Decreased leptin levels in normal weight women with hypothalamic amenorrhea: the effects of body composition and nutritional intake

Leptin is a protein encoded by the ob gene and expressed in adipocytes. A sensitive marker of nutritional status, leptin is known to correlate with fat mass and to respond to changes in caloric intake. Leptin may also be an important mediator of reproductive function, as suggested by the effects of leptin infusions to restore ovulatory function in an animal model of starvation. We hypothesized that leptin levels are decreased in women with hypothalamic amenorrhea and that leptin may be a sensitive marker of overall nutritional status in this population. We, therefore, measured leptin levels and caloric intake in 21 women with hypothalamic amenorrhea (HA) and 30 age-, weight-, and body fat-matched eumenorrheic controls. Age (24 +/- 5 vs. 24 +/- 3 yr), body mass index (20.6 +/- 1.3 vs. 21.1 +/- 1.5 kg/m2), percent ideal body weight (94.9 +/- 5% vs. 96.3 +/- 6.3%), and fat mass (14.2 +/- 3.6 vs. 15.5 +/- 2.9 kg, determined by dual energy x-ray absortiometry) did not differ between the groups. Leptin levels were significantly lower in the HA subjects compared with those in the controls (7.1 +/- 3.0 vs. 10.6 +/- 4.9 micrograms/L; P = 0.005). Total caloric intake (1768 +/- 335 vs. 2215 +/- 571 cal/day; P = 0.003), fat intake (333 +/- 144 vs. 639 +/- 261 cal/day; P < 0.0001), and insulin levels (5.6 +/- 1.2 vs. 7.4 +/- 3.2 microU/mL; P = 0.015) were lower in the women with HA than in the eumenorrheic controls. The difference in leptin levels remained significant after controlling for insulin (P = 0.023). These data are the first to demonstrate hypoleptinemia, independent of fat mass, in women with HA. The hypoleptinemia may reflect inadequate calorie intake, fat intake, and/or other subclinical nutritional disturbances in women with HA. The mechanism and reproductive consequences of low leptin in this large population of women remain unknown.