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 scientifically accepted SERMs from a botanical source.

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 uterus and breast
raloxifene	osteoporosis, breast cancer	agonist at bone; antagonist at uterus and breast
tamoxifen	breast cancer	agonist at bone and uterus, antagonist at breast
toremifene	breast cancer

Other members include afimoxifene, arzoxifene, bazedoxifene, and lasofoxifene.

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 Some of the above agents still have significant side-effects which contraindicate widespread use.

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; ) 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.

• 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

• 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

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