Endometrial profile of tamoxifen and low-dose estradiol combination therapy

Combination estrogen + progestin therapy has been associated with increased breast cancer risk in postmenopausal women. Selective estrogen receptor modulators (SERM) are potential alternatives to progestins, although the endometrial safety of estrogen + SERM co-therapies is not known. The goal of this study was to evaluate the endometrial profile of low-dose estradiol and the SERM tamoxifen alone and in combination.

Twenty-four postmenopausal female cynomolgus macaques were randomized by social group to receive placebo, low-dose micronized estradiol (E(2); 0.25 mg/1,800 kcal), the SERM tamoxifen (Tam; 20 mg/1,800 kcal), or E(2) + Tam for 4 months in a parallel-arm design.

Tamoxifen alone resulted in overlapping but distinct effects compared with E(2). Both E(2) and Tam increased uterine weight and endometrial thickness, whereas only E(2) increased endometrial proliferation. Morphologic effects were similar for Tam and E(2) + Tam, which both induced stromal fibrosis and cystic change. Tamoxifen inhibited E(2)-induced proliferation and expression of genes related to cell cycle progression while exhibiting mixed agonist and antagonist effects on gene markers of estrogen receptor activity. The gene expression profile for E(2) + Tam was distinct from either E(2) or Tam alone but dominated by the Tam effect for estrogen-regulated genes. Tam also attenuated E(2) effects on both vaginal maturation and cervical epithelial height.

These findings characterize a novel phenotype resulting from estrogen + SERM co-therapy. The predominance of Tam effects on endometrial proliferation, morphology, and transcriptional profiles suggests that endometrial risks for E(2) + Tam may be similar to Tam alone.