Table 1.

Determinants of bone loss in different forms of functional hypothalamic amenorrhea.

Undernutrition / Eating disorders	Overtraining	Systemic diseases / psychological stress
Delayed menarche, amenorrhea Young age with impaired peak bone mass Inadequate calorie, protein and calcium intake Vitamin D insufficiency/deficiency Hyponatremia Low mechanical-loading physical activity (e.g. running) Low body weight with low fat mass and low lean mass Drugs: Diuretics abuse Selective serotonin re-uptake inhibitors Endocrine modifications:↓Leptin↓GnRH pulsatility, LH, FSH and estrogens↑CRH, ACTH and cortisol↑GH with GH resistance, ↓IGF-1 ↓Androgens ↓Oxytocin, insulin, amylin ? ↑PYY, ghrelin, adiponectin ?	Delayed menarche, amenorrhea Young age with impaired peak bone mass Relative energy deficiency Inadequate protein or calcium intake Vitamin D insufficiency/deficiency Possible coexistence of eating disorders Sports with low or repetitive loading (e.g. endurance running, ballet, swimming) Leanness sports Training intensity Low body weight with low fat mass Endocrine modifications: ↓Leptin ↓GnRH pulsatility, LH, FSH and estrogens ↑CRH, ACTH and cortisol ↓IGF-1 ↑Ghrelin ↑PYY ↑ or = adiponectin ↓Insulin ↓Oxytocin	Delayed menarche, amenorrhea Young age with impaired peak bone mass Underlying conditions and/or drugs: Gastrointestinal malabsorption (inflammatory bowel disease, coeliac disease) Chronic inflammatory diseases with hypermetabolic states (e.g. rheumatoid arthritis) Organ failure (e.g. cystic fibrosis, chronic renal disease, liver disease) Organ transplant and medications (e.g. glucocorticoids, immunosuppressants) HIV infection and medications Diabetes (types 1 and 2) Depression and/or selective serotonin re-uptake inhibitors Endocrine modifications: ↓GnRH pulsatility, LH, FSH and estrogens ↑CRH, ACTH and cortisol Immune stress (IL-1β, IL-6, TNF-α)

GnRH, Gonadotropin-releasing hormone. LH, luteinizing hormone. FSH, follicle-stimulating hormone. CRH, corticotropin-releasing hormone. ACTH, adrenocorticotropic hormone. Up arrow, increase. Down arrow, reduction. =, no variation. GH, growth hormone. IGF-1, insulin-like growth factor 1. PYY, peptide YY. IL-1β, interleukin 1β. IL-6, interleukin 6. TNF-α, tumor necrosis factor α.