Pathophysiology of Endocrine Disorders PDF

PATHOPHYSIOLOGY OF ENDOCRINE DISORDERS – CLI 307 Pharmacy (El-Saheed Lecture Theater) D. O. Soyoye LEARNING OBJECTIVES Revise endocrine system / hormones Understand how hormones elicit their actions Highlight the mechanisms of endocrine disorders Highlights specif...

PATHOPHYSIOLOGY OF ENDOCRINE DISORDERS – CLI 307 Pharmacy (El-Saheed Lecture Theater) D. O. Soyoye LEARNING OBJECTIVES Revise endocrine system / hormones Understand how hormones elicit their actions Highlight the mechanisms of endocrine disorders Highlights specific functions and disorders of major endocrine glands INTRODUCTION The endocrine system is one of the two major systems for coordination and control of organ function. Endocrine system is made up of endocrine organs (glands) which secrete chemical messengers called hormones. Hormones are defined (traditionally) as chemical signals secreted into the bloodstream that act on distant tissues, usually in a regulatory fashion. Substances that provide the chemical basis for communication between cells are called hormones Signaling mechanism in the endocrine system – endocrine, paracrine, autocrine and intracrine. Principal functions of hormones  Control of reproduction  General growth and development of the body  Regulation of electrolyte composition of bodily fluids  Control of energy metabolism CHEMICALLY, HORMONES MAY BE CLASSIFIED INTO THREE MAIN GROUPS  Amino acid (tyrosine) derivatives (from the adrenal medulla and thyroid gland) - Epinephrine, norepinephrine, thyroxine  Steroids, structurally related to cholesterol (from the sex glands and the adrenal cortex) - Cortisol, estrogen, progesterone, testosterone, vitamin D.  Proteins/polypeptides (from the pancreas and pituitary gland) - Insulin, glucagon, GH, PTH, TSH, LH, FSH, TSH, β-hCG, TRH, vasopressin ENDOCRINE GLANDS THAT FUNCTION PRIMARILY TO SECRETE HORMONES 1.Pituitary gland: ADH (vasopressin), oxytocin, ACTH, GH, TSH, LH, FSH, prolactin 2.Thyroid gland: thyroxine, tri-iodothyronine & calcitonin 3.Parathyroid gland: parathyroid hormone 4.Adrenal gland: cortisol, aldosterone, epinephrine & sex steroids 5.Pancreas: insulin, glucagon 6.Ovaries & testicles: androgens, estrogens & progesterone 7.Pineal gland: melatonin OTHERS 1. Heart: atrial natriuretic peptide (ANP) 2. Kidney: erythropoietin 3. Liver: somatomedin (IGF) 4. Skin: vitamin D3 5. Gastrointestinal tract: gastrin, CCK and VIP 6. Adipose tissue: leptin 7. Hypothalamus: CRH, TRH, GnRH, Dopamine ACTION OF HORMONES Hormones usually elicit their effects by binding to receptors – intracellular or cell surface (extracellular)  Amino acid derivatives and peptide hormones interact with cell-surface membrane receptors.  water-soluble hormones that bind to the plasma membrane of the target cell.  regulate intracellular metabolic processes through intermediary molecules, called second messengers (eg c-AMP, c-GMP, phospholipase C-Ca2+ and tyrosine kinase)  ACTION OF HORMONES 2 Steroids, thyroid hormones, vitamin D, and retinoids interact with intracellular nuclear receptors. Transported after secretion by transport proteins Lipophilic. Act in cytosol or the nucleus of target cells. The hormone-receptor complex binds to specific regions of DNA and activates or inactivates specific genes. By selectively affecting gene transcription and the production of the respective messenger RNAs (mRNAs), the amounts of specific proteins are changed, and metabolic processes are influenced. STEROID HORMONES HORMONE FEEDBACK REGULATORY SYSTEM Hypothalamus Hypothalamus releasing/ -ve feedback -ve feedback inhibitory hormones Anterior pituitary Anterior pituitary hormones -ve feedback Target gland Target hormones PITUITARY GLAND 2 glands – Anterior pituitary Adenohypophysis – Posterior pituitary Neurohypophysis Extension of hypothalamus PATHOPHYSIOLOGY OF ENDOCRINE DISEASES Endocrine diseases can be divided into three major types of conditions: (1) hormone excess (hypersecretion) (2) hormone deficiency (hyposecretion) (3) hormone resistance Hypersecretion may result from hyperplasia or hypertrophy of the gland or a combination of the two. Hyposecretion may be caused either destruction of the gland or by conditions that deprive the organ of its normal trophic influence. ENDOCRINE DISORDERS – CONGENITAL OR ACQUIRED Congenital - Genetic hormone-receptor Defects in structure or Structural abnormalities hormone postreceptor biosynthesis signaling mechanisms ENDOCRINE DISORDERS – CONGENITAL OR ACQUIRED ACQUIRED  Neoplasia  Infection  Infiltrative processes  Vascular disorders  Trauma  Immune-mediated injury  Metabolic abnormalities  Drugs. Hormones of the Anterior Pituitary Gland GROWTH HORMONE Functions  Stimulation of cell growth and expansion of bone, cartilage, organomegaly  Antagonizes the actions of insulin Deficiency -caused by hypothalamic or pituitary dysfunction)  →Short stature in children Excess - results from a benign pituitary tumour (adenoma); ectopic release of GH or GHRH from other neuroendocrine tumours can also occur in some rare instances.  → Gigantism  → Acromegaly THYROID STIMULATING HORMONE Primary action is to stimulate the thyroid gland to secrete the thyroid hormones tri-iodothyronine (T3) and thyroxine (T4). This is achieved by: 1. Stimulation of thyroid iodide uptake; 2. Increased synthesis of the thyroidal storage protein, thyroglobulin; 3. Stimulation of T3/T4 synthesis and release, and 4. An increase in the thickness of the follicular epithelium and vascularity of the thyroid gland. Excess TSH can result in an enlarged thyroid (goitre). Hyposecretion produces a clinical picture similar to primary thyroid deficiency. Hypersecretion gives the symptoms of hyperthyroidism similar to Graves’ disease ADRENOCORTICOTROPHIC HORMONE (ACTH) It stimulates the adrenal cortex to secrete glucocorticoids and also small amounts of sex hormones (androgens and oestrogens) Hyposecretion of ACTH (rare) causes failure of cortisol secretion, a general lack of health and well being, a reduced response to stress and skin depigmentation - Hypocortisolism. Hypersecretion (due to a pituitary microadenoma, or ‘ectopic’ non-endocrine tumour) will result in Cushing’s syndrome  FOLLICLE STIMULATING HORMONE (FSH)/ LUTEINIZING HORMONE (LH) Glycoprotein consisting of two glycoprotein subunits α and β. LUTEINIZING HORMONE (LH) In females, a surge of LH (in co-operation with FSH) at midcycle, induces ovulation, then maintains the corpus luteum after ovulation; (this secretes progesterone). In males, it stimulates the interstitial (Leydig) cells in the testes to produce testosterone. FOLLICLE STIMULATING HORMONE (FSH) Along with LH promotes the development of the ovarian follicle and oestrogen production) and stimulates spermatogenesis in males. Hyposecretion of gonadotrophins leads to amenorrhoea, sterility and loss of sexual potency. In the young, the sex organs and secondary sexual characteristics fail to develop (delayed puberty). Hypersecretion of FSH and LH is extremely rare, but in children it could lead to sexual precocity (excessive premature development). PROLACTIN Prolactin (PRL) is a single chain peptide (198 amino acids) with a chemical structure very similar to that of growth hormone (GH). It is principally involved (in co-operation with other hormones) in the development of the female breast, and in the initiation and maintenance of lactation (milk production) shortly after childbirth. Function in human males is unknown, but excess levels can exert powerful inhibitory effects on both male and female gonadal function and libido (sexual drive), primarily via actions on the CNS and by suppression of GnRH release. Hyposecretion of prolactin leads to failure of lactation in women. Hypersecretion of prolactin (hyperprolactinaemia) may result from a pituitary tumour (prolactinoma) or hypothalamic disease. Overproduction of prolactin may also lead to inappropriate (non-pregnant) milk production (galactorrhoea). Hormones of the Posterior Pituitary Gland VASOPRESSIN Its principal action is to stimulate the reabsorption of water from the distal convoluted tubules and collecting ducts of the kidney, thereby reducing urine volume and conserving body fluid; Arginine Vasopression (AVP ) is therefore also referred to as the antidiuretic hormone (ADH). This effect is mediated by specific AVP (V2-type) receptors on the tubular cell surface → intracellular cAMP. In large quantities, AVP has a direct vasoconstrictor action on blood vessels Control of release of AVP is primarily influenced by: 1. Plasma osmolarity 2. Blood volume/arterial pressure: sensory stimuli arising from systemic arterial, venous and atrial baroreceptors (stretch-sensitive) normally inhibit AVP secretion, 3. An increase in AVP release also occurs in response to: severe pain, fear, nausea, general anaesthesia or certain drugs/neurotransmitters e.g. nicotine, morphine (and other opiates), angiotensin II, prostaglandin E2 and noradrenaline. Hyposecretion - caused by damage or dysfunction (e.g. tumours) of the hypothalamus → diabetes insipidus Hypersecretion →SIADH: syndrome of inappropriate ADH - the excess AVP levels can arise from  ectopic AVP-secreting tumour (malignant bronchial neoplasm)  certain pulmonary disorders (e.g. severe pneumonia, acute bronchitis)  brain lesions - head injury  antidepressant/antipsychotic drug therapy (e.g. fluoxetine, sertraline,imipramine, amitryptyline, haloperidol). OXYTOCIN It is present in both sexes, but its effects are well understood only in females. stimulates the rhythmic contractions of uterine smooth muscle during parturition (childbirth), contributes to, but is not essential for initiation or maintenance of labour. stimulates milk ejection from the lactating breast in response to infant suckling Control of release: Activation of sensory nerve endings in the nipple during suckling, and the uterus during childbirth, ultimately stimulate release of oxytocin from the posterior pituitary Disorders of oxytocin secretion are rarely encountered. Adrenal Gland ADRENAL GLAND - CORTEX The outer layer: (zona glomerulosa)  secretes mineralocorticoids (aldosterone) involved in Na+/H2O balance The middle layer: (zona fasciculata)  Secretes glucocorticoids:(cortisol, corticosterone) involved in regulating protein/carbohydrate metabolism  also secretes some sex steroids The inner layer: (zona reticularis)  Secretes glucocorticoids and some sex steroids GLUCOCORTICOIDS Actions  1. Control of carbohydrate, protein and fat metabolism.  2. Suppression of tissue inflammation in response to injury.  3. Suppression of immune response to foreign antigens.  4. Increase in capacity of the body to withstand various noxious stimuli (stresses). Secretion controlled exclusively ACTH Hyposecretion → Addison’s disease Hypersecretion → Cushing’s syndrome MINERALOCORTICOIDS Regulation of mineralocorticoid (mainly aldosterone) secretion - largely mediated by the renin angiotensin system. Plasma Na+ and K+ Concentrations. Either a large decrease in plasma Na+ or a small increase in plasma K+ concentration stimulates the synthesis and release of aldosterone by a direct action on the biosynthetic enzymes in the adrenal cortex. Hyposecretion - isolated deficiency Hypoaldosteronism is rare Hypersecretion – Conn’s disease ADRENAL GLAND - MEDULLA Secretes epinephrine and norepinephrine Secretion of catecholamines into the bloodstream occurs in direct response to stimulation of preganglionic (cholinergic) sympathetic nerve fibres as part of the so-called “fight-or- flight” response to stress. The main abnormality of catecholamine secretion is pheochromocytoma – a neuroendocrine tumour that secretes catecholamines PANCREAS The pancreas is both an exocrine and endocrine gland Endocrine pancreas 1. α-cells - produce glucagon; 2. β-cells – produce insulin; 3. δ-(D) cells - produce somatostatin 4. PP (or F) cells constitute a minor proportion of the islet cells, and secrete pancreatic polypeptide  INSULIN The principal effects of insulin are: 1. Stimulation of glycogen synthesis in skeletal muscle, liver and adipose tissue by a direct increase in glycogen synthase and a decrease in glycogen phosphorylase activity. 2. Increase in hepatic glucose phosphorylation (due to stimulation of glucokinase activity), and a decrease in glucose dephosphorylation (due to inhibition of glucose- 6-phosphatase activity). 3. Increase in glucose metabolism (glycolysis) with a simultaneous decrease in liver gluconeogenesis. 4. Protein Metabolism. Insulin stimulates the cellular active transport of plasma amino acids into muscle 5. Fat Metabolism. Insulin stimulates uptake of glucose into adipose cells and promotes the synthesis (lipogenesis) and storage of fatty acids in the form of triglycerides in both adipose and hepatic Hyposecretion – Diabetes mellitus Hypersecretion - Insulinoma CLASSIFICATION  Type 1 Diabetes Mellitus  Type 2 Diabetes Mellitus  Other Specific Types  Gestational Diabetes Mellitus CLASSIFICATION – OTHER SPECIFIC TYPES A. Genetic defects of beta cell function B Genetic defects in insulin action - Type A insulin resistance, Leprechaunism, Rabson–Mendenhall syndrome, Lipoatrophic diabetes C. Diseases of the exocrine pancreas—pancreatitis, pancreatectomy, neoplasia, hemochromatosis, fibrocalculous pancreatopathy D. Endocrinopathies—acromegaly, Cushing's syndrome, glucagonoma, pheochromocytoma, hyperthyroidism E. Drug- or chemical-induced—glucocorticoids, nicotinic acid, thiazides, hydantoins, protease inhibitors, antipsychotics (atypicals and others) F. Infections—congenital rubella, cytomegalovirus, coxsackievirus G. Uncommon forms of immune-mediated diabetes— "stiff-person" syndrome, anti-insulin receptor antibodies H. Other genetic syndromes sometimes associated with diabetes— Wolfram's syndrome, Down's syndrome, Klinefelter's syndrome, Turner's syndrome, Prader-Willi syndrome PATHOGENESIS/ PATHOPHYSIOLOGY – TYPE 1 Type 1 DM predominantly develops in children and young adults and patient tend to be lean. Immune mediated or Idiopathic Inheritance is complex with no clear Mendelian pattern. Is caused by autoimmune destruction of β cells leading absolute loss of insulin secretion Pathogenesis of autoimmune destruction – genetic, environmental & immunologic factors  PATHOGENESIS/ PATHOPHYSIOLOGY – T1DM CONT. Genetics Prevalence is increased in patients with other autoimmune diseases, such as Graves disease, Hashimoto thyroiditis, and Addison disease etc. Association with human leukocyte antigen (HLA)- DR3 or HLA-DR4, HLA-DQs Environment – viral infection and dietary factors Environmental  viruses (eg mumps, rubella, Coxsackie B4)  toxic chemicals  exposure to cow's milk in infancy, and cytotoxins. PATHOGENESIS/ PATHOPHYSIOLOGY – T2DM Most common, account for ~95% of DM cases T2DM characterized by  increased peripheral resistance to insulin action  impaired insulin secretion  increased hepatic glucose output. Both genetic and environmental factors contribute to the development of T2DM The defects of type 2 diabetes mellitus occur when a diabetogenic lifestyle (ie, excessive calories, inadequate caloric expenditure, obesity) is superimposed upon a susceptible genotype Thyroid gland Main hormones – Thyroxine (T4) and triidothyronine (T3) Synthesis and release of thyroid hormone is controlled by pituitary thyrotrophin (TSH) Functions  Regulates basal metabolic rate  Improves cardiac contractility  Increases the gain of catecholamines  Increases bowel motility  Increases speed of muscle contraction  Decreases cholesterol (LDL)  Required for proper fetal neural growth Disorders – Hyperthyroidism and Hypothyroidism