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1.
J Urol ; 203(5): 940-948, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31845837

RESUMO

PURPOSE: Beyond testosterone, several steroids contribute to the activation of the androgen receptor pathway, but their relative contributions to the activation of the androgen receptor signaling axis in patients with castrated prostate cancer remain unknown. MATERIALS AND METHODS: Serum levels of 9 steroids were measured by mass spectrometry from continuously castrated patients of the PR.7 study (219) and from the PCA24 cohort (116). For each steroid standard curves for dose dependent prostate specific antigen promoter activation were built in castration sensitive (LAPC4) and resistant (VCaP) prostate cancer models. Standard curves were used to determine the androgen receptor activation potency for each steroid measurement from patients in these trials. RESULTS: In LAPC4 and VCaP cells testosterone, dihydrotestosterone and androstenedione induced androgen receptor transcriptional activity, while dehydroepiandrosterone, 5alpha-androstan-3beta,17beta-diol, androstenediol and androsterone stimulated androgen receptor only in VCaP cells. Extragonadal steroids were responsible for 34% (LAPC4) and 88% (VCaP) of the serum total androgen receptor transcriptional activity found in castrated cases. The total androgen receptor transcriptional activity secondary to testosterone, dihydrotestosterone and androstenedione was associated with time to castration resistance in patients from the PR.7 study (HR 2.17, 95% CI 1.12-4.23, p=0.02) in multivariate analysis using the castration sensitive model (LAPC4). Androgen receptor transcriptional activity of extragonadal androstenedione was the only steroid statistically associated with time to castration resistance in univariate analysis (HR 1.89, 95% CI 1.04-3.44, p=0.036). CONCLUSIONS: Extragonadal steroids contribute significantly to the androgen receptor axis activation at castration levels of testosterone in recurrent nonmetastatic prostate cancer and these sustain the development of castration resistance after primary local treatment.


Assuntos
Androstenodiona/farmacologia , Castração/métodos , Recidiva Local de Neoplasia/terapia , Neoplasias da Próstata/terapia , Receptores Androgênicos/metabolismo , Testosterona/análogos & derivados , Testosterona/farmacologia , Anabolizantes/farmacologia , Androgênios/farmacologia , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Seguimentos , Humanos , Masculino , Espectrometria de Massas , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Estudos Prospectivos , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/efeitos dos fármacos , Fatores de Tempo
2.
Acta Histochem ; 121(8): 151441, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31522738

RESUMO

PURPOSE: This study aimed to evaluate the effects of estrogen reduction on amyloid deposition, some lipid metabolism and oxidative stress markers, PSA-like production and p63 expression in the prostate of the adult rat. METHODS: Aromatase inhibitor: Formestane (4-OHA), was administrated to male rats, at a dose of 0.1 mg/kg b.w./day, for 10 days. The control group (CONT) received the same volume of placebo injection (NaCl 0.9%). RESULTS: 4-OHA treatment induced a significant accumulation of intraprostatic cholesterol (138.90 ±â€¯17.64 vs 85.12 ±â€¯2.87, p = 0.01); against an insignificant diminution of malondialdehyde (412.6 ±â€¯54.35 vs 842.70 ±â€¯336.50, p > 0.05) and glutathione (2.40 ±â€¯0.23 vs 3.65 ±â€¯0.88, p > 0.05). This was associated with a significant decrease of nitric oxide (31.76 ±â€¯7.07 vs 179.40 ±â€¯58.35, p = 0.024). Additionally, 4-OHA significantly increased the intraprostatic production of PSA-like (11.12 ±â€¯2.78 vs 3.91 ±â€¯0.43, p = 0.043). The prostatic histology revealed an amyloid deposition, in all prostatic lobes and a smooth muscle layer growth (p < 0.05); especially significant in the dorsal and lateral lobes. Theses lobes manifested a basal cells proliferation, with a 3-fold increase of p63 expression (p < 0.001). The ventral lobe presented epithelial atrophy (37.80 ±â€¯16.20 vs 167.60 ±â€¯5.16, p < 0.05); with occasional and significant proliferative foci (247.00 ±â€¯9.573 vs 167.60 ±â€¯5.16 p < 0.05). DISCUSSION AND CONCLUSION: Aromatase inhibition, in the adult male rat, alters the prostatic function by reducing nitric oxide availability and inducing amyloid deposition along with limiting the differentiation of basal cells, through a lobe-specific p63-overexpression.


Assuntos
Amiloide/metabolismo , Androstenodiona/análogos & derivados , Inibidores da Aromatase/efeitos adversos , Aromatase/metabolismo , Próstata/enzimologia , Androstenodiona/efeitos adversos , Androstenodiona/farmacologia , Animais , Inibidores da Aromatase/farmacologia , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Imuno-Histoquímica , Masculino , Próstata/patologia , Ratos , Ratos Wistar , Fatores de Tempo , Proteínas Supressoras de Tumor/biossíntese
3.
Neurosci Lett ; 701: 65-70, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-30742936

RESUMO

CA1 hippocampal expression of α4ßδ GABAA receptors (GABARs) increases at the onset of puberty in female mice, an effect dependent upon the decline in hippocampal levels of the neurosteroid THP (3α-OH-5α-pregnan-20-one) which occurs at this time. The present study further characterized the mechanisms underlying α4ßδ expression, assessed in vivo. Blockade of pubertal levels of 17ß-estradiol (E2) (formestane, 0.5 mg/kg, i.p. 3 d) reduced α4 and δ expression by 75-80% (P < 0.05) in CA1 hippocampus of female mice, assessed using Western blot techniques. Conversely, E2 administration increased α4 and δ expression by 50-100% in adults, an effect enhanced by more than 2-fold by concomitant administration of the 5α-reductase blocker finasteride (50 mg/kg, i.p., 3d, P < 0.05), suggesting that both declining THP levels and increasing E2 levels before puberty trigger α4ßδ expression. This effect was blocked by ICI 182,780 (20 mg/kg, s.c., 3 d), a selective blocker of E2 receptor-α (ER-α). These results suggest that both the rise in circulating levels of E2 and the decline in hippocampal THP levels at the onset of puberty trigger maximal levels of α4ßδ expression in the CA1 hippocampus.


Assuntos
Região CA1 Hipocampal/metabolismo , Estradiol/farmacologia , Pregnanolona/análogos & derivados , Receptores de GABA-A/metabolismo , Androstenodiona/análogos & derivados , Androstenodiona/farmacologia , Animais , Inibidores da Aromatase/farmacologia , Antagonistas de Estrogênios , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Pregnanolona/antagonistas & inibidores , Pregnanolona/farmacologia
4.
Theriogenology ; 120: 16-24, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30081244

RESUMO

Endocrine effects as 11-ketotestosterone (11-KT), an unaromatizable androgen, regulating the follicles growth in the previtellogenic stage of eel reproduction have been widely elucidated. However, the influence of aromatizable androgens on the brain-pituitary-gonad axis during oogenesis in A. japonica has not been clearly elaborated. In the study, androstenedione (AD) and 17α-methyltestosterone (MT) were employed together to induce ovary development of seven-year-old female Anguilla japonica through feeding or exposure in the migration season. After female A. japonica had been fed with commercial diet containing 5 mg AD and MT kg d-1 body weight respectively for 45 d in fresh water (Trial I), the development of oocytes still remained at the oil droplet stage, but the GSI and follicle diameter increased significantly. The serum 11-KT level and expression of liver vitellogenin mRNA were significantly elevated. After female fish had been exposed to seawater containing 50 µg L-1 AD and MT respectively for 45 d (Trial II), the ovaries of A. japonica almost reached midvitellogenic stage and the GSI and follicle diameter increased significantly. Yolk granular layer was observed in the peripheral ooplasm. The serum 11-KT level maintained consistently low, and the serum E2 level declined significantly to a relatively low level. The expression levels of ovarian arα and cyp19a1, brain (with pituitary together) mGnRH and lhß increased significantly. The results showed that A. japonica in Trial II appeared a higher ovarian development than those in Trial I. These findings indicated that AD and MT increased the oil droplet and enlarged follicle diameter in previtellogenic stage, while the vitellogenesis and gonadotropin release did not occur in Trial I. In Trial II, AD and MT promoted vitellogenesis by stimulating the ovary expression of arα and by up-regulating brain mGnRH and pituitary lhß expression.


Assuntos
Androstenodiona/farmacologia , Anguilla/fisiologia , Metiltestosterona/farmacologia , Ovário/efeitos dos fármacos , Indução da Ovulação/veterinária , Anguilla/crescimento & desenvolvimento , Animais , Feminino , Subunidade beta do Hormônio Folículoestimulante/metabolismo , Hormônio Luteinizante/metabolismo , Ovário/crescimento & desenvolvimento , Ovário/patologia , Indução da Ovulação/métodos , Vitelogeninas/metabolismo
5.
Toxicol Lett ; 292: 39-45, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29702199

RESUMO

4-Hydroxyandrost-4-ene-3,17-dione, also named formestane, is an irreversible aromatase inhibitor and therapeutically used as anti-breast cancer medication in post-menopausal women. Currently, no therapeutical indication led to approval of its 17-hydroxylated analog 4-hydroxytestosterone, an anabolic steroid. However, it is currently investigated in a clinical trial for breast cancer. In context with sports doping, aromatase inhibitors are administered to reduce estrogenic side effects of misused anabolic substances or their metabolites. Therefore, both substances are prohibited in sports by the World Anti-Doping Agency (WADA). Analysis of urinary phase I and phase II metabolites showed similar results for both compounds. In the current investigation, 4-hydroxyandrost-4-ene-3,17-dione, 4-hydroxytestosterone and seven of their described urinary metabolites as well as 2α-hydroxyandrostenedione were tested in the yeast androgen screen and the yeast estrogen screen. Androgenic effects were observed for all tested substances, except for one, which showed anti-androgenic properties. With regard to the yeast estrogen screen, estrogenic effects were observed for only two metabolites at rather high concentrations, while six out of the ten substances tested showed anti-estrogenic properties. In terms of the strong androgenic effect observed for 4-hydroxytestosterone (10-8 M), 4-hydroxyandrost-4-ene-3,17-dione (10-8 M) and two more urinary metabolites, the yeast androgen assay may also be used to trace abuse in urine samples.


Assuntos
Androgênios/farmacologia , Androstenodiona/análogos & derivados , Doping nos Esportes , Receptor alfa de Estrogênio/agonistas , Estrogênios/farmacologia , Hidroxitestosteronas/farmacologia , Substâncias para Melhoria do Desempenho/farmacologia , Receptores Androgênicos/efeitos dos fármacos , Detecção do Abuso de Substâncias/métodos , Congêneres da Testosterona/farmacologia , Leveduras/efeitos dos fármacos , Androgênios/química , Androstenodiona/química , Androstenodiona/metabolismo , Androstenodiona/farmacologia , Biotransformação , Relação Dose-Resposta a Droga , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Estrogênios/química , Estrogênios/metabolismo , Humanos , Hidroxitestosteronas/química , Hidroxitestosteronas/metabolismo , Simulação de Acoplamento Molecular , Substâncias para Melhoria do Desempenho/química , Substâncias para Melhoria do Desempenho/metabolismo , Conformação Proteica , Receptores Androgênicos/química , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Congêneres da Testosterona/química , Congêneres da Testosterona/metabolismo , Leveduras/genética , Leveduras/metabolismo
6.
Ecotoxicol Environ Saf ; 156: 403-408, 2018 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-29587208

RESUMO

This study aimed to determine the effects of Androstenodione (AED) on the transcriptional expression of genes involved in the hypothalamic-pituitary-gonadal (HPG) and the hypothalamic-pituitary-adrenal (HPA) axes in the zebrafish embryos/larvae. Zebrafish embryos were exposed to 0, 4.0, 45.0, 487.0, and 980.0 ng/L of AED from the day of fertilization to 144 h post fertilization (hpf), during which the transcriptional profiles of key genes related to the HPG and HPA axes were examined daily using quantitative real-time PCR. The AED exposure significantly up-regulated several receptor signaling pathways and the key genes involved in various steps of the steroidogenic pathways were also affected. In addition, the AED exposure could significantly modulate the transcriptional profiles of the other target genes related to hypothalamic and pituitary hormones. The findings of this study suggest that AED, at environmentally relevant concentrations, affects the adrenal endocrine systems and the reproduction of zebrafish by interrupting the HPG and HPA axes.


Assuntos
Androstenodiona/farmacologia , Gônadas/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Larva/efeitos dos fármacos , Hipófise/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Animais , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Sistema Endócrino/efeitos dos fármacos , Regulação da Expressão Gênica , Gônadas/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Hipófise/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodução/efeitos dos fármacos , Transcrição Genética , Peixe-Zebra/embriologia
7.
J Appl Toxicol ; 38(5): 628-637, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29205417

RESUMO

A 24 hour in vitro Xenopus oocyte maturation (germinal vesicle breakdown [GVBD]) assay developed by Pickford and Morris (Environmental Health Perspectives, 1999, 107, 285-292) was used to screen a series of substituted glycol ethers (GEs). Substituted GEs included: ethylene glycol monomethyl ether (EGME); EG monoethyl ether (EGEE); EG monopropyl ether (EGPE); EG monobutyl ether (EGBE); EG monohexyl ether (EGHE); diethylene glycol monomethyl ether (DGME); triethylene glycol monomethyl ether (TGME); ethylene glycol monophenyl ether (EGPhE); EG monobenzyl ether (EGBeE); EG diphenyl ether (EGDPhE); and propylene glycol monophenyl ether (PGPhE). The GEs inhibited progesterone- or androstenedione-induced GVBD with the following relative potency: EGPhE > PGPhE > EGME >> EGEE ≥ EGBeE > EGPE >> EGBE >EGHE > EGDPhE >> DGME ≥ TGME, or EGPhE >> PGPhE >> EGBeE > EGDPhE > EGEE > EGME > EGPE > EGBE, EGHE, DGME and TGME, respectively. Further, [3 H]progesterone or [3 H]androstenedione binding affinities to the oocyte plasma membrane progesterone receptor (OMPR) or classical androgen receptor (AR) were: EGME > EGPhE ≥ PGPhE ≥ EGEE > EGBeE >> EGPE >> EGBE ≥ EGHE > EGDPhE, TGME, and DGME, or EGPhE > PGPhE >> EGBeE > EGDPhE >> EGEE ≥ EGME >> EGPE, EGBE, and EGHE > DGME and TGME, respectively. Binary joint mixture studies with the GVBD model using flutamide (AR antagonist) and EGPhE indicated that flutamide/EGPhE mixture acted in a concentration additive manner. The effects of substituted GE series, however, may be mediated through the OMPR; the potency of EGPhE may be the result of bimodal inhibition of both the OMPR and AR pathways.


Assuntos
Bioensaio/métodos , Disruptores Endócrinos/toxicidade , Éteres/toxicidade , Glicóis/toxicidade , Oócitos/efeitos dos fármacos , Androgênios , Androstenodiona/farmacologia , Animais , Etilenoglicóis , Técnicas In Vitro , Oócitos/crescimento & desenvolvimento , Progesterona/farmacologia , Xenopus laevis
8.
Anim Reprod Sci ; 184: 187-195, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28760664

RESUMO

The goal of the present research was to evaluate the efficiency of 11ß-hydroxyandrostenedione (OHA) applied in the diet to achieve sex reversal in the European whitefish (Coregonus lavaretus). At 32day post-hatching, fish were reared in four groups: fish fed with 10ppm of OHA (10 OHA), fish fed with 20ppm of OHA (20 OHA), fish fed without OHA (C) and fish fed without OHA and reared in the water from 20 OHA group (R). The experimental groups were conducted in separate recirculation systems and the first phase of the experiment lasted 63days. For the histological analysis of the gonads, fish from all groups were reared without OHA treatment for an additional 91days (second phase). At the end of the first phase of the experiment, survival of the whitefish ranged from 34.5±11.1% to 51.5±7.3%. The final body weight and coefficient of variation in the weight ranged from 5.6±1.2g to 6.9±1.5g and from 21.5 to 22.7%, respectively. No negative effects of OHA treatment on the growth and the survival of the whitefish were found. Six histological categories of the whitefish gonads were observed. Apart from the typical ovaries and testes, two types of the intersexual gonads (ovotestis and testis-ova) and two types of the sterile-altered gonads were distinguished. No gonadal females were found among fish from any of OHA groups. Gonadal males constituted of 60% and 50% of the fish from 10 OHA and 20 OHA groups, respectively. Intersexes were observed in all groups with the highest proportion found among fish from R variant. Rate of sterile individuals in 10 OHA and 20 OHA groups was 17% and 30%, respectively. The proportion of fish with normal testes to fish with other types of gonad varied from 0.43:1 to 1.5:1 with the higher ratio observed in both OHA groups. Lack of the females among fish from OHA groups suggested OHA affected growth and development of ovaries in the whitefish. However, a high percentage of the sterile fish in both OHA treated groups indicated application of lower doses of OHA for masculinization of the whitefish in the further research.


Assuntos
Androstenodiona/análogos & derivados , Androstenodiona/farmacologia , Salmonidae , Ração Animal/análise , Animais , Dieta , Feminino , Reprodução/efeitos dos fármacos
9.
Biol Sex Differ ; 8(1): 27, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28810930

RESUMO

BACKGROUND: Sexual differentiation of the male brain, and specifically the stress circuitry in the hypothalamus, is primarily driven by estrogen exposure during the perinatal period. Surprisingly, this single hormone promotes diverse programs of sex-specific development that vary widely between different cell types and across the developing male brain. The complexity of this phenomenon suggests that additional layers of gene regulation, including microRNAs (miRNAs), must act downstream of estrogen to mediate this specificity. METHODS: To identify noncanonical mediators of estrogen-dependent sex-specific neural development, we assayed the miRNA complement of the mouse PN2 hypothalamus by microarray following an injection of vehicle or the aromatase inhibitor, formestane. Initially, multivariate analyses were used to test the influence of sex and experimental group on the miRNA environment as a whole. Then, we utilized traditional hypothesis testing to identify individual miRNA with significantly sex-biased expression. Finally, we performed a transcriptome-wide mapping of Argonaute footprints by high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (Ago HITS-CLIP) to empirically characterize targeting relationship between estrogen-responsive miRNAs and their messenger RNA (mRNA) targets. RESULTS: In this study, we demonstrated that the neonatal hypothalamic miRNA environment has robust sex differences and is dynamically responsive to estrogen. Analyses identified 162 individual miRNAs with sex-biased expression, 92 of which were estrogen-responsive. Examining the genomic distribution of these miRNAs, we found three miRNA clusters encoded within a 175-kb region of chromosome 12 that appears to be co-regulated by estrogen, likely acting broadly to alter the epigenetic programming of this locus. Ago HITS-CLIP analysis uncovered novel miRNA-target interactions within prototypical mediators of estrogen-driven sexual differentiation of the brain, including Esr1 and Cyp19a1. Finally, using Gene Ontology annotations and empirically identified miRNA-mRNA connections, we identified a gene network regulated by estrogen-responsive miRNAs that converge on biological processes relevant to sexual differentiation of the brain. CONCLUSIONS: Sexual differentiation of the perinatal brain, and that of stress circuitry in the hypothalamus specifically, seems to be particularly susceptible to environmental programming effects. Integrating miRNA into our conceptualization of factors, directing differentiation of this circuitry could be an informative next step in efforts to understand the complexities behind these processes.


Assuntos
Epigênese Genética , Hipotálamo/crescimento & desenvolvimento , Hipotálamo/metabolismo , MicroRNAs/metabolismo , RNA Mensageiro/metabolismo , Caracteres Sexuais , Androstenodiona/análogos & derivados , Androstenodiona/farmacologia , Animais , Animais Recém-Nascidos , Inibidores da Aromatase/farmacologia , Estrogênios/metabolismo , Redes Reguladoras de Genes , Hipotálamo/efeitos dos fármacos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Análise em Microsséries , Análise Multivariada , Transcriptoma/fisiologia
11.
Reprod Fertil Dev ; 29(11): 2217-2224, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28356185

RESUMO

In vivo, oocyte maturation is triggered by the ovulatory LH surge, whereas in vitro it is precociously induced when the cumulus-oocyte complex is removed from the follicle. Natriuretic peptide C (NPPC) delays germinal vesicle breakdown (GVBD) while increasing oocyte-cumulus communication during in vitro maturation (IVM) in cattle. In the present study we first tested the hypothesis that steroids secreted by the follicle (17ß-oestradiol, progesterone and androstenedione) interact with NPPC to delay GVBD and to maintain oocyte-cumulus communication as assessed by transfer of a dye (Lucifer Yellow) from the oocyte to cumulus cells. Then, we assessed the effects of steroid hormones and NPPC, alone and in combination in a pre-IVM culture, on embryo production. The combination of NPPC with steroids delayed GVDB, increased natriuretic peptide receptor 2 (NPR2) mRNA abundance in cumulus cells during culture, and maintained oocyte-cumulus communication at levels not different from non-cultured controls. The addition of steroids and/or NPPC to a pre-IVM culture did not alter blastocyst rates after IVF, but supplementation with steroids increased blastocyst total cell number. The present study provides evidence, for the first time in cattle, that steroids interact with NPPC to regulate oocyte nuclear maturation and oocyte-cumulus communication, and improve oocyte developmental competence.


Assuntos
Androstenodiona/farmacologia , Células do Cúmulo/metabolismo , Estradiol/farmacologia , Técnicas de Maturação in Vitro de Oócitos/veterinária , Peptídeo Natriurético Tipo C/farmacologia , Oócitos/metabolismo , Progesterona/farmacologia , Animais , Bovinos , Células do Cúmulo/efeitos dos fármacos , Feminino , Oócitos/efeitos dos fármacos , Oogênese/efeitos dos fármacos , Folículo Ovariano/metabolismo
12.
Theriogenology ; 86(6): 1530-1540, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27371972

RESUMO

This study investigated the effect of androstenedione (A4) alone or in association with different concentrations of bovine recombinant FSH on the IVC of isolated goat preantral follicles. Follicles were mechanically isolated from ovarian tissue and cultured for 18 days in α-minimum essential medium supplemented or not with A4 (10 ng/mL) alone or in association with fixed (A4 + FixFSH: 100 ng/mL) or sequential (A4 + SeqFSH: Day 0, 100 ng/mL; Day 6, 500 ng/mL; Day 12, 1000 ng/mL) concentrations of FSH. After 18 days, the oocytes were recovered for IVM and fluorescence analysis. At Day 18 of culture, only A4 + SeqFSH treatment showed a lower (P < 0.05) rate of intact follicles, survival probability, and meiotic resumption, as well as higher (P < 0.05) percentage of degeneration and/or extrusion after antrum formation. Taken together, these results reported a positive correlation between fast-growing follicles and follicles that degenerated and/or extruded after antrum formation. When compared with control, the addition of A4 alone or in association of FSH did not increase (P > 0.05) the estradiol production or androstenedione levels on Day 6. However, on Day 18, the androstenedione levels were significantly lower in A4 + SeqFSH treatment when compared with A4 alone or to A4 + FixFSH treatments, whereas the estradiol production did not differ (P > 0.05). In summary, this study found that accelerated follicle growth negatively impacted the morphology of caprine preantral follicle cultured in vitro. In addition, the association of androstenedione with increasing concentration of FSH was detrimental to follicular survival and oocyte meiotic resumption.


Assuntos
Androstenodiona/farmacologia , Cabras , Meiose/fisiologia , Oócitos/citologia , Folículo Ovariano/crescimento & desenvolvimento , Androstenodiona/biossíntese , Animais , Bovinos , Meios de Cultura , Estradiol/biossíntese , Feminino , Hormônio Foliculoestimulante/administração & dosagem , Hormônio Foliculoestimulante/análise , Técnicas de Maturação in Vitro de Oócitos/veterinária , Meiose/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/metabolismo , Proteínas Recombinantes , Técnicas de Cultura de Tecidos/veterinária
13.
Gen Comp Endocrinol ; 233: 63-72, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27181751

RESUMO

Knowledge about sensitivities and responses of amphibian larvae to sex steroids and the chemicals alike is the first step towards understanding and assessing the effect of diverse chemicals that interfere with gonadal development and other endocrine functions. Herein, we used Microhyla ornata to determine the role of sex steroids on its gonad differentiation and sex ratio. Our results show that the exposure to increasing concentrations of estradiol-17ß throughout larval development did not affect gonad differentiation resulting in 1:1 sex ratio at metamorphosis. But, females emerging from estradiol-17ß treatment had larger ovaries with larger sized follicles. Further, testes of some males contained lumens, the number of which was dose dependent. Similarly, exposure to testosterone propionate had negligible effects on gonad differentiation. However, the mean diameter of the largest follicles was smaller in treated ovaries. Treatment of tadpoles with tamoxifen had no effect on gonad differentiation and ovary development while testicular development was accelerated at the highest concentration. Similarly, treatment of tadpoles with cyproterone acetate had little effect on gonad differentiation as well as development, hence the sex ratios at the end of metamorphosis. Further, in tadpoles exposed to increasing concentrations of formestane, gonad differentiation was normal resulting in 1:1 sex ratio. Thus, in M. ornata, both estradiol and testosterone are essential for the development of ovaries and testes respectively but, they are not critical to gonadal differentiation. Hence, the effects of sex steroids and other endocrine disrupting chemicals could be species-specific; different species may have differential sensitivities to such chemicals.


Assuntos
Anuros/crescimento & desenvolvimento , Hormônios Esteroides Gonadais/farmacologia , Diferenciação Sexual/efeitos dos fármacos , Androstenodiona/análogos & derivados , Androstenodiona/farmacologia , Animais , Inibidores da Aromatase/farmacologia , Diferenciação Celular/efeitos dos fármacos , Estradiol/farmacologia , Feminino , Gônadas/efeitos dos fármacos , Gônadas/crescimento & desenvolvimento , Larva/crescimento & desenvolvimento , Masculino , Metamorfose Biológica/efeitos dos fármacos , Metamorfose Biológica/fisiologia , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Diferenciação Sexual/fisiologia , Razão de Masculinidade , Tamoxifeno/farmacologia , Testículo/efeitos dos fármacos , Testículo/crescimento & desenvolvimento , Testosterona/farmacologia
14.
J Reprod Dev ; 62(4): 379-84, 2016 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-27151093

RESUMO

In vitro growth culture systems for oocytes are being developed in several mammalian species. In these growth culture systems, in vitro grown oocytes usually have lower blastocyst formation than in vivo grown oocytes after in vitro fertilization. Furthermore, there have been a few reports that investigated the fertilization ability of in vitro grown oocytes in large animals. The purpose of this study was to investigate the fertilization process and developmental competence of bovine oocytes grown in vitro. Oocyte-granulosa cell complexes collected from bovine early antral follicles (0.4-0.7 mm in diameter) were cultured for growth with 17ß-estradiol and androstenedione for 14 days and matured in vitro. These oocytes were then inseminated for 6 or 12 h, and further cultured for development up to 8 days in vitro. After growth culture, oocytes grew from 95 µm to around 120 µm and acquired maturation competence (79%). Although fertilization rates of in vitro grown oocytes were low after 6 h of insemination, 34% of in vitro grown oocytes fertilized normally after 12 h of insemination, having two polar bodies and two pronuclei with a sperm tail, and 22% of these oocytes developed into blastocysts after 8 days of culture. The fertilization and blastocyst formation rates were similar to those of in vivo grown oocytes. In addition, blastocyst cell numbers were also similar between in vitro and in vivo grown oocytes. In conclusion, in vitro grown bovine oocytes are similar to in vivo grown oocytes in fertilization ability and can develop into blastocysts.


Assuntos
Fertilização/fisiologia , Técnicas de Maturação in Vitro de Oócitos/veterinária , Oócitos/fisiologia , Oogênese/fisiologia , Folículo Ovariano/fisiologia , Androstenodiona/farmacologia , Animais , Bovinos , Estradiol/farmacologia , Feminino , Fertilização/efeitos dos fármacos , Fertilização In Vitro , Oócitos/citologia , Oócitos/efeitos dos fármacos , Oogênese/efeitos dos fármacos , Folículo Ovariano/citologia , Folículo Ovariano/efeitos dos fármacos
15.
Bioorg Med Chem ; 24(12): 2823-31, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27160054

RESUMO

In this work, new potent steroidal aromatase inhibitors both in microsomes and in breast cancer cells have been found. The synthesis of the 3,4-(ethylenedioxy)androsta-3,5-dien-17-one (12), a new steroid containing a heterocycle dioxene fused in the A-ring, led to the discovery of a new reaction for which a mechanism is proposed. New structure-activity relationships were established. Some 5ß-steroids, such as compound 4ß,5ß-epoxyandrostan-17-one (9), showed aromatase inhibitory activity, because they adopt a similar A-ring conformation as those of androstenedione, the natural substrate of aromatase. Moreover, new chemical features to increase planarity were disclosed, specifically the 3α,4α-cyclopropane ring, as in 3α,4α-methylen-5α-androstan-17-one (5) (IC50=0.11µM), and the Δ(9-11) double bond in the C-ring, as in androsta-4,9(11)-diene-3,17-dione (13) (IC50=0.25µM). In addition, induced-fit docking (IFD) simulations and site of metabolism (SoM) predictions helped to explain the recognition of new potent steroidal aromatase inhibitors within the enzyme. These insights can be valuable tools for the understanding of the molecular recognition process by the aromatase and for the future design of new steroidal inhibitors.


Assuntos
Androstanos/química , Androstanos/farmacologia , Androstenodiona/química , Androstenodiona/farmacologia , Inibidores da Aromatase/química , Inibidores da Aromatase/farmacologia , Aromatase/metabolismo , Neoplasias da Mama/enzimologia , Linhagem Celular Tumoral , Feminino , Humanos , Simulação de Acoplamento Molecular , Esteroides/química , Esteroides/farmacologia , Relação Estrutura-Atividade
16.
Horm Behav ; 75: 41-4, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26232614

RESUMO

Aromatase, the enzyme that aromatizes androstenedione (A) to estrone and testosterone (T) to estradiol (E), affects androgen control of male sex behavior in many vertebrates. In male monkeys, rats and quail, E mimics the ability of T to promote mating, and aromatase inhibitors block mating induced by T but not E. Aromatase inhibitors include androgens with different A-rings than T and A, e.g., 1,4,6-androstatriene-3,17-dione (ATD), azoles, e.g., fadrozole, and androgens α-halogenated at carbon 6, e.g., 6α-bromoA, 6α-fluoroA and 6α-fluoroT. 6α-FluoroT is the only 6α-halogenated androgen studied in regard to mating. It promotes mating in male rats and quail and was studied, before it was known to inhibit aromatase, because it cannot be aromatized yet has the same A-ring as T. 6α-FluoroT might promote mating by binding estrogen receptors (ER) directly, i.e., unassisted, or by metabolism to an androgen that binds ER. Since neither process would require aromatase, this study tested both hypotheses by determining how mating induced in castrated male rats by 6α-fluoroT is affected by ATD and fadrozole. Both aromatase inhibitors inhibited the effects of 6α-fluoroT on mating. Thus, 6α-fluoroT does not promote mating by direct ER binding or metabolism to another androgen. Since aromatase underlies a process in which 6α-fluoroT, unlike most nonaromatizable androgens, mimics T effects on male sex behavior, the process must involve a feature that 6α-fluoroT shares with T but not other nonaromatizable androgens. A-ring structure is a candidate. A hypothesis is also offered for how aromatase may participate without aromatizing the androgen.


Assuntos
Androstatrienos/farmacologia , Inibidores da Aromatase/farmacologia , Fadrozol/farmacologia , Comportamento Sexual Animal/efeitos dos fármacos , Testosterona/análogos & derivados , Androgênios/farmacologia , Androstenodiona/farmacologia , Animais , Interações Medicamentosas , Estradiol/farmacologia , Estrona/farmacologia , Feminino , Masculino , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Reprodução/efeitos dos fármacos , Testosterona/antagonistas & inibidores , Testosterona/farmacologia
17.
J Exp Biol ; 218(Pt 14): 2241-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25987739

RESUMO

Avian egg yolks contain various amounts of maternally derived androgens that can modify offspring phenotype and adjust their development to the post-hatching environment. Seemingly adaptive variation in yolk androgen levels with respect to breeding density conditions or male attractiveness has been found in numerous studies. One important consideration that has been overlooked in previous research is the likely non-linear nature of hormone effects. To examine possible complex dose-response effects of maternal androgens on chick development, we experimentally administered three different androgen doses of the naturally occurring mixture of yolk testosterone and androstenedione to spotless starling eggs (Sturnus unicolor). We found that yolk androgens induce a non-linear dose-response pattern in several traits. Androgens had a stimulatory effect on hatchling body mass and nestling skeletal growth, but maximum values were found at intermediate doses, whereas our highest dose resulted in a decrease. However, the opposite U-shaped effect was found on nestling body mass. We also detected linear negative and positive effects on embryonic development period and nestling gape width, respectively. Our results suggest differential tissue responsiveness to yolk androgens, which may result in compromises in maternal allocation to produce adapted phenotypes. Because of the non-linear dose-response pattern, future investigations should carefully consider a wide range of concentrations, as the balance of costs and benefits may strongly differ depending on concentration.


Assuntos
Androgênios/farmacologia , Androstenodiona/farmacologia , Estorninhos/embriologia , Estorninhos/crescimento & desenvolvimento , Testosterona/farmacologia , Androgênios/metabolismo , Androstenodiona/metabolismo , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Desenvolvimento Ósseo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Gema de Ovo/química , Gema de Ovo/metabolismo , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Masculino , Fenótipo , Estorninhos/metabolismo , Testosterona/metabolismo
18.
Steroids ; 98: 80-91, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25759119

RESUMO

The reaction of androstenedione with bromine gave the 16-bromo derivative 2. The latter reacted with either cyanothioacetamide or thiourea to give the 2-cyanomethylthiazole derivative 4 and the 2-aminothiazole derivative 13. Compound 4 and 13 were used underwent some condensation, coupling and heterocyclization reactions to give thiophene, pyridine and pyran derivatives. The anti-inflammatory and anti-ulcer evaluations of the newly synthesized products were evaluated and the results showed that 23f showed the maximum antiulcer activity. In addition, toxicity of the most active compounds was studied against shrimp larvae and showed that compounds 2, 23c and 23f showed non-toxicity against the tested organisms.


Assuntos
Androstenodiona , Anti-Inflamatórios , Antiulcerosos , Edema/tratamento farmacológico , Androstenodiona/análogos & derivados , Androstenodiona/síntese química , Androstenodiona/química , Androstenodiona/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antiulcerosos/síntese química , Antiulcerosos/química , Antiulcerosos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Edema/induzido quimicamente , Edema/patologia , Piranos/química , Piridinas/química , Ratos , Tiazóis/química , Tiofenos/química
19.
J Steroid Biochem Mol Biol ; 150: 86-96, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25797375

RESUMO

Analysing effects of pharmaceutical substances and training on feedback mechanisms of the hypothalamic-pituitary-gonadal axis may be helpful to quantify the benefit of strategies preventing loss of muscle mass, and in the fight against doping. In this study we analysed combined effects of anabolic steroids and training on the hypothalamic-pituitary-gonadal axis. Therefore intact male Wistar rats were dose-dependently treated with metandienone, estradienedione and the selective androgen receptor modulator (SARM) S-1. In serum cortisol, testosterone, 17ß-estradiol (E2), prolactin, inhibin B, follicle-stimulating hormone (FSH), luteinizing hormone (LH), Insulin-like growth factor 1 (IGF-1), and thyroxine (T4) concentrations were determined. Six human volunteers were single treated with 1-androstenedione. In addition abusing and clean body builders were analysed. Serum concentrations of inhibin B, IGF-1, cortisol, prolactin, T4, thyroid-stimulating hormone (TSH), testosterone and LH were determined. In rats, administration of metandienone, estradienedione and S-1 resulted in an increase of muscle fiber diameter. Metandienone and estradienedione but not S-1 administration significantly decreases LH and inhibin B serum concentration. Administration of estradienedione resulted in an increase of E2 and S-1 in an increase of cortisol. Single administration of 1-androstenedione in humans decreased cortisol and inhibin B serum concentrations. LH was not affected. In abusing body builders a significantly decrease of LH, TSH and inhibin B and an increase of prolactin, IGF-1 and T4 was detected. In clean body builders only T4 and TSH were affected.


Assuntos
Anabolizantes/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Atividade Motora , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Testículo/efeitos dos fármacos , Amidas/farmacologia , Androstenodiona/farmacologia , Compostos de Anilina/farmacologia , Animais , Estradiol/sangue , Estrenos/farmacologia , Hormônio Foliculoestimulante/sangue , Hormônio Liberador de Gonadotropina/sangue , Humanos , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/metabolismo , Inibinas/sangue , Injeções Subcutâneas , Fator de Crescimento Insulin-Like I/metabolismo , Hormônio Luteinizante/sangue , Masculino , Metandrostenolona/farmacologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Prolactina/sangue , Ratos , Ratos Wistar , Testículo/metabolismo , Testosterona/sangue , Tiroxina/sangue
20.
Curr Pharm Des ; 21(23): 3395-401, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-23782143

RESUMO

A variety of physiological and pharmacological factors are known to influence stress responses. Cold restraint stress (CRS) induced gastric ulcerogenesis in both the sexes but such ulceration was found to be markedly higher in male than in female rats. In males, CRS induced significant increases in both ulcer number and ulcer severity; while the females though showed a trend towards increase in both the parameters, the extent of changes was far less than in males. Pre-administration of the NO mimetic, L-Arginine (500 and 1000 mg/kg), prior to CRS, dose dependently decreased ulcer number and severity in male rats. In female rats, L-Arginine also induced a gastric cytoprotective effect during CRS but to a much lesser extent. On the other hand, inhibition of NO synthesis by LNAME (25 and 50 mg/kg) further aggravated such stress ulcerogensis in both males and females, with aggravations being more extensive in males. CRS induced ulcerogenesis was associated with reductions in levels of brain and plasma NOx and GSH levels while MDA levels were elevated in both male and female rats- the magnitude of these changes being higher in males than in females. In female rats, pretreatment with formestane (aromatase inhibitor) but not tamoxifen (estrogen receptor blocker) aggravated stress ulcer formation as compared to vehicle treated CRS exposed rats. Formestane pretreatment also induced greater suppressions in brain NOx and GSH and elevations in brain MDA, as compared to vehicle treated CRS rats. These results indicate that estrogen and its interactions with oxidative stress markers and NO plays a key role in the gender based differences in stress induced gastric ulcerogenesis. It may be speculated that, in males, CRS induces greater reductions in brain NO and enhancement in oxidative injury resulting in greater severity of gastric ulceration. On the other hand, greater resistance of females to ulcerogenic effects of CRS may be due to the protection conferred by estrogen and this effect seems to be related to interactions with brain NO.


Assuntos
Encéfalo/metabolismo , Óxido Nítrico/metabolismo , Úlcera Gástrica/etiologia , Estresse Psicológico/complicações , Androstenodiona/análogos & derivados , Androstenodiona/farmacologia , Animais , Arginina/farmacologia , Inibidores da Aromatase/farmacologia , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estrogênios/metabolismo , Feminino , Glutationa/metabolismo , Masculino , Malondialdeído/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Ratos Wistar , Índice de Gravidade de Doença , Fatores Sexuais , Transdução de Sinais/efeitos dos fármacos , Úlcera Gástrica/metabolismo , Úlcera Gástrica/prevenção & controle , Úlcera Gástrica/psicologia , Estresse Psicológico/metabolismo
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