LCRS: Endocrinology Usama Asif

ENDOCRINOLOGY SESSION 1:
Anterior pituitary disorders

NB: Before we start, most of the functional lectures in this years endocrinology course are a revision of last
years endocrinology course. Therefore, I will refer heavily to them in these notes. If there is anything in
this years course that wasnt there last year, then itll be here. The main things to take away are the
pharmacology lecture. They will contain new information on drugs and other things

Also, some of these lectures are all over the place, Ive tried to order them properly, so the information is all
there, just not in the order that the lectures have them in

LECTURE 1:
Hyposecretion of anterior pituitary hormones
PROFESSOR JOHN LAYCOCK (j.laycock@imperial.ac.uk)

Learning objectives

1. Distinguish between primary, secondary and tertiary disease states relating to pituitary function.
2. Define the term pan-hypopituitarism (Simmonds disease) and describe the specific aetiology of the
form of hypopituitarism called Sheehans syndrome.
3. Describe the more common signs and symptoms of pan-hypopituitarism.
4. Describe how a) anatomical pituitary disruption and b) pituitary hormone deficiency can be evaluated,
including the use of stimulation tests.
5. Describe how the endocrine consequences of pan-hypopituitarism can be treated, using the term
hormone replacement therapy
6. List the various possible individual pituitary hormone deficiencies that can occur and explain how the
conditions can be diagnosed and treated (when appropriate).
7. 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).
8. State that short stature can also be related to non-endocrine causes such as malabsorption, malnutrition
and psychological deprivation.
9. 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.
10. Explain why provocative tests are useful in the diagnosis of pituitary insufficiency. Give examples of
tests used to diagnose GH deficiency.
11. 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.

- To the right is an overview of the hypothalamo-
adenohypophysial axis
- Hypopituitarism is the decreased production of all
anterior pituitary hormones (panhypopituitarism), or
the decreased production of specific hormones
- Panhypopituitarism is very rare and even rarer is it
caused by congenital defects (such as developmental
defects) and gene mutations (such as in PROP1)
- It can also occur after radiotherapy
LCRS: Endocrinology Usama Asif

- In adults, there is progressive loss of pituitary secretion, often (but not invariably) in the following
order:
o Gonadotrophins (LH and FSH)
o GH
o TSH
o ACTH
o (Prolactin deficiency is uncommon)

Simmonds disease

- The German physician Dr. Morris Simmonds made the first description of hypopituitarism in
1914
- Simmonds disease is insidious (slow) in onset
- It is caused by various things, including by not limited to:
o Infiltrative processes (e.g. lymphocytic)
o Pituitary adenomas
o Craniopharyngiomas
o Cranial injury
o Following surgery
- Unsurprisingly so, the symptoms are due mainly to decreased thyroidal, adrenal and gonadal
function
- The result is:
o Secondary amenorrhoea or oligomenorrhoea in women
o Impotence in men
o Loss of libido
o Tiredness
o Waxy skin
o Loss of body hair
o Hypotension
o Other things to do with a loss of the hormones, etc.

Sheehans syndrome

- Sheehans syndrome is hypopituitarism specifically in women
- It develops acutely following post-partum haemorrhage, whereby blood loss and hypovolaemic
shock causes vasoconstrictor spasm of the hypophysial arteries, leading to ischaemia and
subsequent necrosis of the pituitary gland
- The pituitary is enlarged during pregnancy, so this loss of blood supply is bad

Pituitary apoplexy

- Pituitary apoplexy is also an infarction or haemorrhage of the pituitary gland, but in the presence
of a pituitary adenoma
- It has dramatic presentation in patients who have pre-existing pituitary tumours that suddenly
infarct
- Many patients can be treated with supportive treatment alone. In some cases surgical
decompression can be necessary although indications for intervention are controversial


LCRS: Endocrinology Usama Asif

Lack in individual hormones, specifically GH

- As we discovered last year, it is possible to have a deficiency in a single adenohypophysial
hormone, resulting in secondary endocrine gland failure
- For example, a lack of gonadotrophins leading to hypogonadism etc. These lacks are covered in
future lectures
- Lack of somatotrophin (GH) in children results in pituitary dwarfism or short stature
- In adults, the effect of the loss of GH is uncertain because by that point most of the growing is
complete
- Causes of short stature include:
o Genetic determination
o Malnutrition
o Emotional deprivation
o Endocrine disorders see image to
the right:
Laron dwarfism is caused by a
GH receptor defect on the
liver, meaning that there is no
response to any amount of GH
that the body makes
Hypopituitary dwarfism is
when there is a lack of GH
made by the body
A pygmy is when there is an
IGF-I receptor defect so IGF-I
doesnt work
o Other various and often unknown causes.
- GH deficiency in children can be congenital but this is rare. It can be due to:
o Deficiency of hypothalamic GHRH
o Mutations of the GH gene (very rare)
o Developmental abnormalities (e.g. aplasia or hypoplasia of the pituitary)
- Acquired GH deficiency is more common, and can be due to:
o Tumours of the hypothalamus or pituitary
o Other intracranial tumours nearby (e.g. optic nerve glioma)
o Secondary to cranial irradiation
o Head injury
o Infection or inflammation
o Severe psychosocial deprivation
- It must be remembered that the hormone can only work if the receptor and post-receptor
mechanisms are working, so it is not always a disorder of hormone production see above

Tertiary hypopituitarism

o Tertiary hypopituitarism involves specific hypothalamic hormone defects
o For example, Kallmanns syndrome is caused by a deficiency of GnRH and leads to
decreased functioning of the glands that produce sex hormones
o Prader-Willi syndrome is a rare genetic disorder in which seven genes on chromosome 15 are
deleted or unexpressed on the paternal chromosome. One of the symptoms manifests itself as
hypogonadism
LCRS: Endocrinology Usama Asif

Diagnosing hypopituitarism
- In order to make a diagnosis of hypopituitarism, one must take basal plasma values of pituitary or
target endocrine gland hormones
- These are particularly useful if measured after a stimulation or provocation test, for example
using a combined function test involving rapid IV sequential administration of GHRH, CRH,
GnRH and TRH
- For example, growth hormone insufficiency may be diagnosed by measuring plasma GH before
and after one of the following:
o GHRH (IV)
o Insulin (IV)
o Arginine (IV)
o Exercise (e.g. 10 minute step climbing)
All of the above are meant to stimulate GH production
- The graph shows typical GH responses to insulin in a normal
subject and one with GH deficiency
- For individual hormones, more specific tests can be used e.g.
insulin-induced hypoglycaemia for GH
- This is known as insulin-induced growth hormone secretion
- Two hours is the window needed to see the GH level response
to administration of insulin

Treating hypopituitarism

- The principal aim of the treatment of pituitary deficiency is to restore homeostasis by replacing
missing hormones
- An accurate diagnosis is therefore critical
- ACTH, TSH and LH/FSH produce their biological actions largely through stimulating the
production of hormones by the adrenal cortex, thyroid and gonads respectively
- As these hormones (or analogues) are easier to administer than the pituitary hormones
themselves, they are used in preference in replacement therapy



















LCRS: Endocrinology Usama Asif

Growth hormone therapy
- Growth hormone therapy in children accelerates linear growth and decreases body fat
- The effects are most marked in the first year of treatment and younger children respond better and
obese children respond better
- However, resistance may develop via antibody formation
- If GH deficiency is associated with generalised hypopituitarism, then replacement therapy with
other hormones will be required
- In growth hormone therapy, the preparation is human recombinant GH (approved name
somatotropin)
- The administration is a subcutaneous or intramuscular injection given daily, or 4-5 times per
week, and the dose is adjusted to the patients size
- The absorption and distribution gives a maximal plasma concentration in 2 to 6 hours
- Metabolism is hepatic or renal, and the half-life is short (approximately 20 minutes)
- The duration of action lasts well beyond plasma clearance with peak IGF-1 levels at
approximately 20 hours
- The adverse effects of growth hormone therapy include:
o Lipoatrophy at the injection site
o Intracranial hypertension
o Headaches
o Increased incidence of leukaemia

Growth hormone deficiency in adults
- Growth hormone deficiency in adults presents with various signs and symptoms. This includes
o Reduced lean mass
o Increased adiposity
o Increased waist to hip ratio
o Reduced muscle strength/bulk
o Reduced exercise performance
o Decreased plasma HDL-cholesterol and raised LDL-cholesterol
o Impaired psychological wellbeing
o Reduced quality of life
- GH production tends to decrease in people over 60
- A diagnosis is made by a lack of response to the GH stimulation test (e.g. to insulin), marked by a
low plasma IGF-I and low plasma IGF-BP3
- The potential benefits of GH therapy in adults include:
o Improved body composition
o Improved muscle strength
o Exercise capacity
o Normalisation of HDL-cholesterol
o Increased bone mineral content
o Improved psychological wellbeing and quality of life.
- The potential risks of GH therapy in adults include:
o Increased risk of cardiovascular accidents
o Increased soft tissue growth (leading to e.g. cardiomegaly)
o Increased susceptibility to cancer




LCRS: Endocrinology Usama Asif

LECTURE 2:
Hypersecretion of anterior pituitary hormones
PROFESSOR JOHN LAYCOCK (j.laycock@imperial.ac.uk)

Learning objectives

1. Explain why suppression tests are useful in the diagnosis of excessive pituitary hormone secretion.
How do the GH responses to oral glucose differ in acromegalics and normal subjects?
2. List the individual pituitary hormone excess states that can develop, and describe the principal
consequences of each hypersecretory state.
3. Describe the principal signs and symptoms of growth hormone hypersecretion in the child and the
adult.
4. Describe how gigantism and acromegaly are diagnosed.
5. List the principal treatments available for the treatment of gigantism and acromegaly.
6. State that prolactinoma is the most common tumour of the pituitary gland.
7. Describe the principal signs and symptoms of hyperprolactinaemia.
8. Describe how hyperprolactinaemia is diagnosed.
9. List the principal treatments available for the treatment of hyperprolactinaemia.
10. Explain why hyperthyroidism, precocious puberty and Cushings syndrome can be primary, secondary
(or even tertiary) disease states depending on the site of the lesion.
11. Name two dopamine receptor agonists used in the treatment of hyperprolactinaemia. Explain the
unwanted effects of these drugs and note their main pharmacokinetic features.
12. Name a somatostatin analogue used in the treatment of growth hormone excess and describe its main
biological actions and pharmacokinetic features. List the potential unwanted effects of these drugs and
identify other conditions in which they may also be useful.
13. State that acromegaly may also be treated with dopamine receptor agonists.

- Hyperpituitarism is usually due to isolated pituitary tumours but can also be due to ectopic (i.e.
from non-endocrine tissue) hormone
production
- It can quite often be associated with visual
field (namely bitemporal hemianopia) and
other (e.g. cranial nerve) defects, as well as
endocrine-related signs and symptoms
- The symptoms are associated with the
excess production of the adenohypophysial
hormones, as covered later on
- Bitemporal (heteronymous) hemianopia
occurs when a pituitary tumour presses
nerves that run through the optic chiasm
(which site above the pituitary), which
leads to the disruption of vision
- Excess of pituitary hormones can result in
a number of different scenarios. For example:
o Excess corticotrophin (ACTH) can lead to Cushings disease
o Excess thyrotrophin (TSH) can lead to thyrotoxicosis
o Excess gonadotrophins (LH and FSH) can lead to precocious puberty in children
o Excess prolactin can lead to hyperprolactinaemia
o Excess somatotrophin can lead to gigantism or acromegaly
LCRS: Endocrinology Usama Asif

Hyperprolactinaemia

- Hyperprolactinaemia is caused by excess circulating prolactin when not due to a physiological
cause such as pregnancy or breast-feeding
- It is usually due to a prolactinoma (often microadenomas less than 10mm in diameter)
- In women this results in galactorrhoea (milk production), secondary amenorrhoea or
oligomenorrhoea, loss of libido and infertility
- In men this results in galactorrhoea (uncommon since appropriate steroid background is usually
inadequate), loss of libido, impotence and infertility

Excess GH gigantism and acromegaly

- Excess somatotrophin in childhood results in gigantism, and in an adult results in acromegaly
- Gigantism results in large people. They usually die younger, due to cardiovascular events though
- Acromegaly is insidious in onset, with signs and symptoms progressing gradually over many
years; it can remain undiagnosed for 15-20 years
- Untreated, gigantism and acromegaly are associated with an increased morbidity and mortality
due to cardiovascular and/or respiratory complications
- Acromegaly involves:
o Increased growth of periosteal bone causing things such as prognathism (protruding jaw),
overdevleoped supraorbital rides and soft tissues
o Cartilage, fibrous tissue
o Connective tissue
o Internal organs (cardiomegaly, splenomegaly, hepatomegaly, etc.)
- The metabolic effects of increased GH is a cascade A
o An increased plasma insulin response to oral glucose load leads to increased insulin
resistance, resulting in
o an impaired glucose tolerance test in 50% of patients and
o diabetes mellitus in 10% of patients
- Acromegalic people commonly clinically manifest with:
o Enlargement of supraorbital ridges and nose, hands and feet
o Thickening of lips and general coarseness of features
o Excessive sweating
o Mandible growth (leading to protrusion of lower jaw aka prognathism)
o Carpal tunnel syndrome and joint pain
o Barrel chest and curvature of spine (kyphosis) leading to respiratory complications
o Galactorrhoea
o Menstrual abnormalities
o Decreased libido and impotence
o Hypertension
o Abnormal glucose tolerance
o Symptoms of diabetes mellitus

Diagnosing hyperpituitarism

- Diagnosis of pituitary hypersecretory states uses suppression tests
- As for pituitary underactivity, preliminary diagnosis may be made on the basis of the signs and
symptoms the patient presents with
LCRS: Endocrinology Usama Asif

- However, a definitive diagnosis requires biochemical measurements of the hormone concerned
- Since hormones are secreted episodically and
the normal range is broad, tests for pituitary
overactivity normally involve measurement
of circulating hormone levels before and
after treatment with an agent that normally
causes suppression of hormone release
- For example, acromegaly may be diagnosed
by measuring plasma GH before and after
an oral glucose load this should decrease it,
but in acromegaly, it will not

Treating excess GH
- Treatment options are variable, including somatostatin analogues such as octreotide and
dopamine agonists such as bromocriptine (yes, GH is also inhibited by dopamine)
- Other non-drug treatments include trans-sphenoidal surgery, radiotherapy and chemotherapy for
adenomas
- Octreotide can be used as short-term treatment before pituitary surgery (trans-sphenoidal), or as
long-term treatment in those not controlled by other means
o As it inhibits GH release, it can also be used to treat other neuroendocrine tumours e.g.
carcinoid tumours
o Octreotide is administered subcutaneously or intramuscularly 3 times per day, with a
depot preparation once GH levels are under control
o The dose is adjusted according to need
o It is distributed by being retained in the extracellular fluid
o Its metabolism is hepatic/renal
o It has a half-life of 2 to 4 hours
o Unwanted side effects may include GI tract disturbances, initial reduction in insulin
secretion; transient hyperglycaemia; and in rare cases, gallstones

Treating hyperprolactinaemia
- Hyperprolactinaemia is treated using dopamine receptor agonists to decrease prolactin secretion
and reduce tumour size
- Examples of dopamine agonists include bromocriptine and cabergoline
- Bromocriptine is a D2 agonist, administered by mouth once daily
o It is highly plasma protein bound (93%) with a typical half-life of about 7 hours
o Hepatic metabolism
o Unwanted effects of bromocriptine include:
Nausea/vomiting/abdominal cramps
Dyskinesias
Psychomotor excitation
Postural hypotension
Vasospasm in fingers and toes (caution: Raynauds disease)
o Other uses of bromocriptine include suppression of lactation, cyclical benign breast
tumours, acromegaly and Parkinsons disease
- Cabergoline is a D2 receptor agonist with moderate D1 receptor activity. It is longer lasting than
bromocriptine, taken orally once or twice a week with a half-life of over 45 hours. The unwanted
effects are those of bromocriptine, but less pronounced

LCRS: Endocrinology Usama Asif

TUTORIAL 1:
Anterior pituitary hormones
PROFESSOR KARIM MEERAN (k.meeran@imperial.ac.uk)

Case history
A 58-year old woman complaining of frequent headaches and general tiredness was seen by her GP. Her
body mass index was calculated to be 31 kg/m
2
. On questioning, she remarked that she often felt thirsty
and was drinking more than usual. Also, she was having problems with her feet, and had recently bought
some shoes with an increased width size to improve the comfort of walking. She could no longer remove
the ring on her finger. She was not aware of any specific neuromuscular problems other than the
occasional annoying tingling of her fingers and back pain; her knee reflex was normal. She also
complained of slight loss of peripheral vision in both her eyes. The GP had a urine sample analysed for
glucose and a low positive finding was made. Perimetry indicated some loss of peripheral vision in both
eyes. On the basis of the initial findings, the GP arranged for the woman to visit an endocrine clinic at the
local general hospital. Her consultant there arranged for her to have a) a glucose tolerance test (GTT), and
b) a MRI scan of the brain. The results of these tests are given below.

a) GTT (after overnight fast)
Time (min) Blood glucose (mmol/l)
0 7.9
30 13.8
60 13.6
90 12.7
120 11.5

GH levels measured at the same time intervals indicated a raised initial value with subsequent values
fluctuating but not decreasing much despite the increased blood glucose concentration.

b) MRI scan: The MRI scan showed evidence of a pituitary tumour with suprasellar extension impinging
on the optic chiasma.

What might be the first suspicions of the GP relating to possible diagnosis during the patients visit? Explain your
reasoning, based on the initial history.
First suspicions might have been diabetes due to her being overweight and thirsty
Or too much GH as she has lateral growth her feet and hands have gotten bigger
How does the presence of glucose in the urine fit in with the GPs initial provisional diagnosis?
Glycosuria is a classic presentation of diabetes insufficient glucose reabsorption
What other signs and symptoms could be present (if latent) if the initial diagnosis is correct?
Diabetic neuropathy, retinopathy, nephropathy and other micro- or macrovascular disease
Which signs and symptoms are explained by the presence of a suprasellar extension of the pituitary tumour?
Her bitemporal hemianopia
Describe and explain the results of the patients GTT.
Increased glucose and maintained greater than 7.0 = T2DM. Caused by increased growth hormone in the
body causing increased glucose
What is the diagnosis of this patients condition?
Acromegaly secondary to a pituitary adenoma secreting excess GH
What treatment(s) would be appropriate?
Surgery, drugs (such as bromocriptine or octreotide, maybe tumour will shrink?), and radiotherapy are
options