OBJECTIVES: Loss of PTEN tumor suppressor gene function characterizes most (63%) endometrial precancerous lesions (endometrial intraepithelial neoplasia, EIN) and up to 83% of endometrioid endometrial cancers. Because systemic progestins are known to promote involution of precancerous endometrial lesions, we tested the hypothesis that this therapy preferentially leads to clearance of immunohistochemically detected PTEN-null endometrial glands in a variety of histopathologic settings. METHODS: PTEN immunohistochemistry of pre and postprogestin-treated endometria was successfully performed on 17 women presenting with an intake endometrial biopsy diagnosis of "hyperplasia". Intake biopsies were rediagnosed using EIN criteria as 5 normal (proliferative or secretory), 4 anovulatory, 3 polyps, and 5 EIN endometria. The persistence of PTEN-null glands in progestin-treated patients was compared to that seen previously in rebiopsied normal proliferative endometrium of endogenously cycling premenopausal women. RESULTS: Ten of 17 women prehormonal therapy had PTEN-null glands in the initial biopsy, and 90% (9/10) of these disappeared in the postprogestin sample. This contrasts with only 17% (2/12) involution in the endometria of normal cycling women (Fishers exact test P=0.002, Odds Ratio 45). CONCLUSIONS: We conclude that progestin therapy promotes involution, or disappearance, of PTEN-null endometrial glands relative to the persistence rate seen for normal cycling women. This effect occurs among PTEN-null glands having a variety of histopathologic presentations.