Several studies have shown that treatment with a gonadotropin-releasing hormone (GnRH) analogue can reduce uterine volume in women with leiomyomata. However, no study to date has used a controlled population for comparison, nor has any study delineated the physiologic mechanism of volume reduction. We performed a double-blind, placebo-controlled study of a depot form of a GnRH analogue (leuprolide) given monthly for 24 weeks in 11 patients with symptomatic uterine leiomyomata. Patients initially treated with placebo were subsequently treated with active drug for 24 weeks. Magnetic resonance imaging was used to identify specifically the total uterine volume, total myoma volume, and total non-myoma volume. Treated patients had a significant reduction in total uterine and non-myoma volumes as compared with placebo patients (P less than .02). Total myoma volume was also reduced, but only to a P = .06 level. Pre- versus post-therapy values for all 11 patients showed significant reduction in all three volumes (P less than .02). Most symptoms were markedly improved. By 24 weeks post-therapy, all volumes had returned to baseline levels, although symptomatic improvement commonly persisted. The non-myoma volume was proportionally reduced to a greater extent than the myoma volume (42.7 versus 30.4%), and we therefore could explain the reenlargement seen when treatment was discontinued. Side effects were well tolerated and there were no study dropouts. We conclude that temporary hypoestrogenism induced by GnRH analogues can produce significant though temporary reduction in uterine volumes, and that the non-myoma volume is responsible for much of the reduction and reenlargement.(ABSTRACT TRUNCATED AT 250 WORDS)