The Role of Oral Growth Hormone Secretagogues in Anti-Aging Therapy
Presented at the European International Conference on Quality of Life and Longevity Medicine September 28-30, 1998 Background Based on the increasing body of evidence that adults with human growth hormone (hGH) deficiency exhibit signs of impaired health, many countries have approved the use of hGH (somatotropin) as a replacement therapy in deficient adults. The results and efficacy of hGH therapy are strikingly consistent. Untreated hGH deficient adults are shown to have increased cardiovascular mortality, reduced skeletal muscle strength, reduced exercise capacity, reduced glomerular filtration and renal plasma flow, defective thermo-regulation and sweat secretion, reduced energy expenditure and basal metabolic rate, reduced myocardial function, clinical signs of premature atherosclerosis, and abnormal thyroid metabolism. Body composition has been found to be abnormal in these patients, as evidenced by decreased lean body mass, increased fat mass, visceral obesity, reduced bone mineral content, and reduced extracellular fluid volume, while independent groups have reported impaired psychological well being. Somatotropin deficiency has distinct clinical consequences, all of which can be totally or partially alleviated by rhGH replacement therapy. Safety and cost considerations associated with growth hormone replacement have generated interest in several research studies focused on oral growth hormone releasers, also known as hGH secretagogues. This class of compounds works by directly stimulating the pituitary to release hGH and by affecting contiguous endocrine organs, like the hypothalamus. There are several known factors that affect hGH release and response, including insulin regulation, somatotroph receptors, GHRH, somatostatin, liver function, and IGF-1 receptor sites. 8-10, 17 Pharmacologically correlating these factors with the action of the anterior pituitary peptides, a sequenced glycoamino acid complex, and botanical regulators of insulin and IGF-1 has led to the development of Symbiotropin, which promotes hGH release & IGF-1 formation. Clinically, the efficacy of Symbiotropin has been evaluated through IGF-1 measurements and patient self-assessments. Somatotropin is one of several endocrine hormones, like testosterone, estrogen, progesterone, and DHEA - that decline in circulation as we age. While many of these hormones are replaced to deter some of the effects of aging, somatotropin goes far beyond the effect of any of these other hormones, to not only inhibit biological aging, but to significantly reverse many of the effects of aging. Research has demonstrated that rhGH therapy can reverse the biological markers of aging by as much as twenty years within six months of therapy. 7, 13 Somatotropin is secreted by somatotrophs located in the anterior portion of the pituitary gland. Somatotropin secretion peaks during adolescence when accelerated growth occurs. After age 30, secretion decreases by about 14% per decade.
Daily release of growth hormone averages about 500 mcg at age 20, then declines to 200 mcg at age 40, and 25 mcg at age 80. hGH secretion is regulated primarily by the hypothalamus, which releases Growth Hormone Releasing Hormone (GHRH) through a negative feedback regulatory process from the pituitary to release hGH.
It is known that the aging pituitary somatotroph cells are capable of secreting as much hGH as the young somatotroph cells when they are adequately stimulated. The primary influences on age-related decrease in hGH secretion include reduced production of GHRH and increased production of Somatostatin, the hypothalamic inhibitor of hGH release. Research has shown that aging leads to reduced responsiveness of the precursor hormone GHRH to signals from the hypothalamus. Research also suggests that overall metabolic response to available hGH diminishes due to decreased sensitivity of cellular receptor sites. Some hGH secretagogues work by stimulating GHRH, inhibiting somatostatin, and/or affecting pituitary receptors that are not yet clearly defined. 5, 8, 9 The physiological effects associated with hGH are now assessed through the evaluation of IGF-1. Circulating hGH (1/2 life = 20 minutes) stimulates the liver to release IGF-1 (1/2 life = 20 hours). Serum IGF-1 levels are more sustained, and therefore a more practical indicator of growth hormone status. hGH improves utilization of fat as a source of energy by stimulating lipolysis and fat oxidation. The significance of these effects is reflected in the finding of increased adiposity in hGH deficiency and reduced fat mass in acromegaly. Studies under fully controlled conditions in vitro have indicated that cortisol and insulin facilitate lipid accumulation by expressing lipoprotein lipase (LPL). hGH and testosterone inhibit the expression of LPL, which markedly stimulates lipolysis. 16 hGH affects protein metabolism in a manner that increases lean body mass through stimulation of protein synthesis, and reduction of protein oxidation. It does not inhibit protein catabolism. 21 Long term IGF-1 deficiency affects carbohydrate metabolism, leading to insulin resistance and exacerbated obesity. These effects can be reversed with hGH therapy. hGH increases glucose turnover, making it more readily available metabolically as a primary fuel. 21
Characteristics of GH Deficiency
Reduced lean body mass and/or skeletal muscle mass Reduced skeletal muscle strength Reduced exercise performance Increased total body fat Increased abdominal and visceral fat
Elevated LDL cholesterol Decreased HDL cholesterol Elevated apolipoprotein-B
Osteopenia (lack of bone)
Insulin resistance (in obese people) Hypoglycemia Possible abnormal resting metabolic rate Reduced T4 to T3 conversion
Thin skin Lack of collagen Decreased size of organs Decreased nail and hair growth
Reduced glomerular filtration and renal plasma flow Reduced sweating - inability to thermoregulate Reduced cardiac output (potentially) Increased vein resistance
Reduced energy Emotional instability Poor memory and concentration Depression Lack of social interaction Lack of purpose Reduced sex drive
Action of Secretagogues
Functional studies demonstrated that GHRH and secretagogues act through different mechanisms, and distinct receptor sites. Somatotrophs stimulated with secretagogues release hGH in response to both GHRH and the secretagogue. Efficacious secretagogue peptides, work at the level of the hypothalamus, to affect hGH releasing factors, and at the level of the pituitary to release stored hGH in a synergistic fashion. Pituitary receptors have been identified that respond to specific hGH releasing peptides. 10, 17 Since somatostatin increases with age to lower levels of hGH, it is important for effective secretagogue peptides to inhibit the action of this hormone. Hypothalamic receptors have been identified that respond to peptides that inhibit somatostatin and stimulate GHRH. Many studies have evaluated the effectiveness of oral amino acids and peptides. Oral absorption studies have demonstrated very erratic absorption rates. Orally ingested peptides must be formulated in a delivery system that will endure the acid pH of the stomach in order to be absorbed effectively and arrive at appropriate receptor sites. Absorption of the hGH molecule has been examined through various means of delivery, e.g. mucosal surfaces, the mouth and nose. These studies have demonstrated very ineffective absorption rates of around 5-10 %. Studies indicate that absorption rate and efficacy of amino acid secretagogues are enhanced when administered in a carbonated solution. 1, 2, 3 Management of hGH secretion through the use of peptides and other synergistic compounds has been shown to increase the amplitude and frequency of hGH release within age-related physiologic boundaries.
Thirty-six individuals were evaluated clinically for changes in existing symptomatology and serum IGF-1 levels over a period of 12 weeks while being administered Symbiotropin, a combination or anterior pituitary peptides, sequenced glycoamino acid complex, phamaceutical saccharides, and botanical regulators of insulin and IGF-1. Initial IGF-1 measurements ranged from 21 to 276. Patients were instructed to take two Symbiotropin effervescent tablets dissolved in water four hours after the last meal and prior to retiring. This schedule was maintained in five-day cycles, with two days separating each cycle for a term of twelve weeks. IGF-1 levels were measured before the onset of Symbiotropin therapy and then at four week intervals. Patient self-assessments were performed every four weeks throughout the twelve week term. Additional clinical observations were made during routine office visits. Patient self-assessments in areas of endurance and body composition, hair and skin, sexual function, healing and immunity, and mental function reflect significant improvement in all 23 areas of evaluation, with range of 21% - 74% of patients reporting improvement in these areas. Additional clinical observations reflect significant improvement in blood sugar management in diabetic patients, lowered prostate-specific antigen (PSA), improved cardiac and pulmonary function, blood pressure management, and improvement in menopausal symptoms.
Areas of IGF-1 Activity
Synthesized by Leukocytes Restores Lymphoid Organ Size Stimulates Proliferation of Leukemic Blasts and T Lymphocytes Increases Uptake and Degradation of LDL by Macrophages Estrogens Influence Formation of IGF-1 and IGF-1 BP's Nitrogen Retention/Sodium Excretion Parathyroid-Vitamin D Axis Increased Circulating Osteocalcin Increased Urinary Hydroxyproline Secretion IGF-1 Levels Do Not Exhibit Diurnal Variations IGF-1 Measurements Reflect Integrated GH Secretion and Bioactivity
The results of patient self-assessments indicate symptomatic response to Symbiotropin within the first four weeks in all patients, with continued improvement between the fourth and twelfth week. Improved energy, endurance, and body composition were among the most frequently reported improvements within the first four weeks. New hair growth, restoration of hair color, thickening or skin, and disappearance of skin discoloration generally occurred between the eighth and twelfth weeks, with continued improvement beyond the twelve week term. It should be noted that the results of this patient self-assessment are not adjusted for areas that did not apply to each individual. No side effects were observed that could be attributed to Symbiotropin. One female patient was removed from the study due to a citric acid allergy that was aggravated by Symbiotropin. IGF-1 measurements indicate an overall increase in IGF-1 throughout the twelve week term. Measurements taken during the first four weeks indicate increases of over 200% and averaging over 18%. Eight week measurements indicate increases of over 100% and averaging 24%. Twelve week measurements indicate a 30% average increase in IGF-1. Rate of symptomatic response occurred independent of the rate of IGF-1 increase such that fluctuations in IGF-1 measurements were associated with concurrent symptomatic improvements, even when IGF-1 levels are decreased.
In the case of a 46 year old male, after 6 months of therapy with Symbiotropin, significant reductions in total cholesterol and triglycerides were observed. HDL was also increased by nearly 10%. A 10% increase in HDL has been shown to correlate to a reduction on a cardiovascular mortality by 35%.
In this 41 year old male, significant reductions in elevated liver enzymes were observed with four months of therapy
In the case of a 52 year old female, the left ventricular ejection fraction (LVEF) improved from 15% to 45% after 3 months of therapy. LVEF was evaluated with color Doppler echocardiography.
In a 58 year old female with chronic primary biliary cirrhosis - liver function tests, LDL's, and blood pressure all improved with ten months of therapy
IGF-1 and Prostate Cancer
A recent study presented by Cass Terry, MD analyzed the relationship of IGF-1 levels and prostate cancer in 749 men. Because IGF-1 is mitogenic, and may effect cell differentiation, its role in increasing prostate cancer was evaluated. The incidence of prostate cancer increases with age, whereas blood levels of IGF-1 decline significantly with age, at about 14% per decade after the age of thirty.
This frequency histogram of IGF-1 blood levels includes 593 patients aged 22 to 86 years many of whom were on hGH injections. The dosage ranged from 4-10 IU's per week, in twice daily injections. Mean age of all men was 55.1 years.
This table demonstrates no correlation between IGF-1 and median PSA levels, when comparing the highest and lowest quartiles.
This table grouped PSA levels greater than 4.0 ng/ml, and PSA levels less than 4.1 ng/ml. There was no correlation between PSA and IGF-1 levels in the group of men with a PSA of less than 4.1. In the group of men with PSA levels greater than 4.0, there was a negative correlation between PSA and IGF-1 levels. A significant finding was that the mean IGF-1 levels were essentially the same in both groups, but the median PSA in the group who had PSA levels greater than 4.0 had median PSA levels that were greater than 6 times higher than the group with values less than 4.1.
This graph demonstrates the negative correlation of IGF-1 levels with PSA levels greater than 4.0.
This graph demonstrates no correlation of IGF-1 and levels of PSA less than 4.1 ng/ml.
In this study, circulating IGF-1 levels had no relationship to PSA levels, or prostate cancer. Dr. Terry also reports that in a patient population of approximately 3,000, no increase in prostate cancer, or any other malignancy has been observed in those receiving long-term hGH injections.
Conclusion IGF-1, PSA, and Risk for Prostate Cancer
PSA levels were found to increase with increasing age. As PSA levels increase to levels greater than 4.0 ng/ml, there is a negative correlation of PSA and IGF-1 levels. The PSA levels in this group are greater than 6 times higher than those with levels of PSA less than 4.1 ng/ml. Higher PSA levels correlate with lower IGF-1 levels. In those patients with PSAs less than 4.1 ng/ml, there is no correlation of IGF-1 levels and PSA.
Conclusion: Oral Secretagogues as an Adjunct to Growth Hormone Injections
Many physicians in the United States and abroad are using rhGH injections concomitantly with oral secretagogues. In combination, patients have been able to use lower doses of rhGH, and have reported clinical improvements beyond what they had previously experienced with injections alone. In some cases, rhGH injections are associated with a decrease in IGF-1 as a lean body mass increases. Some of these patients have had to increase the daily dose of rhGH in order to maintain their clinical response as well as IGF-1 levels. These inconsistencies in response to rhGH therapy are thought to be related to developed resistance and receptor site sloughing. hGH therapy has been typically monitored by laboratory analysis with IGF-1. To date, IGF's 2-7 have been identified, but the relative significance of these other insulin growth factors - as they relate to longevity assessments and their individual functions - has not been fully elucidated. Due to the lack of consistent correlation between IGF-1 and symptomatic improvement, patient assessments may allow clinicians to make clearer discernment's about therapeutic recommendations to patients. As an oral secretagogue, Symbiotropin has been found to be a safe and effective hGH therapy capable of improving many of the clinical signs and symptoms associated with the process of aging. It has been found to be profoundly efficacious as a single therapy and as an adjunct to rhGH injections. There are several known factors that effect hGH release and response, including insulin regulation, somatotroph receptors, GHRH, somatostatin, liver function, and IGF-1 receptor sites. Pharmacologically correlating these factors with the action of the anterior pituitary peptides, a sequenced glycoamino acid complex, and botanical regulators of insulin and IGF-1 has led to the development of an effective growth hormone secretagogue therapy. Clinically, the efficacy of Symbiotropin has been verified through IGF-1 measurements and patient assessments.
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RhIGF-1 Administration Many physicians in the United States and abroad are using rhGH injections concomitantly with oral secretagogues. In combination, patients have been able to use lower doses of rhGH, and have reported clinical improvements beyond what they had previously experienced with injections alone. In some cases, rhGH injections are associated with a decrease in IGF-1 as a lean body mass increases. Some of these patients have had to increase the daily dose of rhGH in order to maintain their clinical response as well as IGF-1 levels. These inconsistencies in response to rhGH therapy are thought to be related to developed resistance and receptor site sloughing. hGH therapy has been typically monitored by laboratory analysis with IGF-1. To date, IGF's 2-7 have been identified, but the relative significance of these other insulin growth factors - as they relate to longevity assessments and their individual functions - has not been fully elucidated. Due to the lack of consistent correlation between IGF-1 and symptomatic improvement, patient assessments may allow clinicians to make clearer discernment's about therapeutic recommendations to patients. As an oral secretagogue, Symbiotropin has been found to be a safe and effective hGH therapy capable of improving many of the clinical signs and symptoms associated with the process of aging. It has been found to be profoundly efficacious as a single therapy and as an adjunct to rhGH injections. There are several known factors that effect hGH release and response, including insulin regulation, somatotroph receptors, GHRH, somatostatin, liver function, and IGF-1 receptor sites. Pharmacologically correlating these factors with the action of the anterior pituitary peptides, a sequenced glycoamino acid complex, and botanical regulators of insulin and IGF-1 has led to the development of an effective growth hormone secretagogue therapy. 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