ENDOCRINOLOGY IISarah E. French, MDJuly 19, 2014

ThyroidPituitaryAdrenalGonadsBone

Medical-Content Category Relative PercentageCardiovascular 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 questionsDiabetes 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

QuestionA 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-depressants3. Begin stimulants4. Order TSH and Free T45. 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 hyperthyroidismIncreased Production of

Thyroid Hormones- Graves disease- Toxic multinodular goiter- Molar Pregnancy (hCG)- Iodine-induced (Jod-

Basedow)- TSH-pituitary adenoma

Leakage or Extra-Thyroidal 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

Acropachy

Proptosis

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 casesYoung patient with soft goiter, bruit, weight loss

Grave’s Disease RAI ablation

Patient with sore throat, fever, painful goiterSubacute thyroiditis Supportive care +/- steroids

Patient with hepatitis C on a-INF. Mildly thyrotoxic, non-tender goiterSilent 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!!

QuestionAn 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 D502. Levothyroxine 300mcg IV 3. Levothyroxine 300mcg IV and hydrocortisone 100mg IV4. Levothyroxine 300mcg IV and one amp of D50 IV5. Levothyroxine 200mcg PO

QuestionA 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 peri-orbital 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 doses2. Administer thyroxine 500mcg IV and triiodothyronine 20mcg IV daily for

three days.3. Begin levothyroxine 300mcg PO daily4. Begin levothyroxine 100mcg PO daily5. Begin levothyroxine 25mcg PO daily

Replace levothyroxine slowly in elderly or cardiac patientsThere is no scenario where you should need to pick T3 over T4.

Hypothyroidism Scenarios83 yo woman with depression, clearly hypothyroid. Otherwise getting

along okay. Therapy?

47 yo man with CABG 8 months ago, hypothyroid. Treatment?

74 yo NH resident with thyroidectomy scar, on no meds comes in with altered mental status, severe hypothyroidism. Glucose is 56. Treatment?

Low dose levothyroxine therapy (25mcg/day) and advance slowly to reach goal.

Low dose levothyroxine therapy (25mcg/day) and advance slowly to reach goal.

Hydrocortisone 100mg IV and Levothyroxine IV.

Hypothyroidism cases27 year old woman with Hashimotos on levothyroxine

75mcg daily, 2 weeks pregnant.

45 year old woman with Hashimotos has a rapidly enlarging goiter

32 year old man begins abusing heroin, has high Total T4

Estrogens increase TBG, so increase levothyroxine dose by 30-50% during pregnancy

Thyroid Lymphoma - FNA diagnosis and irradiate

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

Kronenberg, et al. Williams Textbook of Endocrinology. 2008

NEVER BIOPSY AN ANDRENAL MASS WITHOUT RULING OUT PHEO FIRST!!

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 24-hr 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 cases60 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?

Confirmatory Test?

Electrolytes corrected and he feels better. Ready for surgery now?

Renin/Aldosterone ratio >20 with Aldo >15 Primary Hyperaldosteronism

Salt load and then 24 hour urine aldo >12 OR 2 liter NS bolus with plasma aldo >10.

Bilateral adrenal vein sampling first.

Adrenal cases24 yo man with resistant HTN, short stature, history of

genitourinary surgeries as a child, low potassium. Likely diagnosis?

45 yo farmer who dips tobacco, has resistant HTN with hypokalemia.

Congenital Adrenal Hyperplasia (17-alpha hydroxylase deficiency)Renin low, aldosterone low, deoxycorticosterone high

Licorice (glycyrrhizic acid) inhibits conversion of hydrocortisone to cortisoneRenin 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 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• 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 InsufficiencyACTH

Cushing’s Disease Slow onset

Classic phenotypeHTN/diabetesosteoporosisSkin thinning, ecchymoses

ACTHSalt craving,

nausea, “vague abdominal pain”,

FeverHYPOGLYCEMIA

Weight lossPubertal hair loss

GHAcromegaly

Slow OnsetSleep apnea

Carpal TunnelHTN/DiabetesColon polyps

Skin tags

GHYoung

Short stature

Older“Decreased

Vigor”

TSHRare.

Hyperthyroidism with “normal” or increased TSH

TSHRare.

Hypothyroidism with “normal” or decreased TSH

FSH/LHAmazingly rare

Precocious puberty

McCune Albright Syndrome

FSH/LHVERY COMMONHypogonadism with atrophic gonads and

“normal” or low FSH/LH

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

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

42 yo woman with Cushingoid features. Serum K 3.0. CT chest: lung nodule. Nonsmoker. MRI pituitary: normal. IPSS/Periphery 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

Cushing’s disease (pituitary). ACTH < 200Next Step ----> Surgery.

Bronchial carcinoid. ACTH > 200.IPSS/periphery ACTH ratio < 2

Small cell lung cancer

Pituitary cases

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• Turner syndrome• Radiation• Chemotherapy• Autoimmune destruction

of ovaries (APS)

Secondary• Kallman syndrome• Hyperprolactinemia• Anorexia nervosa• Strenuous exercise

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

25 yo man with decreased libido, decreased testicular volume, otherwise normal. AST/ALT elevated. Next Test?

47 yo man with rheumatoid arthritis on chronic opiate therapy with prednisone 10mg daily; hypogonadal symptoms. Likely diagnosis?

37 yo man with decreased libido, develops gynecomastia and galactorrhea. Beta-hCG normal, labs confirm low LH and low testosterone. Next test?

Hypogonadism cases

Hemochromatosis - Iron saturation > 45 is quite suggestive. May all see arthritis, risk for Type I DM.

Glucocorticoid-induced hypogonadism Suppresses GnRH release and reverses with removal of steroids.

Hyperprolactinemia Check prolactin level to confirm

Hypogonadism cases18 yo man with cryptorchidism, delayed puberty, cleft

palate, abnormal movements. Diagnosis?

27 yo female marathon runner with amenorhea.

Test to check in long term hypogonadism DEXA scan

High risk for osteoporosis!

Kallman Syndrome – Neuronal Migration disorder – also associated with anosmia

Exercise-Induced Amenorrhea – Mediated by low GnRHAlso seen with anorexia, low body fat

BONE

Risk factors for osteoporosis• Thin• Caucasian• Female gender• First degree relative with osteoporosis

• Alcohol• Smoking• 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 therapyDrug Spine Hip

Bisphosphonates + +Raloxifene + -Tamoxifen + +

Calcitonin + -Teriparatide + +

Stop use after 2 years → risk of osteosarcoma.Useful for bone pain.

Tachyphylaxis limits use.

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!