01 Anterior Pituitary Disijorders (1)

8/11/2019 01 Anterior Pituitary Disijorders (1)

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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 hormonesPROFESSORJOHN LAYCOCK([email protected])

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 termhormone 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 oftests 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 itcaused by congenital defects (such as developmental

defects) and gene mutations(such as in PROP1)

- It can also occur after radiotherapy


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- In adults, there is progressivelossof pituitarysecretion, often(but not invariably) in the following

order:

o Gonadotrophins (LH and FSH)

o GH

o TSH

o

ACTHo (Prolactin deficiency is uncommon)

Simmonds disease

-

The German physician Dr. Morris Simmonds made the first description of hypopituitarism in

1914

- Simmonds diseaseis insidious (slow) in onset

- It is causedby variousthings, including by not limited to:

o Infiltrativeprocesses(e.g. lymphocytic)

o

Pituitary adenomaso Craniopharyngiomas

o Cranial injury

o Followingsurgery

- Unsurprisingly so, the symptoms are due mainly to decreased thyroidal, adrenal and gonadal

function

- The result is:

o Secondary amenorrhoeaor oligomenorrhoeain women

o Impotencein men

o Lossof libido

o

Tirednesso Waxy skin

o Lossof body hair

o Hypotension

o Other things to do with a lossof the hormones, etc.

Sheehans syndrome

- Sheehans syndromeis hypopituitarism specificallyin women

- It develops acutely following post-partum haemorrhage, whereby blood loss and hypovolaemic

shock causes vasoconstrictor spasm of the hypophysial arteries, leading to ischaemia andsubsequentnecrosisof the pituitarygland

- The pituitary is enlargedduring pregnancy, so this loss of blood supply is bad

Pituitary apoplexy

- Pituitary apoplexyis also an infarctionor haemorrhageof the pituitarygland, 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 surgicaldecompression can be necessary although indications for intervention are controversial


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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 glandfailure

-

For example, a lackof gonadotrophins leading to hypogonadismetc. These lacksare covered in

future lectures- Lack of somatotrophin(GH) in childrenresults in pituitary dwarfismor short stature

- In adults, the effect of the loss of GH is uncertainbecause by that point most of the growing is

complete

- Causesof short stature include:

o Genetic determination

o Malnutrition

o Emotional deprivation

o Endocrine disorders see image to

the right:

Laron dwarfismis caused by aGH receptor defect on the

liver, meaning that there is no

responseto 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 worko Other various and often unknown causes.

- GH deficiencyin childrencan be congenitalbut this is rare. It can be due to:

o Deficiencyof hypothalamicGHRH

o Mutationsof the GHgene(very rare)

o Developmentalabnormalities(e.g. aplasiaor hypoplasiaof the pituitary)

- Acquired GH deficiencyis more common, and can be due to:

o Tumoursof the hypothalamusor pituitary

o Other intracranialtumoursnearby(e.g. opticnerveglioma)

o Secondary to cranial irradiation

o

Head injuryo Infectionor 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 hypopituitarisminvolves specifichypothalamichormonedefects

o For example, Kallmanns syndrome iscaused by a deficiency of GnRH and leads to

decreased

functioningof the glandsthat produce sex hormoneso 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


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Diagnosing hypopituitarism

- In order to make a diagnosisof hypopituitarism, one must take basal plasma valuesof pituitaryor

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,

GnRHand TRH- For example, growth hormoneinsufficiencymay be diagnosedby measuringplasmaGH before

and afterone 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 meantto stimulate GH production

- The graph shows typical GH responses to insulin in a normal

subjectand 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

- Twohoursis the windowneeded to see the GH level response

to administration of insulin

Treating hypopituitarism

- The principalaim of the treatmentof pituitarydeficiency is to restore homeostasisby replacing

missinghormones

-

An accuratediagnosisis therefore critical- ACTH, TSH and LH/FSH produce their biological actions largely through stimulating the

productionof hormonesby the adrenal cortex, thyroidand gonadsrespectively

- As these hormones (or analogues) are easier to administer than the pituitary hormones

themselves, they are used in preferencein replacementtherapy


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Growth hormone therapy

- Growthhormonetherapyin childrenaccelerateslineargrowthand decreases body fat

- The effects are most marked in the firstyearof treatmentand youngerchildrenrespondbetterand

obesechildrenrespond better

-

However, resistancemay developvia antibodyformation

-

If GH deficiency is associated with generalisedhypopituitarism, then replacement therapywithother 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 doseis adjustedto the patients size

- The absorptionand distributiongives a maximal plasma concentrationin 2 to 6 hours

- Metabolismis hepaticor renal, and the half-lifeis short(approximately 20 minutes)

- The duration of action lasts well beyond plasma clearance with peak IGF-1 levels at

approximately 20 hours

-

The adverseeffectsof growthhormonetherapyinclude:o Lipoatrophyat the injectionsite

o Intracranialhypertension

o Headaches

o Increasedincidenceof leukaemia

Growth hormone deficiency in adults

- Growth hormone deficiency in adultspresents with various signsand symptoms. This includes

o Reducedlean mass

o Increasedadiposity

o

Increasedwaistto hip ratioo Reducedmuscle strength/bulk

o Reduced exercise performance

o Decreased plasma HDL-cholesteroland raisedLDL-cholesterol

o Impairedpsychological wellbeing

o Reducedqualityof life

- GH production tends to decreasein peopleover 60

- A diagnosis is made by a lack of responseto the GHstimulationtest(e.g. to insulin), marked by a

lowplasmaIGF-I andlow plasma IGF-BP3

- The potential benefitsof GH therapy inadultsinclude:

o

Improved body compositiono 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 potentialrisksof GHtherapyin adultsinclude:

o Increasedriskof cardiovascularaccidents

o Increasedsofttissuegrowth(leading to e.g. cardiomegaly)

o Increasedsusceptibilityto cancer


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LECTURE 2:

Hypersecretion of anterior pituitary hormonesPROFESSORJOHN LAYCOCK([email protected])

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.

- Hyperpituitarismis usually due to isolatedpituitarytumoursbut can also be due to ectopic (i.e.

from non-endocrine tissue) hormone

production

- It can quite oftenbe associatedwith visual

field(namely bitemporal hemianopia)and

other(e.g. cranial nerve) defects, as well as

endocrine-relatedsignsand symptoms

-

The symptoms are associated with theexcess 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

- Excessof pituitaryhormonescan resultin

a number of differentscenarios. For example:

o

Excess corticotrophin(ACTH) can lead toCushings diseaseo Excess thyrotrophin(TSH) can lead to thyrotoxicosis

o Excess gonadotrophins(LHand FSH) can lead to precociouspubertyin children

o Excess prolactincan lead to hyperprolactinaemia

o Excess somatotrophincan lead to gigantismor acromegaly


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Hyperprolactinaemia

- Hyperprolactinaemia is caused by excess circulating prolactin when not due to a physiological

cause such as pregnancyor breast-feeding

-

It is usually due to a prolactinoma(often microadenomasless than 10mm in diameter)

-

In women this results in galactorrhoea (milk production), secondary amenorrhoea oroligomenorrhoea, lossof libidoand infertility

- In menthis results in galactorrhoea (uncommonsince appropriate steroidbackgroundis usually

inadequate), lossof libido, impotenceand infertility

Excess GH gigantism and acromegaly

- Excess somatotrophinin childhoodresults in gigantism, and in an adultresults in acromegaly

- Gigantismresults in large people. They usually die younger, due to cardiovascular eventsthough

- Acromegaly is insidious in onset, with signs and symptoms progressing gradually over many

years; it can remain undiagnosedfor 15-20 years- Untreated, gigantismand acromegalyare associatedwith an increasedmorbidityand mortality

due to cardiovascularand/or respiratorycomplications

- Acromegalyinvolves:

o Increased growth of periosteal bonecausing things such as prognathism(protruding jaw),

overdevleoped supraorbital ridesand soft tissues

o Cartilage, fibroustissue

o Connectivetissue

o Internalorgans(cardiomegaly, splenomegaly, hepatomegaly, etc.)

- The metaboliceffects of increased GH is a cascadeA

o

An increased plasma insulin response to oral glucose load leads to increased insulinresistance, resulting in

o an impaired glucose tolerancetest in 50% of patientsand

o diabetes mellitusin 10% of patients

- Acromegalic people commonly clinically manifest with:

o Enlargementof supraorbital ridgesand nose,handsandfeet

o Thickeningof lipsand generalcoarsenessof features

o Excessivesweating

o Mandiblegrowth(leading to protrusionof lower jaw aka prognathism)

o Carpaltunnelsyndromeand jointpain

o

Barrelchestand curvatureof spine(kyphosis) leading to respiratorycomplicationso Galactorrhoea

o Menstrualabnormalities

o Decreasedlibidoand impotence

o Hypertension

o Abnormalglucosetolerance

o Symptoms of diabetesmellitus

Diagnosing hyperpituitarism

-

Diagnosis of pituitary hypersecretorystatesuses suppressiontests- As for pituitary underactivity, preliminarydiagnosismay be made on the basisof the signsand

symptomsthe patient presents with


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- However, a definitivediagnosisrequires biochemicalmeasurementsof the hormone concerned

- Since hormones are secretedepisodicallyand

the normalrangeis broad, testsfor pituitary

overactivity normally involve measurement

of circulating hormone levels before and

after treatment with an agent that normallycauses suppressionof hormone release

- For example, acromegaly may be diagnosed

by measuring plasma GH before and after

an oralglucoseloadthis should decrease it,

but in acromegaly, it will not

Treating excess GH

- Treatment options are variable, including somatostatin analogues such as octreotide and

dopamine agonistssuch as bromocriptine(yes, GH is also inhibited by dopamine)

-

Other non-drug treatments include trans-sphenoidal surgery, radiotherapyand chemotherapyforadenomas

- Octreotidecan be used as short-term treatment before pituitary surgery(trans-sphenoidal), or as

long-term treatmentin those not controlled by othermeans

o As it inhibits GH release, it can also be used to treat other neuroendocrine tumourse.g.

carcinoidtumours

o Octreotide is administered subcutaneously or intramuscularly 3 times per day, with a

depotpreparationonce GH levelsare undercontrol

o The dose is adjusted accordingto need

o It is distributedby being retainedin the extracellularfluid

o

Its metabolismis hepatic/renalo It has a half-lifeof 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

- Hyperprolactinaemiais treatedusing dopaminereceptoragoniststo decreaseprolactinsecretion

and reducetumoursize

- Examples of dopamineagonistsinclude bromocriptineand cabergoline

- Bromocriptineis a D2agonist, administered by mouthonce daily

o

It is highly plasma protein bound(93%) with a typical half-lifeof about 7 hourso Hepatic metabolism

o Unwanted effectsof bromocriptineinclude:

Nausea/vomiting/abdominal cramps

Dyskinesias

Psychomotorexcitation

Posturalhypotension

Vasospasmin fingersand toes(caution: Raynauds disease)

o Other uses of bromocriptine include suppression of lactation, cyclical benign breast

tumours, acromegalyand Parkinsonsdisease

-

Cabergolineis a D2receptor agonistwith moderate D1receptor activity. It is longer lastingthanbromocriptine, taken orally once or twice a weekwith a half-lifeof over 45 hours. The unwanted

effectsare thoseof bromocriptine, but lesspronounced


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TUTORIAL 1:

Anterior pituitary hormonesPROFESSOR KARIM MEERAN([email protected])

Case historyA 58-year old woman complaining of frequent headachesand general tirednesswas seen by her GP. Her

body mass indexwas calculated to be 31 kg/m2. On questioning, she remarked that she often felt thirsty

and was drinkingmorethan usual. Also, shewas having problemswith her feet, and had recently bought

some shoeswith an increasedwidthsizeto improvethe comfortof 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 lossof peripheral vision in bothher eyes. The GP had a urinesample analysed for

glucoseand a low positive findingwas made. Perimetry indicated some loss of peripheral visionin both

eyes. On the basis of the initial findings, the GP arranged for the woman to visit an endocrineclinicat the

local general hospital. Her consultant there arranged for her to have a) a glucose tolerance test (GTT), andb) 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 valuewith subsequent values

fluctuatingbut not decreasingmuch despitethe increased blood glucose concentration.

b) MRI scan: The MRI scan showed evidence of a pituitarytumourwith suprasellarextensionimpinging

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 biggerHow 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 thispatients 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

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01 Anterior Pituitary Disijorders (1)