The Investigations of the Pituitary Gland - LASSEN · PDF file2011-09-26 Pituitary Gland 2 The...

2011-09-26 Pituitary Gland 1

The Investigations of the Pituitary Gland

©lassen-nielsen.com

Essential for understanding this presentation:

1) Anatomy: The Pituitary Gland and it’ssurroundings

2) Biochemistry: Hormones produced bythe Pituitary Gland

3) Physiology: Function of the hormonesproduced by the Pituitary Gland

First then can one start on a journey toinvestigate abnormal functions of the Pituitarygland




Objectives:

1) Describe the mechanisms of endocrinehypofunction and hyperfunction.

2) Differentiate among primary, secondaryand tertiary endocrine disorders.

3) Discuss - based on the normalphysiology - the rationale behind theinvestigations of the functions of thePituitary Gland.




Essential for understanding the investigations

1) Anatomy:

2) Biochemistry:

3) Physiology:

4) Diseases


Essential anatomy


Connections to/fromhypothalamus (nerveand vessels) to thepituitary gland

The hypophysealportal system

AnteriorPosterior

From Porth and Matfin Pathophysiology –Concepts of Altered Health states 2009

2011-09-26 Pituitary Gland 5©lassen-nielsen.com

Location

Neighboringstructures:(the optic chiasm,sinuses, bone-structures, vessels)

AnteriorPosteriorThe Visible Human Project®

Essential anatomy

Which way would you take toreach the Pituitary Gland foran operation?

Through the nose


Essential anatomy


Visualize it

You need that skillwhen interpretingimages(ultrasound, X-rays,CT- and MRI scansetc.)




Histology

Three lobesanterior, intermediate,and posterior( Neurohypophysis,Adenohypophysis )

Anterior Posterior

Basophil: ACTH ‘family’,TSH, FSH, LH and ICSH

Acidophil: GH, STH andPRL

Pictures from http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/histo_adeno.html





1) Anatomy:

2) Biochemistry:

3) Physiology:

4) Diseases


Essential biochemistry


The structure of the hormones:

Polypeptide:ACTH, MSH, GH, PRL, ADH and Oxytocin.

Glycoprotein:TSH, FSH, and LH.


Pro-opiomelanocortin derived peptidesPOMC

Biochemical Journal 2010 428, 305-324 - Kathleen G. Mountjoy



Note the name: it has something to do with opioids(opio), Melatonin (melano) and corticotropin (cortin).

It is a polypeptide build of 241 amino acids

It is split into nine segments, the numbers 126/129shows the number in the sequence of the amino acidsbetween which the cleavage will take place



POMC is the precursor for ACTH Lipotropin




POMC is the precursor for MSH, melanocyte-stimulating hormone(Collectively also known asmelanotropin or intermedin)




POMC is the precursor for

CLIP, corticotropin-like intermediatelobe peptide

EP, endorphin




Melanocortin peptides, derived from POMC, are produced in:1) the ARH (arcuate nucleus of the hypothalamus)2) neurons and the neurons in the commissural NTS (nucleus of thesolitary tract) of the brainstem,3) in anterior and intermediate lobes of the pituitary,4) skin and a wide range of peripheral tissues, includingreproductive organs.

Remember !!

This does not onlyapply for thepituitary gland



The enzymesinvolved isidentified(the colored ovals)

Note thee areseveral ACTH’s

We will treatthem as if there isonly ‘one soup’for now.Biochemical Journal 2010 428, 305-324 - Kathleen G. Mountjoy



Personal note:This illustrate thatwe have to realizethat working withmedicine meansconstantly

LearningDe-learning



Pro-opiomelanocortin derived peptidesNew Horizon

Biochemical Journal 2010 428, 305-324 - Kathleen G.Mountjoy


Pro-opiomelanocortin derived peptides


Central and peripheral regulation of energy homoeostasismediated through the central melanocortin system





1) Anatomy:

2) Biochemistry:

3) Physiology:

4) Diseases


Physiology


Gland

Target Organ

If the hormone makes thetarget organ increase its‘product’ it stimulates

H+Product

If the product makes thegland decrease its releaseof hormone it is callednegative feed back

General rule: Negative feed back create simple stable systems

Inhibits


Physiology


Gland

Target Organ

H+Product

If the product makes thegland increase its release ofhormone it is calledpositive feed back

General rule: Positive feed back create unstable systems –Constantly spiraling upward (additional control mechanisms needed)

Stimulate




Gland

Target Organ

If the hormone makes thetarget organ decrease its‘product’ it inhibits

H-Product

That stops the constantupward spiraling positivefeedback mechanism –hence inhibitors areimportant elements instopping positive feedback.

H+




Gland

Target Organ

A new element is addedthe Controlling Gland

H +

Product

It releases hormones thatcontrols the Gland(releasing hormone)

ControllingGland

R+

If the hormone from thegland inhibits theControlling Gland we havea normal negative feedback system

H -




Gland

Target Organ

If the product from theTarget Organ also inhibitsthe controlling gland wehave a double negativefeed back system

H +

Product

ControllingGland

R+

• Controlling Gland > Gland• Gland > Target OrganBoth Short loops

H -

Controlling gland >TargetOrgan is a Long Loop


Physiology


Gland

Target Organ

Tertiary diseaseThe cause can be found inthe Controlling GlandTarget Organ

H +

Product

ControllingGland

R+

Secondary diseaseThe cause can be found in thegland controlling the TargetOrgan

H -

Primary diseaseThe cause can be found inthe Target Organ


Which hormones are secreted


Hor-mone

Function(Stimulates)

Releasingfactors

ACTH Adrenal corticalhormone

CRH

MSH Melanocytes CRH

TSH Thyroid hormone TRH

FSH F: Ovulation,M: Sperm

GnRH

LH Corpus luteum GnRH

GH Growth GHRH

PRL Breast feeding

ADH Water reabsorb Neurogenic Diabetesinsipidus

Hyponatremia

Oxytocin Uterus Contract Neurogenic Uterinecontractions

decreased bonedensity and fat ?





1) Anatomy:

2) Biochemistry:

3) Physiology:

4) Diseases


Hyper - & Hypo-functions


In principle only two things can go wrong:

Increased production (over production) ofhormones: Hyper…..dism

Decreased production (under production) ofhormones: Hypo…..dism

Of cause there can be many underlying causes:Tumor, starvation, infections …….


Hypo - ACTH


Hor-mone


Releasingfactors

Hypo function

ACTH Adrenal corticalhormones

CRH

MSH Melanocytes CRH



GnRH


GH Growth GHRH

PRL Breast feeding

ADH Water reabsorb Neurogenic

Oxytocin Uterus Contract Neurogenic

What will be the result of adecrease ACTH Production in thepituitary gland?

It will be decreased production ofglucocorticoids from the adrenalgland.

Second. Adrenalhypofunction


Hyper - ACTH


Hor-mone


Releasingfactors

Hypo function

ACTH Adrenal corticalhormones

CRH Second. Adrenalhypofunction

MSH Melanocytes CRH



GnRH


GH Growth GHRH

PRL Breast feeding

ADH Water reabsorb Neurogenic

Oxytocin Uterus Contract Neurogenic

What will be the result of aincreased ACTH Production in thepituitary gland?

It will be increased production ofglucocorticoids from the adrenalgland.

Cushing disease

It should be call secondary adrenalhyperfunction. Traditional it iscalled Cushing Disease


Hormone prioritizing


Hor-mone


Releasingfactors

Hypo function Hyper –Function

Priority



Cushing disease

MSH Melanocytes CRH Skin pigmentation

TSH Thyroid hormone TRH Second.Hypothyroidism

Second.Hyperthyroidism


GnRH Infertility Precociouspupperty

LH Corpus luteum GnRH Sec. hypogonadism

GH Growth GHRH Short statute Acromegaly orgigantism

PRL Breast feeding Lactation failure AmenorrhoeaGalactorrhoea

ADH Water reabsorb neurogenic Diabetesinsipidus

Hyponatremia

Oxytocin Uterus Contract neurogenic Uterinecontractions


The gland has a tendency toprioritize it production –Safeguarding the production of themost important at the expense ofthe least important.

How would prioritize ?




Hor-mone


Releasingfactors


Priority



Cushing disease

MSH Melanocytes CRH Skin pigmentation





LH Corpus luteum GnRH Sec. hypogonadism




Hyponatremia






Hor-mone


Releasingfactors


Priority



Cushing disease 1

MSH Melanocytes CRH Skin pigmentation 1?



2



3

LH Corpus luteum GnRH Sec. hypogonadism 4


5


6?


Hyponatremia



Mnemonic: Go Look For The Adenoma

Meaning first goes GH then LH ……. Last ATCH





1) Anatomy:

2) Biochemistry:

3) Physiology:

Diagnose

4) Diseases


Suppression tests


Suppression tests are used mainly for the differentialdiagnoses of excessive hormone secretion.

Gland

Target Organ

Product

Inhibits

The substance or an analoguethat normally suppress secretionby negative feedback isadministered in a sufficient highdose

The response is measured.Failure to suppress implies thatsecretion is not under normalfeedback control (autonomoussecretion)


Simulation tests


Simulation tests are used mainly for the differentialdiagnoses of deficient hormone secretion.

Gland

Target Organ

Product

Inhibits

The tropic hormone thatnormally stimulates secretion isadministered in a sufficient highdose

The response is measured. Anormal response exclude andabnormality of the target glandwhereas failure to respondconfirms it.


Test both trophic and ‘product’


Hormone secretion may very predictable overa 24 hour (circadian) or longer. It may beepisodic or may respond predictably tophysiological stimuli such as stress.

Simultaneous measurement of both thetrophic hormones and their controllingfactors, whether hormones or metabolicproducts, may be more informative than themeasurement of either alone.


Test both trophic and ‘product’


An important endocrine principle is that anapparently normal hormone results should beinterpreted in the context of the associatehormone axis.

For example a plasma PTH concentrationwithin the reference range may be abnormalif the plasma calcium concentration iselevated.


Clinical findings of Adrenal insufficiency


Hyperpigmentation:Skin (bronze tone)Body creases, nipples,And mucous membranes

HypoglycemiaPoor tolerance to stress,fatiguemuscle weakness

Loss of weight:Emaciation, anorexiavomiting, and diarrhea

Cardiac insufficiency,hypotension

Adrenal atrophy,destruction

Urinary losses,sodium, water

Retention of potassium





Findings Primary Secondary

Anorexia and weight loss Yes 100% Yes 100%

Fatigue and weakness Yes 100% Yes 100%

Gastrointestinal symptoms, nausea, diarrhea Yes 50% Yes 50%

Myalgia, arthralgia, abdominal pain Yes 10% Yes 10%

Orthostatic hypotension Yes Yes

Hyponatremia Yes 85-90% Yes 60%

Hyperkalemia Yes 60-65% No

Hyperpigmentation Yes >90 No

Secondary deficiencies of testosterone, GH, thyroxin,ADH

No Yes

Associated autoimmune conditions Yes No





Findings Primary Secondary

Anorexia and weight loss Yes 100% Yes 100%

Fatigue and weakness Yes 100% Yes 100%

Gastrointestinal symptoms, nausea, diarrhea Yes 50% Yes 50%

Myalgia, arthralgia, abdominal pain Yes 10% Yes 10%

Orthostatic hypotension Yes Yes

Hyponatremia Yes 85-90% Yes 60%

Hyperkalemia Yes 60-65% No

Hyperpigmentation Yes >90 No

Secondary deficiencies of testosterone, GH, thyroxin,ADH

No Yes

Associated autoimmune conditions Yes No

Why is the symptoms at the top the same in both primary and secondary insufficiency?

Why is the symptoms at the bottom different in primary and secondary insufficiency?

What would the symptoms be in tertiary insufficiency?




Testing

Synacthen stimulation test:Blood is taken for basal cortisol assaySynacthen 250 μg IM, Blood at 30 and 60 minutesPlasma cortisol should increase with at least 200nmol/l and should reach > 580 nmol/l. Should peak inapproximately 30 minutes.

Plasma CortisolIf plasma Cortisol > 580 nmol/l addison’s adrenalhypofunction unlikely


What do you think Synacthen is?A tetracosactrin (Synacthen®) is a ACTH analogbut lacks the antigenic part




Testing

CHR stimulation test:When the response to the ACTH test is abnormal, aCRH stimulation test is helpful in determining thecause of adrenal insufficiency. A synthetic CRH isinjected, and the plasma cortisol and ACTH ismeasured before and after the injection.High levels of ACTH but little cortisol = Addison.Low levels of ACTH but little cortisol = secondaryadrenal insufficiency is suspected.

Plasma ACTHRange 10-60 pg/mLIf high indicate Addison diseaseIf low could be secondary adrenal insufficiency



Glucocorticoid Hormone Excess


A note on nomenclature


Cushing syndrome refers to themanifestations of hypercortisolismfrom any cause

Cushing disease refers tohypercortisolism from excessiveproduction of ACTH by thepituitary gland

Is Cushing disease a primary /secondary or tertiary disease?

Typical clinical findings


Glucocorticoid Hormone Excess - testing



Screening:Salivary cortisol level

24 hour urine collection analyzed for freecortisol.(5% false-negative rate = if 3separate collections are normal Cushing'ssyndrome is most unlikely.

Suppression test:Low-dose overnight dexamethasonesuppression test.1 mg of dexamethasone given atmidnight. Blood test for cortisol assay at8:00 -9:00 the following morning.Failure to suppress to < 50 nmol/lindicates further testing is needed




48 hours low dose suppression test:0.5 mg of low dose dexamethasone orally every 6 hours. Blood testfor cortisol assay at 9:00 after 48 hours.Failure to suppress to < 50 nmol/l indicates further testing isneeded.That is Plasma ACTH and plasma CRH is avaiable.

From Crook, Clinical Chemistry and Metabolic Medicine 2006

High Dose Dexamethasone Suppression Test:Patients are given 2.0 mg dexamethasone by mouth every 6 hoursfor 2 days. A 24 hour urine collection for cortisol is performed onthe second day of the test. Cortisol suppression suggests a pituitarytumor.A similar test is performed using a single dose of 8.0 mg at midnight,and a fasting blood draw for cortisol the next morning.




Test Pituitarydependent

Ectopic ACTH AdrenocorticalCarcinoma Adenoma

Plasma cortisol morning Raised or normal Raised Raised Raised or normal

Plasma cortisol evening Raised Raised Raised Raised

After low-dose dexamethasone No suppression No suppression No suppression No suppression

After high-dose dexamethasone Suppressed No suppression No suppression No suppression

Urinary free cortisol Raised Raised Raised Raised

Plasma ACTH Raised or normal Raised Low Low

From Crook, Clinical Chemistry and Metabolic Medicine 2006

What would you call that procedure ?




25-year-old woman with Cushing's disease.

50-year-old man with Cushing's disease.

The ultimate test: Combining imaging and blood test

Bilateral inferior petrosal sinuses sampling (BIPSS): this test may be required to separatepituitary from ectopic causes of ACTH-dependent Cushing's syndrome in patients with anormal pituitary gland on brain MRI scan.

Kaskarelis IS, Tsatalou EG, Benakis SV, Malagari K, Komninos I, Vasiliadou D et al. Bilateral Inferior Petrosal Sinuses Sampling in the RoutineInvestigation of Cushing's Syndrome: A Comparison with MRI. American Journal of Roentgenology 2006; 187(2):562-570.


Hyperthyroidism



Fine Hair

Exophtalmos

Muscle wasting

Oligomenorrhea

NervousnessRestlessnessEmotional instabilityInsomnia

Goiter

Tachycardia, palpitations,high output failure

Sweating,Heat intoleranceIncreasedappetite

Weight loss

Fine tremor

Pretibialmyxedema


Hyperthyroidism


Total T4 Total T3 FreeT4

FreeT3

TBG TSH

Euthyroid Normal Normal normal normal normal normal

Hyperthyroid ˄ ˄ ˄ ˄ normal ˅ if primary˄ if Secondary

T3 toxicosis Normal ˄ normal ˄ normal ˅

Hypothyroid ˅ ˅ ˅ ˅ normal ˄ if primary˅ if secondary

TBG excess ˄ ˄ normal normal ˄ Normal

TBG deficiency ˅ ˅ normal normal ˅ Normal

T4 displacementby drugs

˅ normal Normal or ˅

normal normal Normal

Diagnose ?


Hyperthyroidism



FreeT3

TBG TSH










Diagnose ?

˄ = high ˅ = low


Hyperthyroidism



FreeT3

TBG TSH










Diagnose ?

˄ = high ˅ = low


Hyperthyroidism



FreeT3

TBG TSH










Diagnose ?

˄ = high ˅ = low


Hyperthyroidism



FreeT3

TBG TSH











Hypothyroidism



Gland

Target Organ

TSH

ControllingGland

TRH

T3 + T4


Hypothyroidism


TSH T3 T4 TRH Conclusion

Slightlyelevated

normal Normal Compensated hypothyroidismTest for antiTBO and antiTg

Raised Low fT4 Normal/elevated

Primary hypothyroidismTest for antiTBO and antiTg

Low Low fT4 low Tertiary hypothyroidism

Low Low fT4 High Secondary hypothyroidism

Raised Raised/normal

Normal But patient has hypothyroidismsymptomsConsider thyroid hormone resistance

Diagnose ?


Hypothyroidism



Slightlyelevated








Diagnose ?


Hypothyroidism



Slightlyelevated








Diagnose ?


Hypothyroidism



Slightlyelevated








Diagnose ?


Hypothyroidism



Slightlyelevated








Diagnose ?


Growth hormone


GHRH

+

- SomatostatinGH-release inhibiting hormone

-

Modified from Porth and Matfin Pathophysiology –Concepts of Altered Health states 2009


Growth hormone Excess


Before puberty ends

Normal proportions

but tall

From anatomy:Closure of metaphysisDetermine age by bone structure / appearance

Name ?Gigantism



Growth hormone Excess after puberty


Acromegalic face

Goiter

Cardiomegaly (hypertension)

Abnormal glucose tolerance(secondary to insulin resistance)

Male sexual dysfunction (ormenstrual disorders in women)

Degenerative arthritis

Somatotrophic adenoma ofpituitary

Hyperostosis (Thoracic vertebrae)

Increased size (hands, feet)

Peripheral neuropathy

Thickened skin (hypertrophy ofsebaceous and sweat glands)

Name ?Acromegaly



Growth hormone Excess -Tests


Plasma IGF-1 has a longhalf life = sensitivescreening test

Plasma GH

Measure plasma GH after a 75 g glucose loadIf plasma GH does not fall below 1mU/L thediagnose is confirmed

Look for tumor MRI, Plasma GHRH

Growth hormone deficiency

2011-09-26 66

In adults, GH deficiency rarely causes clinical symptoms

Short statueconfirmed

Yes

E.G Turner’s syndrome

Assess bodyproportions

disproportionate

E.G. achondroplasia ?

Evidence ofdysmorphicfeatures orsyndrome?

If not

yes

Chronic diseaseChronic diseaseor social

deprivationpresent?

no

no

yes


Growth hormone deficiency

2011-09-26 67

In adults, GH deficiency rarely causes clinical symptoms

Growth velocitynormal?

Consider rare causes ?

Low birth weightbaby?

yes

Hypothyroidpresent?

no

yes

yes

yesConsider constitutional orConsider constitutional orfamilial short stature

no

Stop

yes

Considermalabsorption /

nutritionaldisorder

no

GH deficiency

no

no

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