Les surrénales Flashcards
(77 cards)
1
Q
What is the embryological origin of the adrenal cortex?
A
Mésoderme
2
Q
What is the embryological origin of the adrenal medulla?
A
Ectoderme
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)
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
5
Q
Which hormones are produced in the renal cortex?
A
Zona glomerulosa –> Aldostérone (minéralocorticoïde)
Zona fasciculata –> Cortisol (glucocorticoïde)
Zona reticularis –> androgènes et cortisol
6
Q
Which hormones are produced in the renal medulla?
A
catecholamines
7
Q
How is CRH stimulated?
A
Circadian cycle
Stress:
- Illness/fever
- Trauma, shock, pain
- Hypoglycemia
8
Q
How is ACTH stimulated?
A
CRH
AVP (role –> unknown)
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
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
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
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
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
14
Q
What conditions increase CBG levels?
A
Estrogen/oral contraceptives
Pregnancy
HyperT4
15
Q
What conditions decrease CGB levels?
A
Insuff. hépatique
Syndrome néphrotique
HypoT4
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
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)
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
19
Q
What stimulation tests are available for cortisol? and how do they work?
A
-
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
-
Test au CRH:
- Injection with CRH to test pituitary.. should cause a release in ACTH
- If no response: SECONDARY
- Injection with CRH to test pituitary.. should cause a release in ACTH
-
Stimulation au cortrosyn:
- Inject synthetic ACTH which should cause a release in cortisol
- If no response: PRIMARY
- Inject synthetic ACTH which should cause a release in cortisol
LOOKING FOR CORTISOL LEVELS > 500 after stimulation
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
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+
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
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 +++)
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)
25
Cardio-vascular effects of cortisol on glucose and lipids:
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**
26
Cutaneous effects of cortisol:
Decreased fibroblast activity
Decreased collagen and conjunctive tissue
**Consequences:**
* Peau mince
* Ecchymosis
* Decreased scarring and increased healing time
* Vergetures pourpres
27
Osseous effects of cortisol:
* 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
28
Hematological and immune system effects of cortisol:
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)
29
Effect of cortisol on the axe somatotrope:
Decrease GHRH and GH and IGF-1 production (foie)
Consequences:
* Decreased growth
* Increased truncal obesity (weight gain and visceral fat)
30
Effect of cortisol on the axe gonadotrope:
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
31
Effect of cortisol on the axe thyréotrope:
Decrease TRH and TSH
Decrease conversion of T4 --\> T3
BUT the effects aren't really noticible
32
Effects of cortisol on the SNC/psy:
Anxiety
Insomnia
Emotional liability
Depression
Euphoria/psychosis
Decreased cognitive function
33
Effects of cortisol on gastro and opthalmo:
**Opthalmo:**
* Cataracts
* Intra-ocular pressure
* Chorioretinopathy
**Gastro:** observed dim. of gastric protection but not proven yet
34
Physiology of adrenal androgens
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
How are adrenal androgens measured?
**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
What is the form of circulating androgens?
60% bound to SHBG
38% bound to albumin
\< 2% libre
37
What is the biological effect of androgènes surrénaliens in men?
\< 5% of androgenic effects
Excess --\> quite negligible unless it's in children, then it'll cause early puberty
38
What is the biological effect of androgènes surrénaliens in women?
**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
How is aldosterone regulated?
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
How does aldosterone work?
via mineralocorticoid receptor on distal renal tubules:
* Increase Na+ and H2O reception
* Decrease K+ reabsorption
41
How are mineralocorticoids metabolized?
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
How is aldosterone measured?
**Seric**: must also measure renin and use a ratio to normalize
Aldo urinaire 24 hours (useful for excess)
43
Dynamic testing for aldosterone:
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
Embryogenesis of the medulla:
45
Physiology of catécholamines:
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
What are the systemic effects of catecholamines?
Act via adrenergic receptors
Regulate TA
Counter regulate hypoglycemia:
* Glycogénolyse (foie, muscle)
* Néoglucogenèse (foie)
* Lipolyse (adipocytes)
47
Review of adrenal hormones:
48
What are the most common symptoms of adrenal insufficiency?
* Fatigue/feeble
* N/V
* Abdominal pain
* Hypoglycemia
* Anorexia
* Hypotension/shock/orthostatic
* **Salt craving**
* Androgen deficit --\> decreased axial/pubic hair, decreased libido
49
What are the most common signs of adrenal insufficiency?
Anorexia
Hyperthermia
Tachy/hypoTA/HTO
Cutaneous hyperpigmentation (IS primaire --\> ACTH production --\> MSH)
Generalized muscular weakness
Abdominal pain
50
How to treat an adrenal crisis (choc surrénalien)?
**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
How to treat chronic adrenal insufficiency?
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
Glucocorticoid and mineralocorticoid doses and effects:
53
Primary vs secondary adrenal insufficiency:
54
Blood test levels during primary vs central adrenal insufficiency:
55
What dynamic tests are available to confirm adrenal insufficiency? (2)
**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
What are the causes of destructive primary renal insufficiency?
Auto-immune (Addison's)
Auto-immune polyglandular syndrome (2 kinds)
Adrénoleucodystrophie
Other causes:
* Thromboembolic
* Hemorrhage
* Infectious (ex: TB)
* Neoplasia
* Infiltration
57
What are the causes of primary renal insufficiency (synthesis)?
**Steroidogenesis anomalies**
Congenital adrenal hyperplasia (Block 21-hydroxylase)
Medications
Other causes:
* Cortisol resistance
* Familial glucocorticoid deficiency
* Congenital hypoplasia
58
What is Addison's disease?
Most frequent cause of primary adrenal insufficiency
1/15-25 000
3F:1H
Diagnosis typically between 30-40 years old
59
What is the pathophysiology of Addison's disease?
Antibodies (anti0210hydroxylase) destroy cortex (medulla remians intact)
Sx start once \> 90% destruction
Often caused by trauma/infection
Glucocorticoid deficit usually before mineralocorticoid
60
What are auto-immune polyglandular syndromes (APS)?
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
What is APS type 1?
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
What are the manifestations of APECED?
**Endocrine:**
* Insuff. ovarienne (50%)
* HypoT4 (\<10%)
* Db type 1 (\<5%)
* Hypophysite (\<1%)
**Others:**
* Alopecia, hepatitis, vitiligo, pernicious anemia, nail dysplasia, keratoconjontivitis
63
What is APS type 2?
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
What are the manifestations of APS-2?
**Endocrine:**
* Ins. ovarienne (50%)
* HypoPTH (rare)
**Other:**
* Vitiligo (4%)
* Pernicious anemia, myasthenia gravis, PTI, Sjogren syndrome, rheumatoid arthritis (\<1%)
65
What is adrénoleucodystrophie?
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
Clinical presentation of adrénoleucodystrophie:
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
What are some other destructive causes of ISP?
**Infectious**:
* Tb
* CMV
* VIH
* Histoplasmosis
* Coccidioidomycosis
**Metastatic cancers**: breasts, lung, GI, kidney
**Infiltrative**:
* Amyloidosis
* Hemochromatosis
* Sarcoidosis
68
What is congenital adrenal hyperplasia (CAH)?
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
+++ 21-hydroxylase blockage in CAH:
Salt-wasting:
* At birth
* Crise surrénalienne
* HypoNa+, hyperK+, acidosis, dehydration
* Sexual ambiguity (F)
70
Moderate 21-hydroxylase blockage in CAH:
Simple virilisante (20%)
* Childhood
* No crise surrénalien
* Virilisation et croissance rapide
* Ambiguïté sexuelle possible (F)
71
Low 21-hydroxylase blockage in CAH:
Non-classique (tardive)
* (F) during adolescence and adulthood
* Oligomenorrhea, hirsutism, infertility
72
How is CAH diagnosed?
**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
How to treat CAH?
Depending on severity --\> replacement therapy
* Glucocorticoids --\> lower ACTH levels
* Mineralocorticoids
74
What are some other causes of corticosteroid synthesis/resistance anomalies?
**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
Causes of secondary/tertiary adrenal insufficiency:
**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
What are the effects of chronic corticotherapy?
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
How to dx secondary/tertiary IS?
**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
