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.
Lina Schiffer, Punith Kempegowda, Wiebke Arlt, and Michael W O’Reilly
Michael W O'Reilly, Gloria Avalos, Michael C Dennedy, Eoin P O'Sullivan, and Fidelma Dunne
Gestational diabetes (GDM) is associated with adverse fetal and maternal outcomes, and identifies women at risk of future type 2 diabetes mellitus (T2DM). Breast-feeding may improve post partum maternal glucose tolerance. Our objective was to identify the prevalence of post partum dysglycemia after GDM, to delineate associated factors and to examine the effect of lactation on post partum glucose tolerance.
We compared post partum 75 g oral glucose tolerance test (OGTT) results from 300 women with GDM and 220 controls with normal gestational glucose tolerance (NGT) in five regional centers. Breast-feeding data was collected at time of OGTT.
Post partum OGTT results were classified as normal (fasting plasma glucose (FPG) <5.6 mmol/l, 2 h <7.8 mmol/l) and abnormal (impaired fasting glucose (IFG), FPG 5.6–6.9 mmol/l; impaired glucose tolerance (IGT), 2 h glucose 7.8–11 mmol/l; IFG+IGT; T2DM, FPG ≥7 mmol/l±2 h glucose ≥11.1 mmol/l). Binary logistic regression was used to identify factors predictive of persistent hyperglycemia.
Five hundred and twenty women were tested; six (2.7%) with NGT in pregnancy had post partum dysglycemia compared with 57 (19%) with GDM in index pregnancy (P<0.001). Non-European ethnicity (odds ratio (OR) 3.40; 95% confidence interval (CI) 1.45–8.02, P=0.005), family history of T2DM (OR 2.14; 95% CI 1.06–4.32, P=0.034), and gestational insulin use (OR 2.62; 95% CI 1.17–5.87, P=0.019) were associated with persistent dysglycemia. The prevalence of persistent hyperglycemia was significantly lower in women who breast-fed vs bottle-fed post partum (8.2 vs 18.4%, P<0.001).
Non-European ethnicity, gestational insulin use, family history of T2DM, and elevated body mass index were associated with persistent dysglycemia after GDM. Breast-feeding may confer beneficial metabolic effects after GDM and should be encouraged.
Aoife Garrahy, Martin Cuesta, Brian Murphy, Michael W O’Reilly, William P Tormey, Mark Sherlock, and Chris J Thompson
Severe hyponatraemia (plasma sodium concentration, pNa <120 mmol/L) is reported to be associated with mortality rates as high as 50%. Although there are several international guidelines for the management of severe hyponatraemia, there are few data on the impact of treatment.
Design and methods
We have longitudinally reviewed rates of specialist input, active management of hyponatraemia, treatment outcomes and mortality rates in patients with severe hyponatraemia (pNa <120 mmol/L) in 2005, 2010 and 2015, and compared the recent mortality rate with that of patients with pNa 120–125 mmol/L.
Between 2005 and 2010 there was a doubling in the rate of specialist referral (32 to 68%, P = 0.003) and an increase in the use of active management of hyponatraemia in patients with pNa <120 mmol/L (63 to 88%, P = 0.02), associated with a reduction in mortality from 51 to 15% (P < 0.001). The improved rates of intervention were maintained between 2010 and 2015, but there was no further reduction in mortality. When data from all three reviews were pooled, specialist consultation in patients with pNa <120 mmol/L was associated with a 91% reduction in mortality risk, RR 0.09 (95% CI: 0.03–0.26), P < 0.001. Log-rank testing on in-hospital survival in 2015 found no significant difference between patients with pNa <120 mmol/L and pNa 120–125 mmol/L (P = 0.56).
Dedicated specialist input and active management of severe hyponatraemia are associated with a reduction in mortality, to rates comparable with moderate hyponatraemia.
Anuradhaa Subramanian, Astha Anand, Nicola J Adderley, Kelvin Okoth, Konstantinos A Toulis, Krishna Gokhale, Christopher Sainsbury, Michael W O’Reilly, Wiebke Arlt, and Krishnarajah Nirantharakumar
Several recent observational studies have linked metabolic comorbidities to an increased risk from COVID-19. Here we investigated whether women with PCOS are at an increased risk of COVID-19 infection.
Population-based closed cohort study between 31 January 2020 and 22 July 2020 in the setting of a UK primary care database (The Health Improvement Network, THIN).
The main outcome was the incidence of COVID-19 coded as suspected or confirmed by the primary care provider. We used Cox proportional hazards regression model with stepwise inclusion of explanatory variables (age, BMI, impaired glucose regulation, androgen excess, anovulation, vitamin D deficiency, hypertension, and cardiovascular disease) to provide unadjusted and adjusted hazard risks (HR) of COVID-19 infection among women with PCOS compared to women without PCOS.
We identified 21 292 women with a coded diagnosis of PCO/PCOS and randomly selected 78 310 aged and general practice matched control women. The crude COVID-19 incidence was 18.1 and 11.9 per 1000 person-years among women with and without PCOS, respectively. Age-adjusted Cox regression analysis suggested a 51% higher risk of COVID-19 among women with PCOS compared to women without PCOS (HR: 1.51 (95% CI: 1.27–1.80), P < 0.001). After adjusting for age and BMI, HR reduced to 1.36 (1.14–1.63)], P = 0.001. In the fully adjusted model, women with PCOS had a 28% increased risk of COVID-19 (aHR: 1.28 (1.05–1.56), P = 0.015).
Women with PCOS are at an increased risk of COVID-19 infection and should be specifically encouraged to adhere to infection control measures during the COVID-19 pandemic.
Women with polycystic ovary syndrome (PCOS) have an increased risk of cardio-metabolic disease, which have been identified as a risk factor for COVID-19. To investigate whether the increased metabolic risk in PCOS translates into an increased risk of COVID-19 infection, we carried out a population-based closed cohort study in the UK during its first wave of the SARS-CoV-2 pandemic (January to July 2020), including 21 292 women with PCOS and 78 310 controls matched for sex, age and general practice location. Results revealed a 52% increased risk of COVID-19 infection in women with PCOS, which remained increased at 28% above controls after adjustment for age, BMI, impaired glucose regulation and other explanatory variables.
Jan Idkowiak, Yasir S Elhassan, Pascoe Mannion, Karen Smith, Rachel Webster, Vrinda Saraff, Timothy G Barrett, Nicholas J Shaw, Nils Krone, Renuka P Dias, Melanie Kershaw, Jeremy M Kirk, Wolfgang Högler, Ruth E Krone, Michael W O’Reilly, and Wiebke Arlt
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.
Retrospective review of all children undergoing serum androgen measurement at a single center over 5 years.
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.
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.
Patterns and severity of childhood androgen excess provide pointers to the underlying diagnosis and can be used to guide further investigations.
Rosemary Dineen, Julie Martin-Grace, Khalid Mohamed Saeed Ahmed, Isolda Frizelle, Anjuli Gunness, Aoife Garrahy, Anne Marie Hannon, Michael W O’Reilly, Diarmuid Smith, John McDermott, Marie-Louise Healy, Amar Agha, Agnieszka Pazderska, James Gibney, Chris J Thompson, Lucy-Ann Behan, and Mark Sherlock
Adrenal insufficiency (AI) is associated with increased cardiovascular morbidity and mortality and reduced quality of life (QoL). Optimum glucocorticoid (GC) dosing and timing are crucial in the treatment of AI, yet the natural circadian secretion of cortisol is difficult to mimic. The once-daily dual-release hydrocortisone (DR-HC) preparation (Plenadren®), offers a more physiological cortisol profile and may address unmet needs.
An investigator-initiated, prospective, cross-over study in patients with AI. Following baseline assessment of cardiometabolic risk factors and QoL, patients switched from their usual hydrocortisone regimen to a once-daily dose equivalent of DR-HC and were reassessed after 12 weeks of treatment.
Fifty-one patients (21 PAI/30 SAI) completed the study. Mean age was 41.6 years (s.d. 13), and 58% (n = 30) were male. The median daily HC dose before study entry was 20 mg (IQR 15–20 mg). After 3 months on DR-HC, the mean SBP decreased by 5.7 mmHg, P = 0.0019 and DBP decreased by 4.5 mmHg, P = 0.0011. There was also a significant reduction in mean body weight (−1.23 kg, P = 0.006) and BMI (−0.3 kg/m2, P = 0.003). In a sub-analysis, there was a greater reduction in SBP observed in patients with SAI when compared to PAI post-DR-HC. Patients reported significant improvements in QoL using three validated QoL questionnaires, with a greater improvement in PAI.
Dual-release hydrocortisone decreases BP, weight and BMI compared with conventional HC treatment, even at physiological GC replacement doses. Additionally, DR-HC confers significant improvements in QoL compared to immediate-release HC, particularly in patients with PAI, which is also reflected in the patient preference for DR-HC.
Balachandran Kumarendran, Dana Sumilo, Michael W O’Reilly, Konstantinos A Toulis, Krishna M Gokhale, Chandrika N Wijeyaratne, Arri Coomarasamy, Wiebke Arlt, Abd A Tahrani, and Krishnarajah Nirantharakumar
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.
Population-based retrospective cohort study utilizing The Health Improvement Network (THIN), UK.
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.
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.
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.