ENDOCRINOLOGY II Sarah E. French, MD July 19, 2014 Thyroid Pituitary Adrenal Gonads Bone Medical-Content Category Relative Percentage Cardiovascular Disease 14% Pulmonary Disease 10% Gastroenterology 9% Infectious Disease 9% Rheumatology/Orthopedics 8% Endocrinology 8% Medical Oncology 7% Hematology 6% Nephrology/Urology 6% Psychiatry 4% Neurology 4% Allergy/Immunology 3% Dermatology 3% Miscellaneous 3% Obstetrics/Gynecology 2% Ophthalmology 2% Otorhinolaryngology 2% Endocrinology (8%) 17–19 questions Diabetes mellitus 5–8 Thyroid disorders 2–4 Lipid disorders 2–3 Calcium metabolism and bone 1–5 Male reproductive health 1–2 Adrenal disorders 0–2 Hypertension 0–1 Female reproductive health 0–1 Hypothalamic disorders 0–1 Anterior pituitary disorders 0–1 Posterior pituitary/water metabolism 0–1 Endocrine tumors and endocrine manifestations of tumors 0–1 Hypoglycemia not due to insulinoma 0–1 Polyglandular disorders 0–1 Nutritional disorders 0–1 Women’s health endocrine issues 0–1 Miscellaneous endocrine disorders 0–1 THYROID Thyroid function tests (TFTs) • TSH • If ↓ TSH → hyperthyroidism • If ↑ TSH → hypothyroidism • Use to screen and follow thyroid replacement • Total T4 • All T4 (but 99.98% protein-bound) • ↑TBG , ↑ total T4, normal free T4 • Pregnancy, estrogens, tamoxifen, HIV, phenothiazines • ↓ TBG , ↓ total T4, normal free T4 • Androgens, glucocorticoids, nephrotic syndrome, cirrhosis Thyroid function tests (TFTs) • Free T4 • Key in diagnosis of central hypothyroidism • Evaluate degree of hypothyroidism • Diagnosis and response to therapy in hyperthyroidism • Total/free T3 • Check if suspect T3 toxicosis • Thyroglobulin • Low in factitious thyrotoxicosis • Used to monitor thyroid cancer Thyroid function tests (TFTs) • Thyroid uptake • Normal uptake 10-15% • ↑uptake: Graves, toxic multinodular goiter, solitary toxic adenoma • ↓uptake: thyroiditis, factitious hyperthyroidism • Thyroid scan • Hot nodule = benign • Cold nodule > 1 cm needs FNA Euthyroid sick syndrome • Seen in critically ill patients • Impairs body’s ability to peripherally convert T4 to T3 • T4 converts to reverse T3 • See normal TSH, normal T4, and free T3 As disease severity progresses, free T3 and T4 decreases • DON’T CHECK TFTs IN SICK PATIENTS unless you think it’s thyroid storm or myxedema coma • • DON’T GIVE THYROID REPLACEMENT Question A patient of yours comes to see you and complains about being tired. She gave birth to a healthy child about 6 months ago and tells you that the baby is doing fine. Her obstetrician reported to you that the pregnancy and delivery were uneventful. At first everything was perfect. She had plenty of energy and lost the baby weight without difficulty and had no difficulty staying up late at night to take care of the baby. After about two months she began to feel more tired and her fatigue steadily worsened such that now she can barely function. She is having difficulty with nursing. She blames herself for everything that’s wrong and begins to cry. Which of the following should you do next? 1. Tell her that the symptoms of her “post-partum blues” will soon pass. 2. Begin anti-depressants 3. Begin stimulants 4. Order TSH and Free T4 5. Refer her to a psychiatrist for evaluation. • 24 yo woman evaluated for 1 week history of neck discomfort • • • • that radiates to jaw, palpitations, fast heart rate, anxiety and fever. Reports having sore throat 4 weeks ago that resolved after a few days. No other symptoms. No personal history of thyroid or other endocrine disorders. On physical exam, she appears anxious. Temperature 37.5 C (99.5F), BP 140/60, pulse 110. + tachycardia. Thyroid gland slightly enlarged and tender with no nodules. No thyroid bruit. No cervical lymphadenopathy. No eye findings or pretibial myxedema is noted. + fine bilateral hand tremor. Lab: sed rate 45, TSH <0.01, free T4 4.1, T3 300. Doppler thyroid ultrasound showed enlarged thyroid with heterogenous echotexture. No significant vascular flow is evident. What is most appropriate next step in management? • Bilateral fine-needle aspiration biopsy • Methimazole • Serum thyroglobulin measurement • 24-hour radioactive iodine uptake test Causes of hyperthyroidism Increased Production of Thyroid Hormones - Graves disease - Toxic multinodular goiter - Molar Pregnancy (hCG) - Iodine-induced (Jod- Basedow) - TSH-pituitary adenoma Leakage or ExtraThyroidal Sources - Subacute Thyroiditis - Silent/post-partum thyroiditis - Thyrotoxicosis factitia - Struma ovarii Hyperthyroidism • Patient < 40 yrs—#1 Graves, #2 toxic adenoma • Patient > 60 yrs—#1 multinodular goiter, #2 Grave, #3 toxic adenoma • Will increase metabolism of many drugs • Warfarin may need LOWER dose due to increased metabolism of clotting factors • Apathetic hyperthyroidism in elderly • May only present with weight loss and fatigue Graves disease Proptosis Acropachy Therapy for hyperthyroidism • Immediate effect • Beta blocker • Iodine • Surgery • Latent effect—begins at 2-3 wks, full effect at 6 wks • Propylthiouracil—pregnant patients (1st trimester), thyroid storm • Monitor for hepatitis, agranulocytosis • Methimazole—everybody else • Monitor for cholestasis, agranulocytosis • Later effect • Radioactive iodine—takes 2-3 months Amiodarone and the thyroid • Euthyroid hyperthyroxinemia • Seen in < 3 months of therapy • Observe • Amiodarone-induced thyrotoxicosis • Type 1: iodine induced. + underlying goiter • Type 2: destructive thyroiditis • Dx: Doppler ultrasound (low flow in type 2) • Both have low RAI uptake • Amiodarone-induced hypothyroidism • Underlying + TPO antibodies • Give levothyroxine Risk factors for thyroid cancer • Family history • History of head/neck radiation • New nodule in patient <20 or >60 years old • Nodule that is firm, fixed and growing • Nodule with regional cervical LAD or Horner’s syndrome • Cold nodule on scan • Microcalcifications ± central bloodflow on US • Dysphagia, hoarseness, respiratory obstruction, pain Evaluation to thyroid nodule • Obtain TSH. • If hyperthyroid, get thyroid scan • If hot nodule, treat with RAI ablation • Do NOT biopsy a hot nodule! They’re benign. • If euthyroid or hypothyroid and >1 cm, perform FNA • Smaller lesions with concerning features may be considered for biopsy Cancer derived from follicles • Papillary thyroid cancer • Most common • Grows slowly • Lymphangetic spread • Follicular thyroid cancer • Hematogenous spread • Anaplastic thyroid cancer • Extremely poor prognosis Medullary thyroid cancer • Most are sporadic but often familial (MEN II) • Calcitonin levels helpful • Genetic tests available (RET oncogene) Thyroid storm • Severe hyperthyroidism • Decreased mental status and fever • Give PTU first!! • Then iodine, beta blockers, and glucocorticoids Thyroid cases Young patient with soft goiter, bruit, weight loss Grave’s Disease RAI ablation Patient with sore throat, fever, painful goiter Subacute thyroiditis Supportive care +/- steroids Patient with hepatitis C on a-INF. Mildly thyrotoxic, non-tender goiter Silent thyroiditis Supportive care Thyroid cases • Old pt. with weakness, weight loss, atrial fibrillation, goiter – Apathetic hyperthyroidism (Toxic MNG) • Young woman with molar pregnancy, hyperthyroid – Very High hCG acts as TSH analog • Patient with h/o goiter s/p contrasted CT scan, hyperthyroid sx. – Job-Basedow’s Disease (iodine induced) • Nurse with hyperthyroidism, no goiter, low RAIU – Facticious (taking synthroid) Check thyroglobulin Primary vs Secondary Hypothyroidism • Primary hypothyroidism • Problem is the gland itself • Will see ↑TSH and ↓free T4 • Secondary hypothyroidism • Problem is outside the gland (ie pituitary, etc) • Will see ↓ or ↔TSH and ↓free T4 • Remember inappropriate normals!! Question An 84 yo lady with a history of dementia and no other medical problems presents from the nursing home with altered mental status. She is on no medications. She is unable to provide any history but on your examination of her you find that she has a well healed transverse scar across her neck. She is hypothermic, bradycardic, has doughy skin and brittle hair. Labs are pending, but you find a fingerstick glucose of 52. Which of the following is the most reasonable next step in her care? 1. Give her one amp of D50 2. Levothyroxine 300mcg IV 3. Levothyroxine 300mcg IV and hydrocortisone 100mg IV 4. Levothyroxine 300mcg IV and one amp of D50 IV 5. Levothyroxine 200mcg PO Question A psychiatrist in your community refers an 80 year old woman being treated for depression. She reports generalized weakness, fatigue, dry skin, weight gain and constipation. Her past medical history includes CHF and stable angina. Your examination reveals periorbital edema, skin that is cool and dry, loss of the lateral third of her eyebrow, mild bradycardia and a slow relaxation phase of her deep tendon reflexes. You strongly suspect hypothyroidism and check TSH and Free T4. The TSH is 95 units/mL and Free T4 is 0.1ng/dL (0.7-1.5ng/dL). She obviously has severe hypothyroidism. Which of the following should you do next? 1. Administer thyroxine 500mcg IV daily for 5 doses 2. Administer thyroxine 500mcg IV and triiodothyronine 20mcg IV daily for three days. 3. Begin levothyroxine 300mcg PO daily 4. Begin levothyroxine 100mcg PO daily 5. Begin levothyroxine 25mcg PO daily Replace levothyroxine slowly in elderly or cardiac patients There is no scenario where you should need to pick T3 over T4. Hypothyroidism Scenarios 83 yo woman with depression, clearly hypothyroid. Otherwise getting along okay. Therapy? Low dose levothyroxine therapy (25mcg/day) and advance slowly to reach goal. 47 yo man with CABG 8 months ago, hypothyroid. Treatment? Low dose levothyroxine therapy (25mcg/day) and advance slowly to reach goal. 74 yo NH resident with thyroidectomy scar, on no meds comes in with altered mental status, severe hypothyroidism. Glucose is 56. Treatment? Hydrocortisone 100mg IV and Levothyroxine IV. Hypothyroidism cases 27 year old woman with Hashimotos on levothyroxine 75mcg daily, 2 weeks pregnant. Estrogens increase TBG, so increase levothyroxine dose by 30-50% during pregnancy 45 year old woman with Hashimotos has a rapidly enlarging goiter Thyroid Lymphoma - FNA diagnosis and irradiate 32 year old man begins abusing heroin, has high Total T4 Increased TBG due to heroin (also seen with methadone) ADRENAL Primary aldosteronism • Screening • Hypertension with hypokalemia • Refractory hypertension (>3 BP meds) • Even if normal K • Work-up • Calculate aldosterone/renin activity ratio • Ratio >20 with aldo >15 ng/dL → high likelihood • Confirmation • Urine aldo > 12 mcg/24 hrs while on high salt diet (urine Na >200 mEq) • Plasma aldo > 10mg/dL after 2 L of saline over 4 hours Primary aldosteronism • Classification • Aldosterone-producing adenoma • Bilateral zone glomerulosa hyperplasia • Adrenal carcinoma (rare) • Glucocorticoid-remediable aldosteronism (rare) • Treatment • Adenoma: medically or surgery • Hyperplasia: only medically, spironolactone • If gynecomastia, switch to eplerenone Primary aldosteronism • If age <40, CT may be sufficient for localization • If age >60, do bilateral adrenal vein sampling • GOLD STANDARD Pheochromocytoma • Symptoms due to catecholamine excess • Pressure • Perspiration • Palpitation • Pallor • Pain • Blood pressure • Sustained hypertension in 1/2 • Paroxysmal hypertension in 1/3 • Normal blood pressure in 1/5 Diagnosing pheochromocytoma • Plasma 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 NEVER BIOPSY AN ANDRENAL MASS WITHOUT RULING OUT PHEO FIRST!! Kronenberg, et al. Williams Textbook of Endocrinology. 2008 Treatment of pheochromocytoma • Surgery is treatment of choice • Laproscopic surgery is an option • Preparation for surgery • Alpha blockade with phenoxybenzamine (alternative: terazosin) • Titrate until patient is orthostatic or patient is at maximum dose • Then start beta blocker • If surgery is not an option (ie metastatic tumor) • Metyrosine • Chemotherapy and radiation • 61 yo man with epigastric pain found to have 7 cm R • • • • adrenal mass. No change in weight. No history of HTN, palpitations, headaches or excessive sweating. Physical exam shows normal features. BP 122/76 and pulse 74. No plethora, muscle wasting, weakness or ecchymosis. Labs: normal serum electrolytes, cortisol, ACTH, and 24hr urine metanephrines. Dexamethasone suppression test normal. CT scan showed 7cm R adrenal mass with 77 Hounsfield units. Normal L adrenal gland. No lymphadenopathy. What is most appropriate management? • Biopsy of adrenal mass • Right adrenalectomy • Serum aldosterone to plasma renin activity ratio determination • 24-hour measurement of urine cortisol excretion 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 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 • Young adulthood • Hirsutism, menstral irregularities • Mimics PCOS • Treatment: prednisone • + fludrocortisone if needed Adrenal insufficiency • Symptoms • Weakness, fatigue, abdominal pain, nausea, vomiting • Signs • Hyponatremia, hypotension, hypoglycemia • Women have loss of axillary and pubic hair • Due to loss of adrenal androgens • Primary adrenal insufficiency • Hyperpigmentation (↑ ACTH) • Hyperkalemia (mineralocorticoid deficiency) BEFORE AFTER Primary adrenal insufficiency • Addison’s disease • Occurs when 90% of gland destroyed • Involves all 3 layers of gland • Most common cause in US: autoimmune adrenalitis • Most common cause worldwide: TB • Other causes: histoplasmosis, HIV, metastatses, adrenal hemorrhage, Waterhouse-Friderichsen syndrome • Diagnosis with Cosyntropin stim test • Cortisol >18 at any time rules out primary adrenal insufficiency Adrenal cases 60 yo man with hypokalemia, U waves on EKG, HTN (190/120), weakness, extreme thirst and polyuria. Normal glucose. CT scan shows 1cm nodule on right adrenal gland. First diagnostic step? Renin/Aldosterone ratio >20 with Aldo >15 Primary Hyperaldosteronism Confirmatory Test? Salt load and then 24 hour urine aldo >12 OR 2 liter NS bolus with plasma aldo >10. Electrolytes corrected and he feels better. Ready for surgery now? Bilateral adrenal vein sampling first. 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 Anterior pituitary hormones • Adrenocorticotropic hormone (ACTH) • CRH stimulates release of ACTH • Growth hormone (GH) • GHRH stimulates release of GH • Thyroid stimulating hormone (TSH) • TRH stimulates release of TSH • Luteinizing hormone (LH) • GnRH stimulates release of LH • Follicle-stimulating hormone (FSH) • GnRH stimulates release of LH • Prolactin • Under continuous hypothalamic inhibition by dopamine Pituitary tumors • Is it hormonally active? • 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 and TSH • Beware low free T4 but “normal” TSH! • Remember inappropriate normals!! 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 • Severe-long standing primary hypothyroidism will ↑ TRH →↑PRL and ↑growth of thyrotrophs → pituitary mass → give levothyroxine • 26 yo woman evaluated for hyperprolactinemia after recent labwork showed serum prolactin of 55 (normal 1026). 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 • Drugs: metoclopramide, amytriptyline, phenothiazines, antidopaminergics • Other tumors that compress pituitary stalk Acromegaly • Diagnosis often overlooked and late (>10 years) • Often macroadenoma (>1 cm) • Frontal bossing, enlarging hands and feet • Sleep apnea, HTN, carpal tunnel, skin tags, colon polyps • Screening: ↑ IGF-1 • GH too pulsatile! • 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 Growth Hormone Excess Cushing’s syndrome • Make diagnosis • Overnight 1 mg dexamethasone suppression test • Elevated urinary free cortisol in 24-hour urine • Elevated midnight salivary cortisol • Localize site of problem • ACTH-producing pituitary tumor (70%) • Ectopic ACTH (15%) • Most common—bronchial carcinoid • Adrenal adenoma or carcinoma (15%) Cushing’s syndrome • Check ACTH • < 5—adrenal adenoma or carcinoma • >20—pituitary or ectopic ACTH • >200—most likely ectopic ACTH • Primary versus ectopic ACTH • High dose dexamethasone suppression test • Not so good as some ectopics will suppress • Inferior petrosal sinus sampling • GOLD STANDARD Cushing’s syndrome • Visualize lesion • Cushing’s disease—MRI pituitary • Ectopic—CT chest/abdomen/pelvis • Adrenal—CT or MRI adrenal • Remember pituitary or adrenal mass may be just an incidentaloma! Cushing’s Syndrome • 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 • Severe headache, altered mental status, ophthalmoplegia • CT/MRI: high density mass within pituitary • Administer stress doses of steroids • Contact neurosurgery for possible decompression Diabetes insipidus • Problem with ADH • Central—no ADH production • Nephrogenic—no ADH action • Remember that hypokalemia and hypercalcemia can cause nephrogenic DI • Persistent non-concentrated polyuria with dehydration • Hypernatremia, hyperosmolarity (>295), low urine osmolarity (<300) • Confirm with water deprivation test Diabetes insipidus • Distinguish central from nephrogenic diabetes insipidus with 1 mcg desmopressin • Central: increases urine osmolarity >50% • Nephrogenic: no response • Treatment • Central: DDAVP • Nephrogenic: thiazide diuretics 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 • Conivaptan—ADH receptor antagonist; acute tx • Demeclocycline—blocks ADH at collecting tubal, chronic tx Excess Insufficiency ACTH GH ACTH GH Cushing’s Disease Slow onset Classic phenotype HTN/diabetes osteoporosis Skin thinning, ecchymoses Acromegaly 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 TSH FSH/LH TSH FSH/LH Rare. Hyperthyroidism with “normal” or increased TSH Amazingly rare Precocious puberty Rare. Hypothyroidism with “normal” or decreased TSH VERY COMMON Hypogonadism with atrophic gonads and “normal” or low FSH/LH McCune Albright Syndrome Older “Decreased Vigor” Complications of pituitary irradiation • Hypopituitarism • Low prolactin supports diagnosis • Can see hypothyroidism and adrenal insufficiency • Can develop years after radiation treatment • Visual defects • Due to damage to optic chiasm • Second tumor development Pituitary cases 32 yo ♂ with severe HA’s, double vision, 2.5cm pituitary mass compressing the optic chiasm, prolactin level 3,215. Cause and Treatment? Prolactinoma (PRL > 200). Medical therapy first: Try dopamine receptor agonist (cabergoline, bromocriptine). If fails, surgery. 22 yo ♂ with HA’s, 1.5cm cystic-solid sellar mass with calcification. PRL 70. Cause? Craniopharyngioma with Stalk effect Interruption of hypothalamic inhibition. 32 yo with low energy, missed menstrual cycle, PRL 68 Pregnant (check HCG) 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 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 Small cell lung cancer GONADS 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 Red flags for tumors • Recent onset and/or rapid progression • Late onset (ie post-menopausal) • Virilization—voice change, clitomegaly • Total testosterone >200 ng/dL PCOS • Usually evident at puberty • Anovulatory cycles with continuous stimulation of ovary by • • • • LH Oligomenorrhea or amenorrhea Hyperandrogenism Total testosterone elevated but <200 ng/dL LH:FSH ratio usually >2:1 • Lacks sensitivity and specificity PCOS treatment • Hirustism • Mechanical hair removal • OCPs + spironolactone (anti-androgen) • Weight loss • Infertility • Clomiphene • Metformin 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 Secondary • Turner syndrome • Kallman syndrome • Radiation • Hyperprolactinemia • Chemotherapy • Anorexia nervosa • Autoimmune destruction • Strenuous exercise of ovaries (APS) training • Stress • Hypothalamic/pituitary disease Turner syndrome • Primary amenorrhea with ↑FSH and ↑LH • 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 Osteoporos 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 • Check hCG • Rule out pituitary disease or ovarian failure • Check prolactin and FSH • Progestrin challenge (Provera 10mg x 10 days) • If bleeding, anovulatory cycles (PCOS) • If no bleeding, anatomic defect 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 • Form of primary hypogonadism • Due to abnormal development of GnRH producing neurons • Also close to olfactory system • Get isolated hypogonadotrophic hypogonadism with anosmia • Normal karyotype (46 XY) • Small testes (but larger than Klinefelter) • Infertility treated with LHRH infusion pump Gynecomastia • Occurs when estrogen/androgen balance favors estrogen • ↑ estrogens: cirrhosis, hyperthyroidism, β-hCG/estrogen- secreting tumors • ↓androgens: testicular surgery/trauma, renal failure, hyperprolactinemia, drugs • drugs: spironolactone, ketoconazole, calcium channel blockers, phenothiazines, TCAs 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 • Small testicles, gynecomastia, low sperm count • Women • Hirsutism, small breast, enlarged clitoris, deepening voice • Both • HTN, increased CVD, acne, male-pattern baldness, irritability, psychosis Hypogonadism cases 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. 47 yo man with rheumatoid arthritis on chronic opiate therapy with prednisone 10mg daily; hypogonadal symptoms. Likely diagnosis? Glucocorticoid-induced hypogonadism Suppresses GnRH release and reverses with removal of steroids. 37 yo man with decreased libido, develops gynecomastia and galactorrhea. Beta-hCG normal, labs confirm low LH and low testosterone. Next test? Hyperprolactinemia Check prolactin level to confirm Hypogonadism cases 18 yo man with cryptorchidism, delayed puberty, cleft palate, abnormal movements. Diagnosis? Kallman Syndrome – Neuronal Migration disorder – also associated with anosmia 27 yo female marathon runner with amenorhea. Exercise-Induced Amenorrhea – Mediated by low GnRH Also seen with anorexia, low body fat Test to check in long term hypogonadism DEXA scan High risk for osteoporosis! BONE Risk factors for osteoporosis • Thin • Alcohol • Caucasian • Smoking • Female gender • First degree relative with osteoporosis • Rheumatoid arthritis • Use of glucocorticoids Indications for bone mineral density • Female > 65 years old • Post-menopausal female <65 years if: • 1st degree relative, smoker, weight < 127 lbs • Male >70 years old • Fragility fracture • Glucocorticoids >3 months • Medical condition associated with osteoporosis • Hyperparathyroidism, Cushing’s disease, etc Interpreting DEXA results • T-score compares patient to 30-year woman • Z-score compares patient to age-related controls • Normal—T-score > -1 • Osteopenia—T-score > -1 but < -2.5 • Use FRAX score to determine who to treat • If risk >3% hip and >20% any, treat patient • Osteoporosis—T-score < -2.5 • 66 yo woman comes for management of osteoporosis • • • • noted on screening DEXA scan. No personal history of fracture. No family history of parathyroid disease or low bone mineral density. Has HTN controlled by lisinopril. No other medications or supplements. Vital signs normal. Good dentition. Physical exam normal except for mild kyphosis. Lab: albumin 4.0, calcium 8.7, creatinine 0.7, phosphorus 2.9, PTH 176. DEXA showed T-score -2.1 in lumbar spine, -3.0 in femoral neck, and -2.5 in total hip. What is most appropriate next step in management? • Measure 1,25-dihydroxyvitamin D • Measure 25-hydroxyvitamin D • Parathyroidectomy • Repeat DEXA scan in 1 year Osteoporosis therapy Drug Spine Hip Bisphosphonates + + Raloxifene + - Tamoxifen + + Calcitonin + - Teriparatide + + Useful for bone pain. Tachyphylaxis limits use. Stop use after 2 years → risk of osteosarcoma. Paget’s Disease • Disease of increased bone turnover • Bone pain with elevated alkaline phosphatase • Bone scan: focal uptake with no evidence of cancer. • If affecting skull osteoporosis circumscripta • Risk of cranial nerve palsies, particularly CN VIII • Risk of fracture at site of bone turnover • Therapy–pamidronate or alendronate daily Osteoporosis circumscripta Osteomalacia • Decreased bone mineralization usually from vitamin D deficiency • In kids, we call it ricketts • Typically older patient with bone pain and proximal muscle weakness • “bilateral symmetric pseudofractures” • Check 25-OH vitamin D and replace to >30 • Also see ↓ Ca, ↓ PO4, ↑ alk phos, ↑ PTH • Work-up vitamin D deficiency Psuedofracture of Looser’s zone MISCELLANEOUS Nutritional deficiencies after bariatric surgery • Iron • Vitamin D • B12 • Folic acid • Thiamine (B1) • Vitamin A • Zinc Good luck on the boards!