LECTURE 3

HYPOPHYSEAL

Frequency:
10-15% of intracranial tumors.

Necroptic studies
6-23% asymptomatic hypophyseal tumors.

neurological symptoms (tumoral

syndrome)

functional symptoms (endocrine

syndrome)

 direct compression

intracranial hypertension

 secondary to the alteration of

hypophysial
and
peripheral glands function.
Functional consequences may be:
secretory deficiency
secretory excess

anterior portion-flanked by:

posterior projections of the sphenoid wings,
the anterior clinoid processes

posterior wall
dorsum sellae
its upper corners project into the posterior
clinoid processes.

The lateral walls:

in direct apposition to the cavernous sinuses .

Hypophyseal fossa

1. SULCUS CHIASMATICUS
2. TUBERCULUM SELLAE
3. TURKISH SADDLE APERTURE
4.
5.
6.
7.
8.
9.

POSTERIOR CLINOID PROCESSES

QUADRILATERAL LAMINA
DORSUM SELLAE
ANTERIOR CLINOID PROCESSES
LAMINA DURA
SPHENOIDAL SINUS

Hypophyseal fossa

the roof:
the gland is surrounded by dura mater,
formed by a reflection of the dura attached to the
clinoid processes = the diaphragma sellae.

The optic chiasm lies :

5-10 mm above the diaphragma sellae and
anterior to the stalk.

4 stages(Hardy):

1- microadenoma (<10 mm diameter);

sella turcica dimensions are not changed;
2- macroadenoma (>10 mm diameter);
with /without suprasellar extension;
sellar dimensions could be modified;
3- macroadenoma with local invasion ;
sella turcica - bigger than normal;
with/without suprasellar extension
4 -macroadenoma diffuse invasion
with/without suprasellar extension.

Adenoame hipofizare invazive imagini radiografice

 Adenoame hipofizare invazive imagini radiografice

 acidophilic adenomas
basophilic adenomas
chromophobic adenomas
There is not a direct corelation between:
- the histologic appearence and
- a specific endocrine activity.

Adenomas:
Functional
Non-functional

Hypophyseal tumors:
most are adenomas
adenocarcinoma
a rare condition
very invasive.
it may produce: GH,PRL,ACTH.

hypophyseal tumors

occasionally associated to adenomas

- in other endocrine glands

Pancreas,
Parathyroid
= defining Multiple Endocrine Neoplasia
syndrome
(MEN).

FUNCTIONING ADENOMAS
SOMATOTROPINOMA
PROLACTINOMA
CORTICOTROPINOMA
GLYCOPROTEIC HORMONES SECRETING ADENOMA
GONADOTROPINOMA
THYROTROPINOMA

Pathogenesis -3 theories :
a.Hypothalamic theory:

somatoliberine release- increase

somatostain release- decrease

b.Intrinsic hypophyseal theory:

a genic mutation.

c.Local growth factors theory:

these factors

released in a paracrine or autocrine manner and

produce increase in adenoma size.

40% of hypophyseal adenomas

a.Hypothalamic cause:
hypothalamic-dopamine-inhibitor tonusdecrease

b.Hypophyseal origin:
gene mutations

spontaneous or induced
followed by hormone or growth cellular
factors involvement

basophilic microadenoma (88-90 %)

macroadenoma (very rare)- high local invasive
potential.

Pathogenesis unknown- 2 theories:

a. Hypothalamic theory - it could not have been proved
b. Hypophyseal theory :
ACTH secretion capacity - increased,
corticotropic cells sensibility to hypercortisolism
decreased
sustained by:
inhibition of this hyperfunction with dexamethasone
(synthetic glucocorticoid).

very agressive macroadenoma

occurs in patients presenting:

bilateral adrenalectomy for Cushings

disease
receiving low or inadequate doses of
glucocorticoid therapy.

capacity to secrete ACTH( subclinical

adenoma !)
only in few secretory granules.

slowly evolutive

may have perisellar development - with

neurological symptoms

25 % of hypophyseal macroadenomas in
men:

long-evolutive primary hypogonadism

promotor effect on gonadotropic cells
hyperplasia :
a. gonadotropin-releasing hormone
(GnRH) - stimulates especially
alpha-chains synthesis
b. activine- stimulates beta-chains
synthesis

less than 1 %
May be:
a.primary thyrotropinoma- secretes TSH
that may produce hyperthyroidism
rare condition

b.secondary thyrotropinoma:
a reactive hyperlasia of thyrotropic cells
Occurs as a result of primary hypothyroidism

Do not present systemic secretory

capacity.

Histological studies (electronomicroscopy

and immunohistochemical studies)
adenomatous cells secrete glycoproteic
subunits ( beta-FSH and alpha-FSH; LH)
whitout systemic effect.

depend on tumoral size and extension

direction:

Headache
due to dura mater distention
could be:
retrorbital,
frontotemporal,
bitemporal or
occipital(rare).

Visual field modifications:

occur in large tumors with suprasellar
extension
due to optochiasmatic system:
compression,
infiltration or
intracranial hypertension.
40 % of cases- bitemporal hemianopsy
! A very precocious sign - pale optic papilla.

Cranial nerves dysfunction (III,IV,V and VI)-

due to lateral extension:

loss of pupilar reactivity
blepharoptosis
diplopia

Temporal lobe epilepsy due to temporal lobes compression

Liquorrhea due to perforation of lamina cribrosa ;

frequent complication: recurent meningitis.

Sphenoidal sinusitis due to:

invasion of sphenoidal sinus;
the tumor may grow into the sinus
without symptoms.

Hypophyseal apoplexy:
acute hemorrhagic infarct
represents a neurosurgical emergency.
Symptoms:

intense headache,
vomiting,
visual alterations and even blindness,
ophthalmoplegia;
Hemorrhagic CSF

Sometimes - a real autohypophysectomy

appears

Partial

Total
Deficiency depends on:

tumoral growth speed

patients age

There is a strict order in deficit installation:

gonadotrops(LH,FSH)

growth hormone(GH)

thyrotropin(TSH)

corticotropin(ACTH)

Prolactin (PRL) is rarely decreased.

Particularity !!! = a secreting adenoma

(GH,PRL,ACTH-secreting adenoma ) may
be accompanied by symptoms specific for
deficiency of other hormones.
Exemple:
Acromegaly and hypogonadism
Amenorrhea and galactorrhea
Cushings disease, galactorhea and
hypogonadism.

Secreting adenomas produce specific

disease:

develops on lactotropic hypophyseal cells

predominant in women- possibly due to

hyperestrogenism

It could be:

Microprolactinoma (more frecquent in

women)

Macroprolactinoma (more frequent in

men)

Clinical manifestation depend on:

gender
age
duration of evolution.

Functional effects usually

preceed

tumoral mass effects

Hyperprolactinemia inhibits pulsatile

release of gonadoliberine,resulting in:
alteration of pubertal sexualization process
alteration of menstrual cycle in women
alteration of sexual dynamic in men

Effects on mammary gland:

galactorrhea in women,rarely in men

gynecomastia in men.

The association amenorrhea-galactorrhea

=

hyperprolactinemia in 75 % of cases
and
prolactinoma in 30 % of cases.

Prolactin directly stimulates adrenal cortex

androgen excess Hyperandrogenic syndrome in women:

Seborrhea
Acne
Hypertricosis

Neurologic symptoms - supraselar extension :

intracranial hypertension

optochiasmatic compression syndrome

with / without ophtalmoplegia .

more frequent in:

men and
women at menopause.

Laboratory findings:

basal PRL
> 200 ng/dL=macroprolactinoma
100-200ng/dL (in the absence of pregnancy) =
microprolactinoma or
adenoma + compressing the hypophyseal stalk
< 100 ng/dL drugs, polycystic ovary, hepatic / renal
chronic failure

dynamic tests useful ( with limited diagnostic

value):
inhibiting tests - levo-dopa,bromocriptine,nomiphensine
stimulating tests - TRH,chlorpromazine,domperidone.

physiologic causes:

neonatal
gestational
during breast feeding
mechanical stimulation of the nipple
stress
sleep
transient: postprandial, during ovulation.

Drug induced :

estrogens,
neuroleptics,
cimetidine,
verapamil,
enalapril,
metoclopramid

Idiopathic

GH excess

Somatoliberine excess (GH-RH) rarely

1. hypophyseal secreting adenoma:

- GH
- GH and PRL
- plurihormonal
2. ectopic hypophyseal tumors:
- in the sphenoidal sinus
- parapharyngial
3. extrahypophyseal tumors:
- pancreatic
-pulmonary
- ovarian
- mammary

1. hypothalamic tumors

2. ectopic tumors:

lung cancer,

adrenal adenoma

Almost all body structures are affected.

Efects of GH:
directly or
through its effectors- somatomedins (or insulinelike growth factors-IGF-I) :

in adults- promotes grotesque and exagerated

growth=
acromegaly
in child and adolescent- accelerates growth
rate= gigantism

GH excess:
cannot be reduced only at esthetic
aspects

GH is involved in:
intermediary metabolism
visceral functionality
cellular replication process

increase in basal metabolism, hyperhydrosis, heat

intolerance
glucose intolerance and even diabetes mellitus
hypercalcemia,hypercalciuria,nephrolithiasis
hyperphosphoremia,increased alkaline
phosphatase
alteration in hypophyseal hormones secretion :
hyperprolactinemia,
hypopituitarism,
diabetes insipidus
thyroid alterations: nodular goiter, hypothyroidism
possible association to other endocrine neoplasia=
multiple endocrine neoplasia syndrome(MEN)

* carpal tunnel syndrome

* hypertrophic neuropathy
* nerve compression
* proximal myopathy

Low sonorous, nasonant voice

obstructions of upper respiratory tract

increased lung volume

apnea during sleep

thick bone cortex

degenerative arthropathy

rachidian spondylosis

bone megalization

Giganto-acromegaly

GIGANTO-ACROMEGALY

hypertension

cardiomyopathy, angina, heart failure

complications of diabetes:
microangiopathy

thick skin, folds

sweating, seborrhea, pigmentation,
hirsutism
papilomas, lipomas

Characteristics
Slow evolution delayed diagnosis ( 10
years)

Diagnosis is made when somatic modifications

are irreversible --- in most cases !!!

increased serum GH:

permanent
or intermittent (more often)

increased IGF-1:
constantly

inhibition test with glucose:

in normal persons: GH - inhibited;
in acromegaly - a paradoxal increase of GH values

TRH and GH-RH tests - similar response.

cerebral gigantism (Sotos)

Paget disease

pachydermoperiostosis

leontiassis ossea

myxoedema

prognatism

Sotos syndrome

Pagets disease

Pachydermoperiostosis

Leontiassis ossea

Myxoedema

Simple prognatism (constitutional)

ACROMEGALOID FACE

Parkes-Weber syndrome (hemicorporeal hypertrophy)

90 % of cases microadenoma

responsible for Cushings disease

symptoms and signs - due to:

excessive ACTH adrenal cortex
hyperstimulation increase in
glucocorticoid level

rare disease (5 cases/1million/year)

Clinical features

Moon-face,
telangiectasia

Complications:

cardiovascular,
infectious,
diabetes mellitus

IMAGING STUDIES IN
HYPOPHYSEAL ADENOMAS

Conventional skull x-ray: lateral or anterior

Tomography
Angiography
Pneumoencephalography
CT scan; (with iodinated contrast
substance - more precise)
MRI (with gadolinium - more precise)
Catheterism of petrous inferior sinuses

incompetence of sellar roof with

arachnoidal hernia;

hypophyseal functionis:
usually normal.

may be either:
primary (congenital ) or
secondary (following surgery).

CSF - enlarges sella turcica.

Empty sella

TREATMENT
NEUROSURGERY
RADIOTHERAPY
MEDICAL THERAPY

Transsphenoidalmicroadenomas

Transfrontalsuprasellar
developing
adenomas

Transsphenoidal ( for microadenomas):

microscopic view
economic resection
minimal postoperative complications and
neglectible mortality (0,1%)

Transfrontal- suprasellar developing adenoma

!!! Mortality -10-15%
Postoperative complications :

hypophyseal insufficiency,

liquorrhea,

blindness,

ocular nerves paralysis.

Postoperatory expectancies:

normalization of involved hormone

level
normalization of other hormones.

conventional radiotherapy
X-rays and
gamma-rays

radioactive isotopes implantation

Yttrium 90 or
Iridium 192

irradiation with heavy particles

multifascicular irradiation with Cobalt 60-Gamma

Knife

The last two methods are the most used.

Radiotherapy - useful in:

GH-secreting adenomas (before and after
surgery)
PRL secreting adenoma resistent to
radiotherapy.
ACTH-secreting adenomas (before and after
surgery)
!!! Any inoperable adenoma

Gammaknife
stereotactic
radiosurgery

Damage of:
optic chiasma,
optic nerves,
cranial nerves
ischemia leading to cerebral necrosis
cerebral edema
pulmonary acute edema
convulsions
hypophyseal insufficiency
radiation dermatitis

Bromocriptine ( dopamine agonist) :

decrease in PRL synthesis

inhibition of cellular multiplication

Side effects:
nausea,
vomiting,
hypotension,
anaphylactic shock.

Treatment:
starts with low doses- 1,25mg/d,
progressively increase to 10-20 mg/d
orally

Other drugs:

Pergolide
Lisurid
Quingolide
CABERGOLINUM

Periodical assessment of:

serum PRL level,

sellar dimensions,
campimetry

Bromocriptine- 20-30 mg/d

Cabergolinum 1- 4g/ week
Somatostatine (Octreotide, Lanreotide) :
orally,
intranasal,
s.c.,
i.m.- once every 2-4 weeks.
decrease in:
tumoral size in 50 % of cases
serum GH level in 80 % of cases
Bromocriptine+ Somatostatine

Pegvinsomantum
GH-receptor
antagonist that opens a new line in the
treatement of acromegaly;
In the future GH-RH- receptor
inhibitors.

Bromocriptine/Cabergolinum

Sodium valproate

Octreotide

Surgery/ Cabergolinum(?)

Selection of patients that respond to

medical therapy with Octreotide:
tomography with positrons emission ( with FDG)
and
scintigraphy with Octreotide marked with Iodine
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