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1.
Sci Rep ; 11(1): 17743, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493761

RESUMO

Androgens have been implicated in autism pathophysiology as recently, prenatal exposure to elevated androgens has been proposed as risk factor. However, published data on postnatal sex hormone levels in autistic children are controversial and the source of prenatal androgen exposure in autism remains unknown. Therefore, this study investigated postnatal sex hormone levels and dehydroepiandrosterone (DHEA) to shed light on a potential role for the adrenal gland in autism pathophysiology. A case-control study investigating estradiol (E2), DHEA, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels was conducted with 31 Saudi males with autism and 28 healthy, age-matched boys plasma. Moreover, correlation analysis with measured hormones and previously measured total testosterone (TT) and free testosterone (FT) in the same group of autism was conducted. DHEA was significantly higher (p < 0.05) in the autism group compared to controls. DHEA positively correlated with previously measured TT (r = + 0.79, p < 0.001) and FT (r = + 0.72, p < 0.001) levels in the same autism group. FSH levels were also significantly higher in the autism group than in the control group (p < 0.01). To the best of our knowledge, this is the first study to report a strong positive correlation between TT, FT and DHEA, suggesting an adrenal source for elevated androgen levels.


Assuntos
Glândulas Suprarrenais/fisiopatologia , Transtorno Autístico/fisiopatologia , Antropometria , Transtorno Autístico/sangue , Estudos de Casos e Controles , Sulfato de Desidroepiandrosterona/sangue , Estradiol/sangue , Hormônio Foliculoestimulante/sangue , Humanos , Hormônio Luteinizante/sangue , Masculino , Globulina de Ligação a Hormônio Sexual/análise , Testosterona/sangue
2.
Chem Res Toxicol ; 34(4): 1150-1160, 2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33821626

RESUMO

Prophylactic antiretroviral therapy (ART) in HIV infected pregnant mothers and their newborns can dramatically reduce mother-to-child viral transmission and seroconversion in the neonate. The ritonavir-boosted lopinavir regimen, known as Kaletra, has been associated with premature birth and transient adrenal insufficiency in newborns, accompanied by increases in plasma dehydroepiandrosterone 3-sulfate (DHEA-S). In the fetus and neonates, cytochrome P450 CYP3A7 is responsible for the metabolism of DHEA-S into 16α-hydroxy DHEA-S, which plays a critical role in growth and development. In order to determine if CYP3A7 inhibition could lead to the adverse outcomes associated with Kaletra therapy, we conducted in vitro metabolic studies to determine the extent and mechanism of CYP3A7 inhibition by both ritonavir and lopinavir and the relative intrinsic clearance of lopinavir with and without ritonavir in both neonatal and adult human liver microsomes (HLMs). We identified ritonavir as a potent inhibitor of CYP3A7 oxidation of DHEA-S (IC50 = 0.0514 µM), while lopinavir is a much weaker inhibitor (IC50 = 5.88 µM). Furthermore, ritonavir is a time-dependent inhibitor of CYP3A7 with a KI of 0.392 µM and a kinact of 0.119 min-1, illustrating the potential for CYP3A mediated drug-drug interactions with Kaletra. The clearance rate of lopinavir in neonatal HLMs was much slower and comparable to the rate observed in adult HLMs in the presence of ritonavir, suggesting that the addition of ritonavir in the cocktail therapy may not be necessary to maintain effective concentrations of lopinavir in neonates. Our results suggest that several of the observed adverse outcomes of Kaletra therapy may be due to the direct inhibition of CYP3A7 by ritonavir and that the necessity for the inclusion of this drug in the therapy may be obviated by the lower rate of lopinavir clearance in the neonatal liver. These results may lead to a reconsideration of the use of ritonavir in neonatal antiretroviral therapy.


Assuntos
Antirretrovirais/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/metabolismo , Sulfato de Desidroepiandrosterona/antagonistas & inibidores , Lopinavir/farmacologia , Ritonavir/farmacologia , Adulto , Antirretrovirais/química , Inibidores do Citocromo P-450 CYP3A/química , Sulfato de Desidroepiandrosterona/sangue , Sulfato de Desidroepiandrosterona/metabolismo , Combinação de Medicamentos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Recém-Nascido , Lopinavir/química , Conformação Molecular , Oxirredução , Ritonavir/química
3.
Am J Respir Crit Care Med ; 204(3): 285-293, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33779531

RESUMO

Rationale: Androgens are potentially beneficial in asthma, but AR (androgen receptor) has not been studied in human airways.Objectives: To measure whether AR and its ligands are associated with human asthma outcomes.Methods: We compared the effects of AR expression on lung function, symptom scores, and fractional exhaled nitric oxide (FeNO) in adults enrolled in SARP (Severe Asthma Research Program). The impact of sex and of androgens on asthma outcomes was also evaluated in the SARP with validation studies in the Cleveland Clinic Health System and the NHANES (U.S. National Health and Nutrition Examination Survey).Measurements and Main Results: In SARP (n = 128), AR gene expression from bronchoscopic epithelial brushings was positively associated with both FEV1/FVC ratio (R2 = 0.135, P = 0.0002) and the total Asthma Quality of Life Questionnaire score (R2 = 0.056, P = 0.016) and was negatively associated with FeNO (R2 = 0.178, P = 9.8 × 10-6) and NOS2 (nitric oxide synthase gene) expression (R2 = 0.281, P = 1.2 × 10-10). In SARP (n = 1,659), the Cleveland Clinic Health System (n = 32,527), and the NHANES (n = 2,629), women had more asthma exacerbations and emergency department visits than men. The levels of the AR ligand precursor dehydroepiandrosterone sulfate correlated positively with the FEV1 in both women and men.Conclusions: Higher bronchial AR expression and higher androgen levels are associated with better lung function, fewer symptoms, and a lower FeNO in human asthma. The role of androgens should be considered in asthma management.


Assuntos
Asma/genética , Sulfato de Desidroepiandrosterona/sangue , RNA Mensageiro/metabolismo , Receptores Androgênicos/genética , Mucosa Respiratória/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/sangue , Asma/fisiopatologia , Testes Respiratórios , Broncoscopia , Feminino , Volume Expiratório Forçado , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Qualidade de Vida , Fatores Sexuais , Capacidade Vital , Adulto Jovem
4.
J Ovarian Res ; 14(1): 32, 2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33583431

RESUMO

BACKGROUND: The aims of this study were to compare the efficacy of different androgens measured by liquid chromatography-mass spectrometry (LC-MS/MS) in representing hyperandrogenemia and to evaluate adrenal-origin androgens with a dexamethasone suppression test in patients with polycystic ovary syndrome (PCOS). METHODS: One hundred and two patients with PCOS and 41 healthy volunteers were recruited and total serum testosterone (TT), androstenedione (AD), dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) were measured by LC-MS/MS. ROC analysis was performed to compare the efficacy of different androgens in representing hyperandrogenemia. Dexamethasone suppression test was performed in 51 patients with PCOS and above indicators were measured after dexamethasone administration. The prediction efficacy of DHEA and DHEA-S at baseline in the dexamethasone suppression test was evaluated with ROC analysis. RESULTS: The AUCs of TT, AD, free androgen index (FAI) and DHEA-S in ROC analysis for representing hyperandrogenemia were 0.816, 0.842, 0.937 and 0.678, respectively. The optimal cutoff value of TT was 0.337 ng/ml, with a sensitivity of 72.0% and specificity of 82.93%. The optimal cutoff value for AD was 1.309 ng/ml, with a sensitivity of 81.0% and specificity of 73.17%. The optimal cutoff value of the FAI was 2.50, with a sensitivity of 87.0% and specificity of 92.68%. Alternatively, AD or FAI more than the optimal cutoff values as evidence of hyperandrogenemia had the highest sensitivity of 91.18%. The levels of cortisol, DHEA and DHEA-S were all suppressed to narrow ranges after dexamethasone administration. Nine and 8 of 51 patients with PCOS had significant decreases in TT and AD, respectively. DHEA can be used as a indicator for predicting significant decrease of TT in dexamethasone suppression test with cutoff value of 13.28 ng/ml. A total of 27.5% (14/51) of patients had DHEA-S excess, but only 1 of 9 patients who had a significant decrease in TT had elevated level of DHEA-S at baseline. CONCLUSIONS: AD measured by LC-MS/MS can represent hyperandrogenemia in PCOS patients and, combined with TT or FAI, can improve the screening efficiency of hyperandrogenemia. Seventeen percent of PCOS patients had adrenal-origin androgen dominance, with TT significantly decreasing after 2 days of dexamethasone administration. Adrenal-origin androgen dominance was not parallel with DHEA-S excess in patients with PCOS.


Assuntos
Androstenodiona/sangue , Sulfato de Desidroepiandrosterona/sangue , Desidroepiandrosterona/sangue , Hiperandrogenismo/sangue , Síndrome do Ovário Policístico/sangue , Testosterona/sangue , Testes de Função do Córtex Suprarrenal , Adulto , Área Sob a Curva , Estudos de Casos e Controles , Cromatografia Líquida , Dexametasona , Feminino , Hormônio Foliculoestimulante/sangue , Glucocorticoides , Humanos , Hiperandrogenismo/diagnóstico , Hormônio Luteinizante/sangue , Valor Preditivo dos Testes , Curva ROC , Sensibilidade e Especificidade , Globulina de Ligação a Hormônio Sexual/metabolismo , Espectrometria de Massas em Tandem
5.
Fertil Steril ; 115(6): 1557-1568, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33602559

RESUMO

OBJECTIVE: To examine the relation of menstrual cyclicity abnormalities to hyperandrogenism (HA) and dynamic state insulin resistance (IR) in oligo-ovulatory women with polycystic ovary syndrome (PCOS). DESIGN: Prospective cross-sectional study. SETTING: Tertiary-care academic center. PATIENT(S): Fifty-seven women with PCOS (1990 National Institutes of Health criteria) and 57 healthy control women matched by body mass index (BMI). INTERVENTION(S): Short insulin tolerance test (ITT). MAIN OUTCOME MEASURE(S): Menstrual cyclicity, sex hormone-binding globulin (SHBG), measures of HA (i.e., modified Ferriman-Gallwey score, total and free testosterone, dehydroepiandrosterone sulfate), and the rate constant for plasma glucose disappearance (kITT) derived from the short ITT. RESULT(S): Adjusting for age, BMI, and ethnicity, the mean androgen measures were higher and SHBG trended lower, kITT was lower, and the prevalence of IR was higher in PCOS than in controls, independent of menstrual cyclicity. The optimal cutoff point for IR was set at kITT value of 3.57%/minute or lower. Overall, 79% of the women with PCOS had IR. To control further for the effect of ethnicity, a subgroup of 46 non-Hispanic white PCOS participants were studied; those who exhibited amenorrhea (n = 15) or oligomenorrhea (n = 19) had or tended toward having a lower kITT and a higher prevalence of IR than the women with PCOS and oligo-ovulatory eumenorrhea (n = 12). The kITT trended lower and the prevalence of IR trended higher in women with PCOS and amenorrhea than those with oligomenorrhea. The measures of SHBG and HA were similar across the three menstrual groups. CONCLUSION(S): Oligo-ovulatory women with PCOS and overt oligo/amenorrhea have greater degrees of IR but not HA when compared with oligo-ovulatory eumenorrheic women with PCOS, suggesting that IR and hyperinsulinemia but not HA play a role in determining the degree of menstrual dysfunction, which can be used as a clinical marker for the degree of IR in oligo-ovulatory PCOS.


Assuntos
Hiperandrogenismo/etiologia , Resistência à Insulina , Ciclo Menstrual , Distúrbios Menstruais/etiologia , Síndrome do Ovário Policístico/complicações , Adulto , Biomarcadores/sangue , Glicemia/análise , Estudos de Casos e Controles , Estudos Transversais , Sulfato de Desidroepiandrosterona/sangue , Feminino , Humanos , Hiperandrogenismo/sangue , Hiperandrogenismo/diagnóstico , Hiperandrogenismo/fisiopatologia , Distúrbios Menstruais/sangue , Distúrbios Menstruais/diagnóstico , Distúrbios Menstruais/fisiopatologia , Ovulação , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/fisiopatologia , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Globulina de Ligação a Hormônio Sexual/análise , Testosterona/sangue , Fatores de Tempo , Adulto Jovem
6.
Cochrane Database Syst Rev ; 1: CD013211, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33482034

RESUMO

BACKGROUND: Statins are one of the most prescribed classes of drugs worldwide. Atorvastatin, the most prescribed statin, is currently used to treat conditions such as hypercholesterolaemia and dyslipidaemia. By reducing the level of cholesterol, which is the precursor of the steroidogenesis pathway, atorvastatin may cause a reduction in levels of testosterone and other androgens. Testosterone and other androgens play important roles in biological functions. A potential reduction in androgen levels, caused by atorvastatin might cause negative effects in most settings. In contrast, in the setting of polycystic ovary syndrome (PCOS), reducing excessive levels of androgens with atorvastatin could be beneficial. OBJECTIVES: Primary objective To quantify the magnitude of the effect of atorvastatin on total testosterone in both males and females, compared to placebo or no treatment. Secondary objectives To quantify the magnitude of the effects of atorvastatin on free testosterone, sex hormone binding globin (SHBG), androstenedione, dehydroepiandrosterone sulphate (DHEAS) concentrations, free androgen index (FAI), and withdrawal due to adverse effects (WDAEs) in both males and females, compared to placebo or no treatment. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to 9 November 2020: the Cochrane Hypertension Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; ;two international trials registries, and the websites of the US Food and Drug Administration, the European Patent Office and the Pfizer pharmaceutical corporation. These searches had no language restrictions. We also contacted authors of relevant articles regarding further published and unpublished work. SELECTION CRITERIA: RCTs of daily atorvastatin for at least three weeks, compared with placebo or no treatment, and assessing change in testosterone levels in males or females. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the citations, extracted the data and assessed the risk of bias of the included studies. We used the mean difference (MD) with associated 95% confidence intervals (CI) to report the effect size of continuous outcomes,and the risk ratio (RR) to report effect sizes of the sole dichotomous outcome (WDAEs). We used a fixed-effect meta-analytic model to combine effect estimates across studies, and risk ratio to report effect size of the dichotomous outcomes. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included six RCTs involving 265 participants who completed the study and their data was reported. Participants in two of the studies were male with normal lipid profile or mild dyslipidaemia (N = 140); the mean age of participants was 68 years. Participants in four of the studies were female with PCOS (N = 125); the mean age of participants was 32 years. We found no significant difference in testosterone levels in males between atorvastatin and placebo, MD -0.20 nmol/L (95% CI -0.77 to 0.37). In females, atorvastatin may reduce total testosterone by -0.27 nmol/L (95% CI -0.50 to -0.04), FAI by -2.59 nmol/L (95% CI -3.62 to -1.57), androstenedione by -1.37 nmol/L (95% CI -2.26 to -0.49), and DHEAS by -0.63 µmol/l (95% CI -1.12 to -0.15). Furthermore, compared to placebo, atorvastatin increased SHBG concentrations in females by 3.11 nmol/L (95% CI 0.23 to 5.99). We identified no studies in healthy females (i.e. females with normal testosterone levels) or children (under age 18). Importantly, no study reported on free testosterone levels. AUTHORS' CONCLUSIONS: We found no significant difference between atorvastatin and placebo on the levels of total testosterone in males. In females with PCOS, atorvastatin lowered the total testosterone, FAI, androstenedione, and DHEAS. The certainty of evidence ranged from low to very low for both comparisons. More RCTs studying the effect of atorvastatin on testosterone are needed.


Assuntos
Atorvastatina/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Síndrome do Ovário Policístico/sangue , Testosterona/sangue , Idoso , Androgênios/sangue , Androstenodiona/sangue , Atorvastatina/efeitos adversos , Viés , Sulfato de Desidroepiandrosterona/sangue , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Masculino , Placebos/farmacologia , Síndrome do Ovário Policístico/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores Sexuais , Globulina de Ligação a Hormônio Sexual/análise , Globulina de Ligação a Hormônio Sexual/efeitos dos fármacos
7.
Biomed Chromatogr ; 35(4): e5027, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33179271

RESUMO

The quantification of the circulating dehydroepiandrosterone sulfate (DHEAS) might be of diagnostic help for several diseases. For the DHEAS quantification, LC/ESI-MS/MS has the advantage of a high specificity compared with immunoassay, whereas LC/ESI-MS/MS has room to improve the analysis throughput. One of the promising solutions to enhance the analysis throughput is sample-multiplexing in the same injection, which can reduce the total LC/ESI-MS/MS run time. In this study, a quadruplex LC/ESI-MS/MS method was developed to quantify DHEAS in four different serum samples in a single run. After the four samples were separately deproteinized and derivatized with one of four Girard reagents (Girard reagent T, P and their isotopologs), the resulting samples were mixed, then injected into the LC/ESI-MS/MS. The applicability and advantage of the developed method were evaluated based on the analysis of nine batches of serum samples from healthy subjects (total 36 samples). The limit of quantitation was 0.050 µg/ml, which was sensitive enough for clinical laboratory use. The method was precise (intra- and inter-assay RSDs ≤ 3.6%), accurate (94.4-108.1%) and robust for the matrix effects. The analysis time was also shortened by about 60% for 36 samples by the introduced method compared with the conventional method.


Assuntos
Cromatografia Líquida/métodos , Sulfato de Desidroepiandrosterona/sangue , Espectrometria de Massas em Tandem/métodos , Adulto , Sulfato de Desidroepiandrosterona/química , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização por Electrospray/métodos
8.
Clin Nutr ; 40(2): 394-403, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32698957

RESUMO

BACKGROUND: The investigation was designed to assess the effects of synbiotic supplementation on glycemic profile, insulin-like growth factor-1 (IGF-1) and sex hormones in overweight and obese postmenopausal breast cancer survivors (BCSs) who had hormone-receptor-positive breast cancer. METHODS: This randomized, triple-blind, placebo-controlled trial was conducted on 76 overweight and obese BCSs aged 57.43 (5.82) years. All participants were given a specified low calorie diet and were randomly assigned into two groups to intake 109 CFU/day of synbiotic supplement (n = 38) or placebo (n = 38) for 8 weeks. Body composition, physical activity, glycemic profile, IGF-1, estradiol, testosterone and dehydroepiandrosterone sulfate (DHEA-S) were measured at baseline and after 8 weeks. RESULTS: A significant reduction in serum insulin (median change (Q1, Q3) from baseline of -1.05 (-2.36, 0.32) µIU/mL; P = 0.006) and insulin resistance (HOMA-IR) (mean change (SD) from baseline of -4.0 (0.9); P = 0.007) were seen over the 8 weeks in the synbiotic group. However, no significant changes were observed in serum insulin, fasting plasma glucose, HbA1c, HOMA-IR, IGF-1, estradiol, testosterone, DHEA-S and sex hormone binding globulin between-groups at the end of the intervention. CONCLUSIONS: Overall, as the 8-week synbiotic consumption compared with placebo had insignificant-reducing effects on glycemic profile, IGF-1 and sex hormones among overweight and obese postmenopausal BCSs, synbiotics may exert considerable beneficial consequences, which need to be further assessed in future clinical trials. TRIAL REGISTRATION: IRCT, IRCT2015090223861N1. Registered 02 February 2017, http://www.irct.ir: IRCT2015090223861N1.


Assuntos
Neoplasias da Mama/sangue , Dieta Redutora/métodos , Obesidade/dietoterapia , Sobrepeso/dietoterapia , Simbióticos/administração & dosagem , Idoso , Glicemia/metabolismo , Neoplasias da Mama/complicações , Sobreviventes de Câncer , Sulfato de Desidroepiandrosterona/sangue , Estradiol/sangue , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Insulina/sangue , Resistência à Insulina , Fator de Crescimento Insulin-Like I/metabolismo , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/microbiologia , Sobrepeso/complicações , Sobrepeso/microbiologia , Projetos de Pesquisa , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/sangue , Resultado do Tratamento
9.
Scand J Clin Lab Invest ; 80(8): 672-680, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33258387

RESUMO

Quantitation of endogenous steroids and their precursors is essential for diagnosis of a wide range of endocrine disorders. Usually, these analyses have been carried out using immunoassays. However, immunoassays often overestimate concentrations due to assay interference by other endogenous steroids, especially for low concentrations. Mass spectrometry based methods offer superior specificity, accuracy, and sensitivity. We therefore present a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with automated sample preparation for determination of 17α-hydroxyprogesterone (17OHP), cortisol, cortisone, dehydroepiandrosterone sulfate (DHEAS), androstenedione (A4), testosterone (T), and estrone sulfate (E1S). Samples were prepared using protein precipitation and 96-well filter plates, fully automated in a pipetting robot and analyzed by LC-MS/MS. Serum samples from 187 healthy children and adolescents aged 5-18 years were used to study hormone changes in relation to sex and pubertal stage. Lower limit of quantification for 17OHP was 0.7 nmol/L, for cortisol 11 nmol/L, for cortisone 2 nmol/L, for DHEAS 0.1 µmol/L, and for A4, T, and E1S, 0.2 nmol/L. This study showed a general increase in 17OHP, DHEAS, A4, T and E1S in both genders during puberty. In boys, A4 and T increased significantly throughout pubertal development. Girls had significantly higher A4 and E1S concentrations, while boys had higher T concentrations. No sex- or puberty-specific differences were seen in cortisol or cortisone concentrations. To the best of our knowledge, this is the first presentation of changes in serum E1S concentrations during pubertal development in healthy children.


Assuntos
Androstenodiona/sangue , Cortisona/sangue , Sulfato de Desidroepiandrosterona/sangue , Estrona/análogos & derivados , Hidrocortisona/sangue , Hidroxiprogesteronas/sangue , Testosterona/sangue , Adolescente , Criança , Pré-Escolar , Cromatografia Líquida/normas , Estrona/sangue , Feminino , Humanos , Limite de Detecção , Masculino , Puberdade/sangue , Robótica/instrumentação , Fatores Sexuais , Espectrometria de Massas em Tandem/normas
10.
Artigo em Inglês | MEDLINE | ID: mdl-33322590

RESUMO

BACKGROUND: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, anovulation, infertility, obesity, and insulin resistance, which results in increased concentrations of testosterone (T), which disturbs follicular growth and ovulation. This study aimed to assess PCOS women's clinical, endocrinological, and metabolic parameters concerning hyperandrogenism severity. RESULTS: 314 women (mean age 27.3 ± 4.6; mean body mass index (BMI) 25.7 ± 5.6) with PCOS, were divided into terciles according to T concentrations: <0.64 ng/mL (group 1), 0.64 to 0.84 ng/mL (Group 2) and >0.84 ng/mL (group 3). The mean concentration of T in all women was 0.59 ng/mL and correlated negatively with the number of menstrual cycles per year (MPY) (r = -0.36; p < 0.0001) and positively with Ferriman-Gallway score (FG) (r = 0.33; p < 0.0001), luteinizing hormone (LH) (r = 0.19; p < 0.0001) and dehydroepiandrosterone sulfate (DHEAS) (r = 0.52; p < 0.0001). Positive correlation between BMI and hirsutism (r = 0.16; p < 0.0001), total cholesterol (TC) (r = 0.18; p < 0.0001), low-density lipoprotein (LDL) (r = 0.29; p < 0.0001), and triglycerides (TG) (r = 0.40; p < 0.0001) was demonstrated. The division into subgroups confirmed the lowest MPY, highest LH, and hirsutism in group 3. BMI, insulin sensitivity indices, and lipid profile parameters were not different between the three T subgroups. CONCLUSIONS: We found no correlation between testosterone levels and insulin sensitivity or dyslipidemia in women with PCOS. Metabolic abnormalities may contribute more significantly than hyperandrogenemia to PCOS development.


Assuntos
Hormônio Luteinizante/sangue , Síndrome do Ovário Policístico/metabolismo , Adulto , Índice de Massa Corporal , Sulfato de Desidroepiandrosterona/sangue , Dislipidemias , Feminino , Hirsutismo , Humanos , Resistência à Insulina , Testosterona/sangue , Adulto Jovem
11.
Environ Health ; 19(1): 124, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33239073

RESUMO

BACKGROUND: Endocrine disrupting chemicals (EDCs) such as metals have been reported to alter circulating reproductive hormone concentrations and pubertal development in animals. However, the relationship has rarely been investigated among humans, with the exception of heavy metals, such as Pb and Cd. Our aim was to investigate measures of in utero and peripubertal metal exposure in relation to reproductive hormone concentrations and sexual maturation and progression among boys from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) cohorts. METHODS: Our analysis included 118 pregnant women and their male children from the ELEMENT study. Essential and non-essential metals were measured in urine collected from the mothers during the third trimester of pregnancy and their male children at 8-14 years. Reproductive hormone concentrations [serum testosterone, estradiol, dehydroepiandrosterone sulfate (DHEA-S), inhibin B, and sex hormone-binding globulin (SHBG)] were measured in blood samples from the children at 8-14 years. We also assessed Tanner stages for sexual maturation (genital, pubic hair development, and testicular volume), at two time points (8-14, 10-18 years). We used linear regression to independently examine urinary metal concentrations in relation to each peripubertal reproductive hormones adjusting for child age and BMI. Generalized estimation equations (GEEs) were used to evaluate the association of in utero and peripubertal metal exposures with sexual maturation and progression during follow-up based on Tanner staging and testicular volume. RESULTS: In utero and prepubertal concentrations of some urinary metals were associated with increased concentrations of peripubertal reproductive hormones, especially non-essential metal(loid)s As and Cd (in utero), and Ba (peripubertal) as well as essential metal Mo (in utero) in association with testosterone. More advanced pubic hair developmental stage and higher testicular volume at the early teen visit was observed for boys with higher non-essential metal concentrations, including in utero Al and peripubertal Ba, and essential metal Zn concentration (peripubertal). These metals were also associated with slower pubertal progression between the two visits. CONCLUSION: These findings suggest that male reproductive development may be associated with both essential and non-essential metal exposure during in utero and peripubertal windows.


Assuntos
Arsênio/urina , Poluentes Ambientais/urina , Exposição Materna , Metais/urina , Efeitos Tardios da Exposição Pré-Natal , Maturidade Sexual , Adolescente , Adulto , Criança , Cidades , Sulfato de Desidroepiandrosterona/sangue , Estradiol/sangue , Feminino , Humanos , Inibinas/sangue , Masculino , Troca Materno-Fetal , México , Gravidez , Globulina de Ligação a Hormônio Sexual/análise , Testosterona/sangue , Adulto Jovem
12.
Artigo em Inglês | MEDLINE | ID: mdl-33013704

RESUMO

Objective: This study aimed to explore the relationship between the fecal metabolites and gut microbiota in obese patients with PCOS and provide a new strategy to elucidate the pathological mechanism of obesity and PCOS. Methods: The fecal samples of obese patients with PCOS (n = 18) and obese women without PCOS (n = 15) were analyzed by 16S rRNA gene sequencing and untargeted metabolomics. The peripheral venous blood of all subjects was collected to detect serum sex hormones. The association among fecal metabolites, gut microbiota, and serum sex hormones was analyzed with the R language. Results: A total of 122 named differential fecal metabolites and 18 enrichment KEGG pathways were obtained between the groups. Seven fecal metabolites can be used as characteristic metabolites, including DHEA sulfate. The richness and diversity of gut microbiota in the obese PCOS group were lower than those in the control group. Lachnoclostridium, Fusobacterium, Coprococcus_2, and Tyzzerela 4 were the characteristic genera of the obese patients with PCOS. Serum T level significantly and positively correlated with the abundance of fecal DHEA sulfate (p < 0.05), and serum DHEAS level significantly and negatively correlated with the abundance of fecal teasterone (p < 0.05). Conclusion: Specific fecal metabolites may be used as characteristic metabolites for obese patients with PCOS. The closely relationship among gut microbiota, fecal metabolites, and serum sex hormones may play a role in the related changes caused by hyperandrogenemia.


Assuntos
Fezes/microbiologia , Microbioma Gastrointestinal/fisiologia , Obesidade/microbiologia , Síndrome do Ovário Policístico/microbiologia , Adolescente , Adulto , Sulfato de Desidroepiandrosterona/sangue , Feminino , Humanos , Metabolômica , Síndrome do Ovário Policístico/sangue , Testosterona/sangue , Adulto Jovem
13.
J Clin Endocrinol Metab ; 105(10)2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32866966

RESUMO

CONTEXT: Chronic opioid use may lead to adrenal insufficiency because of central suppression of the hypothalamic-pituitary-adrenal axis. However, the prevalence of opioid-induced adrenal insufficiency (OIAI) is unclear. OBJECTIVE: To determine the prevalence of OIAI and to identify predictors for the development of OIAI in patients taking opioids for chronic pain. DESIGN: Cross-sectional study, 2016-2018. SETTING: Referral center. PATIENTS: Adult patients taking chronic opioids admitted to the Pain Rehabilitation Center. MAIN OUTCOME MEASURE: Diagnosis of OIAI was considered if positive case detection (cortisol < 10 mcg/dL, ACTH < 15 pg/mL, and dehydroepiandrosterone sulfate < 25 mcg/dL), and confirmed after endocrine evaluation. Daily morphine milligram equivalent (MME) was calculated. RESULTS: In 102 patients (median age, 53 years [range, 22-83], 67% women), median daily MME was 60 mg (3-840), and median opioid therapy duration was 60 months (3-360). Abnormal case detection testing was found in 11 (10.8%) patients, and diagnosis of OIAI was made in 9 (9%). Patients with OIAI were on a higher daily MME (median, 140 [20-392] mg vs 57 [3-840] mg, P = 0.1), and demonstrated a 4 times higher cumulative opioid exposure (median of 13,440 vs 3120 mg*months, P = 0.03). No patient taking  20 mg); however, specificity of MME cutoff >20 mg was only 19%. After opioid discontinuation, 6/7 patients recovered adrenal function. CONCLUSION: The prevalence of OIAI was 9%, with MME cumulative exposure being the only predictor for OIAI development. Patients on MME of 20 mg/day and above should be monitored for OIAI.


Assuntos
Insuficiência Adrenal/epidemiologia , Analgésicos Opioides/efeitos adversos , Dor Crônica/tratamento farmacológico , Insuficiência Adrenal/sangue , Insuficiência Adrenal/induzido quimicamente , Insuficiência Adrenal/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/administração & dosagem , Estudos Transversais , Sulfato de Desidroepiandrosterona/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Prevalência , Estudos Prospectivos , Adulto Jovem
14.
Thorax ; 75(10): 835-841, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32796118

RESUMO

BACKGROUND: Allostatic load, a measure of early ageing or 'wear and tear' from adapting to environmental challenges, has been suggested as a framework with which to understand the stress-related disruption of multiple biological systems which may be linked to asthma. Considering the socioeconomic context is also critical given asthma and allostatic overload are more common in lower socioeconomic groups. AIMS: Estimate the relationship between allostatic load and its constituent biomarkers, asthma and corticosteroid prescribing while controlling for socioeconomic status. METHODS: Data from Understanding Society (a nationally representative survey of UK community-dwelling adults) waves 1-3 (2009-2012) allowed the identification of a sex-specific risk profile across 12 biomarkers used to construct an Allostatic Load Index for a sample of 9816 adults. Regression analyses were used to examine the association of asthma status and corticosteroid prescriptions with allostatic load and its constituent biomarkers while controlling for socioeconomic status (n=9805). RESULTS: Subjects with currently treated asthma and no corticosteroid prescription have an allostatic load 1.21 times higher than those without asthma (p<0.001). Asthmatic subjects in receipt of inhaled corticosteroids had an allostatic load, approximately 1.12 times higher than those without asthma (p<0.001). This association persisted in sensitivity analyses and appeared to be driven by an association with specific biomarkers (dehydroepiandrosterone-sulfate, waist-to-height ratio and C-reactive protein). CONCLUSION: Early ageing, in the form of a higher allostatic load, was present even in the mildest asthma group not receiving inhaled corticosteroids. Allostatic load is helpful in understanding the increased all-cause mortality and multimorbidity observed in asthma.


Assuntos
Corticosteroides/uso terapêutico , Envelhecimento/fisiologia , Alostase/fisiologia , Asma/complicações , Asma/metabolismo , Adulto , Idoso , Asma/terapia , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Estudos Transversais , Sulfato de Desidroepiandrosterona/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Fatores Socioeconômicos , Razão Cintura-Estatura
15.
J Clin Endocrinol Metab ; 105(12)2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32785663

RESUMO

CONTEXT: Lower dehydroepiandrosterone-sulfate (DHEA-S) levels have been inconsistently associated with coronary heart disease (CHD) and mortality. Data are limited for heart failure (HF) and association between DHEA-S change and events. OBJECTIVE: Assess associations between low DHEA-S/DHEA-S change and incident HF hospitalization, CHD, and mortality in older adults. DESIGN: DHEA-S was measured in stored plasma from visits 4 (1996-1998) and 5 (2011-2013) of the Atherosclerosis Risk in Communities study. Follow-up for incident events: 18 years for DHEA-S level; 5.5 years for DHEA-S change. SETTING: General community. PARTICIPANTS: Individuals without prevalent cardiovascular disease (n = 8143, mean age 63 years). MAIN OUTCOME MEASURE: Associations between DHEA-S and incident HF hospitalization, CHD, or mortality; associations between 15-year change in DHEA-S (n = 3706) and cardiovascular events. RESULTS: DHEA-S below the 15th sex-specific percentile of the study population (men: 55.4 µg/dL; women: 27.4 µg/dL) was associated with increased HF hospitalization (men: hazard ratio [HR] 1.30, 95% confidence interval [CI], 1.07-1.58; women: HR 1.42, 95% CI, 1.13-1.79); DHEA-S below the 25th sex-specific percentile (men: 70.0 µg/dL; women: 37.1 µg/dL) was associated with increased death (men: HR 1.12, 95% CI, 1.01-1.25; women: HR 1.19, 95% CI, 1.03-1.37). In men, but not women, greater percentage decrease in DHEA-S was associated with increased HF hospitalization (HR 1.94, 95% CI, 1.11-3.39). Low DHEA-S and change in DHEA-S were not associated with incident CHD. CONCLUSIONS: Low DHEA-S is associated with increased risk for HF and mortality but not CHD. Further investigation is warranted to evaluate mechanisms underlying these associations.


Assuntos
Doenças Cardiovasculares/sangue , Sulfato de Desidroepiandrosterona/sangue , Idoso , Doenças Cardiovasculares/epidemiologia , Doença das Coronárias/sangue , Doença das Coronárias/epidemiologia , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pós-Menopausa/sangue , Fatores de Risco
16.
Biochem Med (Zagreb) ; 30(3): 030701, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32774123

RESUMO

Introduction: There is a growing amount of evidence showing the significant analytical bias of steroid hormone immunoassays, but large number of available immunoassays makes conduction of a single comprehensive study of this issue hardly feasible. Aim of this study was to assess the analytical bias of six heterogeneous immunoassays for serum aldosterone, cortisol, dehydroepiandrosterone sulphate (DHEAS), testosterone, 17-hydroxyprogesterone (OHP) and progesterone using the liquid chromatography coupled to the tandem mass spectrometry (LC-MS/MS). Materials and methods: This method comparison study included 49 serum samples. Testosterone, DHEAS, progesterone and cortisol immunoassays were performed on the Abbott Architect i2000SR or Alinity i analysers (Abbott Diagnostics, Chicago, USA). DiaSorin's Liaison (DiaSorin, Saluggia, Italy) and DIAsource's ETI-Max 3000 analysers (DIAsource ImmunoAssays, Louvain-La-Neuve, Belgium) were chosen for aldosterone and OHP immunoassay testing, respectively. All immunoassays were evaluated against the LC-MS/MS assay relying on the commercial kit (Chromsystems, Gräfelfing, Germany) and LCMS-8050 analyser (Shimadzu, Kyoto, Japan). Analytical biases were calculated and method comparison was conducted using weighted Deming regression analysis. Results: Depending on the analyte and specific immunoassay, mean relative biases ranged from -31 to + 137%. Except for the cortisol, immunoassays were positively biased. For none of the selected steroids slope and intercept 95% confidence intervals simultaneously contained 0 and 1, respectively. Conclusions: Evaluated immunoassays failed to satisfy requirements for methods' comparability and produced significant analytical biases in respect to the LC-MS/MS assay, especially at low concentrations.


Assuntos
Cromatografia Líquida de Alta Pressão , Imunoensaio , Esteroides/sangue , Espectrometria de Massas em Tandem , 17-alfa-Hidroxiprogesterona/sangue , Adulto , Aldosterona/sangue , Automação , Viés , Sulfato de Desidroepiandrosterona/sangue , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Progesterona/sangue , Kit de Reagentes para Diagnóstico , Testosterona/sangue , Adulto Jovem
17.
J Clin Endocrinol Metab ; 105(10)2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32770207

RESUMO

CONTEXT: Sex differences exist in heart failure (HF) phenotypes, but there is limited research on the role of sex hormones in HF and its subtypes. OBJECTIVE: To examine the associations of total testosterone, dehydroepiandrosterone sulfate (DHEA-S), and sex hormone-binding globulin (SHBG) with incident HF, HF with preserved ejection fraction (HFpEF), and HF with reduced ejection fraction (HFrEF). DESIGN: Atherosclerosis Risk in Communities (ARIC) study (prospective cohort study). Median follow-up is 19.2 years. SETTING: General community. PARTICIPANTS: 4107 men and 4839 postmenopausal women, with mean age of 63.2 (standard deviation [SD] 5.7) and 62.8 (5.5) years, respectively. EXPOSURE: Plasma sex hormone levels were measured at visit 4 (1996-1998). MAIN OUTCOME MEASURES: Incident HF events were identified through hospital discharge codes and death certificates. RESULTS: The Hazard Ratios for HF associated with 1 SD decrease in log-transformed total testosterone, DHEA-S, and SHBG were 1.10 (95% confidence interval 1.03, 1.17), 1.07 (1.00, 1.15), and 1.04 (0.96, 1.11) in men, and 1.05 (0.99, 1.13), 1.17 (1.09, 1.24), and 0.93 (0.85, 1.01) in women, respectively. The associations between sex hormones with subtypes of HF had similar patterns but were attenuated and became statistically insignificant. CONCLUSION: In this prospective cohort, lower levels of endogenous testosterone and DHEA-S in men and DHEA-S in postmenopausal women were associated with the development of HF. Similar directions of association in both sexes and both HF subtypes suggest that sex hormones play a role in the development of HF through common pathways regardless of sex.


Assuntos
Aterosclerose/epidemiologia , Sulfato de Desidroepiandrosterona/sangue , Insuficiência Cardíaca/epidemiologia , Globulina de Ligação a Hormônio Sexual/análise , Testosterona/sangue , Idoso , Aterosclerose/sangue , Aterosclerose/complicações , Feminino , Seguimentos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Pós-Menopausa/sangue , Estudos Prospectivos , Fatores Sexuais , Volume Sistólico/fisiologia
18.
Endocr J ; 67(12): 1199-1205, 2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-32741887

RESUMO

An increase in arterial stiffness with advance aging is a risk for cardiovascular disease. Cardiovascular dysfunction is associated with the imbalance of adrenal cortex hormones, especially with the cortisol/dehydroepiandrosterone sulfate (DHEAs) ratio. However, the impact of aerobic fitness on arterial stiffness and cortisol/DHEAs ratio is unclear. The aim of this study was to investigate the relationship between aerobic fitness, arterial stiffness, and cortisol/DHEAs ratio. A total of 198 middle-aged and older adults (aged 50-79 years old) participated in this study. The aerobic fitness evaluated by peak oxygen consumption (VO2peak), carotid-femoral pulse wave velocity (cfPWV) as an indicator of arterial stiffness, and serum cortisol and DHEAs and their ratio were measured. The subjects were divided into the lower (n = 100) and the higher (n = 98) aerobic fitness groups based on the median value of VO2peak. There were no significant differences in serum cortisol and DHEAs concentration alone between the lower and higher fitness groups. However, the cortisol/DEHAs ratio and cfPWV in the higher fitness group was smaller than in the lower fitness group (p < 0.05). The cortisol/DHEAs ratio was significantly correlated with cfPWV (r = 0.159, p < 0.05). These findings suggest that the cortisol/DHEAs ratio is associated with aerobic fitness and arterial stiffness in middle-aged and older adults.


Assuntos
Sulfato de Desidroepiandrosterona/sangue , Exercício Físico/fisiologia , Hidrocortisona/sangue , Aptidão Física/fisiologia , Rigidez Vascular/fisiologia , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio/fisiologia
19.
J Clin Endocrinol Metab ; 105(10)2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32750115

RESUMO

CONTEXT: The levels of adrenal androgens are increased through the action of steroidogenic enzymes with morphological changes in the adrenal zona reticularis. OBJECTIVE: We investigated longitudinal changes in androgen levels and steroidogenic enzyme activities during early childhood. DESIGN AND PARTICIPANTS: From a prospective children's cohort, the Environment and Development of Children cohort, 114 boys and 86 girls with available blood samples from ages 2, 4, and 6 years were included. OUTCOME MEASUREMENTS: Serum concentrations of adrenal androgens using liquid chromatography-tandem mass spectrometry and steroidogenic enzyme activity calculated by the precursor/product ratio. RESULTS: During ages 2 to 4 years, 17,20-lyase and dehydroepiandrosterone (DHEA) sulfotransferase activities increased (P < 0.01 for both in boys). During ages 4 to 6 years, 17,20-lyase activity persistently increased, but 3ß-hydroxysteroid dehydrogenase (HSD) and 17ß-HSD activities decreased (P < 0.01 for all). Serum DHEA sulfate (DHEA-S) levels persistently increased from 2, 4, to 6 years, and DHEA, 17-hydroxyprogesterone, and androstenedione levels increased during ages 4 to 6 years (P < 0.01 for all). Serum DHEA-S levels during early childhood were associated with body mass index z-scores (P = 0.001 in only boys). CONCLUSION: This study supports in vivo human evidence of increased 17,20-lyase and DHEA sulfotransferase activities and decreased 3ß-HSD activity during early childhood.


Assuntos
3-Hidroxiesteroide Desidrogenases/sangue , Adrenarca/sangue , Androgênios/sangue , Esteroide 17-alfa-Hidroxilase/sangue , Sulfotransferases/sangue , 17-Hidroxiesteroide Desidrogenases/sangue , 17-Hidroxiesteroide Desidrogenases/metabolismo , 17-alfa-Hidroxiprogesterona/sangue , 17-alfa-Hidroxiprogesterona/metabolismo , 3-Hidroxiesteroide Desidrogenases/metabolismo , Adrenarca/metabolismo , Androgênios/metabolismo , Androstenodiona/sangue , Androstenodiona/metabolismo , Criança , Pré-Escolar , Sulfato de Desidroepiandrosterona/sangue , Sulfato de Desidroepiandrosterona/metabolismo , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos , Esteroide 17-alfa-Hidroxilase/metabolismo , Sulfotransferases/metabolismo , Zona Reticular/metabolismo
20.
Curr Opin Pediatr ; 32(4): 574-581, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32692055

RESUMO

PURPOSE OF REVIEW: Adrenarche is the pubertal maturation of the innermost zone of the adrenal cortex, the zona reticularis. The onset of adrenarche occurs between 6 and 8 years of age when dehydroepiandrosterone sulfate (DHEAS) concentrations increase. This review provides an update on adrenal steroidogenesis and the differential diagnosis of premature development of pubic hair. RECENT FINDINGS: The complexity of adrenal steroidogenesis has increased with recognition of the alternative 'backdoor pathway' and the 11-oxo-androgens pathways. Traditionally, sulfated steroids such as DHEAS have been considered to be inactive metabolites. Recent data suggest that intracellular sulfated steroids may function as tissue-specific intracrine hormones particularly in the tissues expressing steroid sulfatases such as ovaries, testes, and placenta. SUMMARY: The physiologic mechanisms governing the onset of adrenarche remain unclear. To date, no validated regulatory feedback mechanism has been identified for adrenal C19 steroid secretion. Available data indicate that for most children, premature adrenarche is a benign variation of development and a diagnosis of exclusion. Patients with premature adrenarche tend to have higher BMI values. Yet, despite greater knowledge about C19 steroids and zona reticularis function, much remains to be learned about adrenarche.


Assuntos
Glândulas Suprarrenais , Adrenarca/metabolismo , Adrenarca/fisiologia , Desenvolvimento Infantil/fisiologia , Puberdade Precoce , Puberdade/fisiologia , Zona Reticular/fisiologia , Glândulas Suprarrenais/crescimento & desenvolvimento , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/fisiologia , Androgênios , Criança , Sulfato de Desidroepiandrosterona/sangue , Sulfato de Desidroepiandrosterona/metabolismo , Feminino , Humanos , Gravidez , Esteroides/metabolismo
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