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Risk factors

FHA is caused by a chronic energy deprivation and negative energy balance, with links to three main risk factors: stress, weight, and exercise. It can occur in females of all ages, with the cause usually involving at least two out of the three factors. When energy levels are low, FHA has been postulated to present as an adaptive mechanism that enables energy to be properly allocated for the purpose of survival rather than high energetic cost of reproduction. Thus, inadequate energy intake to fuel these processes results in the initiation of a number of energy conservation strategies, including suppression of T, IGF-1, leptin, insulin, as well as increases in peptide YY (PYY), cortisol, growth hormone (GH), and ghrelin. All of these modulators cause energy to be moved away from growth and reproduction in order to maintain vital cellular processes, thereby suppressing the aforementioned processes. The effect of nutrition/metabolic status on reproduction is mediated through GnRH secretion. GABA neurons, KNDy neurons, and leptin are specifically responsible for alterations in GnRH secretion. GABA and KNDy neurons synapse with GnRH neurons at sites where leptin receptors are absent to favor LH release. Decreased leptin results in decreased LH release and is observed in periods of long term caloric restriction and fasting. These effects appear to be dose-dependent, where cases of more severe energy restriction (due to inadequate caloric intake or excess exercise) result in greater alterations of LH pulsatility. It is easy to see from these interplays why anorexics with decreased leptin and athletes who consume less calories than they expend are likely to present with FHA as a mechanism to preserve energy for processes critical to survival. 1