Functional hypogonadism in men: key causes and neuroendocrine mechanisms of its development

Abstract

Modern concepts of hypogonadism in men are undergoing significant transformation. The concept of functional hypogonadism, which is gaining increasing support among expert communities today, is based on the reversibility of symptomatic hypotestosteronemia after eliminating the causal factor or disease in men with an intact hypothalamic-pituitary-gonadal system. This makes the diagnosis of functional hypogonadism an exclusion diagnosis of organic hypogonadism, which can be congenital (genetic) or acquired (destructive or structural) irreversible disorder occurring at any level of the hypothalamic-pituitary-gonadal axis. Functional hypogonadism in men is becoming more common, attributed to its association with non-infectious pandemics such as obesity, type 2 diabetes, and other comorbid pathologies. Additionally, age-related hypogonadism meets the criteria of functional hypogonadism, as accumulating age-associated comorbidities have been shown to play a significant role in testosterone decline in aging men. Moreover, excessive physical activity, drastic calorie restriction, high psycho-emotional stress, injuries, surgeries, and the use of certain medications can also be causes of functional hypogonadism. Despite the wide range and heterogeneity of diseases and conditions underlying functional hypogonadism, the mechanisms driving its development are quite similar since in most cases, this androgen deficiency is secondary hypogonadotropic (central). However, in some cases, functional hypogonadism can be primary or mixed. Therefore, understanding the pathogenesis of functional hypogonadism is crucial as it involves a variety of biological pathways depending on the etiological factor or disease, which is detailed through a literature review. The article pays special attention to the evolutionary significance of the phenomenon of functional hypogonadism, an adapted classification of its causes, and describes the achievements of Russian researchers who have studied the impact of acute conditions and extreme influences on the hypothalamic-pituitary-gonadal system in men.