Pituitary Diseases

Pituitary diseases
By Dr. Haitham Nabeel
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Introduction to pituitary
diseases

Hypothalamus
• Function
• Regulation of hormonal secretion by the anterior pituitary gland via
the hypothalamic-pituitary axis
• Secretion/storage of ADH and oxytocin
• ADH and oxytocin are produced in the supraoptic
nucleus and paraventricular nucleus of the hypothalamus.
• Both hormones are transported to the posterior
pituitary via neurophysins (a group of carrier proteins) and released into
the circulation as needed.
• Reception and integration of sensory inputs
• Thirst and hunger regulation
• Autonomic function control
• Thermoregulation
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Hypothalamus
• Hormones
• Inhibiting hormones
• Function: decrease hormonal secretion from the pituitary gland
• Examples: somatostatin, dopamine
• Releasing hormones
• Function: increase hormonal secretion from the pituitary gland
• Examples: thyrotropin-releasing hormone (TRH), corticotropin-
releasing hormone (CRH), gonadotropin-releasing
hormone (GnRH), growth hormone-releasing hormone (GHRH)

Functional anatomy
of the hypothalamic-
pituitary axis
ADH and oxytocin are produced and secreted
from neuroendocrine cells within the
hypothalamus, from where they are
transported to the neurohypophysis before
being released into the bloodstream. The
release of these hormones is controlled by
hypothalamic neurons. Other tropic
hormones (i.e., GH, FSH, LH, TSH, ACTH) are
released from the adenohypophysis into the
bloodstream according to the action of
releasing and release-inhibiting hormones
produced by the hypothalamus. The
regulation of these releasing and release-
inhibiting hormones occurs via negative
feedback mechanisms exerted by the tropic
hormones themselves.
Source: © AMBOSS

Pituitary gland (hypophysis)
• “Master gland”
• Located in the sella turcica (midline depression of
the sphenoid bone) of the middle cranial fossa
• Connected to the hypothalamus via the pituitary stalk
• Consists of two major parts:
• Anterior pituitary gland (adenohypophysis): develops from
oral ectoderm (Rathke pouch)
• Posterior pituitary gland (neurohypophysis): develops
from neural ectoderm


The most common local complication of a
large pituitary tumour is compression of
the optic pathway.
Clinical pearl!

• The three major types of pituitary cells are:
• Acidophil cells
• Secrete prolactin and growth hormone (GH)
• Basophilic cells
• Secrete adrenocorticotropic hormone (ACTH), thyroid-stimulating
hormone (TSH), luteinizing hormone (LH), and follicle-stimulating
hormone (FSH)
• Chromophobe cells
• Do not secrete hormones
• Stain poorly with both acidic and basic dyes

• Function
• Anterior pituitary gland
• Regulation of endocrine gland function via the release of tropic
hormones
• Secretion of nontropic hormones with direct peripheral effects
• Posterior pituitary gland: storage/release
of ADH and oxytocin in pituicytes (glial cells)
• Hormones
• Tropic hormones: act on endocrine glands to mediate their
effects
• Nontropic hormones: act directly on target-tissue cells

Hypothalamic-pituitary axis
11
Hypothalamus and anterior pituitary
• Tropic hormones
Axis Hypothalamus Pituitary gland Endocrine target
organ
Hypothalamic- Corticotropin- ACTH Adrenal cortex
pituitary-adrenal releasing hormone
axis (CRH)
Hypothalamic- Thyrotopin- TSH Thyroid gland
pituitary-thyroid releasing hormone
axis (TRH)
Hypothalamic- Gonadotropin- LH/FSH Gonads
pituitary-gonadal releasing
axis hormone(GnRH)

Hypothalamus and anterior pituitary
• Non-Tropic hormones
Axis Hypothalamus Pituitary gland
Hypothalamic- Growth hormone- GH
pituitary- releasing hormone
somatotropic axis (GHRH)
Somatostatin
Hypothalamic- Dopamine (prolactin Prolactin
pituitary-prolactin -inhibiting
axis hormone)
Thyrotopin-
releasing hormone
(TRH)

Hypothalamus and posterior pituitary
• Neurons originate in hypothalamus

• Contains axons and nerve terminals
• Secretes ADH (vasopressin) and oxytocin

Classification of diseases of the pituitary
and hypothalamus

By far the most common
disorder is an adenoma
of the anterior pituitary gland.
Quick hit!

How to investigate patients with
suspected pituitary hypothalamic disease

MRI reveals ‘abnormalities’ of the pituitary gland in
as many as 10% of ‘healthy’ middle-aged people. It
should therefore be performed only if there is a
clear biochemical abnormality or if a patient
presents with clinical features of pituitary tumour.
Clinical pearl!

How do patients with pituitary disease
present?

Pituitary tumor

Epidemiology
• Prevalence
• Approx. 80 cases per 100,000 individuals
• Pituitary adenomas account for ∼ 15% of
primary intracranial tumors.
• Peak incidence: 35–60 years

Etiology
• Most cases occur sporadically.

• Some cases (∼ 5%) have a genetic/familial
association:
• Multiple endocrine neoplasia type 1

Pathophysiology
• Tumor classification according to size
• Pituitary microadenoma: ≤ 10 mm
• Pituitary macroadenoma: > 10 mm
• Tumor classification according to ability to secrete hormones
• Nonsecretory pituitary adenomas
• Nonfunctioning tumors account for 15–45% of all pituitary adenomas.
• Secretory pituitary adenomas: hormone secretion
• Most exclusively proliferate in only one type of endocrine cell and
therefore secrete only one pituitary hormone.
• The presence of multiple pituitary hormones should also raise suspicions
for atypical pituitary adenomas or pituitary carcinomas.

Pathophysiology of secretory adenomas
Origin Relative frequency (as a Pathophysiology

percentage of
all pituitary adenomas(
Lactotroph 40% Hyperprolactinemia
adenoma (prolactinoma)
Somatroph adenoma 10-15% ↑ Growth hormone → acromegaly
or gigantism
Corticotroph adenoma (Cushing 5% ↑ ACTH → secondary

disease) hypercortisolism
Thyrotroph adenoma 1% ↑ TSH → secondary hyperthyroidism
Gonadotroph adenoma Rare ↑ LH and FSH

Prolactinomas are the most
common pituitary adenoms
Quick hit!

Clinical features

The symptoms associated
with pituitary adenomas depend on the
size of the tumor and whether
the tumor produces hormones
Clinical pearl!

Clinical features
• Visual field defects

• The classical abnormalities associated with compression
of the optic chiasm are bitemporal hemianopia
• suprasellar extension of a tumour may compress the optic
nerve (unilateral loss of acuity or scotoma) or the optic
tract (homonymous hemianopia).

Bitemporal
heteronymous
hemianopia
Visual field test (perimetry). Left eye of
patient corresponds to left eye on
image.
There are areas of complete visual loss
(black) and partial visual loss (grey
hatching) in the outer (temporal) visual
fields bilaterally. The area of complete
visual loss is larger in the right eye, but
there is sparing of the right macula,
while the left macula is affected.

Overview of visual
field defects
(1) Left anopia
(2) Bitemporal heteronymous
hemianopia
(3) Right homonymous hemianopia
(4) Contralateral upper homonymous
quadrantanopia
(5) Contralateral lower homonymous
quadrantanopia
(6) Homonymous hemianopia with
macular sparing
(7) Homonymous central scotoma

Bitemporal hemianopia
Paris in the eyes of a patient with a
Paris in the eyes of a normal person pituitary macroadenoma


Diagnostics
Presentation Initial evaluation Further evaluation
Hormone assays to determine
whether:
Imaging studies to confirm the •The pituitary adenoma is
Symptoms of mass effect to
presence of a pituitary adenoma secretory or nonsecretory
the pituitary
•Concomitant hormonal
deficiencies exist
(i.e., hypopituitarism)
Symptoms Hormone assays to If pituitary endocrine
of hypopituitarism or confirm pituitary endocrine dysfunction is confirmed:
hyperpituitarism dysfunction imaging studies
Pituitary incidentaloma Complete clinical assessment Hormone assays to screen
for hypopituitarism
or hyperpituitarism
33
In patients with endocrine dysfunction,
order hormone assays before imaging to
prevent overdiagnosis of pituitary
incidentalomas.
Clinical pearl!

Diagnostics
• Hormone assays
• Indications for testing
• First-line tests for all patients with symptomatic endocrine dysfunction
• Pituitary mass detected on imaging
• Prior to planned pituitary surgery
• Initial studies
• Choice of studies
• Symptomatic patients: Studies are chosen according to clinical presentation.
• Asymptomatic patients: general screening
• Interpretation
• ↓ Hormone levels suggest hypopituitarism
• ↑ Hormone levels suggest hyperpituitarism

Diagnostics
• Imaging studies
• MRI sella with IV contrast (gold standard)
• Indications
• First-line diagnostic modality for suspected secretory or
nonsecretory pituitary adenomas
• Postsurgical surveillance after resection of a pituitary mass
• Characteristic finding: intrasellar mass

Pituitary mass
MRI head (T1-weighted; with contrast;
coronal plane) of a male patient with
headache, retroorbital pressure, fatigue, and
elevated serum prolactin
A large enhancing mass (indicated by arrows)
is seen in the midline in the area of the sella
turcica. The normal left internal carotid
artery (encircled) is shown as a hypointense
structure because of flow-related signal loss.
In light of the patient's history, a prolactin-
secreting macroadenoma (prolactinoma) of
the pituitary gland is the most likely
diagnosis.

Treatment
• Refer all patients to endocrinology.

• Treatment is based on the tumor type, tumor size, and
presence of symptoms.
• Initial treatment options include surgery,
pharmacotherapy, and observation.
• Refractory tumors : consider (repeat) transsphenoidal
hypophysectomy, medical management, and/or
pituitary irradiation.

Treatment

Treatment
• Urgent treatment is required if there is evidence of pressure
on visual pathways. The chances of recovery of a visual field
defect are proportional to the duration of symptoms, with full
recovery unlikely if the defect has been present for longer than
4 months.
• In the presence of a sellar mass lesion, it is crucial that serum
prolactin is measured before emergency surgery is
performed. If the prolactin is over 5000 mIU/L (236 ng/mL),
then the lesion is likely to be a macroprolactinoma and should
respond to a dopamine agonist with shrinkage of the lesion,
making surgery unnecessary.

Treatment
• Most operations on the pituitary are performed using

the trans-sphenoidal approach via the nostrils.
• All operations on the pituitary carry a risk of
damaging normal endocrine function; this risk
increases with the size of the primary lesion.
• Pituitary function should be retested 4–6 weeks
following surgery, primarily to detect the
development of any new hormone deficits.
Hypopituitarism

Definition
• Hypopituitarism describes combined deficiency of any

of the anterior pituitary hormones.

Etiology
44
Pathophysiology
• Hypopituitarism becomes symptomatic when more than 80%
of pituitary cells are damaged.
• In most cases, hypopituitarism develops slowly (e.g., adenomas,
postirradiation)
• Certain cases of hypopituitarism develop rapidly (e.g., pituitary
apoplexy).
• Hypopituitarism refers to deficiency of one or more anterior
pituitary hormones
• GH deficiency → growth retardation (during childhood), ↓ bone density,
muscle atrophy, hypercholesterolemia
• Prolactin deficiency → lactation failure following delivery
• FSH/LH deficiency → hypogonadotropic hypogonadism (secondary
hypogonadism)
• TSH deficiency → secondary hypothyroidism
• ACTH deficiency → secondary adrenal insufficiency 45
Hypothalamic-pituitary axis
46
The golden rule is: you lose
first what you neeed least!
Clinical pearl!

Clinical features
• Symptoms are variable and depend on
• the specific hormone deficiency,
• the age of disease onset,
• the rate at which hypopituitarism develops, and
• the underlying cause of hypopituitarism.
• General symptoms: Intrasellar/parasellar masses (e.g., pituitary
macroadenomas, craniopharyngiomas) can manifest with headache, visual
field defects (bitemporal hemianopsia), and/or diplopia.
• GH deficiency
• During childhood: short stature
• During adulthood
• Usually asymptomatic
• Subtle findings include weight gain, weakness, and depression.

Clinical features
• Prolactin deficiency
• Women: lactation failure following delivery
• Men: asymptomatic
• FSH/LH deficiency
• Women: primary amenorrhea (delayed puberty), secondary amenorrhea,
irregular menstrual cycles, infertility
• Men: delayed puberty, loss of libido, infertility, testicular atrophy, loss of facial,
axillary and/or pubic hair, gynecomastia
• ACTH deficiency: weight loss, weakness, hypotension, chronic hyponatremia,
hypoglycemia
• TSH deficiency: weight gain, cold intolerance, lethargy, constipation, dry skin
• Central diabetes insipidus: polyuria, polydipsia

During childhood, growth retardation is
often the presenting feature, and in
adults, hypogonadism is the earliest
symptom.
Clinical pearl!


The presence of
regular menstrual cycles in
women rules
out hypogonadism.
Clinical pearl!

Treatment
• All patients require pituitary hormone replacement to
treat the conditions that result from hypopituitarism.
• Treat all patients for secondary adrenal insufficiency,
secondary hypothyroidism, hypogonadism, and diabetes
insipidus.
• Treat growth hormone deficiency in all children and consider
treatment in adults.
• No treatment is indicated for deficiencies of prolactin,
oxytocin.
• Identify and treat the underlying cause
• (e.g., transsphenoidal resection in some cases of pituitary
macroadenomas).
In addition to pituitary
hormone replacement, the underlying
cause of hypopituitarism should be
treated.
Clinical pearl!

Maintenance therapy for pituitary
hormone deficiencies
Hormone replacement in hypopituitarism
Secondary adrenal insufficiency Routine management: glucocorticoids with dose increases during
periods of stress
Secondary hypothyroidism New diagnosis: Rule out ACTH deficiency before starting treatment,
as levothyroxine increases the clearance of cortisol and may
precipitate an adrenal crisis.
Routine management: levothyroxine
Monitor treatment efficacy with free T4 levels (not TSH)
Secondary hypogonadism Men
Testosterone replacement
If fertility is desired, exogenous gonadotropins (e.g., hCG)
Females: estrogen replacement with progesterone
Growth hormone deficiency Children: growth hormone replacement
Adults: GH replacement may be offered but is not usually required.

Pituitary apoplexy
• Infarction of the pituitary gland as a result of ischemia and/or hemorrhage
• Most commonly occurs in patients with a preexisting pituitary adenoma
• Primarily affects the anterior pituitary gland because it receives its blood
supply from a relatively low-pressure arterial system and is, therefore,
vulnerable to ischemia and infarction
• Pituitary apoplexy is a life threatening emergency manifests with acute onset
of:
• Severe headache
• Hypopituitarism
• Bilateral hemianopia, diplopia (due to damage to CN III)
• Severe hypoglycemia, sudden hypotension, possibly shock
• Give immediate IV hydrocortisone without waiting for diagnostic confirmation
• If there is significant or progressive visual loss or LOC then urgent surgical
decompression.
56
Pituitary apoplexy, which results in
acute hypocortisolism and hypothyroidim
, can manifest with severe headache,
sudden hypotension, and hypovolemic
shock.
Clinical pearl!

Sheehan syndrome
• Postpartum necrosis of the pituitary gland.
• Usually occurs following postpartum hemorrhage
• During pregnancy, hypertrophy of prolactin-
producing regions increases the size of the pituitary gland,
making it very sensitive to ischemia.
• Blood loss during delivery/postpartum
hemorrhage → hypovolemia → vasospasm of
hypophyseal vessels → ischemia of the pituitary gland
• Present with lactation failure following delivery
Hyperprolactinemia

Prolactin
• Protein hormone
• Regulates milk production in mothers

Stimulation of milk
production and
ejection
The suckling stimulus at the nipple triggers the
secretion of oxytocin by the hypothalamus and
inhibits the secretion of hypothalamic
dopamine (prolactin-inhibiting hormone) and
GnRH.
Normally, dopamine inhibits the secretion of
prolactin (prolactin triggers milk production).
The inhibition of dopamine by the suckling
stimulus, therefore, promotes milk production.
At the same time, the suckling stimulus
promotes the production of oxytocin in the
hypothalamus and its secretion in the posterior
pituitary, leading to milk ejection.
The suckling stimulus also inhibits the secretion
of GnRH by the hypothalamus, which, in turn,
inhibits the secretion of LH and FSH in the
anterior pituitary (→ lactational amenorrhea).
Source: AMBOSS

Prolactin
• Under inhibitory control from hypothalamus

• Hypothalamus releases dopamine
• Inhibits lactotrophs via binding to D2 receptors
• Destruction of hypothalamus: ↑ prolactin
• Prolactin feedback on hypothalamus
• Increases dopamine release → ↓ prolactin

Prolactin
• Many other substances affect prolactin release

• VIP, Oxytocin, TRH, others
• TRH (thyrotropin-releasing hormone)
• Elevated in hypothyroidism
• Hypothyroidism predisposes to hyperprolactinemia
• Hypothyroidism in differential for:
• Pituitary enlargement
• Hyperprolactinemia
Prolactin in Pregnancy
• Estrogen stimulates prolactin release

• Stimulates gene transcription
• Stimulates release from lactotrophs
• Marked increase in lactotrophs during pregnancy
• Pituitary can grow in size
• Prolactin inhibits GnRH release
• Results in cessation of ovulation/menstruation

Prolactin in Pregnancy
• Milk production in pregnancy does not occur

• Estradiol and progesterone block prolactin effect on milk
• After childbirth → ↓ estradiol and progesterone
• Milk production occurs

Epidemiology
• Sex: ♀ > ♂
• Prevalence
• ∼ 0.4% of the general population
• Hyperprolactinemia is the most common form
of hyperpituitarism.

Etiology

Pituitary adenomas are the
most common cause (∼ 50%)
of pathological
hyperprolactinemia.
Clinical pearl!

Pathophysiology
• ↑ Prolactin → galactorrhea
• ↑ Prolactin → suppression of GnRH → ↓ LH, ↓ FSH
→↓ estrogen, ↓ testosterone → hypogonadotropic
hypogonadism.

Clinical features
Hormonal changes Female Male
↑ Prolactin Galactorrhea Galactorrhea is rare.
(especially premenopausal women)
↓ LH + ↓ FSH Primary and/or secondary Clinical features of ↓ testosterone
amenorrhea, or irregular menses
Infertility
↓ Testosterone Loss of libido Loss of libido, erectile dysfunction
infertility
Gynecomastia
Reduced facial and body hair
Osteoporosis
↓ Estrogen Atrophic endometrium and vaginal Little to no noticeable effects
atrophy (menopausal symptoms)
Osteoporosis (after several years)
Timing of presentation Earlier presentation Later presentation
(microprolactinoma)
70
Patients with hyperprolactinemia due to
a pituitary adenoma may also present
with bitemporal
hemianopsia and headache
Clinical pearl!

Prolactin-secreting cells of
the anterior pituitary share a common
lineage with GH-secreting cells, so
occasionally prolactinomas can secrete
excess GH and cause acromegaly.
Quick hit!

Investigations
• Pregnancy should first be excluded before further

investigations are performed in women of child-
bearing potential.
• Basal prolactin level
• TSH, T4 levels: to exclude primary hypothyroidism
• Cranial contrast MRI: to rule out pituitary adenomas

Investigations
Interpretation of prolactin level
Prolactin level Interpretation

500 mIU/L (24 ng/mL) Upper limit of normal
500–1000 mIU/L likely to be induced by stress or drugs in non-pregnant and non-lactating
(24–47 ng/mL) patients and a repeat measurement is indicated.
1000 and 5000 mIU/L (47–236 drugs, a microprolactinoma or ‘disconnection’ hyperprolactinaemia
ng/mL)
<5000 mIU/L (236 ng/mL) highly suggestive of a macroprolactinoma

Unlike most other pituitary adenomas in
which hormone levels do not correlate with the size
of the pituitary adenoma, serum prolactin levels
closely reflect the size of prolactinomas.
Clinical pearl!

Management
• If possible, the underlying cause should be corrected (e.g.
cessation of offending drugs and giving levothyroxine
replacement in primary hypothyroidism).
• If gonadal dysfunction is the primary concern, sex steroid
replacement therapy may be indicated.
• Troublesome physiological galactorrhoea can also be
treated with dopamine agonists.
• If dopamine antagonists are the cause, then dopamine
agonist therapy is contraindicated.
• What about prolactinoma?
Management of prolactinoma
• Medical
• Dopamine agonist drugs are first-line therapy for the majority of
patients.
• They usually reduce serum prolactin concentrations and cause
significant tumour shrinkage after several months of therapy, but
visual field defects, if present, may improve within days of first
administration.
• It is possible to withdraw dopamine agonist therapy without
recurrence of hyperprolactinaemia after a few years of treatment in
some patients with a microadenoma.
• In patients with macroadenomas, drugs can be withdrawn only after
curative surgery or radiotherapy and under close supervision.
Dopamine agonist therapy

• Surgery and radiotherapy
• Surgical decompression is usually necessary only when a
macroprolactinoma has failed to shrink sufficiently with dopamine
agonist therapy, and this may be because the tumour has a
significant cystic component.
• Surgery may also be performed in patients who are intolerant of
dopamine agonists.
• Microadenomas can be removed selectively by trans-sphenoidal
surgery with a cure rate of about 80%, but recurrence is possible; the
cure rate for surgery in macroadenomas is substantially lower.
• External irradiation may be required for some macroadenomas to
prevent regrowth if dopamine agonists are stopped.
• Pregnancy
• Hyperprolactinaemia often presents with infertility, so
dopamine agonist therapy may be followed by pregnancy.
• Patients with microadenomas should be advised to withdraw
dopamine agonist therapy as soon as pregnancy is
confirmed.
• In contrast, macroprolactinomas may enlarge rapidly under
oestrogen stimulation and these patients should continue
dopamine agonist therapy and need measurement of
prolactin levels and visual fields during pregnancy.
• All patients should be advised to report headache or visual
disturbance promptly.
Shrinkage of a
macroprolactinoma following
treatment with a dopamine
agonist.
MRI scan showing a pituitary
macroadenoma (T) compressing the
optic chiasm (C).
MRI scan of the same tumour following
treatment with a dopamine agonist. The
macroadenoma, which was a
prolactinoma, has decreased in size
substantially and is no longer
compressing the optic chiasm.

Acromegaly

Growth Hormone
Somatotropin
• Protein hormone
• Important for linear (height) growth in childhood
• Released in a pulsatile manner
• Between pulses levels may become undetectable

Hypothalamic-
pituitary-
somatotropic axis
Hypothalamic hormone GHRH (growth
hormone-releasing hormone) stimulates the
release of growth hormone (GH) from the
acidophilic cells of the pituitary gland. GH-
release is inhibited by somatostatin (growth
hormone-inhibiting hormone, GHIH), which
is produced in the hypothalamus and D cells
(pancreas, duodenum). Ghrelin (produced in
stomach) acts as another stimulator of GH-
release.
As a nontropic hormone, GH either directly
stimulates target cells or acts indirectly via
synthesis of insulin-like growth factors (IGFs).
GH-release is inhibited by GH itself and IGFs,
GHRH-release only by IGFs.
Source: AMBOSS

Growth Hormone
Somatotropin
• Many stimulants and suppressors

• Pituitary release stimulated by:
• GHRH
• Exercise
• Sleep (very high just after onset of sleep)
• Hypoglycemia
• Released inhibited by:
• Glucose
• Somatostatin (released in response to IGF-1; GH)
• IGF-1 (direct and indirect)

Growth Hormone
Somatotropin
• Liver contains many growth hormone receptors

• GH → Liver → IGF-1 secreted
• Insulin-like growth factor 1/Somatomedin
• Hormone that mediates many growth hormone effects
• Can be measured in serum as indicator of GH function

Growth Hormone
Direct Effects
• ↓ glucose uptake by cells

• Anti-insulin
• Will raise blood sugar (“Diabetogenic”)
• Peripheral tissues become insulin resistant
• Hyperinsulinemia
Your Footer Here 87

Growth Hormone
Direct Effects
• Promotes lipolysis
• Activates hormone sensitive lipase
• Production of IGF-1 from liver

Growth Hormone
IGF-1 effects
• Chondrocytes
• Increased linear growth
• Muscle
• Lean muscle mass
• Organs
• Increased organ size

Epidemiology
• Prevalence: 1–9/100,000 in the US

• Age of onset: 3rd decade of life (mean age at diagnosis
usually 40–45 years)
• Sex: ♀ = ♂

Etiology
• Benign growth hormone-secreting pituitary

adenoma (> 95% of cases)
• Usually macroadenoma

Pathophysiology
• Effects of a pituitary adenoma

• Overproduction of GH → abnormally high serum IGF-1
levels → overstimulation of cell growth and proliferation
→ symptoms of acromegaly
• Tumor mass compresses neighboring structures
(e.g., optic chiasm) → symptoms of mass effect
• Impaired secretion of other pituitary hormones,
especially gonadotropins → ↓ LH and FSH → ↓ estrogen
and testosterone
Excess GH secretion before the conclusion of
longitudinal growth (i.e., prior to epiphyseal
plate closure) leads to pituitary gigantism with a
possible height of ≥ 2 m. After epiphyseal
plate closure, GH excess causes acromegaly, but no
change in height!
Clinical pearl!

Clinical features
• Tumor mass effects
• Headache, vision loss (bitemporal hemianopsia), cranial nerve palsies
• ♀: Oligomenorrhea, secondary amenorrhea, galactorrhea, vaginal atrophy
• ♂: Erectile dysfunction, decreased libido, ↓ testicular volume
• Soft tissue effects
• Doughy skin texture, hyperhidrosis
• Deepening of the voice, macroglossia with fissures, obstructive sleep
apnea
• Skeletal effects
• Coarsening of facial features slowly progressing with age: enlarged nose,
forehead, and jaw (macrognathia)
• Widened hands, fingers, and feet
• Painful arthropathy (ankles, knees, hips, spine)
Clinical features

Clinical features of
acromegaly progress slowly
over a period of years!
Clinical pearl!

Acromegalic facies
There is significant enlargement of the
nose, chin, supraorbital region, lips, and
zygomatic arch. The protrusion of the
lower jaw is especially prominent
(prognathism).
Source: “Figure 2, in: Acromegaly” by

Philippe Chanson, Sylvie Salenave, Orphanet
Journal of Rare Diseases.

Hand in acromegaly
The hand of a patient with acromegaly
(right) is visibly enlarged with thickened
fingers, when compared to the hand of
a male, of roughly the same age and
height, without acromegaly (left)
Source: “Figure 1. in: Acromegaly” by

Philippe Chanson and Sylvie
Salenave, Orphanet Journal of Rare
Diseases.

Spacing of teeth in
acromegaly
Pronounced gaps can be seen between
the incisors in the lower row of teeth.
This is caused by abnormal jaw growth,
which has pushed the teeth apart. The
gaps between the teeth are a
characteristic finding in patients with
acromegaly.
Source: "Acromegalyteethgapping", Offices

of Kenneth Yamanaka, DDS - my dentist's
office, Wikimedia Commons licensed under
Public Domain

Investigations
• Hormone analysis
• Serum IGF-1 concentration: the most sensitive test
• Elevated IGF-1 level: acromegaly suspected; conduct oral glucose tolerance
test (OGTT).
• Normal IGF-1 level: acromegaly ruled out
• OGTT with baseline GH and measure GH after 2 hours: the most specific
test
• If GH suppressed: acromegaly ruled out
• If GH not suppressed: confirmed acromegaly; conduct pituitary MRI to
determine the source of excess GH
• Pituitary MRI
• Imaging modality of choice
• Usually shows a visible mass: confirmed GH-secreting pituitary adenoma

Diagnosis of
acromegaly
Source: AMBOSS

Treatment
• Transsphenoidal adenomectomy is the method of

choice for treating acromegaly.
• In patients with inoperable tumors or unsuccessful
surgery, medication and radiotherapy are indicated to
reduce tumor size and limit the effects of GH and
IGF-1.

Treatment
• Surgery
• The first line of treatment and may result in cure of GH
excess, especially in patients with microadenomas.
• More often, surgery serves to debulk the tumour and
further second-line therapy is required, according to post-
operative imaging and glucose tolerance test results.

Treatment
• Radiotherapy
• External radiotherapy is usually employed as second-line
treatment if acromegaly persists after surgery, to stop
tumour growth and lower GH levels.
• However, GH levels fall slowly (over many years)

Danger of hypopituitarism
following surgery or
radiotherapy!
Clinical pearl!

Treatment
• Medication
• Somatostatin analogs (e.g., octreotide, lanreotide)
• Dopamine agonists (e.g., cabergoline): reduce tumor size
and GH secretion
• GH receptor antagonists (e.g., pegvisomant)
• Used if acromegaly persists after surgery, to lower GH levels
and to normalise IGF-1 concentrations.
• Somatostatin analogues can also be used as primary therapy
for acromegaly either as an alternative or in advance of
surgery

Complications
• Complications lead to increased mortality.
• Cardiovascular complications: the main cause of death
• Hypertension (∼ 30% of cases)
• Left ventricular hypertrophy and cardiomyopathy
• Arrhythmia
• Valvular disease
• Impaired glucose tolerance and diabetes mellitus (up to 50% of cases)
• Colorectal polyps and cancer…. Diagnostic Colonoscopy ?
• Thyroid enlargement and cancer
• Carpal tunnel syndrome
• Cerebral aneurysm
• Hypopituitarism
• Psychological impairment (↓ quality of life, anxiety, ↓ self-esteem)

Diabetes inspidus

Antidiuretic Hormone
ADH; Vasopressin
• Retention of free water

• Major physiologic trigger is plasma osmolality
• Sensed by hypothalamus
• ADH released by posterior pituitary gland
• ADH →free water resorption by kidneys
• Water retention adjusted to maintain normal osmolality

Hormonal feedback
control of ADH
secretion
(1) Receptors in the hypothalamus measure
plasma osmolality. If the osmolality exceeds a
set point, ADH is released in the
hypothalamus.
(2) ADH travels from the hypothalamus to
the posterior pituitary via the neurosecretory
hypothalamo-neurohypophyseal tract.
(3) ADH is released from the posterior
pituitary into the bloodstream.
(4) ADH increases renal reabsorption of
water (inclusion of aquaporins in the
collecting tubules).
(5) Reabsorption of water results in
decreased urination.
(6) Receptors in the hypothalamus detect
falling osmolality and reduce ADH secretion.
Source: AMBOSS

Effect of ADH on the
kidney
ADH is essential for the regulation of fluid balance as it
stimulates the water reabsorption in the collecting duct
system of the kidney. ADH is produced in the hypothalamus,
from where it travels to the posterior pituitary, over an
axonal transport, and is released when required.
ADH secretion is stimulated through an increased blood
osmolarity and an increased angiotensin II as well as low
blood pressure or low blood volume, whereas it is inhibited
through ethanol.
If ADH is released in the posterior pituitary, it becomes
effective in the kidney by binding to an ADH receptor (V2
receptor) in the collecting duct system, which then leads to
a stimulation of adenylate cyclase (= catalyzes the
conversion of ATP to cAMP).
The increased cAMP level activates the cAMP-dependent
protein kinase A (PKA), which phosphorylates and activates
aquaporin 2 with several intermediate steps. Aquaporin 2
exists in vesicles in the cytoplasm – if it is activated, it
reaches the luminal cell wall and they merge together.
Water can now flow into the cell through the aquaporin 2
channels, which then reaches into the interstitium of the
kidney through aquaporin 3 and 4 channels.
Source: AMBOSS

Water balance

Epidemiology
• Prevalence in the US: 3:100,000

• Sex: ♀=♂

Etiology
• Diabetes inspidus is classified into:

• cranial diabetes insipidus, in which there is deficient
production of vasopressin by the hypothalamus
• nephrogenic diabetes insipidus, in which the renal
tubules are unresponsive to vasopressin

Etiology

Pathophysiology
• ADH enables the integration of aquaporins into the plasma
membrane of collecting duct cells → reabsorption of free
water
• Either ↓ ADH (central DI) or defective renal ADH receptors
(nephrogenic DI) → impaired ability of the kidneys to
concentrate urine (hypotonic collecting ducts) → dilute
urine (low urine osmolarity)
• Urine osmolality changes
• Normal: 500–800 mOsmol/kg
• Partial DI (300–500 mOsmol/kg)
• Complete DI (< 300 mOsmol/kg, often < 100 mOsmol/kg)
Pathophysiology
• Hyperosmotic volume contraction
• Loss of fluid with urine → increased extracellular
fluid osmolarity → passage of fluid from the intracellular to
the extracellular space → equalization of the osmolarities of
the extracellular and intracellular fluid
• Due to the loss of fluid, the osmolarities of intracellular and
extracellular compartments are now higher (hyperosmotic)
than the initial values.
• The fluid volume is redistributed between the two
compartments to equalize the osmolarities and remains lower
than the initial values in each of them (volume contraction)
Clinical features
• Polyuria with dilute urine (the patient may pass 5–20 L or
more of urine in 24 hours, this is of low specific gravity and
osmolality)
• Nocturia → restless sleep, daytime sleepiness
• Polydipsia (excessive thirst, If the patient has an intact thirst
mechanism, is conscious and has access to oral fluids, then he
or she can maintain adequate fluid intake).
• In cases of low water intake (unconscious patient or a patient
with damage to the hypothalamic thirst centre) → severe
dehydration (altered mental status, lethargy, seizures, coma)
and hypotension
Differential diagnosis
• Primary polydipsia (Excessive oral intake of fluid in

the absence of physiologic stimulus to drink. May
include psychogenic polydipsia secondary to
psychoses or other mental disorders or non-
psychogenic varieties.)
• Diabetes mellitus

Diagnostics
• If DI is suspected, sodium, plasma osmolality, and urine
osmolality are tested.
• A water deprivation test then allows DI to be
differentiated from primary polydipsia.
• The patient's response to the administration
of desmopressin, furthermore, distinguishes CDI from
NDI.
• If CDI is diagnosed, a CT scan or MRI of the head should
be conducted to rule out brain tumors (especially
craniopharyngioma).

Diagnosis of DI
Source: AMBOSS

Water deprivation test (confirmatory test)
• After obtaining baseline lab values, patients stop drinking water for 2–3 hours before
the first measurement
• After 2–3 hours without drinking water
• Test urine volume and osmolality every hour
• Test sodium and plasma osmolality every two hours
• Water deprivation continues until one of the following occurs:
• Urine osmolality rises and reaches a normal value (> 600 mOsmol/kg) → DI ruled out
and primary polydipsia confirmed
• No change in urine osmolality despite a rising plasma osmolality (> 290 mOsmol/kg)
• Plasma osmolality > 295–300 mOsmol/kg or sodium ≥ 145 meq/L
• In the latter two situations → administer desmopressin (a synthetic ADH analog)
• Monitor urine osmolality testing every 30 minutes for 2 hours
• In CDI: Urine osmolality rises after desmopressin administration (renal ADH receptors are intact).
• In NDI: Urine osmolality remains low after desmopressin administration (defective
renal ADH receptors).

Water deprivation test (confirmatory test)

Water deprivation
test

DDAVP should not be administered to
patients with primary polydipsia, since it
will prevent excretion of water and there
is a risk of severe water intoxication if the
patient continues to drink fluid to excess.
Clinical pearl!

Treatment
• Treat the underlying condition, ensure sufficient fluid

intake, and initiate a low-sodium, low-protein diet.
• Central diabetes insipidus
• Desmopressin: synthetic vasopressin without
vasoconstrictive effects
• Administration: intranasal (preferred), subcutaneous, or
oral
• Important side effect: hyponatremia

Treatment
• Nephrogenic diabetes insipidus

• Discontinuation of the causative agent
(e.g., lithium, demeclocycline) in medication-induced NDI
• Thiazide diuretics
• NSAIDs (e.g., indomethacin)
• Amiloride
• Indicated in patients with lithium-induced NDI
• Amiloride blocks lithium entry through the sodium channel.

Thiazides ! How?
• Thiazide diuretics lead to sodium depletion, which

causes sodium and water reabsorption in
the proximal tubules. As a result, less water reaches
the ADH-sensitive distal collecting tubules and volume
of urine decreases.

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Pituitary Diseases

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Pituitary Diseases

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Pituitary diseases

By Dr. Haitham Nabeel

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• Neurons originate in hypothalamus

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• Most cases occur sporadically.

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Origin Relative frequency (as a Pathophysiology

Corticotroph adenoma (Cushing 5% ↑ ACTH → secondary

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• Visual field defects

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• Refer all patients to endocrinology.

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• Most operations on the pituitary are performed using

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• Hypopituitarism describes combined deficiency of any

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• Under inhibitory control from hypothalamus

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