- Overview: GHRH; GHRPs
- Hypothalamic growth
hormone-releasing hormone (GHRH) ® pituitary
growth hormone (GH) secretion
- GHRH belongs to a family of
molecules including:
- secretin, VIP,
gastric inhibitory peptide (GIP),
glucagon
- Major site of GHRH
production: arcuate nucleus hypothalamus;
- GHRH receptor:
- G protein-coupled
transmembrane receptor
- Activation ® GH gene transcription,
synthesis & GH release (cAMP
mediated)
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- Clinical use:GHRH
& GHRP
- GHRH: evaluation of short children with
subnormal GH response to:
- insulin-induced
hypoglycemia, oral L-DOPA, IV
arginine
- Normal
response in this group® GH deficiency secondary
to hypothalamic dysfunction
- Subnormal
response in this group ® pituitary or
hypothalamic dysfunction
- Growth
hormone level increase following
GHRH ® favorable clinical
response to GHRH treatment
- Toxicity: GHRH & GHRP:
- facial flushing; injection
site discomfort (nasal GHRP- 2-- well
tolerated)
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Somatostatin
(Growth hormone-inhibiting
hormone, Somatotropin release-inhibiting hormone)
- Overview:somatostatin
- 14- and 28-amino acid peptide
forms, most widely distributed of the
hypothalamic releasing hormones
- 14-amino acid
peptide form: more abundant, less
bioactive in GH inhibition
(compared to 28-of the glass of
form)
- Localization:
hypothalamus & other CNS locations
- periventricular & medial
pre-optic areas of anterior
hypothalamus
- neurosecretory granules at nerve
terminals in the median eminence
- serves as
neurotransmitter in the spinal
cord, cerebral cortex, brain stem
-- in addition to hormonal action
- also
gastrointestinal & pancreatic
location
- Pancreatic D cells
(somatostatin-secreting)
-- insulin & glucagon
regulation {paracrine
action}
- Inhibits growth hormone
release
- also decreases GH
responds to secretagogues without
altering GH mRNA levels
- somatostatin
lowers serum TSH in response to
TRH
- Precursor: Prosomatostatin
- Pharmacokinetics: somatostatin
- half-life-- 1-3
minutes
- significant renal
metabolism
- renal excretion
- limited
clinical usefulness due to short
duration of action and multiple
effects on many secretory
processes
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- Overview: octreotide:
- Somatostatin analog -- longer
plasma elimination half-life (80 minutes)
- > 40X more potent than
somatostatin in inhibiting growth hormone
release
- only 2X more potent in
decreasing insulin secretion
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- Clinical
Use: octreotide
- Relatively small effect on
insulin secretion (compared to
somatostatin) allows clinical use without
concern for inducing hyperglycemic states
- Octreotide
used to manage:
- acromegaly, thyrotropin-secreting pituitary
adenomas & carcinoid tumors
- acute bleeding
control: esophageal varices
Following
subcutaneous doses every eight hours ® reduced symptoms from hormones secreted by
hormone-secreting tumors
acromegaly
|
carcinoid
syndrome
|
gastrinoma
|
glucagonoma
|
nesidioblastosis
|
watery
diarrhea
|
hypokalemia
|
achlorhydria
syndrome
|
"diabetic
diarrhea"
|
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- Adverse
Effects: octreotide
- Gastrointestinal
disturbances
- Biliary sludge; gallstones
(frequency: 20-30% {> 6 months
treatment}; symptomatic gallstones:
yearly frequency -- 1%)
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Growth Hormone (Somatotropin,
GH)
- Overview: GH
- Peptide
hormone: synthesized in anterior
pituitary
- Growth
promotion:
- at open epiphyses:
mechanism --
- stimulation
of insulin-like growth
factor I (IGF-I,
somatomedins C)
- Promotes lipolysis: adipose tissue
- Promotes skeletal muscle growth
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Growth
Hormone: Regulation
Type
of Agent
|
Stimulation
(+)
|
Inhibition
(-)
|
| Hypothalamic
factors |
GHRH |
somatotropin |
Biogenic amines
|
a-2 adrenergic receptor agonists
(clonidine, norepinephrine
|
b- adrenergic agonists
|
| |
b-adrenergic receptor antagonists (e.g.,
propranolol)
|
a-2 adrenergic receptor antagonists
(e.g., yohimbine)
|
| |
5-HT (serotonin)
stimuli (e.g.,L-tryptophan)
|
5-HT (serotonin)
receptor antagonists (e.g., cyproheptadine, methysergide)
|
| |
Dopaminergic
stimuli (e.g., L-DOPA, apomorphine, bromocriptine)
|
Dopaminergic
antagonists (e.g., chlorpromazine)
|
| Hormones |
Decreased IGF-I |
Increased IGF-I |
| |
Estrogen
|
Progestins
|
| |
Vasopressin
|
Glucocorticoids
(acutely, glucocorticoids increase growth hormone
release)
|
| |
Glucagon (cholinergic-mediated)
|
|
| |
Hypoglycemia
(a-adrenergic mediated)
|
Increased
blood sugar
|
| |
Decreased
free fatty acids
|
Increased
free fatty acids
|
| |
Amino
acid (arginine; cholinergic-mediated)
|
|
Others
|
Exercise--a-adrenergic
mediated
|
Antimuscarinic
agents (e.g., atropine)
|
| |
Stress--a-adrenergic
mediated
|
|
| |
Sleep --cholinergic-mediated
|
|
| |
Cholinergic-muscarinic
stimulation (e.g., pyridostigmine)
|
|
| Adapted
from Table 328-3 Biller, Beverly, M. K. and
Daniels, Gilbert, H. Neuroendocrine Regulation
and Diseases of the Anterior Pituitary and
Hypothalamus, In Harrison's Principles
of Internal Medicine 14th
edition, (Isselbacher, K.J., Braunwald, E.,
Wilson, J.D., Martin, J.B., Fauci, A.S. and
Kasper, D.L., eds) McGraw-Hill, Inc (Health
Professions Division), 1998, p. 1979. |
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- Chemistry:growth hormone
- 191-amino acid peptide
- structurally similar to
prolactin and chorionic somatomammotropin
- recombinant DNA growth
hormone
- somatotropin (191-amino
acid form)
- somatrem (192 amino acid form
(additional methionine)
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- Pharmacological Effects:growth hormone
- Initial insulin-like effects
- increase glucose
uptake
- increased amino
acid uptake
- decreased
lipolysis
- Delayed anti-insulin
effect -- impaired glucose uptake;
increase lipolysis
- Promotes
longitudinal growth indirectly through:
- Somatomedins, insulin-like growth
factors (IGFs)
- GH stimulates growth
plate cartilage & liver
synthesis of:
- Somatomedins:
mediator of processes promoting
bone growth --e.g., increased of
DNA thymidine incorporation &
increased RNA uridine
incorporation --
- cellular
proliferation
- increased
proline to hydroxyproline
conversion (cartilage
synthesis)
- GH deficiency
® reduced
somatomedin ® short stature
- Short stature:
- IGF-I deficiency
(in the presence of high GH): ® Laron dwarfism
- Absence of IGF-I
pubertal surge (pygmies)
- Criteria for growth
hormone deficiency:
- growth rate
index -- < 4 cm/year
- lack of increase
serum GH following growth
hormone secretagogue
challenge
- Causes of congenital
growth hormone deficiencies:
- Most frequent
cause: lack of
hypothalamic growth
hormone-releasing
factors, usually due to
pit-I gene abnormality
- hypophyseal-pituitary
disease, e.g.
craniopharyngiomas
- Growth
hormone deficiency manifestation
of the newborn:
- GH
deficiency often associated with
multiple pituitary hormonal
deficiencies
- Growth Hormone-Responsive
Clinical Conditions
- GH
deficiencies
- some non-GH deficiencies -- delayed
bone age/slow growth rate + GH ® increased growth
(short-term GH treatment)
- Girls with
Turner's syndrome: high-dose
treatment effective
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- Adverse Effects:growth
hormone
- Following rapid growth:
- slipped capital
femoral epiphyses ®limp; lower extremity
pain (rare)
- leukemia incidence (slight
increase -- may not be causal)
- Screening suggested for
hypothyroidism & diabetes during GH
treatment
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