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Progesterone
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Progesterone is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans and other species. Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen.
Progesterone should not be confused with progestins, which are synthetically produced progestogens.
Progesterone is commonly manufactured from the yam family, Dioscorea.
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Encyclopedia
Progesterone is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans and other species. Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen.
Progesterone should not be confused with progestins, which are synthetically produced progestogens.
Progesterone is commonly manufactured from the yam family, Dioscorea. Dioscorea produces large amounts of a steroid called diosgenin, which can be converted into progesterone in the laboratory. There is debate at how much if any conversion may occur between Dioscorea spp to progesterone in humans.
Plant sources
Outside progesterone-producing animals such as humans, progesterone-like steroids are found in Dioscorea mexicana. Dioscorea mexicana is a plant that is part of the yam family and resides in 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 has been discovered to indirectly contain progesterone is Dioscorea pseudojaponica that resides in Taiwan. Research has showed that the Taiwanese yam contained saponins, steroids, which are converted to diosgenin. From diosgenin, it can produce progesterone.
Another plant that is found to contain these steroids that convert to progesterone is a wild yam called Dioscorea villosa. One study showed that the Dioscorea villosa contains 3.5% of diosgenin. There are many other Dioscorea species of the yam family that contribute to the production of progesterone, but there is one new species found. Dioscorea polygonoides has been researched and found 2.64% of diosgenin that was recognized by testing it with gas chromatography-mass spectrometry. Many of the Dioscorea species that originate from the yam family grow in countries that have tropical and subtropical climates.
Chemistry
Progesterone was independently discovered by four research groups.
Willard Myron Allen co-discovered progesterone with his anatomy professor George Washington Corner at the University of Rochester Medical School in 1933. Allen first determined its melting point, molecular weight, and partial molecular structure. He also gave it the name Progesterone derived from 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.
Biosynthesis
Cholesterol undergoes oxidation and NADPH twice to make 2. It then again undergoes oxidation and NADPH to produce pregnenolone 3 and performs NAD+ to form 4. Afterwards, keto-enol tautomerism turns 4 into 5. Lastly, it tautomerizes by enol-keto to produce progesterone. A study has proven that pregenolone and progesterone can also be biosynthesized by yeast.
Synthesis
Progesterone, like all other steroid hormones, is synthesized from pregnenolone, a derivative of cholesterol. This conversion takes place in two steps. The 3-hydroxyl group is converted to a keto group and the double bond is moved to C-4, from C-5.
Progesterone 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.
The synthesis of progesterone begins with 7 reacting with PhLi in THF to produce 8. Then it mixes with the reagent of step 1 while the temperature increases from -70°C to -30°C and follows it up with reacting again with PhLi along with a surplus amount of MeOH at -30°C to make 9. Afterwards, 0.1 N HCl at an increased temperature of 40°C is added into the reaction that leads to 10. EtOH and 2% of NaOH then close the ring to form 11 yielding 40%. The next step is the reaction undergoes methylation and hydroxylation to develop 12 at a high yield of 99%. The reactant next transforms into chair conformation 13 after reacting in TFA at 0°C. In the following step, it undergoes cation-p cyclization to produce 14. The next step produces 15 after yielding 72% by breaking off the cation. After that, the ring is opened and oxidized at -70°C and then increases from -15°C to 23°C to produce 16. Finally, it reacts with water and 5% of KOH with a ratio of 5:2, at 23°C, to produce progesterone at a decent yield of 51%.
The next semi-synthesis of progesterone is much simpler than the previous one because it will only focus on the regioselectivity. In this semi-synthesis, there are two ways to produce progesterone, but each way ends with a different yield. For the first semi-synthesis, desoxycorticosterone reacts with Me3SiI in CHCl3 to lose a hydroxyl group and produce progesterone. Using CHCl3 as a solvent, it gives the product at lower yield, but it produces progesterone at a greater amount of 90%. As for the second semi-synthesis, descoxycorticosterone reacts with Me3SiI in MeCN to make progesterone as a result of losing a hydroxyl group. MeCN as a solvent produces progesterone at a higher yield, but at a lower production amount of 78%.
Animal Sources
Progesterone is produced in the ovaries, the gonads (specifically after ovulation in the corpus luteum), the brain, and, during pregnancy, in the placenta.
In humans, increasing amounts of progesterone are produced during pregnancy:
- Initially, the source is the corpus luteum that has been "rescued" by the presence of human chorionic gonadotropins (hCG) from the conceptus.
- However, after the 8th week production of progesterone shifts to the placenta. The placenta utilizes maternal cholesterol as the initial substrate, and most of the produced progesterone enters the maternal circulation, but some is picked up by the fetal circulation and used as substrate for fetal corticosteroids. At term the placenta produces about 250 mg progesterone per day.
- An additional source of progesterone is milk products. They contain much progesterone because on dairy farms cows are milked during pregnancy, when the progesterone content of the milk is high. After consumption of milk products the level of bioavailable progesterone goes up. This observation has resulted in concern that diets high in dairy products might induce pet and human diseases.
Levels
In women, progesterone levels are relatively low during the preovulatory phase of the menstrual cycle, rise after ovulation, and are elevated during the luteal phase. Progesterone levels tend to be < 2 ng/ml prior to ovulation, and > 5 ng/ml after ovulation. If pregnancy occurs, progesterone levels are initially maintained at luteal levels. With the onset of the luteal-placental shift in progesterone support of the pregnancy, levels start to rise further and may reach 100-200 ng/ml at term. Whether a decrease in progesterone levels is critical for the initiation of labor has been argued and may be species-specific. After delivery of the placenta and during lactation, progesterone levels are very low.
Progesterone levels are relatively low in children and postmenopausal women. Adult males have levels similar to those in women during the follicular phase of the menstrual cycle.
Effects
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.
Reproductive system
Progesterone is sometimes called the "hormone of pregnancy", and it has many roles relating to the development of the fetus:
- Progesterone converts the endometrium to its secretory stage to prepare the uterus for implantation. At the same time progesterone affects the vaginal epithelium and cervical mucus, making the mucus thick and impermeable to sperm. If pregnancy does not occur, progesterone levels will decrease, leading, in the human, to menstruation. Normal menstrual bleeding is progesterone withdrawal bleeding.
- During implantation and gestation, progesterone appears to decrease the maternal immune response to allow for the acceptance of the pregnancy.
- Progesterone decreases contractility of the uterine smooth muscle.
- In addition progesterone inhibits lactation during pregnancy. The fall in progesterone levels following delivery is one of the triggers for milk production.
- A drop in progesterone levels is possibly one step that facilitates the onset of labor.
The fetus metabolizes placental progesterone in the production of adrenal mineralo- and glucosteroids.
Nervous system
Progesterone, like pregnenolone and dehydroepiandrosterone, belongs to the group of neurosteroids that are found in high concentrations in certain areas in the brain and are synthesized there.
Neurosteroids affect synaptic functioning, are neuroprotective, and affect myelination. They are investigated for their potential to improve memory and cognitive ability.
Progesterone as neuroprotectant affects regulation of apoptotic genes.
Its effect as a neurosteroid works predominantly through the GSK-3 beta pathway, as an inhibitor. (Other GSK-3 beta inhibitors include bipolar mood stabilizers, lithium and valproic acid.)
Other systems
- It raises epidermal growth factor-1 levels, a factor often used to induce proliferation, and used to sustain cultures, of stem cells.
- It increases core temperature (thermogenic function) during ovulation.
- It reduces gall-bladder activity.
- It normalizes blood clotting and vascular tone, zinc and copper levels, cell oxygen levels, and use of fat stores for energy.
- It may affect gum health, increasing risk of gingivitis (gum inflammation) and tooth decay.
- It appears to prevent endometrial cancer (involving the uterine lining) by regulating the effects of estrogen.
Medical applications
The use of progesterone and its analogues have many medical applications -- both to address acute situations, and to address the long-term decline of natural progesterone levels. Because of the poor bioavailability of progesterone when taken orally, many synthetic progestins have been designed. 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.
Bioavailability
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.
"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.
Specific uses
- Progesterone is used to support pregnancy in Assisted Reproductive Technology (ART) cycles such as In-vitro Fertilization (IVF). While daily intramuscular injections of progesterone-in-oil (PIO) have been the standard route of administration, PIO injections are not FDA-approved for use in pregnancy. A recent meta-analysis showed that the intravaginal route with an appropriate dose and dosing frequency is equivalent to daily intramuscular injections. In addition, a recent case-matched study comparing vaginal progesterone with PIO injections showed that live birth rates were nearly identical with both methods.
- Progesterone is used to control anovulatory bleeding. It is also used to prepare uterine lining in infertility therapy and to support early pregnancy. Patients with recurrent pregnancy loss due to inadequate progesterone production may receive progesterone.
- Progesterone is being investigated as potentially beneficial in treating multiple sclerosis, since the characteristic deterioration of nerve myelin insulation halts during pregnancy, when progesterone levels are raised; deterioration commences again when the levels drop.
- Vaginally dosed progesterone is being investigated as potentially beneficial in preventing preterm birth in women at risk for preterm birth. The initial study by Fonseca suggested that vaginal progesterone could prevent preterm birth in women with a history of preterm birth.
A subsequent and larger study showed that vaginal progesterone was no better than placebo in preventing recurrent preterm birth in women with a history of a previous preterm birth, 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 is used in hormone therapy for transsexual women and other women with intersex conditions - especially when synthetic progestins have been ineffective or caused side-effects - since normal breast tissue cannot develop except in the presence of both progestogen and estrogen. Mammary glandular tissue is otherwise fibrotic, the breast shape conical and the areola immature. Progesterone can correct those even after years of inadequate hormonal treatment. Research usually cited against such value was conducted using Provera, a synthetic progestin. Progesterone also has a role in skin elasticity and bone strength, in respiration, in nerve tissue and in female sexuality, and the presence of progesterone receptors in certain muscle and fat tissue may hint at a role in sexually-dimorphic proportions of those.
Note that methods of hormonal contraception do not contain progesterone but a progestin.
Progesterone may affect male behavior.
Progesterone is starting to be used in the treatment of the skin condition hidradenitis suppurativa.
Aging
Since most progesterone in males is created during testicular production of testosterone, and most in females by the ovaries, the shutting down (whether by natural or chemical means), or removal, of those inevitably causes a considerable reduction in progesterone levels. Previous concentration upon the role of progestagens (progesterone and molecules with similar effects) in female reproduction, when progesterone was simply considered a "female hormone", obscured the significance of progesterone elsewhere in both sexes.
The tendency for progesterone to have a regulatory effect, the presence of progesterone 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.
Brain damage
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.
See also
Additional images
External links
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