Endocrinology

Pituitary and Adrenal disease

Introduction

The anterior pituitary resembles a number 6 shape and secretes 6 peptide hormones

Anatomy and physiology of the pituitary

  • Gland lies within the sella turcica within the sphenoid bone bounded by the sphenoidal sinus below and laterally the cavernous sinuses containing cranial nerves III, IV, V1, V2, VI from top down
  • Above lies the optic chiasma and hypothalamus and the pituitary stalk
  • Anterior pituitary produces 6 Hormones - ACTH, TSH, Prolactin, LH, FSH, GH under the stimulation or inhibition of hypothalamic factors released into the hypophyseal veins which are then transported to the anterior pituitary where they act.
  • Posterior pituitary stores and releases 2 hormones - Oxytocin and ADH (Vasopressin)
  • Secretion, Symptoms and signs:by a pituitary hormone deficiency (often more than one is low at same time)
  • ACTH release peaks at 8 am and is lowest in the evening

Hypopituitary - reduced pituitary function results in

  • Reduced cortisol (but preserved mineralocorticoids compared with Addison's disease)
  • Prolactin release may be increased if stalk compressed and not inhibited by dopamine. Proactin levels on the other hand can be low (sheehan's syndrome). Loss causes Loss of ability to lactate.
  • Reduced LH, FSH causes infertility. They are released due to pulsatile GnRH release. Continuous GnRH reduces LH FSH . Deficiency causes decreased sex drive, impotence, amenorrhoea
  • GH : pulsatile secretion during day peaks early in sleep. Stimulates IGF-1. Loss causes reduced growth and height in before epiphyses fuse. Loss of sense of well being and muscle bulk.
  • TSH ? leads to hypothyroidism. Stimulated by hypothalamic TRH. TSH stimulates release of T3 T4

Clinical of hormone excess ususally due to benign adenomas

  • ACTH : increased cortisol (Cushing's disease) with Cushing's syndrome stimulates adrenal formation of steroids from cholesterol
  • Prolactin : stimulates lactation post partum
  • hyperprolactinaemia - lactation and hypogonadism
  • GH : stimulates connective tissue cells to release Insulin like growth factor 1 which causing Acromegaly and Giantism
  • TSH : leads to hyperthyroidism which is very rarely due to excess TSH
  • LH, FSH - very rare - They stimulate gonadal function.

Symptoms caused by a pituitary mass ? ?3 H of Headache, hemianopia, hypopituitarism

  • Morning headache, CSF rhinorrhoea
  • Bitemporal hemianopia from damage to optic chiasma
  • Cavernous sinus extension - III, IV and VI causing ophthalmoplegia and V1 and V2 causing facial pain
  • Mild raised prolactin "Stalk effect" : see below
  • Hypopituitarism : see below

Hypopituitarism Loss usually in following order

  • GH ? reduced growth and stature in children and hypoglycaemia in children
  • Loss of muscle mass and body mass in adults.
  • FSH/LH : amenorrhoea and loss of secondary sexual characteristics
  • TSH - hypothyroidism
  • ACTH ? secondary hypoadrenalism but mineralocorticoids unaffected than with Addison?s disease
  • Prolactin : failure of postpartum lactation
  • Other findings - thin fine wrinkled skin
  • Truncal fat and reduced muscle bulk
  • Loss or reduced axially and pubic hair (secondary sexual characteristics).

Causes

  • Pituitary adenoma (functioning or non functioning)
  • Sheehan's syndrome (ask About post partum bleeding)
  • Empty sella syndrome
  • Post surgical or radiation

Clinical

  • Impotence (men), amenorrhoea (women) , weakness, tiredness, cold
  • Loss of axillary and pubic hairs and beard growth in men
  • Hypotension and Bitemporal hemianopia and headache if tumour - Keep a close watch on fields and acuity
  • Cavernous sinus extension - III, IV and VI causing ophthalmoplegia and V1 and V2 causing facial pain
  • Mild raised prolactin "Stalk effect" ? compression of pituitary stalk leads to loss of dopamine inhibition on pituitary and rise in prolactin

Investigations

  • Anaemia and hyponatraemia, hypernatraemia if Diabetes insipidus
  • Hypoglycaemia if GH deficient
  • Low testosterone, Low T4 and low TSH
  • Deficient cortisol response to ACTH, slight raise prolactin due to stalk effect
  • MRI pituitary - Tumours are Graded by Vertical height on MRI : > 10 mm = macroadenoma , 10 mm = mesoadenoma, < 10 mm = microadenoma, Look for local destructive lesion.

Management

  • Surgical removal of tumour, medical management of prolactinoma
  • Replacement of hormones
    • FSH/LH - Testosterone patch or im in adult males
    • Oestrogen in women.
    • TSH - Thyroxine to normalise T4
    • ACTH - Hydrocortisone 20 mg am and 10 mg pm
    • GH - often no replacement except in children and adults who meet certain criteria. There is a cost issue.

Prolactinoma

Introduction

  • Commonest secreting pituitary tumour causing nearly 30% of pituitary tumours.
  • However often asymptomatic in men and found not uncommonly at Post mortem.
  • Diagnosed more in women who get menstrual irregularities.

Clinical

  • Often none and silent until late - found post mortem if at all.
  • Galactorrhoea when PRL very high, Amenorrhoea
  • Reduced oestrogen causes breast and vaginal atrophy
  • Hypogonadism as PRL suppresses testosterone level
  • Tumour effects : headache, hemianopia, hypopituitary

Investigations

  • PRL high usually > 2000
  • Testosterone low due to PRL effect and not necessarily hyopituitary
  • MRI shows adenoma - micro/meso/macro
  • Assess for pituitary hypofunction

Management

  • Medical - The only pituitary tumour where medical treatment is the usually sufficient and curative
  • Cabergoline/Bromocriptine is effective in most cases to shrink tumour. May be continued with surveillance.
  • Transphenoidal hypophysectomy if medical treatment fails or radiotherapy

Acromegaly

Introduction

  • Pituitary somatotroph adenomas, usually an 'acidophil' macroadenoma
  • Some are due to specific G-protein mutations

Clinical

  • Acromegaly commences before the epiphysis have fused then the result is giantism with increased length of long bones
  • Hypertension, Sweating, Enlarged nose, Increased space between teeth, Gigantisms if onset before epiphyses fuse,
  • Spade like hands and thick skin, Hat and Rings don?t fit, Prominent supraorbital ridges with enlarged frontal sinuses and Prognathism (lower jaw increased growth)
  • Enlarged Liver, Heart, tongue, lips, nose, hands, carpal tunnel syndrome, feet, heel pad thickness
  • Hyperglycaemia and Type 2 DM and Myopathy
  • Colonic cancer in 5% ( age > 50, duration of acromegaly > 10 years and the presence of 3 or more skin tags)
  • Headache, hemianopia, hypopituitarism

Investigations

  • IGF-1 Elevated : The best single screening test for the diagnosis of acromegaly
  • GH level: Varies and so of little use except that undetectable levels rule out Acromegaly
  • However usually it is elevated but that is not diagnostic.
  • GH level fails to fall in response to a Glucose tolerance tests : Hyperglycaemia should cause a reduction in GH level but not in patients with acromegaly
  • There is a failure to suppress GH with an OGTT and sometimes a Paradoxical GH rise with an OGTT
  • MRI : Adenoma seen in 90% with enlarged sella and thickened skull and prognathism
  • Prolactin raised in about 30 %

Management

  • Surgical - Selective transsphenoidal surgical resection is the treatment of choice for patients with somatotroph adenomas that are small or large but still resectable
  • Transfrontal surgery is only used for rare massive tumours.
  • Medical - Octreotide and lanreotide are analogs of somatostatin and reduce GH secretion and may be used as therapy
  • Cabergoline a dopamine agonist may also be given in addition.
  • External beam Radiotherapy to the pituitary tends to be used post surgery
  • Growth hormone antagonists shows good results but is used currently as adjunctive therapy to the other treatments e.g
  • Pegvisomant has been shown to improve symptoms and lower IGF1 in those with acromegaly
  • Pituitary hormones replacement

Cushing's disease

Introduction

  • Cushing's syndrome due to a pituitary ACTH secreting adenoma

Clinical

  • Systemic effects as for Cushing's syndrome
  • Tumour effects usually minimal as microadenoma or hyperplasia
  • Possible Hypopituitarism

Investigations

  • U&E: Hypokalaemia
  • 24 hr urinary free cortisol elevated, Plasma ACTH high
  • Cortisol fails to be suppressed even after 1 mg Dexamethasone suppression test (Give Dexamethasone 1 mg at 10 pm and check 8 am cortisol)
  • Localising source - Dexamethasone 2 mg qds for 2 days suppresses pituitary disease and cortisol levels by 50% but not when due to other causes.
  • Pituitary MRI (50% are normal)
  • Petrosal sinus ACTH sampling if MRI Normal

Management

  • Transphenoidal pituitary resection
  • Untreated 50% 5 year mortality

Sheehan's syndrome

Introduction

  • Pituitary hyperplasia and hypertrophy of the lactotrophs at end of pregnancy vulnerable to ischaemia with any drops in perfusion such as postpartum haemorrhage
  • Does not show clinically until later and the clues are postpartum failure to lactate and amenorrhoea

Clinical

  • Gradual appearance of signs and symptoms of hypopituitarism.
  • Posterior pituitary involvement may result in diabetes insipidus.
  • No Symptoms - However, up to 70% of the anterior pituitary mass

Investigations

  • Prolactin is low and biochemically Hypopitutary

Management

  • Hormone replacement

Pituitary apoplexy

Introduction

  • A pituitary tumour either haemorrhages or infarcts
  • Seen more so with larger macroadenomas

Clinical

  • Pre-existing symptoms of a macroadenoma and then severe headache, coma
  • Hypotensive shocked with secondary hypoadrenalism
  • Ophthalmoplegia, Bitemporal hemianopia, Subarachnoid haemorrhage

Investigations

  • U&E, Random cortisol low, TFTs - Low TSH
  • CT/MRI ?may show a pituitary tumour, local haemorrhage or subarachnoid bleed and haemorrhage within the tumour
  • Hypopituitarism

Management

  • Hormone replacement Hydrocortisone 100 mg im stat and then qds to manage acute period.
  • Urgent neurosurgical referral and transphenoidal surgery
  • Pituitary hormone replacement

ADRENAL GLAND

Introduction

Physiology of the Adrenal Medulla

  • Secretes Catecholamines but no clinic effects of losing adrenal medulla
  • Catecholamines are produced from the amino acid Tyrosine which is hydroxylated to Dopa
  • Dopa then decarboxylated to Dopamine and hydroxylated to Noradrenaline
  • Noradrenaline is N-methylated to Adrenaline (coenzyme is S-adenosylmethionine SAM)

Physiology of Adrenal cortex

  • Zona glomerulosa : secretes Aldosterone maintains sodium homeostasis and extracellular volume
  • Zona fasciculata : secretes glucorticoids (21 carbons)
  • Zona reticularis : secretes glucorticoids and Androgens (19 carbons)

Addison's Disease

Note: Have a low threshold for doing a Short SYNACTHEN test

Introduction

  • Loss of adrenal cortical function - steroid and glucocorticoid function
  • Potentially fatal if missed and untreated

Causes

  • Autoimmune disease in 90% (associated Pernicious anaemia, thyroid disease etc.)
  • Local destruction - malignancy, Tuberculosis
  • Withdrawal of long term steroids (Adrenals are suppressed)
  • Haemorrhage with Meningococcal septicaemia
  • Adrenal vein thrombosis
  • HIV disease and opportunistic infections
  • Secondary to pituitary disease and loss of ACTH

Clinical :

  • Weight loss, anorexia, lethargy, dehydration, hypotension, postural hypotension, vitiligo, depression
  • Acutely with abdominal pain, weakness and hypovolaemia and an adrenal crisis
  • Pigmentation (due to excess ACTH) of skin creases, buccal cavity (not seen with pituitary hypoadrenalism)

Investigations

  • FBC - increased WCC : mainly neutrophils and eosinophils
  • U&E hyponatraemia, hyperkalaemia and raised urea and hypoglycaemia
  • Cortisol can be assessed at 8 am and is < 180 nmol/l in hypoadrenalism
  • Short SynACTHen test - Cortisol levels is low and fails to rise in response to ACTH 250 mcg IM or IV
  • 30 minute cortisol < 500 nmol/L suggests hypoadrenalism
  • CT/MRI adrenals may show localised disease or atrophy or haemorrhage
  • TSH can be mildly elevated
  • CXR - Tuberculosis or lung cancer, some quote small cardiac
  • Calcium can be elevated

Management

  • Acute Adrenal crises - Hydrocortisone 100 mg im stat then 6 hrly iv or im
  • 1 L 0.9% saline over 30 minutes and fluid replaced as guided clinically, pulse, BP, JVP, CVP
  • IV dextrose if hypoglycaemia
  • Long term : Hydrocortisone 20 mg on waking and 10 mg evening dose Fludrocortisone 50-300 mcg od titrated to Blood pressure and U&E (not needed usually when hypoadrenalism due to pituitary as mineralocorticoid responses not affected significantly) Medic-alert bracelet and instruction to increase steroid dose (double) when sick and seek medical help.

Primary hyperaldosteronism (Conn's syndrome)

Note: Interestingly oedema is not seen (unlike many causes of secondary hyperaldosteronism) - Aldosterone induces sodium and water retention but this is followed within a few days by a spontaneous diuresis (called aldosterone escape) that returns excretion to the level of intake and partially lowers the extracellular fluid volume toward normal thus avoiding any clinically significant oedema

Introduction

  • A cause of hypokalaemic hypertension

Causes

  • Aldosterone secreting adrenal adenoma - 75%
  • Bilateral Adrenal Hyperplasia 25%
  • Adrenal carcinoma - rare
  • Glucocorticoid remedial aldosteronism - rare

Clinical

  • Hypertension, hypokalaemic
  • Lethargy, weakness, polyuria, nocturnal

Investigations

  • Mild hypernatraemia, Low Potassium, Low magnesium, Raised Cl- , raised bicarbonate (Mild Metabolic alkalosis)
  • Raised Aldosterone and Low Renin
  • Aldosterone/Renin Ratio > 30:1 : morning sample standing for some time
  • Correct hypokalaemia and stop diuretics, beta blockers and NSAIDs first
  • Localise with CT/MRI and confirm with adrenal venous sampling

Management

  • Bilateral adrenal hyperplasia - Spironolactone and surgery generally not advised
  • Adenoma - Spironolactone and then (Laparoscopic) Surgery for adenoma/carcinoma
  • Aldosterone blockers are under trial e.g. Eplerenone
  • Dexamethasone for glucorticoid remedial aldosteronism
  • Antihypertensive agents as hypertension may not resolve

Phaeochromocytoma

Note : Approximately 10% are malignant,extraadrenal, familial, seen in children, bilateral, calcify, recur after removal

Introduction

  • Rare cause of hypertension which may be paroxysmal

Associations and gene mutation (Bilateral disease more common)

  • Von Hippel-Lindau syndrome (VHL tumour suppressor gene)
  • Neurofibromatosis Type 1
  • MEN type (2 RET oncogene)
  • Paragangliomas : Succinate dehydrogenase subunits D and B

Clinical

  • Hypertension sometimes paroxysmal or sustained can cause stroke and heart failure
  • Paroxysmal Headaches, sweating and palpitations, Impaired glucose tolerance and diabetes
  • Chest pain and anginal Symptoms, Epigastric pain, sense of impending doom

Investigations

  • Elevated 24 hour urinary catecholamines/urinary metanephrines (VMA and HVA) should be measured
  • CT or MRI best identify tumour and can look in thorax if no adrenal lesion seen
  • Histology - nests of chromaffin cells
  • I-123 MIBG scan is sensitive and specific as it is taken up by chromaffin cells and can show up disease outside the adrenals
  • Selective venous sampling in selected cases

Management

  • Avoid beta blockade alone as this can worsen BP or cause pulmonary oedema
  • Doxazosin is often used first line.
  • Surgical resection (laparoscopically) should be proceeded by first alpha blockade with phenoxybenzamine and then Beta blockade eg propranolol.
  • Blood pressure can fall precipitously intraoperatively as the tumour is removed and the patient may need volume replacement
  • Metyrosine (alpha methyltyrosine) (blocks catecholamine synthesis) for inoperable tumours

Beta blockers given alone can worsen the hypertension with phaeochromocytomas

Cushing's syndrome

Introduction - a clinical syndrome due to excessive corticosteroids irrespective of source

Causes

  • Exogenous Steroids used long term or intermittently for Asthma, Rheumatoid arthritis, PMR, Ulcerative colitis, Transplant and where immunosuppression required
  • Pituitary adenoma producing ACTH (Cushing disease) : High ACTH and high cortisol, May have pituitary tumour causing headache and hypopituitarism
  • Ectopic ACTH seen with Malignancy : Small cell carcinoma of lung, Bronchial carcinoid, Pancreatic tumours with a high ACTH
  • Adrenal adenoma/carcinoma : Low ACTH and high cortisol and systemic symptoms of malignancy

Clinical

  • Obesity - centripetal truncal and livid purple striae
  • Hypertension and headache, Moon face and Facial plethora and acne, Osteopenia and back pain and proximal myopathy
  • Thin fragile skin and bruising
  • Avascular necrosis of femoral head
  • Diabetes and Impaired glucose tolerance
  • Psychosis and neuropsychiatric disorders
  • Menstrual disorders and impotence
  • Dorsocervical fat pad "Buffalo hump"
  • Impaired growth in children
  • Septicaemia, Immunosuppression, TB reactivation

Investigations

  • U&E: Hypokalaemia is more likely when there is a malignant source of ACTH
  • Screening tests - either 24 hr urinary free cortisol elevated or more simply the low dose Dexamethasone suppression test (Give Dexamethasone 1 mg at 10 pm and check 8 am cortisol)
  • High dose Dexamethasone suppression test 1 mg 6 hrly for 48 hrs and then measure cortisol
  • Pituitary Cushing's are suppressed and adrenal and ectopic ACTH Cushings is not suppressed.
  • Plasma ACTH high with Pituitary
  • Plasma ACTH low with Adrenal Cushings
  • Adrenal CT/MRI for suspected adrenal source of cortisol
  • Pituitary MRI if pituitary ACTH adenoma suspected
  • Petrosal sinus ACTH sampling if MRI Normal (50% are normal)

Management

  • Pituitary - Transphenoidal pituitary resection
  • Adrenal - Surgical resection
  • Ectopic - treat source and/or metyrapone or aminoglutheamide

Congenital Adrenal hyperplasia

Introduction

  • An inherited Enzyme defect in one or more of the pathways to produce glucocorticoids, mineralocorticoids and sex steroids can lead to failure to suppress ACTH and secondary adrenal hyperplasia and overproduction of other steroid hormones along functioning pathways.

Different types

  • Autosomal recessive Cytochrome p450 enzyme mutations leads to deficiencies of cortisol, mineralocorticoids and sex hormones
  • Lack of negative feedback leads to increased ACTH and adrenal hyperplasia
  • 90% are 21 Hydroxylase gene defects - various mutations and phenotypes
  • 5% are 11 beta hydroxylase deficiency and 17 alpha hydroxylase

Clinical

  • 21 Hydroxylase deficiency (CYP21) : Classical Deficiency of aldosterone and cortisol and excess androgens (ambiguous genitals in female) and Acute illness with adrenal crisis and salt wasting sometimes in newborn
  • Hypotension, Hyponatraemia, hyperkalaemia and hypoglycaemia, virilised females with clitoromegaly and fused labia - "ambiguous genitalia"
  • Male babies show signs of early puberty
  • There are various non classical more low key presentaitons with mild virilisation.
  • 11 beta hydroxylase deficiency (CYP11B1) :Ambiguous genitals in female and virilsation of male and eventual Hypertension due to excess mineralocorticoid activity
  • 17 alpha hydroxylase (CYP17) : Defects in cortisol and sex hormones
  • Delayed puberty in females.

Investigations

  • CYP21 - Low cortisol and aldosterone, Markedly elevated 17 (OH) progresterone, Elevated Testosterone and Androstenedione, ACTH levels elevated (not in milder forms)
  • CYP11B1: Low cortisol and aldosterone, Slight increase in 17(OH)progesterone, Elevated 11-deoxycortisol and testosterone and androstenedione
  • CYP17: Low cortisol and aldosterone, Low 17(OH) progesterone, Low testosterone and DHA and androstenedione

Management

  • Suppress activity with Steroids, Hydrocortisone, Fludrocortisone

Adrenal Incidentalomas

  • Adrenal masses may be picked up on CT/MRI
  • Screen for Cushing's and Phaeochromocytoma
  • Consider Resection for large masses

Multiple endocrine neoplasia

MEN Type 1 Wermer's syndrome

  • Autosomal dominant - Menin gene Chromosome 11
  • Inactivation of tumour suppressor gene MEN1
  • Parathyroid adenoma with hypercalcaemia
  • Pituitary adenoma
  • Pancreatic endocrine tumour - gastrinoma, insulinoma

MEN Type IIa Sipple syndrome

  • Autosomal dominant inherited
  • Activating mutation on the RET proto oncogene chromosome 10.
  • Primary Hyperparathyroidism with hypercalcaemia
  • Medullary carcinoma of the thyroid with hypocalcaema due to calcitonin
  • Phaeochromocytoma

MEN Type IIb

  • Autosomal dominant activating mutation on the RET proto oncogene chromosome 10.
  • Primary Hyperparathyroidism- hypercalcaemia
  • Medullary carcinoma of the thyroid- calcitonin induces hypocalcaemia
  • Phaeochromocytoma
  • Ganglineuromas on face and lips, tongue and a Marfanoid appearance

Investigations

  • Genetic studies
  • MEN 1 : Ca/PTH, Glucose, Insulin, Gut hormone scan, Chromogranin A, PRL, IGF-1, MRI of pancreas and pituitary
  • MEN II: calcitonin, urinary catecholamines, Adrenal MRI

Management

  • As for individual tumours