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

1116 ZORBTIVE); somatrem refers to a derivative of GH with an
additional methionine at the amino terminus that is no
longer available in the U.S.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Chemistry. Although the bacterial or yeast systems used to express
the recombinant GH subtly affect the structures of these preparations,
they all have similar biological actions and potencies (3 IU/mg). An
FDA-approved, encapsulated form of somatropin (NUTROPIN DEPOT)
injected intramuscularly, either monthly (1.5 mg/kg body weight) or
every 2 weeks (0.75 mg/kg body weight), has been discontinued by
the manufacturer.
Pharmacokinetics. As a peptide hormone, GH is administered subcutaneously,
with a bioavailability of 70%. Although the circulating
t 1/2
of GH is only 20 minutes, its biological t 1/2
is considerably
longer, and once-daily administration is sufficient. To match the
usual pattern of secretion, GH typically is administered at bedtime,
although this is not essential.
Indications for Growth Hormone Treatment. GH deficiency in
children is a well-accepted cause of short stature, and replacement
therapy has been used for half a century to treat children with severe
GH deficiency. With the advent of essentially unlimited supplies of
recombinant GH, therapy has been extended to children with other
conditions associated with short stature despite adequate GH production,
including Turner’s syndrome, Noonan’s syndrome, Prader-
Willi syndrome, chronic renal insufficiency, children born small for
gestational age, and children with idiopathic short stature (i.e., >2.25
standard deviations below mean height for age and sex but with normal
laboratory indices of growth hormone levels).
Attention also has shifted to the proper role of GH therapy in
GH-deficient adults. The consensus of experts is that at least the most
severely affected GH-deficient adults may benefit from GH replacement
therapy (Molitch et al., 2006). The FDA also has approved GH
therapy for AIDS-associated wasting and for malabsorption associated
with the short bowel syndrome. The latter indication is based on
the finding that GH stimulates the adaptation of gastrointestinal
epithelial cells.
Contraindications. Based on controlled clinical trials showing
increased mortality, GH should not be used in patients with acute
critical illness due to complications after open heart or abdominal
surgery, multiple accidental trauma, or acute respiratory failure. GH
also should not be used in patients who have any evidence of neoplasia,
and antitumor therapy should be completed before GH therapy
is initiated. Other contraindications include proliferative retinopathy
or severe nonproliferative diabetic retinopathy. In Prader-Willi
syndrome, sudden death has been observed when GH was given to
children who were severely obese or who had severe respiratory
impairment.
Therapeutic Uses. In GH-deficient children, somatropin typically is
administered in a dose of 25-50 μg/kg per day subcutaneously in the
evening; higher daily doses (e.g., 50-67 μg/kg) are employed for
patients with Noonan’s syndrome or Turner’s syndrome, who have
partial GH resistance. In children with overt GH deficiency, measurement
of serum IGF-1 levels sometimes is used to monitor initial
response and compliance; long-term response is monitored by close
evaluation of height, sometimes in conjunction with measurements of
serum IGF-1 levels (Cohen et al., 2007). Although the most pronounced
increase in growth velocity occurs during the first 2 years of
therapy, GH is continued until the epiphyses are fused and also may
be extended into the transition period from childhood to adulthood.
In view of the effects of GH on bone density and visceral adiposity
and the manifestations of GH deficiency in adults, many
experts now continue therapy into adulthood for children with GH
deficiency (Radovick and DiVall, 2007). However, many patients
who were GH deficient in childhood based on provocative testing,
especially those with idiopathic, isolated GH deficiency, respond
normally to provocative tests as adults. Thus, it is essential to confirm
GH deficiency after full growth has been achieved, ideally after
discontinuation of GH replacement for at least 1 month, to identify
patients who will benefit from continuing GH treatment.
For adults, weight-based dosing largely has been supplanted
by initiation with relatively low doses irrespective of weight, followed
by dose titration as tolerated to raise IGF-1 levels to the mid-normal
range adjusted for age and sex. A typical starting dose is 150-300 μg
per day, with higher doses used in younger patients transitioning from
pediatric therapy; lower doses are used in older patients (e.g., >60 years
of age). Either an elevated serum IGF-1 level or persistent side effects
mandates a decrease in dose; conversely, the dose can be increased
(typically by 100-200 μg per day) if serum IGF-1 has not reached the
normal range after 2 months of GH therapy. Because estrogen inhibits
GH action, women taking oral—but not transdermal—estrogen may
require larger GH doses to achieve the target IGF-1 level. In the setting
of AIDS-related wasting, considerably higher doses (e.g., 100
μg/kg) have been used. Studies are also underway to assess the effect
of GH therapy on reducing visceral adiposity and increasing lean body
mass in HIV-infected patients with the adipose redistribution syndrome
(Grunfeld et al., 2007; Lo et al., 2008).
Based on the known age-related decline in GH levels, the use
of GH therapy to ameliorate or even reverse the consequences of
aging has been widely promoted. Many of the studies supporting
this use were not placebo controlled and involved small numbers of
subjects. Moreover, one review concluded that there was no significant
improvement in strength or aerobic performance with GH therapy
in elderly subjects (Liu et al., 2007). Thus, this remains an area
of considerable debate. In violation of regulations and standard medical
practice, some athletes also use injected GH preparations as anabolic
agents to enhance performance (Gibney et al., 2007). In
addition to the parenteral GH preparations, oral preparations containing
“stacked” amino acids that reputedly stimulate GH release
have been marketed as nutritional supplements. Despite the absence
of validation in controlled trials, these formulations are part of
multibillion dollar anti-aging and performance-enhancing programs
(Olshansky and Perls, 2008).
Adverse Effects of Growth Hormone Therapy. In children, GH therapy
is associated with remarkably few side effects. Rarely, generally
within the first 8 weeks of therapy, patients develop intracranial
hypertension, with papilledema, visual changes, headache, nausea,
and/or vomiting. Because of this, funduscopic examination is recommended
at the initiation of therapy and at periodic intervals thereafter.
Leukemia has been reported in some children receiving GH
therapy; a causal relationship has not been established, and conditions
associated with GH deficiency (e.g., Down’s syndrome, cranial
irradiation for CNS tumors) probably explain the apparent increased