PROF. N.

SYABBALO
MB., ChB., PhD., FCCP., FRS., FIBA

Professor of Physiology & Medicine

THE PITUITARY GLAND
INTRODUCTION
The pituitary gland, or hypophysis, lies in a pocket
of the sphenoid bone at the base of the brain
It is a coordinating center for control of many
downstream endocrine glands, some of which are
discussed in the subsequent chapters
In many ways, it can be considered to consist of at
least two (and in some species, three) separate
endocrine organs that contain a plethora of
hormonally active substances
THE PITUITARY GLAND
The anterior pituitary secretes thyroid-stimulating
hormone (TSH), adrenocorticotropic hormone
(ACTH), luteinizing hormone (LH), follicle-
stimulating hormone (FSH), prolactin, and
growth hormone
It receives almost its blood supply from the portal
hypophysial vessels that pass initially through the
median eminence, a structure immediately below the
hypothalamus
TABLE NS 1-1 Hormones secreted by
the anterior pituitary gland
Adrenocorticotropic hormone (corticotropin, ACTH)
Thyroid stimulating hormone (thyrotropin, TSH)
Growth hormone
Follicle- stimulating hormone (FSH)
Luteinizing hormone (LH)
Prolactin (PRL)
Polypeptide β-lipotropin (β-LPH)
THE PITUITARY GLAND
This vascular arrangement positions the cells of the
anterior pituitary to respond efficiently to regulatory
factors release from the hypothalamus
Of the listed hormones, prolactin acts on the breast
The remaining five are, at least in part, tropic hormones;
that is they stimulate secretion of hormonally active
substances by other endocrine glands or, in the case of
growth hormone, the liver and other tissues
Another example is TSH, which stimulates secretion of
the thyroid gland
THE PITUITARY GLAND
The tropic hormones for some endocrine glands are
discussed in the chapter on that gland
However, the gonadotropins FSH and LH, along with
prolactin, are covered here
The posterior pituitary in mammals consists
predominantly of nerves that have their cell bodies in
the hypothalamus (supraoptic and paraventricular and
nuclei)
It stores oxytocin and vasopressin in the terminals
of these neurons
THE PITUITARY GLAND
The hypothalamus and median eminence plays an
overall role in regulating both the anterior and
posterior pituitary hormones
In some species, there is also a well developed
intermediate lobe of the pituitary, whereas in
humans it is rudimentary
Nevertheless, the intermediate lobe, as well as the
anterior pituitary contain active derivatives of the
proopiomelanocortin (POMC) molecule that
regulate skin pigmentation, among other functions
THE PITUITARY GLAND
This chapter will focus predominantly on growth
hormone and its role in growth and in facilitating the
activity of other hormones, along with a number of
general consideration about the pituitary
The melanocyte-stimulating hormones (MSH) of the
intermediate lobe of the pituitary, α-MSH and β-
MSH,will also be touched upon
MORPHOLOGY
GROSS ANATOMY
The anatomy of the pituitary gland is summarized in
Figure 18-1 and discussed in detail in Chapter 17
The posterior pituitary is made up largely of the
endings of axons from the supraoptic and
paraventricular nuclei of the hypothalamus and arises
initially as an extension of this structure
The anterior pituitary, on the other hand, contains
endocrine cells that store its characteristic hormones,
and arises embryologically from an invagination of the
pharynx (Rathke’s pouch)
MORPHOLOGY
GROSS ANATOMY
In species where it is well developed, the intermediate
lobe is formed in the embryo from the dorsal half of
Rathke’s pouch, but is closely adherent to the posterior
lobe in the adult
It is separated from the anterior lobe by the remains of
the cavity in Rathke’s pouch, the residual cleft
HISTOLOGY
In the posterior lobe, the endings of the supraoptic
and paraventricular axons can be observed in close
relation to blood vessels
Pituicytes, stellate cells that are modified astrocytes
are also present
The intermediate lode is rudimentary in humans and
a few other mammal species
In these species, most of its cells are incorporated in
the anterior lobe
HISTOLOGY
Along the residual cleft are small thyroid-like follicles, some
containing a little colloid
The function of the colloid, if any, is unknown
The anterior pituitary is made up of interlacing cell cords
and an extensive network of sinusoidal capillaries
The endothelium of the capillaries is fenestrated, like that in
other endocrine organs
The cells contain granules of stored hormones that are
extruded from the cell by exocytosis
Their constituents then enter the capillaries to be conveyed
to target tissues or endocrine glands
CELL TYPES IN THE ANTERIOR
PITUITARY
Five types of secretory cells have been identified in the
anterior pituitary by immunocytochemistry and electron
microscopy
The cell types are the somatotropes, which secrete growth
hormone
The lactotropes (also called mammotropes), which secrete
prolactin
The corticotropes, which secrete ACTH
The thyrotropes, which secrete TSH; and gonadotropes,
which secrete FSH and LH
The characteristics of these cells are summarized in Table 18-1
TABLE 18-1 Hormone-secreting cells of
the human anterior pituitary gland
Cell type Hormone % of Total cells
Somatotrope GH 50
Lactotrope Prolactin 10-30
Corticotrope ACTH 10
Thyrotrope TSH 5
Gonadotrope FSH, LH 20

Percentage of total secretory cells (%)

CELL TYPES IN THE ANTERIOR
PITUITARY
Some cells may contain two or more hormones, for
example, gonadotropes which contain both FSH and
LH in their granules
It is also notable that the three pituitary glycoproteins
hormones, FSH, LH, and TSH, while being made up of
two subunits, all share a common α-subunit that is the
product of a single gene
It has the same amino acid composition in each
hormone, although their carbohydrate residue vary
CELL TYPES IN THE ANTERIOR
PITUITARY
The α-subunit must be combined with a β-subunit
characteristic of each hormone for maximal
physiologic activity
The β-subunit, which are produced by separate genes
and differ in structure, confer hormonal specificity
The α-subunit, are remarkably interchangeable and
hybrid molecules can be created
In addition, the placental glycoprotein gonadotropin
human chorionic gonadotropin (hCG) has α and β
subunits
CELL TYPES IN THE ANTERIOR
PITUITARY
The anterior pituitary also contains folliculostellate cells that
send processes between the granulated secretory cells
These cells produce paracrine factors that regulate growth and
function of secretory cells
Indeed, the anterior pituitary can adjust the relative proportion
of secretory cell type to meet varying requirements for different
hormones at different life stages
This plasticity has recently been ascribed to the presence of a
small number of pluripotent stem cells that persist in the adult
gland
These pluripotent cells may different into different secretory cells
PROOPIOMELANOCORTIN AND
DERIVATIVES
BIOSYNTHESIS
Intermediate-like cells, if present, and corticotropes of
the anterior lobe both synthesize a large precursor
protein that is cleaved to form a family of hormones
After the removal of the signal peptide, this
prohormone is known as proopiomelanocortin
(POMC)
This molecule is also synthesized in the
hypothalamus, the lungs, the gastrointestinal tract,
and the placenta
PROOPIOMELANOCORTIN AND DERIVATIVES
The structure of POMC, as well as its derivatives is
shown in Figure 18-2
In corticotropes, it is hydrolyzed to ACTH and β-
lipotropin (LPH), plus a small amount of β-
endorphin, and these substances are secreted
In the intermediate lobe cells, POMC is hydrolyzed to
corticotropin-like intermediate-lobe peptide (CLIP), γ-
LPH, and appreciable quantities of β-endorphin
PROOPIOMELANOCORTIN AND
DERIVATIVES
The functions, if any, of CLIP and γ-LPH are unknown
whereas β-endorphin is an opioid peptide that has the
five amino acid residues of met-enkephalin at its
amino terminal end
 The melanotropins α and β-MSH are also formed
However, the intermediate lobe in humans is
rudimentary, and it appears that neither α-MSH nor β-
MSH is secreted in adults
In some species, however, the melanotropins have
important physiological functions
CONTROL OF SKINCOLORATION
AND PIGMENT ABNORMALITIES
Fish, reptiles, and amphibia change the color of their
skin for thermoregulation, camouflage, and behavioral
displays
They do this in part by moving black or brown
granules into or out of the periphery of pigmented
cells called melanophores
The granules are made up of melanins, which are
synthesized from dopamine and dopaquinone
CONTROL OF SKIN COLORATION
AND PIGMENT ABNORMALITIES
The movement of these granules is controlled by a
variety of hormones and neurotransmitters, including
α- and β-MSH, melanin-concentrating hormone,
melatonin, and catecholamine
Mammals have no melanophores containing pigment
granules that disperse and aggregate, but they do have
melanocytes, which have multiple processes
containing melanin granules
Melanocytes express melanotropin-1 receptors
CONTROL OF SKIN COLORATION
AND PIGMENT ABNORMALITIES
Treatment with melanotropins accelerates melanin
synthesis, causing readily detectable darkening of the skin
in humans in 24 h
As noted above, α- and β-MSH do not circulate in adult
humans, and their function is unknown
However, ACTH binds to melanotropin-1 receptors
Indeed, the pigmentary changes in several human
endocrine diseases are due to changes in circulating ACTH
For example, abnormal pallor is a hallmark of
hypopituitarism
CONTROL OF SKIN COLORATION
AND PIGMENT ABNORMALITIES
Hyperpigmentation occurs sometimes in patients with
Cushing’s syndrome, Addison’s disease, and Nelson’s
disease due to primary adrenal disease
In Cushing disease pigmentation occur most often
following administration of synthetic steroids or
ACTH
In Addison’ s disease there is destruction of the entire
adrenal cortex
Reduced cortisol levels lead, through feedback, to
increased CRH and ACTH production
CONTROL OF SKINCOLORATION
AND PIGMENT ABNORMALITIES
Indeed, the presence of hyperpigmentation in association with
adrenal insufficiency rules out the possibility that the
insufficiency is secondary to pituitary or hypothalamic disease
because in these conditions plasma ACTH is not increased
Other disorders of pigmentation result from peripheral
mechanisms or genetic mechanisms and include oculocutaneous
albinism and vitiligo
Oculocutaneous albinism
Oculocutaneous albinos result from a range of genetic
abnormalities that lead to reduced melanin biosynthesis in the
skin, hair and eyes; or a congenital inability to synthesize melanin
CONTROL OF SKIN COLORATION
AND PIGMENT ABNORMALITIES
The number of melanocytes is normal (in contrast to vitiligo)
This can result from a variety of different genetic defects in the
pathways for melanin synthesis
Albinism is usually inherited as an autosomal recessive trait and
there are several different types
Type 1 albinism is due to a defect in tyrosinase gene, whose
product is rate-limiting in the production of melanin
Affected individuals have an almost complete absence of pigment
in the skin and hair at birth, and failure of melanin production in
the iris and retina
Patients have photophobia, poor vision, and rotational
nystagmus
CONTROL OF SKIN COLORATION
AND PIGMENT ABNORMALITIES
A second type is due to a defect in the P gene, which
encodes an ion channel protein in the melanosome
Patients may have gross reduction of melanin in the
skin and eyes, but are more mildly affected than type 1
albinos
Oculocutaneous albinos are at grossly increased risk
of sunburn and skin cancer
In equatorial regions, many die from squamous cell
carcinoma (SCC) or, more rarely melanoma in early
adult life
CONTROL OF SKIN COLORATION
AND PIGMENT ABNORMALITIES
Piebaldism is characterized by patches of skin that lack
melanin as a result of congenital defects in the migration
of the pigment cell precursors from the neural crest
during embryonic development
Not only the condition but also the precise pattern of the
loss is passed from one generation to the next
Vitiligo is an acquired condition affecting 1% of the
population worldwide
It involves a similar patchy loss of melanin, but the loss
develop progressively after birth secondary to an
autoimmune process that target the melanocytes
CONTROL OF SKIN COLORATION
AND PIGMENT ABNORMALITIES
This type of disease is associated with other autoimmune disease
A positive family history of vitiligo or other organ-specific
autoimmune disease is relatively common in those with the
disease
Generalized vitiligo is often symmetrical and frequently involves
face, hands, wrist, knees, neck, genitalia, and around body
orifices
The hair of the scalp, beard, eyebrows and lashes may also
depigment
Sensation in the depigmented patches is normal (unlike in
tuberculoid leprosy)
GROWTH HORMONE
BIOSYNTHESIS AND CHEMISTRY
The long arm of human chromosome 17 contains the
growth hormone-hCS cluster that contains five genes;
one, hGH-N codes for the most abundant (“normal”)
form of growth hormone
A second, hGH-V, codes for the variant form of growth
hormone
Two code for human chorionic somatomammatropin
(hCS); and the fifth is probably an hCS peudogene
GROWTH HORMONE
BIOSYNTHESIS AND CHEMISTRY
Growth hormone that is secreted into the circulation
by the pituitary gland consists of a complex mixture of
hGH-N, peptides derived from this molecule with
varying degrees of posttranslational modifications,
such as glycosylation, and a splice variant of hGH-N
that lacks amino acids 32-46
The physiologic significance of this complex array of
hormones has yet to be fully understood
Particularly since their structural similarities make it
difficult to assay for each species separately
GROWTH HORMONE
BIOSYNTHESIS AND CHEMISTRY
Nevertheless, there is emerging evidence that, while
the various peptides share a broad range of functions,
they may occasionally exert actions in opposition to
one another
hGH-V and hCS, on the other hand, are primarily
products of the placenta, and as a consequence are
only found in appreciable quantities in the circulation
during pregnancy (see Chapter 22)
SPECIES SPECIFICITY
The structure of growth hormone varies considerably
from one species to another
Porcine and simian growth hormones have only a
transient effect in the guinea pig
In monkeys and humans, bovine and porcine growth
hormones do not even have a transient effect on
growth, although monkey and human growth
hormone are fully active in both monkeys and humans
SPECIES SPECIFICITY
These fact are relevant to public health discussions
surrounding the presence of bovine growth hormones
(used to increase milk production) in dairy products
As well as the popularity of growth hormone
supplements, marketed via the internet, with body
builders
Controversially, recombinant human growth hormone
has also been given in children who are short in
stature, but otherwise healthy (ie, without growth
hormone deficiency), with apparently limited results
PLASMA LEVELS, BINDING, AND
METABOLISM
A portion of circulating growth hormone is bound to a
plasma protein that is a large fragment of the
extracellular domain of the growth hormone receptor
It appears to be produced by cleavage of receptors in
humans, and its concentration is an index of the
number of growth hormone receptors in the tissues
Approximately 50% of the circulating pool of growth
hormone activity is in the bound form, providing a
reservoir of the hormone to compensate for the wide
fluctuation that occur in secretion
PLASMA LEVELS, BINDING, AND
METABOLISM
The basal plasma growth hormone level measured by
radioimmunoassay in adult humans is normally less
than 3 ng/ml
This represents both the protein-bound and the free
form
Growth hormone is metabolized rapidly, at least in
part in the liver
The half-life of circulating growth hormone in
humans is 6-20 min, and the daily growth hormone
output has been calculated to be 0.2-1.0 mg/d in adults
GROWTH HORMONE RECEPTORS
The growth hormone receptor is a 620-amino-acid
protein with a large extracellular portion, a
transmembrane domain, and a large cytoplasmic
portion
It is a member of the cytokine receptor superfamily
Growth hormone has two domains that can bind to its
receptor, and when it binds one receptor, the second
binding site attracts another, producing a homodimer
Dimerization is essential for receptor activation which
leads to several principal signaling pathways
GROWTH HORMONE RECEPTORS
Growth hormone has widespread effects in the body,
so even though it is not yet possible precisely to
correlate intracellular and whole body effects
It is also not surprising that, like insulin, growth
hormone activates many different intracellular
signaling cascades
Of particular note is its activation of the JAK2-STAT
pathway
JAK2 is a member of the Janus family of cytoplasmic
tyrosine kinases
GROWTH HORMONE RECEPTORS
STATs (for signal transducers and activators of
transcription) are a family of cytoplasmic transcription
factors that, upon phosphorylation by JAK kinases,
migrate to the nucleus where they activate various
genes
JAK-STAT pathways are known also to mediate the
effect of prolactin and other growth factors
EFFECT ON GROWTH
In young animals in which the epiphyses have not yet
fused to the long bones, growth is inhibited by
hypophysectomy and stimulated by growth hormone
Chondrogenesis is accelerated, and the cartilaginous
epiphysial plate widen, they lay down more bone
matrix at the end of the long bones
In this way, stature is increased
Prolonged treatment of young animals with growth
hormone leads to gigantism
EFFECT ON GROWTH
When the epiphyses are closed, linear growth is no
longer possible
In this case, an overabundance of growth hormone
produces the pattern of bone and soft tissue
deformation known to humans as acromegaly
The size of most of the viscera are increased
The protein content of the body is increased, and the
fat content is decreased (see Clininal Box 18-1)
EFFECTS ON PROTEIN & ELECTROLYTE
HOMEOSTASIS
Growth hormone is a protein anabolic hormone and
produces a positive nitrogen and phosphorus balance,
a rise in plasma phosphorus, and a fall in blood urea
nitrogen and amino acid levels
In adults with growth hormone deficiency,
recombinant growth hormone produces an increase in
lean body mass and a decrease in body fat, along with
an increase in metabolic rate and a fall in plasma
cholesterol
EFFECTS ON PROTEIN & ELECTROLYTE
HOMEOSTASIS
Gastrointestinal absorption of Ca is increased, Na and
K excretion is reduced by an action independent of the
adrenal glands, probably because these electrolytes are
diverted from the kidneys to the growing tissues
On the other hand, excretion of amino 4-
hydroxyproline is increased during the growth,
reflective of the ability of growth hormone to facilitate
the synthesis of soluble collagen
EFFECT ON CARBOHYDRATE & FAT
METABOLISM
The action of growth hormone on carbohydrate
metabolism are discussed in Chapter 24
At least some form of growth hormone are diabetogenic
because they increase hepatic glucose output and exert
an anti-insulin effect on muscle
Growth hormone is also ketogenic and increases
circulating free fatty acids (FFS) levels
The increase in FFA, which takes several hours to
develop, provide a ready source of energy for the tissues
during hypoglycaemia, fasting, and stressful stimuli
EFFECT ON CARBOHYDRATE & FAT
METABOLISM
Growth hormone does not stimulate β cells of the
pancreas directly, but it increases the ability of the
pancreas to respond to insulinogenic stimuli such as
arginine and glucose
This is an additional way growth hormone promotes
growth, since insulin has a protein anabolic effect
TABLE 18-5 DIRECT AND INDIRECT ACTIONS
OF GROWTH HORMONE AND IGF1
Growth hormone
Epiphyseal growth
Cartilage growth
Protein synthesis
Lipolysis
Decreased insulin sensitivity
Na retention
IGF1
Epiphyseal growth
Protein synthesis
Antilipolytic activity
Insulin-like activity
SOMATOMEDINS
The effects of growth hormone on growth, cartilage,
and protein metabolism depend on an interaction
between growth hormone and somatomedins
Somatomedins are polypeptide growth factors
secreted by the liver and other tissues
The first of these factors isolated was called sulfation
factor because it stimulated the incorporation of
sulfate into cartilage
However, it also stimulates collagen formation, and its
name was changed to somatomedin
SOMATOMEDINS
It then became clear that there are a variety of different
somatomedins and that they are members of an
increasingly large family of growth factors that affect
many different tissues and organs
The principal (and in humans probably the only)
circulating somatomedins are insulin-like growth
factor I (IGF-I, somatomedin C), and IGF II
These factors are closely related to insulin, except that
their C chains are not separated and they have an
extension of the A chain called the D domain (Figure
18.4)
SOMATOMEDINS
The hormone relaxin is also a member of this family
Humans have two related relaxin isoforms, and both
resemble IGF-II
In humans a variant form of IGF-1 lacking three amino
terminals amino acid residues has been found in the
brain, and there are several variant forms of human
IGF-II (Figure 18-4)
SOMATOMEDINS
The mRNAs for IGF-I and IGF-II are found in the liver, in
cartilage, and in many other tissues, indicating that they
are likely synthesized in these tissues
The properties of IGF-I, IGF-II, and insulin are compared
in Table 18-2
Both IGF-I and IGF-II are tightly bound to proteins in
plasma, and, at least for IGF-I, this prolongs their half-life
in the circulation
Six different IGF-binding proteins, with different patterns
of distribution in various tissues, have been identified
SOMATOMEDINS
All are present in plasma, with IGF-binging protein-3
(IGFBP-3) accounting for 95% of the binding in the
circulation
The contribution of the IGFs to the insulin-like activity in
blood is discussed in Chapter 24
The IGF-I receptor is very similar to the insulin receptor
and probably uses similar or identical intracellular
signaling pathways
The IGF-II receptor has a distinct structure and is involved
in intracellular targeting of acid hydrolases and other
proteins to intracellular organelles
SOMATOMEDINS
Secretion of IGF-I is independent of growth hormone
before birth but it is stimulated by growth hormone
after birth, and it has pronounced growth-stimulating
activity
Its concentration in plasma rises during childhood
and peaks at the time of puberty, then declines to low
levels in old age
IGF-II is largely independent of growth hormone and
plays a role in the growth of the fetus before birth
SOMATOMEDINS
In human fetuses in which it is overexpressed, several
organs, especially the tongue, other muscles, kidneys,
heart, and liver, develop out of proportion to the rest
of the body
In adults, the gene for IGF-II is expressed only in the
choroid plexus and meninges
TABLE 18-2 Comparison of insulin
and the insulin-like growth factors
Insulin IGF-I
Other name … Somatomedin C
No. of amino acids 51 70
Source Pancreas Liver, other tissues
Regulation Glucose Growth hormone
Plasma level 0.3-2 ng/ml 10-700 ng/ml
Plasma BP No Yes
Physiologic role Metabolism Skeletal and cartilage growth

IGF-I peaks at puberty; BP, binding proteins

TABLE 18-2 Comparison of insulin
and the insulin-like growth factors
Insulin IGF-II
Other names … MSA
No. of amino acids 51 67
Source Pancreas Diverse
Regulation Glucose Unknown
Plasma level 0.3-2 ng/ml 300-800 ng/ Plasma BP No Yes
Physiologic role Metabolism Growth during fetal
development

MSA, Multiplication stimulating activity

CLINICAL BOX 18-1
GIGANTISM & ACROMEGALY
Tumors of the somatotropes of the anterior pituitary
(pituitary adenomas or somatotroph adenomas)
secrete large amounts of growth hormone, leading to
gigantism in children (if acquired before epiphyseal
fusion) and acromegaly in adults
If the tumor arises before puberty, the individual may
grow to an extraordinary height
After linear growth is no longer possible, on the other
hand, the characteristic features of acromegaly arise
CLINICAL BOX 18-1
GIGANTISM & ACROMEGALY
These include changes in appearance, enlargement of
the hands and feet, vertebral changes attributable to
osteoarthritis, hirsutism, and protruding of the
supraorbital ridges and lower jaw (prognathism)
Enlargement of lips, nose and tongue
Cardiomyopathy, hypertension and enlargement of
the liver
Sweating, headache, soft tissue swelling and sleep
apnoeas are particular useful features of persistent GH
secretion
CLINICAL BOX 18-1
GIGANTISM & ACROMEGALY
Headache is very common in acromegaly and may be
severe even with small tumours
It is often improved after surgical cure or with
somatostatin analogues
In the remainder the diagnosis is made by an alert
observer in another clinic, eg, GP, diabetic, hypertension,
dermatology, dental
Abnormal growth of the internal organs, eg
cardiomyopathy and liver may eventually impair their
function such that the condition, which has an insidious
onset, can prove fatal if left untreated
TABLE NS 18-1 Symptoms and
signs of acromegaly
Change in appearance
Increased size of hands/feet
Headache
Excessive sweating
Visual disturbance
Sleep apnoea
Amenorrhoea or oligomenorrhoea
Galactorrhoea
Impotence or loss of libido
TABLE NS 18-1 Symptoms and
signs of acromegaly
Deep voice
Breathlessness
Polyuria/polydipsia
Pain/tingling in hands
Joint pains
Muscular weakness
CLINICAL BOX 18-1
GIGANTISM & ACROMEGALY
The overall incidence of gigantism is approximately 3-4
million per year and the prevalence is 50-80/million world-
wide
Acromegaly usually occurs sporadically although gene
mutations can rarely give rise to familial acromegaly,
typically the AIP gene in familial isolated pituitary
adenoma
One-third of patients present with change in appearance,
one-quarter with visual field defects or headache
Sleep apnoea is common and requires investigation and
treatment
CLINICAL BOX 18-1
GIGANTISM & ACROMEGALY
Hypersecretion of growth hormone is accompanied by
hypersecretion of prolactin in 20-40% of patients with
acromegaly
Approximately 4% of the patients with acromegaly
develop lactation in the absence of pregnancy
About 25% of patients have impaired glucose tolerance
tests, and 10% have type 2 diabetes mellitus
Acromegaly can be caused by extra-pituitary as well as
intrapituitary growth hormone secreting tumors and by
hypothalamic tumors that secrete GRH, but the latter are
rare
THERAPEUTIC HIGHLIGHTS
Untreated acromegaly result in markedly reduced survival
Most death occur from heart failure, coronary artery
disease, and hypertension-related causes
In addition, there is an increase in death due to neoplasia,
particularly colonic cancer (2-3 times)
Therefore treatment is indicated in all except the elderly
or those with minimal abnormalities
The mainstay of therapy remains the use of somatostatin
analogues that inhibit the secretion of growth hormone
THERAPEUTIC HIGHLIGHTS
Octreotide and lanreotide are synthetic analogues of
somatostatin that selectively act on somatostatin
receptor subtypes (SST2 and SST5), which are highly
expressed in growth-hormone secreting tumors
They reduce GH and IGF levels in most patients but not
all achieve treatment target
Dopamine agonists
Dopamine agonists act on D2 receptors and can be
given to shrink tumors prior to definite therapy or to
control symptoms and persisting GH secretion
THERAPEUTIC HIGHLIGHTS
They are probably most effective in mixed growth-
hormone producing (somatotroph) and prolactin-
producing (mammotroph) tumors
Typical doses are bromocriptine 10-60 mg daily or
cabergoline 0.5 mg daily (higher than for
prolactinoma)
A growth hormone receptor antagonist has recently
become available and has been found to reduce plasma
IGF-I and produce a clinical improvement in cases of
acromegaly that fail to respond to other treatments
THERAPEUTIC HIGHLIGHTS
Pegvisomant (a genetically modified analogue of GH)
is a GH receptor antagonist which has its effect by
binding to and preventing deminerization of the GH
receptor
It does not lower GH levels or reduce tumor size but has
been shown to normalize IGF-I levels in 90% of patients
It is given by a daily injection and its main role at
present is treatment of patients in whom GH and IGF
levels cannot be reduced to safe levels with somatostatin
analogues alone
THERAPEUTIC HIGHLIGHTS
Surgical removal of the pituitary tumor is helpful in both
acromegaly and gigantism, but sometimes challenging to
perform due to the tumor’s often invasive nature
Trans-sphenoidal surgery is the appropriate first-line
therapy
It will result in clinical remission in a majority of cases
(60-90%) with pituitary microadenomas but only 50% of
those with macroadenomas
In any case, adjuvant pharmacological therapy must often
be continued after surgery to control ongoing symptoms
THERAPEUTIC HIGHLIGHTS
Pituitary radiotherapy
External radiotherapy is normally used after pituitary
surgery fails to normalize GH levels rather than a
primary therapy
It is usually combined with a somatostatin analogue,
dopamine agonist or GH antagonist because of the
slow biochemical response to radiotherapy
The response may take 10 years or more, and is then
associated with hypopituitarism which makes it un
attractive in patients of reproductive age