An estrogen (E) is a type of
medication
Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...
which is used most commonly in
hormonal birth control and
menopausal hormone therapy, and as part of
feminizing hormone therapy for
transgender women.
They can also be used in the treatment of
hormone-sensitive cancers like
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 ...
and
prostate cancer
Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
and for various other indications. Estrogens are used alone or in combination with
progestogens.
They are available in a wide variety of
formulations and for use by many different
routes of administration.
Examples of estrogens include
bioidentical estradiol,
natural conjugated estrogens,
synthetic steroid
A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration.
Steroids have two principal biological functions: as important components of cell membranes t ...
al estrogens like
ethinylestradiol, and synthetic
nonsteroidal estrogens like
diethylstilbestrol.
Estrogens are one of three types of
sex hormone agonists, the others being
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 ...
s/
anabolic steroid
Anabolic steroids, also known as anabolic-androgenic steroids (AAS), are a class of drugs that are structurally related to testosterone, the main male sex hormone, and produce effects by binding to the androgen receptor (AR). Anabolism, Anaboli ...
s like
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 ...
and
progestogens like
progesterone.
Side effect
In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects.
A drug or procedure usually use ...
s of estrogens include
breast tenderness,
breast enlargement,
headache
A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
,
nausea, and
edema among others.
Other side effects of estrogens include an increased risk of
blood clots,
cardiovascular disease, and, when combined with most progestogens,
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 men, estrogens can cause
breast development,
feminization,
infertility
In biology, infertility is the inability of a male and female organism to Sexual reproduction, reproduce. It is usually not the natural state of a healthy organism that has reached sexual maturity, so children who have not undergone puberty, whi ...
,
low testosterone levels, and
sexual dysfunction among others.
Estrogens are
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 ...
s of the
estrogen receptors, the
biological target
A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...
s of
endogenous estrogens like
estradiol. They have important effects in many
tissues in the body, including in the
female reproductive system (
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 ...
,
vagina
In mammals and other animals, the vagina (: vaginas or vaginae) is the elastic, muscular sex organ, reproductive organ of the female genital tract. In humans, it extends from the vulval vestibule to the cervix (neck of the uterus). The #Vag ...
, and
ovaries
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 endocr ...
), 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,
bone
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...
,
fat, the
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 ...
, and 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 ...
among others.
Unlike other medications like
progestin
A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a '' synthetic'' progestogen. ...
s and anabolic steroids, estrogens do not have other hormonal activities.
Estrogens also have
antigonadotropic effects and at sufficiently high dosages can strongly suppress
sex hormone production.
Estrogens mediate their contraceptive effects in combination with progestins by inhibiting
ovulation.
Estrogens were first introduced for medical use in the early 1930s. They started to be used in birth control in combination with progestins in the 1950s.
A variety of different estrogens have been marketed for clinical use in humans or use in
veterinary medicine
Veterinary medicine is the branch of medicine that deals with the prevention, management, medical diagnosis, diagnosis, and treatment of disease, disorder, and injury in non-human animals. The scope of veterinary medicine is wide, covering all a ...
, although only a handful of these are widely used.
These medications can be grouped into different types based on origin and
chemical structure
A chemical structure of a molecule is a spatial arrangement of its atoms and their chemical bonds. Its determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target m ...
.
Estrogens are available widely throughout the world and are used in most forms of hormonal birth control and in all menopausal hormone therapy regimens.
Medical uses
Birth control
Estrogens have
contraceptive effects and are used in combination with
progestin
A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a '' synthetic'' progestogen. ...
s (
synthetic progestogens) in
birth control to prevent
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 ...
in women. This is referred to as
combined hormonal contraception. The contraceptive effects of estrogens are mediated by their
antigonadotropic effects and hence by inhibition of
ovulation. Most
combined oral contraceptives contain ethinylestradiol or its
prodrug mestranol as the estrogen component, but a few contain estradiol or estradiol valerate. Ethinylestradiol is generally used in oral contraceptives instead of estradiol because it has superior
oral pharmacokinetics (higher
bioavailability and less
interindividual variability) and controls
vaginal bleeding more effectively. This is due to its synthetic nature and its resistance to
metabolism
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 certain
tissues such as the
intestines,
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 ...
, and
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 ...
relative to estradiol. Besides oral contraceptives, other forms of combined hormonal contraception include
contraceptive patches,
contraceptive vaginal rings, and
combined injectable contraceptives. Contraceptive patches and vaginal rings contain ethinylestradiol as the estrogen component, while combined injectable contraceptives contain estradiol or more typically an
estradiol ester.
Hormone therapy
Menopause

Estrogen and other hormones are given to postmenopausal women in order to prevent
osteoporosis as well as treat the symptoms of menopause such as hot flashes, vaginal dryness, urinary stress incontinence, chilly sensations, dizziness, fatigue, irritability, and sweating. Fractures of the spine, wrist, and hips decrease by 50 to 70% and spinal bone density increases by approximately 5% in those women treated with estrogen within 3 years of the onset of menopause and for 5 to 10 years thereafter.
Before the specific dangers of conjugated estrogens were well understood, standard therapy was 0.625 mg/day of conjugated estrogens (such as Premarin). There are, however, risks associated with conjugated estrogen therapy. Among the older postmenopausal women studied as part of the
Women's Health Initiative (WHI), an orally administered conjugated estrogen supplement was found to be associated with an increased risk of dangerous
blood clotting. The WHI studies used one type of estrogen supplement, a high oral dose of conjugated estrogens (Premarin alone and with medroxyprogesterone acetate as ''Prempro'').
In a study by the NIH, esterified estrogens were not proven to pose the same risks to health as conjugated estrogens.
Menopausal hormone therapy has favorable effects on serum cholesterol levels, and when initiated immediately upon menopause may reduce the incidence of cardiovascular disease, although this hypothesis has yet to be tested in randomized trials. Estrogen appears to have a protector effect on atherosclerosis: it lowers LDL and triglycerides, it raises HDL levels and has endothelial vasodilatation properties plus an anti-inflammatory component.
Research is underway to determine if risks of estrogen supplement use are the same for all methods of delivery. In particular, estrogen applied
topically may have a different spectrum of side effects than when administered orally,
and transdermal estrogens do not affect clotting as they are absorbed directly into the systemic circulation, avoiding first-pass metabolism in the liver. This route of administration is thus preferred in women with a history of
thromboembolic disease.
Estrogen is also used in the therapy of vaginal atrophy, hypoestrogenism (as a result of hypogonadism,
oophorectomy, or primary ovarian failure), amenorrhea, dysmenorrhea, and oligomenorrhea. Estrogens can also be used to suppress
lactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The process ...
after child birth.
Synthetic estrogens, such as 17α-substituted estrogens like
ethinylestradiol and its C3
ester
In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...
s and
ethers
mestranol,
quinestrol, and
ethinylestradiol sulfonate, and
nonsteroidal estrogens like the
stilbestrols
diethylstilbestrol,
hexestrol, and
dienestrol, are no longer used in menopausal hormone therapy, owing to their disproportionate effects on
liver protein synthesis and associated health risks.
Hypogonadism
Estrogens are used along with progestogens to treat
hypogonadism
Hypogonadism means diminished functional activity of the human gonad, gonads—the testicles or the ovary, ovaries—that may result in diminished biosynthesis, production of sex hormones. Low androgen (e.g., testosterone) levels are referred t ...
and
delayed puberty
Delayed puberty is when a person lacks or has incomplete development of specific sexual characteristics past the usual age of onset of puberty. The person may have no physical or hormone, hormonal signs that puberty has begun. In the United States ...
in women.
Transgender women
Estrogens are used along with
antiandrogens and progestogens as a component of
feminizing hormone therapy for
transgender women and other
transfeminine individuals.
Hormonal cancer
Prostate cancer
High-dose estrogen therapy with a variety of estrogens such as
diethylstilbestrol,
ethinylestradiol,
polyestradiol phosphate,
estradiol undecylate,
estradiol valerate, and
estradiol has been used to treat
prostate cancer
Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
in men.
It is effective because estrogens are functional
antiandrogens, capable of suppressing testosterone levels to
castrate concentrations and decreasing free testosterone levels by increasing
sex hormone-binding globulin (SHBG) production. High-dose estrogen therapy is associated with poor
tolerability and safety, namely
gynecomastia and
cardiovascular complications such as
thrombosis. For this reason, has largely been replaced by newer antiandrogens such as
gonadotropin-releasing hormone analogues and
nonsteroidal antiandrogens. It is still sometimes used in the treatment of prostate cancer however,
and newer estrogens with atypical profiles such as
GTx-758 that have improved tolerability profiles are being studied for possible application in prostate cancer.
Breast cancer
High-dose estrogen therapy with
potent synthetic estrogens such as
diethylstilbestrol and
ethinylestradiol was used in the past in the
palliation treatment of
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 ...
.
Its effectiveness is approximately equivalent to that of
antiestrogen therapy with
selective estrogen receptor modulators (SERMs) like
tamoxifen and
aromatase inhibitors like
anastrozole.
The use of high-dose estrogen therapy in breast cancer has mostly been superseded by antiestrogen therapy due to the improved
safety
Safety is the state of being protected from harm or other danger. Safety can also refer to the control of recognized hazards in order to achieve an acceptable level of risk.
Meanings
The word 'safety' entered the English language in the 1 ...
profile of the latter.
High-dose estrogen therapy was the standard of care for the palliative treatment of breast cancer in women up to the late 1970s or early 1980s.
Other uses
Infertility
Estrogens may be used in treatment of
infertility
In biology, infertility is the inability of a male and female organism to Sexual reproduction, reproduce. It is usually not the natural state of a healthy organism that has reached sexual maturity, so children who have not undergone puberty, whi ...
in women when there is a need to develop
sperm
Sperm (: sperm or sperms) is the male reproductive Cell (biology), cell, or gamete, in anisogamous forms of sexual reproduction (forms in which there is a larger, female reproductive cell and a smaller, male one). Animals produce motile sperm ...
-friendly
cervical mucus or an appropriate
uterine lining.
Pregnancy support
Estrogens like
diethylstilbestrol were formerly used in high doses to help support
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 ...
.
However, subsequent research showed diethylstilbestrol to be ineffective as well as harmful.
Lactation suppression
Estrogens can be used to suppress
lactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The process ...
, for instance in the treatment of
breast engorgement or
galactorrhea. However, high doses are needed, the effectiveness is uncertain, and high doses of estrogens in the
postpartum period can increase the risk of
blood clots.
Tall stature
Estrogen has been used to induce
growth attenuation in tall girls.
Estrogen-induced growth attenuation was used as part of the controversial
Ashley Treatment to keep a
developmentally disabled girl from growing to adult size.
Acromegaly
Estrogens have been used to treat
acromegaly.
This is because they suppress
growth hormone-induced
insulin-like growth factor 1 (IGF-1) production in the
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 ...
.
Sexual deviance
High-dose estrogen therapy has been used successfully in the treatment of
sexual deviance such as
paraphilia
A paraphilia is an experience of recurring or intense sexual arousal to atypical objects, places, situations, fantasies, behaviors, or individuals. It has also been defined as a sexual interest in anything other than a legally consenting human ...
s in men.
However, it has been found to produce many
side effect
In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects.
A drug or procedure usually use ...
s (e.g.,
gynecomastia,
feminization,
cardiovascular disease,
blood clots), and so is no longer recommended for such purposes.
High-dose estrogen therapy works by suppressing testosterone levels, similarly to high-dose
progestogen therapy and
gonadotropin-releasing hormone (GnRH)
modulator therapy.
Lower dosages of estrogens have also been used in combination with high-dose progestogen therapy in the treatment of sexual deviance in men.
High incidence of
sexual dysfunction has similarly been associated with high-dose estrogen therapy in men treated with it for
prostate cancer
Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
.
Breast enhancement
Estrogens are involved in
breast development and may be used as a form of hormonal breast enhancement to increase the
size of the breasts.
However, acute or temporary
breast enlargement is a well-known side effect of estrogens, and increases in breast size tend to regress following discontinuation of treatment.
Aside from those without prior established breast development, evidence is lacking for a sustained increase in breast size with estrogens.
Depression
Published 2019 and 2020 guidelines from the
North American Menopause Society (NAMS) and
European Menopause and Andropause Society (EMAS) have reviewed the topic of estrogen therapy for
depressive symptoms in the
peri- and
postmenopause.
There is some evidence that estrogens are effective in the treatment of depression in perimenopausal women. The magnitude of benefit appears to be similar to that of classical
antidepressant
Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction.
Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...
s.
There is also some evidence that estrogens may improve
mood and
well-being
Well-being is what is Intrinsic value (ethics), ultimately good for a person. Also called "welfare" and "quality of life", it is a measure of how well life is going for someone. It is a central goal of many individual and societal endeavors.
...
in non-depressed perimenopausal women.
Estrogens do not appear to be effective in the treatment of depression in
postmenopausal women.
This suggests that there is a window of opportunity for effective treatment of depressive symptoms with estrogens.
Research on combined estrogen and
progestogen therapy for depressive symptoms in the peri- and postmenopause is scarce and inconclusive.
Estrogens may augment the mood benefits of antidepressants in middle-aged and older women.
Menopausal hormone therapy is not currently approved for the treatment of depressive symptoms in the peri- or postmenopause in either the
United States
The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...
or the
United Kingdom
The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Northwestern Europe, off the coast of European mainland, the continental mainland. It comprises England, Scotlan ...
due to insufficient evidence of effectiveness.
More research is needed on the issue of estrogen therapy for depressive symptoms associated with
menopause.
Schizophrenia
Estrogens appear to be useful in the treatment of
schizophrenia
Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
in both women and men.
Acne
Systemic estrogen therapy at adequate doses is effective for and has been used in the treatment of
acne
Acne ( ), also known as ''acne vulgaris'', is a long-term Cutaneous condition, skin condition that occurs when Keratinocyte, dead skin cells and Sebum, oil from the skin clog hair follicles. Typical features of the condition include comedo, ...
in both females and males, but causes major side effects such as
feminization and
gynecomastia in males.
Available forms
Estrogens that have been marketed come in two major types,
steroid
A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration.
Steroids have two principal biological functions: as important components of cell membranes t ...
al estrogens and
nonsteroidal estrogens.
Steroidal estrogens
Estradiol,
estrone, and
estriol have all been approved as
pharmaceutical drug
Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the ...
s and are used medically.
Estetrol is currently under development for medical indications, but has not yet been approved in any country. A variety of synthetic
estrogen esters, such as
estradiol valerate,
estradiol cypionate,
estradiol acetate,
estradiol benzoate,
estradiol undecylate, and
polyestradiol phosphate, are used clinically.
The aforementioned compounds behave as
prodrugs to estradiol, and are much longer-lasting in comparison when administered by intramuscular or subcutaneous injection.
Esters of estrone and estriol also exist and are or have been used in clinical medicine, for example
estrone sulfate (e.g., as
estropipate),
estriol succinate, and
estriol glucuronide (as
Emmenin and
Progynon).
Ethinylestradiol is a more potent synthetic
analogue of estradiol that is used widely in
hormonal contraceptives.
Other synthetic derivatives of estradiol related to ethinylestradiol that are used clinically include
mestranol,
quinestrol,
ethinylestradiol sulfonate,
moxestrol, and
methylestradiol.
Conjugated estrogens (brand name Premarin), an estrogen product manufactured from the urine of pregnant
mare
A mare is an adult female horse or other equidae, equine. In most cases, a mare is a female horse over the age of three, and a filly is a female horse three and younger. In Thoroughbred horse racing, a mare is defined as a female horse more th ...
s and commonly used in menopausal hormone therapy, is a mixture of natural estrogens including estrone sulfate and
equine estrogens such as
equilin sulfate and
17β-dihydroequilin sulfate.
A related and very similar product to conjugated estrogens, differing from it only in composition, is
esterified estrogens.
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 ...
,
prasterone (dehydroepiandrosterone; DHEA),
boldenone (δ
1-testosterone), and
nandrolone (19-nortestosterone) are naturally occurring
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 ...
s/
anabolic steroid
Anabolic steroids, also known as anabolic-androgenic steroids (AAS), are a class of drugs that are structurally related to testosterone, the main male sex hormone, and produce effects by binding to the androgen receptor (AR). Anabolism, Anaboli ...
s (AAS) which form estradiol as an
active metabolite in small amounts and can produce estrogenic effects, most notably
gynecomastia in men at sufficiently high dosages.
Similarly, a number of synthetic AAS, including
methyltestosterone
Methyltestosterone, sold under the brand names Android, Metandren, and Testred among others, is an androgen and anabolic steroid (AAS) medication which is used in the treatment of low testosterone levels in men, delayed puberty in boys, at low ...
,
metandienone,
normethandrone, and
norethandrolone, produce
methylestradiol or
ethylestradiol as an active metabolite in small quantities, and can produce estrogenic effects as well.
A few progestins, specifically the
19-nortestosterone derivatives
norethisterone
Norethisterone, also known as norethindrone and sold under the brand name Norlutin among others, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medicatio ...
,
noretynodrel, and
tibolone, metabolize into estrogens (e.g., ethinylestradiol) and can produce estrogenic effects as well.
Nonsteroidal estrogens
Diethylstilbestrol is a
nonsteroidal estrogen that is no longer used medically. It is a member of the
stilbestrol group. Other stilbestrol estrogens that have been used clinically include
benzestrol,
dienestrol,
dienestrol acetate,
diethylstilbestrol dipropionate,
fosfestrol,
hexestrol, and
methestrol dipropionate.
Chlorotrianisene,
methallenestril, and
doisynoestrol are nonsteroidal estrogens structurally distinct from the stilbestrols that have also been used clinically. While used widely in the past, nonsteroidal estrogens have mostly been discontinued and are now rarely if ever used medically.
Contraindications
Estrogens have various
contraindications.
An example is history of
thromboembolism (blood clots).
Side effects
The most common
side effect
In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects.
A drug or procedure usually use ...
s of estrogens in general include
breast tenderness,
breast enlargement,
headache
A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
,
nausea,
fluid retention, and
edema. In women, estrogens can additionally cause
vaginal bleeding,
vaginal discharge, and
anovulation, whereas in men, estrogens can additionally cause
gynecomastia (male
breast development),
feminization,
demasculinization
Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens.
Virilization is a medical terminology, term commonly used in thr ...
,
sexual dysfunction (
reduced libido and
erectile dysfunction
Erectile dysfunction (ED), also referred to as impotence, is a form of sexual dysfunction in males characterized by the persistent or recurring inability to achieve or maintain a Human penis, penile erection with sufficient rigidity and durat ...
),
hypogonadism
Hypogonadism means diminished functional activity of the human gonad, gonads—the testicles or the ovary, ovaries—that may result in diminished biosynthesis, production of sex hormones. Low androgen (e.g., testosterone) levels are referred t ...
,
testicular atrophy, and
infertility
In biology, infertility is the inability of a male and female organism to Sexual reproduction, reproduce. It is usually not the natural state of a healthy organism that has reached sexual maturity, so children who have not undergone puberty, whi ...
.
Estrogens can or may increase the risk of uncommon or rare but potentially serious issues including
endometrial hyperplasia,
endometrial cancer,
cardiovascular complications (e.g.,
blood clots,
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 ...
,
heart attack
A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...
),
cholestatic hepatotoxicity,
gallbladder disease (e.g.,
gallstones),
hyperprolactinemia,
prolactinoma, and
dementia
Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
. These adverse effects are moderated by the concomitant use of a
progestogen, the type of progestogen used, and the dosage and route of estrogen used.
Around half of women with
epilepsy
Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...
who
menstruate have a lowered
seizure threshold around
ovulation, most likely from the heightened estrogen levels at that time. This results in an increased risk of
seizures in these women.
High doses of
synthetic estrogens like
ethinylestradiol and
diethylstilbestrol can produce prominent untoward side effects like
nausea,
vomiting,
headache
A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
,
malaise, and
dizziness, among others.
Conversely, natural estrogens like estradiol and conjugated estrogens are rarely associated with such effects.
The preceding side effects of synthetic estrogens do not appear to occur in
pregnant
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 ...
women, who already have very high estrogen levels.
This suggests that these effects are due to estrogenic activity.
Synthetic estrogens have markedly stronger effects on the
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 ...
and
hepatic protein synthesis than natural estrogens.
This is related to the fact that synthetic estrogens like ethinylestradiol are much more resistant to
metabolism
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 liver than natural estrogens.
Long-term effects
Endometrial hyperplasia and cancer
Unopposed estrogen therapy stimulates the growth of the
endometrium and is associated with a dramatically increased risk of
endometrial hyperplasia and
endometrial cancer in postmenopausal women.
The risk of endometrial hyperplasia is greatly increased by 6 months of treatment ( = 5.4) and further increased after 36 months of treatment ( = 16.0).
This can eventually progress to endometrial cancer, and the risk of endometrial cancer similarly increases with duration of treatment (less than one year, = 1.4; many years (e.g., more than 10 years), = 15.0).
The risk of endometrial cancer also stays significantly elevated many years after stopping unopposed estrogen therapy, even after 15 years or more ( = 5.8).
Progestogens prevent the effects of estrogens on the endometrium.
As a result, they are able to completely block the increase in risk of endometrial hyperplasia caused by estrogen therapy in postmenopausal women, and are even able to decrease it below baseline ( = 0.3 with continuous estrogen–progestogen therapy).
Continuous estrogen–progestogen therapy is more protective than sequential therapy, and a longer duration of treatment with continuous therapy is also more protective.
The increase in risk of endometrial cancer is similarly decreased with continuous estrogen–progestogen therapy ( = 0.2–0.7).
For these reasons, progestogens are always used alongside estrogens in women who have intact uteruses.
Cardiovascular events
Estrogens affect
liver protein synthesis and thereby influence the
cardiovascular system.
They have been found to affect the production of a variety of
coagulation and
fibrinolytic factors, including increased
factor IX,
von Willebrand factor,
thrombin–antithrombin complex (TAT),
fragment 1+2, and
D-dimer and decreased
fibrinogen,
factor VII,
antithrombin,
protein S,
protein C,
tissue plasminogen activator (t-PA), and
plasminogen activator inhibitor-1 (PAI-1).
Although this is true for oral estrogen, transdermal estradiol has been found only to reduce PAI-1 and protein S, and to a lesser extent than oral estrogen.
Due to its effects on liver protein synthesis, oral estrogen is
procoagulant, and has been found to increase the risk of
venous thromboembolism (VTE), including of both
deep vein thrombosis (DVT) and
pulmonary embolism (PE).
Conversely, modern oral contraceptives are not associated with an increase in the risk of
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 ...
and
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...
(heart attack) in healthy, non-
smoking
Smoking is a practice in which a substance is combusted, and the resulting smoke is typically inhaled to be tasted and absorbed into the bloodstream of a person. Most commonly, the substance used is the dried leaves of the tobacco plant, whi ...
premenopausal women of any age, except in those with
hypertension
Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
(high blood pressure).
However, a small but significant increase in the risk of stroke, though not of myocardial infarction, has been found in menopausal women taking hormone replacement therapy.
An increase in the risk of stroke has also been associated with older high-dose oral contraceptives that are no longer used.
Menopausal hormone therapy with replacement dosages of estrogens and progestogens has been associated with a significantly increased risk of cardiovascular events such as VTE.
However, such risks have been found to vary depending on the type of estrogen and the route of administration.
The risk of VTE is increased by approximately 2-fold in women taking oral estrogen for menopausal hormone therapy.
However, clinical research to date has generally not distinguished between conjugated estrogens and estradiol.
This is of importance because conjugated estrogens have been found to be more resistant to hepatic metabolism than estradiol and to increase clotting factors to a greater extent.
Only a few clinical studies have compared oral conjugated estrogens and oral estradiol.
Oral conjugated estrogens have been found to possess a significantly greater risk of thromboembolic and cardiovascular complications than oral estradiol ( = 2.08) and oral
esterified estrogens ( = 1.78).
However, in another study, the increase in VTE risk with 0.625 mg/day oral conjugated estrogens plus medroxyprogesterone acetate and 1 or 2 mg/day oral estradiol plus
norethisterone acetate was found to be equivalent ( = 4.0 and 3.9, respectively).
Other studies have found oral estradiol to be associated with an increase in risk of VTE similarly ( = 3.5 in one, = 3.54 in first year of use in another).
As of present, there are no
randomized controlled trials comparing oral conjugated estrogens and oral estradiol in terms of thromboembolic and cardiovascular risks that would allow for unambiguous conclusions, and additional research is needed to clarify this issue.
In contrast to oral estrogens as a group, transdermal estradiol at typical menopausal replacement dosages has not been found to increase the risk of VTE or other cardiovascular events.
Both combined birth control pills (which contain ethinylestradiol and a progestin) and pregnancy are associated with about a 4-fold increase in risk of VTE, with the risk increase being slightly greater with the latter ( = 4.03 and 4.24, respectively).
The risk of VTE during the postpartum period is 5-fold higher than during pregnancy.
Other research has found that the rate of VTE is 1 to 5 in 10,000 woman-years in women who are not pregnant or taking a birth control pill, 3 to 9 in 10,000 woman-years in women who are on a birth control pill, 5 to 20 in 10,000 women-years in pregnant women, and 40 to 65 in 10,000 women-years in postpartum women.
For birth control pills, VTE risk with high doses of ethinylestradiol (>50 μg, e.g., 100 to 150 μg) has been reported to be approximately twice that of low doses of ethinylestradiol (e.g., 20 to 50 μg).
As such, high doses of ethinylestradiol are no longer used in combined oral contraceptives, and all modern combined oral contraceptives contain 50 μg ethinylestradiol or less.
The absolute risk of VTE in pregnancy is about 0.5 to 2 in 1,000 (0.125%).
Aside from type of estrogen and the route of administration, the risk of VTE with oral estrogen is also moderated by other factors, including the concomitant use of a progestogen, dosage, age, and
smoking
Smoking is a practice in which a substance is combusted, and the resulting smoke is typically inhaled to be tasted and absorbed into the bloodstream of a person. Most commonly, the substance used is the dried leaves of the tobacco plant, whi ...
.
The combination of oral estrogen and a progestogen has been found to double the risk of VTE relative to oral estrogen alone ( = 2.05 for estrogen monotherapy, and = 2.02 for combined estrogen–progestogen therapy in comparison).
However, while this is true for most progestogens, there appears to be no increase in VTE risk relative to oral estrogen alone with the addition of oral progesterone or the atypical progestin
dydrogesterone.
The dosage of oral estrogen appears to be important for VTE risk, as 1 mg/day oral estradiol increased VTE incidence by 2.2-fold while 2 mg/day oral estradiol increased VTE incidence by 4.5-fold (both in combination with norethisterone acetate).
The risk of VTE and other cardiovascular complications with oral estrogen–progestogen therapy increases dramatically with age.
In the oral conjugated estrogens and medroxyprogesterone acetate arm of the WHI, the risks of VTE stratified by age were as follows: age 50 to 59, = 2.27; age 60 to 69, = 4.28; and age 70 to 79, = 7.46.
Conversely, in the oral conjugated estrogens monotherapy arm of the WHI, the risk of VTE increased with age similarly but was much lower: age 50 to 59, = 1.22; age 60 to 69, = 1.3; and age 70 to 79, = 1.44.
In addition to menopausal hormone therapy, cardiovascular
mortality has been found to increase considerably with age in women taking ethinylestradiol-containing combined oral contraceptives and in pregnant women.
In addition, smoking has been found to exponentially increase cardiovascular mortality in conjunction with combined oral contraceptive use and older age.
Whereas the risk of cardiovascular death is 0.06 per 100,000 in women who are age 15 to 34 years, are taking a combined oral contraceptive, and do not smoke, this increases by 50-fold to 3.0 per 100,000 in women who are age 35 to 44 years, are taking a combined oral contraceptive, and do not smoke.
Moreover, in women who do smoke, the risk of cardiovascular death in these two groups increases to 1.73 per 100,000 (29-fold higher relative to non-smokers) and 19.4 per 100,000 (6.5-fold higher relative to non-smokers), respectively.
Although estrogens influence the hepatic production of coagulant and fibrinolytic factors and increase the risk of VTE and sometimes stroke, they also influence the liver synthesis of
blood lipids and can have beneficial effects on the cardiovascular system.
With oral estradiol, there are increases in circulating
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 ...
s,
HDL cholesterol,
apolipoprotein A1, and
apolipoprotein A2, and decreases in total
cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils.
Cholesterol is biosynthesis, biosynthesized by all anima ...
,
LDL cholesterol,
apolipoprotein B, and
lipoprotein(a).
Transdermal estradiol has less-pronounced effects on these proteins and, in contrast to oral estradiol, reduces triglycerides.
Through these effects, both oral and transdermal estrogens can protect against
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
and
coronary heart disease in menopausal women with intact
arterial endothelium that is without severe
lesions.
Approximately 95% of orally ingested estradiol is inactivated during first-pass metabolism.
Nonetheless, levels of estradiol in the liver with oral administration are supraphysiological and approximately 4- to 5-fold higher than in circulation due to the first-pass.
This does not occur with parenteral routes of estradiol, such as transdermal, vaginal, or injection.
In contrast to estradiol, ethinylestradiol is much more resistant to hepatic metabolism, with a mean oral
bioavailability of approximately 45%,
and the transdermal route has a similar impact on hepatic protein synthesis as the oral route.
Conjugated estrogens are also more resistant to hepatic metabolism than estradiol and show disproportionate effects on hepatic protein production as well, although not to the same magnitude as ethinylestradiol.
These differences are considered to be responsible for the greater risk of cardiovascular events with ethinylestradiol and conjugated estrogens relative to estradiol.
High-dosage oral synthetic estrogens like diethylstilbestrol and ethinylestradiol are associated with fairly high rates of severe cardiovascular complications.
Diethylstilbestrol has been associated with an up to 35% risk of cardiovascular toxicity and death and a 15% incidence of VTE in men treated with it for prostate cancer.
In contrast to oral synthetic estrogens, high-dosage polyestradiol phosphate and transdermal estradiol have not been found to increase the risk of cardiovascular mortality or thromboembolism in men with prostate cancer, although significantly increased cardiovascular morbidity (due mainly to an increase in non-fatal
ischemic heart events and
heart decompensation) has been observed with polyestradiol phosphate.
Sex hormone-binding globulin (SHBG) levels indicate hepatic estrogenic exposure and may be a
surrogate marker for
coagulation and VTE risk with estrogen therapy, although this topic has been debated.
SHBG levels with birth control pills containing different progestins are increased by 1.5 to 2-fold with
levonorgestrel, 2.5- to 4-fold with
desogestrel and
gestodene, 3.5- to 4-fold with
drospirenone and
dienogest, and 4- to 5-fold with
cyproterone acetate
Cyproterone acetate (CPA), sold alone under the brand name Androcur or Ethinylestradiol/cyproterone acetate, with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the tre ...
.
Contraceptive vaginal rings and
contraceptive patches likewise have been found to increase SHBG levels by 2.5-fold and 3.5-fold, respectively.
Birth control pills containing high doses of ethinylestradiol (>50 μg) can increase SHBG levels by 5- to 10-fold, which is similar to the increase that occurs during pregnancy.
Conversely, increases in SHBG levels are much lower with estradiol, especially when used parenterally.
High-dose parenteral
polyestradiol phosphate therapy has been found to increase SHBG levels by about 1.5-fold.
Breast cancer
Estrogens are responsible for
breast development and, in relation to this, are strongly implicated in the development of
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 addition, estrogens stimulate the growth and accelerate the progression of
ER-positive breast cancer.
In accordance,
antiestrogens like the
selective estrogen receptor modulator (SERM)
tamoxifen, the ER antagonist
fulvestrant, and the
aromatase inhibitors (AIs)
anastrozole and
exemestane are all effective in the treatment of ER-positive breast cancer.
Antiestrogens are also effective in the prevention of breast cancer.
Paradoxically,
high-dose estrogen therapy is effective in the treatment of breast cancer as well and has about the same degree of effectiveness as antiestrogen therapy, although it is far less commonly used due to adverse effects.
The usefulness of high-dose estrogen therapy in the treatment of ER-positive breast cancer is attributed to a bimodal effect in which high concentrations of estrogens signal breast cancer cells to undergo
apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
, in contrast to lower concentrations of estrogens which stimulate their growth.
A 2017
systematic review and
meta-analysis
Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...
of 14 studies assessed the risk of
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 perimenopausal and postmenopausal women treated with estrogens for menopausal symptoms.
They found that treatment with estradiol only is not associated with an increased risk of breast cancer ( = 0.90 in and = 1.11 in
observational studies).
This was in accordance with a previous analysis of estrogen-only treatment with estradiol or conjugated estrogens which similarly found no increased risk ( = 0.99).
Moreover, another study found that the risk of breast cancer with estradiol and conjugated estrogens was not significantly different ( = 1.15 for conjugated estrogens versus estradiol).
These findings are paradoxical because
oophorectomy in premenopausal women and antiestrogen therapy in postmenopausal women are well-established as considerably reducing the risk of breast cancer ( = 0.208 to 0.708 for chemoprevention with antiestrogens in postmenopausal women).
However, there are indications that there may be a ceiling effect such that past a certain low concentration threshold (e.g., approximately 10.2 pg/mL for estradiol), additional estrogens alone may not further increase the risk of breast cancer in postmenopausal women.
There are also indications that the fluctuations in estrogen levels across the normal
menstrual cycle
The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that makes pregnancy possible. The ovarian cycle controls the production and release of eg ...
in premenopausal women may be important for breast cancer risk.
In contrast to estrogen-only therapy, combined estrogen and progestogen treatment, although dependent on the progestogen used, is associated with an increased risk of breast cancer.
The increase in risk is dependent on the duration of treatment, with more than five years ( = 2.43) having a significantly greater risk than less than five years ( = 1.49).
In addition, sequential estrogen–progestogen treatment ( = 1.76) is associated with a lower risk increase than continuous treatment ( = 2.90), which has a comparably much higher risk.
The increase in risk also differs according to the specific progestogen used.
Treatment with estradiol plus
medroxyprogesterone acetate ( = 1.19),
norethisterone acetate ( = 1.44),
levonorgestrel ( = 1.47), or a mixed progestogen subgroup ( = 1.99) were all associated with an increased risk.
In a previous review, the increase in breast cancer risk was found to not be significantly different between these three progestogens.
Conversely, there is no significant increase in risk of breast cancer with bioidentical
progesterone ( = 1.00) or with the atypical progestin
dydrogesterone ( = 1.10).
In accordance, another study found similarly that the risk of breast cancer was not significantly increased with estrogen–progesterone ( = 1.00) or estrogen–dydrogesterone ( = 1.16) but was increased for estrogen combined with other progestins ( = 1.69).
These progestins included
chlormadinone acetate,
cyproterone acetate
Cyproterone acetate (CPA), sold alone under the brand name Androcur or Ethinylestradiol/cyproterone acetate, with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the tre ...
,
medrogestone,
medroxyprogesterone acetate,
nomegestrol acetate,
norethisterone acetate, and
promegestone, with the associations for breast cancer risk not differing significantly between the different progestins in this group.
In contrast to cisgender women, breast cancer is extremely rare in men and transgender women treated with estrogens and/or progestogens, and gynecomastia or breast development in such individuals does not appear to be associated with an increased risk of breast cancer.
Likewise, breast cancer has never been reported in women with
complete androgen insensitivity syndrome, who similarly have a male
genotype
The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...
(46,XY), in spite of the fact that these women have well-developed breasts.
The reasons for these differences are unknown. However, the dramatically increased risk of breast cancer (20- to 58-fold) in men with
Klinefelter's syndrome, who have somewhat of a hybrid of a male and a female genotype (47,XXY), suggests that it may have to do with the
sex chromosomes.
Cholestatic hepatotoxicity
Estrogens, along with progesterone, can rarely cause
cholestatic hepatotoxicity, particularly at very high concentrations.
This is seen in
intrahepatic cholestasis of pregnancy, which occurs in 0.4 to 15% of
pregnancies (highly variable depending on the country).
Gallbladder disease
Estrogen therapy has been associated with
gallbladder disease, including risk of
gallstone formation.
A 2017 systematic review and meta-analysis found that menopausal hormone therapy significantly increased the risk of gallstones ( = 1.79) while oral contraceptives did not significantly increase the risk ( = 1.19).
Biliary sludge appears in 5 to 30% of women during pregnancy, and definitive gallstones persisting postpartum become established in approximately 5%.
Overdose
Estrogens are relatively safe in
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. and symptoms manifest mainly as reversible feminization.
Interactions
Inducers of
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 ...
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 ...
s like
carbamazepine and
phenytoin can accelerate the
metabolism
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 ...
of estrogens and thereby decrease their
bioavailability and circulating levels.
Inhibitors of such enzymes can have the opposite effect and can increase estrogen levels and bioavailability.
Pharmacology
Pharmacodynamics
Estrogens act as
selective 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 ...
s of the
estrogen receptors (ERs), the
ERα and the
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 ...
. They may also bind to and activate
membrane estrogen receptors (mERs) such as the
GPER. Estrogens do not have
off-target activity
Off-target activity is biological activity of a drug that is different from and not at that of its intended biological target. It most commonly contributes to side effects. However, in some cases, off-target activity can be taken advantage of for t ...
at other
steroid hormone receptors such as the
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 ...
,
progesterone,
glucocorticoid, or
mineralocorticoid receptors, nor do they have
neurosteroid activity by interacting with
neurotransmitter receptors, unlike various
progestogens and some other steroids. Given by
subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.
Estrogens have
antigonadotropic effects at sufficiently high concentrations via activation of the ER and hence can suppress the
hypothalamic–pituitary–gonadal axis. This is caused by
negative feedback
Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused ...
, resulting in a suppression in
secretion and decreased circulating levels of
follicle-stimulating hormone (FSH) and
luteinizing hormone (LH). The antigonadotropic effects of estrogens interfere with
fertility and
gonad
A gonad, sex gland, or reproductive gland is a Heterocrine gland, mixed gland and sex organ that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gon ...
al
sex hormone production. They are responsible for the hormonal contraceptive effects of estrogens. In addition, they allow estrogens to act as functional
antiandrogens by suppressing gonadal testosterone production. At sufficiently high doses, estrogens are able to suppress testosterone levels into the castrate range in men.
Estrogens differ significantly in their pharmacological properties.
For instance, due to structural differences and accompanying differences in
metabolism
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 ...
, estrogens differ from one another in their
tissue selectivity; synthetic estrogens like
ethinylestradiol and
diethylstilbestrol are not inactivated as efficiently as estradiol in tissues like the
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 ...
and
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 as a result have disproportionate effects in these tissues.
This can result in issues such as a relatively higher risk of
thromboembolism.
''In-vitro'' pharmacodynamics
''In-vivo'' pharmacodynamics
Pharmacokinetics
Estrogens can be administered via a variety of
routes, including
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 ...
,
sublingual,
transdermal/
topical (
gel,
patch),
vaginal (gel, tablet,
ring),
rectal,
intramuscular,
subcutaneous,
intravenous
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
, and
subcutaneous implant
In medicine, a subcutaneous implant is an implant (medicine), implant that is delivered under the skin into the subcutaneous tissue, subcutaneous tissue (biology), tissue by surgery or injection (medicine), injection and is used to deliver a drug ...
. Natural estrogens generally have low oral
bioavailability while synthetic estrogens have higher bioavailability.
Parenteral routes have higher bioavailability. Estrogens are typically bound to
albumin and/or
sex hormone-binding globulin in the circulation. They are
metabolized in the
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 ...
by
hydroxylation (via
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 ...
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 ...
s),
dehydrogenation (via
17β-hydroxysteroid dehydrogenase), and
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 ...
(via
sulfation and
glucuronidation). The
elimination half-lives of estrogens vary by estrogen and route of administration. Estrogens are
eliminated mainly by the
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 ...
s via the
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 ...
as conjugates.
Chemistry
Estrogens can be grouped as steroidal or nonsteroidal. The steroidal estrogens are
estranes and include
estradiol and its
analogues, such as
ethinylestradiol and
conjugated estrogens like
equilin sulfate. Nonsteroidal estrogens belong predominantly to the
stilbestrol group of compounds and include
diethylstilbestrol and
hexestrol, among others.
Estrogen esters are
ester
In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...
s and
prodrugs of the corresponding
parent
A parent is either the progenitor of a child or, in humans, it can refer to a caregiver or legal guardian, generally called an adoptive parent or step-parent. Parents who are progenitors are First-degree relative, first-degree relatives and have ...
estrogens. Examples include
estradiol valerate and
diethylstilbestrol dipropionate, which are prodrugs of estradiol and diethylstilbestrol, respectively. Estrogen esters with fatty acid esters have increased
lipophilicity and a prolonged duration of action when administered by intramuscular or subcutaneous injection. Some estrogen esters, such as
polyestradiol phosphate,
polyestriol phosphate, and
polydiethylstilbestrol phosphate, are in the form of
polymer
A polymer () is a chemical substance, substance or material that consists of very large molecules, or macromolecules, that are constituted by many repeat unit, repeating subunits derived from one or more species of monomers. Due to their br ...
s.
History
Ovarian extracts were available in the late 1800s and early 1900s, but were inert or had extremely low estrogenic activity and were regarded as ineffective.
In 1927, Selmar and Aschheim discovered that large amounts of estrogens were present in the
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 ...
of
pregnant
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 ...
women.
This rich source of estrogens, produced by the
placenta, allowed for the development of potent estrogenic formulations for
scientific
Science is a systematic discipline that builds and organises knowledge in the form of testable hypotheses and predictions about the universe. Modern science is typically divided into twoor threemajor branches: the natural sciences, which stu ...
and
clinical use.
The first pharmaceutical estrogen product was a
conjugated estriol called ''Progynon'', a placental
extract, and was introduced for medical use by the
German pharmaceutical company Schering in 1928.
In 1929,
Adolf Butenandt and
Edward Adelbert Doisy independently isolated and purified
estrone, the first estrogen to be discovered.
The estrogen preparations ''Amniotin'' (Squibb), ''Progynon'' (Schering), and ''Theelin'' (Parke-Davis) were all on the market by 1929,
and various additional preparations such as ''Emmenin'', ''Folliculin'', ''Menformon'', ''Oestroform'', and ''Progynon B'', containing purified estrogens or mixtures of estrogens, were on the market by 1934.
Estrogens were originally known under a variety of different names including ''estrogens'', ''estrins'', ''follicular hormones'', ''folliculins'', ''gynecogens'', ''folliculoids'', and ''female sex hormones'', among others.
An
estrogen patch was reportedly marketed by
Searle in 1928,
and an estrogen
nasal spray was studied by 1929.
In 1938, British scientists obtained a patent on a newly formulated nonsteroidal estrogen,
diethylstilbestrol (DES), that was cheaper and more powerful than the previously manufactured estrogens. Soon after, concerns over the side effects of DES were raised in scientific journals while the drug manufacturers came together to lobby for governmental approval of DES. It was only until 1941 when estrogen therapy was finally approved by the Food and Drug Administration (FDA) for the treatment of menopausal symptoms.
Conjugated estrogens (brand name Premarin) was introduced in 1941 and succeeded Emmenin, the sales of which had begun to drop after 1940 due to competition from DES.
Ethinylestradiol was
synthesized in 1938 by Hans Herloff Inhoffen and Walter Hohlweg at
Schering AG in
Berlin
Berlin ( ; ) is the Capital of Germany, capital and largest city of Germany, by both area and List of cities in Germany by population, population. With 3.7 million inhabitants, it has the List of cities in the European Union by population withi ...
and was approved by the in the on 25 June 1943 and marketed by
Schering as Estinyl.
[ search: Estinyl]
Micronized estradiol, via the oral route, was first evaluated in 1972,
and this was followed by the evaluation of vaginal and intranasal micronized estradiol in 1977.
Oral micronized estradiol was first approved in the
United States
The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...
under the brand name Estrace in 1975.
Society and culture
Availability
Estrogens are widely available throughout the world.
Research
Male birth control
High-dose estrogen therapy is effective in suppressing
spermatogenesis and
fertility in men, and hence as a
male contraceptive.
It works both by strongly suppressing
gonadotropin secretion and
gonad
A gonad, sex gland, or reproductive gland is a Heterocrine gland, mixed gland and sex organ that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gon ...
al
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 and via direct effects on the
testes.
After a sufficient course of therapy, only
Sertoli cells and
spermatogonia remain in the
seminiferous tubules of the testes, with a variety of other testicular abnormalities observable.
The use of estrogens for contraception in men is precluded by major side effects such as
sexual dysfunction,
feminization,
gynecomastia, and
metabolic
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 ...
changes.
In addition, there is evidence that with long-term therapy, fertility and gonadal
sex hormone production in men may not return following discontinuation of high-dose estrogen therapy.
Eating disorders
Estrogen has been used as a treatment for women with
bulimia nervosa, in addition to
cognitive behavioral therapy, which is the established standard for treatment in bulimia cases. The estrogen research hypothesizes that the disease may be linked to a hormonal imbalance in the brain.
Miscellaneous
Estrogens have been used in studies which indicate that they may be effective in the treatment of
traumatic liver injury.
In humans and mice, estrogens promote
wound healing.
Estrogen therapy has been proposed as a potential treatment for
autism but clinical studies are needed.
Notes
References
Further reading
*
*
*
*
*
*
External links
*
{{Portal bar, Medicine
Antigonadotropins
Estrogens
Hepatotoxins
Hormonal antineoplastic drugs
Galactagogues
Prolactin releasers