A prospective, randomized trial of gonadotropin-releasing hormone agonist plus estrogen-progestin or progestin "add-back" regimens for women with leiomyomata uteri.

Abstract

Treatment of women with myomas with GnRH agonists (GnRH-a) for 3-6 months will result in profound hypoestrogenism, a significant but temporary reduction in uterine volume, and menstrual suppression. Long-term (i.e. > 6 months) treatment with a GnRH-a is not recommended because of accelerated bone resorption and the presence of hypoestrogenic symptoms. In this 2-yr study, women with myomas were treated with GnRH-a plus one of two steroid "add-back" regimens to minimize adverse sequelae of chronic hypoestrogenism. Fifty-one premenopausal women with large, symptomatic uterine myomas all received the GnRH-a, leuprolide acetate depot (LAD), every 4 weeks for 12 weeks at which time the women were randomized to receive LAD plus either an estrogen-progestin or progestin-only add-back regimen for an additional 92 weeks. Efficacy parameters assessed included serial uterine volumes, hemoglobin concentrations, and hematocrits; safety parameters evaluated included serial bone mineral density measurements, lipid profiles, and medication-related symptoms. This report analyzes the first 52 weeks of study data. Mean uterine volume decreased to 64% of pretreatment size at 12 weeks of LAD treatment in both groups. The estrogen-progestin add-back group had no significant regrowth of uterine volume, which was 75% of pretreatment size at treatment week 52; in contrast, the progestin add-back group had a mean uterine volume of 92% of pretreatment size by treatment week 52. Both groups demonstrated significant improvements in mean hemoglobin concentrations and hematocrits. The progestin add-back group had a significant decline in mean high density lipoprotein-cholesterol concentration, which was not seen in the estrogen-progestin add-back group. Finally, after a significant 3% bone loss during the first 12 weeks of treatment, bone mineral density stabilized in both add-back regimen groups. GnRH-a/steroid add-back regimens provide a useful long-term treatment strategy in women with large, symptomatic uterine myomas and may obviate the need for surgical intervention in selected cases. The estrogen-progestin add-back regimen was superior or equal to the progestin add-back regimen in all efficacy and safety parameters assessed.

Effects of the Selective Progesterone Receptor Modulator Asoprisnil on Uterine Artery Blood Flow, Ovarian Activity, and Clinical Symptoms in Patients with Uterine Leiomyomata Scheduled for Hysterectomy

“…Contrary to previous understanding that leiomyoma growth is mainly estrogen related, recent data from clinical and in vitro studies indicate that progesterone plays a pivotal role (6,7). Some clinical studies have shown that synthetic progestins reverse the effect of GnRH agonists on leiomyoma volume, which indirectly indicates the effects of GnRH agonists on leiomyomata may be due partly to cessation of progesterone secretion (8). Furthermore, a reduction in mean leiomyoma volume was demonstrated in small, uncontrolled, clinical studies with the progesterone receptor antagonist mifepristone (9).…”

Cell-Type Specific Actions of Progesterone Receptor Modulators in the Regulation of Uterine Leiomyoma Growth

“…[14][15][16] PR-A and PR-B contents are higher in leiomyomas than in the adjacent myometrium with a significant dominance of PR-A over PR-B. 15,16 Evidence from clinical studies suggests that synthetic progestins stimulate leiomyoma growth, [17][18][19] whereas progesterone receptor antagonist (defined here as a progesterone receptor modulator, or PRM), RU-486 (mifepristone), has opposite effects. [20][21][22] RU-486 is the first PRM that was shown to decrease leiomyoma volume in clinical trials.…”

Uterine Myomas: Treatment Options

“…In a prospective randomized trial of Gn-RH agonist plus estrogen-progesterone or progestin add-back regimens for women with uterine myomas, Friedman, Daly, Juneau-Norcross, Rcin, and Gleason (1 993) concluded that Gn-RH agonists addback regimens provide a useful long-term treatment strategy in women with large, symptomatic uterine myomas. They found that the estrogen-progesterone addback regimen was superior or equal to the progestin add-back regimen in efficacy and safety parameters assessed (Friedman et al, 1993). The value and safety o f long-term Gn-RH agonists and add-back therapy require further study.…”