activity in some tissues, such as bone and the liver, and antiestrogenic activity in other tissues, such as the breasts and uterus. Its affinity (Kd) for the ERα is approximately 50 pM, which is similar to that of estradiol. Relative to estradiol, raloxifene has been reported to possess about 8 to 34% of the affinity for the ERα and 0.5 to 76% of the affinity for the ERβ. Raloxifene acts as a partial agonist of the ERα and as a pure antagonist of the ERβ. In contrast to the classical ERs, raloxifene is an agonist of the G protein-coupled estrogen receptor (GPER) ( = 10–100 nM), a membrane estrogen receptor. Clinical effects Raloxifene has antiestrogenic effects in the mammary glands in preclinical studies. In accordance, raloxifene reduces breast density in postmenopausal women, a known risk factor for breast cancer. It does not stimulate the uterus in postmenopausal women, and results in no increase in risk of endometrial thickening, vaginal bleeding, endometrial hyperplasia, or endometrial cancer. At the same time, raloxifene has minimal antiestrogenic effect in the uterus in premenopausal women. This may possibly be due to inadequate tissue exposure of the uterus to raloxifene in these estrogen-rich individuals. In premenopausal women, raloxifene increases levels of follicle-stimulating hormone (FSH) and estradiol. Conversely, in postmenopausal women, raloxifene has been found to reduce levels of the gonadotropins, luteinizing hormone (LH) and FSH, while not affecting levels of estradiol. Raloxifene also decreases prolactin levels in postmenopausal women. In men, raloxifene has been found to disinhibit the hypothalamic–pituitary–gonadal axis (HPG axis) and thereby increase total testosterone levels. Due to the simultaneous increase in sex hormone-binding globulin (SHBG) levels however, free testosterone levels often remain unchanged in men during therapy with raloxifene. Raloxifene has estrogenic effects on liver protein synthesis. It increases SHBG levels in both pre- and postmenopausal women as well as in men. The medication decreases levels of total and low-density lipoprotein (LDL) cholesterol, C-reactive protein, apolipoprotein B, and homocysteine. Conversely, it has little effect on levels of triglycerides and high-density lipoprotein (HDL). Raloxifene has been shown to inhibit the oxidation of LDL cholesterol in vitro. The medication has been found to decrease insulin-like growth factor 1 (IGF-1) levels in pre- and postmenopausal women as well as in men. It has also been found to increase insulin-like growth factor binding protein 3 (IGFBP-3) levels in pre- and postmenopausal women. Due to activation of estrogen