Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs),
are a class of
drug
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...
s that act on the
estrogen receptor
Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen ( 17β-estradiol). Two classes of ER exist: nuclear estrogen receptors (ERα and ERβ), which are members of the ...
(ER).
A characteristic that distinguishes these substances from pure ER
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
s and
antagonists
An antagonist is a character in a story who is presented as the chief foe of the protagonist.
Etymology
The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
(that is,
full agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
s and
silent antagonist
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of recep ...
s) is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.
Medical uses
SERMs are used for various estrogen-related diseases, including treatment of ovulatory dysfunction in the management of infertility, treatment and prevention of postmenopausal osteoporosis, treatment and reduction in risk of breast cancer
and treatment of dyspareunia due to menopause. SERM is also used in combination with conjugated estrogens indicated for the treatment of estrogen deficiency symptoms, and vasomotor symptoms associated with menopause.
SERMs are used dependent on their pattern of action in various tissues:
Tamoxifen
Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has b ...
is a first-line hormonal treatment of ER-positive metastatic breast cancer. It is used for breast cancer risk reduction in women at high risk, and as
adjuvant treatment In pharmacology, an adjuvant is a drug or other substance, or a combination of substances, that is used to increase the efficacy or potency of certain drugs. Specifically, the term can refer to:
* Adjuvant therapy in cancer management
* Analgesi ...
of
axillary node
Axillary means "related to the axilla (armpit)" or "related to the leaf axils".
"Axillary" may refer to: Biology
* Axillary artery
* Axillary border
* Axillary fascia
* Axillary feathers
* Axillary hairs
* Axillary lines
* Axillary lymph nodes
...
-negative and node-positive, ductal carcinoma ''
in situ
''In situ'' (; often not italicized in English) is a Latin phrase that translates literally to "on site" or "in position." It can mean "locally", "on site", "on the premises", or "in place" to describe where an event takes place and is used in ...
''.
Tamoxifen treatment is also useful in the treatment of bone density and
blood lipids
Blood lipids (or blood fats) are lipids in the blood, either free or bound to other molecules. They are mostly transported in a protein capsule, and the density of the lipids and type of protein determines the fate of the particle and its influence ...
in postmenopausal women. Adverse effects include
hot flushes
Hot flashes (also known as hot flushes) are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and ...
and more serious is two to three times higher relative risk of developing
endometrial cancer
Endometrial cancer is a cancer that arises from the endometrium (the lining of the uterus or womb). It is the result of the abnormal growth of cells that have the ability to invade or spread to other parts of the body. The first sign is most o ...
compared to women of an age-matched population.
Toremifene
Toremifene, sold under the brand name Fareston among others, is a medication which is used in the treatment of advanced breast cancer in postmenopausal women.https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020497s006lbl.pdf It is taken ...
, a chlorinated tamoxifen derivative, causes fewer
DNA adducts in liver than seen with tamoxifen in
preclinical studies
In drug development, preclinical development, also termed preclinical studies or nonclinical studies, is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and drug ...
and was developed to avoid hepatic carcinomas. It is used as endocrine therapy in women with ER/PR-positive stage 4 or recurrent metastatic breast cancer
and has demonstrated similar efficacy compared to tamoxifen as adjuvant treatment of breast cancer and in the treatment of metastatic breast cancer.
Raloxifene
Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids. For osteoporosis it is less preferred than bisphosphonates. It is also used to ...
is used for prevention and treatment of postmenopausal osteoporosis and breast cancer prevention in high-risk postmenopausal women with osteoporosis.
Preclinical and clinical reports suggest that it is considerably less potent than estrogen for the treatment of osteoporosis. It is associated with an acceptable endometrial profile and has not demonstrated tamoxifen-like effects in the uterus but has been associated with adverse effects such as
venous thromboembolism
Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...
and vasomotor symptoms, including hot flushes.
Ospemifene
Ospemifene (brand names Osphena and Senshio produced by Shionogi) is an oral medication indicated for the treatment of dyspareuniapain during sexual intercourseencountered by some women, more often in those who are post-menopausal. Ospemifene is ...
is an analogous metabolite of toremifene. Unlike tamoxifen, toremifene is not a rat
hepatocarcinogen and therefore ospemifene would also be a safer SERM than tamoxifen.
It is used for the treatment of moderate to severe dyspareunia, a symptom of
vulva
The vulva (plural: vulvas or vulvae; derived from Latin for wrapper or covering) consists of the external sex organ, female sex organs. The vulva includes the mons pubis (or mons veneris), labia majora, labia minora, clitoris, bulb of vestibu ...
r and
vaginal atrophy
Atrophic vaginitis is inflammation of the vagina as a result of tissue thinning due to not enough estrogen. Symptoms may include pain with sex, vaginal itchiness or dryness, and an urge to urinate or burning with urination. It generally does no ...
associated with menopause. Clinical data on breast cancer are not available, but both in vitro and in vivo data suggest that ospemifene may have chemopreventive activity in breast tissue.
Bazedoxifene
Bazedoxifene, used as bazedoxifene acetate, is a medication for bone problems and possibly (pending more study) for cancer. It is a third-generation selective estrogen receptor modulator (SERM). Since late 2013 it has had U.S. FDA approval for ba ...
is used as treatment for osteoporosis in postmenopausal women at increased risk of fracture. It has been shown to be relatively safe and well tolerated. It shows no breast or endometrial stimulation and in the first two years, the small increase is better in venous thromboembolism, and similar in the long term to other SERMs. The advantage of bazedoxifene over raloxifene is that it increases endothelial nitric oxide synthase activity and does not antagonize the effect of 17β-estradiol on vasomotor symptoms.
The first tissue selective estrogen complex (TSEC) combines conjugated estrogens and the SERM bazedoxifene to blend their activities. The combination therapy is used in the treatment of moderate to severe vasomotor symptoms associated with menopause, prevention of postmenopausal osteoporosis as well as treatment of estrogen deficiency symptoms in non-hysterectomized postmenopausal women. The combination allows for the benefits of estrogen with regard to relief of vasomotor symptoms without estrogenic stimulation of the endometrium.
Available forms
Pharmacology
Pharmacodynamics
SERMs are competitive
partial agonist
In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonistic e ...
s of the ER.
Different tissues have different degrees of sensitivity to the activity of
endogenous
Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell.
In contrast, exogenous substances and processes are those that originate from outside of an organism.
For example, es ...
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
s, so SERMs produce
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
ic or
antiestrogen
Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or inhi ...
ic effects depending on the specific tissue in question as well as the percentage of
intrinsic activity
Intrinsic activity (IA) and efficacy refer to the relative ability of a drug-receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind to its mol ...
(IA) of the SERM.
An example of a SERM with high IA and thus mostly estrogenic effects is
chlorotrianisene
Chlorotrianisene (CTA), also known as tri-''p''-anisylchloroethylene (TACE) and sold under the brand name Tace among others, is a nonsteroidal estrogen related to diethylstilbestrol (DES) which was previously used in the treatment of menopausal s ...
, while an example of a SERM with low IA and thus mostly antiestrogenic effects is
ethamoxytriphetol
Ethamoxytriphetol (developmental code name MER-25) is a synthetic nonsteroidal antiestrogen that was studied clinically in the late 1950s and early 1960s but was never marketed. MER-25 was first reported in 1958, and was the first antiestrogen ...
. SERMs like
clomifene
Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. Use results in a greater chance of twins. It is taken by mouth once a day, with a course ...
and
tamoxifen
Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has b ...
are comparatively more in the middle in their IA and their balance of estrogenic and antiestrogenic activity.
Raloxifene
Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids. For osteoporosis it is less preferred than bisphosphonates. It is also used to ...
is a SERM that is more antiestrogenic than tamoxifen; both are estrogenic in bone, but raloxifene is antiestrogenic in the
uterus
The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The uter ...
while tamoxifen is estrogenic in this part of the body.
Binding site
SERM act on the estrogen receptor (ER), which is an
intracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
, ligand-dependent
transcriptional activator
A transcriptional activator is a protein (transcription factor) that increases transcription of a gene or set of genes. Activators are considered to have ''positive'' control over gene expression, as they function to promote gene transcription and, ...
and belongs to the
nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...
family.
Two different subtypes of ER have been identified,
ERα
Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein)
that is activated by the sex ...
and
ERβ
Estrogen receptor beta (ERβ) also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2) is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by ...
. ERα is considered the main medium where estrogen signals are transduced at the transcriptional level and is the predominant ER in the female reproductive tract and mammary glands while ERβ is primarily in vascular
endothelial cells
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
, bone, and male prostate tissue.
ERα and ERβ concentration are known to be different in tissues during development, aging or disease state.
Many characteristics are similar between these two types such as size (~600 and 530 amino acids) and structure. ERα and ERβ share approximately 97% of the amino-acid sequence identity in the
DNA-binding domain
A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a genera ...
and about 56% in the
ligand-binding domain
In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...
.
The main difference of the ligand-binding domains is determined by
Leu-384 and
Met-421 in ERα, which are replaced by Met-336 and
Ile
Ile may refer to:
* iLe, a Puerto Rican singer
* Ile District (disambiguation), multiple places
* Ilé-Ifẹ̀, an ancient Yoruba city in south-western Nigeria
* Interlingue (ISO 639:ile), a planned language
* Isoleucine, an amino acid
* Anothe ...
-373, respectively, in ERβ.
The variation is greater on the N-terminus between ERα and ERβ.
DNA-binding domain consists of two
subdomains
In the Domain Name System (DNS) hierarchy, a subdomain is a domain that is a part of another (main) domain. For example, if a domain offered an online store as part of their website example.com, it might use the subdomain shop.example.com .
O ...
. One with a proximal box that is involved in DNA recognition while the other contains a distal box responsible for DNA-dependent, DNA-binding domain
dimerization
A dimer () (''wikt:di-, di-'', "two" + ''-mer'', "parts") is an oligomer consisting of two monomers joined by bonds that can be either strong or weak, Covalent bond, covalent or Intermolecular force, intermolecular. Dimers also have significant im ...
. The proximal box sequence is identical between ERα and ERβ, which indicates similar specificity and affinity between the two subgroups. DNA-binding domain's globular proteins contain eight
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
s and allow for a tetrahedral coordination of two
zinc
Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...
ions. This coordination makes the binding of ER to estrogen response elements possible.
Ligand-binding domain is a globular, three-layered structure made of 11
helix
A helix () is a shape like a corkscrew or spiral staircase. It is a type of smooth space curve with tangent lines at a constant angle to a fixed axis. Helices are important in biology, as the DNA molecule is formed as two intertwined helices, ...
es and contains a pocket for the natural or synthetic ligand.
Influencing factors for binding affinity are mainly the presence of a
phenol
Phenol (also called carbolic acid) is an aromatic organic compound with the molecular formula . It is a white crystalline solid that is volatile. The molecule consists of a phenyl group () bonded to a hydroxy group (). Mildly acidic, it req ...
moiety, molecular size and shape, double bonds and
hydrophobicity
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, th ...
.
The differential positioning of the activating function 2 (AF-2) helix 12 in the ligand-binding domain by the bound ligand determines whether the ligand has an agonistic and antagonistic effect. In agonist-bound receptors, helix 12 is positioned adjacent to helices 3 and 5. Helices 3, 5, and 12 together form a binding surface for an NR box motif contained in coactivators with the canonical sequence LXXLL (where L represents leucine or isoleucine and X is any amino acid). Unliganded (apo) receptors or receptors bound to antagonist ligands turn helix 12 away from the LXXLL-binding surface that leads to preferential binding of a longer leucine-rich motif, LXXXIXXX(I/L), present on the corepressors NCoR1 or SMRT. In addition, some cofactors bind to ER through the terminals, the DNA-binding site or other binding sites. Thus, one compound can be an ER agonist in a tissue rich in
coactivators but an ER antagonist in tissues rich in
corepressors.
Mechanism of action
Estrogenic compounds span a spectrum of activity ranging from:
* Full agonists (agonistic in all tissues) such as the natural endogenous hormone
estradiol
Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development of f ...
* Mixed agonists/antagonistics (agonistic in some tissues while antagonistic in others) such as tamoxifen (a SERM).
* Pure antagonists (antagonistic in all tissues) such as
fulvestrant
Fulvestrant, sold under the brand name Faslodex among others, is a medication used to treat hormone receptor (HR)-positive metastatic breast cancer in postmenopausal women with disease progression as well as HR-positive, HER2-negative advanced br ...
.
SERMs are known to stimulate estrogenic actions in tissues such as the liver, bone and cardiovascular system but known to block estrogen action where stimulation is not desirable, such as in the breast and the uterus.
This agonistic or antagonistic activity causes varied structural changes of the receptors, which results in activation or repression of the estrogen target genes.
SERMs interact with receptors by diffusing into cells and there binding to ERα or ERβ subunits, which results in
dimerization
A dimer () (''wikt:di-, di-'', "two" + ''-mer'', "parts") is an oligomer consisting of two monomers joined by bonds that can be either strong or weak, Covalent bond, covalent or Intermolecular force, intermolecular. Dimers also have significant im ...
and structural changes of the receptors. This makes it easier for the SERMs to interact with estrogen response elements which leads to the activation of estrogen-inducible genes and mediating the estrogen effects.
SERMs unique feature is their tissue- and cell-selective activity. There is growing evidence to support that SERM activity is mainly determined by selective recruitment of corepressors and coactivators to ER target genes in specific types of tissues and cells.
SERMs can impact coactivator protein stability and can also regulate coactivator activity through
post-translational modification
Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosome ...
s such as
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
. Multiple growth signaling pathways, such as
HER2
Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...
,
PKC,
PI3K
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
and more, are
downregulated
In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proce ...
in response to anti-estrogen treatment. Steroid receptor coactivator 3 (SRC-3) is phosphorylated by activated
kinase
In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
s that also enhance its coactivator activity, affect cell growth and ultimately contribute to drug resistance.
The ratio of ERα and ERβ at a target site may be another way SERM activity is determined. High levels of cellular proliferation correlate well with a high ERα:ERβ ratio, but repression of cellular proliferation correlates to ERβ being dominant over ERα. The ratio of ERs in
neoplastic
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
and normal breast tissue could be important when considering
chemoprevention
Chemoprevention (also chemoprophylaxis) refers to the administration of a medication for the purpose of preventing disease or infection. Antibiotics, for example, may be administered to patients with disorders of immune system function to prevent b ...
with SERMs.
When looking at the differences between ERα and ERβ, Activating Function 1 (AF-1) and AF-2 are important. Together they play an important part in the interaction with other co-regulatory proteins that control
gene transcription
Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules calle ...
.
AF-1 is located in the amino terminus of the ER and is only 20% homologous in ERα and ERβ. On the other hand, AF-2 is very similar in ERα and ERβ, and only one amino acid is different.
Studies have shown that by switching AF-1 regions in ERα and ERβ, that there are specific differences in transcription activity. Generally, SERMs can partially activate engineered genes through ERα by an estrogen receptor element, but not through ERβ.
Although, raloxifene and the active form of tamoxifen can stimulate AF-1-regulated reporter genes in both ERα and ERβ.
Because of the discovery that there are two ER subtypes, it has brought about the synthesis of a range of receptor specific ligands that can switch on or off a particular receptor.
However, the external shape of the resulting complex is what becomes the catalyst for changing the response at a tissue target to a SERM.
X-ray crystallography
X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
of estrogens or antiestrogens has shown how ligands program the receptor complex to interact with other proteins. The ligand-binding domain of the ER demonstrates how ligands promote and prevent coactivator binding based on the shape of the estrogen or antiestrogen complex. The broad range of ligands that bind to the ER can create a spectrum of ER complexes that are fully estrogenic or antiestrogenic at a specific target site.
The main result of a ligand-binding to ER is a structural rearrangement of the ligand-binding pocket, primarily in the AF-2 of the C-terminal region. The binding of ligands to ER leads to the formation of a
hydrophobic
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, th ...
pocket that regulates cofactors and receptor pharmacology. The correct
folding
Fold, folding or foldable may refer to:
Arts, entertainment, and media
* ''Fold'' (album), the debut release by Australian rock band Epicure
*Fold (poker), in the game of poker, to discard one's hand and forfeit interest in the current pot
*Above ...
of ligand-binding domain is required for activation of transcription and for ER to interact with a number of coactivators.
Coactivators are not just protein partners that connect sites together in a complex. Coactivators play an active role in modifying the activity of a complex. Post-translation modification of coactivators can result in a dynamic model of steroid hormone action by way of multiple kinase pathways initiated by cell surface
growth factor receptor
A growth factor receptor is a receptor that binds to a growth factor. Growth factor receptors are the first stop in cells where the signaling cascade for cell differentiation and proliferation begins. Growth factors, which are ligands that bind to ...
s. Under the guidance of a multitude of protein remodelers to form a multiprotein coactivator complex that can interact with the phosphorylated ER at a specific gene promoter site, the core coactivator first has to recruit a specific set of cocoactivators. The proteins that the core coactivator assembles as the core coactivated complex have individual enzymatic activities to methylate or acetylate adjacent proteins. The ER substrates or
coenzyme A
Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...
can be
polyubiquitinated by multiple cycles of the reaction or, depending on linkage proteins, they can either be activated further or degraded by the
26S proteasome
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by whi ...
.
Consequently, to have an effective gene transcription that is programmed and targeted by the structure and phosphorylation status of the ER and coactivators, it is required to have a dynamic and cyclic process of remodeling capacity for transcriptional assembly, after which the transcription complex is then instantly routinely destroyed by the proteasome.
Structure and function
Structure–activity relationships
The core structure of SERMs simulates the
17β-estradiol
Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development of f ...
template. They have two
aromatic
In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...
rings separated by 1-3 atoms (often a
stilbene Stilbene may refer to one of the two stereoisomers of 1,2-diphenylethene:
* (''E'')-Stilbene (''trans'' isomer)
* (''Z'')-Stilbene (''cis'' isomer)
See also
* Stilbenoids, a class of molecules found in plants
* 1,1-Diphenylethylene
1,1-Diphenyl ...
-type of arrangement). Between the two
phenyl
In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydrogen ...
s of the core, SERMs typically have a 4-substituted phenyl group that, when bound to ER, projects from a position of an estratriene nucleus so that helix 12 moves from the receptor opening and blocks the space where coactivator proteins would normally bind and cause ER agonist activity. There has been a lot of variations in the core portion of SERMs while there has been less flexibility with what is tolerated in the side chain.
SERMs can be classified by their core structure.
First-generation triphenylethylenes
![4OHT vs E2 2](https://upload.wikimedia.org/wikipedia/commons/3/36/4OHT_vs_E2_2.png)
The first main structural class of SERM-type molecules reported are the triphenylethylenes. The stilbene core (similar to the
nonsteroidal estrogen
A nonsteroidal estrogen is an estrogen with a nonsteroidal chemical structure. The most well-known example is the stilbestrol estrogen diethylstilbestrol (DES). Although nonsteroidal estrogens formerly had an important place in medicine, they hav ...
,
diethylstilbestrol
Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used. In the past, it was widely used for a variety of indications, including pregnancy support for those with a ...
) essentially mimics steroidal estrogens such as 17β-estradiol, while the side chain overlays with the 11th position of the steroid nucleus.
Triphenylethylene derivatives have an additional phenyl group attached to the ethylene bridge group. The 3-position H-bonding ability of phenols is a significant requirement for ER binding.
![Clomifene2](https://upload.wikimedia.org/wikipedia/commons/8/8f/Clomifene2.png)
The first drug, clomifene,
has a chloro-substituent on the ethylene side chain which produces similar binding affinities as the later discovered drug tamoxifen. Clomifene is a mixture of estrogenic (
cis-form) and antiestrogenic
isomer
In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers.
Iso ...
s (
trans-form).
Cis and trans are defined in terms of the geometric relationships of the two unsubstituted phenyl rings.
The two isomers of clomifene have different profiles, where the trans-form has activity more similar to tamoxifen while the cis-form behaves more like 17β-estradiol.
Cis is approximately ten times more potent than trans. However, trans isomer is the most potent stimulator of epithelial cell hypertrophy since clomifene is antagonistic at low doses and agonistic at high doses.
The antagonist isomers may cause inhibitory estrogenic effects in the uterus and mammary cancers, but the estrogenic isomer could combine with novel receptors to produce estrogen-like effects in bone.
![Tamoxifen2DACS](https://upload.wikimedia.org/wikipedia/commons/8/8d/Tamoxifen2DACS.svg)
Tamoxifen has become the treatment of choice for women diagnosed with all stages of hormone-responsive breast cancer, that is, breast cancer that is both ER and/or progesterone positive. In the US, it is also administered for prophylactic chemoprevention in women identified as high risk for breast cancer. Tamoxifen is a pure antiestrogenic trans-isomer and has differential actions at estrogen target tissues throughout the body. Tamoxifen is selectively antiestrogenic in the breast but estrogen-like in bones and endometrial cancer.
Tamoxifen undergo
phase I metabolism
Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism (from the Greek xenos "stranger" and biotic "related to living beings") is the set o ...
in the liver by microsomal
cytochrome P450 (CYP) enzymes. The major metabolites of tamoxifen are ''N''-desmethyltamoxifen and
4-hydroxytamoxifen
Afimoxifene, also known as 4-hydroxytamoxifen (4-OHT) and by its tentative brand name TamoGel, is a selective estrogen receptor modulator (SERM) of the triphenylethylene group and an active metabolite of tamoxifen. The drug is under development ...
.
The crystallographic structure of 4-hydroxytamoxifen
interacts with the amino acids of the ER within the ligand-binding domain.
The contact between the phenolic group, water molecule, and glutamate and arginine in the receptor (ERα; Glu 353/Arg 394) resolves in high affinity binding so that 4-hydroxy tamoxifen, with a phenolic ring that resembles the A ring of 17β-estradiol, has more than 100 times higher relative binding affinity than tamoxifen, which has no phenol. If its OH group is eliminated or its position is changed the binding affinity is reduced.
The triphenylethylene moiety and the side chain are required for tamoxifen binding to the ER, whereas for 4-hydroxytamoxifen, the side chain, and the phenyl-propene do not appear as crucial structural elements for binding to the ER. The
basicity
In chemistry, there are three definitions in common use of the word base, known as Arrhenius bases, Brønsted bases, and Lewis bases. All definitions agree that bases are substances that react with acids, as originally proposed by G.-F. Rou ...
and length of the side chain do not seem to play a crucial role for tamoxifen binding affinity to the ER nor the β-ring of tamoxifen, but the stilbene moiety of tamoxifen is necessary for binding to the ER. The hydroxyl group is of particular importance for ER binding of 4-hydroxytamoxifen, and the ethyl side chain of tamoxifen protrudes out of the ligand-binding domain of the ER.
Few tamoxifen users have had increased rates of uterine cancer, hot flushes, and thromboembolisms. The drug can also cause
hepatocarcinomas in rats. This is likely due to the ethyl group of the tamoxifen stilbene core that is subject to
allylic oxidative activation causing DNA
alkylation
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting ...
and strand scission. This problem is later corrected in toremifene.
Tamoxifen is more promiscuous than raloxifene in target sites because of the relationship between ER's amino acid in Asp-351 and the antiestrogenic side chain of the SERM. The side chain for tamoxifen cannot neutralize Asp-351, so the site allosterically influences AF-1 at the proximal end of the ER. This issue is mended with the second-generation drug raloxifene.
Toremifene is a chlorinated derivative of the nonsteroidal triphenylethylene antiestrogen tamoxifen
with a chloro substituent at the ethylene side chain producing similar binding affinities to that of tamoxifen.
The structure and activity relationship of toremifene is similar to that of tamoxifen, but it has a substantial improvement from the older drug in regards to DNA alkylation. The presence of the added chlorine atom reduces the stability of
cation
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
s formed from activated allylic metabolites and thus decreases alkylation potential, and indeed toremifene does not display DNA adduct formation in rodent
hepatocyte
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, ...
s. Toremifene protects against bone loss in ovariectomized rat models and affects bone resorption markers clinically in a similar fashion to tamoxifen.
Toremifene undergoes phase I metabolism by microsomal cytochrome P450 enzymes, like tamoxifen, but primarily by the CYP3A4 isoform. Toremifene forms its two major metabolites N-desmethyltoremifene and
deaminohydroxy-toremifene (ospemifene) by undergoing
N-demethylation Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen ato ...
and deamination-hydroxylation. N-desmethyltoremifene has similar efficacy as toremifene while 4-hydroxytoremifene has a higher binding affinity to the ER than toremifene.
4-hydroxytoremifene has a role similar to that of 4-hydroxytamoxifen.
Second-generation benzothiophenes
Raloxifene belongs to the second-generation
benzothiophene
Benzothiophene is an aromatic organic compound with a molecular formula C8H6S and an odor similar to naphthalene (mothballs). It occurs naturally as a constituent of petroleum-related deposits such as lignite tar. Benzothiophene has no househol ...
SERM drugs. It has a high affinity for the ER with potent antiestrogenic activity and tissue-specific effects distinct from estradiol.
Raloxifene is an ER agonist in bone and the cardiovascular system, but in breast tissue and the endometrium it acts as an ER antagonist. It is extensively metabolized by
glucuronide conjugation
A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides.
Glucuronidation, the conversion of chemical compounds to glucu ...
in the gut and because of that has a low bioavailability of only 2% while that of tamoxifen and toremifene is approximately 100%.
The advantage of raloxifene over the triphenylethylene tamoxifen is reduced effect on the uterus. The flexible hinge group, as well as the antiestrogenic phenyl 4-piperidinoethoxy side chain, are important for minimizing uterine effects. Because of its flexibility the side chain can obtain an orthogonal disposition relative to the core
so that the amine of raloxifens side chain is 1 Å closer than tamoxifens to amino acid Asp-351 in ERα's ligand-binding domain.
The critical role of the intimate relationship between the hydrophobic side chain of raloxifene and the hydrophobic residue of the receptor to change both the shape and charge of the external surface of a SERM-ER complex has been confirmed with raloxifene derivatives. When the interactive distance between raloxifene and Asp-351 is increased from 2.7 Å to 3.5-5 Å it causes increased estrogen-like action of the raloxifene-ERα complex. When the piperidine ring of raloxifene is replaced by
cyclohexane
Cyclohexane is a cycloalkane with the molecular formula . Cyclohexane is non-polar. Cyclohexane is a colorless, flammable liquid with a distinctive detergent-like odor, reminiscent of cleaning products (in which it is sometimes used). Cyclohexan ...
, the ligand loses antiestrogenic properties and becomes a full agonist. The interaction between SERM's antiestrogenic side chain and amino acid Asp-351 is the important first step in silencing AF-2. It relocates helix 12 away from the ligand-binding pocket thereby preventing coactivators from binding to the SERM-ER complex.
Third-generation
![Nafoxidine3](https://upload.wikimedia.org/wikipedia/commons/3/35/Nafoxidine3.png)
Third-generation compounds display either no uterine stimulation, improved potency, no significant increases in hot flushes or even a combination of these positive attributes.
Modifications of the first dihydronapthalene SERM,
nafoxidine
Nafoxidine (; developmental code names U-11,000A) or nafoxidine hydrochloride () is a nonsteroidal selective estrogen receptor modulator (SERM) or partial antiestrogen of the triphenylethylene group that was developed for the treatment of adv ...
that was a clinical candidate for the treatment of breast cancer but had side effects including severe phototoxicity, resulted in lasofoxifene. Nafoxidine has all three phenyls constrained in a coplanar arrangement like tamoxifen. But with hydrogenation, the double bond of nafoxidene were reduced, and both phenyls are cis-oriented. The amine-bearing side chain can then adopt an axial conformation and locate this group orthogonally to the plane of the core, like ralofoxifene and other less uterotropic SERMs.
![Lasofoxifene](https://upload.wikimedia.org/wikipedia/commons/d/d8/Lasofoxifene.png)
Lasofoxifene is among the most potent SERMs reported in protection against bone loss and cholesterol reduction. The excellent oral potency of lasofoxifene has been attributed to reduced intestinal glucuronidation of the phenol.
Unlike raloxifene, lasofoxifene satisfies the requirement of a
pharmacophore
300px, An example of a pharmacophore model.
A pharmacophore is an abstract description of molecular features that are necessary for molecular recognition of a ligand by a biological macromolecule. IUPAC defines a pharmacophore to be "an ensemble o ...
model that predicts resistance to gut wall glucuronidation. The structural requirement is a non-planar topology with the steric bulk close to the plane of a fused bicyclic aromatic system.
The interactions between the ER and lasofoxifene are consistent with the general features of SERM-ER recognition. Lasofoxifenes large flexible side chain terminates in a pyrrolidine head group and threads its way out toward the surface of the protein, where it interferes directly with the positioning of the AF-2 helix. A salt bridge forms between lasofoxifene and Asp-351. The charge neutralization in this region ER may explain some antiestrogenic effects exerted by lasofoxifene.
![Bazedoxifene 2](https://upload.wikimedia.org/wikipedia/commons/1/1e/Bazedoxifene_2.png)
The
indole system has served as a core unit in SERMs, and when an amine is attached to the indole with a benzyloxyethyl, the resultant compounds were shown to have no preclinical uterine activity while sparing rat bone with full efficacy at low doses. Bazedoxifene is one of those compounds. The core binding domain consists of a 2-phenyl-3-methyl indole and a hexamethylenamine ring at the side chain affecter region. It is metabolized by glucuronidation, with the absolute bioavailability of 6.2%, 3-fold higher than that of raloxifene. It has agonistic effects on bone and lipid metabolism but not on breast and uterine endometrium.
It is well tolerated and displays no increase in hot flush incidences, uterine hypertrophy or breast tenderness.
![Ospemifene 2](https://upload.wikimedia.org/wikipedia/commons/d/d0/Ospemifene_2.png)
Ospemifene is a triphenylethylene and a known metabolite of toremifene. It's structurally very similar to tamoxifen and toremifene. Ospemifene does not have 2-(dimethylamino)ethoxy group as tamoxifen. Structure–activity relationship studies shoved that by removing that group of tamoxifen agonistic activity in the uterus was significantly reduced, but not in bone and cardiovascular system. Preclinical and clinical data show that ospemifene is well tolerated with no major side effects. Benefits that ospemifene may have over other SERMs is its neutral effect on hot flushes and ER-agonist effect on the vagina, improving the symptoms of vaginal dryness.
Binding modes
The SERMs are known to feature four distinctive modes of binding to ER. One of those features are strong
hydrogen bonds
In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...
between the ligand and ERα's Arg-394 and Glu-353 that line the "A-ring pocket" and help the ligand to stay in ER's binding pocket. This is unlike 17β-estradiol which is hydrogen bonded to His-524 in the "D-ring pocket".
Other distinctive bindings to the ligand-binding pocket are with a nearly planar "core" structure typically composed of a biaryl
heterocycle
A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different chemical element, elements as members of its ring(s). Heterocyclic chemistry is the branch of organic chemistry dealing with the synthesis ...
, equivalent to the A-ring and B-ring of 17β-estradiol, to the corresponding binding site; a bulky side chain from the
biaryl
Biphenyl (also known as diphenyl, phenylbenzene, 1,1′-biphenyl, lemonene or BP) is an organic compound that forms colorless crystals. Particularly in older literature, compounds containing the functional group consisting of biphenyl less one ...
structure, analogous to the B-ring of 17β-estradiol and finally a second side group that is the C- and D-ring equivalent and usually aromatic, fills the remainder volume of the ligand-binding pocket.
The small differences between the two subtypes of ER have been used to develop subtype-selective ER modulators, but the high similarity between the two receptors make the development very challenging. Amino acids in the ligand-binding domains differ at two positions, Leu-384 and Met-421 in ERα and Met-336 and Ile-373 in ERβ, but they have similar hydrophobicity and occupying volumes. However, the shapes and the rotational barrier of the amino acid residues are not the same, leading to distinguish α- and β-face of the binding cavity between ERα and ERβ. This causes ERα-preferential-binding of ligand
substituent
A substituent is one or a group of atoms that replaces (one or more) atoms, thereby becoming a moiety in the resultant (new) molecule. (In organic chemistry and biochemistry, the terms ''substituent'' and ''functional group'', as well as ''side ...
s that are aligned downwards facing Met-336 while ligand substituents aligned upwards facing Met-336 are more likely to bind to ERβ. Another difference is in Val-392 in ERα, which is replaced by Met-344 in ERβ. ERβ's binding pocket volume is slightly smaller and the shape a bit different from ERα's. Many ERβ-selective ligands have a largely planar arrangement as the binding cavity of ERβ is slightly narrower than that of ERα, however, this by itself leads to modest selectivity. To attain strong selectivity, the ligand must place substituents very close to one or more of the amino acid differences between ERα and ERβ in order to create a strong repulsive force towards the other subtype receptor. In addition, the structure of the ligand must be rigid. Repulsive interactions may otherwise lead to conformational change of the ligand and, therefore, creating alternative binding modes.
First-generation triphenylethylenes
Tamoxifen is converted by the liver cytochrome P450 into the 4-hydroxytamoxifen
and is a more selective antagonist of the ERα subtype than ERβ.
4-hydroxytamoxifen binds to ERs within the same binding pocket that recognizes 17β-estradiol. The receptor recognition of 4-hydroxytamoxifen appears to be controlled by two structural features of 4-hydroxytamoxifen, the phenolic A ring, and the bulky side chain. The phenolic A ring forms hydrogen bonds to the side groups of ER's Arg-394, Glu-354 and to structurally conserved water. The bulky side chain, protruding from the binding cavity, displaces helix 12 from ligand-binding pocket to cover part of the coactivator binding pocket. The ER-4-hydroxytamoxifen complex formation recruits corepressors proteins. This leads to decreased DNA synthesis and inhibition of estrogen activity.
Clomifene and torimefene produce binding affinities similar to that of tamoxifen.
Thus, these two drugs are more selective antagonists of the ERα subtype than ERβ.
Second-generation benzothiophenes
![Raloxifene AnDring](https://upload.wikimedia.org/wikipedia/commons/2/27/Raloxifene_AnDring.png)
Raloxifene, like 4-hydroxytamoxifen, binds to ERα with the hydroxyl group of its phenolic "A ring" through hydrogen bonds with Arg-394 and Glu-353. In addition to these bonds, raloxifene forms a second hydrogen bond to ER through the side group of His-524 because of the presence of a second hydroxyl group in the "D ring". This hydrogen bond is also unlike that between 17β-estradiol and His-524, as the
imidazole ring
Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole, and has non-a ...
of His-524 is rotated to counteract the difference of the oxygen position in raloxifene and in 17β-estradiol. Just like in 4-hydroxytamoxifen, the bulky side chain of raloxifene displaces helix 12.
Third-generation
Lasofoxifene interaction with ERα is typical of those between SERM-ERα such as a nearly planar
topology
In mathematics, topology (from the Greek language, Greek words , and ) is concerned with the properties of a mathematical object, geometric object that are preserved under Continuous function, continuous Deformation theory, deformations, such ...
(the tetrahydronapthalene carbocycle), hydrogen bonding with Arg-394 and Glu-353 and the phenyl side chains of lasofoxifene filling the C-ring and D-ring volume of the ligand-binding pocket. Lasofoxifene diverts helix 12 and prevents the binding of coactivator proteins with LXXLL motives. This is achieved by lasofoxifene occupying the space normally filled by Leu-540's side group and modulating the conformation of residues of helix 11 (His-524, Leu-525). Furthermore, lasofoxifene also directly interferes with helix 12 positioning by the drug's ethyl
pyrrolidine group.
In vitro studies indicate that bazedoxifene competitively blocks 17β-estradiol by high and similar binding to both ERα and ERβ. Bazedoxifenes main binding domain consists of the 2-phenyl-3-methylindole and a hexamethylenamine ring at the side chain affected region.
Ospemifene is an oxidative deaminated metabolite of toremifene as has a similar binding to ER as toremifene and tamoxifen. The competitive binding to ERα and ERβ of the three metabolites 4-hydroxy Ospemifene, 4'-hydroxy Ospemifene and the 4-hydroxy-, side chain carboxylic acid Ospemifene is at least as high as the parent compound.
History
![Selective estrogen receptor modulator timeline](https://upload.wikimedia.org/wikipedia/commons/c/c2/Selective_estrogen_receptor_modulator_timeline.svg)
The discovery of SERMs resulted from attempts to develop new contraceptives.
Clomifene
Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. Use results in a greater chance of twins. It is taken by mouth once a day, with a course ...
and
tamoxifen
Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has b ...
prevented conception in rats but did the opposite in humans. Clomifene successfully induced ovulation in
subfertile women
Female infertility refers to infertility in women. It affects an estimated 48 million women, with the highest prevalence of infertility affecting women in South Asia, Sub-Saharan Africa, North Africa/Middle East, and Central/Eastern Europe and Cen ...
and on February 1, 1967, it was approved in the US for the treatment o
ovulatory dysfunctionin women who were trying to conceive.
Toxicological
Toxicology is a scientific discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnosing and treating expos ...
issues prevented long term use of clomifene and further drug development for other potential applications such as
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
treatment and prevention.
It was another ten years before tamoxifen was approved in December 1977, not as a contraceptive but as a hormonal treatment to treat and prevent breast cancer.
The discovery in 1987 that the SERMs tamoxifen and
raloxifene
Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids. For osteoporosis it is less preferred than bisphosphonates. It is also used to ...
, then thought to be
antiestrogen
Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or inhi ...
s because of antagonist effects in breast tissue, showed estrogenic effects in preventing bone loss in
ovariectomized rat An ovariectomized rodent (OVX) is a female rat or mouse whose ovaries have been removed. Currently there is no single animal model that identically represents the stages of osteoporosis in humans although there are some animals that are relatively ...
s had a great effect on our understanding of the function of estrogen receptors and
nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...
s in general.
The term SERM was introduced to describe these compounds that have a combination of estrogen
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
, partial agonist, or antagonist activities depending on the tissue.
Toremifene has been shown to be compatible with tamoxifen, and in 1996 it was approved for use in the treatment of breast cancer in postmenopausal women.
Raloxifene originally failed as a breast cancer drug due to its poor performance in comparison to tamoxifen in the laboratory
but the estrogenic effects of raloxifene on bone led to its rediscovery and approval in 1997.
It was approved for prevention and treatment of osteoporosis and was the first clinically available SERM to prevent both osteoporosis and breast cancer.
Ospemifene
Ospemifene (brand names Osphena and Senshio produced by Shionogi) is an oral medication indicated for the treatment of dyspareuniapain during sexual intercourseencountered by some women, more often in those who are post-menopausal. Ospemifene is ...
was approved on February 26, 2013, for the treatment of moderate to severe
dyspareunia
Dyspareunia ( ) is painful sexual intercourse due to medical or psychological causes. The term ''dyspareunia'' covers both female dyspareunia and male dyspareunia, but many discussions that use the term without further specification concern the f ...
, which is a symptom, due to
menopause
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...
, of vulvar and vaginal
atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply t ...
. Combined therapy with
conjugated estrogen
Conjugated estrogens (CEs), or conjugated equine estrogens (CEEs), sold under the brand name Premarin among others, is an estrogen medication which is used in menopausal hormone therapy and for various other indications. It is a mixture of the ...
s and the SERM
bazedoxifene
Bazedoxifene, used as bazedoxifene acetate, is a medication for bone problems and possibly (pending more study) for cancer. It is a third-generation selective estrogen receptor modulator (SERM). Since late 2013 it has had U.S. FDA approval for ba ...
, was approved on October 3, 2013, for the treatment of
vasomotor symptoms
Hot flashes (also known as hot flushes) are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and ...
linked with menopause. Bazedoxifene is also used in the prevention of postmenopausal osteoporosis.
The search for a
potent SERM with bone efficacy and better bioavailability than raloxifene led to the discovery of lasofoxifene.
Although lasofoxifene was approved in 2009, it was not marketed for three years following the approval, so the marketing authorization for it has expired.
In Europe, bazedoxifene is indicated for the treatment of osteoporosis in postmenopausal women at increased risk of fracture while in India
ormeloxifene
Ormeloxifene, also known as centchroman, is one of the selective estrogen receptor modulators, or SERMs, a class of medication which acts on the estrogen receptor. It is best known as a nonsteroidal oral contraceptive which is taken once per we ...
has been used for
dysfunctional uterine bleeding
Abnormal uterine bleeding (AUB), also known as (AVB) or as atypical vaginal bleeding, is vaginal bleeding from the uterus that is abnormally frequent, lasts excessively long, is heavier than normal, or is irregular. The term dysfunctional uterin ...
and birth control.
See also
*
Estrogen deprivation therapy
Estrogen deprivation therapy, also known as endocrine therapy, is a form of hormone therapy that is used in the treatment of breast cancer. Modalities include antiestrogens or estrogen blockers such as selective estrogen receptor modulators (SERMs) ...
*
List of selective estrogen receptor modulators
This is a list of selective estrogen receptor modulators (SERMs).
Approved
SERMs that have been approved for medical use include anordrin (+mifepristone (Zi Yun)), bazedoxifene ( +conjugated estrogens (Duavee)), broparestrol (Acnestrol), clomi ...
*
Selective androgen receptor modulator
Selective Androgen Receptor Modulators or SARMs are a class of androgen receptor ligands that maintain some of the desirable effects of androgens, such as preventing osteoporosis and muscle loss while reducing risks of developing prostate cancer ...
*
Selective estrogen receptor degrader
A selective estrogen receptor degrader or downregulator (SERD) is a type of drug which binds to the estrogen receptor (ER) and, in the process of doing so, causes the ER to be degraded and thus downregulated. They are used to treat estrogen recep ...
*
Selective receptor modulator
In 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 modu ...
*
Timeline of cancer treatment development
This is a historical timeline of the development and progress of cancer treatments, which includes time of discovery, progress, and approval of the treatments.
Ancient Era
Cancer was traditionally treated with surgery, heat, or herbal (chemical) ...
References
External links
AACR Cancer Concepts Factsheet on SERMs*
ttp://www.femarelle.com Femarelle official sitebr>
Raloxifene (Evista) official site
{{Estrogen receptor modulators
Hormonal antineoplastic drugs
Progonadotropins