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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
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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