androgenesis, was partially prevented. Accordingly, presented data provide new molecular/transcriptional base for "fight/adaptation" of steroidogenic cells and new molecular insights into the role of α1-ADRs in stress-impaired Leydig cells steroidogenesis. The results are important in term of wide use of α1-ADRs selective antagonists, alone/in combination, to treat high blood pressure, nightmares associated with posttraumatic stress disorder and disrupted sexual health.
- Factors associated with initiation of testosterone replacement therapy in aging males. [Journal Article]
- Value Health 2013 May; 16(3):A71.
- Utilization trends of various formulations of testosterone: An analysis of the ramq database. [Journal Article]
- Value Health 2013 May; 16(3):A175.
- 24 bp duplication of CHIT1 gene and determinants of human chitotriosidase activity among participants of EPISONO, a population-based cross-sectional study, São Paulo, Brazil. [JOURNAL ARTICLE]
- Clin Biochem 2013 May 18.
OBJECTIVES:We investigated whether plasma chitotriosidase activity is related to Obstructive Sleep Apnea (OSA) conditions and correlated with biochemical variables present in the EPISONO database. This is the first study conducted in an epidemiological and nutritional transition country using subjects from the EPISONO population-based cross-sectional study.
METHODS:Chitotriosidase (CHIT) activity was determined by fluorimetric assay. OSA classification was defined as an apnea-hypopnea index. The correlations were investigated using a multiple regression linear model and statistical criteria, with CHIT as the dependent variable and correlated variables (from the EPISONO database) as independent variables, to access the contribution of each one to the variation in CHIT activity.
RESULTS:No significant difference was observed when comparing the mean CHIT activities of different apnea groups. The prevalence of the CHIT1 24-bp duplication from patients with severe apnea was higher than in controls. In a multiple regression linear model, CHIT concentration was positively associated with age, creatine and testosterone. Age was the strongest predictor of CHIT variation, followed by gender, waist circumference and TNFα levels. The whole regression model explained 14% of the CHIT variation.
CONCLUSION:Many variables are related to CHIT activity and show evidence of the multifactor and potentially synergistic character of this enzyme. In this study, we found that age, gender, TNFα, Hcy, sleep efficiency and waist circumference were responsible for approximately 14% of CHIT variation. Further studies are needed to elucidate additional parameters that may be related to CHIT activity.
- Cyclic guanosine monophosphate-enhancing reduces androgenic extracellular regulated protein kinases-phosphorylation/Rho kinase II-activation in benign prostate hyperplasia. [JOURNAL ARTICLE]
- Int J Urol 2013 May 20.
OBJECTIVES:To investigate whether 7-[2-[4-(2-chlorophenyl) piperazinyl] ethyl]-1,3-di-methylxanthine (KMUP-1) inhibits the effects of testosterone on the development of benign prostatic hyperplasia and sensitizes prostate contraction.
METHODS:A benign prostatic hyperplasia animal model was established by subcutaneous injections of testosterone (3 mg/kg/day, s.c.) for 4 weeks in adult male Sprague-Dawley rats. Animals were divided into six groups: control, testosterone, testosterone with KMUP-1 (2.5, 5 mg/kg/day), sildenafil (5 mg/kg/day) or doxazosin (5 mg/kg/day). After 4 weeks, the animals were killed, and prostate tissues were prepared for isometric tension measurement and western blotting analysis. KMUP-1, Y27632, zaprinast, doxazosin or tamsulosin were used at various concentrations to determine the contractility sensitized by phenylephrine (10 μmol/L).
RESULTS:KMUP-1 inhibited testosterone-induced phosphorylation of extracellular signal-regulated phosphorylated protein kinase and mitogen-activated protein kinase kinase and Rho kinase-II activation. Sildenafil and doxazosin significantly decreased benign prostatic hyperplasia-induced mitogen-activated protein kinase kinase and Rho kinase-II activation. The decreased expressions of soluble guanylate cyclase α1 was reversed by KMUP-1, doxazosin and sildenafil. Soluble guanylate cyclase β1 and protein kinase G were increased by KMUP-1, doxazosin, and sildenafil in the testosterone-treated benign prostatic hyperplasia group. Phosphodiesterase-5A was increased by testosterone and inhibited by KMUP-1 (5 mg/kg/day) or sildenafil (5 mg/kg/day). KMUP-1 inhibited phenylephrine-sensitized prostate contraction of rats treated with testosterone.
CONCLUSIONS:Mitogen-activated protein kinase 1/extracellular regulated protein kinases kinase, soluble guanylate cyclase/cyclic guanosine monophosphate, protein kinase/protein kinase G and Rho kinase-II are related to prostate smooth muscle tone and proliferation induced by testosterone. KMUP-1 inhibits testosterone-induced prostate hyper-contractility and mitogen-activated protein kinase 1/extracellular regulated protein kinases kinase-phosphorylation, and it inactivates Rho kinase-II by cyclic guanosine monophosphate, protein kinase and α1A-adenergic blockade. Thus, KMUP-1 might be a beneficial pharmacotherapy for benign prostatic hyperplasia.
- Inhibin B levels in hypothyroid males. [JOURNAL ARTICLE]
- Thyroid 2013 May 22.
Background:The primary role of inhibin B is the regulation of gametogenesis via negative feedback on the production of FSH by the pituitary.
Methods:We studied 14 males with primary hypothyroidism due to various etiologies to determine if they exhibited hypogonadotrophic hypogonadism involving the reproductive segment of the gonadotrophic axis. Levels of Inhibin B, FSH, LH, testosterone, free T4 and TSH were measured.
Results:The mean level of inhibin B in males with primary hypothyroidism was found to be approximately half that of normal males. The FSH level remained within the normal range and no reciprocal increase was observed, as occurs in other conditions with reduced inhibin B.
Conclusions:Our results indicate that primary hypothyroidism has a significant effect on inhibin B levels without reciprocal increase in FSH consistent with a hypogonadotrophic hypogonadal state affecting the reproductive segment of the gonadotrophic axis.
- [Issues associated with sexual development during adolescence: from urological perspectives]. [English Abstract, Journal Article]
- Seishin Shinkeigaku Zasshi 2013; 115(3):290-4.
"Sex" is defined by several factors, such as chromosomes, gonads, and internal and external genitalia. Males basically have a Y chromosome and testes. The testis produces and secretes Mullerian inhibiting substance and testosterone. These two factors induce internal and external genitalia to develop into the male phenotype. The degree of sexual differentiation relates to the levels of Müllerian inhibiting substance and testosterone. The treatment strategy for patients with sexual differentiation should be decided based on the degree of abnormality of internal and external genitalia.