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1.
Artigo em Inglês | MEDLINE | ID: mdl-31665449

RESUMO

CONTEXT: Urine steroid metabolomics, combining mass spectrometry-based steroid profiling and machine learning, has been described as a novel diagnostic tool for detection of adrenocortical carcinoma (ACC). OBJECTIVE, DESIGN, SETTING: This proof-of-concept study evaluated the performance of urine steroid metabolomics as a tool for post-operative recurrence detection after microscopically complete (R0) resection of ACC. PATIENTS AND METHODS: 135 patients from 14 clinical centers provided post-operative urine samples, which were analyzed by gas chromatography-mass spectrometry. We assessed the utility of these urine steroid profiles in detecting ACC recurrence, either when interpreted by expert clinicians, or when analyzed by Random Forest, a machine learning-based classifier. Radiological recurrence detection served as the reference standard. RESULTS: Imaging detected recurrent disease in 42 of 135 patients; 32 had provided pre- and post-recurrence urine samples. 39 patients remained disease-free for ≥3 years. The urine "steroid fingerprint" at recurrence resembled that observed before R0 resection in the majority of cases. Review of longitudinally collected urine steroid profiles by three blinded experts detected recurrence by the time of radiological diagnosis in 50-72% of cases, improving to 69-92%, if a pre-operative urine steroid result was available. Recurrence detection by steroid profiling preceded detection by imaging by more than 2 months in 22-39% of patients. Specificities varied considerably, ranging from 61 to 97%. The computational classifier detected ACC recurrence with superior accuracy (sensitivity=specificity=81%). CONCLUSION: Urine steroid metabolomics is a promising tool for post-operative recurrence detection in ACC; availability of a pre-operative urine considerably improves the ability to detect ACC recurrence.

2.
Front Horm Res ; 53: 33-49, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31499495

RESUMO

Adipose tissue is an important target of androgen action in humans. Androgens exert important effects on adipose tissue biology, including fat mass expansion and distribution, insulin signalling and lipid metabolism. In conditions of female androgen excess such as polycystic ovary syndrome (PCOS), androgens exert metabolically deleterious effects on adipose tissue function in a depot-specific manner. Androgen excess in women is metabolically deleterious, and adverse metabolic effects may be mediated by effects on preadipocyte differentiation and adipocyte hypertrophy. Circulating androgen burden correlates with adiposity in women, and drives visceral fat mass accumulation. Adipose tissue is also an important organ of pre-receptor androgen metabolism, and is host to a complex network of androgen activating and inactivating enzymes. Adipose androgen generation is increased in subcutaneous (SC) adipose tissue in women with PCOS, and intra-adipose concentrations of potent androgens may exceed those measured in peripheral circulation. Increased expression of the key androgen-activating enzyme aldo-ketoreductase type 1C3 in PCOS SC adipose tissue leads to high concentrations of testosterone and dihydrotestosterone. Enhanced local androgen generation may further contribute to the adverse metabolic profile of women with PCOS by exerting lipotoxic effects on local adipose biology.

3.
Ann Intern Med ; 171(2): 107-116, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31234202

RESUMO

Background: Adrenal incidentalomas are mostly benign nonfunctioning adrenal tumors (NFATs) or adenomas causing mild autonomous cortisol excess (MACE), but their natural history is unclear. Purpose: To summarize the follow-up data of adults with NFAT or MACE to determine the proportions of tumor growth, malignant transformation, and incident changes in hormone function; the prevalence of incident cardiometabolic comorbid conditions; and mortality. Data Sources: MEDLINE, Embase, Cochrane, and Scopus (January 1990 to February 2019) and bibliographies of identified articles, without language restriction. Study Selection: Studies that included 20 or more conservatively managed patients with NFAT or MACE and reported outcomes at baseline and after at least 12 months of follow-up. Data Extraction: Pairs of reviewers extracted outcomes and assessed methodological quality. Data Synthesis: Thirty-two studies reported outcomes of 4121 patients with NFAT or MACE, 61.5% of whom were women; the mean age was 60.2 years, and mean follow-up was 50.2 months. Mean tumor growth was 2 mm over 52.8 months. Clinically significant tumor enlargement (≥10 mm) occurred in 2.5% of patients, and none developed adrenal cancer. Clinically overt hormone excess was unlikely to develop (<0.1%) in patients with NFAT or MACE. Only 4.3% of patients with NFAT developed MACE, and preexisting MACE was unlikely to resolve (<0.1%). Hypertension, obesity, dyslipidemia, and type 2 diabetes were highly prevalent (60.0%, 42.0%, 33.7%, and 18.1% of patients, respectively) and were more likely to develop and worsen in MACE than NFAT. New cardiovascular events were more prevalent in MACE (15.5%) than NFAT (6.4%). Mortality was 11.2% and was similar between NFAT and MACE. Limitation: Evidence was scarce, and definitions of MACE and comorbid conditions were heterogeneous. Conclusion: During follow-up, NFAT and MACE do not show clinically relevant changes in size or hormonal function, but they may carry an increased risk for cardiometabolic comorbid conditions. Primary Funding Source: None.

4.
Eur J Endocrinol ; 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30763274

RESUMO

OBJECTIVE: Obesity is very common in patients with obstructive sleep apnoea (OSA) and polycystic ovary syndrome (PCOS). Longitudinal studies assessing OSA risk in PCOS and examining the role of obesity are lacking. Our objective was to assess the risk of OSA in women with vs. without PCOS and to examine the role of obesity in the observed findings. DESIGN: Population-based retrospective cohort study utilizing The Health Improvement Network (THIN), UK. METHODS: 76,978 women with PCOS and 143,077 age-, BMI- and location-matched women without PCOS between January 2000 and May 2017 were identified. Hazard Ratio (HR) for OSA among women with and without PCOS were calculated after controlling for confounding variables using multivariate Cox models. RESULTS: Median patient age was 30 (IQR: 25 - 35) years; median follow-up was 3.5 (IQR: 1.4 - 7.1) years. We found 298 OSA cases in PCOS women vs. 222 in controls, with incidence rates for OSA of 8.1 and 3.3 per 10,000 person years, respectively. Women with PCOS were at increased risk of developing OSA (Adjusted HR=2.26, 95% CI: 1.89 - 2.69, p<0.001), with similar HRs for normal weight, overweight and obese PCOS women. CONCLUSIONS: Women with PCOS are at increased risk of developing OSA compared to control women irrespective of obesity. Considering the significant metabolic morbidity associated with OSA, clinicians should have a low threshold to test for OSA in women with PCOS. Whether OSA treatment has an impact on PCOS symptoms and outcomes needs to be examined.

5.
JCI Insight ; 4(6)2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30753168

RESUMO

Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology, characterized by elevated intracranial pressure frequently manifesting with chronic headaches and visual loss. Similar to polycystic ovary syndrome (PCOS), IIH predominantly affects obese women of reproductive age. In this study, we comprehensively examined the systemic and cerebrospinal fluid (CSF) androgen metabolome in women with IIH in comparison with sex-, BMI-, and age-matched control groups with either simple obesity or PCOS (i.e., obesity and androgen excess). Women with IIH showed a pattern of androgen excess distinct to that observed in PCOS and simple obesity, with increased serum testosterone and increased CSF testosterone and androstenedione. Human choroid plexus expressed the androgen receptor, alongside the androgen-activating enzyme aldoketoreductase type 1C3. We show that in a rat choroid plexus cell line, testosterone significantly enhanced the activity of Na+/K+-ATPase, a surrogate of CSF secretion. We demonstrate that IIH patients have a unique signature of androgen excess and provide evidence that androgens can modulate CSF secretion via the choroid plexus. These findings implicate androgen excess as a potential causal driver and therapeutic target in IIH.

6.
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
7.
Artigo em Inglês | MEDLINE | ID: mdl-30256433

RESUMO

OBJECTIVE: Previous studies suggest that androgens have a sexually dimorphic impact on metabolic dysfunction. However, the sex-specific link between circulating androgens and risk of type 2 diabetes mellitus (T2DM) has not been examined in a large scale, longitudinal cohort, a task we undertook in this study. DESIGN: A retrospective cohort study in a UK primary care database. PATIENTS: We included men and women with available serum testosterone and sex hormone-binding globulin (SHBG) results. MEASUREMENTS: We categorized serum concentrations according to clinically relevant cut-off points and calculated crude and adjusted T2DM Incidence Rate Ratios (IRRs and aIRRs). RESULTS: Serum testosterone concentrations were available in 70 541 men and 81 889 women; serum SHBG was available in 15 907 men and 42 034 women. In comparison to a reference cohort with serum testosterone ≥20 nmol/L, men with lower serum testosterone had a significantly increased risk of T2DM, with the highest risk in those with serum testosterone <7 nmol/L (aIRR 2.71, 95% CI 2.34-3.14, P < 0.001). In women, the risk of T2DM started to increase significantly when serum testosterone concentrations exceeded 1.5 nmol/L, with the highest risk in women with serum testosterone ≥3.5 nmol/L (aIRR 1.98, 95% CI 1.55-2.52, P < 0.001). These observations were verified in a continuous rather than categorized analysis. The risk of T2DM increased in men and women with serum SHBG <40 and <50 nmol/L, respectively. CONCLUSIONS/INTERPRETATION: In this longitudinal study, we found sexually dimorphic associations between serum testosterone and risk of incident T2DM. Androgen deficiency and excess should be considered important risk factors for diabetes in men and women, respectively.

8.
Neuroophthalmology ; 42(2): 99-104, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29563954

RESUMO

Idiopathic intracranial hypertension (IIH) is strongly associated with obesity. We aimed to utilise dual-energy X-ray absorptiometry (DEXA) to characterise fat distribution, and to evaluate change in fat mass and distribution following weight loss. IIH patients (n = 24) had a similar fat distribution to body mass index (BMI)- and gender-matched obese controls (n = 47). In the IIH cohort, truncal fat mass correlated with lumbar puncture pressure. Weight loss in IIH patients resulted in a significant reduction in disease activity and fat mass, predominantly from the truncal region (-4.40 ± 1.6%; p = 0.008) compared with the limbs (+0.79 ± 6.5%; p = 0.71). These results indicate that, contrary to previous studies using waist-hip ratios, IIH adiposity is centripetal, similar to simple obesity. Future studies should establish the risk of the metabolic syndrome and the role of adipose tissue depot-specific function in IIH.

9.
PLoS Med ; 15(3): e1002542, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29590099

RESUMO

BACKGROUND: Androgen excess is a defining feature of polycystic ovary syndrome (PCOS), which affects 10% of women and represents a lifelong metabolic disorder, with increased risk of type 2 diabetes, hypertension, and cardiovascular events. Previous studies have suggested an increased risk of nonalcoholic fatty liver disease (NAFLD) in individuals with PCOS and implicated androgen excess as a potential driver. METHODS AND FINDINGS: We carried out a retrospective longitudinal cohort study utilizing a large primary care database in the United Kingdom, evaluating NAFLD rates in 63,120 women with PCOS and 121,064 age-, body mass index (BMI)-, and location-matched control women registered from January 2000 to May 2016. In 2 independent cohorts, we also determined the rate of NAFLD in women with a measurement of serum testosterone (n = 71,061) and sex hormone-binding globulin (SHBG; n = 49,625). We used multivariate Cox models to estimate the hazard ratio (HR) for NAFLD and found that women with PCOS had an increased rate of NAFLD (HR = 2.23, 95% CI 1.86-2.66, p < 0.001), also after adjusting for BMI or dysglycemia. Serum testosterone >3.0 nmol/L was associated with an increase in NAFLD (HR = 2.30, 95% CI 1.16-4.53, p = 0.017 for 3-3.49 nmol/L and HR = 2.40, 95% CI 1.24-4.66, p = 0.009 for >3.5 nmol/L). Mirroring this finding, SHBG <30 nmol/L was associated with increased NAFLD hazard (HR = 4.75, 95% CI 2.44-9.25, p < 0.001 for 20-29.99 nmol/L and HR = 4.98, 95% CI 2.45-10.11, p < 0.001 for <20 nmol/L). Limitations of this study include its retrospective nature, absence of detailed information on criteria used to diagnosis PCOS and NAFLD, and absence of data on laboratory assays used to measure serum androgens. CONCLUSIONS: We found that women with PCOS have an increased rate of NAFLD. In addition to increased BMI and dysglycemia, androgen excess contributes to the development of NAFLD in women with PCOS. In women with PCOS-related androgen excess, systematic NAFLD screening should be considered.

10.
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
11.
Neuroophthalmology ; 41(6): 326-329, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29238388

RESUMO

Idiopathic intracranial hypertension (IIH), a condition of raised intracranial pressure, is characterised by headaches and visual disturbances. Its pathogenesis is currently unknown; however, dysregulation of androgens may be implicated. Here, the authors present a case of a 22-year-old patient undergoing female-to-male (FTM) gender reassignment who developed IIH shortly after commencing testosterone therapy. This interesting case presents the possibility of androgens having a pathogenic role in IIH.

12.
J Clin Endocrinol Metab ; 102(9): 3327-3339, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28645211

RESUMO

Context: Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder occurring in up to 10% of women of reproductive age. PCOS is associated with insulin resistance and cardiovascular risk. Androgen excess is a defining feature of PCOS and has been suggested as causally associated with insulin resistance; however, mechanistic evidence linking both is lacking. We hypothesized that adipose tissue is an important site linking androgen activation and metabolic dysfunction in PCOS. Methods: We performed a human deep metabolic in vivo phenotyping study examining the systemic and intra-adipose effects of acute and chronic androgen exposure in 10 PCOS women, in comparison with 10 body mass index-matched healthy controls, complemented by in vitro experiments. Results: PCOS women had increased intra-adipose concentrations of testosterone (P = 0.0006) and dihydrotestosterone (P = 0.01), with increased expression of the androgen-activating enzyme aldo-ketoreductase type 1 C3 (AKR1C3) (P = 0.04) in subcutaneous adipose tissue. Adipose glycerol levels in subcutaneous adipose tissue microdialysate supported in vivo suppression of lipolysis after acute androgen exposure in PCOS (P = 0.04). Mirroring this, nontargeted serum metabolomics revealed prolipogenic effects of androgens in PCOS women only. In vitro studies showed that insulin increased adipose AKR1C3 expression and activity, whereas androgen exposure increased adipocyte de novo lipid synthesis. Pharmacologic AKR1C3 inhibition in vitro decreased de novo lipogenesis. Conclusions: These findings define an intra-adipose mechanism of androgen activation that contributes to adipose remodeling and a systemic lipotoxic metabolome, with intra-adipose androgens driving lipid accumulation and insulin resistance in PCOS. AKR1C3 represents a promising therapeutic target in PCOS.


Assuntos
3-Hidroxiesteroide Desidrogenases/metabolismo , Adipócitos/efeitos dos fármacos , Desidroepiandrosterona/farmacologia , Hidroxiprostaglandina Desidrogenases/metabolismo , Síndrome do Ovário Policístico/metabolismo , Gordura Subcutânea/metabolismo , Adipócitos/metabolismo , Adolescente , Adulto , Membro C3 da Família 1 de alfa-Ceto Redutase , Análise de Variância , Androgênios/metabolismo , Área Sob a Curva , Biomarcadores/sangue , Estudos de Casos e Controles , Células Cultivadas , Feminino , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos , Lipólise , Síndrome do Ovário Policístico/patologia , Reação em Cadeia da Polimerase em Tempo Real/métodos , Valores de Referência , Estatísticas não Paramétricas , Adulto Jovem
13.
Eur J Endocrinol ; 177(3): R125-R143, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28566439

RESUMO

Female androgen excess and male androgen deficiency manifest with an overlapping adverse metabolic phenotype, including abdominal obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease and an increased risk of cardiovascular disease. Here, we review the impact of androgens on metabolic target tissues in an attempt to unravel the complex mechanistic links with metabolic dysfunction; we also evaluate clinical studies examining the associations between metabolic disease and disorders of androgen metabolism in men and women. We conceptualise that an equilibrium between androgen effects on adipose tissue and skeletal muscle underpins the metabolic phenotype observed in female androgen excess and male androgen deficiency. Androgens induce adipose tissue dysfunction, with effects on lipid metabolism, insulin resistance and fat mass expansion, while anabolic effects on skeletal muscle may confer metabolic benefits. We hypothesise that serum androgen concentrations observed in female androgen excess and male hypogonadism are metabolically disadvantageous, promoting adipose and liver lipid accumulation, central fat mass expansion and insulin resistance.


Assuntos
Androgênios/metabolismo , Doenças Metabólicas/metabolismo , Caracteres Sexuais , Composição Corporal/fisiologia , Feminino , Humanos , Metabolismo dos Lipídeos/fisiologia , Masculino , Doenças Metabólicas/diagnóstico , Obesidade/diagnóstico , Obesidade/metabolismo
14.
Artigo em Inglês | MEDLINE | ID: mdl-28458888

RESUMO

SUMMARY: We describe three patients presenting with diabetic ketoacidosis secondary to ketosis prone type 2, rather than type 1 diabetes. All patients were treated according to a standard DKA protocol, but were subsequently able to come off insulin therapy while maintaining good glycaemic control. Ketosis-prone type 2 diabetes (KPD) presenting with DKA has not been described previously in Irish patients. The absence of islet autoimmunity and evidence of endogenous beta cell function after resolution of DKA are well-established markers of KPD, but are not readily available in the acute setting. Although not emphasised in any current guidelines, we have found that a strong family history of type 2 diabetes and the presence of cutaneous markers of insulin resistance are strongly suggestive of KPD. These could be emphasised in future clinical practice guidelines. LEARNING POINTS: Even in white patients, DKA is not synonymous with type 1 diabetes and autoimmune beta cell failure. KPD needs to be considered in all patients presenting with DKA, even though it will not influence their initial treatment.Aside from markers of endogenous beta cell function and islet autoimmunity, which in any case are unlikely to be immediately available to clinicians, consideration of family history of type 2 diabetes and cutaneous markers of insulin resistance might help to identify those with KPD and are more readily apparent in the acute setting, though not emphasised in guidelines.Consideration of KPD should never alter the management of the acute severe metabolic derangement of DKA, and phasing out of insulin therapy requires frequent attendance and meticulous and cautious surveillance by a team of experienced diabetes care providers.

15.
J Clin Endocrinol Metab ; 102(4): 1091-1101, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28323916

RESUMO

Context: Glucocorticoids have pleiotropic metabolic functions, and acute glucocorticoid excess affects fatty acid metabolism, increasing systemic lipolysis. Whether glucocorticoids exert adipose tissue depot-specific effects remains unclear. Objective: To provide an in vivo assessment of femoral and abdominal adipose tissue responses to acute glucocorticoid administration. Design and Outcome Measures: Nine healthy male volunteers were studied on two occasions, after a hydrocortisone infusion (0.2 mg/kg/min for 14 hours) and a saline infusion, respectively, given in randomized double-blind order. The subjects were studied in the fasting state and after a 75-g glucose drink with an in vivo assessment of femoral adipose tissue blood flow (ATBF) using radioactive xenon washout and of lipolysis and glucose uptake using the arteriovenous difference technique. In a separate study (same infusion design), eight additional healthy male subjects underwent assessment of fasting abdominal ATBF and lipolysis only. Lipolysis was assessed as the net release of nonesterified fatty acids (NEFAs) from femoral and abdominal subcutaneous adipose tissue. Results: Acute hypercortisolemia significantly increased basal and postprandial ATBF in femoral adipose tissue, but the femoral net NEFA release did not change. In abdominal adipose tissue, hypercortisolemia induced substantial increases in basal ATBF and NEFA release. Conclusions: Acute hypercortisolemia induces differential lipolysis and ATBF responses in abdominal and femoral adipose tissue, suggesting depot-specific glucocorticoid effects. Abdominal, but not femoral, adipose tissue contributes to the hypercortisolemia-induced systemic NEFA increase, with likely contributions from other adipose tissue sources and intravascular triglyceride hydrolysis.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Síndrome de Cushing/induzido quimicamente , Hidrocortisona/administração & dosagem , Lipólise/efeitos dos fármacos , Gordura Subcutânea Abdominal/efeitos dos fármacos , Abdome , Absorciometria de Fóton , Tecido Adiposo/metabolismo , Adulto , Síndrome de Cushing/metabolismo , Método Duplo-Cego , Fêmur , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Gordura Subcutânea Abdominal/metabolismo , Coxa da Perna , Adulto Jovem
16.
J Clin Endocrinol Metab ; 102(6): 1889-1897, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28323946

RESUMO

Context: Despite the major risk of regrowth of clinically nonfunctioning pituitary adenomas (CNFAs) after primary treatment, systematic data on the probability of further tumor progression and the effectiveness of management approaches are lacking. Objective: To assess the probability of further regrowth(s), predictive factors, and outcomes of management approaches in patients with CNFA diagnosed with adenoma regrowth after primary treatment. Patients, Design, and Setting: Retrospective cohort study of 237 patients with regrown CNFA managed in two UK centers. Results: Median follow-up was 5.9 years (range, 0.4 to 37.7 years). The 5-year second regrowth rate was 35.3% (36.2% after surgery; 12.5% after radiotherapy; 12.7% after surgery combined with radiotherapy; 63.4% with monitoring). Of those managed with monitoring, 34.8% eventually were offered intervention. Type of management and sex were risk factors for second regrowth. Among those with second adenoma regrowth, the 5-year third regrowth rate was 26.4% (24.4% after surgery; 0% after radiotherapy; 0% after surgery combined with radiotherapy; 48.3% with monitoring). Overall, patients with a CNFA regrowth had a 4.4% probability of a third regrowth at 5 years and a 10.0% probability at 10 years; type of management of the first regrowth was the only risk factor. Malignant transformation was diagnosed in two patients. Conclusions: Patients with regrown CNFA after primary treatment continue to carry considerable risk of tumor progression, necessitating long-term follow-up. Management approach to the regrowth was the major factor determining this risk; monitoring had >60% risk of progression at 5 years, and a substantial number of patients ultimately required intervention.


Assuntos
Adenoma/terapia , Recidiva Local de Neoplasia/terapia , Procedimentos Neurocirúrgicos , Neoplasias Hipofisárias/terapia , Radioterapia Adjuvante , Radioterapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Neoplasia Residual , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Reino Unido/epidemiologia , Adulto Jovem
17.
J Clin Endocrinol Metab ; 102(3): 840-848, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-27901631

RESUMO

Context: Androgen excess is a defining feature of polycystic ovary syndrome (PCOS), but the exact origin of hyperandrogenemia remains a matter of debate. Recent studies have highlighted the importance of the 11-oxygenated C19 steroid pathway to androgen metabolism in humans. In this study, we analyzed the contribution of 11-oxygenated androgens to androgen excess in women with PCOS. Methods: One hundred fourteen women with PCOS and 49 healthy control subjects underwent measurement of serum androgens by liquid chromatography-tandem mass spectrometry. Twenty-four-hour urinary androgen excretion was analyzed by gas chromatography-mass spectrometry. Fasting plasma insulin and glucose were measured for homeostatic model assessment of insulin resistance. Baseline demographic data, including body mass index, were recorded. Results: As expected, serum concentrations of the classic androgens testosterone (P < 0.001), androstenedione (P < 0.001), and dehydroepiandrosterone (P < 0.01) were significantly increased in PCOS. Mirroring this, serum 11-oxygenated androgens 11ß-hydroxyandrostenedione, 11-ketoandrostenedione, 11ß-hydroxytestosterone, and 11-ketotestosterone were significantly higher in PCOS than in control subjects, as was the urinary 11-oxygenated androgen metabolite 11ß-hydroxyandrosterone. The proportionate contribution of 11-oxygenated to total serum androgens was significantly higher in patients with PCOS compared with control subjects [53.0% (interquartile range, 48.7 to 60.3) vs 44.0% (interquartile range, 32.9 to 54.9); P < 0.0001]. Obese (n = 51) and nonobese (n = 63) patients with PCOS had significantly increased 11-oxygenated androgens. Serum 11ß-hydroxyandrostenedione and 11-ketoandrostenedione correlated significantly with markers of insulin resistance. Conclusions: We show that 11-oxygenated androgens represent the majority of circulating androgens in women with PCOS, with close correlation to markers of metabolic risk.


Assuntos
Androgênios/metabolismo , Glicemia/metabolismo , Hiperandrogenismo/metabolismo , Insulina/metabolismo , Obesidade/metabolismo , Síndrome do Ovário Policístico/metabolismo , Adulto , Androstenodiona/análogos & derivados , Androstenodiona/metabolismo , Androstenos/metabolismo , Estudos de Casos e Controles , Cromatografia Líquida , Desidroepiandrosterona/metabolismo , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Hidroxitestosteronas/metabolismo , Hiperandrogenismo/complicações , Resistência à Insulina , Obesidade/complicações , Síndrome do Ovário Policístico/complicações , Espectrometria de Massas em Tandem , Testosterona/análogos & derivados , Testosterona/metabolismo , Adulto Jovem
18.
PLoS One ; 11(9): e0163777, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27685706

RESUMO

AIMS: The aim of this study was to assess depot-specific expression and secretion of secreted frizzled-related protein 2 (sFRP2) by adipose tissue and its effect on adipocyte biology. We measured serum sFRP2 concentrations in 106 patients in vivo to explore its relationship to fat mass, glycaemia and insulin resistance. METHODS: Expression of sFRP2 in mouse and human tissues was assessed using polymerase chain reaction and Western blot. Western blot confirmed secretion of sFRP2 by adipose tissue into cell culture medium. Effects of recombinant sFRP2 on lipogenesis and preadipocyte proliferation were measured. Preadipocyte expression of the angiogenic genes vascular endothelial growth factor (VEGF) and nuclear factor of activated T-cells 3 (NFATC3) was measured after recombinant sFRP2 exposure. Complementary clinical studies correlating human serum sFRP2 with age, gender, adiposity and insulin secretion were also performed. RESULTS: sFRP2 messenger RNA (mRNA) was expressed in mouse and human adipose tissue. In humans, sFRP2 mRNA expression was 4.2-fold higher in omental than subcutaneous adipose. Omental adipose tissue secreted 63% more sFRP2 protein than subcutaneous. Treatment with recombinant sFRP2 did not impact on lipogenesis or preadipocyte proliferation but was associated with increased VEGF mRNA expression. In human subjects, circulating insulin levels positively correlated with serum sFRP2, and levels were higher in patients with abnormal glucose tolerance (34.2ng/ml) compared to controls (29.5ng/ml). A positive correlation between sFRP2 and BMI was also observed. CONCLUSIONS: Circulating sFRP2 is associated with adipose tissue mass and has a potential role to drive adipose angiogenesis through enhanced VEGF expression.

19.
Clin Endocrinol (Oxf) ; 85(5): 748-756, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27327840

RESUMO

CONTEXT AND OBJECTIVE: Nonfunctioning pituitary adenomas (NFPAs) are the most common subtype of pituitary tumour. Hypopituitarism is observed in NFPAs due to tumour- or treatment-related factors and may increase mortality risk. Here, we analysed the associations of hypopituitarism, hormone replacement and mortality in a large NFPA cohort derived from two large European centres. DESIGN, SETTING AND PARTICIPANTS: Case note review of all patients treated for NFPA in University Hospitals Birmingham and Beaumont Hospital Dublin between 1999 and 2014 was performed. MAIN OUTCOME MEASURES: Clinical presentation, treatment strategies, pituitary function and vitality status were recorded in each patient. A multivariate Cox regression model was used to examine the association between hypopituitarism, hormone replacement and premature mortality. RESULTS: A total of 519 patients were included in the analysis. Median duration of follow-up was 7·0 years (0·5-43). A total of 81 deaths were recorded (15·6%). On multivariate analysis, adrenocorticotropic hormone (ACTH) and gonadotropin (Gn) deficiencies were associated with an increased relative risk of death (OR 2·26, 95% CI 1·15-4·47, P = 0·01 and OR 2·56, 95% CI 1·10-5·96, P = 0·01, respectively). Increased hydrocortisone (HC) (P-trend = 0·02) and lower levothyroxine (LT4) doses (P-trend = 0·03) were associated with increased risk of death. Mortality increased with the degree of pituitary failure observed (P-trend = 0·04). CONCLUSION: ACTH and gonadotropin-deficient patients have higher mortality rates compared to those with intact hormonal axes. Excessive HC and suboptimal LT4 replacement may also increase risk of death. Complex associations between hormone deficiency and replacement underpin the increased mortality risk in NFPA patients.


Assuntos
Adenoma , Hormônio Adrenocorticotrópico/deficiência , Gonadotropinas/deficiência , Neoplasias Hipofisárias/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Europa (Continente) , Feminino , Seguimentos , Terapia de Reposição Hormonal , Humanos , Hidrocortisona/administração & dosagem , Hipopituitarismo , Masculino , Pessoa de Meia-Idade , Mortalidade , Prognóstico , Tiroxina/administração & dosagem , Adulto Jovem
20.
Liver Int ; 36(11): 1704-1712, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27178444

RESUMO

BACKGROUND AND AIMS: Alström syndrome (AS) is a recessive monogenic syndrome characterized by obesity, extreme insulin resistance and multi-organ fibrosis. Despite phenotypically being high risk of non-alcoholic fatty liver disease (NAFLD), there is a lack of data on the extent of fibrosis in the liver and its close links to adipose in patients with AS. Our aim was to characterize the hepatic and adipose phenotype in patients with AS. METHODS: Observational cohort study with comprehensive assessment of metabolic liver phenotype including liver elastography (Fibroscan® ), serum Enhanced Liver Fibrosis (ELF) Panel and liver histology. In addition, abdominal adipose histology and gene expression was assessed. We recruited 30 patients from the UK national AS clinic. A subset of six patients underwent adipose biopsies which was compared with control tissue from nine healthy participants. RESULTS: Patients were overweight/obese (BMI 29.3 (25.95-34.05) kg/m2 ). A total of 80% (24/30) were diabetic; 74% (20/27) had liver ultrasound scanning suggestive of NAFLD. As judged by the ELF panel, 96% (24/25) were categorized as having fibrosis and 10/21 (48%) had liver elastography consistent with advanced liver fibrosis/cirrhosis. In 7/8 selected cases, there was evidence of advanced NAFLD on liver histology. Adipose tissue histology showed marked fibrosis as well as disordered pro-inflammatory and fibrotic gene expression profiles. CONCLUSIONS: NAFLD and adipose dysfunction are common in patients with AS. The severity of liver disease in our cohort supports the need for screening of liver fibrosis in AS.


Assuntos
Tecido Adiposo/patologia , Síndrome de Alstrom/complicações , Cirrose Hepática/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Adulto , Estudos de Coortes , Feminino , Fibrose , Expressão Gênica , Humanos , Resistência à Insulina , Fígado/patologia , Cirrose Hepática/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações , Reino Unido , Adulto Jovem
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