Pituitary Hormones and Their Function. Pituitary Hormones and Their Function. Pituitary Hormones and Their Function

Transcription

1 Endocrinology Update Endocrinology Update Robert J. Rushakoff, MD Robert J. Rushakoff, MD Professor of Medicine University of California, San Francisco Feedback control 1

2 Golden Rule of Endocrinology If overproduction is suspected, try to suppress production. If underproduction is suspected, try to stimulate production. Pituitary Hormones and Their Function Hormone Increased by Decreased by Excess Deficiency Notes ADH Thirst, high Low serum serum osmolality osmolality, low serum K + SIADH ACTH CRH, Stress High cortisol Cushing s syndrome TSH TRH High T 4 and/or T 3 LH/FSH GnRH GH GHRH, hypoglycemia, dopamine Prolactin Pregnancy, nursing, TRH, stress Gonadal sex steroids Somatostatin Dopamine DI Adrenal insufficiency Hyperthyroidism Hypothyroidism Childhood: gigantism Adulthood: acromegaly Galactorrhea, hypogonadism Hypogonadism Child: short stature Adult: poor sense of well-being Diurnal variation (peak at 3 4 a.m.) In men, inhibin inhibits FSH Inability to lactate Under tonic inhibition by hypothalamic dopamine Pituitary Hormones and Their Function Hormone Increased by Decreased by Excess Deficiency Notes Pituitary Hormones and Their Function Hormone Increased by Decreased by Excess Deficiency Notes ADH Thirst, high serum osmolality Low serum osmolality, low serum K + SIADH DI ACTH CRH, Stress High cortisol Cushing s syndrome Adrenal insufficiency Diurnal variation (peak at 3 4 a.m.) ADH Thirst, high serum osmolality Low serum osmolality, low serum K + SIADH DI TSH TRH High T4 Hyperthyroidism and/or T3 Hypothyroidism ACTH CRH, Stress High cortisol Cushing s syndrome Adrenal insufficiency Diurnal variation (peak at 3 4 a.m.) LH/FSH GnRH Gonadal sex steroids Hypogonadism In men, inhibin inhibits FSH TSH TRH High T 4 and/or T 3 Hyperthyroidism Hypothyroidism LH/FSH GnRH Gonadal sex steroids Hypogonadism In men, inhibin inhibits FSH GH GHRH, hypoglycemia, Somatostatin Childhood: gigantism Child: short stature dopamine Adulthood: acromegaly Adult: poor sense of well-being Prolactin Pregnancy, nursing, TRH, stress Dopamine Galactorrhea, hypogonadism Inability to lactate Under tonic inhibition by hypothalamic dopamine GH GHRH, hypoglycemia, Somatostatin Childhood: gigantism Child: short stature dopamine Adulthood: acromegaly Adult: poor sense of well-being Prolactin Pregnancy, nursing, TRH, stress Dopamine Galactorrhea, hypogonadism Inability to lactate Under tonic inhibition by hypothalamic dopamine 2

3 Pituitary Hormones and Their Function Hormone Increased by Decreased by Excess Deficiency Notes Pituitary Hormones and Their Function Hormone Increased by Decreased by Excess Deficiency Notes ADH Thirst, high serum osmolality Low serum osmolality, low serum K + SIADH DI ACTH CRH, Stress High cortisol Cushing s syndrome Adrenal insufficiency Diurnal variation (peak at 3 4 a.m.) TSH TRH High T 4 and/or T 3 Hyperthyroidism Hypothyroidism LH/FSH GnRH Gonadal sex steroids Hypogonadism In men, inhibin inhibits FSH ADH Thirst, high serum osmolality Low serum osmolality, low serum K + SIADH DI ACTH CRH, Stress High cortisol Cushing s syndrome Adrenal insufficiency Diurnal variation (peak at 3 4 a.m.) TSH TRH High T 4 and/or T 3 Hyperthyroidism Hypothyroidism LH/FSH GnRH Gonadal sex steroids Hypogonadism In men, inhibin inhibits FSH GH GHRH, hypoglycemia, dopamine Somatostatin Childhood: gigantism Adulthood: acromegaly Child: short stature Adult: poor sense of well-being GH GHRH, hypoglycemia, Somatostatin dopamine Childhood: gigantism Adulthood: acromegaly Child: short stature Adult: poor sense of wellbeing Prolactin Pregnancy, nursing, TRH, stress Dopamine Galactorrhea, hypogonadism Inability to lactate Under tonic inhibition by hypothalamic dopamine Prolactin Pregnancy, nursing, TRH, stress Dopamine Galactorrhea, hypogonadism Inability to lactate Under tonic inhibition by hypothalamic dopamine Hypothalamus - Hormone Action TRH + - SOMATOSTATIN PITUITARY TSH (+) Thyroid TSH + PIT - T 4 T3 T 4, T 3 (-) T 4, T 3 (+) Thyroid Hormone Action 3

4 Hormone Action Thyroid Failure Hormone Action Primary Hyperthyroidism PITUITARY TSH (+) Thyroid X PITUITARY TSH (+) Thyroid T 4, T 3 (-) T 4, T 3 (+) Thyroid Hormone Action T 4, T 3 (-) T 4, T 3 Excess Thyroid Hormone Action Thyroid Function Tests Total Thyroid Hormone T 4 T 3 Free Thyroid Hormone direct and indirect measurement FT 4, FT 3 Tests for Thyroid hormone binding protein T 3 U TBG TSH normal Euthyroid Primary Hyperthyroid Primary Hypothyroid 4

5 Radioactive Iodine Uptake 123 I given orally Gamma counter over area of thyroid measures radioactivity at 24 hours Useful for differential diagnosis of thyrotoxicosis NOT A TEST FOR ASSESSMENT OF THYROID FUNCTION Dependent on iodine intake Radioactive Iodine Scanning Image of thyroid obtained after the administration of RAI NOT A TEST FOR ASSESSMENT OF THYROID FUNCTION Useful for when thyrotoxic nodular disease is suspected. Thyroid Function and Oral Contraceptives Patient ASBP Patient TDF Hyperthyroid Euthyroid Euthyroid Serum T 4 T 3 Uptake Free T 4 TSH Serum T 4 T 3 Uptake TSH Free T 4 Anabolic Steroids 5

6 Patient SF FH + for mother with thyroid disease Medications: none Exam: Thin female, hyperactive Pulse regular at 120. BP: 98/60 HEENT: + stare, + lid lag at 98mm measure 17mm bilat Patient SF Neck: thyroid enlarged 2X, beefy, no nodules Heart: + Means-Lerman systolic scratch (rubbing together of normal pleural and pericardial surfaces) Ext: fine tremor, no rash Do you suspect that the patient has hyperthyroidism? Symptoms of Hyperthyroidism Palpitations nervousness fatigue hyperkinesia hyperdefication sweating Heat intolerance weight loss (with increased appetite) Neck swelling Neck pain Changes in eyes decrease in menstrual periods 6

7 Symptoms of Hyperthyroidism Signs of Hyperthyroidism Palpitations nervousness fatigue hyperkinesia hyperdefication sweating Heat intolerance weight loss (with increased appetite) Neck swelling Neck pain Changes in eyes decrease in menstrual periods Tachycardia Lid lag Stare exophthalmus (Graves disease) Tremor Thyroid enlargement Onycholysis (separation of the nail from its bed) brisk reflexes Dermopathy (thickened skin, most often pretibial) Patient SF 7

8 Is the patient thyrotoxic? FT 4 is 36 (nl 12-24) TSH is 0 (nl 0.5-5) TSH FT 4 TSH FT 4 Laboratory Tests for Thyrotoxicosis Primary thyrotoxicosis Secondary thyrotoxicosis 8

9 Laboratory Tests for Thyrotoxicosis Laboratory Tests Not Usually Needed for Diagnosis TSH FT 4 TSH FT 4 FT 3? T 3 toxicosis T 3 toxicosis TSI Thyroid Antibodies Causes of Thyrotoxicosis Common Causes Graves Disease autoimmune disease - B lymphocytes produce TSI Female:Male 5:1 Peak age Toxic Multinodular Goiter (TMNG) older patients with history of multinodular goiter may be precipitated by iodine Causes of Thyrotoxicosis Common Causes Toxic Nodule (Plummer s Nodule) Single autonomous nodule (>3cm) Age usually > 40 Subacute thyroiditis Young patient history of malaise, neck pain, viral infection thyroid may be slightly large and tender 9

10 Causes of Thyrotoxicosis Less Common Causes Jod Basedow iodine induced (usually in patient with underlying goiter) Silent Thyroiditis factitious excessive thyroid hormone ingested, usually for weight control Most often someone in medical field Causes of Thyrotoxicosis Less Common Causes hypothalamic-pituitarypituitary post-partum partum postpartum depression followed by hypothyroidism molar pregnancy high levels of hcg Struma Ovarii teratoma of ovary containing thyroid tissue Tests for Differential Diagnosis Tests for Differential Diagnosis Graves Disease Subacute Thyroiditis TSH FT 4 24h RAI uptake Graves Disease Subacute Thyroiditis TSH FT 4 24h RAI uptake Graves gland beefy Thyroiditis gland hard ESR high in Subacute thyroiditis Graves gland beefy Thyroiditis gland hard ESR high in Subacute thyroiditis 10

11 Tests for Differential Diagnosis Graves Disease Treatment TSH FT 4 FT 3 24h RAI uptake TMNG Toxic Nodule TMNG : feel a multinodular goiter, scan shows hot spots Toxic nodule: palpate a single large nodule, scan shows single hot spot Antithyroid Drugs Radioactive iodine Surgery Treatment for Subacute Thyroiditis Treatment of symptoms Treat with beta blocker titrated to lower pulse Antithyroid medications of no use ASA or NSAIA for pain toxic state should resolve in 2-3 months Treatment for Subacute Thyroiditis After toxic period, may have transient hypothyroidism (in some patients permanent). May choose to just watch patient during this time and most will be euthyroid in another 2-4 months. May start on levothyroxine and then stop in a year to see if needed long term 11

12 Symptoms of Hypothyroidism Fatigue Cold intolerance Weight gain constipation heavy, frequent menstrual periods muscle cramps Dry skin Signs of Hypothyroidism puffy face and hands hoarse slow reflexes Laboratory Tests for Hypothyroidism Laboratory Tests for Hypothyroidism TSH FT 4 Primary hypothyroidism TSH FT 4 Subclinical hypothyroidism TSH FT 4 Secondary hypothyrodism Clinical significance not clear. Patients with TSH >20 or + thyroid antibodies have >80% chance to become clinically hypothyroid within 5 years 12

13 Etiology of Hypothyroidism Primary Hashimoto s Thyroiditis automimmune +/- goiter After RAI or surgery for Graves disease subacute thyroiditis inborn errors of thyroid hormone synthesis Secondary hypothalamic or hypopituitarism Thyroid Hormone Preparations Levothyroxine (T 4 ) most physiologic treatment of choice daily dose t 1/2 1 week average dose mg/d Thyroid Hormone Preparations Liothyronine (T 3 ) tid dosing not physiologic bypass normal T to T 4 3 conversion t 1/2 1 day Thyroid Hormone Preparations Desiccated thyroid potency variable variable T 4 and T levels 3 monitoring difficult bypass normal T to T 4 3 conversion 80% of patients on this preparation shown not to require any thyroid hormone replacement 13

14 Monitoring Thyroid Hormone Replacement Goal is for normal TSH Minimal time after any change in thyroid hormone dose before rechecking TSH level is 6-8 weeks. It takes this long to reach steady state. More frequent testing will be not only a waste of money but potentially misleading. Decreased Absorption: Drugs, supplements: calcium, iron, soy, Cholestyramine Decreased gastric acid: H. pylori infection, omeprazole Monitoring Thyroid Hormone Replacement TSH FT 4 Subclinical hyperthyroidism Associated with decreased bone density. Associated with atrial arrhythmias in older patients. Patient needs decrease in thyroid hormone dose. Thyroid Nodules Fine needle aspiration first diagnostic test Thyroid scans not helpful to determine if nodule is benign or malignant Experienced pathologist of key importance Hypopituitarism Although primary organ failure is more common, hypopituitarism is in the differential diagnosis in cases of hypothyroidism, hypoadrenalism and hypogonadism GH, gonadotrophins, TSH, ACTH, Prolactin (loss in this order) ADH deficiency only if posterior pituitary involved 14

15 Etiologies 9 I s Invasive tumors, metastasis Infarction Sheehan s, apoplexy Iatrogenic radiation, surgery Infiltrative sarcoid, hemochromatosis, histiocytosis X Injury head trauma (also can see DI) Immunologic lymphocytic hypophysitis Infections TB, syphilis or fungi Idiopathic Isolated Kallman s GnRH deficiency with anosmia X linked dominant decreased expression of KAL 1 Hypopituitarism: Dx and Tx In general, treat underlying cause Central hypothyroidism TSH is not reliable for screening or for monitoring Diagnosis depends on low Free T4 Tx: LT4 therapy, but do not start until adrenal insufficiency has been ruled out Hypopituitarism: Dx and Tx cont d Central adrenal insufficiency Aldosterone secretion intact so no hyperkalemia Hyponatremia due to decreased GFR & inability to excrete water load (+ increased ADH secretion +/- hypothyroidism) Dx: cosyntropin stimulation test (random cortisol or ACTH level not useful) Tx: hydrocortisone mg/d, 2/3 in the morning and 1/3 in the evening. Prolactin deficiency inability to lactate Pituitary tumors Microadenomas are < 1cm Macroadenomas are >1cm Types of tumors 60% prolactinomas 20% GH producing 10% ACTH producing 10% non-functioning Rare: TSH, LH/FSH or α-subunit producing 15

16 Pituitary tumors - Presentation Symptoms/Exam: Neurological syx (h/a, visual field cuts, nerve palsies) Hormonal excess or deficiency Incidental discovery on imaging study up to 10% general population have pituitary incidentalomas Pituitary tumors - Evaluation Once tumor is identified, must determine if functional or not: TSH, FT4 Prolactin ACTH, cortisol Cosyntropin stimulation test if suspect deficiency 24 hr urinary cortisol or dexamethasone suppression test if suspect excess LH/FSH + testosterone in men Pituitary tumors - Treatment Surgery: transsphenoidal approach is successful in approximately 90% of patients with microadenomas Medical: Dopamine agonists for prolactinomas Somatostatin analogues for GH producing tumors Radiotherapy after surgery and/or medical therapy fails or poor surgical candidates: Conventional XRT or Gamma knife Hyperprolactinemia 16

17 Hyperprolactinemia Physiologic: Pregnancy (prolactin can reach 200 ng/ml in 2 nd trimester) Lactation Nipple stimulation Exercise Coitus Stress Sleep Pathologic: Pituitary tumors mostly microadenomas Pituitary stalk lesions Hypothalamic lesions Chest wall /spinal cord lesions Hypothyroidism Chronic kidney disease Cirrhosis Hyperprolactinemia Cont d Pharmacologic: Estrogen Dopamine antagonists (phenothiazines, haloperidol, risperidone, metoclopramide, methyldopa, opioids, amoxapine) Monoamine oxidase inhibitors Cimetidine and Ranitidine SSRI s Tricyclic antidepressants Verapamil Liquorice Hyperprolactinemia: Syx/exam Women galactorrhea, amenorrhea or oligomenorrhea with anovulation and infertility in 90% Amenorrhea: 18% prolactinoma Galactorrhea: 37% Prolactinoma Both: 75% Prolactinoma Microadenoma: 64% Men impotence, decreased libido, galactorrhea (very rare) 91% macroadenoma Both local tumor extension symptoms - headache, visual field cuts, hypopituitarism Hyperprolactinemia: Diagnosis Elevated prolactin: PRL >200 ng/ml virtually diagnostic of prolactinoma PRL usually prolactinoma PRL may be microadenoma but exclude other causes Normal TFT s and negative pregnancy test MRI of pituitary 17

18 Hyperprolactinemia: Treatment Medical 1 st line in most cases Dopamine agonists: bromocriptine or cabergoline SE: nausea, fatigue, nasal stuffiness and postural hypotension Restores fertility and gonadal function in most patients Leads to tumor shrinkage During pregnancy, risk of growth is <5% for microprolactinomas and 20-40% for macroprolactinomas Hyperprolactinemia: Treatment Surgical: For patients intolerant or resistant to medications If need urgent decompression of the sella turcica for visual field defects unresponsive to trial of dopamine agonists Pituitary Tumors: GH Tumors 80% are macroadenomas 15% co-secrete prolactin Very rarely (<1% cases), acromegaly due to ectopic GH or GHRH production Lung CA, carcinoid, or pancreatic islet cell tumors Pituitary Tumors: GH Tumors Clinical features due to excess IGF-I and mass effect of the tumor. Hypertension Glucose intolerance or DM Increased colonic polyp frequency Soft tissue proliferation: coarsening of facial features, hand and feet enlargement Sweaty palms and soles Carpal Tunnel Syndrome Hypogonadism Visual field cuts and h/a s 18

19 Pituitary Tumors: GH Tumors Gigantism Identical twins, 22 years old, excess GH secretion 19

20 Pituitary Tumors: GH Tumors Diagnosis: Elevated IGF-1 is the hallmark Dx: oral glucose tolerance test 100 g glucose given 60 minutes GH<1 ng/ml rules out acromegaly Random GH level not helpful Therapy: Surgery: curative in 60-80% Radiation therapy: adjuvant therapy Medical: Octreotide LAR (SS analog) Pegvisomant (GH receptor antagonist) Adrenal Insufficiency: Etiologies Primary AI: Autoimmune Metastatic malignancy & lymphoma Hemorrhage: pregnancy, anticoagulation, antiphospholipid antibody syndrome Infiltrative disorders: amyloid, hemochromatosis Drugs: ketoconazole, metyrapone, aminoglutethimide, trilostane, mitotane, etomidate Rare: congenital adrenal hyperplasia, adrenal leukodystrophy Secondary AI: Iatrogenic: glucocorticoids & anabolic steroids Pituitary or hypothalamic tumors AI: Clinical Features Vague syx: Weakness Fatigue Anorexia Weight loss Nausea Vomiting Diarrhea Unexplained abdominal pain Postural lightheadedness Hyperpigmentation characteristic of primary adrenal insufficiency 20

21 AI: Diagnosis Labs: hyponatremia, hyperkalemia, eosinophilia, mild metabolic acidosis, hypercalcemia Step 1: confirm diagnosis Any random cortisol 18 µg/dl rules out AI Cortrosyn stimulation test Cortrosyn stimulation test Obtain baseline cortisol and ACTH Inject Cortrosyn 250 µg IM or IV Check cortisol level minutes later Normal if post stimulation cortisol 18 µg/dl Step 2: distinguish 1 o from 2 o Step 3: evaluate cause (CT abdomen or MRI pituitary) AI: Treatment Hydrocortisone mg/day 2/3 in the morning 1/3 in evening Stress doses: Minor stress double usual dose Major stress: 50 mg IV q 6-8 hrs, and taper For 1 o AI, also need: Fludrocortisone mg/day 21

22 Cushing s Syndrome Exogenous steroids: #1 cause Endogenous: Cushing s disease (70%): due to ACTH secretion from pituitary adenoma Ectopic ACTH (15%): from non pituitary tissue making ACTH Small cell lung CA most common Bronchial carcinoids Adrenal (15%): Adenoma Carcinoma Nodular adrenal hyperplasia 24 h Urine Cortisol _ Normal Cushing s Diagnosis Low (<5) Adrenal CT Adrenals ACTH Pituitary or Ectopic Petrosal Sinus ACTH Peripheral Ectopic ACTH-producing tumor + High (>10 pg/ml) _ MRI pituitary Central + Pituitary source Primary Aldosteronism (PA) Accounts for % cases htn Results from autonomous aldosterone prdctn, due to: Idiopathic hyperaldosteronism (1/3) Adenoma (60-65%) Glucocorticoid suppressible (~1%) Cancer (<1%) 22

23 Primary Aldosteronism: Features Hypertension Hypokalemia May be absent Exacerbated by diuretics Paresthesias if severe hypokalemia Mild alkalosis on laboratories Primary Aldosteronism: Dx Screening: Must first replete potassium Plasma aldosterone (PA)/ Plasma Renin Activity (PRA) ratio > suggestive Confirmatory test: Salt load: 1 g NaCl tid for 3 days 24 hr urine aldosterone>12 mcg/24 hr with concomitant 24 hr urine Na>200 mmol/d Primary Aldosteronism cont d CT Unilateral lesion Bilateral Hyperplasia, or no lesion seen: Adrenal vein sampling measure cortisol and aldosterone to lateralize source of aldosterone excess Management: Unilateral lesion resect Bilateral hyperplasia or no lesion medical rx with spironolactone or eplerenone Pheochromocytoma Rare tumors Produce epinephrine and/or norepinephrine Symptoms: Episodic throbbing in the chest, trunk and head Headaches Diaphoresis Palpitations Tremor, anxiety, nausea, vomiting, fatigue Abdominal or chest pain Weight loss Cold hands and feet 23

24 Pheochromocytoma cont d In ¼ of cases, hypertension is episodic Orthostasis usually present Rule of 10 s: 10% normotensive 10% occur in children 10% are bilateral 10% are malignant 10% are extra-adrenal adrenal (called paragangliomas) Pheochromocytoma cont d First make BIOCHEMICAL dx: 24-hr urinary metanephrine and normetanephrine or plasma free metanephrine (levels usually 2-3 x normal) If biochemical diagnosis made, localize: CT or MRI of the adrenal If CT or MRI negative, can use 123 I-MIBG to localize extra-adrenal adrenal pheo and mets Adrenal Incidentalomas Found in ~10% of autopsies Prevalence increases with age 2 questions for evaluation: Is lesion functioning or not? Is lesion benign or malignant? Incidentaloma: is it functional? In all patients: Screen for pheochromocytoma: 24 hr urine for metanephrines or Plasma metanephrines Screen for subclinical Cushing s 1 mg overnight dexamethasone suppression test 24 hour urine cortisol In patients with hypertension: Screen for primary aldosteronism: PA/PRA ratio 24

25 Incidentaloma: Benign or not? More likely to be BENIGN if: <4 cm Low density on unenhanced CT (<10 HU) It contains fat (suggests myelolipoma) Incidentaloma: Management Adrenalectomy Yes Adrenalectomy Functional? No Size on CT >4 cm <4 cm Re-image at 6, 12 and 24 mos Increase in size >1 cm No further f/u if no change in size HIGH Primary HPT FHH Lithium PTHrP Solid tumors T cell lymphoma Malignancy 1,25 Vit D lymphoma Hypercalcemia PTH LOW Local osteoclastic Lesions Myeloma, leukemia Lymphoma Others Milk-alkali syndrome Immobilization Endocrine Thyroid, adrenal, Pheo, VIPOMA Acromegaly Granulomas 1,25 Vit D Sarcoid, TB, Cocci, Histo, pulm eosinophilia Primary Hyperparathyroidism PTH, Ca, Phos 0.4% women over 60; 2-3Xs the rate in men Single adenoma 80 %, rest hyperplasia Associated with MEN1, MEN 2A, isolated familial Tx: Surgical if indicated 25

26 Primary Hyperparathyroidism Treatment: Surgery if Serum Ca >1.0 mg/dl above UNL 24 hr urine Calcium>400 mg/d CrCl reduced by > 20% BMD T-score <-2.5 at any site Age <50 yrs If no surgery, follow with: Ca 2x/yr Cr q yr BMD q yr Familial Benign Hypocalciuric Hypercalcemia (FBHH) Mutation in calcium sensor Autosomal dominant inheritance Lifelong asymptomatic hypercalcemia Urine Ca < 50 mg/24 hr Calcium creatinine clearance ratio < 0.01 urine Ca X Serum Creat serum Ca X Urine Creat No need for treatment! 26