Progesterone also known as P4 ( p regn- 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.

Progesterone was independently discovered by four research groups.

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 Proge stational Ster oidal ket one .

Like other steroids, 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.

Animal

Progesterone is produced in the ovaries (to be specific, after ovulation in the corpus luteum), the adrenal glands (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:

• At first, the source is the corpus luteum that has been "rescued" by the presence of human chorionic gonadotropins ( hCG ) 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. They contain much progesterone because on dairy farms cows are milked during pregnancy, when the progesterone content of the milk is high. After consumption of milk products the level of bioavailable progesterone goes up.

Plants

In at least one plant, Juglans regia, progesterone has been detected. 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 saponins ??? 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.

Biosynthesis

In mammals, progesterone ( 6 ), like all other steroid hormones, 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 tautomerization 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.

Laboratory

An economical semisynthesis of progesterone from the plant steroid diosgenin isolated from yams was developed by Russell Marker in 1940 for the Parke-Davis pharmaceutical company (see figure to the right).

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 groups of 9 are hydrolyzed to produce the diketone 10 , which in turn is cyclized to from 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 ??-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.

== Levels ==

In women, progesterone levels are relatively low during the preovulatory phase of the menstrual cycle, rise after ovulation, and are elevated during the luteal phase. Progesterone levels tend to be < 2 ng/ml prior to ovulation, and > 5 ng/ml after ovulation. If pregnancy occurs, progesterone levels are initially maintained at luteal levels. With the onset of the luteal-placental shift in progesterone support of the pregnancy, 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.

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|File:Estradiol and progesterone in menstrual cycle.svg|thumb|600px|Reference ranges for blood tests|Reference ranges for estradiol and ''progesterone'' in the menstrual cycle, expressed in mass and molar concentration. Because of slightly different molar mass, the relative concentrations differ somewhat. The scale is Logarithmic scale|logarithmic.

Progesterone exerts its primary action through the intracellular progesterone receptor although a distinct, membrane bound progesterone receptor has also been postulated.

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.

Reproductive system

Progesterone has key effects via non-genomic signalling on human sperm as they migrate through the female tract before fertilisation occurs, though the receptor(s) as yet remain unidentified.

Progesterone is sometimes called the "hormone of pregnancy", and it has many roles relating to the development of the fetus:

• Progesterone converts the endometrium to its secretory stage to prepare the uterus for implantation. At the same time progesterone affects the vaginal epithelium and cervical mucus , making it thick and impenetrable to sperm. If pregnancy does not occur, progesterone levels will decrease, leading, in the human, to menstruation. Normal menstrual bleeding is progesterone-withdrawal bleeding.

• During implantation and gestation, progesterone appears to decrease the maternal immune response to allow for the acceptance of the pregnancy.

• Progesterone decreases contractility of the uterine smooth muscle.

• In addition progesterone inhibits lactation 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 metabolizes placental progesterone in the production of adrenal steroids.

Nervous system

Progesterone, like pregnenolone 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 myelination. 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.)

Other syndromes

• It raises epidermal growth factor-1 levels, a factor often used to induce proliferation, and used to sustain cultures, of stem cells.

• It increases core temperature (thermogenic function) during ovulation.

• It reduces spasm and relaxes smooth muscle. Bronchi are widened and mucus regulated. ( Progesterone receptors are widely present in submucosal tissue .)

• It acts as an antiinflammatory agent and regulates the immune response.

• It reduces gall-bladder activity.

• It normalizes blood clotting and vascular tone, zinc and copper levels, cell oxygen 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 cancer (involving the uterine lining) by regulating the effects of estrogen.

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, migraine, 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.

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. Progesteone was approved by the United States Food and Drug Administration 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.

Bioavailability

The route of administration impacts the effect of the drug. Given orally, progesterone has a wide person-to-person variability in absorption and bioavailability 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 , transdermally 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 the human body can convert its active ingredient ( diosgenin, the plant steroid that is chemically converted to produce progesterone industrially

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 anovulatory bleeding. It is also used to prepare uterine lining in infertility therapy and to support early pregnancy. Patients with recurrent pregnancy loss due to inadequate progesterone production may receive progesterone.

• Progesterone is being investigated as potentially beneficial in treating multiple sclerosis, since the characteristic deterioration of nerve myelin 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.

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,

• Progesterone is used in hormone therapy for male to female transsexuals and other women with intersex conditions - especially when synthetic progestins have been ineffective or caused side-effects - since normal breast tissue cannot develop except in the presence of both progestogen and estrogen. Mammary glandular tissue is otherwise fibrotic , the breast shape conical and the areola immature. Progesterone can correct those even after years of inadequate hormonal treatment. Research usually cited against such value was conducted using Provera, a synthetic progestin. Progesterone also has a role in skin elasticity and bone strength, in respiration , 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-dimorphic proportions of those.

• Progesterone receptor antagonists, or selective progesterone receptor modulators (SPRM)s, such as RU-486 ( Mifepristone), can be used to prevent conception or induce medical abortions.

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.

Aging

Since most progesterone in males is created during testicular production of testosterone, 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 progestagens (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.

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 injury and this protective effect has been hypothesized to be caused by increased circulating levels of estrogen and progesterone in females.

The mechanism of progesterone protective effects may be the reduction of inflammation that follows brain trauma.

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• General discussion document on Progesterone, its uses and applications