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Pituitary and Hypothalamic Disorders


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Pituitary and Hypothalamic Disorders

  1. 1. Seminars for the 5th year international students Prof. MUDr. Jiří Horák Pituitary and Hypothalamic Disorders Physiology Growth Hormone is a 191-amino acid peptide. Secretion is stimulated by two hypothalamic growth hormone-releasing hormones and inhibited by the hypothalamic tetradecapeptide somatostatin. GH binds to receptors in the liver and induces insulin-like growth factor 1, which mediates most of the growth- promoting effects of the growth hormone. Prolactin has 198 amino acids. Its secretion is under inhibitory control by hypothalamic dopamine. TRH and vasoactive intestinal polypeptide (VIP) are prolactin-releasing factors. Prolactin levels increase during pregnancy, enhancing breast development. Postpartum prolactin stimulates milk production. Evaluation of prolactin reserve: prolactin levels increase 3 to 5fold 15 to 30 minutes after TRH administration (200 µg i.v.) Thyroid-stimulating hormone (TSH) 28,000 dalton glycoprotein hormone. TSH secretion is stimulated by the hypothalamic tripeptide TRH. Negative feedback inhibition of TSH secretion by peripheral thyroid hormones. Adrenocorticotropic Hormone (ACTH) A 39-amino acid peptide. Hypothalamic corticotropin-releasing hormone (CRH) stimulates ACTH secretion. Cortisol exerts a negative feedback effect on ACTH and CRH. Gonadotropins (LH and FSH) Hypothalamic GnRH regulates LH and FSH secretion. Gonadal steroids exert both positive and negative feedback effects on gonadotroph secretion. LH stimulates gonadal steroid secretion by testicular Leydig cells and by the ovarian follicles. In females, the ovulatory LH surge results in rupture of the follicle and then luteinization. In males, FSH stimulates Sertoli cell spermatogenesis, and in females, follicular development. 1/10
  2. 2. Seminars for the 5th year international students Prof. MUDr. Jiří Horák Pituitary adenomas Clin: headache, visual loss (typically bitemporal hemianopia), syndromes of hypopituitary hormone hypersecretion and hyposecretion, and incidentally discovered sellar enlargement. Hypothalamic dysfunction In children and young adults, craniopharyngioma is the most frequent cause of hypothalamic dysfunction. Clin: visual loss, symptoms of raised intracranial pressure {headache and vomiting), hypopituitarism including growth failure, and diabetes insipidus. Hypothalamic disturbances: disorders of thirst (dehydration or polydipsia and polyuria), appetite (hyperphagia and obesity), temperature regulation, behaviour, and consciousness (somnolence and emotional lability). Craniopharyngeoma is treated primarily with surgical resection and then radiotherapy. Hypopituitarism results from diminished secretion of one or more pituitary hormones. Pituitary insufficiency is usually a slow, insidious disorder. Growth Hormone Deficiency during infancy and childhood growth retardation, short stature, and fasting hypoglycemia. In adults: increased abdominal adiposity, reduced strength and exercise capacity, cold intolerance, impaired psycho-social well-being. Adult GH deficiency is usually accompanied by other symptoms of panhypopituitarism. TSH deficiency causes thyroid gland involution and hypofunction. Clin: lethargy, constipation, cold intolerance, bradycardia, weight gain, dry skin, poor appetite, and delayed reflex relaxation time. Dg: low TSH + low T4 and T3 2/10
  3. 3. Seminars for the 5th year international students Prof. MUDr. Jiří Horák Etiology of hypopituitarism type of disorder congenital septo-optic dysplasia Prader-Willi syndrome Lawrence-Moon-Biedle syndrome isolated anterior pituitary hormone or RF deficiency tumors pituitary secretory adenomas nonsecretory adenomas hypothalamic craniopharyngioma hamartoma pinealoma dermoid epidermoid glioma lymphoma meningioma immunological autoimmune lymphocytic hypophysitis infiltrative hemochromatosis Langerhans cell histiocytosis sarcoidosis metastatic carcinoma amyloidosis infectious tuberculosis mycoses syphilis physical trauma cranial trauma and hemorrhage ionizing radiation stalk section surgery 3/10
  4. 4. Seminars for the 5th year international students Prof. MUDr. Jiří Horák vascular postpartum pituitary necrosis (Sheehan's syndrome) pituitary apoplexy carotid aneurysm Gonadotropin deficiency Central hypogonadism in childhood results in failure to enter normal puberty. Females have delayed breast development, scant pubic and axillary hair, and primary amenorrhea. In boys, the phallus and testes remain small, and body hair is sparse. Sex steroids are required for closure of the epiphyses of the long bones. Clin: tall adolescents with eunuchoid proportions. In adult women, hypogonadism presents as breast atrophy, loss of pubic and axillary hair, and secondary amenorrhea. Hypogonadal adult males develop testicular atrophy, decreased libido, impotence, and loss of body hair. ADH (vasopressin) deficiency occurs with posterior pituitary dysfunction and leads to DI with polyuria, polydipsia, and nocturia. Dg of pituitary hormone deficiency Quadruple Bolus Test for Anterior Pituitary Reserve hypothalamic releasing hormone pituitary hormone TRH 200 µg TSH, prolactin CRF 1 µg/kg ACTH GHRH 1 µg/kg GH gonadotropin RH 100 µg FSH, LH Th of panhypopituitarism replacement of thyroxine, glucocorticoids, and sex steroids. Children with short stature should receive GH replacement therapy. Testosterone therapy in males restores libido and potency, beard growth, and muscle strength. Estrogen replacement therapy in females maintains secondary sex characteristics and prevents hot flashes. Human menopausal gonadotropins and human chorionic gonadotropin given i.m. or 4/10
  5. 5. Seminars for the 5th year international students Prof. MUDr. Jiří Horák gonadotropin RH administered by infusion pumps may be given to induce ovulation. In patients with combined TSH and ACTH deficiency, glucocorticoids should be replaced prior to thyroxine, as thyroxine may precipitate acute adrenal failure. Empty Sella Syndrome occurs when the arachnoid membranes herniate through an incompetent diaphragma sella and extend into the sella turcica, partially filling it with cerebrospinal fluid and compressing the pituitary gland. Primary empty sella syndrome is the most common cause of an enlarged sella turcica. This results from a congenital weakness in the diaphragma sella. Secondary empty sella syndrome can occur following pituitary surgery or radiation therapy or in Sheehan's syndrome. Empty sella syndrome is usually asymptomatic and detected incidentally on routine imaging of the head. Endocrine function is usually normal; partial hypopituitarism may be present. Dg: MRI - fluid in sella turcica Pituitary tumours Prolactinomas are the most common secretory pituitary tumours. Secretory pituitary tumours: signs and symptoms due to hypersecretion of the particular pituitary trophic hormone. GH adenomas: acromegaly, prolactinomas: amenorrhoea + galactorrhea in females and sexual dysfunction in males, ACTH-secreting adenomas: Cushing disease. Large pituitary adenomas (secretory or nonsecretory) can result in signs and symptoms due to pressure on surrounding structures. Headache is a frequent symptom. Extension of the tumour into the suprasellar space → compression of the optic chiasm bitemporal hemianopia. Lateral extension into the cavernous sinus can result in ophthalmoplegia, diplopia, or ptosis due to dysfunction of the third, fourth, fifth, and sixth cranial nerves. Compression of surrounding normal pituitary tissue due to an enlarging tumor mass can cause hyposecretion of one or several pituitary trophic hormones. Destructive pituitary lesions result in hormone loss in the following pattern: GH - LH/FSH - TSH - ACTH - prolactin. 5/10
  6. 6. Seminars for the 5th year international students Prof. MUDr. Jiří Horák Prolactinomas Hyperprolactinemia in women: hypogonadism → estrogen deficiency. Gonadotropin levels are normal, and sex steroids are decreased. Prolactin inhibits pulsatility in gonadotropin secretion → anovulation. In hyperprolactinemic males, testosterone levels are usually suppressed. Clin: in women, amenorrhea, galactorrhea, and infertility. Estrogen deficiency may cause osteopenia, vaginal dryness, hot flashes, and irritability. Prolactin stimulates adrenal androgen production → weight gain and hirsutism. Males usually present with loss of libido and impotence due to hypogonadism. Dg: basal serum prolactin level > 200 ng/ml; MRI. Th: bromocriptine (a dopamine agonist) at a dosage of 2.5 to 15 mg/day orally in divided doses restores gonadal function and fertility in a majority of patients. Bromocriptine may cause tumour shrinkage. Surgery is indicated in patients with visual field abnormalities or neurologic symptoms. Trans-sphenoidal microsurgery is the procedure of choice. Acromegaly and gigantism In childhood, hypersecretion of GH leads to gigantism, in adults acromegaly (local overgrowth of bone in the acral areas). Clin: acral enlargement - widening of the hand and feet and coarsening of the facial features. The mandible grows downward and forward → prognathism and widely spaced teeth. Ring, glove, and shoe size increase. Dg: insulin-like growth factor-1 mediates the classical acral changes that occur with acromegaly. IGF-1 levels are elevated. GH levels 2 hours after an oral glucose load of 100g. In healthy persons, GH levels are suppressed to < 2 ng/ml. MRI or CT of the pituitary Th: trans-sphenoidal microsurgery is the treatment of choice. Radiotherapy has a high incidence of hypopituitarims. Medical management: bromocriptine (effective only in a minority of patients) and octreotide (a long-acting somatostatin analogue - very effective). It is administered as a s.c. injection three times daily. 6/10
  7. 7. Seminars for the 5th year international students Prof. MUDr. Jiří Horák Clinical features of acromegaly type of change change manifestation somatic acral changes enlarged hands and feet musculoskeletal arthralgias changes prognathism carpal tunnel syndrome proximal myopathy skin changes sweating colon changes polyps carcinoma cardiovascular cardiomegaly hypertension visceromegaly tongue thyroid liver endocrine reproduction menstrual abnormalities problems galactorrhea decreased libido carbohydrate impaired glucose tolerance metabolism diabetes mellitus lipid metabolism hypertriglyceridemia Gonadotropin-Secreting Pituitary Tumours Mainly in males, are rare. Secrete usually FSH only. Clin: • signs of local pressure (visual impairment); • hypogonadism Th: surgical removal ± subsequent radiotherapy Thyrotropin-Secreting Pituitary Tumour Extremely rare Dg: increased TSH + increased T4 7/10
  8. 8. Seminars for the 5th year international students Prof. MUDr. Jiří Horák Th: surgery + radiotherapy The Posterior Pituitary Gland ADH is a 1084-dalton nonapeptide. It binds to receptors on the renal tubule, increasing the water permeability of the luminal membrane of the collecting duct epithelium, thus facilitating reabsorption of water. Maximal ADH effect results in a small volume of concentrated urine with osmolarity as high as 1200 mOsm/kg. Deficiency of ADH results in a large volume of very dilute urine (as low as 100 mOsm/kg). ADH also binds to peripheral arteriolar receptors, causing vasoconstriction and increase in blood pressure; however, it also causes bradycardia and inhibition of sympathetic nerve activity. Deficiency of ADH or insensitivity of the kidney to ADH → diabetes insipidus manifested as polyuria and polydipsia. Inappropriate secretion of ADH → the syndrome of inappropriate ADH secretion (SIADH) → a hyponatremic state. Oxytocin is a 1007-dalton nonapeptide that causes uterine smooth muscle contraction. It is released by nipple stimulation and facilitates milk ejection by causing mammary duct myoepithelial cell contraction in response to nipple stimulation. Diabetes Insipidus Central (neurogenic) or renal (nephrogenic). Patients are polyuric, secreting large volumes of diluted urine dehydration → thirst → polydipsia. Causes of Diabetes Insipidus Causes of Central Diabetes Insipidus • idiopathic • familial • hypophysectomy • infiltration of hypothalamus and posterior pituitary • Langerhans cell histiocytosis • granulomas • infection • tumors 8/10
  9. 9. Seminars for the 5th year international students Prof. MUDr. Jiří Horák • autoimmune Causes of nephrogenic diabetes insipidus • idiopathic • familial • chronic renal disease (pyelonephritis, polycystosis) • hypokalemia • hypercalcemia • sickle cell anemia • drugs lithium fluoride demeclocycline colchicine DD: primary polydipsia → decreased ADH secretion → water diuresis. Random simultaneous samples of plasma and urine for sodium and osmolarity: in diabetes insipidus, urine osmolarity < plasma osmolarity. Plasma osmolarity may be elevated, depending on the patient's state of hydration. In primary polydipsia, both plasma and urine are dilute. The water deprivation test: the patient is denied fluids for 12 to 18 hours, and body weight, blood pressure, urine volume, urine specific gravity, and plasma and urine osmolarity are measured every 2 hours. If the body weight falls more than 3%, the study should be terminated. A normal response is a decrease in urine output to 0.5 ml/min, as well as an increase in urine concentration to greater than that of plasma. Patients with DI maintain a high urine output, which continues to be dilute (specific gravity < 1.005 {200 mOsm/kg of water}). Patients with primary polydipsia increase their urine osmolarity to values > plasma osmolarity. Water deprivation is continued until the urine osmolarity plateaus (an hourly increase of < 30 mOsm/kg for three successive hours). At that point, 5 µg of vasopressin is administered s.c., and the urine osmolarity is measured after 1 hour. Patients with complete central DI increase urine osmolarity above plasma osmolarity, whereas in nephrogenic DI the urine osmolarity increases less than 50%. Patients with primary polydipsia have increases < 10%. 9/10
  10. 10. Seminars for the 5th year international students Prof. MUDr. Jiří Horák Th: central DI - desmopressin acetate (DDAVP), a synthetic analog of ADH, is administered intranasally. Adequacy of replacement is monitored by serum osmolarity and sodium. Nephrogenic DI As far as possible, the underlying disease process should be reversed. Diuretics with dietary salt restriction can be used. SIADH Plasma ADH concentrations are inappropriately high for plasma osmolarity, resulting in water retention leading to hyponatremia and decreased plasma osmolarity (< 280 mOsm/kg). Urine osmolarity is higher than the plasma osmolarity. Disorders Associated with SIADH type of disorder disorder pulmonary disorders malignant (oat cell carcinoma) benign (TBC, pneumonia, abscess) CNS disorders meningitis brain abscess head trauma adverse drug effects clofibrate chlorpropamide cyclophosphamide phenothiazine carbamazepine tumours (ectopic lymphoma production of ADH) sarcoma carcinoma of pancreas or duodenum Th: the underlying condition should be treated. Fluid restriction is the cornerstone of treatment. -------------- 10/10