Glucocorticoid Receptor Antagonism Improves Glucose Metabolism in a Mouse Model of Polycystic Ovary Syndrome

Sheng Li; Zhixiong Ying; Max Gentenaar; Patrick C N Rensen; Sander Kooijman; Jenny A Visser; Onno C Meijer; Jan Kroon

doi:10.1210/jendso/bvad162

Glucocorticoid Receptor Antagonism Improves Glucose Metabolism in a Mouse Model of Polycystic Ovary Syndrome

J Endocr Soc. 2023 Dec 20;8(1):bvad162. doi: 10.1210/jendso/bvad162. eCollection 2023 Dec 1.

Authors

Sheng Li^{1

2}, Zhixiong Ying^{1

2}, Max Gentenaar^{1

2}, Patrick C N Rensen^{1

2}, Sander Kooijman^{1

2}, Jenny A Visser³, Onno C Meijer^{1

2}, Jan Kroon^{1

2}

Affiliations

¹ Department of Medicine, Division of Endocrinology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands.
² Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333ZA Leiden, the Netherlands.
³ Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, the Netherlands.

Abstract

Context: Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with obesity, insulin resistance, and dyslipidemia. Hyperandrogenism is a major characteristic of PCOS. Increased androgen exposure is believed to deregulate metabolic processes in various tissues as part of the PCOS pathogenesis, predominantly through the androgen receptor (AR). Notably, various metabolic features in PCOS are similar to those observed after excess glucocorticoid exposure.

Objective: We hypothesized that glucocorticoid receptor (GR) signaling is involved in the metabolic symptoms of PCOS.

Methods: In a PCOS model of chronic dihydrotestosterone (DHT) exposure in female mice, we investigated whether GR signaling machinery was (de)regulated, and if treatment with a selective GR antagonist alleviated the metabolic symptoms.

Results: We observed an upregulation of GR messenger RNA expression in the liver after DHT exposure. In white adipose tissues and liver we found that DHT upregulated Hsd11b1, which encodes for the enzyme that converts inactive into active glucocorticoids. We found that preventive but not therapeutic administration of a GR antagonist alleviated DHT-induced hyperglycemia and restored glucose tolerance. We did not observe strong effects of GR antagonism in DHT-exposed mice on other features like total fat mass and lipid accumulation in various tissues.

Conclusion: We conclude that GR activation may play a role in glucose metabolism in DHT-exposed mice.

Keywords: androgen receptor; dihydrotestosterone; glucocorticoid receptor; metabolism; polycystic ovary syndrome.