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1.
J Urol ; 203(4): 743-750, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31580749

RESUMO

PURPOSE: We evaluated the timeliness of androgen deprivation therapy dosing, the impact of dosing nonadherence on testosterone, and the frequency of testosterone and prostate specific antigen testing in patients with prostate cancer. MATERIALS AND METHODS: We retrospectively analyzed the records of 22,860 patients with prostate cancer treated with luteinizing hormone-releasing hormone agonists. Analyses were done using 2 definitions of month, including a 28-day month (late dosing after day 28, 84, 112 or 168) and an extended month (late after day 32, 97, 128 or 194) for 1, 3, 4 and 6-month formulations, respectively. The prevalence of late dosing, associated testosterone values, and the frequency of testosterone and prostate specific antigen testing were assessed. Statistical significance was assessed with the unpaired t-test. RESULTS: Of the injections 84% and 27% were late for the 28-day and extended month analyses, respectively. For the 28-day month 60% and 29% of injections were late by more than 1 and more than 2 weeks, respectively. Of testosterone values 4% were greater than 50 ng/dl for early/on time injections using both definitions, and 15% and 27% were greater than 50 ng/dl when late, and for the 28-day month and the extended month, respectively. For early/on time vs late injections 22% vs 31% of testosterone values were greater than 20 ng/dl for the 28-day month and 21% vs 43% for the extended month. Mean testosterone was higher when late (49 ng/dl for 28-day month, 79 ng/dl for extended month) vs early/on time (both 21 ng/dl). Of the injections prostate specific antigen measurements were performed in 83% and testosterone assessment was done in only 13%. CONCLUSIONS: Luteinizing hormone-releasing hormone agonists were frequently (84%) administered later than the schedules used in pivotal trials. Nearly half of the late testosterone values for the extended month were greater than 20 ng/dl and mean testosterone was almost double the castration level. Elevated testosterone remained unidentified with infrequent testing.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Hormônio Liberador de Gonadotropina/agonistas , Adesão à Medicação/estatística & dados numéricos , Neoplasias da Próstata/tratamento farmacológico , Testosterona/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Calicreínas/sangue , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Estudos Retrospectivos , Testosterona/sangue , Fatores de Tempo , Estados Unidos , Adulto Jovem
2.
Niger J Physiol Sci ; 34(1): 69-75, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31449274

RESUMO

Anti-androgenic substances, mainly prostate 5α-reductase inhibitors, used in the treatment of benign prostatic hyperplasia (BPH) have been associated with side effects in man and animals. To reduce these side effects as well as suppress BPH development, the management of the condition has come to include dietary interventions. This study investigated the effect of some cooking oils on testosterone-induced hyperplasia of the prostate in rats. Male Sprague-dawley rats were distributed into eighteen groups (n=6) as A-R. A negative control group was injected subcutaneously with soya oil; while prostatic hyperplasia was induced subcutaneously in groups B-R with 3mg/kg testosterone daily for 14days. Group B was the positive control (BPH group) while groups C-R were also administered orally 800mg/kg of coconut, castor, canola, cottonseed, pomegranate, blackseed, sheabutter, olive oil, codliver, sardine, palm, repeatedly heated palm (RHPO), vegetable, repeatedly-heated vegetable (RHVO), sesame, and groundnut oils respectively, daily, for 14 days. Blood sample was drawn via retro-orbital sinus for the estimation of serum testosterone(T) and dihydrotestosterone (DHT) level and rats were thereafter euthanized to obtain the prostates for T and DHT determination as well as tissue weights. Data are mean ± SEM, compared by ANOVA. The oils significantly reduced the increase in prostate weight (PW) to body weight (BW) ratio induced by testosterone. Apart from the fact that all the oils reduced the PW:BW ratio, the blackseed, sheabutter, sardine, vegetable and groundnut oils suppressed the DHT level in the serum, while pomegranate, olive, RHPO reduced DHT level in the prostate compared to the BPH rats. This study suggests that blackseed, sheabutter, sardine, vegetable, groundnut, pomegranate, olive, and RHPO oils could inhibit testosterone-induced hyperplasia of the prostate and therefore may be beneficial in the management of BPH.


Assuntos
Modelos Animais de Doenças , Ácidos Graxos/administração & dosagem , Óleos Vegetais/administração & dosagem , Hiperplasia Prostática/sangue , Hiperplasia Prostática/tratamento farmacológico , Testosterona/sangue , Administração Oral , Animais , Masculino , Hiperplasia Prostática/patologia , Ratos , Ratos Sprague-Dawley , Testosterona/antagonistas & inibidores
3.
Physiol Res ; 68(4): 689-693, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31342755

RESUMO

The increasing worldwide production of bisphenols has been associated to several human diseases, such as chronic respiratory and kidney diseases, diabetes, breast cancer, prostate cancer, behavioral troubles and reproductive disorders in both sexes. The aim of the present in vitro study was to evaluate the potential impact bisphenols A, B, S and F on the cell viability and testosterone release in TM3 Leydig cell line. Mice Leydig cells were cultured in the presence of different concentrations of bisphenols (0.04-50 µg.ml-1) during 24 h exposure. Quantification of the cell viability was assessed using the metabolic activity assay, while the level of testosterone in cell culture media was determined by enzyme-linked immunosorbent assay. Within the panel of substances under investigations, the higher experimental concentrations (10; 25 and 50 µg.ml-1) significantly (P<0.001) decreased Leydig cells viability, while the same doses of BPA and BPB also reduced testosterone production significantly (P<0.001). Taken together, the results of our study reported herein is a consistent whit the conclusion that higher experimental doses of bisphenols have a cytotoxic effect and could have a dose-dependent impact on testosterone production.


Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Células Intersticiais do Testículo/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fenóis/toxicidade , Testosterona/antagonistas & inibidores , Animais , Compostos Benzidrílicos/administração & dosagem , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Disruptores Endócrinos/administração & dosagem , Estrogênios não Esteroides/administração & dosagem , Estrogênios não Esteroides/toxicidade , Células Intersticiais do Testículo/metabolismo , Masculino , Camundongos , Mitocôndrias/metabolismo , Fenóis/administração & dosagem , Testosterona/metabolismo
4.
Medicina (Kaunas) ; 55(7)2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31336641

RESUMO

Background and Objectives: Anabolic androgenic steroids (AASs) are a complex group of molecules that include both steroidal androgens and synthetic compounds, derived from testosterone. AASs are commonly used to support pharmacological therapy in cases of primary or secondary hypogonadism, major burns, and neoplastic cachexia. Their prolonged and supra-physiological consumption can provoke several adverse effects on various organs and systems. Among these, the physiopathological mechanisms that induce neuropsychiatric disorders related to AAS abuse are poorly known. For this reason, the proposed review aims to retrace the pathway of action of testosterone to focus on the effects on the central nervous system and specifically highlight the effects of AASs on neuropsychiatric and behavioral functions, as well as on lifestyle. Materials and Methods: This review was conducted using PubMed and Google Scholar databases. On these database websites, we searched for articles from 1 January 1980 to March 2019 using the key terms: "AAS," "Anabolic Androgenic Steroids," "brain," and "neurology." Results: The use of AASs through self-administration yields circulating androgens levels, inducing neuron apoptosis, which is linked to thinner cortex and, in general, less cortical volume. The same alterations affect the putamen. These differences were more evident when correlated with longer use. From a functional point of view, prolonged AAS consumption seemed to be related to lower connectivity between amygdala and frontal, striatal, limbic, hippocampal and visual cortical areas. On the other hand, AAS use seems to negatively condition the positive effects of the sport exercise, reducing its important anti-apoptotic and pro-proliferative functions on the hippocampus, implicated in anxiolytic control. Conclusion: This review clarifies the major aspects of the side effects related to AAS use/abuse highlighting the complex mechanisms on neuropsychiatric and cognitive pathological alterations and also the emotional and behavioral dysfunctions.


Assuntos
Comportamento Problema/psicologia , Transtornos Relacionados ao Uso de Substâncias/complicações , Congêneres da Testosterona/efeitos adversos , Fatores Etários , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Humanos , Transtornos Relacionados ao Uso de Substâncias/psicologia , Testosterona/antagonistas & inibidores , Testosterona/metabolismo , Congêneres da Testosterona/química
5.
Steroids ; 149: 108415, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31152826

RESUMO

A variety of pesticides including vinclozolin, its metabolite M2 (3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide), and prochloraz have been shown to exert antiandrogenic effects in animal models by competing with androgen binding to nuclear androgen receptors (nAR) and decreasing transcription of androgen-responsive genes. However, it is not known whether these pesticide antiandrogens also interfere with rapid (often described as nongenomic, nonclassical) androgen actions mediated by membrane androgen receptors (mARs). We recently discovered that ZIP9, a member of the zinc transporter ZIP (SLC39A) family, is a specific, high-affinity mAR that mediates rapid testosterone-dependent signaling, zinc influx, and apoptosis in breast and prostate cancer cell lines. Possible disruption by prochloraz, vinclozolin, and M2 of androgen actions through this mAR was investigated in vitro in PC-3 prostate cancer cells (nAR-) over expressing human ZIP9 (PC3-ZIP9 cells). Single-point competitive binding assays showed 1 µM and 10 µM concentrations of all three pesticides displaced specific [3H]-testosterone binding to PC3-ZIP9 cell membranes with binding affinities <10% that of testosterone. The pesticides also exerted antiandrogen actions through ZIP9. Co-treatments with 100 nM prochloraz, vinclozolin and M2 blocked or attenuated the 20 nM testosterone-induced increases in apoptosis, intracellular free zinc levels, and expression of the proapoptotic gene, Bax. Prochloraz also attenuated testosterone activation of MAPkinase. The finding that prochloraz, vinclozolin and M2 are effective competitors of [3H]-testosterone binding to ZIP9 and block testosterone actions mediated through ZIP9 in vitro at nanomolar concentrations suggests that androgen functions mediated by ZIP9 are also susceptible to disruption by pesticide antiandrogens with potential adverse effects on human health.


Assuntos
Apoptose/efeitos dos fármacos , Proteínas de Transporte de Cátions/metabolismo , Disruptores Endócrinos/metabolismo , Disruptores Endócrinos/farmacologia , Fungicidas Industriais/metabolismo , Fungicidas Industriais/farmacologia , Testosterona/antagonistas & inibidores , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Humanos , Células PC-3 , Ligação Proteica , Receptores Androgênicos/metabolismo , Testosterona/farmacologia
6.
Horm Behav ; 110: 10-18, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30735664

RESUMO

In many passerine birds, testosterone stimulates song and aggression but inhibits paternal care, but few studies have explored whether such effects can be reversed with testosterone blockers. We explored the effect of testosterone blockers on song, aggression and paternal care of Lapland longspurs (Calcarius lapponicus), an arctic passerine with a short breeding season. Twenty-one "blocker males" received implants containing an androgen receptor blocker and an aromatase inhibitor, compared to 27 control males with empty or no implants. Song, aggression and other behaviors were evaluated with simulated territorial intrusions (STI) during mate-guarding, and with focal observations (without STI) during mate-guarding and incubation. Nests were monitored and nestlings weighed as an indirect measure of paternal care. During STI, blocker males exhibited similar song rates, significantly lower aggression, and were significantly less likely to be found on territory than control males. Focal observations revealed no differences in spontaneous song, aggression, foraging, preening, or flight activity. Blocker males' nestlings had greater body mass on day 5 after hatching, but this difference disappeared by fledging, and both groups fledged similar numbers of young. Two blocker males exhibited unusual paternal care: incubation and brooding of young, or feeding of nestlings at another male's nest. In sum, testosterone blockers affected aggression but not song, contrasting with results from previously published testosterone implant studies. Effects on paternal care were concordant with testosterone implant studies. These patterns may be related to rapid behavioral changes characteristic of the short breeding season of the Arctic.


Assuntos
Agressão/efeitos dos fármacos , Antagonistas de Receptores de Andrógenos/farmacologia , Comportamento de Nidação/efeitos dos fármacos , Passeriformes/fisiologia , Comportamento Paterno/efeitos dos fármacos , Testosterona/antagonistas & inibidores , Vocalização Animal/efeitos dos fármacos , Animais , Regiões Árticas , Masculino , Receptores Androgênicos/metabolismo , Reprodução/efeitos dos fármacos , Estações do Ano , Territorialidade , Testosterona/farmacologia
7.
Chemosphere ; 222: 722-731, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30738315

RESUMO

Veterinary tetracyclines drugs are emerging organic pollutants detected at high concentrations in the urine of school children and a potential public health risk. However, the implications of early-life exposure to tetracyclines on testosterone production, being new endocrine disruptors, remain unknown. We investigated whether the early-life exposure to low-doxycycline, a widely used tetracycline, on mitochondria dysfunction and testosterone disruption in Leydig cells in vitro and in vivo. Next, we determined the mRNA levels of testis cells markers for early-life exposure to low-doxycycline outcomes of testis health in later-life. Finally, we compared the weight gain performance exposed to low- and therapeutic-doses through 15 weeks and examined the role of the microbiota during development. Our results showed doxycycline disturbed steroidogenesis process by mitochondrial dysfunction in mouse Leydig tumor cell line (MLTC-1) cells in vitro. Leydig cells mitochondrial function was disrupted by early-life exposure to low-doxycycline from birth to 49 days, causing testosterone deficiency and decreased quality of the sperm in mice. Early-life exposure to low-doxycycline significantly altered the mRNA levels of key genes in Leydig cells (Cyp11a1, Cyp17a1 and 17ß-HSD) and spermatogenic cells (Grfal, Plzf, and Stra8) in later-life in mice. Subchronic low- and therapeutic-doses doxycycline changed gut microbiota differences in diversity reduction and compositional alteration. Moreover, the weight gain effects of doxycycline were only observed in low-dose in male mice. Overall, these results provide insight into the effects of doxycycline on both testis and gut microbiota health. The results provide insight that environmental antibiotics are needed additional research to classify as ECDs.


Assuntos
Doxiciclina/efeitos adversos , Disruptores Endócrinos/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Testosterona/antagonistas & inibidores , Tetraciclinas/efeitos adversos , Animais , Poluentes Ambientais , Células Intersticiais do Testículo/efeitos dos fármacos , Masculino , Camundongos , RNA Mensageiro/sangue , Esteroide 17-alfa-Hidroxilase/genética , Testículo/efeitos dos fármacos , Testosterona/biossíntese
8.
Stress ; 22(1): 133-141, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30369279

RESUMO

Stress signals during fetal or early postnatal periods may disorganize reproductive axis development at different levels. This study was aimed to test the hypothesis that prenatal immunological stress induced by bacterial endotoxin, lipopolysaccharide (LPS), has impact on structure and function of the reproductive system in female offspring. Adult female Wistar rats were divided into two groups, a control group (n = 5) and a LPS group (n = 12). Rats were injected with LPS 50 µg/kg body or 0.9% saline intraperitoneally on the 12th day of pregnancy. After birth the female pups (n = 20 in each group) were divided into four groups: (group 1) 0.9% saline prenatally, sesame oil (vehicle) postnatally; (group 2) LPS prenatally, sesame oil postnatally; (group 3) LPS prenatally, fulvestrant postnatally; (group 4) LPS prenatally, flutamide postnatally. Pups were injected subcutaneously into the neck with fulvestrant (estrogen receptor antagonist), 1.5 mg/kg in sesame oil, from postnatal day (PND) 5 to PND14; or flutamide (androgen receptor antagonist), 20 mg/kg in sesame oil, from PND14 to PND30. Rats of the control group were injected with sesame oil during the same time period. Parameters were evaluated by ELISA (serum estradiol and testosterone) and ovarian histology. The main findings were: (1) prenatal stress during the critical period resulted in delayed vaginal opening, decreased body weight and serum concentrations of sex steroids, and significant disorders in ovarian development; (2) postnatal estradiol and testosterone antagonist treatments decreased follicular atresia through increasing the number of healthy follicles and restored endogenous steroid production. Lay summaryImmunological stress, caused by simulating infection through exposure to a bacterial toxin (LPS), during a critical period of fetal development in laboratory rats results in delayed reproductive maturity, decreased body weight and decreased secretion of sex steroids in female offspring, and abnormalities in the ovaries like those in polycystic ovarian syndrome. These prenatally toxin-induced sexual disorders in females could be corrected by estradiol/testosterone antagonists during the postnatal period.


Assuntos
Estradiol/imunologia , Estradiol/fisiologia , Genitália/imunologia , Lipopolissacarídeos/farmacologia , Testosterona/fisiologia , Animais , Feminino , Lipopolissacarídeos/imunologia , Masculino , Síndrome do Ovário Policístico/imunologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Wistar , Estresse Psicológico/imunologia , Testosterona/antagonistas & inibidores , Testosterona/sangue
9.
Artigo em Inglês | MEDLINE | ID: mdl-30315922

RESUMO

Nonylphenol (NP) and Cadmium (Cd) are two common contaminants that can be detected in aquatic environments. Nevertheless, the combined toxicity of NP and Cd at environmentally relevant concentrations in aquatic organisms has not been thoroughly characterized to date. In the present study, the interactions between NP and Cd on male Sebastiscus marmoratus were studied. After 21 days of exposure, the brain aromatase activity was observed to be significantly induced by 100 ng/L NP and 40 µg/L Cd, whereas all of the concentrations of co-treatment resulted in an increase in brain aromatase activity. Additionally, NP could also reduce plasma testosterone concentration, while NP, Cd and their mixture could induce plasma 17ß-estradiol (E2) concentration and VTG concentration. The interactions between NP and Cd on the reproductive physiology were antagonism. Our results also support the notion of using these indicators as biomarkers for exposure to EDCs and further extend the boundary of biomonitoring to environmental levels.


Assuntos
Cádmio/toxicidade , Genitália Masculina/efeitos dos fármacos , Infertilidade Masculina/veterinária , Perciformes/fisiologia , Fenóis/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Aromatase/química , Aromatase/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Sinergismo Farmacológico , Disruptores Endócrinos/toxicidade , Biomarcadores Ambientais/efeitos dos fármacos , Estradiol/agonistas , Estradiol/sangue , Doenças dos Peixes/sangue , Doenças dos Peixes/induzido quimicamente , Doenças dos Peixes/metabolismo , Doenças dos Peixes/fisiopatologia , Proteínas de Peixes/agonistas , Proteínas de Peixes/metabolismo , Genitália Masculina/fisiopatologia , Infertilidade Masculina/induzido quimicamente , Infertilidade Masculina/metabolismo , Infertilidade Masculina/fisiopatologia , Masculino , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Concentração Osmolar , Perciformes/sangue , Testosterona/antagonistas & inibidores , Testosterona/sangue , Testes de Toxicidade Crônica , Vitelogeninas/sangue , Vitelogeninas/química
10.
Int J Radiat Oncol Biol Phys ; 103(5): 1068-1076, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30543857

RESUMO

PURPOSE: It is unclear if additional serum testosterone suppression below the castrate threshold of 50 ng/dL improves clinical outcomes in patients with localized prostate cancer undergoing definitive therapy. METHODS AND MATERIALS: We examined the association of subcastrate testosterone nadir with prostate-specific antigen (PSA) response and long-term clinical outcomes in 764 U.S. veterans with intermediate- or high-risk localized prostate cancer treated with androgen deprivation therapy and definitive radiation therapy from 2000 to 2015. Patients were categorized into testosterone nadir groups based on the minimum testosterone measurement during continuous gonadotropic-releasing hormone agonist therapy (<20 ng/dL vs 20-49 ng/dL). Outcomes included PSA response (3-month post-radiation therapy PSA and 2-year PSA nadir; multivariable linear regression) and long-term clinical outcomes (biochemical recurrence, metastasis, and prostate cancer-specific mortality; Fine-Gray competing risk regression). RESULTS: A testosterone nadir of 20 to 49 ng/dL was associated with higher 3-month post-radiation therapy PSA compared to <20 ng/dL (ß = 0.16, 95% confidence interval [CI], 0.06-0.26, P = .001) and higher 2-year PSA nadir (ß = 0.12, 95% CI, 0.04-0.21, P = .005). Compared to the <20-ng/dL group, the 20 to 49-ng/dL group showed higher 10-year biochemical recurrence rates (28.1% vs 18.3%) and metastasis rates (12.9% vs 7.8%) persisting on multivariable analyses (biochemical recurrence: sub-distribution hazard ratio [SDHR], 1.62 for 20-49 ng/dL, 95% CI, 1.07-2.45, P = .02; metastasis: SDHR, 2.19, 95% CI, 1.21-3.94, P = .009). There was a trend toward inferior prostate cancer-specific mortality for the 20 to 49-ng/dL group (SDHR, 1.95, 95% CI, 0.90-4.22, P = .09). CONCLUSIONS: Additional serum testosterone suppression below 50 ng/dL was associated with improved PSA responses and lower rates of biochemical recurrence and metastasis in this cohort of patients with localized prostate cancer.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Recidiva Local de Neoplasia/sangue , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Testosterona/sangue , Intervalos de Confiança , Seguimentos , Hormônio Liberador de Gonadotropina/agonistas , Humanos , Modelos Lineares , Masculino , Metástase Neoplásica , Orquiectomia , Neoplasias da Próstata/patologia , Valores de Referência , Risco , Testosterona/antagonistas & inibidores , Fatores de Tempo , Veteranos
12.
Andrologia ; 50(10): e13119, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30084497

RESUMO

Cigarette smoking is suggested to influence androgen milieu, which is closely associated with pathogenesis and prognosis of prostate cancer. In this study, we investigated the association between serum testosterone level before or during androgen-deprivation therapy (ADT) as well as prognoses and cigarette smoking status among men with metastatic prostate cancer. Serum testosterone level before ADT in current smokers (n = 6, median [interquartile range, IQR]; 454 ng/ml [426-478 ng/ml]) was significantly higher than that in nonsmokers (n = 26, median [IQR]; 397 ng/ml [312-435 ng/ml]). Serum testosterone level during ADT in current smokers (n = 7, median [IQR]; 7 ng/ml [3-11 ng/ml]) was comparable with that in nonsmokers (n = 55, median [IQR]; 9 ng/ml [3-20 ng/ml]). Progression-free survival and overall survival were comparable between current smokers and nonsmokers when adjusted with serum testosterone level before ADT or during ADT. These results suggest adequate pharmacological effect of ADT, even in current smokers. However, serum testosterone level before ADT was higher in current smokers. Thus, we need to interpret serum testosterone level in current smokers with caution.


Assuntos
Antagonistas de Androgênios/uso terapêutico , não Fumantes/estatística & dados numéricos , Neoplasias da Próstata/sangue , Fumantes/estatística & dados numéricos , Testosterona/sangue , Idoso , Antagonistas de Androgênios/farmacologia , Progressão da Doença , Humanos , Japão/epidemiologia , Masculino , Prognóstico , Intervalo Livre de Progressão , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Testosterona/antagonistas & inibidores , Resultado do Tratamento
13.
Pak J Pharm Sci ; 31(4(Supplementary)): 1565-1570, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30058549

RESUMO

Prevalence of hepatitis C virus (HCV) has been seen in more than 15% of Pakistani population. For the treatment of this infection, only two medicines, interferon, and ribavirin were approved in 1998. The concerned physicians evaluate side effects of these two antiviral drugs only during the treatment period. The long-term extra hepatic side effects are being neglected. This retrospective study was conducted with reference to induced infertility in HCV treated 40 male patients from the period 2008-2015. Possible effects of interferon therapy on fertility hormones and seminal parameters were assessed. Level of fertility hormones like serum Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), and testosterone was measured. For seminal parameters, guidelines from World Health Organization (WHO) were followed. Among forty cases of HCV patients who received interferon, only 14 (35%) have children and 26 (65%) could not conceive (p = 0.0372). After HCV treatment, HCV positive patients showed a significant change in the level of FSH, LH (p<0.05). Especially, it decreased testosterone level (p=0.0096). Similarly, HCV treatment significantly decreased sperm count (p=0.001) and motility (p=0.0005).


Assuntos
Antivirais/efeitos adversos , Infertilidade Masculina/sangue , Infertilidade Masculina/induzido quimicamente , Interferons/efeitos adversos , Motilidade Espermática/efeitos dos fármacos , Adulto , Hormônio Foliculoestimulante/antagonistas & inibidores , Hormônio Foliculoestimulante/sangue , Hepatite C/sangue , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Humanos , Infertilidade Masculina/diagnóstico , Hormônio Luteinizante/antagonistas & inibidores , Hormônio Luteinizante/sangue , Masculino , Pessoa de Meia-Idade , Motilidade Espermática/fisiologia , Testosterona/antagonistas & inibidores , Testosterona/sangue , Adulto Jovem
14.
DNA Cell Biol ; 37(7): 600-608, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29746152

RESUMO

Over the past decades, an increase has been described in exposure to environmental toxins; consequently, a series of studies has been carried out with the aim of identifying problems associated with health. One of the main risk factors is exposure to heavy metals. The adverse effects that these compounds exert on health are quite complex and difficult to elucidate, in that they act at different levels and there are various signaling pathways that are implicated in the mechanisms of damage. The Sertoli cells plays a role of vital importance during the process of spermatogenesis, and it has been identified as one of the principal targets of heavy metals. In the present review, cadmium, lead, and arsenic are broached as altering the physiology of the Sertoli cells, citing mechanisms that have been cited in the literature.


Assuntos
Arsênico/toxicidade , Cádmio/toxicidade , Poluentes Ambientais/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Chumbo/toxicidade , Células de Sertoli/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/genética , Hormônio Foliculoestimulante/genética , Hormônio Foliculoestimulante/metabolismo , Humanos , Hormônio Luteinizante/genética , Hormônio Luteinizante/metabolismo , Masculino , Células de Sertoli/citologia , Células de Sertoli/metabolismo , Transdução de Sinais , Espermatogênese/efeitos dos fármacos , Espermatogênese/genética , Testosterona/antagonistas & inibidores , Testosterona/genética , Testosterona/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Artigo em Inglês | MEDLINE | ID: mdl-29729480

RESUMO

Semicarbazide (SMC), a new marine pollutant, has anti-estrogenic effects on female Japanese flounder (Paralichthys olivaceus). However, whether SMC also affects the reproductive endocrine system of male marine organisms is currently unclear. In this study, Japanese flounder embryos were exposed to 1, 10, and 100 µg/L SMC for 130 days. Plasma testosterone (T) and 17ß-estradiol (E2) concentrations were significantly decreased in male flounders after SMC exposure. The expression of genes involved in T and E2 synthesis, including steroidogenic acute regulatory protein, cytochrome P450 11A1, 17α-hydroxylase, 17ß-hydroxysteroid dehydrogenase and cytochrome P450 19A, was down-regulated in the gonads, which may explain the decrease in plasma sex hormones levels. Moreover, SMC-mediated changes in the transcription of these steroidogenic genes were associated with reduced levels of follicle-stimulating hormone beta subunit (fshß), luteinizing hormone beta subunit (lhß), follicle-stimulating hormone receptor (fshr) and luteinizing hormone receptor (lhr) mRNA. In addition, down-regulated transcription of fshß and lhß in the SMC exposure groups was affected by reduced mRNA levels of seabream gonadotropin-releasing hormone (sbgnrh), g-protein-coupled receptor 54 (gpr54) in the kisspeptin/gpr54 system, as well as the gamma-aminobutyric acid (GABA) synthesis enzyme glutamic acid decarboxylase (gad). Overall, our results showed that environmentally relevant concentrations of SMC exerted anti-androgenic effects in male flounders via impacting HPG axis, kiss/gpr54 system and GABA synthesis, providing theoretical support for investigating reproductive toxicity of environmental pollutants that interfere with the neuroendocrine system.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Linguados/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Semicarbazidas/toxicidade , Testículo/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Antagonistas de Androgênios/toxicidade , Animais , Aquicultura , China , Embrião não Mamífero/metabolismo , Desenvolvimento Embrionário/efeitos dos fármacos , Repressão Enzimática/efeitos dos fármacos , Estradiol/biossíntese , Estradiol/sangue , Estradiol/química , Antagonistas de Estrogênios/toxicidade , Proteínas de Peixes/antagonistas & inibidores , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Linguados/sangue , Linguados/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/crescimento & desenvolvimento , Sistema Hipotálamo-Hipofisário/metabolismo , Kisspeptinas/antagonistas & inibidores , Kisspeptinas/genética , Kisspeptinas/metabolismo , Masculino , Distribuição Aleatória , Testículo/crescimento & desenvolvimento , Testículo/metabolismo , Testosterona/antagonistas & inibidores , Testosterona/biossíntese , Testosterona/sangue , Testes de Toxicidade Crônica
16.
Syst Biol Reprod Med ; 64(4): 246-259, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29613814

RESUMO

Cisplatin (CIS) is widely applied for its antihematological malignancies properties and as antisolid tumors drugs. However, it could cause testicular damage related with oxidative stress and testosterone synthesis disorder. Studies reported that grape seed procyanidins extract (GSPE) could improve CIS induced-testes lesion via scavenging free radicals in animals, although its mechanisms were unclear. Therefore, the purpose of the present study was to explore the antagonistic mechanisms of GSPE on CIS-induced testes lesion. Rats were treated with 10 mg/kg by weight CIS by intraperitoneal injection singly on the 11th day, and different doses of GSPE were administrated via intragastric gavage for 15 days consecutively. The results showed that GSPE improved the pathological changes of testicular tissue, and the decreased concentrations of testosterone in serum induced by CIS. GSPE inhibited CIS-induced oxidative/nitrative stress, as well as increased the mRNA and protein levels of testosterone synthetase in rat testes. In conclusion, the main protection exerted by GSPE on CIS-induced testicular toxicity is related to its effects including suppressing oxidative/nitrative stress and up-regulating expression of testosterone synthetase. ABBREVIATIONS: CIS: Cisplatin; GSPE: grape seed procyanidins extract; LH: luteinizing hormone; FSH: follicle-stimulating hormone; STAR: steroidogenic acute regulatory protein; CYP11A1: P450 side chain cleavage enzyme; HSD3B1: 3ß-hydroxysteroid dehydrogenase; CYP17A1: 17α-hydroxylase; HSD17B: 17ß-hydroxysteroid dehydrogenase; ROS: reactive oxygen species; O2-: superoxide anion; H2O2: hydrogen peroxide; •OH: hydroxyl radicals; SOD: superoxide dismutase; CAT: catalase; GSH-Px: glutathione peroxidase; LPO: lipid peroxidation; 8-OHdG: 8-hydroxy-2-deoxyguanosine; HO-1: heme oxygenase-1; MT-1: metallothionein-1; NO: nitric oxide; ONOO-: peroxynitrite; NOS: nitric oxide synthases; nNOS: neuronal NOS; iNOS: inducible NOS; eNOS: endothelial NOS; MDA: malondialdehyde; GSH: glutathione; T-AOC: total antioxidant capacity; TNOS: total nitric oxide synthases; Lhcgr: luteinizing hormone receptor; Scarb1: lipoprotein-receptor; Cyp19a1: 19α-hydroxylase; ELISA: enzyme linked immunosorbent assay; RT-qPCR: reverse transcription-quantitative polymerase chain reaction; PAS: periodic acid-Schiff; MTs: Metallothioneins; cAMP: cyclic adenosine monophosphate; cDNA: complementary DNA; RIPA: radioimmunoprecipitation buffer; PMSF: phenylmethanesulfonyl fluoride; PVDF: polyvinylidenedifluoride; ß-actin: beta-actin.


Assuntos
Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Extrato de Sementes de Uva/uso terapêutico , Proantocianidinas/uso terapêutico , Testículo/efeitos dos fármacos , Testosterona/biossíntese , Animais , Avaliação Pré-Clínica de Medicamentos , Extrato de Sementes de Uva/farmacologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Proantocianidinas/farmacologia , Distribuição Aleatória , Ratos Wistar , Testículo/enzimologia , Testículo/patologia , Testosterona/antagonistas & inibidores , Vitis
17.
Toxicol Mech Methods ; 28(7): 507-519, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29606031

RESUMO

BACKGROUND: Cryptorchidism is a common condition of childhood, and it is known to impair fertility potential. However, the underlying mechanisms remain unclear. METHODS: This study constructed two cryptorchid rat models to investigate the roles of apoptosis and autophagy in testicular impairment induced by cryptorchidism. Pregnant rats were randomly divided into three groups. Group I: non-treated rats were used as controls. Group II: injected with drug Flutamide (Flu) 25 mg/kg/bw/d from gestation day (GD) 11-19. Group III: daily intragastric administration of 750 mg/kg/bw/d di-2-ethylhexylphosphate (DEHP) from GD 7-19. The cubs were feed normally and the testes were excised on postnatal day (PND) 30. RESULTS: Our results demonstrated cryptorchidism models induced noticeable decreased fertility, significantly reduced sperm count, increased sperm abnormality rate, decreased testosterone and severe testicular damage in histomorphology. Intriguingly, the level of apoptosis marker FAS, Cytochrome C and caspase-3 increased in Flu-induced and DEHP-induced groups. DEHP-induced treatment simultaneously increased the number of autophagosomes and the levels of autophagy marker LC3-II and p62. Significant decrease of autophagy gene (LC3-II and p62) expression is found in Flu-induced rats testes. CONCLUSION: Taken together, deficient autophagy is involved in testicular spermatogenesis damage of cryptorchidism rats. And this autophagy defect is caused by deficient degradation.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Criptorquidismo/induzido quimicamente , Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Flutamida/toxicidade , Testículo/efeitos dos fármacos , Antagonistas de Androgênios/toxicidade , Animais , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Autofagossomos/patologia , Autofagossomos/ultraestrutura , Biomarcadores/sangue , Biomarcadores/metabolismo , Criptorquidismo/sangue , Criptorquidismo/metabolismo , Criptorquidismo/patologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Masculino , Troca Materno-Fetal , Microscopia Eletrônica de Transmissão , Plastificantes/toxicidade , Gravidez , Distribuição Aleatória , Ratos Sprague-Dawley , Espermatogênese/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Testículo/ultraestrutura , Testosterona/antagonistas & inibidores , Testosterona/sangue
18.
Molecules ; 23(4)2018 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-29662027

RESUMO

This study developed the pharmacokinetic (PK)-pharmacodynamic (PD) model of the testosterone-suppressive effect of leuprolide for evaluation of the sustained release (SR) depot and leuprolide solution in rats with or without prostate cancer. Six groups of rats were divided by the routes of administration (intravenous and subcutaneous injection) and kinds of formulation (vehicle, leuprolide solution, and SR depot). The PK profile after subcutaneous injection of leuprolide solution could be well-described by the one-compartment model. The absorption rate constant, the total body clearance, and the volume of distribution were estimated at 16.67 h-1, 514.46 mL/h, and 487.40 mL. Using PK parameters in the solution-administered group, the PK model for the SR depot was developed. The PK-PD model was constructed by describing the testosterone-suppressive effect of leuprolide using the feedback turnover model. The response of testosterone after administration of each formulation was well described using this PK-PD model for the estimation of PD parameters (EC50, Emax, h) and systemic parameters (kin, kout, kf on, kf off). The developed PK-PD model containing an inhibitory feedback system could successfully describe the testosterone-suppressive effect of leuprolide in the type of formulation. The PK-PD model developed would be useful for evaluating the formulation of similar drugs whose effect is regulated through the feedback mechanism.


Assuntos
Leuprolida/farmacocinética , Leuprolida/uso terapêutico , Modelos Biológicos , Neoplasias da Próstata/tratamento farmacológico , Testosterona/antagonistas & inibidores , Animais , Área Sob a Curva , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Leuprolida/administração & dosagem , Leuprolida/química , Masculino , Ratos Wistar
19.
Eur J Med Chem ; 150: 930-945, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29602039

RESUMO

The aldo-keto reductase 1C3 (AKR1C3) isoform plays a vital role in the biosynthesis of androgens and is considered an attractive target in prostate cancer (PCa). No AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid and indomethacine are non-steroidal anti-inflammatory drugs known to inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. Recently, we employed a scaffold hopping approach to design a new class of potent and selective AKR1C3 inhibitors based on a N-substituted hydroxylated triazole pharmacophore. Following a similar strategy, we designed a new series focused around an acidic hydroxybenzoisoxazole moiety, which was rationalised to mimic the benzoic acid role in the flufenamic scaffold. Through iterative rounds of drug design, synthesis and biological evaluation, several compounds were discovered to target AKR1C3 in a selective manner. The most promising compound of series (6) was found to be highly selective (up to 450-fold) for AKR1C3 over the 1C2 isoform with minimal COX1 and COX2 off-target effects. Other inhibitors were obtained modulating the best example of hydroxylated triazoles we previously presented. In cell-based assays, the most promising compounds of both series reduced the cell proliferation, prostate specific antigen (PSA) and testosterone production in AKR1C3-expressing 22RV1 prostate cancer cells and showed synergistic effect when assayed in combination with abiraterone and enzalutamide. Structure determination of AKR1C3 co-crystallized with one representative compound from each of the two series clearly identified both compounds in the androstenedione binding site, hence supporting the biochemical data.


Assuntos
Membro C3 da Família 1 de alfa-Ceto Redutase/antagonistas & inibidores , Antineoplásicos/farmacologia , Benzoxazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Ácido Flufenâmico/farmacologia , Membro C3 da Família 1 de alfa-Ceto Redutase/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Benzoxazóis/síntese química , Benzoxazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ácido Flufenâmico/síntese química , Ácido Flufenâmico/química , Humanos , Estrutura Molecular , Antígeno Prostático Específico/antagonistas & inibidores , Antígeno Prostático Específico/metabolismo , Relação Estrutura-Atividade , Testosterona/antagonistas & inibidores , Testosterona/biossíntese
20.
Toxicol Lett ; 288: 17-24, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29447956

RESUMO

Chlorocholine chloride (CCC) is widely used to regulate plant growth. Considerable attention has been focused on its reproductive and developmental toxicities. In order to investigate the effects of pubertal CCC exposure on testicular testosterone (T) synthesis, male SD rats were exposed to CCC by oral gavage at doses of 0, 75, 150 and 300 mg/kg bw/day from postnatal day 23 to 70. We observed that pubertal CCC exposure lowered the body weight and the mean Johnsen's score. The percentage of seminiferous tubules with deciduous spermatogenic cells was increased in the 75 and 150 mg/kg bw/day groups. In addition, pubertal CCC exposure reduced the testicular absolute weights in the 75 and 300 mg/kg bw/day groups as well as the sperm motility in epididymides in the 150 mg/kg bw/day group. A significant decrease of testicular T was observed while levels of hypothalamic gonadotropin-releasing-hormone (GnRH) and serum luteinizing hormone (LH) were increased. Protein levels of steroidogenic acute regulatory (StAR), cholesterol side-chain cleavage enzyme (P450scc) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) were decreased. Taken together, these results indicate that pubertal CCC exposure in rats might decrease testicular T synthesis by suppressing the expression of steroidogenic enzymes, which partially lead to an impairment on spermatogenesis.


Assuntos
Clormequat/toxicidade , Esteroides/biossíntese , Testículo/metabolismo , Testosterona/biossíntese , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Epididimo/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Tamanho do Órgão , Ratos , Ratos Sprague-Dawley , Túbulos Seminíferos/efeitos dos fármacos , Maturidade Sexual , Motilidade Espermática/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Esteroides/antagonistas & inibidores , Testículo/efeitos dos fármacos , Testículo/enzimologia , Testosterona/antagonistas & inibidores
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