Selective Estrogen Receptor Modulator-Like Activities of Herba epimedii Extract and its Interactions With Tamoxifen and Raloxifene in Bone Cells and Tissues.

Liping Zhou,Wenxuan Yu,Huihui Xiao,Chi-On Chan,Ka-Ying Wong,Christina Chui-Wa Poon,Daniel Kam-Wah Mok,Man-Sau Wong,Yan Zhang

doi:10.3389/fphar.2020.571598

Abstract

Herba epimedii (HEP), a kidney-tonifying herb, has been commonly used alone or in formula for strengthening kidney function and treating bone disorders. Its bone protective activity has been demonstrated to be via estrogen receptor (ERs). HEP activates the phosphorylation of ERα in an estrogen response element- (ERE-) dependent manner. We examined the bone protective effects of HEP and its potential interactions with Selective Estrogen Receptor Modulators (SERMs, such as tamoxifen and raloxifene) as they act via the same ERs. Six-month-old mature Sprague Dawley sham-operated (Sham) or ovariectomized (OVX) rats were treated with either vehicle, 17ß-estradiol (1.0 mg/kg.day), tamoxifen (Tamo, 1.0 mg/kg.day), raloxifene (Ralo, 3.0 mg/kg.day), HEP (0.16 g/kg.day), or its combinations with respective SERMs (HEP + Tamo; HEP + Ralo) for 12 weeks. HEP and SERMs as well as their combinations significantly restored changes in bone mineral density (BMD), trabecular bone properties, and bone turnover biomarkers induced by ovarian sex hormone deficiency in ovariectomized rats. Besides the increase in serum estradiol, inhibition on follicle stimulating hormone (FSH) might also be involved in the osteoprotective activities of HEP and SERMs. HEP interacted with SERMs to protect bones from ovarian sex hormone deficiency without altering SERMs’ bone protective activities. HEP neither induced changes in uterus weight nor altered the uterotrophic activity of SERMs in OVX rats. In human osteosarcoma MG-63 cells, HEP-treated serum (HEP-Ts) significantly promoted alkaline phosphatase (ALP) activity like the crude HEP extract did but did not stimulate ERE activity. Our study also reported that biologically activated HEP interacted with SERMs to promote ALP activity without altering the action of SERMs at most of the concentrations tested in MG-63 cells. HEP exerted bone protective activity and the use of HEP did not alter the bone protective activities of SERMs when they were used simultaneously in an estrogen-deficient rat model.

Highlights

At menopause, circulating estrogen level dramatically declines and results in various distressing symptoms in postmenopausal women
Effects of Herba epimedii (HEP) Alone and its Combinations With Tamoxifen or Raloxifene on Body Weight, Uterus Weight and Biochemical Parameters in OVX Rats The effects of HEP alone and its combinations with Selective Estrogen Receptor Modulators (SERMs) on body weight gain and uterus weight as well as serum and urine biochemical parameters were measured in mature OVX rats after oral administration for 3 months
No significant changes in serum Ca, P or urine Ca, P excretion were observed in OVX rats treated with E2, tamoxifen, raloxifene, HEP alone, or the combinations of HEP and SERMs in OVX rats (Table 1)

Summary

Introduction

At menopause, circulating estrogen level dramatically declines and results in various distressing symptoms in postmenopausal women Among these symptoms, osteoporosis is a long-term silent but serious disorder characterized by bone loss and increased risk of fracture, a condition that affects one in three postmenopausal women over the age of 50 and brings a high socioeconomic burden to both their families and the society (Sözen et al, 2017; Shuai et al, 2019). The first-generation SERM that is clinically prescribed for treatment of breast cancer, has been demonstrated to exert osteoprotective activity in both human and animals. It increases the risk of endometrium cancer (Tzeng et al, 2015). Raloxifene does not stimulate the growth of uterus tissues and is a potent estrogen antagonist in breast tissues (Martinkovich et al, 2014)

Methods

Results

Conclusion