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

Hypothalamus
Anterior
pituitary
Target
tissue
Suckling
Breast
TRH
Prolactin
Dopamine
Other
tissues
Figure 38–4. Prolactin secretion and actions. Prolactin is the
only anterior pituitary hormone for which a unique stimulatory
releasing factor has not been identified. Thyrotropin-releasing
hormone (TRH), however, can stimulate prolactin release and
dopamine can inhibit it. Suckling induces prolactin secretion,
and prolactin affects lactation and reproductive functions but also
has varied effects on many other tissues. Prolactin is not under
feedback control by peripheral hormones.
pathological conditions, such as severe primary hypothyroidism,
persistently elevated levels of TRH can induce hyperprolactinemia.
Unlike GH, which plays important roles throughout life in
both sexes, prolactin acts predominantly in women, both during
pregnancy and in the postpartum period in women who breast-feed.
Serum prolactin levels remain low in men but are elevated somewhat
in normal cycling females. During pregnancy, the maternal serum
prolactin level starts to increase at 8 weeks of gestation, increases to
peak levels of 250 ng/mL at term, and declines thereafter to prepregnancy
levels unless the mother breast-feeds the infant. Suckling or
breast manipulation in nursing mothers transmits signals from the
breast to the hypothalamus via the spinal cord and the median forebrain
bundle, which, in turn, stimulate circulating prolactin levels.
Prolactin levels can rise 10- to 100-fold within 30 minutes of stimulation.
This response is distinct from milk letdown, which is mediated
by oxytocin release from the posterior pituitary gland. The sucklinginduced
prolactin secretion involves both decreased secretion of
dopamine by tuberoinfundibular neurons and possibly increased
release of factors that stimulate prolactin secretion. The suckling
response becomes less pronounced after several months of breastfeeding,
and prolactin concentrations eventually decline to prepregnancy
levels.
Prolactin also is synthesized in lactotropes near the end of
the luteal phase of the menstrual cycle and by decidual cells early in
pregnancy; the latter source is responsible for the very high levels of
prolactin in amniotic fluid during the first trimester of human pregnancy.
The function of this prolactin and what regulates its expression
are not known.
Molecular and Cellular Bases of Somatotropic Hormone
Action. All of the effects of GH and prolactin result
from their interactions with specific membrane receptors
on target tissues (Figure 38–5). Both the GH and
prolactin receptors are widely distributed cell surface
receptors that belong to the cytokine receptor superfamily
and thus share structural similarity with the receptors
for leptin, erythropoietin, granulocyte-macrophage
colony-stimulating factor, and several of the interleukins.
Like other members of the cytokine receptor
family, these receptors contain an extracellular
hormone-binding domain, a single membrane-spanning
region, and an intracellular domain that mediates signal
transduction.
The mature human GH receptor contains 620 amino acids,
approximately 250 of which are extracellular, 24 of which are transmembrane,
and ~350 of which are cytoplasmic. It exists as a preformed
homodimer that forms a ternary complex with one molecule
of GH. The formation of the GH-GH receptor ternary complex is
initiated by high-affinity interaction of GH with one monomer of the
GH receptor dimer (mediated by GH site 1), followed by a second,
lower affinity interaction of GH with the GH receptor mediated by
GH site 2; these interactions induce a conformational change that
activates downstream signaling. As discussed later, pegvisomant is
a GH analog with amino acid substitutions that disrupt site 2; it binds
the receptor and causes its internalization but cannot trigger the conformational
change that stimulates downstream events in the signal
transduction pathway. Amino acid–substituted versions of human
prolactin that act as antagonists at the prolactin receptor are also
under development (Goffin et al., 2006).
The ligand-occupied GH receptor dimer lacks inherent tyrosine
kinase activity. Rather, it provides docking sites for two molecules
of JAK2, a cytoplasmic tyrosine kinase of the Janus kinase
family. The juxtaposition of two JAK2 molecules leads to transphosphorylation
and autoactivation of JAK2, with consequent tyrosine
phosphorylation of cytoplasmic proteins that mediate
downstream signaling events (Lanning and Carter-Su, 2006). These
include STAT proteins (Signal Transducers and Activators of
Transcription), Shc (an adapter protein that regulates the Ras/MAPK
signaling pathway), and IRS-1 and IRS-2 (insulin-receptor substrate
proteins that activate the PI3K pathway). One critical target of
STAT5 is the gene encoding IGF-1 (Figure 38–5). The fine control
of GH action also involves feedback regulatory events that subsequently
turn off the GH signal. As part of its action, GH induces the
expression of a family of SOCS (suppressor of cytokine signaling)
proteins and a group of protein tyrosine phosphatases that, by different
mechanisms, disrupt the communication of the activated GH
receptor with JAK2 (Flores-Morales et al., 2006).
Some studies have shown that the GH receptor can translocate
to the nucleus and act as a coregulator to activate transcription
and cell proliferation (Swanson and Kopchick, 2007). The precise
role of this signal transduction pathway in GH physiology and pathophysiology
remains to be defined.
The effects of prolactin on target cells also result from interactions
with a cytokine receptor that is widely distributed and signals
through many of the same pathways as the GH receptor. Alternative
splicing of the prolactin receptor gene on chromosome 5 gives rise
to multiple forms of the receptor that are identical in the extracellular
domain but differ in their cytoplasmic domains. In addition,
soluble forms that correspond to the extracellular domain of the
receptor are found in circulation. Unlike human GH and placental
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CHAPTER 38
INTRODUCTION TO ENDOCRINOLOGY: THE HYPOTHALAMIC-PITUITARY AXIS