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by Bryan Haycock --
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
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).
Insulin
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
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.
More Information About Prostaglandin Use in Bodybuilding
Bodybuilding eBooks
America's Nuremberg -
Human Experimentation in Anabolic Steroid Research
Beyond Steroids by Anthony Roberts - The Newest and Most Effective Bodybuilding
Drugs
Burn the
Fat, Feed the Muscle by Tom Venuto - Secrets of the World's Best Bodybuilders
& Fitness Models
Chemical Muscle Enhancement by Author L Rea - Bodybuilder's Desk Reference
Chemical Wizardry by George Spellwin - The Definitive Anabolic Steroid and
Physique Enhancement Database
The Layman's Guide
to Steroids - Mick Hart's Anabolic Steroid Guides
Muscle Building Nutrition by Will Brink - Serious Lean Muscle Gains without
the Bodyfat
Publication Date:
November 10, 2005
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