Endocrinol Metab Clin N Am

37 (2008) 1–22

Normal Physiology of Hypothalamic

Pituitary Regulation
Susan Sam, MDa, Lawrence A. Frohman, MDb,*
a
Section of Endocrinology, Diabetes, and Metabolism (M/C 640), College of Medicine,
University of Illinois at Chicago, 1819 West Polk Street, 625 CMW, Chicago, IL 60612, USA
b
Section of Endocrinology, Diabetes, and Metabolism (M/C 275), College of Medicine,
University of Illinois at Chicago, 1747 West Roosevelt Road, Room 517,
Chicago, IL 60608, USA

The anterior pituitary is a heterogeneous gland with multiple cell types

that secrete hormones with unique functions. Each of its secreted hormones
participates in complex regulatory systems involving peripheral glands or
target tissues, is controlled by separate and distinct hypothalamic regulatory
mechanisms and by feedback systems, and is modulated by intrapituitary in-
fluences that are still only partially understood. The pituitary hormones are
essential for reproduction, growth, metabolic homeostasis, and responses to
stress, and they are critical for adapting to changes in the external environ-
ment. This article reviews the regulation of secretion of the individual ante-
rior pituitary hormones and their neuroendocrine, intrapituitary (autocrine/
paracrine), and peripheral (endocrine and metabolic) control mechanisms.

Growth hormone
Growth hormone (GH) is a single-chain 191–amino acid polypeptide with
a molecular size of 22 kilodaltons (kDa). It is synthesized in and released
from somatotrope cells, which constitute the most numerous cell type in
the anterior pituitary. GH exerts a broad spectrum of effects, resulting in
growth promotion and the regulation of carbohydrate, protein, lipid, and
mineral metabolism. These are mediated by direct effects on peripheral tis-
sues and indirect effects on the liver and other tissues through the generation
of insulin-like growth factor-1 (IGF-1). Nearly 80% of circulating IGF-1 is
of hepatic origin. The synthesis and secretion of GH are regulated primarily

* Corresponding author.
E-mail address: frohman@uic.edu (L.A. Frohman).

0889-8529/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.ecl.2007.10.007 endo.theclinics.com
2 SAM & FROHMAN

through the actions of hypothalamic neuropeptides that integrate hormonal,

metabolic, and neurogenic signals. In addition to its most abundant chemical
form, alternative mRNA processing leads to a shorter 20-kDa molecule, re-
ferred to as ‘‘variant GH,’’ which accounts for up to 10% to 20% of pituitary
GH. It is cosecreted with 22-kDa GH and has similar growth-promoting, al-
though reduced anti–insulin-like, activity [1]. The half-life of GH in serum is
20 to 25 minutes [2]; the secretion rate in young adult men is approximately
600 mg/d, and it is approximately 900 mg/d in young adult women [3].

Neuroendocrine control
The regulation of GH secretion occurs through the integrated action of
numerous peptides and nonpeptide hormones. The neuroendocrine control
is mediated primarily through the hypophysiotropic hormones growth hor-
mone–releasing hormone (GHRH) and somatostatin (somatotrope release-
inhibiting factor [SRIF]).
GHRH is a 44–amino acid peptide synthesized in and secreted from neu-
rons in the arcuate nucleus of the hypothalamus and serves as the primary
stimulatory regulator of GH [4]. It binds to a stimulatory G protein–coupled
somatotrope receptor, resulting in activation of adenylyl cyclase, causing an
increase in intracellular cyclic adenosine monophosphate (cAMP) levels and
a mobilization of intracellular Ca2þ, which triggers the release of GH. In ad-
dition, GHRH stimulates the synthesis of GH and is required for somato-
trope proliferation during development. When present in excess, it can
result in somatotrope hyperplasia and increased GH secretion. The regula-
tion of GHRH secretion is mediated by neuropeptides and monoaminergic
neurotransmitters and by feedback from peripheral sources. A dual function
of many of these neuropeptides in feeding behavior and metabolic regula-
tion underscores the importance of nutrient control in GH secretion.
Somatostatin is a 14–amino acid peptide and has a widespread distribu-
tion within the central nervous system. SRIF-containing neurons affecting
GH secretion are located primarily in the periventricular hypothalamic nu-
cleus and, after release into the portal vascular system, bind to somatotrope
receptors. There are five distinct SRIF receptors, of which types 2 and 5 ex-
ert the most potent effects on GH secretion. Binding of SRIF to its receptors
results in activation of inhibitory G-proteins, which leads to lowering of
cAMP levels and inhibition of GH secretion. Although SRIF does not sup-
press basal GH synthesis, it inhibits the stimulatory effects of GHRH. SRIF
secretion is similarly regulated by neuropeptide and monoamine transmit-
ters, in addition to peripheral feedback signals.
Ghrelin, a 28–amino acid octanoylated peptide, located primarily in the
stomach but also in the hypothalamus, binds to a specific GH secretagogue
(GHS) receptor on the somatotrope and stimulates GH secretion [5,6]. GHS
receptors are also present in the hypothalamus, and direct effects on GHRH
 HYPOTHALAMIC PITUITARY REGULATION 3

release have been observed in animal studies. Although peripheral levels of

ghrelin are linked to nutritional status, a physiologic role for this peptide on
GH secretion remains controversial.

Intrapituitary regulation
In addition to the important role of hypothalamic hormones in the gener-
ation of pulsatile GH secretion, it has recently been shown that the pituitary
contains a large-scale network organization of somatotropes that are
connected to one another by adherens junctions (anchoring connections of
the cytoskeleton of adjacent cells). This network has been proposed as being
responsible for integrated amplification during the pulses of GH secretion [7].

Pulsatility of growth hormone secretion

GH secretion occurs in a pulsatile manner in humans and in all other spe-
cies examined, with from 8 to 12 pulses occurring in a 24-hour period [8]. In
men, approximately 70% of GH secretion occurs during the early hours of
the night, in association with deep (electroencephalographic [EEG] stage
III–IV, or slow wave) sleep [9], whereas daytime pulses are of lesser magni-
tude and interspersed with troughs that are at or beneath the level of sensi-
tivity of most GH assays. In women, the relative proportion of daytime GH
secretion is greater and the interpeak troughs are slightly higher than in men
[10]. Similar and more pronounced gender differences are seen in the rat.
GH pulsatility is also affected by nutrient status, with obesity impairing
and fasting enhancing pulsatile GH secretion [11]. Experimental data
from animals [12] and humans [13] support the role of GHRH as the prin-
cipal regulator of GH pulsatility.

Age
GH secretion is maximal during puberty and through the third decade,
after which it declines progressively with age. A similar decline in slow-
wave sleep occurs during this same period, suggesting at least partial en-
trainment of GH with sleep. Sleep-associated GH secretion can be inhibited
by cholinergic muscarinic receptor blockade [14].

Feedback regulation
GH secretion is under a complex multilevel feedback regulatory control.
In the hypothalamus, GH feeds back to stimulate SRIF release and inhibit
GHRH release, thereby inhibiting its own secretion from the pituitary.
4 SAM & FROHMAN

IGF-1 has similar actions in the hypothalamus and also feeds back at the
level of the pituitary to inhibit basal and GHRH-stimulated GH secretion.
SRIF inhibits GHRH release, and GHRH stimulates SRIF release within
the hypothalamus. Together, these hormones create a dynamic control sys-
tem that also modulates the GH responses to all other stimuli. In addition,
feedback effects on the pituitary receptors for GHRH, SRIF, and ghrelin
add another level of control, although they likely contribute to a greater ex-
tent to long-term rather than to short-term regulation. Studies in humans
using a GHRH antagonist indicate that gender differences exist in GH feed-
back regulation [10].

Nutrient regulation
The profound metabolic effects of GH are associated with reciprocal ef-
fects of nutrients on GH secretion. Hyperglycemia in man leads to a marked
suppression of GH secretion for 1 to 3 hours, followed by a rebound in-
crease in GH [15]. In contrast, hypoglycemia is a profound stimulus for
GH secretion [16]. Studies in mice suggest that these changes are mediated
by effects on GHRH and SRIF [17]. GH enhances amino acid uptake and
protein synthesis, whereas protein intake and especially certain amino acids,
notably arginine, stimulate GH secretion [18]. The additive effect of arginine
and GHRH and the responses to cholinergic agonists imply that this re-
sponse is mediated by an inhibition of SRIF release [19]. GH exerts pro-
found lipolytic effects and causes marked increases in free (nonesterified)
fatty acids. Acute elevations in free fatty acids, in turn, cause suppression
of GH secretion in response to GHRH [20], suggesting an effect mediated
by enhanced SRIF release. This observation is consistent with the reduced
GH secretion seen in obesity in which free fatty acids are elevated but not
with food deprivation, in which free fatty acid levels are also elevated.
This seeming paradox may be explained by the decreases in IGF-1 during
starvation.

Gonadal hormones
The activation of gonadal steroids at puberty and their decline during ag-
ing parallel the changes in GH secretion at these periods, although a causal
relation between the two has not been clearly demonstrated. Although some
studies report conflicting results, most animal studies suggest that the effects
of gonadal steroids occur primarily at the level of the pituitary and on GH
synthesis. In humans, evidence points to a stimulatory role of estrogens but
not androgens, except those that are aromatizable to estrogens [21]. These
effects are seen initially at puberty and can be demonstrated throughout
adult life. Estrogens and androgens also have opposite effects on hepatic
IGF-1 production, with estrogens inhibiting and androgens stimulating
 HYPOTHALAMIC PITUITARY REGULATION 5

IGF-1 synthesis. In humans, these effects tend to complicate the interpreta-

tion of gonadal steroids on GH secretion.

Glucocorticoid and thyroid hormones

Acute administration of glucocorticoids stimulates GH secretion [22].
However, chronic glucocorticoid therapy and endogenous hypercortisolism
decrease the GH response to stimulation. Although glucocorticoids have
direct stimulatory effects on the somatotrope, they also have effects on the
hypothalamic hormones affecting GH secretion and on the generation of
IGF-1, which makes interpretation of their overall effects complex. Simi-
larly, GH responses are reduced in both hypothyroidism and hyperthyroid-
ism. Thyroid hormone is required for GH gene expression, but its effects on
GH secretion also involve actions in the hypothalamus.

Prolactin
Prolactin is synthesized in lactotrope cells in the anterior pituitary that
account for 10% to 20% of pituitary cells [23,24]. However, this percentage
increases dramatically to approximately 40% in response to elevated estro-
gen levels, particularly during pregnancy [23–25]. Lactotropes are derived
from somatomammotropes (common precursor cell line to lactotropes
and somatotropes) and are the last pituitary cell line to differentiate during
embryonic development [24,25]. Pituitary development and anterior pitui-
tary cell differentiation involve the sequential expression of several tran-
scription factors, among which Pit-1 and PROP-1 (prophet of Pit-1) are
essential for differentiation of lactotropes and transcription of prolactin
[26]. Mutations in these genes are a cause of combined pituitary hormone
deficiency that involves GH, prolactin, and thyroid-stimulating hormone
(TSH) but may also involve gonadotropins [27].
Prolactin is a single-chain protein of 198 amino acids with a molecular
size of 23 kDa that shares extensive structural similarity to GH. The main
physiologic function of prolactin in mammals is stimulation of lactation
and modulation of maternal behavior. The physiologic effects of prolactin
are mediated by the prolactin receptor, a single membrane-bound protein
that belongs to the type 1 cytokine receptor family [28]. Activation of the
prolactin receptor involves ligand-induced dimerization of the receptor
and activation of Janus kinase 2 (JAK2), which results in tyrosine phosphor-
ylation of the receptor and other proteins, such as the signal transducer and
activator of transcription proteins (STAT 1–5) and Src-related protein
kinases (SH2-PK) [24,25,28]. Prolactin receptors are present in many tissues,
but the highest densities are in the liver, ovary, and mammary glands
[29].
6 SAM & FROHMAN

Hypothalamic regulation
In contrast to other anterior pituitary hormones, prolactin regulation is
unique in that the predominant hypothalamic influence on its secretion is
inhibitory rather than stimulatory. This regulation is provided primarily
by tonic inhibition by hypothalamic dopamine. Hence, disruption of the
hypothalamic-pituitary stalk increases prolactin secretion. The brain con-
tains several dopaminergic systems, of which the hypothalamic tuberoinfun-
dibular dopaminergic (TIDA) system is the main regulator of prolactin
secretion [25]. Dopamine reaches the lactotropes through the hypotha-
lamic-pituitary portal system and inhibits prolactin release, prolactin gene
expression, and lactotrope proliferation. Inhibition of prolactin release
occurs within seconds of exposure to dopamine on binding to type 2 (D2)
dopamine receptors, followed by hyperpolarization of the cell membrane
and inactivation of voltage-gated calcium channels [24,25]. Inhibition of
prolactin gene expression occurs within minutes or hours. Dopamine recep-
tors are members of the G protein–coupled receptor family, and the D2
receptor interacts with Gi proteins and inhibits adenylyl cyclase and inositol
phosphate metabolism [29–31]. The inhibition of lactotrope proliferation
occurs within days and is mediated by blockade of cAMP actions that are
mitogenic in lactotropes [24,25].

Prolactin autoregulation
Prolactin regulates its own release through a short-loop feedback mech-
anism by binding to prolactin receptors on the hypothalamic dopaminergic
system [24]. This feedback mechanism is mediated by modulating the activ-
ity of tyrosine hydroxylase (TH), the rate-limiting enzyme for synthesis of
dopamine, in TIDA neurons [24,25]. An increase in circulating prolactin
levels increases the activity of this enzyme in TIDA neurons, thereby in-
creasing dopamine synthesis. Conversely, a reduction in circulating prolac-
tin levels decreases TH activity in TIDA neurons and decreases dopamine
synthesis and release [24,25]. The mechanisms regulating these events are
not fully understood. This regulation seems to be lost in certain physiologic
and pathologic conditions, such as pregnancy, lactation, and prolactinomas
that are associated with elevated prolactin levels [25].

Prolactin-releasing factors
Several known stimulators of prolactin secretion include hypothalamic
peptides, such as thyrotropin-releasing hormone (TRH), oxytocin, growth
factors, and estrogen [23,24]. Even though TRH is a potent stimulator of
prolactin release in vitro [32], its significance in vivo has been questioned,
because primary hypothyroidism does not consistently lead to
 HYPOTHALAMIC PITUITARY REGULATION 7

hyperprolactinemia [23,24]. Both oxytocin and prolactin secretion are in-

creased during lactation [33] and in response to nipple stimulation [34]. Es-
trogen stimulates PRL gene transcription and secretion [23–25,35] and
affects prolactin homeostasis in the hypothalamus and pituitary [25], leading
to higher PRL levels in women of reproductive age as compared with post-
menopausal women and men [36]. Prolactin levels in humans are also sleep
dependent and rise with the onset of sleep [37].

Thyroid-stimulating hormone
TSH is a 28-kDa heterodimeric glycoprotein hormone consisting of two
noncovalently linked subunits. TSH is secreted from thyrotrope cells, which
constitute 5% of anterior pituitary cells. The a-subunit is common to TSH,
follicle-stimulating hormone (FSH), and luteinizing hormone (LH) (and
also chorionic gonadotropin) and contains 92 amino acids. The b-subunit,
which contains 110 amino acids, is unique to the thyrotrope and confers
specificity of biologic action. Both subunits are glycosylated on asparagine
residues, and appropriate glycosylation is necessary for correct molecular
folding and optimal biologic activity [38]. Glycosylation not only enhances
TSH biologic activity on the thyroid but increases the metabolic clearance
rate of the hormone. Approximately 40 to 150 mU of TSH is secreted daily,
and the hormone’s half-life in circulation is approximately 30 minutes [39].

Neuroendocrine regulation
The primary neuroendocrine regulation of TSH is mediated through TRH.
TRH is a tripeptide present in many regions of the nervous system and in non-
neural tissue. However, the TRH-containing neurons that control TSH secre-
tion are located exclusively in the periventricular and medial parvocellular
subdivisions of the hypothalamic paraventricular nucleus. TRH secretion is
regulated by numerous neuropeptides, including leptin, proopiomelanocortin
(POMC), neuropeptide Y (NPY), Agouti-related peptide (AGRP), and co-
caine- and amphetamine-related transcript (CART), which integrate the influ-
ence of energy metabolism on thyroid hormone secretion [40,41]. The
physiologic importance of TRH is reflected by the absence of an increase in
serum TSH despite subnormal thyroxine (T4) levels in patients who have hy-
pothalamic disorders. In addition to its feedback effects on the pituitary, thy-
roid hormone also exerts inhibitory effects on TRH biosynthesis and secretion
into the hypophyseal-portal circulation [42,43].
Somatostatin inhibits TSH as well as GH secretion, although it is less po-
tent on the thyrotrope than on the somatotrope [44]. Even though SRIF
analogues are useful in treating TSH-secreting tumors, their long-term use
in acromegaly does not lead to hypothyroidism. Dopamine also suppresses
TSH secretion by its inhibitory effects on adenylyl cyclase [45]. However,
long-term use of dopamine agonists does not result in hypothyroidism.
8 SAM & FROHMAN

Intrapituitary regulation
TSH synthesis and secretion are regulated primarily by the interplay of
TRH and thyroid hormone. TRH stimulates and thyroid hormone sup-
presses the transcription of both a- and b-subunits. TRH, in addition, en-
hances posttranslational processing of TSH, primarily by increasing
glycosylation. TRH action is initiated by its binding to a specific thyrotrope
membrane receptor that is coupled to a G protein, with cyclic guanosine nu-
cleotide (cGMP) serving as a second messenger. The G protein also activates
phospholipase C, increasing inositol triphosphate (IP3) leading to mobiliza-
tion of Ca2þ and release of TSH from secretory granules. Thyroid hormone
inhibits the stimulatory effect of TRH on TSH release. This acute inhibitory
effect requires conversion of T4 to triiodothyronine (T3), which is produced
by type II deiodinase (D2) within the pituitary.
Recent studies have implicated another pituitary cell type, the folliculo-
stellate (FS) cell, as the exclusive site of D2 in the pituitary, and it has been
proposed that this cell plays a critical intermediary role in the effects of thy-
roid hormone on the thyrotrope [46]. FS cells are organized into a three-
dimensional network within which the hormone-secreting cells reside. This
network forms a functional intrapituitary circuit that can transport small
signaling molecules (eg, Ca2þ and T3) throughout the anterior pituitary to
various cell types [47].
Evidence also exists from animal studies for a paracrine/autocrine regu-
lation of the thyrotrope by locally produced pituitary peptides [48]. The
most consistent data relate to neuromedin B, a bombesin-like peptide, which
seems to exert an inhibitory effect. The relevance of these regulatory
peptides in humans is presently unclear.

Pulsatility
TSH secretion occurs in a pulsatile manner. The ultradian pattern con-
sists of secretory pulses that occur every 2 to 3 hours with constant low
levels of secretion between pulses. There is also a diurnal pattern of TSH se-
cretion with a nocturnal surge that occurs before the onset of sleep [49].
Sleep onset seems to have an inhibitory effect, because the surge is enhanced
if sleep is delayed, whereas early sleep onset and prolonged sleep result in
a diminished surge and shorter duration of TSH secretion. The pulsatility
is independent of circulating thyroid and glucocorticoid hormone levels,
and thus is most likely neurally driven.

Aging
As individuals age, the daily secretion of TSH is reduced and the circulating
levels decrease [50]. Although free T4 levels in serum remain unchanged, the
 HYPOTHALAMIC PITUITARY REGULATION 9

T3/T4 ratio decreases in the eighth and ninth decades. It is uncertain whether
these changes have clinical consequences other than the need for a reduction in
T4 dose (by approximately 20%) in patients receiving exogenous hormone.

Feedback control
The feedback regulation of TSH secretion occurs principally as the result
of changes in peripheral thyroid hormone levels. Feedback occurs primarily
in the pituitary, mediated by mechanisms described previously. The effects
can be seen within a few hours of elevations of thyroid hormone levels
and occur initially by reducing the TSH secretory response to TRH and later
by effects on TSH synthesis. Thyroid hormone feedback also occurs on
TRH-producing neurons, but these effects are believed to be of lesser
magnitude than those on the thyrotrope. Suppression of the hypothalamic
component of the axis can be observed after long periods of thyroid hor-
mone administration, but the severity of hypothyroidism and the duration
of the recovery of function are much less pronounced than is seen with
the hypothalamic-pituitary-adrenal axis.
In addition to this classic feedback loop, evidence exists for both short-loop
feedback (inhibitory effects of TSH on hypothalamic TRH) and ultrashort-
loop feedback (inhibitory effects of TSH within the pituitary) mechanisms
[51]. The latter is believed to involve the FS cells, which express the TSH recep-
tor. The physiologic role of this loop may be in the fine-tuning of the secretory
patterns of TSH and the generation of pulsatile hormone secretion.

Nutritional effects
TSH, T3, and T4 concentrations are decreased by both short-term and
long-term fasting in people, as are reductions in pulsatile and circadian
TSH secretion [52]. In animal studies, decreased TRH release into portal
blood and reduced pro-TRH mRNA have been observed [53,54]. The medi-
ation of these changes has been attributed to the decrease in leptin produc-
tion that occurs during food deprivation. Leptin directly stimulates TRH
mRNA and also indirectly affects TRH through its interactions with other
hypothalamic neuropeptides that regulate nutrient homeostasis [55].

Exercise and stress

Acute physical activity induces an increase in TSH levels within minutes
of its onset. The changes are most pronounced at night, when TSH secretion
is normally increased [56]. The mediation of this response is not fully under-
stood but appears to be independent of glucocorticoid activation, which
would be expected to suppress TSH secretion [57]. Stress is associated
10 SAM & FROHMAN

with decreased activation of the hypothalamic-pituitary-thyroid axis. This

inhibition is in part mediated by indirect negative feedback effects on the
hippocampus that counterbalance the direct stimulatory effect of glucocor-
ticoids on TRH production in TRH-containing neurons.

Corticotropin
The synthesis and secretion of glucocorticoids from the adrenal cortex
are under the regulation of the hypothalamic-pituitary axis. Glucocorticoids
are essential for maintenance of vascular tone, endothelial integrity, cardiac
contractility, and response to stress. The hypothalamic-pituitary-adrenal
(HPA) axis is tightly regulated to ensure adequate glucocorticoid secretion
in response to stress and to avoid excess glucocorticoid release.

The corticotrope
Corticotrope cells comprise 20% of anterior pituitary cells and are the
first anterior pituitary cell type to differentiate during embryonic develop-
ment [23]. Transcription factor Tbx19/T-pit is essential for differentiation
of pituitary corticotropes during embryonic development, and mutations
in this gene are associated with isolated corticotropin (ACTH) deficiency
in humans [58]. The corticotropes are located in the central median portion
of the pituitary and produce ACTH by enzymatic cleavage of the precursor
hormone, POMC [23,59]. The POMC gene coding for this precursor hor-
mone is highly expressed in the corticotropes and is transcribed by the pitu-
itary promoter P1 to an approximately 1200-nucleotide POMC mRNA
transcript. The primary translation product of POMC is cleaved by prohor-
mone convertase 1 in the pituitary gland, resulting in an N-terminal peptide,
ACTH(1–39), and b-lipotropin [60]. In addition to stimulating adrenocortical
steroidogenesis and secretion, ACTH is essential for maintenance of adrenal
gland size and structure [23,61]. The adrenal cortex undergoes atrophy and
loses its secretory capacity in the absence of ACTH [61,62].

Hypothalamic regulation of corticotropin

Pituitary ACTH release is stimulated primarily by corticotropin-releasing
hormone (CRH) that is synthesized by CRH neurons located in the para-
ventricular hypothalamus [63,64]. These neurons project to the median
eminence and release CRH into the hypophysial portal system. CRH
stimulates ACTH secretion initially by the release of preformed peptide
from pituitary cells but concurrently stimulates ACTH synthesis by increas-
ing POMC gene expression in corticotropes [65]. These actions are mediated
by CRH type 1 receptor, a G protein–coupled receptor predominantly
 HYPOTHALAMIC PITUITARY REGULATION 11

expressed on corticotropes, which signals through cAMP [23,61,66,67]. In

addition to CRH, vasopressin and oxytocin directly stimulate ACTH re-
lease, although these effects are weak. However, these hormones can act
in synergy with CRH to potentiate ACTH release [61,68,69]. Furthermore,
many CRH neurons express vasopressin and upregulate its expression in re-
sponse to stimulation [61,70]. Additional factors regulating POMC gene ex-
pression include neurotransmitters, such as dopamine, serotonin, and
catecholamines [59], and cytokines, such as leukemia inhibitory factor,
a proinflammatory cytokine that is expressed in the pituitary and acts
synergistically with CRH to stimulate the release of ACTH [71].

Glucocorticoid feedback action

Glucocorticoids suppress POMC expression in pituitary corticotropes
[61,72] and inhibit secretion of CRH and vasopressin, leading to inhibition
of ACTH secretion [73]. This feedback inhibition is classified according
to time of the phenomena: fast (within 30 minutes of glucocorticoid
administration), delayed (minutes to hours), and slow (hours to days)
[23,61,67,72,73]. The first two occur under physiologic conditions, such as
after moderate stress, and involve inhibition of stimulated ACTH secretion.
Slow feedback affects basal and stimulated ACTH secretion and occurs after
chronic exposure to glucocorticoids, such as in Cushing’s syndrome or with
sustained high-dose exogenous glucocorticoid administration [61,72].
Glucocorticoids exert their actions by binding to two receptors: glucocor-
ticoid receptor (GR) and mineralocorticoid receptor (MR) [67]. GR is ex-
pressed widely in many peripheral tissues and the brain, including the
pituitary and hypothalamus, whereas the expression of MR is generally re-
stricted to peripheral mineralocorticoid target tissues, such as the kidney
and limited areas in the brain [61,74,75]. Glucocorticoids bind to MR
with greater affinity than to GR [61], but are unable to activate peripheral
MR due to enzymatic inactivation [76]. The negative feedback actions of
the glucocorticoids on the HPA axis involve binding to GR in the pituitary
and hypothalamus and to MR in other areas of the brain, such as the hip-
pocampus [61,74]. Although glucocorticoid feedback on basal HPA activity
is mediated by MR and GR [77,78], suppression of stimulated ACTH secre-
tion only occurs through binding to GR in pituitary corticotropes and hy-
pothalamic CRH neurons [61,67].

Circadian rhythmicity
Levels of ACTH and glucocorticoids follow a circadian rhythm, and in
humans, the levels peak in the early morning and gradually decline during
the day to reach a nadir at midnight [59]. This circadian rhythm is generated
in the suprachiasmatic nucleus, which sends neuronal afferents into the
12 SAM & FROHMAN

paraventricular nucleus of the hypothalamus and regulates CRH expres-

sion. The amplitude rather than the frequency of ACTH pulses regulates
glucocorticoid levels; thus, the amplitude of ACTH pulses is much higher
during the peaks of cortisol secretion. Furthermore, glucocorticoid feedback
action is essential for the control of this circadian rhythm [59,61] and this
feedback regulation is mediated by GR and MR actions [61,78,79].

Luteinizing hormone and follicle-stimulating hormone

The regulation of gonadal function in men and women is under the con-
trol of the hypothalamus and the pituitary gland by means of negative and
positive feedback mechanisms. This regulation is complex, and the details
have only begun to be understood in recent years. Endocrine, paracrine,
and autocrine mechanisms are involved, and the regulators include hypotha-
lamic and pituitary hormones, neurotransmitters, and endogenous opioids
in addition to steroidal and nonsteroidal hormones from the gonads.

The hypothalamus and gonadotropin-releasing hormone

Gonadotropin-releasing hormone (GnRH)–producing neurons originate
from the olfactory area and migrate during embryogenesis to their primary
location within the arcuate nucleus of the hypothalamus [23]. In mammals,
two forms of GnRH have been identified [80,81]. GnRH I, a 10–amino acid
peptide, is synthesized in GnRH neurons and is released into the hypophy-
seal portal system to stimulate the synthesis and secretion of LH and FSH
from anterior pituitary gonadotropes [82,83]. A second GnRH, GnRH II,
differs from GnRH I by three amino acids and is found in the midbrain re-
gion and may be important in sexual behavior, although its exact physio-
logic function is not yet determined [84]. In this review, the term GnRH
refers to GnRH I.
GnRH is released in a pulsatile manner, which is essential for mainte-
nance of normal gonadotropin synthesis and secretion. The importance of
the pulsatile secretion of GnRH was initially observed in monkeys with hy-
pothalamic lesions in which normal gonadotropin secretion was restored by
pulsatile but not continuous GnRH administration [85]. GnRH neurons se-
crete in a coordinated pulsatile manner and may have an intrinsic pulse-gen-
erating capacity [23]. The term GnRH pulse generator has often been used to
represent this coordinated pulsatile release. The frequency of the GnRH
pulses is a critical factor that determines LH and FSH synthesis and secre-
tion. The endogenous frequency of the GnRH pulse generator in primates is
approximately one pulse per hour. This pulse frequency selectively enhances
pituitary LH release, whereas FSH release is favored by slower GnRH pulse
frequency, one pulse every 3 to 4 hours [86]. Furthermore, the pattern of
GnRH pulse frequency is crucial in differential gonadotropin b-subunit
 HYPOTHALAMIC PITUITARY REGULATION 13

gene transcription [87,88]. In rats [89], fast-frequency GnRH pulses increase

a-subunit mRNA levels and the LHb primary transcript. However, a sus-
tained increase in FSHb transcription requires slower GnRH pulses [89].
The mechanisms for differential activation of gonadotropin subunit gene
transcription by changes in GnRH pulse frequency have not yet been clearly
identified and may involve several signaling pathways [90].

Central regulators of gonadotropin-releasing hormone

Many neurotransmitters and peptides from various brain regions convey
information to GnRH neurons. These systems include neurons that contain
norepinephrine, epinephrine, dopamine, serotonin, g-aminobutyric acid
(GABA), glutamate, endogenous opiate peptides, NPY, and galanin. In
general, catecholamines stimulate GnRH release, whereas endogenous opi-
oid peptides and prolactin inhibit GnRH secretion [91]. Sex steroids are im-
portant regulators of GnRH and gonadotropins, as is discussed elsewhere
in this article. Recently, a new family of peptides, kisspeptins, have been
identified that markedly stimulate GnRH-induced gonadotropin secretion
in rodents and humans on central or peripheral administration [92]. These
peptides are endogenous ligands for the G protein–coupled receptor
GPR54, and mutations in the gene coding for this receptor result in hypo-
gonadotropic hypogonadism in men [93,94]. Kisspeptin-GPR54 signaling
may have a crucial role in the regulation of puberty by contributing to
the pubertal re-emergence of pulsatile GnRH release [95]. Recent data
also indicate that this signaling pathway may mediate the positive and neg-
ative feedback regulation of GnRH by sex steroids [92].

Gonadotropin-releasing hormone action

GnRH action on gonadotropes is initiated by binding to its cell membrane
receptor. The GnRH receptor (GnRH-R) is a seven-transmembrane protein,
and, on binding to its ligand, activates multiple signal transduction pathways
that stimulate the synthesis and release of gonadotropins [84]. GnRH is the
main regulator of GnRH-R concentrations, which increase when endogenous
GnRH levels are increased [96,97]. The ability of GnRH to induce its own re-
ceptor is termed upregulation and only occurs with certain physiologic fre-
quencies of pulsatile GnRH that differ among species [91]. In contrast,
continuous GnRH exposure leads to GnRH-R downregulation, termed de-
sensitization [91].

The pituitary gonadotropes

Gonadotropes constitute 7% to 15% of the cells in the anterior pituitary
and are located in the lateral portion of the gland [91]. LH and FSH are
14 SAM & FROHMAN

glycoproteins with a common a-subunit and distinct b-subunits that confer

specificity to each hormone. Most gonadotropes are capable of synthesizing
and secreting LH and FSH. Both gonadotropins are synthesized and re-
leased in a pulsatile manner in response to pulsatile GnRH [98]. As previ-
ously discussed, the pattern of GnRH pulse frequency determines the
differential synthesis of gonadotropin b-subunits, with slower GnRH pulses
favoring FSH synthesis and release and faster pulses favoring LH synthesis
and release [86–89]. Additionally, GnRH enhances pituitary responsiveness
to subsequent pulses of GnRH, leading to increased LH secretion, a phenom-
enon referred to as a self-priming effect, which is further enhanced by estra-
diol [91] and is essential for the midcycle LH surge during the female
menstrual cycle.

Intrapituitary regulation of gonadotropins

In addition to GnRH and sex steroids, inhibins, activins, and follistatin
are important regulators of gonadotropin synthesis and secretion [99]. All
three latter compounds were initially isolated from the gonads but are
widely expressed in other tissues, including pituitary gonadotropes [99–
101]. Inhibins and activins are members of the transforming growth fac-
tor-b (TGFb) superfamily [101–103]. Inhibins are dimers of an a-subunit
and a bA (inhibin A) or bB subunit (inhibin B), whereas activins are homo-
dimers of bA or bB subunits, activin A (bA, bA) and activin B (bB, bB) [104].
Follistatin is an activin-binding protein that neutralizes, and thus modu-
lates, all action of activins [105]. Although inhibins are considered to act
in an endocrine manner to regulate FSH release, the actions of activins
and follistatin seem to be of an autocrine/paracrine nature [99,102].
Activin and follistatin synthesized locally by the pituitary are important
physiologic regulators of FSH production [99,102]. Activin is a potent stim-
ulator of FSH secretion in vivo and in vitro [106,107] and has been shown to
increase FSHb mRNA expression in pituitary cell cultures [108,109]. Mono-
clonal antibodies against activin inhibit FSH release from pituitary cells
[110]. Furthermore, transgenic mice with defects in activin receptor type
IIA have reduced levels of FSH [111]. Inhibin/activin subunits, activin
receptors, activin B, and follistatin are all synthesized in the pituitary
[99,102], supporting an autocrine/paracrine mode of regulation. Follistatin
is an activin-binding protein [112] that interferes with activin binding to
its receptors (activin type-I and activin type-II), thereby inhibiting activin’s
actions [113]. Follistatin mRNA levels are directly regulated by GnRH pulse
frequency. Fast GnRH pulses increase follistatin mRNA levels and result in
activin inhibition and reduced FSH production, whereas slower frequency
GnRH pulses have the opposite effect [89,114]. In addition to follistatin,
inhibins antagonize activin’s stimulation of FSH synthesis and release by
interfering with activin binding to its receptors [102].
 HYPOTHALAMIC PITUITARY REGULATION 15

Sex steroid feedback

Sex steroids are important regulators of GnRH and gonadotropin release
through classic feedback mechanisms in the hypothalamus and the pituitary.
In the hypothalamus, estradiol, progesterone, and testosterone all slow the
frequency of GnRH release by negative feedback action [23]. Even though
GnRH neurons express steroid hormone receptors, such as estrogen receptor
b [115], the feedback actions of sex steroids on GnRH are widely believed to
be mediated by other neuronal pathways [23,116]. As an example, in primates,
the progesterone-mediated negative feedback actions on GnRH secretion are
mediated by hypothalamic b-endorphin–containing neurons and can be
blocked by naloxone, an opiate receptor blocker [117,118]. Kisspeptins
have also been implicated in sex steroid feedback regulation of GnRH secre-
tion by acting directly on GnRH neurons [119]. Kisspeptin-secreting neurons
in the hypothalamus express sex steroid receptors, and sex steroids can alter
the expression of the kisspeptin gene, and hence GnRH secretion [92,119].
Sex steroids also exert negative feedback at the level of the pituitary, al-
though this feedback is most significant for estradiol. Estradiol is unique
among sex steroids in its ability to exert positive and negative feedback ac-
tions at the level of the hypothalamus and pituitary [23,91]. Estradiol’s ac-
tions on gonadotropes are characterized by an initial suppression and
subsequent increase in LH [91,120]. Numerous studies have confirmed these
observations, and the time course of the biphasic action depends on the spe-
cies and dose of estradiol. In women, GnRH administration suppresses LH
levels for the first 36 hours; however, after 48 hours, the LH response is aug-
mented and persists for several days [121,122]. The mechanisms involve en-
hancement of the GnRH self-priming effect [123] and increased gonadotrope
sensitivity to GnRH stimulation [124]. The ability of estradiol to stimulate
LH secretion by positive feedback is essential for the midcycle LH surge
in women [23,91].

Inhibins and regulation of hypothalamic pituitary gonadal axis

Inhibins are an additional important regulator of FSH biosynthesis and
secretion in men and women. In both genders, inhibins are synthesized and
released by the gonads and act in an endocrine manner to inhibit FSH secre-
tion [99,102]. The mechanism most likely involves interaction with an in-
hibin coreceptor, betaglycan (type III TGFb receptors) [125,126]. This
interaction interferes with activin binding to its receptor, and thus antago-
nizes activin’s actions. In women, inhibin A and B are important regulators
of FSH, and each is distinctly regulated. Inhibin A levels peak during the
midluteal phase, and thus inhibit FSH secretion in the luteal phase of the
menstrual cycle [91,99]. In contrast, inhibin B levels peak in the midfollicular
phase and act synergistically with estradiol to reduce FSH levels in the late
follicular phase of the cycle. In men, inhibin B is the main form of
16 SAM & FROHMAN

circulating inhibin [127]. It is synthesized in the testes predominantly by Ser-

toli cells and is regulated by spermatogenesis [99,128,129]. Inhibin B levels
decrease with suppression of spermatogenesis and increase when spermato-
genesis is stimulated [99].

Summary
This article has focused on the physiology of secretion of the anterior pi-
tuitary hormones. It has reviewed the individual pituitary hormones, the
cells from which they are secreted, and the mechanisms of regulation of their
secretion. Emphasis has been given to the integration of neural control
mechanisms, intracellular pathways involved in the secretory process, feed-
back control by peripheral hormones, pulsatility of secretion, and the close
interrelation between nutritional status and metabolic factors.

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