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Mark L.; Gordon, Erin F; Gordon, Alison M; Gordon, Rochelle H. ;Anand, Sidharth. Journal of
Anti Aging Protocology. March 17, 2009
Objective: To examine the efficacy of a compound of mixed amino acids, GABA, and Mucuna pruriens
enveloped in a nanoliposomal delivery system to increase the production of GH, IGF-1, and IGFBP-3, in Design and Method: Within a private medical office, healthy individuals were screened for growth
hormone insufficiency (150-101 ng/ml IGF-1) and deficiency (less than 100 ng/ml IGF-1) prior to being given the secretagogue (Secretropin®). A morning dose of the preparation, 0.20 cc (600 mg) was placed under the tongue for 30 seconds prior to swallowing. A bedtime dose of 0.40 cc (1200 mg) was placed under the tongue for 30 seconds prior to swallowing. At both times the participant refrained from eating or drinking for at least 30 minutes prior to and after taking the secretagogue. Laboratory testing of at least IGF-1 and IGFBP-3 was performed prior to starting the secretagogue and at 1, 3, and 6 months.
Results: After a twelve month testing period, the secretagogue was shown to increase patients’
circulating levels of IGF-1 by 50-200% in 92% of the participants.
Conclusion: This nanoliposome delivered secretagogue was shown to be capable of elevating natural
growth hormone production and release in healthy individuals, as evident by elevated levels of IGF-1 and INTRODUCTION
The recognition and acceptance of non peptide, synthetic complexes as potent growth hormone (GH) secretagogues has been less than positive due to a number of perceived limitations.
These perceptions were based upon our lack of scientific evidence to support the supposition that something other than a complex peptide, such as growth hormone releasing hormone (GHRH) could increase a hormone’s production.1 Additionally, we lacked the scientific knowledge about flexible receptors that could accept a broad range of chemical structures that would lead to the stimulated production or suppression of a hormone.2 Finally, we are starting to understand more about the complex influences that hormones, peptides, and amino acids have on the hypothalamic-pituitary axis.3,4 Firstly, past research data was based upon small test groups of individuals that were given large quantities of mixed amino acids designed to enhance GH production and release. Although many of these compounds demonstrated a measurable elevation in the GH/IGF-1 axis, many were also associated with osmotic diarrhea, making it a difficult pill to swallow.5,6 Secondly, delivery of amino acids by mouth has a poor bioavailability due to its destruction and inactivation by gastric acid.
compensatory dose is then needed to correct for this diminished availability thereby, leading to the side- effect of diarrhea. Thirdly, since the action of a secretagogue is to increase the amplitude and duration of intrinsic GH secretion, the normal regulatory or homeostatic mechanism (positive feedback and negative feedback) is preserved. When a secretagogue elevates the intrinsic production of GH above the body’s inherent set-point, Somatostatin release (also known as somatotrope release inhibiting factor (SRIF)) causes the suppression of intrinsic GH production. This, in turn, can lead to the waxing and waning of GH/IGF-1 levels, making it difficult to accurately assess the net affect.
These issues have generated the majority of resistance to the use of secretagogues in healthy individuals with low GH, IGF-1, and IGFBP-3 levels.
This paper will present current, evidence-based scientific literature, and clinical results to support the use of a secretagogue as a responsible “first step” approach to the treatment of growth hormone Amino Acids as Growth Hormone Secretagogues
Ornithine is derived from the amino acid arginine. High doses of oral ornithine have successfully raised GH levels. Bucci et al investigated the effect of 40, 100 and 170 mg/kg of oral L-ornithine HCl. 25% of the subjects experienced a significant increase in their serum GH level at the two lower doses, while 50% of the subjects showed an increase in GH at the highest dose. GH levels increased up to four times Secretropin, the responsible first step in Growth Hormone therapy.
Arginine (Arg), when taken in large quantities, has also been noted to increase the serum levels of GH, IGF-1 and IGFBP-3.8 The mechanism of this stimulated increase has since been found to be due to the suppression of somatostatin release.9,10 Ornithine-alpha-ketoglutarate (OKG) Ornithine alpha-ketoglutarate (OKG) is formed of two molecules of ornithine and one molecule of alpha-ketoglutarate. OKG is a promising anti-catabolic agent that promotes wound healing and protein synthesis. Researchers have hypothesized that OKG fulfills these functions by encouraging the secretion of insulin and GH, and by upregulating glutamine and arginine production. When fed enterally to trauma patients, OKG significantly increased both IGF-1 and GH levels.11 During resting conditions, GH was significantly elevated 60 minutes after consumption of arginine and lysine compared with the placebo trial. The researchers concluded that ingestion of 1500 mg arginine and 1500 mg lysine before resistance exercise did not alter exercise-induced changes in GH in young men. However, when the same amino acid mixture was ingested under resting conditions, an acute Glycine is a non-essential amino acid contained in gelatin protein and is an important component of collagen. Although early research focused on glycine’s ability to increase strength in athletes, more recent research has shown the reason this occurred was the result of its GH-boosting capabilities (with females experiencing a 22% increase and men a 32% increase in cycle ergometry workloads after ingestion of 5-12 g of glycine daily).13,14 One study clearly illustrated glycine’s ability to act as a GH secretagogue. When 19 normal, non- obese subjects consumed 6.75 g of glycine orally, GH levels significantly increased for 3 hours, reaching a maximum of 3 to 4 times that of baseline at 2 hours. According to the researchers, glycine is one of the stimulatory agents inducing the pituitary gland to secrete GH.14 Secretropin, the responsible first step in Growth Hormone therapy.
Glutamine is the most abundant amino acid in human muscle and plasma, directly regulating both the production and wearing-down of protein, as well as immune cell activity.15 When healthy subjects consumed 2 g of oral glutamine 45 minutes after a light breakfast, 89% of the subjects experienced elevated plasma GH within 90 minutes. These findings demonstrate that a small oral glutamine load is capable of elevating plasma GH. Glutamine is converted into citrulline in the small intestine, which in turn triggers the synthesis of arginine, an amino acid shown to increase the release of GH by suppressing somatostatin release.9,10 Moreover, glutamine is converted into glutamate, which directly enhances GH Gamma-aminobutyric acid (GABA) is the brain’s major inhibitory neurotransmitter. Studies have shown that GABA is responsible for both the rise of GH (when at rest) and the inhibition of GH (when exercising). Oral GABA supplementation has increased GH levels in humans. In one study, a single oral dose of 5 g of GABA administered to 19 subjects significantly elevated plasma GH levels compared to placebo-treated controls.20 A number of studies have demonstrated that alcohol consumption abolishes the ability of GABA to affect the secretion of GH.21 Also known as the velvet bean, Mucuna contains a significant amount of extractable L-dopa (L- 3,4-dihydroxyphenylalanine) in its seeds and roots.22 Unique to this natural form of L-dopa is its rapid absorption and bio-availability with a low potential for toxicity when compared to the pharmaceutical, When L-dopa/dopamine binds to the DR2 cell receptors in the brain, an atypical neuroregulatory mechanism leads to the stimulation of GH production and release.25, 26 The elucidation of this relationship has been tested in obese premenopausal women who have suppression of dopamine production by virtue of their obesity. Bromocriptine use improved upon the circadian GH secretion which added support to the role of Dopamine Receptor-2 as an adjunctive means of stimulation of GH secretion.27 Secretropin, the responsible first step in Growth Hormone therapy.
A liposome is a spherical vesicle composed of a bilayer membrane. In biology, this refers to a membrane composed of phospholipids, and a cholesterol bilayer. Liposomes can be composed of naturally-derived phospholipids with mixed lipid chains (like egg phosphatidylethanolamine), or of pure surfactant components like DOPE (dioleoylphosphatidylethanolamine). Liposomes, usually but not by definition, contain a core of aqueous solution; lipid spheres that contain no aqueous material are called micelles, however, reverse micelles can be made to encompass an aqueous environment.28 Liposomes were first described by British hematologist Dr Alec D Bangham FRS in 1961, at the Babraham institute, Cambridge. They were discovered when Bangham and R. W. Horne were testing the institute's new electron microscope by adding negative stain to dry phospholipids. The resemblance to the plasmalemma was obvious, and the microscopic pictures served as the first real evidence for the cell membrane being a bilayer lipid structure.29 Liposomes are used as drug delivery systems due to their unique properties. A liposome encapsulates a region of aqueous solution inside a hydrophobic membrane, preventing dissolved hydrophilic solutes from readily passing through the lipids. Hydrophobic chemicals can be dissolved into the membrane, and in this way the liposome can carry both hydrophobic molecules and hydrophilic molecules. To deliver the molecules to sites of action, the lipid bilayer can fuse with other bilayers such as the cell membrane, thus delivering the liposome contents. By making liposomes in a solution of DNA or medication (which would normally be unable to diffuse through the membrane) they can be (indiscriminately) delivered past the lipid bilayer.29 Liposomes can also be designed to deliver drugs in other ways. Liposomes that contain low (or high) pH can be constructed such that dissolved aqueous drugs will be charged in solution (i.e., the pH is outside the drug's pH range). As the pH naturally neutralizes within the liposome (protons can pass through some membranes), the drug will also be neutralized, allowing it to freely pass through a membrane. These liposomes work to deliver drug by diffusion rather than by direct cell fusion. Another strategy for liposome drug delivery is to target endocytosis events. Liposomes can be made in a particular size range that makes them viable targets for natural macrophage phagocytosis. These liposomes may be digested while in the macrophage's phagosome, thus releasing its drug. Liposomes can also be decorated with opsonins and ligands to activate endocytosis in other cell types.30 Secretropin, the responsible first step in Growth Hormone therapy.
The goal for the study was to enroll 50 healthy male and female participants. Enrollment into the study was open with the only restriction being; no active use of psychotropic medication or recombinant human growth hormone (rhGH). Each participant had a comprehensive chemical and hormonal panel drawn prior to starting the secretagogue. Instructions for the use of the secretagogue were standardized to 600 mg in the morning (by oral delivery) and 1200 mg at bed time (by oral delivery). Each participant was instructed to avoid eating and drinking for 30 minutes prior and after delivery of the product. Two pumps (0.2 cc) of the spray were delivered under the tongue and held for 30 second in the morning and 4 pumps (0.4 cc) at bed time. With each dosing the participant was instructed to hold the fluid under their tongue for 30 seconds and then swallow.
Participants were acting as self controls, since their baseline hormone levels were obtained prior to initiation of secretagogue treatment and therefore, upon stopping, the anticipated drop-off in IGF-1 and IGFBP-3 would be used to indicate withdrawal of the products effects.
An attempt was made to standardize patient laboratory testing (Table 1) at 0, 1, 3, 6, and 12 months. Laboratory testing included at minimum serial IGF-1 and IGFBP-3 levels. Additional testing was patient-specific as indicated in Table I.
A response to the secretagogue was identified based upon elevation of IGF-1 and/or IGFBP-3.
Important to the efficacy of the secretagogue is that all underlying hormone insufficiencies are corrected Table I: Laboratory Testing
Insulin-Like Growth Factor Binding Protein - 3 Secretropin, the responsible first step in Growth Hormone therapy.
The following study results represent 49 participants who completed at least 6 months of active secretagogue use with clinical follow-up.
Table II: Study Results
Secretropin, the responsible first step in Growth Hormone therapy.
A review of the above results shows a wide range of patient-specific improvement in IGF-1 and IGFBP-3 levels. As opposed to a comparative analysis of these results, we chose to use patient-specific improvement as a marker for response to the secretagogue. The concept of patient-specific improvement deals with the evaluation of an individual’s unique response to the secretagogue over their baseline IGF-1 and IGFBP-3 levels, and not across the spectrum of all patients in the study. For example, patient #34 had an initial IGF-1 of 147 ng/ml and a subsequent level of 226 ng/ml at 3 months, representing a 54% increase. Patient #17 had an initial IGF-1 of 154 ng/ml and a subsequent level of 309.6 ng/ml at 3 months, representing a 101% increase. Finally, patient #20 had an initial IGF-1 of 99 ng/ml and a subsequent level of 267 ng/ml at 3 months, representing a 169% increase.
correlated best with the percentage increase rather than the actual numerical increase in IGF-1 levels.
The need to measure IGFBP-3(BP-3) is based upon research that shows approximately 95% of the IGF-I is bound to BP-3, which makes this protein the major carrier of IGFs in plasma. A principal function of BP-3 is to extend the half-life of the IGFs from 8 minutes to hours. The serum level of BP-3 appears to be constant over 24 hours and the protein was found to be Growth Hormone dependent, which makes the detection of BP-3 very useful in the evaluation of Growth Hormone secretion as generated by a secretagogue. A single BP-3 measurement correlates significantly with the logarithm of spontaneous GH secretion. In this study, there were noted participants who achieved a measurable elevation in BP-3 while the change in the level of IGF-1 was negligible.
Growth hormone production is regulated through circadian homeostasis. Any increase above the physiological level induces Somatostatin release from the hypothalamic supra optic nuclei precipitating Secretropin, the responsible first step in Growth Hormone therapy.
feedback inhibition. Somatostatin works through three central mechanisms, (1) inhibition of GHRH production from the hypothalamic periventricular nuclei, (2) down-regulation of GHRH receptors, and (3) direct inhibition of pituitary somatotroph substrate-receptor interaction. Therefore, it is not unexpected to find patients with subsequent levels of GH markers lower than pre-treatment levels after use of a secretagogue. What has happened on a physiologic basis is that the level of GH exceeded the natural set point for that individual, causing inhibition of further GH production.
At this point in the on-going study of this secretagogue, there was an 8% failure to respond in the study population. This may be explained by issues of patient compliance, secondary hormonal deficiencies, abnormal gastric absorption, or adverse interactions from other medications.
The key issue relative to patient compliance was the lack of proper application, dosing, and timing of administration of the secretagogue.
With regard to secondary hormonal deficiencies, the literature clearly cites a diminished responsiveness to GHRH when there is a concurrent deficiency of DHEA, testosterone, estrogen, DHT, dopamine, melatonin, and thyroid hormones. Therefore, if a secretagogue is used to upregulate the production of growth hormone, any deficiencies of the aforementioned hormones would lead to a less than optimal production of growth hormone. 32 33 Abnormal gastric absorption refers to conditions such as food allergies, inflammatory bowel disease, ulcers, and underlying bacterial infections (H. Pylori) that may have influenced the absorption of the secretagogue by the gastrointestinal tract.
Finally, there are a number of medications which are known to affect Growth Hormone regulation which may have influenced the effectiveness of the secretagogue (see Table III).
In life, growth hormone homeostasis is influenced by a number of internal and external factors (Table III), many of which are coupled together in a synergistic relationship to maximize the efficiency of the body to produce more. It would seem from the vast number of articles reviewed, that the production and preservation of both growth hormone and IGF-1 is of paramount importance to the persistent function of our body. The fact that growth hormone has a 20 minute half-life, IGF-1 an 8 minute half-life, IGF-1 bound to IGFBP-3 a 20 hour half-life (± 4hours), and IGF-1/IGFBP-3 bound to Acid Labile Subunit (ALS) a 200+ hour half-life, indicates that the continued presence of IGF-1 is important to our survival.
Secretropin, the responsible first step in Growth Hormone therapy.
The ability of a secretagogue to elevate production and release of Growth Hormone is a complex process predicated by the net affect of factors that stimulate and those that suppress. The markers for identifying this net affect are based upon changes seen in both IGF-1 and IGFBP-3 levels. In this study using a secretagogue, the changes seen in IGF-1 and BP-3 levels were comparable to those levels seen Therefore, it would stand to reason that the responsible first step to growth hormone replacement therapy is the administration of a growth hormone secretagogue.
TABLE III : Regulation of GH Production
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18. Bulus N, Cersosimo E, Ghishan F, Abumrad NN. Physiologic importance of glutamine. Metabolism. 19. Jackson NC, Carrol PV, Russel -Jones DL, Sönksen PH, Treacher DF, Umpleby AM. Ef ects of glutamine supplementation, GH, and IGF-I on glutamine metabolism in critical y il patients. Am J Physiol Endocrinol 20. Cavagnini F, Invit i C, Pinto M, Maraschini C, Di Landro A, Dubini A, Marel i A. Effect of acute and repeated administration of gamma aminobutyric acid (GABA) on growth hormone and prolactin secretion in man. Acta Endocrinol (Copenh). 1980;93:149-154.
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26. Vance ML, Kaiser DL, Frohman LA, Rivier J, Vale WW, Thorner MO.Role of dopamine in the regulation of growth hormone secretion: dopamine and bromocriptine augment growth hormone (GH)-releasing hormone- stimulated GH secretion in normal man. J Clin Endocrinol Metab. 1987;64:1136-1141.
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27. Kok P, Roelfsema F, Frölich M, van Pelt J, Meinders AE, Pijl H. Short-term treatment with bromocriptine improves impaired circadian growth hormone secretion in obese premenopausal women. J Clin Endocrinol 28. Torchilin VP. Multifunctional nanocarriers. Adv Drug Deliv Rev. 2006;58:1532-1555.
29. Ostro MJ, Cul is PR. Use of liposomes as injectable-drug delivery systems. Am J Hosp Pharm.
30. Hauffa BP, Lehmann N, Bet endorf M, Mehls O, Dörr HG, Stahnke N, Steinkamp H, Said E, Ranke MB; German KIGS Board/Medical Outcome Study Group. Central laboratory reassessment of IGF-I, IGF-binding protein-3, and GH serum concentrations measured at local treatment centers in growth-impaired children: implications for the agreement between outpatient screening and the results of somatotropic axis functional testing. Eur J Endocrinol. 2007;157:597-603.
31. Radioimmunoassay of Growth Hormone-Dependent Insulin-Like Growth Factor Binding Protein in Human Plasma. J Clinical Investigations, 1986, 78(6):1504-12. Baxter RC and Martin JL, 32. Suárez C, Vela J, García-Tornadú I, Becu-Vil alobos D. Dehydroepiandrosterone (DHEA) modulates GHRH, somatostatin and angiotensin II action at the pituitary level. J Endocrinol. 2005;185:165-172.
33. Brooke AM, Kalingag LA, Miraki-Moud F, Camacho-Hübner C, Maher KT, Walker DM, Hinson JP, Monson JP. Dehydroepiandrosterone (DHEA) replacement reduces growth hormone (GH) dose requirement in female hypopituitary patients on GH replacement. Clin Endocrinol (Oxf). 2006;65:673-680.
34. Gordon ML, Arand S. Secretropin – The responsible first step in growth hormone therapy. Journal of Anti- Aging Protocology. 2009 pending.
Secretropin, the responsible first step in Growth Hormone therapy.


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