—Drs Hanson and Melzer express astonishment that the PEPI trial investigators were allowed to randomize women with an intact uterus to an unopposed estrogen arm. A detailed description of the rationale and design of the PEPI trial has been published previously.1 Nonetheless, we welcome this opportunity to explain again our reasons for this inclusion.During the design phase of PEPI, the investigators concluded that assigning women with a uterus to an unopposed estrogen arm was scientifically important and ethically appropriate because (1) information on the association between estrogen and cardiovascular disease had been obtained almost exclusively from studies of unopposed estrogen; (2) excluding women with a uterus from 1 treatment group would limit the inferences that could be drawn from PEPI; and (3) the American College of Obstetricians and Gynecologists includes unopposed estrogen as a treatment option in women with a uterus, provided an annual endometrial biopsy is obtained.
Bush TL. Estrogen Replacement Therapy: New Options, Continuing Concerns-Reply. JAMA. 1997;277(19):1516. doi:10.1001/jama.1997.03540430028018