Buy Now

Study - Integrative Med


Rashid A. Buttar, DO, FAAPM, FACAM
Dean C. Viktora, PhD
Michael E. Quinn, EMT-P

As published in the "Journal of Integrative Medicine"

A patient outcome based study was conducted to investigate the possible efficacy of certain somatotroph and hypothalamotroph specific poly-peptide combinants which appear to emulate the action of GHRH resulting in a highly efficacious release of endogenous GH.

Although the GH injections and secretagogues do offer many benefits for the limitations of aging, the need for a safer and more effective modality of therapy has long been warranted.

Of the 35 patients that were started on the study, 30 completed the full study. Groups were divided into sedentary and athletic groups. A total of 22 subjective criteria were monitored including: sense of well being, overall energy, mental clarity, emotional stability, memory improvement, mood improvement, skin thickness, skin elasticity, wrinkle disappearance, new hair growth, skin texture, healing of old injuries, healing of overall injuries, range of motion, incidence of illness, body contour change, facial contour change, sexual frequency, sexual stamina, libido, quality of erection/arousal, and change in nocturia. Objective criteria measured were muscle strength, overall energy, exercise endurance and quality of sleep. Laboratory data consisting of pre- and post- treatment IGF-1 levels and base line chemistries were also obtained. Changes were recorded by a self-assessment methodology utilizing a scale of -5 to +5 with 0 as base line. This accepted modality of evaluation with previous precedent having been set was chosen for this patient outcome based study.

Within the first week, changes experienced were overwhelmingly positive. Improvements were reported of 282.98% in the female subjects and 352.38% in male subjects. Muscle strength increased by 81.0%. Endurance increased by 60.0%. Quality of sleep improved by 92.6%. Overall energy increased by 71.4%. Total mean improvement of all 4 objective criteria increased by 76.6%. Interestingly, the 3 week post study IGF-1 levels dropped 20.39% within both athletic and sedentary study groups with a 27.16% drop in IGF-1 levels in the female patients and a 14.61% drop in IGF-1 levels in the male patient population.

Efficacy based upon subjective criteria was far beyond expectation. Objectively measured increases in muscular strength conclusively show this TD-GHRH-A (trans-dermal GHRH analog) to be clinically superior for resistance training as compared to hGH (Human Growth Hormone) injections. Simplicity of trans-dermal administration also appears to lead to a greater level of patient compliance. Substantial improvements in all criteria are further validation of this TDGHRH- A (brand name Trans-D Tropin®) as not only an effective alternative to hGH (Human Growth Hormone) injections but perhaps a replacement of the more costly, potentially dangerous and less compliant injection treatments. The lack of correlation between clinical improvement and increasing IGF-1 levels als o warrants re-evaluation of our currently accepted understanding of IGF-1. These results strongly warrant further clinical research of this TD-GHRH-A.

The advent of Anti-Aging Medicine and man's long quest for the "Fountain of Youth" have propelled the concept of Longevity from a figment of yesterday's fantasies into a viable and effective medical based science of today. The age-reversal effects of GH (human growth hormone or hGH) injections have been conclusively shown in a number of published studies.1,2,3,28 Efficacy was evidenced by consistent improvement in a variety of subjective and objectively measured factors.33,41,45 These included an increase in lean body mass, decrease in body fat, increase in stamina and endurance, improved cognitive function, improvement in libido, immune enhancement, faster resolution of injuries and various other attributes of youth.46,47,48,57 However, there are numerous side effects with the injection therapies such as joint effusions, cardiomyopathy, peripheral edema, allergic reactions, and decrease in endogenous hGH (Human Growth Hormone) production.1,2,29 In addition, the obvious lack of compliance as with any injection treatment and the high cost associated with treatments, led to the advent and the rapid popularity of the oral growth hormone secretagogues. Although far safer than the injections, the results of the secretagogues are less impressive and far more subtle, sometimes taking more than a few months before changes are noted. Difficulty with achieving consistent results with the secretagogues involve the immense vacillation in gut absorption in our population as well as the necessity of ingesting the secretagogues on a stomach empty for 4 hours. These issues lead to a great variability in absorption and compliance, and thus in efficacy of the secretagogues.

The numerous potential benefits associated with GH (human growth hormone or hGH) treatment have generated a number of studies on variable anti-aging treatments and extensive research to further the understanding of the aging process. Simply to extend life is no longer the challenge, but rather to improve the duration of life as well as the quality of that extended life. The answer that we seek as clinicians is how to effectively inhibit, or at least slow down this aging process and thus prevent the associated debilitating limitations which are accepted by society as being inevitable as we grow older.1,3,6,48,57

Although the GH injections and secretagogues do offer many benefits to counteract these limitations associated with aging,3,48,57 the need for a safer and more effective modality of therapy has been warranted.1 The necessity for a therapy offering a greater spectrum of results, providing an accelerated and rapid onset of subjective and objectively measurable efficacy, with a safer profile, a more efficient delivery mechanism, and an ease of administration leading to better patient compliance has led to the advent of Trans-D Tropin®

Trans-D Tropin® is a unique combination of a number of various multi-chained somatotroph-specific and hypothalamotroph-specific15 poly-peptide combinants, synthesized together with an isolated complex of plant derived supporting precursors. The active polypeptide combinants are designed with the goal to mimic GHRH (GH releasing hormone) action.28,29 The result is a unique GHRH analog which results in potentiation and release of endogenous GH.4,26,29 The final substance is then synthesized into a proprietary base of essential fatty acids16 known as EvitoTM, a technologically advanced mechanism of trans-dermal delivery.25

The trans-dermal delivery mechanism allows frequent dosing up to 4 times daily21,61 without compliance being an issue. This method of delivery allows for rapid onset of action and provides a means by which the body's own natural response can be mimicked. The small but frequent pulsatile stimulation by this unique poly-peptide complex referred to as a GHRH analog (Trans-D Tropin®), imitates the body's natural mechanism of releasing GHRH and results in an effective and superior release of endogenous GH.18,26,27

The majority of patients on GH injections achieve a less than satisfactory response to therapy within the first few months due to inhibition of GH responsiveness to GHRH.7,8,9,14,17,24 As a result, a short duration study was determined to be the most accurate method of ascertaining the rapid efficacy of this GHRH analog as compared to GH injection therapy as well as the lesser effective and over sensationalized oral secretagogues. The patients chosen for the study were divided into two groups. The first group was comprised of well trained, conditioned athletes and the second comprised of average activity to sedentary individuals. Ages varied from 25 to 85 years of age. The wellconditioned athletic group was chosen based upon level of physical fitness and a history of consistently high intensity athletic activity, for a minimum of 12 consecutive months prior to onset of the study. All but two patients in this category were competitive power lifters, body builders, or professional athletes.

All subjects had preliminary IGF-1 levels measured. Most were within the normal reference range for their respective ages but a few were well below the normal values. In addition, baseline chemistries with liver functions, cholesterol and triglycerides were measured. The "n" number for this preliminary study was 30 with a total of 14 men and 16 women. A multi-centered study with a much larger "n" has been initiated.

The athletic group was anticipated to be the least responsive group since attaining a rapid response in a trained and conditioned athlete is a significantly more difficult outcome to achieve.5,6,10,52 This may be due to higher levels of circulating GH found in athletes due to the exercise induced effects.5,6,10,48,52,57 The older group was selected since GH levels begin decreasing noticeably as we age.6,7,8,10 The result is 40% of all individuals over the age of 60 years are deficient in GH and are suffering from various sequelae of GH33,58 deficiency usually attributed to aging.2,3,29,41,42,43,44,49

However, as previous studies have already established, the level of circulating GH may not be as important as establishing GH responsiveness to GHRH.7,8,9,14,17,24 The decrease in responsiveness of GH as we age may be due to insufficient GHRH secretion or possibly by a change in regulation of somatostatin (a GH antagonist).13,15,19 It appears that this dysfunction at the pituitary-hypothalamic axis is where the effects of this GHRH analog seems to be most apparent9,17

All study subjects were provided with a detailed log sheet and required to document all changes for each criteria on a scale of -5 to +5 with 0 being no change and +5 being maximum improvement. Since all study patients showed a net positive effect, the negative scale on the graphs is not displayed. Baseline for all criteria was zero at the initiation of the study. This methodology of assessment for a clinical study by ranking positive and negative changes on a +5 to -5 scale is an accepted modality of evaluation with previous studies having set the precedent.20

Study subjects applied a specified number of drops 3 times a day on the flexor surface of the forearms with a number of days off per week.18,21,22,29,61 Times of application corresponded to the natural release of GHRH in humans.21,22,29 The study was designed to show the accelerated changes within the first 3 weeks of usage but due to the rapid results seen within just a few days, the study duration was changed. All subjective data was recorded at 12 hour intervals with study duration being 84 hours (7 data samplings).

Study subjects applied a specified number of drops 3 times a day on the flexor surface of the forearms with a number of days off per week. Times of application corresponded to the natural release of GHRH in humans. The study was designed to show the accelerated changes within the first 3 weeks of usage but due to the rapid results seen within just a few days, the study duration was changed. All subjective data was recorded at 12 hour intervals with study duration being 84 hours (7 data samplings).

The subjective criteria that patients were required to record included the following: sense of well being, overall energy, mental clarity, emotional stability, memory improvement, mood improvement, skin thickness, skin elasticity, wrinkle disappearance, new hair growth, skin texture, healing of old injuries, healing of overall injuries, range of motion, incidence of illness, body contour change, facial contour change, sexual frequency, sexual stamina, libido, quality of erection/arousal, and change in nighttime urination.3 The major objective criteria measured was muscle strength, but overall energy, exercise endurance and quality of sleep were also objectively measured.

Lastly, to rule out or minimize placebo affect, the number of repetitions of the last set during exercise was used as a measurement of improvement as opposed to maximum lift capacity. Although all the study subjects dramatically increased their maximum lift capacities, the number of repetitions of the last set (performed at a higher weight) were deemed to be more significant since placebo effects are usually not reproducible. The logic used was that it would be difficult to attribute an increase in strength by 50 lbs. in a specific exercise to a placebo effect when the exercise was performed for 10 to 12 repetitions.

The noticeable improvement in all criteria monitored reveals the true benefits of increasing endogenous GH production and its effect on increasing GH responsiveness to GHRH.7,8,9,14,17,24 An important benefit associated with effective increase in GH levels and the subsequent reversal of the aging process is actually a sequelae of the natural upregulation of all the various hormonal levels.11,12,41,44 Clinical confirmation was established during the study by changes in such criteria as libido, sleep and stamina.

Graph A indirectly depicts the improvement in many of these secondary hormonal responses. All changes in subjective and objective criteria that were monitored and measured in the form of patient experience within the first 84 hours of treatment are represented below with the plotted values detailed and explained.

Means of All Individual Criteria per Sex
12 H 24 H 36 H 48 H 60 H 72 H 84 H
F 15.67 14.33 30.67 33.33 35.33 43.33 44.33
M 14.00 26.33 34.33 35.33 37.00 38.67 49.33

Total improvement per patient was summed and negative changes subtracted from the total, per time period. This number represented the total sum of changes experienced by each individual study patient. The numbers generated (representing each patient's total net improvement) were then combined to obtain the mean of all study patients per time period with the calculated values plotted below by sex.

Overall Changes in Males/Females

The mean overall improvement measured by changes experienced by the study group from 12 hours post onset of study to 84 hours post onset of study increased substantially, with a 282.98 % change in female test subjects and 352.38 % change in male test subjects. The change experienced was overwhelmingly positive.

Objective Change in All Patients

Graph B depicts the sum totals for all four specific objective criteria per 12 hour time period as represented by one data point per time period. Each data point represents two objectively measured quantitative criteria, specifically muscle strength and exercise endurance, as well as two qualitative objective criteria, specifically quality of sleep and overall energy.

The data (plotted on Graph B) shows the mean improvement measured from 12 hours to 84 hours post onset of study to have also increased substantially. Changes were as follow: Muscle strength increased by 81.0%. Endurance increased by 60.0%. Quality of sleep improved by 92.6%. Overall energy increased by 71.4%. Total mean improvement of all 4 objective criteria increased by 76.6%. It is important to note that this percent change (increase) does not reflect the initial changes that became evident within the first 12 hours of initiating treatment.

Sum Totals for All Objective Criteria
12 H 24 H 36 H 48 H 60 H 72 H 84 H
Strength 4 11 15 16 20 24 21
Energy 10 12 19 19 21 19 25
Enduranse 2 11 18 19 22 26 27
Sleep 6 15 17 19 19 21 21
Totals 22 49 69 73 82 90 94

Initial and three week post treatment IGF-1 levels and chemistries (comprehensive metabolic profile) were drawn to assess improvements in glucose stabilization, as well as cholesterol / triglyceride levels to further delineate objective improvements. An interesting observation was noted in the pre-study IGF-1 levels obtained in the conditioned athletic group compared to the sedentary patient population, contradicting the conventionally accepted principals regarding the interrelationship between GH and IGF-1 levels. This observation was further substantiated with the post study IGF-1 levels obtained 3 weeks after treatment was initiated.

The oldest patient in the conditioned athletic group was 38 years old. All were in excellent health and medical condition. Conversely, the sedentary group ranged in ages from 32 to 85 years old with variable health, some with extensive medical conditions. Yet, in overall comparison, the sedentary patient population had a statistically significant higher measurement of pre-study IGF-1 levels than the athletic group.

The highest IGF-1 level measured in the athletic group was only 196 ng/ml. In comparison, a few patients in the sedentary group had IGF-1 levels in the 200 to 300 ng/ml levels with the highest measured at 304 ng/ml.

Yet, the sedentary group represented a mean patient population far older than that of the athletic group. In general, the female patients appeared to have a slightly higher mean IGF-1 level in both patient populations.

Pre and Post IGF-1 Levels

The 3 week post study IGF-1 levels, on the average, dropped across the board in both the athletic and sedentary study groups. The female pre-study IGF-1 mean was 186.3 ng/ml and decreased to a post-study IGF-1 mean of 137.5 ng/ml, representing a 27.16% drop in IGF-1 levels in approximately a 3 week period. The same observation in the males of both study groups was also noted, with a pre-study IGF-1 mean of 159.7 ng/ml decreasing to a post-study IGF-1 mean of 136.3 ng/ml, representing a 14.61% drop in IGF-1 levels in the same time period. The overall drop in IGF-1 levels was 20.39% within both study groups.

Percent Drop in IGF-1 Levels

The effects of GH do not appear to alter the pituitaryhypothalmic axis at the blood chemistry level.The preliminary data accumulated during this study further indicates the unreliability of IGF-1 levels as a predictor of GH treatment efficacy.34,35,53,54 Further review of the literature supports an inverse correlation between GH levels and IGF-1 levels.31,32,36,37,39 Only one reference was found showing an increase in IGF-1 after GH therapy but only after 6 to 12 months of treatment.60

A possible correlation between stress and lower levels of IGF-1 became apparent as the data accumulated. Individuals found to be under significant mental and emotional stress (life style or vocational factors), who subjected their bodies to a higher level of physical stress (athletes or body builders under caloric restrictions) and those suffering from chronic pain or depression, were noted to have the lowest measured IGF-1 levels. This observation is further evidenced and extensively supported in the literature.30,43,44,50,51,55

The last set of graphs displayed in the next column represent the changes in the objective criteria for a typical study patient from each of the two test groups. The first patient, representing the older, sedentary test group was a 65 year old, obese male with severe atherosclerotic coronary artery disease and a history of multiple myocardial infarctions in the past. The second patient, representing the trained, conditioned athletic test group was a 30 year old male with no previous medical history and with a 15 year history of lifting weights. Further review of the patient's history revealed a use of amphetamines to facilitate workouts and steroid use 2 years prior to the onset of the study.

The information presented in the above graphs clearly displays an accelerated rate of response to Trans-D Tropin® in both patient subjects. In addition, the recovery time post exercise was substantially decreased in both patients, especially in the 65 year old, obese male with a history of multiple myocardial infarctions. Prior to therapy, onset of angina occurred within 7 to 10 minutes of initiating exercise activity on a treadmill. Within the first three weeks of treatment, exercise tolerance substantially increased to 35 minutes of the same type activity on the treadmill with no evidence of angina. This clinical observation attributed to increased GH levels was further supported in the literature.46,47,56 In the "Overall Energy" graph, it should also be noted that the drop at 72 hours in the conditioned athlete was secondary to the patient having missed three doses at the 72 hour time period (two doses before and one dose after). However, as evident on the graph, recovery of overall energy was virtually immediate once treatment was resumed.

Although of less significance from a medical standpoint, there were a number of aesthetic improvements noted among the great majority of study subjects within the first 10 to 14 days after beginning treatment with this GHRH analog. Despite one patient who had a noticeable change in facial wrinkles around the eyes within 3 days after initiating treatment, most physical changes were not evident within the first 84 hours by the majority of study subjects.

However, almost all noted either a facial and/or body contour change within the first 21 days after initiating treatment . All subjects over the age of 25 noted some type of improvement in skin texture described either as "tightening" or a decrease in "flabbiness" in areas such as the facial cheeks, under the chin, upper arms (older females especially), hips, thighs and abdominal areas. Within 30 days, all obese patients experienced loss of inches in various areas without any significant change in exercise routine or lifestyle modification.

Other changes noted that were felt to be of significance included the resolution of chronic debilitating injuries such as shoulder and low back injuries (in 3 cases the injuries were refractory to multiple treatment modalities, each over a period of 2 years or more). In addition, improvement in hormonal imbalances (hot flashes refractory to treatment), menstrual pain, libido, range of motion and accelerated healing of recent wounds with minimal scarring were noted.

No side effects were reported. However, onset of acne was noted in a number of patients which was attributed to physiological changes consistent with reestablishinga younger biological age closer to adolescence. An increase in nocturnal micturition was also noted in most study subjects but an increased consumption of water was found to be the etiology of the polyuria. Virtually all patients described an increased craving for water and protein within the first few days of treatment. In light of the increase in metabolism and the decrease in body fat experienced by the study subjects, the increase in water and protein consumption is a logical conclusion. Water is the most abundant substrate and protein is life's building block, both found in all living organisms and essential for existence.

The physiological changes attained with Trans-D Tropin® up to this point, have been unprecedented. Efficacy was far beyond expectation. Response was not secondary to increase in sympathetic tone as evidenced by all patient's vital signs remaining well within normal range. Furthermore, although an increase in energy was noted, a marked improvement in quality of sleep was experienced throughout the study group, despite taking the last daily dose immediately prior to bedtime, indicating that energy increase was not due to sympatheto-mimetic changes.

The significance of this study's results become more dramatic when the relatively short time period is considered in which the levels of improvement were attained.21In addition, it appears that just the simplicity of trans-dermal administration would in itself, lead to a greater compliance and improved treatment efficacy.24

The preliminary results of this study warrant further research to assess the various medical applications in which Trans-D Tropin® administration may offer a greater benefit compared to GH injections. Further clinical trials are necessary to determine the efficacy of this GHRH analog in diabetes, atherosclerosis3, HTN, chronic injuries41, GI disorders45, obesity, cognitive dysfuntion58, compromised immunity33,44, chronic medial conditions1,2 and critically ill patients.49

All patients experienced rapid improvements in a relatively short period of time. Yet, the unexpected and sustained drop in IGF-1 levels in virtually all patients in the study was diametrically opposed to the generally expected increase in IGF-1 levels. The consistent lack of correlation between clinical improvement and increasing IGF-1 levels warrants further research and re-evaluation of our currently accepted understanding of IGF-1 levels34,35,40,53,54

The objectively measured increase in muscular strength conclusively shows this GHRH analog to be clinically superior in maximizing all aspects of resistance training (as in power lifting and body building) as well as significantly improving endurance and recovery time compared to hGH (Human Growth Hormone) injections. The rapid and substantial improvements in all other criteria are further validation of Trans-D Tropin® as not only an effective alternative to hGH (Human Growth Hormone) injections but perhaps a replacement of the more costly, potentially dangerous and less compliant injection treatments.

At the one year post study interval, nine of the original 30 patients were lost to follow-up. Of the remaining 21 patients, 17 patients were found to have continued using Trans-D Tropin®. All 17 patients reported continued improvement in all subjective responses monitored. All patients reported experiencing further changes which included facial contour and body contour changes, as well as changes in skin, hair and peripheral adipose distribution. Of these 17 patients who continued treatment, 11 still participated in a regular exercising regimen. Two of the patients reported adverse outcomes consisting of comedogenic lesions and the return of menstrual flow in a post-menopausal female patient. However, both findings are consistent with and indicative off a reversion to that of a younger physiological state.

Preliminary results of a multi-centered, double blind, placebo controlled, cross-over study conclusively demonstrate the efficacy of this trans-dermal GHRH analog. Serial serum hGH (Human Growth Hormone) radio-immuno assay levels were measured from baseline to 90 minutes post Trans-D Tropin® administration with interval measurements at 30 minutes and 60 minutes post treatment. Measurements were taken at treatment initiation, with subsequent measurements at week 2, week 5 and week 8. Control group was then crossed over into the experimental group.

An average increase of 462% in endogenous hGH (Human Growth Hormone) levels was noted at 90 minutes, compared to baseline during initial treatment. Within 5 weeks of treatment initiation, the response of endogenous hGH (Human Growth Hormone) increased to 1754% at 90 minutes post treatment, compared to baseline using this trans-dermal GHRH analog.

Other interesting objective observations were also noted, indicating the need for revision of our current understanding regarding GH replacement therapy. Cortisol levels and IGF-1 levels consistently dropped in the experimental (trans-dermal GHRH analog) group. The final results of this study will be released upon completion. Multiple other studies are already underway to further assess the efficacy of this transdermal GHRH analog, which shows promise as an effective method of increasing endogenous GH levels.

  1. Rattan SI: Is gene therapy for aging possible? Indian Journal of Experimental Biology 1998 March; 36(3): 233-236.
  2. Hakkaart-Van RL, Roijen L, et al: The burden of illness of hypo-pituitary adults with growth hormone deficiency. Pharmacoeconomics 1998 October; 14(4): 395-403.
  3. Barry MC, Mealy K, et al: Nutritional, respiratory, and psychological effects of recombinant human growth hormone in patients ndergoing abdominal aortic aneurysm repair. Journal of Parenteral and Enteral Nutrition 1999 May-June; 23(3): 128-135.
  4. Hendrix DK, Klien TE, Kuntz ID: Macromolecular docking of a three-body system: the recognition of human growth hormone by its receptor. Protein Science 1999 May; 8(5): 1010- 1022.
  5. Marcell TJ, Wiswell RA, Hawkins SA, et al: Age-related blunting of growth hormone secretion during exercise may not be soley due to increased somatostatin tone. Metabolism 1999 May; 48(5): 665-670.
  6. Giusti M, Marini G, Sessarego P, et al: Effect of cholinergic tone on GHRH induced secretion of growth hormone in normal aging. Aging 1992 September;4(3): 231-237.
  7. Giusti M, Marini G, Sessarego P, et al: GH secretion in aging. Effect of pyridostigmine on growth hormone responsiveness to growth hormone-releasing hormone. Recenti Progress Medicine 1991 December; 82(12): 665-668.
  8. Ghigo E, Goffi S, Arvat E, et al: Pyridostigmine partially restores the GH responsiveness to GHRH in normal aging. Acta Endocrinology (Copenh) 1990 August; 123(2): 169-73.
  9. Jaffe CA, DeMott-Friberg R, et al: Endogenous GHRH is required for GH responses to pharmacological stimuli. Journal of Clinical Investigation 1996 February 15;97(4): 934-940.
  10. Pyka G, Wiswell RA, Marcus R: Age-dependent effect of resistance exercise on growth hormone secretion in people. Journal of Clinical Endocrinology and Metabolism 1992 August; 75(2): 404-407.
  11. Coiro V, Volpi R, Capretti L, et al: Age-dependent decrease in the GH response to GHRH in normally cycling women. Fertility, Sterility 1996 August; 66(2): 230-234.
  12. Spoudeas HA, Matthews DR, Brook CG, et al:The effect of changing somatostatin tone on the pituitary GH and TSH responses to their
    respective releasing factor stimuli. Journal of Clinical Endocrinology and Metabolism 1992 August; 75(2): 453-458.
  13. Kelijman M, Frohman LA: Impaired inhibitory effects of somatostatin on GHRH stimulation of GH secretion after short term infusion. Journal of Clinical Endocrinology and Metabolism 1990 July; 71(1): 157-163.
  14. Giustina A, Bossoni S, Bodini C, et al: The role of cholinergic tone in modulating the GH response to GHRH in normal man. Metabolism 1991 May; 40(5): 519-523.
  15. Ross RJ, Tsagarakis S, Grossman A, et al: GH feedback occurs through modulation of hypothalamic somatostatin under cholinergic
    control: studies with pyridostigmine and GHRH. Clinical Endocrinology (Oxf) 1987 December; 27(6): 727-733.
  16. Pontiroli AE, Lanzi R, Monti LD, et al: GH autofeedback on GH response to GHRH. Role of free fatty acids and somatostatin. Journal of Clinical Endocrinology and Metabolism 1991 February; 72(2): 492-495.
  17. Vance ML, Kaiser DL, et al: Dual effects of GHRH infusion in normal men: somatotroph desensitization and increase in releasable GH. Journal of Clinical Endocrinology and Metabolism 1986 March; 62(3): 591-594.
  18. Jaffe CA, Ho PJ, et al: Effects of a prolonged GHreleasing peptide infusion on pulsatile GH secretion in normal men. Journal of Clinical Endocrinology and Metabolism 1993 December; 77(6): 1641-1647.
  19. Martha PM Jr, Blizzard RM, et al: A persistent pattern of varying pituitary responsivity to GHRH in GH-deficient children: evidence supporting periodic somatostatin secretion. Journal of Clinical Endocrinology and Metabolism 1988 September; 67(3): 449-454.
  20. Khalsa, DS: Exelon: A new drug for Alzheimer's Disease. International Journal of Anti-Aging Medicine 1998 June (Premier Issue); 1(1): 54-46.
  21. Spoudeas HA, Winrow AP, et al: Low-dose GHRH tests: a dose-response study. European Journal of Endocrinology 1994 September; 131(3): 238-245.
  22. Casanueva FF, Burguera B, et al: Depending on the time of administration, dexamethasone potentiates or blocks GHRH-induced GH. Neuroendocrinology 1988 January; 47(1): 46-49.
  23. Barbarino A, Corsello SM, et al: Corticotropinreleasing hormone inhibition of GHRH-induced GH release in man. Journal of Clinical Endocrinology and Metabolism 1990 November; 71(5): 1368-1374.
  24. Giustina A, Doga M, Bodini C, et al: Acute effects of cortisone acetate on GH response to GHRH in normal adult subjects. Acta Endocrinol (Copenh) 1990 February; 122(2): 206-210.
  25. Evans WS, Vance ML, Kaiser DL, et al: Effects of IV, SQ, and intranasal administration of GHRH-40 on serum GH concentration in adult men. Journal of Clinical Endocrinology and Metabolism 1985 November; 61(5): 846-850.
  26. Gupta SK, Krishnan RR, Ellinwood EH, et al: Pharmacokinetics of GH secretion in humans induced GHRH. Life Sciences 1990; 47(21): 1887-1893.
  27. Vance ML, Kaiser DL, Evans WS, et al: Evidence for a limited GHRH-releasable quantity of GH: effects of 6-hour infusions of GHRH on GH secretion in normal man. Journal of Clinical Endocrinology and Metabolism 1985 February; 60(2): 370-375.
  28. Low LC: GHRH clinical studies and therapeutic aspects. Neuroendocrinology 1991; 53 Suppl 1: 37-40.
  29. Review of Medical Physiology, 15th Edition, by Ganong, WF, Lange, J, et al. Appleton & Lange, © 1991, Ch 14, pg 214 - 236 and Chapter 20, pages 350-352.
  30. Mazzoccoli G, Giuliani A, Bianco G, et al: Decreased serum levels of insulin-like growth factor (IGF)-I in patients with lung cancer: temporal relationship with (GH) levels. Anticancer Research 1999 March/April; 19(2B): 1397-9.
  31. Norrelund H, Fisker S, Vahl N, et al: Evidence supporting a direct suppressive effect of growth hormone on serum IGFBP-1 levels. Growth Horm IGF Res (Denmark) 1999 February; 9(1): 52-60.
  32. Borges MH, Pinto AC, DiNinno FB, et. al: IGF-I levels rise and GH responses to GHRH decrease during long-term prednisone treatment in man. Journal of Endocrinological Investigation 1999 January; 22(1): 12-7.
  33. Gelato MC: Aging and immune function: a possible role for growth hormone. Hormonal Research 1996; 45(1-2): 46-9.
  34. Furlanetto RW: Insulin-like growth factor measurements in the evaluation of growth hormone secretion. Hormonal Research 1990;33 Suppl 4:25-30.
  35. Kawai N, Kanzaki S, Takano-Watou S, et al: Serum free insulin-like growth factor I (IGF-I), total IGF-I, and IGF- binding protein-3
    concentrations in normal children and children with growth hormone deficiency. Journal of Clinical Endocrinology and Metabolism 1999 January; 84(1): 82-9.
  36. Yohay D, Lunenfeld E, Giat Y, et al: Do changes in growth hormone levels correlate with IGF-I levels in patients undergoing IVF-ET? Gynecological Endocrinology 1997 August; 11(4): 269-74.
  37. Jorgensen JO, Pedersen SB, Borglum J, et al: Serum concentrations of insulin-like growth factors (IGFs), IGF binding proteins 1 and 3 and growth hormone binding protein in obese women and the effects of growth hormone administration: a double-blind, placebo- controlled study. European Journal of Endocrinology 1995 July; 133(1): 65-70.
  38. Chapman IM, Hartman ML, Pieper KS, et al: Recovery of growth hormone release from suppression by exogenous insulin-like growth factor I (IGF-I): evidence for a suppressive action of free rather than bound IGF-I. Journal of Clinical Endocrinology and Metabolism 1998 August; 83(8): 2836-42.
  39. Murphy LJ, Seneviratne C, Moreira P, et al: Enhanced expression of insulin-like growth factorbinding protein-I in the fasted rat: the effects of insulin and growth hormone administration. Endocrinology 1991 February; 128(2): 689-96.
  40. Juul A, Andersson AM, Pedersen SA, et al: Effects of growth hormone replacement therapy on IGF-related parameters and on the pituitarygonadal axis in GH-deficient males. A doubleblind, placebo-controlled crossover study. Hormonal Research 1998; 49(6): 269-78.
  41. Rooyackers OE, Nair KS: Hormonal regulation of human muscle protein metabolism. Annual Review in Nutrition 1997 Annual; 17: 457-485.
  42. Attard-Montalto SP, Camachoo-Hubner C, Cotterill AM: Changes in protein turnover, IGF-1 and IGF binding proteins in children with cancer. Acta Paediatrica 1998 January; 87(1): 54-60.
  43. Chwals WJ, Bistrian BR: Role of exogenous GH and IGF-1 in malnutrition and acute metabolic stress: a hypothesis. Critical Care Medicine 1991 October; 19(10): 1317-1322.
  44. Malarkey WB, Burleson M, Cacioppo JT, et al: Differential effects of estrogen and medroxyprogesterone on basal and stress-induced growth hormone release, IGF-1 levels, and cellular immunity in postmenopausal women. Endocrine 1997 October; 7(2): 227-233.
  45. Balteskard L, Unneberg K, Mjaaland M, et al: GH and IGF-1 promote intestinal uptake and hepatic release of glutamine in sepsis. Annals of Surgery 1998 July; 228(1): 131-139.
  46. Isgaard J, Tivesten A, Friberg P, et al: The role of the GH / IGF-1 axis for cardiac function and structure. Hormonal Metabolism Research 1999 February-March; 31(2-3): 50-54.
  47. Cittadini A, Longobardi S, Fazio S, et al: Growth hormone and the heart. Miner Electrolyte Metabolism 1999 January-April; 25(1-2): 51-55.
  48. Bates AS, Evans AJ, Jones P, et al: Assessment of GH status in adults with GH deficiency using serum GH, serum IGF-1 and urinary GH excretion. Clinical Endocrinology 1995 April; 42(4): 425-430.
  49. Wolf SE, Barrow RE, Herndon DN: GH and IGF- 1 therapy in the hypercatabolic patient. Baillieres Clinical Endocrinology Metabolism 1996 July; 10(3): 447-463.
  50. Ferraccioli G, Guerra P, Rizzi V, et al: Somatomedin C (IGF-1) levels decrease during acute changes of stress related hormones. Relevance for fibromyalgia. Journal of Rheumatology 1994 July; 21(7): 1332-1334.
  51. Farmer C, Dubreuil P, Couture Y, et al: Hormonal changes following an acute stress in control and somatostatin-immunized pigs. Domestic Animal Endocrinology 1991 October; 8(4): 527-536.
  52. Hagberg JM, Seals DR, Yerg JE, et al: Metabolic responses to exercise in young and older athletes and sedentary men. Journal of Applied Physiology 1988 August; 65(2): 900-908.
  53. McCusker RH: Controlling IGF activity and the modulation of IGF binding protein and receptor binding. Journal of Dairy Science 1998 June; 81(6): 1790-1800.
  54. Aimaretti G, Corneli G, Razzore P, et al: Usefulness of IGF-1 assay for the diagnosis of GH deficiency in adults. Journal of Endocrinology Investigation 1998 September; 21(8): 506-511.
  55. Houston-Bolze MS, Downing MT, Sayed AM, et al: Serum IGF binding protein-3 responds differently to trauma in men and women. Critical Care Medicine 1996 December; 24(12): 1988- 1992.
  56. Stromer H, Cittadini A, Douglas PS, et al: Exogenously administered GH and IGF-1 alter intracellular Ca2+ handling and enhance cardiac performance. In vitro evaluation in the isolated isovolumic buffer-perfused rat heart. Critical Research 1996 August; 79(2): 227-236.
  57. Kozakowski J, Adamkiewicz M, Krassowski J, et al: The beneficial effects of GH replacement therapy on elderly men. Polish Merkuriusz Lek 1999 March; 6(33): 131-134.
  58. Rollero A, Murialdo G, Fonzi S, et al: Relationship between cognitive function, GH and IGF-1 plasma levels in aged subjects. Neuropsychobiology 1998; 38(2): 73-79.
  59. Girard N, Boulanger L, Denis S, et al: Differential in vivo regulation of the pituitary GHRH (GH releasing hormone) receptor by GHRH in young and aged rats. Endocrinology 1999 June; 140(6): 2836-2842.
  60. Carani C, Granata AR, De Rosa M, et al: The effect of chronic treatment with GH on gonadal function in men with isolated GH deficiency. European Journal of Endocrinology 1999 March; 140(3): 224-230.
  61. Bulow B, Erfurth EM: A low individualized GH dose in young patients with childhood onset GH deficiency normalized serum IGF-1 without significant deterioration in glucose tolerance. Clinical Endocrinology 1999 January; 50(1): 45- 55.
  62. Janssen YJ, Helmerhorst F, Frolich M, Roelfsema F, et al: A switch from oral (2 mg/day) to transdermal (50 micro/day) 17 beta-estradiol therapy increases serum IGF-I levels in recombinant hGH (Human Growth Hormone) substituted women with GH deficiency. Journal of Clinical Endocrinology and Metabolism 2000 January 85 (1): 464-466.
  63. Inuki T, Takanashi K, Takebayashi K, Fuiwara Y, Tayama K, Takemura Y, et al: Thyroid hormone modulates insulin-like growth factor-1(IGF-1) and IGF-binding protein-3, without mediation by growth hormone, in patients with autoimmune thyroid disease. Metabolism Research 1999 October 31 (10): 576 – 579.
  64. Yaker S, et al: Normal growth and development in the absence of hepatic IGF-1. Proc. Natl. Acad. Sci. USA 1999; 96: 7324-7329.
  65. Ohlsson C, Sjogren K, Jansson JO and Isaksson OG: The relative importance of endocrine versus autocrine/paracrine IGF-1 in the regulation of body growth. Pediatric Nephrology 2000;14: 541-543.
  66. Cohen, Pinchas, et al. Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins in primary cultures of prostate epithelial cells. Journal of Clinical Endocrinology and Metabolism 1991;73(2): 401-407.
  67. Rosenfeld, RG, et al. Insulin-like growth factor binding proteins in neoplasia (meeting abstract). Hormones and Growth Factors in Development and Neoplasia, Fogarty International Conference 1995 June 26-28, Bethesda, MD: 24.
  68. Lippman, Marc E. The development of biological therapies for breast cancer. Science 1993 January 29;259: 631-632.
  69. Papa, Vincenzo, et al. Insulin-like growth factor-I receptors are overexpressed and predict a low risk in human breast cancer. Cancer Research 1993;53: 3736-3740.
  70. Chan, June M., et al. Plasma insulin-like growth factor I and prostate cancer risk: a prospective study. Science 1998 January 23; 279: 563-566
  71. Stoll, BA. Breast cancer: further metabolicendocrine risk markers? British Journal of Cancer 1997;76(12): 1652-1654.
  72. LeRoith, Derek, et al. The role of the insulin-like growth factor-I receptor in cancer. Annals New York Academy of Sciences 1995 September 7;766: 402-408.
  73. Mantzoros, CS, et al. Insulin-like growth factor 1 in relation to prostate cancer and benign prostatic hyperplasia. British Journal of Cancer 1997; 76(9): 1115-1118.
  74. Cascinu, S., et al. Inhibition of tumor cell kinetics and serum insulin growth factor I levels by octreotide in colorectal cancer patients.
    Gastroenterology 1997 September;113: 767-772.
  75. Yu, Herbert and Rohan, Thomas. Role of Insulin- Like Growth Factor Family in Cancer Development and Progression. Journal of the National Cancer Institute 2000 September 20; 92(18): 1472- 1489.

Rashid A. Buttar, DO, FAAPM, FACAM practices preventive medicine as well as emergency medicine. He is the medical director of Advanced Concepts in Medicine, a Preventive Medicine Clinic in Charlotte, NC specializing in the care of patients who have failed conventional medical treatments. Dean C. Viktora, PhD is a biochemist and biochemical engineer with a strong interest in clinical nutrition. Michael E. Quinn is an EMT-paramedic who serves as a research assistant for Dr. Buttar and Dr. Viktora in their clinical research.

Philadelphia Seminar