Ghrelin en la Amenorrea Hipotalámica Funcional relacionada con la desnutrición

Functional Hypothalamic Amenorrhoea (FHA) reflects a homeostatic adaptive process resulting from a negative energy balance (increased caloric output/expenditure with inadequate nutrient replenishment). Hypothalamic hormones and peripheral neuropeptides from the fat tissue (leptin, adiponectin and other adipokines), the upper gastrointestinal tract (Ghrelin) and pancreas (insulin) are involved in this syndrome. This "peripheral circuit” is functionally interrelated with the central hypothalamic circuit controlling appetite and satiety. The decrease in leptin, an anorexigenic signal, potentiates the orexigenic effect of Ghrelin (the basal levels of Ghrelin are elevated in FHA) and induces an increased CRH activity within the hypothalamus. This hormone, in turn, inhibits pulsatile GnRH secretion. Besides its potent GH secretagogue activity, Ghrelin is a peptide that influences insulin secretion and affects the metabolism of carbohydrates and lipids. Usually, a preprandial increase in Ghrelin levels is observed, followed by a postprandial decrease related to satiety. In obese subjects, this decrease is less marked and slower. Conversely, in anorexic women, the drop in this orexigenic peptide is faster. Both behaviours are unfavourable for the pathologies in which they occur. Ghrelin administration induces a rapid increase in blood glucose and a decrease in insulin levels. The fact that an increase in blood glucose precedes a decrease in insulin might suggest that Ghrelin could directly stimulate hepatic glucogenolysis activity. Thus, hyperghrelinemia might be considered as a potential defence mechanism to prevent hypoglycaemia in undernourished amenorrheic patients. Basal hyperghrelinemia in FHA is secondary to insulin resistance and it is induced by elevated free fatty acids resulting from lipolysis, a process that is increased in patients with FHA. The negative correlation between insulin and Ghrelin is probably mediated by the vagal system, as suggested by the increase in the pancreatic polypeptide, a reliable marker of vagal activity. Additionally, the hypercortisolism that typically occurs in patients with FHA, and possibly somastotatin through its pancreas receptors, could negatively regulate the activity of insulin receptors, with a consequent increase in Ghrelin. Conclusion: the increase in Ghrelin in FHA and its particular interrelations with insulin and the hypothalamic-pituitary-adrenal axis reflect an attempt to maintain the homeostatic balance, contributing to facilitate the supply of energy metabolites in these undernourished patients. These patients commonly develop osteoporosis, immunosuppression and a high risk of cardiovascular disease.