2016 L6 Endocrinology

Endocrine Systems

A form of information signalling system

• Slow to initiate compared to NS, but responses are longer lasting bc of hormones

• Endocrine glands are highly vascular and ductless (unlike exocrine glands)

• Target organs are distant and reached through circulatory system (unlike paracrine sustems)

Hormones

Chemical substances acting as messengers via receptors, eliciting a cellular response after signal transduction.

• Steroid - lipid derived from cholesterol

• Peptide - made of short polypeptide chains

• Amine - derived from amino acids

Hormone axes

Number of glands that signal each other in sequence

Hypothalmic-Pituitary-Thyroid Axis

• Hypothalmus: Hormone 1, Thyrotropin-releasing hormone

• Anterior pituitary: Hormone 2, Thyroid-stimulating hormone

• Intermediary glands e.g. thyroid gland: Hormone 4, T4/T3

Act on target organs to increase metabolism, growth and development, Works on negative feedback.

Endocrine Disease Types

• Hyposecretion e.g. Type I diabetes

• Hypersecretion e.g. insulinoma

• Resistance e.g. Type II diabetes

May affect endocrine tissues or others, and may be both hypo and hyper secretion at the same time

Causes of Endocrine Diseases

• Congenital e.g. congenital adrenal hyperplasia

• Acquired e.g.

  • autoimmune: Addison’s disease

  • tumour/hyperplasia: Cushing’s

  • physical injury: diabetes insipidus after head injury

  • inability to synthesise sufficient hormone: Rickets

Hypothalamus

• In brain, secretes hormones that stimulate or suppress hormone production by pituitary gland

• Hormones passed to pituitary gland via portal systems, prevents dilution in systemic circulation

• Also controls water balance, sleep, temperature, appetite and pressure

Pituitary Gland

• At base of brain, pea sized

• Two parts with embryological origins

  • anterior, receives hormones from pituitary via portal vein

  • posterior, extension of hypothalamus composed of hypothalamic neuron axons

Axes regulation

• CNS inputs

• Diurnal/monthly rhythms

• Stress/drugs

• Pulsatile secretion

• Negative feedback

Hypopituitarism

Insufficient hormone production from the pituitary gland

Hypopituitarism Causes

• Infection

• Infarction

• Pituitary surgery/irradiation

• Head injury

• Tumours

Hypopituitarism Consequences

• ↓ LH & FSH = hypogonadism (infertility)

• ↓ GH = ↓ growth in children, non-specific effect in adults

• ↓ ACTH = adrenal hypofunction

• ↓ TSH = hypothyroidism

Hypopituitarism Treatments

• Oral replacement of cortisol and thyroxine

• Replacement of sec steroids

• GH injections

Pituitary Tumours

• Destructive

• Functional

Both lead to headache, visual field defects, disorders of eye movement

Destructive Pituitary Tumours

• Destructive nature + stalk compression = disruption of normal pituitary gland function, a cause of hypopituitarism

Functional Pituitary Tumours

• May also become destructive

• Leads to hyper-secretion of pituitary hormones, most commonly prolactinoma

  • benign, most are microadenomas

  • clinical presentation: infertility, menstrual cycle disturbance and galactorrhea

• Cushing’s: adrenocorticotropic hormone (ACTH) hypersecretion

• Acromegaly: growth hormone (GH) hypersecretion

• TSH, LH or FSH secreting adenomas are very rare

Hyperprolactinaemia & Secondary Causes

Elevated levels of prolactin in the blood, mostly not due to prolactinoma, but by other causes e.g.

• drugs (most common) - antipsychotics, antidepressants, oestrogen

• pregnancy and breastfeeding (physiological rise)

• stress

• seizures

• untreated primary hypothyroidism

Can also manifest as macroprolactin, a benign complex of IgG and prolactin

Acromegaly

• Functional pituitary tumour > elevated growth hormone

• Childhood acromegaly causes gigantism

• Increased mortality due to

  • inc. cardiovascular and cerebrovascular risk

  • hypertension

  • type 2 diabetes

  • greater risk of cancer

Gigantism

• Result of growth hormone secreting tumours

• Elongation of bones, hands, feet, jaw, internal organs, excess hair and sweating

• Occurs due to epiphyses not fusing childhood before epiphyseal closure, leading to excessive growth.

Acromegaly Investigations

• One off raised growth hormone can be due to stress or spontaneous pulsing (rhythmic caliber oscillations of one or multiple major retinal veins at the site of the optic nerve head) - NOT a diagnosis for acromegaly

• Perform GTT (glucose tolerance tests) and measure GH levels - should suppress glucose response

• Insulin-like growth factor 1 (IGF1) usually raised

Acromegaly Treatment

Aims

• reduce GH conc

• reduce metabolic effects

• reversal of somatic changes (usually doesnt fully revert to pre-disease state)

Treatment

• octreotide (£8k/year)

• trans-sphenoidal hypophysectomy

• radiotherapy

Hypothalamic-pituitary-adrenal axis

1. Hypothalmus, CRH

2. Anterior pituitary, ACTH

Target the adrenal cortex, creating cortisol. Stress can increase cortisol levels and disrupt the circadian rhythm.

Adrenal Gland Cortex

Produces 3 types of steroid hormones, essential for life

• Mineralocorticoids e.g. aldosterone

• Glucocorticoids e.g. cortisol

• Androgens e.g. DHEA, androstenedione

Adrenal Gland Medulla

Functional part of sympathetic nervous system, not essential for life

Aldosterone

• Mineralocorticoid, adrenocortical steroid

• Found in zona glomerulosa in adrenal gland

• Maintains water, electrolytes and blood pressure

Cortisol

• Glucocorticoid, adrenocortical steroid

• Found in zona fasiculata in adrenal gland

• Regulated by ACTH (HPA axis)

  • Hepatic gluconeogenesis (anti-insulin effects)

  • protein catabolism

  • maintains blood pressure

Androgens

• Adrenocortical steroid

• Found in zona reticularis of adrenal gland

• Required for male embryonic sexual development

• Determines secondary sexual characteristics

Renin-Angiotensin-Aldosterone System

1. Renin-secreting cells in kidney are sensitive to changes in blood flow and pressure > renin released into blood following decreased blood flow

2. Activates angiotensinogen to angiotensin I, which is converted to angiotensin II by angiotensin converting enzyme (ACE) in lungs

3. Leads to aldosterone release from adrenal glands, increased blood pressure, and sodium retention

Aldosterone in the Kidney

• Causes distal tube and collecting ducts to reabsorb sodium from filtrate in exchange for potassium

• Water follows sodium by osmosis

• Restores BP and electrolyte balance

Conn Syndrome

• Primary hyperaldosteronism

• Excessive reabsorption of Na and water

• Leads to hypertension due to plasma volume expansion - suspect Conn’s if young or resistant to treatment

• Hypokalaemia

Caused by

• Adrenal adenoma (benign tumour, most common)

• bilateral hyperplasia (diffuse enlargement of both adrenal glands)

• other rare causes

Conn Syndrome Investigation

• Looking into plasma renin and aldosterone

• Wide variation in reference range, aldosterone/renin ratio used

  • < 1000 Conn’s unlikley, 1000 - 2000 equivocal, repeat after excluding meds, 2000+ Conn’s very likely

Conn Syndrome Treatment

• Chronic hypertension > glomerular damage, ↑ risk of heart attack and stroke

• Adenoma or unilateral hyperplasia - adrenalectomy

• Bilateral hyperplasia - spironolactone, aldosterone antagonist that may cause gynaecomastia

Cushing Syndrome Causes

• Glucocorticoid (cortisol) excess

• Pituitary adenomas producing excess ACTH

• Ectopic ACTH e.g. by lung carcinoma

• Benign or malignant adrenal tumours (rarer, ACTH is suppressed)

• Large doses of glucocorticoid .e.g prednisolone for diseases ex. rheumatoid arthritis

• Alcoholic pseudo-Cushing’s - normalises after abstinence

Dexamethasone Suppression Test

Synthetic steroid, for diagnosis of Cushing as random cortisol not informative

• 1mg dexamethasone (synthetic steroid) orally 11pm

• Measure cortisol 9am next day

• Should suppress to < 50nmol/L due to neg feedback of dex on pituitary gland

24hr Urine Free Cortisol

• For diagnosis of Cushing

• Cortisol circulates bound to cortisol binding globulin (CBG) and albumin, very little unbound in free form

• In Cushing carrier proteins are saturated

  • inc. free cortisol

  • appears in urine (protein-bound cortisol not filtered at glomerulus)

• Normal <146 nmol/24h

Adrenal Insufficiency Causes

Primary

• 75% autoimmune (Addison’s)

• 25% TB

Secondary

• Pituitary disease

• Iatrogenic e.g. adrenalectomy

Hydroadrenal crisis may be precipitated by infection - increased requirement for stress hormones

Adrenal Insufficiency Clinical Features

• Early: Anorexia, lethargy and weakness

• Hyperpigmentation on skin if primary

• Postural hypotension

• Nausea and vomitting

Addisonian Crisis

• Acute Adrenal insufficiency

• Post surgery/trauma

• Infection

• Hypotension, nausea and vomitting

Adrenal Insufficiency Investigations

• Raised lymphocytes and eosinophil

• Hyperkalaemia, hypnotaemia

• Hypoglycaemia

• Raised urea aka dehydration

• Low 9am cortisol

• Low aldosterone, raised renin

• Adrenal autoantibodies

Short Synacthen Test

For assessing adrenal insufficiency, dynamic function test

• Scynacthen is an ACTH analogue

• Basal cortisol measured

• GIve 250mg of synacthen IV

• Normal: 30min cortisol >450nmol/L

Hypoadrenal Patient

Cannot produce sufficient rise in cortisol in response to synacthen, usually also has low baseline cortisol

Adrenal Insufficiency Treatment

Replace deficient mineralocorticoids e.g. hydrocortisone and fludrocortisone

Adenal Medulla

• SNS

• Chromaffin cells secrete catecholamines e.g. adrenaline and noradrenaline

• Metabolised into metadrenaline

• Normetadrenaline

Catecholamines

• Dilates pupils

• Dilates bronchi

• ↑ heart rate

• ↑ blood to muscles

• ↑ blood pressure

• ↑ blood glucose

• ↓ digestion

Phaechomocytoma

• Tumours of chromaffin tissue in adrenal medulla

• Secrete excess catecholamines

Phaeochromocytoma Clinical Features

• Hypertension

• Anxiety

• Headaches

• Tachycardia and palpitations

• Flushing and sweating

Phaeochromocytoma Investigations

• 24h urine collection for metadrenalines

• Measured by HPLC with electrochemical detection

• Can also measure in plasma by tandem mass spectrum

Thyroid Hormones

• Controls basal metabolic rate, growth and development

• Derived from tyrosine (also contain iodine)

• Thyroxine (T4) prduced by thyroid gland

• Tri-iodothyronine (T3) produced by de-iodination of T4 in peripheral tissues

• Synthesis stimulated by TSH from pituitary

• Replace thyroxine

Hypothyroidism Causes

Primary (↑ TSH, ↓ T4)

• Hashimoto’s thyroiditis: chronic autoimmune lymphocytic destruction of gland

• Iodine deficiency

• Presents with goiters

• Iatrogenic e.g. thyroidectomy, radioiodine, anti-thyroid drugs

Secondary (↓ /N TSH, ↓ T4)

• Hypopituitarism from tumours, radiotherapy, surgery

• Defective TSH synthesis (genetic)

• Need to check other pituitary hormone axes in case of pan-hypopituitarism

Treatment: Replace thyroxine

Hypothyroidism Symptoms

• Hair loss

• Apathy, lethargy

• Dry skin

• Muscle aches

• Constipation

• Intolerance to cold

• Facial and eyelid edema

• Thick tongue

• Anorexia

• Brittle nails and hair

Hyperthyroidism Causes

Primary (suppressed TSH, ↑ T4, ↑ T3)

• Graves disease, from antibodies that stimulate TSH, presents with goiters

• Thyroid nodules, single or multiple - autonomous production of T4 and T3

Secondary is rare

Facititious, buying things online to lose weight

Treatment anti-thyroid drugs, thrydectomy, radioiodine abblation. Symptoms treated with β blockers

Hyperthyroidism Symptoms

• Finger clubbing

• Tremors

• Diarrhoea

• Amenorrhea

• Intolerance to heat

• Bulging eyes, facial flushing

• Tachycardia

• Muscle loss/wasting