The Endocrine System (MEDP 315) PDF

THE ENDOCRINE SYSTEM (MEDP 315) Introduction Hypothalamus & Anterior Pituitary Gland  Outline Introduction to endocrinology Pituitary disorders – Hypopituitarism – Hyperpituitarism – Mass effect Prolactin Growth hormone The Endocrine Syste...

THE ENDOCRINE SYSTEM (MEDP 315) Introduction Hypothalamus & Anterior Pituitary Gland  Outline Introduction to endocrinology Pituitary disorders – Hypopituitarism – Hyperpituitarism – Mass effect Prolactin Growth hormone The Endocrine System A highly integrated and widely distributed group of organs that maintains a state of metabolic equilibrium or homeostasis, among the various organs of the body  Introduction Focus on hormones and the endocrine glands that secrete them Hormones:- – chemical messengers that are secreted into the blood stream and stimulate the physiology of cells in another tissue or organ (have a specific regulatory effect) often a considerable distance away  Introduction Function Broadly classified as those that: 1. Affect growth and development e.g. gonadal steroids, growth hormone, cortisol and thyroxine 2. Exert homeostatic control of metabolic pathways e.g. insulin, parathyroid hormone, antidiuretic hormone (ADH) 3. Regulate the production, use and storage of energy e.g. adiponectin, glucagon  Introduction Classification of hormones 1. Polypeptide or protein hormones E.g. Adrenocorticotropic hormone (ACTH), insulin, parathyroid hormone Water soluble Circulate freely in plasma as the whole molecule or active or inactive fragments Have a short half life and wide fluctuations in their concentrations may be seen in several physiological and pathological conditions Initiate their response by binding to cell membrane receptors  Introduction Classification of hormones 2. Steroid hormones E.g. Cortisol and estrogen Hydrophobic and water insoluble Circulate in plasma reversibly bound to transport proteins e.g. cortisol binding globulin and sex hormone binding globulin Only a small fraction is unbound to exert physiological action Half life is longer than protein hormones Free steroid hormones enter the cell by passive diffusion and bind with intracellular receptors in the cytosol or nucleus  Introduction Classification of hormones 3. Amino acid related hormones E.g. thyroxine and catecholamines Water soluble Circulate either bound to proteins or free Half life varies Initiate their response by binding to cell membrane receptors  Introduction Hormone transport Peptides are hydrophilic and do not need transport proteins Steroids are hydrophobic and must bind to hydrophilic transport proteins A hormone attached to a transport protein is called a bound hormone and one which is not attached is called unbound Transport proteins also prolong the half life of the bound hormones e.g. thyroid hormones  Introduction Hormone receptors Hormones only stimulate cells that have receptors for them Increased activity of the target tissue often down regulates the activity of the gland that secretes the stimulating hormone- feedback inhibition Receptor defects lie at the heart of several endocrine diseases such as:- – Type II Diabetes mellitus – Laron Dwarfism – Androgen insensitivity syndrome  Introduction Hormone clearance Most are taken up and degraded by the liver and kidneys and then excreted in the bile or urine Some are degraded by their target cells  Introduction Endocrine disorders are classified as: – Diseases of deficiency/underproduction (congenital or acquired) or excess/ overproduction ( endogenous or exogenous of hormone(s) or from resistance to the action of hormones – Diseases associated with the development of mass lesions  Anatomy Hypothalamus Forms the floor and wall of the 3rd ventricle of the brain Regulates primitive functions of the body Many of its functions are carried out by the pituitary gland, which is closely associated with it  Anatomy Pituitary gland The pituitary gland is suspended from the hypothalamus by a stalk (infundibulum) and housed in the sella turcica of the sphenoid bone It is usually approx. 1.3 cm (0.5 g) in diameter but grows larger in pregnancy (50%) It is composed of 2 structures: the adenohypophysis and neurohypophysis which arise independently in the embryo and have separate functions Dual blood supply Anatomy  Hormones Hypothalamus Hormone Principal Effects Thyrotropin releasing hormone Promotes TSH and PRL (TRH) secretion Corticotropin releasing Promotes ACTH secretion hormone (CRH) Gonadotropin releasing Promotes FSH and LH hormone (GnRH) secretion Prolactin inhibiting hormone Inhibits PRL secretion (Dopamine) Growth hormone releasing Promotes GH secretion (GHRH) Growth hormone inhibiting Inhibits GH and TSH secretion hormone (Somatostatin) *Oxytocin and antidiuretic hormone (ADH)  Hormones Anterior Pituitary Hormone Target Principal effects organ Follicle Ovaries, Female: Growth of ovarian follicles stimulating Testes and secretion of estrogen hormone (FSH) Male: Sperm production Luteinizing Ovaries, Female: Ovulation, maintenance of hormone (LH) Testis corpus luteum Male: Testosterone secretion Thyroid Thyroid Growth of thyroid, secretion of stimulating gland thyroid hormones hormone (TSH) Adenocorticotropi Adrenal Growth of the adrenal cortex, c hormone (ACTH) cortex secretion of corticosteroids Prolactin Mammary Female: milk synthesis glands, Male: Increased LH sensitivity testes  Hormones Posterior Pituitary Consists of modified glial cells (pituicytes) and axonal processes extending from the hypothalamus through the pituitary stalk Produces no hormones of its own but only stores and releases oxytocin and Antidiuretic hormone (ADH) also called vasopressin PITUITARY DISORDERS  Introduction The manifestations of pituitary disorders are as follows: Hypopituitarism- deficiency of tropic hormones This may be caused by congenital, destructive, inflammatory and neoplastic processes Hyperpituitarism- Excess secretion of tropic hormones. This may be due to hyperplasia, adenomas and carcinomas Local mass effect- may manifest with radiographic abnormalities, visual field changes and features of raised intra-cranial pressure  Hypopituitarism Refers to decreased secretion of pituitary hormones May result from hypothalamic or pituitary diseases Hypofunction of the pituitary results when approximately 75% of the parenchyma is lost or absent The causes may be congenital or acquired Partial hypopituitarism is more common than complete loss of pituitary function  Hypopituitarism If accompanied by evidence of posterior pituitary dysfunction, the cause is almost always hypothalamic in origin The presenting features depend on the extent and severity of the hormone deficiencies and the age at presentation Anorexia nervosa may clinically resemble hypopituitarism  Hypopituitarism Causes 1. Tumors and other mass lesions – Pituitary- adenoma, craniopharyngioma – Cerebral tumors – primary, secondary – Rathke cleft cyst 2. Vascular diseases – Postpartum necrosis e.g. Sheehan's syndrome – Pituitary apoplexy – Severe hypotension – Cranial arteritis  Apoplexy means bleeding into an organ or loss of blood flow to an organ. Pituitary apoplexy is commonly caused by bleeding inside a noncancerous (benign) tumor of the pituitary.  Temporal Arteritis is a systemic, autoimmune, rheumatic condition in which the temporal arteries, which supply blood to the head and brain, become inflamed or damaged. Also known as Cranial Arteritis or Giant Cell Arteritis, this condition is a type of vasculitis.  Hypopituitarism 3. Hypothalamic disorders – Tumors, inflammation and infection 4. Infections – Meningitis, syphilis 5. Miscellaneous – Sarcoidosis, hemochromatosis 6. Iatrogenic - Surgery, therapeutic skull irradiation (empty sella syndrome) 7. Genetic defects- congenital deficiency of transcription factors 8. Trauma  Sarcoidosis- The growth of tiny collections of inflammatory cells in different parts of the body.  Hypopituitarism Clinical features Hormone Features of deficiency Growth Children: Growth retardation hormone Adults: Decreased muscle bulk, osteopenia, impaired psychological well being, atherogenic lipid profile, tendency to hyperglycemia may be accentuated Prolactin Failure of lactation Gonadotrophi Children: Delayed puberty ns Females: oligomenorrhea, infertility, atrophy of breasts and genitalia Males: impotence, azoospermia, testicular atrophy Both sexes: decreased libido, loss of body hair, fine wrinkling of the skin  Hypopituitarism Clinical Features Hormone Features of deficiency ACTH Weight loss, weakness, hypotension, hypoglycemia TSH Weight gain, cold intolerance, fatigue Vasopressin Thirst, polyuria  Hyperpituitarism Arises from excess secretion of trophic hormones Causes – Pituitary adenoma, hyperplasia and carcinoma – Secretion of hormones by non pituitary tumors – Hypothalamic disorders The most common cause is a pituitary adenoma arising in the anterior lobe Pituitary adenomas may be Functional (associated with hormone excess and clinical manifestations thereof) or Silent Pituitary adenomas are classified on the basis of the hormone produced by the neoplastic cells  Hyperpituitarism Cell type Hormon Tumor type Syndrome e Corticotroph ACTH ACTH cell adenoma Cushing syndrome Nelsons syndrome Somatotroph GH GH cell adenoma Gigantism Acromegaly Lactotroph Prolactin Prolactin cell Galactorrhea, adenoma amenorrhea Mammosomatotrop Prolactin, Mammosomatotrop Combined h GH h features of GH and prolactin excess Thyrotroph TSH TSH cell adenoma Hyperthyroidism Gonadotroph FSH, LH Gonadotroph Hypogonadism,  Pituitary adenomas Clinically diagnosed pituitary adenomas are responsible for about 10% of intracranial neoplasms Usually found in adults- peak incidence from 35 -60 years Microadenomas are less than 1 cm while macroadenomas exceed 1 cm Non functioning adenomas are often diagnosed late May be associated with genetic abnormalities  Pituitary Adenomas Morphology- gross Soft, well circumscribed lesion that may be confined to the sella turcica Larger lesions extend to the suprasellar region where they compress the optic chiasma They may erode the sella turcica and anterior clinoid processes They may have foci of hemorrhage and necrosis  Pituitary adenomas Morphology- Microscopic appearance Composed of relatively uniform, polygonal cells arrayed in sheets or cords Mitotic activity is sparse Cytoplasm may be acidophilic, basophilic or chromophobic  Pituitary adenomas Noted radiographically as expansion of the sella turcica, bone erosion Visual field abnormalities due to compression of the optic chiasm -- Bitemporal Hemianopia Elevated intracranial pressure – headache, vomiting, nausea  Other pituitary tumors Rathke cleft cyst Craniopharyngioma Cysts lined by ciliated Thought to be derived cuboidal epithelium from a vestigial with occasional goblet remnant of Rathke cells and anterior pouch pituitary cells May be solid or cystic Can accumulate proteinaceous fluid Bimodal age and expand, distribution compromising the Composed of normal gland squamous cells  Prolactin 198 aa polypeptide hormone Principal action is to initiate and sustain lactation Secreted by the lactotropes (mammotropes) These greatly increase in size and number during pregnancy Secretion is controlled by dopamine from the hypothalamus which inhibits the process  Prolactin Physiological Release - stress, sleep, suckling, pregnancy Levels rise during pregnancy but it usually has no effect until after delivery then, it stimulates the mammary gland to produce milk In Males, it has a gonadotrophic effect that makes the testes more sensitive to LH  Hyperprolactinaemia Common endocrine abnormality It is an important cause of infertility in both males and females (menstrual irregularities) This is thought to be due to inhibition of pulsatility of GnRH Pathologic hyperprolactinemia can also result from lactotroph hyperplasia caused by loss of dopamine-mediated inhibition of prolactin secretion  Hyperprolactinaemia 1. Drugs – Dopaminergic receptor blockers e.g. Haloperidol – Dopamine depleting agents e.g. Methyl dopa 2. Pituitary disorders – Prolactin secreting tumors (prolactinoma), damaged dopaminergic neurons of the hypothalamus, pituitary stalk section 3. Others – Hypothyroidism, ectopic secretion and chronic renal failure  Hyperprolactinaemia Clinical Features Females – Oligomenorrhea, amenorrhea – Infertility – Galactorrhoea – Loss of libido Males – Impotence – Infertility – Gynaecomastia – Loss of libido  Hyperprolactinaemia Prolactinomas Most frequent type of hyper functioning pituitary adenomas Range from small microadenomas to large tumors associated with substantial mass effect Propensity to undergo dystrophic calcification Diagnosis is made more readily in women between the ages of 20 – 40 yr It is the underlying cause in ¼ cases of amenorrhea Treated with dopamine agonists (Bromocriptine, Cabergoline) or surgery  Hypoprolactinemia Uncommon disorder Presents in patients with hypopituitarism due to various causes Failure to lactate; breast atrophy  Growth hormone Also called somatotropin, a 191 aa peptide Secreted by the somototropes General effect is to promote mitosis and cellular differentiation Widespread effects on the body especially on cartilage, bone, muscle and fat It exerts its effects directly and indirectly Indirect effect- induces the liver and other tissues to produce growth stimulants called insulin like growth factors (IGF) or somatomedins  Growth hormone GH has a short t ½ (6-20 min); IGF has a longer t ½ (20hrs) Concentration varies throughout the day Physiological secretion occurs in sporadic bursts lasting 1-2 hours, mainly during sleep Secretion can be stimulated by stress, exercise, a fall in blood glucose concentration and fasting Secretion is inhibited by a rise in blood glucose Concentration declines with age  Growth hormone The effects of GH- IGF include: – Protein synthesis (anabolic) – Increased hepatic glucose production and decreased tissue glucose uptake (diabetogenic) – Lipid metabolism- lipolysis- (ketogenic) – Electrolyte balance- Na+, K+, Cl-, Ca2+ Negative feedback effect on the pituitary and hypothalamus by both GH and IGF GROWTH HORMONE DISORDER S  Growth hormone excess Acromegaly and gigantism Result from excessive GH secretion by a pituitary tumor (95%) 5% of cases are due to ectopic secretion of GHRH e.g. by a tumor Results in increased growth of soft tissue and bone If it occurs before the epiphyses have fused, growth of long bones occurs leading to gigantism More commonly, GH secreting tumors occur in adults producing acromegaly with increased growth of soft tissues, hands, feet, jaw and internal organs Growth hormone excess  Growth hormone excess Clinical features 1. Somatic Increased growth of skin, subcutaneous tissue, skull, jaw (prognathism), with broadening of the lower face; hands, feet (broad sausage like fingers) and long bones (before fusion of the epiphysis) Nerve compression (carpal tunnel syndrome) Excessive sweating, greasy skin, acne Goitre Cardiomegaly  Growth hormone excess 2. Metabolic Elevated, non suppressible plasma GH concentration Diabetes mellitus Hypercalcemia 3. Local tumor effects Headache, visual field defects, hypopituitarism  Growth hormone excess Laboratory evaluation GH measurement Oral glucose tolerance test IGF- I measurement Treatment Surgery External irradiation Drugs- analogues of somatostatin e.g. ocreotide, lanreotide and GH receptor antagonist- pegvisomant Growth hormone deficiency In adults presents as reduced physical performance and psychological well being Some patients are asymptomatic History of pituitary tumor treated with surgery or radiation or history of trauma Physical examination- reduced skeletal muscle mass Growth hormone deficiency In children it may be congenital due to an abnormal pituitary gland or acquired in trauma, infections or cranial irradiation Children present with growth retardation Laboratory investigations Exclude other cause of failure to thrive- – Hypothyroidism Treatment Subcutaneous dose of GH  Text books Endocrine pathology- Churchill Livingstone, Thompson L D R Endocrine pathology- Differential diagnosis and molecular advances- Humana press, Lloyd R V Deja Review Pathology, Davis J and King E