endocrine glands

ENDOCRINE GLANDS

• CONTROL OF SECRETIONS

• FUNCTIONAL TESTS

David Adams

INTRODUCTION• the hypothalamus is part of the brain• thus receives neural signals directly from

the body’s nervous system


the body’s nervous system• the hypothalamus links the neural and the

endocrine systems


the body’s nervous system• the hypothalamus links the neural and the

endocrine systems• signals from the hypothalamus go to the

pituitary which controls the endocrinefunctions

HYPOTHALAMIC HORMONES

• and the posterior pituitary– there is a direct neural connection between the

hypothalamus and the posterior pituitary


• and the posterior pituitary– there is a direct neural connection between the

hypothalamus and the posterior pituitary– three peptides are synthesised by the

hypothalamus and are stored by the posteriorpituitary

POSTERIOR PITUITARYHORMONES

• antidiuretic hormone (ADH)– controls water retention by the kidneys



• oxytocin– controls ejection of milk from the lactating

breast and has a role in initiating uterinecontraction during labour



• oxytocin– controls ejection of milk from the lactating

breast and has a role in initiating uterinecontraction during labour

• neurophysin– function unclear– may aid transport and storage of the former two

hormones


• and the anterior pituitary– no direct neural connection


• and the anterior pituitary– no direct neural connection– localised blood supply carries hypothalamic

controlling hormones directly to the anteriorpituitary


• and the anterior pituitary– no direct neural connection– localised blood supply carries hypothalamic

controlling hormones directly to the anteriorpituitary

– these stimulate or inhibit secretions by theanterior pituitary

ANTERIOR PITUITARYHORMONES

• growth hormone– controls development and growth



• excess leads to gigantism• deficiency leads to dwarfism




• prolactin– stimulates lactation




• prolactin– stimulates lactation

• excess leads to infertility• deficiency leads to lactation failure

ANTERIOR PITUITARYHORMONES cont.

• tropins - stimulate other endocrine organs


• tropins - stimulate other endocrine organs– thyrotropin (TSH)

• stimulates thyroid gland


• tropins - stimulate other endocrine organs– thyrotropin (TSH)

• stimulates thyroid gland

– gonadotropins - follicle stimulating hormoneand luteinising hormone

• necessary for normal gonadal development &function


– pro-opiocortin - this is a pro-hormone for bothadrenocorticotropin (ACTH) and β-lipotropin



• ACTH stimulates adrenals to to secrete a variety ofsteroids (other than aldosterone)



• ACTH stimulates adrenals to to secrete a variety ofsteroids (other than aldosterone)

• β-lipotropin is a precursor of endorphins (naturallyoccurring opiates)

SUMMARYBRAIN

HYPOTHALAMUS

POSTERIOR ANTERIORPITUITARY PITUITARY

anti-diuretic hormone&

oxytocin& tropins growth prolactin

neurophysin hormone

growth

thyrotropin gonadotropins pro-opiocortin

stimulates FSH & LHthyroid

stimulategonads

adrenocortico- β-lipotropintropin

(ACTH)endorphins

stimulatesadrenals

NOMENCLATURE

• liberins - stimulate anterior pituitary

NOMENCLATURE

• liberins - stimulate anterior pituitary– corticoliberin = corticotropin releasing factor

= CRF• stimulates release of adrenocorticotropin (ACTH)

and ß-lipotropin

NOMENCLATURE

• liberins - stimulate anterior pituitary– corticoliberin = corticotropin releasing factor

= CRF• stimulates release of adrenocorticotropin (ACTH)

and ß-lipotropin

– somatoliberin = growth hormone releasingfactor = GHRF

• stimulates release of growth hormone (somatotropin)

NOMENCLATURE• liberins (cont.)

– prolactoliberin = prolactin releasing factor = PRF

• stimulates release of prolactin

NOMENCLATURE• liberins (cont.)

– prolactoliberin = prolactin releasing factor = PRF

• stimulates release of prolactin

– gonadoliberin = gonadotropin releasing factor = GnRF& luteinizing hormone releasing factor

= LHRF• stimulates release of follicle stimulating hormone

(FSH) and luteinizing hormone (LH)

NOMENCLATURE

• liberins (cont.)– thyroliberin = thyrotropin releasing hormone

= TRH• stimulates release of thyrotropin

= thyroid stimulating hormone (TSH)

NOMENCLATURE• statins - inhibit release of hormones by

anterior pituitary


anterior pituitary– somatostatin

• inhibits release of growth hormone




– prolactostatin = prolactin inhibiting factor = PIF

• inhibits release of prolactin




– prolactostatin = prolactin inhibiting factor = PIF

• inhibits release of prolactin

– other statins corresponding to the remainingliberins probably also occur

PITUITARY HORMONES - TROPINS

• pituitary secretions stimulate theirrespective endocrine organs


• pituitary secretions stimulate theirrespective endocrine organs– thyroid, adrenals and gonads


• pituitary secretions stimulate theirrespective endocrine organs– thyroid, adrenals and gonads– these in turn produce hormones which target

specific organs



specific organs– the target cells must possess specific receptors

for the hormones



specific organs– the target cells must possess specific receptors

for the hormones• a combination of the density of receptors on the

target cells and the concentration of hormone in thecirculation will determine the effect of the hormoneon the target tissues

HORMONE TYPES

• divided into two broad classes depending onthe events which follow binding to thetarget tissue

HORMONE TYPES

• divided into two broad classes depending onthe events which follow binding to thetarget tissue– those which primarily affect the properties of

the plasma membrane itself

HORMONE TYPES

• divided into two broad classes depending onthe events which follow binding to thetarget tissue– those which primarily affect the properties of

the plasma membrane itself– those which enter the target cells

HORMONES WHICH INTERACT WITHTHE CELL MEMBRANE

• they do not enter cell but cause an effect by settingoff a cascade of reactions after binding– one of two different mechanisms may occur


– stimulate adenyl cyclase, thus increaseintracellular levels of cAMP causing activationof specific protein kinases e.g. adrenalinee andglucagon (and many others)


– stimulate adenyl cyclase, thus increaseintracellular levels of cAMP causing activationof specific protein kinases e.g. adrenaline andglucagon (and many others)

• or– alter membrane permeability

• e.g. adrenaline changes Ca++ flow into cells• insulin increases the permeability of some cells to

amino acids and glucose

HORMONES WHICH ENTER TARGETCELLS

• second group are taken into cell andtransported to nucleus

HORMONES WHICH ENTER TARGETCELLS

• second group are taken into cell andtransported to nucleus– they affect mRNA transcription and

subsequently synthesis of certain proteins• thyroid hormones and all steroids act in this way

CONTROL OF ENDOCRINE SECRETIONSBRAIN

stimulates

HYPOTHALAMUS

liberins

ANTERIORPITUITARY

tropins

TARGET ENDOCRINE

ORGAN

hormone

negative

feedback

negative

feedback

negative

feedback

ENDOCRINE DISEASES

• either hypo-secretion or hyper-secretion canoccur

ENDOCRINE DISEASES

• either hypo-secretion or hyper-secretion canoccur– the abnormality can be of hypothalamic origin

• lack of liberins• or excess of liberins

ENDOCRINE DISEASES

• either hypo-secretion or hyper-secretion canoccur– the abnormality can be of hypothalamic origin

• lack of liberins• or excess of liberins

– or of pituitary origin• lack of tropins• or excess of tropins

ENDOCRINE DISEASES• hyposecretion

– is a result of lack of function of either thehypothalamus or the pituitary



– may be caused by• destruction of tissue by a tumor



– may be caused by• destruction of tissue by a tumor• infarction



– may be caused by• destruction of tissue by a tumor• infarction• surgery or irradiation



– may be caused by• destruction of tissue by a tumor• infarction• surgery or irradiation• genetic defect in synthesis or release of the hormone



– may be caused by• destruction of tissue by a tumor• infarction• surgery or irradiation• genetic defect in synthesis or release of the hormone• infection

ENDOCRINE DISEASES• hypersecretion

– may be a result of• loss of feedback control


– may be a result of• loss of feedback control• a tumor of the hypothalamus or pituitary causing

overproduction of a hormone



overproduction of a hormone• ectopic production of a hormone



overproduction of a hormone• ectopic production of a hormone

• all of these diseases may affect secretion ofindividual hormones or may affect secretionof a number of hormones simultaneously

ENDOCRINE DISEASES

• laboratory investigations– assay hypothalamic secretions

ENDOCRINE DISEASES


• this is specialist testing as the concentrations arevery low - tests are expensive

ENDOCRINE DISEASES


• this is specialist testing as the concentrations arevery low - tests are expensive

– assay pituitary secretions• more commonly done

ASSAY OF PITUITARYSECRETIONS

• three questions arise


• three questions arise– is the output by the anterior pituitary normal?


• three questions arise– is the output by the anterior pituitary normal?– does the anterior pituitary have a normal

reserve capacity of hormone(s)?


• three questions arise– is the output by the anterior pituitary normal?– does the anterior pituitary have a normal

reserve capacity of hormone(s)?– does hormone output respond to normal control

mechanisms?


• normal output as measured by single plasmameasurements does not necessarily reflect acorrectly functioning anterior pituitary



• generally, the anterior pituitary function must beinvestigated by assessing its response to specificstimulation or suppression



• generally, the anterior pituitary function must beinvestigated by assessing its response to specificstimulation or suppression

• done by applying an appropriate dynamic functiontest


• hormones are assayed by immunoassaymost commonly


• hormones are assayed by immunoassaymost commonly– important to differentiate immunoreactivity

from biological activity


• hormones are assayed by immunoassaymost commonly– important to differentiate immunoreactivity

from biological activity– problems encountered are

• cross-reactivity• non-specific interference

DYNAMIC FUNCTION TESTS

• 3 examples will be discussed

– ACTH and cortisol

– growth hormone

– triple function test

DYNAMIC TESTING OF ACTHSECRETION

• can be measured by immunoassay, butresults are unreliable, therefore cortisol ismeasured in preference


• can be measured by immunoassay, butresults are unreliable, therefore cortisol ismeasured in preference– this is satisfactory because

• plasma cortisol levels directly reflect ACTH levels



• plasma cortisol levels directly reflect ACTH levels• the hormone cascade effect means that small

quantities of ACTH are amplified to relatively largeamounts of cortisol



• plasma cortisol levels directly reflect ACTH levels• the hormone cascade effect means that small

quantities of ACTH are amplified to relatively largeamounts of cortisol

• cortisol assay is quick and simple

REVISION - CORTISOL EFFECTS

• increases blood glucose• insulin antagonist



– decreases glucose utilisation



– decreases glucose utilisation– increases gluconeogenesis




• increases liver glycogen storage




• increases liver glycogen storage• increases fat mobilisation

DYNAMIC TESTING OF ACTHSECRETION cont.

• hyposecretion– if a lack of cortisol secretion is suspected, it

may be due to• adrenal insufficiency (where cortisol itself is not

synthesised even though ACTH secretion isadequate)


• hyposecretion– if a lack of cortisol secretion is suspected, it

may be due to• adrenal insufficiency (where cortisol itself is not

synthesised even though ACTH secretion isadequate)

• anterior pituitary insufficiency (lack of ACTH tostimulate the adrenals)


• adrenal insufficiency is checked usingsynacthen (synthetic form of thebiologically active portion of ACTH)


• adrenal insufficiency is checked usingsynacthen (synthetic form of thebiologically active portion of ACTH)– after injection cortisol levels should rise

significantly if the adrenals are functioningnormally


• to test whether there is adequate secretion ofACTH, a physiological stress is placed onthe patient


• to test whether there is adequate secretion ofACTH, a physiological stress is placed onthe patient– because stress ---> inc. CRF ---> inc. ACTH

---> inc. cortisol



---> inc. cortisol• hypoglycaemia is produced by insulin injection



---> inc. cortisol• hypoglycaemia is produced by insulin injection• the extent of the hypoglycaemia is assessed by

plasma glucose measurements and plasma cortisolmeasurements are performed at regular intervals



---> inc. cortisol• hypoglycaemia is produced by insulin injection• the extent of the hypoglycaemia is assessed by

plasma glucose measurements and plasma cortisolmeasurements are performed at regular intervals

• the plasma cortisol should rise significantly within2 hours if the anterior pituitary is normal


• high circulating cortisol levels may be dueto– adrenal hyperplasia



• due to excess stimulation of adrenals by ACTH(control is set too high)




• adrenal tumor - lack of feed back inhibition





– excess ACTH secretion by the anterior pituitary





– excess ACTH secretion by the anterior pituitary– ectopic ACTH production

INVESTIGATION OF HIGHCIRCULATING CORTISOL

• negative feedback control should suppressACTH secretion (and hence cortisol levels)when cortisol levels are high


• negative feedback control should suppressACTH secretion (and hence cortisol levels)when cortisol levels are high– this can be assessed by the dexamethasone

suppression test


• negative feedback control should suppressACTH secretion (and hence cortisol levels)when cortisol levels are high– this can be assessed by the dexamethasone

suppression test– dexamethasone is a synthetic steroid with about

25 times the potency of cortisol

DEXAMETHASONE SUPPRESSIONTEST

• interpretation– high circulating cortisol levels may be due to

simple obesity



simple obesity• a low dose of dexamethasone will suppress the

cortisol level in this case





– high circulating cortisol may be due to anteriorpituitary hyperplasia (i.e. causing excess ACTHproduction)






• a low dexamethasone dose will not suppress thecortisol level, however a higher dose will






• a low dexamethasone dose will not suppress thecortisol level, however a higher dose will

• this condition is Cushing’s syndrome


• if there is no suppression even at the higherdose, the excess cortisol production is dueto– adrenal hyperplasia (excess cortisol production

even without the stimulation of ACTH)



even without the stimulation of ACTH)– ectopic ACTH production




• these two alternatives could be differentiated bydirect plasma ACTH measurement





• in the former, ACTH will be low





• in the former, ACTH will be low• in the latter, ACTH will be high

GROWTH HORMONE

• growth hormone levels are affectedmarkedly by– food, exercise, sleep & stress

GROWTH HORMONE

• growth hormone levels are affectedmarkedly by– food, exercise, sleep & stress– the concentration changes significantly with

these factors

GROWTH HORMONE


these factors– it is not possible to distinguish normal from

deficient with spot tests

GROWTH HORMONE


these factors– it is not possible to distinguish normal from

deficient with spot tests– dynamic testing is essential

DYNAMIC TESTING OF GROWTHHORMONE SECRETION

• stimulation of growth hormone secretion


• stimulation of growth hormone secretion– these tests are designed to assess the pituitary

reserves of growth hormone (GH)


• stimulation of growth hormone secretion– these tests are designed to assess the pituitary

reserves of growth hormone (GH)• they are generally performed when a deficiency of

GH is suspected

DYNAMIC TESTING OF GROWTHHORMONE SECRETION cont.

– sleep• deep sleep causes a reproducible marked elevation

in plasma GH levels, particularly in children andadolescents




• blood samples are obtained by in-dwelling catheterwhilst sleeping subject is monitored by EEG





• samples collected every 30 min. for 3 - 4 hours afteronset of sleep






• the spurt of GH generally occurs within 30 - 90 min.of sleep onset and lasts for 1 - 2 hours






• the spurt of GH generally occurs within 30 - 90 min.of sleep onset and lasts for 1 - 2 hours

• the sleep peak is absent in both deficiency andacromegaly (due to hypersecretion)


• exercise– hard physical exercise stimulates a marked

increase in GH in normal individuals



increase in GH in normal individuals– basal GH levels are determined and patients are

given a standardised workload using a bicycleergometer



increase in GH in normal individuals– basal GH levels are determined and patients are

given a standardised workload using a bicycleergometer

– the normal response is a rise in GH levels toabout 10 times basal levels


• arginine load– certain amino acids, including arginine,

stimulate GH release



stimulate GH release• basal levels are determined, arginine infusion is

begun and samples are taken at specified times.



stimulate GH release• basal levels are determined, arginine infusion is

begun and samples are taken at specified times.• normal individuals show a rise in GH levels to about

10 times the basal level


• insulin hypoglycaemia– one effect of GH is to increase the blood

glucose level (as a response to hypoglycaemia)



glucose level (as a response to hypoglycaemia)– therefore induced hypoglycaemia causes a

release of GH in the normal individual (to about10 times basal level)



glucose level (as a response to hypoglycaemia)– therefore induced hypoglycaemia causes a

release of GH in the normal individual (to about10 times basal level)

– little or no rise is seen in the deficientindividual


• suppression


• suppression– the suppression tests are designed to

differentiate those patients with high circulatinglevels of GH due to a pathological cause fromthose with high levels due to stress or othernon-pathological causes


• glucose suppression test– hyperglycaemia will suppress GH levels in the

normal individual



normal individual– suppression to within reference range or to

undetectable levels indicates a normal response



normal individual– suppression to within reference range or to

undetectable levels indicates a normal response– in acromegaly and gigantism there is a failure

to suppress significantly

TRIPLE FUNCTION TEST

• A deficiency of a single pituitary hormoneis rare


• A deficiency of a single pituitary hormoneis rare– clinical suggestion of pituitary dysfunction

generally requires that the pituitary reserve ofall hormones be evaluated


• A deficiency of a single pituitary hormoneis rare– clinical suggestion of pituitary dysfunction

generally requires that the pituitary reserve ofall hormones be evaluated

– this can be accomplished by combining severalof the stimulatory dynamic function tests in amodified form


• procedure– blood samples are taken by in-dwelling catheter


• procedure– blood samples are taken by in-dwelling catheter– basal levels of glucose, cortisol, GH, TSH, LH,

FSH and PRL are measured



FSH and PRL are measured– insulin, TRH (thyroliberin) and GnRH

(gonadoliberin) are injected IV simultaneously



FSH and PRL are measured– insulin, TRH (thyroliberin) and GnRH

(gonadoliberin) are injected IV simultaneously– the above hormones (and glucose) are measured

at 30 min. intervals for 2 hours

TRIPLE FUNCTION TEST cont.

• procedure cont.– glucose is measured to ensure an adequate

hypoglycaemia has been induced to permitinterpretation of cortisol levels in response tohypoglycaemia




– synacthen may be injected and cortisol levelsmeasured at 30 and 60 min




– synacthen may be injected and cortisol levelsmeasured at 30 and 60 min

– this approach allows all the secretions of thepituitary to be assessed at one time on the patientwithout subjecting them to multiple testing

EXAMPLES OF CASES (1)

Glucose Cortisol GH TSH PRL LH FSH mmol/l nmol/l mU/l mU/l µg/l IU/l IU/l

Time (3.0-5.0) (140-690) (<5.5) (<30) (1.6-9.0) (1.1-6.4)

09.00 3.9 220 <1.0 4.3 7.0 4.6 1.5

Insulin: 9.0 units; TRH: 200 µg; GnRH: 100 µg

09.30 1.3 210 <1.0 12.0 67 36.0 2.7 09.50 50 g oral dextrose, 12.5 g dextrose IV 10.00 8.3 435 >40 9.7 >200 36.0 2.7 11.00 4.6 625 >40 9.7 150 36.0 3.6



Time (3.0-5.0) (140-690) (<5.5) (<30) (1.6-9.0) (1.1-6.4)

09.00 4.8 212 <1.0 <2.5 296 0.8 1.6 Insulin: 9.0 units; TRH: 200 µg; GnRH: 100 µg

09.30 1.8 209 <1.0 <2.5 350 1.9 2.7 10.00 2.9 335 <1.0 <2.5 390 1.3 2.7 11.00 4.6 188 <1.0 <2.5 300 1.1 1.7

synacthen 250 µg 11.45 195 12.15 220



Time (3.0-5.0) (140-690) (<5.5) (<30) (1.6-9.0) (1.1-6.4)

09.00 4.6 325 1.0 4.4 >200 1.2 1.3

Insulin: 8.0 units; TRH: 200 µg; GnRH: 100 µg

09.30 1.3 520 2.0 18.0 >200 4.5 1.9 10.00 3.2 710 5.5 15.0 >200 5.2 2.2 11.00 3.3 545 4.0 9.8 >200 5.4 2.3


mU/l Reference range____________________________________________ Plasma GH <1 not quoted

Time GH (mU/l)_______________________19.30 <122.00 1.924.00 46.008.00 2.0

EXAMPLES OF CASES (5)Time (min) GH (mU/l)_______________________ 0 2.5

18 min pedalling against a load 2 9.5 20 15

Time GH (mU/l)_________________________ 0 <1Arginine (0.5g/kg body weight)as 10% solution IV over 30 min.45 1660 36


Glu.(mmol/l) GH (mU/l)Time (3.0-5.5)

_______________________________________08.40 10.2 36

75 g glucose09.10 9.9 2809.40 9.5 3210.10 9.8 3010.40 9.1 3011.10 7.8 3811.40 5.9 56

endocrine glands

Documents