RESUMO
Gender-related methodology in biomedical sciences receives considerable attention, with numerous studies highlighting biological differences between cisgender males and females. These differences influence the clinical symptoms of various diseases and impact therapeutic approaches. In this in vitro study, we investigate the potential role of sex-chromosome-related dimorphism on steroidogenic enzymes, androgen receptor (AR) expression, and cellular translocation in primary human skeletal muscle cells before and after exposure to testosterone. We analyzed 46XY and 46XX cells for 17ß-hydroxysteroid dehydrogenase (17ß-HSD), 5α-reductase (5α-R2), aromatase (Cyp-19), and AR gene expression. We also compared AR expression and intracellular translocation after increasing exposure to testosterone. At baseline, we observed higher mRNA expression for 5α-R2 and AR in 46XY cells and higher Cyp-19 mRNA expression in 46XX cells. Following testosterone exposure, we observed an increase in AR expression and translocation in 46XX cells, even at the lowest dose of 0.5 nM, while significant changes in 46XY cells were observed only from 10 nM. Our in vitro results demonstrate that the diverse sex chromosome assets reflect important differences in muscle steroidogenesis. They support the concept that chromosomal disparities between males and females, even in vitro, lead to pivotal variations in cellular physiology and response. This understanding represents a crucial starting point in gender medicine, ensuring a precise approach in clinical practice, sports, and exercise settings and facilitating the translation of in vitro data to in vivo applicability.
Assuntos
Receptores Androgênicos , Testosterona , Masculino , Feminino , Humanos , Testosterona/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Caracteres Sexuais , Androgênios/metabolismo , Oxirredutases/metabolismo , Colestenona 5 alfa-Redutase/genética , Músculo Esquelético/metabolismo , Cromossomos Sexuais/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Androgenic alopecia (AGA) is the most prevalent type of progressive hair loss and has psychological repercussions. Nevertheless, the effectiveness of current pharmacological treatments remains limited, in part because the molecular basis of the disease has not been fully elucidated. Our group previously highlighted the important roles of aromatase and 5α-reductase (5α-R) in alopecia in young women with female pattern hair loss. Additionally, an association has been proposed between AGA and prostate cancer (PCa), suggesting that genes implicated in PCa would also be involved in AGA. A low-invasive, sensitive, and precise method was used to determine mRNA levels of aromatase, 5α-R isozymes, and 84 PCa-related genes in samples of plucked hair from young men with AGA and controls. Samples were obtained with a trichogram from the vertex scalp, and mRNA levels were quantified using real-time RT-PCR. The men with AGA had significantly higher 5α-R2 mRNA levels in comparison to controls; interestingly, some of them also showed markedly elevated mRNA levels of 5α-R1 or 5α-R3 or of both, which may explain the varied response to 5α-R inhibitor treatments. The men with AGA also showed significant changes versus controls in 6 out of the 84 genes implicated in PCa. This study contributes greater knowledge of the molecular bases of AGA, facilitating early selection of the most appropriate pharmacological therapy and opening the way to novel treatments.
Assuntos
Colestenona 5 alfa-Redutase , Neoplasias da Próstata , Masculino , Humanos , Colestenona 5 alfa-Redutase/genética , Aromatase/genética , Isoenzimas/uso terapêutico , RNA Mensageiro/genética , Cabelo , Alopecia/genética , Alopecia/tratamento farmacológico , Neoplasias da Próstata/genéticaRESUMO
Decidualization is the hormone-dependent process of endometrial remodeling that is essential for fertility and reproductive health. It is characterized by dynamic changes in the endometrial stromal compartment including differentiation of fibroblasts, immune cell trafficking and vascular remodeling. Deficits in decidualization are implicated in disorders of pregnancy such as implantation failure, intra-uterine growth restriction, and pre-eclampsia. Androgens are key regulators of decidualization that promote optimal differentiation of stromal fibroblasts and activation of downstream signaling pathways required for endometrial remodeling. We have shown that androgen biosynthesis, via 5α-reductase-dependent production of dihydrotestosterone, is required for optimal decidualization of human stromal fibroblasts in vitro, but whether this is required for decidualization in vivo has not been tested. In the current study we used steroid 5α-reductase type 1 (SRD5A1) deficient mice (Srd5a1-/- mice) and a validated model of induced decidualization to investigate the role of SRD5A1 and intracrine androgen signaling in endometrial decidualization. We measured decidualization response (weight/proportion), transcriptomic changes, and morphological and functional parameters of vascular development. These investigations revealed a striking effect of 5α-reductase deficiency on the decidualization response. Furthermore, vessel permeability and transcriptional regulation of angiogenesis signaling pathways, particularly those that involved vascular endothelial growth factor (VEGF), were disrupted in the absence of 5α-reductase. In Srd5a1-/- mice, injection of dihydrotestosterone co-incident with decidualization restored decidualization responses, vessel permeability, and expression of angiogenesis genes to wild type levels. Androgen availability declines with age which may contribute to age-related risk of pregnancy disorders. These findings show that intracrine androgen signaling is required for optimal decidualization in vivo and confirm a major role for androgens in the development of the vasculature during decidualization through regulation of the VEGF pathway. These findings highlight new opportunities for improving age-related deficits in fertility and pregnancy health by targeting androgen-dependent signaling in the endometrium.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase , Decídua , Remodelação Vascular , Animais , Feminino , Camundongos , Gravidez , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Androgênios/farmacologia , Colestenona 5 alfa-Redutase/genética , Colestenona 5 alfa-Redutase/metabolismo , Decídua/efeitos dos fármacos , Decídua/metabolismo , Di-Hidrotestosterona/farmacologia , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Remodelação Vascular/efeitos dos fármacos , Remodelação Vascular/genética , Remodelação Vascular/fisiologiaRESUMO
BACKGROUND: 5-α reductase inhibitors (5-ARIs) are first-line drugs for managing benign prostatic hyperplasia (BPH). Unfortunately, some patients do not respond to 5-ARI therapy and may even show worsening symptoms. The decreased expression of steroid 5-α reductase type 2(SRD5A2) in BPH tissues may explain the failure of 5-ARI therapy, however, the mechanisms underlying SRD5A2 decreased remained unelucidated. OBJECTIVES: To investigate microRNA-mediated regulation of the expression of SRD5A2 resulting in 5-ARI therapy failure. MATERIALS AND METHODS: The expression of SRD5A2 and microRNAs in BPH tissues and prostate cells were detected by immunohistochemistry, western blotting, and quantitative real-time PCR. Dual-luciferase reporter assay was performed to confirm that microRNA directly combine to SRD5A2 mRNA. The apoptosis of prostatic cells was detected by flow cytometry. RESULTS: SRD5A2 expression was variable; it was negative, weak, and strong in 13.6%, 28.8%, and 57.6% of BPH tissues respectively. The normal human prostatic epithelial cell line RWPE-1 strongly expressed SRD5A2, whereas the immortalized human prostatic epithelial cell line BPH-1 weakly expressed SRD5A2. miR-1199-5p expression was remarkably higher in BPH-1 than in RWPE-1 cells(P<0.001), and miR-1199-5p expression was significantly upregulated in BPH tissues with negative SRD5A2 expression than those with positive SRD5A2 expression. Transfection of miR-1199-5p mimics in RWPE-1 cells led to a marked decrease in SRD5A2 expression, whereas miR-1199-5p inhibitor increased SRD5A2 expression in BPH-1 cells. Dual-luciferase reporter assay showed that miR-1199-5p could bind the 3'untranslated region of SRD5A2 mRNA. miR-1199-5p also decreased the RWPE-1 sensibility to finasteride, an inhibitor of SRD5A2. CONCLUSION: Our results show that SRD5A2 expression varies in BPH tissues and miR-1199-5p might be one of the several factors contributing to differential SRD5A2 expression in BPH patients.
Assuntos
MicroRNAs , Hiperplasia Prostática , Masculino , Humanos , Hiperplasia Prostática/tratamento farmacológico , Colestenona 5 alfa-Redutase/genética , Colestenona 5 alfa-Redutase/metabolismo , Regulação para Cima , Oxirredutases/genética , Oxirredutases/metabolismo , Oxirredutases/uso terapêutico , RNA Mensageiro , MicroRNAs/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genéticaRESUMO
The synergetic effect of estrogens and androgens is known to play a crucial role in the physiopathology of the prostate gland. Bisphenol A (BPA) is an endocrine disrupting compound that can interfere with endocrine hormone functioning and thereby influence prostate development. The objective of this study was to examine the impact on prostate expression of aromatase, 5α-R isozymes, and prostate cancer-related genes of exposure to low doses of BPA from perinatal period to adulthood. Vehicle or BPA (2.5 µg/kg b.w./day) was administered to gestating Wistar rats from gestational day 12 (GD12) to parturition and then to their male pups from postnatal day 1 (PND1) until euthanization on PND90. Their prostate glands were examined by qRT-PCR, Western blot, PCR array, and morphological study. mRNA and protein levels of 5α-R2 were significantly reduced and mRNA and protein levels of aromatase were significantly increased in BPA-treated animals, which also showed modifications of 8 out of the 84 key genes implicated in the development of prostate cancer. Because BPA interferes with genes involved in intraprostatic androgen and estrogen production and others implicated in prostate cancer, research is warranted into the prostate disease risk associated with chronic low-dose BPA exposure throughout life.
Assuntos
Colestenona 5 alfa-Redutase , Neoplasias da Próstata , Adulto , Androgênios , Animais , Aromatase/genética , Aromatase/metabolismo , Compostos Benzidrílicos/toxicidade , Colestenona 5 alfa-Redutase/genética , Colestenona 5 alfa-Redutase/metabolismo , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Parto , Fenóis , Gravidez , Neoplasias da Próstata/induzido quimicamente , Neoplasias da Próstata/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Testosterona/metabolismoRESUMO
BACKGROUND: Women facing increased energetic demands in childhood commonly have altered adult ovarian activity and shorter reproductive lifespan, possibly comprising a strategy to optimize reproductive success. Here, we sought to understand the mechanisms of early-life programming of reproductive function, by integrating analysis of reproductive tissues in an appropriate mouse model with methylation analysis of proxy tissue DNA in a well-characterized population of Bangladeshi migrants in the UK. Bangladeshi women whose childhood was in Bangladesh were found to have later pubertal onset and lower age-matched ovarian reserve than Bangladeshi women who grew-up in England. Subsequently, we aimed to explore the potential relevance to the altered reproductive phenotype of one of the genes that emerged from the screens. RESULTS: Of the genes associated with differential methylation in the Bangladeshi women whose childhood was in Bangladesh as compared to Bangladeshi women who grew up in the UK, 13 correlated with altered expression of the orthologous gene in the mouse model ovaries. These mice had delayed pubertal onset and a smaller ovarian reserve compared to controls. The most relevant of these genes for reproductive function appeared to be SRD5A1, which encodes the steroidogenic enzyme 5α reductase-1. SRD5A1 was more methylated at the same transcriptional enhancer in mice ovaries as in the women's buccal DNA, and its expression was lower in the hypothalamus of the mice as well, suggesting a possible role in the central control of reproduction. The expression of Kiss1 and Gnrh was also lower in these mice compared to controls, and inhibition of 5α reductase-1 reduced Kiss1 and Gnrh mRNA levels and blocked GnRH release in GnRH neuronal cell cultures. Crucially, we show that inhibition of this enzyme in female mice in vivo delayed pubertal onset. CONCLUSIONS: SRD5A1/5α reductase-1 responds epigenetically to the environment and its downregulation appears to alter the reproductive phenotype. These findings help to explain diversity in reproductive characteristics and how they are shaped by early-life environment and reveal novel pathways that might be targeted to mitigate health issues caused by life-history trade-offs.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Colestenona 5 alfa-Redutase , Kisspeptinas , Proteínas de Membrana/metabolismo , Adaptação Fisiológica , Animais , Colestenona 5 alfa-Redutase/genética , Colestenona 5 alfa-Redutase/metabolismo , Epigênese Genética , Feminino , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Humanos , Kisspeptinas/genética , Kisspeptinas/metabolismo , CamundongosRESUMO
Congenital anomalies of the female reproductive tract that present with primary amenorrhea involve Müllerian aplasia, also known as Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS), and cervical and vaginal anomalies that completely obstruct the reproductive tract. Karyotype abnormalities do not exclude the diagnosis of MRKHS. Familial cases of Müllerian anomalies and associated malformations of the urinary and skeletal systems strongly suggest a complex genetic etiology, but so far, the molecular mechanism in the vast majority of cases remains unknown. Primary amenorrhea may also be the first presentation of complete androgen insensitivity syndrome, steroid 5α-reductase type 2 deficiency, 17ß-hydroxysteroid dehydrogenase type 3 deficiency, and Leydig cells hypoplasia type 1; therefore, these disorders should be considered in the differential diagnosis of the congenital absence of the uterus and vagina. The molecular diagnosis in the majority of these cases can be established.
Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/patologia , Amenorreia/genética , Amenorreia/patologia , Colo do Útero/anormalidades , Anormalidades Congênitas/patologia , Ductos Paramesonéfricos/anormalidades , Vagina/anormalidades , 17-Hidroxiesteroide Desidrogenases/deficiência , 17-Hidroxiesteroide Desidrogenases/genética , Síndrome de Resistência a Andrógenos/genética , Síndrome de Resistência a Andrógenos/patologia , Colo do Útero/embriologia , Colestenona 5 alfa-Redutase/deficiência , Colestenona 5 alfa-Redutase/genética , Anormalidades Congênitas/diagnóstico , Transtorno 46,XY do Desenvolvimento Sexual/genética , Transtorno 46,XY do Desenvolvimento Sexual/patologia , Feminino , Humanos , Masculino , Ductos Paramesonéfricos/patologia , Testículo/anormalidades , Testículo/patologia , Vagina/embriologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Psoralea corylifolia L. seed (PCL), commonly known as "Poguzhi" or "BuguZhi", has been widely used to treat kidney yang deficiency in traditional Chinese medicine (TCM) where tonifying the yang deficiency is a representative understanding for treatment of hormonal deficiency disorders such as enuresis, oliguria, and prostatic diseases. Although PCL has been commonly used to treat problems of the urinary system, its efficacy against benign prostatic hyperplasia (BPH) has not yet been reported. AIM OF THE STUDY: In the present study, we aimed to assess the in vitro and in vivo efficacy of PCL against BPH, a condition which negatively impacts quality of life in men. MATERIALS AND METHODS: Normal human prostate cell lines, RWPE-1 and WPMY-1 cells, were stimulated with 10 nM dihydrotestosterone (DHT) to establish an in vitro BPH model. Subsequently, cells were treated with 100 or 200 µg/ml PCL, which inhibited cell proliferation without cytotoxicity, to evaluate the anti-BPH effect of PCL. Eight-week-old male Wistar rats were castrated, except for those in the control group (Con), and BPH was induced by subcutaneous injection of 10 mg/kg testosterone propionate (TP). Concurrent with daily TP injections, 5 mg/kg of finasteride (Fina) and 50 or 100 mg/kg PCL were orally administrated daily for four weeks, excluding the weekends. RESULTS: In DHT-stimulated RWPE-1 and WPMY-1 cells, expression of androgen receptor (AR) androgen signaling-related markers such as 5α-reductase 2 (5AR2), AR, and prostate-specific antigen (PSA) was upregulated, whereas 100 or 200 µg/ml of PCL treatment downregulated these markers. Furthermore, PCL significantly reduced the mRNA expression of anti-apoptotic genes and increased the mRNA expression of pro-apoptotic gene. In vivo, administration of PCL reduced prostate size and weight in TP-induced BPH rats. Moreover, histological alterations in epithelium thickness were significantly restored by the administration of PCL. Immunohistochemical analysis revealed increased expression of AR and proliferating cell nuclear antigen (PCNA) in TP-induced BPH prostates; these changes were suppressed by administration of 50 or 100 mg/kg PCL. CONCLUSIONS: We demonstrated the effect of PCL against BPH, mediated by the regulation of prostate cell proliferation and apoptosis, in DHT-stimulated normal human prostate cell lines and TP-induced BPH rats. These findings suggest that PCL could be a potential therapeutic agent against BPH.
Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Hiperplasia Prostática/tratamento farmacológico , Psoralea/química , Animais , Linhagem Celular , Colestenona 5 alfa-Redutase/genética , Colestenona 5 alfa-Redutase/metabolismo , Di-Hidrotestosterona/toxicidade , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Antígeno Prostático Específico/genética , Antígeno Prostático Específico/metabolismo , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/patologia , Ratos Wistar , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Propionato de Testosterona/toxicidadeRESUMO
BACKGROUND: 5α-reductase inhibitors (5-ARIs) inhibit the pathway of converting the testosterone to dihydrotestosterone and are widely used in benign prostatic hyperplasia patients. Since androgen receptor activation may play a role in urothelial tumorigenesis, we conducted this retrospective cohort study to determine whether 5α-reductase inhibitors (5-ARIs) administration is associated with bladder cancer mortality, bladder cancer recurrence and upper tract urothelial carcinoma mortality, using the Taiwan National Health Insurance database. METHODS: The data of this retrospective cohort study were sourced from the Longitudinal Health Insurance Database of Taiwan, compiled by the Taiwan National Health Insurance database from 1996 to 2010. It consists of 18,530 men with bladder cancer, of whom 474 were 5-ARIs recipients and 4384 men with upper tract urothelial carcinoma, of whom 109 were 5-ARIs recipients. Propensity Score Matching on the age and geographic data was done at the ratio of 1:10. We analyzed the odds ratios (OR) and 95% confidence interval (CI) of the risk of bladder cancer death, bladder cancer recurrence rate and upper tract urothelial carcinoma related death by the 5-ARIs administration. RESULTS: Those who received 5-ARIs showed a lower risk of bladder cancer related death compared to nonusers in multivariable adjusted analysis (OR 0.835, 95% CI 0.71-0.98). However, there was no significant difference in the bladder cancer recurrence rate (OR 0.956, 95% CI 0.82-1.11) and upper tract urothelial carcinoma related mortality in multivariable adjusted analysis (OR 0.814, 95% CI 0.6-1.1). CONCLUSIONS: Patients who receive 5-ARIs have lower bladder cancer related mortality compared to those who don't. 5-ARIs may prove to be a viable strategy to improve bladder cancer outcomes.
Assuntos
Inibidores de 5-alfa Redutase/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma/tratamento farmacológico , Colestenona 5 alfa-Redutase/genética , Inibidores de 5-alfa Redutase/efeitos adversos , Idoso , Carcinoma/genética , Carcinoma/mortalidade , Carcinoma/patologia , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Dutasterida/administração & dosagem , Finasterida/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Prognóstico , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/genética , Hiperplasia Prostática/mortalidade , Hiperplasia Prostática/patologia , Receptores Androgênicos/genética , Taiwan/epidemiologia , Urotélio/efeitos dos fármacos , Urotélio/patologiaRESUMO
The enzymatic complex 5α-reductase (5α-R) and 3α/3ß-hydroxysteroid oxidoreductase (HSOR) is expressed in the nervous system, where it transforms progesterone (PROG) and testosterone (T) into neuroactive metabolites. These metabolites regulate myelination, brain maturation, neurotransmission, reproductive behavior and the stress response. The expression of 5α-R and 3α-HSOR and the levels of PROG and T reduced metabolites show regional and sex differences in the nervous system and are affected by changing physiological conditions as well as by neurodegenerative and psychiatric disorders. A decrease in their nervous tissue levels may negatively impact the course and outcome of some pathological events. However, in other pathological conditions their increased levels may have a negative impact. Thus, the use of synthetic analogues of these steroids or 5α-R modulation have been proposed as therapeutic approaches for several nervous system pathologies. However, further research is needed to fully understand the consequences of these manipulations, in particular with 5α-R inhibitors.
Assuntos
3-Hidroxiesteroide Desidrogenases/fisiologia , Colestenona 5 alfa-Redutase/fisiologia , Progesterona/metabolismo , Testosterona/metabolismo , 3-Hidroxiesteroide Desidrogenases/genética , Animais , Encéfalo/enzimologia , Colestenona 5 alfa-Redutase/genética , Feminino , Expressão Gênica , Humanos , Masculino , Transtornos Mentais/enzimologia , Doenças Neurodegenerativas/enzimologia , Fármacos Neuroprotetores , Caracteres SexuaisRESUMO
BACKGROUND: Cellular senescence, a phenomenon of irreversible growth arrest of mammalian cells, is involved in various age-related phenomena in organisms. Hair follicle dermal papilla (DP) cells play important roles in the regulation of hair growth and loss. AIMS: We examined the implication of cellular senescence of DP cells in androgenetic alopecia (AGA), the most common form of male hair loss, and searched for the compounds that have a beneficial effect on the prevention of AGA. PATIENTS/METHODS: Expression of the 5α-reductase type II (SRD5A2) gene, which plays a key role in the development of AGA, was examined by quantitative RT-PCR and Western blotting analysis in DP cells. Besides, DP cells were cultured with the extracts of herbs used in traditional Ayurvedic medicine to search for the compounds that have a beneficial effect on the growth of DP cells. RESULTS: We found that expression of the SRD5A2 was up-regulated in senescent DP cells. We also found that the herbal extract of Plumbago zeylanica (root) enhanced the growth of DP cells and down-regulated the expression of SRD5A2 in DP cells. Further, plumbagin, an ingredient of P zeylanica, would be responsible for the above effects of P zeylanica. CONCLUSION: These results suggested the possibility that senescent DP cells may have a role in the development of AGA through up-regulating SRD5A2 expression, and the P zeylanica extract and plumbagin may suppress its development through enhancing the growth of DP cells and down-regulating SRD5A2 expression in DP cells.
Assuntos
Folículo Piloso , Plumbaginaceae , Animais , Colestenona 5 alfa-Redutase/genética , Regulação para Baixo , Masculino , Extratos Vegetais/farmacologiaRESUMO
The effect of Rhodiola sachalinensis Boriss extract irradiated with 50 kGy gamma rays (HKC) on benign prostatic hyperplasia (BPH) was investigated. Seven-week-old male SD rats received a subcutaneous injection of 20 mg/kg of testosterone propionate (TP) to induce BPH. Then, the testosterone only group received testosterone, the testosterone + finasteride group received testosterone and finasteride (5 mg/kg), the testosterone + HKC group received testosterone and HKC extract (500 mg/kg). Prostate weight and the dihydrotestosterone (DHT) levels in serum or prostate tissue were determined. The mRNA expressions of 5-alpha reductase (AR) in prostate tissue were also measured. Compared to the control group, prostate weight was significantly improved in the TP group and decreased in the HKC and finasteride-treated groups. Furthermore, the mRNA expression of 5-AR in the prostate was significantly reduced in the HKC and finasteride-treated groups. Similarly, the expression levels of α-smooth muscle actin (α-SMA) and cytokeratin, which are associated with prostatic enlargement in the HKC and finasteride groups, were much lower than in the TP group. HKC treatment showed similar efficacy to finasteride treatment on rats with testosterone-induced BPH. HKC may be explored as a potential new drug for BPH treatment.
Assuntos
Colestenona 5 alfa-Redutase/metabolismo , Raios gama , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Rhodiola/química , Testosterona/metabolismo , Testosterona/toxicidade , Animais , Colestenona 5 alfa-Redutase/genética , Masculino , Hiperplasia Prostática/sangue , Ratos , Ratos Sprague-Dawley , Testosterona/sangueRESUMO
The steroid hormones not only exert various endocrine functions but also act as the autocrine or paracrine factors in different tissues of mammals. In the present study, the seasonal expressions of androgen receptor (AR), estrogen receptors alpha and beta (ERα and ERß), aromatase cytochrome P450 (P450arom) and 5α-reductase 1, 2 were investigated in the epididymis of the muskrat. HE staining showed enlarged lumen and abundant sperm in the breeding season while reduced lumen with no sperm in the non-breeding season. The staining of AR was presented in nuclei of epithelial cells of the epididymis in both seasons. The immunostaining of ERα was localized in both nuclei and cytoplasm of epithelial cells of the epididymis during the breeding season, while the weak staining of ERα was only in the nuclei of epithelial cells during the non-breeding season. In contrast, ERß signal was negative in the epididymis of the muskrat in both seasons. The positive signals for P450arom and 5α-reductase 1, 2 were found in the cytoplasm of epithelial and smooth muscle cells during both seasons. Moreover, the protein and mRNA expression levels of AR, ERα, P450arom and 5α-reductase 1, 2 were significantly higher in the epididymis during the breeding season than those of the non-breeding season, and the expression level of 5α-reductase 1 was higher when compared with 5α-reductase 2. In addition, the levels of testosterone (T) and dihydrotestosterone (DHT) in the epididymis and serum were remarkably higher during the breeding season. Taken together, these findings suggested androgen and estrogen might play an important endocrine or autocrine/paracrine role to regulate the epididymal functions of the muskrat.
Assuntos
Aromatase/metabolismo , Colestenona 5 alfa-Redutase/metabolismo , Epididimo/metabolismo , Receptores Androgênicos/metabolismo , Receptores de Estrogênio/metabolismo , Animais , Aromatase/genética , Arvicolinae , Colestenona 5 alfa-Redutase/genética , Masculino , RNA Mensageiro/metabolismo , Receptores Androgênicos/genética , Receptores de Estrogênio/genética , Reprodução , Estações do AnoRESUMO
CONTEXT: Pituitary luteinizing hormone (LH) stimulates testicular production of testosterone (T) which is metabolized to dihydrotestosterone (DHT) by 5α-reductase and to oestradiol (E2) by aromatase. How the activity of population variants in these enzymes impacts on gonadal function is unclear. We examined whether polymorphisms in 5α-reductase (SRD5A2) and aromatase (CYP19A1) genes predict circulating sex hormone concentrations. DESIGN: Cross-sectional analysis of 1865 community-dwelling men aged 50.4 ± 16.8 years. MEASUREMENTS: Early morning sera assayed for T, DHT and E2 (mass spectrometry), and SHBG and LH (immunoassay). Two SRD5A2 and eleven CYP19A1 polymorphisms were analysed by PCR. Regression models were adjusted for age and cardiometabolic risk factors. RESULTS: SRD5A2 polymorphism rs9282858 GA vs. GG was associated with higher serum T (+1.5 nmol/L, P < 0.001) and higher SHBG (+3.3 nmol/L, P = 0.001). CYP19A1 polymorphisms were associated with higher serum E2 and lower LH in reciprocal fashion, from which the two-copy haplotype rs10046 = T/rs2899470 = G/rs11575899 = I/rs700518 = G/rs17703883 = T was associated with higher E2 (63.4 vs. 56.5 pmol/L, P = 0.001) and lower LH (3.9 vs. 4.5 IU/L, P = 0.001) compared to null copies. Conversely, rs10046 = C/rs2899470 = T/rs11575899 = D/rs700518 = A/rs17703883 = C was associated with lower E2 (51.8 vs. 62.0 pmol/L, P = 0.001) and higher LH (5.7 vs. 3.9 IU/L, P < 0.001). These haplotypes were associated primarily with differences in E2 in men <65 years and LH in men ≥65 years. CONCLUSIONS: A 5α-reductase polymorphism predicts circulating T and SHBG, while aromatase polymorphisms predict E2 and LH in reciprocal fashion. Age and aromatase polymorphisms interact to affect E2 and LH. How these functional polymorphisms impact on male reproductive and general health outcomes requires further study.
Assuntos
Aromatase/genética , Colestenona 5 alfa-Redutase/genética , Estradiol/sangue , Hormônio Luteinizante/sangue , Polimorfismo de Nucleotídeo Único , Globulina de Ligação a Hormônio Sexual/análise , Testosterona/sangue , Adulto , Fatores Etários , Idoso , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Benign prostatic hyperplasia (BPH) is commonly observed in men > 50 years worldwide. Phytotherapy is one of the many treatment options. Sorghum (Sorghum bicolor L.) contains various health-improving phytochemicals with antioxidant and inhibitory activities on cell proliferation, both in vitro and in vivo. To confirm the effects of Donganme sorghum ethyl-acetate extract (DSEE) on BPH, we induced BPH in Spragye-Dawley rats using exogenous testosterone. We measured prostate weight, examined prostrates histopathologically, and analyzed mRNAs associated with male hormones and proteins associated with cell proliferation in the prostate. DSEE inhibited weight gain of the prostate; decreased mRNA expressions of androgen receptor and 5α-reductase II; and improved histopathological symptoms, the protein-expressed ratio of Bax/Bcl-2, and the oxidative status of BPH induced by testosterone in SD rats. Therefore, DSEE may have potential as a preventive or therapeutic agent against BPH.
Assuntos
Acetatos/química , Extratos Vegetais/farmacologia , Hiperplasia Prostática/prevenção & controle , Sorghum/química , Animais , Proliferação de Células/efeitos dos fármacos , Colestenona 5 alfa-Redutase/genética , Colestenona 5 alfa-Redutase/metabolismo , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Próstata/efeitos dos fármacos , Próstata/patologia , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/patologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/efeitos dos fármacos , Receptores Androgênicos/genética , TestosteronaRESUMO
The impact of bisphenol A (BPA) on the prostate gland has taken center stage, with a special focus placed on understanding how BPA affects prostate physiopathology. In this study, we evaluated the ability of lower doses of BPA to induce alterations in 5α-R isozymes and aromatase, in the prostate of juvenile rats exposed during developmental stage. Gestating Wistar rats were treated s.c with either vehicle or BPA (2.4 and 10⯵g/kg b.w./day) from gestational day 12 to parturition. Then, male pups were s.c treated from postnatal day 1 through day 21, when they were euthanized and qRT-PCR, western blot and hormone levels determination were performed. We found that BPA at dose of 2.4 and 10⯵g/kg b.w./day significantly decreased the mRNA and protein levels of 5α-R2. However, neither 5α-R1 nor 5α-R3 was affected by this exposure. BPA at dose of 10⯵g/kg b.w./day significantly increased the mRNA and protein levels of aromatase. BPA also decreased plasma levels of both testosterone and dihydrotestosterone and increased estradiol. These data lend support that low-dose BPA during fetal and neonatal prostate development interfere with in situ estrogen and androgen production in the prostate gland of juvenile rats through the enzymes aromatase and 5α-Reductase.
Assuntos
Aromatase/metabolismo , Compostos Benzidrílicos/toxicidade , Colestenona 5 alfa-Redutase/metabolismo , Fenóis/toxicidade , Próstata/efeitos dos fármacos , Próstata/enzimologia , Androgênios/metabolismo , Animais , Aromatase/genética , Colestenona 5 alfa-Redutase/genética , Feminino , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Exposição Materna/efeitos adversos , Próstata/crescimento & desenvolvimento , Ratos , Ratos Wistar , Testosterona/metabolismoRESUMO
A double-blind, randomized, placebo-controlled clinical trial assessed the efficacy and safety of Ageratum conyzoides in treating benign prostatic hypertrophy (BPH). In this study, 109 men with medically diagnosed BPH, aged 41-76 years, were administered the investigational product, A. conyzoides extract at a dose of 250 mg/d or placebo, q.d. for 12 weeks. The primary outcome measures were the International Prostate Symptom Score (IPSS), daily urinary frequency and safety evaluations. The secondary outcome measures were testosterone, dihydrotestosterone, oestradiol, sex hormone binding globulin (SHBG), Dehydroepiandrosterone sulfate (DHEA-S) and cortisol levels, and prostate specific antigen (PSA), lipids, blood glucose, the Aging Male's Symptom (AMS) Score and sexual function assessed by Derogatis Interview for Sexual Functioning-Self Report (DISF-SR). The effect of A. conyzoides L extract on gene expression of 5-alpha-reductase in human prostate cells was also investigated to elucidate a potential mechanism of action. The clinical study, showed a significant reduction in total IPSS score (p < 0.01) and day- and night-time urinary frequency (P < 0.01) over time after treatment with A. conyzoides. Steroid hormones, SHBG, PSA levels, lipids, and blood glucose remained within healthy reference range in both groups. There were no changes in AMS or DISF-SR in either group. Gene arrays demonstrated that A. conyzoides extract was effective in reducing the expression of mRNA coding for 5-alpha-reductase types 2 and 1 in human prostate epithelial cells. The overall results indicate that A. conyzoides may be an effective treatment for reducing symptoms of BPH in healthy men, in part, through inhibition of 5-alpha-reductase enzyme activity. © 2017 BioFactors, 43(6):789-800, 2017.
Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Ageratum/química , Anti-Inflamatórios/farmacologia , Colestenona 5 alfa-Redutase/genética , Próstata/efeitos dos fármacos , Hiperplasia Prostática/tratamento farmacológico , Inibidores de 5-alfa Redutase/isolamento & purificação , Adulto , Idoso , Anti-Inflamatórios/isolamento & purificação , Biomarcadores/sangue , Glicemia/metabolismo , Linhagem Celular , Colestenona 5 alfa-Redutase/metabolismo , Sulfato de Desidroepiandrosterona/sangue , Di-Hidrotestosterona/sangue , Método Duplo-Cego , Estradiol/sangue , Humanos , Hidrocortisona/sangue , Calicreínas/sangue , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/química , Próstata/metabolismo , Próstata/patologia , Antígeno Prostático Específico/sangue , Hiperplasia Prostática/sangue , Hiperplasia Prostática/genética , Hiperplasia Prostática/patologia , Globulina de Ligação a Hormônio Sexual/genética , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/sangue , Resultado do Tratamento , Micção/efeitos dos fármacosRESUMO
Benign prostatic hyperplasia (BPH) is characterized by uncontrolled proliferation of the prostate gland. Cynanchum wilfordii has been reported to improve sexual behavior in male rats. In this study, we investigated the protective effect of an aqueous extract of C. wilfordii (CWW) against BPH development in a testosterone-induced BPH rat model. The rats were divided into the following six groups: sham/vehicle; BPH/vehicle; BPH/finasteride; and three CWW doses (50, 100, and 200 mg/kg). After a 4-week treatment with CWW, the rats were euthanized at scheduled times, and their prostates were weighed, followed by a histopathological examination. Prostate growth inhibition rates in rats administered CWW 50, 100, and 200 mg/kg were 54.5%, 51.8%, and 50.1%, respectively. The BPH/CWW group showed decreased serum testosterone and dihydrotestosterone (DHT) levels compared to the BPH/vehicle group. Furthermore, the BPH/CWW group showed reduced prostate testosterone and DHT levels compared to the BPH/vehicle group. Mechanistically, the reverse transcription-polymerase chain reaction revealed downregulated mRNA expression levels of the androgen receptor, 5α-reductase, and B-cell lymphoma-2 (Bcl-2) in the BPH/CWW200 group compared with those in the testosterone-induced groups. In conclusion, these findings show the effectiveness of CWW in slowing the progression of testosterone-induced BPH in rats.
Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Antagonistas de Receptores de Andrógenos/farmacologia , Proliferação de Células/efeitos dos fármacos , Colestenona 5 alfa-Redutase/metabolismo , Cynanchum , Extratos Vegetais/farmacologia , Próstata/efeitos dos fármacos , Hiperplasia Prostática/prevenção & controle , Receptores Androgênicos/efeitos dos fármacos , Testosterona , Inibidores de 5-alfa Redutase/isolamento & purificação , Antagonistas de Receptores de Andrógenos/isolamento & purificação , Animais , Colestenona 5 alfa-Redutase/genética , Cynanchum/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Tamanho do Órgão , Extratos Vegetais/isolamento & purificação , Raízes de Plantas , Próstata/enzimologia , Próstata/patologia , Antígeno Prostático Específico/sangue , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/enzimologia , Hiperplasia Prostática/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-Dawley , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Fatores de TempoRESUMO
Cytochrome P450 17A1 (P450c17) is the key enzyme required for the production of androgenic sex steroids by converting progestogens to androgens. 5α-reductases are enzymes that convert testosterone (T) to dihydrotestosterone (DHT), which has a greater affinity for androgen receptors (AR) and stronger action than T. Our previous studies revealed that the scented glands of male muskrats expressed AR during the breeding and nonbreeding seasons. To further seek evidence of the activities of androgens in scented glands, the expression patterns of P450c17 and 5α-reductase 2 were investigated in the scented glands of male muskrats during the breeding and nonbreeding seasons. The weight and size of scented glands in the breeding season were significantly higher than those of the nonbreeding season. Immunohistochemical data showed that P450c17 and 5α-reductase 2 were presented in the glandular cells and epithelial cells of scented glands in both the seasons. The protein and mRNA expression of P450c17 and 5α-reductase 2 were significantly higher in the scented gland during the breeding season than those during the nonbreeding season. In addition, the levels of DHT and T in the scented gland were remarkably higher during the breeding season. Taken together, these results suggested that the scented glands of male muskrats were capable of locally synthesizing T and DHT, and T and DHT might play an important role in the scented glandular function via an autocrine or paracrine manner.
Assuntos
Arvicolinae/anatomia & histologia , Arvicolinae/metabolismo , Colestenona 5 alfa-Redutase/metabolismo , Glândulas Odoríferas/enzimologia , Estações do Ano , Esteroide 17-alfa-Hidroxilase/metabolismo , Animais , Sequência de Bases , Colestenona 5 alfa-Redutase/genética , Di-Hidrotestosterona/metabolismo , Regulação Enzimológica da Expressão Gênica , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Glândulas Odoríferas/citologia , Esteroide 17-alfa-Hidroxilase/genética , Testosterona/metabolismoRESUMO
BACKGROUND: Acorus gramineus has been reported to exhibit various pharmacological effects including inhibition of cholesterol synthesis, enhancement of lipid metabolism, prevention of dementia and inhibition of mast cell growth. According to the Chinese compendium of materia media, it has been reported that Acorus spp. is effective for sedation, dementia prevention as well as diuretic effect. In addition, it showed more than equivalent activity compared to furosoemide, a drug known to be effective in diuretic action in animal model study. However, their effectiveness against benign prostatic hyperplasia (BPH) of Acorus gramineus has not been reported. This study was designed to evaluate the effect of Acorus gramineus root hot water extract (AG) against BPH in vivo. METHODS: Male rats, 10 weeks of age and weighing 405 g ± 10 g, were used for this study. Biomarkers were evaluated including prostate weight, prostate weight ratio, hormonal changes, 5-α reductase type II androgen receptor (AR) of the prostate gland and anti-oxidant activation factors related to BPH. These biomarkers were measured in vivo test. RESULTS: AG showed significant effect at the 250 and 500 mg/kg/day in rats. Groups treated with AG displayed significantly lower levels of prostate gland weight (0.79 g) compared to the BPH induced group (1.19 g). Also, dihydrotestosterone (DHT) level was decreased from 61.8 to 100% and androgen receptor expression level was decreased from 111 to 658%. Any hematological toxicity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level wasn't observed. CONCLUSION: This study indicated that AG was effective for reducing BPH symptoms. TRIAL REGISTRATION: Not applicable.