Progesterone
Encyclopedia
Progesterone also known as P4 (pregn-4-ene-3,20-dione) is a C-21 steroid hormone
involved in the female
menstrual cycle
, pregnancy
(supports gestation
) and embryogenesis
of humans and other species. Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen.
Progesterone is commonly manufactured from the yam family
, Dioscorea
. Dioscorea produces large amounts of a steroid called diosgenin
, which can be converted into progesterone in the laboratory.
Willard Myron Allen
co-discovered progesterone with his anatomy professor George Washington Corner at the University of Rochester Medical School in 1933. Allen first determined its melting point, molecular weight, and partial molecular structure. He also gave it the name Progesterone derived from Progestational Steroidal ketone.
0
Like other steroid
s, progesterone consists of four interconnected cyclic hydrocarbons. Progesterone contains ketone
and oxygenated functional groups, as well as two methyl branches. Like all steroid hormones, it is hydrophobic.
), the adrenal gland
s (near the kidney), and, during pregnancy, in the placenta
. Progesterone is also stored in adipose (fat) tissue.
In humans, increasing amounts of progesterone are produced during pregnancy:
s are found in Dioscorea mexicana
. Dioscorea mexicana is a plant that is part of the yam
family native to Mexico
. It contains a steroid called diosgenin
that is taken from the plant and is converted into progesterone. Diosgenin and progesterone are found in other Dioscorea
species as well.
Another plant that contains substances readily convertible to progesterone is Dioscorea pseudojaponica native to Taiwan
. Research has shown that the Taiwanese yam contains saponin
s — steroids that can be converted to diosgenin and thence to progesterone.
Many other Dioscorea species of the yam family contain steroidal substances from which progesterone can be produced. Among the more notable of these are Dioscorea villosa and Dioscorea polygonoides. One study showed that the Dioscorea villosa contains 3.5% diosgenin. Dioscorea polygonoides has been found to contain 2.64% diosgenin as shown by gas chromatography-mass spectrometry
. Many of the Dioscorea species that originate from the yam family grow in countries that have tropical and subtropical climates.
In mammals, progesterone (6), like all other steroid
hormone
s, is synthesized from pregnenolone
(3), which in turn is derived from cholesterol
(1) (see the upper half of the figure to the right).
Cholesterol (1) undergoes double oxidation to produce 20,22-dihydroxycholesterol (2). This vicinal diol
is then further oxidized with loss of the side chain starting at position C-22 to produce pregnenolone (3). This reaction is catalyzed by cytochrome
P450scc.
The conversion of pregnenolone to progesterone takes place in two steps. First, the 3-hydroxyl
group is oxidized to a keto
group (4) and second, the double bond
is moved to C-4, from C-5 through a keto/enol
tautomer
ization reaction. This reaction is catalyzed by 3beta-hydroxysteroid dehydrogenase/delta(5)-delta(4)isomerase
.
Progesterone in turn (see lower half of figure to the right) is the precursor of the mineralocorticoid aldosterone
, and after conversion to 17-hydroxyprogesterone
(another natural progestogen) of cortisol
and androstenedione
. Androstenedione can be converted to testosterone
, estrone
and estradiol
.
Pregenolone and progesterone can also be synthesized by yeast.
isolated from yams was developed by Russell Marker in 1940 for the Parke-Davis
pharmaceutical company (see figure to the right). This synthesis is known as the Marker degradation
. Additional semisyntheses of progesterone have also been reported starting from a variety of steroids. For the example, cortisone
can be simultaneously deoxygenated at the C-17 and C-21 position by treatment with iodotrimethylsilane in chloroform
to produce 11-keto-progesterone (ketogestin), which in turn can be reduced at position-11 to yield progesterone.
A total synthesis
of progesterone was reported in 1971 by W.S. Johnson
(see figure to the right). The synthesis begins with reacting the phosphonium salt
7 with phenyl lithium
to produce the phosphonium ylide 8. The ylide 8 is reacted with an aldehyde
to produce the alkene
9. The ketal protecting group
s of 9 are hydrolyzed to produce the diketone 10, which in turn is cyclized to form the cyclopentenone 11. The ketone of 11 is reacted with methyl lithium to yield the tertiary alcohol 12, which in turn is treated with acid to produce the tertiary cation 13. The key step of the synthesis is the π-cation cyclization of 13 in which the B-, C-, and D-rings of the steroid are simultaneously formed to produce 14. This step resembles the cationic cyclization reaction used in the biosynthesis of steroids and hence is referred to as biomimetic. In the next step the enol
orthoester
is hydrolyzed to produce the ketone 15. The cyclopentene A-ring is then opened by oxidizing with ozone to produce 16. Finally, the diketone 17 undergoes an intramolecular aldol condensation
by treating with aqueous potassium hydroxide to produce progesterone.
, rise after ovulation
, and are elevated during the luteal phase, as shown in diagram below. Progesterone levels tend to be < 2 ng/ml prior to ovulation, and > 5 ng/ml after ovulation. If pregnancy
occurs, human chorionic gonadotropin
is released maintaining the corpus leuteum allowing it to maintain levels of progesterone. At around 12 weeks the placenta begins to produce progesterone in place of the corpus leuteum, this process is named the luteal-placental shift. After the luteal-placental shift progesterone levels start to rise further and may reach 100-200 ng/ml at term. Whether a decrease in progesterone levels is critical for the initiation of labor has been argued and may be species-specific. After delivery of the placenta and during lactation, progesterone levels are very low.
Progesterone levels are relatively low in children and postmenopausal women. Adult males have levels similar to those in women during the follicular phase of the menstrual cycle.
Progesterone exerts its primary action through the intracellular progesterone receptor
although a distinct, membrane bound progesterone receptor has also been postulated. In addition, progesterone is a highly potent antagonist of the mineralocorticoid receptor
(MR, the receptor for aldosterone
and other mineralocorticosteroids). It prevents MR activation by binding to this receptor with an affinity exceeding even those of aldosterone and other corticosteroids such as cortisol and corticosterone.
Progesterone has a number of physiological effects that are amplified in the presence of estrogen
. Estrogen through estrogen receptors upregulates the expression
of progesterone receptors. Also, elevated levels of progesterone potently reduce the sodium-retaining activity of aldosterone, resulting in natriuresis and a reduction in extracellular fluid volume. Progesterone withdrawal, on the other hand, is associated with a temporary increase in sodium retention (reduced natriuresis, with an increase in extracellular fluid volume) due to the compensatory increase in aldosterone production, which combats the blockade of the mineralocorticoid receptor by the previously elevated level of progesterone.
Progesterone modulates the activity of CatSper
(cation channels of sperm) voltage-gated
Ca2+ channels. Since eggs release progesterone, sperm may use progesterone as a homing signal to swim toward eggs (chemotaxis
). Hence substances that block the progesterone binding site on CatSper channels could potentially be used in male contraception.
Progesterone is sometimes called the "hormone of pregnancy", and it has many roles relating to the development of the fetus:
The fetus
metabolizes placental progesterone in the production of adrenal steroids.
and dehydroepiandrosterone
, belongs to the group of neurosteroids. It can be synthesized within the central nervous system
and also serves as a precursor to another major neurosteroid, allopregnanolone
.
Neurosteroids
affect synaptic functioning
, are neuroprotective, and affect myelin
ation. They are investigated for their potential to improve memory
and cognitive ability
. Progesterone affects regulation of apoptotic
genes.
Its effect as a neurosteroid works predominantly through the GSK-3
beta pathway, as an inhibitor. (Other GSK-3 beta inhibitors include bipolar
mood stabilizers, lithium
and valproic acid
.)
, asthma, cardiac or renal dysfunction. Blood clots that can result in strokes and heart attacks, which may lead to death or long-term disability, may develop; pulmonary embolus or breast cancer
can also develop as a result of progesterone therapy. Progesterone is associated with an increased risk of thrombotic disorders such as thrombophlebitis
, cerebrovascular disorders, pulmonary embolism
, and retinal thrombosis.
Common adverse effects include cramps, abdominal pain, skeletal pain, perineal pain, headache, arthralgia, constipation, dyspareunia
, nocturia
, diarrhea, nausea, vomiting, breast enlargement, joint pain, flatulence, hot flushes, decreased libido, thirst, increased appetite, nervousness
, drowsiness, excessive urination at night. Psychiatric effects including depression, mood swings, emotional instability, aggression, abnormal crying, insomnia, forgetfulness, sleep disorders.
Less frequent adverse effects that may occur include allergy, anemia, bloating, fatigue, tremor, urticaria
, pain, conjunctivitis, dizziness, vomiting, myalgia, back pain, breast pain, genital itching, genital yeast infection, upper respiratory tract infection, cystitis
, dysuria
, asthenia, xerophthalmia
, syncope
, dysmenorrhea
, premenstrual tension, gastritis
, urinary tract infection, vaginal discharge, pharyngitis
, sweating, hyperventilation, vaginal dryness, dyspnea
, fever, edema
, flu-like symptoms, dry mouth, rhinitis, leg pain, skin discoloration, skin disorders, seborrhea, sinusitis, acne.
Current research suggests that progesterone plays an important role in the signaling of insulin release and pancreatic function, and may affect the susceptibility to diabetes. It has been shown that women with high levels of progesterone during pregnancy are more likely to develop glucose abnormalities.
as vaginal gel
on July 31, 1997, an oral capsule on May 14, 1998 in an injection
form on April 25, 2001 and as a vaginal insert on June 21, 2007. In Italy and Spain, Progesterone is sold under the trademark Progeffik.
while synthetic progestins are rapidly absorbed with a longer half-life
than progesterone and maintain stable levels in the blood.
Progesterone does not dissolve in water and is poorly absorbed when taken orally unless micronized in oil. Products are often sold as capsules containing micronised progesterone in oil. Progesterone can also be administered through vaginal or rectal suppositories
or pessaries
, transdermal
ly through a gel or cream, or via injection
(though the latter has a short half-life
requiring daily administration).
"Natural progesterone" products derived from yams
do not require a prescription, but there is no evidence that the human body can convert its active ingredient (diosgenin
, the plant steroid that is chemically converted to produce progesterone industrially) into progesterone.
A subsequent and larger study showed that vaginal progesterone was no better than placebo in preventing recurrent preterm birth in women with a history of a previous preterm birth, but a planned secondary analysis of the data in this trial showed that women with a short cervix at baseline in the trial had benefit in two ways: a reduction in births less than 32 weeks and a reduction in both the frequency and the time their babies were in intensive care. In another trial, vaginal progesterone was shown to be better than placebo in reducing preterm birth prior to 34 weeks in women with an extremely short cervix at baseline. An editorial by Roberto Romero discusses the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment.
Note that methods of hormonal contraception
do not contain progesterone but a progestin
.
Progesterone may affect male behavior.
Progesterone is starting to be used in the treatment of the skin condition hidradenitis suppurativa
.
, and most in females by the ovaries, the shutting down (whether by natural or chemical means), or removal, of those inevitably causes a considerable reduction in progesterone levels. Previous concentration upon the role of progestagen
s (progesterone and molecules with similar effects) in female reproduction, when progesterone was simply considered a "female hormone", obscured the significance of progesterone elsewhere in both sexes.
The tendency for progesterone to have a regulatory effect, the presence of progesterone receptor
s in many types of body tissue, and the pattern of deterioration (or tumor
formation) in many of those increasing in later years when progesterone levels have dropped, is prompting widespread research into the potential value of maintaining progesterone levels in both males and females.
and this protective effect has been hypothesized to be caused by increased circulating levels of estrogen
and progesterone in females. A number of additional animal studies have confirmed that progesterone has neuroprotective effects when administered shortly after traumatic brain injury. Encouraging results have also been reported in human clinical trials.
The mechanism of progesterone protective effects may be the reduction of inflammation that follows brain trauma.
Steroid hormone
A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestogens...
involved in the female
Female
Female is the sex of an organism, or a part of an organism, which produces non-mobile ova .- Defining characteristics :The ova are defined as the larger gametes in a heterogamous reproduction system, while the smaller, usually motile gamete, the spermatozoon, is produced by the male...
menstrual cycle
Menstrual cycle
The menstrual cycle is the scientific term for the physiological changes that can occur in fertile women for the purpose of sexual reproduction. This article focuses on the human menstrual cycle....
, pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
(supports gestation
Gestation
Gestation is the carrying of an embryo or fetus inside a female viviparous animal. Mammals during pregnancy can have one or more gestations at the same time ....
) and embryogenesis
Embryogenesis
Embryogenesis is the process by which the embryo is formed and develops, until it develops into a fetus.Embryogenesis starts with the fertilization of the ovum by sperm. The fertilized ovum is referred to as a zygote...
of humans and other species. Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen.
Progesterone is commonly manufactured from the yam family
Yam (vegetable)
Yam is the common name for some species in the genus Dioscorea . These are perennial herbaceous vines cultivated for the consumption of their starchy tubers in Africa, Asia, Latin America and Oceania...
, Dioscorea
Dioscorea
Dioscorea is a genus of over 600 species of flowering plants in the family Dioscoreaceae, native throughout the tropical and warm temperate regions of the world. The vast majority of the species are tropical, with only a few species extending into temperate climates...
. Dioscorea produces large amounts of a steroid called diosgenin
Diosgenin
Diosgenin, a steroid sapogenin, is the product of hydrolysis by acids, strong bases, or enzymes of saponins, extracted from the tubers of Dioscorea wild yam, such as the Kokoro...
, which can be converted into progesterone in the laboratory.
Chemistry
Progesterone was independently discovered by four research groups.Willard Myron Allen
Willard Myron Allen
Willard Myron Allen was an American gynecologist. He was born in 1904 in Farmington, New York, near Rochester, New York. As an undergraduate student at Hobart College in Geneva, New York, Allen had studied organic chemistry...
co-discovered progesterone with his anatomy professor George Washington Corner at the University of Rochester Medical School in 1933. Allen first determined its melting point, molecular weight, and partial molecular structure. He also gave it the name Progesterone derived from Progestational Steroidal ketone.
0
Like other steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
s, progesterone consists of four interconnected cyclic hydrocarbons. Progesterone contains ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
and oxygenated functional groups, as well as two methyl branches. Like all steroid hormones, it is hydrophobic.
Animal
Progesterone is produced in the ovaries (to be specific, after ovulation in the corpus luteumCorpus luteum
The corpus luteum is a temporary endocrine structure in mammals, involved in production of relatively high levels of progesterone and moderate levels of estradiol and inhibin A...
), the adrenal gland
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
s (near the kidney), and, during pregnancy, in the placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
. Progesterone is also stored in adipose (fat) tissue.
In humans, increasing amounts of progesterone are produced during pregnancy:
- At first, the source is the corpus luteum that has been "rescued" by the presence of human chorionic gonadotropins (hCGHuman chorionic gonadotropinHuman chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not...
) from the conceptus.
- However, after the 8th week, production of progesterone shifts to the placenta. The placenta utilizes maternal cholesterol as the initial substrate, and most of the produced progesterone enters the maternal circulation, but some is picked up by the fetal circulation and used as substrate for fetal corticosteroids. At term the placenta produces about 250 mg progesterone per day.
- An additional source of progesterone is milk products. After consumption of milk products the level of bioavailable progesterone goes up.
Plants
In at least one plant, Juglans regia, progesterone has been detected. In addition, progesterone-like steroidSteroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
s are found in Dioscorea mexicana
Dioscorea mexicana
Mexican yam or barbasco de placa is a species of yam in the genus Dioscorea. It ranges from the state of Veracruz in Mexico south to Panama. It is notable for its production of diosgenin, which is a precursor for the synthesis of hormones such as progesterone. Russell Marker developed the...
. Dioscorea mexicana is a plant that is part of the yam
Yam (vegetable)
Yam is the common name for some species in the genus Dioscorea . These are perennial herbaceous vines cultivated for the consumption of their starchy tubers in Africa, Asia, Latin America and Oceania...
family native to Mexico
Mexico
The United Mexican States , commonly known as Mexico , is a federal constitutional republic in North America. It is bordered on the north by the United States; on the south and west by the Pacific Ocean; on the southeast by Guatemala, Belize, and the Caribbean Sea; and on the east by the Gulf of...
. It contains a steroid called diosgenin
Diosgenin
Diosgenin, a steroid sapogenin, is the product of hydrolysis by acids, strong bases, or enzymes of saponins, extracted from the tubers of Dioscorea wild yam, such as the Kokoro...
that is taken from the plant and is converted into progesterone. Diosgenin and progesterone are found in other Dioscorea
Dioscorea
Dioscorea is a genus of over 600 species of flowering plants in the family Dioscoreaceae, native throughout the tropical and warm temperate regions of the world. The vast majority of the species are tropical, with only a few species extending into temperate climates...
species as well.
Another plant that contains substances readily convertible to progesterone is Dioscorea pseudojaponica native to Taiwan
Taiwan
Taiwan , also known, especially in the past, as Formosa , is the largest island of the same-named island group of East Asia in the western Pacific Ocean and located off the southeastern coast of mainland China. The island forms over 99% of the current territory of the Republic of China following...
. Research has shown that the Taiwanese yam contains saponin
Saponin
Saponins are a class of chemical compounds, one of many secondary metabolites found in natural sources, with saponins found in particular abundance in various plant species...
s — steroids that can be converted to diosgenin and thence to progesterone.
Many other Dioscorea species of the yam family contain steroidal substances from which progesterone can be produced. Among the more notable of these are Dioscorea villosa and Dioscorea polygonoides. One study showed that the Dioscorea villosa contains 3.5% diosgenin. Dioscorea polygonoides has been found to contain 2.64% diosgenin as shown by gas chromatography-mass spectrometry
Gas chromatography-mass spectrometry
Gas chromatography–mass spectrometry is a method that combines the features of gas-liquid chromatography and mass spectrometry to identify different substances within a test sample. Applications of GC-MS include drug detection, fire investigation, environmental analysis, explosives investigation,...
. Many of the Dioscorea species that originate from the yam family grow in countries that have tropical and subtropical climates.
Biosynthesis
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s, is synthesized from pregnenolone
Pregnenolone
Pregnenolone is a steroid hormone involved in the steroidogenesis of progesterone, mineralocorticoids, glucocorticoids, androgens, and estrogens. As such it is a prohormone. Pregnenolone sulfate is a GABAA antagonist and increases neurogenesis in the hippocampus.-Chemistry:Like other steroids,...
(3), which in turn is derived from cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
(1) (see the upper half of the figure to the right).
Cholesterol (1) undergoes double oxidation to produce 20,22-dihydroxycholesterol (2). This vicinal diol
Diol
A diol or glycol is a chemical compound containing two hydroxyl groups A geminal diol has two hydroxyl groups bonded to the same atom...
is then further oxidized with loss of the side chain starting at position C-22 to produce pregnenolone (3). This reaction is catalyzed by cytochrome
Cytochrome
Cytochromes are, in general, membrane-bound hemoproteins that contain heme groups and carry out electron transport.They are found either as monomeric proteins or as subunits of bigger enzymatic complexes that catalyze redox reactions....
P450scc.
The conversion of pregnenolone to progesterone takes place in two steps. First, the 3-hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
group is oxidized to a keto
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
group (4) and second, the double bond
Double bond
A double bond in chemistry is a chemical bond between two chemical elements involving four bonding electrons instead of the usual two. The most common double bond, that between two carbon atoms, can be found in alkenes. Many types of double bonds between two different elements exist, for example in...
is moved to C-4, from C-5 through a keto/enol
Enol
Enols are alkenes with a hydroxyl group affixed to one of the carbon atoms composing the double bond. Alkenes with a hydroxyl group on both sides of the double bond are called enediols. Deprotonated anions of enols are called enolates...
tautomer
Tautomer
Tautomers are isomers of organic compounds that readily interconvert by a chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond...
ization reaction. This reaction is catalyzed by 3beta-hydroxysteroid dehydrogenase/delta(5)-delta(4)isomerase
3-beta-HSD
3-β-HSD is an enzyme that catalyses the synthesis of progesterone from pregnenolone, 17-hydroxyprogesterone from 17-hydroxypregnenolone, and androstenedione from dehydroepiandrosterone in the adrenal gland...
.
Progesterone in turn (see lower half of figure to the right) is the precursor of the mineralocorticoid aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
, and after conversion to 17-hydroxyprogesterone
17-Hydroxyprogesterone
17-Hydroxyprogesterone is a C-21 steroid hormone produced during the synthesis of glucocorticoids and sex steroids.As a hormone, 17OHP also interacts with the progesterone receptor.-Production:...
(another natural progestogen) of cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
and androstenedione
Androstenedione
Androstenedione is a 19-carbon steroid hormone produced in the adrenal glands and the gonads as an intermediate step in the biochemical pathway that produces the androgen testosterone and the estrogens estrone and estradiol.-Synthesis:Androstenedione is the common precursor of male and female sex...
. Androstenedione can be converted to testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
, estrone
Estrone
Estrone is an estrogenic hormone secreted by the ovary as well as adipose tissue.Estrone is one of several natural estrogens, which also include estriol and estradiol...
and estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
.
Pregenolone and progesterone can also be synthesized by yeast.
Laboratory
An economical semisynthesis of progesterone from the plant steroid diosgeninDiosgenin
Diosgenin, a steroid sapogenin, is the product of hydrolysis by acids, strong bases, or enzymes of saponins, extracted from the tubers of Dioscorea wild yam, such as the Kokoro...
isolated from yams was developed by Russell Marker in 1940 for the Parke-Davis
Parke-Davis
Parke-Davis is a subsidiary of the pharmaceutical company Pfizer. Although no longer an independent corporation, it was once America's oldest and largest drug maker, and played an important role in medical history.- History :...
pharmaceutical company (see figure to the right). This synthesis is known as the Marker degradation
Marker degradation
The Marker degradation is a three-step synthetic route in steroid chemistry developed by American chemist Russell Earl Marker in 1938–40. It is used for the production of cortisone and mammalian sex hormones from plant steroids, and established Mexico as a world center for steroid production in...
. Additional semisyntheses of progesterone have also been reported starting from a variety of steroids. For the example, cortisone
Cortisone
Cortisone is a steroid hormone. It is one of the main hormones released by the adrenal gland in response to stress. In chemical structure, it is a corticosteroid closely related to corticosterone. It is used to treat a variety of ailments and can be administered intravenously, orally,...
can be simultaneously deoxygenated at the C-17 and C-21 position by treatment with iodotrimethylsilane in chloroform
Chloroform
Chloroform is an organic compound with formula CHCl3. It is one of the four chloromethanes. The colorless, sweet-smelling, dense liquid is a trihalomethane, and is considered somewhat hazardous...
to produce 11-keto-progesterone (ketogestin), which in turn can be reduced at position-11 to yield progesterone.
Total synthesis
In organic chemistry, a total synthesis is, in principle, the complete chemical synthesis of complex organic molecules from simpler pieces, usually without the aid of biological processes. In practice, these simpler pieces are commercially available in bulk and semi-bulk quantities, and are often...
of progesterone was reported in 1971 by W.S. Johnson
William Summer Johnson
William Summer Johnson was an American chemist and teacher. From 1940 to 1958, Dr. Johnson was an instructor and then professor at the University of Wisconsin–Madison. In 1958, he moved to Stanford University in California where he spent the remainder of his scientific career...
(see figure to the right). The synthesis begins with reacting the phosphonium salt
Phosphonium salt
A phosphonium salt is a salt containing the phosphonium ion such as phosphonium iodide . More commonly, phosphonium refers to a quaternary organic derivative such as tetraphenylphosphonium chloride, 4P+ Cl- and tetramethylphosphonium iodide, [P4]+I−.Alkyltriphenylphosphonium salts are widely...
7 with phenyl lithium
Organolithium reagent
An organolithium reagent is an organometallic compound with a direct bond between a carbon and a lithium atom. As the electropositive nature of lithium puts most of the charge density of the bond on the carbon atom, effectively creating a carbanion, organolithium compounds are extremely powerful...
to produce the phosphonium ylide 8. The ylide 8 is reacted with an aldehyde
Aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
to produce the alkene
Alkene
In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...
9. The ketal protecting group
Protecting group
A protecting group or protective group is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction...
s of 9 are hydrolyzed to produce the diketone 10, which in turn is cyclized to form the cyclopentenone 11. The ketone of 11 is reacted with methyl lithium to yield the tertiary alcohol 12, which in turn is treated with acid to produce the tertiary cation 13. The key step of the synthesis is the π-cation cyclization of 13 in which the B-, C-, and D-rings of the steroid are simultaneously formed to produce 14. This step resembles the cationic cyclization reaction used in the biosynthesis of steroids and hence is referred to as biomimetic. In the next step the enol
Enol
Enols are alkenes with a hydroxyl group affixed to one of the carbon atoms composing the double bond. Alkenes with a hydroxyl group on both sides of the double bond are called enediols. Deprotonated anions of enols are called enolates...
orthoester
Orthoester
In organic chemistry, an orthoester is a functional group containing three alkoxy groups attached to one carbon atom, i.e. with the general formula RC3. The name can also refer to any organic compound that contains this functional group. An example of an orthoester is ethyl orthoacetate, CH3C3,...
is hydrolyzed to produce the ketone 15. The cyclopentene A-ring is then opened by oxidizing with ozone to produce 16. Finally, the diketone 17 undergoes an intramolecular aldol condensation
Aldol condensation
An aldol condensation is an organic reaction in which an enol or an enolate ion reacts with a carbonyl compound to form a β-hydroxyaldehyde or β-hydroxyketone, followed by a dehydration to give a conjugated enone....
by treating with aqueous potassium hydroxide to produce progesterone.
Levels
In women, progesterone levels are relatively low during the preovulatory phase of the menstrual cycleMenstrual cycle
The menstrual cycle is the scientific term for the physiological changes that can occur in fertile women for the purpose of sexual reproduction. This article focuses on the human menstrual cycle....
, rise after ovulation
Ovulation
Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...
, and are elevated during the luteal phase, as shown in diagram below. Progesterone levels tend to be < 2 ng/ml prior to ovulation, and > 5 ng/ml after ovulation. If pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
occurs, human chorionic gonadotropin
Human chorionic gonadotropin
Human chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not...
is released maintaining the corpus leuteum allowing it to maintain levels of progesterone. At around 12 weeks the placenta begins to produce progesterone in place of the corpus leuteum, this process is named the luteal-placental shift. After the luteal-placental shift progesterone levels start to rise further and may reach 100-200 ng/ml at term. Whether a decrease in progesterone levels is critical for the initiation of labor has been argued and may be species-specific. After delivery of the placenta and during lactation, progesterone levels are very low.
Progesterone levels are relatively low in children and postmenopausal women. Adult males have levels similar to those in women during the follicular phase of the menstrual cycle.
| Person type | | Reference range for blood test | ||
|---|---|---|---|
| Lower limit | Upper limit | Unit | |
| Female - menstrual cycle | (see diagram below) | ||
| Female - postmenopausal | <0.2 | 1 | ng/mL |
| <0,6 | 3 | nmol/L Litre pic|200px|right|thumb|One litre is equivalent to this cubeEach side is 10 cm1 litre water = 1 kilogram water The litre is a metric system unit of volume equal to 1 cubic decimetre , to 1,000 cubic centimetres , and to 1/1,000 cubic metre... |
|
| Female on oral contraceptive Oral contraceptive The combined oral contraceptive pill , often referred to as the birth-control pill or colloquially as "the Pill", is a birth control method that includes a combination of an estrogen and a progestin . When taken by mouth every day, these pills inhibit female fertility... s |
0.34 | 0.92 | ng/mL |
| 1.1 | 2.9 | nmol/L | |
| Males ≥16 years | 0.27 | 0.9 | ng/mL |
| 0.86 | 2.9 | nmol/L | |
| Female or male 1-9 years | 0.1 | 4.1 or 4.5 | ng/mL |
| 0.3 | 13 | nmol/L | |
Effects
Progesterone receptor
The progesterone receptor also known as NR3C3 , is an intracellular steroid receptor that specifically binds progesterone...
although a distinct, membrane bound progesterone receptor has also been postulated. In addition, progesterone is a highly potent antagonist of the mineralocorticoid receptor
Mineralocorticoid receptor
The mineralocorticoid receptor , also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, is a protein that in humans is encoded by the NR3C2 gene that is located on chromosome 4q31.1-31.2.MR is a receptor with high affinity for mineralocorticoids...
(MR, the receptor for aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
and other mineralocorticosteroids). It prevents MR activation by binding to this receptor with an affinity exceeding even those of aldosterone and other corticosteroids such as cortisol and corticosterone.
Progesterone has a number of physiological effects that are amplified in the presence of estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
. Estrogen through estrogen receptors upregulates the expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
of progesterone receptors. Also, elevated levels of progesterone potently reduce the sodium-retaining activity of aldosterone, resulting in natriuresis and a reduction in extracellular fluid volume. Progesterone withdrawal, on the other hand, is associated with a temporary increase in sodium retention (reduced natriuresis, with an increase in extracellular fluid volume) due to the compensatory increase in aldosterone production, which combats the blockade of the mineralocorticoid receptor by the previously elevated level of progesterone.
Reproductive system
Progesterone has key effects via non-genomic signalling on human sperm as they migrate through the female tract before fertilization occurs, though the receptor(s) as yet remain unidentified. Detailed characterisation of the events occurring in sperm in response to progesterone has elucidated certain events including intracellular calcium transients and maintained changes, slow calcium oscillations, now thought to possibly regulate motility. Interestingly progesterone has also been shown to demonstrate effects on octopus spermatozoa.Progesterone modulates the activity of CatSper
Cation channels of sperm
The cation channels of sperm also known as Catsper channels or CatSper, are ion channels that are related to the two-pore channels and distantly related to TRP channels. The four members of this family form voltage-gated Ca2+ channels that seem to be specific to sperm. These channels are required...
(cation channels of sperm) voltage-gated
Voltage-gated ion channel
Voltage-gated ion channels are a class of transmembrane ion channels that are activated by changes in electrical potential difference near the channel; these types of ion channels are especially critical in neurons, but are common in many types of cells....
Ca2+ channels. Since eggs release progesterone, sperm may use progesterone as a homing signal to swim toward eggs (chemotaxis
Chemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...
). Hence substances that block the progesterone binding site on CatSper channels could potentially be used in male contraception.
Progesterone is sometimes called the "hormone of pregnancy", and it has many roles relating to the development of the fetus:
- Progesterone converts the endometriumEndometrium-Function:The endometrium is the innermost glandular layer and functions as a lining for the uterus, preventing adhesions between the opposed walls of the myometrium, thereby maintaining the patency of the uterine cavity. During the menstrual cycle or estrous cycle, the endometrium grows to a...
to its secretory stage to prepare the uterus for implantation. At the same time progesterone affects the vaginal epitheliumEpitheliumEpithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
and cervical mucus, making it thick and impenetrable to spermSpermThe term sperm is derived from the Greek word sperma and refers to the male reproductive cells. In the types of sexual reproduction known as anisogamy and oogamy, there is a marked difference in the size of the gametes with the smaller one being termed the "male" or sperm cell...
. If pregnancy does not occur, progesterone levels will decrease, leading, in the human, to menstruationMenstruationMenstruation is the shedding of the uterine lining . It occurs on a regular basis in sexually reproductive-age females of certain mammal species. This article focuses on human menstruation.-Overview:...
. Normal menstrual bleeding is progesterone-withdrawal bleeding. If ovulation does not occur and the corpus luteum does not develop, levels of progesterone may be low, leading to anovulatory dysfunctional uterine bleeding. - During implantation and gestationGestationGestation is the carrying of an embryo or fetus inside a female viviparous animal. Mammals during pregnancy can have one or more gestations at the same time ....
, progesterone appears to decrease the maternal immuneImmune systemAn immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
response to allow for the acceptance of the pregnancy. - Progesterone decreases contractility of the uterine smooth muscleSmooth muscleSmooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...
. - In addition progesterone inhibits lactationLactationLactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, however it predates mammals. In humans the process of feeding milk is called breastfeeding or nursing...
during pregnancy. The fall in progesterone levels following delivery is one of the triggers for milk production. - A drop in progesterone levels is possibly one step that facilitates the onset of labor.
The fetus
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
metabolizes placental progesterone in the production of adrenal steroids.
Nervous system
Progesterone, like pregnenolonePregnenolone
Pregnenolone is a steroid hormone involved in the steroidogenesis of progesterone, mineralocorticoids, glucocorticoids, androgens, and estrogens. As such it is a prohormone. Pregnenolone sulfate is a GABAA antagonist and increases neurogenesis in the hippocampus.-Chemistry:Like other steroids,...
and dehydroepiandrosterone
Dehydroepiandrosterone
5-Dehydroepiandrosterone is a 19-carbon endogenous steroid hormone. It is the major secretory steroidal product of the adrenal glands and is also produced by the gonads and the brain. DHEA is the most abundant circulating steroid in humans....
, belongs to the group of neurosteroids. It can be synthesized within the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
and also serves as a precursor to another major neurosteroid, allopregnanolone
Allopregnanolone
Allopregnanolone is a prototypic neurosteroid present in the blood and also the brain. It is a metabolite of progesterone and potent modulator of GABAA receptors...
.
Neurosteroids
Neuroactive steroid
Neuroactive steroids rapidly alter neuronal excitability through interaction with neurotransmitter-gated ion channels. In addition, these steroids may also exert effects on gene expression via intracellular steroid hormone receptors...
affect synaptic functioning
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
, are neuroprotective, and affect myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
ation. They are investigated for their potential to improve memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
and cognitive ability
Cognition
In science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...
. Progesterone affects regulation of apoptotic
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
genes.
Its effect as a neurosteroid works predominantly through the GSK-3
GSK-3
Glycogen synthase kinase 3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules on certain serine and threonine amino acids in particular cellular substrates...
beta pathway, as an inhibitor. (Other GSK-3 beta inhibitors include bipolar
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
mood stabilizers, lithium
Lithium
Lithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number 3. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...
and valproic acid
Valproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
.)
Other syndromes
- It raises epidermal growth factor-1 levels, a factor often used to induce proliferation, and used to sustain cultures, of stem cellStem cellThis article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
s. - It increases core temperature (thermogenic function) during ovulation.
- It reduces spasmSpasmIn medicine a spasm is a sudden, involuntary contraction of a muscle, a group of muscles, or a hollow organ, or a similarly sudden contraction of an orifice. It is sometimes accompanied by a sudden burst of pain, but is usually harmless and ceases after a few minutes...
and relaxes smooth muscleSmooth muscleSmooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...
. Bronchi are widened and mucusMucusIn vertebrates, mucus is a slippery secretion produced by, and covering, mucous membranes. Mucous fluid is typically produced from mucous cells found in mucous glands. Mucous cells secrete products that are rich in glycoproteins and water. Mucous fluid may also originate from mixed glands, which...
regulated. (Progesterone receptorProgesterone receptorThe progesterone receptor also known as NR3C3 , is an intracellular steroid receptor that specifically binds progesterone...
s are widely present in submucosal tissueMucous membraneThe mucous membranes are linings of mostly endodermal origin, covered in epithelium, which are involved in absorption and secretion. They line cavities that are exposed to the external environment and internal organs...
.) - It acts as an antiinflammatoryInflammationInflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
agent and regulates the immune response. - It reduces gall-bladder activity.
- It normalizes bloodBloodBlood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
clotting and vascular tone, zincZincZinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
and copperCopperCopper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...
levels, cellCell (biology)The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
oxygenOxygenOxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
levels, and use of fat stores for energy. - It may affect gum health, increasing risk of gingivitis (gum inflammation) and tooth decay.
- It appears to prevent endometrial cancerEndometrial cancerEndometrial cancer refers to several types of malignancies that arise from the endometrium, or lining, of the uterus. Endometrial cancers are the most common gynecologic cancers in the United States, with over 35,000 women diagnosed each year. The incidence is on a slow rise secondary to the...
(involving the uterine lining) by regulating the effects of estrogen.
Adverse effects
Pill form of progesterone (actually a synthetic version such as Progestogen) taken at 400 mg as cited by the following patent can cause increased fluid retention, which may result in epilepsy, migraineMigraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
, asthma, cardiac or renal dysfunction. Blood clots that can result in strokes and heart attacks, which may lead to death or long-term disability, may develop; pulmonary embolus or breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
can also develop as a result of progesterone therapy. Progesterone is associated with an increased risk of thrombotic disorders such as thrombophlebitis
Thrombophlebitis
Thrombophlebitis is phlebitis related to a thrombus . When it occurs repeatedly in different locations, it is known as "Thrombophlebitis migrans" or "migrating thrombophlebitis".-Signs and symptoms:...
, cerebrovascular disorders, pulmonary embolism
Pulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
, and retinal thrombosis.
Common adverse effects include cramps, abdominal pain, skeletal pain, perineal pain, headache, arthralgia, constipation, dyspareunia
Dyspareunia
Dyspareunia is painful sexual intercourse, due to medical or psychological causes. The symptom is reported almost exclusively by women, although the problem can also occur in men. The causes are often reversible, even when long-standing, but self-perpetuating pain is a factor after the original...
, nocturia
Nocturia
Nocturia , also called nycturia , is the need to get up in the night to urinate, thus interrupting sleep. Its occurrence is more frequent in pregnant women and in the elderly...
, diarrhea, nausea, vomiting, breast enlargement, joint pain, flatulence, hot flushes, decreased libido, thirst, increased appetite, nervousness
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, drowsiness, excessive urination at night. Psychiatric effects including depression, mood swings, emotional instability, aggression, abnormal crying, insomnia, forgetfulness, sleep disorders.
Less frequent adverse effects that may occur include allergy, anemia, bloating, fatigue, tremor, urticaria
Urticaria
Urticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes...
, pain, conjunctivitis, dizziness, vomiting, myalgia, back pain, breast pain, genital itching, genital yeast infection, upper respiratory tract infection, cystitis
Cystitis
Cystitis is a term that refers to urinary bladder inflammation that results from any one of a number of distinct syndromes. It is most commonly caused by a bacterial infection in which case it is referred to as a urinary tract infection.-Signs and symptoms:...
, dysuria
Dysuria
In medicine, specifically urology, dysuria refers to painful urination.Difficult urination is also sometimes described as dysuria.It is one of a constellation of irritative bladder symptoms, which includes urinary frequency and haematuria....
, asthenia, xerophthalmia
Xerophthalmia
Xerophthalmia is a medical condition in which the eye fails to produce tears. It may be caused by a deficiency in vitamin A and is sometimes used to describe that lack, although there may be other causes....
, syncope
Syncope
In phonology, syncope is the loss of one or more sounds from the interior of a word; especially, the loss of an unstressed vowel. It is found bothin Synchronic analysis of languages and Diachronics .-Found synchronically:...
, dysmenorrhea
Dysmenorrhea
Dysmenorrhea is a gynecological medical condition of pain during menstruation that interferes with daily activities, as defined by ACOG and others. Still, dysmenorrhea is often defined simply as menstrual pain, or at least menstrual pain that is excessive...
, premenstrual tension, gastritis
Gastritis
Gastritis is an inflammation of the lining of the stomach, and has many possible causes. The main acute causes are excessive alcohol consumption or prolonged use of nonsteroidal anti-inflammatory drugs such as aspirin or ibuprofen. Sometimes gastritis develops after major surgery, traumatic...
, urinary tract infection, vaginal discharge, pharyngitis
Pharyngitis
Pharyngitis is an inflammation of the throat or pharynx. In most cases it is quite painful, and is the most common cause of a sore throat.Like many types of inflammation, pharyngitis can be acute – characterized by a rapid onset and typically a relatively short course – or chronic....
, sweating, hyperventilation, vaginal dryness, dyspnea
Dyspnea
Dyspnea , shortness of breath , or air hunger, is the subjective symptom of breathlessness.It is a normal symptom of heavy exertion but becomes pathological if it occurs in unexpected situations...
, fever, edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
, flu-like symptoms, dry mouth, rhinitis, leg pain, skin discoloration, skin disorders, seborrhea, sinusitis, acne.
Current research suggests that progesterone plays an important role in the signaling of insulin release and pancreatic function, and may affect the susceptibility to diabetes. It has been shown that women with high levels of progesterone during pregnancy are more likely to develop glucose abnormalities.
Medical applications
The use of progesterone and its analogues have many medical applications, both to address acute situations and to address the long-term decline of natural progesterone levels. Because of the poor bioavailability of progesterone when taken orally, many synthetic progestins have been designed with improved oral bioavailability. Progesterone was approved by the United States Food and Drug AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
as vaginal gel
Gel
A gel is a solid, jelly-like material that can have properties ranging from soft and weak to hard and tough. Gels are defined as a substantially dilute cross-linked system, which exhibits no flow when in the steady-state...
on July 31, 1997, an oral capsule on May 14, 1998 in an injection
Injection (medicine)
An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...
form on April 25, 2001 and as a vaginal insert on June 21, 2007. In Italy and Spain, Progesterone is sold under the trademark Progeffik.
Bioavailability
The route of administration impacts the effect of the drug. Given orally, progesterone has a wide person-to-person variability in absorption and bioavailabilityBioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
while synthetic progestins are rapidly absorbed with a longer half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
than progesterone and maintain stable levels in the blood.
Progesterone does not dissolve in water and is poorly absorbed when taken orally unless micronized in oil. Products are often sold as capsules containing micronised progesterone in oil. Progesterone can also be administered through vaginal or rectal suppositories
Suppository
A suppository is a drug delivery system that is inserted into the rectum , vagina or urethra , where it dissolves.They are used to deliver both systemically-acting and locally-acting medications....
or pessaries
Pessary
A pessary is a small plastic or silicone medical device which is inserted into the vagina or rectum and held in place by the pelvic floor musculature. - Therapeutic pessaries :...
, transdermal
Transdermal
Transdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution. Examples include transdermal patches used for medicine delivery, and transdermal implants used for medical or aesthetic purposes....
ly through a gel or cream, or via injection
Injection (medicine)
An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...
(though the latter has a short half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
requiring daily administration).
"Natural progesterone" products derived from yams
Yam (vegetable)
Yam is the common name for some species in the genus Dioscorea . These are perennial herbaceous vines cultivated for the consumption of their starchy tubers in Africa, Asia, Latin America and Oceania...
do not require a prescription, but there is no evidence that the human body can convert its active ingredient (diosgenin
Diosgenin
Diosgenin, a steroid sapogenin, is the product of hydrolysis by acids, strong bases, or enzymes of saponins, extracted from the tubers of Dioscorea wild yam, such as the Kokoro...
, the plant steroid that is chemically converted to produce progesterone industrially) into progesterone.
Specific uses
- Progesterone is used to support pregnancy in Assisted Reproductive Technology (ART) cycles such as In-vitro Fertilization (IVF). While daily intramuscular injections of progesterone-in-oil (PIO) have been the standard route of administration, PIO injections are not FDA-approved for use in pregnancy. A recent meta-analysis showed that the intravaginal route with an appropriate dose and dosing frequency is equivalent to daily intramuscular injections. In addition, a recent case-matched study comparing vaginal progesterone with PIO injections showed that live birth rates were nearly identical with both methods.
- Progesterone is used to control persistent anovulatory bleeding. It is also used to prepare uterine lining in infertilityInfertilityInfertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
therapy and to support early pregnancy. Patients with recurrent pregnancy lossHabitual abortionHabitual abortion, recurrent miscarriage or recurrent pregnancy loss is the occurrence of three or more pregnancies that end in miscarriage of the fetus, usually before 20 weeks of gestation...
due to inadequate progesterone production may receive progesterone. - Progesterone is also used in nonpregnant women with a delayed menstruation of one or more weeks, in order to allow the thickened endometrial lining to slough off. This process is termed a progesterone withdrawal bleed. The progesterone is taken orally for a short time (usually one week), after which the progesterone is discontinued and bleeding should occur.
- Progesterone is being investigated as potentially beneficial in treating multiple sclerosisMultiple sclerosisMultiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
, since the characteristic deterioration of nerve myelinMyelinMyelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
insulation halts during pregnancy, when progesterone levels are raised; deterioration commences again when the levels drop. - Vaginally dosed progesterone is being investigated as potentially beneficial in preventing preterm birth in women at risk for preterm birth. The initial study by Fonseca suggested that vaginal progesterone could prevent preterm birth in women with a history of preterm birth. According to a recent study, women with a short cervix that received hormonal treatment with a progesterone gel had their risk of prematurely giving birth reduced. The hormone treatment was administered vaginally every day during the second half of a pregnancy.
A subsequent and larger study showed that vaginal progesterone was no better than placebo in preventing recurrent preterm birth in women with a history of a previous preterm birth, but a planned secondary analysis of the data in this trial showed that women with a short cervix at baseline in the trial had benefit in two ways: a reduction in births less than 32 weeks and a reduction in both the frequency and the time their babies were in intensive care. In another trial, vaginal progesterone was shown to be better than placebo in reducing preterm birth prior to 34 weeks in women with an extremely short cervix at baseline. An editorial by Roberto Romero discusses the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment.
- Progesterone also has a role in skin elasticity and bone strength, in respirationRespiration (physiology)'In physiology, respiration is defined as the transport of oxygen from the outside air to the cells within tissues, and the transport of carbon dioxide in the opposite direction...
, in nerve tissue and in female sexuality, and the presence of progesterone receptors in certain muscle and fat tissue may hint at a role in sexually-dimorphicSexual dimorphismSexual dimorphism is a phenotypic difference between males and females of the same species. Examples of such differences include differences in morphology, ornamentation, and behavior.-Examples:-Ornamentation / coloration:...
proportions of those. - Progesterone receptor antagonistReceptor antagonistA receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
s, or selective progesterone receptor modulatorSelective progesterone receptor modulatorA selective progesterone receptor modulator is an agent that acts on the progesterone receptor. A characteristic that distinguishes such substances from receptor full agonists and full antagonists is that their action differs in different tissues...
s (SPRM)s, such as RU-486 (MifepristoneMifepristoneMifepristone is a synthetic steroid compound used as a pharmaceutical. It is a progesterone receptor antagonist used as an abortifacient in the first months of pregnancy, and in smaller doses as an emergency contraceptive. During early trials, it was known as RU-38486 or simply RU-486, its...
), can be used to prevent conception or induce medical abortionMedical abortionA medical abortion is a type of non-surgical abortion in which abortifacient pharmaceutical drugs are used to induce abortion. An oral preparation for medical abortion is commonly referred to as an abortion pill....
s.
Note that methods of hormonal contraception
Hormonal contraception
Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The original hormonal method—the combined oral contraceptive...
do not contain progesterone but a progestin
Progestin
A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...
.
Progesterone may affect male behavior.
Progesterone is starting to be used in the treatment of the skin condition hidradenitis suppurativa
Hidradenitis suppurativa
Hidradenitis suppurativa is a skin disease that most commonly affects areas bearing apocrine sweat glands or sebaceous glands, such as the underarms, breasts, inner thighs, groin and buttocks.-Overview:...
.
Aging
Since most progesterone in males is created during testicular production of testosteroneTestosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
, and most in females by the ovaries, the shutting down (whether by natural or chemical means), or removal, of those inevitably causes a considerable reduction in progesterone levels. Previous concentration upon the role of progestagen
Progestagen
Progestogens are a group of hormones including progesterone.The progestogens are one of the five major classes of steroid hormones, in addition to the estrogens, androgens, mineralocorticoids, and glucocorticoids. All progestogens are characterized by their basic 21-carbon skeleton, called a...
s (progesterone and molecules with similar effects) in female reproduction, when progesterone was simply considered a "female hormone", obscured the significance of progesterone elsewhere in both sexes.
The tendency for progesterone to have a regulatory effect, the presence of progesterone receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s in many types of body tissue, and the pattern of deterioration (or tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
formation) in many of those increasing in later years when progesterone levels have dropped, is prompting widespread research into the potential value of maintaining progesterone levels in both males and females.
Brain damage
Previous studies have shown that progesterone supports the normal development of neurons in the brain, and that the hormone has a protective effect on damaged brain tissue. It has been observed in animal models that females have reduced susceptibility to traumatic brain injuryTraumatic brain injury
Traumatic brain injury , also known as intracranial injury, occurs when an external force traumatically injures the brain. TBI can be classified based on severity, mechanism , or other features...
and this protective effect has been hypothesized to be caused by increased circulating levels of estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
and progesterone in females. A number of additional animal studies have confirmed that progesterone has neuroprotective effects when administered shortly after traumatic brain injury. Encouraging results have also been reported in human clinical trials.
The mechanism of progesterone protective effects may be the reduction of inflammation that follows brain trauma.
See also
- Willard Myron AllenWillard Myron AllenWillard Myron Allen was an American gynecologist. He was born in 1904 in Farmington, New York, near Rochester, New York. As an undergraduate student at Hobart College in Geneva, New York, Allen had studied organic chemistry...
- EndometrinEndometrinEndometrin Vaginal Insert 100 mg is a brand of micronized progesterone inserts from Ferring Pharmaceuticals in Parsippany, New Jersey, which was FDA-approved in June 2007 for use in the United States....
- AKR1C1AKR1C1Aldo-keto reductase family 1 member C1 is an enzyme that in humans is encoded by the AKR1C1 gene.This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their...
- the enzyme that deactivates progesterone - Percy JulianPercy JulianPercy Lavon Julian was an African American research chemist and a pioneer in the chemical synthesis of medicinal drugs from plants...
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