C H A P T E R
15
Hypothalamic–Pituitary Regulation
S. Melmed
Cedars-Sinai Medical Center, Los Angeles, CA, United States
The pituitary gland, weighing about 600 mg
and situated at the base of the brain, is located
within the sella turcica and abuts the cavernous
sinuses, cranial nerves, and optic chiasm. These
anatomic constraints confine an expanding pitu-
itary mass, and result in compression of pituitary
tissue leading to compromised pituitary hor-
mone reserve function. As the gland is encased
by bony structures, the path of least resistance
for intrasellar mass extension leads to invasion
of the cavernous sinuses laterally, and lifting of
the optic chiasm dorsally.
Hypothalamic-releasing and -inhibiting hor-
mones are synthesized centrally and secreted into
pituitary stalk portal vessels to impinge on specific
pituitary cells to release or inhibit pituitary tro-
phic hormone release into the systemic circulation.
The anterior pituitary gland comprises at least six
functional and terminally differentiated cell com-
partments, each expressing a unique gene prod-
uct encoding a trophic hormone (Fig. 15.1). These
hormones are synthesized and secreted into the
systemic circulation to regulate the repertoire of
endocrine gland function, including thyroid, adre-
nal, gonadal, breast, metabolic, growth, and body
composition functions. This complex central endo-
crine control system is mediated by six hormones,
each produced by a highly differentiated cell type:
somatotrophs produce growth hormone (GH);
Conn’s Translational Neuroscience
http://dx.doi.org/10.1016/B978-0-12-802381-5.00025-7 317
lactotrophs produce prolactin (PRL); corticotrophs
express proopiomelanocortin (POMC), the precur-
sor of adrenocorticotropin (ACTH), melanocortin
hormone (MSH), lipotropic hormone (LPH), and
endorphins; gonadotrophs produce luteinizing
hormone (LH) and follicle stimulating hormone
(FSH); and thyrotrophs produce thyroid stimu-
lating hormone (TSH). The heterodimeric glyco-
protein hormones TSH, LH, and FSH comprise a
common α-subunit and a specific β-subunit, stabi-
lized by disulfide bonding. Specificity of h ­ ormone
action is determined by the β-subunit which
also is the interactive moiety binding a cognate
­receptor for each of the three hormones. GH, PRL,
and ACTH are single-chain polypeptides. Each
­pituitary hormone elicits distinct trophic responses
in target glands, which in turn exert negative and
positive feedback control at the hypothalamus and
pituitary to regulate pituitary synthesis and secre-
tion (Fig. 15.2).
Pituitary hormones are synthesized and
then secreted into the systemic circulation in
a controlled fashion to regulate the repertoire
of endocrine gland cell survival and hormone
synthesis and secretion (Fig. 15.3). Overall,
thyroid, adrenal, gonadal, breast, metabolic,
growth, and body composition functions are
maintained in homeostasis by finely tuned cen-
tral pituitary hormone actions (Table 15.1).
Copyright © 2017 Elsevier Inc. All rights reserved.
318 15.  HYPOTHALAMIC-PITUITARY REGULATION
FIGURE 15.1  The hypothalamic–pituitary unit and
relationships of neural structures and hormone secretion.
Hypothalamic-oxytocin and -vasopressin neurons ter-
minate directly in the posterior pituitary. Hypothalamic
neurons produce growth hormone-releasing hormone
(GHRH), corticotropin releasing hormone (CRH), thyrotro-
pin-releasing hormone (TRH), and gonadotropin releasing
hormone (GnRH) which traverse the hypophyseal–portal
circulation surrounding the pituitary stalk and penetrate
the anterior pituitary. Hypothalamic-neurohormones signal
through cognate GPCRs to differentiated anterior pituitary
cells to secrete growth hormone (GH), adrenocorticotropin
hormone (ACTH), thyroid stimulating hormone (TSH),
luteinizing hormone (LH), and follicle stimulating hor-
mone (FSH), respectively. Dopamine neurons signal
tonically to inhibit PRL secretion, while hypothalamic
somatostatin inhibits both GH and TSH release. Adapted from
Melmed S, Pituitary. In: Dale DC, Federman DD, editors. ACP
Medicine, vol. 1; 2006. pp. 571–86.
REGULATION OF PITUITARY
HORMONE SECRETION
The six functional and highly differentiated
cell compartments each expressing a unique
gene product are all regulated by specific signals.
The pituitary response, acting as the master con-
ductor, transduces central neuronal signals that
effectively impact peripheral endocrine target
glands by biochemical signaling. Integrated
control of pituitary function is subserved by
three tiers of regulation (Fig. 15.4). The first tier
comprises control by hypothalamic hormones,
the second tier incorporates paracrine and auto-
crine intrapituitary hormones, cytokine and
growth factor signals, and the third tier com-
prises feedback regulation enabled by periph-
eral hormones which regulate their respective
pituitary- or hypothalamic-control systems. The
integrated net result of these three signaling
levels is to enable synthesis of appropriate hor-
mone abundance, and generation of uniquely
timed and sized pituitary hormone secretory
pulses into the systemic circulation.
PITUITARY TRANSCRIPTION
FACTORS
Highly differentiated nuclear transcription
factors determine pituitary trophic cell-specific
development, differentiation, and specific hor-
mone production. POUIF-1 determines lacto-
troph and somatotroph specificity, while T-Pit
directs cell-specific POMC transcription in cor-
ticotroph cells. Gonadotroph cell differentia-
tion is mediated by DAX-1 and STAR proteins,
and thyrotrophs by several factors includ-
ing GATA-1. Disruptions of these factors by
hereditary mutations leads to failed pituitary
function. For example, inactivating POU1F-1
mutations lead to GH deficiency and short
stature. Some of these inherited mutations
may involve more proximal transcription fac-
tors (eg, PROP-1) leading to multiple pituitary
hormone deficiencies (Fig. 15.2).
Pituitary hormone synthesis and secre-
tion may proceed in an uncontrolled fashion
leading to hypersecretory syndromes, espe-
cially caused by pituitary tumors. In these
patients, there is loss of physiological control
 Pituitary Transcription Factors 319

FIGURE 15.2  Human anterior pituitary gland development and cell lineage determination by cell-specific transcription
factors. Pituitary trophic cells are depicted with transcription factors which determine cell-specific hormone gene expres-
sion. From Melmed S, Kleinberg DL, Ho K. Pituitary physiology and diagnostic evaluation. In: Melmed S, Polonsky KS, Larsen PR,
Kronenberg HM, editors. Williams Textbook of Endocrinology, 12th ed. Philadelphia: Elsevier-Saunders Publication; 2011. pp 175–228.

FIGURE 15.3  Control of anterior pituitary hormone secretion is achieved by hypothalamic hormone, which traverse the
portal vein, cell-specific transcription factors, and negative feedback control POU1F1 (pituitary-specific transcription fac-
tor) denotes POU domain, class 1, transcription factor 1; Prop-1 Prophet of Pit-1. From Melmed S. Acromegaly. N Engl J Med
2006;355:2558–73. Available from: http://www.nejm.org/doi/full/10.1056/NEJMra062453.
320 15.  HYPOTHALAMIC-PITUITARY REGULATION

TABLE 15.1 Anterior Pituitary Hormone Expression and Regulation

Cell Corticotroph Somatotroph Lactotroph Thyrotroph Gonadotroph

Tissue-specific T-Pit Prop-1, Pit-1 Prop-1, Pit-1 Prop-1, Pit-1, TEF SF-1, DAX-1
transcription
factor

Fetal appearance 6 weeks 8 weeks 12 weeks 12 weeks 12 weeks

Hormone POMC GH PRL TSH FSH LH

Protein Polypeptide Polypeptide Polypeptide Glycoprotein α, β Glycoprotein α, β

subunits subunits

Amino acids 266 (ACTH 1–39) 191 199 211 210, 204

Stimulators CRH, AVP, gp-130 GHRH, ghrelin Estrogen, TRH, TRH GnRH, activins,
cytokines VIP estrogen

Inhibitors Glucocorticoids Somatostatin, Dopamine T3, T4, dopamine Sex steroids,

IGF-I somatostatin inhibin
glucocorticoids

Target gland Adrenal Liver, bone, other Breast, other Thyroid Ovary, testis
tissues tissues

Trophic effect Steroid production IGF-I production, Milk production T4 synthesis and Sex steroid
growth secretion production, follicle
induction insulin growth, germ cell
antagonism maturation

Normal circulating ACTH, 4–22 pg/L <0.5 μg/La M < 15; F < 20 μg/L 0.1–5 mU/L M, 5–20 IU/L, F

range in humans (basal), 5–20 IU/L
aHormone levels integrated over 24 h.
M, male; F, female. For other abbreviations, see text.
Modified from Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, (eds.). Williams Textbook of Endocrinology, 12th ed. Philadelphia: Elsevier-Saunders
Publication; 2011.

and erratic adenomatous hormone secretion acromegaly/gigantism, lactotroph tumors to

ensues with resultant clinical disturbances.
Pituitary tumors may arise from any of the
hormone-secreting cell types. These are invari-
ably benign adenomas which may be small
(<10 mm) micro-adenomas or larger macro-
adenomas. Some of these tumors are par-
ticularly aggressive and lead to compressed
normal pituitary function, with invasion of
vital vascular structures (eg, cavernous sinus)
or cranial nerve compression leading to visual
impairment. Clinical phenotypes associated
with pituitary adenomas are determined by
the cell of origin and the specific overproduced
hormone. Thus, somatotroph tumors lead to
infertility and lactation, corticotroph tumors
to hypercortisolism with Cushing disease,
and thyrotroph tumors to hyperthyroidism
and goiter. Tumors arising from gonadotroph
cells are usually nonsecreting, but may pres-
ent with hypogonadism. This may be due to
several factors. Sustained nonpulsatile secre-
tion of gonadotrophin hormones may lead to
downregulation of their peripheral receptors.
Furthermore, the adenoma may also not effi-
ciently synthesize gonadotrophins. Finally, an
expanding pituitary mass, regardless of eti-
ology, may compress normal pituitary tissue
and compromise gonadotropin secretion.
 Hypothalamic Factors Regulating Pituitary Function
FIGURE 15.4  Hypothalamic–pituitary–target axes are
regulated by three tiers of control. Hypothalamic neurons
synthesize hormones which are released into the hypophy-
seal–portal circulation to impinge on anterior pituitary cells
to mediate brain-pituitary signal transduction resulting in
release to the circulation, ultimately reaching target glands
and organs. Within the pituitary, local cytokines, and growth
factors also regulate anterior pituitary hormone synthesis
and release. Distal target glands secrete hormones that elicit
the required effects on peripheral tissues, and also feed-
back to regulate respective hypothalamic–pituitary control
hormones. From Ben-Shlomo A, Melmed S. Hypothalamic
regulation of anterior pituitary function. In: Melmed S, editor. The
Pituitary, 3rd ed.; 2010. pp 21–45.
HYPOTHALAMIC FACTORS
REGULATING PITUITARY
FUNCTION
Cajal proposed the functional concept of
hypothalamic regulation of the anterior pituitary,
which was subsequently proven by Harris, who
demonstrated that direct hypothalamic electrical
stimulation was sufficient to induce ovulation.
This finding supported the hypothesis for exis-
tence of a humoral mechanism whereby chemical
messengers traverse the hypothalamic–pituitary
321
portal venous system to impinge upon and
signal to the anterior pituitary. The role of the
hypothalamic–pituitary unit has now been well
defined, and mechanisms underlying pituitary
control well established.
The hypothalamus, located below the third
ventricle, comprises distinct yet heterogeneous
neurosecretory nuclei, whose axons extend
to the median eminence which extends to the
infundibular stalk. Complex electrical signals
emanating from brain centers terminate at
hypothalamic nuclei to regulate synthesis and
release of hypothalamic-peptide hormones. The
derivation of these brain signals is diverse and
intricate, and may include stress, temperature
sensation, fluid and electrolyte balance, as well
as higher functions.
Hypothalamic-neuronal bodies synthesize
and package pituitary control factors: thyro-
tropin-releasing hormone (TRH), gonadotro-
phin releasing hormone (GnRH), corticotropin
releasing hormone (CRH), growth hormone-
releasing hormone (GHRH), and somatostatin
(somatotropin releasing–inhibiting factor, SRIF),
mostly located in the medial hypothalamus.
Each of these hormones binds to a cognate
receptor expressed on a respective differenti-
ated pituitary target cell membrane. The median
eminence functionally links the hypothalamus
and the pituitary. Superior hypophyseal arter-
ies which derive from the internal carotid arter-
ies, supply the hypothalamus, and form median
eminence capillaries outside the blood–brain
barrier. Hypophyseal portal vessels form the
hypothalamic–portal circulation, the predomi-
nant anterior pituitary blood source. Hypotha-
lamic-axonal termini are functionally linked
to fenestrated pituitary portal venous capil-
lary endothelium, enabling release of hypo-
thalamic peptides into the hypophyseal–portal
circulation to reach anterior pituitary trophic
hormone-secreting cells (Fig. 15.3). Accord-
ingly, concentrated levels of hypothalamic-
releasing and -inhibiting hormones traverse
these vessels to reach the pituitary trophic
322 15.  HYPOTHALAMIC-PITUITARY REGULATION
hormone–producing cells without significant
systemic dilution. Further control systems for
hypothalamic hormone vascular transit include
regulated portal capillary contractility, as well
as bidirectional hypothalamic–pituitary control
enabled by retrograde flow of portal blood from
the pituitary dorsally towards the median emi-
nence. This complex vascular mechanism allows
exquisite regulation of anterior pituitary hor-
mone secretion by highly specific hypothalamic-
releasing and -inhibitory factors.
The overarching transduction of brain signals
to affect peripheral endocrine chemical mes-
sages is characterized by both qualitative, tem-
poral, and quantitative features. The abundance
of hypothalamic, pituitary, or peripheral mes-
senger molecules at each level, as determined
by both half-life as well as concentration syn-
thesized, increases incrementally. At each level
of pituitary control, an increasing magnitude of
amplified hormonal release occurs. Thus, nano-
molar concentrations of hypothalamic factors
are transduced to elicit micromolar concentra-
tions of secreted pituitary hormones, which in
turn elicit millimolar concentrations of periph-
eral hormones. Furthermore, the circulating
half-life of hypothalamic peptides is very short
(minutes), pituitary hormone half-life is usu-
ally minutes (eg, 12 min for GH) to hours, while
peripheral hormone circulating half-life may be
days (eg, thyroid hormones; IGF-I). Pituitary
cells are therefore targets for sensitive and highly
leveraged hypothalamic regulation by timed
hypothalamic-hormone secretory patterns.
Brain signaling to peripheral hormone-
secreting target glands transduced by the
hypothalamic–pituitary unit is characterized
by several physiological features. For example,
target gland actions are controlled by unique
patterns of secretion at each level. Thus, cir-
cadian, pulsatile, or acute central stimuli
signal to secrete specific hypothalamic hor-
mones into the hypophyseal–portal circulation
with specific secretory profiles. Subsequent
pituitary hormone secretion to the systemic
circulation is controlled in a diurnal and/or
pulsatile fashion, and then bind distal recep-
tors expressed on target organs which regulate
peripheral endocrine hormone production.
Disrupted secretory patterns may lead to endo-
crine dysfunction or failure of peripheral target
glands to appropriately respond to pituitary sig-
nals. Thus, continued erratic secretion of gonad-
otrophin hormones by a pituitary adenoma may
lead to downregulation of gonadal function.
Negative feedback regulation of hormone secre-
tion exists at all levels of control, but mostly
by target gland hormones which usually sup-
presses both pituitary and hypothalamic-
hormone synthesis and secretion. Negative
feedback suppression of pituitary hormone
production usually overrides positive central
signals. Accordingly, hypersecretion of periph-
eral hormones by secreting tumors (eg, thyroid,
adrenal) leads to suppressed pituitary hormone
production as well as suppressed trophic cell
proliferation. Conversely, ablation or failure of
peripheral gland function results in exuberant
hypersecretion of pituitary trophic hormones.
HYPOTHALAMIC–PITUITARY–
ADRENAL AXIS
This vital pituitary axis is essential for cell
survival and response of the organism to stress
(Fig. 15.5). Adrenal cortisol regulates multiple
cellular processes essential for maintaining fuel
and energy metabolism, immunity and cardio-
vascular homeostasis, as well as central nervous
system functions.
Corticotroph cells comprise about 20% of the
functional hormone-secreting anterior pituitary
cells, and appear early by the 8th week of ges-
tation. These are the first human pituitary cells
to develop, differentiate, and mature. Prominent
neurosecretory granules (150–400  nm) within
the corticotroph contain POMC gene prod-
ucts, including 1–39 ACTH, β-lipotropin, and
endorphins. Each of these hormones contains
 Hypothalamic–Pituitary–Adrenal axis
FIGURE 15.5 Hypothalamic corticotropin releas-
ing hormone (CRH) stimulates the corticotroph to
synthesize and release adrenocorticotropin hormone
(ACTH), which in turn stimulates the adrenal glands
to produce and release c­ortisol and androgens. Corti-
sol acting in a negative-­ feedback loop inhibits further
release of both CRH and ACTH. Melmed S. Mechanisms
for pituitary tumorigenesis: theplastic pituitary. J Clin Invest
2003;112(11):1603–18.
a prominent carbohydrate moiety. Within the
human pituitary, POMC is exclusively expressed
in corticotroph cells. TPit/Tx19 is the critical cell-
specific transcriptional factor for corticotroph
cell differentiation and POMC transcription.
CRH, a 41-aa peptide synthesized in the para-
ventricular nucleus as well as in higher brain
centers, is the central regulator of the hypotha-
lamic–pituitary–adrenal (HPA) axis. Neuronal
CRH production is controlled by multiple affer-
ent inputs from hypothalamic, limbic forebrain
and brain stem inputs to enable fine-tuned
control of basal and stress-induced CRH action
to induce POMC-derived peptides including
ACTH and β-endorphin.
Pituitary CRH action is mediated by the trans-
membrane corticotroph receptors, CRHR1, which
signals to induce corticotroph POMC transcrip-
tion and ACTH production. CRHR1, a G-protein
coupled receptor (GPCR), is also widely distrib-
uted in the brain and is coupled to the Gαs unit,
323
induces cAMP and activates phosphokinase-A
(PKA). CRHR1 is desensitized and internalized
upon prolonged CRH stimulation. CRH-binding
protein (CRH-BP) transiently binds with high
affinity to CRH and also urocortins, and may
competitively inhibit CRH action. Intravenous
CRH administration elicits rapid ACTH release
peaking in the circulation at 30 min, and fol-
lowed by adrenal cortisol secretion which usually
peaks at 60 min after injection. The adrenal GPCR
for ACTH (melanocortin-2 receptor) signals to
induce a cascade of steroidogenic enzymes lead-
ing to cortisol production. Both urocortin 1 and
arginine vasopressin (AVP) also act to induce
ACTH and cortisol albeit less robustly than CRH.
In the corticotroph cell, the POMC prohor-
mone is processed by convertase enzymes to
yield ACTH and β-lipotropin, as well as inactive
peptide fragments. β-lipotropin is further cleaved
to yield β-endorphin and other peptides, espe-
cially in the intermediate pituitary region. ACTH
is secreted to the systemic circulation to stimu-
late adrenal gland steroid hormone synthesis
and secretion by maintaining adrenal cortical cell
integrity and inducing steroidogenesis pathways.
POMC synthesis is suppressed by glucocorti-
coids acting as negative feedback regulators, and
stimulated mainly by CRH, as well as by AVP,
and pro-inflammatory cytokines.
CRH release controls a 24-h diurnal rhythm
for both ACTH and cortisol secretion required.
This secretory pattern is an important determi-
nant for maintaining adrenal function ACTH
and cortisol levels start rising between 1 and 4
am and hormone levels peak at about 6 am. A
lower cortisol peak is evident in the early after-
noon, continues to fall during the afternoon
and evening, then reaches a midnight nadir
level. Circadian rhythmicity is likely more char-
acterized by changes in hormone pulse ampli-
tude rather than pulse frequency. Interestingly,
CRH infusion to CRH KO mice restores diurnal
corticosterone patterns pointing to the CRH
requirement for maintaining normal circadian
ACTH rhythm.
324 15.  HYPOTHALAMIC-PITUITARY REGULATION

The HPA axis functions to sustain the to mount an effective stress response due to
neuroendocrine stress response and maintain suppressed ACTH.
overall metabolic homeostasis. The HPA stress
response is a summated outcome of hypotha-
lamic, intrapituitary, and peripheral hormone HYPOTHALAMIC–PITUITARY–
and cytokine signals acting to regulate adrenal THYROID AXIS
cortisol production with subsequent appropri-
ately integrated immune, cardiovascular, and The thyroid axis regulates development,
hormonal functions. Inflammatory cytokines energy metabolism, and growth and the axis
activate hypothalamic-CRH and -AVP secretion, is controlled by complex central and periph-
pituitary POMC gene expression, and ACTH eral signals mediated mainly by hypothalamic
release. Inflammatory-associated central gluco- TRH and pituitary TSH (Fig. 15.6). Thyrotroph
corticoid receptor resistance also attenuates the cells express TSH and comprise about 5% of the
ability of glucocorticoids to suppress the HPA, functional hormone-secreting anterior pituitary
further enabling ACTH secretion. Inflammatory cells with relatively small secretory granules
cytokines and neurotransmitters, thus, increase ranging from 120 to 150 μm. TSH comprises a
CRH release to stimulate ACTH and adrenal specific β-subunit and common α-subunit
cortisol secretion. Induced cortisol levels, in shared with LH and FSH. TSH binds to a GPCR
turn, limit inflammation and confer host protec-
tion. Several other peptides also regulate ACTH
by acting centrally. For example, leptin stimu-
lates CRH release, while somatostatin inhibits
hypothalamic-CRH release.
CRH release and ACTH levels are enhanced
by both pathologic and physiological stressors
including cytokines, hemorrhage, adrenalec-
tomy, and hypoglycemia. In contrast, glucocor-
ticoid-mediated negative feedback results in
dual suppression of both hypothalamic-CRH,
pituitary POMC synthesis, and ACTH release.
As a clinical sequel, loss of cortisol feedback
inhibition relieves the corticotroph cell of nega-
tive restraint, and results in high ACTH levels.
This is exemplified clinically as encountered
after surgical adrenalectomy or primary adrenal
failure. Although severe stress and subsequent
increased CRH levels can override glucocorti-
coid negative feedback inhibition, steroids act to
physiologically suppress CRH gene and protein
expression, CRH secretion to the portal system FIGURE 15.6  Hypothalamic TRH stimulates pituitary
and ultimately adrenal function. thyrotrophs to synthesize and release TSH which induces
An important clinical consequence of this the thyroid gland to produce thyroid hormones which nega-
tively regulate further release of both TSH and TRH. SRIF
potent central glucocorticoid action is that also inhibits both TRH and TSH. Melmed S. Mechanisms
patients receiving chronic glucocorticoid ther- for pituitary tumorigenesis: theplastic pituitary. J Clin Invest
apy (eg, for asthma and arthritis) are unable 2003;112(11):1603–18.
 HYPOTHALAMIC–PITUITARY–GH AXIS 325
on thyroid follicular cells to stimulate thyroid damage, postoperatively, after radioactive abla-
hormone (T4) synthesis and release. T4 is con- tion, thyroiditis, and thyroiditis.
verted in the periphery to the more active T3
which elicits most thyroid cellular actions.
TRH is a hypothalamic tripeptide (pyroglu- HYPOTHALAMIC–PITUITARY–
tamyl histidyl-prolinamide) that acts through GH AXIS
a transmembrane rhodopsin family GPCR
expressed on the thyrotroph surface to stimulate GH acts to regulate linear growth in children,
TSH synthesis and secretion; it also stimulates and to maintain homeostatic body composition
the lactotroph to secrete PRL. TRH is derived and muscle mass in adults (Fig. 15.7). Although
from hypothalamic preproTRH (242 aa) which GH acts directly on peripheral tissues (espe-
is cleaved to generate the tripeptide. TRH cially liver, muscle, cartilage, adipocytes, heart),
synthesis is induced by cold, thereby activating most growth-promoting functions of GH are
the thyroid hormone response to hypothermia. mediated by GH-induced IGF-1.
Hypothalamic-TRH signaling is mediated pri- Cells expressing both PRL and GH (lactoso-
marily by Gq/11 proteins, hydrolysis of phospha- matotrophs) arise from acidophilic stem cells,
tidylinositol 4,5-P2 (PIP2), and intracellular Ca2+ and mature somatotrophs comprise 35–45% of
and phosphokinase C (PKC) activation. TRH
also regulates TSH glycosylation. TSH synthe-
sis and production are markedly suppressed
by several factors including thyroid hormones,
dopamine, somatostatin, and glucocorticoids.
These molecules act to inhibit TSH production
overriding central TRH induction. Intravenous
TRH injection in humans rapidly elicits up to
22-fold increase in TSH synthesis and secretion,
reflected as a biphasic release pattern measured
as circulating TSH levels.
Thyroid hormones feedback to potently
suppress the thyroid axis by inhibiting TRH
gene transcription, and TSH synthesis and
release. During states of hypothyroidism, SRIF
also inhibits TRH-induced TSH. As thyroid
hormone negative feedback inhibition on the
axis is so powerful, thyrotroph proliferation
and TSH production are both released from
restraint when thyroid hormones are removed.
Thus, untreated thyroid gland failure relieves FIGURE 15.7  Hypothalamic GHRH stimulates the
the thyrotroph of negative feedback inhibition somatotroph to synthesize and release growth hormone
and results in exuberant TSH synthesis with (GH), which in turn stimulates the liver to produce IGF-
resultant elevated TSH levels. Furthermore, 1. Peripheral GH action may be either IGF-I dependent or
as thyroid hormones suppress thyrotroph cell independent. Both GH and IGF-1 act in a negative feed-
back loop to suppress both GHRH and GH, while SRIF also
proliferation, patients with low thyroid hormone inhibits both GHRH and GH release. Melmed S. Mechanisms
levels may also exhibit thyrotroph hyperplasia. for pituitary tumorigenesis: theplastic pituitary. J Clin Invest
Increased levels of TSH are seen with thyroid 2003;112(11):1603–18.
326 15.  HYPOTHALAMIC-PITUITARY REGULATION
pituitary cells, that is, these are the most prepon-
derant pituitary cell type. Somatotrophs contain
abundant GH secretory granules up to 700 μm
in diameter.
Hypothalamic-GHRH neurons in the arcuate
and ventromedial nuclei project into the median
eminence, and terminate on hypophyseal–por-
tal capillaries to release GHRH into the portal
venous system. The precursor GHRH pre-pro-
hormone comprises 108 amino acids, and is sub-
sequently processed to GHRH (1–40)-OH and
GHRH (1–44)-NH2, with fragments as short as
GHRH (1–29)-NH2 exhibiting potent GH-releas-
ing activity. GHRH is structurally similar to the
secretin family, including glucagon and vasoac-
tive intestinal polypeptide (VIP). GHRH recep-
tor (GHRHR), a transmembrane GPCR mostly
expressed on pituitary somatotroph cells, sig-
nals to induce both cell proliferation as well
as GH synthesis and secretion via intracellular
calcium fluxes, increased cAMP, and activated
phosphatidyl inositol and MAPK pathways.
The pancreatic GHRH signals to regulate insulin
and glucagon release.
The GH gene encodes a 191 aa polypep-
tide in the pituitary, and about 15% of circu-
lating GH comprises a shorter 176 aa peptide
derived by alternative splicing. Basal GH
secretion as well as periodic pulse patterns
are engendered by coordinated hypothalamic
GHRH– and SRIF–release patterns. GH syn-
thesis, secretion, and secretory patterns are
controlled by a myriad of hypothalamic and
peripheral factors. Inducing factors include
hypothalamic GHRH, which primarily stimu-
lates somatotroph GH synthesis and release,
and Ghrelin, an octanoylated gastric-derived
peptide, which also induces GH. Inhibitory
signals derive mainly from hypothalamic
somatostatin (SRIF)] which inhibits GH secre-
tion. Somatostatin binds five distinct receptor
subtypes (SST1 to SST5) and somatotrophs
expresses predominantly SST2 and SST5 sub-
types which signal to suppress GH secretion.
GH synthesis is also suppressed by negative
feedback exerted by IGF-1, the peripheral tar-
get hormone for GH which directly suppresses
GH, while indirectly inducing hypothalamic
SRIF to suppress GH.
Peripheral GH tissue responses and especially
growth rates appear to be gender specific. For
example, male somatostatin and GHRH expres-
sion are higher than in females, leading to higher
pulsatile GH peaks and lower troughs. Conse-
quently, GH levels are higher in men, compared
with continuous basal GH secretion observed
in women. These observations may at least in
part explain gender differences in linear growth
pattern differences and liver enzyme induction.
These differences may also be accounted for by
sex steroids which regulate both somatostatin
and GHRH neurons, and which may also contrib-
ute to sexually dimorphic GH secretion patterns.
Both GH and IGF-1 cause negative feedback
suppression of hypothalamic-GHRH release.
Hypothalamic SRIF is also released in response
to GH, thus indirectly contributing to the nega-
tive feedback loop suppressing GHRH and GH
itself. Interestingly, mutant mice which are null
for SSTR2 are refractory to negative GH feed-
back implying that GH-stimulated SRIF directly
inhibits GHRH release, in addition to releasing
SRIF into the hypophyseal–portal circulation to
further inhibit pituitary GH.
Abundant IGF-1 receptors are expressed
in both the pituitary and hypothalamus, and
IGF-1, the GH target hormone directly inhibits
pituitary GH synthesis at the level of the GH
gene, as well as acting indirectly via the hypo-
thalamus by inducing SRIF.
GH is also induced by several neuropeptides
and amino acids including ghrelin, l-arginine,
glucagon, dopamine, galanin, and apomorphine,
as well as α-adrenergic agonists induce GH.
β-Adrenergic blockade also induces basal GH and
enhances GHRH- and insulin-evoked GH release.
Ghrelin, a gut-derived 28-aa GH secretagogue
signals via the ghrelin receptor to increase intra-
cellular pituitary calcium via inositol phosphate to
dose-dependently induce GH release. Ghrelin also
 Hypothalamic–Pituitary–Gonadal axis 327
induces hypothalamic GHRH to stimulate GH, superfamily and is abundantly expressed
and Ghrelin and GHRH cotreatment is synergis- on liver, cartilage, and adipocytes. GH sig-
tic for GH induction likely acting to allosterically nals through JAK/STAT pathway to regulate
regulate pituitary GHRH receptors. expression of target genes mediated by both
Most GH secretory peaks occur at night, and STAT and also non-STAT signaling pathways.
GH is elevated with deep sleep, exercise, physi- Importantly, IGF-I, the potent growth factor,
cal stress, and sepsis. Integrated 24-h GH secre- is generated in response to GH, mainly in the
tion is higher in women and is also enhanced by liver. Chondrocyte cell proliferation and lin-
estrogens which likely increase peripheral GH ear growth are determined by GH and IGF-I
resistance. as well as other hormones including thyroid
Randomly measured GH values are very hormone and sex steroids.
low or even undetectable in about 50% of
daytime samples, especially in obese and elderly
patients. Nutritional status is a strong determi-
HYPOTHALAMIC–PITUITARY–
nant of GH secretion. Thus, a glucose load will
GONADAL AXIS
normally suppress serum GH to <0.7 μg/L in
women and even lower to <0.07 μg/L in men.
The gonadal axis regulates sex steroid synthesis
In contrast, chronic malnutrition, or undernu-
and secretion, as well as germ cell development
trition, or hypoglycemia, are associated with
and function. Thus, axis controls sexual develop-
increased GH levels.
ment and function, as well as fertility (Fig. 15.8).
GHRH dose-dependently elicits secretory
serum GH peaks at 15–45 min after injection,
returning to baseline levels within 90–120 min.
Unlike CRH, repeated or constant GHRH
administration does not down-regulate the GH
response. Administration of estrogens, gluco-
corticoids, or the presence of malnutrition, all
lead to enhanced GH responses to GHRH. In
contrast, GH response to GHRH is blunted by
somatostatin administration, obesity, and aging.
GHRH also acts as a somatotroph trophic factor
and leads to induced proliferation and if per-
sistently oversecreted (eg, by a hypothalamic
or neuroendocrine tumor) results in pituitary
hyperplasia. Transgenic mice overexpress-
ing GHRH exhibit somatotroph hyperplasia in
enlarged pituitary glands. Clinically, neuroen-
docrine tumor ectopic GHRH production leads
to somatotroph hyperplasia and GH hyperse- FIGURE 15.8  Hypothalamic GnRH stimulates the
cretion with acromegaly. GHRH action may gon­adotroph to synthesize and release both FSH and LH
also be constitutively enhanced as a result of Gαs which stimulate the gonads to produce sex steroid hor-
subunit mutations observed in up to 40% of GH- mones and regulate germ cell function. Estradiol and
testosterone regulate release of central GnRH, FSH, and
secreting pituitary adenomas. LH in both females and males. Melmed S. Mechanisms
The GH receptor dimer exhibits structural for pituitary tumorigenesis: theplastic pituitary. J Clin Invest
homology with the cytokine/hematopoietic 2003;112(11):1603–18.
328 15.  HYPOTHALAMIC-PITUITARY REGULATION
GnRH neurons arise from the olfactory
placode and migrate to the hypothalamus
upon a scaffolding of neurons and glial cells,
as well as in response to chemotactic and adhe-
sion signals. GnRH-I neurons have been pro-
posed to also arise from the anterior pituitary
placode, as exemplified in zebrafish mutants
lacking a pituitary but with intact olfactory
organs, yet devoid of hypothalamic GnRH-I
neurons. Hypothalamic GnRH-I neuronal net-
works coordinate a pulse generator for GnRH
release and project to the median eminence
and stalk to terminate on the hypophyseal–
portal capillaries.
Hypothalamic GnRH is essential for synthesis
and release of the gonadotrophin hormones FSH
and LH. GnRH-I is the predominant hypotha-
lamic peptide and while GnRH-II is expressed
mostly outside the brain. The GnRH-I gene
encodes a 92 aa protein that is processed to the
10 aa GnRH molecule, retaining a pyroGlu at the
N-terminus and a Gly-amide at the C-terminus,
both required for bioactivity.
The GnRH receptor, a transmembrane GPCR,
lacks a typical intracellular C-terminal cyto-
plasmic domain and mostly binds Gαq/11 to
activate phospholipase C, diacylglycerol–PKC,
and inositol-3-phosphate pathways to increase
intracellular calcium and induce glucoprotein
synthesis. Continuous GnRH exposure down-
regulates GnRH receptors and desensitizes
gonadotrophs mainly by receptor trafficking
including internalization and degradation.
GnRH neurons exhibit a highly coordinated
pulsatile pattern of GnRH release into the
hypophyseal–portal circulation discreet pulsing
every 60–120 min elicits rhythmic LH and FSH
secretion patterns. In fact, discreet pituitary-
derived LH pulses are observed within minutes
after a hypothalamic-GnRH spike. GnRH pulse
patterns and frequency determine rates of FSH/
LH release, ratios of FSH and LH, and LH and
FSH glycosylation, which all are required to
determine appropriate gonadal actions of the
gonadotrophins. LH rather than FSH is a more
reliable indicator of GnRH pulsatility. Gonado-
troph GnRH has also been proposed to commu-
nicate with hypothalamic GnRH by retrograde
neurohypophyseal flow exemplifying a short-
loop regulatory feedback that controls both LH
and GnRH secretion. Discreet GnRH pulses
prime basal gonadotroph secretory responsive-
ness, in contrast to continuous GnRH exposure
which may down-regulate the axis by induc-
ing GnRH receptor desensitization. This may
explain why patients with androgen-dependent
prostate cancer experience suppressed gonadal
function induced by parenteral long-acting
GnRH agonist treatments.
Kisspeptin enhances GnRH pulse ampli-
tude and duration and kisspeptin neurons also
express leptin receptors. This central path-
way links the reproductive system to nutri-
tion and energy metabolism at the level of the
hypothalamus.
In general, estradiol, progesterone, and tes-
tosterone attenuate GnRH pulse frequency
and GnRH release to the hypophyseal–por-
tal circulation. In humans, pituitary LH/FSH
are suppressed by chronic estradiol exposure
while acute estrogen peaks, as characterized by
the preovulatory mid-estrous surge, result in
positive feedback to enhance both GnRH release
and subsequent FSH/LH pulse frequency and
amplitude. Progesterone acts mainly at the
hypothalamus to attenuate GnRH pulse fre-
quency, while testosterone negative feedback
regulation occurring mainly at the hypotha-
lamic and pituitary levels is mediated in part by
conversion to estrogens.
Numerous other factors are known to regu-
late the hypothalamic–pituitary gonadal axis.
Galanin-like peptide induce GnRH in the pres-
ence of estradiol, excitatory amino acids, cat-
echolamines, NPY, and neurotensin may also all
act to enhance estradiol stimulation of gonado-
trophins. Noradrenergic and adrenergic neurons
stimulate GnRH release, while neural inhibitors
of estradiol effects on GnRH include GABA and
opioids, which also suppress the LH surge.
 Prolactin
Gonadotroph cells express both the gonado-
troph hormones, FSH and LH, and comprise
about 10–15% of functional anterior pituitary
cells. They contain two groups of secretory gran-
ules; large 350–450 nm and smaller 150–250 nm
granules packaged in vesicles. Both bihormonal
and monohormonal groups of gonadotrophs are
evident. Gonadotroph-specific differentiation
is characterized by GnRH receptor expression
and by steroidogenic factor 1 (SF-1) and DAX-1
nuclear receptors. Gonadotroph cells synthesize
and secrete both LH and FSH, glycoprotein hor-
mones that comprise α and β subunits. Hormone
specificity of action at the level of the gonads is
conferred by the unique β subunits, while the α
subunit is common to FSH, LH, and TSH.
Activins secreted by the gonads also induce,
while inhibin suppresses FSH. Gonadotropins
bind to respective GPCRs expressed in the ovary
and testis signaling to regulate germ-cell devel-
opment and function and estrogen or testos-
terone synthesis. Ovarian follicle development
and ovarian estrogen production are regulated
by FSH, and ovulation and maintenance of the
corpus luteum are controlled by LH. Testicular
Leydig cell testosterone synthesis and secre-
tion is induced by LH, and seminiferous tubule
development and spermatogenesis are under
FSH control.
SOMATOSTATIN
Hypothalamic somatostatin is produced
predominantly in the anterior periventricular
nucleus, as well as in paraventricular, arcuate,
and ventromedial hypothalamic nuclei. These
neurons project into the median eminence,
and their fibers terminate on the hypophyseal–
portal circulation to release the peptide into the
portal circulation reaching anterior pituitary
cells. Endocrine transport of the peptide to the
anterior pituitary is also enabled by CSF leak-
age from the third ventricle to the portal system,
peripheral somatostatin, and short portal blood
329
vessels crossing from the posterior to the ante-
rior pituitary.
Somatostatins are cyclic peptides with a
single covalent bond between two Cys residues
and a bioactive core composed of a Phe–Trp–
Lys–Thr amino acid sequence. Both SRIF14
and SRIF28 are derived from posttranslational
cleavage of pro-somatostatin by PC1 and PC2
and carboxypeptidase E. Somatostatin signals
through five GPCR somatostatin receptor sub-
types, SSTR1, 2, 3, 4, and 5. Somatostatin 14
exhibits high binding affinity to all the recep-
tor subtypes, with highest affinity to SSTR2,
the subtype responsible for inhibiting GH. SRIF
receptors bind the Gαi/o subunit of the Gαβγ tet-
ramer, reduce cAMP levels, opening potassium
channels and closure of calcium channels. Pitu-
itary SSTR2 is suppressed by chronic glucocor-
ticoids. SSTR2 also signals constitutively in the
absence of ligand to suppress GH and ACTH
secretion. The primary function of somatosta-
tin is to inhibit pituitary hormone secretion.
There is also evidence that SRIF may restrain
pituitary tumor cell growth, especially somato-
trophs. SRIF inhibits secretion of GH, TSH, as
well as ACTH in the presence of low gluco-
corticoid levels. SRIF also exerts ubiquitous
inhibitory effects on multiple gastrointestinal,
pancreatic, and vascular functions. In patients
with acromegaly, somatostatin analogs are
administered to control excess GH secretion,
normalize IGF-I levels, and stabilize or shrink
the pituitary adenoma mass.
PROLACTIN
Lactotroph cells comprise about 15–25% of
functioning anterior pituitary cells and likely
arise from a common GH-producing precursor
cell. PRL secretory granules (250–800 nm) are
evenly distributed, while smaller (200–350 nm)
granules are more scattered. Mammosomato-
troph cells co-secrete both PRL and GH within
the same granule. Lactotroph hyperplasia occurs
330 15.  HYPOTHALAMIC-PITUITARY REGULATION

during pregnancy and lactation, and resolves expression of lactotroph dopamine receptor
within several months of delivery. expression. Most neuroleptic drugs that inhibit
Hypothalamic dopamine is released from dopamine secretion or receptor signaling also
the arcuate and anterior periventricular nuclei. increase prolactin levels. Thus, patients receiv-
The anterior pituitary also receives dopaminer- ing chronic anti-psychotic medications often
gic signals derived from the posterior pituitary exhibit hyperprolactinemia and galactorrhea.
through interconnecting short portal veins. Other central peptides inconsistently stimulate
Dopamine binds to lactotroph dopamine recep- prolactin secretion including TRH, vasopressin,
tor subtype 2 (D2R) to inhibit prolactin synthesis VIP, angiotensin II, galanin, substance P, bombe-
and release, and lactotroph proliferation. This sin-like peptides, and neurotensin.
potent inhibition is further reinforced by obser- PRL is a 199 aa polypeptide with about 40%
vations that D2R null mice develop lactotroph homology to GH. PRL signals through a dimeric
hyperplasia, hyperprolactinemia, and pituitary transmembrane receptor (PRLR), a member of
lactotroph adenomas. D2R, a GPCR, couples the cytokine/emythropoeitin family. Subse-
the Gαi/o subunit to decrease cAMP, increase quent signaling is mediated by JAK2 and StatS
potassium influx, inhibit inositol phosphate which translocates to the nucleus to elicit target
production, and decrease intracellular calcium gene transcription. In the primed breast, PRL is
to acutely inhibit prolactin synthesis and secre- required to initiate and maintain lactation. PRL
tion, usually within minutes. induces growth of and maintains the developed
As the predominant hypothalamic control of
PRL secretion is inhibitory, mediated by hypo-
thalamic dopamine, PRL levels are high with
pituitary stalk section compromising portal
dopamine passage, as seen with compressive
mass sellar lesions. Lactotroph dopamine type
2 (D2) receptors signal to inhibit PRL synthe-
sis and secretion. Targeted knockout of the D2
receptor results in murine hyperprolactinemia
and associated with lactotroph proliferation.
Lactotroph hyperplasia induced by estrogen
occurs during pregnancy and lactation. Serum
PRL levels are about 10–25 μg/L in women and
10–20 μg/L in men.
Pituitary prolactin secretion is under tonic inhi-
bition by hypothalamic dopamine (Fig. 15.9).
As a consequence, compromised dopamine por-
tal transit, or antagonized dopamine receptor
signaling, as seen with pituitary stalk damage
or dopamine antagonist drugs, leads to marked
increase in lactotroph production and PRL
secretion.
As dopaminergic neurons express PRL FIGURE 15.9  Hypothalamic dopamine traverses the
portal vasculature to exert tonic suppression of lacto-
receptors, a short negative feedback loop of troph PRL synthesis and release. Melmed S. Mechanisms
prolactin on dopamine synthesis is operative. for pituitary tumorigenesis: theplastic pituitary. J Clin Invest
Estrogen increases prolactin mainly by reducing 2003;112(11):1603–18.
 Further Reading
mammary gland to enable breast milk produc-
tion and suckling. In lower vertebrates, PRL also
regulates fluid and water balance.
High PRL acts to suppress female and male
gonadal functions. This role for PRL is thought
to preserve species survival by preventing
pregnancy in a lactating mother. Thus, females
exhibit ovulation inhibition and amenorrhea
and males develop azoospermia and impotence.
Accordingly, hyperprolactinemia, especially
encountered in patients with PRL-secreting
pituitary adenomas, leads to galactorrhea and
infertility.
Further Reading
[1] Melmed S. Mechanisms for pituitary tumorigenesis: the
plastic pituitary. J Clin Invest 2003;112(11):1603–18.
[2] Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan
K, Maudsley SR. Gonadotropin-releasing hormone
receptors. Endocr Rev 2004;25(2):235–75.
331
[3] Clemmons DR. The diagnosis and treatment of growth
hormone deficiency in adults. Curr Opin Endocrinol
Diabetes Obes 2010;17:377–83.
[4] Brooks AJ, Waters MJ. The growth hormone receptor:
mechanism of activation and clinical implications. Nat
Rev Endocrinol 2010;6:515–25.
[5] Melmed S. Pathogenesis of pituitary tumors. Nat Rev
Endocrinol 2011;7(5):257–66.
[6] Langlais D, Couture C, Kmita M, Drouin J. Adult pitu-
itary cell maintenance: lineage-specific contribution of
self-duplication. Mol Endocrinol 2013;27(7):1103–12.
[7] Gittleman H, Ostrom QT, Farah PD, et al. Descriptive
epidemiology of pituitary tumors in the United States,
2004–2009. J Neurosurg 2014:1–9.
[8] Ho KK. The year in pituitary 2014. J Clin Endocrinol
Metab 2014;99(12):4449–54.
[9] Ntali G, Capatina C, Grossman A, Karavitaki N. Clini-
cal review: functioning gonadotroph adenomas. J Clin
Endocrinol Metab 2014;99(12):4423–33.
[10] Bernard V, Young J, Chanson P, Binart N. New insights in
prolactin: pathological implications. Nat Rev Endocrinol
2015;11(5):265–75.