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1.
Clin Endocrinol (Oxf) ; 98(1): 82-90, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35581594

RESUMO

OBJECTIVE: Turner syndrome (TS) is associated with short stature, delayed puberty, primary ovarian insufficiency, and other features. Most girls with TS require oestrogen replacement for pubertal induction. There is paucity of data in adult TS on pubertal outcomes, including breast satisfaction. Here, we assess breast satisfaction in TS with the BREAST-Q questionnaire, a well-validated patient-related outcome measure (PROM). DESIGN: International survey distributed online through TS support groups. PATIENTS: Adult women aged 18-45 years with TS (self-reported). MEASUREMENTS: The questionnaire contained demographics, health history and the four domains of the BREAST-Q. BREAST-Q scores were matched on a one-to-one basis for age, body mass index (BMI) and educational background to a normative data set derived from the 'Army of Women', an online community of healthy volunteers. RESULTS: Of 97 total responses, 74 could be matched to the control cohort. Median age was 32 years (18-45 years) and 97% were White Caucasian. Median age at menarche was 15.5 years (12-34 years), 86% had received pubertal induction therapy as teenagers. We found significantly lower BREAST-Q scores in TS in the domains 'Satisfaction with Breast' (p = .021), 'Psychosocial Wellbeing' (p < .0001) and 'Sexual Wellbeing' (p < .0001). TS who had received oestrogen replacement therapy reported lower scores compared to TS who had not received oestrogen therapy (p < .0001). Lower BMI and previous growth hormone therapy were associated with lower breast satisfaction. CONCLUSIONS: TS women who received oestrogen replacement for pubertal induction self-report lower breast satisfaction scores and late menarche, suggesting that type, mode of delivery, dose and timing of hormone supplements merit prospective study.


Assuntos
Síndrome de Turner , Humanos , Adulto , Feminino , Adolescente , Síndrome de Turner/tratamento farmacológico , Estudos Prospectivos
2.
Artigo em Inglês | MEDLINE | ID: mdl-37964596

RESUMO

The adolescent period is characterised by fundamental hormonal changes, which affect sex steroid production, cortisol metabolism and insulin sensitivity. These physiological changes have a significant impact on patients with congenital adrenal hyperplasia (CAH). An essential treatment aim across the lifespan in patients with CAH is to replace glucocorticoids sufficiently to avoid excess adrenal androgen production but equally to avoid cardiometabolic risks associated with excess glucocorticoid intake. The changes to the hormonal milieu at puberty, combined with poor adherence to medical therapy, often result in unsatisfactory control exacerbating androgen excess and increasing the risk of metabolic complications due to steroid over-replacement. With the physical and cognitive maturation of the adolescent with CAH, fertility issues and sexual function become a new focus of patient care in the paediatric clinic. This requires close surveillance for gonadal dysfunction, such as irregular periods/hirsutism or genital surgery-associated symptoms in girls and central hypogonadism or testicular adrenal rest tumours in boys. To ensure good health outcomes across the lifespan, the transition process from paediatric to adult care of patients with CAH must be planned carefully and early from the beginning of adolescence, spanning over many years into young adulthood. Its key aims are to empower the young person through education with full disclosure of their medical history, to ensure appropriate follow-up with experienced physicians and facilitate access to multispecialist teams addressing the complex needs of patients with CAH.

3.
Hum Reprod ; 36(2): 506-518, 2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33313884

RESUMO

STUDY QUESTION: Is there an (epi)genetic basis in patients with central precocious puberty (CPP) associated with multiple anomalies that unmasks underlying mechanisms or reveals novel genetic findings related to human pubertal control? SUMMARY ANSWER: In a group of 36 patients with CPP associated with multiple phenotypes, pathogenic or likely pathogenic (epi)genetic defects were identified in 12 (33%) patients, providing insights into the genetics of human pubertal control. WHAT IS KNOWN ALREADY: A few studies have described patients with CPP associated with multiple anomalies, but without making inferences on causalities of CPP. Genetic-molecular studies of syndromic cases may reveal disease genes or mechanisms, as the presentation of such patients likely indicates a genetic disorder. STUDY DESIGN, SIZE, DURATION: This translational study was based on a genetic-molecular analysis, including genome-wide high throughput methodologies, for searching structural or sequence variants implicated in CPP and DNA methylation analysis of candidate regions. PARTICIPANTS/MATERIALS, SETTING, METHODS: A cohort of 197 patients (188 girls) with CPP without structural brain lesions was submitted to a detailed clinical evaluation, allowing the selection of 36 unrelated patients (32 girls) with CPP associated with multiple anomalies. Pathogenic allelic variants of genes known to cause monogenic CPP (KISS1R, KISS1, MKRN3 and DLK1) had been excluded in the entire cohort (197 patients). All selected patients with CPP associated with multiple anomalies (n = 36) underwent methylation analysis of candidate regions and chromosomal microarray analysis. A subset (n = 9) underwent whole-exome sequencing, due to presenting familial CPP and/or severe congenital malformations and neurocognitive abnormalities. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 36 selected patients with CPP, the more prevalent associated anomalies were metabolic, growth and neurocognitive conditions. In 12 (33%) of them, rare genetic abnormalities were identified: six patients presented genetic defects in loci known to be involved with CPP (14q32.2 and 7q11.23), whereas the other six presented defects in candidate genes or regions. In detail, three patients presented hypomethylation of DLK1/MEG3:IG-DMR (14q32.2 disruption or Temple syndrome), resulting from epimutation (n = 1) or maternal uniparental disomy of chromosome 14 (n = 2). Seven patients presented pathogenic copy number variants: three with de novo 7q11.23 deletions (Williams-Beuren syndrome), three with inherited Xp22.33 deletions, and one with de novo 1p31.3 duplication. Exome sequencing revealed potential pathogenic variants in two patients: a sporadic female case with frameshift variants in TNRC6B and AREL1 and a familial male case with a missense substitution in UGT2B4 and a frameshift deletion in MKKS. LIMITATIONS, REASONS FOR CAUTION: The selection of patients was based on a retrospective clinical characterization, lacking a longitudinal inclusion of consecutive patients. In addition, future studies are needed, showing the long-term (mainly reproductive) outcomes in the included patients, as most of them are not in adult life yet. WIDER IMPLICATIONS OF THE FINDINGS: The results highlighted the relevance of an integrative clinical-genetic approach in the elucidation of mechanisms and factors involved in pubertal control. Chromosome 14q32.2 disruption indicated the loss of imprinting of DLK1 as a probable mechanism of CPP. Two other chromosomal regions (7q11.23 and Xp22.33) represented new candidate loci potentially involved in this disorder of pubertal timing. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grant number 2018/03198-0 (to A.P.M.C.) and grant number 2013/08028-1 (to A.C.V.K) from the São Paulo Research Foundation (FAPESP), and grant number 403525/2016-0 (to A.C.L.) and grant number 302849/2015-7 (to A.C.L.) and grant number 141625/2016-3 (to A.C.V.K) from the National Council for Scientific and Technological Development (CNPq). The authors have nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.


Assuntos
Puberdade Precoce , Adulto , Brasil , Feminino , Testes Genéticos , Humanos , Masculino , Puberdade , Puberdade Precoce/genética , Proteínas de Ligação a RNA , Estudos Retrospectivos , Ubiquitina-Proteína Ligases
4.
Pediatr Diabetes ; 22(2): 249-260, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33205572

RESUMO

OBJECTIVES: Create and evaluate the effectiveness of a structured education program in children and young people (CYP) with type 1 diabetes using continuous glucose monitoring (CGM). DESIGN AND METHODS: Step 1: CGM devices were evaluated for predetermined criteria using a composite score. Step 2: The education program was developed following review of international structured education guidance, dynamic glucose management (DynamicGM) literature, award-winning diabetes educators' websites, and CGM user feedback. Step 3: Program effectiveness was assessed at six months by change in time below range (TBR) (<3.9mmol/L), time in range (TIR) (3.9-10.0mmol/L), time above range level 2 (TAR2) (>13.9mmol/L), severe hypoglycemia and HbA1c using a paired T-test. A DynamicGM score was developed to assess proactive glucose management. Factors predicting TBR and TIR were assessed using regression analysis. RESULTS: Dexcom G6 was chosen for integrated CGM (iCGM) status and highest composite score (29/30). Progressive DynamicGM strategies were taught through five sessions delivered over two months. Fifty CYP (23 male) with a mean (±SD) age and diabetes duration of 10.2 (±4.8) and 5.2 (±3.7) years respectively, who completed the education program were prospectively evaluated. Evaluation at six months showed a significant reduction in TBR (10.4% to 2.1%, p<.001), TAR2 (14.1% to 7.3%, p<.001), HbA1c [7.4 to 7.1% (57.7 to 53.8 mmol/mol), p<.001] and severe hypoglycemic episodes (10 to 1, p<.05); TIR increased (47.4% to 57.0%, p<.001). Number of Dexcom followers (p<.05) predicted reduction in TBR and DynamicGM score (p<.001) predicted increased TIR. CONCLUSION: Teaching DynamicGM strategies successfully improves TIR and reduces hypoglycemia.


Assuntos
Automonitorização da Glicemia/instrumentação , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Educação de Pacientes como Assunto , Adolescente , Fatores Etários , Glicemia/metabolismo , Criança , Estudos de Coortes , Diabetes Mellitus Tipo 1/complicações , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemia/diagnóstico , Hipoglicemia/etiologia , Masculino , Fatores de Tempo
5.
J Biol Chem ; 293(25): 9724-9735, 2018 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-29743239

RESUMO

The high-energy sulfate donor 3'-phosphoadenosine-5'-phosphosulfate (PAPS), generated by human PAPS synthase isoforms PAPSS1 and PAPSS2, is required for all human sulfation pathways. Sulfotransferase SULT2A1 uses PAPS for sulfation of the androgen precursor dehydroepiandrosterone (DHEA), thereby reducing downstream activation of DHEA to active androgens. Human PAPSS2 mutations manifest with undetectable DHEA sulfate, androgen excess, and metabolic disease, suggesting that ubiquitous PAPSS1 cannot compensate for deficient PAPSS2 in supporting DHEA sulfation. In knockdown studies in human adrenocortical NCI-H295R1 cells, we found that PAPSS2, but not PAPSS1, is required for efficient DHEA sulfation. Specific APS kinase activity, the rate-limiting step in PAPS biosynthesis, did not differ between PAPSS1 and PAPSS2. Co-expression of cytoplasmic SULT2A1 with a cytoplasmic PAPSS2 variant supported DHEA sulfation more efficiently than co-expression with nuclear PAPSS2 or nuclear/cytosolic PAPSS1. Proximity ligation assays revealed protein-protein interactions between SULT2A1 and PAPSS2 and, to a lesser extent, PAPSS1. Molecular docking studies showed a putative binding site for SULT2A1 within the PAPSS2 APS kinase domain. Energy-dependent scoring of docking solutions identified the interaction as specific for the PAPSS2 and SULT2A1 isoforms. These findings elucidate the mechanistic basis for the selective requirement for PAPSS2 in human DHEA sulfation.


Assuntos
Carcinoma Adrenocortical/metabolismo , Sulfato de Desidroepiandrosterona/metabolismo , Complexos Multienzimáticos/metabolismo , Sulfato Adenililtransferase/metabolismo , Sulfotransferases/metabolismo , Sítios de Ligação , Núcleo Celular/metabolismo , Cristalografia por Raios X , Citosol/metabolismo , Sulfato de Desidroepiandrosterona/química , Humanos , Simulação de Acoplamento Molecular , Complexos Multienzimáticos/química , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Sulfato Adenililtransferase/química , Sulfotransferases/química , Células Tumorais Cultivadas
7.
Eur J Endocrinol ; 191(1): 64-74, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38924056

RESUMO

OBJECTIVE: Pediatric adrenocortical carcinoma (pACC) is rare, and prognostic stratification remains challenging. We aimed to confirm the prognostic value of the previously published pediatric scoring system (pS-GRAS) in an international multicenter cohort. DESIGN: Analysis of pS-GRAS items of pACC from 6 countries in collaboration of ENSAT-PACT, GPOH-MET, and IC-PACT. METHODS: We received patient data of the pS-GRAS items including survival information from 9 centers. PS-GRAS score was calculated as a sum of tumor stage (1 = 0; 2-3 = 1; 4 = 2 points), grade (Ki67 index: 0%-9% = 0; 10%-19% = 1; ≥20% = 2 points), resection status (R0 = 0; RX/R1/R2 = 1 point), age (<4 years = 0; ≥4 years = 1 point), and hormone production (androgen production = 0; glucocorticoid-/mixed-/no-hormone production = 1 point) generating 8 scores and 4 groups (1: 0-2, 2: 3-4, 3: 5, 4: 6-7). Primary endpoint was overall survival (OS). RESULTS: We included 268 patients with median age of 4 years. The analysis of the pS-GRAS score showed a significantly favorable prognosis in patients with a lower scoring compared to higher scoring groups (5-year OS: Group 1 98%; group 2 87% [hazard ratio {HR} of death 3.6, 95% CI of HR 1.6-8.2]; group 3 43% [HR of death 2.8, 95% CI 1.9-4.4]; group 4: OS 18% [HR of death 2.1, 95% CI 1.7-2.7]). In the multivariable analysis, age (HR of death 3.5, 95% CI 1.8-7.0), resection status (HR of death 5.5, 95% CI 2.7-11.1), tumor stage (HR of death 1.9, 95% CI of HR 1.2-3.0), and Ki67 index (HR of death 1.7, 95% CI 1.2-2.4) remained strong independent outcome predictors. Especially infants < 4 years showed more often low-risk constellations with a better OS for all tumor stages. CONCLUSION: In an international multicenter study, we confirmed that the pS-GRAS score is strongly associated with overall survival among patients with pACC. Age, resection status, stage, and Ki67 index are important parameters for risk stratification.


Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Humanos , Neoplasias do Córtex Suprarrenal/mortalidade , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/patologia , Masculino , Feminino , Prognóstico , Criança , Pré-Escolar , Carcinoma Adrenocortical/mortalidade , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/patologia , Adolescente , Lactente , Estudos de Coortes , Estadiamento de Neoplasias
8.
Eur J Endocrinol ; 190(4): G15-G24, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38552173

RESUMO

OBJECTIVE: Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects. METHODS: A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements. RESULTS: We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stages III and IV and with incomplete resection/tumor spillage. For stage II patients, mitotane is not generally indicated. The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14 and 20 mg/L. Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2-4 weeks), along with evaluation and assessment of laboratory values, are required. CONCLUSIONS: The Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.


Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Criança , Mitotano/efeitos adversos , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/patologia , Antineoplásicos Hormonais/efeitos adversos , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/patologia
10.
Front Clin Diabetes Healthc ; 4: 1228820, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38090274

RESUMO

Introduction: Language barriers can pose a significant hurdle to successfully educating children and young people with type 1 diabetes (CYPD) and their families, potentially influencing their glycaemic control. Methods: Retrospective case-control study assessing HbA1c values at 0, 3, 6, 9, 12 and 18 months post-diagnosis in 41 CYPD requiring interpreter support (INT) and 100 age-, sex- and mode-of-therapy-matched CYPD not requiring interpreter support (CTR) in our multi-diverse tertiary diabetes centre. Data were captured between 2009-2016. English indices of deprivation for each cohort are reported based on the UK 2015 census data. Results: The main languages spoken were Somali (27%), Urdu (19.5%), Romanian (17%) and Arabic (12%), but also Polish, Hindi, Tigrinya, Portuguese, Bengali and sign language. Overall deprivation was worse in the INT group according to the Index of Multiple Deprivation (IMD [median]: INT 1.642; CTR 3.741; p=0.001). The median HbA1c was higher at diagnosis in the CTR group (9.95% [85.2 mmol/mol] versus 9.0% [74.9 mmol/mol], p=0.046) but was higher in the INT group subsequently: the median HbA1c at 18 months post diagnosis was 8.3% (67.2 mmol/mol; INT) versus 7.9% (62.8 mmol/mol; CTR) (p=0.014). There was no hospitalisation secondary to diabetes-related complications in either cohorts. Summary and conclusions: Glycaemic control is worse in CYPD with language barriers. These subset of patients also come from the most deprived areas which adds to the disadvantage. Health care providers should offer tailored support for CYP/families with language barriers, including provision of diabetes-specific training for interpreters, and explore additional factors contributing to poor glycaemic control. The findings of this study suggest that poor health outcomes in CYPD with language barriers is multifactorial and warrants a multi-dimensional management approach.

11.
Eur J Endocrinol ; 184(1): 51-64, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33112263

RESUMO

CONTEXT: The incidence of gestational diabetes mellitus (GDM) has been on the rise, driven by maternal obesity. In parallel, pubertal tempo has increased in the general population, driven by childhood obesity. OBJECTIVE: To evaluate the available evidence on pubertal timing of boys and girls born to mothers with GDM. DATA SOURCES: We searched MEDLINE, EMBASE, CINAHL Plus, Cochrane library and grey literature for observational studies up to October 2019. STUDY SELECTION AND EXTRACTION: Two reviewers independently selected studies, collected data and appraised the studies for risk of bias. Results were tabulated and narratively described as reported in the primary studies. RESULTS: Seven articles (six for girls and four for boys) were included. Study quality score was mostly moderate (ranging from 4 to 10 out of 11). In girls born to mothers with GDM, estimates suggest earlier timing of pubarche, thelarche and menarche although for each of these outcomes only one study each showed a statistically significant association. In boys, there was some association between maternal GDM and earlier pubarche, but inconsistency in the direction of shift of age at onset of genital and testicular development and first ejaculation. Only a single study analysed growth patterns in children of mothers with GDM, describing a 3-month advancement in the age of attainment of peak height velocity and a slight increase in pubertal tempo. CONCLUSIONS: Pubertal timing may be influenced by the presence of maternal GDM, though current evidence is sparse and of limited quality. Prospective cohort studies should be conducted, ideally coupled with objective biochemical tests.


Assuntos
Diabetes Gestacional , Efeitos Tardios da Exposição Pré-Natal , Puberdade/fisiologia , Adolescente , Fatores Etários , Criança , Desenvolvimento Infantil/fisiologia , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Maturidade Sexual/fisiologia , Fatores de Tempo
12.
Eur J Endocrinol ; 185(5): 729-741, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34524979

RESUMO

CONTEXT: 17α-Hydroxylase/17,20-lyase deficiency (17OHD) caused by mutations in the CYP17A1 gene is a rare form of congenital adrenal hyperplasia typically characterised by cortisol deficiency, mineralocorticoid excess and sex steroid deficiency. OBJECTIVE: To examine the phenotypic spectrum of 17OHD by clinical and biochemical assessment and corresponding in silico and in vitro functional analysis. DESIGN: Case series. PATIENTS AND RESULTS: We assessed eight patients with 17OHD, including four with extreme 17OHD phenotypes: two siblings presented with failure to thrive in early infancy and two with isolated sex steroid deficiency and normal cortisol reserve. Diagnosis was established by mass spectrometry-based urinary steroid profiling and confirmed by genetic CYP17A1 analysis, revealing homozygous and compound heterozygous sequence variants. We found novel (p.Gly111Val, p.Ala398Glu, p.Ile371Thr) and previously described sequence variants (p.Pro409Leu, p.Arg347His, p.Gly436Arg, p.Phe53/54del, p.Tyr60IlefsLys88X). In vitro functional studies employing an overexpression system in HEK293 cells showed that 17,20-lyase activity was invariably decreased while mutant 17α-hydroxylase activity retained up to 14% of WT activity in the two patients with intact cortisol reserve. A ratio of urinary corticosterone over cortisol metabolites reflective of 17α-hydroxylase activity correlated well with clinical phenotype severity. CONCLUSION: Our findings illustrate the broad phenotypic spectrum of 17OHD. Isolated sex steroid deficiency with normal stimulated cortisol has not been reported before. Attenuation of 17α-hydroxylase activity is readily detected by urinary steroid profiling and predicts phenotype severity. SIGNIFICANCE STATEMENT: Here we report, supported by careful phenotyping, genotyping and functional analysis, a prismatic case series of patients with congenital adrenal hyperplasia due to 17α-hydroxylase (CYP17A1) deficiency (17OHD). These range in severity from the abolition of function, presenting in early infancy, and unusually mild with isolated sex steroid deficiency but normal ACTH-stimulated cortisol in adult patients. These findings will guide improved diagnostic detection of CYP17A1 deficiency.


Assuntos
Esteroide 17-alfa-Hidroxilase/genética , Adolescente , Hiperplasia Suprarrenal Congênita/genética , Amenorreia/genética , Simulação por Computador , Corticosterona/urina , Insuficiência de Crescimento/enzimologia , Insuficiência de Crescimento/genética , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Hormônios Esteroides Gonadais/deficiência , Ginecomastia/etiologia , Ginecomastia/genética , Células HEK293 , Humanos , Hidrocortisona/deficiência , Lactente , Recém-Nascido , Masculino , Mineralocorticoides/metabolismo , Mutação/genética , Fenótipo , Esteroides/urina , Adulto Jovem
13.
Endocr Rev ; 40(6): 1605-1625, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31294783

RESUMO

Steroid biosynthesis and metabolism are reflected by the serum steroid metabolome and, in even more detail, by the 24-hour urine steroid metabolome, which can provide unique insights into alterations of steroid flow and output indicative of underlying conditions. Mass spectrometry-based steroid metabolome profiling has allowed for the identification of unique multisteroid signatures associated with disorders of steroid biosynthesis and metabolism that can be used for personalized approaches to diagnosis, differential diagnosis, and prognostic prediction. Additionally, steroid metabolome analysis has been used successfully as a discovery tool, for the identification of novel steroidogenic disorders and pathways as well as revealing insights into the pathophysiology of adrenal disease. Increased availability and technological advances in mass spectrometry-based methodologies have refocused attention on steroid metabolome profiling and facilitated the development of high-throughput steroid profiling methods soon to reach clinical practice. Furthermore, steroid metabolomics, the combination of mass spectrometry-based steroid analysis with machine learning-based approaches, has facilitated the development of powerful customized diagnostic approaches. In this review, we provide a comprehensive up-to-date overview of the utility of steroid metabolome analysis for the diagnosis and management of inborn disorders of steroidogenesis and autonomous adrenal steroid excess in the context of adrenal tumors.


Assuntos
Doenças das Glândulas Suprarrenais/metabolismo , Metaboloma , Erros Inatos do Metabolismo de Esteroides/metabolismo , Doenças das Glândulas Suprarrenais/diagnóstico , Diagnóstico Diferencial , Humanos , Erros Inatos do Metabolismo de Esteroides/diagnóstico
14.
Eur J Endocrinol ; 180(3): 213-221, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30566905

RESUMO

Objective Androgen excess in childhood is a common presentation and may signify sinister underlying pathology. Data describing its patterns and severity are scarce, limiting the information available for clinical decision processes. Here, we examined the differential diagnostic value of serum DHEAS, androstenedione (A4) and testosterone in childhood androgen excess. Design Retrospective review of all children undergoing serum androgen measurement at a single center over 5 years. Methods Serum A4 and testosterone were measured by tandem mass spectrometry and DHEAS by immunoassay. Patients with at least one increased androgen underwent phenotyping by clinical notes review. Results In 487 children with simultaneous DHEAS, A4 and testosterone measurements, we identified 199 with androgen excess (140 pre- and 59 post-pubertal). Premature adrenarche (PA) was the most common pre-pubertal diagnosis (61%), characterized by DHEAS excess in 85%, while A4 and testosterone were only increased in 26 and 9% respectively. PCOS was diagnosed in 40% of post-pubertal subjects, presenting equally frequent with isolated excess of DHEAS (29%) or testosterone (25%) or increases in both A4 and testosterone (25%). CAH patients (6%) predominantly had A4 excess (86%); testosterone and DHEAS were increased in 50 and 33% respectively. Concentrations increased above the two-fold upper limit of normal were mostly observed in PA for serum DHEAS (>20-fold in the single case of adrenocortical carcinoma) and in CAH for serum androstenedione. Conclusions Patterns and severity of childhood androgen excess provide pointers to the underlying diagnosis and can be used to guide further investigations.


Assuntos
Androgênios/sangue , Doenças do Sistema Endócrino/epidemiologia , Doenças do Sistema Endócrino/etiologia , Puberdade/sangue , Adolescente , Androstenodiona/sangue , Criança , Pré-Escolar , Desidroepiandrosterona/sangue , Sulfato de Desidroepiandrosterona/sangue , Doenças do Sistema Endócrino/sangue , Doenças do Sistema Endócrino/patologia , Feminino , Humanos , Masculino , Puberdade Precoce/sangue , Puberdade Precoce/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Maturidade Sexual/fisiologia , Testosterona/sangue
15.
Horm Res Paediatr ; 89(5): 292-310, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29874650

RESUMO

Disorders of adrenal steroidogenesis comprise autosomal recessive conditions affecting steroidogenic enzymes of the adrenal cortex. Those are located within the 3 major branches of the steroidogenic machinery involved in the production of mineralocorticoids, glucocorticoids, and androgens. This mini review describes the principles of adrenal steroidogenesis, including the newly appreciated 11-oxygenated androgen pathway. This is followed by a description of pathophysiology, biochemistry, and clinical implications of steroidogenic disorders, including mutations affecting cholesterol import and steroid synthesis, the latter comprising both mutations affecting steroidogenic enzymes and co-factors required for efficient catalysis. A good understanding of adrenal steroidogenic pathways and their regulation is crucial as the basis for sound management of these disorders, which in the majority present in early childhood.


Assuntos
Doenças das Glândulas Suprarrenais/enzimologia , Doenças das Glândulas Suprarrenais/genética , Doenças Genéticas Inatas/enzimologia , Doenças Genéticas Inatas/genética , Mutação , Doenças das Glândulas Suprarrenais/terapia , Androgênios/genética , Androgênios/metabolismo , Colesterol/genética , Colesterol/metabolismo , Doenças Genéticas Inatas/terapia , Glucocorticoides/genética , Glucocorticoides/metabolismo , Humanos , Mineralocorticoides/genética , Mineralocorticoides/metabolismo
16.
J Clin Endocrinol Metab ; 103(3): 1214-1223, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29342266

RESUMO

Context: Androgen excess in women is predominantly due to underlying polycystic ovary syndrome (PCOS). However, there is a lack of clarity regarding patterns and severity of androgen excess that should be considered predictive of non-PCOS pathology. Objective: We examined the diagnostic utility of simultaneous measurement of serum dehydroepiandrosterone sulfate (DHEAS), androstenedione (A4), and testosterone (T) to delineate biochemical signatures and cutoffs predictive of non-PCOS disorders in women with androgen excess. Design: Retrospective review of all women undergoing serum androgen measurement at a large tertiary referral center between 2012 and 2016. Serum A4 and T were measured by tandem mass spectrometry and DHEAS by immunoassay. Patients with at least one increased serum androgen underwent phenotyping by clinical notes review. Results: In 1205 women, DHEAS, A4, and T were measured simultaneously. PCOS was the most common diagnosis in premenopausal (89%) and postmenopausal women (29%). A4 was increased in all adrenocortical carcinoma (ACC) cases (n = 15) and T in all ovarian hyperthecosis (OHT) cases (n = 7); all but one case of congenital adrenal hyperplasia (CAH; n = 18) were identified by increased levels of A4 and/or T. In premenopausal women, CAH was a prevalent cause of severe A4 (59%) and T (43%) excess; severe DHEAS excess was predominantly due to PCOS (80%). In postmenopausal women, all cases of severe DHEAS and A4 excess were caused by ACC and severe T excess equally by ACC and OHT. Conclusions: Pattern and severity of androgen excess are important predictors of non-PCOS pathology and may be used to guide further investigations as appropriate.


Assuntos
Androgênios/sangue , Hiperandrogenismo/etiologia , Doenças Ovarianas/complicações , Neoplasias do Córtex Suprarrenal/sangue , Neoplasias do Córtex Suprarrenal/complicações , Hiperplasia Suprarrenal Congênita/sangue , Hiperplasia Suprarrenal Congênita/complicações , Carcinoma Adrenocortical/sangue , Carcinoma Adrenocortical/complicações , Adulto , Androstenodiona/sangue , Sulfato de Desidroepiandrosterona/sangue , Feminino , Humanos , Hiperandrogenismo/sangue , Pessoa de Meia-Idade , Doenças Ovarianas/sangue , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/complicações , Pós-Menopausa/sangue , Valor Preditivo dos Testes , Pré-Menopausa/sangue , Valores de Referência , Estudos Retrospectivos , Índice de Gravidade de Doença , Testosterona/sangue
17.
J Clin Endocrinol Metab ; 101(5): 2069-75, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26990942

RESUMO

CONTEXT: Polycystic ovary syndrome (PCOS) is a heritable, complex genetic disease. Animal models suggest that androgen exposure at critical developmental stages contributes to disease pathogenesis. We hypothesized that genetic variation resulting in increased androgen production produces the phenotypic features of PCOS by programming during critical developmental periods. Although we have not found evidence for increased in utero androgen levels in cord blood in the daughters of women with PCOS (PCOS-d), target tissue androgen production may be amplified by increased 5α-reductase activity analogous to findings in adult affected women. It is possible to noninvasively test this hypothesis by examining urinary steroid metabolites. OBJECTIVE: We performed this study to investigate whether PCOS-d have altered androgen metabolism during early childhood. DESIGN, SETTING, AND PARTICIPANTS: Twenty-one PCOS-d, 1-3 years old, and 36 control girls of comparable age were studied at an academic medical center. MAIN OUTCOME MEASURES: Urinary steroid metabolites were measured by gas chromatography/mass spectrometry. Twenty-four hour steroid excretion rates and precursor to product ratios suggestive of 5α-reductase and 11ß-hydroxysteroid dehydrogenase activities were calculated. RESULTS: Age did not differ but weight for length Z-scores were higher in PCOS-d compared to control girls (P = .02). PCOS-d had increased 5α-tetrahydrocortisol:tetrahydrocortisol ratios (P = .04), suggesting increased global 5α-reductase activity. There was no evidence for differences in 11ß-hydroxysteroid dehydrogenase activity. Steroid metabolite excretion was not correlated with weight. CONCLUSIONS: Our findings suggest that differences in androgen metabolism are present in early childhood in PCOS-d. Increased 5α-reductase activity could contribute to the development of PCOS by amplifying target tissue androgen action.


Assuntos
Filho de Pais com Deficiência , Colestenona 5 alfa-Redutase/metabolismo , Núcleo Familiar , Síndrome do Ovário Policístico , Adulto , Pré-Escolar , Feminino , Humanos , Lactente , Tetra-Hidrocortisol/urina , Adulto Jovem
18.
J Clin Endocrinol Metab ; 101(6): 2545-53, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27003302

RESUMO

CONTEXT: Steroid sulfatase (STS) cleaves the sulfate moiety off steroid sulfates, including dehydroepiandrosterone (DHEA) sulfate (DHEAS), the inactive sulfate ester of the adrenal androgen precursor DHEA. Deficient DHEA sulfation, the opposite enzymatic reaction to that catalyzed by STS, results in androgen excess by increased conversion of DHEA to active androgens. STS deficiency (STSD) due to deletions or inactivating mutations in the X-linked STS gene manifests with ichthyosis, but androgen synthesis and metabolism in STSD have not been studied in detail yet. PATIENTS AND METHODS: We carried out a cross-sectional study in 30 males with STSD (age 6-27 y; 13 prepubertal, 5 peripubertal, and 12 postpubertal) and 38 age-, sex-, and Tanner stage-matched healthy controls. Serum and 24-hour urine steroid metabolome analysis was performed by mass spectrometry and genetic analysis of the STS gene by multiplex ligation-dependent probe amplification and Sanger sequencing. RESULTS: Genetic analysis showed STS mutations in all patients, comprising 27 complete gene deletions, 1 intragenic deletion and 2 missense mutations. STSD patients had apparently normal pubertal development. Serum and 24-hour urinary DHEAS were increased in STSD, whereas serum DHEA and testosterone were decreased. However, total 24-hour urinary androgen excretion was similar to controls, with evidence of increased 5α-reductase activity in STSD. Prepubertal healthy controls showed a marked increase in the serum DHEA to DHEAS ratio that was absent in postpubertal controls and in STSD patients of any pubertal stage. CONCLUSIONS: In STSD patients, an increased 5α-reductase activity appears to compensate for a reduced rate of androgen generation by enhancing peripheral androgen activation in affected patients. In healthy controls, we discovered a prepubertal surge in the serum DHEA to DHEAS ratio that was absent in STSD, indicative of physiologically up-regulated STS activity before puberty. This may represent a fine tuning mechanism for tissue-specific androgen activation preparing for the major changes in androgen production during puberty.


Assuntos
Sulfato de Desidroepiandrosterona/metabolismo , Desidroepiandrosterona/metabolismo , Ictiose Ligada ao Cromossomo X/metabolismo , Puberdade/metabolismo , Esteril-Sulfatase/genética , Testosterona/metabolismo , Adolescente , Adulto , Criança , Colestenona 5 alfa-Redutase/genética , Colestenona 5 alfa-Redutase/metabolismo , Estudos Transversais , Desidroepiandrosterona/sangue , Desidroepiandrosterona/urina , Sulfato de Desidroepiandrosterona/sangue , Sulfato de Desidroepiandrosterona/urina , Humanos , Ictiose Ligada ao Cromossomo X/genética , Masculino , Metaboloma , Metabolômica , Reação em Cadeia da Polimerase Multiplex , Mutação , Testosterona/sangue , Testosterona/urina , Adulto Jovem
19.
Endocr Rev ; 36(5): 526-63, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26213785

RESUMO

Steroid sulfation and desulfation are fundamental pathways vital for a functional vertebrate endocrine system. After biosynthesis, hydrophobic steroids are sulfated to expedite circulatory transit. Target cells express transmembrane organic anion-transporting polypeptides that facilitate cellular uptake of sulfated steroids. Once intracellular, sulfatases hydrolyze these steroid sulfate esters to their unconjugated, and usually active, forms. Because most steroids can be sulfated, including cholesterol, pregnenolone, dehydroepiandrosterone, and estrone, understanding the function, tissue distribution, and regulation of sulfation and desulfation processes provides significant insights into normal endocrine function. Not surprisingly, dysregulation of these pathways is associated with numerous pathologies, including steroid-dependent cancers, polycystic ovary syndrome, and X-linked ichthyosis. Here we provide a comprehensive examination of our current knowledge of endocrine-related sulfation and desulfation pathways. We describe the interplay between sulfatases and sulfotransferases, showing how their expression and regulation influences steroid action. Furthermore, we address the role that organic anion-transporting polypeptides play in regulating intracellular steroid concentrations and how their expression patterns influence many pathologies, especially cancer. Finally, the recent advances in pharmacologically targeting steroidogenic pathways will be examined.


Assuntos
Esteroides/metabolismo , Esteril-Sulfatase/metabolismo , Sulfotransferases/metabolismo , Animais , Transporte Biológico Ativo , Humanos , Terapia de Alvo Molecular , Complexos Multienzimáticos/metabolismo , Mutação , Neoplasias/metabolismo , Sulfato Adenililtransferase/metabolismo
20.
PLoS One ; 10(4): e0124582, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25867024

RESUMO

Triple A syndrome is caused by mutations in AAAS encoding the protein ALADIN. We investigated the role of ALADIN in the human adrenocortical cell line NCI-H295R1 by either over-expression or down-regulation of ALADIN. Our findings indicate that AAAS knock-down induces a down-regulation of genes coding for type II microsomal cytochrome P450 hydroxylases CYP17A1 and CYP21A2 and their electron donor enzyme cytochrome P450 oxidoreductase, thereby decreasing biosynthesis of precursor metabolites required for glucocorticoid and androgen production. Furthermore we demonstrate that ALADIN deficiency leads to increased susceptibility to oxidative stress and alteration in redox homeostasis after paraquat treatment. Finally, we show significantly impaired nuclear import of DNA ligase 1, aprataxin and ferritin heavy chain 1 in ALADIN knock-down cells. We conclude that down-regulating ALADIN results in decreased oxidative stress response leading to alteration in steroidogenesis, highlighting our knock-down cell model as an important in-vitro tool for studying the adrenal phenotype in triple A syndrome.


Assuntos
Córtex Suprarrenal/metabolismo , Androgênios/biossíntese , Glucocorticoides/biossíntese , Proteínas do Tecido Nervoso/fisiologia , Complexo de Proteínas Formadoras de Poros Nucleares/fisiologia , Estresse Oxidativo/fisiologia , Córtex Suprarrenal/citologia , Linhagem Celular , Núcleo Celular/enzimologia , Núcleo Celular/metabolismo , Inativação Gênica , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Homeostase , Humanos , Peróxido de Hidrogênio/metabolismo
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