Endocrine Board Review

Ria Dancel, MD

6/22/2009

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Hyperprolactinemia in pt with secondary amenorrhea

• Secondary amenorrhea = Absence of menses for 3 or more consecutive months in a woman who has menstruated previously

• First test is always pregnancy test!• PCOS is the most common cause of secondary

amenorrhea but hyperprolactinemia must be excluded to make the Dx of PCOS

• Prolactin is unique in that it is under chronic dopaminergic inhibition by the hypothalamus.

• Prolactin causes amenorrhea by suppressing GnRH

Hyperprolactinemia in pt with secondary amenorrhea

Causes of hyperprolactinemia:• Physiologic:

– Pregnancy– Lactation

• Pharmacologic:– Antipsychotics, MAOI, SSRI, antiemetics– Calcium channel blockers, estrogens, opiates, cocaine

• Pathologic:– Primary hypothyroidism (Low thyroid hormones increased

thyrotropin releasing hormone increase in TSH and secondary increase in prolactin)

– Prolactinoma (Most common pituitary tumor)– Tumor disrupting stalk– Hepatic failure (Decreased secretion of prolactin)– Renal failure (Decreased secretion of prolactin)

Copyright ©2003 Canadian Medical Association or its licensors

Serri, O. et al. CMAJ 2003;169:575-581

Causes of hyperprolactinemia

Hyperprolactinemia in pt with secondary amenorrhea

History: Classic s/sx are amenorrhea, galactorrhea, infertility– Headaches prolactinoma or tumor disrupting stalk– Fatigue, weakness, weight gain, cold intolerance

hypothyroidism

Physical exam:– Galactorrhea– Bitemporal hemianopsia tumor

Labs:– Prolactin > 200, think TUMOR– TSH, T4 if hypothyroidism is suspected

Treatment:– Dopamine agonists: bromocriptine and cabergoline– Surgery reserved for refractory cases, invasive disease,

persistent visual field deficits

Hyperprolactinemia in pt with secondary amenorrhea

MKSAP QuestionA 26-year-old woman is evaluated for amenorrhea. Her last menstrual

period was 3 months ago, and three home pregnancy tests have been negative. She states that she has no other symptoms and takes no medications. Menarche occurred at age 12 years, and her menstrual cycle has been regular until 3 months ago. Upon further questioning, she recounts weekly headaches and occasional galactorrhea on breast palpation. Physical examination, including neurological examination, is normal. Deep tendon reflexes are normal. Serum prolactin level is 1665 ng/mL (1665 mg/L)

Which of the following is the most likely cause of this patient's hyperprolactinemia?

A. PregnancyB. CirrhosisC. Primary hypothyroidD. Prolactin-producing pituitary tumor

MKSAP QuestionA 34-year-old woman is evaluated for fatigue, weight gain, irregular

menstrual cycles, and milky discharge from both breasts for 6 months. She has had no change in vision and is not taking any medications.

Physical examination reveals a small goiter, dry skin, bilateral expressible galactorrhea, and normal visual fields. Laboratory results include a negative pregnancy test and a serum prolactin level of 55 ng/mL (55 mg/L). MRI of the head shows an enlarged pituitary gland that extends to within 1 mm of the optic chiasm.

Which of the following is the most appropriate next step in the management of this patient?

A. Re-measure serum prolactin levelB. Start estrogen/progesterone cyclic therapyC. Start dopamine agonist therapyD. Measure TSH and free T4E. Refer to neurosurgeon for pituitary surgery

The Adrenal Gland

Glucocorticoids – Cortisol

Mineralocorticoids – Aldosterone

Sex steroids – Testosterone, Estrogen

Catecholamines – Norepi, epi, DA

Confirm pheochromocytoma

• Adrenal medullary tumor of neural crest origin; secretes norepi, epi, and dopamine

• Rule of 10’s: 10% extramedullary, 10% familial, 10% malignant, 10% asymptomatic

• In hypertensive patients, the triad of sudden severe headaches, diaphoresis, and palpitations has 94% specificity and 91% sensitivity for pheo

Step 1: Draw plasma fractionated metanephrines, sensitivity 97% but specificity 85%

Step 2: Confirm with 24 hour urine collection for metanephrines, specificity > 94%

Step 3: Localize with abdominal CT, with special attention to the adrenal glands

Cushing’s: Hypothalamic-pituitary-adrenal axis

Kirk LF, Hash RB, Katner HP, Jones T. Cushing’s disease: Clinical manifestations and diagnostic evaluation. Am Fam Physician. 2000 Sep 1;62(5):1119-27, 1133-4

ACTH and corisol highest in the AM, lowest in PM and at night

Cushing’s disease and Cushing’s syndrome

• Caused by excess glucocorticoids• Cortisol is the major natural glucocorticoid• Signs/Sx: central adiposity, moon facies, buffalo hump,

violaceous striae, hyperglycemia, hypertension, hirsutism, amenorrhea, acne, proximal muscle weakness, osteoporosis

• Causes – most to least common1. Exogenous glucocorticoids2. ACTH-secreting corticotroph adenoma of the pituitary =

Cushing’s disease. 80% of cases of endogenous excess3. Unilateral adrenal adenoma = Cushing’s syndrome. 10% of

cases of endogenous excess4. Paraneoplastic syndrome. 10% of cases of endogenous excess

Cushing’s disease and Cushing’s syndrome

Step 1: Confirm glucocorticoid excess– Salivary cortisol concentration– Overnight dexamethasone suppression test. Give

1 mg dexamethasone at 23:00, measure cortisol at 08:00. Should be < 5 μg/dL. (98% sensitivity, 80% specificity)

– 24 hour urine cortisol (>95% specificity and sensitivity)

– False positives caused by depression, chronic EtOH, obesity = pseudo-Cushings

Step 2: Determine if excess glucocorticoid is ACTH dependent or ACTH independent by drawing a late PM level of ACTH.

Cushing’s disease and Cushing’s syndrome

TUMOR

Late PM ACTH > 10 pg/ml (2 pmol/L)

ACTH DEPENDENT

•Cushing’s disease

•Ectopic ACTH (tumor)

Late PM ACTH < 5 pg/ml (1 pmol/L)

ACTH INDEPENDENT

•Adrenal adenoma

•Iatrogenic

High dose dexamethasone

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No effect

Further testing: CRH stimulation test, inferior petrosal sinus sampling

MKSAP Question

A 38-year-old woman is evaluated for an elevated salivary cortisol concentration collected at 2300 hrs (9.3 nmol/L [256.59 nmol/L]) on two separate occasions. The patient has poorly controlled diabetes mellitus and signs of cortisol excess. The serum ACTH is 29 pg/mL (6.39 pmol/L)

Which of the following is the most appropriate next diagnostic test in this patient?

A. Dexamethasone 8 mg overnight suppression test

B. MRI of the head

C. Somatostatin receptor scintigraphy

D. Inferior petrosal sinus sampling

Cushing’s and osteoporosis

• Exogenous corticosteroid use is the most common cause of secondary osteoporosis

• DEXA scan prior to starting steroids• 1500 mg/day of Ca, 800 IU/day of vit D• Start bisphosphonate therapy if pt will be

exposed to > 5 mg prednisone (or its equivalent) daily x 3 months

• Repeat DEXA scan 6-12 months into steroid therapy

Manage incidental adrenal tumor

• Most incidentalomas are hormonally silent and have no malignant potential BUT up to 30% secrete cortisol, aldosterone, androgens, or catecholamines

Step 1: Assess hormonal activity– Rule out Cushing’s syndrome– Rule out pheochromocytoma– Rule out aldosterone secreting tumor in hypertensive pts with plasma

aldosterone : plasma renin activity ratios. PA:PRA > 20:1 suggests primary aldosteronism with > 90% sensitivity and specificity

Step 2: Assess malignant potential with CT– Benign lesions: < 6cm, smooth borders, < 10 Hounsfield units, no

enhancement with contrast– Malignant lesions: 25% of tumors > 6cm are carcinomas, ragged

borders, > 10 Hounsfield units, enhance with contrast

• Hypersecreting adenomas, pheochromocytomas, and tumors 6 cm or greater in diameter should be surgically resected

• FNA lesions only when pt is known to have primary malignancy elsewhere

• Repeat radiographic imaging and lab work in 6-12 months for lesions < 6 cm unless worrisome radiographic findings present

Manage incidental adrenal tumor

MKSAP QuestionA 26-year-old woman is evaluated in the emergency department for lower

abdominal/pelvic discomfort. The blood pressure during the episode is 160/90 mm Hg, but she has no history of hypertension. She has been in good health until her present episode, which started several hours before the visit.

Her BMI is 26, and she has no hirsutism, striae, or central adiposity. Hematologic findings and plasma glucose and serum electrolytes are normal. During her evaluation, the discomfort lessens and resolves spontaneously and she is released. CT scan of the abdomen done during the evaluation shows a 1.8-cm irregularity in the right adrenal gland.

Which of the following would be the most appropriate follow-up of this finding?

A. MRI of the abdomenB. Observation onlyC. Repeat CT scan in 1-3 monthsD. Screen for pheochromocytoma, Cushing’s syndrome, and primary aldosteronism

MKSAP QuestionA 56-year-old man is evaluated for anorexia and a 5-kg (11-lb) unintentional

weight loss over the preceding 4 months. He has vague abdominal discomfort and occasional flank pain.

On physical examination, the BMI is 27 and the blood pressure is 108/72 mm Hg. Examination is unremarkable.

CT scan of the abdomen shows a 6-cm left adrenal mass. Attenuation value of the mass is 32 Hounsfield units. The margins of the lesion are irregular and the consistency is heterogeneous. Radiographic evaluation of the lungs and kidneys reveals no other abnormality.

Plasma fractionated metanephrines are normal. Plasma aldosterone/plasma renin activity (ARR) is 6 (normal <12). Serum cortisol at 0800 hrs after dexamethasone 1 mg the preceding evening is 1.4 µg/dL (38.63 nmol/L).

Which of the following is the most appropriate next step in the management of this patient?

A. Selective adrenal venous samplingB. Repeat biochemical testing and CT in 6 monthsC. Iodocholesterol imaging of adrenalsD. Referral for surgical resection of mass

Solitary thyroid nodule

• 5% of thyroid nodules are malignant• Poor prognostic factors: male, middle-age,

tumor size > 4-5 cm, local invasion, distant mets

• Types of thyroid cancer– Papillary: 75%– Follicular: 15-20%– Medullary: <5%, derived from calcitonin-producing

C-cells. 75% sporadic, remainder are inherited– Anaplastic: <5%, 10-year survival ~15%

Solitary thyroid nodule• Multiple endocrine neoplasia

– Autosomal dominant inheritance– RET proto-oncogene mutations

• MEN type 2A:– Medullary thyroid carcinoma: 95-100% penetrance– Unilateral or bilateral pheochromocytomas: 40-50%

penetrance– Hyperparathyroidism: 10-20% penetrance

• MEN type 2B: – Medullary thyroid carcinoma: 95-100% penetrance– Pheochromocytomas: 50% penetrance– Mucosal neuromas (tongue, under eyelids, intestinal)– Marfanoid body habitus

Solitary thyroid nodule - diagnosis

1. Measure TSH– Normal TSH “cold”, nonfunctioning nodule– Low TSH “hot”, hyperfunctioning nodule

2. Ultrasound– Distinguish solitary nodule from multinodular goiter– Establish baseline size– Eval for suspicious features; eg. stippled

calcifications

3. FNA all cold nodules4. In multinodular goiter, nodules > 1.5 cm or fast

growing nodules are typically aspirated

Solitary thyroid nodule - management

• Papillary and follicular thyroid cancer total thyroidectomy and 131I at high doses. 10 year survival > 90%

• Medullary thyroid cancer total thyroidectomy/neck dissection. – Since these are derived from C-cells and

secrete calcitonin, radioactive iodine has no effect

– Follow with calcitonin and CEA levels

MKSAP questionA 45-year-old woman is evaluated for a sensation of fullness in her neck

and occasional difficulty swallowing. She feels well otherwise. She has no history of head and neck radiation therapy. Her mother developed a goiter in her 40s.

On physical examination, the thyroid gland is enlarged to approximately twice the normal size and there is a dominant 2-cm nodule in the left lobe. No cervical lymph nodes are palpable. The serum thyroid-stimulating hormone (TSH) level is 1.8 µU/mL (1.8 mU/L). Thyroid ultrasound reveals multiple small nodules in both lobes and a 2.2-cm dominant nodule in the left lobe.

Which of the following is the most appropriate next step in the evaluation of this patient?

A. Thyroid scanB. FNA of dominant noduleC. Serum thyroglobulin levelD. Serum antithyroid peroxidase and antithyroglobulin antibodiesE. Serial US measurements

MKSAP questionA 42-year-old man is evaluated for an anterior neck mass. He has a family

history of thyroid cancer and hyperparathyroidism. On physical examination, the blood pressure is 147/85 mm Hg and the pulse rate is 88/min; he has a 3-cm right thyroid nodule and bilateral anterior cervical lymphadenopathy. Lungs are clear and cardiac examination reveals a 2/6 systolic ejection murmur; there is no pedal edema. Laboratory testing shows a serum thyroid-stimulating hormone of 1.4 µU/mL (1.4 mU/L) and calcium of 10.6 mg/dL (2.64 mmol/L), and microscopic hematuria. Fine-needle aspiration biopsy of the nodule suggests medullary thyroid cancer.

Which of the following tests is the most appropriate next test in the evaluation of this patient?

A. Serum calcitonin levelB. Repeat biopsy with immunostaining with calcitoninC. Serum PTH levelD. Urine metanephrinesE. Urine calcium, phosphate, and citrate

Key point: Screen all patients with suspected medullary thyroid cancer for pheochromocytoma before sending them to surgery!

Confirm thyrotoxicosis factitia

• Signs/Sx of thyrotoxicosis: lid retraction, lid lag, fine finger tremor, moist/warm skin, tachycardia.– Other signs/sx: heat intolerance, weight loss,

arrhythmia/palpitations, brisk DTR, anxiety, diarrhea, hair loss, bone loss

• When to suspect factitious disease:– Absence of exophthalmos, pretibial myxedema– Unpalpable thyroid

• Exams:– Low TSH– Low TRH– High T4 or T3 (depending on levothyroxine or liothyronine)– Normal ESR– Low radio-iodine uptake

Confirm acute thyroiditis

• AKA acute suppurative thyroiditis• Staphylococcus aureus, Streptococcus

hemolyticus, and pneumococcus• Sx: fever, chills, neck pain and erythema (may

be unilateral), sore throat, hoarseness, and dysphagia

• Labs: Leukocytosis with left shift, increased ESR, NORMAL thyroid function tests

• Studies: Radioactive iodine scanning unnecessary, needle aspiration and culture helpful if abscess suspected

Diagnose iodine-induced hyperthyroidism

• Exposure to betadine, amiodarone, radiographic contrast dye in pt with pre-existing nodular goiter

• Nodular goiters can be autonomous – lacking autoregulatory mechanisms against excess iodine

• High index of suspicion in middle-aged/elderly pts with enlarged thyroid or nodule in the correct setting

• Measure TSH, T4, and urine and serum iodine• Tx: Remove source of iodine. May need

methimazole or PTU

Manage primary hyperparathyroidism

• Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient setting

• Single parathyroid adenoma is the cause in 85% of cases• Double adenoma or multi-gland hyperplasia in 15% of cases. Usually

associated with MEN type 1 or MEN type 2 syndromes

2002 National Institutes of Health consensus conference guidelines for the management of asymptomatic primary hyperparathyroidism

Indications for surgery– Serum calcium level >1 mg/d above upper limit of normal– 24-Hour urine calcium excretion > 400 mg– Creatinine clearance reduced by ≥ 30%– Bone mineral density: T-score <−2.5 at any site– Age younger than 50 years

Recommended follow-up measurements for patients not undergoing surgery

– Biannual serum calcium– Annual serum creatinine– Annual bone mineral density (lumbar spine, proximal femur, distal forearm)

MKSAP questionA 51-year-old man is undergoing a routine physical examination. He has

no significant personal or family medical history. He still exercises regularly, running 2 to 3 miles at least three times a week. He does not smoke, drink alcohol, or use recreational drugs. Physical examination is normal. Laboratory tests are normal other than a calcium level of 11.0 mg/dL (2.74 mmol/L). A subsequent serum parathyroid level is 120 pg/mL (120 ng/L). A 24-hour urine calcium excretion is 250 mg (6.3 mmol). The creatinine clearance is normal. A DEXA scan shows a T score of 0.99 at the left femoral neck, 0.68 at the lumbar spine, and −2.5 at the distal third of the forearm.

Which of the following is the most appropriate management for this patient?

A. Calcium and vit D supplementationB. AlendronateC. ParathyroidectomyD. Nasal calcitoninE. Ibandronate

Confirm diabetes mellitus

ADA criteria:1. Fasting glucose level > 126. Fasting = no caloric

intake for 8 hours.2. Casual glucose level > 200 + symptoms of

hyperglycemia (polydipsia, polyuria, weight loss, blurred vision).

3. 2-h plasma glucose >200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT).

Confirm with repeat levelUse of the HgbA1C for the diagnosis of diabetes

is not recommended at this time.

American Diabetes Association (ADA). Standards of medical care in diabetes. I. Classification and diagnosis. Diabetes Care 2008 Jan;31(Suppl 1):S12-3.

Order the appropriate dx test for a man with hypogonadism

• Testosterone < 100 ng/dL in a young man is nearly always pathologic

• Image pituitary with MRI of sella