ROLE
OF ARGININE IN ANABOLIC ACTIONS
Dietary arginine is required for the anabolic actions of androgens
in humans.
Depletion and/or restriction of dietary arginine prevents
body weight gain induced by testosterone treatment, elucidating
the role of dietary arginine in the pharmacologic action of
synthetic analogs of testosterone used in clinical therapy.
Dietary (oral) arginine plays a major role in the anabolic
action of testosterone, as arginine modulates androgen action,
though not exclusively, through an influence on insulin-like-growth
factors; IGFs and IGF-B’s.
Conversely, dietary arginine deficiencies alter the expression
of IGF-1, IGF-BP1 and IGF-1R in the kidney and IGF-BP1 in
the liver.
Changes and deficiencies in the levels of plasma arginine
affect the action of muscle and kidney testosterone, which
acts independently of the mechanisms involved in the interaction
between testosterone and arginine.
One such mechanism involving the production of testosterone
and other anabolic hormones via the arginine-pathway is growth
hormone (GH).
GH & OBESITY
Low growth hormone (GH) levels in humans leads to increases
in total body fat accompanied by a loss of lean body mass.
Both GH and cortisol are key hormones involved in the pathogenesis
of obesity, and GH levels, in response to exercise, are blunted
in obese persons.
GH increases lipolysis as a direct effect of GH on the adipocyte,
as well as lipid oxidation by increasing substrate availability.
ATHLETES & GH
| • |
The ArgMatrix® Patent (s) include the use of
Arginine & Branched Chain Amino Acids (BCAA).
The combination of L-Arginine and BCAA
provide a quicker recovery from muscle fatigue following
exercise training. |
| • |
The
ArgMatrix® Patent (s) include L-Arginine with
a Low Glycemic carbohydrate. The addition of arginine
with a carbohydrate reduces the rate of carbohydrate
oxidation post-exercise and therefore increases the
availability of glucose for muscle glycogen storage
during recovery. |
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Chronic
L-arginine supplementation enhances endurance exercise
tolerance in heart failure patients. |
Growth Hormone (GH) in athletes increases fatty acid availability
and reduces oxidative protein loss, particularly during exercise,
and increases lean body mass. GH improves exercise performance
including maximal oxygen uptake and ventilatory threshold
through increased oxygen delivery to exercising muscle, increased
fatty acid availability with glycogen sparing, increased muscle
strength, improved body composition, and improved thermoregulation
(U.S. Patent held by Dr. Ann de Wees Allen).
The use of human growth hormone (HGH) to improve athletic
performance has received worldwide attention. This practice,
often called sports doping, is banned by most professional
sports leagues and associations, including the International
Olympic Committee, Major League Baseball, and the National
Football League.
Growth hormone is used to enhance athletic performance and
has been called the most anabolic substance known.
Though HGH is illegal, natural GH is legal via L-Arginine
transport, thus ArgMatrix® is legal for use by any athlete
that is screened or tested for banned substances, such as
HGH.
NATURAL PRODUCTION OF GH: THE MECHANISM
Growth Hormone (GH) stimulates targeted tissues and activates
a complex intracellular signaling cascade, wherein anabolic
hormones and internal thermogenesis, and anti-aging hormones
are produced.
In humans, GH is produced via the hypothalamic/pituitary axis
in youth (under age 23) and in response to high-dose oral
L-arginine (over age 23).
After age 23, GH begins its dramatic decline, resulting in
weight gain, aging, lack of muscle mass, thin skin, imbalanced
blood glucose levels, lowered immune function, and added adipose
tissue body fat.
Baby-Boomers and persons over age 40 have very low levels
of growth hormone (GH). As aging progressing GH levels decline
further. ArgMatrix® virtually normalizes acute GH release
in older individuals. Pituitary GH release is stimulated
by the secretagogue ArgMatrix®, and is decreased
in aging.
Low-to-zero GH secretion in aging is not attributable to augmented
IGF-I negative feedback since older men and women show relative
resistance to infused IGF-I’s inhibition of GH release.
ArgMatrix® stimulation of growth hormone (GH) in humans occurs
at the GH axis, wherein a high-dose (10,000 mg elemental)
of L-Arginine is piggybacked on a Blind Amino Acid Rider
to cross the Blood-Brain-Barrier (BBB), generating a pulsatile
burst of GH.
This mechanism reflects the actions of ArgMatrix® as a stimulus
of endogenous GHRH secretion and other putative secretagogues
(responsive-somatotropes) within the anterior pituitary gland.
The successful activation and release of growth hormone (GH)
per this specific neurotransmitter pathway is dependent on
sufficient releasable growth hormone (GH) pools, and is directly
related to the ArgMatrix® formula, which was designed to trigger
this stimulus.
ArgMatrix® is a widely employed provocative test to evaluate
the GH axis, and is the standard for identifying GH axis performance
in humans.
ArgMatrix® accesses the correct neurotransmitter pathway,
as well as peripheral feedback signals, to regulate growth
hormone secretion by acting directly on the anterior pituitary
gland and by modulating GH-releasing hormone and
somatostatin release from the hypothalamus (hypothalamic/pituitary
axis).
In humans, high doses of ArgMatrix® (10,000 elemental mg)
regulates GH secretion by acting directly on the anterior
pituitary gland. This requires an intricate knowledge of the
appropriate Isoform neurotransmitter pathway taken by the
amino acid arginine, which will result in Delta sleep cycle
stimulation of the GH hypothalamus/pituitary axis.
An understanding of neuroregulatory mechanisms and their relevance
to clinical alterations in GH control is required in order
to elicit a significant GH response in humans.
Growth hormone and IGF insulin-like growth factors modulate
androgen action, interacting with different co-activators
or co-repressors. GH, IGF-factors, serum L-arginine, and BBB
crossover of L-arginine, all translate to increased testosterone
in humans. All of these mechanisms can act in tandem or individually.
When oral ArgMatrix® acts as a secretagogue of growth hormone
(GH) in humans by crossing the BBB during Delta sleep, all
of the anabolic/androgen interactions take place in a metabolically
coordinated fashion, increasing and balancing levels of GH,
testosterone, and IGF-factors.
EXERCISE-INDUCED
GH
Oral ArgMatrix® attenuates the growth hormone response to
resistance exercise (not aerobics), via uptake of L-arginine
and generation of GH in response to small fissures in muscle
generated by intense weight training.
The addition of oral L-Arginine in doses of 10-15 elemental
grams taken 30-mins prior to resistance exercise results dramatic
increases in growth hormone (in both men and women) by 10-20
fold.
The protocol requires taking a minimum of 10 grams of elemental
arginine (ArgMatrix®) 30 minutes prior to resistance exercise
on an empty stomach (for 2 hours prior to resistance exercise),
which includes restriction of all beverages other than water.
IGF & GH
IGF-1 is a ubiquitous tissue mediator of growth hormone (GH),
which is maintained under homeostasis in the hypothalamic
loci, the pituitary gland, and the circulation by an interplay
of highly complex feedback signals involving basic poly-peptides.
IGF-related cancers, such as prostate cancer, are encouraged
by ingestion of red meat and high-purine foods, and not by
re-generation of age-related decline in anabolic hormones,
such as testosterone. As age-related testosterone drops, prostate
cancer risk increases, showing that testosterone
is not the culprit in the development of prostate cancer,
though reduction of testosterone is recommended once prostate
cancer has been diagnosed.
NITRIC OXIDE
L-arginine is the biological precursor to Nitric Oxide (NO).
The enzymes that convert L-arginine to Nitric Oxide
are called Nitric Oxide Synthase (NOS). In humans, NO occurs
in a minimum of three isoforms, which are expressed in neural,
vascular, and other tissues.
NOS is inhibited by N-Monomethyl-L-arginine (L-NMMA), N-Nitro-L-arginine
methyl ester (L-NAME), derivatives modified at the terminal
guanidino group.
In humans, no direct evidence exists for a role of nitric
oxide in basal or L-arginine-stimulated growth hormone neuroregulation.
Nitric oxide (NO) is a potent endogenous vasodilator and has
shown to inhibit key processes of atherosclerosis like monocyte
adhesion, platelet aggregation, and vascular smooth muscle
cell proliferation.
Impaired endothelial NO production is a main feature of endothelial
dysfunction, which by itself is an early step in the course
of atherosclerotic vascular disease. NO deficiencies and NO-pathways
are directly related to cardiovascular disease, and patients
with growth hormone deficiency are characterized by a 1.9
fold higher risk of death from cardiovascular disease.
NITRIC OXIDE & GH
Growth hormone (GH) produces Nitric Oxide (NO, but NO does
not produce GH.
Reduced endogenous systemic production of NO was found in
patients with growth hormone deficiency, and treatment
with recombinant growth hormone normalized NO production.
This shows that GH helps produce normal NO levels in humans,
and can reinstate low NO levels via IGF-1.
The effects of growth hormone on NO are mediated by insulin-like
growth factor-I (IGF-I), which stimulates NO synthesis. The
onset of IGF-I increase in healthy volunteers treated with
GH is evident after 12 hours. The maximum effect takes place
between 5 to 8 days. In adults with growth hormone deficiency,
the major effects of growth hormone treatment on IGF-I levels
are observed within 2 weeks. After discontinuation of growth
hormone therapy, IGF-1 levels return to base line within 2-3
days.
Growth hormone treatment enhances systemic NO bioavailability
via IGF-1 and may be beneficial in certain cardiovascular
diseases.*
Aging is related to increased cardiovascular disease, which
is related to lowered growth hormone levels, and resulting
lowered nitric oxide levels.
| * |
AUGUST 28, 2007. Journal of Clinical Endocrinology &
Metabolism. Growth hormone treatment improves markers
of systemic nitric oxide bioavailability via insulin-like
growth factor-1. |
SAY
“NO” TO L-CITRULLLINE
NOS enzymes release NO as a mediator gas from the terminal
guanidine nitrogen group of L-arginine, producing L-citrulline
as a by-product. This is precisely why the addition of L-citrulline
to any arginine formula is a chemical absurdity. L-arginine
formulas do not require, and in fact are inhibited by the
presence of L-citrulline, as L-arginine produces L-citrulline.
MANDATORY LOW GLYCEMIC PROFILE
A Low Glycemic, Non-Cephalic (CPIR) profile is mandated in
any L-Arginine formula that is designed to elicit GH, Testosterone,
and other anabolic, anti-aging hormones.
| • |
Aging causes decreased growth hormone (GH)
and increased cortisol, leading to reduced
muscle mass and increased body fat. |
| • |
Low
fasting glycemic and insulin levels modulates the effectiveness
of growth hormone in humans, including higher natural
IGF-1 levels, by allowing higher levels of IGF-1 to
be produced by the liver, since high blood glucose and/or
insulin levels reduce IGF-1 production through
a negative feedback loop. |
| • |
Clinical
trials have shown that oral high glycemic agents inhibit
growth hormone secretion induced by human pancreatic
growth hormone releasing factor. |
Chemiluminescence-based
GH assay (sensitivity of 0.002–0.005 µg/liter) confirms that
glucose ingestion reduces serum GH concentrations typically
to less than 0.07 µg/liter in men, and less than 0.7 µg/liter
in women.
Glucose
and other high glycemic agents found in L-Arginine products
and formulas suppress serum GH.
Agents
that elevate blood glucose (High Glycemic) and/or insulin
levels (Cephalic) are contraindicated in arginine formulas.
Said agents include sucrose, honey, maltodextrins, dextrin,
high-fructose corn syrup, fruit juice, Stevia, sugar alcohols,
artificial and chemical sweeteners that are not bound
to Blind Amino Acid Riders, and other sweeteners.
Further,
L-arginine formulas that contain -0- calories or carbohydrates
do not cross the Blood-Brain-Barrier (BBB), as Cephalic synthetic
or chemical sweeteners are not recognized by the BBB and are
denied access.
MUSCLE
MASS IN ATHLETES:
DOWN-REGULATING CORTISOL
In
terms of lean muscle mass and body fat levels in athletes,
L-Arginine formulas are required to be Low Glycemic
and Non-Cephalic in order to facilitate GH production and
down-regulation of Cortisol.
GH
stimulates the production of lean muscle mass, while
Cortisol triggers negative skeletal muscle feedback and muscle
wastage.
It
is also important to down-regulate Cortisol in any protein
or L-Arginine formula, as Cortisol reduces muscle mass and
increases body fat.
Cortisol is recognized for its propensity to become negatively
elevated in response to stress. Though this is a factor, Cortisol
is also stimulated by factors other than stress.
Aging elevates Cortisol levels, which is partly responsible
for weight gains as aging progresses.
Research has shown that with advancing age, spontaneous
secretion of Cortisol is increased in non-stressed individuals,
whereas GH release decreases in women and men, particularly
at night.
Jeff Krushell, the current International Director of Strength
& Conditioning for Major League Baseball (MLB) has
stated that “Elevated Cortisol reduces sports performance
and muscle integrity in professional athletes. Therefore,
it is crucial to down-regulate Cortisol in all athletes.”
To
that end, in March 2009, Human Sports Performance dedicated
over $ 1 million dollars in funding for Cortisol research
(CortisolScience.com) in athletes.
ArgMatrix®
is the only arginine formula in the world that contains a
Cortisol Down-Regulator (see: www.CortisolScience.com).
QUANTIFICATION
OF GH PARAMETERS IN HUMANS
The dynamics of secretory functions, such as GH, are quantifiable
in a variety of different methods and tests, some more accurate
than others.
The clinical goal is to quantify the duration and amplitude
of GH release in humans, and provide insight related to the
frequency and amplitude of serum hormone concentration peaks
and can disclose insights into neuroendocrine mechanisms that
control this ultradian pituitary release activity
The preferred method is MLM (Maximum-Likelihood-Methodology)
based on feedback concepts within a neuroendocrine axis, ultradian
pulsatility linked to circadian variations (GH is produced
during Delta segment of the Circadian sleep cycle), using
a stochastic differential equation.
One method, Pulse Analysis (PA) provides data on brain-pituitary
interface and anterior pituitary GH secretion, but there are
challenges in accuracy and reproducible data. Further, there
is no disclosure on neuroendocrine mechanisms identified with
ultradian pituitary release of GH.
Blood sampling (every 30 sec) during sleep identifies
the strongly correlated pattern of episodic growth hormone
release and the onset of slow-wave (stages III and IV) sleep.
Clinical studies validate that aging (over age 23) and obesity
is directly associated with low GH levels and decreased GH
secretion. This is quantified by GH ULSEN assay plus deconvolution
analysis.
This is validated by the fact that 97 percent of daytime samples
for serum GH concentrations in older and/or obese subjects
are “undetectable.”
NATURAL TESTOSTERONE
| • |
Dietary
L-arginine is relevant to the anabolic action of testosterone,
and this effect is mediated by changes in the insulin-like
growth factor system. |
| • |
Dietary
L-arginine is required for the anabolic action of androgens.
Restriction of dietary arginine prevents lean muscle
mass body weight gain induced by testosterone. |
The
amino acid L-Arginine is capable of elevating natural testosterone
in humans, when administered in sufficient doses and in formulas
designed to access testosterone-driven mechanisms.
The Journal of Endocrinology states that dietary
arginine supplementation can improve the pharmacologic action
of synthetic analogs of testosterone used in clinical therapy.
(Influence of dietary arginine on the anabolic effects of
androgens).
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