Pituitary Adenomas Classified based on the basis of hormones produced + whether they are functional (associated with hormonal excess) or non-functioning (without clinical symptoms of hormone excess) Non-functional adenomas typically are larger at the time of diagnosis due to the lack of clinical syndromes associated with hormone release Peak incidence from 35-60 years of age Microadenomas < 1cm in diameter Macroadenoma > 1cm in diameter

Pituitary Cell typeHormoneTumor TypeAssociated Syndrome

CorticotrophACTH and other POMC derived peptidesACTH cell adenomaCushing syndrome + Nelson syndrome

SomatotrophGHGH cell adenomaGigantism (children)/ Acromegally (adults)

LactotrophProlactinProlactin cell adenomaGalactorrhea and amenorrhea (females), sexual dysfunction, infertility

MammosomatotrophProlactin + GHMammosomatotrophCombined GH and prolactin symptoms

ThyrotrophTSHTSH cell adenomaHyperthyroidism

GonadotrophFSH + LHGonadotroph null cell oncocytic adenomasHypogonadism, mass effects and hypopituitarism

G-protein mutations are common in pituitary tumours 95% of adenomas are sporadic in nature (5% arise from an inherited predisposition) As many as 30% of adenomas are not grossly encapsulated and can infiltrate the cavernous and sphenoid sinuses, dura and occasionally the brain itself Cavernous sinus contains III, IV and VI cranial nerves so nerve lesions may occur with invasion Headache can arise from the bony structures or meninges Mass effect on the hypothalamus ( altered appetite, obesity, thirst, somnolence/wakefulness or precocious puberty Sphenoid sinus invasion can cause CSF rhinorrhoea Generalised signs: radiographic abnormalities, visual field abnormalities, raised intra-cranial pressure and occasionally hypopituitarism

Prolactinomas

Most frequent type of hyperfunctioning pituitary adenoma (30% of cases) Proportionally the serum prolactin concentrations tend to correlate with the size of the adenoma Increased serum levels of prolactin ( amenorrhea, galactorrhea, loss of libido and infertility Diagnosis is made more readily in women due to the disruption of menses Prolactinoma underlies almost 25% of cases of amenorrhoea In men and older women diagnosis may be more difficult Physiologic hyperprolactinaemia occurs in pregnancy and during breast feeding; pathologic HP also results from lactotroph hyperplasia (abnormality in dopaminergic inhibition); any mass in in the suprasellar compartment disturbs pituitary secretion therefore prolactin may be slightly increased in other tumoursGH Cell Adenomas

Second most common type Children ( gigantism generalised increase in body size with disproportionately long asms and legs Post-epiphyseal plate closure ( acromegaly growth in skin, soft tissues, viscera (thyroid, heart, liver and adrenals), and bones of the face, hands and feet ( protrusion of the jaw (prognathism), broadening of the lower face, enlarged hands and feet Also associated with gonadal dysfunction, diabetes mellitus, generalised muscle weakness, hypertension, arthritis, CCF, and increased risk of gastrointestinal cancers

ACTH Cell Adenomas

Hypercortisolism ( Cushing syndrome Large destructive adenomas can develop in patients after surgical removal of the adrenals (for treatment of Cushings) due to the loss of the inhibitory function of adrenal corticosteroids = Nelson syndromeInvestigations MRI Visual fields Hormone serologyAcromegaly A rare, potentially life-threatening condition that involves increased and unregulated growth hormone (GH) production, usually caused by a GH-secreting pituitary tumour (somatotroph tumour)

Epidemiology 1 in 3-4 million people Mean age of 40-45 years Mortality rate is twice that of normal population Have increased risk of cardiorespiratory, cerebrovascular diseases, diabetes and neoplasis, esp colon cancer Occurs with equal frequency in males and females

Pathophysiology More than 95% of cases caused by pituitary adenoma that secretes excess amounts of GH 5% caused by:

increased GHRH (GH releasing hormone) from hypothalamic tumours ectopic GHRH from non-endocrine tumours ectopic GH secretion by non-endocrine tumours Pathologic effects of excess GH Acral overgrowth macrognathia; enlargement of the facial bone structure; enlarged hands and feet; visceral overgrowth, including macroglossia and enlarged heart muscle, thyroid, liver, kidney Insulin antagonism Nitrogen retention Increased risk of colon polyps/tumours

Clinical Features Acromegaly can be an insidious disease. Symptoms might precede diagnosis by several years. Symptoms can be divided into 2 groups:

Symptoms due to local mass effects of the tumourSymptoms depend on the size of the intracranial tumour Headaches and visual field defects are the most common symptoms. Visual field defects depend on which part of the optic nerve pathway is compressed. Bitemporal hemianopsia due to pressure on the optic chiasm. Hyperprolactinemia dueto tumor damage to the pituitary stalk which cause loss of inhibitory regulation of prolactin secretion by the hypothalamus. Damage to normal pituitary tissue can cause deficiencies of glucocorticoids, sex steroids, and thyroid hormone. Loss of end organ hormones is due to diminished anterior pituitary secretion of corticotropin (ie, adrenocorticotropic hormone [ACTH]), gonadotropins (eg, luteinizing hormone [LH], follicle-stimulating hormone [FSH]), and thyrotropin (ie, thyroid-stimulating hormone [TSH]). Symptoms due to excess of GH/IGF-I Soft tissue swelling and enlargement of extremities Increase in ring and/or shoe size Hyperhidrosis Coarsening of facial features Frontal bossing Nose thickening Macroglossia (tongue hypertrophy) Prognathism (abnormal protrusion of mandible)

Arthritis Increased incidence of obstructive sleep apnea Increased incidence of glucose intolerance or frank diabetes mellitus, hypertension, and cardiovascular disease Hyperphosphatemia, hypercalcuria, and hypertriglyceridemia possible Increased incidence of congestive heart failure, which might be due to uncontrolled hypertension or to an intrinsic form of cardiomyopathy attributable to excess GH/IGF-I Increased incidence of colonic polyps and adenocarcinoma of the colon

Investigations Because GH secretion is inhibited by glucose, measurement of glucose nonsuppressibility might be useful. Two baseline GH levels are obtained prior to ingestion of 75 or 100 g of oral glucose, and additional GH measurements are made at 30, 60, 90, and 120 minutes following the oral glucose load. CT scan of the abdomen/pelvis evaluates for pancreatic, adrenal, or ovarian tumors secreting GH/GHRH. Chest CT scanning evaluates for bronchogenic carcinoma secreting GH/GHRH.

Management Surgery as the first line of treatment, followed by medical therapy for residual disease Surgery: Transsphenoidal hypophysectomy has the dual advantage of rapidly improving symptoms caused by mass effect of the tumor and significantly reducing or normalizing GH/IGF-I concentrations Medical: Somatostatin and dopamine analogues and GH receptor antagonists are the mainstays of medical treatment and are generally used after failure of primary surgery to induce complete remission

Diabetes Insipidus

Definition and Pathophysiology

A disorder that causes the patient to produce tremendous quantities of dilute urine. The massively increased urine output is usually accompanied by intense thirst. Central/cranial DI : Due to decreased secretion of antidiuretic hormone (ADH) by hypothalamusalso known as arginine vasopressin (AVP)which gives rise to polyuria and polydipsia by diminishing the patients ability to concentrate urine. Result of a defect in 1 or more sites involving the hypothalamic osmoreceptors, the supraoptic or paraventricular nuclei, or the supraopticohypophyseal tract. Nephrogenic DI Decrease in the ability to concentrate urine due to unresponsiveness of renal tubules to ADH. Nephrogenic DI can be observed in chronic renal insufficiency, lithium toxicity, hypercalcemia, hypokalemia, and tubulointerstitial disease; rarely, diabetes insipidus may be hereditary.Epidemiology Uncommon in the United States, with a prevalence of 1 case per 25,000 population. No significant sex differences in central or nephrogenic diabetes insipidus exist: male and female prevalences are equal. The prognosis is generally excellent, depending upon the underlying illness. Mortality is rare in adults as long as water is available. Complication: Severe dehydration, hypernatremia, fever, cardiovascular collapse, and death can ensue in children, elderly people, or in those with complicating illnesses.Etiology

30% of DI cases are idiopathic, 25% are related to malignant or benign tumors of the brain or pituitary, 20% follow cranial surgery, and 16% are secondary to head trauma. Genetic: autosomal dominant Idiopathic DI ( destruction of cells in the hypothalamus, often as part of an autoimmune process Structural hypothalamic or high stalk lesion Primary or secondary tumours, cyst, haemorrhage The most common causes of postoperative polyuria are excretion of excess fluid administered during surgery and an osmotic diuresis resulting from treatment for cerebral edema. Metabolic abnormality: hypokalaemia, hypercalcaemia Chronic kidney disease: polycystic kidney disease, etcDifferential Diagnosis

Diabetes mellitus Primary polydipsia (often seen in psychiatric pt)Clinical Features

The clinical presentation of diabetes insipidus (DI) depends on the cause, the severity, and the associated medical condition(s) of the patient. History Polyuria, polydipsia, and nocturia (from 3-18 L) are the predominant symptoms.

urine is of low specific gravity and osmolality

if pt is conscious -> can maintain adequate fluid intake

if pt is unconscious -> DI is lethal

In infants, crying, irritability, growth retardation, hyperthermia, and weight loss may be the most apparent signs.

In children, enuresis, anorexia, linear growth defects, and fatigability typically predominate.

Pregnancy is associated with an increased risk of DI.

Many patients have a predilection for drinking cold liquids, often water. Neurologic symptoms vary with the patients access to water; patients with free access may have no symptoms at all. Physical Examination

Varies with the severity and chronicity of DI.

The examination findings may be entirely normal.

Hydronephrosis, bladder enlargement, and signs of dehydration are common.

Investigations Water deprivation testing Use: to establish diagnosis of DI and differentiate cranial and nephrogenic causes Measure plasma osmolality and urine osmolality hourly after water intake is withheld DI is confirmed if plasma osmolality is elevated (>300mOsm/kg, normal is 275-299) with a urine osmolality is 850) If healthy: water deprivation leads to urine osmolality that is 2-4 times greater than plasma osmolality Cranial DI: if urine osmolality arises by at least after admisitration of exogenous ADH Nephrogenic: kidney fails to respond to exogenous ADH to concentrate the urine

Management

DDAVP (des-amino-des-aspartate-arginine vasopressin desmospressin An ADH analogue -> to reliev inadequate thirst in central DI Polyuria in nephrogenic insipidus is improved by thiazide diuretics, amiloride and NSAIDsSyndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)Definition The hyponatremia and hypo-osmolality resulting from inappropriate, contined secretion or action of the hormone despite normal or increased plasma volume, which results in impaired water excretionPathophysiology

Nonphysiological secretion of ADH results in enhanced water absorption, leading to dilutional hyponatremia and volume expansion Volume receptors are activated and natriuretic peptides are secreted, which causes natriuresis and some degree of accompanying potassium secretion. Eventually, a steady state is reached and the amount of Na+ excreted in the urine matches Na+ intake Ingestion of water is an important factor to the development of the syndrome; regardless of cause, hyponatremia does not occur if water intake is severely restrictedEtiology

Most often caused by either inappropriate hypersecretion of ADH from its normal hypothalamic source or by ectopic production Can be divided into 4 broad categories:

Nervous system disorders

Neoplasia

Pulmonary diseases

Drug induced (which include those that [1] stimulate AVP release, [2] potentiate effects of AVP action, or [3] have an uncertain mechanism)

Clinical Features In general, slowly progressive hyponatremia is associated with fewer symptoms than is a rapid drop of serum Na+to the same value Some patients with profound hyponatremia may be relatively asymptomatic. Anorexia, nausea, and malaise are early symptoms and may be seen when the serum Na+ level is less than 125 mEq/L. A further decrease in the serum Na+ level can lead to headache, muscle cramps, irritability, drowsiness, confusion, weakness, seizures, and comaInvestigations Laboratory testing:

Electrolytes (low Na+ level)

Creatinine

Blood urea nitrogen

Uric acid (usually low)

TSH (to rule out hypothyroidism)

8 am cortisol (to rule out adrenal insufficiency)

Urinalysis: increased osmolarity