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

postnatal growth retardation is unresponsive to GH but
responsive to recombinant human IGF-1, and by the
association of mutations in the IGF-1 receptor with
intrauterine growth retardation (Walenkamp and
Wit, 2008).
After its synthesis and release, IGF-1 interacts with receptors
on the cell surface that mediate its biological activities. The type 1
IGF receptor is closely related to the insulin receptor and consists of
a heterotetramer with intrinsic tyrosine kinase activity. This receptor
is present in essentially all tissues and binds IGF-1 and the related
growth factor, IGF-2, with high affinity; insulin also can activate the
type 1 IGF receptor but with an affinity approximately two orders of
magnitude less than that of the IGFs. The signal transduction pathway
for the insulin receptor is described in detail in Chapter 43.
Unlike GH, prolactin does not induce the synthesis
of a second hormone that then mediates many of its
effects in an indirect manner. Rather, prolactin effects
are limited to tissues that express the prolactin receptor,
particularly the mammary gland. A number of
hormones—including estrogens, progesterone, placental
lactogen, and GH—stimulate development of the
breast and prepare it for lactation. Prolactin, acting via
prolactin receptors, plays an important role in inducing
growth and differentiation of the ductal and lobuloalveolar
epithelia and is essential for lactation. Target genes,
by which prolactin induces mammary development,
include those encoding milk proteins (e.g., caseins),
genes important for intracellular structure (e.g., keratins),
genes important for cell-cell communication
(e.g., amphiregulin and Wnt4), and components of the
extracellular matrix (e.g., laminin and collagen).
Prolactin receptors are present in many other sites, including
the hypothalamus, liver, adrenal, testes, ovaries, prostate, and
immune system, suggesting that prolactin may play multiple roles
outside of the breast. The physiological effects of prolactin at these
sites remain poorly characterized, and specific defects in their function
that result from prolactin deficiency have not been defined.
Pathophysiology of the Somatotropic
Hormones
Distinct endocrine disorders result from either excessive
or deficient GH production. In contrast, prolactin
predominantly impacts endocrine function when produced
in excess.
Excess Production of Somatotropic Hormones.
Syndromes of excess secretion of GH and prolactin typically
are caused by somatotrope or lactotrope adenomas
that oversecrete the respective hormones. These
adenomas often retain some features of the normal
regulation described earlier, thus permitting pharmacological
modulation of secretion—an important modality
in therapy.
Clinical Manifestations. GH excess causes distinct clinical
syndromes depending on the age of the patient. If
the epiphyses are unfused, GH excess causes increased
longitudinal growth, resulting in gigantism. In adults,
GH excess causes acromegaly. The symptoms and signs
of acromegaly (e.g., arthropathy, carpal tunnel syndrome,
generalized visceromegaly, macroglossia, hypertension,
glucose intolerance, headache, lethargy, excess
perspiration, and sleep apnea) progress slowly, and diagnosis
often is delayed. Mortality is increased at least
2-fold relative to age-matched controls, predominantly
due to increased death from cardiovascular disease.
Hyperprolactinemia is a relatively common
endocrine abnormality that can result from hypothalamic
or pituitary diseases that interfere with the delivery
of inhibitory dopaminergic signals, from renal failure,
from primary hypothyroidism associated with increased
TRH levels, or from treatment with dopamine receptor
antagonists. Most often, hyperprolactinemia is caused
by prolactin-secreting pituitary adenomas—either
microadenomas (≤1 cm in diameter) or macroadenomas
(>1 cm in diameter). Manifestations of prolactin excess
in women include galactorrhea, amenorrhea, and infertility.
In men, hyperprolactinemia causes loss of libido,
erectile dysfunction, and infertility.
Diagnosis of Somatotropin Hormone Excess. Although acromegaly
should be suspected in patients with the appropriate symptoms and
signs, diagnostic confirmation requires the demonstration of increased
circulating GH or IGF-1. The “gold standard” diagnostic test for
acromegaly is the oral glucose tolerance test. Whereas normal subjects
suppress their GH level to <1 ng/mL in response to an oral glucose
challenge (the absolute value may vary depending on the
sensitivity of the assay), patients with acromegaly either fail to suppress
or show a paradoxical increase in GH level.
In patients with hyperprolactinemia, the major question is
whether conditions other than a prolactin-producing adenoma are
responsible for the elevated prolactin level. A number of medications
that inhibit DA signaling can cause moderate elevations in prolactin
(e.g., antipsychotics, metoclopramide), as can primary
hypothyroidism, pituitary mass lesions that interfere with dopamine
delivery to the lactotropes, and pregnancy. Thus thyroid function and
pregnancy tests are indicated, as is magnetic resonance imaging
(MRI) to look for a pituitary adenoma or other defect that might elevate
serum prolactin.
Impaired Production of the Somatotropic Hormones.
Prolactin deficiency may result from conditions that
damage the pituitary gland, but prolactin is not given
as part of endocrine replacement therapy.
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CHAPTER 38
INTRODUCTION TO ENDOCRINOLOGY: THE HYPOTHALAMIC-PITUITARY AXIS