Selective estrogen-receptor modulator
Selective estrogen receptor modulators (SERMs) are a class of compounds that act on the estrogen receptor. A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues. Phytoserms are SERMs from a botanical source.
Members and uses
SERMs are used dependent on their pattern of action in various tissues:
|clomifene||used in anovulation||antagonist at hypothalamus|
|femarelle||managing menopause symptoms, osteoporosis||agonist at brain and bone|
|ormeloxifene||contraception||agonist at bone; antagonist at breast and uterus|
|raloxifene||osteoporosis, breast cancer||agonist at bone; antagonist at breast and uterus|
|tamoxifen||breast cancer||agonist at bone and uterus, antagonist at breast|
|lasofoxifene||osteoporosis, breast cancer, vaginal atrophy||agonist at the bone, antagonist at breast and uterus|
|ospemifene||vaginal atrophy, dysparunia||agonist at the bone, antagonist at breast and uterus|
Some SERMs may be good replacements for hormone replacement therapy (HRT), which had been commonly used to treat menopause symptoms until the publication of wide scale studies showing that HRT slightly increases the risk of breast cancer  and thrombosis. Some of the above agents still have significant side-effects that contraindicate widespread use.
Mechanism of action
Estrogenic compounds span a spectrum of activity ranging from:
- full agonists (agonistic in all tissues) such as the natural endogenous hormone estrogen
- mixed agonists/antagonistics (agonistic in some tissues while antagonist in others) such as tamoxifen (a SERM)
- pure antagonists (antagonistic in all tissues) such as fulvestrant (ICI-182780).
The mechanism of mixed agonism/antagonism may differ depending on the chemical structure of the SERM, but, for at least for some SERMs, it appears to be related to (1) the ratio of co-activator to co-repressor proteins in different cell types and (2) the conformation of the estrogen receptor induced by drug binding, which in turn determines how strongly the drug/receptor complex recruits co-activators (resulting in an agonist response) relative to co-repressors (resulting in antagonism). For example, the prototypical SERM tamoxifen acts as an antagonist in breast and conversely an agonist in uterus. The concentration of steroid receptor co-activator 1 (SRC-1; NCOA1) is higher in uterus than in breast, therefore SERMs such as tamoxifen are more agonistic in uterus than in breast. In contrast, raloxifene behaves as an antagonist in both tissues. It appears that raloxifene more strongly recruits co-repressor proteins and consequently is still an antagonist in the uterus despite the higher concentration of co-activators relative to co-repressors.
The actions of SERMs on various tissues:
- Bone turnover and postmenopausal osteoporosis respond favorably to most SERMs, although premenopausal women may experience bone loss with some SERMs including tamoxifen.
- Breast - all SERMs decrease breast cancer risk, and tamoxifen is mainly used for its ability to inhibit growth in estrogen receptor-positive breast cancer.
- Cholesterol and triglycerides - levels respond favorably to SERMs.
- Deep venous thrombosis - the risk may be elevated in at least some SERMs.
- Hot flashes are increased by some SERMs.
- Pituitary gland - clomifene blocks estrogen action, leading to an increase of follicle-stimulating hormone and luteinizing hormone.
- Uterus - tamoxifen may increase endometrial carcinoma risk, but raloxifene and femarelle do not. Data on toremifene and clomifene is insufficient.
- Selective receptor modulator
- Selective androgen receptor modulator
- Selective progesterone receptor modulator
- Selective glucocorticoid receptor agonist
- Riggs BL, Hartmann LC (2003). "Selective estrogen-receptor modulators -- mechanisms of action and application to clinical practice". N Engl J Med 348 (7): 618–29. doi:10.1056/NEJMc030651. PMID 12584371.
- Reeves GK, Beral V, Green J, Gathani T, Bull D (November 2006). "Hormonal therapy for menopause and breast-cancer risk by histological type: a cohort study and meta-analysis". Lancet Oncol. 7 (11): 910–8. doi:10.1016/S1470-2045(06)70911-1. PMID 17081916.
- Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J; Writing Group for the Women's Health Initiative Investigators (July 2002). "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial". JAMA 288 (3): 321–33. doi:10.1001/jama.288.3.321. PMID 12117397.
- Shang Y, Brown M (2002). "Molecular determinants for the tissue specificity of SERMs". Science 295 (5564): 2465–8. doi:10.1126/science.1068537. PMID 11923541.
- Smith CL, O'Malley BW (2004). "Coregulator function: a key to understanding tissue specificity of selective receptor modulators". Endocr Rev 25 (1): 45–71. doi:10.1210/er.2003-0023. PMID 14769827.
- AACR Cancer Concepts Factsheet on SERMs
- STAR: a head-to-head comparison of tamoxifen and raloxifene as breast-cancer preventatives
- Femarelle official site
- Raloxifene (Evista) official site