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A 100% Natural
Growth Hormone
Secretagogue
© 2006 -2013 Millennium Health Centers, Inc.
08-01-2013
®
Secretropin
The Logical “First Step” in GH
Therapy.
© 2006 -2013 Millennium Health Centers, Inc.
A secretagogue is a substance that
causes another substance to be
secreted.
SRx
Simulates
GHRF
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Youthful production of GH and Older Production
The number of pulses and the amplitude of hormone
production decreases as we get older.
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Low Dose GH Stimulation vs. High Dose Stimulation
Somatostatin
Over stimulation of the AP leads to an elevation in the production of
Somatostatin with a corresponding decrease in the release of GHRH
leading to down regulation in the production of growth hormone.
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The Threshold Theory of GH Production
1. GH is a central and peripheral trigger of the feed-back loop.
i. Down regulation of GHRH-receptors
ii. Down regulation of Arcuate Nucleus production of GHRH
iii. Up-regulation of Somatostatin (SRIF) from the Paraventricular
nucleus of the hypothalamus.
2. IGF-1 is a peripheral trigger of the central feed-back loop.
i. Down regulation of GHRH-receptors
ii. Down regulation of Arcuate Nucleus production of GHRH
iii. Up-regulation of Somatostatin (SRIF) from the Paraventricular
nucleus of the hypothalamus.
© 2006 -2013 Millennium Health Centers, Inc.
The Threshold Theory of GH Production
1. When GH reaches the individual’s threshold
for Negative Feedback:
i. Somatostatin increases thereby downregulating GH production and release.
2. When IGF-1 reaches the individual’s threshold
for Negative Feedback:
i. Somatostatin increases thereby downregulating GHRH and GHRH-r production.
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Neuroendocrine Control of Growth Hormone Secretion.
PHYSIOLOGICAL REVIEWS Vol. 79, No. 2, April 1999. Eugenio E. Muller, Vittorio Locatelli, Daniela Cocchi,
Department of Pharmacology, Chemotherapy, and Toxicology, University of Milan, Milan; and Department of Biomedical
and Biotechnology Sciences, University of Brescia, Brescia, Italy
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Homologous Down-Regulation of Growth HormoneReleasing Hormone Receptor mRNA Levels* Endocrinology
138: 1058–1065, 1997 Grazia Aleppo, Stanley F. MOSKAL II, Paula A. De Grandis, Rhonda D. Kineman,Lawrence A.
Frohman, Department of Medicine, Section of Endocrinology and Metabolism, University of Illinois at Chicago, Chicago,
Illinois 60612
 Repeated stimulation of pituitary cell cultures
with GH-releasing hormone results in diminished
responsiveness, a phenomenon referred to as
homologous desensitization.
 One
component
of
GHRH-induced
desensitization is a reduction in GHRH-binding
sites, which is reflected by the decreased ability
of GHRH to stimulate a rise in intracellular
cAMP.
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Many Secretagogues
Arginine
Vitamin D3
GHRFs
GHRH
DHEA
Peptides
Dopamine
Non-Peptides
Amino Acids
Melatonin
GH
GH
GH
GH
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© 2006 -2013 Millennium Health Centers, Inc.
Growth hormone secretagogues: recent advances and
applications. DRUG DISCOVERY TODAY 1999 Nov;4(11):497-506 Ankersen Novo Nordisk
A/S, Novo Nordisk Park, DK-2760 Malov, Denmark.
 The discovery of a new class of compounds that
stimulate the release of growth hormone (GH) in a
manner distinctly different from growth hormonereleasing hormone (GHRH) is advancing the
understanding of the mechanisms that control GH
secretion.
These compounds, the GH secretagogues, act at
both pituitary and hypothalamic levels, and even
elicit effects in the CNS and peripheral systems.
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Growth Hormone-Releasing Peptide (GHRP).
Cell
Mol Life Sci. 1998; 54(12):1316-29. Bowers CY. Tulane University Medical School, New Orleans,
Louisiana 70112, USA.
 Growth Hormone-Releasing Peptides and
Non-Peptides are a chemical class of Growth
Hormone secretagogues with a chemistry that
ranges from small synthetic peptides to
peptidomimetics (natural) substances.
 They have no structural homology with
(GHRH) but act via specific receptors, which
are present at both the pituitary and
hypothalamic levels.
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Specific
receptors
for
synthetic
GH
Secretagogues in the human brain and pituitary
gland. Journal of Endocrinology (1998) 157, 99–106. G Muccioli, Et Al. Department of
Anatomy, Pharmacology and Forensic Medicine, Department of Biomedical Sciences and Human
Oncology, Department of Internal Medicine, University of Turin, Turin, Italy, Pharmacia and
Upjohn, Stockholm, Sweden, Europeptides, Argenteuil, France, and Faculty of Pharmacy,
University of Montreal, Montreal, Canada.
 A number of research centers have identified
specific receptors in the human brain and pituitary
gland that are unique for sGHS.
 These compounds are believed to be the
synthetic counterpart of an endogenous GH
secretagogue involved in the neuroendocrine
control of GH secretion ( Ghrelin).
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Endocrine and non-endocrine activities of growth
hormone secretagogues in humans. Hormone Research. 1999;
51 Suppl 3:9-15. Ghigo E; Arvat E; Broglio F; Giordano R; Gianotti L; Muccioli G; Papotti M;
Graziani A; Bisi G; Deghenghi R; Camanni F Department of Internal Medicine, University of
Turin, Italy.
 Furthermore, these secretagogues (s-GHS)
have been found to possess strong, dosedependent and reproducible GH releasing effects.
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Dehydroepiandrosterone modulates GHRH, Somatostatin, and
angiotensin II action at the pituitary level. Journal of Endocrinology (2005) 185,
165–172C Suárez, J Vela, I García-Tornadú and D Becu-Villalobos Instituto de Biología y Medicina Experimental,
CONICET, V, Obligado 2490, Buenos Aires 1428, Argentina.
 DHEA in vitro, directly or indirectly through
conversion into metabolites, is able to modulate the
hormonal response of the pituitary to hypothalamic
regulators.
 DHEA enhances pituitary prolactin release and
induces GH secretion.
 These effects could help explain some of the beneficial
side effects observed in patients on prolonged DHEA
treatments, and therefore, should be taken into account
when considering its use.
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Dehydroepiandrosterone (DHEA) replacement reduces growth hormone
(GH) dose requirement in female hypopituitary patients on GH
replacement. Clin Endocrinol (Oxf). 2006; 65(5):673-80,Brooke AM; Centre for Clinical Endocrinology, William
Harvey Research Institute, St.Bartholomew's Hospital, QMUL, London, UK.
 DHEA replacement in female patients lead to a
20% reduction in the dose of GH for a constant
serum IGF-I.
 This was maintained for 12 months and there
was a significant fall in serum IGF-I two months
after withdrawal of DHEA.
 Therefore, take at night and not in the morning
to enhance GH production.
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Allelic variations of the D2 dopamine receptor gene in
children with idiopathic short stature. J Hum Genet. 1999;44(1):26-9. Miyake H,
Nagashima K, Onigata K, Nagashima T, Takano Y, Morikawa A.Department of Pediatrics, Gunma University School of
Medicine, Japan.
 The Dopamine receptor (DRD2) plays a
major role in growth hormone (GH)
secretion.
 Binding to D2R increases the production and
release of Growth Hormone.
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Stimulation of Human-Growth-Hormone Secretion by LDopa. N Engl J Med 1970; 283:1425-1429 Dec. 24, 1970. A. E. Boyd, III, M.D., Harold E. Lebovitz, M.D., and John
B. Pfeiffer, M.D. From the divisions of Endocrinology and Neurology, Department of Medicine, Duke University Medical
Center.
 The effect of L-dopa, on GH secretion was
studied in a group of patients with Parkinson's
disease undergoing treatment with the drug.
 The rise in plasma GH persisted for 120
minutes after the administration of the drug.
( The L-dopa-induced rise in plasma GH could
not be blocked by either oral or intravenous
glucose administration. )
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Use of amino acids as growth hormone-releasing
agents by athletes. Nutrition. 2002 Jul-Aug;18(7-8):657-61. Chromiak JA, Antonio
J.Department of Health, Physical Education, Recreation and Sport, Mississippi State University, PO Box 6186,
Mississippi State, MS 39762-6186, USA.
 Specific amino acids, such as arginine, lysine
and ornithine, have been shown to stimulate GH
release when infused intravenously or
administered orally.
Although parenteral administration consistently
leads to increased circulating GH concentration,
oral doses that are great enough to induce
significant GH release are also likely to cause GI
discomfort and diarrhea.
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Product(s)
Response
Arginine
250mg/kg/day 60% increase in GH
Ornithine
400% increase in baseline
IV Ornithine
500% increase of GH over baseline.
Alpha-Keto
Glutarate
Significant increase in GH in TBI patients.
Glutamine
2 grams increase GH
GABA
5 grams increase GH
Glycine
6.7grams increased GH 300-400%
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Arginine stimulates growth hormone secretion by
suppressing endogenous Somatostatin secretion.
Journal of Clinical Endocrinology & Metabolism, Vol 67, 1186-1189, 1988. J Alba-Roth, OA
Muller, J Schopohl, K von Werder Medizinische Klinik Innenstadt, University of Munich, West
Germany.
 Arginine administered with GHRH led to
higher serum GH levels than did a maximally
stimulatory dose of GHRH or Arginine alone.
This indicated that the stimulatory effects of
Arginine are mediated by suppression of
endogenous Somatostatin secretion (SRIF).
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Vitamin D and growth hormone regulate growth
hormone/insulin-like growth factor (GH–IGF) axis gene
expression in human fetal epiphyseal chondrocytes. Growth
Hormone & IGF Research Volume 19, Issue 3, June 2009, Pages 232–237. M. Fernández-Cancio,
Vitamin D, dose-dependently, stimulated
GHR, IGF-I , and IGFBP-3 expression.
24
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Peripheral estrogen receptor alpha selectively modulates the
waveform of GH secretory bursts in healthy women. Veldhuis JD,
Keenan DM, Bowers CY. Am J Physiol Regul Integr Comp Physiol. 2007 Oct;293(4):R1514-21. Epub 2007 Aug .
Endocrine Research Unit, Mayo Medical and Graduate Schools, Clinical Translational Research Unit, Mayo Clinic,
Rochester, MN55905, USA.
 Estradiol
drives GH secretion via
estrogen receptors (ER-α) located in the
hypothalamus and pituitary gland.
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Testosterone supplementation in healthy older men drives GH
and IGF-I secretion without potentiating peptidyl secretagogue
efficacy. Eur J Endocrinol. 2005; 153(4):577-86 Veldhuis JD; et. Al, . Dept of Internal Medicine, Mayo Medical and
Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, MN 55905, USA.
 Supraphysiological testosterone concentrations
increase GH and IGF-I production in the elderly
male without altering maximal somatotrope
responses to single and combined GHRH and
GHRP-2 drive, thus predicting multifactorial
mechanisms of testosterone up-regulation.
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Item
Increase
Melatonin
+
Estradiol
+
Dopamine
+
DHEA
+
Testosterone
+
Tamoxifen
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Decrease
--
Sermorelin
+
Vitamin D
+
Alcohol
--
FATS
-
Carbohydrates
-
Obesity
--
Summary
- The research
literature supports the ability of
atypical substances to increase the production and
release of Growth Hormone through a number of
receptor pathways.
- These substances have been found to be amino
acids, non-peptides, peptides, synthetic peptides,
DHEA, Dopamine, which enhance the activity level
of Somatotropes increasing production of GH.
-
To work they must be introduced into a
homeostatic hormonal environment.
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TBImedlegal.com
© 2010 Millennium Health Centers, Inc.
HCl
HCl
Dopamine
Amino Acids
Melatonin
DHEA
Arginine
HCl
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Vitamin D
Peptides
Protection from Acid
Destruction.
Nano-Liposomes filled with SRx
Nano-spheres or emulsions
to diffuse into the blood.
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Analytical methods for the control of liposomal delivery
systems. Revue TrAC. Trends in analytical chemistry, 2006, vol. 25, pp. 167-178. Gomez-Hen. ; FernandezRomero J. M.
 Liposomal delivery systems are effective
vehicles to incorporate active agents into
compartmentalized structures for the delivery
of pharmaceutical, cosmetic, food and
nutritional products.
 A major benefit of liposomal delivery systems
is that they allow for spatial and temporal
distribution of a drug in the body, reducing
unwanted toxic side effects and increasing
efficiency of treatment.
© 2006 -2013 Millennium Health Centers, Inc.
Product to Deliver
Delivery
Absorption
Vitamin C (1000mg)
Oral
19%
Vitamin C (1000mg)
Liposomal
97%
1 gram of orally ingested Vitamin C had a 19% absorption
while 1 gram in a Nanoliposomal based product had a
97% delivery.
© 2006 -2013 Millennium Health Centers, Inc.
 The original clinical testing of Secretropin
was performed in 2001. The original formula
delivered by nanoliposomes was found to
increase the production of GH based upon a
measurable increase in IGF-1.
 At that time, IGF-1 was the only test used to
monitor responsiveness to the product. Today
IGFBP-3 has been shown to be logarithmically
proportional to GH production.
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© 2010 Millennium Health Centers, Inc.
© 2006 -2013 Millennium Health Centers, Inc.
The October 2006 Study Sequence
The March 2008 Report. The March 2009 Report and pending March 2013.
Goal to have 100 patients followed for 6
– 12 months with labs drawn initially and
monthly thereafter.
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300
257.93
250
200
211.49
231.83
150
100
50
129.77
Initial
0
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1 month
3 months
6 months
62.9%
78.6%
98.7%
MK. 50 y/o Female 233%
Stopped SRx due to increased muscularity. Levels dropped.
Result
6/21/2007
3/22/2007
1/09/2007
IGF-1
125.4
230.8
213
99.1
IGFBP-3
3652
5262
5147
4135
© 2006 -2013 Millennium Health Centers, Inc.
JC, 47 y/o Male. 238% Increase
TBI case, 5 TBI, 3 LOC, one hospitalization.
Result
Range
9/06/2007
4/04/2007
12/26/2006
IGF-1
246.9
> 200 ng/ml
276.2
290
122
IGFBP-3
5693
> 4000 ng/ml
6527
6527
5450
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NJ: 34 y/o Male 199.2%
Cryptorchism.
Result
Range
1/10/2008
10/30/2007
2/20/2007
IGF-1
306.9
> 200 ng/ml
290.8
240
154
IGFBP-3
3824
> 4000 ng/ml
3767
3882
2830
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IGF-1 Results at approx. 1 month intervals (3mos)
350
Continuous
4 - sprays
300
250
200
6
5
4
150
100
50
Patient 1
Patient 2
Patient 3
Patient 4*
3
1
2
Patient 5
Patient 6
0
Generally speaking: High initial IGF-1/BP-3 are more prone to shut down then those
with initial low IGF-1/BP-3 levels.
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Initial Treatment
Secretropin (SRx)
1mo Laboratory
3mos
Increase
No Change/Decrease
3mos
Continue
Adjust Dosing
Failed
© 2006 -2013 Millennium Health Centers, Inc.
Program
Secretropin
Growth Hormone
Initial Protocol
4 sprays to start
None
Combined protocol
4 sprays, adjust
0.1mg – 0.3mg
Established GH Use
4 sprays to start.
Reduce GH based upon response.
Post-GH Shutdown
4 Sprays, adjust.
None
1. In a GH deficient or insufficient patient start SRx and adjust dose for
maximal response. Monitor over 3 months.
2. Starting a new patient on both GH and SRx allows for the use of a lower
dose of GH with comparable results in both IGF-1 and BP-3 levels.
3. In a patient already on GH, add SRx and adjust for maximal IGF-1/BP-3
levels. You should have a spike in GH production within 3 months.
4. Patients who have been on GH for 6 months or more should start SRx
having both IGF-1 and GH monitored. Before starting SRx, wait 4 weeks
before taking initial IGF-1 and BP-3 levels for baseline. Monitor
Q3months.
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© 2006 -2013 Millennium Health Centers, Inc.