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1.
Eur J Endocrinol ; 182(4): 413-421, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32045360

RESUMO

Context: The human adrenal is the dominant source of androgens in castration-resistant prostate cancer (CRPC) and classic 21-hydroxylase deficiency (21OHD). Abiraterone, derived from the prodrug abiraterone acetate (AA), inhibits the activity of cytochrome P450 17-hydroxylase/17,20-lyase (CYP17A1), the enzyme required for all androgen biosynthesis. AA treatment effectively lowers testosterone and androstenedione in 21OHD and CRPC patients. The 11-oxygenated androgens are major adrenal-derived androgens, yet little is known regarding the effects of AA administration on 11-oxygenated androgens. Objective: To test the hypothesis that AA therapy decreases 11-oxygenated androgens. Design: Samples were obtained from 21OHD or CRPC participants in AA or AA plus prednisone (AAP)-treatment studies, respectively. Methods: We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the 11-oxygenated androgens, 11ß-hydroxyandrostenedione, 11-ketoandrostenedione, 11ß-hydroxytestosterone, and 11-ketotestosterone, in plasma or serum samples from six 21OHD and six CRPC patients before and after treatment with AA or AAP, respectively. Results: In CRPC patients, administration of AAP (1000 mg/day AA with prednisone and medical castration) lowered all four 11-oxygenated androgens to below the lower limits of quantitation (<0.1-0.3 nmol/L), equivalent to 64-94% reductions from baseline. In 21OHD patients, administration of AA (100-250 mg/day for 6 days) reduced all 11-oxygenated androgens by on average 56-77% from baseline. Conclusions: We conclude that AA and AAP therapies markedly reduce the production of the adrenal-derived 11-oxygenated androgens, both in patients with high (21OHD) or normal (CRPC) 11-oxygenated androgens at baseline, respectively. Reduction of 11-oxygenated androgens is an important aspect of AA and AAP pharmacology.


Assuntos
Acetato de Abiraterona/farmacologia , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Androgênios/sangue , Androstenos/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Hiperplasia Suprarrenal Congênita/sangue , Adulto , Cromatografia Líquida , Quimioterapia Combinada , Humanos , Masculino , Prednisona/administração & dosagem , Neoplasias da Próstata/sangue , Espectrometria de Massas em Tandem , Testosterona/sangue
2.
Horm Metab Res ; 51(10): 639-648, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31578050

RESUMO

The aim of the study is to determine the impact of different anthropometric measurements of fat distribution on baseline sex-steroid concentrations and corticosteroidogenic enzyme activity in women with polycystic ovary syndrome compared to those with regular menstrual cycles. The current cross-sectional study included 106 normal cycling controls and 268 polycystic ovary syndrome patients. Patients with polycystic ovary syndrome, diagnosed by Rotterdam criteria, were divided in normoandrogenemic (n=91) and hyperandrogenemic (n=177). Anthropometric, biochemical, and hormone parameters were assessed and correlated with corticosteroidogenic enzyme activities in all three groups. Corticosteroidogenic enzyme activities were calculated using product-to-precursor ratios. Regarding sex-steroids individually, anthropometric parameters correlated with the concentrations of several androgens in polycystic ovary syndrome patients, most of them in patients with biochemical hyperandrogenism. The androgen precursors androstenedione, 17-hydroxyprogesterone, and dehydroepiandrosterone were less correlated with anthropometric parameters. The 17,20 lyase activity, in both Δ4 and Δ5 pathways, correlated with several anthropometric measurements in normo- and hyperandrogenemic polycystic ovary syndrome patients. The 17,20 lyase enzyme activity (Δ4 pathway) also correlated with conicity index, visceral adiposity index, and lipid accumulation product in the control group. 17-Hydroxylase activity positively correlated with waist-height ratio in both polycystic ovary syndrome groups. In contrast, 17-hydroxilase negatively correlated with the conicity index. Anthropometric markers of adiposity are associated with androgen levels and their precursors in blood. Body fat distribution correlates with the activities of some steroidogenic enzyme in both normo-and hyperandrogenemic polycystic ovary syndrome phenotypes. The molecular mechanisms involved in these associations are largely unclear and more investigations are required.


Assuntos
Androgênios/sangue , Biomarcadores/análise , Distribuição da Gordura Corporal , Hiperandrogenismo/fisiopatologia , Síndrome do Ovário Policístico/fisiopatologia , Esteroide 17-alfa-Hidroxilase/metabolismo , Adulto , Idoso , Antropometria , Estudos de Casos e Controles , Estudos Transversais , Feminino , Seguimentos , Humanos , Hiperandrogenismo/metabolismo , Pessoa de Meia-Idade , Síndrome do Ovário Policístico/metabolismo , Prognóstico
3.
J Ovarian Res ; 12(1): 86, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31526389

RESUMO

AIMS: This study was designed to evaluate the protective effects of AMPKα and SIRT1 on insulin resistance in PCOS rats, and to illuminate the underlying mechanisms. METHODS: An in vitro PCOS model was established by DHEA (6 mg/(100 g•d)), and the rats were randomly divided into the metformin group (MF group, n = 11), the exenatide group (EX group, n = 11), the PCOS group (n = 10), and the normal control group (NC group, n = 10). The MF group was administered MF 300 mg/(kg•d) daily. The EX group was subcutaneously injected EX 10µg/(kg•d) daily. After 4 weeks of continuous administration, fasting blood glucose and serum androgen, luteinizing hormone and other biochemical indicators were measured. Western and Real-time PCR were used to determine the expression of AMPKα and SIRT1 in the ovaries of each group. RESULTS: After 4 weeks of drug intervention, compared with untreated PCOS group, EX group and MF group had visibly decreased body weight (222.64 ± 16.57, 218.63 ± 13.18 vs 238.30 ± 12.26 g, P = 0.026), fasting blood glucose (7.71 ± 0.72, 8.17 ± 0.54 vs 8.68 ± 0.47 mmol/L, P < 0.01), HOMA-IR (8.26 ± 2.50, 7.44 ± 1.23 vs 12.66 ± 1.44, P < 0.01) and serum androgen (0.09 ± 0.03, 0.09 ± 0.03 vs 0.53 ± 0.41 ng/ml, P < 0.01) and the expressions of AMPKα and SIRT11 were increased progressively (P < 0.05). CONCLUSIONS: Both metformin and exenatide can improve the reproductive and endocrine functions of rats with PCOS via the AMPKα-SIRT1 pathway, which may be the molecular mechanism for IR in PCOS and could possibly serve as a therapeutic target.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Exenatida/farmacologia , Metformina/farmacologia , Síndrome do Ovário Policístico/tratamento farmacológico , Sirtuína 1/genética , Androgênios/sangue , Animais , Glicemia/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Resistência à Insulina/genética , Hormônio Luteinizante/genética , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/genética , Ratos
4.
J Toxicol Sci ; 44(9): 575-584, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474739

RESUMO

The adrenal gland is the most common toxicological target of drugs within the endocrine system, and inhibition of adrenal steroidogenesis can be fatal in humans. However, methods to evaluate the adrenal toxicity are limited. The aim of the present study was to verify the usefulness of simultaneous measurement of blood levels of multiple adrenal steroids, including precursors, as a method to evaluate drug effects on adrenal steroidogenesis in cynomolgus monkeys. With this aim, physiological and drug-induced changes in blood levels of adrenal steroids, including cortisol, aldosterone, androgen, and their precursors were examined. First, for physiological changes, intraday and interday changes in blood steroid levels were examined in male and female cynomolgus monkeys. The animals showed circadian changes in steroid levels that are similar to those in humans, while interday changes were relatively small in males. Next, using males, changes in blood steroid levels induced by ketoconazole and metyrapone were examined, which suppress adrenal steroidogenesis via inhibition of CYP enzymes. Consistent with rats and humans, both ketoconazole and metyrapone increased the deoxycorticosterone and deoxycortisol levels, probably via CYP11B1 inhibition, and the increase was observed earlier and with greater dynamic range than the changes in cortisol level. Changes in other steroid levels reflecting the drug mechanisms were also observed. In conclusion, this study showed that in cynomolgus monkeys, simultaneous measurement of blood levels of adrenal steroids, including precursors, can be a valuable method to sensitively evaluate drug effects on adrenal steroidogenesis and to investigate the underlying mechanisms.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Aldosterona/sangue , Aldosterona/metabolismo , Androgênios/sangue , Androgênios/metabolismo , Cromatografia Líquida/métodos , Hidrocortisona/sangue , Hidrocortisona/metabolismo , Cetoconazol/toxicidade , Metirapona/toxicidade , Espectrometria de Massas em Tandem/métodos , Animais , Ritmo Circadiano , Desoxicorticosterona/metabolismo , Feminino , Humanos , Macaca fascicularis , Masculino , Esteroide 11-beta-Hidroxilase/antagonistas & inibidores
5.
J Ovarian Res ; 12(1): 78, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31470879

RESUMO

BACKGROUND: Reduction of the body iron stores can improve hyperandrogenemia and insulin resistance. This study aimed to compare clinical and para-clinical responses to the treatment of phlebotomy using oral contraceptive pills (OCs) containing cyproterone acetate in women with PCOS. METHODS: In this randomized clinical trial, 64 patients with PCOS were randomly assigned to the phlebotomy and OCs groups (n = 32 in each group). The intervention group, using a single treatment procedure, underwent venesection of 450 mL of whole blood at the early follicular phase of the spontaneous or progesterone-induced menstrual cycle. The control group received OCs pills for 3 months from the 1th day of spontaneous or progesterone-induced menstrual cycle onwards for 3 weeks, followed by a pill-free interval of 7 days. The women were evaluated after the 3-month intervention. The primary outcome measure was a change in the HOMA-IR and free androgen index (FAI). Secondary outcomes were changes in the Ferriman-Gallwey (FG) score and other clinical, biochemical and hormonal changes from the baseline (pre-treatment) to week 12. RESULTS: In the phlebotomy group, 27 (84.3%) and in the OCs group 30 (93.7%) of the women completed the 3-month follow-up. The median HOMA-IR significantly decreased from 3.5 to 2.7 in the phlebotomy, and from 3.1 to 2.8 in the OCs group, and the changes were comparable between the groups. Median changes in the FAI significantly decreased in both groups, but the differences were not statistically significant between the groups (P = 0.061). With regard to secondary outcomes, mean FG scores in both groups significantly decreased [from 16.8 (6) to 13.3 (7.4), P < 0.028] in the phlebotomy group and [from 14.3 (7) to 9.8 (7.6) in the OCs group, P = 0.001] after 3 months of treatment, but such changes had no statistically significant differences between the groups. During treatment, menstrual cycles became regular in all women in the OCs group and in 12.27 (44.4%) of the women in the phlebotomy group, and the difference was statistically significant (P = 0.001). Despite no statistically significant differences in lipid profiles between the groups at the baseline, triglycerides were significantly higher in the OCs group compared to the phlebotomy at end of follow up (p = 0.019). CONCLUSION: Both treatment modalities had similar beneficial effects on insulin resistance and on androgenic profiles. However, OCs was reported more effective in treating menstrual irregularities and phlebotomy had less adverse effects on triglyceride concentrations. TRIAL REGISTRATION: Code: IRCT2013080514277N1 .


Assuntos
Antagonistas de Androgênios/uso terapêutico , Anticoncepcionais Orais/uso terapêutico , Acetato de Ciproterona/uso terapêutico , Flebotomia , Síndrome do Ovário Policístico/terapia , Adolescente , Adulto , Androgênios/sangue , Androstenodiona/sangue , Colesterol/sangue , Feminino , Humanos , Insulina/sangue , Resistência à Insulina , Síndrome do Ovário Policístico/sangue , Testosterona/sangue , Triglicerídeos/sangue , Adulto Jovem
6.
Gen Comp Endocrinol ; 283: 113235, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31369730

RESUMO

Deer antlers offer a unique model to study organ regeneration in mammals. Antler regeneration relies on the pedicle periosteum (PP) cells and is triggered by a decrease in circulating testosterone (T). The molecular mechanism for antler regeneration is however, unclear. Label-free liquid chromatography-mass spectrometry (LC-MS/MS) was used to identify differentially-expressed proteins (DEPs) in the regeneration-potentiated PP (under low T environment) over the non-regeneration-potentiated PP (under high T environment). Out of total 273 DEPs, 189 were significantly up-regulated and 84 were down-regulated from these comparisons: after castration vs before castration, natural T vs before castration, and exogenous T vs before castration. We focused on the analysis only of those DEPs that were present in fully permissive environment to antler regeneration (low T). Nine transduction pathways were identified through the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, including the estrogen signaling pathway. A total of 639 gene ontology terms were found to be significantly enriched in regeneration-potentiated PP (low T) from the DEPs. Reliability of the label free LC-MS/MS was determined by qRT-PCR to estimate the expression level of selected genes. The results suggest that up-regulated heat shock proteins (HSP90AB1, HSP90B1), peptidyl-prolyl cis-trans isomerase 4 (FKBP4), mitogen-activated protein kinase 3 (MAPK3) and calreticulin (CALR) and down-regulated SHC-transforming protein 1 (SHC1), heat shock protein family A member 1A (HSPA1A) and proto-oncogene tyrosine-protein kinase (SRC) may be associated directly or indirectly with antler regeneration. Further studies are required to investigate the roles of these proteins in regeneration using appropriate in vivo models.


Assuntos
Androgênios/metabolismo , Chifres de Veado/fisiologia , Cervos/metabolismo , Proteômica , Regeneração/fisiologia , Androgênios/sangue , Animais , Cromatografia Líquida , Regulação da Expressão Gênica , Ontologia Genética , Mapas de Interação de Proteínas , Proteoma/genética , Proteoma/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais , Espectrometria de Massas em Tandem , Testosterona/sangue
7.
Clin Interv Aging ; 14: 1227-1241, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31413553

RESUMO

Purpose: Abdominal aortic aneurysm (AAA) demonstrates many features of autoimmune diseases. Y chromosome, sex-determining region of the Y chromosome (SRY) gene, androgen receptor (AR) gene, and androgen appear as potential candidates for influence of the male immune function. This study investigated Y chromosome numbers, SRY gene, AR gene, and androgen levels in male AAAs. We also investigated the correlation between Y chromosome loss (LOY) ratio, SRY expression, androgen levels, and age. Patients and methods: We investigated LOY by fluorescence in situ hybridization (FISH) in 37 AAAs and compared with 12 patients with abdominal aortic atherosclerotic occlusive disease (AOD) and 91 healthy controls (HC). We investigated SRY and AR expression at mRNA level by real-time PCR in peripheral T lymphocytes in AAA compared with AOD and HC, and AR protein levels by immunohistochemistry (IHC) in AAA. LOY, SRY expression, androgen levels, and age were examined for correlations using the Spearman's rank correlation coefficient. Results: LOY ratio in peripheral T lymphocytes was significantly higher in the AAA group compared with the HC (9.11% vs 5.56%, P<0.001) and AOD groups (9.11% vs 6.42%, P=0.029). The SRY mRNA expression in peripheral T lymphocytes was 4.7-fold lower expressed in the AAA group than in the HC group (P<0.001). Free plasma testosterone levels were lower in the AAA group compared with the HC group (P=0.036), whereas sex hormone-binding globulin levels were higher (P=0.020). LOY ratio and expression of SRY mRNA level increased with age in the AAA group (R=0.402 and, R=0.366, respectively). A significant correlation between AR mRNA level (R=0.692) and aortic diameter was detected. Simultaneously, in AAA tissue, the rate of LOY increased with age (R=0.547) and also positively associated with LOY in peripheral blood T lymphocytes (R=0.661). Conclusion: This study identified a prominent Y chromosome loss in male AAAs, which is correlated to age, lower level of SRY expression and free testosterone, providing a new clue for the mechanisms of AAA.


Assuntos
Androgênios/sangue , Aneurisma Dissecante/epidemiologia , Aneurisma da Aorta Abdominal/epidemiologia , Cromossomos Humanos Y/fisiologia , Receptores Androgênicos/genética , Proteína da Região Y Determinante do Sexo/genética , Fatores Etários , Idoso , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , RNA Mensageiro , Aberrações dos Cromossomos Sexuais
8.
Arch Endocrinol Metab ; 63(3): 190-198, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31340240

RESUMO

OBJECTIVE: To summarize current evidence regarding testosterone treatment for women with low sexual desire. MATERIALS AND METHODS: The Female Endocrinology and Andrology Department of the Brazilian Society of Endocrinology and Metabolism invited nine experts to review the physiology of testosterone secretion and the use, misuse, and side effects of exogenous testosterone therapy in women, based on the available literature and guidelines and statements from international societies. RESULTS: Low sexual desire is a common complaint in clinical practice, especially in postmenopausal women, and may negatively interfere with quality of life. Testosterone seems to exert a positive effect on sexual desire in women with sexual dysfunction, despite a small magnitude of effect, a lack of long-term safety data, and insufficient evidence to make a broad recommendation for testosterone therapy. Furthermore, there are currently no testosterone formulations approved for women by the relevant regulatory agencies in the United States, Brazil, and most other countries, and testosterone formulations approved for men are not recommended for use by women. CONCLUSION: Therefore, testosterone therapy might be considered if other strategies fail, but the risks and benefits must be discussed with the patient before prescription. Arch Endocrinol Metab. 2019;63(3):190-8.


Assuntos
Androgênios/uso terapêutico , Libido/efeitos dos fármacos , Disfunções Sexuais Fisiológicas/tratamento farmacológico , Testosterona/uso terapêutico , Adolescente , Adulto , Idoso , Androgênios/efeitos adversos , Androgênios/sangue , Feminino , Humanos , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Sociedades Médicas , Testosterona/efeitos adversos , Testosterona/sangue , Adulto Jovem
9.
Turk J Med Sci ; 49(4): 1117-1125, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31286756

RESUMO

Background/aim: This study aims to investigate the association between polycystic ovary syndrome (PCOS) and obesity and insulin resistance (IR) with respect to anti-Müllerian hormone (AMH), inhibin A (INH-A), inhibin B (INH-B), and insulin-like peptide 3 (INSL3) levels, all factors which may have an impact on IR. Materials and methods: In this cross sectional study, 52 adolescent girls diagnosed with PCOS[groups:nonobese (NO), n = 23; overweight/obese (OW/O), n = 29] were included. Blood samples were obtained to measure AMH, INH-B, INH-A, and INSL3 levels, together with hormonal and biochemical assessments. Oral glucose tolerance test (OGTT) was performed and the indexes of IR [homeostasis model assessment: insulin resistance (HOMA-IR) and Matsuda index] were calculated. Results: Insulin resistance was 56.5% with OGTT and 30.4% with HOMA-IR in nonobese-PCOS girls. There was a correlation between INH-A and HOMA-IR even when controlled for body mass index (BMI). INH-B and FAI also had correlations with HOMA-IR which disappeared when controlled for BMI. In regression analyses, AMH (odds ratio = [0.903, P = 0.015) and FAI (odds ratio = 1.353, P = 0.023) are found to be contributors to IR. Their effect was BMI-independent. In ROC analysis, the cutoff value for FAI was 5.93 (sensitivity 71%) to define IR in PCOS girls. Conclusion: AMH and FAI may contribute to IR (defined by OGTT) in PCOS. FAI might be used as a supporting IR marker (defined by OGTT) in adolescent girls with PCOS.


Assuntos
Androgênios/sangue , Hormônio Antimülleriano/sangue , Inibinas/sangue , Resistência à Insulina/fisiologia , Insulina/sangue , Síndrome do Ovário Policístico , Adolescente , Adulto , Glicemia/análise , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Obesidade , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/epidemiologia , Síndrome do Ovário Policístico/fisiopatologia , Proteínas , Curva ROC , Adulto Jovem
11.
Andrologia ; 51(9): e13344, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31206753

RESUMO

To investigate whether low androgen status affects erectile function by regulating the expression of adenosine A2A and A2B receptors in rat penile corpus cavernosum. Thirty-six 8-week-old male Sprague-Dawley rats were randomly divided into six groups: sham-operated group (4w-sham, 8w-sham), castration group (4w-cast, 8w-cast) and androgen replacement group (4w-cast+T, 8w-cast+T). The rats in the androgen replacement groups were subcutaneously injected with testosterone propionate (3 mg/kg) every other day after castration. The maximum intracavernous pressure/mean arterial pressure (ICPmax/MAP), the expression of A2A , A2B , AKT and eNOS and the concentrations of cAMP and cGMP in the corpus cavernosum were detected at the 4th and 8th weeks after the operation. The serum testosterone level and the ratio of ICPmax/MAP decreased significantly in the castration group as compared to other groups (p < 0.01). There was no significant difference in the expression of A2A receptor among groups, while the expression of A2B , AKT and eNOS and the concentrations of cAMP and cGMP in the castration group were significantly lower than in other groups (p < 0.01). Low androgen status inhibits the AKT/eNOS/cGMP signalling pathways and the production of cAMP in the corpus cavernosum of castrated rats by down-regulating the expression of A2B receptor, and results in decreased of ICPmax/MAP.


Assuntos
Androgênios/metabolismo , Disfunção Erétil/fisiopatologia , Pênis/metabolismo , Receptor A2A de Adenosina/metabolismo , Receptor A2B de Adenosina/metabolismo , Androgênios/sangue , Animais , Pressão Arterial/efeitos dos fármacos , Pressão Arterial/fisiologia , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/etiologia , Terapia de Reposição Hormonal/métodos , Humanos , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Orquiectomia/efeitos adversos , Ereção Peniana/efeitos dos fármacos , Ereção Peniana/fisiologia , Pênis/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Propionato de Testosterona/administração & dosagem
12.
PLoS One ; 14(5): e0216951, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31083690

RESUMO

Hyperandrogenism is a risk factor of cerebrovascular diseases as androgens can alter markedly the regulation of cerebrovascular tone. We examined the combined impact of androgen excess and vitamin D deficiency (VDD), a common co-morbidity in hyperandrogenic disorders, on remodeling and testosterone-induced vascular responses of anterior cerebral arteries (ACA) in order to evaluate the interplay between androgens and VDD in the cerebral vasculature. Male and female Wistar rats were either fed with vitamin D deficient or vitamin D supplemented diet. Half of the female animals from both groups received transdermal testosterone treatment. After 8 weeks, vessel lumen, wall thickness and testosterone-induced vascular tone of isolated ACA were determined using pressure microangiometry and histological examination. Androgen receptor protein expression in the wall of cerebral arteries was examined using immunohistochemistry. In female rats only combined VDD and testosterone treatment decreased the lumen and increased the wall thickness of ACA. In males, however VDD by itself was able to decrease the lumen and increase the wall thickness. Vascular reactivity showed similar alterations: in females, testosterone constricted the ACA only after combined VDD and hyperandrogenism, whereas in males VDD resulted in increased testosterone-induced contractions in spite of decreased androgen receptor expression. In conclusion, a marked interplay between hyperandrogenism and VDD results in inward remodeling and enhanced testosterone-induced constrictions of cerebral arteries, which might compromise the cerebral circulation and thus, increase the risk of stroke in the long term. In addition, the early cerebrovascular manifestation of VDD appears to require androgen excess and thus, depends on gender.


Assuntos
Androgênios/efeitos adversos , Hiperandrogenismo/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Testosterona/efeitos adversos , Deficiência de Vitamina D/fisiopatologia , Administração Oral , Androgênios/administração & dosagem , Androgênios/sangue , Animais , Artéria Cerebral Anterior , Dieta , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Hiperandrogenismo/sangue , Hiperandrogenismo/induzido quimicamente , Hiperandrogenismo/complicações , Masculino , Ratos , Ratos Wistar , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Risco , Fatores Sexuais , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/induzido quimicamente , Acidente Vascular Cerebral/etiologia , Testosterona/administração & dosagem , Testosterona/sangue , Vasoconstrição/efeitos dos fármacos , Vitamina D/administração & dosagem , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/induzido quimicamente , Deficiência de Vitamina D/complicações
13.
Endokrynol Pol ; 70(4): 330-335, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30938834

RESUMO

INTRODUCTION: The free androgen index (FAI) values differ among patients with polycystic ovarian syndrome; however, the differences are not fully understood or known. The aim of the study was to evaluate FAI in women with polycystic ovary syndrome (PCOS) in regard to the phenotype of the PCOS and insulin resistance status. MATERIAL AND METHODS: Anthropometric, hormonal, and biochemical parameters were assessed in 312 recruited women with PCOS. The FAI values were calculated in the reproductive and metabolic phenotypes of PCOS in groups of insulin resistance status based on the homeostasis model assessment-insulin resistance (HOMA-IR) > 2.0 or fasting insulin (FI) > 10 mmol/L. To test the relationship between individual variables, Spearman's correlation analysis, the Kolmogorov-Smirnov test, and Student's t-test were used. RESULTS: The correlation between FAI values and HOMA-IR and FI was 0.42 and 0.47, respectively, in PCOS patients. A two fold higher FAI value was observed in metabolic PCOS phenotype when compared to the reproductive one (8.51 ± 5.56 vs. 4.40 ± 2.45 for HOMA-IR and 8.73 ± 6.09 vs. 4.31 ± 3.39 for FI, respectively; p < 0.05). CONCLUSIONS: PCOS patients are not a homogenous group in terms of FAI value. Patients with metabolic PCOS phenotype are characterised by two-fold higher FAI values compared with reproductive PCOS phenotype. Further studies on the metabolic and androgenic status of different types of PCOS phenotypes should be carried out.


Assuntos
Androgênios/sangue , Hiperandrogenismo/etiologia , Resistência à Insulina , Síndrome do Ovário Policístico/complicações , Adolescente , Adulto , Feminino , Humanos , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/metabolismo , Adulto Jovem
14.
J Steroid Biochem Mol Biol ; 190: 242-249, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30959151

RESUMO

The androgen precursors, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are produced in high amounts by the adrenal cortex primarily in humans and a few other primates. The human adrenal also secretes 11-oxygenated androgens (11-oxyandrogens), including 11ß-hydroxyandrostenedione (11OHA4), 11-ketoandrostenedione (11KA4), 11ß-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT), of which 11OHT and 11KT are bioactive androgens. The 11-oxyandrogens, particularly 11KT, have been recognized as biologically important testicular androgens in teleost fishes for decades, but their physiological contribution in humans has only recently been established. Beyond fish and humans, however, the presence of 11-oxyandrogens in other species has not been investigated. This study provides a comprehensive analysis of a set of C19 steroids, including the traditional androgens and 11-oxyandrogens, across 18 animal species. As previously shown, serum DHEA and DHEAS were much higher in primates than all other species. Circulating 11-oxyandrogens, especially 11KT, were observed in notable amounts in male, but not in female trout, consistent with gonadal origin in fish. The circulating concentrations of 11-oxyandrogens ranged from 0.1 to 10 nM in pigs, guinea pigs and in all the primates studied (rhesus macaque, baboon, chimpanzee and human) but not in rats or mice, and 11OHA4 was consistently the most abundant. In contrast to fish, serum 11KT concentrations were similar in male and female primates for each species, despite significantly higher circulating testosterone in males, suggesting that 11KT production in these species is not testis-dependent and primarily originates from adrenal-derived 11-oxyandrogen precursors.


Assuntos
Androgênios/sangue , Sulfato de Desidroepiandrosterona/sangue , Desidroepiandrosterona/sangue , Testosterona/análogos & derivados , Animais , Feminino , Masculino , Especificidade da Espécie , Testosterona/sangue
15.
Pharmacol Rep ; 71(3): 417-421, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31003151

RESUMO

BACKGROUND: Individuals with non-classic congenital adrenal hyperplasia (NC-CAH) often show evidence of hyperandrogenism, including premature pubarche, accelerated linear growth velocity, short final height, hirsutism, acne, alopecia, impaired ovulation, menstrual dysfunction and subfertility. Although statins were found to reduce elevated levels of androgens in subjects with this disorder, no previous study has investigated whether 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors affect cardiometabolic risk factors in patients with NC-CAH. METHODS: We studied 12 women with NC-CAH, 6 of whom because of coexisting hypercholesterolemia received atorvastatin (20-40 mg daily). Circulating levels of lipids, glucose homeostasis markers, plasma levels of androgens, 17-hydroxyprogesterone, high-sensitivity C-reactive protein (hsCRP), uric acid, fibrinogen, homocysteine and 25-hydroxyvitamin D, as well as urinary albumin-to-creatinine ratio (UACR) were determined at the beginning of the study and 12 weeks later. RESULTS: Beyond affecting plasma lipids, atorvastatin reduced circulating levels of testosterone, dehydroepiandrosterone sulphate, androstenedione and 17-hydroxyprogesterone, and decreased free androgen index. Moreover, atorvastatin caused a decrease in plasma levels/urinary loss of uric acid, hsCRP, homocysteine and UACR, and insignificantly increased circulating levels of 25-hydroxyvitamin D. The drug produced no effect on plasma fibrinogen. The effect of atorvastatin on hsCRP, uric acid, homocysteine, 25-hydroxyvitamin D and UACR correlated with the magnitude of reduction in 17-hydroxyprogesterone and androgens. CONCLUSION: Our results suggest that statin therapy reduces cardiometabolic risk in women with NC-CAH.


Assuntos
Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Atorvastatina/farmacologia , Doenças Cardiovasculares/induzido quimicamente , Hiperplasia Suprarrenal Congênita/sangue , Hiperplasia Suprarrenal Congênita/metabolismo , Adulto , Androgênios/sangue , Androgênios/metabolismo , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/metabolismo , Sulfato de Desidroepiandrosterona/sangue , Feminino , Fibrinogênio/metabolismo , Homocisteína/sangue , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/metabolismo , Projetos Piloto , Fatores de Risco , Testosterona/sangue , Ácido Úrico/sangue , Vitamina D/análogos & derivados , Vitamina D/sangue
16.
Gynecol Endocrinol ; 35(9): 767-771, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30935252

RESUMO

ß-endorphin is a neuropeptide involved in several brain functions: its plasma levels are higher in obese women and its release increases after oral glucose tolerance test (OGTT) in normal or obese women. The study included 46 healthy women and evaluated the effect of oral dehydroepiandrosterone [DHEA] (50 mg/day) in early postmenopausal women (50-55 years) both of normal weight (group A, n = 12, BMI = 22.1 ± 0.5) and overweight (group B, n = 12, BMI = 28.2 ± 0.5), and late postmenopausal women (60-65 years) both normal weight (group C, n = 11, BMI = 22.5 ± 0.6) and overweight (group D, n = 11, BMI = 27.9 ± 0.4) undergone OGTT, in order to investigate if DHEA could restore/modify the control of insulin and glucose secretion and ß-endorphin release in response to glucose load. The area under the curve (AUC) of OGTT evaluated plasma levels of different molecules. DHEA, DHEAS, and ß-endorphin plasma levels were lower in baseline conditions in older women than younger women. Considering the AUC of ß-endorphin response to OGTT, all groups showed a progressive significant increase after 3 and also after 6 months of treatment in comparison to baseline and 3 months of treatment.


Assuntos
Desidroepiandrosterona/administração & dosagem , Glucose/farmacologia , Pós-Menopausa/sangue , Pós-Menopausa/efeitos dos fármacos , beta-Endorfina/metabolismo , Administração Oral , Idoso , Androgênios/sangue , Feminino , Teste de Tolerância a Glucose , Humanos , Peso Corporal Ideal/efeitos dos fármacos , Peso Corporal Ideal/fisiologia , Insulina/sangue , Pessoa de Meia-Idade , Sobrepeso/sangue , Sobrepeso/metabolismo , Sobrepeso/fisiopatologia , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/sangue , Fatores de Tempo , beta-Endorfina/sangue
17.
Syst Biol Reprod Med ; 65(4): 281-287, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30994373

RESUMO

The aim of the study was to determine if serum testosterone (T) and dehydroepiandrosterone (DHEAS) levels are a factor in determining increased risk for embryonic aneuploidy in karyotypically normal women undergoing in vitro fertilization (IVF) and preimplantation genetic testing screening for aneuploidy (PGT-A). This is a retrospective cohort study of IVF cycles with PGT-A performed during 2015-2016. A total of 256 cycles with 725 embryos were initially considered for inclusion. A total of 208 cycles and 595 embryos determined to be either euploid or aneuploid were included in the analysis. The mean age of women was 37.4 ± 4.4 years. There were 193 (32.44%) euploid, and 338 (56.81%) aneuploid blastocysts. Sixty-four (10.76%) had 'no diagnosis' after PGT-A. The 32 embryos with 'no diagnosis' after first PGT-A were biopsied again and after the second analysis, 7 were found to be euploid and 3 aneuploid. The remaining 32 embryos were not reanalyzed due to the lack of patients' consent for the second biopsy. The relationship between embryo ploidy and levels of serum testosterone and dehydroepiandrosterone sulfate was assessed using ordinal multivariable regression analysis. The model, adjusted for both anti-Mullerian hormone (AMH) and age, showed no association between ploidy status and serum levels of the two hormones. We concluded that the serum levels of testosterone and DHEAS do not influence embryo ploidy in karyotypically normal women undergoing IVF. Abbreviations: T: testosterone; DHEAS: dehydroepiandrosterone; IVF: in vitro fertilization; PGT-A: preimplantation genetic testing screening for aneuploidy; AMH: anti-Mullerian hormone; FSH: follicle-stimulating hormone; LH: luteinizing hormone; E2: oestradiol; P: progesterone.


Assuntos
Androgênios/fisiologia , Blastocisto/ultraestrutura , Ploidias , Adulto , Androgênios/sangue , Desidroepiandrosterona/sangue , Feminino , Fertilização In Vitro , Humanos , Cariótipo , Masculino , Gravidez , Fatores de Risco , Testosterona/sangue
18.
Gynecol Endocrinol ; 35(9): 825-828, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30990090

RESUMO

The aim of this study is to review the natural course, clinical features, and reproductive prognosis of ovarian tumors associated with hyperandrogenemia. We retrospect 33 patients of ovarian tumors with hyperandrogenemia. Thirty cases (91%) were sex cord-stromal tumors. Sertoli-Leydig cell tumors, Leydig cell tumors, and steroid cell tumors were the most common types. It is not possible, to predict the pathological subtypes based on androgen levels alone. Most of these tumors were solid masses, with an average diameter of 3.9 cm. These tumors are soft or fragile, no clear boundary with normal tissue, thus excision is superior to exfoliation. The average disease course of the top three tumors was 32.6, 35.4, and 67.7 months, respectively. Among 11 married women with a desire to get pregnant, nine cases resumed menstrual periods after surgery and became pregnant naturally. Hyperandrogenemia might predict a better prognosis. The asynchronism of hyperandrogenemia and undetectable tumor may cause irreversible change and emotional depress, the methods of early diagnosis need further study.


Assuntos
Hiperandrogenismo/complicações , Hiperandrogenismo/diagnóstico , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/diagnóstico , Tumores do Estroma Gonadal e dos Cordões Sexuais/complicações , Tumores do Estroma Gonadal e dos Cordões Sexuais/diagnóstico , Adolescente , Adulto , Idoso , Androgênios/sangue , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Criança , Pré-Escolar , Progressão da Doença , Feminino , Preservação da Fertilidade , Humanos , Hiperandrogenismo/patologia , Hiperandrogenismo/cirurgia , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Prognóstico , Estudos Retrospectivos , Tumor de Células de Sertoli-Leydig/complicações , Tumor de Células de Sertoli-Leydig/diagnóstico , Tumor de Células de Sertoli-Leydig/patologia , Tumor de Células de Sertoli-Leydig/cirurgia , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/cirurgia , Carga Tumoral , Adulto Jovem
19.
Reprod Domest Anim ; 54(6): 855-863, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30924551

RESUMO

Puberty is considered a critical period on development that involved sexual maturation and morphological changes. Isoflavones have been described as endocrine disruptors in male rats. Therefore, the present study attempt to evaluate the effect that daily intake of low and high doses of isoflavones exert into the hormonal regulation that take place during puberty by analyzing the levels of serum and testes steroid and pituitary hormones. 108 male pre-puberal Wistar rats (30 days old) were randomly divided into three groups; control, low and high doses of isoflavones. Experimental animals were daily dosed orally with low and high doses of a mixture of two soy isoflavones (genistein and daidzein) during 6 weeks. An EIA was performed in serum and testes homogenates for analyzing FSH, LH, P5, P4, DHEA, A4, T, DHT, SO4E1 and E2 hormone concentrations. Results revealed a decrease of an oestrogen environment in testes stimulates the secretion of FSH and LH leading to the production of androgens in the testes at the onset of puberty. Low doses of isoflavones resulted in a significant increase of testes oestrogens that consequently produced a delay on the onset of puberty; however at high doses of isoflavones the maintained oestrogenic environment in the testes prevent the stimulation of the secretion of pituitary hormones and the production of T abolishing the onset of puberty. These results clarify the hormonal mechanisms that take place on puberty and determine the effect of high and low doses of isoflavones at the onset of puberty.


Assuntos
Genisteína/farmacologia , Isoflavonas/farmacologia , Maturidade Sexual/efeitos dos fármacos , Leite de Soja/administração & dosagem , Androgênios/sangue , Animais , Estrogênios/sangue , Genisteína/administração & dosagem , Isoflavonas/administração & dosagem , Masculino , Distribuição Aleatória , Ratos Wistar , Testículo/efeitos dos fármacos
20.
Andrologia ; 51(5): e13259, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30873638

RESUMO

Our objectives were to assess sperm alteration and adipose tissue (AT) genes expression related to steroid metabolism subsequent to fatty acids consumption. Twenty-nine mature male mice were divided into: fat diet (FD; n = 15) and the control group (n = 14). FD group was fed with low level of trans and saturated fatty acids source for 60 days. Sperm parameters, levels of hormones and the mRNA abundance of the target genes in AT were assessed. The sperm concentration, total and progressive motilities were lower in FD group compared to that of control (p < 0.01). Blood estradiol levels increased in FD (p < 0.001), whereas no significant difference was observed in testosterone. The mRNA levels of StAR, CYP11A1, CYP17A1, 17ßHSD7 and 17ßHSD12 in AT of FD were higher than those of the control (p < 0.05). In contrast, mRNA level of Cyp19a1 in FD was significantly (p < 0.05) lower than that of control. 17ßHSD12 and 17ßHSD7 (as oestrogenic genes) increased, while 17ßHSD5 and 17ßHSD3 (as androgenic genes) remained unchanged, indicating that dietary trans/saturated fatty acids affect AT genes expression. Probably, sperm parameters were altered by increment of expression level of genes involved in oestrogenic metabolism rather than those engaged in androgenic metabolism after fatty acids consumption.


Assuntos
Tecido Adiposo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/efeitos adversos , Ácidos Graxos/efeitos adversos , Esteroides/metabolismo , Androgênios/sangue , Androgênios/metabolismo , Animais , Estrogênios/sangue , Estrogênios/metabolismo , Masculino , Camundongos , Modelos Animais , Contagem de Espermatozoides
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