The hormonal pathway to frailty in older men

Frailty, which is a state of high vulnerability that imparts a high risk of developing adverse health outcomes, affects many elderly subjects, especially men and women aged 80 yr and older (1). Although many different definitions of frailty have been proposed (2), a large portion of the recent literature has focused on the definition developed by L. Fried et al. (1) using the data from the Cardiovascular Health Study. Although this definition has not been officially recognized as the "gold standard" for the diagnosis of frailty, nonetheless most of the studies on frailty in the last 5 yr have used this definition. Several mechanisms have been hypothesized to have an important role in the development of frailty, including inflammation, coagulation and oxidative stress (3). Many authors implicate age-related hormonal changes to be directly or indirectly involved in the development of the frailty syndrome (4). Alterations in hypothalamic- pituitary-testicular, hypothalamic-pituitary-adrenal (HPA) and GH-IGF-I axes that accompany aging have been associated with single components of frailty, such as reduced muscle strength, bone strength or poor mobility (5, 6). However, most of these studies have focused on single hormonal changes rather than evaluating the parallel effect of aging on multiple hormonal axes. In addition, no interventional studies have specifically targeted frail older subjects (7). Since frailty by definition is a multi-system disorder, it is unlikely that changes in one axis (leading to a change in a single hormone) will explain the complexity of the dysregulation leading to frailty. Therefore, global measures of endocrine dysregulation that can discriminate between specific endocrine diseases and endocrine senescence should be developed. Observational and interventional studies will be needed to better define the role of "hormonal dysregulation", alone and in combination with other pathways, in the development of frailty in older men.