|Systematic (IUPAC) name|
|Melt. point||126 °C (259 °F)|
|Bioavailability||prolonged absorption, half-life approx 25-50 hours|
|Metabolism||hepatic to pregnanediols and pregnanolones|
|Half life||34.8-55.13 hours|
|Pregnancy cat.||B (USA)|
(what is this?) (verify)|
Progesterone also known as P4 (pregn-4-ene-3,20-dione) is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans and other species. Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen.
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.
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.
Progesterone is produced in the ovaries (specifically 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:
In at least one plant, Juglans regia, progesterone has been detected. 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. It contains a steroid called diosgenin that is taken from the plant and is converted into progesterone. Diosgenin and progesterone are found in other Dioscorea species as well.
Another plant that contains substances readily convertible to progesterone is Dioscorea pseudojaponica native to Taiwan. Research has shown that the Taiwanese yam contains 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.
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). Biologically, 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.
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). 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 be deoxygenated at the C-17 and C-21 position by treatment with iodotrimethylsilane in chloroform to produce 11-keto-progesterone (ketogestin) which in turn can be reduced at position-11 to yield progesterone.
A total synthesis of progesterone was reported in 1971 by W.S. Johnson (see figure to the right). The synthesis begins with reacting the phosphonium salt 7 with phenyl lithium to produce the phosphonium ylide 8. The ylide 8 is reacted with an aldehyde to produce the alkene 9. The ketal protecting 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 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.
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.
Progesterone exerts its primary action through the intracellular progesterone receptor although a distinct, membrane bound progesterone receptor has also been postulated. Additionally, progesterone is a highly potent antagonist of the mineralocorticoid receptor (MR, the receptor for aldosterone and other mineralocorticosteroids). It prevents MR activation by binding to this receptor with an affinity exceeding even those of aldosterone and other corticosteroids such as cortisol and corticosterone.
Progesterone has a number of physiological effects which are amplified in the presence of estrogen. Estrogen through estrogen receptors upregulates the expression of progesterone receptors. Also, elevated levels of progesterone potently reduce the sodium-retaining activity of aldosterone, resulting in natriuresis and a reduction in extracellular fluid volume. Progesterone withdrawal, on the other hand, is associated with a temporary increase in sodium retention (reduced natriuresis, with an increase in extracellular fluid volume) due to the compensatory increase in aldosterone production which combats the blockade of the mineralocorticoid receptor by the previously elevated level of progesterone.
Progesterone is sometimes called the "hormone of pregnancy", and it has many roles relating to the development of the fetus:
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.
Progesterone can cause increased fluid retention which may result in epilepsy, migraine, asthma, cardiac or renal dysfunction. Blood clots may develop which can result in strokes and heart attacks which may lead to death or long-term disability; 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, 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 which may occur include; allergy, anemia, bloating, cramps, fatigue, tremor, urticaria, pain, conjunctivitis, dizziness, vomiting, myalgia, back pain, breast pain, difficult or painful intercourse, genital itching, genital yeast infection, upper respiratory tract infection, cystitis, dysuria, asthenia, xerophthalmia, syncope, dysmenorrhea, genital pruitis, premenstrual tension, gastritis, urinary tract infection, urinary tract infection, vaginal discharge, pharyngitis, sweating, hyperventilation, vaginal dryness, dyspnea, fever, edema, flu-like symptoms, gastrointestinal discomfort, gas, abdominal swelling, dry mouth, rhinitis, back pain, pruritis, rash, leg pain, skin discoloration, skin disorders, seborrhea, sinusitis, upper respiratory tract infection, asthma, acne, itching, painful or difficult urination, frequent urination.
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. However, the roles of progesterone may not be fulfilled by the synthetic progestins which in some cases were designed solely to mimic progesterone's uterine effects.
Progesterone is poorly absorbed by oral ingestion unless micronised and in oil, or with fatty foods; it does not dissolve in water. Products such as Prometrium, Utrogestan, Minagest and Microgest are therefore capsules containing micronised progesterone in oil - in all three mentioned the oil is peanut oil, which may cause serious allergic reactions in some people, but compounding pharmacies, which have the facilities and licenses to make their own products, can use alternatives. Vaginal and rectal application is also effective, with products such as ENDOMETRIN (progesterone) Vaginal Insert 100 mg, approved by the FDA in June 2007 to support embryo implantation and early pregnancy. Other products are CRINONE and PROCHIEVE bioadhesive progesterone vaginal gels (the first progesterone products FDA-approved for use in infertility and during pregnancy) and Cyclogest, which is progesterone in cocoa butter in the form of pessaries. Progesterone can be given by injection, but because it has a short half-life they need to be daily. Marketing of progesterone phamaceutical products, country to country, varies considerably, with many countries having no oral progesterone products marketed, but they can usually be specially imported by pharmacies through international wholesalers.
Progesterone can be absorbed through the skin when administered as a skin cream, thus avoiding the breakdown by the liver that occurs when it is ingested.
"Natural progesterone" products derived from yams, do not require a prescription. Wild yams contain a plant steroid called diosgenin, however there is no evidence that the human body can metabolize diosgenin into progesterone. Diosgenin can however be chemically converted into progesterone in the lab.
A subsequent and larger study showed that vaginal progesterone was no better than placebo in preventing recurrent preterm birth in women with a history of a previous preterm birth, but a planned secondary analysis of the data in this trial showed that women with a short cervix at baseline in the trial had benefit in two ways: a reduction in births less than 32 weeks and a reduction in both the frequency and the time their babies were in intensive care. In another trial, vaginal progesterone was shown to be better than placebo in reducing preterm birth prior to 34 weeks in women with an extremely short cervix at baseline. An editorial by Roberto Romero discusses the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment.
Progesterone may affect male behavior.
Progesterone is starting to be used in the treatment of the skin condition hidradenitis suppurativa.
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 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.
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. A number of additional animal studies have confirmed that progesterone has neuroprotective effects when administered shortly after traumatic brain injury. Encouraging results have also been reported in human clinical trials.
The mechanism of progesterone protective effects may be the reduction of inflammation which follows brain trauma.
Progesterone is a hormone that is normally found in women and it reaches particularly high levels during pregnancy. Progestins are synthetic drugs that mimic the biological actions of progesterone and they have been widely prescribed to women. This learning project allows Wikiversity participants to explore health-related topics that involve progesterone and synthetic drugs that act on progesterone receptors.
The Wikipedia articles on breast cancer and progestins do not mention that breast cancer rates appear to be increased by progestin use. Wikipedia articles for the Women's Health Initiative and Hormone replacement therapy do mention some of the clinical trial results that link progestin use to increased breast cancer risk. Recent studies suggest mechanisms by which progesterone receptors might stimulate breast tumor growth. The Wikipedia article on Bioidentical hormone replacement therapy raises the question: might progesterone use pose less breast cancer risk than use of synthetic progestins?
Progestins are widely used by both younger women and older women. Younger women of reproductive age often use progestins for hormonal contraception. Older women have frequently been prescribed combinations of estogen and progestins as Hormone replacement therapy when endogenous levels of estrogen decline. Combined estrogen and progestin administration is used to limit the incidence of estrogen supplement-induced endometrial cancer.
This is a running list of news reports related to progestrone, progestins and related health issues such as breast cancer.
October 30, 2007. "Wyeth is facing more than 5,000 lawsuits from those who believe they were harmed by the hormone replacement drugs, which have been used by millions of women to control the effects of menopause." Wyeth is the manufacturer of Premarin and Prepro, a mixture of medroxyprogesterone and Premarin.
The Women's Health Initiative estrogen-plus-progestin study reported an increased rate of breast cancer for women using Prempro. The Food and Drug Administration now requires that the Women's Health Initiative results for breast cancer be provided to patients who use Prempro (Label).
December 15, 2006. Following the release of results from the WHI Prempro clinical trial (see above), "Within six months, the drug's sales had fallen by 50 percent." Breast cancer incidence also declined during this time: "The reason, researchers believe, may be that millions of women during that time abandoned hormone treatment for the symptoms of menopause"
Epidemiological studies report that since women started to become aware of the risks associated with progestin use, decreases in incidence of breast cancer parallels the decline in progestin use, consistent with the known increased risk of breast cancer among women who use progestins.
January 16, 2007. The North American Menopause Society (NAMS) is a nonprofit organization concerned with menopause. T.V. correspondent Dr. Emily Senay reported that the NAMS has urged doctors not to prescribe natural hormones like progesterone for menopausal women Large clinical trials have not been performed to test the efficacy and safety of natural hormones like progesterone for treating the symptoms of menopause.
Who would pay for clinical research studies on progesterone? One possibility is that government funding would be provided in an attempt to find alternatives to synthetic progestins, but is there a level playing field for discussion of such studies when drug companies make large profits from synthetic progestins? The International Academy of Compounding Pharmacists has suggested that The North American Menopause Society is not an independent voice because it is supported by progestin manufacturers.North American Menopause Society’s Ties to Wyeth Pharmaceuticals
One recent reviewer concluded that there needs to be more research on bioidentical hormones and that there is, "evidence to support their preferred use over that of their synthetic cousins." Other reviewers have reached the opposite conclision. 
A major concern for use of progesterone rather than synthetic progestins is that progesterone is rapidly metabolized in the body. There are many different formulations of mixtures of estrogen and progesterone and various methods for administering them. There has been concern about quality control for progesterone both in terms of variability in amounts and efficiency of absorption. Some women have used bioidentical hormone treatments for extended periods of time without monitoring for possible stimulation of uterine tissue growth.  Women should not assume that bioidentical hormone treatments are safe just because they use natural hormones. Supplements containing natural estrogen can cause endometrial cancer.