New treatment paradigm of combined raloxifene and conjugated estrogen for postmenopausal symptoms in VCD-induced menopausal rats

Abstract

Introduction: The decreased ovarian estrogen production that occurs at menopause, results in osteoporosis and climacteric manifestations, and decreases women’s quality of life. The hormone replacement therapy (HRT) is the primary treatment options but has been associated with increased oncogenic potential. The tissue selective estrogen complex (TSEC) is a novel therapy, partnering a selective estrogen receptor modulator (SERM) with one or more estrogens.

Aim: Our study was done to evaluate the potential relative estrogenic agonist activities of a SERM, raloxifene (RLX), when dosed alone and its antagonist activities when paired with conjugated estrogen (CE), as a TSEC and its potential use for the postmenopausal osteoporosis, vulvar/vaginal atrophy (VVA) in VCD induced menopausal rat model.

Material and methods: Female rats were dosed daily with 4-vinylcyclohexene diepoxide (VCD) (80 mg/kg/d, IP) for 15 days to induce ovarian failure, followed by one month free drug. VCD injected rats received 12 weeks of RLX, CE, or combined RLX/CE with 17b-estradiol (E2), vehicle treated groups used as positive and negative controls, respectively. The bone turnover markers (BTM) were measured. The uterotropic activity was assessed by the uterine index and peroxidase assay. Vaginal wet weight (wt.) and glycogen were measured to evaluate the vaginotropic effects. Uterine and vaginal (ER) protein levels were assayed.

Results: Our findings showed that the appropriate RLX/CE dose combination exhibits significant bone sparing with minimal vaginal stimulation and neutral uterine effect.

Conclusion: We can conclude that appropriate RLX/CE combination could effectively be a promising alternative for the prevention of postmenopausal osteoporosis and VVA with no oncogenic risk.

Keywords: Raloxifene; Estrogen; Osteoporosis; Vulvar/vaginal atrophy