Adrenal Cortex Flashcards
What is adrenocorticotropic hormone, what is it regulated by and what does it do
- 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
Describe the CRH-ACTH-adrenal gland axis
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
What is aldosterone, what is it regulated by and what does it do
- 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)
Layers of the adrenal cortex from outside to inside
Zona Glomerulosa produces mineralocorticoids (aldosterone)
Zona Fasciculata produces glucocorticoids (cortisol)
Zona Reticularis produces androgens (DHEA, androstenedione)
Renin-angiotensin-aldosterone axis
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
What is cortisol and what does it do
- 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
Physiological effefcts of glucocorticoids
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
What are androgens, what are they regulated by and what do they do
- 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
Adrenocortical functional workup
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
Approach to mineralocorticoid excess syndromes
Is there hypertension and hypokalemia?
- 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
Primary hyperaldosteronism definition
• primary hyperaldosteronism (PH): excess aldosterone production (intra-adrenal cause)
Secondary hyperaldosteronism definition
• secondary hyperaldosteronism (SH): aldosterone production in response to excess RAAS (extra-adrenal cause)
Types of mineralocorticoid excess syndromes
Primary and secondary hyperaldosteronism
Primary hyperaldosteronism etiologies
■ aldosterone-producing adrenal adenoma (Conn’s syndrome)
■ bilateral or idiopathic adrenal hyperplasia
■ glucocorticoid-remediable aldosteronism
■ aldosterone-producing adrenocortical carcinoma
■ unilateral adrenal hyperplasi
mineralocorticoid excess syndrome clinical features
- 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
mineralocorticoid excess syndrome diagnosis
• 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
mineralocorticoid excess syndrome treatment
- inhibit action of aldosterone: spironolactone, eplerenone, triamerene, amiloride (act on sodium channels)
- surgical excision of adrenal adenoma
- secondary hyperaldosteronism: treat underlying cause
Cushing’s Syndrome definition
results from chronic glucocorticoid excess (endogenous or exogenous sources)
Cushing’s Syndrome etiology
• 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
Cushing’s Syndrome clinical features
- 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
Cushing’s Syndrome diagnosis
- 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)
Cushing’s Syndrome treatment
• 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
Hyperandrogenism definition
state of having excessive secretion of androgens (DHEA, DHEA sulfate, testosterone)
Hyperandrogenism etiology and pathophysiology
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
Hyperandrogenism clinical features
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
Hyperandrogenism investigations
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
Hyperandrogenism treatment
- 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)
Conditions that do NOT represent true hirsutism
- Androgen-independent hair (e.g. lanugo hair)
- Drug-induced hypertrichosis (e.g. phenytoin, diazoxide, cyclosporine, minoxidil)
- Topical steroid use
Adrenocortical insufficiency definition
state of inadequate cortisol and/or aldosterone production by the adrenal glands
Primary Adrenocortical insufficiency (Addison’s Disease) etiology
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
Secondary adrenocortical insufficiency definition
Inadequate pituitary ACTH secretion
Secondary adrenocortical insufficiency etiologies
Multiple etiologies including withdrawal of exogenous steroids
Clinical features of primary and secondary adrenal insufficiency
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
Primary Adrenal insufficiency diagnostic test
Insulin tolerance test
Cosyntropin Stimulation Test
High morning plasma ACTH
Secondary Adrenal insufficiency
Insulin tolerance test
Cosyntropin Stimulation Test
Low morning plasma ACTH
Adrenal insufficiency treatment
• 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
