Dysregulation of the Hypothalamic-Pituitary-Testicular Axis due to Energy Deficit.

Abstract

While gonadal axis dysregulation due to energy deficit is well recognised in women, the effects of energy deficit on the male gonadal axis have received much less attention. To identify relevant articles, we conducted PubMed searches from inception to May 2021. Case series and mechanistic studies demonstrate that energy deficit (both acutely over days or chronically over months) either due to inadequate energy intake and/or excessive energy expenditure can lower serum testosterone concentration as a result of hypothalamic-pituitary-testicular (HPT) axis dysregulation in men. The extent to which this has clinical consequences that can be disentangled from the effects of nutritional insufficiency, concomitant endocrine dysregulation (e.g., adrenal and thyroid axis), and co-existing comorbidities (e.g., depression and substance abuse) is uncertain. HPT axis dysfunction is primarily due to the loss of Gonadotrophin Releasing Hormone (GnRH) pulsatility resulting from a failure of leptin to induce kisspeptin signaling. The roles of neuroendocrine consequences of depression, hypothalamic-pituitary-adrenal axis activation, proinflammatory cytokines, Ghrelin and genetic susceptibility remain unclear. In contrast to hypogonadism due to organic pathology of the HPT axis, energy deficit-associated HPT dysregulation is functional, and generally reversible by restoring energy balance. The clinical management of such men should aim to restore adequate nutrition and achieve and maintain a healthy body weight. Psychosocial co-morbidities must be identified and addressed. There is no evidence that testosterone treatment is beneficial. Many knowledge gaps regarding epidemiology, pathophysiology, and treatment remain and we highlight several areas that require future research.