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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/11/19 05:31:35」(JST)

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Progesterone (pregn-4-ene-3,20-dione; abbreviated as P4) is an endogenous steroid hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species.^[1] It belongs to a group of steroid hormones called the progestogens,^[1] and is the major progestogen in the body. Progesterone is also a crucial metabolic intermediate in the production other endogenous steroids, including the sex hormones and the corticosteroids, and plays an important role in brain function as a neurosteroid.^[2]

1 Chemistry
2 Sources
- 2.1 Animal
- 2.2 Plants
3 Synthesis
- 3.1 Biosynthesis
- 3.2 Semisynthesis
- 3.3 Total synthesis
4 Levels
5 Function
- 5.1 Activity profile
- 5.2 Reproductive system
- 5.3 Female breasts
- 5.4 Nervous system
- 5.5 Aging
- 5.6 Brain damage
  - 5.6.1 Proposed mechanism
  - 5.6.2 Combination treatments
  - 5.6.3 Clinical trials
- 5.7 Addiction
- 5.8 Other effects
6 Medical uses
- 6.1 Pharmacokinetics
- 6.2 Prevention of preterm birth
- 6.3 Other uses
7 See also
8 References
9 Additional images
10 External links

Chemistry

Progesterone was independently discovered by four research groups.^[3]^[4]^[5]^[6]

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.^[7]

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.

Sources

Animal

Progesterone is produced in high amounts in the ovarie (by the corpus luteum) from the onset of puberty to menopause, and is also produced in smaller amounts by the adrenal glands after the onset of adrenarche in both males and females. To a lesser extent, progesterone is produced in nervous tissue, especially in the brain, and in adipose (fat) tissue, as well.

During human pregnancy, progesterone is produced in increasingly high amounts by the ovaries and placenta. At first, the source is the corpus luteum that has been "rescued" by the presence of human chorionic gonadotropin (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 animal source of progesterone is milk products. After consumption of milk products the level of bioavailable progesterone goes up.^[8]

Plants

In at least one plant, Juglans regia, progesterone has been detected.^[9] In addition, progesterone-like steroids are found in Dioscorea mexicana. Dioscorea mexicana is a plant that is part of the yam family native to Mexico.^[10] It contains a steroid called diosgenin that is taken from the plant and is converted into progesterone.^[11] 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.^[12]

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.^[13] Dioscorea polygonoides has been found to contain 2.64% diosgenin as shown by gas chromatography-mass spectrometry.^[14] Many of the Dioscorea species that originate from the yam family grow in countries that have tropical and subtropical climates.^[15]

Synthesis

Biosynthesis

Top: Conversion of cholesterol (1) into pregnenolone (3) to progesterone (6).

Bottom: Progesterone is important for aldosterone (mineralocorticoid) synthesis, as 17-hydroxyprogesterone is for cortisol (glucocorticoid), and androstenedione for sex steroids.

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.^[16] 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.

Pregnenolone and progesterone can also be synthesized by yeast.^[17]

Semisynthesis

The Marker semisynthesis of progesterone from diosgenin.^[18]

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.^[18] 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.^[19]

Stigmasterol to progesterone synthesis.^[20]^[21]^[22]^[23]^[24]

Progesterone can also be made from the stigmasterol found in soybean oil also. c.f. Percy Julian.

Total synthesis

The Johnson total synthesis of progesterone.^[25]

A total synthesis of progesterone was reported in 1971 by W.S. Johnson.^[25] 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 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.^[25]

The last reaction shows an Oppenauer oxidation of pregnenolone to progesterone.

Progesterone synthesis:^[26]^[20]^[27] U.S. Patent 2,379,832 U.S. Patent 2,379,832 U.S. Patent 2,232,438 U.S. Patent 2,420,489

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, 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 luteum allowing it to maintain levels of progesterone. Between 7–9 weeks the placenta begins to produce progesterone in place of the corpus luteum, this process is named the luteal-placental shift.^[28] 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.^[29] Adult males have levels similar to those in women during the follicular phase of the menstrual cycle.

Blood test results should always be interpreted using the reference ranges provided by the laboratory that performed the results. Example reference ranges are listed below.

Person type	Reference range for blood test
Person type	Lower limit	Upper limit	Unit
Female - menstrual cycle	(see diagram below)
Female - postmenopausal	<0.2^[30]	1^[30]	ng/mL
Female - postmenopausal	<0,6^[31]	3^[31]	nmol/L
Female on oral contraceptives	0.34^[30]	0.92^[30]	ng/mL
Female on oral contraceptives	1.1^[31]	2.9^[31]	nmol/L
Males ≥16 years	0.27^[30]	0.9^[30]	ng/mL
Males ≥16 years	0.86^[31]	2.9^[31]	nmol/L
Female or male 1–9 years	0.1^[30]	4.1^[30] or 4.5^[30]	ng/mL
Female or male 1–9 years	0.3^[31]	13^[31]	nmol/L

Progesterone levels during the menstrual cycle.
- The ranges denoted By biological stage may be used in closely monitored menstrual cycles in regard to other markers of its biological progression, with the time scale being compressed or stretched to how much faster or slower, respectively, the cycle progresses compared to an average cycle.
- The ranges denoted Inter-cycle variability are more appropriate to use in non-monitored cycles with only the beginning of menstruation known, but where the woman accurately knows her average cycle lengths and time of ovulation, and that they are somewhat averagely regular, with the time scale being compressed or stretched to how much a woman's average cycle length is shorter or longer, respectively, than the average of the population.

- The ranges denoted Inter-woman variability are more appropriate to use when the average cycle lengths and time of ovulation are unknown, but only the beginning of menstruation is given.

Function

Activity profile

Micrograph showing changes to the endometrium due to progesterone (decidualization) H&E stain.

Progesterone is the most important progestogen in the body, the result of its action as a potent agonist of the nuclear progesterone receptor (nPR).^[1] In addition, progesterone is a non-selective ligand of the recently discovered membrane progesterone receptors (mPRs),^[32] as well as a ligand of the PGRMC1 (progesterone receptor membrane component 1; formerly known as the σ₂ receptor).^[33] Lastly, progesterone is also known to be an antagonist of the σ₁ receptor,^[34]^[35] a negative allosteric modulator of the nACh receptors,^[2] and a potent antagonist of the mineralocorticoid receptor (MR).^[36] Progesterone prevents MR activation by binding to this receptor with an affinity exceeding even those of aldosterone and glucocorticoids such as cortisol and corticosterone.^[36]

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). As a result, it has been suggested that substances that block the progesterone binding site on CatSper channels could potentially be used in male contraception.^[37]^[38]

Progesterone has a number of physiological effects that are amplified in the presence of estrogens. Estrogens through estrogen receptors (ERs) upregulate the expression of PRs.^[39] 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.^[40]

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.^[41] Detailed characterisation of the events occurring in sperm in response to progesterone has elucidated certain events including intracellular calcium transients and maintained changes,^[42] slow calcium oscillations,^[43] now thought to possibly regulate motility.^[44] Interestingly, progesterone has also been shown to demonstrate effects on octopus spermatozoa.^[45]

Progesterone is sometimes called the "hormone of pregnancy",^[46] 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. 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 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.^[46]
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.

Female breasts

Progesterone plays an important role in mammary gland development in females. In conjunction with prolactin, it induces lobuloalveolar maturation of the breasts during pregnancy to allow for milk production, and thus lactation and breastfeeding, after childbirth.^[47]

Progesterone also appears to be involved in the development of breast cancer, though its role, and whether it is a promoter or inhibitor of breast cancer risk, has not been fully elucidated.^[48]

Nervous system

Progesterone, like pregnenolone and dehydroepiandrosterone (DHEA), belongs to an important group of endogenous steroids called neurosteroids. It can be synthesized within the central nervous system and also serves as a precursor to another major neurosteroid, allopregnanolone.

Neurosteroids are neuromodulators, and are neuroprotective, neurogenic, and regulate neurotransmission and myelination.^[49] The effects of progesterone as a neurosteroid are mediated predominantly through its interactions with non-nuclear PRs, namely the mPRs and PGRMC1, as well as certain other receptors, such as the σ₁ and nACh receptors.

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 progestogens 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 receptors 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.^{[citation needed]}

Brain damage

Studies as far back as 1987 show that female sex hormones have an effect on the recovery of traumatic brain injury.^[50] In these studies, it was first observed that pseudopregnant female rats had reduced edema after traumatic brain injury. Recent clinical trials have shown that among patients that have suffered moderate traumatic brain injury, those that have been treated with progesterone are more likely to have a better outcome than those who have not.^[51]

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.^[52] A number of additional animal studies have confirmed that progesterone has neuroprotective effects when administered shortly after traumatic brain injury.^[53] Encouraging results have also been reported in human clinical trials.^[54]^[55]

Proposed mechanism

The mechanism of progesterone protective effects may be the reduction of inflammation that follows brain trauma.^[56]

Damage incurred by traumatic brain injury is believed to be caused in part by mass depolarization leading to excitotoxicity. One way in which progesterone helps to alleviate some of this excitotoxicity is by blocking the voltage-dependent calcium channels that trigger neurotransmitter release.^[57] It does so by manipulating the signaling pathways of transcription factors involved in this release. Another method for reducing the excitotoxicity is by up-regulating the GABA_A, a widespread inhibitory neurotransmitter receptor.^[58]

Progesterone has also been shown to prevent apoptosis in neurons, a common consequence of brain injury.^[50] It does so by inhibiting enzymes involved in the apoptosis pathway specifically concerning the mitochondria, such as activated caspase 3 and cytochrome c.

Not only does progesterone help prevent further damage, it has also been shown to aid in neuroregeneration. One of the serious effects of traumatic brain injury includes edema. Animal studies show that progesterone treatment leads to a decrease in edema levels by increasing the concentration of macrophages and microglia sent to the injured tissue.^[57]^[59] This was observed in the form of reduced leakage from the blood brain barrier in secondary recovery in progesterone treated rats. In addition, progesterone was observed to have antioxidant properties, reducing the concentration of oxygen free radicals faster than without.^[58] There is also evidence that the addition of progesterone can also help remyelinate damaged axons due to trauma, restoring some lost neural signal conduction.^[58] Another way progesterone aids in regeneration includes increasing the circulation of endothelial progenitor cells in the brain.^[60] This helps new vasculature to grow around scar tissue which helps repair the area of insult.

Combination treatments

Vitamin D and progesterone separately have neuroprotective effects after traumatic brain injury, but when combined their effects are synergistic.^[61] When used at their optimal respective concentrations, the two combined have been shown to reduce cell death more than when alone.

One study looks at a combination of progesterone with estrogen. Both progesterone and estrogen are known to have antioxidant-like qualities and are shown to reduce edema without injuring the blood-brain barrier. In this study, when the two hormones are administered alone it does reduce edema, but the combination of the two increases the water content, thereby increasing edema.^[62]

Clinical trials

The clinical trials for progesterone as a treatment for traumatic brain injury have only recently begun. ProTECT, a phase II trial conducted in Atlanta at Grady Memorial Hospital in 2007, the first to show that progesterone reduces edema in humans. Since then, trials have moved on to phase III. The National Institute of Health began conducting a nationwide phase III trial in 2011 led by Emory University.^[51] A global phase III initiative called SyNAPSe®, initiated in June 2010, is run by a U.S.-based private pharmaceutical company, BHR Pharma, and is being conducted in the United States, Argentina, Europe, Israel and Asia.^[63]^[64] Approximately 1,200 patients with severe (Glasgow Coma Scale scores of 3-8), closed-head TBI will be enrolled in the study at nearly 150 medical centers.

Addiction

Progesterone enhances the function of serotonin receptors in the brain, so an excess or deficit of progesterone has the potential to result in significant neurochemical issues. This provides an explanation for why some people resort to substances that enhance serotonin activity such as nicotine, alcohol, and marijuana when their progesterone levels fall below optimal levels.^[65]

To examine the effects of progesterone on nicotine addiction, participants in one study were either treated orally with a progesterone treatment, or treated with a placebo. When treated with progesterone, participants exhibited enhanced suppression of smoking urges, reported higher ratings of “bad effects” from IV nicotine, and reported lower ratings of “drug liking”. These results suggest that progesterone not only alters the subjective effects of nicotine, but reduces the urge to smoke cigarettes.^[66]
Sex differences in hormone levels may induce women to respond differently than men to nicotine. When women undergo cyclic changes or different hormonal transition phases (menopause, pregnancy, adolescence), there are changes in their progesterone levels.^[67] Therefore, females have an increased biological vulnerability to nicotine’s reinforcing effects compared to men and progesterone may be used to counter this enhanced vulnerability. This information helps us to understand how the female hormones profoundly impact brain functioning, and, thus behavior.^[65]
Similar to nicotine, cocaine also increases the release of dopamine in the brain. The neurotransmitter is involved in the reward center and is one of the main neurotransmitters involved with substance abuse and reliance. In a study of cocaine users, it was reported that progesterone reduced craving and the feeling of being stimulated by cocaine. Thus, progesterone was suggested as an agent that decreases cocaine craving by reducing the dopaminergic properties of the drug.^[68]

Other effects

Progesterone raises epidermal growth factor-1 (EGF-1) levels, a factor often used to induce proliferation, and used to sustain cultures, of stem cells.
Progesterone increases core temperature (thermogenic function) during ovulation.^[69]
Progesterone reduces spasm and relaxes smooth muscle. Bronchi are widened and mucus regulated. (PRs are widely present in submucosal tissue.)
Progesterone acts as an antiinflammatory agent and regulates the immune response.
Progesterone reduces gall-bladder activity.^[70]
Progesterone normalizes blood clotting and vascular tone, zinc and copper levels, cell oxygen levels, and use of fat stores for energy.
Progesterone may affect gum health, increasing risk of gingivitis (gum inflammation).^[71]
Progesterone appears to prevent endometrial cancer (involving the uterine lining) by regulating the effects of estrogen.
Progesterone plays an important role in the signaling of insulin release and pancreatic function, and may affect the susceptibility to diabetes or gestational diabetes.^[72]^[73]
Progesterone may play a role in male behavior.^[74]

Medical uses

Prometrium 100 mg Oral Capsule

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 and have been used long before progesterone formulations became available.^[75] Progesterone was approved by the United States Food and Drug Administration as vaginal gel on July 31, 1997,^[76] an oral capsule on May 14, 1998^[77] in an injection form on April 25, 2001^[78] and as a vaginal insert on June 21, 2007.^[79] Progesterone is marketed under a large number of different brand names throughout the world.^[80]

Progesterone has very poor pharmacokinetics (including low bioavailability and a half-life of only 5 minutes) when taken orally unless micronized.^[1]^[81] As such, it is sold in the form of oil-filled capsules containing micronized progesterone for oral use (Utrogestan, Prometrium, Microgest), termed oral micronized progesterone (OMP).^[80]^[81] Progesterone is also available in the forms of vaginal or rectal suppositories or pessaries (Cyclogest),^[80] transdermally-administered gels or creams (Crinone, Endometrin, Progestogel, Prochieve),^[80]^[82] or via injection (Progesterone, Strone).^[80]^[81]

Transdermal products made with progesterone USP (i.e., "natural progesterone") do not require a prescription. Some of these products also contain "wild yam extract" derived from Dioscorea villosa, 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^[18]) into progesterone.^[83]^[84]

Pharmacokinetics

The route of administration impacts the effects of progesterone. OMP has a wide inter-individual variability in absorption and bioavailability. In contrast, progestins are rapidly absorbed with a longer half-life than progesterone and maintain stable levels in the blood.^[85] The absorption and bioavailability of oral micronized progesterone is increased approximately two-fold when it is taken with food.^[86]

Progesterone has a relatively short half-life in the body. As such, OMP is usually prescribed for twice or thrice-daily administration or once-daily administration when taken by injection.^[81] Via the oral route, peak concentrations are seen about 2–3 hours after ingestion, and the half-life is about 16–18 hours.^[81] Significantly elevated serum levels of progesterone are maintained for about 12 hours, and levels do not return to baseline until at least 24 hours have passed.^[81]

OMP is prescribed in divided doses of 25–400 mg/daily,^[87] but in the range of 100–300 mg per day most commonly. Oral doses of 100–200 mg will result in serum progesterone levels greater than 10 ng/mL.^[88] Notably, a percentage of progesterone is converted into pregnanolone and allopregnanolone, which are neurosteroids and potent potentiators of GABA_A receptors.^[88]^[89] It is for this reason that common reported side effects of progesterone include dizziness, drowsiness or sedation, sleepiness, and fatigue, especially at high doses.^[88]^[89] As a result, some physicians may instruct their patients to take their progesterone before bed.^[88]

Progesterone, when taken orally, undergoes gastrointestinal (especially hepatic) metabolism to form hydroxylated metabolites, which in turn are metabolized into sulfate and glucuronide derivatives.^[90] Enzymes involved in the hepatic metabolism of progesterone include, particularly, CYP2C19 and CYP3A4, as well as CYP2C9.^[91]^[92]

Prevention of preterm birth

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.^[93] 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.^[94] 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,^[95] 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.^[96] 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.^[97] An editorial by Roberto Romero discusses the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment.^[98] A meta-analysis published in 2011 found that vaginal progesterone cut the risk of premature births by 42 percent in women with short cervixes.^[99] The meta-analysis, which pooled published results of five large clinical trials, also found that the treatment cut the rate of breathing problems and reduced the need for placing a baby on a ventilator.^[100]

Other uses

Progesterone is used for luteal support in Assisted Reproductive Technology (ART) cycles such as In-vitro Fertilization (IVF).
Progesterone is used to control persistent 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 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.^{[citation needed]}
Progesterone can be used to treat catamenial epilepsy by supplementation during certain periods of the mensutral cycle.^[101]
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.
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.^[102]^{[copyright violation?]}
Antiprogestins and selective progesterone receptor modulators (SPRM)s, such as 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 is starting to be used in the treatment of the skin condition hidradenitis suppurativa.^{[citation needed]}
Progesterone is sometimes employed as a component of hormone replacement therapy for trans women.^[103]

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Additional images

Steroidogenesis, showing progesterone among the progestogens in yellow area.

Pregnenolone

Deoxycorticosterone

External links

Progesterone MS Spectrum
Progesterone at the US National Library of Medicine Medical Subject Headings (MeSH)
Kimball JW (2007-05-27). "Progesterone". Kimball's Biology Pages. Retrieved 2008-06-18.
"Progesterone Resource Center". PMS, Menopause, and Progesterone Resource Center. Oasis Advanced Wellness, Inc. Retrieved 2008-06-18.
Progesterone - Lab Tests Online

UpToDate Contents

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1. 子宮内避妊：器具、候補および選択 intrauterine contraception devices candidates and selection
2. 全身性エリテマトーデス女性患者における避妊に対するアプローチ approach to contraception in women with systemic lupus erythematosus
3. 遺伝性血管浮腫：疫学、臨床症状、増悪因子、および予後 hereditary angioedema epidemiology clinical manifestations exacerbating factors and prognosis
4. 遺伝性血管浮腫：一般診療および長期予防 hereditary angioedema general care and long term prophylaxis

English Journal

Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding.

Lethaby A1, Duckitt K, Farquhar C.
The Cochrane database of systematic reviews.Cochrane Database Syst Rev.2013 Jan 31;1:CD000400. doi: 10.1002/14651858.CD000400.pub3.
BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in premenopausal women. Although surgery is often used as a treatment, a range of medical therapies are also available. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce prostaglandin levels, which are elevated in wom
PMID 23440779

Immediate post-partum insertion of intrauterine devices.

Grimes DA1, Lopez LM, Schulz KF, Van Vliet HA, Stanwood NL.
The Cochrane database of systematic reviews.Cochrane Database Syst Rev.2010 May 12;(5):CD003036. doi: 10.1002/14651858.CD003036.pub2.
BACKGROUND: Insertion of an intrauterine device (IUD) immediately after delivery is appealing for several reasons. The woman is known not to be pregnant, her motivation for contraception may be high, and the setting may be convenient for both the woman and her provider. However, the risk of spontane
PMID 20464722

Nonsteroidal anti-inflammatory drugs for heavy menstrual bleeding.

Lethaby A1, Augood C, Duckitt K, Farquhar C.
The Cochrane database of systematic reviews.Cochrane Database Syst Rev.2007 Oct 17;(4):CD000400.
BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in premenopausal women. Although surgery is often used as a treatment, a range of medical therapies are also available. Nonsteroidal anti-inflammatory drugs reduce prostaglandin levels which are elevated in women with exc
PMID 17943741

Related Pictures

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★リンクテーブル★

リンク元

「プロゲステロン」

Progesterone
Systematic (IUPAC) name
	Pregn-4-ene-3,20-dione
Clinical data
Trade names	Utrogestan, Prometrium, Endometrin, Crinone
AHFS/Drugs.com	monograph
MedlinePlus	a604017
Pregnancy cat.	B (USA);
Legal status	?
Routes	oral, implant, transdermal
Pharmacokinetic data
Bioavailability	prolonged absorption, half-life approx 25-50 hours
Protein binding	96%-99%
Metabolism	hepatic to pregnanediols and pregnanolones
Half-life	34.8-55.13 hours
Excretion	renal
Identifiers
CAS number	57-83-0
ATC code	G03DA04
PubChem	CID 5994
IUPHAR ligand	2377
DrugBank	DB00396
ChemSpider	5773
UNII	4G7DS2Q64Y
KEGG	C00410
ChEBI	CHEBI:17026
ChEMBL	CHEMBL103
Synonyms	4-pregnene-3,20-dione
Chemical data
Formula	C21H30O2
Mol. mass	314.46
	SMILES CC(=O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CCC4=CC(=O)CC[C@]34C)C;
	InChI InChI=InChI=1S/C21H30O2/c1-13(22)17-6-7-18-16-5-4-14-12-15(23)8-10-20(14,2)19(16)9-11-21(17,18)3/h12,16-19H,4-11H2,1-3H3/t16-,17+,18-,19-,20-,21+/m0/s1 ; Key:RJKFOVLPORLFTN-LEKSSAKUSA-N ;
Physical data
Melt. point	126 °C (259 °F)
Spec. rot	[α]D
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　　[★]

英: progesterone (Z), P4
同: 黄体ホルモン corpus luteum hormone、プロジェステロン
商: プロゲホルモンルテウムプロゲストン, Crinone, Prochieve, Progestasert
関: エストロゲン、月経周期、ホルモン

分類

卵巣ホルモン

性状

ステロイド

産生組織

G10M.37

月経黄体
妊娠黄体(妊娠0-10週)
胎盤(妊娠10週以降)

標的組織

生理作用

	エストロゲン	プロゲステロン
子宮内膜	増殖期：増殖分泌期：プロゲステロンと協調して分泌期維持	分泌期：分泌期誘導
卵巣	卵胞の成長顆粒細胞に作用してエストロゲン受容体発現↑ →エストロゲンの正のフィードバック →エストロゲンの大量分泌
子宮筋	オキシトシンに対する感受性↓ 肥大増殖	オキシトシンに対する感受性↑
中枢神経への作用	視床下部、下垂体　少量→負のフィードバック　多量→正のフィードバック	視床下部体温中枢　刺激
その他	・子宮頚管粘液　量：↑、牽引性：↑、羊歯葉状結晶：↑ ・膣スメアの変化　成熟した表層細胞の出現　　角化、核濃縮、好酸性	・乳腺　腺房発育

子宮内膜：プロスタグランジンの合成を制御(増殖期には低値、月経期には高値)　→　月経前症候群・月経困難症との関連
妊娠中には下垂体前葉に作用してLHの分泌を抑制し、排卵を抑制する。(G10M.37)
乳腺組織のPRL受容体を減少させ、乳汁分泌を抑制する。(G10M.37)

作用機序

分泌調節

性周期・月経・妊娠との関連

非妊時

卵胞期：低値
排卵期～黄体期：高値
黄体期後期：漸減

妊娠時

妊娠時には0-10週にかけてなだらかに上昇してから下降するが、以降漸増する。(NGY.47)
妊娠時には10週までなだらかに増加し、以降増加。(G10M.37)

LAB.724

		エストロゲン			プロゲステロン
		エストロン	エストラジオール	エストリオール
		(pg/ml)	(pg/ml)	(pg/ml)	(ng/ml)
女性	卵胞期	10～60	10～150	0～20	0.5～1.5
	排卵期	25～100	50～380	5～40	1.5～6.8
	黄体期	25～80	30～300	5～40	5.0～28.0
	更年期	20～80	10～50	0～20	0.3～0.4
男性		30～60	10～60	0～15	0.2～0.4

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