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"Attention to health is life's greatest hindrance."                            "Plato was a bore."
                                               -Plato                                                 -Nietzsche    


Secretagogue: that which stimulates secreting organs. Many substances stimulate the release of growth hormone from the pituitary gland. Amino acids, drugs, and exercise are among the provocateurs. Despite the phenomenal success of synthetic GH, scientists are in hot pursuit of factors that can be taken orally to stimulate the pituitary to release GH. Recombinant GH is problematic: it has to be injected-in most cases several times a day. It is expensive-way outside the budget of many people who would otherwise benefit. It has side effects and probably down regulates receptors, which means that its effects diminish over time. Researchers realize that what is needed is something that can be taken orally to stimulate the natural secretion of GH. This must be accomplished in a way that will prevent over stimulation to the point of down-regulation, but at the same time increase the hormone to a level that will elicit a response. Some of the important advantages to GH secretagogues include preservation of feedback mechanisms that modulate GH response and generation of pulsatile patterns of GH release, which more closely mimic natural secretion.

Possible Side Effects Associated with GH Injections

  • Cancer
  • Hypotension
  • Congestive Heart Disease
  • Uncontrolled Bleeding
  • Carpal Tunnel Syndrome
  • Reduced Insulin Sensitivity
  • Hypoglycemia
  • Hyperglycemia
  • G.I. Disturbances
  • Gynecomastia
  • Edema
  • Leukemia in Children
  • Ketogenesis
  • Allergic Response


The Evolution of Secretagogue Research

Synthesis of GH in the '80s. led to an explosion of GH research. The list of potential beneficiaries grew to include AIDS patients, burn victims, patients with Turner's syndrome, those receiving glucocorticoids and chemotherapy, and of course the elderly.

While some researchers pursued the effects of injected synthetic GH, others focused on finding GH secretagogues.
In 1977, Dr. Roger Guillemin was awarded the Nobel Prize for his work on GH. Guillernin discovered the two hormones that are known to control GH. Both originate in the hypothalamus. One is called growth hormone releasing hormone (GHRH) and the other is somatostatin. GHRH stimulates growth hormone release, while somatostatin inhibits it.
The discovery of these hormones marked the recognition of auxiliary substances that would affect GH status,
and initiated a search for the perfect secretagogue.


The Morphine Connection

Frank Momany, Cyril Bowers and their group discovered the first synthetic secretagogue. It was called growth hormone releasing peptide 6 (GHRP-6) in reference to its six constituent amino acids. Strangely enough, the discovery of GHRP-6 came from research on morphine addiction.

In the 1920s, it was noted that female morphine addicts were often sterile. A few curious scientists tried to study the phenomenon by recreating the situation in rats. But no matter how much morphine they injected, sterility could not be induced. In 1934, a researcher named Ko tried it in mice and it worked. Three years later another researcher, Dun, did the same in rabbits with the same result. But because the model couldn't be recreated in rats, researchers shied away from studying it further.

In 1949, Dr. Charles Barraclough and his colleague Everett discovered that the hormone that induces the reproductive cycle is released only at a certain time of the day. Previous researchers had been injecting rats at the wrong time! Barraclough and another colleague, Sawyer, quickly demonstrated that if given at the right time of the day, morphine blocked the reproductive cycle in rats. At that time, they theorized that the signal that caused the pituitary to release the reproductive hormone originated in the hypothalamus. While it didn't seem very significant at the time, the knowledge that morphine affected pituitary hormone eventually became very important.

In 1972, Dr. Paul Cushman was looking to define more specifically the effect that morphine has on the pituitary.
At that time, GH was considered the "most sensitive index of pituitary function". So Cushman set up studies to measure GH in morphine addicts. Unfortunately, because of problems in methodology and the small number of people studied,
he could draw no sound conclusions about the effects of morphine on the pituitary or GH. But the first inkling that GH is under control of an opioid was had. The following year, researchers at the University California, Irvine demonstrated conclusively that morphine increases GH.

Three years later, it was shown that morphine initially increases GH levels, then causes them to decline.
That same year, researchers found "natural" morphine in the body, and the pieces of the puzzle started coming together. Did natural morphine, like synthetic morphine, increase GH? Later that year, Dr. John Hughes and his group synthesized natural morphine. It turned out to be two pentapeptides (5 amino acids). They called the substance "enkephalin". Enkephalin caused the release of GH. It was a natural secretagogue. For the next 5 years, dozens of researchers shuffled the amino acid sequence of enkephalin, hoping to find a GH secretagogue they could patent. Many analogues of enkephalin were reported to increase GH, but nothing was pursued for commercial use. Gradually, most researchers abandoned the hunt for the perfect peptide.

Momany and Bowers of Tulane University continued refining their sequences until finally, in 1979, they came up with a peptide that was active orally. The hexapeptide (6 amino acids) was known as "growth hormone releasing peptide-6" (GHRP-6). The peptide is: His-DTrp-Ala-Trp-DPhe-LysNH2. Although GHRP-6 was active when taken orally, it didn't cause enough GH enhancement to be patented and sold as a drug. Momany, Bowers and others have used GHRP-6 as a launching pad to create other, more potent secretagogues. One of them, Hexarelin, is currently undergoing trials. Momany continues to study potential secretagogues for GH and other hormones, using sophisticated computer modeling to combine and recombine the amino acids.

You may note the "D" prefix to some of the amino acids in the GHRP-6 sequence. This is common to all major secretagogue peptides that have been studied. The natural form of these constituent amino acids is the "L" form,
but for proprietary and stability reasons-they have been replaced with the synthetic "D" form. This is not the case
with the naturally derived peptide secretagogues that we will describe later.

GHRP-6 and its derivatives are peptide secretagogues, but non-peptide secretagogues have been created.
Using molecular modeling, researchers at Merck have designed a drug (presently known as MK677) that mimics
the effect of GHRP-6. It works by artificially inducing similar kinds of changes in' cell membranes caused by GHRP-6.
Its chemical structure is similar to benzodiazepine drugs.

It is interesting to note that, like growth hormone injections, none of the synthesized secretagogues address the systemic influences of GH such as IGF-1 1 formation and receptor sites. This probably explains the mixed results that they have produced in terms of consistent IGF- 1 stimulation and the lack of symptomatic improvement, which have impeded their success.

In this assessment, we cannot ignore the natural GH secretagogues that originate within the body (endogenous) and outside the body (exogenous). Estrogen and testosterone enhance GH, as do the amino acids arginine and ornithine.
The vitamin niacin (B3, niacinamide) enhances GH by reducing free fatty acids. Fasting enhances GH, and so does intense, sustained exercise. However, none of these by themselves increase GH enough, or in the proper way, to be considered a true GH enhancement therapy. But, as you are about to discover, the proper combination of peptides, pharmaceutical sugars, amino acids, diet, and exercise can produce significant and measurable age reversing effects. And it's a lot simpler than it sounds.


Intrinsic Factors that Affect GH Release

There are several factors that control GH release in a manner that may limit response to secretagogue therapies.
We have reviewed the hypothalamic hormones, GHRH and somatostatin, and their direct role in regulating GH secretion, but GH regulation is far more complex. In addition to pituitary receptors for which corresponding hormones have not yet been identified, there are direct influences that come from each of the minerals potassium, magnesium, calcium, and zinc. The dominant memory neurotransmitter, acetyl-choline, regulates GH secretion, while blood pH and feedback mechanism from IGF-1 and IGF-2 play important roles. Other factors, such as hGH binding proteins and metabolic clearance rate directly limit symptomatic response to growth hormone.

These are only some of the intrinsic factors that have been identified, and upon examining them, we begin to gain an appreciation for the years of research that have been performed on hGH secretagogues and the complexity involved in
a substance that works not only to elicit GH release, but consistent symptomatic response.

Model depicting the pathways responsible for the GHRH - induced increase in [Ca+ +], and GH release in somatotrophs.


This graphic representation illustrates some of the known mechanisms by which calcium (Ca++) elicits the release of GH from pituitary somatotrophs. Ca++ increase is associated with an increase in GHRH.

Interestingly, any rise in Ca++, independent of GHRH, will cause the release of GH, and any fall in Ca++ will cause a diminished release of GH. The pulsatile secretion pattern of growth hormone has been directly associated with rhythmic rises in Ca++. One of the mechanisms by which somatostatin works to block GH secretion is through inhibition of Ca++ and potentiation of potassium (K+).

Zinc deficiency is known to profoundly affect the GH/IGF-I axis. Many of the signs of zinc deficiency are directly associated with the action of growth hormone, including poor wound healing, reduced protein synthesis, immuno-suppression, and reduced hormone concentrations. Zinc, magnesium, and potassium deficiencies can all negatively affect circulating IGF-1.

In addition to the intricacies involved in its release, there is a great degree of complexity associated with the growth hormone molecule itself. Although most attention in focused on 22-kd hGH, "free GH", which accounts for only 20% of the over 100 naturally occurring forms of hGH that have been identified, the role of the other 80% of various forms of hGH is not yet fully understood. Research shows that GH bound to growth hormone with GH binding protein (hGH(hGHbP)2 plays an important role in maintaining and enhancing the activity of growth molecule hormone. Interestingly, the hGH(hGHbp)2 is structurally identical to the free form of porcine growth hormone -the form that is predominant in the porcine pituitary, a primary ingredient in Symbiotropin.

Some of the details, which we have merely brushed the surface of here, begin to give us a flavor for the complexity of an effective GH secretagogue. Individual amino acids, vitamins, peptides and prescription drugs may bring about some type of GH release, but without creating the proper environment, results are limited.


I do not have to get up to urinate at night as frequently.

- O.B. (Male, Age 76)

I had severe emphysema, and it has improved greatly.

- F.B. (Male, Age 67)


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