Mechanisms in endocrinology: hypogonadism and metabolic health in men-novel insights into pathophysiology

Hypogonadism in men is associated with an adverse metabolic phenotype and increased mortality. Reciprocally, obesity and insulin resistance can suppress the hypothalamic-pituitary-gonadal axis in the absence of structural organic disease, further perpetuating a cycle of metabolic dysfunction and low testosterone. The mechanisms underpinning this bidirectional association are complex as hypogonadism is a heterogenous syndrome, and obesity is associated with metabolic perturbations in glucose and lipid metabolism even in the presence of normal testicular function. However, distinct molecular defects specific to testosterone deficiency have been identified in pathways relating to glucose and lipid metabolism in target metabolic depots such as adipose tissue and skeletal muscle. This review discusses the etiology and prevalence of metabolic disease in male hypogonadism, with a specific focus on both disease mechanisms and novel potential approaches to enhance our understanding.