Disorders of the hypothalamus and pituitary • Endocrinology is the study of the biological systems in the body that communicate with each other through the release of hormones. • The diagnosis and management of endocrine diseases rely heavily on laboratory tests often using a blood sample taken in the basal state. • Occasionally, stimulation or suppression testing may have to be performed to uncover more subtle abnormalities. Endocrine glands in the human head and neck and their hormones

2 Factors which regulate the release of anterior pituitary hormones. The principal hormones released by the posterior pituitary are oxytocin and . • The hypothalamus The hypothalamus is a complex region in the brain that coordinates many behavioural and circadian rhythms in addition to enforcing homeostatic mechanisms, on specific target glands. The hypothalamus secretes a number of hormones and other chemical agents that to the pituitary, where they regulate the release of anterior pituitary hormones. Concentrations of hypothalamic hormones in peripheral blood do not reflect hypothalamic activity and their measurement is not considered to be of clinical relevance. Factors that regulate the release of anterior pituitary hormones. • The The anterior pituitary is influenced by a variety of stimulatory and inhibitory hormones through these capillaries. The posterior pituitary is a collection of specialized nerve endings that derive from the hypothalamus. • Anterior pituitary hormones ‐ TSH (‐stimulating hormone), acts specifically on the thyroid gland to elicit secretion of thyroid hormones. ‐ ACTH (adrenocorticotrophic hormone) acts specifically on the adrenal cortex to elicit secretion of cortisol. ‐ LH (luteinizing hormone) and FSH ( follicle‐stimulating hormone), known jointly as the gonadotrophins, act cooperativelyontheovariesinwomenandthetestesin men to stimulate sex hormone secretion and reproductive processes. ‐ GH (growthhormone)actsdirectlyon many tissues to modulate metabolism. Metabolic fuels (e.g. glucose, free fatty acids) in turn modify GH secretion. ‐ Prolactin acts directly on the mammary glands to control lactation. Gonadal function is impaired by elevated circulating prolactin concentrations. The hypothalamic factors that control anterior pituitary hormone secretion are shown in this figure. Hypothalamic factors that regulate anterior pituitary functions. Pathophysiology • Abnormalities of the pituitary gland result from: – Oversecretion or; – Undersecretion • Abnormalities of posterior and anterior lobes can occur independently. • Oversecretion most commonly involves ACTH leading to Cushing’s syndrome, or GH leading to acromegaly. • Undersecretion: Involves the anterior pituitary hormones. • Deficient production of the ADH → , which is the most common disorder of the posterior lobe in which abnormally large volumes of dilute urine are excreted. 9

• It is hypofunction of the pituitary gland. • It results from disease of the pituitary gland itself (destruction of the anterior lobe) or of the hypothalamus. • Panhypopituitarism is total absence of all pituitary secretions and is rare. Postpartum pituitary necrosis is more likely to occur in women with severe blood loss, hypovolemia, and hypotension at the time of delivery. • Is a complication of radiation therapy. The total destruction of the pituitary gland results in extreme weight loss, emaciation, atrophy of all endocrine glands and organs, hair loss, impotence, amenorrhea, hypometabolism, and hypoglycemia. Coma and death may occur.

10 • Hyperprolactinaemia Hyperprolactinaemia is common and can cause infertility in both sexes. Causes of hyper‐ prolactinaemia include: ‐ stress (venepuncture is sufficient to raise plasma prolactin in some patients). ‐ drugs (e.g. oestrogens, phenothiazines, metoclopramide, α‐methyl dopa). ‐ seizures (acutely). ‐ primary hypothyroidism (prolactin is stimulated by the raised TRH). ‐ other pituitary disease. If these causes are excluded, the differential diagnosis is between: ‐ a prolactinoma (a prolactin‐secreting pituitary tumour, commonly a microadenoma). ‐ idiopathic hypersecretion, which may be due to impaired secretion of dopamine, the hypothalamic factor that inhibits prolactin release. A rise in serum prolactin following administration of TRH or metoclopramide is observed in idiopathic hyperprolactinaemia but not in the presence of a pituitary tumour. • Posterior pituitary hormones Hypothalamic neurons synthesize arginine vasopressin (AVP) and oxytocin, which pass along axonal nerve fibres in the pituitary stalk to the posterior pituitary where they are stored in granules in the terminal bulbs of nerves in close proximity to systemic veins. Secretion of AVP, also known as antidiuretic hormone (ADH), is stimulated by: ‐ increased plasma osmolality via hypothalamic osmoreceptors. ‐ severe blood volume depletion via cardiac baroreceptors ‐ stress and nausea. • Pituitary tumours Diagnosis Pituitary tumours may be either functional (that is they secrete hormones) or non‐functional.

Incidence of different types of pituitary tumours. Pituitary Tumors

• Are usually benign. • Their location and effects on hormone production can be life threatening. • Comprehensive assessment of anterior pituitary reserve requires a combined anterior pituitary function test. • TRH, GnRH and insulin are administered. All hormones are assessed at 0, 30 and 60 minutes, and GH additionally at 90 and 120 minutes. It is usual also to assess basal thyroid (thyroxine) and gonadal (testosterone or oestradiol) function.

15 Normal responses in a combined anterior pituitary function test. Clinical Manifestations Associated with Pituitary Tumors

• Gigantism : The affected person is – > 7 feet tall and large in all proportions – so weak that s(h)e can hardly stand • Excessive skeletal growth occurs only in the feet, the hands, the molar eminences, the nose, and the chin, giving rise to acromegaly.

17 • Cushing’s syndrome. Features include: – Masculinization & amenorrhea in women, truncal obesity, hypertension, osteoporosis, and polycythemia. • Patients are often obese and somnolent [feeling sleepy]. • Exhibit fine, scanty [inadequate] hair, dry, soft skin. • Experience headaches, loss of libido, and visual defects progressing to blindness. Other signs and symptoms include polyuria, polyphagia, and a subnormal body temperature.

18 Assessment and Diagnostic Findings

• Careful history and physical examination. – Assessment of visual acuity and visual fields. • Computed tomography (CT) and magnetic resonance imaging (MRI). • Serum levels of pituitary hormones. • Serum levels of hormones of target organs (eg, thyroid, adrenal).

19 Treatment ‐ Medical. Dopamine agonist drugs like bromocriptine and cabergoline are widely used to treat hyper‐ prolactinaemia, They may also be used to shrink large suprasellar prolactinomas before surgery. ‐ Surgery. Trans‐sphenoidal is the standard procedure. For the same reason, postoperative assessment of pituitary reserve should be deferred for several days. ‐ Radiation. The impact of radiation on pituitary function is cumulative, and irradiated patients require annual dynamic function testing of their anterior pituitary reserve thereafter. Diabetes Insipidus

• Diabetes insipidus is a disorder of the posterior lobe of the pituitary gland. • ADH is deficient. • Causes could be head trauma, brain tumor, or irradiation of the pituitary gland, infections of the CNS (meningitis, encephalitis, tuberculosis) or tumors (eg, metastatic disease, lymphoma of the breast or lung). Another cause is failure of the renal tubules to respond to ADH; this may be related to hypokalemia, hypercalcemia, and a variety of medications (eg, lithium,Declomycin).

21 Clinical Manifestations

• Enormous daily output of very dilute, water‐like urine. • Intensethirst:Thepatientdrinks2to20litersof fluid daily. • Fluid intake cannot be limited; otherwise the patient will experience crave for fluid and would develop hypernatremia and severe dehydration.

22 Assessment and Diagnostic Findings

• Fluid deprivation test for 8 to 12 hours. • The patient is weighed frequently during the test. • Perform plasma and urine osmolality studies before and after the test. • Low specific gravity and weight loss, rising serum osmolality, and elevated serum sodium levels. • Terminate the test if tachycardia, excessive weight loss, or hypotension develops. • Plasma levels of ADH (vasopressin) and plasma and urine osmolality.

23 Medical Management

Aims to: • Replace ADH • Ensure adequate fluid replacement • Identify and correct the underlying cause

24 Pharmacologic Therapy • Desmopressin (DDAVP), a synthetic vasopressin. • Intramuscular administration of ADH. • Clofibrate, a hypolipidemic agent, has an antidiuretic effect. • Chlorpropamide (Diabinese) and thiazide diuretics areusedinmildformsofthediseaseasthey potentiate the action of vasopressin. • Thiazide diuretics and prostaglandin inhibitors (ibuprofen, indomethacin, and aspirin) are used to treat the nephrogenic form of the disease.

25 Hypopituitarism There are many causes of hypopituitarism, a relatively uncommon condition in which there is failure of one or more pituitary functions. These causes include tumour, infarction, trauma, congenital malformation, infection and hypothalamic disorder. The clinical presentation of hypopituitarism depends on the age of the patient. In infancy, short stature or impaired development may point to the condition. In the reproductive years, womenmaypresentwithamenorrhoea or infertility. Men may present with decreased libido or a lack of male secondary sex characteristics. Elderly patients may complain of symptoms relating to ACTH or TSH deficiency such as hypoglycaemia or hypothermia.