DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1112 Clinical Manifestations of Growth Hormone Deficiency. Clinically, children
with GH deficiency present with short stature, delayed bone age,
and a low age-adjusted growth velocity. Specific etiologies associated
with GH deficiency in children include genetic disorders that affect
pituitary development and can cause deficiencies of multiple pituitary
hormones, pituitary or hypothalamic tumors, previous CNS irradiation,
and infiltrative processes such as histiocytosis. In most patients,
however, the deficiency is idiopathic, with normal production of other
pituitary hormones and no obvious structural abnormalities.
GH deficiency in adults does not impair linear growth, which
ceases with closure of the epiphyses. Rather, GH deficiency in adults
is associated with decreased muscle mass and exercise capacity,
decreased bone density, impaired psychosocial function, and
increased mortality from cardiovascular causes, probably secondary
to deleterious changes in fat distribution, increases in circulating
lipids, and increased inflammation (Molitch et al., 2006).
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Diagnosis of Growth Hormone Deficiency. Because GH secretion is
highly pulsatile, random sampling of serum GH is insufficient to
diagnose GH deficiency. Whereas tests for substances that provide
an estimate of integrated GH levels over time (e.g., IGF-1 and
IGFBP-3) are more useful, provocative tests usually are required.
After excluding other causes of poor growth, the diagnosis of GH
deficiency should be entertained in children with height >2 to 2.5
standard deviations below normal, delayed bone age, a decreased
growth velocity, and a predicted adult height substantially below the
mean parental height. In this setting, a serum GH level <10 ng/mL
following provocative testing (e.g., insulin-induced hypoglycemia,
arginine, levodopa, clonidine, or glucagon) indicates GH deficiency;
a stimulated value <5 ng/mL reflects severe deficiency.
In adults, overt GH deficiency usually results from pituitary
lesions caused by a functioning or nonfunctioning pituitary adenoma,
secondary to trauma, or related to surgery or radiotherapy for a pituitary
or suprasellar mass (Molitch et al., 2006). Almost all patients
with multiple deficits in other pituitary hormones also have deficient
GH secretion, and some experts incorporate the number of other
pituitary deficiencies into a diagnostic algorithm for diagnosing GH
deficiency. Others accept a serum IGF-1 level below the age- and sexadjusted
normal range as indicative of GH deficiency in a patient with
known pituitary disease. The converse is not true because an IGF-1
level within the normal range does not exclude adult GH deficiency.
Some experts require an inadequate GH response to provocative testing
(i.e., a value <5 ng/mL), with either insulin-induced hypoglycemia
or a combination of Arg and GHRH as the preferred
stimulus for GH secretion. Finally, in patients with known hypothalamic/pituitary
disease of recent onset, Arg alone can be used as the
stimulus, with the hGH cutoff set at 1.4 ng/mL. The risk of falsepositive
provocative tests (i.e., a subnormal GH response) is increased
in obese subjects.
Pharmacotherapy of Disorders
of the Somatotropin Hormones
Pharmacotherapy of Growth Hormone Excess. Treatment
options in gigantism/acromegaly include transphenoidal
surgery, radiation, and drugs that inhibit GH secretion
or action. Pituitary surgery traditionally has been the
treatment of choice. In patients with microadenomas,
skilled neurosurgeons can achieve cure rates of 65-85%;
however, the long-term success rate for patients with
macroadenomas typically is <50%. In addition, there is
increasing appreciation that acromegalic patients previously
considered cured by pituitary surgery actually have
persistent GH excess, with its attendant complications.
Pituitary irradiation may be associated with significant
long-term complications, including visual deterioration
and pituitary dysfunction. Thus, increased attention has
been given to the pharmacological management of
acromegaly, either as primary treatment or for the treatment
of persistent GH excess after transphenoidal surgery
or irradiation. Another area receiving increased
investigation is the potential role of medical therapy
before surgery to improve outcome (Carlsen et al., 2008).
The favored therapy has been with SST analogs,
although the GH receptor antagonist pegvisomant
increasingly is used. In patients who refuse these injected
treatments, DA agonists may be used, although they are
much less effective.
Somatostatin Analogs. The development of synthetic
analogs of SST (Figure 38–3) revolutionized the medical
treatment of acromegaly. The goal of treatment is
to decrease GH levels to <2.5 ng/mL after an oral glucosetolerance
test and to bring IGF-1 levels to within the
normal range for age and sex. Some have argued that a
basal GH level of <1 ng/mL indicates cure, whereas a
basal level of >2 ng/mL is highly suggestive of persistent
disease.
Chemistry. Structure-function studies of SST and its derivatives
established that the amino acid residues in positions 7-10 of the SST-14
peptide (Phe-Trp-Lys-Thr) are the major determinants of biological
activity. Residues Trp 8 and Lys 9 appear to be essential, whereas
conservative substitutions at Phe 7 and Thr 10 are permissible. Active
SST analogs retain this core segment constrained in a cyclic structure,
formed either by a disulfide bond (octreotide, lanreotide,
vapreotide) or an amide linkage (seglitide, pasireotide) that stabilizes
the optimal conformation (Pawlikowski and Melen-Mucha,
2004). The endogenous peptides, SST-14 and SST-28, do not show
specificity for SST receptor subtypes except for SST 5
, which preferentially
binds SST-28. Some SST analogs exhibit greater selectivity.
For example, the octapeptides octreotide and lanreotide bind to
the SST subtypes with the following order of selectivity: SST 2
>
SST 5
> SST 3
>> SST 1
and SST 4
. The cyclohexapeptide, pasireotide
(SOM230), binds with high affinity to all but the SST 4
receptor.
Small nonpeptide agonists that exhibit high selectivity for SST
receptor subtypes have been isolated from combinatorial chemical
libraries; these compounds may lead to a new class of highly selective,
orally active SST mimetics (Weckbecker et al., 2003).
A chimeric compound that activates SST receptors and the
D 2
receptor (BIM-23A387) is now in clinical trials for therapy of