Selective estrogen receptor modulator
Encyclopedia
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 agonist
s 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. Phytoserm
s are SERMs from a botanical source.
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
and thrombosis
. Some of the above agents still have significant side-effects that contraindicate widespread use.
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.
Estrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
. A characteristic that distinguishes these substances from pure receptor agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
s and antagonists
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues. Phytoserm
Phytoserm
PhytoSERM are botanically derived substances that possess SERM qualities, similar to synthetically manufactured drugs of the same category.-Mechanism of action:...
s are SERMs from a botanical source.
Members and uses
SERMs are used dependent on their pattern of action in various tissues:| Name | Uses | Effects/location |
|---|---|---|
| clomifene Clomifene Clomifene or clomiphene or Clomid or Clomifert is a selective estrogen receptor modulator that increases production of gonadotropins by inhibiting negative feedback on the hypothalamus... |
used in anovulation Anovulation An anovulatory cycle is a menstrual cycle during which the ovaries do not release an oocyte. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause... |
antagonist at hypothalamus |
| femarelle | managing menopause Menopause Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining... symptoms, osteoporosis Osteoporosis Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered... |
agonist at brain and bone |
| ormeloxifene | contraception Contraception Contraception is the prevention of the fusion of gametes during or after sexual activity. The term contraception is a contraction of contra, which means against, and the word conception, meaning fertilization... |
agonist at bone; antagonist at breast and uterus |
| raloxifene Raloxifene Raloxifene is an oral selective estrogen receptor modulator that has estrogenic actions on bone and anti-estrogenic actions on the uterus and breast... |
osteoporosis Osteoporosis Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered... , breast cancer Breast cancer Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas... |
agonist at bone; antagonist at breast and uterus |
| tamoxifen Tamoxifen Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist... |
breast cancer Breast cancer Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas... |
agonist at bone and uterus, antagonist at breast |
| toremifene Toremifene Toremifene citrate is an oral selective estrogen receptor modulator which helps oppose the actions of estrogen in the body. Licensed in the United States under the brand name Fareston, toremifene citrate is FDA-approved for use in advanced breast cancer... |
breast cancer Breast cancer Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas... |
|
| lasofoxifene Lasofoxifene Lasofoxifene is a non-steroidal selective estrogen receptor modulator which is under development by Pfizer for the prevention and treatment of osteoporosis and for the treatment of vaginal atrophy, and the result of an exclusive research collaboration with Ligand Pharmaceuticals .In September... |
osteoporosis Osteoporosis Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered... , breast cancer Breast cancer Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas... , vaginal atrophy |
agonist at the bone, antagonist at breast and uterus |
Other members include afimoxifene
Afimoxifene
Afimoxifene is a selective estrogen receptor modulator which is the active metabolite of tamoxifen. Afimoxifene is a transdermal gel formulation and is being developed by Ascend Therapeutics, Inc...
, arzoxifene
Arzoxifene
Arzoxifene is a selective estrogen receptor modulator. It is a potent estrogen antagonist in mammary and uterine tissue while acting as an estrogen agonist to maintain bone density and lower serum cholesterol...
, and bazedoxifene
Bazedoxifene
Bazedoxifene is a third generation selective estrogen receptor modulator , under development by Pfizer following the completion of their takeover of Wyeth Pharmaceuticals. Pfizer are seeking approval for bazedoxifene in the prevention and treatment of postmenopausal osteoporosis...
.
Some SERMs may be good replacements for hormone replacement therapy
Hormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
(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
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
and thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
. 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 estrogenEstrogenEstrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
- mixed agonists/antagonistics (agonistic in some tissues while antagonist in others) such as tamoxifen (a SERM)
- pure antagonists (antagonistic in all tissues) such as fulvestrantFulvestrantFulvestrant, also known as ICI 182,780, is a drug treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy. It is an estrogen receptor antagonist with no agonist effects, which works both by down-regulating and...
(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
Coactivation (Transcription)
Coactivation is a process by which the transcription of RNA is increased. Proteins called coactivators are recruited to DNA-binding transcription factors through their activation domains and increase transcription by relaxing the chromatin structure to allow greater access to a gene or by bringing...
to co-repressor
Corepressor (genetics)
In molecular genetics, a corepressor is a substance that inhibits the expression of genes. A corepressor downregulates the expression of genes not through direct interaction with a gene promoter , but rather indirectly through interaction with repressor proteins that in turn bind to the...
proteins in different cell types and (2) the conformation
Tertiary structure
In biochemistry and molecular biology, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates.-Relationship to primary structure:...
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.
Actions
The actions of SERMs on various tissues:- BoneBoneBones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
turnover and postmenopausal osteoporosisOsteoporosisOsteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
respond favorably to most SERMs, although premenopausal women may experience bone loss with some SERMs including tamoxifen. - BreastBreastThe breast is the upper ventral region of the torso of a primate, in left and right sides, which in a female contains the mammary gland that secretes milk used to feed infants.Both men and women develop breasts from the same embryological tissues...
- all SERMs decrease breast cancer risk, and tamoxifen is mainly used for its ability to inhibit growth in estrogen receptor-positive breast cancer. - CholesterolCholesterolCholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
and triglycerideTriglycerideA triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
s - 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 glandPituitary glandIn vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
- clomifene blocks estrogen action, leading to an increase of follicle-stimulating hormoneFollicle-stimulating hormoneFollicle-stimulating hormone is a hormone found in humans and other animals. It is synthesized and secreted by gonadotrophs of the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and Luteinizing hormone act...
. - UterusUterusThe uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...
- tamoxifen may increase endometrial carcinoma risk, but raloxifene and femarelle do not. Data on toremifene and clomifene is insufficient.
See also
- Selective receptor modulatorSelective receptor modulatorIn the field of pharmacology, a selective receptor modulator or SRM is a type of drug that has different effects in different tissues. A SRM may behave as an agonist in some tissues while as an antagonist in others. Hence selective receptor modulators are sometimes referred to as tissue selective...
- Selective androgen receptor modulatorSelective androgen receptor modulatorSelective androgen receptor modulators or SARMs are a novel class of androgen receptor ligands. They are intended to have the same kind of effects as androgenic drugs like anabolic steroids but be much more selective in...
- Selective progesterone receptor modulatorSelective progesterone receptor modulatorA selective progesterone receptor modulator is an agent that acts on the progesterone receptor. A characteristic that distinguishes such substances from receptor full agonists and full antagonists is that their action differs in different tissues...
- Selective glucocorticoid receptor agonistSelective glucocorticoid receptor agonistA selective glucocorticoid receptor agonist , sometimes called a dissociated glucocorticoid receptor agonist , is a type of experimental drug that is designed to share many of the desirable anti-inflammatory and immunosuppressive properties of classical glucocorticoid drugs but with fewer side...