Tamoxifen, sold under the brand name Nolvadex among others, is a

selective estrogen receptor modulator Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonists/antagonists (ERAAs), are a class of drugs that act on estrogen receptors (ERs). Compared to pure ER agonists–antagonists (e.g., full agonists and silent ...

used to prevent

breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

in women and men. It is also being studied for other types of

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

. It has been used for Albright syndrome. Tamoxifen is typically taken daily

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

for five years for breast cancer. Serious side effects include a small increased risk of

uterine cancer Uterine cancer, also known as womb cancer, includes two types of cancer that develop from the tissues of the uterus. Endometrial cancer forms from the lining of the uterus, and uterine sarcoma forms from the muscles or support tissue of the ute ...

stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...

, vision problems, and

pulmonary embolism Pulmonary embolism (PE) is a blockage of an pulmonary artery, artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include dyspnea, shortness of breath, chest pain ...

. Common side effects include irregular periods, weight loss, and hot flashes. It may cause harm to the baby if taken during

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...

. It is a

selective estrogen-receptor modulator Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonists/antagonists (ERAAs), are a class of drugs that act on estrogen receptors (ERs). Compared to pure ER agonists–Receptor antagonist, antagonists (e.g., full a ...

(SERM) and works by decreasing the growth of breast cancer cells. It is a member of the

triphenylethylene Triphenylethylene (TPE) is the organic compound with the formula . It is a colorless solid. Synthesis and reactions The compound is prepared in two steps from benzophenone via the intermediacy of 1,2,2-triphenylethanol. Triphenylethylene reacts ...

group of compounds. Tamoxifen was initially made in 1962, by chemist Dora Richardson. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. Tamoxifen is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

. In 2020, it was the 317th most commonly prescribed medication in the United States, with more than 900thousand prescriptions.

Medical uses

Dysmenorrhea

Dysmenorrhea Dysmenorrhea, also known as period pain, painful periods or menstrual cramps, is pain during menstruation. Its usual onset occurs around the time that menstruation begins. Symptoms typically last less than three days. The pain is usually in th ...

is the term for menstrual pain, usually centered in the lower abdomen but often spreading to the back and inner thighs. It is a common gynecological condition that can seriously affect daily activities and well-being. Tamoxifen has been identified and used to effectively improve blood flow, reduce uterine contractility and pain in dysmenorrhea patients.

Breast cancer

Tamoxifen is used for the treatment of both early and advanced

estrogen receptor Estrogen receptors (ERs) are proteins found in cell (biology), cells that function as receptor (biochemistry), receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen ...

-positive (ER-positive or ER+) breast cancer in pre- and

postmenopausal Menopause, also known as the climacteric, is the time when menstrual periods permanently stop, marking the end of the reproductive stage for the female human. It typically occurs between the ages of 45 and 55, although the exact timing can ...

women. Tamoxifen increases the risk of postmenopausal bleeding,

endometrial polyp An endometrial polyp or uterine polyp is a tumor, mass in the inner lining of the uterus. They may have a large flat base (Sessility (medicine), sessile) or be attached to the uterus by an elongated wikt:pedicle, pedicle (pedunculated). Peduncul ...

hyperplasia Hyperplasia (from ancient Greek ὑπέρ ''huper'' 'over' + πλάσις ''plasis'' 'formation'), or hypergenesis, is an enlargement of an organ or tissue caused by an increase in the amount of Tissue (biology), organic tissue that results from ...

, and

endometrial cancer Endometrial cancer is a cancer that arises from the endometrium (the epithelium, lining of the uterus or womb). It is the result of the abnormal growth of cells (biology), cells that can invade or spread to other parts of the body. The first s ...

; using tamoxifen with an

intrauterine system A hormonal intrauterine device (IUD), also known as an intrauterine system (IUS) with progestogen and sold under the brand name Mirena among others, is an intrauterine device that releases a progestogenic hormonal agent such as levonorgestrel ...

releasing

levonorgestrel Levonorgestrel is a hormonal medication used in a number of birth control methods. It is combined with an estrogen to make combination birth control pills. As an emergency birth control, sold under the brand names Plan B One-Step and Julie, ...

might increase vaginal bleeding after 1 to 2 years, but reduces somewhat endometrial polyps and hyperplasia, but not necessarily endometrial cancer. Additionally, it is the most common hormone treatment for male breast cancer. It is also approved by the

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

for the prevention of breast cancer in women at high risk of developing the disease. The effectiveness of tamoxifen is primarily influenced by estrogen receptor (ER) status, which was the key predictor of the proportional benefits observed. It has been further approved for the reduction of

contralateral Standard anatomical terms of location are used to describe unambiguously the anatomy of humans and other animals. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position prov ...

(in the opposite breast) cancer. Five years of adjuvant tamoxifen treatment significantly lowers the 15-year risk of breast cancer recurrence and mortality. The overall use of tamoxifen is recommended for 10 years. In 2006, the large STAR clinical study concluded that

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 ...

is also effective in reducing the incidence of breast cancer. Updated results after an average of 6.75 years of follow up found that raloxifene retains 76% of tamoxifen's effectiveness in preventing invasive breast cancer, with 45% fewer

s and 25% fewer blood clots in women taking raloxifene than in women taking tamoxifen.

Infertility

Tamoxifen is used for

ovulation induction Ovulation induction is the stimulation of ovulation by medication. It is usually used in the sense of stimulation of the development of ovarian follicles to reverse anovulation or oligoovulation. Scope The term ''ovulation induction'' can p ...

to treat infertility in women with

anovulatory Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovul ...

disorders. It is given at days three to seven of a woman's cycle. Tamoxifen improves fertility in males with infertility by disinhibiting the

hypothalamic–pituitary–gonadal axis The hypothalamic–pituitary–gonadal axis (HPG axis, also known as the hypothalamic–pituitary–ovarian/testicular axis) refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single en ...

(HPG axis) via ER antagonism and thereby increasing the secretion of

luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (G ...

(LH) and

follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, puberty, pubertal maturat ...

(FSH) and increasing testicular

testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

production. Some animal studies have suggested tamoxifen could have negative effects on sperm quality and prostatic and gonadal health.

Gynecomastia

Benign enlargement of the male breast, whether

asymptomatic Asymptomatic (or clinically silent) is an adjective categorising the medical conditions (i.e., injuries or diseases) that patients carry but without experiencing their symptoms, despite an explicit diagnosis (e.g., a positive medical test). P ...

or painful, is a common condition thought to result from an increased estrogen/testosterone ratio or from heightened

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

ic or reduced

androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...

ic activity via receptor interactions.Tamoxifen is used to prevent and treat

gynecomastia Gynecomastia (also spelled gynaecomastia) is the non-cancerous enlargement of one or both breasts in men due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse (10 Novemb ...

. It is taken as a preventative measure in small doses, or used at the onset of any symptoms such as nipple soreness or sensitivity. Current treatments typically involve pain relief through medication or surgery. However, targeting the underlying estrogenic stimulation may offer a more specific therapeutic approach. In a double-blind crossover study, patients were given either a placebo or tamoxifen (10 mg orally twice daily) for one month, in random order. Seven out of ten patients saw a reduction in gynecomastia size with tamoxifen (P < 0.005), and the overall reduction for the group was statistically significant (P < 0.01). No benefits were observed with the placebo (P > 0.1). Additionally, all four patients with painful gynecomastia experienced relief of their symptoms, and no toxicity was noted. Although the breast size reduction was partial, this suggests that longer treatment may be necessary. Follow-up examinations conducted 9 to 12 months after treatment revealed no significant changes, except in two cases: one tamoxifen responder had a recurrence of breast tenderness after six months, and one non-responder developed increased breast size and new tenderness after ten months. Other medications are taken for similar purposes such as

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. It is taken by mouth. Common side effects include pelvic pain and hot flashes. Oth ...

and

aromatase inhibitor Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and in men, and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when supplementing testosterone exo ...

drugs; which are used in order to try to avoid the hormone-related adverse effects. Overall, tamoxifen appears to be a safe and effective treatment option for selected cases of gynecomastia.

Early puberty

Tamoxifen is useful in the treatment of peripheral precocious puberty, for instance due to

McCune–Albright syndrome McCune–Albright syndrome is a complex genetic disorder affecting the bone, skin and endocrine systems. It is a mosaic disease arising from somatic activating mutations in '' GNAS'', which encodes the alpha-subunit of the Gs heterotrimeric G ...

, in both girls and boys. It has been found to decrease growth velocity and the rate of

bone maturation Bone age is the degree of a person's skeletal development. In children, bone age serves as a measure of physiological maturity and aids in the diagnosis of growth abnormalities, endocrine disorders, and other medical conditions. As a person grows ...

in girls with precocious puberty, and hence to improve final

height Height is measure of vertical distance, either vertical extent (how "tall" something or someone is) or vertical position (how "high" a point is). For an example of vertical extent, "This basketball player is 7 foot 1 inches in height." For an e ...

in these individuals.

Available forms

Tamoxifen is available as a tablet or oral solution.

Contraindications

Tamoxifen has a number of

contraindication In medicine, a contraindication is a condition (a situation or factor) that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a rea ...

s, including known

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) is an abnormal physiological condition in which there is an undesirable and adverse immune response to an antigen. It is an abnormality in the immune system that causes Imm ...

to tamoxifen or other ingredients, individuals taking concomitant

coumarin Coumarin () or 2''H''-chromen-2-one is an aromatic organic chemical compound with formula . Its molecule can be described as a benzene molecule with two adjacent hydrogen atoms replaced by an unsaturated lactone ring , forming a second six-me ...

-type

anticoagulant An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which ...

therapy, and women with a history of

venous thromboembolism Venous thrombosis is the 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 lun ...

(

deep vein thrombosis Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enl ...

Side effects

A report in September 2009 from Health and Human Services' Agency for Healthcare Research and Quality suggests that tamoxifen, raloxifene, and tibolone used to treat breast cancer significantly reduce invasive breast cancer in midlife and older women, but also increase the risk of adverse side effects.

Endometrial cancer

Tamoxifen is a

(SERM). Even though it is an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

on the

endometrium The endometrium is the inner epithelium, epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The funct ...

and has been linked to

in some women. Therefore, endometrial changes, including cancer, are among tamoxifen's side effects. With time, risk of endometrial cancer may be doubled to quadrupled, which is a reason tamoxifen is typically only used for five years. The

American Cancer Society The American Cancer Society (ACS) is a nationwide non-profit organization dedicated to eliminating cancer. The ACS publishes the journals ''Cancer'', '' CA: A Cancer Journal for Clinicians'' and '' Cancer Cytopathology''. History The society w ...

lists tamoxifen as a known

carcinogen A carcinogen () is any agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and biologic agents such as viruse ...

, stating that it increases the risk of some types of uterine cancer while lowering the risk of breast cancer recurrence.

Cardiovascular and metabolic

Tamoxifen treatment of postmenopausal women is associated with beneficial effects on serum lipid profiles. However, long-term data from clinical trials have failed to demonstrate a cardioprotective effect. For some women, tamoxifen can cause a rapid increase in

triglyceride A triglyceride (from '' tri-'' and '' glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and other vertebrates ...

concentration in the blood. In addition, there is an increased risk of

thromboembolism Thromboembolism is a condition in which a blood clot (thrombus) breaks off from its original site and travels through the bloodstream (as an embolus) to obstruct a blood vessel, causing tissue ischemia and organ damage. Thromboembolism can affe ...

especially during and immediately after major surgery or periods of immobility. Use of tamoxifen has been shown to slightly increase risk of

, and

Liver toxicity

Tamoxifen has been associated with a number of cases of

hepatotoxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury (DILI) is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdr ...

. Several different varieties of hepatotoxicity have been reported. Tamoxifen can also precipitate

non-alcoholic fatty liver disease An alcohol-free or non-alcoholic drink, also known as a temperance drink, is a version of an alcoholic drink made without alcohol, or with the alcohol removed or reduced to almost zero. These may take the form of a non-alcoholic mixed drink or n ...

in obese and overweight women (not in normal weight women) at an average rate of 40% after a year use with 20 mg/day.

Overdose

Acute

overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.

of tamoxifen has not been reported in humans. In dose-ranging studies, tamoxifen was administered at very high doses in women (e.g., 300 mg/m²) and was found to produce acute

neurotoxicity Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...

including

tremor A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...

hyperreflexia Hyperreflexia is overactive or overresponsive bodily reflexes. Examples of this include twitching and spastic tendencies, which indicate disease of the upper motor neurons and the lessening or loss of control ordinarily exerted by higher brain ...

, unsteady gait, and

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

. These symptoms occurred within three to five days of therapy and disappeared within two to five days of discontinuation of therapy. No indications of permanent neurotoxicity were observed.

QT prolongation QT or Qt may refer to: Businesses * The Qt Company, a Finnish software developer * QT Hotels & Resorts, an Australasian hospitality provider * QT Inc., an American bracelet manufacturer * QuikTrip, an American convenience store chain People * ...

was also observed with very high doses of tamoxifen. There is no specific

antidote An antidote is a substance that can counteract a form of poisoning. The term ultimately derives from the Greek term φάρμακον ἀντίδοτον ''(pharmakon antidoton)'', "(medicine) given as a remedy". An older term in English which is ...

for overdose of tamoxifen. Instead, treatment should be based on

symptom Signs and symptoms are diagnostic indications of an illness, injury, or condition. Signs are objective and externally observable; symptoms are a person's reported subjective experiences. A sign for example may be a higher or lower temperature ...

Interactions

Patients with variant forms of the gene

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2 ...

may not receive full benefit from tamoxifen because of too slow metabolism of the tamoxifen prodrug into its active metabolites. On 18 October 2006, the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about this gene in the package insert. Certain CYP2D6 variations in breast cancer patients lead to a worse clinical outcome for tamoxifen treatment.

Genotyping Genotyping is the process of determining differences in the genetic make-up (genotype) of an individual by examining the individual's DNA sequence using bioassay, biological assays and comparing it to another individual's sequence or a reference seq ...

therefore has the potential for identification of women who have these CYP2D6 phenotypes and for whom the use of tamoxifen is associated with poor outcomes. Recent research has shown that 7–10% of women with breast cancer may not receive the full medical benefit from taking tamoxifen due to their genetic make-up. DNA Drug Safety Testing can examine DNA variations in the CYP2D6 and other important drug processing pathways. More than 20% of all clinically used medications are metabolized by CYP2D6 and knowing the CYP2D6 status of a person can help the doctor with the future selection of medications. Other molecular biomarkers may also be used to select appropriate patients likely to benefit from tamoxifen. Recent studies suggest that taking the

selective serotonin reuptake inhibitors Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by blo ...

(SSRIs) antidepressants

paroxetine Paroxetine ( ), sold under the brand name Paxil among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used to treat major depressive disorder, obsessive-compulsive disorder, o ...

(Paxil),

fluoxetine Fluoxetine, sold under the brand name Prozac, among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used for the treatment of major depressive disorder, Anxiety disorder, anx ...

(Prozac), and

sertraline Sertraline, sold under the brand name Zoloft among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used to treat major depressive disorder, generalized anxiety disorder, socia ...

(Zoloft) can decrease the effectiveness of tamoxifen, as these drugs compete for the CYP2D6 enzyme which is needed to metabolize tamoxifen into its active forms. A U.S. study presented at the American Society of Clinical Oncology's annual meeting in 2009 found that after two years, 7.5% of women who took only tamoxifen had a recurrence, compared with 16% who took either paroxetine, fluoxetine or sertraline, drugs considered to be the most potent CYP2D6 inhibitors. That difference translates to a 120% increase in the risk of breast cancer recurrence. Patients taking the SSRIs Celexa (

citalopram Citalopram, sold under the brand name Celexa among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive compulsive disorder, panic disorder, and soci ...

), Lexapro (

escitalopram Escitalopram ( ), sold under the brand names Lexapro and Cipralex, among others, is an antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class. It is mainly used to treat major depressive disorder, generalized ...

), and Luvox (

fluvoxamine Fluvoxamine, sold under the brand name Luvox among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is primarily used to treat major depressive disorder and, perhaps more-especially, obsessive–compu ...

) did not have an increased risk of recurrence, due to their lack of competitive metabolism for the CYP2D6 enzyme. A newer study demonstrated a clearer and stronger effect from paroxetine in causing the worst outcomes. Patients treated with both paroxetine and tamoxifen have a 67% increased risk of death from breast cancer, from 24% to 91%, depending on the duration of coadministration. Tamoxifen interacts with certain other

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 inh ...

s. The

aminoglutethimide Aminoglutethimide (AG), sold under the brand names Elipten, Cytadren, and Orimeten among others, is a medication which has been used in the treatment of seizures, Cushing's syndrome, breast cancer, and prostate cancer, among other indications. ...

induces the metabolism of tamoxifen. Conversely, the aromatase inhibitor

letrozole Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor medication that is used in the treatment of breast cancer for post-menopausal women. It was patented in 1986 and approved for medical use in 1996. In 2021, ...

does not affect the metabolism of tamoxifen. However, tamoxifen induces the metabolism of letrozole and significantly reduces its concentrations.

Pharmacology

Pharmacodynamics

Selective estrogen receptor modulator activity

Tamoxifen acts as a

(SERM), or as a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

of the

s (ERs). It has mixed

ic and

ic activity, with its profile of effects differing by tissue. For instance, tamoxifen has predominantly antiestrogenic effects in the

breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...

s but predominantly estrogenic effects in the

uterus The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the hollow organ, organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic development, embryonic and prenatal development, f ...

and

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

. In breast tissue, tamoxifen acts as an ER

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.transcription of estrogen-responsive genes is inhibited. A beneficial side effect of tamoxifen is that it prevents bone loss by acting as an ER

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

(i.e., mimicking the effects of estrogen) in this cell type. Therefore, by inhibiting

osteoclasts An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated ...

, it prevents

osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...

. When tamoxifen was launched as a drug, it was thought that tamoxifen would act as an ER antagonist in all tissues, including bone, and therefore it was feared that it would contribute to osteoporosis. It was therefore very surprising that the opposite effect was observed clinically. Hence tamoxifen's tissue selective action directly led to the formulation of the concept of SERMs. Tamoxifen is a long-acting SERM, with a nuclear retention of the ER–tamoxifen (or metabolite) complex of greater than 48 hours. It has relatively little

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the ERs itself and instead acts as a

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

active metabolite An active metabolite, or pharmacologically active metabolite is a biologically active metabolite of a xenobiotic substance, such as a drug or environmental chemical. Active metabolites may produce therapeutic effects, as well as harmful effects. ...

s such as

endoxifen Endoxifen, also known as 4-hydroxy-''N''-desmethyltamoxifen, is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group as well as a protein kinase C (PKC) inhibitor. It is under development for the treatment ...

(4-hydroxy-''N''-desmethyltamoxifen) and

afimoxifene 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 ...

(4-hydroxytamoxifen; 4-OHT). These metabolites have approximately 30 to 100 times greater affinity for the ERs than tamoxifen itself. Per one study, tamoxifen had 7% and 6% of the affinity of

estradiol Estradiol (E2), also called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible ...

for the

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 se ...

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 t ...

, respectively, whereas afimoxifene had 178% and 338% of the affinity of estradiol for the ERα and ERβ, respectively. Hence, afimoxifene showed 25-fold higher affinity for the ERα and 56-fold higher affinity for the ERβ than tamoxifen. The antiestrogenic potencies of endoxifen and afimoxifene are very similar. However, endoxifen occurs in much higher concentrations than afimoxifene and is now thought to be the major active form of tamoxifen in the body. Tamoxifen binds to ER competitively (with respect to the endogenous agonist estrogen) in tumor cells and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It is a nonsteroidal agent with potent antiestrogenic properties which compete with estrogen for

binding sites In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...

in breast and other tissues. Tamoxifen causes cells to remain in the G₀ and G₁ phases of the

cell cycle The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...

. Because it prevents (pre)cancerous cells from dividing but does not cause cell death, tamoxifen is cytostatic rather than cytocidal. Tamoxifen binds to ER, the ER/tamoxifen complex recruits other proteins known as co-repressors, and the complex then binds to DNA to modulate gene expression. Some of these proteins include NCoR and SMRT. Tamoxifen function can be regulated by a number of different variables including growth factors. Tamoxifen needs to block growth factor proteins such as ErbB2/HER2 because high levels of ErbB2 have been shown to occur in tamoxifen resistant cancers. Tamoxifen seems to require a protein PAX2 for its full anticancer effect. In the presence of high PAX2 expression, the tamoxifen/ER complex is able to suppress the expression of the pro-proliferative

ERBB2 Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The ...

protein. In contrast, when AIB-1 expression is higher than PAX2, tamoxifen/ER complex upregulates the expression of ERBB2 resulting in stimulation of breast cancer growth. Tamoxifen is

antigonadotropic An antigonadotropin is a drug which suppresses the activity and/or downstream effects of one or both of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This results in an inhibition of the hypothalamic-pituita ...

women and partially suppresses levels of the

gonadotropin Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. They are central to the complex endocrine system that regulates normal growth, sexual development, and reproductive function. T ...

(LH) and

(FSH) in such women. However, it has

progonadotropic A progonadotropin, or hypergonadotropin, also known as a gonad stimulant, is a type of drug which increases the secretion of one or both of the major gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This, in turn, r ...

effects in

premenopausal Menopause, also known as the climacteric, is the time when menstrual periods permanently stop, marking the end of the reproductive stage for the female human. It typically occurs between the ages of 45 and 55, although the exact timing can ...

women and increases estrogen levels by 6-fold in them. Due to the nature of tamoxifen as a competitive ER ligand, this increase in estrogen levels is liable to interfere with the antiestrogenic efficacy of tamoxifen. The effects of tamoxifen on

Ki-67 expression,

sex hormone-binding globulin Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it is called androgen-binding prot ...

(SHBG) levels, and IGF-1 levels are dose-dependent across a dosage range of 1 to 20 mg/day in women with breast cancer. Tamoxifen has been found to decrease

insulin-like growth factor 1 Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in tertiary structure, molecular structure to insulin which plays an important role in childhood growth, and has Anabolism, anabolic effects in adults. In the ...

(IGF-1) levels by 17 to 38% in women and men. Suppression of IGF-1 production in the liver is a well-known action of estrogens and SERMs. A 10 mg/day dosage of tamoxifen is nearly as effective as a 20 mg/day dosage in suppressing IGF-1 levels.

Other activities

Afimoxifene is an

of the

G protein-coupled estrogen receptor G protein-coupled estrogen receptor 1 (GPER), also known as G protein-coupled receptor 30 (GPR30), is a protein that in humans is encoded by the ''GPER'' gene. GPER binds to and is activated by the female sex hormone estradiol and is responsible ...

(GPER) with relatively low

. Its affinity for the receptor is in the range of 100 to 1,000 nM, relative to 3 to 6 nM for estradiol. In addition to its activity as a SERM, afimoxifene binds to both the

estrogen-related receptor β Estrogen-related receptor beta (ERR-β), also known as ESRRB or NR3B2 (nuclear receptor subfamily 3, group B, member 2), is a nuclear receptor that in humans is encoded by the ''ESRRB'' (Estrogen Related Receptor Beta) gene In biology, th ...

and

estrogen-related receptor γ Estrogen-related receptor gamma (ERR-gamma), also known as NR3B3 (nuclear receptor subfamily 3, group B, member 3), is a nuclear receptor that in humans is encoded by the ESRRG (EStrogen Related Receptor Gamma) gene. It behaves as a constitutive ...

and is an antagonist of the

(ERRγ).

Norendoxifen Norendoxifen, also known as 4-hydroxy-''N'',''N''-didesmethyltamoxifen, is a nonsteroidal aromatase inhibitor (AI) of the triphenylethylene group that was never marketed. It is an active metabolite of the selective estrogen receptor modulator ( ...

(4-hydroxy-''N'',''N''-didesmethyltamoxifen), another

of tamoxifen, has been found to act as a potent

competitive Competition is a rivalry where two or more parties strive for a common goal which cannot be shared: where one's gain is the other's loss (an example of which is a zero-sum game). Competition can arise between entities such as organisms, indi ...

( IC₅₀ = 90 nM), and may also be involved in the antiestrogenic activity of tamoxifen. In addition to its activity as a SERM, tamoxifen is a potent and selective

protein kinase C In cell biology, protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

, and is active in this regard at therapeutic concentrations. This action is thought to underlie the efficacy of tamoxifen in the treatment of

bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...

. Tamoxifen is an inhibitor of

P-glycoprotein P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...

. In 2018, it was discovered that tamoxifen directly interacts with the

dopamine transporter The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in humans by the ''SLC6A3'' gene (also known as ''DAT1''), that pumps the neurotransmitter dopamine out of the synaptic cleft ba ...

(DAT) and acts as an atypical

dopamine reuptake inhibitor A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dop ...

(DRI). It has weak

potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of ho ...

(54% inhibition of dopamine uptake at 10μM) and lacks any

stimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition, ...

depressant Depressants, also known as central nervous system depressants, or colloquially known as "downers", are drugs that lower neurotransmission levels, decrease the electrical activity of brain cells, or reduce arousal or stimulation in various ...

effects when administered by itself. However, tamoxifen dose-dependently blocks

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

-mediated dopamine release and psychostimulant-like effects in animals. This unusual profile of DRI activity has made tamoxifen of potential interest as a starting point for structural modification to develop novel pharmaceutical drugs for treatment of

stimulant use disorder Stimulant use disorder is a type of substance use disorder where the use of stimulants caused clinically significant impairment or distress. It is defined in the DSM-5 as "the continued use of amphetamine-type substances, cocaine, or other stimul ...

Pharmacokinetics

Absorption

Tamoxifen is rapidly and extensively absorbed from the

intestine The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. T ...

s with

oral administration Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. The

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of tamoxifen is approximately 100%, which is suggestive of minimal

first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the ...

in the intestines and

. Following intake, peak levels of tamoxifen occur after three to seven hours. Steady state levels of tamoxifen are reached typically after 3 to 4 weeks but possibly up to 16 weeks of daily administration. Steady state levels of afimoxifene are achieved after 8 weeks of daily tamoxifen administration. Peak levels of tamoxifen after a single 40 mg oral dose were 65 ng/mL and steady state levels at 20 mg/day were 310 ng/mL. Levels of tamoxifen show clear

dose dependency Dose or Dosage may refer to: Music * ''Dose'' (Gov't Mule album), 1998 * ''Dose'' (Latin Playboys album) * ''Dosage'' (album), by the band Collective Soul * "Dose" (song), a 2018 song by Ciara * "Dose", song by Filter from the album '' Short ...

across a dosage range of 1 to 20 mg/day. Endoxifen levels are approximately 5 to 10 times higher than afimoxifene levels, with large interindividual variability. Endoxifen levels have been reported as 10.8 to 15.9 ng/mL at steady state in

normal metabolizers during therapy with 20 mg/day tamoxifen. The most abundant

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s of tamoxifen in terms of circulating concentrations are ''N''-desmethyltamoxifen, ''N'',''N''-didesmethyltamoxifen, (''Z'')-endoxifen, and tamoxifen ''N''-oxide.

Distribution

The

volume of distribution In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...

of tamoxifen is 50 to 60 L/kg and its clearance has been estimated as 1.2 to 5.1 L/hour. High concentrations of tamoxifen have been found in

, liver,

kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...

lung The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...

pancreas The pancreas (plural pancreases, or pancreata) is an Organ (anatomy), organ of the Digestion, digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a ...

, and

ovary The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/ oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are end ...

tissue in animals and humans. Levels of tamoxifen in the uterus have been found to be 2- to 3-fold higher than in the circulation and in the breasts 10-fold higher than in the circulation. The

plasma protein binding Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse o ...

of tamoxifen and afimoxifene is greater than 99%. A majority of tamoxifen is bound to

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...

. Albumin alone binds 98.8% of tamoxifen while other

plasma protein Plasma proteins, sometimes referred to as blood proteins, are proteins present in blood plasma. They perform many different functions, including transport of hormones, vitamins and minerals in activity and functioning of the immune system. Other b ...

s are not greatly involved.

Metabolism

Tamoxifen is a

and is

metabolized Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

in the

by the

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, t ...

, and

into

s such as

(4-hydroxy-''N''-desmethyltamoxifen) and

(4-hydroxytamoxifen). Conversion of tamoxifen by ''N''-demethylation into ''N''-desmethyltamoxifen, which is catalyzed primarily by CYP3A4 and

CYP3A5 Cytochrome P450 3A5 is a protein that in humans is encoded by the ''CYP3A5'' gene. Tissue distribution ''CYP3A5'' encodes a member of the cytochrome P450 superfamily of enzymes. Like most of the cytochrome P450, the CYP3A5 is expressed in the ...

, is responsible for approximately 92% of tamoxifen metabolism. Conversely, 4-hydroxylation of tamoxifen into afimoxifene is responsible for only about 7% of tamoxifen metabolism. Following its formation, ''N''-desmethyltamoxifen is

oxidized Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

into several other metabolites, the most notable of which is endoxifen. Another active metabolite,

norendoxifen Norendoxifen, also known as 4-hydroxy-''N'',''N''-didesmethyltamoxifen, is a nonsteroidal aromatase inhibitor (AI) of the triphenylethylene group that was never marketed. It is an active metabolite of the selective estrogen receptor modulator ( ...

(4-hydroxy-''N'',''N''-didesmethyltamoxifen), is formed via ''N''-demethylation of endoxifen or 4-hydroxylation of ''N'',''N''-didesmethyltamoxifen. Tamoxifen and its metabolites undergo

conjugation Conjugation or conjugate may refer to: Linguistics *Grammatical conjugation, the modification of a verb from its basic form *Emotive conjugation or Russell's conjugation, the use of loaded language Mathematics *Complex conjugation, the change o ...

, including

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gly ...

and

sulfation Sulfation (sometimes spelled sulphation in British English) is the chemical reaction that entails the addition of SO3 group. In principle, many sulfations would involve reactions of sulfur trioxide (SO3). In practice, most sulfations are effected ...

. Tamoxifen may inhibit its own metabolism.

Elimination

Tamoxifen has a long

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of typically 5 to 7 days, with a range of 4 to 11 days. Similarly, the half-life of afimoxifene is 14 days. Conversely, the half-life of

is 50 to 70 hours (2–3 days). The long half-lives of tamoxifen and afimoxifene are attributed to their high plasma protein binding as well as to

enterohepatic recirculation Enterohepatic circulation is the circulation of biliary acids, bilirubin, drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver. Enterohepa ...

. Upon discontinuation of treatment, levels of tamoxifen and its metabolites persist in the circulation for at least 6 weeks. Tamoxifen is excreted in

bile Bile (from Latin ''bilis''), also known as gall, is a yellow-green/misty green fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is primarily composed of water, is pro ...

and is eliminated in

feces Feces (also known as faeces American and British English spelling differences#ae and oe, or fæces; : faex) are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the ...

, while small amounts are eliminated in

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

Chemistry

Tamoxifen is a

nonsteroidal A nonsteroidal compound is a drug that is not a steroid nor a steroid derivative. Nonsteroidal anti-inflammatory drugs (NSAIDs) are distinguished from corticosteroids as a class of anti-inflammatory agents. List of nonsteroidal steroid receptor mo ...

SERM of the

family and was structurally derived from

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 ...

-like estrogens and

s such as

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 ...

and

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 t ...

. Initially,

was synthesized, and tamoxifen was developed subsequently. Tamoxifen is closely related structurally to other triphenylethylenes, such as clomifene,

nafoxidine Nafoxidine (; developmental code names U-11,000A) or nafoxidine hydrochloride () is a nonsteroidal selective estrogen receptor modulator (SERM) or partial agonist, partial antiestrogen of the triphenylethylene group that was developed for the tre ...

, ospemifene, toremifene, and numerous others. Other SERMs, like

, are structurally distinct from tamoxifen and other triphenylethylenes.

History

In the late 1950s, pharmaceutical companies were actively researching a newly discovered class of anti-estrogen compounds in the hope of developing a morning-after contraceptive pill. Arthur L Walpole was a reproductive

endocrinologist Endocrinology (from ''endocrine'' + '' -ology'') is a branch of biology and medicine dealing with the endocrine system, its diseases, and its specific secretions known as hormones. It is also concerned with the integration of developmental events ...

who led such a team at the

Alderley Park Alderley Park was a country estate at Nether Alderley, Cheshire, England, between Macclesfield and Knutsford. It was the residence of the Stanley family of Alderley from the 1500s. It became the headquarters of ICI Pharmaceuticals in the 1950s. ...

research laboratories of ICI Pharmaceuticals. It was there in 1962 that chemist Dora Richardson first synthesized tamoxifen, back then known as ICI-46,474, when she was looking to create triphenylethylene derivatives for the contraceptive pill project that her team was researching. This compound was originally created to work as an estrogen inhibitor, but instead was found to stimulate ovulation in participants of the drug testing trial. Walpole and his colleagues filed a UK patent covering this compound in 1962, but patent protection on this compound was repeatedly denied in the US until the 1980s. Tamoxifen did eventually receive marketing approval as a fertility treatment, but the class of compounds never proved useful in human contraception. A link between estrogen and breast cancer had been known for many years, but cancer treatments were not a corporate priority at the time, and Walpole's personal interests were important in keeping support for the compound alive in the face of this and the lack of patent protection. It was only when Walpole threatened to leave his position that corporate decided to allow trials and testing for tamoxifen as a drug that could be used to treat breast cancer. Without Walpole's effort towards defending the work that his team had done in discovering a possibly revolutionary source for breast cancer treatment, tamoxifen could have become a discarded or under-researched idea. Walpole's team consisted of Dora Richardson and G. A. Snow, who worked on the chemistry portion of the project, along with G. E. Paget and J. K. Walley, who focused primarily on the biological side. Tamoxifen is one of three drugs in an anti-angiogenetic protocol developed by Dr. Judah Folkman, a researcher at Children's Hospital at Harvard Medical School in Boston. Folkman discovered in the 1970s that

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...

– the growth of new blood vessels – plays a significant role in the development of cancer. Since his discovery, an entirely new field of cancer research has developed. Clinical trials on

angiogenesis inhibitor An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through pharmaceutical ...

s have been underway since 1992 using many different drugs. The Harvard researchers developed a specific protocol for a golden retriever named Navy who was cancer-free after receiving the prescribed cocktail of

celecoxib Celecoxib, sold under the brand name Celebrex among others, is a COX-2 inhibitor and nonsteroidal anti-inflammatory drug (NSAID). It is used to treat the pain and inflammation in osteoarthritis, acute pain in adults, rheumatoid arthritis, psor ...

doxycycline Doxycycline is a Broad-spectrum antibiotic, broad-spectrum antibiotic of the Tetracycline antibiotics, tetracycline class used in the treatment of infections caused by bacteria and certain parasites. It is used to treat pneumonia, bacterial p ...

, and tamoxifen – the treatment subsequently became known as the Navy Protocol. Furthermore, tamoxifen treatment alone has been shown to have anti-angiogenetic effects in animal models of cancer which appear to be, at least in part, independent of tamoxifen's ER antagonist properties. Other antiestrogens, such as

(MER-25) and

(MRL-41), were assessed for treatment of breast cancer and found to be effective before tamoxifen, but were plagued with

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacteria, bacterium, or plant, as well as the effect o ...

issues. The first clinical study of tamoxifen took place at the

Christie Hospital The Christie, formerly known as Christie Hospital and The Christie Hospital and Holt Radium Institute, is a specialist National Health Service, National Health Service (NHS) single site cancer centre in Manchester, United Kingdom. The hospital is ...

in 1971, and showed a convincing effect in advanced breast cancer, but nevertheless ICI's development programme came close to termination when it was reviewed in 1972. In an unpublished article from the early days of the trial, Dora Richardson documented her team's excitement about tamoxifen's effects in counteracting infertility problems and the early positive effects found in breast cancer patients. Unfortunately, this work was not well received by everyone, as the team was supposed to be looking for a contraceptive pill. Tamoxifen's further development may have been bolstered by a second clinical study by Harold W.C. Ward at the

Queen Elizabeth Hospital, Birmingham The Queen Elizabeth Hospital Birmingham is a major, 1,215 bed, tertiary NHS and military hospital in the Edgbaston area of Birmingham, situated very close to the University of Birmingham. The hospital, which cost £545 million to construc ...

. Ward's study showed a more definitive response to the drug at a higher dosage. Walpole also may have helped to convince the company to market tamoxifen for late stage breast cancer in 1973. He was also instrumental in funding V. Craig Jordan to work on tamoxifen. In 1972, ICI Pharmaceuticals Division abandoned development of tamoxifen for financial reasons. The drug was subsequently reinvented from a failed contraceptive, to become tamoxifen, the gold standard for the adjuvant treatment of breast cancer and the pioneering medicine for chemprevention for high-risk women. Two books, ''Estrogen Action, Selective Estrogen Receptor Modulators and Women's Health'' (Imperial College Press 2013) and ''Tamoxifen: Pioneering Medicine in Breast Cancer'' (Springer 2013) tell this story. 1980 saw the publication of the first trial to show that tamoxifen given in addition to chemotherapy improved survival for patients with early breast cancer. In advanced disease, tamoxifen is now only recognized as effective in ER+ patients, but the early trials did not select ER+ patients, and by the mid-1980s the clinical trial picture was not showing a major advantage for tamoxifen. Nevertheless, tamoxifen had a relatively mild side-effect profile, and a number of large trials continued. The pharmacology of SERMs was discovered, defined, and deciphered during the 1980s. A clinical strategy was described that led to the creation of SERMs as a group of multifunctional medicines aimed at the treatment or prevention of many conditions in postmenopausal women, e.g. osteoporosis and breast cancer. The early sales of tamoxifen in both the UK and in the U.S. far exceeded ICI's original estimate, but despite this, at the annual portfolio review ICI's board members still asserted that "there was no market for cancer", leaving the drug's marketing success to rely on its clinical results and clinicians' and scientists' interests in it. Shortly after, Dora Richardson published a history of tamoxifen that, unusually for that type of paper, included personal accounts and letters from patients who attributed their healing to the drug. This testimony from cancer patients using tamoxifen helped to shape and push forward research, by justifying it both morally and scientifically to corporations. It was not until 1998 that the meta-analysis of the Oxford-based Early Breast Cancer Trialists' Collaborative Group showed definitively that tamoxifen was effective for early breast cancer.

Society and culture

Brand names

Tamoxifen is marketed under the brand names Nolvadex and Soltamox, and a variety of other brand names throughout the world.

Economics

Global sales of tamoxifen in 2001 were approximately $1.02 billion. Since the expiration of the patent in 2002, it is widely available as a

generic drug A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

around the world. , tamoxifen was the world's largest selling hormonal drug for the treatment of breast cancer.

Research

In McCune-Albright syndrome (MAS) tamoxifen has been used to treat premature puberty and the consequences of premature puberty. Tamoxifen has been seen to decrease rapid

which is the result of excessive estrogen and alter predicted adult height (PAH). The same effects have also been seen in short pubertal boys. However, one ''in vitro'' study in 2007 and later an ''in vivo'' study in 2008 have shown that tamoxifen induces apoptosis in growth plate chondrocytes, reduces serum

(IGF-1) levels and causes persistent retardation of longitudinal and cortical radial bone growth in young male rats, leading the researchers to express concern giving tamoxifen to growing individuals. Tamoxifen has been studied in the treatment of the rare conditions of

retroperitoneal fibrosis Retroperitoneal fibrosis or Ormond's disease is a disease featuring the proliferation of fibrous tissue (fibrosis) in the retroperitoneum, the compartment of the body containing the kidneys, aorta, renal tract, and various other structures. It m ...

and

idiopathic sclerosing mesenteritis Idiopathic sclerosing mesenteritis (ISM) is a rare disease of the small intestine, characterized by chronic inflammation and eventual fibrosis of the mesentery. It has also been called mesenteric lipodystrophy, or retractile mesenteritis. Signs ...

. It has also been proposed as part of a treatment plan for

Riedel's thyroiditis Riedel's thyroiditis (also known as invasive fibrous thyroiditis), is a chronic form of thyroiditis. It is now believed that Riedel's thyroiditis is one manifestation of a systemic disease that can affect many organ systems called IgG4-related di ...

. Tamoxifen is used as a research tool to trigger tissue-specific gene expression in many conditional expression constructs in

genetically modified animal Genetically modified animals are animals that have been genetically modified for a variety of purposes including producing drugs, enhancing yields, increasing resistance to disease, etc. The vast majority of genetically modified animals are at t ...

s including a version of the

Cre-Lox recombination Cre-Lox recombination is a site-specific recombinase technology, used to carry out deletions, insertions, translocations and inversions at specific sites in the DNA of cells. It allows the DNA modification to be targeted to a specific cell typ ...

technique. While widely used in transgenic research, the strong anabolic effect of tamoxifen on bone might confound this approach, especially as it relates to bone-targeted constructs. Tamoxifen may be effective in the treatment of

mania Mania, also known as manic syndrome, is a Psychiatry, psychiatric Abnormality (behavior), behavioral syndrome defined as a state of Abnormality (behavior), abnormally elevated arousal, affect (psychology), affect, and energy level. During a mani ...

in people with

. This is thought to be due to blockade of

(PKC), an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

that regulates

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

activity in the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

. Researchers believe PKC is overactive during the mania in bipolar patients. ,

, a major active metabolite of tamoxifen with a 4-fold more potent PKC inhibition, was in phase III clinical trials for bipolar disorder.

References

External links

* {{Portal bar , Medicine Aromatase inhibitors Chemopreventive agents Dimethylamino compounds Dopamine reuptake inhibitors Drugs developed by AstraZeneca Glycine receptor agonists GPER agonists Hepatotoxins Hormonal antineoplastic drugs IARC Group 1 carcinogens Mood stabilizers Orphan drugs Phenol ethers Prodrugs Progonadotropins Selective estrogen receptor modulators Triphenylethylenes World Health Organization essential medicines Wikipedia medicine articles ready to translate Ethanolamines

Medical uses

Dysmenorrhea

Breast cancer

Infertility

Gynecomastia

Early puberty

Available forms

Contraindications

Side effects

Endometrial cancer

Cardiovascular and metabolic

Liver toxicity

Overdose

Interactions

Pharmacology

Pharmacodynamics

Selective estrogen receptor modulator activity

Other activities

Pharmacokinetics

Absorption

Distribution

Metabolism

Elimination

Chemistry

History

Society and culture

Brand names

Economics

Research

References

Further reading

External links