Service evaluation suggests variation in clinical care provision in adults with congenital adrenal hyperplasia in the UK and Ireland.

BACKGROUND: Congenital adrenal hyperplasia (CAH) encompasses a rare group of autosomal recessive disorders, characterised by enzymatic defects in steroidogenesis. Heterogeneity in management practices has been observed internationally. The International Congenital Adrenal Hyperplasia registry (I-CAH, https://sdmregistries.org/) was established to enable insights into CAH management and outcomes, yet its global adoption by endocrine centres remains unclear. DESIGN: We sought (1) to assess current practices amongst clinicians managing patients with CAH in the United Kingdom and Ireland, with a focus on choice of glucocorticoid, monitoring practices and screening for associated co-morbidities, and (2) to assess use of the I-CAH registry. MEASUREMENTS: We designed and distributed an anonymised online survey disseminated to members of the Society for Endocrinology and Irish Endocrine Society to capture management practices in the care of patients with CAH. RESULTS: Marked variability was found in CAH management, with differences between general endocrinology and subspecialist settings, particularly in glucocorticoid use, biochemical monitoring and comorbidity screening, with significant disparities in reproductive health monitoring, notably in testicular adrenal rest tumours (TARTs) screening (p = .002), sperm banking (p = .0004) and partner testing for CAH (p < .0001). Adoption of the I-CAH registry was universally low. CONCLUSIONS: Differences in current management of CAH continue to exist. It appears crucial to objectify if different approaches result in different long-term outcomes. New studies such as CaHASE2, incorporating standardised minimum datasets including replacement therapies and monitoring strategies as well as longitudinal data collection, are now needed to define best-practice and standardise care.

Standardising the biochemical confirmation of adult male hypogonadism: A joint position statement by the Society for Endocrinology and Association of Clinical Biochemistry and Laboratory Medicine.

BACKGROUND: Inter-assay variation between different immunoassays and different mass spectrometry methods hampers the biochemical confirmation of male hypogonadism. Furthermore, some laboratories utilise assay manufacturer reference ranges that do not necessarily mirror assay performance characteristics, with the lower limit of normality ranging from 4.9 nmol/L to 11 nmol/L. The quality of the normative data underlying commercial immunoassay reference ranges is uncertain. DESIGN: A working group reviewed published evidence and agreed upon standardised reporting guidance to augment total testosterone reports. RESULTS: Evidence-based guidance on appropriate blood sampling, clinical action limits, and other major factors likely to affect the interpretation of results are provided. CONCLUSIONS: This article aims to improve the quality of the interpretation of testosterone results by non-specialist clinicians. It also discusses approaches for assay harmonisation which have been successful in some but not all healthcare systems.

Adrenal insufficiency is common amongst kidney transplant recipients receiving maintenance prednisolone and can be predicted using morning cortisol.

BACKGROUND: Long-term glucocorticoid therapy is a key component of immunosuppression for kidney transplant recipients (KTRs), leading to significant cumulative glucocorticoid exposure. The aims of this study are to investigate the prevalence of adrenal insufficiency (AI) in KTRs taking prednisolone and to develop a screening algorithm to identify patients at the highest risk of AI. METHODS: In this cross-sectional cohort study, 67 KTRs receiving prednisolone underwent a short synacthen test (SST) and measurement of cumulative glucocorticoid exposure. RESULTS: A total of 72% (n = 48) of participants failed the SST. Participants with AI had a higher daily prednisolone dose (4.9 versus 4.2 mg/day; P = .002) and greater cumulative glucocorticoid exposure (289 versus 111 mg/kg; P = .03) than those with intact adrenal function. Participants with AI had lower baseline cortisol than participants with intact adrenal function (143 versus 303 nmol/L; P < .001). Morning cortisol of >288 nmol/L predicted a normal SST with 100% specificity [95% confidence interval (CI) 92-100] and 70% sensitivity (95% CI 56-78%), therefore excluding AI. CONCLUSIONS: Our results suggest KTRs are at a higher risk for AI than previously reported. A morning serum cortisol measurement is a useful screening tool in this cohort, reducing the need for stimulatory testing by 44%. KTRs with AI need education regarding glucocorticoid sick rules, similar to patients with other forms of AI.

Emotional and psychosexual well-being is influenced by ethnicity and birthplace in women and individuals with polycystic ovary syndrome in the UK and India.

OBJECTIVE: To assess the association of ethnicity and birthplace on emotional and psychosexual well-being in women with polycystic ovary syndrome (PCOS). DESIGN: Cross-sectional study. SETTING: Community recruitment via social media campaigns. POPULATION: Women with PCOS completing an online questionnaire in September-October 2020 (UK) and May-June 2021 (India). METHODS: The survey has five components, with a baseline information and sociodemographic section followed by four validated questionnaires: Hospital Anxiety and Depression Scale (HADS); Body Image Concern Inventory (BICI); Beliefs About Obese Persons Scale (BAOP); and Female Sexual Function Index (FSFI). MAIN OUTCOME MEASURES: We used adjusted linear and logistic regression models, adjusting for age, education, marital status and parity, to evaluate the impact of ethnicity and birthplace on questionnaire scores and outcomes (anxiety and/or depression, HADS ≥ 11; body dysmorphic disorder (BDD), BICI ≥ 72). RESULTS: A total of 1008 women with PCOS were included. Women of non-white ethnicity (613/1008) reported higher rates of depression (OR 1.96, 95% CI 1.41-2.73) and lower BDD (OR 0.57, 95% CI 0.41-0.79) than white women (395/1008). Women born in India (453/1008) had higher anxiety (OR 1.57, 95% CI 1.00-2.46) and depression (OR 2.20, 95% CI 1.52-3.18) but lower BDD rates (OR 0.42, 95% CI 0.29-0.61) than women born in the UK (437/1008). All sexual domains, excluding desire, scored lower for non-white women and women born in India. CONCLUSIONS: Non-white women and women born in India reported higher emotional and sexual dysfunction, whereas white women and women born in the UK reported higher body image concerns and weight stigma. Ethnicity and birthplace need to be considered for tailored, multidisciplinary care.

Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study.

BACKGROUND: Benign adrenal tumors are commonly discovered on cross-sectional imaging. Mild autonomous cortisol secretion (MACS) is regularly diagnosed, but its effect on cardiometabolic disease in affected persons is ill defined. OBJECTIVE: To determine cardiometabolic disease burden and steroid excretion in persons with benign adrenal tumors with and without MACS. DESIGN: Cross-sectional study. SETTING: 14 endocrine secondary and tertiary care centers (recruitment from 2011 to 2016). PARTICIPANTS: 1305 prospectively recruited persons with benign adrenal tumors. MEASUREMENTS: Cortisol excess was defined by clinical assessment and the 1-mg overnight dexamethasone-suppression test (serum cortisol: <50 nmol/L, nonfunctioning adrenal tumor [NFAT]; 50 to 138 nmol/L, possible MACS [MACS-1]; >138 nmol/L and absence of typical clinical Cushing syndrome [CS] features, definitive MACS [MACS-2]). Net steroid production was assessed by multisteroid profiling of 24-hour urine by tandem mass spectrometry. RESULTS: Of the 1305 participants, 49.7% had NFAT (n = 649; 64.1% women), 34.6% had MACS-1 (n = 451; 67.2% women), 10.7% had MACS-2 (n = 140; 73.6% women), and 5.0% had CS (n = 65; 86.2% women). Prevalence and severity of hypertension were higher in MACS-2 and CS than NFAT (adjusted prevalence ratios [aPRs] for hypertension: MACS-2, 1.15 [95% CI, 1.04 to 1.27], and CS, 1.37 [CI, 1.16 to 1.62]; aPRs for use of ≥3 antihypertensives: MACS-2, 1.31 [CI, 1.02 to 1.68], and CS, 2.22 [CI, 1.62 to 3.05]). Type 2 diabetes was more prevalent in CS than NFAT (aPR, 1.62 [CI, 1.08 to 2.42]) and more likely to require insulin therapy for MACS-2 (aPR, 1.89 [CI, 1.01 to 3.52]) and CS (aPR, 3.06 [CI, 1.60 to 5.85]). Urinary multisteroid profiling revealed an increase in glucocorticoid excretion from NFAT over MACS-1 and MACS-2 to CS, whereas androgen excretion decreased. LIMITATIONS: Cross-sectional design; possible selection bias. CONCLUSION: A cardiometabolic risk condition, MACS predominantly affects women and warrants regular assessment for hypertension and type 2 diabetes. PRIMARY FUNDING SOURCE: Diabetes UK, the European Commission, U.K. Medical Research Council, the U.K. Academy of Medical Sciences, the Wellcome Trust, the U.K. National Institute for Health Research, the U.S. National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.

Polycystic ovary syndrome and risk of adverse obstetric outcomes: a retrospective population-based matched cohort study in England.

BACKGROUND: Polycystic ovary syndrome (PCOS) affects up to one in five women of childbearing age. Observational studies assessing the association between maternal PCOS and adverse obstetric outcomes have reported varying results, depending on patient population, diagnostic criteria for PCOS and covariates accounted for in their analyses. We aimed to assess the risk of obstetric outcomes among a population-based representative cohort of women with PCOS compared to an age-matched cohort of women without PCOS. METHODS: A retrospective cohort study was conducted of pregnancies of women in England aged 15-49 years identified from the Clinical Practice Research Datalink (CPRD) GOLD pregnancy register and linked Hospital Episodes Statistic (HES) data between March 1997 and March 2020. Pregnancies from the register that had a linked HES delivery record were included. Linked CPRD primary care data was used to ascertain maternal PCOS exposure prior to pregnancy. To improve detection of PCOS, in addition to PCOS diagnostic codes, codes for (1) polycystic ovaries or (2) hyperandrogenism and anovulation together were also considered. Sensitivity analysis was limited to only pregnant women with a diagnostic code for PCOS. Primary outcomes ascertained from linked HES data were (1) preterm delivery (gestation < 37 weeks), (2) mode of delivery, (3) high (> 4000 g) or low birthweight (< 2500 g) and (4) stillbirth. Secondary outcomes were (1) very preterm delivery (< 32 weeks), (2) extremely preterm delivery (< 28 weeks), (3) small and (4) large for gestational age. Conditional logistic regression models were performed adjusting for age, ethnicity, deprivation, dysglycaemia, hypertension, thyroid disorders, number of babies born at index pregnancy, and pre-gravid BMI. Multiple imputation was performed for missing outcome data. RESULTS: 27,586 deliveries with maternal PCOS were matched for age (± 1 year) to 110,344 deliveries without PCOS. In the fully adjusted models, maternal PCOS was associated with an increased risk of (1) preterm birth [aOR: 1.11 (95% CI 1.06-1.17)], and (2) emergency caesarean, elective caesarean and instrumental vaginal compared to spontaneous delivery [aOR: 1.10 (1.05-1.15), 1.07 (1.03-1.12) and 1.04 (1.00-1.09), respectively]. There was absence of association with low birthweight, high birthweight and stillbirth. In the sensitivity analysis, the association with preterm birth [aOR: 1.31 (95% CI 1.13-1.52)], emergency caesarean [aOR: 1.15 (95% CI 1.02-1.30)], and elective caesarean [aOR: 1.03 (95% CI 1.02-1.03)] remained. While there was no significant association with any of the secondary outcomes in the primary analysis, in the sensitivity analysis maternal PCOS was associated with increased risk of extremely preterm delivery [aOR: 1.86 (95% CI 1.31-2.65)], and lower risk of small for gestational age babies [aOR: 0.74 (95% CI 0.59-0.94)]. CONCLUSIONS: Maternal PCOS was associated with increased risk of preterm and caesarean delivery. Association with low birthweight may be largely mediated by lower gestational age at birth.

Approach to androgen excess in women: Clinical and biochemical insights.

Androgen excess in women typically presents clinically with hirsutism, acne or androgenic alopecia. In the vast majority of cases, the underlying aetiology is polycystic ovary syndrome (PCOS), a common chronic condition that affects up to 10% of all women. Identification of women with non-PCOS pathology within large cohorts of patients presenting with androgen excess represents a diagnostic challenge for the endocrinologist, and rare pathology including nonclassic congenital adrenal hyperplasia, severe insulin resistance syndromes, Cushing's disease or androgen-secreting tumours of the ovary or adrenal gland may be missed in the absence of a pragmatic screening approach. Detailed clinical history, physical examination and biochemical phenotyping are critical in risk-stratifying women who are at the highest risk of non-PCOS disorders. Red flag features such as rapid onset symptoms, overt virilization, postmenopausal onset or severe biochemical disturbances should prompt investigations for underlying neoplastic pathology, including dynamic testing and imaging where appropriate. This review will outline a proposed diagnostic approach to androgen excess in women, including an introduction to androgen metabolism and provision of a suggested algorithmic strategy to identify non-PCOS pathology according to clinical and biochemical phenotype.

Outcomes of endoscopic transsphenoidal surgery for Cushing's disease.

BACKGROUND: Transsphenoidal surgery (TSS) to resect an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma is the first-line treatment for Cushing's disease (CD), with increasing usage of endoscopic transsphenoidal (ETSS) technique. The aim of this study was to assess remission rates and postoperative complications following ETSS for CD. METHODS: A retrospective analysis of a prospective single-surgeon database of consecutive patients with CD who underwent ETSS between January 2012-February 2020. Post-operative remission was defined, according to Endocrine Society Guidelines, as a morning serum cortisol < 138 nmol/L within 7 days of surgery, with improvement in clinical features of hypercortisolism. A strict cut-off of < 50 nmol/L at day 3 post-op was also applied, to allow early identification of remission. RESULTS: A single surgeon (MJ) performed 43 ETSS in 39 patients. Pre-operative MRI localised an adenoma in 22 (56%) patients; 18 microadenoma and 4 macroadenoma (2 with cavernous sinus invasion). IPSS was carried out in 33 (85%) patients. The remission rates for initial surgery were 87% using standard criteria, 58% using the strict criteria (day 3 cortisol < 50 nmol/L). Three patients had an early repeat ETSS for persistent disease (day 3 cortisol 306-555 nmol/L). When the outcome of repeat early ETSS was included, the remission rate was 92% (36/39) overall. Remission rate was 94% (33/35) when patients with macroadenomas were excluded. There were no cases of CSF leakage, meningitis, vascular injury or visual deterioration. Transient and permanent diabetes insipidus occurred in 33 and 23% following first ETSS, respectively. There was one case of recurrence of CD during the follow-up period of 24 (4-79) months. CONCLUSION: Endoscopic transsphenoidal surgery produces satisfactory remission rates for the primary treatment of CD, with higher remission rates for microadenomas. A longer follow-up period is required to assess recurrence rates. Patients should be counselled regarding risk of postoperative diabetes insipidus.

Natural History of Adrenal Incidentalomas With and Without Mild Autonomous Cortisol Excess: A Systematic Review and Meta-analysis.

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.

Serum testosterone, sex hormone-binding globulin and sex-specific risk of incident type 2 diabetes in a retrospective primary care cohort.

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.

Polycystic ovary syndrome, androgen excess, and the risk of nonalcoholic fatty liver disease in women: A longitudinal study based on a United Kingdom primary care database.

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.

Evaluating the Fat Distribution in Idiopathic Intracranial Hypertension Using Dual-Energy X-ray Absorptiometry Scanning.

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.

What Do Transgender Patients Teach Us About Idiopathic Intracranial Hypertension?

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.

ACTH and gonadotropin deficiencies predict mortality in patients treated for nonfunctioning pituitary adenoma: long-term follow-up of 519 patients in two large European centres.

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.

Advanced non-alcoholic fatty liver disease and adipose tissue fibrosis in patients with Alström syndrome.

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.

Fertility and pregnancy in adrenal insufficiency.

Despite the availability of adrenal hormone replacement therapy, patients with adrenal insufficiency can be affected by reduced fertility and parity. Patients with well-managed adrenal insufficiency are expected to have uneventful pregnancies and favourable outcomes, but an increased risk of maternal and neonatal complications has been reported in some cases. Many physiological changes occur to the hypothalamic-pituitary-adrenal (HPA) axis during pregnancy, often making a new diagnosis and management of adrenal insufficiency challenging. The management of adrenal insufficiency also needs to reflect the physiologic changes of pregnancy, often requiring increased doses of glucocorticoid as pregnancy progresses and in some circumstances mineralocorticoid replacement (in primary adrenal insufficiency patients only), especially in the third trimester. To date, there are no prospective data guiding management of adrenal insufficiency in pregnancy. In this review, we focus on the impact of adrenal insufficiency on fertility and parity based on the aetiology of adrenal insufficiency and provide a practical approach to the management of patients with adrenal insufficiency before and during pregnancy.

Iatrogenic adrenal insufficiency in adults.

Iatrogenic adrenal insufficiency (IAI) is the most common form of adrenal insufficiency in adult patients, although its overall exact prevalence remains unclear. IAI is associated with adverse clinical outcomes, including adrenal crisis, impaired quality of life and increased mortality; therefore, it is imperative that clinicians maintain a high index of suspicion in patients at risk of IAI to facilitate timely diagnosis and appropriate management. Herein, we review the major causes, clinical consequences, diagnosis and care of patients with IAI. The management of IAI, particularly glucocorticoid-induced (or tertiary) adrenal insufficiency, can be particularly challenging, and the provision of adequate glucocorticoid replacement must be balanced against minimizing the cardiometabolic effects of excess glucocorticoid exposure and optimizing recovery of the hypothalamic-pituitary-adrenal axis. We review current treatment strategies and their limitations and discuss developments in optimizing treatment of IAI. This comprehensive Review aims to aid clinicians in identifying who is at risk of IAI, how to approach screening of at-risk populations and how to treat patients with IAI, with a focus on emergency management and prevention of an adrenal crisis.

A comparative quality assessment of evidence-based clinical guidelines in endocrinology.

CONTEXT: Evidence-based clinical guidelines in endocrinology attempt to improve and standardize patient care. There has been an expansion in guideline production although some of the heterogeneous methods used to assess the quality of the underlying evidence base might limit interpretation and implementation. DESIGN: Current and archived guidelines from major endocrine organizations were accessed. The organizations used six different methods to rate underlying evidence, including Grading of Recommendations Assessment, Development and Evaluation (GRADE). To allow direct comparison between guidelines produced by different organizations, the levels of evidence used to generate them were graded according to the standardized system: 'high' based on randomized, controlled trials and meta-analyses, 'moderate' based on nonrandomized studies and 'low' based on expert opinion. RESULTS: There was an increase in guideline production over time (1995-2000 = 9, 2001-2005 = 12, 2006-2011 = 36). Three guidelines were updated with an average delay of 4·3 years and an increase in recommendations per guideline (21·1%). Encouragingly, whilst updates had similar levels of 'high'-quality evidence, there was increased reliance on 'moderate'-category evidence and less on 'low''-quality evidence' ('high', 6·3% vs 6·5%; 'moderate', 46·1% vs 59·1%; 'low', 47·7% vs 34·4%). A high proportion of 'low'-category evidence was seen throughout all organizations. Rarer conditions and recommendations concerning treatment efficacy were particularly reliant on 'low'-category evidence. CONCLUSIONS: The level of evidence underpinning current guidelines highlights areas in need of well-designed, collaborative clinical research. Furthermore, criteria to define when guideline updates are necessary are currently lacking. A standardized method of assessment, such as GRADE, would promote understanding and compliance by guideline users with the ultimate aim of enhancing patient care.

The clinical and biochemical significance of 11-oxygenated androgens in human health and disease.

For many decades, the prevailing paradigm in endocrinology was that testosterone and 5α-dihydrotestosterone are the only potent androgens in the context of human physiology. The more recent identification of adrenal derived 11-oxygenated androgens and particularly 11-ketotestosterone have challenged these established norms, prompting a revaluation of the androgen pool, particularly in women. Since being recognized as bone fide androgens in humans, numerous studies have focused their attention on understanding the role of 11-oxygenated androgens in human health and disease and have implicated them as role players in conditions such as castration resistant prostate cancer, congenital adrenal hyperplasia, polycystic ovary syndrome, Cushing's syndrome, and premature adrenarche. This review therefore provides an overview of our current knowledge on the biosynthesis and activity of 11-oxygenated androgens with a focus on their role in disease states. We also highlight important analytical considerations for measuring this unique class of steroid hormone.

Clinical Utility of GnRH Analogues in Female Androgen Excess: Highlighting Diagnostic and Therapeutic Applications.

Female androgen excess typically presents with hirsutism, acne, and frontotemporal alopecia. Although the majority of cases are due to underlying polycystic ovary syndrome, non-polycystic ovary syndrome pathology can present a diagnostic and therapeutic challenge. We present 3 cases highlighting the utility of GnRH analogues in diagnosis and treatment of ovarian hyperandrogenism. In case 1, we highlight the role of GnRH analogue testing to localize severe postmenopausal androgen excess, allowing full resolution of symptoms following resection of a benign ovarian steroid-cell tumor. Our second case demonstrates the dual utility of GnRH analogues as both a diagnostic and therapeutic agent for hyperandrogenism in a premenopausal woman with severe insulin resistance. We observed suppression of serum testosterone coupled with significant improvement in hirsutism scores. The final case describes GnRH analogue suppression as a therapeutic option for a postmenopausal woman with ovarian hyperthecosis wishing to avoid surgical intervention, with successful symptom resolution. This case series delineates the applications of GnRH analogue suppression in a variety of clinical contexts, in particular their potential role in controlling symptoms in cases of refractory androgen excess and an alternative to surgery in cases of benign ovarian hyperandrogenism.