Does Androgen Withdrawal Reverse the Deleterious Cardiometabolic Effects Triggered by Hyperandrogenemia in PCOS?
Authors: Torres‐Fernandez Edgar D , Adams Kristen , Syed Maryam , Romero Damian G , Reckelhoff Jane F , Cardozo Licy L Yanes 
Published: November 2023

Introduction

Polycystic Ovary Syndrome (PCOS), the most common endocrine disorder in young women, is characterized by hyperandrogenemia and ovarian dysfunction. PCOS is also frequently associated with increased incidence of cardiometabolic risk factors such as obesity, insulin resistance and hypertension. Several lines of evidence indicate that there is a positive association between circulating levels of androgens, obesity, insulin resistance and blood pressure (BP) in PCOS. We have previously reported that exposure of female rats to dihydrotestosterone (DHT) before puberty resembles many characteristics found in PCOS women: increase in food intake, body weight, fat/lean mass, BP and renal injury. The DHT‐mediated increase in BP was associated with activation of renal renin angiotensin system (RAS). In the present study, we tested the hypothesis that androgen withdrawal reverses the deleterious cardiometabolic effects triggered by hyperandrogenemia in PCOS.

Methods

Female SD rats, 4 wks. old, were randomized to DHT (7.5 mg/90 days) or placebo (n=10/grp). After 6 months, DHT pellets were discontinued (Ex‐DHT). During additional 6 months food intake, body weight and body composition (Echo‐MRI), insulin resistance (area under the curve (AUC) during oral glucose tolerance test) and QUICKI test (log of fasting glucose and insulin) were analyzed. At 12 months, mean arterial blood pressure (MAP), baseline and after administration of enalapril (RAS blocker, at 250 mg/L, drinking water), was measured by radiotelemetry for 5 days. At the end of the study: insulin, leptin, adiponectin, androgens, estrone and estradiol were measured by RIA and MS/MS. Renal gene expression of androgen receptor and RAS's components were quantified by qRT‐PCR.

Results

After 6 months DHT withdrawal, body weight (330 ± 9 vs. 265 ± 4 g, p<0.001), fat mass (44.60 ± 4.1 vs. 26.6 ± 1.5 g, p<0.001), lean mass (269.7 ± 6.6 vs. 222.1 ± 4.9 g, p<0.0001) and food intake were significantly higher in Ex‐DHT female rats. Fasting plasma insulin (29.8 ± 1.7 vs. 19.7±2.2 μIU/mL, p<0.05), leptin (1,917 ± 445 vs. 837 ± 100 pg/mL, p<0.05) and adiponectin (24.9 ± 1.5 vs. 20.2 ± 1.3 ng/mL, p<0.05) were increased in Ex‐DHT. AUC and QUICKI test were significantly higher in Ex‐DHT indicating insulin resistance. Plasma DHT (72.6 ± 5.0 vs. 105.4 ± 6.9 pg/mL, p<0.001) and testosterone (3.6 ± 0.2 vs. 5.9 ± 0.5 ng/dL, p<0.001) were decreased in Ex‐DHT. MAP was significantly higher in Ex‐DHT than placebo (122 ± 1 vs. 110 ± 1 mm Hg, p<0.001). Enalapril normalized MAP in Ex‐DHT rats. Renal injury, glomerular sclerosis were significantly higher in Ex‐DHT rats, and renal expression (qRT‐PCR) of androgen receptor, angiotensinogen and AT‐1 receptor were upregulated.

In summary, despite normalization of hyperandrogenemia in PCOS, females still exhibit profound irreversible negative cardiometabolic effects previously triggered by androgens. Activation of renal RAS that persist after DHT withdrawal plays a major role in PCOS hypertension. These irreversible deleterious effects may be related to the renal androgen receptor upregulation.