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2.
Gen Comp Endocrinol ; 286: 113245, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31415730

RESUMO

Dihydrotestosterone (DHT) and 17ß-estradiol (E2) are sex hormones that regulate human hair follicle (HF) growth and are produced by peripheral reduction and aromatization of testosterone. However, the expression patterns of DHT and E2 synthesis-related proteins and their receptors in male yak skin during different HF stages (telogen, anagen, and catagen) are unknown. In this study, we found that both 5α-red and androgen receptor (AR) were expressed in epithelial cells and AR was expressed in the dermal papilla. Additionally, the transcription level of 5α-red1 at different HF stages was significantly higher than that of 5α-red2 mRNA at the same stage; 5α-red1 and 5α-red2 proteins peaked during the anagen and telogen periods of HF, respectively. However, AR protein was only expressed in the skin during the anagen phase of HF. Aromatase and estrogen receptors (ERα and ERß) were expressed in cutaneous epithelial cells, whereas ERα and ERß were expressed in the dermal papilla; the transcription level of ERα in HFs at each stage was much higher than that of ERß. From the catagen to telogen phase, aromatase protein expression was down-regulated, while ERα protein expression was up-regulated. Based on our results, we speculate that 5α-red1 is essential for the synthesis of DHT in male yak skin epithelial cells and promotes the growth of HFs through AR. E2 synthesized by male yak skin epithelial cells may inhibit the growth of male yak skin HFs by ERα. These results provide a foundation for further study on the mechanism of hormone-regulated male yak skin HFs.


Assuntos
Antígeno 12E7/metabolismo , Di-Hidrotestosterona/metabolismo , Folículo Piloso/crescimento & desenvolvimento , Animais , Bovinos , Folículo Piloso/metabolismo , Masculino
3.
Gynecol Endocrinol ; 35(12): 1094-1098, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31674860

RESUMO

Considerable researches on sex steroids and insulin action have suggested a mutual interaction between hyperandrogenemia and insulin resistance (IR). The objective of present study was to evaluate the androgens levels in young females with emphasis on the association of 17OHP with IR. Serum concentrations of glucose, insulin, and androgens in 80 young females were measured by standard routine procedures. Total testosterone (TT), dihydrotestosterone (DHT), dehydroepiandrosterone sulfate (DHEAS), androstenedione (ASD), and 17-hydroxyprogesterone (17OHP) levels were higher in patients with IR compared to healthy controls (p < .05). 17OHP was associated with IR and other androgens tested in young females. According to the results, androgen excess was associated with IR in young females and TT appeared to be independent predictor of IR in these patients. These data may suggest that simultaneous quantification of an androgen profile including at least TT, DHT, and 17OHP can present useful clinical information for assessment of androgen excess.


Assuntos
17-alfa-Hidroxiprogesterona/metabolismo , Androgênios/metabolismo , Glicemia/metabolismo , Resistência à Insulina , Insulina/metabolismo , Adulto , Androstenodiona/metabolismo , Estudos de Casos e Controles , Sulfato de Desidroepiandrosterona/metabolismo , Di-Hidrotestosterona/metabolismo , Feminino , Humanos , Testosterona/metabolismo , Adulto Jovem
4.
Am J Physiol Endocrinol Metab ; 317(6): E1182-E1192, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31689143

RESUMO

Androgens exert important effects both in androgen-responsive tissues and in the intestinal tract. To determine the impact of the gut microbiota (GM) on intestinal androgen metabolism, we measured unconjugated (free) and glucuronidated androgen levels in intestinal contents from the small intestine, with a low bacterial density, and from cecum and colon, with a high bacterial density. Using a specific, sensitive gas chromatography-tandem mass spectrometry method, we detected high levels of glucuronidated testosterone (T) and dihydrotestosterone (DHT) in small intestinal content of mice of both sexes, whereas in the distal intestine we observed remarkably high levels of free DHT, exceeding serum levels by >20-fold. Similarly, in young adult men high levels of unconjugated DHT, >70-fold higher than in serum, were detected in feces. In contrast to mice with a normal GM composition, germ-free mice had high levels of glucuronidated T and DHT, but very low free DHT levels, in the distal intestine. These findings demonstrate that the GM is involved in intestinal metabolism and deglucuronidation of DHT and T, resulting in extremely high free levels of the most potent androgen, DHT, in the colonic content of young and healthy mice and men.


Assuntos
Androgênios/metabolismo , Microbioma Gastrointestinal/fisiologia , Mucosa Intestinal/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Animais , Ceco/metabolismo , Ceco/microbiologia , Colo/metabolismo , Colo/microbiologia , Di-Hidrotestosterona/análogos & derivados , Di-Hidrotestosterona/metabolismo , Fezes/química , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Expressão Gênica , Vida Livre de Germes , Humanos , Intestino Delgado/metabolismo , Intestino Delgado/microbiologia , Masculino , Camundongos , Testosterona/análogos & derivados , Testosterona/metabolismo , Adulto Jovem
5.
J Steroid Biochem Mol Biol ; 193: 105411, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31207361

RESUMO

Reductive 17ß-hydroxysteroid dehydrogenases (17ß-HSDs) and 11ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2) play crucial roles in respectively regulating steroids and glucocorticoids for the progression of hormone-dependent breast cancer. Most studies focused on the function and individual regulation of these enzymes. However, mutual regulation of these enzymes and the induced modulation on the estrogen and androgen receptors for breast cancer promotion are not yet clear. In this study, MCF-7 and T47D cells were treated with inhibitors of 17ß-HSD1, 17ß-HSD7, aromatase or steroid sulfatase (STS), then mRNA levels of 17ß-HSD7, STS, 11ß-HSD 2, estrogen receptors α (ERα) and androgen receptor (AR) were determined by Q-PCR. ER negative cell line MDA-MB-231 was used as a negative control. Our results demonstrate that 17ß-HSD7, STS and 11ß-HSD2 are all regulated by the same estrogen estradiol via ERα. When the gene of ERα (ESR1) was knocked down, there was no longer significant mutual regulation of these enzymes. Our results demonstrate that important steroidogenic enzymes transcriptionally regulated by ERα, can be mutually closely correlated. Inhibition of one of them can reduce the expression of another, thereby amplifying the role of the inhibition. Furthermore, inhibition of 17ß-HSD7 increases the expression of AR gene which is considered as a marker for better prognosis in ER + breast cancer, while maintaining ERα level. Thus, our mechanistic finding provides a base for further improving the endocrine therapy of ER + breast cancer, e.g., for selecting the target steroid enzymes, and for the combined targeting of human 17ß-HSD7 and ERα.


Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Receptores Androgênicos/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , 17-Hidroxiesteroide Desidrogenases/genética , Inibidores da Aromatase/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Di-Hidrotestosterona/metabolismo , Estradiol/metabolismo , Feminino , Humanos , Esteril-Sulfatase/antagonistas & inibidores , Esteril-Sulfatase/genética , Esteril-Sulfatase/metabolismo
6.
Autoimmunity ; 52(3): 117-125, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31134819

RESUMO

Background: Graves' disease (GD) is an autoimmune disease that affects more women than men. In our previous study, a potent bioactive androgen, 5α-dihydrotestosterone (DHT) showed a protective effect against GD in female BALB/c mice. Evidence indicates that abnormal oxidative stress and immunosuppressive cytokines (TGF-ß, IL-35) play critical roles in the pathogenesis and development of GD. The purpose of this research is to measure these cytokines and oxidative stress markers to explore potential protective mechanisms of DHT in a BALB/c mouse model of GD. Methods: GD was induced in female BALB/c mice by intramuscular injection of an adenovirus expressing the A-subunit of the TSH receptor (Ad-TSHR289). DHT or a matching placebo was injected every 3 days. Mice were sacrificed four weeks after the third virus immunization to obtain blood, thyroid and spleen for further analysis. Results: Thyroid hormones were significantly reduced in DHT treated GD mice. In addition, DHT attenuated thyroid oxidative injuries in GD mice, as shown by decreased total antioxidation capability (TAOC), superoxide dismutase (SOD) and the level of malondialdehyde (MDA). The levels of immunosuppressive cytokines (TGF-ß, IL-35) in DHT group were significant higher compared with the GD group. Conclusions: The results demonstrated that DHT could reduce the severity of GD in female BALB/c mice by regulating oxidative stress. The upregulation of immunosuppressive cytokines might be another important protective mechanism.


Assuntos
Citocinas/metabolismo , Di-Hidrotestosterona/metabolismo , Doença de Graves/etiologia , Doença de Graves/metabolismo , Imunomodulação , Estresse Oxidativo , Animais , Autoanticorpos , Di-Hidrotestosterona/farmacologia , Modelos Animais de Doenças , Feminino , Doença de Graves/diagnóstico , Humanos , Imunomodulação/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio/metabolismo , Receptores da Tireotropina/antagonistas & inibidores , Receptores da Tireotropina/imunologia , Receptores da Tireotropina/metabolismo , Índice de Gravidade de Doença , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Hormônios Tireóideos/metabolismo
7.
Hum Cell ; 32(3): 379-389, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31119584

RESUMO

Men are at a higher risk of developing bladder cancer than women. Although the urinary bladder is not regarded as an sex organ, it has the potential to respond to androgen signals. The mechanisms responsible for the gender differences remain unexplained. Androgen receptor (AR) after binding with 5α-dihydrotestosteron (DHT) undergoes a conformational change and translocates to nucleus to induce transcriptional regulation of target genes. However androgen/AR signaling can also be activated by interacting with several signaling molecules and exert its non-genomic function. The aim of present study was to explain whether the progression of bladder cancer in men is dependent on androgen/AR signaling. Studies were carried out on human bladder cancer cell lines: HCV29, T24, HT1376 and HTB9. Bladder cancer cells were treated for 48 h with 10 nM DHT or not, with replacement after 24 h. Expression of cell signaling proteins, was analyzed using Western Blot and RT-PCR. Subcellular localization of protein was studied using the ProteoExtract Subcellular Proteome Extraction Kit and Western blot analysis. We showed that DHT treatment significantly increased AR expression in bladder cell line HCV29. We also observed DHT-mediated activation of Akt/GSK-3ß signaling pathway which plays a central role in cancer progression. Presented results also show that androgen/AR signaling is implicated in phosphorylation of eIF4E which can promote epithelial-mesenchymal transition (EMT). We indicate that AR plays an essential role in bladder cancer progression in male patients. Therefore, androgen-activated AR signaling is an attractive regulatory target for the inhibition or prevention of bladder cancer incidence in men.


Assuntos
Di-Hidrotestosterona/metabolismo , Di-Hidrotestosterona/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Neoplasias da Bexiga Urinária/etiologia , Neoplasias da Bexiga Urinária/genética , Células Cultivadas , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Fator de Iniciação 4E em Eucariotos/metabolismo , Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Terapia de Alvo Molecular , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Risco , Caracteres Sexuais , Transdução de Sinais/genética , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/terapia
8.
Gerontology ; 65(4): 397-406, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31096217

RESUMO

BACKGROUND: Androgen production following exercise has been suggested to contribute anabolic actions of muscle. However, the underlying mechanisms of the androgen receptor (AR) in androgen's action are still unclear. OBJECTIVE: In the present study, we examined androgen/AR-mediated action in exercise, especially for the suppression of myostatin, a potent negative regulator of muscle mass. METHODS: To examine the effects of exercise, we employed low-intensity exercise in mice and electric pulse stimulation (EPS) in C2C12 myotubes. Androgen production by C2C12 myotubes was measured by enzyme-linked immunosorbent assay. To block the action of AR, we pretreated C2C12 myotubes with flutamide. Quantitative real-time polymerase chain reaction was used to determine the expression levels of proteolytic genes including CCAAT/enhancer-binding protein delta (C/EBPδ), myostatin and muscle E3 ubiquitin ligases, as well as myogenic genes such as myogenin and PGC1α. The activation of 5'-adenosine-activated protein kinase and STAT3 was determined by Western blot analysis. RESULTS: Both mRNA and protein levels of AR significantly increased in skeletal muscle of low-intensity exercised mice and C2C12 myotubes exposed to EPS. Production of testosterone and dihydrotestosterone from EPS-treated C2C12 myotubes was markedly increased. Of interest, we found that myostatin was clearly inhibited by EPS, and its inhibition was significantly abrogated when AR was blocked by flutamide. To test how AR suppresses myostatin, we examined the effects of EPS on C/EBPδ because the promoter region of myostatin has several C/EBP recognition sites. C/EBPδ expression was decreased by EPS, and this decrease was negated by flutamide. IL-6 and phospho-STAT3 (pSTAT3) expression, the downstream pathway of myostatin, were decreased by EPS and this was also reversed by flutamide. Similar downregulation of C/EBPδ, myostatin, and IL-6 was seen in skeletal muscle of low-intensity exercised mice. CONCLUSIONS: Muscle AR expression and androgen production were increased by exercise and EPS treatment. As a mechanistical insight, it is suggested that AR inhibited myostatin expression transcriptionally by C/EBPδ suppression, which negatively influences IL-6/pSTAT3 expression and consequently contributes to the prevention of muscle proteolysis during exercise.


Assuntos
Proteína delta de Ligação ao Facilitador CCAAT/genética , Fibras Musculares Esqueléticas/metabolismo , Miostatina/genética , Condicionamento Físico Animal , Receptores Androgênicos/genética , Antagonistas de Androgênios/farmacologia , Animais , Proteína delta de Ligação ao Facilitador CCAAT/efeitos dos fármacos , Di-Hidrotestosterona/metabolismo , Estimulação Elétrica , Flutamida/farmacologia , Técnicas In Vitro , Interleucina-6/metabolismo , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Miogenina/efeitos dos fármacos , Miogenina/genética , Miostatina/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores Androgênicos/metabolismo , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Testosterona/metabolismo , Transcriptoma
9.
J Cosmet Dermatol ; 18(4): 966-975, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30980598

RESUMO

The second most common alopecia-Androgenetic alopecia (AGA)-occurs due to hormonal imbalance. Dihydrotestosterone (DHT) an androgenic hormone is a sex steroid, produced in the gonads. The target sites of DHT are similar to that of testosterone, and it attaches easily remaining bound for 53 minutes as compared to 35 minutes of testosterone. Excess of DHT causes miniaturization of hair reducing the anagen phase and increasing the telogen phase leading to hair loss. Normally up to ten percent of testosterone in the body irreversibly gets converted into DHT by the action of enzyme 5-alpha-reductase. Inadequate blood flow to the scalp can also be another reason for hair loss encountered due to lower oxygen and nutrients reaching it. AGA affects both sexes; however in males, it leads to major hair loss. Conventional drugs such as minoxidil and finasteride are widely used for the treatment. However, several drawbacks such as allergic contact dermatitis, burning, ejaculation disorder, and decreased libido are reported. Available literature suggests the role of herbal drugs to have the action against 5-alpha-reductase enzyme inhibiting it and reducing the hair loss. This can be further potentiated since they exhibit lesser side effects. Recent advancements observed in the medicinal, cosmetic, and engineering fields can prove to be an asset. This article focuses on herbs which can be used in AGA. A review of Saw palmetto (Serenoa repens), Green tea (Camellia sinensis), Pumpkin seed (Curcurbita pepo), Rosemary (Rosmarinus officinalis), Grape seed (Vitis vinifera), and Licorice (Glycyrrhiza glabra) is attempted.


Assuntos
Inibidores de 5-alfa Redutase/uso terapêutico , Alopecia/tratamento farmacológico , Di-Hidrotestosterona/antagonistas & inibidores , Extratos Vegetais/uso terapêutico , Inibidores de 5-alfa Redutase/farmacologia , Alopecia/etiologia , Camellia sinensis/química , Cucurbita/química , Di-Hidrotestosterona/metabolismo , Glycyrrhiza/química , Cabelo/efeitos dos fármacos , Cabelo/crescimento & desenvolvimento , Humanos , Extratos Vegetais/farmacologia , Serenoa/química , Vitis/química
10.
Gerontology ; 65(5): 458-464, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30943489

RESUMO

Benign prostatic hyperplasia (BPH), benign prostatic enlargement (BPE) and lower urinary tract symptoms (LUTS) belong to the most frequent diseases in ageing men. Beyond the 6th decade of life, more than 30% of men suffer from moderate to severe LUTS requiring intervention. The pathophysiology of BPH/BPE is still incompletely understood. The dominant role of the androgen system and the androgen receptor is well defined. Androgen receptors are expressed in BPH tissue in which they are activated by the potent androgen dihydrotestosterone. Synthesis of dihydrotestosterone is under control of the 5α-reductase enzyme, activity of which is antagonized by finasteride and dutasteride. More recently, the impact of prostatic inflammation and metabolic parameters particularly for the development of BPE and LUTS has increasingly been recognized. A better understanding of the pathophysiology is a prerequisite for the development of novel, more effective medical treatment options.


Assuntos
Envelhecimento/metabolismo , Sintomas do Trato Urinário Inferior/metabolismo , Hiperplasia Prostática/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Inibidores de 5-alfa Redutase/uso terapêutico , Envelhecimento/imunologia , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/metabolismo , Di-Hidrotestosterona/metabolismo , Dutasterida/uso terapêutico , Dislipidemias/epidemiologia , Dislipidemias/metabolismo , Finasterida/uso terapêutico , Humanos , Inflamação/imunologia , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Sintomas do Trato Urinário Inferior/epidemiologia , Sintomas do Trato Urinário Inferior/imunologia , Masculino , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/metabolismo , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/epidemiologia , Hiperplasia Prostática/imunologia , Receptores Androgênicos/metabolismo
11.
Horm Cancer ; 10(2-3): 77-88, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30877616

RESUMO

Androgens are thought to cause prostate cancer, but the underlying mechanisms are unclear. Data from animal studies suggest that for androgens to cause prostate cancer, they must be aromatized to estrogen and act in concert with estrogen metabolites. We tested the hypothesis that androgen-receptor and estrogen receptor-mediated effects of androgen and estrogen are necessary, as well as genotoxicity of estrogen metabolites. NBL rats were treated with androgenic and estrogenic compounds for 16-75 weeks through slow-release silastic implants or pellets. Testosterone alone induced cancer in the prostate of 37% of rats. 5α-Dihydrotestosterone, which cannot be converted to estradiol or testosterone, did not cause a significant prostate cancer incidence (4%). Addition of estradiol to 5α-dihydrotestosterone treatment did not markedly enhance prostate cancer incidence (14%), unlike adding estradiol to testosterone treatment which induced a 100% tumor incidence. Testosterone plus estradiol treatment induced a DNA adduct detectable by 32P-postlabeling, oxidative DNA damage (8-hydroxyguanosine), and lipid peroxidation at the site within the prostate where this treatment causes cancers, preceding later cancer formation. The non-estrogenic 4-hydroxy metabolite of estradiol, when combined with testosterone, induced prostatic dysplasia within 16 weeks and, after long-term treatment, a very low incidence of prostate cancer (21%). When an estrogen that cannot be hydroxylated (2-fluoroestradiol) was added to this combined treatment with testosterone and 4-hydroxyestradiol, dysplasia frequency after 16 weeks was doubled. These results strongly support the hypothesis, but additional definitive studies are needed which may identify new targets to interfere with these mechanisms that are clinically feasible in humans.


Assuntos
Androgênios/efeitos adversos , Carcinogênese , Estrogênios/efeitos adversos , Neoplasias da Próstata/induzido quimicamente , Animais , Carcinoma , Adutos de DNA , Dano ao DNA , Di-Hidrotestosterona/metabolismo , Estradiol/metabolismo , Estrogênios de Catecol/química , Guanosina/análogos & derivados , Guanosina/farmacologia , Humanos , Incidência , Masculino , Próstata , Ratos , Receptores Estrogênicos/metabolismo , Testosterona/metabolismo
12.
PLoS Biol ; 17(2): e3000002, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30763313

RESUMO

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


Assuntos
Androgênios/biossíntese , Feto/fisiologia , Masculinidade , Di-Hidrotestosterona/sangue , Di-Hidrotestosterona/metabolismo , Feminino , Humanos , Masculino , Redes e Vias Metabólicas , Ovário/metabolismo , Gravidez , Segundo Trimestre da Gravidez/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Testículo/metabolismo
13.
Mol Cell Endocrinol ; 486: 79-88, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30807787

RESUMO

Adrenal androgens dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) are potential substrates for intracrine production of testosterone (T) and dihydrotestosterone (DHT), or directly to DHT, by prostate cancer (PCa) cells. Production of DHT from DHEAS and DHEA, and the role of steroid sulfatase (STS), were evaluated ex vivo using fresh human prostate tissue and in vitro using human PCa cell lines. STS was expressed in benign prostate tissue and PCa tissue. DHEAS at a physiological concentration was converted to DHT in prostate tissue and PCa cell lines, which was STS-dependent. DHEAS activation of androgen receptor (AR) and stimulation of PCa cell growth were STS-dependent. DHEA at a physiological concentration was not converted to DHT ex vivo and in vitro, but stimulated in vivo tumor growth of the human PCa cell line, VCaP, in castrated mice. The findings suggest that targeting metabolism of DHEAS and DHEA may enhance androgen deprivation therapy.


Assuntos
Glândulas Suprarrenais/metabolismo , Androgênios/metabolismo , Di-Hidrotestosterona/metabolismo , Orquiectomia , Próstata/metabolismo , Neoplasias da Próstata/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Desidroepiandrosterona/metabolismo , Sulfato de Desidroepiandrosterona/metabolismo , Humanos , Masculino , Camundongos Nus , Camundongos SCID , Próstata/patologia , Receptores Androgênicos/metabolismo , Esteril-Sulfatase/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J Steroid Biochem Mol Biol ; 186: 61-65, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30227243

RESUMO

Human 17ß-hydroxysteroid dehydrogenase (17ß-HSD) type 1 and 7 catalyze the final step of estrogen activation and the first step in androgen inactivation. It has been shown in breast cancer cells that DHT has a suppression effect on cell proliferation, counteracting the estrogen growth effect. However, the exact kinetic function of 17ß-HSD7 in steroidogenesis was not determined. Here we report the steady-state kinetics and binding study for 17ß-HSD7 with estrone or DHT as substrates and NADPH as cofactor. 17ß-HSD7 has been overexpressed in E. coli and purified. For both substrates, kinetics of 17ß-HSD7 demonstrates positive cooperativity. The K0.5 value is 5.2 ± 0.4 µM and 14.4 ± 0.8 µM and the kcat is 0.0063 ± 0.0003 s-1 and 0.0153 ± 0.0007 s-1 for the reduction of E1 and DHT, respectively. The binding study shows a similar affinity with a dissociation constant of 5.2 ± 0.5 µM and 11 ± 1 µM for E1 and DHT, respectively. Our kinetic and binding results reveal a positive cooperativity for 17ß-HSD7 to both the E1 and DHT with a similar affinity, while 17ß-HSD1 demonstrated a significantly higher affinity toward E1 than DHT, but with a strong E1 substrate inhibition. These results strongly support that the inhibition of 17ß-HSD7 constitutes the basis of breast cancer cell proliferation decreasing that led to the shrinkage of xenograft ER + breast tumor mice model.


Assuntos
17-Hidroxiesteroide Desidrogenases/metabolismo , Androgênios/metabolismo , Estrogênios/metabolismo , Di-Hidrotestosterona/metabolismo , Estrona/metabolismo , Humanos , Cinética , NADP/metabolismo , Especificidade por Substrato
15.
Prostate ; 79(3): 272-280, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30370569

RESUMO

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


Assuntos
Hormônios Esteroides Gonadais/sangue , Hormônios Esteroides Gonadais/metabolismo , Neoplasias da Próstata/sangue , Neoplasias da Próstata/metabolismo , Idoso , Cistectomia , Di-Hidrotestosterona/sangue , Di-Hidrotestosterona/metabolismo , Estradiol/sangue , Estradiol/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Prostatectomia , Hiperplasia Prostática/sangue , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/cirurgia , Testosterona/sangue , Testosterona/metabolismo , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/cirurgia
16.
World J Urol ; 37(5): 751-757, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30350016

RESUMO

Accumulating evidence has shown that intracrinology in prostate cancer (PCa) has a pivotal role in survival of cancer cell. PCa cells are able to produce androgens from different androgen precursors, such as dehydroepiandrosterone, thereby maintaining androgen receptor signaling. Several drugs have been developed that target intracrinology, some of which are now being used as standard treatment for the so-called castrate-resistant prostate cancer (CRPC) patients. Recently, the US FDA approval has changed the indication of drugs targeting intracrinology, e.g., abiraterone and enzalutamide where it evolved from post-chemotherapy CRPC to hormone-naive metastatic PCa cases. This approval raises question whether those drugs can also be used as the first-line treatment in localized stage PCa cases. In addition, development of additional drugs targeting major components of intracrinology is ongoing. Application of these new drugs and administration of combinations of existing drugs will ultimately lead to an increase in the efficacy of such treatments as well as to reduce the toxicity of the therapy and to prevent the risk of resistance.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Acetato de Abiraterona/uso terapêutico , Androgênios/metabolismo , Desidroepiandrosterona/metabolismo , Di-Hidrotestosterona/metabolismo , Humanos , Masculino , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Testosterona/metabolismo
17.
Aging Male ; 22(4): 228-240, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30354924

RESUMO

Objectives: To assess sex hormones in men with obesity and prostate cancer (PCa) and to study association between androgens and the pathogenesis biology of PCa in vitro. Subjects and methods: One hundred and eighty-one men older than 45 years selected from of a population attending to Urology departments screening for PCa, (78 participants without PCa and 103 patients with PCa). All participants were assessed for body mass index (BMI), age, Gleason score, and PSA. Endocrine profile was determined for LH, total testosterone (TT), 17ß-estradiol (E2), prolactin and leptin. Biochemical profile (HbA1c, triacylglycerols and lipoproteins) was also determined. In vitro experiments were also performed, involving the study of 5α-dihydrotestosterone (DHT) and E2 in the presence of adipocyte-conditioned medium (aCM). Results: All variables were continuous and described a Gaussian distribution unless mentioned. To determine the relation of aggressiveness, variable were transformed into categories. Thus, PCa aggressiveness is associated with the increase of age and BMI (p < .0001) but with is decreased with TT and E2 (p < .05). Moreover, adipocyte-secreted molecules increase aggressiveness of PCa cells in vitro. Lastly, DTH but not E2 enables invasiveness in vitro. Conclusions: It was observed a coexistence of hormone axis profile alteration with sex hormones and BMI in PCa patients, in accordance with the new perspective of PCa pathogenesis.


Assuntos
Estradiol/sangue , Leptina/sangue , Hormônio Luteinizante/sangue , Obesidade , Prolactina/sangue , Neoplasias da Próstata , Testosterona , Tecido Adiposo/metabolismo , Fatores Etários , Idoso , Índice de Massa Corporal , Correlação de Dados , Di-Hidrotestosterona/metabolismo , Detecção Precoce de Câncer/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Obesidade/sangue , Obesidade/diagnóstico , Obesidade/epidemiologia , Portugal/epidemiologia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Fatores de Risco , Testosterona/sangue , Testosterona/metabolismo
18.
Mol Cell Endocrinol ; 489: 3-8, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30508571

RESUMO

17ß-hydroxysteroid dehydrogenase type 3 (17ßHSD3) deficiency is an autosomal recessive disorder of male sex development that results in defective testosterone biosynthesis. Although mutations in the cognate HSD17B3 gene cause a spectrum of phenotypic manifestations, the majority of affected patients are genetic males having female external genitalia. Many cases do not present until puberty, at which time peripheral conversion of androgen precursors causes progressive virilization. Measurement of the testosterone-to-androstenedione ratio is useful to screen for 17ßHSD3 deficiency, and genetic analysis can confirm the diagnosis. As some individuals with 17ßHSD3 deficiency transition from a female sex assignment to identifying as males, providers should ensure stable gender identity prior to recommending irreversible treatments. Gonadectomy is indicated to prevent further virilization if a female gender identity is established. The risk of testicular neoplasia is unknown, a point which should be discussed if patients elect to transition into a male gender role.


Assuntos
17-Hidroxiesteroide Desidrogenases/deficiência , Neoplasias Embrionárias de Células Germinativas/enzimologia , 17-Hidroxiesteroide Desidrogenases/metabolismo , Di-Hidrotestosterona/metabolismo , Humanos , Mutação/genética , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Embrionárias de Células Germinativas/fisiopatologia
19.
J Ethnopharmacol ; 233: 115-122, 2019 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-30508623

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ulmus macrocarpa Hance (UMH), of the family Ulmaceae, is a deciduous tree, widely distributed throughout Korea. UMH has been used as a traditional oriental medicine in Korea for the treatment of urological disorders, including bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS), diuresis, and hematuria. To date, its possible protective effects against benign prostatic hyperplasia (BPH) have not been analyzed. AIM OF THE STUDY: This study investigated the effects of UMH on the development of BPH using a rat model of testosterone propionate (TP)-induced BPH. MATERIALS AND METHODS: BPH was induced by daily subcutaneous injections of testosterone propionate (TP) for four weeks. UMH was administrated daily by oral gavage at a dose of 150 mg/kg during the four weeks of TP injections. Animals were sacrificed, and their prostates were weighed and subjected to histopathological examination, TUNEL assay, and western blot analysis. RESULTS: Treatment of BPH-model rats with UMH significantly reduced prostate weight, serum testosterone concentration and dihydrotestosterone (DHT) concentration in prostate tissue. TP-induced prostatic hyperplasia and the expression of proliferating cell nuclear antigen (PCNA) were significantly attenuated in UMH-treated rats. In addition, UMH administration markedly induced the activation of caspases-3, - 8, and - 9 in prostate tissues of BPH rats, accompanied by upregulation of expression of Fas, Fas-associated protein with death domain (FADD), and Fas ligand (FasL) and a reduction in the ratio of B-cell lymphoma 2 (Bcl-2) to Bcl-2-associated X protein (Bax). CONCLUSIONS: UMH effectively inhibited the proliferation and promoted the apoptosis of prostate cells, suggesting it may be useful for the treatment of BPH.


Assuntos
Extratos Vegetais/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Ulmus , Animais , Apoptose/efeitos dos fármacos , Di-Hidrotestosterona/metabolismo , Masculino , Fitoterapia , Extratos Vegetais/farmacologia , Próstata/efeitos dos fármacos , Próstata/patologia , Próstata/fisiologia , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Ratos Sprague-Dawley , Testosterona/sangue , Propionato de Testosterona
20.
Arch Ital Urol Androl ; 90(3): 199-202, 2018 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-30362688

RESUMO

OBJECTIVES: Benign Prostatic Hyperplasia (BPH) is a form of benign tumor that occurs in humans mainly with ageing. It affects more than 50% of over 50 years old males and it is characterized by an increased synthesis of dihydrotestosterone (DHT), due to the 5α-reductase activity. The BPH therapeutic approach mainly uses 5α-reductase inhibitors, such as the active compounds present in the extracts deriving from species Serenoa repens. Many lipidosterolic extracts are available on the market, which are obtained with different solvents, among them ethanol is recognized as non-toxic and has less handling risks than hexane. The purpose of the present experimental study was to investigate in-vitro the potency of an ethanol extract of S. repens comparing it with an n-hexane one. MATERIALS AND METHODS: Two different lipido-sterolic extracts of S. repens have been tested: ethanol extract and n-hexane extract, two batches for each one. The inhibitory action of the extract was evaluated estimating in-vitro the activity of enzyme 5α-reductase type I (5α-RI), which was mainly active under the experimental condition of pH 7.5. DHT amount, synthesized from testosterone (1 µM), was evaluated in a co-culture model of epithelial cells and fibroblasts resulting from prostatic biopsy of a patient with BPH. RESULTS: The analysis of the resulting dose-response curves showed that the entire S. repens extracts inhibited the 5α-RI showing no difference between the two kinds of extract or between the batches. The resulting IC50 values were the following: 8.809 (95% CI = 5.133-15.56) and 9.464 (95% CI = 5.094- 18.27) for ethanol extracts; 11.08 (95% CI = 6.389-19.98) and 12.72 (95% CI = 7.758-21.53) for n-hexane extracts. CONCLUSIONS: The potency of ethanol extracts of S. repens was comparable with the one of n-hexane extracts.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Colestenona 5 alfa-Redutase/efeitos dos fármacos , Extratos Vegetais/farmacologia , Hiperplasia Prostática/tratamento farmacológico , Inibidores de 5-alfa Redutase/administração & dosagem , Células Cultivadas , Colestenona 5 alfa-Redutase/metabolismo , Técnicas de Cocultura , Di-Hidrotestosterona/metabolismo , Relação Dose-Resposta a Droga , Células Epiteliais/metabolismo , Etanol/química , Fibroblastos/metabolismo , Hexanos/química , Humanos , Técnicas In Vitro , Concentração Inibidora 50 , Masculino , Extratos Vegetais/administração & dosagem , Hiperplasia Prostática/enzimologia , Hiperplasia Prostática/patologia , Solventes/química
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