released at the median eminence. TRH principally stim-
ulates the synthesis and release of thyroid-stimulating
hormone (TSH, thyrotropin) in the anterior pituitary,
and also stimulates the release of prolactin (PRL). Both
effects are mediated by membrane receptors coupled
to the Gq„-phospholipase C-/3-calcium-protein kinase C
second-messenger system (Chapter 30).
Gonadotropin-releasing hormone
(GnRH) or
luteiniz-
ing hormone-releasing hormone
(LHRH) is a decapep-
tide which, like TRH, has a pyroglutamic acid residue in
its N terminus. The presence of histidine and tryptophan
at positions 2 and 3, respectively, is required for biological
activity, while the replacement of glycine at position
6
by
D-Trp increases activity up to 100-fold. The potent syn-
thetic GnRH agonist shown below lacks the glycinamide
terminal and has instead an ethylamide residue and D-Trp
at position
6
:
p G lu '— His2— Trp3— Ser4— Tyr5— D-Trp6— Leu 7— Arg8— Pro9
GnRH-producing neurons are located in the preoptic area
and in the organum vasculosum of the lamina terminalis
but are known to have migrated to these areas from the ol-
factory placode during fetal development. Failure of these
neurons to migrate into the hypothalamus during embryo-
genesis results in infertility secondary to GnRH deficiency
(.
Kallmann’s syndrome).
GnRH stimulates the release of
luteinizing hormone (LH) and follicle-stimulating hor-
mone (FSH), the two gonadotropic hormones produced
by the pituitary. GnRH also occurs in other regions of
the brain and in the placenta. Its pivotal role in the reg-
ulation of gonadotropin release, and thus in reproduc-
tive competence, has led to the formulation of GnRH
antagonists for contraceptive purposes. Paradoxically,
however, synthetic GnRH agonists, when administered
chronically in humans, cause a downregulation of GnRH
receptors that results in suppression of gonadal steroid
production. GnRH action on pituitary gonadotropes be-
gins by occupancy of GnRH receptors by GnRH and in-
volves intracellular mobilization of calcium ions through
the action of G-protein, phospholipase C, and phos-
phatidylinositol pathways (Chapter 30). This suppression
of gonadal function has been referred to as “medical
castration.”
Corticotropin-releasing hormone
(CRH)
is a 41-
amino-acid polypeptide produced in the parvicellular neu-
rons of the paraventricular nucleus and released into the
hypophyseal portal system in the median eminence. An-
tidiuretic hormone (ADH, AVP) is also synthesized and
released by the same neurons, but in humans, unlike the
situation in rats, the amount of ADH released at the me-
dian eminence is too small to influence the function of the
732
anterior pituitary. CRH stimulates the release of ACTH
and /
1
-endorphin by the anterior pituitary corticotrophs by
stimulating the synthesis and posttranslational processing
of their prohormone, pro-opiomelanocortin (POMC).
Growth hormone-releasing hormone
(GHRH) is a 44-
amino-acid polypeptide produced in the tuberoinfundibu-
lar dopaminergic system (TIDA) of the hypothalamus,
which includes the arcuate and ventromedial nuclei.
GHRH stimulates the synthesis and release of GH in an-
terior pituitary somatotrophs by a cAMP-mediated mech-
anism. The efficacy of GHRH in promoting GH release is
strongly modulated by hypothalamic somatostatin.
Somatostatin(growth hormone release-inhibiting hor-
mone)
is a tetradecapeptide with an intrachain disulfide
bridge. Somatostatin neurons are located in the parvi-
cellular neurons of the PVN, the periventricular nuclei
chapter 31
Endocrine Metabolism II: Hypothalamus and Pituitary
and the preoptic nuclei. Somatostatin inhibits the synthesis
and release of GH from the somatotropes by neutralizing
the effect of GHRH, an effect mediated by G,„ inhibition of
adenylyl cyclase. Within the hypothalamus, somatostatin
inhibits the release of GHRH by the same mechanism and
therefore exerts an inhibitory effect at two levels of GH
control. Somatostatin is also produced outside of the CNS,
particularly in the D cells of the islets of Langerhans and in
the gastrointestinal tract. Somatostatin produced at these
extra hypothalamic sites does not normally influence GH
secretion by the anterior pituitary because it is greatly di-
luted by systemic blood.
Prolactin-inhibiting hormone
(PIH), also known as
dopamine, is not a peptide (Chapter 17). It functions as
a neurotransmitter in the CNS and as a precursor of nore-
pinephrine and epinephrine in the adrenal medulla. In the
hypothalamus, it originates in the TIDA and is released at
the median eminence. Dopamine is a potent inhibitor of
PRL release by the lactotropes (and mammosomatotropes)
of the anterior pituitary, and this effect is mediated by D
2
receptors that are coupled to Gj„ inhibition of adenylate
cyclase. The lactotropes are unique in that they do not re-
quire stimulation by the hypothalamus to secrete PRL; in
fact, blockage of the blood flow from the hypothalamus
to the anterior pituitary results in elevated serum levels
of PRL, due to withdrawal of dopamine. Thus, unlike so-
matostatin, the effectiveness of dopamine does not depend
on the presence of a stimulating hormone (Chapter 34).
The existence
prolactin-releasing factor
(PRF), a yet-
to-be-characterized stimulator of PRL release, remains
controversial, particularly in view of the fact that TRH
subserves this role. What is clear, however, is that the
O
— C — NH— C H 2— C H 3
