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Endocrine Physiology and Disorders Endocrine Systems Intercellular communication network Hormones travel from cell to cell through the bloodstream Regulates complex phenomenon: Stress Response Growth and Development Fluid and Electrolyte Balance Reproduction Solubility of Hormones Determines Mechanism of Action Lipid soluble hormones steroid thyroid Water soluble hormones proteins and peptides catecholamines Feedback Regulation liver GH ACTH adrenal cortex anterior posterior ADH kidney TSH thyroid PRL FSH, LH Oxytocin breast uterus Feedback Regulation T3, T4 cortisol somatomedin osmolality GH ACTH anterior posterior ADH TSH Oxytocin PRL FSH, LH Negative Feedback Feedback signals decrease secretion by down regulation of receptor number decreased sensitivity of receptors – eg. thyroid hormone down regulates TRH receptors on thyrotroph cells in the pituitary Primary vs Secondary Disorders Primary Disorders are due to dysfunction of the target gland. Secondary Disorders are due to dysfunction of the pituitary gland. Primary and secondary can be differentiated by looking at feedback loops. Endocrine Disorders Hyperfunction Hypofunction Etiology Etiology autoimmune stimulation autoimmune inhibition nonsecreting tumors secreting tumors surgical removal idiopathic ischemia, infarct receptor defects Treatment surgical removal blocking drugs irradiation Treatment hormone therapy Causes of endocrine disorders Acromegaly GH secreting pituitary adenoma headache, visual disturbances hyperglycemia “diabetogenic” increased lean body mass – bone and soft tissue Treatment hypophysectomy irradiation Thyroid Hormone Synthesis Thyroid Hormone synthesis is done by the enzyme: Thyroid Peroxidase TSH Y T3, T4 secretion thyroglobulin T3 T4 Iodine Triiodothyronine and Thyroxine About 90% is T4 Most abundant About 10% is T3 Most biologically active Actions of Thyroid Hormones T3 T4 T3 rT3 plasma membrane T3 combines with a nuclear receptor--------> affects DNA: increased oxygen use increased BMR increased heat production increased cardiac output increased ventilation gluconeogenesis enhanced SNS actions Hyperthyroidism History Physical weight loss warm, moist skin increased appetite thin, fine hair nervousness increased BP, HR heat intolerance hyperreflexia palpitations fine tremor increase bowel motility eyelid, retraction, lag enlarged thyroid Etiology of Hyperthyroidism Primary Secondary Graves Disease Pituitary adenoma Thyroid tumor Exogenous thyroid Thyroiditis Pathophysiology of Graves Dx Etiology: Autoimmune High association with HLA D3 and B8 Women affected 8 to 1 Pathogenesis: IgG autoantibodies bind to and stimulate TSH receptors on thyroid. Thyroid hyperplasia and hypersecretion result Exophthalmos due to IgG Treatment RAIU ablation Symptom control with beta blockers PTU and thyroxine to inhibit synthesis thyroxine may reduce relapse which often occurs with PTU alone Surgery Thyroiditis Initially: Increased thyroid hormone release leads to hyperthyroidism, but RAIU is low and synthesis is low Next: Hormone depletion leads to a period of hypothyroidism Finally: Most will recover and become euthyroid in 2-6 months RX: b-blockers, NSAID, ASA, steroids Hypothyroidism History Physical weight gain dry, dull skin fatigue coarse hair amenorrhea hoarse voice cold intolerance low HR, BP constipation decreased DTR periorbital edema Hypothyroidism Primary Secondary Hashimoto thyroiditis Iatrogenic (surgery, RAIU ablation) Iodine deficiency Pituitary failure Laboratory Evaluation T3, T4 may initially be normal or low TSH is a better indicator of hypothyroid Primary hypothyroid: high TSH Secondary hypothyroid: low TSH Replacement of thyroid hormone Synthetic T4 (Synthroid) average dose is 110 - 120 mcg/day Monitor TSH level Overtreatment can lead to osteoporosis in postmenopausal women: If TSH too low, reduce replacement dose. Adrenocortical Hormones Sugar: glucocorticoids (cortisol) Salt: mineralocorticoids (aldosterone) Sex: androgens, estrogens Regulation of Cortisol Secretion Sleep-wake pattern light-dark cycle 7-13 Pulses per day of CRH from hypothalamus ACTH secretion Cortisol peak at 2:00-4:00 am Cortisol nadir at 10 pm -midnight Stress pain infection cortisol level Actions of Cortisol Metabolism: gluconeogenesis, insulin antagonist, increased appetite, mobilization of fat stores Muscle: increased contractility, breakdown of protein to form glucose Bone and Connective: decreased bone and collagen formation Vascular: enhances effect of catecholamines, reduces vascular permeability, mineralocorticoid effects Immune: inhibits the immune system in a number of ways CNS: alters auditory, olfactory and taste acuity, mood, sleep Adrenocortical Hypersecretion History Physical weight gain central obesity fatigue muscle wasting menstrual irregularity striae hyperglycemia hypertension hirsutism weakness easy bruising Etiology Cushing Disease Cushing Syndrome Adrenal adenoma Adrenal carcinoma Ectopic ACTH (cancer) Exogenous steroids Pituitary adenoma Laboratory Evaluation 24-hr urinary free cortisol (increased) Dexamethasone suppression test: If suppression of cortisol, then secondary Plasma ACTH (low in primary, high in secondary) CRH stimulation test (increases cortisol in secondary, no effect in primary) Treatment of Cushing Syndrome If on exogenous steroids, try to wean If tumor, surgery or irradiation If inoperable, drugs to inhibit synthesis e.g. Mitotane, and inhibitors of enzymes in the cortisol pathway Adrenocortical Insufficiency History Physical hyperpigmentation tachycardia hypotension hypoglycemia hyperkalemia ACUTE: N&V, headache, bleeding may be asymptomatic weakness weight loss Etiology Primary Secondary autoimmune pituitary failure adrenalectomy steroid withdrawal infarction congenital aplasia congenital enzyme deficiency (Adrenogenital syndrome) Laboratory Evaluation Plasma cortisol level (low) ACTH level (high in primary, low in secondary) ACTH stimulation test (no response in primary) Serum potassium (high if associated deficiency of aldosterone) Serum glucose (low) Replacement Therapy ACUTE CHRONIC Hydrocortisone 100mg now, then continuous infusion for 24 hr. Prednisone, cortisone and hydrocortisone are used Fluid replacement Convert to oral meds if stable Twice daily dosing, 2/3 in am, 1/3 in pm Regulation of Insulin Secretion Glut-2 Liver Releases glucose and ketones GLUCOSE glucagon insulin somatostatin Endocrine Pancreas Increased secretion of Insulin Decreases blood glucose Major Actions of Insulin Action on Cell glucose uptake Effect on Blood blood glucose glycogen formation gluconeogenesis protein synthesis blood amino acids fat deposition blood FFA lipolysis blood ketones K+ uptake blood K+ Figure: 41-4 Metabolism in type 1 diabetes What hormones affect blood glucose level? Hormones that increase glucose: growth hormone catecholamines glucagon thyroid glucocorticoids Hormones that decrease glucose: insulin Somogyi Phenomenon Hypoglycemia Insulin administration Release of: growth hormone catecholamines glucagon cortisol Hyperglycemia Diabetes Mellitus Insulin Dependent (Type 1) Non Insulin Dependent (Type 2) Compare Type 1 and Type 2 Type 1 Type 2 Onset any age adults Weight underweight obese Immune-mediated YES NO Ketoacidosis YES NO Insulin secretion NO YES Beta cell function NO YES HLA-linkage YES NO Diagnostic Criteria Nonpregnant Adults: random glucose > 200 mg% plus symptoms OR: fasting glucose > 126 mg%, twice OR: fasting glucose < 126 mg%, but OGTT is > 200 mg% at 2 hours Impaired Glucose Tolerance: fasting glucose < 126 mg%, 2 hr OGTT is between 126-200, 0-2 hr is > 200 mg% Pathogenesis of Diabetes Impaired Transport of Glucose into Cells CELL ENERGY HYPERGLYCEMIA breakdown of fat and protein blood osmolality cells shrink glycosuria ketogenesis dehydration Fruity Kussmaul Coma breath resp thirst HR warm,dry Compare DKA with HHNS DKA HHNS ketoacidosis no ketoacidosis mod elevated glucose high glucose >800 severe dehydration coma Goals of Treatment Normalize Blood Glucose <180 mg% postprandial, <130 mg% fasting – Self monitor blood glucose routinely – Normal blood glucose: 70-115 mg% – Minimize hypoglycemic events Keep HbA1c < 7.0% (3.9-6.9%) – Reflects glucose level over past 2-3 months – HbA1c increases 1% for each increase of 30mg% in blood glucose Goals of Treatment Avoid Long-term Vascular and Neurological Complications Glycosylated proteins, enzymes contribute to atherosclerotic processes: – retinopathy, nephropathy, MI, CVA, peripheral vascular disease Neurons don’t require insulin, are exposed to high intracellular glucose: – peripheral neuropathy, autonomic neuropathy Treatment of Diabetes Diet: Exercise low in simple sugars, fat. Adequate protein and complex carbohydrates weight loss for obese Type 2 consistent, regular timing Drug therapy Insulin for both Type 1 and Type 2 oral agents for Type 2 only ACE Inhibitors Oral Agents for Diabetes Sulfonylureas (hypoglycemics, increase secretion of insulin from pancreas) First generation: Tolinase, Diabinese Second generation: Diabeta, Glucotrol Biguanides (decrease tissue resistance, do not cause hypoglycemia) metformin (Glucophage) Teaching, Teaching, Teaching Blood glucose monitoring Urine ketone monitoring Drug onset, peak Short and long term complications to monitor When to call the provider, enter the hospital Diet and Exercise plan KNOW THE DIFFERENCE HIGH Blood Sugar Increased thirst and urination ketones in urine aching, weak heavy breathing nausea,vomiting fatigue cold sweats headache trembling pounding heart sleepiness personality change hunger LOW Blood Sugar The End…