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1.
Eur J Endocrinol ; 182(5): 459-471, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32130202

RESUMO

Objective: To evaluate the independent impact of age, obesity and metabolic risk factors on 13 circulating steroid levels; to generate reference intervals for adult men. Design: Cross-sectional study. Methods: Three hundred and fifteen adults, drug-free and apparently healthy men underwent clinical and biochemical evaluation. Thirteen steroids were measured by LC-MS/MS and compared among men with increasing BMI. Moreover, the independent impact of age, BMI and metabolic parameters on steroid levels was estimated. Upper and lower reference limits were generated in steroid-specific reference sub-cohorts and compared with dysmetabolic sub-cohorts. Results: We observed lower steroid precursors and testosterone and increase in estrone levels in men with higher BMI ranges. By multivariate analysis, 17-hydroxyprogesterone and dihydrotestosterone decreased with BMI, while cortisol decreased with waist circumference. Estrone increased with BMI and systolic blood pressure. Testosterone decreased with worsening insulin resistance. 17-hydroxypregnenolone and corticosterone decreased with increasing total/HDL-cholesterol ratio. Age-related reference intervals were estimated for 17-hydroxypregnenolone, DHEA, 17-hydroxyprogesterone, corticosterone, 11-deoxycortisol, cortisol and androstenedione, while age-independent reference intervals were estimated for progesterone, 11-deoxycorticosterone, testosterone, dihydrotestosterone, estrone and estradiol. Testosterone lower limit was 2.29 nmol/L lower (P = 0.007) in insulin resistant vs insulin sensitive men. Furthermore, the upper limits for dihydrotestosterone (-0.34 nmol/L, P = 0.045), cortisol (-87 nmol/L, P = 0.045-0.002) and corticosterone (-10.1 nmol/L, P = 0.048-0.016) were lower in overweight/obese, in abdominal obese and in dyslipidaemic subjects compared to reference sub-cohorts, respectively. Conclusions: Obesity and mild unmedicated metabolic risk factors alter the circulating steroid profile and bias the estimation of reference limits for testosterone, dihydrotestosterone, cortisol and corticosterone. Applying age-dependent reference intervals is mandatory for steroid precursors and corticosteroids.


Assuntos
Peso Corporal/fisiologia , 17-alfa-Hidroxiprogesterona/sangue , Fatores Etários , Androstenodiona/sangue , Índice de Massa Corporal , Cromatografia Líquida , Corticosterona/sangue , Cortodoxona/sangue , Estudos Transversais , Desidroepiandrosterona/sangue , Di-Hidrotestosterona/sangue , Humanos , Hidrocortisona/sangue , Masculino , Análise Multivariada , Obesidade/sangue , Sobrepeso/sangue , Fatores de Risco , Espectrometria de Massas em Tandem
2.
BMC Vet Res ; 15(1): 440, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31805935

RESUMO

BACKGROUND: Prostatic hyperplasia (PH) is one of the most important disorders in intact dogs. In this study, we aimed to induce PH experimentally using the combination of testosterone and estrogen and evaluate important factors associated with this disease. RESULTS: The results showed that in the induction group, prostate volume and prostate specific antigen (PSA) concentration increased significantly on day 21 onwards compared to those of the control group. Canine prostatic specific esterase (CPSE) and dihydrotestosterone (DHT) concentrations increased significantly on day 42 onwards while the testosterone levels increased on day 63. In addition, prostatic acid phosphatase (PAP) concentration did not change significantly in the control and induction groups. Biochemistry profiles and hematologic factors were measured for monitoring the function of liver and kidney, and there were no adverse effects following the induction of PH. CONCLUSIONS: It seems that testosterone and estrogen administration led to prostatic hyperplasia during 2 months. Investigating the size of the prostate, accompanied by prostate markers including CPSE, PSA, DHT, and testosterone, is helpful for the PH diagnosis. However, further studies should be carried out on PAP.


Assuntos
Doenças do Cão/induzido quimicamente , Estrogênios/toxicidade , Antígeno Prostático Específico/sangue , Hiperplasia Prostática/veterinária , Testosterona/toxicidade , Animais , Biomarcadores/sangue , Di-Hidrotestosterona/sangue , Doenças do Cão/sangue , Cães , Esterases/sangue , Masculino , Hiperplasia Prostática/sangue , Hiperplasia Prostática/induzido quimicamente
3.
PLoS One ; 14(12): e0226874, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31887176

RESUMO

During the transition to menopause, women experience a variety of physical and psychological symptoms that are directly or indirectly linked to changes in hormone secretion. Establishing animal models with intact ovaries is essential for understanding these interactions and finding new therapeutic targets. In this study, we assessed the endocrine profile, as well as the estrous cycle, in the 4-vinylcyclohexene diepoxide (VCD)-induced follicular depletion rat model in 10-day intervals over 1 month to accurately establish the best period for studies of the transition period. Twenty-eight-day-old female rats were injected daily with VCD or oil s.c. for 15 days and euthanized in the diestrus phase approximately 70, 80, 90 and 100 days after the onset of treatment. The percentage of rats showing irregular cycles and the plasma level of FSH increased only in the 100-day VCD group. Plasma anti-Müllerian hormone (AMH) and progesterone were lower in all VCD groups compared to control groups, while estradiol remained unchanged or higher. As in control groups, dihydrotestosterone (DHT) progressively decreased in the 70-90-day VCD groups; however, it was followed by a sharp increase only in the 100-day VCD group. No changes were found in plasma corticosterone, prolactin, thyroid hormones or luteinizing hormone. Based on the estrous cycle and endocrine profile, we conclude that 1) the time window from 70 to 100 days is suitable to study a perimenopause-like state in this model, and 2) regular cycles with low progesterone and AMH and normal FSH can be used as markers of the early/mid-transition period, whereas irregular cycles associated with higher FSH and DHT can be used as markers of the late transition period to estropause.


Assuntos
Sistema Endócrino/química , Perimenopausa/sangue , Animais , Hormônio Antimülleriano/sangue , Biomarcadores/sangue , Cicloexenos , Di-Hidrotestosterona/sangue , Ciclo Estral/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Modelos Animais , Progesterona/sangue , Ratos , Fatores de Tempo , Compostos de Vinila
4.
Aquat Toxicol ; 217: 105327, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31703940

RESUMO

Numerous anthropogenic sources, such as pulp mill and sewage treatment effluents, contain androgenic endocrine disrupting compounds that alter the reproductive status of aquatic organisms. The current study injected adult male mummichog (Fundulus heteroclitus) with 0 (control), 1 pg/g, 1 ng/g or 1 µg/g body weight of the model androgen 5α-dihydrotestosterone (DHT) with the intent to induce a period of plasma sex hormone depression, a previously-observed effect of DHT in fish. A suite of gonadal steroidogenic genes were assessed during sex hormone depression and recovery. Fish were sampled 6, 12, 16, 18, 24, 30 and 36 h post-injection, and sections of testis tissue were either snap frozen immediately or incubated for 24 h at 18 °C to determine in vitro gonadal hormone production and then frozen. Plasma testosterone (T) and 11-ketotestosterone (11KT) were depressed beginning 24 h post-injection. At 36 h post-injection plasma T remained depressed while plasma 11KT had recovered. In snap frozen tissue there was a correlation between plasma sex hormone depression and downregulation of key steroidogenic genes including steroidogenic acute regulatory protein (star), cytochrome P450 17a1 (cyp17a1), 3ß-hydroxysteroid dehydrogenase (3ßhsd), 11ß-hydroxysteroid dehydrogenase (11ßhsd) and 17ß-hydroxysteroid dehydrogenase (17ßhsd). Similar to previous studies, 3ßhsd was the first and most responsive gene during DHT exposure. Gene responses from in vitro tissue were more variable and included the upregulation of 3ßhsd, 11ßhsd and star during the period of hormone depression. The differential expression of steroidogenic genes from the in vitro testes compared to the snap frozen tissues may be due to the lack of regulators from the hypothalamo-pituitary-gonadal axis present in whole-animal systems. Due to these findings it is recommended to use snap frozen tissue, not post-incubation tissue from in vitro analysis, for gonadal steroidogenic gene expression to more accurately reflect in vivo responses.


Assuntos
Di-Hidrotestosterona/toxicidade , Fundulidae/fisiologia , 17-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Di-Hidrotestosterona/sangue , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Gônadas/efeitos dos fármacos , Masculino , Fosfoproteínas/metabolismo , Reprodução/efeitos dos fármacos , Esteroide 17-alfa-Hidroxilase/metabolismo , Testículo/efeitos dos fármacos , Testosterona/análogos & derivados , Testosterona/metabolismo , Poluentes Químicos da Água/toxicidade
5.
J Pak Med Assoc ; 69(8): 1090-1093, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31431758

RESUMO

OBJECTIVE: To determine diagnostic accuracy of human chorionic gonadotropins stimulation test in differentiating androgen insensitivity syndrome and 5-alpha reductase deficiency, keeping testosterone to dihydrotestosterone ratio as the gold standard. METHODS: The cross-sectional study was conducted at the Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from January to December, 2016, and comprised patients aged 01 day to 20 years having XY chromosomes on karyotyping and with a spectrum of phenotypes. Blood samples were collected from each subject for basal serum testosterone, serum luteinizing hormone and serum follicular stimulating hormone level. Human chorionic gonadotropins stimulation test was performed in every subject as per the protocol. Sandwich chemiluminescence immunoassay technique was used to analyse serum samples. Serum dihydrotestosterone level was also detected to determine testosterone and dihydrotestosterone ratio. Data was analysed using SPSS 24. . RESULTS: Of the 104 subjects with a mean age of 1.78}0.95 years,96(92.3%) were diagnosed as cases of androgen insensitivity syndrome on the basis of human chorionic gonadotropins stimulation response level, which was 2-9 times of basal serum testosterone level. Also, 8(7.7%) subjects were diagnosed to have 5-alpha reductase deficiency syndrome. In such subjects, post-human chorionic gonadotropins response level of serum testosterone was more than 10 times of the basal level. CONCLUSIONS: The human chorionic gonadotropins stimulation test was found to be comparable to testosterone-to dihydrotestosterone ratio in differentiating between case of androgen insensitivity syndrome and 5-alpha reductase deficiency.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , Síndrome de Resistência a Andrógenos/diagnóstico , Gonadotropina Coriônica , Di-Hidrotestosterona/sangue , Transtorno 46,XY do Desenvolvimento Sexual/diagnóstico , Hipospadia/diagnóstico , Erros Inatos do Metabolismo de Esteroides/diagnóstico , Testosterona/sangue , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , Adolescente , Síndrome de Resistência a Andrógenos/sangue , Criança , Pré-Escolar , Diagnóstico Diferencial , Transtorno 46,XY do Desenvolvimento Sexual/sangue , Hormônio Foliculoestimulante/sangue , Humanos , Hipospadia/sangue , Lactente , Recém-Nascido , Hormônio Luteinizante/sangue , Masculino , Valor Preditivo dos Testes , Erros Inatos do Metabolismo de Esteroides/sangue , Adulto Jovem
6.
Behav Brain Funct ; 15(1): 10, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31256760

RESUMO

BACKGROUND: Age-dependent alterations of hormonal states have been considered to be involved in age related decline of cognitive abilities. Most of the studies in animal models are based on hormonal substitution in adrenal- and/or gonadectomized rodents or infusion of steroid hormones in intact rats. Moreover, the manipulations have been done timely, closely related to test procedures, thus reflecting short-term hormonal mechanisms in the regulation of learning and memory. Here we studied whether more general states of steroid and thyroid hormone profiles, independent from acute experiences, may possibly reflect long-term learning capacity. A large cohort of aged (17-18 months) intact male rats were tested in a spatial hole-board learning task and a subset of inferior and superior learners was included into the analysis. Young male adult rats (16 weeks of age) were also tested. Four to 8 weeks after testing blood plasma samples were taken and hormone concentrations of a variety of steroid hormones were measured by gas chromatography-tandem mass spectrometry or radioimmunoassay (17ß-estradiol, thyroid hormones). RESULTS: Aged good learners were similar to young rats in the behavioral task. Aged poor learners but not good learners showed higher levels of triiodothyronine (T3) as compared to young rats. Aged good learners had higher levels of thyroid stimulating hormone (TSH) than aged poor learning and young rats. Both aged good and poor learners showed significantly reduced levels of testosterone (T), 4-androstenedione (4A), androstanediol-3α,17ß (AD), dihydrotestosterone (DHT), 17-hydroxyprogesterone (17OHP), higher levels of progesterone (Prog) and similar levels of 17ß-estradiol (E2) as compared to young rats. The learning, but not the memory indices of all rats were significantly and positively correlated with levels of dihydrotestosterone, androstanediol-3α,17ß and thyroxine (T4), when the impacts of age and cognitive division were eliminated by partial correlation analyses. CONCLUSION: The correlation of hormone concentrations of individuals with individual behavior revealed a possible specific role of these androgen and thyroid hormones in a state of general preparedness to learn.


Assuntos
Envelhecimento/fisiologia , Cognição/fisiologia , Disfunção Cognitiva/fisiopatologia , Fatores Etários , Animais , Di-Hidrotestosterona/análise , Di-Hidrotestosterona/sangue , Estradiol/análise , Estradiol/sangue , Hormônios/análise , Hormônios/sangue , Aprendizagem/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Esteroides/análise , Esteroides/sangue , Testosterona/análise , Testosterona/sangue , Glândula Tireoide/metabolismo , Hormônios Tireóideos/análise , Hormônios Tireóideos/sangue
7.
Zhongguo Zhong Yao Za Zhi ; 44(9): 1953-1959, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31342726

RESUMO

In this study,mouse models of benign prostatic hyperplasia induced by subcutaneous injection of testosterone propionate was used to investigate the therapeutic effect and mechanism of Urtica hyperborean( UW) extracts on prostate hyperplasia in mice. The effects of UW extracts on prostate index,serum epidermal growth factor( EGF) and dihydrotestosterone( DHT) in model mice were observed,and the EGF and anti-apoptotic factor( Bcl-2) mRNA expression levels were detected as well as pathological changes in prostate tissue. The results showed that the ethyl acetate extraction and alcohol soluble fraction of the UW could significantly reduce the prostate index,reduce the serum DHT and EGF levels( P<0. 01),and significantly decrease the EGF and Bcl-2 mRNA expression( P<0. 01),significantly improved the morphological structure of prostate tissue. The above results confirmed that ethyl acetate extract and alcohol-soluble parts of UW have a good preventive effect on mice prostatic hyperplasia model,and its mechanism may be to reduce androgen levels by regulating polypeptide growth factors and/or inhibiting cell hyperproliferation and promoting apoptosis. This study laid the foundation for the further research on UW.


Assuntos
Medicina Tradicional Tibetana , Extratos Vegetais/farmacologia , Hiperplasia Prostática/tratamento farmacológico , Urticaceae/química , Animais , Di-Hidrotestosterona/sangue , Fator de Crescimento Epidérmico/sangue , Masculino , Camundongos , Hiperplasia Prostática/induzido quimicamente , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Propionato de Testosterona
8.
Int J Pharm ; 565: 20-32, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31051232

RESUMO

The target of the current study is to formulate letrozole loaded nanoemulsion (LET-NE) for the direct nose to brain delivery to reduce peripheral effects of letrozole (LET). LET-NE is compared against intraperitoneally administered free LET in kainic acid (KA) induced status epilepticus (SE) in mice. LET loaded nanoemulsion (LET-NE) was prepared by aqueous microtitration method using Triacetin, Tween 80 and PEG-400 as the oil phase, surfactant, and co-surfactant. Nanoemulsion was studied for droplet size, polydispersity index (PDI), zeta potential, percentage transmittance, drug content, surface morphology. TEM images of developed formulation demonstrated spherical droplets with a mean diameter of 95.59 ±â€¯2.34 nm, PDI of 0.162 ±â€¯0.012 and zeta potential of -7.12 ±â€¯0.12 mV respectively. In in-vitro and ex-vivo drug release, LET-NE showed prolonged drug release profile as compared to suspension. SE was induced by KA (10 mg/kg, i.p.) in Swiss albino mice. Behavioral seizure monitoring, biochemical estimations, and histopathological examination were performed. The onset time of SE was significantly enhanced and % incidence of SE was reduced by intranasal administration of LET-NE as compared to KA and LET administered intraperitoneally. Biochemical estimations revealed that LET-NE effectively decreased levels of 17-ß estradiol while the levels of 5α-Dihydrotestosterone (5α-DHT) and 3α-androstanediol (3α-Diol) were significantly increased in the hippocampus. In cresyl violet staining LET-NE showed better protection of the hippocampus from neurotoxicity induced by KA as compared to LET. Also, in gamma scintigraphy of mouse brain, intranasal administration of nanoemulsion exhibited the presence of high concentration of LET. The study demonstrates the anticonvulsant and neuroprotective effect of LET-NE probably by inhibition of aromatization of testosterone into 17-ß estradiol, proconvulsant, and diverting the pathway into the synthesis of testosterone metabolites, 3α-Diol with known anticonvulsant and neuroprotective action. Brain targeting of LET-NE showed better anticonvulsant and neuroprotective action than LET.


Assuntos
Anticonvulsivantes/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Sistemas de Liberação de Medicamentos , Letrozol/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Estado Epiléptico/tratamento farmacológico , Animais , Anticonvulsivantes/química , Inibidores da Aromatase/química , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Di-Hidrotestosterona/sangue , Desenho de Fármacos , Liberação Controlada de Fármacos , Emulsões , Estradiol/sangue , Cabras , Ácido Caínico , Letrozol/química , Masculino , Camundongos , Mucosa Nasal/metabolismo , Fármacos Neuroprotetores/química , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Polissorbatos/administração & dosagem , Polissorbatos/química , Estado Epiléptico/induzido quimicamente , Triacetina/administração & dosagem , Triacetina/química
9.
Int J Nanomedicine ; 14: 3145-3154, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118628

RESUMO

Background: Gold nanoparticles (AuNps) are promising agents for prostate cancer therapy. Herein, the in vivo effects of 20 and 50 nm sized AuNps on experimentally induced benign prostatic hyperplasia (BPH) was examined. Materials and methods: Adult male rats were divided into four groups (n=6-8 each). A negative control group and three groups were injected daily with testosterone (3 mg/kg/subcutaneously) to induce BPH. Animals receiving testosterone were randomized to untreated BPH group and two BPH groups which were treated intraperitoneally with 20 and 50 nm AuNps (5 mg/kg/daily) in addition to testosterone. After three weeks, histopathological changes and serum levels of testosterone and dihydrotestosterone (DHT) were analyzed. In addition, the prostate tissue levels of transforming growth factor-ß1 (TGF-ß1), vascular endothelial growth factor-a (VEGF-A) and interleukin-6 (IL-6) were measured using ELISA. Results: There were significant increases in the prostate weight/body weight ratio, serum testosterone and DHT and in the prostate tissue content of TGF-ß1, IL-6 and VEGF-A in the untreated BPH group. histological examination showed morphological abnormalities with more proliferation in the glandular epithelial and stromal area and with abundant epithelial papillary folds in the BPH group. Simultaneous administration of 50 nm AuNps with testosterone tended to increase the prostate weight/body weight ratio and increase the tissue level of IL-6 in compared to the BPH group. Conversely, treatment with 20 nm AuNps significantly reduced the elevated tissue content of TGF-ß1, IL-6, and VEGF-A. Histopathological examination also showed that 20 nm but not the 50 nm AuNps administration ameliorates testosterone-induced prostatic hyperplasia. Conclusions: In experimentally induced BPH, AuNps can inhibit the progression of BPH in a size-dependent manner. while 20 nm AuNps ameliorate BPH by its inhibitory effects on the prostatic cell proliferation, inflammation and angiogenesis, the 50 nm AuNps could potentially exacerbate the development of BPH in rats, mainly through enhancing the inflammatory process.


Assuntos
Ouro/uso terapêutico , Nanopartículas Metálicas/uso terapêutico , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/terapia , Animais , Di-Hidrotestosterona/sangue , Modelos Animais de Doenças , Difusão Dinâmica da Luz , Humanos , Interleucina-6/metabolismo , Masculino , Nanopartículas Metálicas/ultraestrutura , Tamanho da Partícula , Hiperplasia Prostática/sangue , Hiperplasia Prostática/patologia , Ratos Sprague-Dawley , Eletricidade Estática , Testosterona/sangue , Fator A de Crescimento do Endotélio Vascular/metabolismo
10.
J Pharm Biomed Anal ; 170: 161-168, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30925273

RESUMO

Prostate cancer is the most common malignancy among men in the Western world. Treatment of this patient population, e.g. by (chemical) castration, is primarily focused on depletion of tumor-stimulating androgens, with testosterone being the major androgenic hormone. After initial therapy, prostate cancer may progress to metastatic castration-resistant prostate cancer. Anti-hormonal drugs abiraterone acetate and enzalutamide are commonly used to treat patients with this disease as both drugs reduce tumor growth and increase time to tumor progression. To evaluate the pharmacodynamic effects of anti-hormonal drugs in this patient population, we developed an LC-MS/MS method for the quantification of testosterone, dihydrotestosterone, androstenedione, cortisol and prednisone in human plasma. The validated assay ranges from 10-10,000 pg/mL for testosterone and androstenedione, 100-10,000 pg/mL for dihydrotestosterone, 50-5000 pg/mL for cortisol and 500-50,000 pg/mL for prednisone. Intra-assay and inter-assay variabilities were within ±15% of the nominal concentrations for quality control (QC) samples at low, medium and high concentrations and within ±20% at the lower limit of quantification (LLOQ), respectively. The applicability of the method was demonstrated in plasma from patients with metastatic castrated-resistant prostate cancer using either abiraterone acetate or enzalutamide.


Assuntos
Androstenodiona/sangue , Di-Hidrotestosterona/sangue , Hidrocortisona/sangue , Plasma/química , Prednisona/química , Neoplasias de Próstata Resistentes à Castração/sangue , Testosterona/sangue , Acetato de Abiraterona/uso terapêutico , Cromatografia Líquida/métodos , Humanos , Masculino , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Espectrometria de Massas em Tandem/métodos
11.
Pharm Biol ; 57(1): 90-98, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30724641

RESUMO

CONTEXT: Lespedeza cuneata G. Don (Fabaceae), has been used as a traditional treatment of various diseases. There is a report L. cuneata effects on hormone replacement therapy for endocrine-related disease. However, studies related to benign prostatic hyperplasia (BPH) have not been investigated. OBJECTIVE: The effects of L. cuneata aqueous extract (LCW) on testosterone-induced prostatic hyperplasia (TPH) were examined. MATERIALS AND METHODS: Male Wistar rats (10 weeks, 330-350 g) were randomly divided to 6 groups (n = 6): Control group; TPH group (3 mg/kg, s.c, daily); TPH + LCW (25, 50, 100 mg/kg); TPH + Finasteride 10 mg/kg for 6 weeks. At the end of treatment, histological change of prostate, serum dihydrotestosterone (DHT) level, mRNA expression of 5α-reductase, inflammatory factors, proliferating cell nuclear antigen (PCNA) and fibroblast growth factor-2 (FGF-2) in prostate were examined. Then, LCW was treated with BPH-1, a human BPH cell line, at 25, 50, 100 µg/mL for 24 h and examine mRNA level of androgen receptor (AR) and prostate-specific antigen (PSA). In addition, the content of vicenin-2 was analyzed. RESULTS: LCW treatment of TPH inhibited serum DHT levels by 54.5, 51.2 and 54.1% and mRNA expression of 5α-reductase were inhibited 54.3, 61.3 and 73.6%, respectively. In addition, mRNA expression of inflammatory factors, PCNA and FGF-2 were decreased in the prostate of rats. Also, LCW attenuated mRNA level of AR and PSA in BPH-1 cell. The content of vicenin-2 in the LCW was analyzed to 0.89 mg/g. DISCUSSION AND CONCLUSIONS: Based on the results, LCW is a potential pharmacological candidate for the treatment of prostatic hyperplasia.


Assuntos
Lespedeza/química , Extratos Vegetais/farmacologia , Hiperplasia Prostática/tratamento farmacológico , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Animais , Citocinas/metabolismo , Di-Hidrotestosterona/antagonistas & inibidores , Di-Hidrotestosterona/sangue , Di-Hidrotestosterona/farmacologia , Finasterida/farmacologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/metabolismo , Próstata/anatomia & histologia , Próstata/efeitos dos fármacos , Antígeno Prostático Específico/metabolismo , Hiperplasia Prostática/sangue , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/patologia , Ratos , Ratos Wistar , Receptores Androgênicos/metabolismo , Testosterona/administração & dosagem
12.
PLoS Biol ; 17(2): e3000002, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30763313

RESUMO

Masculinization of the external genitalia in humans is dependent on formation of 5α-dihydrotestosterone (DHT) through both the canonical androgenic pathway and an alternative (backdoor) pathway. The fetal testes are essential for canonical androgen production, but little is known about the synthesis of backdoor androgens, despite their known critical role in masculinization. In this study, we have measured plasma and tissue levels of endogenous steroids in second trimester human fetuses using multidimensional and high-resolution mass spectrometry. Results show that androsterone is the principal backdoor androgen in the male fetal circulation and that DHT is undetectable (<1 ng/mL), while in female fetuses, there are significantly lower levels of androsterone and testosterone. In the male, intermediates in the backdoor pathway are found primarily in the placenta and fetal liver, with significant androsterone levels also in the fetal adrenal. Backdoor intermediates, including androsterone, are only present at very low levels in the fetal testes. This is consistent with transcript levels of enzymes involved in the alternate pathway (steroid 5α-reductase type 1 [SRD5A1], aldo-keto reductase type 1C2 [AKR1C2], aldo-keto reductase type 1C4 [AKR1C4], cytochrome P450 17A1 [CYP17A1]), as measured by quantitative PCR (qPCR). These data identify androsterone as the predominant backdoor androgen in the human fetus and show that circulating levels are sex dependent, but also that there is little de novo synthesis in the testis. Instead, the data indicate that placental progesterone acts as substrate for synthesis of backdoor androgens, which occurs across several tissues. Masculinization of the human fetus depends, therefore, on testosterone and androsterone synthesis by both the fetal testes and nongonadal tissues, leading to DHT formation at the genital tubercle. Our findings also provide a solid basis to explain why placental insufficiency is associated with disorders of sex development in humans.


Assuntos
Androgênios/biossíntese , Feto/fisiologia , Masculinidade , Di-Hidrotestosterona/sangue , Di-Hidrotestosterona/metabolismo , Feminino , Humanos , Masculino , Redes e Vias Metabólicas , Ovário/metabolismo , Gravidez , Segundo Trimestre da Gravidez/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Testículo/metabolismo
13.
Climacteric ; 22(2): 169-174, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30612472

RESUMO

OBJECTIVE: This study aimed to determine the effect of oophorectomy on baseline serum levels of androgens and estrogens in premenopausal and postmenopausal women. METHODS: Fourteen premenopausal and 10 postmenopausal women underwent total hysterectomy and bilateral oophorectomy for benign disease of the uterus. Serum levels of dehydroepiandrosterone sulfate (DHEAS), androstenedione (A), testosterone (T), dihydrotestosterone (DHT), 5α-androstane-3α,17ß-diol-17ß-glucuronide (3α-diol G), estrone (E1), estradiol (E2), and sex hormone-binding globulin (SHBG) were measured by highly specific immunoassays prior to surgery and 2 weeks afterward. Free T and free E2 were calculated. Differences were determined between preoperative (preop) and postoperative (postop) samples, and between premenopausal and postmenopausal women. RESULTS: In premenopausal women, postop levels of total and free T, DHT, and total and free E2 decreased significantly from preop. Postop levels of DHEAS, A, 3α-diol G, and SHBG were decreased, but not significantly different from preop. In postmenopausal women, postop levels of total and free T and total and free E2 decreased significantly from preop, but there was little change in the other compounds. Significant differences in the mean change from baseline between premenopausal and postmenopausal women were observed only for E1 and total and free E2. CONCLUSION: The significant decrease in serum T in postmenopausal women following oophorectomy adds to the evidence that the postmenopausal ovary continues to produce T.


Assuntos
Androgênios/sangue , Estrogênios/sangue , Ovariectomia/efeitos adversos , Pós-Menopausa/sangue , Pré-Menopausa/sangue , Idoso , Sulfato de Desidroepiandrosterona/sangue , Di-Hidrotestosterona/sangue , Estradiol/sangue , Estrona/sangue , Feminino , Humanos , Histerectomia , Pessoa de Meia-Idade , Globulina de Ligação a Hormônio Sexual/análise , Testosterona/sangue , Doenças Uterinas/cirurgia
14.
Prostate ; 79(3): 272-280, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30370569

RESUMO

BACKGROUND: Currently, there is no consensus regarding the expected concentration levels of intra-prostatic sex steroids in patients with Prostate Cancer (PCa). Our objective was to assess the concentration levels of sex steroids in prostatic tissue and serum, in two cohorts of patients with localized PCa or benign prostatic hyperplasia (BPH). METHODS: Between September 2014 and January 2017, men selected for radical cystectomy (for bladder cancer) or open prostatectomy (for BPH), and men selected for radical prostatectomy for localized PCa were included. Blood samples were collected at baseline before surgery, and steroid concentrations were assessed following the recommendations of the Endocrine Society. Intra-prostatic samples were collected from fresh surgical samples, and assessed by gas chromatography and mass spectrometry (GC/MS). Permanova analysis was performed. Analyses were adjusted for age, prostate weight, and prostate-specific antigen (PSA) level. RESULTS: A total of 73 patients (41 patients with PCa and 32 patients with BPH) were included in this study. Patients with PCa were younger, and had smaller prostate volumes with higher levels of PSA. The levels of Total Testosterone (TT), Di-Hydro-Testosterone (DHT), and Estradiol (E2) in the serum were not significantly different between PCa and BPH. In PCa tissue, TT concentrations were significantly lower (0.11 ng/g vs 0.47 ng/g, P = 0.0002), however its derivative E2 had significantly higher concentrations (31.0 ng/g vs 22.3 ng/g, P = 0.01). DHT tissue concentrations were not significantly different between the two groups (5.55 ng/g vs 5.42 ng/g, P = 0.70). Intra-prostatic TT concentrations were significantly lower in the peripheral zone than in the central zone for the CaP group (0.07 ng/g vs 0.15 ng/g, P = 0.004). CONCLUSIONS: Patients with PCa had lower intra-prostatic TT and higher E2 concentrations levels compared to the patients with BPH. PCa seem to consume more TT and produce more E2, especially in the peripheral zone.


Assuntos
Hormônios Esteroides Gonadais/sangue , Hormônios Esteroides Gonadais/metabolismo , Neoplasias da Próstata/sangue , Neoplasias da Próstata/metabolismo , Idoso , Cistectomia , Di-Hidrotestosterona/sangue , Di-Hidrotestosterona/metabolismo , Estradiol/sangue , Estradiol/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Prostatectomia , Hiperplasia Prostática/sangue , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/cirurgia , Testosterona/sangue , Testosterona/metabolismo , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/cirurgia
15.
Clin Endocrinol (Oxf) ; 90(2): 375-383, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30478933

RESUMO

OBJECTIVE: Low endogenous sex hormones and low physical activity (PA) levels have been associated with CVD risk. Whether these interact to influence CVD outcomes remains unclear. We assessed whether sex hormone concentrations and PA were additively associated with lower central adiposity and CVD risk. PATIENTS: 3351 community-dwelling men, mean age 77 years. MEASUREMENTS: Baseline testosterone (T), dihydrotestosterone (DHT) and oestradiol (E2) were assayed. Levels of PA were ascertained by questionnaire. Men were stratified using median splits into high hormone + high PA (H/H), high hormone + low PA (H/L); low hormone + high PA (L/H) and low hormone + low PA (L/L) groups. RESULTS: A total of 865 CVD events and 499 CVD deaths occurred during 10-year mean follow-up. Men with higher T, DHT or SHBG and higher PA had the lowest BMI, waist circumference and risk of metabolic syndrome. Men with higher T had the lowest risk of incident CVD events, irrespective of PA level. Men with higher T or DHT and higher PA had the lowest risk of dying from CVD (eg, hazard ratios for T/PA H/H 0.76 P = 0.031; H/L 0.85 P = 0.222; L/H 0.80 P = 0.075; L/L 1.00). CONCLUSION: Higher circulating androgens and higher PA were associated with less central adiposity at baseline and fewer CVD deaths during follow-up. These findings are consistent with a potential additive effect of androgens and PA on cardiometabolic outcomes in older men.


Assuntos
Adiposidade , Androgênios/sangue , Doenças Cardiovasculares/prevenção & controle , Exercício Físico , Adulto , Idoso , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Di-Hidrotestosterona/sangue , Estradiol/sangue , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/etiologia , Risco , Testosterona/sangue
16.
Biosci Biotechnol Biochem ; 83(2): 348-356, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30381032

RESUMO

The present study determines whether antler extract (AE) possesses inhibitory effects in a prostate cancer (PC) xenograft model and explores the underlying mechanism. After therapeutic intervention for two weeks, AE significantly inhibited prostate cancer xenograft tumor growth by 65.08%, and prostate-specific antigen (PSA) and serum dihydrotestosterone (DHT) levels. However, AE increased the serum testosterone level compared to the vehicle control group. Furthermore, our investigation of the inhibitory effects on angiogenesis and epithelial-to-mesenchymal transition (EMT)-related genes revealed that AE downregulated matrix metalloproteinase 2 (MMP)-2, (MMP)-9, vascular endothelial growth factor (VEGF), zinc finger protein (SNAIL1), twist-related protein 1 (TWIST1), and zinc-finger E-box-binding homeobox 1 (ZEB1) in vivo. In contrast, AE increased tissue inhibitor of MMP (TIMP)-1, (TIMP)-2, and E-cadherin. The results suggest that AE possesses potent anti-PC activity, and this is the first report on the anti-PC effect of AE in vivo.


Assuntos
Chifres de Veado/química , Xenoenxertos , Neoplasias da Próstata/terapia , Animais , Cervos , Di-Hidrotestosterona/sangue , Regulação para Baixo , Transição Epitelial-Mesenquimal/genética , Perfilação da Expressão Gênica , Humanos , Calicreínas/sangue , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Biológicos , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Testosterona/sangue
17.
Am J Clin Dermatol ; 20(1): 147-153, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30206824

RESUMO

BACKGROUND: The relationship between female pattern hair loss (FPHL) and androgenic hormones is not well established, but some evidence indicates oral finasteride may be efficacious in FPHL. Use of a topical formulation has been proposed to minimize unwanted effects. OBJECTIVES: Our objective was to compare the efficacy and safety of topical 0.25% finasteride combined with 3% minoxidil solution and 3% minoxidil solution as monotherapy in the treatment of FPHL. METHODS: This was a prospective, randomized, double-blind study in 30 postmenopausal women with FPHL. Each participant was randomized to receive either topical 0.25% finasteride combined with topical 3% minoxidil or topical 3% minoxidil solution as monotherapy for 24 weeks. To determine efficacy, the hair density and diameter was measured and global photographic assessment was conducted at baseline and 8, 16, and 24 weeks. Side effects and serum dihydrotestosterone levels were also evaluated. RESULTS: By 24 weeks, hair density and diameter had increased in both groups, and finasteride/minoxidil was significantly superior to minoxidil solution in terms of hair diameter (p = 0.039). No systemic side effects were reported. However, serum dihydrotestosterone levels in the finasteride/minoxidil group significantly decreased from baseline (p = 0.016). CONCLUSION: A topical combination of 0.25% finasteride and 3% minoxidil may be a promising option in the treatment of FPHL with an additional benefit of increasing hair diameter. Nevertheless, as it may be absorbed percutaneously, it should be reserved for postmenopausal women. TRIAL REGISTRATION: clinicaltrials.in.th; identifier TCTR20160912002.


Assuntos
Inibidores de 5-alfa Redutase/uso terapêutico , Alopecia/tratamento farmacológico , Finasterida/uso terapêutico , Minoxidil/uso terapêutico , Vasodilatadores/uso terapêutico , Inibidores de 5-alfa Redutase/farmacologia , Administração Oral , Administração Tópica , Idoso , Alopecia/sangue , Alopecia/patologia , Di-Hidrotestosterona/sangue , Método Duplo-Cego , Quimioterapia Combinada/métodos , Feminino , Finasterida/farmacologia , Cabelo/efeitos dos fármacos , Cabelo/crescimento & desenvolvimento , Cabelo/patologia , Humanos , Pessoa de Meia-Idade , Minoxidil/farmacologia , Pós-Menopausa , Estudos Prospectivos , Resultado do Tratamento , Vasodilatadores/farmacologia
18.
J Steroid Biochem Mol Biol ; 185: 184-188, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30172682

RESUMO

Hyper androgen state frequently can be diagnosed in bulimic women. Eating disorder not otherwise specified (EDNOS) recognized as a less severe form of bulimia nervosa (BN). The objective of the study was to determine whether androgen levels and androgen origin differs in bulimic women compared to control subjects. Forty-six women with bulimia nervosa (BN), 31 with eating disorder not otherwise specified, purging type (EDNOS P) and 56 matched healthy controls were studied with respect to serum testosterone (T), 5alpha-dihydrotestosterone (DHT), sex hormone-binding globulin (SHBG), deyhydroepiahndrosterone sulfate (DHEAS) and luteinizing hormone (LH) and to ovarian morphology. Despite all groups had almost identical androgen and SHBG levels; there were differences in the origin of circulating T and DHT. Correlation analysis suggest major differences in the formation of circulating testosterone (T) and 5α-dihydrotestosterone (DHT) with BN being more like the control subjects with peripheral formation from 4-androsterne-3,17-dione (A-4), dehydroepiandrosterone sulfate (DHEAS) and also from T. While in EDNOS group a possible direct ovarian T secretion and a DHEAS modulating action of androgens on pituitary gonadotropin secretion is present. The origin of circulating T and DHT differs between bulimics. Our findings do probably not reflect direct actions of circulating DHT on pituitary LH secretion in the women with EDNOS, but rather the effect of A-4, T via conversion to DHT in the central nervous system, indicating psych/endocrine differences between the two groups of bulimic women.


Assuntos
Androgênios/sangue , Bulimia Nervosa/sangue , Sulfato de Desidroepiandrosterona/sangue , Di-Hidrotestosterona/sangue , Hormônio Luteinizante/sangue , Globulina de Ligação a Hormônio Sexual/análise , Testosterona/sangue , Adulto , Feminino , Gonadotropinas Hipofisárias/metabolismo , Humanos , Distúrbios Menstruais/complicações , Folículo Ovariano/fisiologia
19.
Mol Cell Endocrinol ; 479: 159-169, 2019 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-30308267

RESUMO

Previous studies evaluating the role of the androgen receptor (AR) for bone mass have used mouse models with global or tissue-specific lifelong inactivation of the AR. However, these mouse models have the AR inactivated already early in life and the relative roles of the AR during development, sexual maturation and in adult mice cannot be evaluated separately. The aim of the present study was to determine the specific roles of the AR in bone during sexual maturation and in adult mice. The AR was conditionally ablated at four (pre-pubertal) or ten (post-pubertal) weeks of age in male mice using tamoxifen-inducible Cre-mediated recombination. Both the pre-pubertal and the post-pubertal AR inactivation were efficient demonstrated by substantially lower AR mRNA levels in seminal vesicle, bone and white adipose tissue as well as markedly reduced weights of reproductive tissues when comparing inducible ARKO mice and control mice at 14 weeks of age. Total body BMD, as analyzed by DXA, as well as tibia diaphyseal cortical bone thickness and proximal metaphyseal trabecular bone volume fraction, as analyzed by µCT, were significantly reduced by both pre-pubertal and post-pubertal AR inactivation. These bone effects were associated with an increased bone turnover, indicating a high bone turnover osteoporosis. Pre-pubertal but not post-pubertal AR inactivation resulted in substantially increased fat mass. In conclusion, the AR is required for maintenance of both trabecular and cortical bone in adult male mice while AR expression during puberty is crucial for normal fat mass homeostasis in adult male mice.


Assuntos
Envelhecimento/metabolismo , Osso e Ossos/anatomia & histologia , Osso e Ossos/metabolismo , Receptores Androgênicos/metabolismo , Adiposidade , Animais , Remodelação Óssea , Osso e Ossos/diagnóstico por imagem , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/metabolismo , Osso Cortical/diagnóstico por imagem , Osso Cortical/metabolismo , Di-Hidrotestosterona/sangue , Feminino , Masculino , Camundongos Knockout , Tamanho do Órgão , Especificidade de Órgãos , Maturidade Sexual , Testosterona/sangue , Timo/anatomia & histologia
20.
J Endocrinol Invest ; 42(4): 453-470, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30132287

RESUMO

BACKGROUND: Studies regarding genetic and clinical characteristics, gender preference, and gonadal malignancy rates for steroid 5-alpha-reductase type 2 deficiency (5α-RD2) are limited and they were conducted on small number of patients. OBJECTIVE: To present genotype-phenotype correlation, gonadal malignancy risk, gender preference, and diagnostic sensitivity of serum testosterone/dihydrotestosterone (T/DHT) ratio in patients with 5α-RD2. MATERIALS AND METHODS: Patients with variations in the SRD5A2 gene were included in the study. Demographic characteristics, phenotype, gender assignment, hormonal tests, molecular genetic data, and presence of gonadal malignancy were evaluated. RESULTS: A total of 85 patients were included in the study. Abnormality of the external genitalia was the most dominant phenotype (92.9%). Gender assignment was male in 58.8% and female in 29.4% of the patients, while it was uncertain for 11.8%. Fourteen patients underwent bilateral gonadectomy, and no gonadal malignancy was detected. The most frequent pathogenic variants were p.Ala65Pro (30.6%), p.Leu55Gln (16.5%), and p.Gly196Ser (15.3%). The p.Ala65Pro and p.Leu55Gln showed more undervirilization than the p.Gly196Ser. The diagnostic sensitivity of stimulated T/DHT ratio was higher than baseline serum T/DHT ratio, even in pubertal patients. The cut-off values yielding the best sensitivity for stimulated T/DHT ratio were ≥ 8.5 for minipuberty, ≥ 10 for prepuberty, and ≥ 17 for puberty. CONCLUSION: There is no significant genotype-phenotype correlation in 5α-RD2. Gonadal malignancy risk seems to be low. If genetic analysis is not available at the time of diagnosis, stimulated T/DHT ratio can be useful, especially if different cut-off values are utilized in accordance with the pubertal status.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Di-Hidrotestosterona/sangue , Transtornos do Desenvolvimento Sexual/complicações , Neoplasias dos Genitais Femininos/etiologia , Neoplasias dos Genitais Masculinos/etiologia , Testosterona/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Aberrações Cromossômicas , Transtornos do Desenvolvimento Sexual/metabolismo , Transtornos do Desenvolvimento Sexual/patologia , Feminino , Estudos de Associação Genética , Neoplasias dos Genitais Femininos/metabolismo , Neoplasias dos Genitais Femininos/patologia , Neoplasias dos Genitais Masculinos/metabolismo , Neoplasias dos Genitais Masculinos/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Maturidade Sexual , Turquia , Adulto Jovem
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