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Endocrinology > Adrenal Cortex > Flashcards

Adrenal Cortex Flashcards

1
Q

What is adrenocorticotropic hormone, what is it regulated by and what does it do

A
  • a polypeptide (cleaved from prohormone POMC), secreted in a pulsatile fashion from the anterior pituitary with diurnal variability (peak: 0200-0400; trough: 1800-2400)
  • secretion regulated by corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP)
  • stimulates growth of adrenal cortex and release of glucocorticoids, androgens and, to a limited extent, mineralocorticoids
  • some melanocyte stimulating activity
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2
Q

Describe the CRH-ACTH-adrenal gland axis

A

Dec blood glucose, trauma, infection, emotion, circadian rhythm –>

CNS –>

Hypothal –> CRH and AVP –>

Pituitary –>
ACTH –>

Adrenal gland –>
Cortisol

Cortisol inhibits pituitary production of ACTH, hypothalamus production of CRH and AVP and CNS

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3
Q

What is aldosterone, what is it regulated by and what does it do

A
  • a mineralocorticoid which regulates extracellular fluid (ECF) volume through Na+ (and Cl–) retention and K+ (and H+) excretion (stimulates distal tubule Na+/K+ ATPase)
  • regulated by the renin-angiotensin-aldosterone system
  • negative feedback to juxtaglomerular apparatus (JGA) by long loop (aldosterone inc volume expansion) and short loop (angiotensin II inc peripheral vasocon-striction)
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4
Q

Layers of the adrenal cortex from outside to inside

A

Zona Glomerulosa produces mineralocorticoids (aldosterone)

Zona Fasciculata produces glucocorticoids (cortisol)

Zona Reticularis produces androgens (DHEA, androstenedione)

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5
Q

Renin-angiotensin-aldosterone axis

A

Dec volume, arterial pressure and Na delivery to macula densa, prostaglandins and sympathetic stimulation –> stimulation of JGA –> Renin (kidney)

Angiotensinogen is acted on by renin –>

Angiotensin 1 which is acted on by angiotensin converting enzyme (lung and kidney) –>

Angiotensin II (with negative feedback to inhihbit JGA) –>

Aldosterone release, arteriolar vasoconstriction and promotion of ADH release –>

Renal Na, retention, K excretion

Increased volume, arterial pressure, dopamine and renal Na retention –> inhibition of JGA

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6
Q

What is cortisol and what does it do

A
  • a glucocorticoid, regulated by the HPA axis
  • involved in regulation of metabolism; counteracts the effects of insulin
  • support blood pressure, vasomotor tone
  • also involved in regulation of behaviour and immunosuppression
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7
Q

Physiological effefcts of glucocorticoids

A

Stimulatory effects -
Glucose: Stimulate hepatic glucose production (gluconeogenesis)
Increase insulin resistance in peripheral tissues
Protein: Increase protein catabolism
White count: Stimulate leukocytosis and lymphopenia
Weight gain: Increase cardiac output, vascular tone, Na retention
Bone density: Increase PTH release, urine calcium excretion

Inhibitory effects
Bone density: Inhibit bone formation, stimulate bone resorption
Skin: Inhibit fibroblasts causing collagen and connective tissue loss
Immune: Suppress inflammation, impair cell-mediated immunity
Growth: Inhibit growth hormone axis
Repro: Inhibit reproductive axis
Vitamins: Inhibit vitamin D3 and calcium uptake

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8
Q

What are androgens, what are they regulated by and what do they do

A
  • sex steroids regulated by ACTH; primarily responsible for adrenarche (growth of axillary and pubic hair)
  • principal adrenal androgens are dihydroepiandrosterone (DHEA), androstenedione, and 11-hydroxyandrostenedione
  • proportion of total androgens (adrenal to gonadal) increases in old age
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9
Q

Adrenocortical functional workup

A

Stimulation test to diagnose hormone deficiencies by measuring target hormone after stimulation with tropic (pituitary) hormone

1 . Tests of Glucocorticoid Reserve
• Cosyntropin (ACTH analogue) Stimulation Test
■ give 1 µg or 250 µg cosyntropin IV, then measure plasma cortisol levels at time 0, 30, and 60 min
■ physiologic response: stimulated plasma cortisol of >500 nmol/L
■ inappropriate response: inability to stimulate increased plasma cortisol
• insulin tolerance is the gold standard test used to diagnose adrenal insufficiency

Suppression tests to diagnose hormone hypersecretion by measuring target hormone after suppression of its tropic (pituitary) hormone

1 . Tests of Pituitary-Adrenal Suppressibility
Dexamethasone (DXM) Suppression Test
■ principle: DXM suppresses pituitary ACTH, plasma cortisol should be lowered if HPA axis is normal
■ Screening Test: Overnight DXM Suppression Test
◆ oral administration of 1 mg DXM at midnight measure plasma cortisol levels the following day at 8 am
◆ physiologic response: plasma cortisol <50 nmol/L, with 50-140 nmol/L being a “grey zone” (cannot be certain if normal or not)
◆ inappropriate response: failure to suppress plasma cortisol
◆ <20% false positive results due to obesity, depression, alcohol, other medications
■ Confirmatory Test: other testing is used to confirm the diagnosis, such as:
◆ 24 h urine free cortisol (shows overproduction of cortisol)
◆ midnight salivary cortisol (if available), shows lack of diurnal variation inappropriate response: remains high (normally will be low at midnight)

2 . Tests of Mineralocorticoid Suppressibility
• principle: expansion of extracellular fluid volume (ECFV); plasma aldosterone should be lowered if HPA axis is normal
• ECFV Expansion with Normal Saline (NS)
■ IV infusion of 500 mL/h of NS for 4 h, then measure plasma aldosterone levels
■ plasma aldosterone >277 pmol/L is consistent with primary hyperaldosteronsim, <140 pmol/L is normal
■ inappropriate response: failure to suppress plasma aldosterone

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10
Q

Approach to mineralocorticoid excess syndromes

A

Is there hypertension and hypokalemia?

  1. Plasma renin activity (PRA) and plasma aldosterone concentration (PAC)
a) Inc PAC and inc PRA 
PAC: PRA ratio = 10 (277 in SI units) 
Then investigate for causes of secondary hyperaldosteronism: 
Renovascular HTN 
Diuretic use 
Renin-secreting tumour 
Malignant HTN 
Coarctation of the aorta

b) Inc PAC and dec PRA
PAC: PRA ratio 20+ (555 in SI units)
PAC 15 ng/dl +
Then investigate for primary aldosteronism

c) Dec PAC and dec PRA 
Then investigate for Congenital adrenal hyperplasia 
Exogenous mineralcorticoid 
DOC-producing tumour 
Cushing's syndrome 
11-beta-HSD deficiency 
Altered aldosterone metabolism 
Liddle's syndrome 
Glucocorticoid resistance
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11
Q

Primary hyperaldosteronism definition

A

• primary hyperaldosteronism (PH): excess aldosterone production (intra-adrenal cause)

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12
Q

Secondary hyperaldosteronism definition

A

• secondary hyperaldosteronism (SH): aldosterone production in response to excess RAAS (extra-adrenal cause)

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13
Q

Types of mineralocorticoid excess syndromes

A

Primary and secondary hyperaldosteronism

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14
Q

Primary hyperaldosteronism etiologies

A

■ aldosterone-producing adrenal adenoma (Conn’s syndrome)

■ bilateral or idiopathic adrenal hyperplasia

■ glucocorticoid-remediable aldosteronism

■ aldosterone-producing adrenocortical carcinoma

■ unilateral adrenal hyperplasi

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15
Q

mineralocorticoid excess syndrome clinical features

A
  • HTN
  • hypokalemia (may have mild hypernatremia), metabolic alkalosis
  • normal K+, low Na+ in Secondary Hyperaldosteronism (low effective circulating volume leads to ADH release) edema
  • increased cardiovascular risk: LV hypertrophy, atrial fibrillation, stroke, MI
  • fatigue, weakness, paresthesia, headache; severe cases with tetany, intermittent paralysis
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16
Q

mineralocorticoid excess syndrome diagnosis

A

• investigate plasma aldosterone to renin ratio in patients with HTN and hypokalemia

Salt loading test
PH - inc urine aldosterone
SH - not performed if normal PAC/PRA

  • confirmatory testing for PH: aldosterone suppression test (demonstrate inappropriate aldosterone secretion with ECF volume expansion)
  • imaging: CT adrenal glands
17
Q

mineralocorticoid excess syndrome treatment

A
  • inhibit action of aldosterone: spironolactone, eplerenone, triamerene, amiloride (act on sodium channels)
  • surgical excision of adrenal adenoma
  • secondary hyperaldosteronism: treat underlying cause
18
Q

Cushing’s Syndrome definition

A

results from chronic glucocorticoid excess (endogenous or exogenous sources)

19
Q

Cushing’s Syndrome etiology

A

• ACTH-dependent (85%) – bilateral adrenal hyperplasia and hypersecretion due to:
■ ACTH-secreting pituitary adenoma (Cushing’s disease; 80% of ACTH-dependent)
■ ectopic ACTH-secreting tumour (e.g small cell lung carcinoma, bronchial, carcinoid, pancreatic islet cell, pheochromocytoma, or medullary thyroid tumours)

• ACTH-independent (15%)
■ long-term use of exogenous glucocorticoids
■ primary adrenocortical tumours: adenoma and carcinoma (uncommon)
■ bilateral adrenal nodular hyperplasia

20
Q

Cushing’s Syndrome clinical features

A
  • symptoms: weakness, insomnia, mood disorders, impaired cognition, easy bruising, oligo-/amenorrhea, hirsutism, and acne (ACTH dependent)
  • signs: central obesity, round face, supraclavicular and dorsal fat pads, facial plethora, proximal muscle wasting, purple abdominal striae, skin atrophy acanthosis nigricans, HTN, hyperglycemia, osteoporosis, pathologic fractures, hyperpigmentation, hyperandrogenism if ACTH-dependent
21
Q

Cushing’s Syndrome diagnosis

A
  • complete a drug history to exclude iatrogenic Cushing’s
  • perform one of:

1) 24 h urine free cortisol,
2) dexamethasone suppression test, or
3) late night salivary cortisol

  • consider reasons for a false positive (e.g. pregnancy, depression, alcoholism, morbid obesity, poorly controlled DM)
  • confirm with one of the remaining tests if necessary (do not rely on random cortisol, insulin tolerance, loperamide, or urinary 17-ketosteroid tests)
22
Q

Cushing’s Syndrome treatment

A

• adrenal
■ adenoma: unilateral adrenalectomy (curative) with glucocorticoid supplementation post-operatively
■ carcinoma: adjunctive chemotherapy often not useful (frequent metastases, poor prognosis)
■ medical treatment: mitotane, ketoconazole to reduce cortisol

• pituitary
■ trans-sphenoidal resection, with glucocorticoid supplement post-operatively
■ if surgery delayed, contraindicated or unsuccessful consider medical management ex. adrenal enzyme inhibitors, glucocorticoid receptor antagonist

• ectopic ACTH tumour (paraneoplastic syndrome): usually bronchogenic cancer (poor prognosis)
■ surgical resection, if possible; chemotherapy/radiation for primary tumour
■ medical treatment with mitotane or ketoconazole to reduce cortisol synthesis. Often required when surgery is delayed, contraindicated, or unsuccessful

23
Q

Hyperandrogenism definition

A

state of having excessive secretion of androgens (DHEA, DHEA sulfate, testosterone)

24
Q

Hyperandrogenism etiology and pathophysiology

A

Consittutional/familial - fam hx, predisposing ethnic background, premature adrenarche

Medications androgen-mediated - anabolic steroids, ACTH, androgens, progestational agents

Ovarian - 
PCOS
Ovarian hyperthecosis 
Theca cell tumours 
Pregnancy - placental sulfatase/aromatase deficiency

Adrenal -
Congenital adrenal hyperplasia
Tumours (adenoma, carcinoma)

Pituitary -
Cushing’s disease (high ACTH)
Hyperprolactinemia

25
Q

Hyperandrogenism clinical features

A

Females
• hirsutism
■ male pattern growth of androgen-dependent termina body hair in women: back, chest, upper abdomen, face, linea alba
■ Ferriman-Gallwey scoring system is used to quantify severity of hirsutism
• virlization
■ masculinization: hirsutism, temporal balding, clitoral enlargement, deepening of voice, acne
■ increase in musculature
• defeminization
■ loss of female secondary sex characteristics (i.e. amenorrhea, dec breast size, infertility)

Males
• minimal effects on hair, muscle mass, etc.
• inhibition of gonadotropin secretion may cause reduction in: testicular size, testicular testosterone production, and spermatogenesis

26
Q

Hyperandrogenism investigations

A

Testosterone, DHEA-S as a measure of adrenal androgen production

LH/FSH (commonly in PCOS >2.5)

17-OH progesterone, elevated in CAH due to 21-OH deficiency; check on day 3 of menstrual cycle with a progesterone level

For virilization: CT/MRI of adrenals and ovaries (identify tumours)

if PCOS, check blood glucose, lipids, 75 g OGTT

27
Q

Hyperandrogenism treatment

A
  • discontinue causative medications
  • antiandrogens, e.g. spironolactone
  • oral contraceptives (increase sex hormone binding globulin, which binds androgens>estrogens; reduce ovarian production of androgens)
  • surgical resection of tumour
  • low dose glucocorticoid ± mineralocorticoid if CAH suspected
  • treat specific causative disorders, e.g. tumours, Cushing’s, etc. • cosmetic therapy (laser, electrolysis)
28
Q

Conditions that do NOT represent true hirsutism

A
  • Androgen-independent hair (e.g. lanugo hair)
  • Drug-induced hypertrichosis (e.g. phenytoin, diazoxide, cyclosporine, minoxidil)
  • Topical steroid use
29
Q

Adrenocortical insufficiency definition

A

state of inadequate cortisol and/or aldosterone production by the adrenal glands

30
Q

Primary Adrenocortical insufficiency (Addison’s Disease) etiology

A

Autoimmune (70-90%)
Isolated adrenal insufficiency
Polyglandular autoimmune syndrome type I and II
Antibodies often directed against adrenal enzymes and 3 cortical zones

Infection TB (7-20%) (most common in developing world)
Fungal: histoplasmosis, paracoccidioidomycosis
HIV, CMV
Syphilis
African trypanosomiasis

Infiltrative 
Metastatic cancer (lung>stomach>esophagus>colon>breast); lymphoma 
Sarcoidosis, amyloidosis, hemochromatosis

Vascular
Bilateral adrenal hemorrhage (risk increased by heparin and warfarin)
Sepsis (meningococcal Pseudomonas)
Coagulopathy in adults or Waterhouse-Friderichsen syndrome in children
Thrombosis, embolism, adrenal infarction

Drugs
Inhibit cortisol: ketoconazole, etomidate, megestrol acetate
Increase cortisol metabolism: rifampin, phenytoin, barbiturates

Others
Adrenoleukodystrophy
Congenital adrenal hypoplasia (impaired steroidogenesis)
Familial glucocorticoid deficiency or resistance

31
Q

Secondary adrenocortical insufficiency definition

A

Inadequate pituitary ACTH secretion

32
Q

Secondary adrenocortical insufficiency etiologies

A

Multiple etiologies including withdrawal of exogenous steroids

33
Q

Clinical features of primary and secondary adrenal insufficiency

A

Skin and mucosa
Primary (Addison’s or Acute AI) - dark (palmar crease, extensor surface)
Secondary AI - Pale

Potassium
Primary - high
Secondary - normal

Sodium
Primary - low
Secondary - normal or low

Metabolic acidosis
primary - present
secondary - absent

Associated symptoms
Primary - weakness, fatigue, weight loss, hypotension, salt craving, postural dizziness, myalga, arthralgia GI: N/V, abdominal pain, diarrhea
Secondary - Same except: No salt craving GI less common

34
Q

Primary Adrenal insufficiency diagnostic test

A

Insulin tolerance test

Cosyntropin Stimulation Test

High morning plasma ACTH

35
Q

Secondary Adrenal insufficiency

A

Insulin tolerance test

Cosyntropin Stimulation Test

Low morning plasma ACTH

36
Q

Adrenal insufficiency treatment

A

• acute condition – can be life hreatening
■ IV NS in large volumes (2-3 L); add D5W if hypoglycemic from adrenal insufficiency
■ hydrocortisone 50 100 mg IV q6-8h for 24h, then gradual tapering
■ identify and correct precipitating factors

• maintenance
■ hydrocortisone 15-20 mg total daily dose, in 2-3 divided doses, highest dose in the AM
■ Florinef® (fludrocortisone, synthetic mineralocorticoid) 005-0.2 mg PO daily if mineralocorticoid deficient increase dose of steroids 2-3 fold for a few days during moderate-severe illness (e.g. with vomiting, fever)
■ major stress (e.g. surgery, trauma) requires 150 300 hydrocortisone IV daily divided into 3 doses
■ medical alert bracelet and instructions for emergency hydrocortisone/dexamethasone IM/SC injection

Endocrinology (9 decks)

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