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.
Jan Idkowiak, Yasir S Elhassan, Pascoe Mannion, Karen Smith, Rachel Webster, Vrinda Saraff, Timothy G Barrett, Nicholas G Shaw, Nils Krone, Renuka P Dias, Melanie Kershaw, Jeremy M Kirk, Wolfgang Högler, Ruth E Krone, Michael W O'Reilly and Wiebke Arlt
Objective: Androgen excess in childhood is a common presentation and may signify sinister underlying pathology. Data describing its patterns and severity are scarce, limiting the information available for clinical decision processes. Here, we examined the differential diagnostic value of serum dehydroepiandrosterone sulfate (DHEAS), androstenedione (A4), and testosterone (T) in childhood androgen excess.
Design: Retrospective review of all children undergoing serum androgen measurement at a single center over 5 years.
Methods: Serum A4 and T were measured by tandem mass spectrometry, DHEAS by immunoassay. Patients with at least one increased androgen underwent phenotyping by clinical notes review.
Results: In 487 children with simultaneous DHEAS, A4, and T 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 T 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 T (25%) or increases in both A4 and T (25%). CAH patients (6%) predominantly had A4 excess (86%); T 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 (>20fold in the single case of adrenocortical carcinoma), and in CAH for serum androstenedione.
Conclusions: Patterns and severity of childhood androgen excess provides pointers to the underlying diagnosis and can be used to guide further investigations.