Download Endocrinology 1a – Hypothalamo-Pituitary Disorders

Endocrinology 1a –Anterior -Pituitary Disorders
Anil Chopra
1. Define the term pan-hypopituitarism (Simmond’s disease) and describe the specific
aetiology of the form of hypopituitarism called Sheehan’s syndrome.
2. Describe the more common signs and symptoms of pan-hypopituitarism.
3. Describe how a) anatomical pituitary disruption and b) pituitary hormone
deficiency can be evaluated, including the use of stimulation tests.
4. Describe how the endocrine consequences of pan-hypopituitarism can be treated,
using the term hormone replacement therapy
5. List the various possible individual pituitary hormone deficiencies that can occur
and explain how the conditions can be diagnosed and treated (when appropriate).
6. List the principal endocrine causes of short stature, identifying those that are
caused by lack or excess of specific hormones and those that are related to receptor
and post-receptor defects (e.g. Laron dwarf).
7. State that short stature can also be related to non-endocrine causes such as
malabsorption, malnutrition and psychological deprivation.
8. Explain how the diagnosis of endocrine-related short stature can be made,
including a description of the use of standard growth charts and stimulation tests.
9. Explain why provocative tests are useful in the diagnosis of pituitary insufficiency.
Give examples of tests used to diagnose GH deficiency.
10. Describe the pharmacodynamic and pharmacokinetic properties of human growth
hormone (hGH) and explain the rationale governing its use in the treatment of GH
deficiency in (a) children and (b) adults.
As the hypothalamo pituitary axis is a 3 hormone system – disorders can occur in any
stage:
1) Endocrine gland  Primary endocrine gland disease
2) Anterior Pituitary  Secondary endocrine gland disease
3) Hypothalamus  Tertiary endocrine gland disease
Somatotrophin
Releasing
Hormone
(SRS, GHRH)
Somatostati
n
+
_ Somatotrophin
(GH)
+
_
IGF-1
Dopamine (DA)
Thyrotrophin Releasing
Hormone
(TRH)
_
Ghrelin
+
GHRP
Prolactin
+
Thyrotrophin
+
Corticotrophin Releasing
+ Corticotrophin (ACTH)
Hormone (CRH)
+
+
Ghrelin
Vasopressin (VP)
+
Gonadotrophin
Luteinizing Hormone
Releasing Hormone +
(LH)
(GnRH)
Follicle Stimulating Hormone
(FSH)
Adenohypophysial Hormones and their main target cells:
 Somatotrophin → General body tissues, particular they liver
 Prolactin → Breasts, particularly in lactating women
 Thyrotrophin → Thyroid
 Gonadotrophins → Testes in men, ovaries in women
 Corticotrophin → Adrenal Cortex
Hypopituitarism
PANHYPOPITUITARISM  all pituitary gland has decreased production. This is a
gradual reduction of pituitary secretion including:
- Gonadotrophin disorders
- Growth hormone
- Thyrotrophin
- Corticotrophin
- Occasionally prolactin although this is uncommon.
Signs and Symptoms of Pan- Hypopituitarism
 Secondary amenorrhoea or oligomenorrhoea in women
 Impotence in men
 Tiredness
 Waxy skin
 Loss of body hair
 Hypotension
 Loss of libido
Testing for Pituitary Disorder
 Measurement of the basal levels of pituitary or primary endocrine gland hormones
– compare to normal
 Use of provocation (stimulation) tests – e.g. a combined function test involving
rapid and sequential infusion of GHRH, CRH, GnRH, and TRH
 Specific tests for individual hormones – e.g. insulin-induced hypoglycaemia for GH
Types:
 Simmonds disease: slow onset
o Causes: infiltrative processes, head injury, pituitary adenomas or cranial
injury after surgery.
o Symptoms: gradual loss of thyroid, adrenal and gonadal function e.g. loss
of periods, loss of libido, hypotension, tiredness, loss of body hair,
impotence, waxy skin.
o Diagnosis: measure plasma hormone values, stimulate endocrine hormones
themselves (i.v.) and then measuring hormones levels. e.g. insulin-induced
hypoglycaemia for GH
o Treatment: Hormone replacement therapy.
 Sheehan’s Syndrome: (specific to WOMEN) sudden onset due to ischaemia of
pituitary.
o Causes: post partum haemorrhage resulting in pituitary infarction. The
blood loss results in the hypophysial arteries vasoconstricting which
results in the ischaemia and necrosis is of the pituitary tissue.
 Pituitary Apoplexy: similar to Sheehan’s in that intra-pituitary haemorrhage can
occur with an often dramatic presentation in patients with pre-existing pituitary
tumours which suddenly infarct.
If there is a deficiency in a particular hormone, then secondary hypopituitarism
develops. These can generally be treated with hormone replacement therapy.
HYPOGONADISM  lack of Gonadotrophins.
HYPOTHYROIDISM  lack of Thyrotrophin
HYPOADREONO-CORTICALISM  lack of corticotrophin
PITUITARY DWARFISM  lack of Somatotrophin in children. In adults, the effects
are uncertain.
NB: the most important hormone to replace is cortisol (life threatening) followed
closely by thyroxine
Causes of Short stature:
- genetic predisposition
- malnutrition
- emotional deprivation
- endocrine disorders
Congenital
- deficiency of GHRH
- mutations of GH gene
- developmental abnormalities of pituitary gland.
Acquired
- tumours of hypothalamus or pituitary (disrupt GH production)
- other intracranial tumours nearby (e.g. optic nerve glioma)
- secondary to cranial irradiation
- head injury
- infection or inflammation
- severe psychosocial deprivation
Laron dwarfism = GH receptor deficiency in the liver.
SOME CAUSES OF
ENDOCRINE-RELATED
SHORT STATURE
hypothalamus
adenohypophysis
liver
IGFI
I
GH
receptor
defect
LARON
DWARFIS
M
IGF
IGFI
receptor
I
defect
PYGM
Y
target tissues
Diagnosis
Mainly used as a confirmation after a preliminary
guess
GH Provocation Tests:
 Insulin Induced Growth Hormone secretion
 Give i.v. GHRH (tells you whether deficiency is
hypothalamic or pituitary)
 Give i.v. arginine (an amino acid)
 Exercise induced growth hormone secretion
SS
GHRH
SOMATOTROPHIN
(GROWTH HORMONE)
Lack of
GH
HYPOPITUITAR
Y
DWARFISM
SS
IGFI
GH
Lack
PYG
LARO
HYPO
IGFI
IGFII
aden
GHR
hypo
targe
liver
SO
of
GH
recept
N
PITUI
MY
SOM
ohyp
H
thala
t
ME
or
DWA
TARY
ATOT
ophy
mus
tissu
defect
RFIS
DWA
CA
ROP
sis
es
M
RFIS
HIN
US
M
(GRO
ES
WTH
HOR
OF
MON
EN
E)
DO
CRI
NEREL
ATE
D
SH
OR
T
STA
TU
RE
Treatment: Hormone replacement
Growth hormone therapy in
Children:
 Acceleration of linear growth
 Decreases body fat.
 Effects are most marked in the
first year of treatment
 Younger children respond
better
 Obese children respond better
 Resistance may develop due to
antibody formation
 Give human recombinant growth hormone
o Somatotropin
 Given intramuscular or subcutaneous
 Daily or 4-5 times per week – adjust dose to size
 Plasma concentration takes effect between 2-6 hrs
 Metabolised in liver/kidney
 Short half life of 20 mins
 Lasts long time – peak effect around 20 hours
 Side effects
o Lipoatrophy (loss of fat) at site
o Intracranial hypertension
o Headaches
o Increased incidence of leukaemia.
GH Deficiency in Adults
Signs
 Reduced lean mass
 Reduced muscle strength & bulk  reduced exercise performance
 Decreased plasma HDL-cholesterol & raised LDL-cholesterol
 Impaired ‘psychological well being’ and reduced quality of life
Diagnosis
 Lack of responose of GH stimulation test
 Low plasma IGF 1
Potential benefits of HRT
 Body composition increases
 Increases lean body mass
 Exercise capacity and strength increases
 Increase bone mineral content
 Psychological well being
 Normalisation HDL and LDL content.
Risks
 Increase of cardiovascular accidents
 Increase size of soft tissue organs (liver)
 Stimulation of tumour development.