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Endocrine Board Review LILLIAN F. LIEN, MD DIVISION CHIEF DIVISION OF ENDOCRINOLOGY, METABOLISM, & DIABETES PROFESSOR OF MEDICINE, UMMC Part II Adrenal Pituitary &Hypothalamus MEN Reproductive Endocrine WITH APPRECIATION TO: SARAH E. FRENCH, MD Disclosures for Dr. Lillian F. Lien The Department of Medicine requests the following disclosures to the lecture audience: Disclose relevant financial relationships with any commercial interest: Commercial Interest Role Medtuit Co-owner Springer Book royalties Sanofi-Aventis Consultant Merck Consultant Eli Lilly Consultant Novo Nordisk Consultant Adrenal Manage an adrenal incidentaloma Diagnose central AI Manage AI and newly diagnosed AI Adjust AI therapy in illness Manage AI in critical illness Diagnose hyperaldosteronism Treat pheochromocytoma Adrenal incidentaloma Only 15% functional Cushing’s > pheochromocytoma > primary aldo Work-up All: 1 mg dex suppression test and plasma metanephrines If HTN: renin and aldosteronism Remove if functional or >6 cm If non-functional and 4-6 cm, monitor very closely Remove if necrosis, hemorrhage, irregular margins If non-functional <4 cm, re-evaluate in 6 months Adrenal Anatomy Zona Glomerulosa Zona Fasciculata Zona Reticularis Adrenal Medulla Adrenal Cortical Hormones Aldosterone - major mineralocorticoid Made in Zona Glomerulosa (outer layer) of the adrenal cortex Stimulates renal tubule reabsorbtion of sodium and excretion of potassium Renin-Angiotensin-Aldosterone pathway Cortisol - major glucocorticoid Made in Zona Fasciculata (and Reticularis) Counters the effects of Insulin Diurnal secretory pattern - highest in AM Anti-inflammatory Androgens Zona (Fasciculata and) Reticularis Testosterone Androstenedione DHEA/DHEA-S (Dehydroepiandrosterone Sulfate) Produced in large amounts by the adrenal gland, but no functional significance in adult life HYPOTHALAMUS CRH PITUITARY Cortisol _ feedback +ACTH Adrenal Glands “Treatment of an adrenal crisis with full recovery of a dangerously ill patient within a few days is one of the greatest achievements of modern medicine” Oelkers, NEJM, Vol 341, No. 14 Definitions PRIMARY Adrenal Insufficiency (AI) Dysfunction at the level of the adrenal gland by a local lesion or disease process SECONDARY Adrenal Insufficiency True “Secondary” AI: at the level of the pituitary gland; inadequate ACTH secretion “Tertiary” AI: any process involving the hypothalamus; interference w/ CRH secretion PRIMARY Adrenal Insufficiency “Addison’s Disease” Involves all 3 zones of the adrenal cortex- ie (usually) a deficiency in glucocorticoid as well as mineralocorticoid & androgen Differential Diagnosis can be narrowed by considering abruptness of onset of diseaseSlow Onset: Autoimmune Adrenalitis Infectious Adrenalitis (see Metastatic CA Isolated glucocorticoid deficiency Congenital Adrenal Hyperplasia Adrenomyeloneuropathy next slide) Primary AI: Etiology Infectious Adrenalitis: Tuberculosis (previously the most common) Systemic Fungal Infections Histoplasmosis Paracoccidioidomycosis HIV/AIDS Syphilis (rarely) Primary AI: Etiology Abrupt Onset: Adrenal hemorrhage, necrosis, thrombosis meningococcal sepsis (Waterhouse-Friderichsen Syndrome ) pseudomonas coagulation disorders antiphospholipid antibody syndrome Primary AI: Clinical Manifestations Hyperpigmentation Primary AI: Clinical Manifestations Hyperpigmentation Salt craving Hyponatremia Hyperkalemia Vitiligo, pallor Autoimmune thyroid disease CNS symptoms in adrenomyeloneuropathy Non specific: -Tiredness, weakness, mental depression -Anorexia, weight loss -Dizziness, orthostatic hypotension -Nausea, vomiting, diarrhea -Hyponatremia -hypoglycemia Secondary/Tertiary AI: Etiology Slow Onset: Abrupt Onset: Pituitary tumor or surgery or radiation Postpartum pituitary necrosis (Sheehan’s) Craniopharyngioma Isolated ACTH Deficiency Megace Necrosis or bleeding into a pituitary macroadenoma (hemorrhage into a pituitary tumor=pit apoplexy) Long-Term Glucocorticoid Therapy Head trauma, lesions of the pituitary stalk Sarcoidosis Hypothalamic Tumor Following Pituitary or adrenal surgery for CUSHING’s syndrome (transient) Secondary/Tertiary AI: Clinical Headache, visual symptoms Thinning of axillary and pubic hair Amenorrhea, decreased libido/potency Prepubertal growth deficit, delayed puberty Secondary hypothyroidism Diabetes Insipidus NO Hyperpigmentation LESS Hypotension DIAGNOSIS-Beyond Basics Plasma AM Cortisol Level Plasma ACTH Level ACTH STIM Test (Hi-Dose) Metyrapone Test Insulin-Induced Hypoglycemia CRH STIM Test DIAGNOSIS - AM Serum Cortisol Normal reference range: 6 to 24 mg/dL So >18 is a normal result – Rules AI Out So < 3 is a positive result – Rules AI In Cortisol below 5 mcg/dL (138 nmol/L) had almost 100 percent specificity, but only 36 percent sensitivity –versus ITT Cortisol of 10 mcg/dL (275 nmol/L) as the criterion for adrenal insufficiency increased the sensitivity to 62 percent, but reduced the specificity to 77 percent. Cortisol more than 15 mcg/dL (415 nmol/L) predicts a normal serum cortisol response to insulin-induced hypoglycemia or a short ACTH test in virtually all patients [12,16-19]. UTD2012 Dx of AI Cortisol greater than 18 mcg/dL is even more reassuring, and if increased CBG levels are not suspected (eg, patient is not on estrogen), then no further testing is required. Between 3-18 range need “dynamic testing”. . . DIAGNOSIS - ACTH Stim Test To rule out/in the presence of any type of AI (primary or secondary) and/or To be used in conjunction w/ plasma ACTH level to diagnose primary VS secondary AI DIAGNOSIS - ACTH Stim Test High Dose ACTH Stim Test Give 250 mg of cosyntropin Measure serum cortisol before, 30 and 60 min after injection Can be given IM ACTH Stim Test - RESULTS INTERPRETATION OF A NORMAL RESPONSE = pre or post cortisol > 18 RULES OUT AI (primary and secondary) (regardless of the amount of increase between pre and post cortisol levels - no need for a minimum increment) ROC curves show that using a cutoff of : 21.7 = sens 100 % , spec of 83% 18 = sens 95%, spec of 96% A Subnormal response confirms AI but doesn’t clarify which kind… DIAGNOSIS of Primary vs Secondary/Tertiary AI Once you have ruled in AI by either a LOW AM cortisol or SUBNORMAL ACTH response, Check the Plasma ACTH level: HIGH (endogenous) ACTH: Levels > 100 would be consistent with PRIMARY AI A NORMAL ACTH level (between 5 - 45 pg/ml) effectively rules out PRIMARY AI: Look for a cause of SECONDARY/TERTIARY AI Cortisol _ feedback +ACTH Adrenal Glands Diagnostic Algorithm for Adrenal Insufficiency Rule In or Out AICheck Plasma Cortisol <3 RULES IN Adrenal Insufficiency Between 3 and 18 Need Dynamic Testing >18 RULES OUT ** NO AI ** ACTH Stim Test NORMAL Response Cortisol > 18 RULES OUT ** NO AI ** SUBNORMAL RESPONSE ** RULES IN AI ** Define Type Plasma ACTH HIGH> 100 DIAGNOSIS LOW or NORMAL ** PRIMARY AI ** Secondary or Tertiary Adrenal Insufficiency CRH STIM Test Exaggerated and Prolonged ACTH Response Absent or Subnormal ACTH Response ** TERTIARY AI ** ** SECONDARY AI ** TREATMENT - Adrenal Crisis Do NOT Wait for Pending Lab Results before beginning Empiric Rx in Crisis Treat HYPOTENSION w/ volume 2 to 3 L of NS or D5NS Give IV DEXAMETHASONE 4mg, or IV HYDROCORTISONE 100mg q8 or 50mg q6 Dexamethasone is Preferred: won’t interfere w/ further diagnostic testing and long acting TREATMENT - Chronic Primary AI Glucocorticoid Maintenance Therapy Hydrocortisone 20mg PO qam and 10mg PO qpm (10mg) to decrease IOP (5mg) Alternatively, Cortisone Acetate 25mg PO qam and 12.5mg po qpm Dexamethasone 0.5mg PO qd (0.25 to 0.75) Prednisone 5mg PO qd (2.5mg to 7.5mg) TREATMENT - Chronic Primary AI Mineralocorticoid Replacement -Essential in Primary Fludrocortisone 0.1 to 0.2 mg qd Adequacy assessed by checking for postural hypotension, orthostasis, serum K, plasma renin, etc “We suggest adjusting the fludrocortisone dose to lower the PRA to the upper normal range” UTD 2012 “It is useful to measure PRA annually in all patients” UTD 2012 Dose may need increasing in the summer when salt loss from perspiration increases! Dose may need to be lowered in pts w/ essential HTN but should not be d/c’d altogether Do not use K sparing Diuretics for anti-HTN rx! TREATMENT Chronic AI: Secondary/Tertiary Same Glucocorticoid Regimens as above except cannot use ACTH levels to assess adequacy of doses! Mineralocorticoid Replacement usually not needed Rem pituitary hormone deficiencies likely also need to be replaced (panhypopituitarism) UTD 2012: “Patients with secondary adrenal insufficiency should receive evaluation and adequate replacement for other pituitary hormone deficiencies. Replacement of thyroid hormone without replacement of glucocorticoids can precipitate acute adrenal insufficiency. Patients with hypopituitarism who have partial or total ACTH deficiency and are receiving suboptimal cortisol or cortisone replacement may be at risk of developing symptoms of cortisol deficiency when growth hormone therapy is initiated. This is due to the inhibitory effect of growth hormone on 11-beta-hydroxysteroid dehydrogenase type 1, the enzyme that converts cortisone to cortisol [33].” ProphylaxisSteroids in Illness In severe illness, give Hydrocortisone 100mg q8hr Cut dose by 50% each day till reach maintenance In some patients undergoing significant stress, the taper of steroids may have to be a lot slower than 50% per day In moderate illness, give hydrocortisone 50mg bid and taper rapidly to maintenance In minor febrile illness or stress, double or triple maintenance of glucocorticoid Adrenal Insufficiency in Critical Illness Cooper M. S., Stewart P. M. Current Concepts: Corticosteroid Insufficiency in Acutely Ill Patients. N Engl J Med 2003; 348:727-734 Adrenal Insufficiency in Critical Illness NEJM = cutoffs are <15 and >34, whereas Stim needs an increment of 9 JCEM: A random serum cortisol level >12 in a critically ill patient WITH HYPOPROTEINEMIA (albumin level <2.5) makes the diagnosis of AI UNLIKELY Arafah BM. Hypothalamic pituitary adrenal function during critical illness: limitations of current assessment methods. JCEM 2006; 91:3725-3745 Overview of Adrenal Disorders Adrenal Insufficiency ACTH STIMULATION tests Cushing’s Syndrome Dexamethasone SUPPRESSION tests Primary Hyperaldosteronism Clinical Findings Hypertension Muscle Symptoms (due to hypokalemia) cramping weakness periodic paralysis Often few clinical findings at all often just suspected after lab abnormalities are noted Primary Hyperaldosteronism Lab Studies and Imaging Chemistry7 (serum K level/HCO3) Hypokalemia, Metabolic alkalosis Serum renin level Serum aldosterone level Low renin, high aldosterone Ratio >20 with aldo >15 ng/dL → high likelihood 24-hour urine aldosterone 24 hr urine aldosterone elevated in the setting of low renin (<5mcg/dL) is suspicious Saline-loading Plasma aldo > 10mg/dL after 2 L of saline over 4 hours Primary Hyperaldosteronism Laboratory Findings CT scan of abdomen, attention adrenal glands 18-OH corticosterone level may find solitary adenoma or carcinoma indicative of aldosterone producing adenoma (APA) Adrenal vein sampling: for localization catheterization of left and right adrenal veins and the IVC, looking for lateralization of elevated aldosterone level If age <40, CT may be sufficient for localization If age >60, do bilateral adrenal vein sampling GOLD STANDARD Primary Hyperaldosteronism Key Points Prior to Evaluation Must be off anti-aldosterone medications spironolactone Preferably off ACE-Inhibitors Preferably off calcium channel blockers May need to consider in-house evaluation At least 150mEq of sodium intake daily to suppress aldosterone production Primary Hyperaldosteronism Treatment Aldosterone Producing Adenoma(Conn’s): SURGICAL Surgery is effective only in patients with unilateral disease Bilateral Hyperplasia of the Zona Glomerulosa (idiopathic hyperaldosteromism) (IHA) or poor surgical candidate…………..…MEDICAL THERAPY Mineralocorticoid receptor antagonists (Aldosterone Spironolactone has long been the drug of choice … versus Eplerenone is a newer more expensive alternative competitive inhibition): If gynecomastia, switch to eplerenone Amiloride no longer recommended Diuretic inhibits DCT aldosterone-induced sodium resorption block the renal effects of aldosterone but persistence of hyperaldosteronism has possible deleterious effect on the heart Calcium channel blockers ACE-Inhibitors (Source: UpToDate 2014) Pheochromocytoma Clinical Findings Classically: The Five P’s: Pain Headaches Pallor Palpitations Pressure (hypertension) Persipiration Orthostatic hypotension from impaired arterial and venous constriction responses Catecholamine release Pheochromocytoma Clinical Findings Rule of 10s • • • • • 10% extra-adrenal 10% bilateral 10% familial………….……….24%* 10% malignant………………..3 to 36%* 10% not associated with hypertension *source NIH: Dr. Pacak NEVER BIOPSY AN ADRENAL MASS WITHOUT RULING OUT PHEO FIRST!! Kronenberg, et al. Williams Textbook of Endocrinology. 2008 Diagnosing pheochromocytoma Plasma free metanephrines Start with this 99% sensitive—good for ruling out pheo False (+)—stress, tobacco, coffee, Tylenol, TCAs 24-hr urine for metanephrines and catecholamines Check if plasma metanephrines are positive If >2-fold increase, 99% specific Pheochromocytoma Key Points in Evaluation Check what other medicines the patient takes Acetaminophen, bronchdilators, captopril, cimetidine, codeine, decongestants, levodopa, labetalol, metoclopramide, caffeine, coffee Look for familial syndromes MEN IIA, IIB Von Hippel-Lindau Von Recklinghausen Neurofibromatosis type 1 Pheochromocytoma Treatment Pharmacologic Alpha Adrenergic-Blockade first phenoxybenzamine or shorter acting alpha blockers Beta-blockade next if necessary Never start before alpha-blockade Calcium Channel Blockers Unopposed alpha-receptor stimulation can lead to worsened hypertensive crises May be better tolerated than alpha-blockade On reserve: can inhibit catecholamine synthesis (Demser) Pheochromocytoma Treatment Surgical resection is treatment of choice May require open laparotomy Consider search of sympathetic chain Need adequate a-blockade pre-operatively Watch for post-operative complications Labile blood pressure Post-resection hypotension/shock Hypoglycemia Congenital adrenal hyperplasia (CAH) 21-hydroxylase is most common Accumulation of 17-OH progesterone →androgens Classical form (complete deficiency) Starts in infancy Salt-wasting, hypotension, virilization Sometimes ambiguous genitalia at birth Partial deficiency / Non classical Young adulthood Hirsutism, menstral irregularities Mimics PCOS Treatment: prednisone + fludrocortisone if needed Adrenal cases 24 yo man with resistant HTN, short stature, history of genitourinary surgeries as a child, low potassium. Likely diagnosis? Congenital Adrenal Hyperplasia (17-alpha hydroxylase deficiency) Renin low, aldosterone low, deoxycorticosterone high 45 yo farmer who dips tobacco, has resistant HTN with hypokalemia. Licorice (glycyrrhizic acid) inhibits conversion of hydrocortisone to cortisone Renin low, Aldosterone low Pituitary/hypothalamus Evaluate hyperprolactinemia Diagnose ectopic ACTH Treat acromegaly after surgery Manage a sellar mass Manage pituitary apoplexy Treat hypopituitarism Diagnose GH deficiency Diagnose lymphocytic hypophysitis Diagnose MEN1, MEN2A/B Anterior pituitary hormones Adrenocorticotropic hormone (ACTH) Growth hormone (GH) GnRH stimulates release of LH Follicle-stimulating hormone (FSH) TRH stimulates release of TSH Luteinizing hormone (LH) GHRH stimulates release of GH Thyroid stimulating hormone (TSH) CRH stimulates release of ACTH GnRH stimulates release of LH Prolactin Under continuous hypothalamic inhibition by dopamine Pituitary tumors Is it hormonally active? (since some are non functional) PRL > GH > ACTH > LH/FSH >> TSH Alpha chain tumors not biologically active Is there any mass effect? Bitemporal hemianopsia, headache, seizures Is it affecting normal production of pituitary hormones? Most critical: ACTH Prolactinoma Most common pituitary tumor Women: secondary amenorrhea and galactorrhea Men: hypogonadism Treatment: dopamine agonist Bromocriptine or carbegoline NOT SURGERY! Suspect another tumor if tumor > 1 cm and PRL < 200 26 yo woman evaluated for hyperprolactinemia after recent labwork showed serum prolactin of 55 (normal 10-26). Mild hyperprolactinemia was detected 6 years ago during evaluation for irregular menstrual cycles. MRI at that time showed pituitary microadenoma. Was treated with dopamine agonist and subsequent serum prolactins were normal until this reading. Patient had menarche at 13 and has irregular periods since then. Vitals normal. Breast development normal but there is breast tenderness present. No galactorrhea, acne, hirsutism, or striae are present. What is most appropriate next diagnostic test? Pregnancy test Random growth hormone measurement Serum cortisol Visual field testing Other causes of hyperprolactinemia Pregnancy Exogenous estrogens Primary hypothyroidism Severe-long standing primary hypothyroidism will ↑ TRH →↑PRL and ↑growth of thyrotrophs → pituitary mass → give levothyroxine Drugs: metoclopramide, amytriptyline, phenothiazines, antidopaminergics Other tumors that compress pituitary stalk (“stalk effect” blocking dopamine Acromegaly Diagnosis often overlooked and late (>10 years) Often macroadenoma (>1 cm) Frontal bossing, enlarging hands and feet Can look at old pictures Sleep apnea, HTN, carpal tunnel, skin tags, colon polyps Screening: ↑ IGF-1 GH too pulsatile to do random GH levels Confirmation: GH does not suppress 1 hour after glucose load (remains >1) Treatment: surgery Acromegaly Use medical therapy if incomplete control after surgery Somatostatin analogues: octreotide, lanreotide GH receptor antagonist: pegvisomant Usually added to somatostatin analogue Goal: normal IGF-1 and normal GH suppression after glucose load Cushing’s Syndrome Cushing’s Syndrome Clinical Features Weight gain / photographs buffalo hump / central adiposity / fat redistribution glucose intolerance HTN, facial plethora purple striae muscle weakness ‘steroid skin,’ acne menstrual irregularity if ACTH dependent: hyperpigmentation (Sources: MKSAP: ACP-ASIM, UpToDate, and Hospital Physician: Endo Board Review Manual 2002) Cushing’s Syndrome Definitions: Cushing’s Syndrome General term for hypercortisolism at any level including adrenal, ectopic, or pituitary source Cushing’s Disease Refers specifically to an ACTH secreting pituitary adenoma with resultant cortisol secretion Cushing’s Syndrome Diagnosis: Confirming Hypercortisolism • First, establish presence of Cushing’s with – 24-hour urine free cortisol (at least twice) • NL~ <50 mcg/24hrs; >200 mcg/24hrs ‘clearly elevated’ • Less reliable if abnormal renal function – LOW-Dose Dexamethasone suppression test – Late night salivary cortisol (at least twice) • Remember-exclude exogenous glucocorticoids • Pseudo-Cushing’s Cushing’s Syndrome Diagnosis: Confirming Hypercortisolism • LOW-Dose Dexamethasone suppression test – Start with LOW-dose because it is more SENSITIVE than HIGH-dose - so a NEGATIVE result rules out cushing’s – “Estrogens increase CBG. Assays measure total cortisol. False + for Overnight DST are seen in 50% of women taking OCP” (Endo Society) – Overnight test • • • • Give dexamethasone 1 mg at 11pm; measure am cortisol Endo Society: cortisol < 1.8 mcg/dL (optional <5) UTD: cortisol < 2 to 5 mcg/dL (assay dependent) is NEGATIVE NIH: “Cortisol < 1.2mcg/dL Not Cushing’s syndrome Higher values Cushing’s OR Pesudo-Cushing’s OR other diseases or Normal” lower cutoff=more sensitive – Standard test : 0.5mg dexam. q6hr X 8doses (for 48 hrs) • NEG if post (6 hrs post last dose) serum cortisol < 1.4 - 1.8 mcg/dL – or measure urine cortisol and 17-OHCS --maybe better specificity Cushing’s Syndrome •Endo Society Guidelines would confirm any abnormal result with another test: •UFC, dex suppression, late night salivary OR •Midnight serum cortisol, Dex-CRH in ‘certain populations’ UFC, 1mg dex, Late nite salivary Any Abnormal Result •Perform 1 or 2 other studies above •Consider repeating abnormal study •Suggest Dex-CRH or MN serum cortisol in certain populations Cushing’s Syndrome Diagnosis: Finding the Source Next, establish ACTH-independent/dependent ACTH-independent: Adrenal lesion (adenoma, carcinoma) -> next step is adrenal CT exogenous source Plasma ACTH level is low (< 5 pg/mL) ACTH-dependent: Plasma ACTH level is normal or high >20—pituitary or ectopic ACTH >200—most likely ectopic ACTH Either ectopic production (ie small cell lung Ca, bronchial carcinoid) OR Pituitary adenoma = Cushing’s Disease accounts for 65-75% of all endogenous cushing’s usually benign and small may not be seen on MRI! (Sources: MKSAP: ACP-ASIM and UpToDate) Cushing’s Syndrome Diagnosis: ACTH-dependent To distinguish between ectopic vs pituitary: CRH-Stimulation test High-dose Dexamethasone suppression Not so good as some ectopics will suppress Inferior Petrosal Sinus Sampling Gold Standard Octreotide scintigraphy to localize ectopic source MRI pituitary or CT Cushing’s Syndrome Treatment: Surgical Resection Transphenoidal microsurgical removal Bilateral Adrenalectomy -> uncommon Pharmacologic adrenal blockade (Sources: MKSAP ACP-ASIM) Pituitary cases 32 yo woman with Cushingoid features. Serum K 4.0. MRI: 0.8 cm pituitary mass. IPSS/Periphery ratio >2 Cushing’s disease (PITUITARY). ACTH < 200 Next Step ----> Surgery. 42 yo woman with Cushingoid features. Serum K 3.0. CT chest: lung nodule. Nonsmoker. MRI pituitary: normal. IPSS/Periphery ratio <2 ECTOPIC - Bronchial carcinoid. ACTH > 200. IPSS/periphery ACTH ratio < 2 3. 69 yo man, smoker. Weight loss, hyperpigmentation, new onset DM and HTN. No Cushingoid features. Serum K 2.3. CT chest: RUL mass with adenopathies IPSS/Periphery ratio <2. ACTH >200 ECTOPIC ACTH - Small cell lung cancer Excess ACTH Insufficiency GH GH Slow Onset Sleep apnea Carpal Tunnel HTN/Diabetes Colon polyps Skin tags Salt craving, nausea, “vague abdominal pain”, Fever HYPOGLYCEMIA Weight loss Pubertal hair loss Young Short stature FSH/LH TSH FSH/LH Cushing’s Disease Slow onset Classic phenotype HTN/diabetes osteoporosis Skin thinning, ecchymoses Acromegaly TSH Rare. Hyperthyroidism with “normal” or increased TSH ACTH Amazingly rare Precocious puberty McCune Albright Syndrome Rare. Hypothyroidism with “normal” or decreased TSH Older “Decreased Vigor” VERY COMMON Hypogonadism with atrophic gonads and “normal” or low FSH/LH 67 yo man evaluated in ER for explosive headache and blurred vision that began 4 hours ago. Reports 3 month history of fatigue, 10 lb weight gain and erectile dysfunction. Physical exam shows pale man who appears uncomfortable. BP 88/56. Visual field exam reveals bitemporal hemianopia. Other than neck stiffness, rest of exam is normal. Sodium 128. CT shows heterogenous sellar mass with suprasellar extension and bowing of optic chiasm. In addition to neurosurgical consult, what is most appropriate initial management? Glucocorticoid administration Insulin tolerance test Lumbar puncture Serum prolactin measurement Pituitary apoplexy Hemorrhagic infarction of pituitary SHEEHAN’s syndrome –pituitary infarction or hemorrhage DURING PREGNANCY DELIVERY Severe headache, altered mental status, ophthalmoplegia CT/MRI: high density mass within pituitary Administer stress doses of steroids Contact neurosurgery for possible decompression Lymphocytic Hypophysitis RARE cause of HYPOPITUITARISM Autoimmune disorder Often during pregnancy, post-partum As with apoplexy, secondary Adrenal Insufficiency is a major cause of morbidity and mortality Treat with STEROIDS If visual field defects develop, surgery may be necessary Panhypopituitarism Of the deficiencies in panhypopit patients: ALWAYS TREAT ADRENAL Insufficiency FIRST = steroids (usually stress dose) Aside- complications of pituitary radiation: Hypopituitarism Replacement for : Secondary hypothyroidism Do not follow TSH in secondary hypothyroidism Secondary Hypogondism GH deficiency Low prolactin supports diagnosis Can see hypothyroidism and adrenal insufficiency Can develop years after radiation treatment Most common anterior deficiency after TBI should only be done AFTER (or at least concurrent with) STEROID replacement Above are ANTERIOR PITUITARY deficiencies Don’t forget the POSTERIOR PITUITARY issues… Visual defects Due to damage to optic chiasm Second tumor development Diabetes insipidus Problem with ADH Central—no ADH production Nephrogenic—no ADH action Persistent non-concentrated polyuria with dehydration Hypernatremia hyperosmolarity (>295) low urine osmolarity (<300) Confirm with water deprivation test, if can be done safely Diabetes insipidus Distinguish central from nephrogenic diabetes insipidus with 1 mcg desmopressin Central: increases urine osmolarity >50% Nephrogenic: no response Treatment Central: DDAVP (usually go home on SQ or intra-nasal) Nephrogenic: thiazide diuretics Posterior-SIADH Excess ACTH Insufficiency GH ACTH GH Slow Onset Sleep apnea Carpal Tunnel HTN/Diabetes Colon polyps Skin tags Salt craving, nausea, “vague abdominal pain”, Fever HYPOGLYCEMIA Weight loss Pubertal hair loss Young Short stature FSH/LH TSH FSH/LH Cushing’s Disease Slow onset Classic phenotype HTN/diabetes osteoporosis Skin thinning, ecchymoses Acromegaly TSH Rare. Hyperthyroidism with “normal” or increased TSH Posterior-DI Amazingly rare Precocious puberty McCune Albright Syndrome Rare. Hypothyroidism with “normal” or decreased TSH Older “Decreased Vigor” VERY COMMON Hypogonadism with atrophic gonads and “normal” or low FSH/LH SIADH Too much ADH Retain too much free water → hyponatremia Hyponatremia, low serum osmolarity (<275), inappropriately urine osmolarity (>100), high urine sodium (>30) Rule out dehydration Check renal, adrenal and thyroid function Treatment Water restriction ADH receptor antagonists – conivaptan, tolvaptan for acute tx Demeclocycline—blocks ADH at collecting tubal, chronic tx Multiple Endocrine Neoplasias MEN 1 MEN 2A MEN 2B (MEN 4) SET OF RARE DISORDERS THAT CAN HAVE PROFOUND IMPLICATIONS FOR EXAMPLE, EARLY DETECTION AND MANAGEMENT OF MEDULLARY THYROID CARCINOMA CAN HAVE A SIGNIFICANT IMPACT ON MORBIDITY/MORTALITY GENETIC TESTING MEN I 3 P’s Pituitary (anterior) Pancreas Prolactinoma, acromegaly, Cushing’s disease, other Gastrinoma, insulinoma, glucagonoma, VIPoma, also gut/bronchial carcinoid Parathyroid Primary hyperparathyroidism (multifocal) chromosome 11 (11q13); MEN-1 gene (menin) Benefit of genetic testing for this gene is NOT as clearly described as in MEN 2 MEN 2A medullary thyroid carcinoma pheochromocytoma hyperparathyroid Variant: FMTC “Familial Non-MEN medullary thyroid carcinoma” MEN 2B medullary thyroid carcinoma Pheochromocytoma Multiple mucosal ganglioneuromas Also Cutaneous lichen amyloidosis and Marfaniod habitus Perform genetic screening for RET mutations in all index patients If mutation found, screen family members Rule out pheo, then total thyroidectomy and cervical exploration to prevent morbidity from MTC Reproductive endocrine Manage hirsutism in PCOS Diagnose hyperandrogenism in pt with neoplasm Diagnose the cause of gynecomastia Evaluate secondary amenorrhea Diagnose the cause of primary ovarian insufficiency Diagnose secondary hypogonadism Diagnose opioid induced secondary hypogonadism Diagnose hypogonadism in pts with obesity Diagnose male infertility Hirsutism Development of androgen-dependent terminal body hair in a woman in places not usually found Variation in different ethnic groups Affects 5-10% of women of reproductive age 2 most common causes are idiopathic hirsutism and PCOS Idiopathic (Familial) PCOS (Polycystic Ovarian Syndrome) Androgen-secreting adrenal adenomas Androgen-secreting adrenal carcinomas Ovarian tumors ACTH-dependent causes Congenital Adrenal Hyperplasia ACTH-dependent Cushing’s Syndrome Glucocorticoid resistance Hirsutism and Virilization Etiology Androgen-secreting adrenal adenomas Rare The high serum androgen concentrations remain elevated in spite of Dexamethasone suppression Androgen-secreting adrenal carcinomas More common than adenomas Usually greater than 5 cm in diameter at diagnosis Very high DHEA, DHEA sulfate concentrations No response to High-Dose Dexamethasone Suppression Red flags for tumors Recent onset and/or rapid progression Late onset (ie post-menopausal) Virilization—voice change, clitomegaly Total testosterone >200 ng/dL Hyperandrogenism Tumor Workup In healthy women, the ovaries and adrenal glands contribute equally to testosterone production. But if above signs of tumor occur, then need to localize. If testosterone is elevated and DHEA is NORMAL = OVARIAN = transvaginal ultrasound first, before CT adrenals CT adrenals first if DHEA S is elevated (over 7.0ug/mL) Hirsutism and Virilization Etiology PCOS (Polycystic Ovarian Syndrome) LH:FSH ratio greater than 2.0 is common About 1/3 of normal women have polycystic ovaries on Ultrasound -> abnormal morphology not essential to diagnosis ie 2003 Rotterdam criteria /NIH2012: two out of three Clinical history is important: Menstrual irregularity (oligomenorrhea/amenorrhea)/ infertility Oligoovulation, Hyperandrogenism, Polycystic ovaries Anovulatory cycles with continuous stimulation of ovary by LH Androgen excess / hirsutism (Total testosterone elevated but <200 ng/dL) Also effects on metabolism/cardiovascular risk: Obesity and insulin resistance (Sources: UpToDate 2014) Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and longterm health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19:41. Hirsutism and Virilization PCOS Treatment Options Oral Contraceptives Beware DVT and other risks (migraines with aura contraindicated) Metformin Anti-androgen - only if NOT pregnant Aldactone (spironolactone) Finasteride Flutamide GynEndo Infertility Treatment Options • Clomiphene citrate (estrogen receptor antagonist) or letrozole (inhibits aromatization of testos to estradiol) • Metformin Hirsutism and Virilization Congenital Adrenal Hyperplasia Enzymatic defects in the adrenal steroid hormone synthesis pathways leading to: inadequate cortisol +/-mineralocorticoid classically with an associated androgen excess Clinical Presentation Numerous Clinical Syndromes Classical Forms: Salt-wasting form Virilizing Syndromes Non-Classical Form: Late-onset: women present with hirsutism and menstrual irregularity which can mimic PCOS In men/boys, androgen excess can be asymptomatic Gynecomastia Occurs when estrogen/androgen balance favors estrogen ↑ estrogens: cirrhosis, hyperthyroidism, βhCG/estrogen-secreting tumors ↓androgens: testicular surgery/trauma, renal failure, hyperprolactinemia, drugs drugs: spironolactone, ketoconazole, calcium channel blockers, phenothiazines, TCAs Hypogonadism Low sex hormone levels Primary hypogonadism—problem with gonad Normal pituitary →↑FSH (women) and ↑LH (men) Secondary—problem with pituitary Tertiary—problem with hypothalamus Secondary and tertiary may have inappropriately normal LH and FSH levels Remember inappropriate normals!! Causes of hypogonadism in women Primary Gonadal dysgenesis Secondary Hyperprolactinemia Absence of ovarian oocytes and follicles Anorexia nervosa Turner syndrome 45X 46,XX and, rarely, 46,XY Functional Hypothalamic amenorrhea Kallman syndrome Congenital GnRH deficiency with anomsia Radiation Chemotherapy Autoimmune destruction of ovaries (APS) Strenuous exercise training Stress Diagnosis of exclusion Hypothalamic/pituitary disease Turner syndrome Primary amenorrhea with ↑FSH and ↑LH = Primary Ovarian Insufficiency(failure) Incidence 1:2000 (>50% mosaicism) Karyotype 45 XO Lymphocytes may be normal. Need fibroblast. If any Y present, ↑gonadoblastoma →prophylactic oophorectomy Physical exam: short stature, webbed neck, broad chest with widely spaced nipples, little breast development ↑ risk of aortic stenosis, aortic coarctation (10%), renal abnormalities (50%) Hypothyroidism from Hashimoto’s thyroditis Osteoporosis from hypogonadism Treatment Estrogen replacement GH for short stature 18 yo woman with 6 month history of amenorrhea. Menarche at 13 and had normal cycles until 6 months ago. No hot flushes, night sweats, weight changes or cold/heat intolerance. No uterine procedures. No family history of thyroid disease or primary ovarian insufficiency. Vital signs normal. BMI 22. No hirsutism, acne, alopecia, clitoromegaly or galactorrhea. Lab results are normal, including FSH, hCG, prolactin, free T4 and TSH. What is most appropriate next diagnostic step? Measure total testosterone and DHEA MRI of pituitary Pelvic ultrasound Progesterone challenge testing Amenorrhea Rule out pregnancy and hypothyroidism Rule out pituitary disease or primary ovarian failure Check hCG, prolactin, TSH Check (MRI infiltration/tumor) prolactin and FSH Progestrin challenge (Provera 10mg x 10 days) If bleeding (enough estrogen), anovulatory cycles=PCOS If no bleeding (low estrogen state): Functional hypothalamic amenorrhea anatomic defect Pelvic Examination Pelvic Ultrasound Male Hypogonadism 25 yo man with decreased libido, decreased testicular volume, otherwise normal. AST/ALT elevated. Next Test? Hemochromatosis - Iron saturation > 45 is quite suggestive. May all see arthritis, risk for Type I DM. 46 yo male with 1 year hx low libido and erectile dysfunction. Normal puberty. BMI 42. Hypertension. What test for testosterone? Free testosterone - is best for diagnosing male hypogonadism in patients with obesity, because Total testosterone may be affected by a decrease in the sex hormone binding globulin(SHBG) caused by obesity 56 year old man with gradual onset low libido and ED over 3 years. Medications are Lisinopril, methadone, and citalopram. Testes small and soft. FSH and LH very low. Testosterone low. What is the cause of the secondary hypogonadism? Opiate-induced hypogonadism- is thought to be secondary(central) hypogonadism, with downregulation of GNRH and thus LH, FSH, resulting in decreased testosterone production Klinefelter syndrome Form of primary male hypogonadism Incidence 1:1000 live births Karyotype 47 XXY Pre-puberal failure with small, firm testes Gynecomastia Sometimes decreased intellectual development Kallman syndrome in men Form of primary (male OR female) hypogonadism Due to abnormal development of GnRH producing neurons Also close to olfactory system Get isolated hypogonadotrophic hypogonadism(IHH) with anosmia Normal karyotype (46 XY) Small testes (but larger than Klinefelter) Infertility treated with LHRH infusion pump Male Infertility Semen analysis is the single best test to assess male infertility Only after semen analysis results are abnormal, then LH, FSH, testosterone would be ordered to assess Leydig and Sertoli cell function / to distinguish between primary and secondary hypogonadism Testicular ultrasound is only performed for infertility if an abnormality is detected first on exam Erectile dysfunction Start with TSH and testosterone level If ↓ testosterone, get prolactin and LH Drugs associated with ED (without hypogonadism): thiazide, beta blockers, anticholinergics, SSRIs, clonidine, morphine Anabolic steroid abuse Men Women Small testicles, gynecomastia, low sperm count Hirsutism, small breast, enlarged clitoris, deepening voice Both HTN, increased CVD, acne, male-pattern baldness, irritability, psychosis
