1. endocrinology part 1

7/26/2019 1. Endocrinology Part 1

http://slidepdf.com/reader/full/1-endocrinology-part-1 1/131

Endocrinology part 1: Adrenal glands

Marcin Adamczak



• Adrenal glands physiology,

• Adrenal cortex diseases,

Cushing’s syndrome

Mineralocorticoid excess

Adrenal insufficiency

Congenital adrenal hyperplasia

•

Adrenal medulla diseases, Pheochromocytoma



paired glands located retroperitoneally at the

upper pole of each kidney

Adrenal glands:



Adrenals: Cross section Cortex = yellow

Medulla= red to grey



Adrenal gland: Cross section



Adrenal glands:

include two distinct endocrine organs:inner medulla part of sympathetic nervous

system, secretes catecholamines,

outer cortex – sectretes numerous of different

steroid hormones;



Zona: reticularis, fasciculata, glomerulosa



CH3

CH3

O

O

OHOHOH

Hydrocortisone(11!,17",21-trihydroxy-

pregn-4-ene-3,20-dione) !

CH3

O

O

OHOH

CHO

Aldosterone(11!,21-dihydroxy-

pregn-4-ene-3,18,20-trione) !

Adrenocorticoids



Hypothalamic-pituitary-adrenal axis



Pituitary - ACTH

•

39 AA; active 1-24 N-terminal fragment

• proopiomelanocortin precursor (ACTH andmelanotropins, lipotropins and B-endorphin) !

•

circadian rhythm peaks in the morning•

Stimulus: CRF - stress, hypoglycemia,

•

CRF-feedback from glucocorticoids in circulation

•

action- adrenal cortex secrete glucocorticoids,lesser aldosterone



Rate Limiting Step•

ACTH stimulated

• Mitochondrial step

• 2 hydroxylations

• side chain cleavage

•

P450SCC( cholestrol 20,22-hydroxylase;

•

20-22 desmolase activity) !

Activation of Pathway=• Increased cholesterol utilisation

• Cholesterol ester ==> free Cholesterol

#

$

Cholesterol synthesis

#

$

Cholesterol uptake by adrenals



P450 C21 hydroxylase

(microsomal) !

11ß-hydroxylase

(mitochondrial) !

CORTISOL

18 hydroxylaseoccur in zona glomerulosa only

18-OH steroid dehydrogenase

ALDOSTERONE

Androgens17

hydroxylase

17,20 desmolase

does not occur in

zona glomerulosa

DHEA &Androstendione

substrate for other

tissues



Adrenocorticoids

Biological Activities1. Glucocorticoid Activity

1.1 Effects on Metabolism1.1.1 Stimulation of gluconeogenesis, particularly in the liver

1.1.2 Mobilization of amino acids from extrahepatic tissues

1.1.3 Inhibition of glucose uptake in muscle and adipose tissue

1.1.4 Stimulation of fat breakdown in adipose tissue

1.2 Effects on Inflammation and Immune Function

1.2.1 Anti-inflammatory properties

1.2.2 Immunosuppressive properties

1.3 Other Effects of Glucocorticoids1.3.1 Multiple effects on fetal development (promote maturation of the lung) !

1.3.2 Miscellaneous effects (Excessive glucocorticoid levels affect many

systems, e.g., inhibition of bone formation, suppression of calcium

absorption and delayed wound healing.) !

2. Mineralocorticoid Activity

2.1 Effect on Electrolytes

2.1.1 Increased re-absorption of sodium2.1.2 Increased renal excretion of potassium

2.2 Effect on Water

2.2.1 Increased re-absorption of water



CORTISOL

reduce APC formation

of certain cytokines(IL-1, IL-6, TNF) !

reduce lymphocyte gene

activation for cytokine

synthesis



ACTH 15-70 pg/ml

Cortisol 5-25 µg%circadian rhythm peaks in the morning (6-8 am) the lowest plasmaconcentration about midnight (60% lower) !

Free cortisol in 24 h urine 50-125 µg/24h

17 hydroksycorticosteroid in 24 h urine 3-16 mg/24h (female) and 6-26 mg/24h (male)

Aldosteron 2-15 ng%

Aldosteron in 24 h urine 5-10 µg/24h




•

Adrenal cortex diseases,





•




Adrenal Cortex Disease

•

Clinical manifestations result from:- – Overproduction or deficiency of:

•

Glucocorticoids

• Mineralocorticoids

•

Androgens

•

Hyper-secretion may presentdifferently depending on the disease

mechanism.

•

Hypo-secretion may only be apparentat times of stress.




•






•




Cushing’s syndrome – refers to the

manifestation of glucocorticoids excess from any

cause (nonspecific designation).

Cushing’s disease – excess production of

ACTH by pituitary gland causing manifestation of

adrenal hypercortisolism.

Overproduction of Glucocorticoids



Cushing’s syndrome - causes:

-

Cushing’s disease – 80%- Adrenal neoplasm (adenomas or carcinomas) –

10-15%

- Ectopic ACTH-producting tumor –

5-10%- Bilateral adrenal hyperplasia with undetectable ACTH – less than 1%

- Iatrogenic Cushing syndrome



Cushing syndrome

ACTH

dependent independent

ACTHACTH

Cortisol

ACTH ACTH

Adenoma Carcinoma

70% 12% 10% 8%



Hypothalamic-pituitary-etiology(Cushing’s disease).

Stress Diurnal rhythm

CRH

ACTH

Cortisol

Hypothalamus

Pituitary

Adrenal glands

?



Cushing’s disease:

- 90% - pituitary adenoma, 10% pituitary

hyperplasia,

- usually basophilic microadenoma,

- bilateral adrenal hyperplasia is due to increased

pituitary secretion of ACTH,

-

more frequently in women than men (female-male ratio 5:1); usually occurs during thechildbearing age,



A

B

C

A= Addsion’s disease or long term corticosteroids

B= Normal

C= ACTH excess: Cushing’s disease or ectopic.

Idiopathic adrenal hyperplasia



Ectopic ACTH syndrome .Stress Diurnal rhythm

CRH

ACTH

Cortisol

Hypothalamus

Pituitary

Adrenal glands

?

Tumor ACTH



Ectopic ACTH syndrome:

- Ectopic ACTH-production by tumours such as oat cell

carcinoma of the lung, carcinoma of the pancreas,bronchial adenoma and others causes adrenalhyperplasia.

- more frequent in men than in women (older age),

-

In addition to increase of cortisol plasma level suchpatients may have greatly increase level ofdeoxycorticosterone (DOC) a potent mineralocorticoid.That can result in severe hypertension, hypokalemia andmetabolic alkalosis.



Primary adrenal neoplasm


CRH

ACTH

Cortisol

Hypothalamus

Pituitary

Adrenal glands



Primary adrenal neoplasm:

- adenomas or carcinomas,

- Carcinomas are the most frequent spontaneusCushing’s syndrome in children.

- Carcinomas are usually large (> 6 cm).

- Adenomas secrete mainly cortisol. Carcinomas

produces usually variety of adrenal hormones(glucocorticoids, mineralocorticoids, androgensand estrogens).



Adrenal gland removed surgically in a patient with Cushing'ssyndrome - adenoma. Some remaining atrophic adrenal is seen

at the right. Histologically, it is composed of well-differentiated

cells resembling cortical fasciculata zone. It is benign.



This is a large adrenal cortical

carcinoma which is displacing

the left kidney downward. Such

neoplasms are usually functional

(secreting corticosteroids or sex

steroids). They have a poor

prognosis.



Cushing’s syndrome-

symptoms (1):

- Central obesity –caused by effect of cortisolon fat distribution. Fataccumulates in the face,neck, trunk, while thelimbs remain thin. ” Themoon face”, ”Buffalohump” (cervical fat pad),supraclavicular fat pads.



Cushing’s syndrome- symptoms (1):

” The moon face”,”Buffalo hump” (cervical fat pad),



Moon face; florid complexion (red face) !





2) Hypertension




2) caused by increase cortisol-induced gluconeogenesisand decreased peripheral glucose utilization; 20% ofpatients have overt diabetes mellitus.

4) Symptoms of androgen excess (oligomenorrhea,hirsutism and acne); in women with Cushing’s disease

stimultion of androgen secretion by ACTH,

5) Purplae striae – linear marks on the abdomen wherethe thin and wasted skin is stretched by underlying fat,



Purplae striae – linear marks on the abdomen



Purplae striae

Moon face

Central obesity




6) Muscle wasting and weakness – caused bycatabolic effects of cortisol on muscle protein.

7) Osteoporosis – caused by cortisol’s effects onincreased bone catabolism and inhibitory effects oncollagen synthesis and calcium absorption,



Osteoporosis




Cushing’s syndrome-

symptoms (3):

8) Susceptibility to bruising –probably caused by enhanced

capillary fragility,

9) Psychiatric disturbances –especially depression.



Cushing’s syndrome- diagnosis (1):

The diagnostic approach in patients who aresuspected of having Cushing’s syndromeconsists of two phases.

1) Does the patients have Cushing’s syndrome?

2) If Cushing’s syndrome is present what is itscause?



Cushing’s syndrome- diagnosis (2):Does the patients have Cushing’s syndrome?

1)

exclusion exogenous cause of Cushing’s syndrome bythe medical history,

2) high urine free-cortisol excretion rate,

3) ”low-dose dexametasone test”

- 1 mg dexametasone orally between 11-12 p.m.,

- measure plasma cortisol level 8 a.m.

plasma cortisol < than 5 g/dl - normal supression,

> than 5 g/dl – Cushing’s syndrome,

needs further study.

This test is sensitive but is not very specific – mental and physical

stress may produce a false positive results




What is the cause of Cushing’s syndrome?

1)

”standard high-dose dexametasone test”

The suppressibility of hypothalamic-pituitary-adrenalaxis is tested by the administration of dexamethasonein high doses. Patients with Cushing’s disease behave as

though their feedback response to glucocoticoid isintact but set a higher than normal level. They respondto high but not to low doses of dexamethasone. Patientswith adrenal tumors and ectopic ACTH secretionproduce corticoid autonomously, without suppression

even by high doses of dexamethasone.





1) ”standard high-dose dexametasone test” c.d.

- 8 mg (2 mg 4 times daily) dexametasone daily orallyduring 2 days,

- measure plasma cortisol level, urinary free cortisol

and urinary 17-hydroxycorticosteroid exctretion rate,

before and in a second day of dexametazone

treatment.

healthy subjects – suppression (decrease > 50 %),

Cushing’s disease - suppression (decrease > 50 %),

adrenal neoplasm – no suppression,

ectopic ACTH syndrome – no supression.





2) Plasma ACTH levelCushing’s disease – high normal or slightly elevated,

ectopic ACTH – markedly elevated,

adrenal neoplasm – extremely low or undetectable.

3) Radiographic finding – localize the primaryabnormality and confirm etiological diagnosis.

- skull X-ray (enlargement of sella turcica – in case of

macroadenomas),

- MRI or computed tomography of pituitary,- ultrasonography, MRI or computed tomography of

adrenal glands.



Petrosal sinus sampling : Pituitary orectopic?

•

Ratio Petrosal/peripheral

ACTH >2:1 if pituitary.

•

Lateralisation ofmicroadenoma : -

– Localisation of microadenoma.

– Ipsilateral ACTH release

of ACTH by adenoma

•

Pituitary not hypothalamicvia CRF:-

– Both sides high ACTH if

CRH secreting tumour



JUGULAR VEIN

Confluent

Pituitary

Veins

Cavernous

Sinus

Inferior Petrosal

Sinus




•




Adrenal insufficiencyCongenital adrenal hyperplasia

•




P450 C21 hydroxylase

(microsomal) !

11ß-hydroxylase

(mitochondrial) !

CORTISOL

18 hydroxylase

18-OH steroid dehydrogenase

ALDOSTERONE

Androgens17

hydroxylase

17,20 desmolase

does not occur in

zona glomerulosa

DHEA &Androstendione

substrate for other

tissues



The renin-angiotensin-aldosterone system

Serum K +

AldosteroneDistal

nephronH+

excretion

K +

excretion

NaCl

reabsorptionEffective

ECF volume

ACTH

BP

Renin AI AII –

–

–

Di t l l t d t b l ll



CYTOPLASM

K +

Na+

ADP + Pi

Pump

K +

ATP

Na

+

Permease

hypothesis

Na+

Distal convoluted tubule cell

Aldosterone

from blood

diffusion

into cell

Apical

membraneBasolateral

membrane

I n t e r s t i t i

um

Nucleus

Induced gene

HREmRNA

Aldosterone-

induced

proteins

cytoplasmic mineralocorticoid receptor (MR) !

homodimeric steroid-

receptor complex

Mitochondrium

Met abolic

hypothesis

T u b u l a r

l u m e n

Na+ pump

hypothesis

Na+ Na+Na+

Na+

K +,H+



Mineralocorticoid Excess (1) !

•

Primary hyperaldosteronism

(overproduction of aldosterone independent of it’snormal chronic regulator Angiotensin 2)

•

Secondary hyperaldosteronism (overproduction of aldosterone dependent of it’snormal chronic regulator Angiotensin 2)



•

Adenoma (50-90%) !

•

Bilateral Adrenalcortical Hyperplasia(10%).

•

Sporadic or Familialhyperaldosteronism(Type FH2).

• ACTH dependantrelease

(dexamethasonesuppressible FH1).






Diagnostic features:

1) High Aldosterone

2) Low Plasma Renin3) High Aldosterone/Plasma Renin Ratio

Mi l ti id E (3) !




Primary hyperaldosteronism:

Conn's syndrome (adrenal adenoma producing aldosterone)- Conn's syndrome (50 - 90% of cases) ishyperaldosteronism due to functional adenoma . The

normal feedback loops are intact so the renin is low. It

most commonly occurs from age 30-50 years andpresents as hypertension. It accounts for less than 1% ofhypertensive patients. In several of patients signs of renal disease (50% develop proteinuria, 15% develop renal

failure).

Laboratory findings include low potassium and highsodium serum concentration.



1.3 cm left adrenal adenoma in a patient with hypertension and

hypokalemia. Such adenomas are typically less than 2 cm in size and

yellow on cut surface.

Conn's syndrome (adrenal adenoma producing aldosterone) !




Secondary hyperaldosteronism: -

–

Renal artery stenosis,

– Renin secreting tumours,

–

Barters syndrome, –

Diuretic and/or laxative abuse.

Diagnostic features:

1) High Aldosterone2) High or Inappropriate Plasma Renin




Biochemical diagnosis•

Primary hyperaldosteronism: -

– Raised/Normal plasma aldosteroneconcentration

–

Suppressed/low PRA – High plasma aldosterone concentration/

PRA ratio.

• Secondary hyperaldosteronism: -

–

Raised plasma aldosterone concentration

– Raised or “normal” (inappropriate) PRA.




Biochemical diagnosis




•





• Adrenal medulla diseases, Pheochromocytoma



Primary adrenal insufficiency.


CRH

ACTH

Cortisol

Hypothalamus

Pituitary

Adrenal glands

MSH

?



Secondary adrenal insufficiency.


CRH

ACTH

Cortisol

Hypothalamus

Pituitary

Adrenal glands

Primary adrenal insufficiency (1):




- uncommon disorders, usually occured between ages 20and 50

- female:male incidence ratio 2.6:1

- clinical symptoms are caused mainly by both cortisol

and aldosterone deficiencies- clinical manifestations do not appear until at least 90%of cortex has been compromised





causes:

- autoimmune (Addison’s disease) (75%),

- tuberculosis (20%),

-

others (5%); among them hemochromatosis, amyloidosis, bilateral adrenal haemorrhage (in the Waterhouse-

Friederichsen syndrome or in patients during

anticoagulation), fungal and CMV infection in patients

with AIDS, metastatic malignancy, after bilateral

adrenadrelectomy, after aminoglutetymide treatment



A

B

C

A= Addsion’s disease or long term corticosteroidsB= Normal

C= ACTH excess: Cushing’s disease or ectopic.

Idiopathic adrenal hyperplasia



Caseating granuloma of tuberculosis in the

adrenal gland.



Hemochromatosis in the adrenal gland.



Amyloidosis in the adrenal gland.




Symptoms of cortisol deficiency:

1) hyperpigmentation of skin - caused by $MSH,

2) hypotension (often orthostatic) - caused by absence ofcortisol’s pressor effect on vasculature and decrease ofcardiac output,

3) anorexia, nausea, vomiting, weight loss,

4) hypoglycaemia - %cortisol-induced gluconeogenesis,

5) mental symptoms – lethargy and confusion,

6) intolerance to stress – severe stress leads to exacerbation of

symptoms (patients can not to increase their steroid outputduring the stress).



Primary

adrenal

insufficiency



Primary adrenal insufficiency




Symptoms of cortisol deficiency:

1) hyperpigmentation of skin - caused by $MSH,

2) hypotension (often orthostatic) - caused by absence ofcortisol’s pressor effect on vasculature and decrease ofcardiac output,

3) weight loss, anorexia, nausea, vomiting, pain in theabdomen

4) hypoglycaemia - %cortisol-induced gluconeogenesis,

5) mental symptoms – lethargy and confusion,

6) intolerance to stress – severe stress leads to exacerbation ofsymptoms.



Primary

adrenal

insufficiency




Symptoms of aldosterone deficiency:

1) sodium loss – volume depletion, hypotension,decrease of cardiac output, % RBF with renalinsufficiency, weight loss,

2) potassium retention – hyperkalemia and cardiacarrhythmias. women loss of axillary and pubic hair




Symptoms of androgens deficiency in females:

1) women loss of axillary and pubic hair

Clinical Features of Primary Adrenal



Clinical Features of Primary AdrenalInsufficiency

• Gradual onset >95%

• Weakness & fatigue 100%

•

Wt loss/anorexia 100%

•

Hyperpigmentation 92%•

Hypotension / tachycardia 88%

•

Hyponatremia 88%

•

Hyperkalemia 64%• Muscle, GI pain 56%




Diagnosis:

-

Plasma cortisol, urinary free cortisol, urinary 17-hydroxycorticosteroid are low (usually without circadianrhythm).

- Plasma ACTH is high ( >200 N:20-100 ng/ml) !

-

Hyponatremia, hyperkalemia, hypoglycemia, chest X-raymay revealed small heart.

- Short ACTH test: synacten (first 24 AA ACTH analog) 0.25mg i.v.or i.m.. Cortisol is measured before injectionand after 30minutes.

Normal response – at least 7 µg% increase in serumcortisol concentration ans should reach 18 µg%.

Lower response – adrenal hypofunction

Ald t d fi i ith t l ti id



Aldosterone deficiency without glucocorticoid

deficiency:

Cause:- deficient secretion of renin – hyporeninemic

hypoaldosteronism (e.g. autonomic insufficiency, -blocker therapy, injury of juxtoglomerular

apparatus),

-

primary abnormality of zona glomerulosa(autoimmune process, critically ill patients, ACEItherapy, corticosterone methyloxidase deficiency).

Clinical features:

-

usually asymptomatic,

- hyperkalemia.

H i i h ld t i



Hyporeninic hypoaldosteronism

Serum K +

Distal

nephron

H+

excretion

K +

excretion

or N

NaCl

reabsorption

or N

Effective

ECF volume

or N

BP

Renin # AI # AII # Aldosterone

P ima h poaldoste onism



Primary hypoaldosteronism

Serum K +

Aldosterone Distal

nephron

H+

excretion

K +

excretion

NaCl

reabsorption

Effective

ECF volume

BP

Renin AI AII



Secondary adrenal insufficiency.


CRH

ACTH

Cortisol

Hypothalamus

Pituitary

Adrenal glands



Secondary adrenal insufficiency (1):

Causes:1) destructive lesions in the hypothalamic-pituitary axis,

2) isolated ACTH secretion defect,

3) prolonged suppression of pituitary-adrenal axis byexogenous glucocorticoids.





Clinical and diagnostic features:

Similar to those for primary glucocorticoid deficiency, butwith several important differences:

1) hyperpigmentation is absent (normal plasma MSHconcentration),

2) hyperkalemia and metabolic alkalosis did not occurred(normal mineralocorticoid level),

3) clinical manifestations of hypogonadism and hypothyreosisfrequently occurred (in case of primary pituitary disease).





Diagnosis:

Prolonged ACTH test:synacten depot i.m. 0,5 mg twice daily during 4 days

Normal response – three-five fold increase in urinarycortisol, urinary 17-hydroxycorticosteroid excretion rate;

a 15-40 g/dl rise in serum cortisol level.

Primary adrenal insufficiency: lower responseSecondary adrenal insufficiency: normal but later than in

haelthy subjects response (lack of response during first

and second day, stepwise increase or normal responseduring by the third or fourth day)

Clinical Features of Secondary Adrenal



Clinical Features of Secondary AdrenalInsufficiency

• Gradual onset >95%

•

Weakness & fatigue 100%

• Weight loss/anorexia 100%

•

Pale 100%

• Hair loss <50%

•

Anemia <50%

•

Electrolytes usually normal

Adrenal insufficiency treatment:



Adrenal insufficiency treatment:•

Glucocorticoid replacement is required in all patients

Daily dose: 37.5 mg cortisone or 30 mg hydrocortisone (2/3 of

dose in the morning) ! • Mineralocorticoid replacement is not required in all patients

Daily dose: Fludrocortison 0.05 – 0.2 mg in the morning

Stress, infection, surgery: dose of glucocorticoids shouldbe higher.

• 40-60 mg daily hydrocortisone during minor stress (e.g.

common cold or dental extraction) !

•

100 mg daily hydrocortisone during moderate stress (e.g.influenza or minor surgery) !

• 300 mg or more daily hydrocortisone during major stress

(e.g. severe infection or major surgery) !



Primary Acute Adrenocortical

InsufficiencyOccurs in a variety of clinical settings:

•

1) Addisonian “crisis” in patients with chronicadrenal insufficiency who are subject to stress

• 2) Rapid withdrawal of steroids in patients ontherapy or failure to supplement patients on therapy

during acute stress

•

3) Massive adrenal hemorrhage

Adrenal crisis (Addisonian crisis):



Adrenal crisis (Addisonian crisis):

Acute life-threating complication of Addison’s disease inwhich the manifestations of adrenal insufficiency are greatlyexaggerated. Adrenal crisis may occur in untreatedAddison’s disease or in a treated patient following acutestress if additional glucocorticoid replacement is notprovided.

Clinical features:

vascular collapse, shock (and as a consequence oliguria), low bodytemperature in the initial phase and fever in the late phase,vomiting, signs of dehydratation, abdominal pain

(pseudoperitonitis), altered mental status.

hypoglycemia, metabolic acidosis, hyperkalemia, hyponatremia(in 90% of cases), plasma sodium/potassium ratio < 30

Adrenal crisis (Addisonian crisis) treatment:



Adrenal crisis (Addisonian crisis) treatment:

•

NaCl and glucose i.v. infusion (up to 4 liters).• Hydrocortison i.v. 100 mg every 6 hours.

Ad l l d h i l




•








Congenital adrenal hyperplasiaStress Diurnal rhythm

CRH

ACTH

Cortisol

Hypothalamus

Pituitary

Adrenal glands

?

Androgens

C i l d l h l i (1)



Congenital adrenal hyperplasia (1):

!

Caused by a defect in one of the enzymes that are necessaryto synthesized cortisol (21-hydroxylase, 11-hydroxylase, 17-hydroxylase deficiency, hydroxylase 3-steroid or 5,4Isomerase deficiency). Cortisol deficiency stimulates ACTHsecretion which, causes hyperplasia adrenal cortex and

overproduction of ACTH dependent steroids (mainlyandrogens).

! Clinical manifestations depend mainly upon androgensoversecretion (ambiguous genitalia or virilisation infemales, macrogenitosomia or precocious puberty inmales).





Diagnosis:! Low plasma cortisol and high plasma ACTH concentration

! High blood testosterone concentration

!

Increase of steroid specific to the enzyme abnormality

C it l d l h l i (2)




!

21-hydroxylase deficiency The most frequent syndrome (1:5000-1:15000 of newborn; 95% cases ofcongenital adrenal hyperplasia ). High 17-OH progesterone plasmaconcentration

! 11-hydroxylase deficiency

High 11-Deoxycorticosterone (DOC) and 11-Deoxycortisol plasmaconcentration


Low plasma cortisol, estrogens and androgens concentrations, high 11-Deoxycorticosterone (DOC) (mineralocorticoid) plasma concentration.

!

hydroxylase 3-steroid or 5,4 Isomerase deficiency Low plasma cortisol, estrogens and androgens concentrations, high 17-OH

pregnenolone and dehydroepiandrosterone (DHEA) plasma concentration



21-Hydroxylase Deficiency

Three distinct syndromes are known:

1) “Classic”, salt-wasting adrenogenitalism related to 21-

hydroxylase deficiency presenting at birth with

virilization in females; cryptorchidism and hypospadias in

males; salt wasting is due to concomitant aldosterone

deficiency

2) A simple virilizing variant with normal aldosterone

activity

3) A “nonclassic” variant with delayed onset of virilization

during late childhood or adolescence





!






!


pregnenolone and dehydroepiandrosterone (DHEA) plasma concentration.

Review of congenital adrenal hyperplasia

syndromes caused by various defects in the

Cholesterol

StAR



Corticosterone (ZF/ZR) !

Aldosterone (ZG) !

Dehydroepiandrosterone(DHEA) ! 17"-OH pregnenolone

17 -hydroxylase

11

-Hydroxylase

Cortisol

11-Deoxycorticosterone (DOC) !

17"-OH progesterone

21-Hydroxylase

11-Deoxycortisol

Progesterone

3

-OHSD/&

5,4 Isomerase salt loss + female: virilized; male: hypogonadal

composite pathway of steroid hormone

biosynthesis .

P-450scc ACTH

Pregnenolone

Cholesterol

salt loss/sexual infantilism

Aldosterone synthase

Hypertension/sexual

infantilism

17

-hydroxylase

ALDOSTERONE

CORTISOLCORTICOSTERONE

salt loss/virilization

hypertension/virilization

initial salt loss

Testosterone

(made in peripheral

tissues by reduction of

androstenedione) !

Androstenedione

Congenital adrenal hyperplasia: 11- hydroxylase deficiency



prominent recession of the hairline characteristic of male baldness,and the patient also has dark hair on the upper lip and acne.





!






!


pregnenolone and dehydroepiandrosterone (DHEA) plasma concentration.



i h f id h

Cholesterol

StAR




Aldosterone (ZG) !


17 -hydroxylase

11

-Hydroxylase

Cortisol


17"-OH progesterone

21-Hydroxylase

11-Deoxycortisol

Progesterone

3

-OHSD/&



biosynthesis .

P-450scc ACTH

Pregnenolone

Cholesterol



Hypertension/sexual

infantilism

17

-hydroxylase

ALDOSTERONE




initial salt loss

Testosterone

(made in peripheral


androstenedione) !

Androstenedione

Congenital adrenal hyperplasia: 17- hydroxylase deficiency



Female with primaryamenorrhea,disproportionately longlimbs relative to the trunk,

absent axillary and pubichair, infantile breast andgenitalia development, anabsent uterus, and anincomplete vagina.

Congenital adrenal hyperplasia: 17 hydroxylase deficiency



it th f t id h

Cholesterol

StARl l / l i f ili




Aldosterone (ZG) !


17 -hydroxylase

11

-Hydroxylase

Cortisol


17"-OH progesterone

21-Hydroxylase

11-Deoxycortisol

Progesterone

3

-OHSD/&



biosynthesis .

P-450scc ACTH

Pregnenolone

Cholesterol



Hypertension/sexual

infantilism

17

-hydroxylase

ALDOSTERONE




initial salt loss

Testosterone

(made in peripheral


androstenedione) !

Androstenedione

Summary of Laboratory Findings



Summary of Laboratory Findings

Cushing's

Syndrome

Cushing's

Disease

Conn's

Syndrome

Addison's

Disease

Na high high high low

K low low low high

glucose high high normal low

cortisol high high normal low

ACTH low high normal usuallyhigh

• Adrenal glands physiology




•








Major hormones of adrenal

medulla:

Catecholamines:

! norepinephrine,

!

epinephrine,

! dopamine.

Ph h



Pheochromocytoma:

- Uncommon but importanttumour of chromaffin cells.

- Occurs most commonly inadrenal gland (90%), but canbe found in any sympatheticganglion. Bilateral or multiple

tumours in 5-10%. 10% ofpheochromocytoma aremalignant.



Pheochromocytoma



Note the grey-tan colour of the tumour compared to the yellowcortex stretched around it and a small remnant of remaining adrenal

at the lower right. This patient had episodic hypertension.

Pheochromocytoma

Pheochromocytoma



chromaffin reaction

(dichromate fixation)

eoc o ocyto a



Pheochromocytoma:



Pheochromocytoma:

Diagnosis:1) Clinical manifestations depend upon catecholamines

oversecretion. Diagnosis is suggested by paroxysmalnature of symptoms.

2) High urinary vanillylmandelic acid (VMA),metanephrine, normetanephrine and free catecholaminesexcretion rate. Hyperglycaemia.

3) Anatomic localization: ultrasonography, MRI orcomputed tomography of adrenal glands, isotope scan

technique with131

I iodobenzylguanidine.

Pheochromocytoma



- noradrenaline (NA) , adrenaline (A),- methoxyamines: normetanephrine (NMN) and metanephrine (MN).

- VMA (vanilmandelic acid) !

Pheochromocytoma

Pheochromocytoma:



Pheochromocytoma:

Diagnosis:1) Clinical manifestations depend upon catecholamines

oversecretion. Diagnosis is suggested by paroxysmalnature of symptoms.

2) High urinary vanillylmandelic acid (VMA),metanephrine, normetanephrine and free catecholaminesexcretion rate. Hyperglycaemia.

3) Anatomic localization: ultrasonography, MRI orcomputed tomography of adrenal glands, isotope scan

technique with131

I iodobenzylguanidine.

Pheochromocytoma:



y

computed tomography ofadrenal glands,

MRI ofadrenal glands,

Pheochromocytoma:



isotope scan technique with 131I iodobenzylguanidine.

1. endocrinology part 1

Documents