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2.
Clin Med (Lond) ; 20(4): 371-378, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32675141

RESUMO

Adrenal insufficiency (AI) is an often-unrecognised endocrine disorder, which can lead to adrenal crisis and death if not identified and treated. Omission of steroids in patients with AI, particularly during physiological stress such as an intercurrent illness or surgery, can also lead to an adrenal crisis. The National Reporting and Learning System (NRLS) identified 78 incidents including two deaths and six incidents of severe harm to patients in a recent 4-year period. This guidance will go through causes of adrenal insufficiency, groups at risk of an adrenal crisis, emergency management and management for surgical procedures. A new NHS Steroid Emergency Card has been developed to be carried by patients at risk of adrenal crisis. We hope the new emergency card and this guidance will increase awareness of the need to start steroids promptly in patients at risk of an adrenal crisis, particularly those presenting in the emergency department or to acute medicine teams and those undergoing surgery or invasive procedures.

3.
J Steroid Biochem Mol Biol ; 202: 105724, 2020 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-32629108

RESUMO

Testosterone and its 5α-reduced form, 5α-dihydrotestosterone, were previously thought to represent the only active androgens in humans. However, recent studies have shown that the potent androgen, 11-ketotestosterone, derived from the adrenal androgen precursor, 11ß-hydroxyandrostenedione, may in fact serve as the primary androgen in healthy women. Yet, despite recent renewed interest in these steroids, their downstream metabolism has remained undetermined. We therefore set out to investigate the metabolism of 11-ketotestosterone by characterising the 5α- or 5ß-reduction commitment step. We show that inactivation of 11-ketotestosterone is predominantly driven by AKR1D1, which efficiently catalyses the 5ß-reduction of 11-ketotestosterone, committing it to a metabolic pathway that terminates in 11-ketoetiocholanolone. We demonstrate that 5α-reduction of 11-ketotestosterone is catalysed by SRD5A2, but not SRD5A1, and terminates in 11-ketoandrosterone, but is only responsible for a minority of 11-ketotestosterone inactivation. However, as 11-ketoetiocholanolone is also generated by the metabolism of the glucocorticoid cortisone, 11-ketoandrosterone should be considered a more specific urinary marker of 11-ketotestosterone production.

5.
Eur J Endocrinol ; 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32567556

RESUMO

PURPOSE: We sought to refine the clinical picture of primary adrenal lymphoma (PAL), a rare lymphoid malignancy with predominant adrenal manifestation and risk of adrenal insufficiency. METHODS: 97 patients from 14 centers in Europe, Canada and the United States were included in this retrospective analysis between 1994 and 2017. RESULTS: Of 81 patients with imaging data, 19 (23%) had isolated adrenal involvement (iPAL), while 62 (77%) had additional extra-adrenal involvement (PAL+). Among patients who had both CT and PET scans, 18FDG-PET revealed extra-adrenal involvement not detected by CT scan in 9/18 cases (50%). The most common clinical manifestations were B symptoms (55%), fatigue (45%), and abdominal pain (35%). Endocrinological assessment was often inadequate. With a median follow-up of 41.6 months, 3-year progression-free (PFS) and overall (OS) survival rates in the entire cohort were 35.5% and 39.4%, respectively. The hazard ratios of iPAL for PFS and OS were 40.1 (95% CI: 2.63-613.7, p=0.008) and 2.69 (95% CI: 0.61-11.89, p=0.191), respectively. PFS was much shorter in iPAL versus PAL+ (median 4 months vs. not reached, p=0.006), and OS also appeared to be shorter (median 16 months vs. not reached), but the difference did not reach statistical significance (p=0.16). Isolated PAL was more frequent in females (OR=3.81; P=0.01) and less frequently associated with B symptoms (OR= 0.159; p=0.004). CONCLUSION: We found unexpected heterogeneity in the clinical spectrum of PAL. Further studies are needed to clarify whether clinical distinction between iPAL and PAL+ is corroborated by differences in molecular biology.

6.
Eur J Endocrinol ; 183(1): G25-G32, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32379699

RESUMO

We provide guidance on prevention of adrenal crisis during the global COVID-19 crisis, a time with frequently restricted access to the usual level of healthcare. Patients with adrenal insufficiency are at an increased risk of infection, which may be complicated by developing an adrenal crisis; however, there is currently no evidence that adrenal insufficiency patients are more likely to develop a severe course of disease. We highlight the need for education (sick day rules, stringent social distancing rules), equipment (sufficient glucocorticoid supplies, steroid emergency self-injection kit) and empowerment (steroid emergency card, COVID-19 guidelines) to prevent adrenal crises. In patients with adrenal insufficiency developing an acute COVID-19 infection, which frequently presents with continuous high fever, we suggest oral stress dose cover with 20 mg hydrocortisone every 6 h. We also comment on suggested dosing for patients who usually take modified release hydrocortisone or prednisolone. In patients with adrenal insufficiency showing clinical deterioration during an acute COVID-19 infection, we advise immediate (self-)injection of 100 mg hydrocortisone intramuscularly, followed by continuous i.v. infusion of 200 mg hydrocortisone per 24 h, or until this can be established, and administration of 50 mg hydrocortisone every 6 h. We also advise on doses for infants and children.


Assuntos
Insuficiência Adrenal/tratamento farmacológico , Betacoronavirus , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Doença Aguda , Insuficiência Adrenal/virologia , Adulto , Criança , Pré-Escolar , Infecções por Coronavirus/virologia , Gerenciamento Clínico , Endocrinologia/métodos , Feminino , Glucocorticoides/administração & dosagem , Humanos , Hidrocortisona/administração & dosagem , Lactente , Masculino , Pandemias , Pneumonia Viral/virologia , Prednisolona/administração & dosagem , Esteroides/administração & dosagem
7.
Artigo em Inglês | MEDLINE | ID: mdl-32395877

RESUMO

OBJECTIVE AND CONTEXT: Maturity onset diabetes of the young due to variants in HNF1A (HNF1A-MODY) is the most common form of monogenic diabetes. Individuals with HNF1A-MODY usually have a lean phenotype which contrasts with type 2 diabetes (T2DM). Data from hepatocytes derived from Hnf1a knock-out mice demonstrated dysregulation of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), which regulates glucocorticoid availability and action in target tissues, together with 11ß-HSD2 and steroid A-ring reductases, 5α- and 5ß-reductase. We proposed that altered glucocorticoid metabolism might underpin some of the phenotypic differences between patients with HNF1A-MODY and those with T2DM. DESIGN: A retrospective matched cohort study. PATIENTS AND MEASUREMENTS: 24-hours urine steroid metabolome profiling was carried out by gas chromatography-mass spectrometry in 35 subjects with HNF1A-MODY, 35 individuals with T2DM and 35 healthy controls matched for age, sex and BMI. The steroid metabolites were expressed as µg/L in all groups and measured in mid-morning urine in diabetic subjects and 24-hour urine collection in healthy controls. Hence, only ratios were compared not the individual steroids. Established ratios of glucocorticoid metabolites were used to estimate 11ß-HSD1/2 and 5α- and 5ß-reductase activities. RESULTS: While 11ß-HSD1 activity was similar in all groups, 11ß-HSD2 activity was significantly lower in subjects with HNF1A-MODY and T2DM than in healthy controls. The ratio of 5ß- to 5α-metabolites of cortisol was higher in subjects with HNF1A-MODY than in T2DM and healthy controls, probably due to increased activity of the 5ß-reductase (AKR1D1) in HNF1A-MODY. CONCLUSIONS: This is the first report of steroid metabolites in HNF1A-MODY. We have identified distinct differences in steroid metabolism pathways in subjects with HNF1A-MODY that have the potential to alter steroid hormone availability. Further studies are required to explore whether these changes link to phenotype.

8.
Aliment Pharmacol Ther ; 51(11): 1188-1197, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32298002

RESUMO

BACKGROUND: The development of accurate, non-invasive markers to diagnose and stage non-alcoholic fatty liver disease (NAFLD) is critical to reduce the need for an invasive liver biopsy and to identify patients who are at the highest risk of hepatic and cardio-metabolic complications. Disruption of steroid hormone metabolic pathways has been described in patients with NAFLD. AIM(S): To assess the hypothesis that assessment of the urinary steroid metabolome may provide a novel, non-invasive biomarker strategy to stage NAFLD. METHODS: We analysed the urinary steroid metabolome in 275 subjects (121 with biopsy-proven NAFLD, 48 with alcohol-related cirrhosis and 106 controls), using gas chromatography-mass spectrometry (GC-MS) coupled with machine learning-based Generalised Matrix Learning Vector Quantisation (GMLVQ) analysis. RESULTS: Generalised Matrix Learning Vector Quantisation analysis achieved excellent separation of early (F0-F2) from advanced (F3-F4) fibrosis (AUC receiver operating characteristics [ROC]: 0.92 [0.91-0.94]). Furthermore, there was near perfect separation of controls from patients with advanced fibrotic NAFLD (AUC ROC = 0.99 [0.98-0.99]) and from those with NAFLD cirrhosis (AUC ROC = 1.0 [1.0-1.0]). This approach was also able to distinguish patients with NAFLD cirrhosis from those with alcohol-related cirrhosis (AUC ROC = 0.83 [0.81-0.85]). CONCLUSIONS: Unbiased GMLVQ analysis of the urinary steroid metabolome offers excellent potential as a non-invasive biomarker approach to stage NAFLD fibrosis as well as to screen for NAFLD. A highly sensitive and specific urinary biomarker is likely to have clinical utility both in secondary care and in the broader general population within primary care and could significantly decrease the need for liver biopsy.

9.
J Clin Endocrinol Metab ; 105(7)2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32300791

RESUMO

CONTEXT: The natural history of adrenal function in autoimmune Addison disease once diagnosed and treated has not been systematically studied, but several case reports of recovery from established adrenal failure suggest it may not be uniform. OBJECTIVE: To ascertain steroidogenic function in autoimmune Addison disease immediately following diagnosis and during prolonged treatment. DESIGN: We studied peak serum cortisol in response to ACTH1-24 in 20 newly diagnosed autoimmune Addison disease patients at first presentation and then again within a month. We also studied 37 patients with established Addison disease (for between 7 months and 44 years) in a medication-free state, measuring peak serum cortisol responses to ACTH1-24 and the urine LC-MS steroid metabolome. RESULTS: Adrenal steroidogenesis declined rapidly after steroid replacement treatment for newly diagnosed Addison disease was started, with a peak serum cortisol falling from 138 ±â€…19 nmol/L (SEM) at presentation to 63 ±â€…13 nmol/L over 4 weeks (P < 0.003).Six of 37 participants (16%) with established Addison disease had detectable serum cortisol and urine glucocorticoid and mineralocorticoid metabolites during repeat testing, indicating variable degrees of residual adrenal function. CONCLUSION: Autoimmune Addison disease is a heterogeneous condition, showing a rapid decline in adrenal steroidogenesis during the first few weeks following diagnosis, but low-level residual function in a minority of patients, which appears to persist for many years.

11.
J Clin Endocrinol Metab ; 105(7)2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32170323

RESUMO

CONTEXT: Patients with adrenal insufficiency require increased hydrocortisone cover during major stress to avoid a life-threatening adrenal crisis. However, current treatment recommendations are not evidence-based. OBJECTIVE: To identify the most appropriate mode of hydrocortisone delivery in patients with adrenal insufficiency who are exposed to major stress. DESIGN AND PARTICIPANTS: Cross-sectional study: 122 unstressed healthy subjects and 288 subjects exposed to different stressors (major trauma [N = 83], sepsis [N = 100], and combat stress [N = 105]). Longitudinal study: 22 patients with preserved adrenal function undergoing elective surgery. Pharmacokinetic study: 10 patients with primary adrenal insufficiency undergoing administration of 200 mg hydrocortisone over 24 hours in 4 different delivery modes (continuous intravenous infusion; 6-hourly oral, intramuscular or intravenous bolus administration). MAIN OUTCOME MEASURE: We measured total serum cortisol and cortisone, free serum cortisol, and urinary glucocorticoid metabolite excretion by mass spectrometry. Linear pharmacokinetic modeling was used to determine the most appropriate mode and dose of hydrocortisone administration in patients with adrenal insufficiency exposed to major stress. RESULTS: Serum cortisol was increased in all stress conditions, with the highest values observed in surgery and sepsis. Continuous intravenous hydrocortisone was the only administration mode persistently achieving median cortisol concentrations in the range observed during major stress. Linear pharmacokinetic modeling identified continuous intravenous infusion of 200 mg hydrocortisone over 24 hours, preceded by an initial bolus of 50-100 mg hydrocortisone, as best suited for maintaining cortisol concentrations in the required range. CONCLUSIONS: Continuous intravenous hydrocortisone infusion should be favored over intermittent bolus administration in the prevention and treatment of adrenal crisis during major stress.

12.
J Clin Endocrinol Metab ; 105(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32101296

RESUMO

CONTEXT: Survival rates after severe injury are improving, but complication rates and outcomes are variable. OBJECTIVE: This cohort study addressed the lack of longitudinal data on the steroid response to major trauma and during recovery. DESIGN: We undertook a prospective, observational cohort study from time of injury to 6 months postinjury at a major UK trauma centre and a military rehabilitation unit, studying patients within 24 hours of major trauma (estimated New Injury Severity Score (NISS) > 15). MAIN OUTCOME MEASURES: We measured adrenal and gonadal steroids in serum and 24-hour urine by mass spectrometry, assessed muscle loss by ultrasound and nitrogen excretion, and recorded clinical outcomes (ventilator days, length of hospital stay, opioid use, incidence of organ dysfunction, and sepsis); results were analyzed by generalized mixed-effect linear models. FINDINGS: We screened 996 multiple injured adults, approached 106, and recruited 95 eligible patients; 87 survived. We analyzed all male survivors <50 years not treated with steroids (N = 60; median age 27 [interquartile range 24-31] years; median NISS 34 [29-44]). Urinary nitrogen excretion and muscle loss peaked after 1 and 6 weeks, respectively. Serum testosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate decreased immediately after trauma and took 2, 4, and more than 6 months, respectively, to recover; opioid treatment delayed dehydroepiandrosterone recovery in a dose-dependent fashion. Androgens and precursors correlated with SOFA score and probability of sepsis. CONCLUSION: The catabolic response to severe injury was accompanied by acute and sustained androgen suppression. Whether androgen supplementation improves health outcomes after major trauma requires further investigation.

13.
J Endocrinol ; 245(2): 207-218, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32106090

RESUMO

Steroid 5ß-reductase (AKR1D1) is highly expressed in human liver where it inactivates endogenous glucocorticoids and catalyses an important step in bile acid synthesis. Endogenous and synthetic glucocorticoids are potent regulators of metabolic phenotype and play a crucial role in hepatic glucose metabolism. However, the potential of synthetic glucocorticoids to be metabolised by AKR1D1 as well as to regulate its expression and activity has not been investigated. The impact of glucocorticoids on AKR1D1 activity was assessed in human liver HepG2 and Huh7 cells; AKR1D1 expression was assessed by qPCR and Western blotting. Genetic manipulation of AKR1D1 expression was conducted in HepG2 and Huh7 cells and metabolic assessments were made using qPCR. Urinary steroid metabolite profiling in healthy volunteers was performed pre- and post-dexamethasone treatment, using gas chromatography-mass spectrometry. AKR1D1 metabolised endogenous cortisol, but cleared prednisolone and dexamethasone less efficiently. In vitro and in vivo, dexamethasone decreased AKR1D1 expression and activity, further limiting glucocorticoid clearance and augmenting action. Dexamethasone enhanced gluconeogenic and glycogen synthesis gene expression in liver cell models and these changes were mirrored by genetic knockdown of AKR1D1 expression. The effects of AKR1D1 knockdown were mediated through multiple nuclear hormone receptors, including the glucocorticoid, pregnane X and farnesoid X receptors. Glucocorticoids down-regulate AKR1D1 expression and activity and thereby reduce glucocorticoid clearance. In addition, AKR1D1 down-regulation alters the activation of multiple nuclear hormone receptors to drive changes in gluconeogenic and glycogen synthesis gene expression profiles, which may exacerbate the adverse impact of exogenous glucocorticoids.

14.
J Clin Endocrinol Metab ; 105(2)2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31532828

RESUMO

CONTEXT: Mortality and infection-related hospital admissions are increased in patients with primary adrenal insufficiency (PAI). However, the risk of primary care-managed infections in patients with PAI is unknown. OBJECTIVE: To estimate infection risk in PAI due to Addison's disease (AD) and congenital adrenal hyperplasia (CAH) in a primary care setting. DESIGN: Retrospective cohort study using UK data collected from 1995 to 2018. MAIN OUTCOME MEASURES: Incidence of lower respiratory tract infections (LRTIs), urinary tract infections (UTIs), gastrointestinal infections (GIIs), and prescription counts of antimicrobials in adult PAI patients compared to unexposed controls. RESULTS: A diagnosis of PAI was established in 1580 AD patients (mean age 51.7 years) and 602 CAH patients (mean age 35.4 years). All AD patients and 42% of CAH patients were prescribed glucocorticoids, most frequently hydrocortisone in AD (82%) and prednisolone in CAH (50%). AD and CAH patients exposed to glucocorticoids, but not CAH patients without glucocorticoid treatment, had a significantly increased risk of LRTIs (adjusted incidence rate ratio AD 2.11 [95% confidence interval (CI) 1.64-2.69], CAH 3.23 [95% CI 1.21-8.61]), UTIs (AD 1.51 [95% CI 1.29-1.77], CAH 2.20 [95% CI 1.43-3.34]), and GIIs (AD 3.80 [95% CI 2.99-4.84], CAH 1.93 [95% CI 1.06-3.52]). This was mirrored by increased prescription of antibiotics (AD 1.73 [95% CI 1.69-1.77], CAH 1.77 [95% CI 1.66-1.89]) and antifungals (AD 1.89 [95% CI 1.74-2.05], CAH 1.91 [95% CI 1.50-2.43]). CONCLUSIONS: There is an increased risk of infections and antimicrobial use in PAI in the primary care setting at least partially linked to glucocorticoid treatment. Future studies will need to address whether more physiological glucocorticoid replacement modes could reduce this risk.

15.
J Clin Endocrinol Metab ; 105(3)2020 Mar 01.
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 postoperative recurrence detection after microscopically complete (R0) resection of ACC. PATIENTS AND METHODS: 135 patients from 14 clinical centers provided postoperative 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 3 blinded experts detected recurrence by the time of radiological diagnosis in 50% to 72% of cases, improving to 69% to 92%, if a preoperative urine steroid result was available. Recurrence detection by steroid profiling preceded detection by imaging by more than 2 months in 22% to 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 postoperative recurrence detection in ACC; availability of a preoperative urine considerably improves the ability to detect ACC recurrence.

16.
J Clin Endocrinol Metab ; 105(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31613957

RESUMO

CONTEXT: No consensus exists for optimization of mineralocorticoid therapy in patients with primary adrenal insufficiency. OBJECTIVE: To explore the relationship between mineralocorticoid (MC) replacement dose, plasma renin concentration (PRC), and clinically important variables to determine which are most helpful in guiding MC dose titration in primary adrenal insufficiency. DESIGN: Observational, retrospective, longitudinal analysis. PATIENTS: A total of 280 patients (with 984 clinical visits and plasma renin measurements) with primary adrenal insufficiency were recruited from local databases and the international congenital adrenal hyperplasia (CAH) registry (www.i-cah.org). Thirty-seven patients were excluded from the final analysis due to incomplete assessment. Data from 204 patients with salt-wasting CAH (149 adults and 55 children) and 39 adult patients with Addison disease (AD) were analysed. MAIN OUTCOME MEASURES: PRC, electrolytes, blood pressure (BP), and anthropometric parameters were used to predict their utility in optimizing MC replacement dose. RESULTS: PRC was low, normal, or high in 19%, 36%, and 44% of patients, respectively, with wide variability in MC dose and PRC. Univariate analysis demonstrated a direct positive relationship between MC dose and PRC in adults and children. There was no relationship between MC dose and BP in adults, while BP increased with increasing MC dose in children. Using multiple regression modeling, sodium was the only measurement that predicted PRC in adults. Longitudinally, the change in MC dose was able to predict potassium, but not BP or PRC. CONCLUSIONS: The relationship between MC dose and PRC is complex and this may reflect variability in sampling with respect to posture, timing of last MC dose, adherence, and concomitant medications. Our data suggest that MC titration should not primarily be based only on PRC normalization, but also on clinical parameters such as BP and electrolyte concentration.

17.
J Clin Endocrinol Metab ; 105(4)2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31863094

RESUMO

CONTEXT: In autoimmune Addison's disease (AAD), exogenous glucocorticoid (GC) therapy is an imperfect substitute for physiological GC secretion. Patients on long-term steroid replacement have increased morbidity, reduced life expectancy, and poorer quality of life. OBJECTIVE: The objective of this article is to restore adrenocortical steroidogenic function in recent-onset AAD. DESIGN: An open-label, multicenter trial of immunotherapy and trophic stimulation in new-onset AAD was conducted. Serial measurement of serum and urine corticosteroids at baseline and throughout a 72-week follow-up period was performed. SETTING: This study was conducted at the.endocrine departments and clinical research facilities at 5 UK tertiary centers. PATIENTS: Thirteen participants (9 female, 4 male; age 19-64 years) were included with AAD confirmed by high adrenocorticotropin, low circulating cortisol (basal < 100 nmol/L or post-tetracosactide < 300 nmol/L), and positive serum 21-hydroxylase antibodies. INTERVENTION: All participants received dual therapy with B-lymphocyte-depleting immunotherapy (rituximab 1 g given twice) and repeated depot tetracosactide (1 mg on alternate days for 12 weeks). MAIN OUTCOME MEASURE: Restoration of normal GC secretion (stimulated cortisol > 550 nmol/L) at week 48 was the main outcome measure. RESULTS: Ten of 13 (77%) participants had detectable stimulated serum cortisol (26-265 nmol/L) at trial entry. Following intervention, 7 of 13 (54%) had an increase in stimulated cortisol measurement, with a peak response of 325 nmol/L at week 18 in 1 participant. Increased steroid metabolites, assayed by urine gas chromatography-mass spectrometry at week 12 and week 48, was detected in 8 of 13 (62%) individuals, reflecting an increase in endogenous steroidogenesis. Four of 13 had residual adrenal function at 72 weeks. CONCLUSION: Combined treatment with rituximab and depot tetracosactide did not restore normal adrenal function. Nevertheless, adrenocortical plasticity is demonstrated in some patients, and this has the potential to be exploited to improve adrenal function.

18.
Proc Natl Acad Sci U S A ; 116(44): 22294-22299, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31611378

RESUMO

Androgen biosynthesis in the human fetus proceeds through the adrenal sex steroid precursor dehydroepiandrosterone, which is converted to testosterone in the gonads, followed by further activation to 5α-dihydrotestosterone in genital skin, thereby facilitating male external genital differentiation. Congenital adrenal hyperplasia due to P450 oxidoreductase deficiency results in disrupted dehydroepiandrosterone biosynthesis, explaining undervirilization in affected boys. However, many affected girls are born virilized, despite low circulating androgens. We hypothesized that this is due to a prenatally active, alternative androgen biosynthesis pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone, which bypasses dehydroepiandrosterone and testosterone, with increased activity in congenital adrenal hyperplasia variants associated with 17α-hydroxyprogesterone accumulation. Here we employ explant cultures of human fetal organs (adrenals, gonads, genital skin) from the major period of sexual differentiation and show that alternative pathway androgen biosynthesis is active in the fetus, as assessed by liquid chromatography-tandem mass spectrometry. We found androgen receptor expression in male and female genital skin using immunohistochemistry and demonstrated that both 5α-dihydrotestosterone and adrenal explant culture supernatant induce nuclear translocation of the androgen receptor in female genital skin primary cultures. Analyzing urinary steroid excretion by gas chromatography-mass spectrometry, we show that neonates with P450 oxidoreductase deficiency produce androgens through the alternative androgen pathway during the first weeks of life. We provide quantitative in vitro evidence that the corresponding P450 oxidoreductase mutations predominantly support alternative pathway androgen biosynthesis. These results indicate a key role of alternative pathway androgen biosynthesis in the prenatal virilization of girls affected by congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.


Assuntos
17-alfa-Hidroxiprogesterona/metabolismo , Androgênios/biossíntese , Fenótipo de Síndrome de Antley-Bixler/genética , Feto/metabolismo , Receptores Androgênicos/genética , Virilismo/metabolismo , Glândulas Suprarrenais/embriologia , Glândulas Suprarrenais/metabolismo , Androgênios/genética , Células Cultivadas , Feminino , Feto/embriologia , Genitália/embriologia , Genitália/metabolismo , Gônadas/embriologia , Gônadas/metabolismo , Humanos , Masculino , Receptores Androgênicos/metabolismo , Diferenciação Sexual , Virilismo/genética
19.
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.


Assuntos
Tecido Adiposo/metabolismo , Membro C3 da Família 1 de alfa-Ceto Redutase/metabolismo , Androgênios/metabolismo , Síndrome do Ovário Policístico/metabolismo , Tecido Adiposo/enzimologia , Feminino , Humanos , Síndrome do Ovário Policístico/enzimologia
20.
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
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