1. Endocrine Review Eric L. Johnson, MD Assistant Professor Department of Family and Community Medicine UNDSMHS Assistant Medical Director Altru Diabetes Center Grand Forks, ND

2. Objectives • Understand basic principles of endocrine function • Understand basic principles of endocrine dysfunction • Understand management and referral of common endocrine diseases

3. Endocrine Pathology • Disease state results from excess or insufficiency of hormone • Clinical challenge is determination of the origin of excess or insufficiency, i.e., Hypothalamus (tertiary), Pituitary (secondary) or target gland (primary)

4. Endocrine Disorders (other than diabetes) • Thyroid • Adrenal • Parathyroid • Pituitary gland • Gonadal • Gout (uric acid)

5. The Endocrine System Brain Hypothalamus Pituitary Hypothyroid Thyroid Pancreas Adrenal Gonads

6. Hypothalamus

7. Hypothalamus AVP = arginine vasopressin CRH = corticotropin-releasing hormone GHRH = growth hormone-releasing hormone GnRH = gonadotropin-releasing hormone SRIF = somatotropin release–inhibiting factor (somatostatin) TRH = thyrotropin-releasing hormone; VIP = vasoactive intestinal polypeptide.DA = dopamine ACTH = adrenocorticotropic hormone LH = lutenizing hormone FSH = follicle-stimulating hormone GH = growth hormone TSH = thyroid-stimulating hormone PRL = prolactin Goldman: Cecil Medicine, 23rd ed. 2007

8. Anterior Pituitary Hormones

9. Anterior Pituitary Hormones • TSH, ACTH, FSH, and LH hormones are tropic hormones that simulate other endocrine glands • TSH-Thyroid • ACTH- Adrenal Cortex • FSH, LH- Gonads

10. Posterior Pituitary Hormones • Vasopressin(ADH)- kidney, baroreceptors (plasma osmolality, water retention, thirst) • Oxytocin- breast, uterus (no known function in males) • Both are synthesized in specialized neurons in the hypothalamus (neurohypophysial neurons)

11. Prolactinomas • Pituitary adenomas may present with visual impairment, headache, or hormonal abnormalities • Prolactinomas most common. Manifest with galactorrhea and gonadal dysfunction • Laboratory testing: serum prolactin, creatinine levels and thyroid function tests • MRI is the imaging modality of choice for the anatomic evaluation of the hypothalamus and pituitary gland

12. Panhypopituiarism • Neoplasm • Radiation • Infiltrative/Infection • Empty sella syndrome (herniation of subarachnoid tissue) • Apoplexy (hemorrage) • Sheehan’s syndrome (pregnancy)

13. Growth Hormone Excess (Acromegaly) • Acromegaly cause: growth hormone–secreting adenoma of the anterior pituitary • Elevated serum levels of IGF-1 are found in acromegaly (best single test) • The diagnosis of acromegaly is confirmed by a glucose tolerance test • Transsphenoidal surgery to remove the pituitary adenoma is the initial treatment of choice in individuals with acromegaly

14. Growth Hormone Excess (Acromegaly) Acromegaly manifestations • Increased hand/foot size • Prognathism/teeth space widening • Frontal bossing/coarsening of facial features • Weakness/fatigue

15. Growth Hormone Excess (Acromegaly) Acromegaly manifestations cont’d • Sweating • HTN>>>cardiomyopathy • Obstructive sleep apnea • Insulin resistance

16. Growth Hormone Excess (Acromegaly) Treatment • Surgical resection Best if tumor small, 10-20% result in pan hypo pit • Radiation Slow to diminish GH, 50% pan hypo pit • Bromocriptine Blocks GH effect • Octreotide Lowers GH secretion, SC route w/frequent dosing

17. Growth Hormone Deficiency • Fatigue or hypoglycemia in the adult • Dwarfism in child Born normal length at birth but growth “falls off curve” • Diagnosis: IGF1 level (GH varies too much) • Treatment: formerly used human pit gland extract, synthetic GH since late 80’s

18. Diabetes Insipidus (ADH) • Deficiency of posterior pituitary hormone ADH (aka vasopressin) • ADH acts on kidney collecting duct to retain free water deficiency causes free water loss • ADH maintains blood volume via: - -Osmoreceptors in brain -Stretch receptors in heart -Baroreceptors in carotids and aorta

19. Diabetes Insipidus (ADH) • Decreased urinary specific gravity (≤1.005) • Decreased urinary osmolarity (<200 mOsm/kg) even in the presence of high serum osmolality    • Hypernatremia, increased plasma osmolarity, hypercalcemia, hypokalemia • Normal Serum osmolarity: 282 - 295 mOsm/kg • Normal Urine osmolarity: 500 - 800 mOsm

20. Diabetes Insipidus (ADH) Etiology -CNS insult -head trauma, surgery, tumor, infection -Genetic -MS, Metastatic Disease -Drugs (lithium is classic) -Nephrogenic vs. Neurogenic vs. Psychogenic Sx –Thirst, polyuria, polydipsia (with a normal glucose)

21. Diabetes Insipidus (ADH) • Diagnostic workup: decreased ADH or insensitivity to ADH? • Water Deprivation Test: -Baseline measurement of weight, ADH, plasma sodium, urine and plasma osmolarity -Patient is deprived of fluids under strict medical supervision.    -Frequent (q2h) monitoring of plasma and urine osmolarity        • Test terminated when plasma osmolarity >295 mOsm/kg or the patient loses ≥3.5% of initial body weight.    • Diabetes insipidus is confirmed if the plasma osmolarity is >295 mOsm/kg and the urine osmolarity is <500 mOsm/kg (typical referral point)

22. Diabetes Insipidus (ADH) • Nephrogenic vs. neurogenic • Patient given 5 U of vasopressin (ADH), change in urine osmolarity is measured • Significant increase (>50%) in urine osmolarity after administration of ADH is indicative of neurogenic diabetes insipidus.

23. Diabetes Insipidus (ADH) Treatment • Desmopressin • Thiazides in mild neurogenic

24. Syndrome of Inappropriate ADH(SIADH) • Hyponatremia • Urinary osmolarity > serum osmolarity • Normal BUN, creatinine,TSH,glucose

25. SIADH • Neoplasm • Pulmonary disorders: pneumonia, emphysema, cystic fibrosis, status asthmaticus, respiratory failure • Intracranial pathology: trauma, neoplasms, infections (meningitis, encephalitis, brain abscess)   • Postoperative period: surgical stress, ventilators with positive pressure, anesthetic agents      • Drugs: chlorpropamide, thiazide diuretics, chemotherapeutic agents carbamazepine, phenothiazines, MAO inhibitors, tricyclic antidepressants, narcotics, nicotine, clofibrate, haloperidol, SSRIs, NSAIDs • Other: acute intermittent porphyria, myxedema, psychosis, delirium tremens, ACTH deficiency (hypopituitarism), general anesthesia, endurance exercise

26. SIADH • Treatment Fluid Restriction Careful use of hypertonic saline IV Resolution/Treatment of underlying problem

27. Cushing’s Disease • Pituitary adenoma>>excess production of ACTH>>excess cortisol production • Distinguished from Cushing’s syndrome, which includes other causes of cortisol excess (ectopic production of ACTH and CRH) • Cushing’s disease causes 60-70% of excess cortisol disease states • Occurs 8 times more often in women than men

28. Cushing’s • Classic Cushing's features: Centripetal obesity, moon facies, and ‘buffalo’ hump • Striae are common • Fine (lanugo) hair growth • Muscle wasting • Bone demineralization • Hypertension • IGT • Psych

29. Cushing’s Diagnosis • Distinguish between: • Cushings Disease -Pituitary Causes • Cushing’s Syndrome -Adrenal causes of cortisol excess; -Ectopic sources of ACTH or Ectopic CRH (Cortisol Releasing Hormone)

30. Cushing’s Diagnosis • Serum Cortisol is elevated • Abnormal tests can be seen in up to 30% of hospitalized and/or depressed patients • 24 hour free urinary cortisol can be a useful adjunct • Overnight Dexamethasone suppression test……

31. Cushing’s Diagnosis • Overnight Dexamethasone Suppression Test: 1 gram at 11pm, measure plasma cortisol at 8 am the next morning • The normal response is suppression to less than 3mcg/dl • If no suppression, they have ectopic or adrenal production • If supression, they may have pituitary cause

32. Cushing’s Diagnosis • Can Measure ACTH -ACTH low in Adrenal gland tumor -ACTH high in ectopic or pituitary adenoma

33. Cushing’s DiagnosisSummary • High serum or 24 hour urine cortisol • Dexamethasone suppression -No supression: Ectopic or adrenal -Supression: Pituitary • ACTH -Low: Adrenal -High: Likely pituitary or ectopic

34. Addison’s Disease(Adrenocortical Hypofunction) • Can result in all loss of corticosteroid production if the adrenal cortex suffers destruction (primary) • Can result from diminished ACTH production (secondary)

35. Addison’s Disease • Loss of cortisol: -Loss of vascular tone and CV output -Hypoglycemia-Cortisol important for Gluconeogenesis -Hypercalcemia (Loss of inhibition of intestinal absorption and renal reabsorption) -Serum ACTH levels are usually used for initial screening (Low)

36. Addison’s Disease • Skin changes-Hyperpigmentation in Palmar creases, scars, oral mucosa • Longitudinal pigmented bands under nails • Vitiligo in up to 15% of patients • Decreased pubic and axillary hair in females • Weakness, fatigue, nausea and vomiting, and a craving for salt

37. Addison’s Disease • Associated with other endocrine insufficiencies (thyroid, parathyroid, type 1 DM, etc) • Treatment is to replace adrenal hormones • Case I’ve seen: Pt. also had Type 1 DM and hypothyroidism; died at age 27 from profound hypoglycemia

38. Aldosterone Disorders • Aldosterone-a mineralocorticoid secreted by the adrenal glands • Primary secretion affected by Angiotensin II>renin (part of fluid and electrolyte balance) • Increased aldosterone-increased sodium retention and increased potassium secretion by the kidney

39. Hyperaldosteronism • Primary-more common in women 3rd to 5th decade of life • Presents with hypertension, weakness, fatigue, hypokalemia, polyuria, polydipsia • Most cases are from benign adenomas (Conn’s Syndrome) • Screening: aldosterone:renin ratio of greater than 30 (off of anti-hypertensives, except Ca++ channel blockers) • CT scanning for adrenal adenomas

40. Secondary Hyperaldosteronism • Usually occurs in edematous states-i.e. CHF, cirrhosis or renal artery stenosis • Causes intravascular volume depletion, stimulating renin production • Elevated renin and aldosterone levels • Can occur in Bartter’s syndrome (impaired chloride re-absorption)

41. Hypoaldosteronism • Sodium wasting and hyperkalemia • May be up to 10% of hyperkalemia • Hyper-reninemic hypoaldosteronism (more common) Defect is in aldosterone synthesis or angiotensin II action Genetic, ACEI, ARB, heparin, Lead poisoning, Severe Illness • Hyporeninemic DM, HTN, renal insufficiency

42. Hypoaldosteronism • Lab: Plasma renin K+ Glucose Kidney functions Hyperchloremic metabolic acidosis

43. Parathyroid • Purpose –Maintain serum calcium levels • Target tissues –Bone, kidney, intestine • Feedback loop –As Calcium rises, PTH lowers –As calcium lowers, PTH rises

44. Hyperparathyroidism • Etiology –Tumor (adenoma) –Hyperplasia –Drugs (lithium is classic) –Ectopic PTH • Secondary Hyperparathryroidism can occur in chronic renal disease

45. Hyperparathyroidism • Elevated PTH, Serum Ca++, urine Ca++ • Polyruia, Polydipsia • Kidney stones • Peptic ulcer disease • Pancreatitis • Nausea, vomiting or loss of appetite • Osteopenia/porosis, leading to an increased risk of fractures • Confusion or poor memory • Muscle weakness or fatigue

46. Hyperparathyroidism • Treatment (loop diuretics, hydration) • Observation • Surgery

47. Hypoparathyroidism • Low PTH (idiopathic, iatrogenic-thyroid surgery) • Low Serum Ca++ (low Vit D?) • Elevated Phosphorous • Parasthesthias • Alopecia/ vitiligo/ candidiasis • Long Q-T on EKG • Muscle cramps or tetany -Chvostek’s sign: facial twitch after a gentle tapping over the facial nerve -Trousseau's sign: carpopedal spasm after inflation of blood pressure cuff above the patient's systolic blood pressure for 2 to 3 minutes

48. Hypoparathyroidism • Ca++ plus Vitamin D • Low Phosphorous diet

49. Hypothyroidism • Incidence in the U.S. is about 1% • Primary hypothyroidism accounts for 90-95% of all cases • Autoimmune most common (Hashimoto’s) • May or may not have enlarged (goitrous) thyroid • End Stage Grave’s/treatment/can result in hypothyroidism • Iatrogenic-surgical • Iodine deficiency

50. Hypothyroidism • Decreased secretion of thyroid hormone from the thyroid gland. Most frequently reflects a disease of the gland itself (primaryhypothyroidism) 95% • Pituitary disease (secondaryhypothyroidism) • Hypothalamic disease (tertiaryhypothyroidism)