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MD1 endocrinologie > Les surrénales > Flashcards

Les surrénales Flashcards

1
Q

What is the embryological origin of the adrenal cortex?

A

Mésoderme

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2
Q

What is the embryological origin of the adrenal medulla?

A

Ectoderme

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3
Q

Different stages of fetal adrenal development:

A

5th week: endocrine cells

6th week: start of steroidogenesis

8th week: formation du médulla (envahissement du cortex pas des cellules de la crête neurale sytpathique)

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4
Q

Anatomy of the adrenal glands:

A

Artères: supra-rénales

Veines: surrénale G et D

Cortex fibreuse

Cortex (90%)

Médulla (10%)

Masse: 8-10g each

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5
Q

Which hormones are produced in the renal cortex?

A

Zona glomerulosa –> Aldostérone (minéralocorticoïde)

Zona fasciculata –> Cortisol (glucocorticoïde)

Zona reticularis –> androgènes et cortisol

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6
Q

Which hormones are produced in the renal medulla?

A

catecholamines

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7
Q

How is CRH stimulated?

A

Circadian cycle

Stress:

  • Illness/fever
  • Trauma, shock, pain
  • Hypoglycemia
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8
Q

How is ACTH stimulated?

A

CRH

AVP (role –> unknown)

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9
Q

Cortisol and the circadian cycle:

A

Cortisol has a pulsatile secretion just like CRH –> ACTH

Cortisol levels:

  • Max: 4-8 am
  • Lower progressively throughout the day
  • Min (Nadir): around midnight
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10
Q

How is ACTH created?

A

Polypeptide hormones created by corticotropic cells in the anterior pituitary

Generated by the cleavage of POMC which forms:

  • ACTH
  • Endorphins
  • MSH –> stimulates melanocytes
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11
Q

What are the effects of ACTH?

A

G-coupled protein receptor –> adenylate cyclase/cAMP –> kinase A –> STAR activation (steroid acute regulatory peptide) –> synthesis of steroid hormones

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12
Q

How are “hormones cortico-surrénaliennes” synthesized?

A

All formed from cholesterol

StAR is activated by ACTH

Cholesterol towards internal paroi of mitochondria

Enzymatic modifications by cytochrome P 450 oxygénase (CYP)

Rate limiting step –> conversion of cholesterol into pregnenolone (p450scc)

Each zone within the cortex has specific enzymes to make the necessary hormones

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13
Q

Physiology of cortisol:

A

Circulating cortisol:

  • 10% free (inactive)
  • 75% to CBG (cortisol binding globulin)
  • 15% to albumin

95% of cortisol conjugated in the liver

Free and conjugated is eliminated in urine

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14
Q

What conditions increase CBG levels?

A

Estrogen/oral contraceptives

Pregnancy

HyperT4

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15
Q

What conditions decrease CGB levels?

A

Insuff. hépatique

Syndrome néphrotique

HypoT4

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16
Q

What do serum cortisol levels indicate?

A

Total cortisol levels

  • Max: 6-8h, min: 24h
  • Plusieurs pics alors assez imprécis
  • Impacted by CBG levels
  • Useful for dépistage d’insuffisance surrénalienne si bas dans le matin
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17
Q

What do urinary cortisol levels indicate?

A

Free cortisol levels

  • Not affected by CGB levels
  • Allow evaluation of 24-hour production
  • Useful for evaluat9ing hypercorticisme

Cortisol salivaire aussi (dépister excès cortisol si élevé à minuit)

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18
Q

What is the “test de suppression à la dexméthasone” and how does it work?

A

Dexamethasone given at 23h the night before, blood test at 8AM

Since dexamethasone should activate the “boucle de contre-régulation” which inhibits CRH/ACTH

Dexa doesn’t influence cortisolémie therefore all of the cortisol measured is endogène

USEFUL FOR HYPERCORTICISM

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19
Q

What stimulation tests are available for cortisol? and how do they work?

A
  1. Glycémie à l’insuline:
    • Glycémie < 2.2 should be considered a stress and increase cortisol levels
    • Helps verify the axe centrale (see if CRH and ACTH are reacting to changes)
      • If no response: SECONDARY AND TERTIARY –> CENTRAL
  2. Test au CRH:
    • Injection with CRH to test pituitary.. should cause a release in ACTH
      • If no response: SECONDARY
  3. Stimulation au cortrosyn:
    • Inject synthetic ACTH which should cause a release in cortisol
      • If no response: PRIMARY

LOOKING FOR CORTISOL LEVELS > 500 after stimulation

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20
Q

Glucocorticoid receptors:

A

Steroid receptors –> intracytoplasmic receptors (therefore migration towards the nucleus and activation of gene transcription)

Found virtually in all cell types

Responsible for the majority of cortisol’s effects

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21
Q

Mineralocorticoid receptors:

A

Binds to aldosterone and DOC and a bit of cortisol

Steroid receptor but mostly found in the kidneys

Possible endothelial cell and cardiac effects and can cause:

  • Rétention hydro-sodée et exceétion du K+
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22
Q

What is the “shunt cortisol-cortisone”?

A

Active cortisol –> inactivated by 11B-HSD2 in the kidneys to protect MR rénaux

Le cortisol est inactivé en cortisone par la 11B-HSD2 a/n du rein

This mechanism can be inhibited/altered in certain pathologies

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23
Q

What are the physiological effects of cortisol?

A

Hormone stimulated by STRESS:

  • maladie, hypoglycémie, jeune/épargne énergétique, hypovolémie, trauma

General effects:

  • catabolic > anabolic
  • suppression of other hormones
  • anti-inflammatory and immunosuppression
  • hypertension (via MR –> pathological +++)
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24
Q

Metabolic effects of cortisol on glucose and lipids:

A

Glucose:

  • Increased neoglucogenesis (liver)
  • Increased glycogen synthesis (liver)
  • Increased insulin resistance (liver, muscles, adipocytes)
  • Increase blood glucose levels

Lipids:

  • Increased lipolysis (glycerol, acides gras libres)
  • Increased adipogenesis (insulin resistance, weight gain)
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25
Q

Cardio-vascular effects of cortisol on glucose and lipids:

A

Cardiac:

  • Increased débit cardiaque
  • Increased peripheral resistance
  • Increased activity and regulation of adrenergic receptors

Renal:

  • Principally via MR
  • Retention Na+
  • Retention H2O
  • Hypokalemia

Long term increase of TA –> HVG

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26
Q

Cutaneous effects of cortisol:

A

Decreased fibroblast activity

Decreased collagen and conjunctive tissue

Consequences:

  • Peau mince
  • Ecchymosis
  • Decreased scarring and increased healing time
  • Vergetures pourpres
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27
Q

Osseous effects of cortisol:

A
  • Decreased intestinal absorption of Ca2+
  • Decreased renal reabsorption of Ca2+
  • Increased PTH
  • Increased osteoclast and decreased osteoblast action

Consequences:

  • Osseous reabsorption/micro-architecture modification
  • Osteoporosis and pathological fractures –> brittle bones
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28
Q

Hematological and immune system effects of cortisol:

A

FSC:

  • Increased hematopoiesis
  • Increase leucocytes (PMN)
    • Moelle osseuse
    • Démargination
    • Survie
  • Decreased monocytes, lymphocytes, and eosinophils

Anti-inflammation: decreased cytokines, and IL-1/PGs

Immunosuppresseur:

  • Decreased cellular immunity
  • Decreased humoral immunity (antibodies)
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29
Q

Effect of cortisol on the axe somatotrope:

A

Decrease GHRH and GH and IGF-1 production (foie)

Consequences:

  • Decreased growth
  • Increased truncal obesity (weight gain and visceral fat)
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30
Q

Effect of cortisol on the axe gonadotrope:

A

Decrease GHRH and GH and IGF-1 production (foie)

Consequences:

  • Decreased growth
  • Increased truncal obesity (weight gain and visceral fat)
  • Hypogonadism
    • H: decrease libido, erectile function, gynecomastia
    • F: oligo/amenorrhea
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31
Q

Effect of cortisol on the axe thyréotrope:

A

Decrease TRH and TSH

Decrease conversion of T4 –> T3

BUT the effects aren’t really noticible

32
Q

Effects of cortisol on the SNC/psy:

A

Anxiety

Insomnia

Emotional liability

Depression

Euphoria/psychosis

Decreased cognitive function

33
Q

Effects of cortisol on gastro and opthalmo:

A

Opthalmo:

  • Cataracts
  • Intra-ocular pressure
  • Chorioretinopathy

Gastro: observed dim. of gastric protection but not proven yet

34
Q

Physiology of adrenal androgens

A

Regulated equally by ACTH

Synthesized in the zone réticulaire

DHEA and androstènedione are transformed into testosterone in the body

DHEA-S –> circulating In the blood and a stable amount of androgens

  • Approximately 50 to 70% of circulating DHEA originates from the desulfation of DHEA-S in peripheral tissues
  • DHEA-S itself originates almost exclusively from the adrenal cortex
35
Q

How are adrenal androgens measured?

A

CAREFUL WITH DOSAGE AND WHEN IT IS DONE

Surrénaliens:

  • DHEA-S
  • Androstènedione
  • 17-OH-progesterone
    • Can be source of error and should be measured in the “phase folliculaire” –> first couple days of ovulation
    • Should be low but if inc. could could be sign of a problem

Total:

  • Testosterone (total)
  • SHBG
36
Q

What is the form of circulating androgens?

A

60% bound to SHBG

38% bound to albumin

< 2% libre

37
Q

What is the biological effect of androgènes surrénaliens in men?

A

< 5% of androgenic effects

Excess –> quite negligible unless it’s in children, then it’ll cause early puberty

38
Q

What is the biological effect of androgènes surrénaliens in women?

A

IMPORTANT contribution to androgenic effets:

  • 70% during phase folliculaire
  • 40% ovulatoire car aug. production d’origine ovarienne

Excess –> hirsutism, oligo/amenorrhea, virilisation (development of male physical characteristics)

39
Q

How is aldosterone regulated?

A

Main –> AG2 (SRAA) and K+

  • SRAA stimulated by hypotension
  • K+ via macula densa

Secondary –> ACTH

Synthesized in the zona glomérulosa (aldostérone synthase –> last enzyme)

40
Q

How does aldosterone work?

A

via mineralocorticoid receptor on distal renal tubules:

  • Increase Na+ and H2O reception
  • Decrease K+ reabsorption
41
Q

How are mineralocorticoids metabolized?

A

In circulation:

  • Bound to CBG (faible)
  • Aldostérone libre –> 30-50%

Very short half-life (15-20 mins) and degraded in the liver

Eliminated in urine (aldo and its metabolites)

Aldo and DOC (salty) have similar affinities for mineralocorticoid receptors (MRs)

42
Q

How is aldosterone measured?

A

Seric: must also measure renin and use a ratio to normalize

Aldo urinaire 24 hours (useful for excess)

43
Q

Dynamic testing for aldosterone:

A

Suppression testing:

  • Salt overload
    • If PO –> supprime aldo urinaire
    • If IV –> supprime aldo sérique
  • Captopril (IECA): Inhibits SRA which should decrease aldo
  • Adrenal vein sampling: blood samples are taken from both adrenal glands to compare the amount of hormone made by each gland
44
Q

Embryogenesis of the medulla:

A
45
Q

Physiology of catécholamines:

A

Mostly regulated by the SNS

Most common precursor –> Tyrosine

Converted into Epi and Norepi by PNMT

Stored in granules called chromogranins

Stress induces degranulation

In circulation: bound weakly to albumin

Very short half-life in circulation (metabolized in liver) and in cells (COMT and MAO)

Excreted in urine (metabolites and catecholamines)

Dosing: collecte urinaire 24 heures

46
Q

What are the systemic effects of catecholamines?

A

Act via adrenergic receptors

Regulate TA

Counter regulate hypoglycemia:

  • Glycogénolyse (foie, muscle)
  • Néoglucogenèse (foie)
  • Lipolyse (adipocytes)
47
Q

Review of adrenal hormones:

A
48
Q

What are the most common symptoms of adrenal insufficiency?

A
  • Fatigue/feeble
  • N/V
  • Abdominal pain
  • Hypoglycemia
  • Anorexia
  • Hypotension/shock/orthostatic
  • Salt craving
  • Androgen deficit –> decreased axial/pubic hair, decreased libido
49
Q

What are the most common signs of adrenal insufficiency?

A

Anorexia

Hyperthermia

Tachy/hypoTA/HTO

Cutaneous hyperpigmentation (IS primaire –> ACTH production –> MSH)

Generalized muscular weakness

Abdominal pain

50
Q

How to treat an adrenal crisis (choc surrénalien)?

A

THIS IS AN EMERGENCY!

  1. Replace glucocorticoids
    • Solucortef 100mg IV (100mg/m2 for peds)
    • 50mg IV 1.6-8h after
  2. NaCl 0.9% IV
  3. Correct hypoglycemia (IV dextrose)
  4. Identify/treat cause
  5. Chronic treatment once the situation has stabilized
51
Q

How to treat chronic adrenal insufficiency?

A

Replace glucocorticoids (Corfef 15mg AM and 10mg PM)

Replace mineralocorticoids (Florinef 0.1mg po AM PRN)

Medic-alert bracelet

Teach patients to recognize symptoms and adjust medication:

  • Increase doses 2-3x if fever or sick+++ (x24-48h)
  • Consult urgent care if vomiting prevents taking medication
    • IV infusion
52
Q

Glucocorticoid and mineralocorticoid doses and effects:

A
53
Q

Primary vs secondary adrenal insufficiency:

A
54
Q

Blood test levels during primary vs central adrenal insufficiency:

A
55
Q

What dynamic tests are available to confirm adrenal insufficiency? (2)

A

Cortrosyn 250mcg IV (huge dose of ACTH)

  • Try to stimulate cortisol production
  • If it stays < 500 –> shows primary

Hypoglycemia (insulin –> gold standard but not as accessible)

  • Verifies the whole axe
  • Get glycemia < 2.5 mmol/L and Cortisol < 500nmol/L means there is something wrong
  • RISK FACTORS: EPILEPSY OR RECENT MCAS/MVAS EVENT ARE C-Is
56
Q

What are the causes of destructive primary renal insufficiency?

A

Auto-immune (Addison’s)

Auto-immune polyglandular syndrome (2 kinds)

Adrénoleucodystrophie

Other causes:

  • Thromboembolic
  • Hemorrhage
  • Infectious (ex: TB)
  • Neoplasia
  • Infiltration
57
Q

What are the causes of primary renal insufficiency (synthesis)?

A

Steroidogenesis anomalies

Congenital adrenal hyperplasia (Block 21-hydroxylase)

Medications

Other causes:

  • Cortisol resistance
  • Familial glucocorticoid deficiency
  • Congenital hypoplasia
58
Q

What is Addison’s disease?

A

Most frequent cause of primary adrenal insufficiency

1/15-25 000

3F:1H

Diagnosis typically between 30-40 years old

59
Q

What is the pathophysiology of Addison’s disease?

A

Antibodies (anti0210hydroxylase) destroy cortex (medulla remians intact)

Sx start once > 90% destruction

Often caused by trauma/infection

Glucocorticoid deficit usually before mineralocorticoid

60
Q

What are auto-immune polyglandular syndromes (APS)?

A

Association of many auto-immune endocrine pathologies

Causes non-endocrine auto-immune manifestations

Different “atteintes” don’t all happen at once… can be spread out over multiple years

61
Q

What is APS type 1?

A

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy

(APECED)

Mutation of AIRE gene

Autosomal recessive and starts early in childhood under 10 years old

Classic triad: >75% of cases

  • Candidiase mucocutanée chronique
  • HypoPTH
  • Addison’s disease
62
Q

What are the manifestations of APECED?

A

Endocrine:

  • Insuff. ovarienne (50%)
  • HypoT4 (<10%)
  • Db type 1 (<5%)
  • Hypophysite (<1%)

Others:

  • Alopecia, hepatitis, vitiligo, pernicious anemia, nail dysplasia, keratoconjontivitis
63
Q

What is APS type 2?

A

Schmidt syndrome

Pathophysiology:

  • Polygenic etiology (HLA)
  • F > H
  • Dx during adolescence or adulthood
  • Most frequent form of APS

Classic triad:

  • Addison’s
  • HypoT4
  • Db type 1
64
Q

What are the manifestations of APS-2?

A

Endocrine:

  • Ins. ovarienne (50%)
  • HypoPTH (rare)

Other:

  • Vitiligo (4%)
  • Pernicious anemia, myasthenia gravis, PTI, Sjogren syndrome, rheumatoid arthritis (<1%)
65
Q

What is adrénoleucodystrophie?

A

Degenerative disease of white matter (demyelinisation)

Mutation on X chromosome –> therefore only in men (1/25 000)

Second most common cause of adrenal insufficiency in men

Mechanism:

  • Deficient B-oxidation
  • Accumulation of long chains of fatty acids (toxic)
    • In: SNC, adrenal glands, testicles, liver
66
Q

Clinical presentation of adrénoleucodystrophie:

A

30% have adrenal sx before neurological sx

Depistage necessary in all young men with ISP

  • Genetic testing
  • Accumulation of C26:0 chains (surrénales)

LARGE spectrum of sx:

  • Can be asx
  • Can just be Addison’s
  • Adrénomyéloneuropathie (20-30 years old)
    • Balance issues and progressive cognitive decline
  • Severe infantile form
    • Paraplegic, blind, deaf
67
Q

What are some other destructive causes of ISP?

A

Infectious:

  • Tb
  • CMV
  • VIH
  • Histoplasmosis
  • Coccidioidomycosis

Metastatic cancers: breasts, lung, GI, kidney

Infiltrative:

  • Amyloidosis
  • Hemochromatosis
  • Sarcoidosis
68
Q

What is congenital adrenal hyperplasia (CAH)?

A

An autosomal recessive genetic disorder that causes defective cortico-adrenal synthesis

  • Mutation that inactivates 21-hydroxylase (>90% of cases)
    • Decreased cortisol and aldosterone synthesis
    • Accumulation of 17-OH-progesterone leads to an increase in androgen synthesis
  • Increased ACTH
  • Secondary hyperplasia of adrenals
69
Q

+++ 21-hydroxylase blockage in CAH:

A

Salt-wasting:

  • At birth
  • Crise surrénalienne
  • HypoNa+, hyperK+, acidosis, dehydration
  • Sexual ambiguity (F)
70
Q

Moderate 21-hydroxylase blockage in CAH:

A

Simple virilisante (20%)

  • Childhood
  • No crise surrénalien
  • Virilisation et croissance rapide
  • Ambiguïté sexuelle possible (F)
71
Q

Low 21-hydroxylase blockage in CAH:

A

Non-classique (tardive)

  • (F) during adolescence and adulthood
  • Oligomenorrhea, hirsutism, infertility
72
Q

How is CAH diagnosed?

A

Clinical:

  • Sexual ambiguity
  • Crise surrénalienne (naissance)
  • Virilisation, hirsutism

Labs:

  • Increased 17-OH-progesterone levels
  • Low cortisol or sub-obtimal cortrosyn
  • DHEA-S, androstènedione
  • Rénine, aldostérone
  • Recherche de mutations génétiques (dépistage)

Imagerie:

  • Increased adrenal size (hyperplasia)
73
Q

How to treat CAH?

A

Depending on severity –> replacement therapy

  • Glucocorticoids –> lower ACTH levels
  • Mineralocorticoids
74
Q

What are some other causes of corticosteroid synthesis/resistance anomalies?

A

Medications:

  • Synthesis inhibitors: antifungal rx
  • Metabolism inhibitors: anticonvulsive rx
  • Receptor antagonists: spironolactone (MR)
  • Others: etomidate, metyrapone, mitotane

Familial GC deficit:

  • Rare/autosomal recessive
  • Resistance to ACTH (receptor)
  • Primary hypocorticocism
  • Déficit MC rare (<25%)

Resistance to cortisol:

  • Central cortisol resistance
  • Increased CRH, ACTH, and circulating cortisol
  • Usually asx
75
Q

Causes of secondary/tertiary adrenal insufficiency:

A

SNC tumours: macroadenomas, craniopharyngiomas, dysgerminomas, meningiomas, gliomas

Radiotherapy

Infiltration: sarcoidosis, histiocytosis, hemochromatosis

Corticotherapy: #1 cause… PO, IV, inhalé, topique, dépôt (inhibent l’axe)

Inflammatory: lymphocytic hypophysitis

Vascular/hemorrhagic: apoplexia, AVC thalamique

Trauma/Fx du plancher sphénoide

Infectious: Tb

Congénital: dysplasia, anomalies du ligne médiane, isolés ou multiples

76
Q

What are the effects of chronic corticotherapy?

A

Central negative feedback

Loss of sensibility to CRH and ACTH

Adrenal atrophy

Can cause ISC –> can cause primary if long term

Usually takes > 3 months for sx to appear but can happen in > 3 weeks if high doses

Sevrage necessaire

Other things to monitor:

  • Osteoporosis
  • Dyspepsia and ulcers
  • Weight gain
  • Dysglycemia
77
Q

How to dx secondary/tertiary IS?

A

ALWAYS ASK ABOUT CORTICOSTEROIDS

Caracteristics:

  • Isolated glucocorticoid insuff.
  • Deficit of MC absent because SRAA is still working
  • No hyperpigmentation

Bilans:

  • Cortisol low/N-low
  • ACTH also low
  • No response to hypoglycemia
  • Cortrosyn can be normal if recent but can be abnormal if atrophy

Usually merits imagery:

  • IRM of pituitary –> TDM si IRM C-I
  • IRM/TDM central

MD1 endocrinologie (6 decks)

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