title: Preadipocyte factor-1 levels are higher in women with hypothalamic amenorrhea and are associated with bone mineral content and bone mineral density through a mechanism independent of leptin.
abstract: BACKGROUND
  Preadipocyte factor 1 (pref-1) is increased in anorexia nervosa and is associated negatively with bone mineral density (BMD). No previous studies exist on pref-1 in women with exercise-induced hypothalamic amenorrhea (HA), which similar to anorexia nervosa, is an energy-deficiency state associated with hypoleptinemia.
  
  
  OBJECTIVE
  Our objective was to evaluate whether pref-1 levels are also elevated and associated with low BMD and to assess whether leptin regulates pref-1 levels in women with HA.
  
  
  METHODS
  Study 1 was a double-blinded, placebo-controlled randomized clinical trial of metreleptin administration in women with HA. Study 2 was an open-label study of metreleptin administration in low physiological, supraphysiological, and pharmacological doses in healthy women volunteers.
  
  
  METHODS
  At Beth Israel Deaconess Medical Center, 20 women with HA and leptin levels higher than 5 ng/ml and nine healthy control women participated in study 1, and five healthy women participated in study 2.
  
  
  METHODS
  For study 1, 20 HA subjects were randomized to receive either 0.08 mg/kg metreleptin (n = 11) or placebo (n = 9). For study 2, five healthy subjects received 0.01, 0.1, and 0.3 mg/kg metreleptin in both fed and fasting conditions for 1 and 3 d, respectively.
  
  
  METHODS
  Circulating pref-1 and leptin levels were measured.
  
  
  RESULTS
  Pref-1 was significantly higher in HA subjects vs. controls (P = 0.035) and negatively associated with BMD (ρ = -0.38; P < 0.01) and bone mineral content (ρ = -0.32; P < 0.05). Metreleptin administration did not alter pref-1 levels in any study reported herein.
  
  
  CONCLUSIONS
  Pref-1 is higher in HA subjects than controls. Metreleptin administration at low physiological, supraphysiological, and pharmacological doses does not affect pref-1 levels, suggesting that hypoleptinemia is not responsible for higher pref-1 levels and that leptin does not regulate pref-1.
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston Veterans Affairs Healthcare System, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Konstantinos N
authors.initials: KN
authors.lastname: Aronis
authors.forename: Holly
authors.initials: H
authors.lastname: Kilim
authors.forename: John P
authors.initials: JP
authors.lastname: Chamberland
authors.forename: Anne
authors.initials: A
authors.lastname: Breggia
authors.forename: Clifford
authors.initials: C
authors.lastname: Rosen
authors.forename: Christos S
authors.initials: CS
authors.lastname: Mantzoros
mesh_terms: D000328:Adult; D000568:Amenorrhea / Q000097:blood* / Q000188:drug therapy; D001823:Body Composition / Q000502:physiology; D015992:Body Mass Index; D001835:Body Weight / Q000502:physiology; D015519:Bone Density / Q000187:drug effects / Q000502:physiology*; D002135:Calcium-Binding Proteins; D003430:Cross-Sectional Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004734:Energy Metabolism / Q000502:physiology; D004958:Estradiol / Q000097:blood; D015444:Exercise / Q000502:physiology; D005260:Female; D006801:Humans; D007027:Hypothalamic Diseases / Q000097:blood* / Q000188:drug therapy; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood*; D020738:Leptin / Q000031:analogs & derivatives / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D008565:Membrane Proteins / Q000097:blood*; D055815:Young Adult
chemical_list: D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D008565:Membrane Proteins; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; C415771:metreleptin