Raloxifene

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Raloxifene is a SERM that acts as an antiestrogen in breast and uterine tissue and an estrogen in bone.[1]

Effects

Bone

Raloxifene is an estrogen receptor agonist in bone, and is used to treat osteoporosis.[2][1]

Uterine tissue

Raloxifene is an estrogen receptor antagonist in uterine tissue.[2][3][1] Unlike tamoxifen, it does not come with an increased risk of endometrial cancer.[3]

Breast tissue

Raloxifene has been shown to reduce ERα expression in breast tissue in premenopausal women.[4] As the synthesis of progesterone receptors (PR) is estrogen-regulated, raloxifene also decreases the expression of PR.[4] Additionally, it was shown to decrease the presence of Ki-67, a biomarker for cell proliferation, in breast tissue of premenopausal women.[5][6]

As a result, it can be used to treat gynecomastia, and has been shown effective in reducing breast size in those with the condition.[7]

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.[8] 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.[8]

Skin elasticity

Raloxifene, like estradiol, has been shown to increase skin elasticity in postmenopausal women.[9] 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.[9]
  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.[9]

Pharmacodynamics

In in vitro assays, raloxifene appears to be a mixed estrogen receptor alpha (ERα) agonist/antagonist and a estrogen receptor beta (ERβ) antagonist.[10]

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.[2] As a result, estrogen-responsive genes that depend on the presence of the coactivator are not expressed.[2] Additionally, raloxifene promotes the recruitment of corepressors to the ER.[4]

ER agonism

The estrogen receptor agonism of raloxifene may be due to nontraditional estrogen response elements on some genes,[2] 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.[11][12] In postmenopausal women with no cardiovascular heath issues, there was not an increased risk of stroke.[11]
  • 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.[13] The magnitude of this risk is similar to the risk of venous thromboembolism with estrogen-progestin therapy[13] (specifically, conjugated equine estrogens plus medroxyprogesterone acetate[14][15]).

Other adverse events:

  • Flu-like symptoms. 16% increase with 60 mg raloxifene daily versus placebo.[14]
  • Hot flashes. 49% increase with 60 mg raloxifene daily versus placebo.[14]
  • Leg cramps. 53% increase with 60 mg raloxifene daily versus placebo.[14]
  • Peripheral edema (swelling due to fluid accumulation, typically legs). 17% increase with 60 mg raloxifene daily versus placebo.[14]

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.

References

  1. ↑ 1.0 1.1 1.2 WebMD. "Selective Estrogen Receptor Modulators (SERMs)." Retrieved 2017-11-11. https://www.webmd.com/osteoporosis/guide/serms
  2. ↑ 2.0 2.1 2.2 2.3 2.4 D. B. Muchmore (2000). "Raloxifene: A Selective Estrogen Receptor Modulator (SERM) with Multiple Target System Effects". The Oncologist. 5 (5): 388–392. doi:10.1634/theoncologist.5-5-388. ISSN 1083-7159.
  3. ↑ 3.0 3.1 Taylor, D. K., & Leppert, P. C. (2012). Treatment for uterine fibroids: searching for effective drug therapies. Drug Discovery Today: Therapeutic Strategies, 9(1), e41-e49. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525705/
  4. ↑ 4.0 4.1 4.2 Rosal, M. A., & Da Silva, B. B. (2011). Evaluation of estrogen and progesterone receptors in non-neoplastic breast tissue of women of reproductive age exposed to tamoxifen and raloxifene: a randomized, double-blind study. Breast cancer research and treatment, 125(3), 797-801. https://doi.org/10.1007/s10549-010-1307-z
  5. ↑ da Silva, B. B., Lopes, I. M. R. S., & Gebrim, L. H. (2006). Effects of raloxifene on normal breast tissue from premenopausal women. Breast cancer research and treatment, 95(2), 99-103. https://doi.org/10.1007/s10549-005-9001-2
  6. ↑ Lima, M. A. V. C., & da Silva, B. B. (2012). Expression of Ki-67 and Bcl-2 biomarkers in normal breast tissue from women of reproductive age treated with raloxifene. Archives of gynecology and obstetrics, 285(1), 223-227. https://doi.org/10.1007/s00404-011-1932-8
  7. ↑ Zehetner, Anthony. "Tamoxifen to treat male pubertal gynaecomastia." International Journal of Pediatrics and Adolescent Medicine 2.3 (2015): 152-156. https://doi.org/10.1016/j.ijpam.2015.09.002
  8. ↑ 8.0 8.1 Francucci C M, Pantaleo D, Iori N, Camilletti A, Massi F, Boscaro M. "Effects of raloxifene on body fat distribution and lipid profile in healthy post-menopausal women". J Endocrinol Invest (2005) 28: 623. https://doi.org/10.1007/BF03347261
  9. ↑ 9.0 9.1 9.2 H. Sumino et al (2009). "Effects of raloxifene and hormone replacement therapy on forearm skin elasticity in postmenopausal women". Maturitas. 62 (1): 53–57. doi:10.1016/j.maturitas.2008.10.005. ISSN 03785122.
  10. ↑ Barkhem T, Carlsson B, Nilsson Y, Enmark E, Gustafsson J-Å, Nilsson S (July 1998). "Differential Response of Estrogen Receptor α and Estrogen Receptor β to Partial Estrogen Agonists/Antagonists". Molecular Pharmacology July 1998, 54 (1) 105-112. https://doi.org/10.1124/mol.54.1.105
  11. ↑ 11.0 11.1 Grady D, Cauley J, Stock J L, Cox D A, Mitlak B H, Song J, Cummings S R (May 2010). "Effect of Raloxifene on All-cause Mortality". The American Journal of Medicine, 123 (5): 469.e1-469.e7. https://doi.org/10.1016/j.amjmed.2009.12.018
  12. ↑ Barrett-Connor E, Mosca L, Collins P, Geiger M J, Grady D, Kornitzer M, McNabb M A, Wenger N K (2006). "Effects of Raloxifene on Cardiovascular Events and Breast Cancer in Postmenopausal Women". N Engl J Med 2006; 355:125-137. https://doi.org/10.1056/NEJMoa062462
  13. ↑ 13.0 13.1 Messalli E M, Scaffa C (2009). "Long-term safety and efficacy of raloxifene in the prevention and treatment of postmenopausal osteoporosis: an update." International Journal of Women’s Health, 1, 11-20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2971719/
  14. ↑ 14.0 14.1 14.2 14.3 14.4 Cauley J A, Norton L, Lippman M E, Eckert S, Krueger K A, Purdie D W, Farrerons J, Karasik A, Mellstrom D, Ng K W, Stepan J J, Powles T J, Morrow M, Costa A, Silfen S L, Walls E L, Schmitt H, Muchmore D B, Jordan V C (2001). "Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial". Breast Cancer Research and Treatment 65: 125-134. https://doi.org/10.1023/A:1006478317173
  15. ↑ Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E (1998 Aug 19). "Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women". JAMA. 280(7): 605-613. https://www.ncbi.nlm.nih.gov/pubmed/9718051
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