Stimulatory Adrenocortical Effects of a Selective Estrogen Receptor Modulator in Ovariectomized Female Macaques

Abstract

Here, we report the effects of estrogen and the selective estrogen receptor modulator (SERM) levormeloxifene on adrenocortical measures in ovariectomized female cynomolgus monkeys ( Macaca fascicularis). Animals were randomized into one of five treatment groups, each containing 23 to 26 animals: (1) placebo, (2) 0.016 mg/kg 17β-estradiol (E2), (3) 0.5 mg/kg levormeloxifene (L1), (4) 1.0 mg/kg levormeloxifene (L2), and (5) 5.0 mg/kg levormeloxifene (L3). Treatments were administered orally each day for 18 mo. All doses of levormeloxifene resulted in adrenal weights at least 50% greater than placebo ( p < .0001 for all). The target dose of levormeloxifene (L2) resulted in higher serum concentrations of cortisol (+63%), dehydroepiandrosterone-sulfate (+73%), and androstenedione (+37%) compared with the placebo group ( p < .05 for all). In contrast, E2 resulted in no significant differences in adrenal weight or adrenocortical steroids. Oral E2 and all SERM doses resulted in similar reductions in serum gonadotropins and at least threefold greater uterine weight versus placebo ( p < .0001 for all). Results indicate that the SERM levormeloxifene, in contrast to E2, may have robust stimulatory effects on adrenocortical hormones in a postmenopausal model. These findings warrant further investigation into long-term SERM effects on adrenocortical function.