Figure 1.

Determinants of skeletal fragility in functional hypothalamic amenorrhea (FHA). Negative energy balance is the prime determinant in FHA physiopathology. Not only the caloric intake, but also the insufficient amount of dietary calcium, vitamin D and proteins impact on bone. In case of overtraining, some features of sports, like mechanical load and exercise intensity, can affect bone health. The reduction in lean mass impairs peak bone mass achievement and cortical bone microarchitecture. The reduction in fat mass is associated with low leptin levels and hypogonadism. Estrogen deficiency contributes to the increased bone resorption (mainly observed in adulthood) and altered trabecular bone mineral density (BMD) and microarchitecture. The low levels of insulin-like growth factor-1 (IGF-1) result from growth hormone resistance and the nutritional deprivation, and participate in lowering bone turnover as observed in adolescent patients, and in disrupting peak bone mass achievement. The hypothalamus-pituitary-adrenal axis is overactive in FHA, resulting in enhanced cortisol secretion which, in turn, inhibits intestinal calcium absorption, increases urinary calcium excretion, inhibits osteoblast proliferation and increases marrow fat content. Further studies are needed to clarify whether testosterone, dehydroepiandrosterone, ghrelin, peptide YY (PYY), adiponectin, insulin, amylin and oxytocin play a role in FHA skeletal involvement (42, 43). (Created with BioRender.com).