Suppressing sex hormones in women for 1 wk reduces resting energy expenditure (REE). The effects of more chronic suppression on REE and other components of total energy expenditure (TEE), and whether the reduction in REE is specifically due to loss of estradiol (E 2), are not known. We compared the effects of 5 mo of sex hormone suppression (gonadotropin releasing hormone agonist therapy, GnRH AG) with placebo (PL) or E 2 add-back therapy on REE and the components of TEE. Premenopausal women received GnRH AG (leuprolide acetate 3.75 mg/mo) and were randomized to receive transdermal therapy that was either E 2 (0.075 mg/d; n= 24; means±SD, aged= 37±8 yr, BMI= 27.3±6.2 kg/m 2) or placebo (n= 21; aged= 34±9 yr, BMI= 26.8±6.2 kg/m 2). REE was measured by using a metabolic cart, and TEE, sleep EE (SEE), exercise EE (ExEE, 2× 30 min bench stepping), non-Ex EE (NExEE), and the thermic effect of feeding (TEF) were measured by using whole room indirect calorimetry. REE decreased in GnRH AG+ PL [mean (95% CI),− 54 (− 98,− 15) kcal/d], but not GnRH AG+ E 2 [+ 6 (− 33,+ 45) kcal/d](difference in between-group changes, P< 0.05). TEE decreased in GnRH AG+ PL [− 128 (− 214,− 41) kcal/d] and GnRH AG+ E 2 [− 96 (− 159,− 32) kcal/d], with no significant difference in between-group changes (P= 0.55). SEE decreased similarly in both GnRH AG+ PL [− 0.07 (− 0.12,− 0.03) kcal/min] and GnRH AG+ E 2 [− 0.07 (− 0.12,− 0.02) kcal/min]. ExEE decreased in GnRH AG+ PL [− 0.46 (− 0.79,− 0.13) kcal/min], but not GnRH AG+ E 2 [− 0.30 (− 0.65,+ 0.06) kcal/min]. There were no changes in TEF or NExEE in either group. In summary, chronic pharmacologic suppression of sex hormones reduced REE and this was prevented by E 2 therapy.