The “Un-GHRT”

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The Un-GHRT

• John Crisler DO
• MSU-COM
• Lansing, MI USA
• www.AllThingsMale.com

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The New GHRTJohn Crisler DOThe following
potential conflict of interest relationships are
germane to my presentation. Equipment
NoneSpeakers Bureau Solvay, AuxiliumStock
Shareholder NoneGrant/Research Support
NoneConsultant None Status of FDA devices
used for the material being presented
NA  Status of off-label use of devices, drugs
or other materials that constitute the subject of
this presentation NA 
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This lecture, as provided here, is incomplete.
You are welcome to contact Dr. Crisler at the
front of the lecture hall for a download of the
complete lecture, or via email at
www.AllThingsMale.com for the completed lecture.
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Tis far better to restore than to replace.
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Growth Hormone

• t1/220 min.
• Released in pulsatile fashion
• Measured indirectly via IGF-1 (t1/2 8 min)
• Inhibition by GHRT shifts somatotroph phenotype
  to mammotroph (PRL) initially
• Actual disease atrophy later on
• GH production is restored (in the capable)
• Expensive
• Tachyphylaxis possible
• For all practical purposes ILLEGAL

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Growth Hormone Production

• Growth Hormone Releasing Hormone (GHRH)
• Ghrelin (GHRP)
• Somatostatin

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Age Related Decline in GH PulsationSonntag et
al., JAAM 4311
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Somatostatin (SS)

• SS aka Growth Hormone Inhibiting Hormone
  (GHIH) or Somatotropin Release-Inhibiting Factor
  (SRIF)
• Produced by hypothalamus et al
• Inhibits GH synthesis and release
• Makes hypothalamus resistant to stimulation by
  GHRH, hypoglycemia, etc.
• Responsible for pulsatile GH inhibition
• Decreases number of somatotropes, not amount of
  GH production by each
• Increases with age

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Growth Hormone Releasing Hormone(GHRH)

• Produced by hypothalamus
• Stimulates GH synthesis and RELEASE
• Binds to GHRH-R in pituitary
• Short half-life
• Increases of somatotropes AND amount of GH from
  each
• No down regulation with supplementation
• Natural production inhibited by fatty acids

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Sermorelin (GHRH)

• GerefSermorelin acetate for injection
• Analog of GHRH
• Used for traditional GH stimulation testing
• First 29 (N-terminal) amino acids
• T ½ 11-12 mins. IV or SC
• Injected SC qhs

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Sermorelin (GHRH) cont

• 30 years of data
• Upregulates own receptor
• Ab formation is transient and non-neutralizing
• Promotes non-REM slow wave sleep
• Produces harmonics of GH release
• Vulnerable to physiological feedback (GHRT is
  not)
• Effective dose approaches of GH

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GH Production S/P GHRH InfusionChapman et al.
JCEM 812874, 1996
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CJC-1295 is a long acting GHRH which will come
into common use.
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Growth Hormone Releasing Peptides (GHRPs)

• Synthetic forms of Ghrelin
• Simple, short-chained amino acid complexes
• As a class Secretogogues (GHSs) (not incl.
  GHRH)
• Bind to GHS-R GH
• Artificial amplification b/c works with
  endogenous GHRH
• GHRP-1, GHRP-2, GHRP-6, MK-0677,
• Hexarelin, Ipamorelin, Ghrelin

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GHRPs

• number of somatotropes
• Does not amount of GH released from each
  somatotrope
• Operate via inhibition of K ion channels
• Less vulnerable to inhibitory influences (i.e.
  Somatostatin, glucose, fatty acids, other hormone
  levels, etc.)
• Not affected by female hormonal cycles
• Produces only one pulse of GH release

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GHRP-6

• First potent GHRP developed (1980)
• Most studied of all GHRPs
• D-Ala-D-2 Nal-Ala-Trp-D-Phe-Lys-NH2(newer
  modified version)
• Increases GH mRNA
• Does not increase PRL or cortisol
• Oral, SL, injectable delivery
• Cost effective

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GHRP-2

• More powerful version
• D-Ala-D-2 Nal-Ala-Trp-D-Phe-Lys-NH2
• 1993
• Oral products 30-40 potency
• Cost effective

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GHSs DIRECT Effects

• Bind to GHS-R (Ghrelin receptor) in pituitary
  to release GH
• Reduce inhibition by Somatostatin at pituitary
• Distinct and separate path than GHRH

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GHSs INDIRECT EFFECTS

• Stimulate GHRH production from hypothalamus
• Inhibit Somatostatin production from hypothalamus

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Oral GHSs

• Powerful reduction in SRIH tone
• No needles
• Must be taken on empty stomach
• Rapid desensitizationbut not really a problem
  given dosing
• Cost effective

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GHRH/GHSs

• GHRH (Sermorelin)

• GHSs (secretogogues)

• Raises total level of GH
• (raises troughs)
• GH harmonics
• No sensitization
• (depot preps possible)
• Must be given on a GH pulse

• Amplifies GH pulse
• (elevates peak)
• One GH pulse only
• Induces sensitization
• (single dose only)
• Induces GH pulse

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DHEA potentiated the GH releaseby GHRH and
partially reversed the inhibitory effect
ofsomatostatin.

• DHEA modulates GHRH, somatostatin and angiotensin
  II action at the pituitary level. Suarez et al.
  Instituto de Biologia y Medicina Experimental,
  Argentina.

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DHEA treatment increased serum GH 1.8 foldGHRH
target cells also increased.

• Mary Iruthayanathan, et al. Department of
  Neurobiology and Developmental Sciences, College
  of Medicine, University of Arkansas for Medical
  Sciences.

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E2 increased percentages of AP cells with GH
protein or mRNA in the aged rats to young levels.

• Mary Iruthayanathan, et al. Department of
  Neurobiology and Developmental Sciences, College
  of Medicine, University of Arkansas for Medical
  Sciences.

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DHEA Administration

• Oral
• --high compliance
• --low, variable bioavailability
• --cheap
• Transdermal (cream)
• --better bioavailability
• --ruins 24 urine testing
• Sublingual (troche/lozenge)
• --better bioavailability
• -- DHEA/DHEA-S

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DHEA troches/lozenges

• Mint
• --covers bitter taste of DHEA well
• --contact dermatitis in some
• Tutti-Fruiti
• --covers flavor okay
• Cinnamon
• --bitterness of DHEA comes through

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Un-GHRT Strategy

• Increase GHRH
• Decrease Somatostatin tone
• DHEA

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The synergistic effect of GHRH and GHS on GH
secretion is not reduced as humans age throughout
the entire lifespan. This holds true even for the
very old.

• Micic D, et al. Preserved Growth Hormone (GH)
  Secretion in Aged and Very Old Subjects after
  Testing with the Combined Stimulus GH-Releasing
  Hormone plus GH-Releasing Hexapeptide-6. J Clin
  Endocrinol Metab. 1998 Jul83(7)2569-72

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The Un-GHRT
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Why are challenges to recovery of GH production?

• Non-diseased pituitary has large GH reserve
• PRL GH colocalization of somatotrophs
• Somatostatin tone SS SS-Rs
• Tincture of time

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GHRH-only Tx with Sermorelin has been
disappointing
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GHRH Stimulation Results

• Note how those with adequate pituitary GH reserve
  (Control) respond the greatest.

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GHRP-6 will start a pulse, and acts
synergistically with GHRH so there is no need
to be concerned about timing if you co-administer
GHRP-6 with Sermorelin.
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Growth Hormone (GH)-Releasing Peptide-6 Requires
Endogenous Hypothalamic GH-Releasing Hormone for
Maximal GH Stimulation, NAUSHIRA PANDYA, ROBERTA
DEMOTT-FRIBERG, CYRIL Y. BOWERS, ARIEL L. BARKAN,
AND CRAIG A. JAFFE, Journal of Clinical
Endocrinology and Metabolism 1998 Vol. 83, No. 4
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Growth Hormone (GH)-Releasing Peptide-6 Requires
Endogenous Hypothalamic GH-Releasing Hormone for
Maximal GH Stimulation
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The Un-GHRT

• Sermorelin
• GHRP-6
• DHEA

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GHRT

• GH
• GHRH
• Growth Hormone Releasing Peptides
• Opiates

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Maximum Dosages

• GHRH 1mcg/kg (IV)
• GHSs 1-2mcg/kg (IV)

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GH Restart

• Inhibition of pituitary recrudescence
• Increase GH reserve
• Increase GH release
• SS control with oral secretogogue?

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Un-GHRT Protocol

• Sermorelin 100 mcgs SC qhs
• GHRP-6 100 mcgs SC qhs
• DHEA 25mg po BID or SL
• Oral Secretagogue (if recovering)

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The First Politician
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Dr. Crisler will be at theANEWrxCompounding
Pharmacyboothto discuss thesetherapies.