Sermorelin as an Alternative to hgh for Treating GH Insufficiency of Aging

Transcription

1 Sermorelin as an Alternative to hgh for Treating GH Insufficiency of Aging Richard F. Walker, Ph.D., R.Ph., Executive Director, Society for Applied Research in Aging (SARA) (

2 SOMATOPAUSE Aging results in reduced production and secretion of growth hormone relative to that which occurs in youth. The primary cause for age-related growth hormone insufficiency is progressive failure of pituitary function resulting in reduced production and secretion of hgh. Reduced hgh leads to diminished production of IGF-1 by the liver. This is a secondary effect! Progressive pituitary failure can be measured by provocative testing as shown in the next slide.

3 AGE CHANGES IN THE GH NEUROENDOCRINE AXIS Serum GH (ng/ml) Stimulated Growth Hormone < Serum IGF-1 (ng/ml) Insulin-Like Growth Factor < > 60 GHRH Time (minutes) Age (Years)

4 Clinical Concomitants of the Somatopause Altered body composition -Fat mass increased -Lean body mass decreased -Skeletal muscle strength decreased Bone mineral density decreased Lipid metabolism abnormal Insulin resistance and abnormal glucose metabolism Diminished quality of life

5 Since acquired GHD during aging resembles pathogenic GHD, which responds favorably to replacement therapy, recombinant hgh has been used to oppose clinical symptoms of the Somatopause by restoring optimal concentrations of hormones and thereby some semblance of a youthful physiology The basis for using hgh in Anti-Aging medicine is legitimate clinical data administration of growth hormone to elderly but otherwise healthy men restored youthful characteristics of body composition Rudman D, Feller AG, Nagraj HS. Effects of human growth hormone in men over 60 years old. New England Journal of Medicine 1990; 323:1-6

6 However there are problems with hgh replacement therapy Efficacy and Safety Concerns Naturally occurring rhythms of hgh secretion are not simulated by rhgh Interactions with other hormones and essential substances are not regulated by physiological feedback mechanisms Failure to accurately determine individual dosage requirements is a safety risk Higher functions (pituitary) of the hgh neuroendocrine axis are not preserved Federal law prohibits dispensing hgh off-label.

7 Growth Hormone Secretory Episodes Decline During Aging Ultradian rhythm in GH secretion absent Low amplitude in partial GHD Attenuated in GHND High amplitude and obvious in young control subjects

8 Age-Related Decline in Episodes of Spontaneous GH Secretion Contribute to Sequelae of Acquired hghd but are not Opposed by rhgh Replacement Therapy young old Sonntag et al., 2001 JAAM 4:311

9 rgh Replacement Causes Non-Physiologic/Square Wave Presentation of the Hormone to Target Tissues Eventually Resulting in Tachyphylaxis Serum GH remains above peak physiological levels for hours Excretory profiles are not stable Non-physiological tissue exposure to GH Monomura et al. Endo J 47 (1):97-101, 2000

10 GH SECRETAGOGUES SUCH AS SERMORELIN RESTORE GH SECRETORY EPISODES LOST DURING AGING GH displays ultradian rhythmic release in youth GH secretory episodes are blunted during aging GH secretagogues restore youthful patterns of GH release

11 Sermorelin versus hgh Sites of Action Brain Liver hgh Pituitary Sermorelin Sermorelin activity is physiologically modulated by feedback while recombinant human growth hormone activity is not!

12 Age-Deficits in Higher Level GH Regulatory-Feedback Elements are not Improved by hgh Replacement Therapy Neural Stimuli Influence SRIF and GHRH Release Humoral Factors Enter Portal Circulation Regulatory Factors Influence Somatotrophs GH Secretion Modified

13 Failure or somatotroph function during aging leads to a cascade of pituitary hormone failure resembling that which occurs during development of pathologic hypopituitarism Wass JAH Clinical Endo, Besser Cudworth eds., Lippencott, Philadelphia, 1987; p24

14 Failure to Sustain Somatotroph Function Causes Transdifferentiation of Growth Hormone to Prolactin Secreting Pituitary Cells (+) GHRH/GHS (-) GHRH/GHS Adapted from Frawley L: GH Secretagogues, Bercu/Walker eds. Springer; 1996 pg 313

15 GH SECRETAGOGUES REJUVENATE PITUITARY GLAND GH and PRL mrna are concentrated in young pituitary glands GH mrna is practically absent in old pituitary glands GH secretagogues restore pituitary mrna to youthful levels (Walker et al. Endocrine 2:633-38, 1994)

16 Endocrine and metabolic effects of long-term administration of growth hormone-releasing hormone-(1-29)-nh2 in age-advanced subjects. Khorram O, Laughlin GA, Yen SS. J Clin Endocrinol Metab May;82(5): Introduction Attenuation of the GH and insulin-like growth factor I (IGF- I) axis in aging may be responsible for changes in body composition and metabolism. This relationship has been confirmed by studies of recombinant human GH replacement in aging men and women, but the adverse effects encountered limit its clinical utility. The use of GHRH or its analogs may be an alternative mode for restoring the GH-IGF-I axis in aging individuals.

17 Endocrine and metabolic effects of long-term administration of growth hormone-releasing hormone-(1-29)-nh2 in age-advanced subjects. Khorram O, Laughlin GA, Yen SS. J Clin Endocrinol Metab May;82(5): Conclusions Here we report the endocrine-metabolic changes in response to a GHRH analog in age-advanced subjects. We conclude that nightly administration of GHRH analog for 4 months in age-advanced men and women activated the somatotropic axis. Increased skin thickness was found, as well as increased lean body mass, insulin sensitivity, general well-being, and libido These observations suggest that GHRH analog administration resulted in youthful- type anabolic effects.

18 SERMORELIN DOSE- RANGING PROTOCOL Background and Hypothesis to be Tested Because the aging pituitary remains responsive to stimulation by growth hormone (GH) secretagogues Sermorelin (GRF 1-29NH 2 ) could potentially be used instead of rhgh to increase GH concentrations in aging. The factors contributing to the age-related decline in GH secretion are largely extrapituitary, and with repeated or continuous administration GHS's can significantly increase GH secretion and elevate levels of insulin-like growth factor-i (IGF-I) to the young adult normal range. Treatment with GHS's has both theoretical and practical potential advantages over GH - preserving feedback regulation by IGF-I to buffer against overtreatment, and yielding a more physiologic pulsatile pattern of GH secretion.

19 Research Objective The purpose of the current clinical investigation is to determine whether a relatively low dosage of sermorelin (GRF 1-29-NH2; the truncated, bioactive form of GHRH 1-44) is effective in stimulating pituitary function in middle aged men. Since this is a pilot study, the only measures of efficacy will be responses to a provocative test using sermorelin (GEREF diagnostic) at the onset of the study, and every month for 3 months thereafter, as well as serum concentrations of insulin like growth factor-1 (IGF-1) during the same time intervals.

20 Test Material Growth Hormone Releasing Factor 1-29 NH 2 Sermorelin acetate is the acetate salt of an amidated synthetic 29- amino acid peptide (GRF 1-29 NH 2 ) that corresponds to the amino-terminal segment of the naturally occurring human growth hormone-releasing hormone (GHRH or GRF) consisting of 44 amino acid residues. The structural formula for sermorelin acetate is: The free base of sermorelin has the empirical formula C 149 H 246 N 44 O 42 S and a molecular weight of 3,358 daltons. Amino Acid Sequence Tyr-Ala-Asp-Ala-Ile-Phe-Thr- Asn-Ser-Tyr-Arg-Lys-Val-Leu- Gly-Gln-Leu-Ser-Ala-Arg-Lys- Leu-Leu-Gln-Asp-Ile-Met-Ser- Arg-Gln-Gln-Gly-Glu-Ser-Asn- Gln-Glu-Arg-Gly-Ala-Arg-Ala- Arg-Leu-NH2 Sermorelin is a much smaller molecule than hgh and thus more inexpensive to produce

21 Procedure Provocative Test: Indwelling iv catheter with heparin block will be inserted. 1cc blood sample will be drawn for baseline measures of serum growth hormone concentrations. Thereafter, Geref (sermorelin) will be administered by intravenous push at time 0. A slow infusion (30 minutes) of arginine (0.5 gm/kg body weight not to exceed 25 gm) will be started at time 0. Blood samples will be drawn from the venous catheter at times 10, 20, 25, 30, 40, 60 and 90 minutes. Heparinized blood samples will used to measure plasma hgh concentrations. IGF-1 measurements: Concentrations of IGF-1 will be measured in the pooled plasma samples from each provocative test, i.e. those taken at onset of the study and on months 1, 2 and 3 thereafter. Seromorelin administration: Each subject will self administer (sc injection once daily approximately at bedtime) 100 ug sermorelin for 90 consecutive days.

22 Outcomes Increased peak responses to the provocative testing following each month of treatment with sermorelin indicate positive feedback to the secreatgogue and suggest pituitary recrudescence as the result of treatment. Increased IGF-1 measures following each month of sermorelin treatment indicates that endogenous hgh production and secretion increased and that the secretagogue has physiological efficacy at the dosage administered.

23 EFFECTS OF GHRH PRIMING ON THE GHRH SECRETORY RESPONSE 14 Serum Growth Hormone (ng/ml) GHRH 20 After 30 Days Treatment Before Treatment TIME (Minutes)

24 Serum IGF-1 values after sc Sermorelin administration for 30 consecutive days Patient ID/Age Baseline (ng/ml) Interim Analysis (ng/ml) BP/ DP/ JA/ LM/ RW/

25 Comparison of rgh and GRF rgh GRF 1-29NH 2 Production Recombinant gene technology Chemical synthesis Source E-coli or Mouse cell N/A Viral potential None None Target tissue Liver Pituitary Time for Tissue exposure Duration of Tissue Exposure Efficacy Instantaneous (GH injected directly; exogenous) Long (square wave) More rapid and pronounced; clinical effects more dramatic Type Pharmacological Physiological Delayed (GH secreted from pituitary after injection; endogenous) Short (episodic release) Less rapid and pronounced; less clinical effect Effect on Pituitary Toxicity Potential Ancillary Effects Shuts down endogenous production and secretion Greater, but dose dependent Direct on bone; may have benefit in relieving joint pain Stimulates production and secretion Very little if any May facilitate natural sleep, direct cardiovascular + effect

26 Conclusion Increased responses to provocative testing and/or elevated concentrations of serum IGF-1 indicate that Sermorelin is suitable for practical application in acquired (age associated) growth hormone insufficiency Unlike hgh, Sermorelin affects a more primary source of agefailure in the GH neuroendocrine axis, has more physiological activity, a better safety profile and its use in anti-aging medicine is not prohibited (as is hgh). A more effective alternative to recombinant growth hormone is available to anti-aging practitioners to support their efforts in providing treatments that better preserve the health and vitality of their patients during aging.