Progesterone

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Progesterone
Progesteron.svg
Progesterone molecule
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 YesY
ATC code G03DA04
PubChem CID 5994
IUPHAR ligand 2377
DrugBank DB00396
ChemSpider 5773 YesY
UNII 4G7DS2Q64Y YesY
KEGG D00066 N
ChEBI CHEBI:17026 YesY
ChEMBL CHEMBL103 YesY
Synonyms 4-pregnene-3,20-dione
Chemical data
Formula C21H30O2 
Mol. mass 314.46
Physical data
Melt. point 126 °C (259 °F)
Spec. rot [α]D
 N (what is this?)  (verify)

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]

Chemistry[edit]

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[edit]

Animal[edit]

Progesterone is produced in high amounts in the ovaries (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[edit]

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[edit]

Biosynthesis[edit]

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]

Laboratory[edit]

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 (see figure to the right).[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]

The Johnson total synthesis of progesterone.[20]

A total synthesis of progesterone was reported in 1971 by W.S. Johnson (see figure to the right).[20] 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.[20]

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

Stigmasterol to progesterone synthesis.[21][22][23][24][25]

Levels[edit]

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. At around 12 weeks the placenta begins to produce progesterone in place of the corpus luteum, 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.[26] 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
Lower limit Upper limit Unit
Female - menstrual cycle (see diagram below)
Female - postmenopausal <0.2[27] 1[27] ng/mL
<0,6[28] 3[28] nmol/L
Female on oral contraceptives 0.34[27] 0.92[27] ng/mL
1.1[28] 2.9[28] nmol/L
Males 16 years 0.27[27] 0.9[27] ng/mL
0.86[28] 2.9[28] nmol/L
Female or male 1–9 years 0.1[27] 4.1[27] or 4.5[27] ng/mL
0.3[28] 13[28] 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[edit]

Activity profile[edit]

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),[29] as well as a ligand of the PGRMC1 (progesterone receptor membrane component 1; formerly known as the σ2 receptor).[30] Lastly, progesterone is also known to be an antagonist of the σ1 receptor,[31][32] a negative allosteric modulator of the nACh receptors,[2] and a potent antagonist of the mineralocorticoid receptor (MR).[33] Progesterone prevents MR activation by binding to this receptor with an affinity exceeding even those of aldosterone and glucocorticoids such as cortisol and corticosterone.[33]

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.[34][35]

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.[36] 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.[37]

Reproductive system[edit]

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.[38] Detailed characterisation of the events occurring in sperm in response to progesterone has elucidated certain events including intracellular calcium transients and maintained changes,[39] slow calcium oscillations,[40] now thought to possibly regulate motility.[41] Interestingly, progesterone has also been shown to demonstrate effects on octopus spermatozoa.[42]

Progesterone is sometimes called the "hormone of pregnancy",[43] 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.[43]
  • 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[edit]

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.[44]

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.[45]

Nervous system[edit]

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.[46] 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[edit]

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[edit]

Studies as far back as 1987 show that female sex hormones have an effect on the recovery of traumatic brain injury.[47] 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.[48]

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.[49] A number of additional animal studies have confirmed that progesterone has neuroprotective effects when administered shortly after traumatic brain injury.[50] Encouraging results have also been reported in human clinical trials.[51][52]

Proposed mechanism[edit]

The mechanism of progesterone protective effects may be the reduction of inflammation that follows brain trauma.[53]

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.[54] 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 GABAA, a widespread inhibitory neurotransmitter receptor.[55]

Progesterone has also been shown to prevent apoptosis in neurons, a common consequence of brain injury.[47] 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.[54][56] 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.[55] There is also evidence that the addition of progesterone can also help remyelinate damaged axons due to trauma, restoring some lost neural signal conduction.[55] Another way progesterone aids in regeneration includes increasing the circulation of endothelial progenitor cells in the brain.[57] This helps new vasculature to grow around scar tissue which helps repair the area of insult.

Combination treatments[edit]

Vitamin D and progesterone separately have neuroprotective effects after traumatic brain injury, but when combined their effects are synergistic.[58] 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.[59]

Clinical trials[edit]

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.[48] 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.[60][61] 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[edit]

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.[62]

  • 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.[63]
  • 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.[64] 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.[62]
  • 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.[65]

Other effects[edit]

  • 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.[66]
  • 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.[67]
  • 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) and tooth decay.[68]
  • 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.[69][70]
  • Progesterone may play a role in male behavior.[71]

Medical uses[edit]

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.[72] Progesterone was approved by the United States Food and Drug Administration as vaginal gel on July 31, 1997,[73] an oral capsule on May 14, 1998[74] in an injection form on April 25, 2001[75] and as a vaginal insert on June 21, 2007.[76] Progesterone is marketed under a large number of different brand names throughout the world.[77]

Progesterone has very poor pharmacokinetics (including low bioavailability and a half-life of only 5 minutes) when taken orally unless micronized.[1][78] 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).[78][77] Progesterone is also available in the forms of vaginal or rectal suppositories or pessaries (Cyclogest),[77] transdermally-administered gels or creams (Crinone, Endometrin, Progestogel, Prochieve),[77][79] or via injection (Progesterone, Strone).[78][77]

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.[80][81]

Pharmacokinetics[edit]

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.[82] The absorption and bioavailability of oral micronized progesterone is increased approximately two-fold when it is taken with food.[83]

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.[78] Via the oral route, peak concentrations are seen about 2–3 hours after ingestion, and the half-life is about 16–18 hours.[78] 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.[78]

OMP is prescribed in divided doses of 25–400 mg/daily,[84] 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.[85] Notably, a percentage of progesterone is converted into pregnanolone and allopregnanolone, which are neurosteroids and potent potentiators of GABAA receptors.[85][86] It is for this reason that common reported side effects of progesterone include dizziness, drowsiness or sedation, sleepiness, and fatigue, especially at high doses.[86][85] As a result, some physicians may instruct their patients to take their progesterone before bed.[85]

Progesterone, when taken orally, undergoes gastrointestinal (especially hepatic) metabolism to form hydroxylated metabolites, which in turn are metabolized into sulfate and glucuronide derivatives.[87] Enzymes involved in the hepatic metabolism of progesterone include, particularly, CYP2C19 and CYP3A4, as well as CYP2C9.[88][89]

Prevention of preterm birth[edit]

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.[90] 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.[91] 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,[92] 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.[93] 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.[94] An editorial by Roberto Romero discusses the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment.[95] A meta-analysis published in 2011 found that vaginal progesterone cut the risk of premature births by 42 percent in women with short cervixes.[96] 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.[97]

Other specific uses[edit]

See also[edit]

References[edit]

  1. ^ a b c d Tekoa L. King; Mary C. Brucker (25 October 2010). Pharmacology for Women's Health. Jones & Bartlett Publishers. pp. 372–373. ISBN 978-1-4496-5800-7. 
  2. ^ a b Baulieu E, Schumacher M (2000). "Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination". Steroids 65 (10-11): 605–12. PMID 11108866. 
  3. ^ Allen WM (1935). "The isolation of crystalline progestin". Science 82 (2118): 89–93. doi:10.1126/science.082.2118.89. PMID 17747122. 
  4. ^ Butenandt A, Westphal U (1934). "Zur Isolierung und Charakterisierung des Corpusluteum-Hormons". Berichte Deu0tsche chemische Gesellschaft 67 (8): 1440–1442. doi:10.1002/cber.19340670831. 
  5. ^ Hartmann M, Wettstein A (1934). "Ein krystallisiertes Hormon aus Corpus luteum". Helvetica Chimica Acta 17: 878–882. doi:10.1002/hlca.193401701111. 
  6. ^ Slotta KH, Ruschig H, Fels E (1934). "Reindarstellung der Hormone aus dem Corpusluteum". Berichte Deutsche chemische Gesellschaft 67 (7): 1270–1273. doi:10.1002/cber.19340670729. 
  7. ^ Allen WM (1970). "Progesterone: how did the name originate?". South. Med. J. 63 (10): 1151–5. doi:10.1097/00007611-197010000-00012. PMID 4922128. 
  8. ^ Goodson III WH, Handagama P, Moore II DH, Dairkee S (2007-12-13). "Milk products are a source of dietary progesterone". 30th Annual San Antonio Breast Cancer Symposium. pp. abstract # 2028. Retrieved 2008-03-12. 
  9. ^ Pauli GF, Friesen JB, Gödecke T, Farnsworth NR, Glodny B (January 2010). "Occurrence of Progesterone and Related Animal Steroids in Two Higher Plants". J Nat Prod 73 (3): 338–45. doi:10.1021/np9007415. PMID 20108949. 
  10. ^ Applezweig N (May 1969). "Steroids". Chem Week 104: 57–72. PMID 12255132. 
  11. ^ Noguchi E, Fujiwara Y, Matsushita S, Ikeda T, Ono M, Nohara T (September 2006). "Metabolism of tomato steroidal glycosides in humans". Chem. Pharm. Bull. 54 (9): 1312–4. doi:10.1248/cpb.54.1312. PMID 16946542. 
  12. ^ Yang DJ, Lu TJ, Hwang LS (October 2003). "Isolation and identification of steroidal saponins in Taiwanese yam cultivar (Dioscorea pseudojaponica Yamamoto)". J. Agric. Food Chem. 51 (22): 6438–44. doi:10.1021/jf030390j. PMID 14558759. 
  13. ^ Hooker E (2004). "Final report of the amended safety assessment of Dioscorea Villosa (Wild Yam) root extract". Int. J. Toxicol. 23 Suppl 2: 49–54. doi:10.1080/10915810490499055. PMID 15513824. 
  14. ^ Niño J, Jiménez DA, Mosquera OM, Correa YM (2007). "Diosgenin quantification by HPLC in a Dioscorea polygonoides tuber collection from colombian flora". Journal of the Brazilian Chemical Society 18 (5): 1073–1076. doi:10.1590/S0103-50532007000500030. 
  15. ^ Myoda T, Nagai T, Nagashima T (2005). "Properties of starches in yam (Dioscorea spp.) tuber". Current Topics in Food Science and Technology. pp. 105–114. ISBN 81-308-0003-9. 
  16. ^ Dewick, Paul M. (2002). Medicinal natural products: a biosynthetic approach. New York: Wiley. p. 244. ISBN 0-471-49641-3. 
  17. ^ Duport C, Spagnoli R, Degryse E, Pompon D (February 1998). "Self-sufficient biosynthesis of pregnenolone and progesterone in engineered yeast". Nat. Biotechnol. 16 (2): 186–9. doi:10.1038/nbt0298-186. PMID 9487528. 
  18. ^ a b c Marker RE, Krueger J (1940). "Sterols. CXII. Sapogenins. XLI. The Preparation of Trillin and its Conversion to Progesterone". J. Am. Chem. Soc. 62 (12): 3349–3350. doi:10.1021/ja01869a023. 
  19. ^ Numazawa M, Nagaoka M, Kunitama Y (September 1986). "Regiospecific deoxygenation of the dihydroxyacetone moiety at C-17 of corticoid steroids with iodotrimethylsilane". Chem. Pharm. Bull. 34 (9): 3722–6. doi:10.1248/cpb.34.3722. PMID 3815593. 
  20. ^ a b c Johnson WS, Gravestock MB, McCarry BE (August 1971). "Acetylenic bond participation in biogenetic-like olefinic cyclizations. II. Synthesis of dl-progesterone". J. Am. Chem. Soc. 93 (17): 4332–4. doi:10.1021/ja00746a062. PMID 5131151. 
  21. ^ . doi:10.1021/ja01162a076.  Missing or empty |title= (help) edit
  22. ^ . doi:10.1021/ja01537a041.  Missing or empty |title= (help) edit
  23. ^ . doi:10.1021/jo00442a044.  Missing or empty |title= (help) edit
  24. ^ "Nova Transcripts: Forgotten Genious". PBS.org. February 6, 2007. 
  25. ^ "Giants of the Past". lipidlibrary.aocs.org. 
  26. ^ NIH Clinical Center (2004-08-16). "Progesterone Historical Reference Ranges". United States National Institutes of Health. Retrieved 2008-03-12. 
  27. ^ a b c d e f g h i Progesterone Reference Ranges, Performed at the Clinical Center at the National Institutes of Health, Bethesda MD, 03Feb09
  28. ^ a b c d e f g h Converted from mass values using molar mass of 314.46 g/mol
  29. ^ Thomas P, Pang Y (2012). "Membrane progesterone receptors: evidence for neuroprotective, neurosteroid signaling and neuroendocrine functions in neuronal cells". Neuroendocrinology 96 (2): 162–71. doi:10.1159/000339822. PMC 3489003. PMID 22687885. 
  30. ^ Meyer C, Schmid R, Schmieding K, Falkenstein E, Wehling M (February 1998). "Characterization of high affinity progesterone-binding membrane proteins by anti-peptide antiserum". Steroids 63 (2): 111–6. PMID 9516722. 
  31. ^ Maurice T, Urani A, Phan VL, Romieu P (November 2001). "The interaction between neuroactive steroids and the sigma1 receptor function: behavioral consequences and therapeutic opportunities". Brain Res. Brain Res. Rev. 37 (1-3): 116–32. PMID 11744080. 
  32. ^ Johannessen M, Fontanilla D, Mavlyutov T, Ruoho AE, Jackson MB (February 2011). "Antagonist action of progesterone at σ-receptors in the modulation of voltage-gated sodium channels". Am. J. Physiol., Cell Physiol. 300 (2): C328–37. doi:10.1152/ajpcell.00383.2010. PMC 3043630. PMID 21084640. 
  33. ^ a b Rupprecht R, Reul JM, van Steensel B, Spengler D, Söder M, Berning B, Holsboer F, Damm K (1993). "Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands". Eur J Pharmacol 247 (2): 145–54. doi:10.1016/0922-4106(93)90072-H. PMID 8282004. 
  34. ^ Strünker T, Goodwin N, Brenker C, Kashikar ND, Weyand I, Seifert R, Kaupp UB (March 2011). "The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm". Nature 471 (7338): 382–6. doi:10.1038/nature09769. PMID 21412338. Lay summaryNature News. 
  35. ^ Lishko PV, Botchkina IL, Kirichok Y (March 2011). "Progesterone activates the principal Ca2+ channel of human sperm". Nature 471 (7338): 387–91. doi:10.1038/nature09767. PMID 21412339. 
  36. ^ Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemeyer H, Chambon P (1990). "Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B". EMBO J. 9 (5): 1603–14. PMC 551856. PMID 2328727. 
  37. ^ Landau RL, Bergenstal DM, Lugibihl K, Kascht ME (1955). "The metabolic effects of progesterone in man". J Clin Endocrinol Metab 15 (10): 1194–215. doi:10.1210/jcem-15-10-1194. PMID 13263410. 
  38. ^ Correia JN, Conner SJ, Kirkman-Brown JC (May 2007). "Non-genomic steroid actions in human spermatozoa. "Persistent tickling from a laden environment"". Semin. Reprod. Med. 25 (3): 208–19. doi:10.1055/s-2007-973433. PMID 17447210. 
  39. ^ Kirkman-Brown JC, Bray C, Stewart PM, Barratt CL, Publicover SJ (June 2000). "Biphasic elevation of [Ca(2+)](i) in individual human spermatozoa exposed to progesterone". Developmental Biology 222 (2): 326–35. doi:10.1006/dbio.2000.9729. ISSN 0012-1606. PMID 10837122. 
  40. ^ Kirkman-Brown JC, Barratt CL, Publicover SJ (March 2004). "Slow calcium oscillations in human spermatozoa". The Biochemical Journal 378 (Pt 3): 827–32. doi:10.1042/BJ20031368. PMC 1223996. PMID 14606954. 
  41. ^ Harper CV, Barratt CL, Publicover SJ (October 2004). "Stimulation of human spermatozoa with progesterone gradients to simulate approach to the oocyte. Induction of [Ca(2+)](i) oscillations and cyclical transitions in flagellar beating". The Journal of Biological Chemistry 279 (44): 46315–25. doi:10.1074/jbc.M401194200. PMID 15322137. 
  42. ^ Tosti E, Di Cosmo A, Cuomo A, Di Cristo C, Gragnaniello G (May 2001). "Progesterone induces activation in Octopus vulgaris spermatozoa". Mol. Reprod. Dev. 59 (1): 97–105. doi:10.1002/mrd.1011. PMID 11335951. 
  43. ^ a b Bowen R (2000-08-06). "Placental Hormones". Retrieved 2008-03-12. 
  44. ^ Macias H, Hinck L (2012). "Mammary gland development". Wiley Interdiscip Rev Dev Biol 1 (4): 533–57. doi:10.1002/wdev.35. PMC 3404495. PMID 22844349. 
  45. ^ Kuhl H, Schneider HP (August 2013). "Progesterone--promoter or inhibitor of breast cancer". Climacteric. 16 Suppl 1: 54–68. doi:10.3109/13697137.2013.768806. PMID 23336704. 
  46. ^ Schumacher M, Guennoun R, Robert F, Carelli C, Gago N, Ghoumari A, Gonzalez Deniselle MC, Gonzalez SL, Ibanez C, Labombarda F, Coirini H, Baulieu EE, De Nicola AF (2004). "Local synthesis and dual actions of progesterone in the nervous system: neuroprotection and myelination". Growth Horm. IGF Res. 14 Suppl A: S18–33. doi:10.1016/j.ghir.2004.03.007. PMID 15135772. 
  47. ^ a b Espinoza TR, Wright DW (2011). "The role of progesterone in traumatic brain injury". J Head Trauma Rehabil 26 (6): 497–9. doi:10.1097/HTR.0b013e31823088fa. PMID 22088981. 
  48. ^ a b Stein DG (September 2011). "Progesterone in the treatment of acute traumatic brain injury: a clinical perspective and update". Neuroscience 191: 101–6. doi:10.1016/j.neuroscience.2011.04.013. PMID 21497181. 
  49. ^ Roof RL, Hall ED (May 2000). "Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone". J. Neurotrauma 17 (5): 367–88. doi:10.1089/neu.2000.17.367. PMID 10833057. 
  50. ^ Gibson CL, Gray LJ, Bath PM, Murphy SP (February 2008). "Progesterone for the treatment of experimental brain injury; a systematic review". Brain 131 (Pt 2): 318–28. doi:10.1093/brain/awm183. PMID 17715141. 
  51. ^ Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, Salomone JP, Dent LL, Harris OA, Ander DS, Lowery DW, Patel MM, Denson DD, Gordon AB, Wald MM, Gupta S, Hoffman SW, Stein DG (April 2007). "ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury". Ann Emerg Med 49 (4): 391–402, 402.e1–2. doi:10.1016/j.annemergmed.2006.07.932. PMID 17011666. 
  52. ^ Xiao G, Wei J, Yan W, Wang W, Lu Z (April 2008). "Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial". Crit Care 12 (2): R61. doi:10.1186/cc6887. PMC 2447617. PMID 18447940. 
  53. ^ Pan DS, Liu WG, Yang XF, Cao F (October 2007). "Inhibitory effect of progesterone on inflammatory factors after experimental traumatic brain injury". Biomed. Environ. Sci. 20 (5): 432–8. PMID 18188998. 
  54. ^ a b Luoma JI, Stern CM, Mermelstein PG (August 2012). "Progesterone inhibition of neuronal calcium signaling underlies aspects of progesterone-mediated neuroprotection". J. Steroid Biochem. Mol. Biol. 131 (1-2): 30–6. doi:10.1016/j.jsbmb.2011.11.002. PMC 3303940. PMID 22101209. 
  55. ^ a b c Stein DG (March 2008). "Progesterone exerts neuroprotective effects after brain injury". Brain Res Rev 57 (2): 386–97. doi:10.1016/j.brainresrev.2007.06.012. PMC 2699575. PMID 17826842. 
  56. ^ Herson PS, Koerner IP, Hurn PD (May 2009). "Sex, sex steroids, and brain injury". Semin. Reprod. Med. 27 (3): 229–39. doi:10.1055/s-0029-1216276. PMC 2675922. PMID 19401954. 
  57. ^ Li Z, Wang B, Kan Z, Zhang B, Yang Z, Chen J, Wang D, Wei H, Zhang JN, Jiang R (January 2012). "Progesterone increases circulating endothelial progenitor cells and induces neural regeneration after traumatic brain injury in aged rats". J. Neurotrauma 29 (2): 343–53. doi:10.1089/neu.2011.1807. PMID 21534727. 
  58. ^ Cekic M, Sayeed I, Stein DG (July 2009). "Combination treatment with progesterone and vitamin D hormone may be more effective than monotherapy for nervous system injury and disease". Front Neuroendocrinol 30 (2): 158–72. doi:10.1016/j.yfrne.2009.04.002. PMC 3025702. PMID 19394357. 
  59. ^ Khaksari M, Soltani Z, Shahrokhi N, Moshtaghi G, Asadikaram G (January 2011). "The role of estrogen and progesterone, administered alone and in combination, in modulating cytokine concentration following traumatic brain injury". Can. J. Physiol. Pharmacol. 89 (1): 31–40. doi:10.1139/y10-103. PMID 21186375. 
  60. ^ "Efficacy and Safety Study of Intravenous Progesterone in Patients With Severe Traumatic Brain Injury (SyNAPSe)". ClinicalTrials.gov. U.S. National Institutes of Health. Retrieved 2012-07-14. 
  61. ^ "SyNAPse: The Global phase 3 study of progesterone in severe traumatic brain injury". BHR Pharma, LLC. 
  62. ^ a b Lynch WJ, Sofuoglu M (2010). "Role of progesterone in nicotine addiction: evidence from initiation to relapse". Exp Clin Psychopharmacol 18 (6): 451–61. doi:10.1037/a0021265. PMC 3638762. PMID 21186920. 
  63. ^ Sofuoglu M, Mitchell E, Mooney M (2009). "Progesterone effects on subjective and physiological responses to intravenous nicotine in male and female smokers". Hum Psychopharmacol 24 (7): 559–64. doi:10.1002/hup.1055. PMC 2785078. PMID 19743227. 
  64. ^ Cosgrove KP, Esterlis I, McKee SA, Bois F, Seibyl JP, Mazure CM, Krishnan-Sarin S, Staley JK, Picciotto MR, O'Malley SS (2012). "Sex differences in availability of β2*-nicotinic acetylcholine receptors in recently abstinent tobacco smokers". Arch. Gen. Psychiatry 69 (4): 418–27. doi:10.1001/archgenpsychiatry.2011.1465. PMC 3508698. PMID 22474108. 
  65. ^ Mello NK, Knudson IM, Kelly M, Fivel PA, Mendelson JH (2011). "Effects of progesterone and testosterone on cocaine self-administration and cocaine discrimination by female rhesus monkeys". Neuropsychopharmacology 36 (11): 2187–99. doi:10.1038/npp.2011.130. PMC 3176575. PMID 21796112. 
  66. ^ Physiology at MCG 5/5ch9/s5ch9_13
  67. ^ Hould FS, Fried GM, Fazekas AG, Tremblay S, Mersereau WA (1988). "Progesterone receptors regulate gallbladder motility". J. Surg. Res. 45 (6): 505–12. doi:10.1016/0022-4804(88)90137-0. PMID 3184927. 
  68. ^ "Hormones and Oral Health". WebMD. 
  69. ^ Picard F, Wanatabe M, Schoonjans K, Lydon J, O'Malley BW, Auwerx J (2002). "Progesterone receptor knockout mice have an improved glucose homeostasis secondary to beta -cell proliferation". Proceedings of the National Academy of Sciences 99 (24): 15644–15648. doi:10.1073/pnas.202612199. PMC 137770. PMID 12438645. 
  70. ^ Brănişteanu DD, Mathieu C (March 2003). "Progesterone in gestational diabetes mellitus: guilty or not guilty?". Trends Endocrinol. Metab. 14 (2): 54–6. doi:10.1016/S1043-2760(03)00003-1. PMID 12591170. 
  71. ^ Schneider JS, Stone MK, Wynne-Edwards KE, Horton TH, Lydon J, O'Malley B, Levine JE (2003). "Progesterone receptors mediate male aggression toward infants". Proc. Natl. Acad. Sci. U.S.A. 100 (5): 2951–6. doi:10.1073/pnas.0130100100. PMC 151447. PMID 12601162. 
  72. ^ Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH (2008). "Classification and pharmacology of progestins". Maturitas 61 (1–2): 171–80. doi:10.1016/j.maturitas.2003.09.014. PMID 19434889. 
  73. ^ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations: 020701". Food and Drug Administration. 2010-07-02. Retrieved 2010-07-07. 
  74. ^ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations: 019781". Food and Drug Administration. 2010-07-02. Retrieved 2010-07-07. 
  75. ^ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations: 075906". Food and Drug Administration. 2010-07-02. Retrieved 2010-07-07. 
  76. ^ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations: 022057". Food and Drug Administration. 2010-07-02. Retrieved 2010-07-07. 
  77. ^ a b c d e Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. p. 880. ISBN 978-3-88763-075-1. 
  78. ^ a b c d e f Zutshi (1 January 2005). Hormones in Obstetrics and Gynaecology. Jaypee Brothers Publishers. p. 74. ISBN 978-81-8061-427-9. 
  79. ^ Lark, Susan (1999). Making the Estrogen Decision. McGraw-Hill Professional. p. 22. ISBN 9780879836962. 
  80. ^ Zava DT, Dollbaum CM, Blen M (1998). "Estrogen and progestin bioactivity of foods, herbs, and spices". Proc. Soc. Exp. Biol. Med. 217 (3): 369–78. doi:10.3181/00379727-217-44247. PMID 9492350. 
  81. ^ Komesaroff PA, Black CV, Cable V, Sudhir K (2001). "Effects of wild yam extract on menopausal symptoms, lipids and sex hormones in healthy menopausal women". Climacteric 4 (2): 144–50. doi:10.1080/713605087. PMID 11428178. 
  82. ^ Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH (2003). "Classification and pharmacology of progestins". Maturitas. 46 Suppl 1: S7–S16. doi:10.1016/j.maturitas.2003.09.014. PMID 14670641. 
  83. ^ Simon JA, Robinson DE, Andrews MC, et al. (July 1993). "The absorption of oral micronized progesterone: the effect of food, dose proportionality, and comparison with intramuscular progesterone". Fertil. Steril. 60 (1): 26–33. PMID 8513955. 
  84. ^ Integrative Medicine. Elsevier Health Sciences. 2012. p. 343. ISBN 1-4377-1793-4. 
  85. ^ a b c d Rebekah Wang-Cheng; Joan M. Neuner; Vanessa M. Barnabei (2007). Menopause. ACP Press. p. 97. ISBN 978-1-930513-83-9. 
  86. ^ a b Niels Bergemann; Anita Riecher-Rössler (27 December 2005). Estrogen Effects in Psychiatric Disorders. Springer Science & Business Media. p. 179. ISBN 978-3-211-27063-9. 
  87. ^ Sushma Deshmukh (30 September 2013). Infertility Management Made Easy. JP Medical Ltd. p. 273. ISBN 978-93-5090-531-9. 
  88. ^ Yamazaki H, Shimada T (October 1997). "Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and 3A4 in human liver microsomes". Arch. Biochem. Biophys. 346 (1): 161–9. doi:10.1006/abbi.1997.0302. PMID 9328296. 
  89. ^ Gerard A. McKay; Matthew R. Walters (6 February 2013). Lecture Notes: Clinical Pharmacology and Therapeutics. John Wiley & Sons. p. 33. ISBN 978-1-118-34489-7. 
  90. ^ da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M (2003). "Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study". Am. J. Obstet. Gynecol. 188 (2): 419–24. doi:10.1067/mob.2003.41. PMID 12592250. 
  91. ^ Harris, Gardiner (2011-05-02). "Hormone Is Said to Cut Risk of Premature Birth". New York Times. Retrieved 5 May 2011. 
  92. ^ O'Brien JM, Adair CD, Lewis DF, Hall DR, Defranco EA, Fusey S, Soma-Pillay P, Porter K, How H, Schackis R, Eller D, Trivedi Y, Vanburen G, Khandelwal M, Trofatter K, Vidyadhari D, Vijayaraghavan J, Weeks J, Dattel B, Newton E, Chazotte C, Valenzuela G, Calda P, Bsharat M, Creasy GW (2007). "Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial". Ultrasound Obstet Gynecol 30 (5): 687–96. doi:10.1002/uog.5158. PMID 17899572. 
  93. ^ DeFranco EA, O'Brien JM, Adair CD, Lewis DF, Hall DR, Fusey S, Soma-Pillay P, Porter K, How H, Schakis R, Eller D, Trivedi Y, Vanburen G, Khandelwal M, Trofatter K, Vidyadhari D, Vijayaraghavan J, Weeks J, Dattel B, Newton E, Chazotte C, Valenzuela G, Calda P, Bsharat M, Creasy GW (2007). "Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: a secondary analysis from a randomized, double-blind, placebo-controlled trial". Ultrasound Obstet Gynecol 30 (5): 697–705. doi:10.1002/uog.5159. PMID 17899571. 
  94. ^ Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH (2007). "Progesterone and the risk of preterm birth among women with a short cervix". N. Engl. J. Med. 357 (5): 462–9. doi:10.1056/NEJMoa067815. PMID 17671254. 
  95. ^ Romero R (2007). "Prevention of spontaneous preterm birth: the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment". Ultrasound Obstet Gynecol 30 (5): 675–86. doi:10.1002/uog.5174. PMID 17899585. 
  96. ^ Hassan SS, Romero R, Vidyadhari D, Fusey S, Baxter JK, Khandelwal M, Vijayaraghavan J, Trivedi Y, Soma-Pillay P, Sambarey P, Dayal A, Potapov V, O'Brien J, Astakhov V, Yuzko O, Kinzler W, Dattel B, Sehdev H, Mazheika L, Manchulenko D, Gervasi MT, Sullivan L, Conde-Agudelo A, Phillips JA, Creasy GW (July 2011). "Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial". Ultrasound Obstet Gynecol 38 (1): 18–31. doi:10.1002/uog.9017. PMID 21472815. Lay summaryWebMD. 
  97. ^ "Progesterone helps cut risk of pre-term birth". Women's health. msnbc.com. 2011-12-14. Retrieved 2011-12-14. 
  98. ^ Orrin Devinsky; Steven Schachter; Steven Pacia (1 January 2005). Complementary and Alternative Therapies for Epilepsy. Demos Medical Publishing. pp. 378–. ISBN 978-1-934559-08-6. 
  99. ^ Sriram, D (2007). Medicinal Chemistry. New Delhi: Dorling Kindersley India Pvt. Ltd. p. 432. ISBN 81-317-0031-3. 
  100. ^ World Professional Association for Transgender Health (September 2011), Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People, Seventh Version 

Additional images[edit]

Steroidogenesis, showing progesterone among the progestogens in yellow area.


External links[edit]