Endocrinology Review

Thyroid, pituitary, adrenal & bone

Dora Liu, MD FRCPC

Basic thyroid physiology

Hypothalamic-Pituitary-Thyroid Axis

Thyroid hormones

From UpToDate

Thyroid hormone transport

• Three major transport proteins:– Thyroxine-binding globulin (TBG)– Thyroxine-binding prealbumin (TBPA)– Albumin

• Free (unbound) hormones are active• Proportion of “free” hormones:

– 0.04% of T4

– 0.4% of T3

Thyrotoxicosis

Clinical features of thyrotoxicosis

• Weight loss• Increased appetite• Heat intolerance• Anxiety, irritability• Fine tremor• Fatigue• Thyroid stare• Systolic HTN

• Tachycardia• Palpitations• Atrial fibrillation• Frequent BM’s• Proximal weakness• Diaphoresis• Moist skin• Fine hair

Thyrotoxicosis - Investigations

• Primary:– Low TSH– Increased fT3 and/or fT4

– Thyroid uptake and scan to determine etiology of 1o hyperthyroidism

• Secondary:– TSH elevated or not suppressed– Increased fT3 and/or fT4

Causes of 1o thyrotoxicosis

• Graves’ disease• Toxic adenoma or toxic multinodular goitre• Thyroiditis• Jod-Basedow (iodine-induced)• Exogenous thyroid hormone• Gestational hyperthyroidism (hCG-induced)

Graves’ disease

• Autoimmune disorder• Thyroid stimulating immunoglobulin

binds TSH receptor• F > M• Any age with peak in 3rd-4th decade• Diffusely enlarged “meaty” goitre

Graves Hyperthyroidism

Graves ophthalmopathy

Pretibial myxedema

Graves diseaseIncreased homogeneous uptake

Treatment of Graves disease

• Methimazole or propylthiouracil (PTU)• Radioactive iodine therapy• Thyroidectomy• Temporary measures:

-blockade until hyperthyroidism improves

– Steroids (decrease T4 to T3 conversion)– Iodine (Wolff-Chaikoff effect)

Toxic adenoma

• Solitary thyroid nodule produces excess hormone

• Accounts for < 5% of hyperthyroidism• Frequency increases with age• F > M• Treatment of choice: radioactive iodine

therapy

Toxic adenoma

Toxic multinodular goitre

2 nodules producing excess hormone• In Canada, most patients are > 50 yrs

old• Younger patients in areas of iodine

deficiency• Compressive symptoms can occur• Treatment of choice: I-131

Toxic multinodular goitre

Toxic multinodular goitre

Thyroiditis

• Destruction of thyroid cells causes release of hormones

• Autoimmune, infectious and toxic causes

• Can occur in post-partum period• Can be associated with fever, painful &

tender gland

Diagnosis & treatment of thyroiditis

• Low uptake on thyroid scan• NSAIDs for painful inflammation• -blockers to control symptoms• Steroids for severe cases• Often followed by hypothyroid phase

Gestational hyperthyroidism

• hCG mimics TSH and stimulates thyroid hormone production

• Associated with hyperemesis gradvidarum, multiple gestation

• Improves by 2nd trimester• Must differentiate from Graves disease-blocker & PTU can be used during

pregnancy

Extrathyroidal sources of thyroid hormone

• Exogenous sources:– Exogenous thyroid hormone– Hamburger thyrotoxicosis

• Endogenous sources:– Struma ovarii– Functioning thyroid cancer

Other causes of hyperthyroidism

• TSH-secreting tumour• Iodine load (Jod-Basedow phenomenon)• Pituitary resistance to thyroid hormone

Hypothyroidism

Hypothyroidism

• 2-3% of population• F:M = 10:1• 1o hypothyroidism (90%)

– Autoimmune (e.g., Hashimoto’s)– Iatrogenic (surgery, RAI, drugs, iodine)– Congenital, intrinsic defect of hormone synthesis– Infiltrative (amyloid, progressive systemic sclerosis)

• 2o hypothyroidism - TSH deficiency• 3o hypothyroidism - TRH deficiency

Clinical features of hypothyroidism

• Fatigue• Cold intolerance• Slow mental & physical

performance• Hoarse voice• Bradycardia• Diastolic hypertension• Edema

• Weight gain• Constipation• Menorrhagia• Dry skin• Macroglossia• Muscle cramps• Delayed DTR• Dyslipidemia

Hypothyroidism - Lab tests

• 1o hypothyroidism– Elevated TSH– Low fT4 and/or fT3

• Central hypothyroidism– Low fT4 and/or fT3– TSH not reliable

Treatment of hypothyroidism

• Typical L-T4 dose 50 - 200 mcg• Start low dose (25 mcg) and titrate up slowly

in elderly• R/O adrenal insufficiency• Check TSH 6-8 wk after dose change & titrate

to normalize TSH for 1o hypothyroidism• Titrate to normalize fT3 for central

hypothyroidism

Myxedema coma• Severe hypothyroidism• Precipitating event (e.g., trauma, sepsis, cold

exposure, MI, narcotics)• Clinical features: Hypothermia, hypoglycemia,

hypotension, bradycardia, hypoventilation• Mortality up to 60%• Treatment:

– ABCs– Stress-dose steroids– L-T4 0.2-0.5 mg IV then 0.1 mg daily

Non-thyroidal illness“Sick euthyroid syndrome”

Non-thyroidal illness• Change in thyroid hormone levels related to

serious illness• Abnormalities in TSH secretion, hormone

binding & metabolism• Decreased T4 to T3 conversion• Typically see low fT3 & high rT3

• More severe illness: fT3, fT4 & TSH can all be low

• Rx: Treat underlying illness

Thyroid nodules and malignancies

Thyroid nodules

• ~ 4% prevalence• ~ 5% malignant• If nodule is identified, check TSH

– Low TSH Thyroid scan• Low probability of malignancy with hot nodules• FNAB if cold nodule is present (15-20% malignant)

– Normal or high TSH FNAB if palpable or > 1 cm in diameter

Thyroid malignancies

• Well-differentiated thyroid carcinomas:– Papillary– Follicular

• Medullary thyroid carcinoma– Familial forms: MEN IIa & IIb, familial medullary

carcinoma– Calcitonin is a tumour marker

• Anaplastic thyroid carcinoma– Very poor prognosis

Well-differentiated thyroid carcinoma

• Total thyroidectomy• I-131 therapy if higher risk

– Multifocal– Large tumour– Capsular invasion– Lymph node or distant metastases

• TSH suppression• Follow thyroglobulin level

Medullary thyroid CA• Look for other features of MEN IIa & IIb

– R/O pheochromocytoma– R/O 1o hyperparathyroidism– RET protooncogene mutation

• Treatment– Surgical resection for cure– Some respond to MIBG or octreotide

• Prophylactic thyroidectomy in affected relatives

MEN syndromes

Medullary thyroid CA

• Look for other features of MEN IIa & IIb– R/O pheochromocytoma– R/O 1o hyperparathyroidism– RET proto-oncogene mutation

• Treatment– Surgical resection for cure– Some respond to MIBG or octreotide

• Prophylactic thyroidectomy in affected relatives

Pituitary - Adrenal Disorders

Basic pituitary & adrenal physiology

Hypothalamic & anterior pituitary hormones

• GHRH Growth hormone (GH)• TRH TSH• Somatostatin GH & TSH• TRH & Prolactin-releasing factors Prolactin• Dopamine Prolactin• CRH ACTH• GnRH LH & FSH

Pituitary hormones

• Anterior– Growth hormone– ACTH– LH– FSH– TSH– Prolactin

• Posterior– ADH (arginine

vasopressin)– Oxytocin

Hyperprolactinemia

Causes of hyperprolactinemia

Physiologic Medications Pathologic

Pregnancy

Nipple stimulation

Sleep

Stress

Exercise

EstrogenAnti-psychoticsMAOIOpioidsCimetidineLicorice

Pituitary tumours

Stalk compression

Chest wall lesions

Hypothyroidism

Renal failure

Severe liver disease

Hyperprolactinemia

• Clinical features:– Galactorrhea, gynecomastia, infertility, low bone

density– Headaches, bitemporal hemianopsia (if

macroadenoma affects optic chiasm)

• Treat underlying cause, if present• 1o Rx for prolactinoma:

– Dopamine agonist (e.g., bromocriptine or cabergoline)

Acromegaly

Clinical features of acromegaly

• Coarse facial features• Acral enlargement• Hyperhidrosis• Heat intolerance• Oily skin• Fatigue• Weight gain• HTN

• Goitre• Cardiomegaly• Insulin resistance• Arthralgias• Parasthesias• Hypogonadism• Headaches

Acromegaly

• Diagnostic tests:– Glucose suppression test– IGF-1 level

• Treatment:– Surgery– Somatostatin analogues (Octreotide)– Radiotherapy– GH receptor antagonist (Pegvisomant)

Posterior pituitary disorders

SIADH Diagnostic criteria

• Plasma osmolality < 275 mOsm/kg H2O, excluding pseudohyponatremia or hyperglycemia

• Inappropriate urine concentration (UOsm > 100 with normal renal function)

• Clinical euvolemia• Elevated urine sodium excretion with normal salt

and water intake• Absence of other potential causes of euvolemic

hypo-osmolality (hypothyroidism, adrenal insufficiency, diuretic use)

Treating SIADH

• Fluid restriction• Loop diuretics• Hypertonic saline if urgent correction

needed• Demeclocycline, lithium (rarely used)• Do not correct Na+ too quickly• Treat underlying cause

Diabetes insipidus

• Clinical features:– Polyuria, polydispsia– Hypernatremia, dehydration– Low urine Na+ & osmolality

• Treatments:– Oral & IV fluids– ddAVP– For nephrogenic DI:

• Na+ restriction, thiazides & PG inhibitors

Hypothalamic Pituitary

Adrenal Axis

From Williams Textbook of Endocrinology

POMC synthesis and cleavage

From Williams Textbook of Endocrinology

Microscopic anatomy

Zone Hormone

Glomerulosa Aldosterone

Fasciculata Cortisol

Reticularis Androgens

Medulla Catecholamines

From Williams Textbook of Endocrinology

Adrenal steroid function

• Glucocorticoids– Affects fuel metabolism, responses to

injury and general cell function• Mineralocorticoids

– Control body Na+ and K+ content• Androgens

– Similar function to male gonadal hormones

Adrenal steroidogenesis

From Williams Textbook of Endocrinology

Sites of glucocorticoid

action

From Williams Textbook of Endocrinology

Cushing’s syndrome

Features of Cushing’s

• Moon facies• Facial plethora• Dorsal &

supraclavicular fat pads

• Mental status change• HTN• Visceral adiposity

• Muscle wasting• Ecchymoses• Thin skin• Purple striae• Osteoporosis• Avascular necrosis• Insulin resistance

Screening tests for Cushing’s syndrome

• 24 hr urinary free cortisol• Low-dose dexamethasone suppression

test• Evening cortisol• Salivary cortisol (23:00)

Working up CushingsDiagnose Cushings

ACTH < 2 ACTH > 2

Adrenal Imaging

Adrenalectomy

High-dose DST

Cushings disease Ectopic Cushingsor Cushings disease

Inferior petrosal sinus sampling

MRI Pituitary

Pituitary surgeryCushings disease Ectopic Cushings

MRI Pituitary

Pituitary surgery

CT Chest/abdoOctreotide scan

Adrenal insufficiency

Clinical features of adrenal insufficiency

• Weight loss• Fatigue• Weakness• Hypoglycemia• Hyponatremia• Anemia

• Addison’s– Hyperpigmentation– Volume depletion– N/V, abdo pain– Hyperkalemia

Adrenal insufficiency

• Treatment– IV fluids– Glucocorticoid therapy– Mineralocorticoid therapy for Addison’s

• Diagnosis– ACTH stimulation test– Insulin tolerance test for central disease

Primary hyperaldosteronism

Aldosterone secretion & actionHypotension Low Na+

Renin

Angiotensinogen Angiotensin I

Angiotensin II

ACE

Blood pressure

Aldosterone

Na+ reabsorption

Assessment of renin-angiotensin-aldosterone axis• Random plasma renin activity not reliable• Plasma aldosterone > 695 pmol/L• Aldosterone:renin ratio • 24 hr urinary aldosterone

– Normal 14-56 nmol– Aldosterone-producing adenoma 125 9 nmol– Idiopathic hyperaldosteronism 75 5 nmol

• Adrenal vein sampling

From UpToDate

Adrenal androgens

Adrenal androgen secretion

• > 50% of circulating androgens in premenopausal females

• Relative contribution smaller in males• Stimulated by ACTH• DHEA and androstenedione levels

demonstrate circadian rhythm (but not DHEAS)

Congenital adrenal hyperplasia

XX

Congenital adrenal hyperplasia

• Autosomal recessive disorder• Presentations of CAH:

– Female neonates: Ambiguous genitalia– Male neonates: Adrenal crisis– Non-classic: Hirsutism & infertility in females

• Treatment:– Glucocorticoid therapy– Mineralocorticoid for salt-wasting varieties

Pheochromocytoma

Clinical features of pheochromocytoma

• Paroxysmal or sustained HTN• Triad: H/A, palpitation/tachycardia,

diaphoreseis• Postural drop in BP• Dilated cardiomyopathy• Tremor, anxiety• Chest pain• Papilledema, blurry vision

Pheochromocytoma

• Diagnosis– Urine metanephrines or plasma

catecholamines– MIBG, octreotide scan

• Treatment -blockade or CCB (not -blocker 1st!)– Volume restoration– Adrenalectomy

Bone & calcium disorders

PTH-Ca2+ feedback loopParathyroid

glands

GI Tract

PTH

ECF Ca2+

1,25 D

-

PTH

-

Ca2+Ca2+ Ca2+

Vitamin D

7-dehydrocholesterol Cholecalciferol

25-OH vitamin D

Calcitriol

PTH

24,25(OH)2 - D

IntestinalCa & PO4

absorption

PTHsecretion

Multiple effectsin bone

Effectsin muscle

Hypercalcemia

Clinical manifestations of hypercalcemia

• General: Weakness• CVS: HTN, valve & arterial calcification• GI: Constipation, anorexia, N/V, pancreatitis• Renal: Stones, DI (polyuria), renal

insufficiency• MSK: Bone pain• CNS: Altered mental status

Mechanisms for hypercalcemia

• Increased bone resorption

• Increased gastrointestinal absorption of calcium

• Decreased renal excretion of calcium

Increased bone resorption• Hyperparathyroidism (usually 1o)• Malignancies

– PTHrP (solid tumours, leukemia)– 1,25(OH)2D (lymphomas)– Ectopic PTH (rare)– Osteolytic lesions

• Hyperthyroidism• Immobilization• Paget’s disease (usually with immobilization)• Estrogen, tamoxifen• Hypervitaminosis A

More causes of hypercalcemia• Increased calcium absorption

– Increased calcium intake– Hypervitaminosis D

• Lithium• Thiazide diuretics• Pheochromocytoma• Adrenal insufficiency• Rhabdomyolysis• Theophylline• Familial hypocalciuric hypercalcemia

Ways to lower calcium

• IV fluids• Furosemide• Calcitonin• Steroids• Bisphosphonates• Dialysis

Hypocalcemia

Clinical features of hypocalcemia• Paresthesia• Laryngospasm• Seizures• Carpopedal spasm• Chvostek’s sign (CN VII)• Trousseau’s sign (carpal spasm)• Hyperreflexia• Mental status changes

Causes of hypocalcemia• Low PTH

– Hypoparathyroidism– Hypomagnesemia

• Vitamin D related– Vitamin D deficiency– 1-hydroxylase activity (renal failure, vit D

dependent rickets)– Vitamin D resistant rickets

• Pseudohypoparathyroidism (PTH resistance)• Drugs (calcitonin, furosemide)

Treatment of hypocalcemia

• ABC’s• Replace calcium

– Calcium gluconate IV– Oral calcium

• Treat hypomagnesemia, if present• May require vitamin D• Correct underlying cause

Osteoporosis

What is osteoporosis?

• Systemic skeletal disorder

• Characterized by compromised bone strength

• Leads to enhanced bone fragility and a consequent increase in fracture risk

What determines bone strength?

• Bone density– Expressed in grams of bone mass over area or

volume of bone– Determined by peak bone mass & amount of

bone loss

• Bone quality– Refers to architecture, damage accumulation

(e.g., microfractures) & mineralization

NIH Consensus Statement 2000

Bone density & quality determine bone strength

Bone volume Tissue volume 22% 13% 22%

Normal bone Low BMD Poor quality

Osteoporosis & fractures

• Osteoporosis is a significant risk factor for fractures

• Fractures occur when a failure-inducing force is applied to osteoporotic bone

Who is at risk for fractures?• Major risk factors:

– Age ≥ 65 years– Vertebral compression fracture– Fragility fracture after age 40– FHx of osteoporotic fracture– Systemic glucocorticoid therapy 3 mos– Malabsorption syndrome– Primary hyperparathyroidism– Propensity to fall– Osteopenia apparent on X-ray film– Hypogonadism– Early menopause (before age 45)

CMAJ 2002; 167(10 Suppl)

Who is at risk for fractures?

• Minor risk factors:– Rheumatoid arthritis– Past history of clinical hyperthyroidism– Chronic anticonvulsant therapy– Low dietary calcium intake– Smoker– Excessive alcohol intake– Excessive caffeine intake– Weight < 57 kg– Weight loss 10% of weight at age 25– Chronic heparin therapy

CMAJ 2002; 167(10 Suppl)

DEXA is used to measure BMD

• The PROS of DEXA scanning– Quick, non-invasive– 1/10 radiation of CXR (background radiation exposure

over 1 day)– Most accurate estimator of fracture risk

• The CONS of DEXA scanning– Not a measure of bone strength (only accounts for ~70%

of strength)– Inter-operator variability, lack of standardization

Who should be screened?

• Indications for BMD scan:– Patients with 1 major or 2 minor risk factors for

osteoporosis– Age ≥ 65 years regardless of risk factors

• Contraindications for BMD scan:– Pregnancy– Recent GI study or nuclear medicine test (wait at

least 72 hr; up to 7 d for long-lived isotopes like gallium)

Interpretation of BMD measurements

• T-score: # of SD’s from average person of same gender at peak bone mass

• Z-score: # of SD’s compared to average person of same gender, age & race

WHO diagnostic categories

Classification Criterion

Normal T-score ≥ - 1.0

Osteopenia T-score between -1.0 and -2.5

Osteoporosis T-score < -2.5

Severe osteoporosisT-score < -2.5 with

Hx of fragility fracture(s)

Secondary causes of osteoporosis

Endocrine & Metabolic

Nutritional DrugsCollagen disorders

Other

HypogonadismCushingsThyrotoxicosisAnorexia nervosaHyperprolactinemiaPorphyriaHypophosphatemiaDiabetesPregnancyHyperparathyroidismAcromegaly

MalabsorptionMalnutritionChronic cholestatic

liver disease

Gastric operationsVitamin D deficiencyCalcium deficiencyAlcoholism

GlucocorticoidsExcessive thyroid

hormoneHeparinGnRH agonistsPhenytoinPhenobarbitalVitamin D toxicity

Osteogenesis imperfecta

HomocystinuriaEhlers-Danlos

syndromeMarfan

syndrome

Rheumatoid arthritisMyeloma & some

cancersImmobilizationRenal tubular acidosisHypercalciuriaCOPDOrgan transplantationMastocytosisThalassemia

Calcium & vitamin D intake Calcium

Children (4-8) 800 mg

Adolescents (9-18) 1300 mg

Premenopausal women 1000 mg

Men <50 1000 mg

Menopausal women 1500 mg

Men > 50 1500 mg

Pregnant or lactating women 1000 mg

Vitamin DAge < 50 400 IU

Age > 50 800 IU

Fall Prevention

• Risk Factors– Sedatives– Previous fall– Cognitive impairment– Visual impairment– Foot problems– Gait abnormalities– Lower extremity

disability

• Prevention measures– Bathroom lights on– Install grab bars– Avoid loose rugs– Remove clutter– Keep wires behind

furniture

Who should receive pharmacotherapy?

• Patients with osteoporosis

• Patients with T-score < -1.5 with 1 major or 2 minor risk factors

• Some argue 10-yr risk for fracture should be used instead

Bisphosphonates

• Similar in structure to pyrophosphate in bone

• Attaches to bone surface and inhibits osteoclastic resorption

• Poorly absorbed orally• GI side effects common

Calcitonin

• Inhibits bone resorption• Analgesic effect• No drug-drug interactions• Well-tolerated• Evidence for reduction in vertebral

fractures, but not non-vertebral fractures

Hormone replacement therapy

• The benefits:– Decreases osteoclastic activity– Increases BMD & lowers fracture risk– Treats symptoms of estrogen deficiency– Decreases colon cancer risk

• The down side:– Increased CVD, VTE & PE risk– Increased breast cancer risk– Adverse effect on cognition

Selective Estrogen Receptor Modulator (SERM)

• Binds to estrogen receptors• Produces an estrogen agonist effect in

some tissues• Produces an estrogen antagonist effect

in others• Examples: Tamoxifen, raloxifene

Guidelines for Teriparatide• 1st line Rx for women ≥ 65 yrs with T < -2.5 and Hx

of vertebral fracture• Preferable to treat bisphosphonate naïve patients• Consider treating post-menopausal women with T <

-3.5 who continue to fracture despite adequate (2 yr) trial of therapy

• Discontinue bisphosphonate prior to PTH• Limit PTH Rx to maximum 18 mos• Administer bisphosphonate therapy after PTH

course

CMAJ 2006; 175:48

Hip protectors

NEJM 2000; 343: 1506

• 1801 frail but ambulatory elderly adults, mean age 82 yrs

• Hip protector : control = 1 : 2• 1 month F/U• Relative hazard of hip fracture = 0.4;

P=0.008

Vertebroplasty & kyphoplasty

• Vertebroplasty = minimally invasive surgical procedure to relieve the pain of compression fractures

• Kyphoplasty = proprietary derivative procedure using polymethylmethacrylate (PMMA) to fix a vertebral body in place after balloon inflation of the body

Good luck!