Role of Obesity and Adrenergic Activation in the Androgen‐Induced Cardiometabolic Abnormalities in PCOS
Authors: Torres Fernandez Edgar D. , McClung Sally J. , Morato Jemylle G. , Everman Steven J. , Pruett Jacob E. , Iliescu Radu , Romero Damian G. , Yanes Cardozo Licy L. 
Published: April 2020

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. PCOS is diagnosed by the combination of hyperandrogenemia, oligo/anovulation, and polycystic ovaries. PCOS is also associated with cardiometabolic abnormalities such as: obesity, insulin resistance, dyslipidemia, increased blood pressure (BP), and renal injury. In PCOS, obesity worsens the metabolic outcomes and evidence suggests that the sympathetic nervous system activation increases BP. However, the mechanisms responsible for elevated BP in women with PCOS are still unclear. We tested the hypothesis that obesity, by activating the sympathetic nervous system, mediates the androgen‐induced cardiometabolic abnormalities in PCOS.Four‐week old female SD rats were randomized to subcutaneously receive dihydrotestosterone (DHT, 7.5 mg/ 90 days) pellets (DHT) or sham surgeries (control). Then, DHT animals were assigned to have access to food either ad libitum or on a daily pair‐feeding schedule based on control food intake (PF‐DHT). Body composition (by EchoMRI) and proteinuria were determined every 4 weeks. At the end of the experiment, α1,β1,2‐adrenergic receptor antagonism response was assessed measuring BP by radiotelemetry in conscious, freely moving animals using propranolol (10mg/kg/d) and terazosin (10mg/kg/d) subcutaneously for 14 days.DHT rats had increased daily food intake (18.7 ± 0.1 vs 15.2 ± 0.1 g, p<0.0001) compared to control. During pair‐feeding, food intake in PF‐DHT was decreased to the same level as control. DHT rats had higher BW, fat, and lean mass compared to control. Pair‐feeding abolished the increase in fat mass (12.5 ± 1.7 vs 22 ± 2.5 g, p<0.001) and attenuated the increase in BW (269 ± 6 vs 308 ± 7 g, p<0.001) and lean mass induced by androgens in PCOS. DHT rats had higher BP and proteinuria compared to control. In PCOS, pair‐feeding normalized BP (103.8 ± 0.6 vs 109.6 ± 0.7 mmHg, p<0.0001) and ameliorated the androgen‐induced increase in proteinuria (11.8 ± 1 vs 31.3 ± 2 mg/24h, p<0.0001). Acute adrenergic antagonism caused a bigger BP decrease in control than in DHT (88.1 ± 0.7 vs 93 ± 0.8 mmHg, p<0.05) or in PF‐DHT (88.1 ± 0.7 vs 93 ± 0.5 mmHg, p<0.05). Chronic adrenergic antagonism, however, normalized BP in PF‐DHT (95.5 ± 0.2 vs 97.3 ± 0.3 mmHg, p<0.05), but it did not in DHT (95.5 ± 0.2 vs 100.1 ± 0.3 mmHg, p<0.05).DHT rats showed increased food intake, fat mass, BP, and proteinuria compared to control rats. PF‐DHT rats had decreased fat mass, BP, and proteinuria compared to ad libitum‐fed DHT. In PCOS, the BP lowering effect of acute adrenergic antagonism is blunted by androgen‐excess independently of obesity. Chronic adrenergic antagonism, however, normalizes BP in PCOS in absence of obesity. In summary, obesity plays a key role mediating the negative cardiometabolic consequences of hyperandrogenemia in women with PCOS. Chronic adrenergic antagonism in addition to weight loss may be a promising therapeutic approach for androgen‐induced hypertension in PCOS.Support or Funding InformationNIH P20 GM‐121334 (L.L.Y.C. and D.G.R) and NIH R21 DK‐113500 (D.G.R.)