Selective estrogen-receptor modulator

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Selective estrogen receptor modulators (SERMs) are a class of compounds that act on the estrogen receptor.[1] 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[edit]

Nolvadex (tamoxifen) 20-milligram tablets (UK)

SERMs are used dependent on their pattern of action in various tissues:

NameUsesEffects/location
clomifeneused in anovulationantagonist at hypothalamus
femarellemanaging menopause symptoms, osteoporosisagonist at brain and bone
ormeloxifenecontraceptionagonist at bone; antagonist at breast and uterus
raloxifeneosteoporosis, breast canceragonist at bone; antagonist at breast and uterus
tamoxifenbreast canceragonist at bone and uterus, antagonist at breast
toremifenebreast cancer
lasofoxifeneosteoporosis, breast cancer, vaginal atrophyagonist at the bone, antagonist at breast and uterus
ospemifenevaginal atrophy, dysparuniaagonist at the bone, antagonist at breast and uterus

Other members include afimoxifene, arzoxifene, and bazedoxifene.

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 [2] and thrombosis.[3] Some of the above agents still have significant side-effects that contraindicate widespread use.

Mechanism of action[edit]

Estrogenic compounds span a spectrum of activity ranging from:

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.[4][5]

Actions[edit]

The actions of SERMs on various tissues:

See also[edit]

References[edit]

  1. ^ 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. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ 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. 
  5. ^ 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. 

External links[edit]