a new paradigm for treating adult- onset growth hormone ......this slide demonstrates the mutitude...

A New Paradigm for Treating Adult-Onset Growth Hormone Deficiency

Richard F. Walker, Ph.D., R.Ph. Executive Director, SARA

Richard Walker

Note

This presentation compares and contrasts the use of rhGH and sermorelin in adult onset GHD. It provides the scientific, medical and legal basis for using sermorelin for pituitary rejuvenation with enhanced production of endogenous hGH in preferenence to administering the exogenous hormone.

Age-Related Rates of Decline in Various Physiological Functions

• A progressive decline in

physiological functions occurs

after reproductive competence is

reached and life progresses into

the third and fourth decades.

• Rates of decline reflect

differential responses to the

magnitude of a specific

challenge, i.e., compliance is

compromised with aging.

(Shock NW: Systems integration, in

Biology of Aging, CE Finch & L Hayflick

(eds.) Van Nostrand, New York,1977, pp

639-655)

Richard Walker

Note

As physiological functions become more complex they also become more vulnerable to deterioration during aging. This is because temporal integration, i.e., the timing of regulatory signals between each of the functional elements of the physiological complex becomes progressively disturbed. Therefore, because of signal "mistiming" the most complex functions suffer the greatest decrements with aging

Brain/Adenohypophyseal Relationships

Richard Walker

Note

Neuroendocrine axes are extremely complex functional entities that require exactly timed signal and feedback control between the environment, specific brain centers, unique pituitary cell types, somatic targets, etc. Because of such complexity, loss of temporal order associated with aging causes inadequate or uncoordinated signalling resulting in progressive loss of hormone production and secretion. The growth hormone neuroendocrine axis is the first to show age-related decrements that occur in most people during their late thirties.

Brain Initiates GH Secretory Cascade

1. Neural pathways impinge on hypothalamic neurosecretory cells

2. GHRH/Ghrelin/SRIF modulate GH secretion

Richard Walker

Note

This slide demonstrates the mutitude of factors that influence growth hormone production and secretion. The final common pathway from the brain to the pituitary gland involves the stimulatory neurohormone GHRH (growth hormone releasing hormone) and the inhibitory one, somatostatin. An interaction of these two factors in combination with a third modulator (ghrelin) promotes episodic synthesis and release of hGH from the pituitary. In addition, the pattern of production and release of endogenous hGH is modulated by environmental input as well as by non-specific neuropeptides and neurotransmitters. In other words, regulation of growth hormone production and secretion is controlled directly by specific neurohormones whose function is in turn regulated by a complex of higher level functions.

Regulation of hGH production and secretion is under strict temporal, quantitative and qualitative feedback control

Richard Walker

Note

In addition to regulatory factors that are external to the GH neuroendocrine axis, physical and chemical feedback relationships exist between GHRH and somatostatin (SRIH) neurosecretory neurons. In addition, IGF-1 from the peripheral circulation modifies the activity of the primary neuropeptides

Primary Regulatory Factors in the hGH Neuroendocrine Axis

� Growth hormone-releasing hormone (GHRH) is a hypothalamic peptide that stimulates both the synthesis and secretion of growth hormone.

� Somatostatin (SS) is a peptide produced by several tissues in the body, including the hypothalamus. Somatostatininhibits growth hormone release in response to GHRH and to other stimulatory factors such as low blood glucose concentration.

� Ghrelin is a peptide hormone secreted from the stomach. Ghrelin binds to receptors on somatotrophs and potently stimulates secretion of growth hormone.

Richard Walker

Note

This slide summarizes the primary factors controlling pituitary growth hormone production and secretion. Positive and negative influences are represented by + and - symbols.

Signals from target tissues superimpose upon primary controllers in brain and pituitary

Richard Walker

Note

Anatomical change such as growth of bone and muscles, as well as chemicals produced by the influence of hGH upon the body provide essential controlling signals for optimal physiological function of the neuroendocrine axis.

The timing of interdependent physiological events becomes disturbed with advancing age. These changes result in suboptimal performance, loss of function and intrinsic disease. Reduced hormone production is one of the earliest signs of age related change and is followed by functional disturbances and ultimately by intrinsic disease

Samis HR, Jr. Aging: Loss of temporal organization. Perspectives Biol Med. 1968:95-102

Low levels or deficiency of a hormone can have dramatic effects on the body’s structure and functions, especially when more than one hormone is deficient as in multiple pituitary hormone deficiency (MPHD)

Richard Walker

Note

Age related pituitary dysfunction is not restricted to the hGH neuroendocrine axis. However, the cascade of failure within the pituitary gland is initiated by somatotroph dysfunction which progesses to failure of the other cell types within the hypophysis. Eventually with progression of aging, a condition develops resembling the pathology, multiple pituitary hormone deficiency

SOMATOPAUSE

Aging results in reduced production and

secretion of growth hormone relative to

that which occurs in youth. This is the first

gross sign of neuroendocrine senescence

that begins during the mid- to late thirties

Richard Walker

Note

The fact that laboratories provide different ranges of normal for IGF-1 rather than simply one range representing the healthy individual demonstrates the confusion that exists regarding the relevance of age-associated endocrine deficiency. If the values accepted and normal (e.g. "healthy") for a 70 year old were detected in a 20 year old they would be considered abnormal and indicative of pathology. How can you have it both ways?

Normal Changes in the Growth

Hormone Axis with Aging

� The rate of GH secretion from the anterior pituitary is highest around puberty, and declines progressively thereafter. This age-related decline in GH secretion involves a number of changes in the GH axis, including decreased serum levels of insulin-like growth factor-1 (IGF-1) and decreased secretion of growth hormone-releasing hormone from the hypothalamus. The cause of the normal age-related decrease in GH secretion is not well understood, but is thought to result, in part, from increased secretion of somatostatin, the GH-inhibiting hormone.

� Normal aging is accompanied by a number of catabolic effects, including a decrease in lean mass, increase in fat mass, and decrease in bone density. Associated with these physiologic changes is a clinical picture often referred to as the somatopause: frailty, muscle atrophy, relative obesity, increased frequency of fractures and disordered sleep.

� These clinical signs of aging are, without doubt, the manifestation of a very complex set of changes which involve, at least in part, the GH-axis. Naturally, this has spurred considerable interest in administering supplemental GH as a "treatment" for aging in humans, and the availability of recombinant human GH has made such studies feasible.

Hypothesis

Replacement therapy intended to restore optimal concentrations of growth hormone may improve or sustain good youthful anatomy, physiology and thereby, good health and vitality during aging

But what hormone should be used in GH replacement therapy?

Compounds for GH Replacement

• Hepatic site of action

• Immediate tissue

availability

• Requires functional

pituitary gland

• Inhibits SRIF and/or

stimulates GHRH

• Synergistic actions

Richard Walker

Note

Currently there are two hormones available for GHRT during aging. One is recombinant hGH which enters the system at the level of the liver. This "short circuits" the GH neuroendocrine axis by eliminating the brain, pituitary and related feedback elements. IGF-1 is not practical for use because of cost and because it completely eliminates other regulatory aspects of the GH axis. GHRH is available as the analog, GRF 1-29 (sermorelin) which stimulates production and secretion of endogenous hGH. This promotes normal physiological action and rejuvenates the pituitary. By eliminating pituitary function rhGH and IGF-1 cause disuse atrophy of the "master gland". The only condition in which sermorelin is ineffective is the absence of a functional pituitary gland which is not the case during aging. Pituitary function declines with advancing age but generally is not terminated until functional cells are lost late in life.

Effective GHRT can be achieved by using recombinant hGH or

recombinant IGF-1

� Direct effects are the result of growth hormone binding its receptor on target cells. Fat cells (adipocytes), for example, have growth hormone receptors, and growth hormone stimulates them to break down triglyceride and supresses their ability to take up and accumulate circulating lipids.

� Indirect effects are mediated primarily by a insulin-like growth factor-I (IGF-I), a hormone that is secreted from the liver and other tissues in response to growth hormone. A majority of the growth promoting effects of growth hormone is actually due to IGF-I acting on its target cells.

Richard Walker

Note

GH has direct effects such as those causing lipolysis and collagen synthesis. It also has indirect effects that are mediated through IGF-1 that is produced by the liver and subsequently affects body composition and bone mineralization.

However, Single Dose Mean Growth Hormone Concentrations are Pharmacologic

Richard Walker

Note

rhGH injection causes the body to experience unnaturally high pharmacologic concentrations of the hormone for extended periods of time. This action increases the risk for side effects and also contributes to tachyphylaxis resulting from prolonged GH receptor stimulation.

And Serum hGH

Profiles are Abnormal

• Serum GH remains

above peak

physiological levels

for hours

• GH isoform ratios

are not stable

• Non-physiological

tissue exposure to

GH

Monomura et al. Endo J 47 (1):97-101, 2000

Richard Walker

Note

In addition to causing abnormally elevated and prolonged levels of GH, injections of the recombinant hormone also alter ratios of GH isoforms (20K and 22K). These alterations have been used to detect abuse by athletes and other using performance enhancers in some cases.

Also, rhGH suppresses pituitary function and thus, may accelerate neuroendocrine senescence

Richard Walker

Note

Injection of rhGH has the potential to cause disuse atrophy of the pituitary gland because it enters the system at the hepatic level producing IGF-1. IGF-1 negatively inhibits stimulatory functions (GHRH) and stimulates inhibitory functions (somatostatin) affecting anterior pituitary function.

GH Neurohormone Relationships

� GHRH stimulates GH production and secretion

� SRIF inhibits GH production, release & activity

� GHRP stimulates GHRH and GH secretion & inhibits SRIF activity

GHRP

Smith et al. Science, 1998

Richard Walker

Note

In contrast to rhGH, sermorelin, a GHRH analog contributes to normal pituitary production and secretion of growth hormone. It also sustains all feedback relationships except that for endogenous GHRH (for which it substitutes).

Considerations for Replacement TherapiesEfficacy and Safety Concerns

• Naturally occurring rhythms (practical

considerations)

• Interactions with other hormones and

essential substances

• Health state of the patient

• Individual dosage requirements

• Biomarkers for evaluation of outcomes

Richard Walker

Note

A primary objective of age-management/longevity medicine is to simulate youthful physiology to the greatest extent possible and thereby to decrease risk for intrinsic disease resulting from age-related internal disorder. Thus, HRT should be prescribed not only in consideration of dosage, but also of pattern, potential for rejuvenation, status of other endogenous hormones with which the administered agent may interact, health-related contraindications, etc. Efficacy of treatment should also be evaluated by measurement of relevent biomarkers, e.g. forced vital capacity, normalization of lab values, performance of simple physical tasks, etc.

Age-related defects in GH production and secretion

seem to involve higher centers

• young

° old

Sonntag et al., 2001 JAAM 4:311

Age-Related Decline in Episodes of Spontaneous GH Secretion

Richard Walker

Note

The main characteristic of aging in the GH neuroendocrine axis is loss of secretory episodes that are quite pronounced in youth. This is true for animals as seen in this slide and also for humans as seen in subsequent slides.

Growth Hormone Secretion Patterns

� Ultradian rhythm in GH secretion absent

� Low amplitude in partial GHD

� Attenuated in GHND

� High amplitude and obvious in normal, control subjects

Richard Walker

Note

This slide demonstrates the degrees of change in physiologic patterns of endogenous hGH secretion as related to severity of GHD. Similar loss of patterns occur across the lifespan. Youthful patterns are presented in the lower graph and old age patterns are presented in the upper graph. Progressive failure of pituitary function is represented by the middle graphs.

Short and Long Term Effects of GHRH Infusion on GH Release

� Episodic GH release occurs at start of infusion

� Dose-dependent pulses of GH are related to infusion

� GH pulses stop with saline infusion

Chapman et al. JCEM 81:2874, 1996

Richard Walker

Note

Constant administration of GHRH (hospitalized patients with indwelling catheter) affects hGH secretory profiles in two way. Upon starting the infusion there is a burst of GH release that is dose dependent (compare top and bottom panels - initial release). Thereafter, continued infusion enhances the endogenous pattern of hGH secretion (episodes) similar to those that occur during youth. When the GHRH infusion is replaced with saline (bottom panel) the episodes revert back to their age appropriate amplitude.

GH Response to GHRH

Thorner et al. Lancet 1:24, 1983

Richard Walker

Note

Compared to placebo (left panel) single injection of GHRH (or its analogs such as sermorelin, GRF 1-29NH2) elicits the same "burst" of hGH release from the pituitary gland as that which occurs upon the initiating an infusion. The amplitude of the burst is dose-related, but is not the same in all individuals. It is higher in young than in old. This is because pituitary reserve is greater in younger adults than in older ones. However, upon repeated daily stimulation of older individuals with GRF, pituitary reserve increases and thus, so does that accompanying burst of hGH. Increased pituitary reserve also increases the amplitudes of episodes following the initial injection and thus, simulates to some extent, the youthful physiological presentation of hGH to the body.

Stimulated GH Secretion

• Highest mean peak of

stimulated GH occurs in

control subjects

• GH response blunted in

GHND subjects

• Marginal or absent

response in GHD

Richard Walker

Note

As previously mentioned, a single injection of GHRH or sermorelin elicits different "burst" amplitudes of hGH. These peak amplitudes are blunted in young individuals with varying degrees of GHD compared to normal individuals (controls). Similar profiles occur with advancing age in that the oldest individuals show more significantly blunted responses to provocative testing with GHRH or GRF1-29NH2 than do middle aged younger persons. However, repeated stimulation with GHRH or sermorelin increases pituitary reserve and thereby causes subsequent bursts to increase in amplitude relative to the first event.

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)

Richard Walker

Note

Repeated stimulation of the pituitary gland with GHRH increases pituitary reserve by enhancing transcription of message for hGH within the somatotrophs. Since pituitary reserve is high in young animals (top panel, right column "saline treated") stimulation with GHRH has minimal effect on GH mRNA (left portion of panel; mRNA measured by northern blot analysis). However, in old animals (bottom panel) whose somatotrophs contain little GH mRNA (see absence of blots in "saline treated" controls) robust increases in message result from repeated stimulation with GH secretagogues (left side of bottom panel).

NORWELL, MA -- April 27, 1998 – SeronoLaboratories, Inc. has launched Geref(R) (sermorelinacetate for injection), the first growth hormone releasing hormone for the treatment of idiopathic growth hormone deficiency (GHD) in children and Geref(R) Diagnostic (sermorelin acetate for injection), a complementary product for the diagnosis of growth disorders in the United States.

Serono Launches Sermorelin

Richard Walker

Note

The GHRH analog GRF 1-29 NH2 (sermorelin) was marketed under the trade name Geref for diagnosis of pituitary reserve and also for treatment of growth retardation in children.

GHD results from either an abnormally low level of pituitary human growth hormone (hGH) or from a biochemical malfunction whereby growth hormone releasing hormone (GHRH) fails to trigger the release of hGH from the anterior pituitary. In the latter case, children with GHD may have endogenous hGH reserves which remain untapped.

Difference between childhood-onset GHD and age-related GHD

Richard Walker

Note

The possibility of restoring somatotroph function and increasing production and secretion of hGH in men and women as they age is analogous to children with GHD who have potentially functional pituitary glands.

As a growth hormone releasing hormone, Geref triggers the release of available reserves so that they can be used by the body. Traditionally, GHD has been treated by substituting natural hGH with a recombinant human growth hormone (r-hGH) product.

Richard Walker

Note

The idea of using sermorelin to treat growth retarded children with their own endogenous hGH rather than recombinant, exogenous hGH is the same for GHRT during aging.

"It is widely believed that treatment should begin early for a child to reach his or her full growth potential, and there are some data to support the initiation of treatment before age five," said Michael Thorner, M.D., a leading expert on growth and chairman of the department of medicine at the

University of Virginia Health Sciences Center.

Richard Walker

Note

As with growth retarded children, adults should consider beginning GHRT by sustaining pituitary function as it begins to fail, i.e. in the late thirties and early forties. This approach delays progression of age-related pituitary failure rather than trying to reverse its maladaptive consequences later in life.

Geref(R) (sermorelin acetate for injection) has demonstrated a favourable safety profile. The most common adverse reactions include local injection reactions (occurring in about one patient in six) characterised by pain, swelling or redness. During clinical trials, only three of 350 patients discontinued therapy due to injection reactions. Other treatment-related adverse events with occurrence rates of less than one percent include: headache, flushing, dysphagia, dizziness, hyperactivity, somnolence and urticaria.

A large portion of patients developed anti-GRF antibodies at least once during treatment with Geref. However, the significance of the antibodies is not clear. The presence of these antibodies does not appear to affect growth or be related to a specific adverse reaction profile and no generalised allergic reactions to Geref have been reported.

Richard Walker

Note

Antibodies to GRF 1-29NH2 are transient and are not neutralizing so that the pituitary stimulating effect of sermorelin continues unabated.

Adverse reactions reported with the use of Geref(R)

Diagnostic (sermorelin acetate for injection), in decreasing order of frequency are: transient warmth and/or flushing of the face, injection site pain, redness and/or swelling at injection site, nausea, headache and vomiting. Approximately one in four patients given repeated doses of GerefDiagnostic has developed antibodies -- the clinical significance of these antibodies is unknown.

Receptors for GRF, coupled to G proteins which activate adenylyl cyclase stimulate somatotroph cell growth, growth hormone gene transcription and growth hormone secretion

G protein-coupled

receptor binding

⇓cAMP production

⇓GH synthesis and secretion

Growth hormone-releasing hormone (GRH or GHRH)

Chemistry:37-, 40- and 44-amino acid single polypeptide chains

Related to GI peptides- secretin, gastrin, VIP, GIP

Preparation used clinically:

sermorelin acetate- first 29 (N-terminal) amino acids

Activity is equivalent to full length forms

Action and mechanism of action:

Half-life: 50 minutes

+

+

Richard Walker

Note

Unlike non-prescription "GH secretagogues", sermorelin binds specifically to somatotrophs and elicits its effects on GH mRNA and hGH production/secretion through a cAMP mechanism. In contrast, the effects of commercially available, OTC secretagogues are unpredictable, non-specific and not dose-related. Their action is similar to that resulting from extreme physical activity. However, because they contain high concentrations of amino acids they present some danger to kidney function and health.

Brain

Liver hGH

Pituitary Sermorelin

Sermorelin versus hGH Sites of Action

Sermorelin activity is physiologically modulated by feedback while recombinant human growth hormone activity is not!

Richard Walker

Note

Because sermorelin acts at the level of the pituitary gland, it preserves most of the feedback relationships within the GH neuroendocrine axis and simulates youthful physiological functions. Also, it sustains pituitary function by direct action upon the somatotrophs and the mechanism for transcription/translation of hGH gene message. In contrast, recombinant hGH "short circuits" feedback relationships within the GH neuroendocrine and promotes "disuse atrophy" of the pituitary gland. Thus, dispite its positive effects on body composition rhGH actually accelerates neuroendocrine senescence.

Comparison of rGH and GRF

rGH GRF

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

Instantaneous (GH injected directly; exogenous)

Delayed (GH secreted from pituitary after injection;

endogenous)Duration of Tissue Exposure

Long (square wave) Short (episodic release)

Efficacy More rapid and pronounced; clinical effects more dramatic

Less rapid and pronounced; less clinical effect

Type Pharmacological Physiological

Effect on Pituitary

Shuts down endogenous production and secretion

Stimulates production and secretion

Toxicity Potential

Greater, but dose dependent; little at doses in protocol

Very little if any

Ancillary Effects

Direct on bone; may have benefit in relieving joint pain

May facilitate natural sleep

Dose Ranging Study

SERMORELIN PROTOCOL

Background and Hypothesis

Because the aging pituitary remains responsive to stimulation by growth hormone (GH) secretagogues, Sermorelin (GRF 1-29NH2) can be used instead of GH itself to increase GH secretion 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 sermorelin has both theoretical and practical advantages over rhGH - preserving feedback regulation by IGF-I to buffer against overdosing and yielding a more physiologic pulsatilepattern of GH secretion.

Research Objective

� The purpose of the clinical investigation was 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 was a pilot study, the only measures of efficacy were 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.

Procedure

� Provocative Test: Indwelling iv catheter with heparin block was inserted. 1cc blood samples were drawn for baseline measures of serum growth hormone concentrations. Thereafter, Geref (sermorelin) was administered by intravenous push at time 0. A slow infusion (30minutes) of arginine (0.5 gm/kg body weight not to exceed 25 gm) was started at time 0. Blood samples were drawn from the venous catheter at times 10, 20, 25, 30, 40, 60 and 90 minutes. Heparinized blood samples were used to measure plasma hGH concentrations.

� IGF-1 measurements: Concentrations of IGF-1 were 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 self administered (sc injection once daily approximately at bedtime) 200 ug sermorelin for 90 consecutive days.

Test MaterialGrowth Hormone Releasing Factor 1-29 NH2

• 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 sermorelinacetate 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

SERMORELIN

� 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-NH2

Outcomes

� Increased IGF-1 measures following each month of sermorelin treatment indicated that endogenous hGH production and secretion increased and that the secretagogue has physiological efficacy at the dosage administered.

� Increased peak responses to the provocative testing following each month of treatment with sermorelin indicated positive feedback to the secretagogue and suggested pituitary recrudescence as the result of treatment.

Serum IGF-1 values after sc Sermorelin

administration for 30 consecutive days

Patient ID/Age Baseline (ng/ml) Interim Analysis

(ng/ml)

BP/50 134 195

DP/52 126 220

JA/53 57.1 150

LM/56 113 126

RW/66 127 199

Richard Walker

Note

IGF-1 was increased in all subjects during interim analysis at 30 days of treatment. Although all subjects responded, their responses were not of equal magnitude. The differences are attributed to differential pituitary reserves in the subjects, i.e., some had greater production of endogenous hGH than did others and thereby produced more (or less) IGF-1.

EFFECTS OF DAILY SERMORELIN ADMINISTRATION ON PITUITARY RESERVE

0

2

4

6

8

10

12

14

0

20

40

60

80

100

120

After 30 Days Treatment

TIME (Minutes)GH

RH

Ser

um

Gro

wth

Horm

on

e (n

g/m

l)

Before Treatment

Richard Walker

Note

This slide demonstrates the mean increases in hGH release from the pituitary gland of subjects receiving sermorelin for 30 consecutive days. The increased peak responses are attributed to sermrelins ability to promote hGH message transcription and translation leading to increased stores of hGH within the pituitary somatotrophs.

Sermorelin Dosage Recommendations

� 3 mg MDV: 200 ug/day for men with BMI from 18.5 – 24.9

� 4.5 mg MDV: 300 ug/day for men with BMI between 25 and 29.9

� 6 mg MDV: 400 ug/day for women or for men with BMI between 25 and 29.9

� 7.5 mg MDV: 500ug/day for women or for men with BMI between 25 and 29.9

Benefits of Sermorelin

� It’s effects are regulated at the level of the pituitary gland by negative feedback and by release of somatostatin so that overdoses of hGH are difficult if not impossible to achieve,

� Tissue exposure to hGH released by the pituitary under the influence of SERMORELIN is episodic not “square wave” preventing tachphylaxis by mimicking normal physiology

� By stimulating the pituitary it preserves more of the growth hormone neuroendocrine axis that is the first to fail during aging.

� Pituitary recrudescence resulting from SERMORELINblocks the cascade of hypophyseal hormone failure that occurs during aging

GHRT Liability ConcernsHuman growth hormone produced by recombinant gene technology has been used extensively for anti-aging therapy during the past decade. Although effective in restoring certain youthful characteristics in aging subjects, hGH has certain medical and legal issues that sometimes restrict practitioners use of the product.

RECOGNIZED MEDICAL CONDITIONS FOR WHICH HGH USE HAS BEEN

AUTHORIZED BY THE SECRETARY OF HEALTH AND HUMAN SERVICES

� Short stature of childhood� Wasting syndrome of AIDS� Growth hormone deficiency in

adults

Richard Walker

Note

Consistent with federal guidelines as published in the Code of Federal Regulations, practitioners may use rhGH only for the three conditions listed on this slide. The only one relevant to age-management/longevity medicine is adult onset GHD. However to make this diagnosis, practitioners must include as part of their evaluation a provocative test with peak responses being <10 ng/ml serum hGH. Since very few practitioners perform the provocative test, they are non-compliant and potentially liable for prosecution. There are no restrictions on the use of sermorelin and thus, it may be prescribed for GHRT without concern for legal issues governing the use of rhGH.

Conclusions

� 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

� Sermorelin dose ranging studies indicate that 200 – 500 ug sc qd hs are appropriate for clinical use

� Unlike hGH, Sermorelin affects a more primary source of age-failure 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.

a new paradigm for treating adult- onset growth hormone ......this slide demonstrates the mutitude...

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