Prostaglandins are part of a class of substances called eicosanoids. Eicosanoids are a group of substances derived from fatty acids and include prostaglandins, thromboxanes, and leukotrienes, all of which are formed from precursor fatty acids by the incorporation of oxygen atoms into the fatty acid chains. This reaction is called oxygenation and is carried out by cyclo-oxygenase enzymes. Prostaglandins and their metabolites have been found in virtually every tissue in the body.
The discovery of prostaglandins and determination of their structure began in 1930, when Raphael Kurzrok and Charles Lieb, both new York gynecologists, observed that human seminal fluid stimulates contraction of isolated uterine muscle. A few years later in Sweden, Ulf von Euler confirmed this report and noted that human seminal fluid also produces contraction in intestinal smooth muscle and lowers blood pressure when injected into the blood stream. It was Von Euler who came up with the name prostaglandin for this mysterious substance. The name prostaglandin seemed appropriate because he thought it originated in the prostate gland. Today, we know that prostaglandin production is not limited to the prostate, in fact, there is virtually no soft tissue in the body that doesn’t produce them. The name, however, has stuck with us through the years. If Von Euler had known his name for prostaglandins would still be with us into the next millennia, I’m sure he would have chosen to name them “Von Eulers” or “UVEs” instead of prostaglandins. By 1960, several specific prostaglandins had been isolated in pure crystalline form and their structures determined. Because our concern with prostaglandins involves primarily PGF2a, and perhaps PGE2, we will not go into detail about the myriad of other prostaglandins. Just know that prostaglandins are abbreviated “PG”. The additional letter and numerical script indicate the type and series. The various types differ in the functional group present in the five-membered ring.
While scientists were studying the structure of these new compounds, other research was being done to determine their role in human physiology and their potential as drugs. Initially these compounds were extremely expensive to synthesize and/or isolate in sufficient quantities for research. In 1969, the price of prostaglandins dropped dramatically with the discovery that the gorgonian sea whip, or sea fan, is a rich source of prostaglandin-like materials. Now however, there is no need to rely on natural sources because chemists have developed highly effective laboratory methods for the synthesis of almost any prostaglandin or prostaglandin analog.
Endogenous production from Arachidonic Acid
Prostaglandins (PGs) are not stored in the tissues of your body. PGs are produced in response to some physiological trigger. The starting material for PG synthesis are unsaturated fatty acids that have 20 carbon structures. The fatty acid that is used to make PGF2a is arachidonic acid.
Functions of prostaglandins in the body
Prostaglandins are classified as autocrine (effecting the same cell that produced it), as well as paracrine (effecting adjacent cells), regulators. They do not really fit into the category of hormones, nor are they neurotransmitters, instead they are simply considered as a corollary of the endocrine system.
The following are some of the regulatory functions of prostaglandins in various organs and systems of the body:
Inflammation & Pain – PGs promote many aspects of the inflammatory response. They are involved in the sensation of pain associated with inflammation and vasoconstriction and/or dilation, and the development of fever. PGs, when injected directly into the hypothalamus, induce fever. Anecdotally, the use of PGF2a also induces a rise in body temperature presumably by interacting with the hypothalamus as well.
Reproductive systems. PGs may play a role in ovulation and corpus luteum function in the ovaries and in contraction of the uterus. Excessive PG production may be involved in premature labor, endometriosis, dysmenorrhea (menstrual cramps), and other gynecological disorders. PGs are often given to induce labor.
Gastrointestinal tract – The stomach and intestine produce PGs. PGs are believed to inhibit gastric secretions and influence gastric motility as well as fluid absorption. Drugs such as aspirin that inhibit prostaglandin production can lead to overproduction of gastric secretion. This predisposes the person to gastric ulcers.
Respiratory System – PGs can cause vasoconstriction as well as vasodilation of blood vessels within the lungs, depending on which PGs are being produced. PGs also cause both dilation and constriction of bronchial smooth muscle. PGs as well as other eicosanoids may play a role in asthma.
Blood vessels – Some PGs are vasoconstrictors, others are vasodilators. The overall effect is determined by which PG is present in greater concentration.
Blood clotting – Thromboxanes, also a product of cyclo-oxygenase, are produced by blood platelets. These eicosanoids promote platelet aggregation and vasoconstriction. Prostacyclin, produced by vascular endothelial cells, inhibits platelet aggregation and causes vasodilation.
Kidneys – PGs are produced in the medulla of the kidneys and cause vasodilation, resulting in increased renal blood flow and increased excretion of water and electrolytes in the urine. In particular, high potassium intake has been shown to selectively increase PGF2a excretion in animals.
Protein synthesis – PGs are known to be regulators of protein synthesis in skeletal muscle. PGE2 and PGF2a being involved in protein breakdown and protein synthesis rates respectively. Stretch induced hypertrophy of skeletal muscle is in part regulated by prostaglandins. More on the role of PGs in protein synthesis in later sections.
Adipogenesis – PGF2a directly inhibits adipogenesis. You should not be surprised to hear that yet another prostaglandin serves to induce adipogenesis, namely PGJ2. PGJ2 derivatives function as activating ligands for peroxisome proliferator-activated receptor (PPAR), a nuclear hormone receptor that is central to fat cell proliferation. PGF2 blocks adipogenesis through activation of mitogen-activated protein kinase (the same kinase involved in insulin action), resulting in inhibitory phosphorylation of PPAR. Both mitogen-activated protein kinase activation and PPAR phosphorylation are required for the anti-adipogenic effects of PGF2. So you have PGs within the cell telling the fat cell to divide while at the same time you have other PGs, such as PGF2a, at the outside preventing it from taking place.
Current uses of PGF2a
Humans – PGF2a is not currently FDA approved for use in humans. Products containing PGF2a should be considered hazardous to women and must be handled with extreme care. PGF2a is readily absorbed through the skin and may result in birth defects and/or instantaneous abortion. Prostaglandins of use today in humans are of the “E” class and are administered to women for abortion or to induce labor. Prostaglandins are also used for impotence in men. In such case it (PGE1) is injected directly into the penis.
Animals – PGF2a has been tested in a wide range of animals from monkeys to horses. In most cases the side effects are increased body temperature, vomiting and diarrhea, bronchial constriction, confusion, loss of coordination, tachycardia, and low blood pressure just to name a few. PGF2a is nontoxic with a serum half life of only minutes.
PGF2a is currently used in animal husbandry to manage breeding. It is used commonly as dinoprost in the form of a tromethamine salt. Upjohn makes a version called Lutalyse® as a sterile solution for subcutaneous and intramuscular injection. It’s purpose is to synchronizing ovulation in cattle by sequential injection of several hormones along with PGF2a. A hormone selected from the group consisting of gonadotropin releasing hormone (GnRH), luteinizing hormone (LH), or human chorionic gonadotropin (hCG) is administered to an open cow during an estrous cycle in order to stimulate follicle development. PGF2a is then administered to initiate corpus luteum regression about five to eight days after administration of the GnRH, LH or hCG. A second dose of GnRH, LH or hCG is then administered concomitantly with the PGF2a injection or up to about three days after the PGF2a injection. This second dose of hormone functions to stimulate the ovulation of a dominant follicle and the cow is then breed within one day of the administration of the second dose of hormone.
The Role of PGF2a in Muscle Growth
After that brief introduction into prostaglandins, we can now begin to discuss more specifically the role of prostaglandins in muscle growth. In a nutshell, mechanical stimulation (i.e. intermittent stretch) results in the production and efflux of two prostaglandins, PGE2 and PGF2a. PGE2 increases protein degradation where as PGF2a increases protein synthesis. Muscle hypertrophy is usually achieved by an increase in protein synthesis as well as a proportionately smaller increase in degradation. The simultaneous release of both PGE2 and PGF2a creates this condition.
It is well known that mechanical stretch, without any electrical activity, is sufficient to induce muscle hypertrophy. Recent studies have shown that the mechanism by which mechanical stretch leads to prostaglandin production and ultimately muscle growth, involves G proteins embedded in the cell membrane. These G proteins increase the amount of cyclo-oxygenase, the enzyme responsible for making prostaglandins from arachidonic acid. Skeletal muscle cyclooxygenase generates PGE2 and PGF2 alpha at a ratio approximately equal to one.
The exact mechanism by which PGF2a increases protein synthesis is not entirely clear. That’s just a spineless way of saying, “I don’t know the exact answer to that!” We are free to speculate though. It may involve short phase protein synthesis and/or long phase protein synthesis.
2 phases of protein synthesis Modulation
Modulation of protein synthesis rates occurs at two levels, the short phase and the long phase. The short phase alteration in protein synthesis rates occurs by altering the activity of existing ribosomes and/or eukaryotic initiation factors (eIFs). This happens within minutes of the appropriate physiological trigger. The long phase modulation of protein synthesis happens by way of increasing the number of myonuclei. This mechanism involves hormones and growth factors such as HGH and IGF-1 bringing about the activation of myogenic stem cells. This can take several days to effect protein synthesis rates. This is a simplified view but for our purposes it is sufficient.
The role of PGF2a in short phase protein synthesis in muscle tissue is speculative at best. In non-muscle tissue, prostaglandins effect calcium fluxes, plasma membrane ionic channel activities, and cyclic nucleotide levels. All of which are important regulators of protein synthesis rates in muscle. PGF2a has been shown to interact with the S6 small ribosomal subunit, increasing its potential to form the ribosomal initiation complex with the large subunits. It is also plausible that PGF2a may effect the activity of eIFs.
Initiation of translation (the binding of mRNA to the ribosomal pre-initiation complex) requires group 4 eukaryotic initiation factors (eIFs). These initiation factors interact with the mRNA in such a way that makes translation (the construction of new proteins from the mRNA strand) possible. Two eIFs, called eIF4A and eIF4B, act in concert to unwind the mRNA strand. Another one called eIF4E binds to what is called the “cap region” and is important for controlling which mRNA strands are translated and also for stabilization of the mRNA strand. Finally, eIF4G is a large polypeptide that acts as a scaffold or framework around which all of these initiation factors and the mRNA and ribosome can be kept in place and proper orientation for translation. There is yet no direct evidence to confirm that PGF2a works through this mechanism however.
Long term modulation of protein synthesis involves the activation of myogenic stem cells or satellite cells. If you recall, when a muscle is stretched it not only produces PGF2a, but also PGE2. PGE2 is a potent inducer of satellite cell proliferation and fusion. This is how existing muscle cells increase the number of nuclei they contain. This is important because in order for a muscle to grow rapidly, it must produce more mRNA. This is done in the nucleus of the muscle cell. The more nuclei you have, the more mRNA you can produce. Within the cell, prostaglandins may also be involved in regulating the number of ribosomes. This could have long term implications on growth and development as well as stretch induced hypertrophy.
The role of other hormones, drugs and diet in the action of PGs.
Because prostaglandins are signaling molecules that get their message across through multi step signal transduction pathways, they are susceptible to modulation by several chemical, hormonal, and dietary factors. I will do my best to shed some light on the subject without bogging you down with meaningless terms and jargon. It is well to remember that the action and interaction of prostaglandins in the human body is complex.
Cortisol effects the production of prostaglandins in muscle tissue by at least two mechanisms. First, cortisol by way of lipocortins, inhibits the action of phospholipase A2. Phospholipase is necessary in order to make arachidonic acid available for PGF2a production. Cortisol also inhibits the production of cyclo-oxygenase mRNA content within cells. As mentioned earlier, cyclo-oxygenase is the enzyme that converts arachidonic acid into prostaglandins. So cortisol inhibits muscle growth by preventing the production of PGF2a in response to training (mechanical stimulation) and eating (insulin action).
As eluded to above, insulin stimulated protein synthesis is linked to the production of phospholipases which lead to increased availability of arachidonic acid. This is a two edged sword. Increased availability of arachidonic acid can increase the amount of PGF2a thereby increasing protein synthesis. On the other hand, arachidonic aid directly suppresses GLUT4 production which is the chief glucose transporter in skeletal muscle. High levels of arachidonic acid can reduce glucose transport by up to 50%. It could be that insulin action is more dependant on the cAMP antagonist, cyclic PIP (prostaglandylinositol cyclic phosphate), a proposed second messenger for insulin and alpha-adrenoceptor action, than on PGF2a. PGE2 however is a different story. Prostaglandin E, myo-inositol and one phosphate are components of cyclic PIP. So increased production of PGE2 may increase insulin mediated glucose transport through this mechanism. Taking this into consideration, exogenous PGF2a should not be considered to replace insulin.
Dietary Fatty Acids
Dietary fatty acids significantly effects prostaglandin production. Diets high in omega-3 fatty acids (fish oil, flax oil) decrease prostaglandin production. Diets high in omega-6 fatty acids (corn oil) increase prostaglandin production. Once again you have pros and cons with trying to manipulate PGF2a production with your diet. By increasing omega-3s, you get lower levels of PGF2a and probably a less intense stimulus of protein synthesis immediately after you workout. On the other hand by increasing omega-3s you reduce inflamation, pain, increase GLUT4 content, and a whole host of other factors related to cardiac risk. I don’t think its as clear cut as Dr. Sears (Zone Diet) would have you believe. Trying to manipulate the diet to control prostaglandin kinetics is fraught with complexity making black and white statements difficult to support.
NSAIDs are non-steroidal anti-inflammatory drugs. An example of such drugs are aspirin, ibuprofen (Motrin), naproxen sodium (Anaprox, Alleve). There are several more but these are the most common to consumers. NSAIDs work by inhibiting the activity of cyclooxygenase. By blocking cyclooxygenase you block prostaglandin production. These drugs have been shown to improve nitrogen balance under conditions of severe physical stress such as after surgery. The effect is abolished when PGE2 is infused linking PGE2 production with the catabolic effect of stress. In the case of PGF2a, the use of NSAIDs also blocks its production in that PGE2 and PGF2a are normally produced in a 1:1 ratio from the same precursor. Using NSAIDS while using exogenous PGF2a may improve the anabolic effect by reducing PGE2 in the presents of elevated PGF2a shifting the ratio towards anabolism.
PGF2a + IGF-1: The ultimate cocktail for localized muscle growth?!
Say good by to lagging body parts forever. It is a special time to be a bodybuilder. With the advent of PGF2a as a localized anabolic agent along with the newly available rhIGF-1 which has also been shown to build muscle where you want it, the future for genetically challenged bodybuilders looks bright indeed. A brief refresher course on locally injected IGF-1. Non-exercised muscle, when injection with 0.9 – 1.9 micrograms/kg/day of rhIGF-1 was shown to mimic the effects of physically loading the muscle. Much the same effect PGF2a but by different mechanisms. With local IGF-1 injections there is an increase in protein content, cross sectional area and DNA content. The increase in muscle DNA is presumed to be a result of increased proliferation and differentiation of satellite cells which donate their nuclei upon fusion with damaged or hypertrophying muscle cells. Take note that the quantities of IGF-1 needed are extremely small, much smaller than studies that have shown relatively poor results from administering IGF-1 systemically which range from 1.0 to 6.9 milligrams/kg/day.
Now add PGF2a to the mix and whalla! You can virtually mimic the mechanical stimulus of training without even picking up a weight. You have PGF2a to accelerate short term protein synthesis by activating ribosomes and/or eIFs and thereby translation, as well as IGF-1 to activate satellite cells to bind and donate additional nuclei to boost the amount of mRNA to be used by the ribosomes. Because the mechanism of action is different, the two compounds should compliment each other delivering results beyond what either one alone could produce.
Are these compounds going to replace traditional training? Not in the near future. The use of site injectable drugs only reaches the surface musculature. Deeper muscles are only stimulated to grow with traditional training. For strength athletes, strength is dependant on neuromuscular training which is not enhanced by simple muscle hypertrophy without actual lifting in a coordinated fashion. Are these compounds going to replace traditional anabolics? No. The reason is basically the same as with training. Deeper muscle groups are only reached by systemically administered anabolics that are carried throughout the entire body. In addition, androgens are needed to influence genetic expression in favor of whole body skeletal muscle growth. Are these compounds going to change the face of bodybuilding? It is very likely that they will, depending on their availability and cost. I would hope that as competitors become educated about these alternatives that we will no longer see implants in top level competitors. It would also be nice to see people have an option when it comes to pumping their muscles full of “stuff” in hopes that it will improve their symmetry. No doubt the future will bring us even more new and exciting drugs like non-steroidal androgens and compounds that alter the expression of myostatin (GDF8). Once again, it is an exciting time in the science of bodybuilding, perhaps now more than any other time since the introduction of testosterone.