OBJECTIVE: Obesity increases risk for endometrial neoplasia, but neither the pathophysiology nor the effects of weight loss on the risk are well established. We attempted to characterize the molecular profile of the endometrium of asymptomatic women with morbid obesity before and following bariatric surgery-induced weight loss. METHODS: 59 asymptomatic, morbidly obese women underwent endometrial sampling before bariatric surgery; 46 (78%) of these returned one year later for re-biopsy (median weight loss of 41kg). Duplicate samples from these specimens were scored for expression of estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), and Ki-67 by two independent, blinded pathologists using an H-score [staining intensity (0-3)×(percent of tissue involved)]. RESULTS: The prevalence of hyperplasia pre-operatively was 7% overall and 10% among patients not on an anti-estrogen. ER H-scores were similar before and after surgery overall (median 190 and 196 respectively, p=0.82), but patients with hyperplasia had higher pre-operative H-scores (median 256, p<0.001) and experienced greater H-score drops, than those without hyperplasia (-112 vs +50, p=0.028). In two patients with persistent hyperplasia at one year, ER H-scores fell to levels that were similar to those without pathology. One patient who developed hyperplasia during the study period had a rising ER H-score. Patients with hyperplasia had higher median PR H-scores pre-operatively (284 vs 188, p=0.01), which normalized through greater drops (75 vs 0, p=0.053). AR H-scores dropped significantly after surgery (13 vs 2, p=0.015), but were similar between patients with and without hyperplasia (p=0.33). Weight loss did not affect Ki-67 proliferation index. CONCLUSION: Asymptomatic morbidly obese patients have a high prevalence of occult hyperplasia, characterized by relatively high hormone receptor expression. These profiles appear to normalize with weight loss and in advance of pathologically identifiable changes. These data suggest a potential role for screening this population as well as the possibility that weight loss may be a valid treatment strategy for risk reduction.