RESUMO
The inhibition of 5-α reductase type 2 (SRD5A2) by finasteride is commonly used for the management of urinary obstruction resulting from benign prostatic enlargement (BPE). Certain BPE patients showing no SRD5A2 protein expression are resistant to finasteride therapy. Our previous work showed that methylated cytosine-phosphate-guanine (CpG) islands in the SRD5A2 gene might account for the absence or reduction of SRD5A2 protein expression. Here, we found that the expression of the SRD5A2 protein was variable and that weak expression of the SRD5A2 protein (scored 0-100) occurred in 10.0% (4/40) of benign adult prostates. We showed that the expression of SRD5A2 was negatively correlated with DNA methyltransferase 1 (DNMT1) expression. In vitro SRD5A2-negative BPH-1 cells were resistant to finasteride treatment, and SRD5A2 was re-expressed in BPH-1 cells when SRD5A2 was demethylated by 5-Aza-2'-deoxycytidine (5-Aza-CdR) or N-phthalyl-L-tryptophan (RG108). Furthermore, we determined the exact methylation ratios of CpG dinucleotides in a CpG island of SRD5A2 through MassArray quantitative methylation analysis. Ten methylated CpG dinucleotides, including four CpG dinucleotides in the promoter and six CpG dinucleotides in the first exon, were found in a CpG island located from -400 bp to +600 bp in SRD5A2, which might lead to the silencing of SRD5A2 and the absence or reduction of SRD5A2 protein expression. Finasteride cannot exert a therapeutic effect on patients lacking SRD5A2, which may partially account for the resistance to finasteride observed in certain BPE patients.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/análise , Finasterida/antagonistas & inibidores , Proteínas de Membrana/análise , Hiperplasia Prostática/tratamento farmacológico , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Resistência a Medicamentos/efeitos dos fármacos , Finasterida/uso terapêutico , Humanos , Masculino , Proteínas de Membrana/sangue , Proteínas de Membrana/genética , Metilação/efeitos dos fármacos , Hiperplasia Prostática/fisiopatologiaRESUMO
BACKGROUND: A deficiency in steroid 5α-reductase type 2 is an autosomal recessive disorder. Affected individuals manifested ambiguous genitalia, which is caused by decreased dihydrotestosterone (DHT) synthesis in the fetus. METHODS: We analyzed 25 patients with 5α-reductase deficiency in China. Seventeen of the 25 patients (68%) were initially raised as females. Sixteen patients changed their social gender from female to male after puberty. RESULTS: Eighteen mutations were identified in these patients. p.Gly203Ser and p.Gln6∗ were found to be the most prevalent mutations. On the basis of the genotype of these patients, we divided them into different groups. There was no significant difference in hormone levels and external masculinization score (EMS) in patients with or without these prevalent mutations. Twelve common single-nucleotide polymorphisms (SNPs) near the p.Gln6∗ mutation were chosen for haplotype analysis. Three haplotypes were observed in 6 patients who had the p.Gln6∗ mutation (12 alleles). CONCLUSION: We analyzed mutations of the SRD5A2 gene in Chinese patients with 5α-reductase deficiency. Although hotspot mutations exist, no founder effect of prevalent mutations in the SRD5A2 gene was detected in the Chinese population.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , Transtorno 46,XY do Desenvolvimento Sexual/genética , Hipospadia/genética , Proteínas de Membrana/genética , Erros Inatos do Metabolismo de Esteroides/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Adolescente , Adulto , Povo Asiático/genética , Criança , Pré-Escolar , China , Di-Hidrotestosterona/sangue , Transtorno 46,XY do Desenvolvimento Sexual/sangue , Transtorno 46,XY do Desenvolvimento Sexual/epidemiologia , Feminino , Haplótipos/genética , Humanos , Hipospadia/sangue , Hipospadia/epidemiologia , Lactente , Recém-Nascido , Masculino , Mutação/genética , Erros Inatos do Metabolismo de Esteroides/sangue , Erros Inatos do Metabolismo de Esteroides/epidemiologia , Adulto JovemRESUMO
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 JovemRESUMO
Steroid 5α-reductase type 2 deficiency (5αRD2) is a congenital disorder of sex development caused by impairment of conversion from testosterone (T) to 5α-dihydrotestosterone (DHT). DHT deficiency leads to various degrees of undervirilized external genitalia including micropenis, primarily correlated with mutations of the SRD5A2 gene that encodes 5α-reductase type 2. Four Japanese boys with isolated micropenis were diagnosed as 5αRD2 by elevated ratios of serum T/DHT, and decreased ratios of urinary 5α/5ß-reduced steroid metabolites. Genetic analyses for SRD5A2 identified that the four patients shared a hypomorphic mutation R227Q that has a residual activity related to the mild-form of 5αRD2. For prepubertal micropenis, DHT was transdermally applied to the four patients at the ages of 4-11 year, increasing a median of stretched penile lengths (SPLs) from 2.6 cm (-2.5 SD) to 4.4 cm (-0.2 SD). Nevertheless, the post-pubertal penile growth was apparently retarded, despite normal levels of T secreted from well-developed testes. The second course of DHT treatment underwent at ages of 12-18 year, but unable to normalize SPLs at a range of 6.0 to 7.0 cm (-3.4 to -2.4 SD). The prostate volumes of two patients were variable at 8.1 and 21 cm3, and a sperm cell count of one patient was normal as young adult. DHT treatment contributes to development of the penis and prostate, which are favorable for the potential fertility of 5αRD2 adults. Meanwhile, the retarded penile growth and a risk of prostate overgrowth may complicate the post-pubertal management with DHT for 5αRD2 males.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , Di-Hidrotestosterona/administração & dosagem , Transtorno 46,XY do Desenvolvimento Sexual/tratamento farmacológico , Doenças dos Genitais Masculinos/tratamento farmacológico , Hipospadia/tratamento farmacológico , Pênis/anormalidades , Pênis/efeitos dos fármacos , Puberdade/efeitos dos fármacos , Erros Inatos do Metabolismo de Esteroides/tratamento farmacológico , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Criança , Pré-Escolar , Transtorno 46,XY do Desenvolvimento Sexual/sangue , Transtorno 46,XY do Desenvolvimento Sexual/genética , Transtorno 46,XY do Desenvolvimento Sexual/patologia , Esquema de Medicação , Doenças dos Genitais Masculinos/sangue , Doenças dos Genitais Masculinos/genética , Humanos , Hipospadia/sangue , Hipospadia/genética , Hipospadia/patologia , Estudos Longitudinais , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Mutação , Pênis/crescimento & desenvolvimento , Pênis/patologia , Puberdade/fisiologia , Maturidade Sexual/efeitos dos fármacos , Erros Inatos do Metabolismo de Esteroides/sangue , Erros Inatos do Metabolismo de Esteroides/genética , Erros Inatos do Metabolismo de Esteroides/patologia , Testosterona/sangue , Fatores de Tempo , Resultado do TratamentoRESUMO
Benign prostatic hyperplasia (BPH), an age-dependent disorder with a prevalence percentage of 60% in the 60s, has been found to involve an androgenic hormone imbalance that causes confusion between cell apoptosis and proliferation. Because general medications for BPH treatment have undesirable side effects, the development of effective alternative medicines has been considered. HBX-5 is a newly developed formula with the aim of improving BPH, and is composed of nine medicinal herbs. BPH was induced in the rats by intramuscular injection of testosterone propionate after castration. Rats were divided into six groups, and the efficacy of HBX-5 on testosterone-induced BPH in rats was estimated. In addition, RWPE-1 and WPMY-1 cells were used to demonstrate the effect of HBX-5 on BPH in vitro model. Compared with the control group, HBX-5 administration group suppressed BPH manifestations, such as excessive development of prostate, and increase of serum dihydrotestosterone and 5α-reductase concentrations. Furthermore, immunohistochemistry analysis revealed that HBX-5 significantly decreased the expression of androgen receptor (AR) and proliferating cell nuclear antigen (PCNA). In addition, results of RWPE-1 and WPMY-1 cells showed that HBX-5 inhibited the over-expression of AR and PSA in DHT-induced prostate hyperplastic microenvironments.
Assuntos
Extratos Vegetais/administração & dosagem , Plantas Medicinais/química , Hiperplasia Prostática/tratamento farmacológico , Propionato de Testosterona/efeitos adversos , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , Animais , Linhagem Celular , Di-Hidrotestosterona/sangue , Modelos Animais de Doenças , Progressão da Doença , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Injeções Intramusculares , Masculino , Extratos Vegetais/farmacologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Hiperplasia Prostática/sangue , Hiperplasia Prostática/induzido quimicamente , Ratos , Receptores Androgênicos/metabolismoRESUMO
5-α-Reductase type 2 enzyme catalyzes the conversion of testosterone into dihydrotestosterone, a potent androgen responsible for male sexual development during the fetal period and later during puberty. Its deficiency causes an autosomal recessive disorder of sex development characterized by a wide range of under-virilization of external genitalia in patients with a 46,XY karyotype. Mutations in the SRD5A2 gene cause 5-α-Reductase deficiency; although it is an infrequent disorder, it has been reported worldwide, with mutational heterogeneity. Furthermore, it has been proposed that there is no genotype-phenotype correlation, even in patients carrying the same mutation. The aim of this review was to perform an extensive search in various databases and to select those articles with a comprehensive genotype and phenotype description of the patients, classifying their phenotypes using the external masculinization score (EMS). Thus, it was possible to objectively compare the eventual genotype-phenotype correlation between them. The analysis showed that for most of the studied mutations no correlation can be established, although the specific location of the mutation in the protein has an effect on the severity of the phenotype. Nevertheless, even in patients carrying the same homozygous mutation, a variable phenotype was observed, suggesting that additional genetic factors might be influencing it. Due to the clinical variability of the disorder, an accurate diagnosis and adequate medical management might be difficult to carry out, as is highlighted in the review.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , Transtorno 46,XY do Desenvolvimento Sexual , Genitália/anormalidades , Genótipo , Hipospadia , Fenótipo , Erros Inatos do Metabolismo de Esteroides , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Transtorno 46,XY do Desenvolvimento Sexual/sangue , Transtorno 46,XY do Desenvolvimento Sexual/genética , Transtorno 46,XY do Desenvolvimento Sexual/patologia , Transtorno 46,XY do Desenvolvimento Sexual/terapia , Humanos , Hipospadia/sangue , Hipospadia/genética , Hipospadia/patologia , Hipospadia/terapia , Erros Inatos do Metabolismo de Esteroides/sangue , Erros Inatos do Metabolismo de Esteroides/genética , Erros Inatos do Metabolismo de Esteroides/patologia , Erros Inatos do Metabolismo de Esteroides/terapiaAssuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , Transtorno 46,XY do Desenvolvimento Sexual/diagnóstico , Disgenesia Gonadal 46 XY/diagnóstico , Hipospadia/diagnóstico , Puberdade , Erros Inatos do Metabolismo de Esteroides/diagnóstico , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Adolescente , Criança , Diagnóstico Diferencial , Transtorno 46,XY do Desenvolvimento Sexual/sangue , Transtorno 46,XY do Desenvolvimento Sexual/genética , Feminino , Disgenesia Gonadal 46 XY/sangue , Humanos , Hipospadia/sangue , Hipospadia/genética , Erros Inatos do Metabolismo de Esteroides/sangue , Erros Inatos do Metabolismo de Esteroides/genéticaRESUMO
BACKGROUND: Inhibin B is a hormone produced by the Sertoli cells that can provide important information for the investigation of disorders of sex development (DSD) with 46,XY karyotype. The aim of this study is to compare two enzyme-linked immunosorbent assay (ELISA) assays for dosage of serum inhibin B in patients with 46,XY DSD with normal testosterone secretion. METHODS: Twenty-nine patients with 46,XY DSD and normal testosterone secretion (partial androgen insensitivity syndrome [PAIS] [n=8]; 5α-reductase deficiency [n=7] and idiopathic 46,XY DSD [n=14]) were included. Molecular analysis of the AR and SRD5A2 genes were performed in all patients and the NR5A1 gene analysis in the idiopathic group. Measurements of inhibin B were performed by two second-generation ELISA assays (Beckman-Coulter and AnshLabs). Assays were compared using the interclass correlation coefficient (ICC) and the Bland-Altman method. RESULTS: ICC was 0.915 [95% confidence interval (CI): 0.828-0.959], however, a discrepancy was observed between trials, which is more evident among higher values when analyzed by the Bland-Altman method. CONCLUSIONS: It is recommended to perform the inhibin B measurement always using the same ELISA kit when several evaluations are required for a specific patient.
Assuntos
Transtorno 46,XY do Desenvolvimento Sexual/sangue , Ensaio de Imunoadsorção Enzimática , Subunidades beta de Inibinas/sangue , Testículo/metabolismo , Testosterona/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Adolescente , Adulto , Síndrome de Resistência a Andrógenos/sangue , Síndrome de Resistência a Andrógenos/diagnóstico , Síndrome de Resistência a Andrógenos/genética , Síndrome de Resistência a Andrógenos/fisiopatologia , Criança , Pré-Escolar , Diagnóstico Diferencial , Transtorno 46,XY do Desenvolvimento Sexual/diagnóstico , Transtorno 46,XY do Desenvolvimento Sexual/genética , Transtorno 46,XY do Desenvolvimento Sexual/fisiopatologia , Hospitais Universitários , Humanos , Hipospadia/sangue , Hipospadia/diagnóstico , Hipospadia/genética , Hipospadia/fisiopatologia , Cariótipo , Masculino , Proteínas de Membrana/genética , Ambulatório Hospitalar , Receptores Androgênicos/genética , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Erros Inatos do Metabolismo de Esteroides/sangue , Erros Inatos do Metabolismo de Esteroides/diagnóstico , Erros Inatos do Metabolismo de Esteroides/genética , Erros Inatos do Metabolismo de Esteroides/fisiopatologia , Fator Esteroidogênico 1/genética , Testículo/fisiopatologia , Adulto JovemRESUMO
BACKGROUND/PURPOSE: Sebum is thought to play an important role in acne vulgaris and sebum excretion rate (SER) is often used as a marker of efficacy in acne studies. This study explored factors that could induce intra-subject variability in SER. METHODS: SER was measured twice, 7 days apart, on the forehead of 40 healthy subjects. At each visit, the following parameters were also evaluated: serum androgen levels, 5-alpha-reductase type I gene expression, forehead temperature, sleep habits, diet, facial washing routine, and UV exposure. RESULTS: There was a positive correlation between the time subjects fell asleep on Day 0 and the change in SER for the left (P = 0.010; R = 0.402) and right sides (P = 0.002; R = 0.467) of the forehead. There was a significant inverse correlation between SER and 5-alpha-reductase type 1 expression and between free testosterone levels and 5-alpha-reductase type 1 expression. In sub-analyses performed on men and women, these correlations were only significant for women. CONCLUSION: Variations in sleep patterns, free testosterone, and 5-alpha-reductase type 1 activity are associated with changes in sebum excretion in women. This could explain some of the inter-subject variability in SER measured between visits in clinical studies.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , Ritmo Circadiano/fisiologia , Glândulas Sebáceas/fisiologia , Sebo/metabolismo , Fases do Sono/fisiologia , Testosterona/sangue , Adulto , Ativação Enzimática , Feminino , Testa/fisiologia , Humanos , Masculino , Caracteres Sexuais , Temperatura Cutânea/fisiologiaRESUMO
OBJECTIVE: To measure serum concentrations of progesterone, estradiol and 5α- and 5ß-reduced progesterone metabolites in the follicular and luteal phases of the menstrual cycle in women with latent acute intermittent porphyria and manifest acute intermittent porphyria in comparison with healthy control women. DESIGN: A descriptive study with repeated measurements during a complete, ovulatory menstrual cycle. SETTING: University hospital out-patient clinic. POPULATION: Thirty-two women with DNA-diagnosed acute intermittent porphyria and 20 healthy control women. METHODS: Blood samples for serum progesterone, estradiol, allopregnanolone and pregnanolone were drawn on predefined menstrual cycle days, twice in the follicular phase and three times in the luteal phase. Serum levels of estradiol and progesterone were analysed with commercial kits. Allopregnanolone and pregnanolone levels were analysed with radioimmunoassay following diethylether extraction and celite column chromatography. MAIN OUTCOME MEASURES: Changes in serum levels of progesterone, estradiol, allopregnanolone and pregnanolone throughout the menstrual cycle. RESULTS: Women with acute intermittent porphyria displayed lower serum concentrations of allopregnanolone in comparison with healthy control women, the difference being most prominent in the luteal phase (p < 0.001). Levels of pregnanolone did not differ significantly between groups. No significant difference was found between women with latent acute intermittent porphyria and manifest acute intermittent porphyria. CONCLUSIONS: Decreased levels of the 5α-reduced progesterone metabolite allopregnanolone were found in the menstrual cycle of women with acute intermittent porphyria. This has not been reported previously and could indicate a reduced 5α-reductase type 1 capacity in the ovary and liver among these women.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , Ciclo Menstrual/sangue , Porfiria Aguda Intermitente/sangue , Adulto , Estudos de Casos e Controles , Estradiol/sangue , Feminino , Humanos , Pessoa de Meia-Idade , Pregnanolona/sangue , Progesterona/sangue , Estatísticas não Paramétricas , SuéciaRESUMO
5ARIs are recommended for men who have moderate-to-severe lower urinary tract symptoms (LUTS) and benign prostatic enlargement (BPE) secondary to benign prostatic hyperplasia. Studies have confirmed the utility of combining 5ARIs with alpha-blockers; the MTOPS study showed that risk of overall clinical progression was significantly reduced after 4.5 years with combination therapy (finasteride/doxazosin) in comparison with either monotherapy, while the ongoing CombAT trial (dutasteride/tamsulosin) has for the first time shown benefit in improving symptoms for combination therapy over monotherapies within 12 months of treatment. Data also suggest roles for 5ARIs in prostate cancer. Several studies indicate that treatment with a 5ARI improves the performance of PSA testing for identifying men with prostate cancer, while the PCPT showed a significant reduction in the risk of developing prostate cancer with finasteride. However, widespread use of finasteride in this setting has been tempered by an apparent increase in high-grade disease observed in the study. The ongoing REDUCE study will provide further insight into prostate cancer prevention with 5ARIs. 5ARI-containing regimens may have utility as less aggressive treatment options for patients who only have rising PSA after definitive local therapy, and in patients with disease resistant to androgen deprivation therapy who have PSA progression. Current evidence therefore shows that 5ARIs are effective in treating LUTS/BPE and preventing disease progression, and may also have a role in the prevention of prostate cancer. The overlap between BPE and prostate cancer may allow a more unified approach to managing these conditions, with 5ARIs having a central role.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , Hiperplasia Prostática/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/prevenção & controle , Testosterona/sangue , Infecções Urinárias/tratamento farmacológico , Inibidores de 5-alfa Redutase , Idoso , Envelhecimento , Azasteroides/uso terapêutico , Di-Hidrotestosterona/sangue , Dutasterida , Inibidores Enzimáticos/uso terapêutico , Finasterida/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Próstata/crescimento & desenvolvimento , Próstata/patologia , Hiperplasia Prostática/complicações , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/patologia , Neoplasias da Próstata/patologia , Sulfonamidas/uso terapêutico , Tansulosina , Infecções Urinárias/complicaçõesRESUMO
OBJECTIVE: The aim of this study was to evaluate whether pretreatment with finasteride, a 5alpha-reductase inhibitor, improves immune functions after trauma-hemorrhage. SUMMARY BACKGROUND DATA: A number of studies have provided evidence for a gender dimorphism in host defense after trauma. Under stress conditions, such as trauma-hemorrhage, androgenic hormones have immunosuppressive effects, leading to increased susceptibility to sepsis, morbidity, and mortality. Testosterone is converted by 5alpha-reductase to 5alpha-dihydrotestosterone (DHT), a more potent androgen. METHODS: Male C3H/HeN mice (8-10 weeks) were randomly assigned to receive finasteride or vehicle for 2 days and were then subjected to trauma-hemorrhage or sham operation. Trauma-hemorrhage was induced by a midline laparotomy and approximately 90 minutes of hemorrhagic shock (blood pressure, 35 mm Hg), followed by fluid resuscitation. Animals were killed 2 hours after resuscitation or sham procedure. Plasma levels and Kupffer cell production of cytokines (TNF-alpha, IL-6, IL-10, MCP-1, KC, and MIP-1alpha), lung neutrophil infiltration, and edema were evaluated. RESULTS: Finasteride administration prevented the increase in cytokine plasma levels, decreased DHT, and increased 17beta-estradiol plasma concentrations. In addition, neutrophil infiltration and edema formation in the lung were reduced by finasteride. The salutary effects of finasteride were abrogated after coadministration with an estrogen receptor inhibitor (ICI 182,780). Increased Kupffer cell cytokine production normally observed after trauma-hemorrhage was prevented by treatment with finasteride. CONCLUSION: These results suggest that inhibition of 5alpha-reductase leads to the conversion of testosterone to 17beta-estradiol, which produces salutary effects on the post-traumatic immune response.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , Citocinas/sangue , Inibidores Enzimáticos/uso terapêutico , Estradiol/sangue , Finasterida/uso terapêutico , Choque Hemorrágico/prevenção & controle , Inibidores de 5-alfa Redutase , Animais , Inibidores Enzimáticos/farmacologia , Finasterida/farmacologia , Células de Kupffer/efeitos dos fármacos , Células de Kupffer/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Infiltração de Neutrófilos/efeitos dos fármacos , Infiltração de Neutrófilos/fisiologia , Edema Pulmonar/sangue , Edema Pulmonar/etiologia , Edema Pulmonar/prevenção & controle , Choque Hemorrágico/sangue , Choque Hemorrágico/imunologiaRESUMO
Controversy exists over the significance of associations between the SRD5A2 (5alpha-reductase type 2) polymorphisms, A49T and V89L, and risk of prostate cancer. These potentially functional polymorphisms may alter life-long exposure to androgens with subsequent effects on male health and aging. The aim of this study was to examine the association of these variants with prostate cancer risk, plasma hormone levels and androgenetic alopecia. Subjects include 827 cases and 736 controls from an Australian population-based case-control study of prostate cancer. Information on prostate cancer risk factors and patterns of balding were collected. Plasma levels of testosterone, 3alpha-diol glucuronide (3alpha-diolG), dehydroepiandrosterone sulfate, androstenedione, sex hormone-binding globulin and estradiol were measured for controls. No associations with the V89L polymorphism were found. Carriers of the rarer A49T A allele were at a 60% higher risk of prostate cancer (OR = 1.60; 95% CI 1.09-2.36; p = 0.02) and 50% lower risk of vertex and frontal balding (p = 0.03) compared with men homozygous for the more common G allele. Although we found little evidence of association between this variant and plasma levels of 5 measured androgens, circulating 3alpha-diolG levels were 34% lower in A49T A allele carriers (p < 0.0001). Our study provides evidence that the SRD5A2 A49T A variant is associated with an increased risk of prostate cancer, lower levels of circulating 3alpha-diolG and decreased risk of baldness. These findings raise important questions with respect to previous assumptions concerning hormonal influences on prostate cancer risk in ageing males.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Alopecia/genética , Androgênios/sangue , Predisposição Genética para Doença , Neoplasias da Próstata/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , Adulto , Idoso , Estudos de Casos e Controles , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo Genético , Vigilância da População , Neoplasias da Próstata/sangue , Fatores de RiscoRESUMO
17beta-hydroxysteroid dehydrogenase (17beta-HSD) and 5alpha-reductase isoenzymes play a crucial role in the formation and metabolism of sex steroids. Not only the key androgens testosterone and dihydrotestosterone but also their precursors are potent activators of the androgen receptor and are, therefore, likely to act as determinants of male sexual differentiation and maturation in a differentially regulated way. The aim of the present study was to relatively quantify the expression of the mRNA of 17beta-HSD isoenzymes, namely, type 1, 2, 3, 4, 5, 7, and 10, together with the 5alpha-reductase type 1 and 2, and the androgen receptor in normal human males and females. RNA was isolated from peripheral blood cells of both sexes and from genital skin fibroblasts (GSFs) of two different localizations (foreskin and scrotal skin) obtained from phenotypically normal males. mRNA expression was semi-quantified by quantitative reverse-transcriptase polymerase chain reaction with the LightCycler Instrument (Roche). The examined enzymes show statistically significant differences in their transcription pattern between the blood and the GSF RNA samples. Within the GSF samples, there are also significant variations between the two examined localizations in the transcription of 17beta-HSD type 1, 2, 4, and 5 as well as for the androgen receptor. We found large interindividual variation of enzyme transcription patterns in all investigated tissues. In peripheral blood cells, no sex-specific differences were seen. We conclude that sex steroid enzymes are expressed not only in genital primary target tissues but also in peripheral blood. The expression in different target tissues may contribute to both the individual sexual and tissue-specific phenotype in humans.
Assuntos
17-Hidroxiesteroide Desidrogenases/biossíntese , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/biossíntese , Hormônios Esteroides Gonadais/biossíntese , Receptores Androgênicos/biossíntese , 17-Hidroxiesteroide Desidrogenases/sangue , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular , Células Cultivadas , Criança , Pré-Escolar , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Prepúcio do Pênis/citologia , Prepúcio do Pênis/metabolismo , Humanos , Lactente , Isoenzimas/biossíntese , Isoenzimas/sangue , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , RNA Mensageiro/biossíntese , Receptores Androgênicos/sangue , Fatores SexuaisRESUMO
Reductase activity of 17beta-hydroxysteroid oxidoreductase in biopsy specimens of prostatic cancer and benign hyperplasia, and prostatic intraepithelial neoplasia and serum concentrations of testosterone, 5alpha-dihydrotestosterone, 4-androstene-3,17-dione were compared in patients and healthy individuals. Reductase activities of 17beta-hydroxysteroid oxidoreductase in soluble fraction of prostatic biopsy specimens decreased in the following order: prostatic cancer>prostatic intraepithelial neoplasia>>benign prostatic hyperplasia. No differences in serum concentrations of testosterone, 5alpha-dihydrotestosterone, 4-androstene-3,17-dione between these three groups of patients were found, while the mean serum concentration of these androgens in patients with prostatic tumors did not surpass the threshold normal values for men. Hence, high reductase activity of 17beta-hydroxysteroid oxidoreductase can be associated with pathogenetic mechanisms of human malignant prostatic tumors.
Assuntos
17-Hidroxiesteroide Desidrogenases/metabolismo , Hiperplasia Prostática/enzimologia , Neoplasia Prostática Intraepitelial/enzimologia , Neoplasia Prostática Intraepitelial/patologia , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , 17-Hidroxiesteroide Desidrogenases/análise , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , Biópsia , Di-Hidrotestosterona/sangue , Humanos , Masculino , Hiperplasia Prostática/cirurgia , Neoplasia Prostática Intraepitelial/cirurgia , Neoplasias da Próstata/cirurgia , Testosterona/sangueRESUMO
OBJECTIVES: To compare men with prostate disease with those from the general population regarding polymorphisms in the androgen receptor gene and in the 5alpha-reductase II (SRD5A2) gene. MATERIALS AND METHODS: The SRD5A2 polymorphisms A49T, V89L and R227Q, the androgen receptor CAG and GGN repeats and sex hormone status was investigated in men with prostate cancer (CaP) (n=89), benign prostate hyperplasia (n=45) and healthy military conscripts (n=223). RESULTS: The SRD5A2 high-activity allele variants A49T AT and V89L LL were more frequent in CaP-patients compared to general population, p=0.026 and p=0.05, respectively. CaP progression was, however, independent of SRD5A2 variants. In contrary, men with GGN<23 had a higher risk of dying from the disease than their counterparts with longer repeats. CONCLUSIONS: Men with CaP were more often genetically predisposed to a higher enzymatic activity in the turn over from T to DHT compared to the general population. In our population, androgen receptor genotype affected CaP outcome.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Alelos , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , Idoso , Alanina , Arginina , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , Di-Hidrotestosterona/sangue , Progressão da Doença , Seguimentos , Predisposição Genética para Doença , Genótipo , Glutamina , Humanos , Leucina , Hormônio Luteinizante/sangue , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Polimorfismo Genético , Hiperplasia Prostática/sangue , Hiperplasia Prostática/epidemiologia , Hiperplasia Prostática/genética , Neoplasias da Próstata/sangue , Neoplasias da Próstata/epidemiologia , Receptores Androgênicos/sangue , Fatores de Risco , Globulina de Ligação a Hormônio Sexual/metabolismo , Suécia/epidemiologia , Sequências Repetidas Terminais , Testosterona/sangue , Treonina , ValinaRESUMO
Dutasteride is a new dual 5alpha-reductase inhibitor for the treatment of benign prostatic hyperplasia. It differs from finasteride as it inhibits both isoenzymes of 5alpha-reductase and results in near-complete suppression of serum dihydro-testosterone. Similar to finasteride, it reduces serum prostatic specific antigen by approximately 50% at 6months and total prostate volume by 25% in 2years. Randomised, placebo-controlled trials conducted over 2years have shown the efficacy of dutasteride in symptomatic relief, improvements in quality of life and peak urinary flow rate, and reduction of acute urinary retention events and the need for surgery. The main side effects are erectile dysfunction, decreased libido, gynaecomastia and ejaculation disorders. However, long-term usage for > 4years did not reveal increased new onset of sexual side effects. In addition, the combination of dutasteride and tamsulosin is well-tolerated and has the added advantage of rapid symptomatic relief. Finally, dutasteride has been shown to possess tumour regression properties invitro and its role in chemoprevention of prostate cancer will be confirmed in the ongoing Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial.
Assuntos
Inibidores de 5-alfa Redutase , Azasteroides/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/enzimologia , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , Azasteroides/farmacologia , Dutasterida , Inibidores Enzimáticos/uso terapêutico , Humanos , Masculino , Hiperplasia Prostática/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricosRESUMO
Polymorphism of the steroid hormone-related genes might affect life-long androgen exposure, thus altering a risk of prostate cancer incidence. To evaluate the effect of the polymorphisms of CYP17 and SRD5A2 on serum steroid hormone levels, the 164 male Japanese cohort were tested for serum hormone levels and the genotype of the polymorphisms of CYP17 (T-C base substitution in the promoter region) and SRD5A2 (V89L). The linear trends across the CYP17 genotypes in serum-free testosterone and androstenedione levels were found, suggesting the importance of the polymorphism of CYP17 in determining the circulating androgen levels.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Androstenodiona/sangue , Biomarcadores Tumorais/sangue , Polimorfismo Genético , Neoplasias da Próstata/genética , Esteroide 17-alfa-Hidroxilase/genética , Testosterona/sangue , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , Idoso , Idoso de 80 Anos ou mais , Androgênios/sangue , Estudos de Coortes , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Genótipo , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/sangue , Neoplasias da Próstata/epidemiologia , Fatores de Risco , Esteroide 17-alfa-Hidroxilase/sangueRESUMO
The Lapland longspur (Calcarius lapponicus) is an arctic-breeding songbird that shows rapid behavioral changes during a short breeding season. Changes in plasma testosterone (T) in the spring are correlated with singing but not territorial aggression in males. Also, T treatment increases song but not aggression in this species. In contrast, in temperate-zone breeders, song and aggression are highly correlated, and both increase after T treatment. We asked whether regional or temporal differences in androgen-metabolizing enzymes in the longspur brain explain hormone-behavior patterns in this species. We measured the activities of aromatase, 5alpha-reductase and 5beta-reductase in free-living longspur males. Aromatase and 5alpha-reductase convert T into the active steroids 17beta-estradiol (E(2)) and 5alpha-dihydrotestosterone (5alpha-DHT), respectively. 5beta-Reductase deactivates T via conversion to 5beta-DHT, an inactive steroid. We examined seven brain regions at three stages in the breeding season. Overall, aromatase activity was high in the hypothalamus, hippocampus, and ventromedial telencephalon (containing nucleus taeniae, the avian homologue to the amygdala). 5beta-Reductase activity was high throughout the telencephalon. Activities of all three enzymes changed over time in a region-specific manner. In particular, aromatase activity in the rostral hypothalamus was decreased late in the breeding season, which may explain why T treatment at this time does not increase aggression. Changes in 5beta-reductase do not explain the effects of plasma T on aggressive behavior.
Assuntos
Comportamento Animal/fisiologia , Estações do Ano , Aves Canoras/fisiologia , Testosterona/sangue , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/análise , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , Agressão , Animais , Animais Selvagens , Aromatase/análise , Aromatase/sangue , Estrogênios/sangue , Hipocampo/química , Hipocampo/enzimologia , Hipotálamo Posterior/química , Hipotálamo Posterior/enzimologia , Masculino , Oxirredutases/análise , Oxirredutases/sangue , Área Pré-Óptica/química , Área Pré-Óptica/enzimologia , Telencéfalo/química , Telencéfalo/enzimologia , Vocalização Animal/fisiologiaRESUMO
A sensitive and specific HPLC method for the determination of turosteride in human plasma was developed and validated. Turosteride was extracted from plasma with diethyl ether. Further purifications of the fraction extracted were performed sequentially by solid-phase extraction using a CN cartridge and by liquid-liquid partition between n-hexane and acetonitrile. Finally the acetonitrile solution containing the test compound was evaporated to dryness and the residue dissolved in the mobile phase, then injected onto the HPLC system. The chromatographic separation was performed isocratically by a reversed-phase column filled with ODS using a water-acetonitrile-methanol mixture. The eluate was monitored at 210 nm. No peak interfering with that of turosteride was observed when blank human plasma was assayed. Linearity was obtained in the turosteride concentration range of 5-1000 ng/ml plasma. Six calibration curves in plasma prepared and run on six different days showed correlation coefficients higher than 0.99 and good reproducibility of the slope (C.V. = 4.3%). The intra-day precision, evaluated at three concentrations (in the low, mid and high range of the standard curve) and expressed as C.V., ranged from 0.81 to 13.25%. The inter-day precision evaluated at the same concentrations was better than 10.7%. The inter-day accuracy evaluated in the same samples and expressed as the ratio of found/added amount of turosteride ranged from 97.66 to 98.38%. The limit of quantitation was 5 ng/ml plasma. The HPLC method described was successfully employed for the determination of turosteride in plasma samples obtained during a phase I clinical trial with the test compound.