Lecture 36 - Hypothalamic-Pituitary-Adrenal Axis Disorders

what are the adrenal glands

located at top of each kidney

adrenal medulla (10% of gland) → secretes catecholamines, stimulus for secretion of sympathetic nervous system

adrenal cortex (90% of gland) → secretes mineralocorticoids/glucocorticoids (corticosteroids), androgens

• mineralocorticoids e.g. aldosterone = promote sodium retention in renal tubules and potassium excretion

• glucocorticoids e.g. cortisol = mediate stress response and homeostasis

• androgens e.g. testosterone and estradiol

what is cholesterol

secreted from cortex of adrenal gland → precursor to steroid hormones

what is cortisol

main hormone of the HPA axis

regulate enzyme levels for metabolism

may act to limit inflammation and immune responses, role in BP maintenance

stress stimulates secretion above basal levels

what are the steps of the activation of the hypothalamic pituitary adrenal axis

stress → act on hypothalamus → release of corticotropin releasing hormone (CRH) → anterior pituitary releases adrenocorticotropic releasing hormone (ACTH) → act on adrenal cortex to stimulate cortisol release → target cells in periphery

cortisol negative feedback loop to inhibit release of CRH and ACTH

how can adrenal disorders be categorized

hypperfunction or hypofunction of the adrenal gland

can have significant clinical functions → hormones help regulate BP, metabolism, immune response, stress response, bodily functions

what are types of hyperfunction of the adrenal glands

Cushing’s Syndrome (hypercortisolism), hyperaldosteronism

what are types of hypofunction of the adrenal glands

Addison’s disease (adrenal insufficiency), genetic abnormalities of steroidogenesis

what is primary adrenocortical insufficiency

destruction or dysfunction of adrenal cortex (Addison’s disease, infection e.g. tuberculosis, trauma, surgery)

usually caused by autoimmune dysfunction

more common in women

results in deficiencies in cortisol, aldosterone, androgens

what is secondary adrenocortical insufficiency

deficient secretion of adrenocorticotropic hormone (ACTH)

glucocorticoid therapy - important implication if therapy is stopped or dose reduced

what is the clinical presentation of adrenocortical insufficiency

weakness, lethargy, fatigue

anorexia, weight loss

abdominal symptoms - nausea, vomiting, abdominal pain

hypoglycemia

hyperpigmentation of skin (only in primary insufficiency from excessive ACTH)

in primary: mineralocorticoid deficiency - hypotension, dehydration, hyponatremia, hyperkalemia

what are lab tests to diagnose adrenocortical insufficiency

morning plasma cortisol (6am - 9am) <80 nmol/L (ref 138-635 nmol/L)

ACTH will be high in primary insufficiency, low in secondary insufficiency

corticotropin (or cosyndropin) stimulation test

• measure plasma cortisol at baseline

• administer 250 ug synthetic ACTH

• repeat plasma cortisol in 30-60min → > 500 nmol/L rules out primary adrenal insufficiency (adrenal cortex still works)

what are drug-test interactions for adrenocortical insufficiency

oral contraceptives → increase cortisol-binding globulin (CBG) = elevated total cortisol levels

what is the appropriate dosing regimen for primary adrenocortical insufficiency

hydrocortisone 15-25 mg/day

• 2/3 dose in the morning, 1/3 dose late in the afternoon → mimic normal endogenous release

mineralocorticoid → fludrocortisone 0.05-0.1mg daily

what is the consideration of stress dosing in primary adrenocortical insufficiency

patient is unable to mount a normal cortisol response (increase in BP and blood glucose) to stressful events → leading cause of adrenal crises

to prevent: increase dose of glucocorticoid during major illness or injury

• increase is individualized based on patient and stressor

• dose is generally doubled during febrile illness

• continue with increased dose until feeling better

injectable hydrocortisone may be required in diarrhea/vomiting

if patient using mineralocorticoid - should increase 2-3x regular dose for hot weather, strenuous exercise (sweating and fluid loss) → watch for fluid retention and HTN

what is secondary adrenocortical insufficiency management

patients may need glucocorticoid replacement, but not mineralocorticoid replacement

• adrenal cortex not damaged

• aldosterone production and release managed by RAAS

dose of corticosteroid depends on symptoms, ACTH levels, and response to corticotropin stimulation test

most patients require stress dose steroids

counselling on tapered withdrawal of corticosteroids important (abrupt withdrawal can cause adrenal crisis)

what is Cushing’s syndrome

clinical condition from chronic, excessive levels of endogenous cortisol or exogenous corticosteroids

most common cause: drug related (prolonged high dose/potency glucocorticoids)

other causes: adrenal adenomas, adrenal carcinomas, ectopic ACTH secretion (neuroendocrine tumours)

what is Cushing’s disease

excessive cortisol levels caused by overproduction and release of ACTH from a pituitary tumour

what is the clinical presentation of adrenal excess

fatigue and weakness

increased body weight, redistribution of body fat (centripetal obesity, facial rounding, thin extremeties)

hypertension

hirsutism

amenorrhea

muscle wasting

thinning of skin

easy bruising

what are lab tests to establish hypercortisolism

measure level of cortisol → 24h urine collection or midnight plasma or salivary cortisol to see if dinural pattern is intact

dexamethasone suppression test

• 1mg administered orally at bedtime

• morning cortisol measured next day: <50nmol/L rules out Cushing syndrome (body responding appropriately), >50nmol/L confirms cushing syndrome

neither test identifies etiology of hypercortisolism

false positive: exogenous glucocorticoid administration, acute illness, pregnancy, oral contraceptive use

what is the management of Cushing disease

surgery or pituitary radiation to reduce size of pituitary tumor

goal: normalize cortisol levels and alleviate symptoms, help with preoperative management or as adjunctive therapy to surgery/radiation if symptoms persist

what are pharmacologic options for managing Cushing disease

enzyme inhibitors to decrease cortisol synthesis:

• ketoconazole (monitor LFTs)

• mitotane (can block thyroxine synthesis)

modulate ACTH secretion from pituitary

• carbergoline (dopamine agonist)

• pasireotide (somatostatin analogue)

what is the management of Cushing syndrome

re-evaluate the indication for corticosteroid ongoing use

warning: continuously monitor for symptoms of adrenal insufficiency if patient using exogenous corticosteroids for prolonged periods of time

• e.g. ≥20mg prednisone for ≥3 weeks

• if using steroids for < 3 weeks or is administering on alternate day therapy = less likely to develop

taper dose to avoid adrenal insufficiency

what is hyperprolactinemia

state of persistently elevated prolactin levels

secretion is regulated primarily by tonic inhibition from dopamine

what are clinical manifestations of hyperprolactinemia

galactorrhea

hypogonadism → irregular menses, sexual dysfunction, infertility, osteoporosis

what are the causes of hyperprolactinemia

usually affects women of reproductive age

most commonly caused by prolactinomas (benign prolactin-secreting pituitary tumor)

drugs that antagonize dopamine:

• antipsychotic medications (dopamine blockade)

• antidepressants (elevated serotonin = stimulates prolactin secretion)

• metoclopramide and domperidone (dopamine antagonists)

less common: elevated TRH (hypothyroidism) or estrogen stimulating lactotrophs (cells that secrete prolactin from anterior pituitary)

what is the management of hyperprolactinemia

stop medications that antagonize dopamine

use dopamine agonists for prolactinomas → cabergoline, bromocriptine

monitor for effectiveness by following prolactin levels