Page 684 - Basic _ Clinical Pharmacology ( PDFDrive )

670 SECTION VII Endocrine Drugs

LH, FSH, GnRH, and dopamine or analogs of these hormones signaling cascades mediated by receptor-associated JAK tyrosine
are commonly used and are described in the following text. kinases and STATs (see Chapter 2). The hormone has complex
effects on growth, body composition, and carbohydrate, protein,
GROWTH HORMONE (SOMATOTROPIN) and lipid metabolism. The growth-promoting effects are mediated
principally, but not solely, through an increase in the production
Growth hormone, an anterior pituitary hormone, is required dur- of IGF-I. Much of the circulating IGF-I is produced by the liver.
ing childhood and adolescence for attainment of normal adult size Growth hormone also stimulates production of IGF-I in bone,
and has important effects throughout postnatal life on lipid and cartilage, muscle, kidney, and other tissues, where it has autocrine
carbohydrate metabolism, and on lean body mass and bone den- or paracrine roles. It stimulates longitudinal bone growth until the
sity. Its growth-promoting effects are primarily mediated via IGF-I epiphyseal plates fuse—near the end of puberty. In both children
(also known as somatomedin C). Individuals with congenital or and adults, GH has anabolic effects in muscle and catabolic effects
acquired deficiency of GH during childhood or adolescence fail to in adipose cells that shift the balance of body mass to an increase
reach their midparental target adult height and have disproportion- in muscle mass and a reduction in adiposity. The direct and indi-
ately increased body fat and decreased muscle mass. Adults with rect effects of GH on carbohydrate metabolism are mixed, in part
GH deficiency also have disproportionately low lean body mass. because GH and IGF-I have opposite effects on insulin sensitiv-
ity. Growth hormone reduces insulin sensitivity, which results in
Chemistry & Pharmacokinetics mild hyperinsulinemia and increased blood glucose levels, whereas
IGF-I has insulin-like effects on glucose transport. In patients who
A. Structure are unable to respond to growth hormone because of severe resistance
Growth hormone is a 191-amino-acid peptide with two sulfhydryl (caused by GH receptor mutations, post-receptor signaling muta-
bridges. Its structure closely resembles that of prolactin. In the tions, or GH antibodies), the administration of recombinant human
past, medicinal GH was isolated from the pituitaries of human IGF-I may cause hypoglycemia because of its insulin-like effects.
cadavers. However, this form of GH was found to be contami-
nated with prions that could cause Creutzfeldt-Jakob disease. For Clinical Pharmacology
this reason, it is no longer used. Somatropin, the recombinant
form of GH, has a 191-amino-acid sequence that is identical with A. Growth Hormone Deficiency
the predominant native form of human GH. Growth hormone deficiency can have a genetic basis, be associated
with midline developmental defect syndromes (eg, septo-optic
B. Absorption, Metabolism, and Excretion dysplasia), or be acquired as a result of damage to the pituitary
Circulating endogenous GH has a half-life of approximately or hypothalamus by a traumatic event (including breech or
20 minutes and is predominantly cleared by the liver. Recom- traumatic delivery), intracranial tumors, infection, infiltrative
binant human GH (rhGH) is administered subcutaneously or hemorrhagic processes, or irradiation. Neonates with isolated
6–7 times per week. Peak levels occur in 2–4 hours, and active GH deficiency are typically of normal size at birth because pre-
blood levels persist for approximately 36 hours. natal growth is not GH-dependent. In contrast, IGF-I is essen-
tial for normal prenatal and postnatal growth. Through poorly
Pharmacodynamics understood mechanisms, IGF-I expression and postnatal growth
Growth hormone mediates its effects via cell surface receptors of become GH-dependent during the first year of life. In childhood,
the JAK/STAT cytokine receptor superfamily. The hormone has GH deficiency typically presents as short stature, often with mild
two distinct GH receptor binding sites. Dimerization of two GH adiposity. Another early sign of GH deficiency is hypoglycemia
receptors is stimulated by a single GH molecule and activates due to the loss of a counter-regulatory hormonal response of GH
to hypoglycemia; young children are at risk for this condition due
to high sensitivity to insulin. Criteria for diagnosis of GH defi-
TABLE 37–3 Diagnostic uses of thyroid-stimulating ciency usually include (1) a subnormal height velocity for age and
hormone and adrenocorticotropin. (2) a subnormal serum GH response following provocative testing
with at least two GH secretagogues. Clonidine (α 2 -adrenergic
Hormone Diagnostic Use agonist), levodopa (dopaminergic agonist), and exercise are factors
that increase GHRH levels. Arginine and insulin-induced hypo-
Thyroid-stimulating- In patients who have been treated surgically
hormone (TSH; for thyroid carcinoma, to test for cancer recur- glycemia cause diminished SST, which increases GH release. The
thyrotropin) rence by assessing TSH-stimulated radioac- prevalence of GH deficiency is approximately 1:5000. If therapy
tive iodine uptake and serum thyroglobulin with rhGH is initiated at an early age, many children with short
level (see Chapter 38)
stature due to GH deficiency will achieve an adult height within
Adrenocorticotropin In patients suspected of adrenal insufficiency, their midparental target height range.
(ACTH) either central (CRH/ACTH deficiency) In the past, it was believed that adults with GH deficiency do
or peripheral (cortisol deficiency), in
particular in suspected cases of congenital not exhibit a significant syndrome. However, more detailed stud-
adrenal hyperplasia. (See Figure 39–1 and ies suggest that adults with GH deficiency often have generalized
Chapter 39.) obesity, reduced muscle mass, asthenia, diminished bone mineral