Gluco Corticoids r 1 Ff 2

7/31/2019 Gluco Corticoids r 1 Ff 2

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(+) POSTERIOR

PITUITARYANTERIOR

PITUITARY

(-)

CRH

HYPOTHALAMUS

HYPOTHALAMIC-PITUITARY

PORTAL SYSTEM

ACTH

CORTISOL

Adrenal Fasiculata

(-)


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Steroid Hormones

The following are all made from Cholesterol

Mineralocorticoids,

Glucocorticoids,

Androgens, Estrogens, Progestogens

In:

Zona glomerulosa

Zona fasciculata

Zona reticularis

respectively


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Goals of Discussion

Review Adrenal Physiology

Identify the clinical features of Adrenal

Insufficiency

Etiologies of Adrenal Insufficiency

Understand testing of adrenal function

Examine rationale behind Treatment ofAdrenal Insufficiency


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Adrenal Development

Cells of origin:

Cortex: Mesenchymal cells

Medulla: Neuroectodermal

cells

Fetal adrenal is present by 2months gestation

Mostly cortex

Glomerulosa and fasiculata

are present at birth Reticularis develops during

first year of life


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Adrenal Anatomy

Adult adrenal

2-3cm wide

1cm thick

4-6 grams

Located

Upper pole of kidneys

Vascular supply 12 small arteries from

aorta


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Adrenal Physiology

Glomerulosa

15% of cortex

releases Aldosterone

controlled by renin-angiotensin

mechanism

Fasciculata

75% of cortex

releases Cortisol, Corticosterone

under ACTH control

Reticularis

releases Androgens and

Estrogens

under ACTH control

Medulla

releases Catecholamines


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Synthesis of steroid hormones


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Adrenal Physiology

ACTH and cortisol

Pulsatile secretion

Highest in AM at wakening

Lowest late afternoon and

evening

DHEA and Androstenedione

regulated by ACTH

Increase in response tostress

Hypoglycemia

Surgery

Illness

Hypotension

Smoking

Cold exposure

Blunted response Chronic illness


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Cortisol

Principal glucocorticoid inplasma

Circulates bound toTranscortin

Plasma concentrationsincreased by oestrogens,including pregnancy andhormonal contraceptives

Marked circadianvariation

Plasma corticosteroids:

Mid night 3-10 g /100ml

0900 h 10-25 g /100ml

Plasma aldosterone: Stilla research procedure


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Circulation of Cortisol and Adrenal

Androgens

Secreted unbound

In circulation bind toplasma proteins

Unbound is active Cortisol

Free: 10%

Bound : 75% (to

corticosteroid-bindingglobulin, CBG))

Albumin: 15%

Androgens

Albumin

Sex Hormone binding

(SHBG) Testosterone


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Cortisol Effects

Connective Tissue Inhibits fibroblasts

Loss of collagen

Thinning of skin

Bone Inhibits bone formation

Stimulates boneresorption

Potentiates actions ofPTH Increased bone

resorption

Calcium metabolism

Decreases intestinal

calcium absorption

Stimulates renal 1-hydroxylase

Increases 1,25 OH

vitamin D synthesis

Increases calciuria Increases phosphaturia


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Cortisol Effects

Growth Accelerates development of

fetal tissues

Lung maturity

Inhibits linear growth

Decreased growthhormone

Erythrocytes Minimal effect

Leukocytes

Increases PMN by increasingrelease from bone marrow

Decreases lymphocytes,monocytes and eosinophils

Immunologic

Inhibits prostaglandin

synthesis

Phospholipase A2

Decreases IL-1

IL-1 stimulates CRH and

ACTH

Impairs AB production

and clearance


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Cortisol Effects

Cardiovascular

Increases peripheral vasculartone

Hypertension

Renal function

Effects on mineralocorticoidreceptors

Na retention

Hypokalemia

HTN Effects on Glucocorticoid

receptors

Increased GFR

Nervous system Enters the brain

Euphoria

Irritability, depression andemotional lability

Hyperkinetic or manicbehavior

Overt psychosis

Increased appetite

Impaired memory orconcentration

Decreased libido

Insomnia Decreased REM and

increased Stage II sleep


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Cortisol Effects

Metabolism

Glycogen

Activates glycogenproduction\

Deactivates glycogen

breakdown

Glucose

Increases hepaticglucose production

Inhibits peripheral tissueutilization of glucose

Lipids

Activates lipolysis inadipose tissue

Redistributes body fat

Sparing of theextremities


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Adrenocortical Hyperactivity:

Causes

Hyperplasia of adrenalcortex

Tumour of adrenal cortex

Both may be secondary toincreased ACTH secretion

Cushings syndrome:

Increased secretion ofcortisol

Often associated withabolition of circadianrhythm of and ACTHsecretion

Overactive anterior pituitary

Non-endocrine: Carcinomaof the bronchus withectopic ACTH

Symptoms

Insulin resistant diabetesand glycosuria

Cessation of growth

Muscular wasting Osteoporosis

Moon face and buffalohump


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Biochemical effects of adrenal

hyperactivity

Moderate alkalosis

Sodium and waterretention

Low plasma potassium Hypertension

Lymphopenia

Eosinopenia

Adrenal androgensecretion little /or notaltered

.

S h i f id h


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Synthesis of steroid hormones


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Congenital Adrenal Hyperplasia

Most adrenal

biosynthetic defects

result in:

Virilized female

Normally virilized male

Deficiencies:

Mineralocorticoid

Glucocorticoid

21-OHase deficiency

11-OHase deficiency


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Deficiency of CYP 17 17- hydroxylase and 17-20

lyase deficiency

Rare cause

Diagnosed due to delayed

pubertal development

Female: 46xx

Hypertensive

+/- Hypokalemic

Primary amenorrhea Absent secondary sex

characteristics


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Deficiency of CYP 17

Male: 46XY

Complete male

pseudohermaphroditism

Female external genitalia

Blind-ended vagina

No mullerian structures

Testes intra-abdominal

Leydig cell hyperplasia

Hypertensive

+/- Hypokalemic

Cortisol sufficient

Tolerates general

anesthesia and surgery

Treatment

Steroids to suppressexcess ACTH

Gonadal steroids

replacement


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3 -Hydroxysteroid

Dehydrogenase

Presents early infancy

Adrenal insufficiency

Females can be virilized

due to DHEA

Males

Normal genitaldevelopment

Hypospadias

Pseudohermaphroditism

Females:

Can present in puberty

with:

Hyperandrogenemia Hirsuitism

Oligomenorrhea

Treatment

Cortisol replacement


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Congenital Adrenal HyperplasiaSteroidogenic Acute Regulatory Protein (StAR)

Congenital Lipoid AdrenalHyperplasia

StAR Deficiency Transports cholesterol to

inner mitochondrialmembrane

Rarest form Autosomal recessive

All adrenal steroids aredeficient

Present with adrenalinsufficiency

Typically fatal infancy

Males Female external genitalia


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Renin and Aldosterone

Renin Enzyme released from the kidneys

(macula densa)

Activates Angiotensinogen

Angiotensin 1 Angiotensin 2

Increased secretion

Low blood pressure

Low sodium

High potassium

Upright posture

Aldosterone

Sodium homeostasis

Regulates arterial pressure

Regulated

Angiotensin 2

Increases

Renal sodium retention

Renal potassium excretion

Low Aldosterone

Adrenal insufficiency

High renin

Hyperkalemia


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Renin and Aldosterone


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Tumours of the adrenal cortex

Benign tumours produce one hormone

Malignant tumours can produce a number of

hormones

Urinary excretion of corticosteroids and 17-

oxosteroids are often both increased to more

than 50mg /24 h


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Primary Aldosteronism (Conns

syndrome)

Tumours producing only excess aldosterone

Sodium retention

Hypokalaemia due to urinary and intestinal

potassium loss Muscular weakness, alkalosis, polyuria and

hypertension

Confirmation:

High urinary aldosterone

Response to aldosterone antagonist:Spironolactone


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Secondary aldosteronism

Found in conditions where there is loss of

sodium from extra-cellular fluid such as:

Nephrotic syndrome

Cirrhosis and ascites

Congestive heart failure

In all the above, hypokalaemia is rare andplasma renin is increased


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Adrenocortical Hypoactivity

May result from hypopituitarism

Aldosterone secretion is maintained so that

Na+ / K + balance is little altered


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Adrenal Hypofunction

Primary lesion of the adrenal glands due to:

Destructive or atrophic disease; tuberculous,

fungal or auto-immune

Deficiency of all adrenocortical hormones

Excess urinary Na+ and Cl- loss and K+ retention

Low renal plasma flow is the result of Na+

deficiency and hypotension leading to pre-

renal azotaemia (high plasma urea)


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Addisons Disease

Other features:

Asthenia

Loss of weight

Hypotension

Gastro-intestinal disturbances Skin pigmentation due to excess ACTH secretion

(melanophore expansion)

Simple screening test: Failure to excrete a water load; contra-indicated in low serum sodium

Low urinary 17-oxosteroids

Increased glucose utilization/ decreased gluconeogenesis hypoglycaemia


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Acute Adrenal Insufficiency

Causes :

Addisons

Long term corticosteroid administration

Waterhouse-Friederichsens syndrome inmeningococcal septicaemia

Results:

Severe Sodium and Water depletion Hypotension

Hypoglycaemia


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Flow of information, Synthetic glucocorticoids,

Cortisol Binding Globulin (CBG)

Flow of info: CRFACTHCortisol

Prednisolone and dexamethasone reduce the

secretion CRF

In circulation glucocorticoids are about 90%

bound to proteins; the main protein being CBG

Metabolism

Glucuronides

17-hydroxy metabolites


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The response to stress

Mediated by CRF and ACTH

Stimuli include surgical operations

Emotional stress

Insulin hypoglycaemia


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Circadian Rhythm

The circadian rhythm of plasma cortisol is relatedto the rhythm of an individuals sleeping-wakingcycle. The pathway for its control also depends onthe CRF and ACTH.

Stimulation of the adrenals by ACTH leads to theincreased release of stored cortisol, androgensand oestrogens

There is also increased new synthesis of cortisol

Long term response is an increase in thesensitivity of the gland and hypertrophy of theadrenal cortex


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Plasma cortisol

Specimens must be collected at standard

times (0800 h and 2200 h) because of the

nychthemeral rhythm)

The most reliable reference ranges have been

defined for these times (160-565 nmol/L) at

800 h and less than 205 nmol/L at 2200 h


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Early in the overproduction of cortisol, the

0800 h plasma level still remains within the

reference range but the 2200 h value

increases much above 205 nmol/L


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Tests of glucocorticoid metabolism

KINDS OF TESTS:

PLASMA/URINE TESTS:

Used in the first place to support a clinical

diagnosis of hypofunction or hyperfunction of theadrenal cortex

STIMULATION/SUPPRESSION:

Further tests which may provide informationabout the nature of the disease process


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Important points to observe when collecting specimens

for measuring plasma cortisol

Anxiety: large increases in plasma cortisol may

be observed in response to emotional stress

Venous stasis: must be avoided because

cortisol is bound to protein (CBG)

Storage: Blood: 4C, do not freeze for short

periods. If analysis is to be delayed more than

12h plasma should be separated immediatelyand then frozen


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Cortisol-binding globulin

Increased in :

Pregnancy

Patients taking oestrogens and oestrogen

containing oral contraceptivesDecreased in:

Hypoproteinaemic states e.g. nephroticsyndrome

Salivary cortisol represents plasma unboundcortisol


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Plasma ACTH

Only a few specialized laboratories do plasma

ACTH

(Follow detailed instructions for collecting,

preserving and transporting the specimens)

Specimens to be collected at 0800 h and 2200

h

Stress should be avoided


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Lipotrophin (LPH)

Secreted by the anterior pituitary in response

to the same stimuli as cause release of ACTH

There are therefore parallel changes in plasma

concentrations of these two compounds

LPH is more stable than ACTH and its plasma

measurement offers some advantages over

that of ACTH


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Urinary glucocorticoids and

metabolites

Urinary free cortisol (measures plasma free unboundcortisol-the level of active hormone to which thetissues are exposed)

Urinary 17-hydroxycorticosteroids (17-OHCS)(almost

the same group of compounds as urinary 17-oxogenicsteroids -17OGS, metabolites of cortisol, 11-deoxycortisol, 17-hydroxyprogesterone). Urinary 17-OHCS and 17-OGS now virtually obsolete

(Many drugs-metabolites of anti-hypertensive agents,cardiac glycosides and tranquilizers interfere with thedeterminations)


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Urinary 17-OS

This comprises a group of metabolites formed

mainly from androgens- adrenal or testicular

or ovarian in origin about 5%-10% of cortisol is

metabolized to 17-OS

Since immunological tests are now available

for individual androgens this test is also

virtually obsolete


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Investigation of disorders of

Glucocorticoid Production

Screening tests.Is a disorder of adrenocorticalfunction (hypofunction or hyperfunction apossibility?)

Confirmatory tests. How can the provisionaldiagnosis be confirmed or excluded

Determining the cause. If adrenal corticaldysfunction is confirmed; (a) what is the site of

the pathological lesion? Adrenal cortex, pituitaryor elsewhere? (b) what is the nature of thepathological lesion?


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Screening tests

Dexamethazone or Bethamethazone

Urinary free cortisol: creatinine ratio

All performed on out-patient basis


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Overproduction of cortisol suspected

Overproduction of cortisolsuspected

Screening tests on outpatients

Tests to confirm there isoverproduction of cortisol(inpatient procedures)

Tests to identify the cause ofCushings Syndrome

Dexamethasone screening test or Urinary free cortisol: creatinine

ratio

Loss of nychthemeral rhythm ofplasma cortisol

24 h excretion of cortisol in theurine

Insulin hypoglycaemia test

Low dose dexamethasone test

Plasma ACTH High dose dexamethasone test

Metyrapone test


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Dexamethazone screening test

excluding the diagnosis of Cushings syndrome

Patient takes a 2 mg tablet of dexamethazone

(or betamethazone) at 2200 h the night before

the test

Blood sample for plasma cortisol is collected

the following morning at 0900 h (ref range

160-565 nmol/L

Normal response: suppression of plasmacortisol to 150 nmol/L or less


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Dexamethazone suppression test

Patients with simple obesity respond to the 2 mgdexamethazone or betamethazone but inpatients with Cushings syndrome plasma cortisolmay be 300 nmol/L

If the dexamethazone suppression test is normalthere is no need for further tests

If it is abnormal, the patient will need furthertests to

1. confirm the diagnosis2. To determine the site of the lesion

C fi i f i l


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Confirmation of cortisol

overproduction

Loss of nychthemeral rhythm

Increased 24 h excretion of urinary free

cortisol

Insulin-hypoglycaemia

low dose dexamethasone


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Stress tests for the HPA axis

Insulin-hypoglycaemia test: Fast overnight, sol insulin0.15 u/kg bdy wt i.v., sampling for cortisol at 30, 45, 60,and 90 min

The most widely used stress test of HPA integrity

Plasma glucose is reduced

The adrenals respond by increasing production ofcortisol which is measured

The test is contra-indicated in patients with epilepsy

or heart disease The test is ended by giving the patient a glucose

containing meal and a drink


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Tetracosactrin (Syncotropin,

Synacthen) TestMethod:

A mid-night sample is collected for diurnal

rhythm studies.

0900h: Collect 10ml heparinized blood for

corticosteroid (cortisol baseline) assay

Inject I.M. 250 g Tetracosactrin in 0.5 ml

water

0930h: Collect blood for corticosteroid

(cortisol) assay.


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Tetracosactrin test

Interpretation: (values may be given in nmol/L)

In a normal subject the baseline value is morethan 7 g /100ml and there is an increase of atleast 10 g / 100ml over the baseline at 30min

In Addisons disease there is a low baseline andless than 5g / 100ml response to tetracosactrin

In hypopituitarism there may be a subnormal riseat 30min

In Cushings syndrome (hyperplasia) there may bean exaggerated response. This does not occurwhen there is a tumour

D t P l d ACTH


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Depot or Prolonged ACTH

stimulation..1

This gives a greater stimulus than theTetracosactrin test

Method. Control period: Collect a 24h

specimen of urine for corticosteroid analysis(0800h -0800h)

First test day: At 0800h and 2000h inject S.C.50u of ACTH gel

Second and third days: Repeat the injectionsand urine collection as on the first day


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Prolonged ACTH stimulation..2

Interpretation

In a normal adult there is a rise incorticosteroid excretion over the control value

of at least about 30 mg /24h by the second orthird test days

In Cushings syndrome due to hyperplasia,there is often an exaggerated response over60 mg /24h. This does not occur if there is atumour


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Prolonged ACTH stimulation..3

Interpretation

In Addisons disease, there is usually a low

value for the control excretion followed by an

absent or very low rise

In hypopituitarism there is usually a delayed

rise


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Dexamethasone suppression test..1

Dexamethasone is a synthetic steroid whichinhibits ACTH secretion and suppresses theplasma and urinary corticosteroids in normalsubjects

The test is used to differentiate adrenalhyperplasia from tumour

Method

Collect 24h urine samples for baseline

corticosteroid estimation for 2 days (days 1 & 2) Collect blood samples for baseline corticosteroid

estimation at 0900h for 2 days (days 1 & 2)


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Dexamethasone is given 6 hourly in 0.5 mg oral

doses for 8 doses (days 3 & 4) followed by 2 mg

oral doses 6 hourly for 8 doses (days 5 & 6)

24 h urine samples are collected forcorticosteroid estimations while on

dexamethasone (days 3, 4, 5, & 6)

Blood samples are collected for corticosteroidassays preceding the dexamethasone doses on

days 4,5,6 and 7


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Interpretation

In a normal subject, the urine and plasmacorticosteroids are suppressed on the lower

dosage below 50% of the baseline values. On the lower dose of dexamethasone, patients

with Cushings syndrome will show nosuppression irrespective of the cause

On the higher dose, those with hyperplasia, havea 50% or more suppression, while those withadenoma or carcinoma are unaffected


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Metyrapone Test..1

Metyrapone (Metapirone) blocks the actions ofthe enzyme 11 hydroxylase in the adrenalcortex, thus inhibiting cortisol synthesis.

This triggers the feed-back mechanism, causingexcess ACTH secretion.

The result is excess adrenocortical secretion of11-deoxycortisol, which is measured as a urinary

corticosteroid. The test is used for investigating hypothalamic or

anterior pituitary deficiency


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Metyrapone Test..2

Method:

Collect 24-h urine samples for baselinecorticosteroid estimation for two days (days 1

& 2) Metyrapone is given 4 hourly in 750mg oral

doses for 6 doses (day 3)

Collect 24-h urine samples for corticosteroidestimation on day of and after Metyraponeadministration (days 3 & 4)


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Metyrapone Test..3

Interpretation

A normal subject shows an increase in urine

corticosteroid values of at least 10 mg /24 h or a

two-fold increase above the resting level. A subnormal response in the presence of normal

adrenocortical function shows deficiency at the

level of hypothalamus or anterior pituitary Patients with autonomous tumours of the

adrenal cortex fail to show a response

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Gluco Corticoids r 1 Ff 2