関: selective estrogen receptor modulator、SERM

WordNet

tending to select; characterized by careful choice; "an exceptionally quick and selective reader"- John Mason Brown
characterized by very careful or fastidious selection; "the school was very selective in its admissions"
a cellular structure that is postulated to exist in order to mediate between a chemical agent that acts on nervous tissue and the physiological response

PrepTutorEJDIC

選択の,染択する / 注意して選ばれた / 淘汰(とうた)の / (無線が)選択度の高い
=sense organ / 受信装置
=estrogen

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/03/07 01:36:27」(JST)

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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

Nolvadex (tamoxifen) 20-milligram tablets (UK)

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

Name	Uses	Effects/location
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
toremifene	breast cancer
lasofoxifene	osteoporosis, breast cancer, vaginal atrophy	agonist 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

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.^[4]^[5]

Actions

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.

References

^ 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. http://jama.ama-assn.org/cgi/pmidlookup?view=long&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.

External links

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

UpToDate Contents

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1. 選択的エストロゲン受容体モジュレーターの作用機序 mechanisms of action of selective estrogen receptor modulators
2. 骨粗鬆症の予防および治療のための選択的エストロゲン受容体調節剤 selective estrogen receptor modulators for prevention and treatment of osteoporosis
3. 乳癌予防のための選択的エストロゲン受容体調節因子およびアロマターゼ阻害剤 selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention
4. 転移性ホルモン受容体陽性乳癌に対する治療アプローチ：内分泌療法 treatment approach to metastatic hormone receptor positive breast cancer endocrine therapy
5. 閉経後の女性における骨粗鬆症のマネージメントの概要 overview of the management of osteoporosis in postmenopausal women

English Journal

Carcinogenicity and hormone studies with the tissue-selective estrogen receptor modulator bazadoxifene.

Wright DJ, Earnhardt JN, Perry R, Bailey S, Komm B, Minck DR, Cukierski MA.SourceDrug Safety Research & Development, Pfizer, Groton, Connecticut. david.wright@pfizer.com.
Journal of cellular physiology.J Cell Physiol.2013 Apr;228(4):724-33. doi: 10.1002/jcp.24219.
Bazedoxifene Acetate (BZA) is a selective estrogen receptor modulator (SERM) that is approved for the prevention and/or treatment of osteoporosis in postmenopausal women. To assess for carcinogenic potential, BZA was administered ad libitum in the diet to rats for 2 years. BZA caused an increase in
PMID 22949219

The molecular mechanisms underlying the pharmacological actions of estrogens, SERMs and oxysterols: Implications for the treatment and prevention of osteoporosis.

Nelson ER, Wardell SE, McDonnell DP.SourceDepartment of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
Bone.Bone.2013 Mar;53(1):42-50. doi: 10.1016/j.bone.2012.11.011. Epub 2012 Nov 17.
Estrogen therapy and hormone therapy are effective options for the prevention and treatment of osteoporosis, although because of their significant side effect profile, long term use for these applications is not recommended. Whereas SERMs (Selective Estrogen Receptor Modulators) exhibit a more favor
PMID 23168292

Pharmacological characterization of an imidazolopyrazole as novel selective androgen receptor modulator.

Zhang X, Allan GF, Tannenbaum P, Sbriscia T, Linton O, Lai MT, Haynes-Johnson D, Bhattacharjee S, Lundeen SG, Sui Z.SourceJanssen Research and Development LLC, Welsh&McKean Roads, Spring House, PA 19477, USA. Electronic address: xzhang5@its.jnj.com.
The Journal of steroid biochemistry and molecular biology.J Steroid Biochem Mol Biol.2013 Mar;134:51-8. doi: 10.1016/j.jsbmb.2012.10.015. Epub 2012 Oct 23.
Selective androgen receptor modulators (SARMs) are androgens with tissue-selective activity. SARMs that have anabolic activity on muscle while having minimal stimulatory activity on prostate are classified as SARM agonists. They can be used to prevent the loss of lean body mass that is associated wi
PMID 23098693

Japanese Journal

6-Carboxymethyl genistein : a novel selective oestrogen receptor modulator (SERM) with unique, differential effects on the vasculature, bone and uterus