Raloxifene

Raloxifene is a SERM that acts as an antiestrogen in breast and uterine tissue and an estrogen in bone.

Bone
Raloxifene is an estrogen receptor agonist in bone, and is used to treat osteoporosis.

Uterine tissue
Raloxifene is an estrogen receptor antagonist in uterine tissue. Unlike tamoxifen, it does not come with an increased risk of endometrial cancer.

Breast tissue
Raloxifene has been shown to reduce ERα expression in breast tissue in premenopausal women. As the synthesis of progesterone receptors (PR) is estrogen-regulated, raloxifene also decreases the expression of PR. Additionally, it was shown to decrease the presence of Ki-67, a biomarker for cell proliferation, in breast tissue of premenopausal women.

As a result, it can be used to treat gynecomastia, and has been shown effective in reducing breast size in those with the condition.

Fat distribution
Raloxifene may promote feminine fat distribution: in a study on 56-66 year old postmenopausal women, there was an increase in fat in the legs and buttocks and a decrease in fat in the abdomen and trunk after 1 year on 60 mg/day raloxifene. It is not yet known how pronounced this effect is, as there have been no comparisons of body fat distribution between raloxifene and estradiol.

Blood lipids
Raloxifene has favorable effects on blood lipids: it increases the concentration of HDL-cholesterol & ApoA1 and decreases the concentration of ApoB.

Skin elasticity
Raloxifene, like estradiol, has been shown to increase skin elasticity in postmenopausal women. While the mechanism by which this occurs is not known, the following mechanisms were theorized:
 * 1) In in vitro assays, raloxifene was found to stimulate collagen biosynthesis, possibly mediated through estrogen receptors. Additionally, it was found to inhibit the expression of matrix metalloproteinases, which initiate the breakdown of collagen.
 * 2) In animal studies, raloxifene was found to increase uterine and coronary blood flow. In postmenopausal women, hormone replacement therapy increases capillary blood flow. Thus, it is thought that raloxifene may have a similar effect on capillary blood flow, providing nutrients to the skin.

Pharmacodynamics
In in vitro assays, raloxifene appears to be a mixed estrogen receptor alpha (ERα) agonist/antagonist and a estrogen receptor beta (ERβ) antagonist.

ER antagonism
Raloxifene binds to the estrogen receptor in the same ligand binding site as estradiol, but causes the estrogen receptor to fold in such a way that prevents coactivators from forming a complex with the estrogen receptor. As a result, estrogen-responsive genes that depend on the presence of the coactivator are not expressed. Additionally, raloxifene promotes the recruitment of corepressors to the ER.

ER agonism
The estrogen receptor agonism of raloxifene may be due to nontraditional estrogen response elements on some genes, allowing the ER-raloxifene complex to activate those genes even in the absence of a coactivator.

Availability
Note that, as of 2018, Raloxifene can be quite expensive (~US$5 per pill), so it may not be a practical option unless covered by insurance.

Side effects
Rare, but serious adverse events:


 * Increased risk of stroke in those predisposed to cardiovascular issues. In postmenopausal women at high risk of cardiovascular events, there was an 50% increase in death due to stroke. In postmenopausal women with no cardiovascular heath issues, there was not an increased risk of stroke.
 * Increased risk of venous thromboembolism (deep vein thrombosis or pulmonary embolism). In postmenopausal women, there was a 210% increase in the incidence of deep vein thrombosis and a 117% increase in the incidence of pulmonary embolism. The magnitude of this risk is similar to the risk of venous thromboembolism with estrogen-progestin therapy (specifically, conjugated equine estrogens plus medroxyprogesterone acetate ).

Other adverse events:


 * Flu-like symptoms. 16% increase with 60 mg raloxifene daily versus placebo.
 * Hot flashes. 49% increase with 60 mg raloxifene daily versus placebo.
 * Leg cramps. 53% increase with 60 mg raloxifene daily versus placebo.
 * Peripheral edema (swelling due to fluid accumulation, typically legs). 17% increase with 60 mg raloxifene daily versus placebo.

This list is non-exhaustive. All research referenced in this section was performed on postmenopausal women. Other populations may experience different rates of adverse effects.