Punith Kempegowda

11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome

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 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone were significantly higher in PCOS than in control subjects, as was the urinary 11-oxygenated androgen metabolite 11β-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 11β-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.

AKR1C3-mediated adipose androgen generation drives lipotoxicity in women with polycystic ovary syndrome

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.

MECHANISMS IN ENDOCRINOLOGY: The sexually dimorphic role of androgens in human metabolic disease

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.

Regular and frequent feedback of specific clinical criteria delivers a sustained improvement in the management of diabetic ketoacidosis

ABSTRACT Efficient management of diabetic ketoacidosis (DKA) improves outcomes and reduces length of stay. While clinical audit improves the management of DKA, significant and sustained improvement is often difficult to achieve. We aimed to improve the management of DKA in our trust through the implementation of quality improvement methodology. Five specific targets (primary drivers: fluid prescription, fixed rate intravenous insulin infusion, glucose measurement, ketone measurement and specialist referral) were selected following a baseline audit. Interventions (secondary drivers) were developed to improve these targets and included monthly feedback to departments of emergency medicine, acute medicine, and diabetes. Following our intervention, the mean average duration of DKA reduced from 22.0 hours to 10.2 hours. We demonstrate that regular audit cycles with interventions introduced through the plan-do-study-act model is an effective way to improve the management of DKA.

Are they high on steroids? Tailored interventions help improve screening for steroid-induced hyperglycaemia in hospitalised patients

Steroid-induced hyperglycaemia (SIH) is a common adverse effect in patients both with and without diabetes. This project aimed to improve the screening and diagnosis of SIH by improving the knowledge of healthcare professionals who contribute to the management of SIH in hospitalised patients. Monitoring and diagnosis of SIH were measured in areas of high steroid use in our hospital from May 2016 to January 2017. Several interventions were implemented to improve knowledge and screening for SIH including a staff education programme for nurses, healthcare assistants and doctors. The Trust guidelines for SIH management were updated based on feedback from staff. The changes to the guideline included shortening the document from 14 to 4 pages, incorporating a flowchart summarising the management of SIH and publishing the guideline on the Trust intranet. A questionnaire based on the recommendations of the Joint British Diabetes Societies for SIH was used to assess the change in knowledge pre-intervention and post-intervention. Results showed an increase in junior doctors’ knowledge of this topic. Although there was an initial improvement in screening for SIH, this returned to near baseline by the end of the study. This study highlights that screening for SIH can be improved by increasing the knowledge of healthcare staff. However, there is a need for ongoing interventions to sustain this change.

Focused educational intervention improves but may not sustain knowledge regarding falls management

Background The number of falls in hospital ranges from 3.8 to 8.6 falls per 1000 bed days. 1 Around 30% of falls as inpatients are injurious, and 4%–6% can result in serious and life-threatening injury. 2 3 This results in significant health burdens and economic burdens due to increased hospital stays following a fall. Junior doctors are usually the first point of contact for managing patients who fall in hospital. It is therefore important they understand the preventative measures and postfalls management. Aim To assess the retention of knowledge regarding falls management in foundation year 1 (FY1) doctors before and after a short educational intervention. Methods A 3-stage quality improvement project was conducted at a West Midlands teaching hospital to highlight issues regarding falls management. A questionnaire assessing areas of knowledge regarding assessment and management of falls was delivered to 31 F1s. This was followed by a short presentation regarding falls management. The change in knowledge was assessed at 6 and 16 weeks postintervention. The questionnaire results were analysed using unpaired t-tests on STATA (V.14.2). Results The mean score for knowledge regarding falls management in the preintervention, early postintervention and late postintervention were 73.7%, 85.2% and 76.4%, respectively. Although there was an improvement in the knowledge at 6 weeks’ postintervention, this returned to almost baseline at 16 weeks. The improvement in knowledge did not translate to clinical practice of falls management during this period. Conclusion Although educational interventions improve knowledge, the intervention failed to sustain over period of time or translate in clinical practice. Further work is needed to identify alternative methods to improve sustainability of the knowledge of falls and bring in the change in clinical practice.

Steroid-induced hyperglycaemia in hospitalised patients – assessing the current knowledge and practice of monitoring and diagnosis

To assess the current knowledge and practice for monitoring and diagnosis of steroid-induced hyperglycaemia (SIH) in hospitalised patients. This study was undertaken on six wards with high frequency of steroid use – oncology, respiratory and neurology – at a large tertiary care centre in the

Management of diabetic ketoacidosis – effect of a quality improvement programme and its long-term follow-up

Patients aged ≥17 years admitted with DKA from April 2014 to September 2016 at a large teaching hospital in the West Midlands were included in the study. Patients managed in intensive care units were excluded to avoid bias from one-toone care. Various interventions were introduced from October 2014 to March 2015 to improve DKA care as part of the QIP. The study period was divided into five groups of 6 months: baseline (52), intervention (52), early (53), intermediate (66) and late(36) follow-up period. Data measuring sociodemographic profile (age, gender, ethnicity) and various aspects of DKA management (presenting aetiology, glucose and ketone monitoring, prescribing fixed-rate insulin infusion and fluids) were collected and analysed using Microsoft Excel (version 2010) Statistical Analysis Software Package version 23 (IBM Corp., USA). The primary outcome of the study was measured by the effect on DKA duration. Results are expressed in percentage and median with interquartile range (IQR) as appropriate.

Thyrotoxicosis in patients with hypothyroidism is not just overtreatment

A 62-year-old Caucasian woman presented with hypothyroid symptoms and biochemical thyrotoxic picture. Previously, she underwent right-sided subtotal thyroidectomy and left partial thyroid lobectomy for thyroid lumps, and treated with thyroxine replacement for hypothyroidism. Although there were no significant findings on clinical examination, investigations confirmed thyrotoxicosis with positive autoimmunity against thyroid gland—all in line with a diagnosis of Graves’ hyperthyroidism. We would like to highlight atypical presentations of thyroid dysfunction and conversion of underactive to overactive thyroid status with this case. Early recognition, diagnosis and intervention are essential to prevent and/or reduce associated morbidity and mortality. When encountered with such clinical conundrums, we recommend seeking opinion from an experienced endocrinologist while interpreting such situation.

THE ANDRO-METABOLIC SIGNATURE OF IIH COMPARED WITH PCOS AND SIMPLE OBESITY

Idiopathic intracranial hypertension (IIH) is a disorder of raised intracranial pressure (ICP) of unknown cause. This condition is primarily seen in obese females of childbearing age, a phenotype similar to that in polycystic ovary syndrome (PCOS). We aimed to characterise the androgen metabolic signature in IIH compared to PCOS and simple obese controls. Age, gender and BMI matched groups of IIH (n=25), PCOS (n=31) and obese controls (n=15) were studied. The IIH group also underwent a weight loss intervention. Serum androgens were measured by liquid chromatography/tandem mass spectrometry (LCMS) and urinary steroids using gas chromatography/mass spectrometry (GCMS). Serum testosterone was significantly higher in IIH and PCOS than in controls (p=0.01). Serum androstenedione was significantly increased in PCOS compared to IIH and controls (p=0.008). Systemic 5a-reductase activity was significantly higher in IIH compared to controls (p=0.04). Following weight loss there were significant reductions in testosterone, 5a-reductase activity and disease activity (intracranial pressure and papilloedema). These results demonstrate a unique androgen metabolic signature in IIH (distinct from PCOS and simple obesity), characterised by increased testosterone but normal androstenedione, potentially driven by increased AKR1C3 activity (which converts androstenedione to its active metabolite testosterone). Further evaluation of AKR1C3 in IIH would be of interest.