Endocrine Board Review LILLIAN F. LIEN, MD DIVISION CHIEF DIVISION OF ENDOCRINOLOGY, METABOLISM, &...
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Transcript of Endocrine Board Review LILLIAN F. LIEN, MD DIVISION CHIEF DIVISION OF ENDOCRINOLOGY, METABOLISM, &...
Endocrine Board Review
LILLIAN F. LIEN, MD
DIVISION CHIEF
DIVISION OF ENDOCRINOLOGY, METABOLISM, & DIABETES
PROFESSOR OF MEDICINE, UMMC
WITH APPRECIATION TO:
SARAH E. FRENCH, MD
Part II -AdrenalPituitary &HypothalamusMENReproductive Endocrine
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
PITUITARY
Adrenal Glands
CRH
+ACTHCortisol
_
feedback
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
“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
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 disease-
Slow Onset:
Autoimmune Adrenalitis
Infectious Adrenalitis (see next slide) Metastatic CA
Isolated glucocorticoid deficiency
Congenital Adrenal Hyperplasia
Adrenomyeloneuropathy
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 ManifestationsHyperpigmentation
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: EtiologySlow Onset:
Pituitary tumor or surgery or radiation
Craniopharyngioma
Isolated ACTH Deficiency
Megace
Long-Term Glucocorticoid Therapy
Sarcoidosis
Hypothalamic Tumor
Abrupt Onset:
Postpartum pituitary necrosis (Sheehan’s)
Necrosis or bleeding into a pituitary macroadenoma (hemorrhage into a pituitary tumor=pit apoplexy)
Head trauma, lesions of the pituitary stalk
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 - RESULTSINTERPRETATION 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
Adrenal Glands
+ACTHCortisol
_
feedback
D ia g no s tic A lg o rith m for A d re n a l In su ffic ie n cy
<3R U L E S IN
A drena l Insu ffic iency
N O R M A L R esp o n seC o rtiso l > 18R U L E S O U T** N O A I **
HIGH> 100D IA G N O S IS
** P R IM A R Y A I **
** T E R T IA R Y A I **
E xag ge ra teda n d P ro lo ng ed
A C T HR e spo n se
** S E C O N D A R Y A I **
A b sen t o r S ub n orm alA C T H
R e spo n se
CRH STIM Test
LOW or NORM ALS econda ry o r T e rtia ryA d rena l Insu ffic iency
Plasm a ACTH
S U B N O R M A LR E S P O N S E
** R U LE S IN A I **D e fin e T ype
ACTH Stim Test
B e twe e n 3 and 18N e ed
D yn a m ic T e s ting
>18R U L E S O U T** N O A I **
R u le In o r O u t A I-Check Plasm a Cortisol
Beyond Basics: Challenges in Dx of Secondary AI:•Lo-Dose ACTH Stim•Metyrapone•Insulin Tolerance Test
TREATMENT - Adrenal CrisisDo 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 (10mg) to decrease IOP
and 10mg PO qpm (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!
TREATMENTChronic 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].”
Prophylaxis-Steroids 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
Arafah BM. Hypothalamic
pituitary adrenal function during critical illness: limitations of current assessment methods.
JCEM 2006; 91:3725-3745
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
Overview of Adrenal Disorders
Adrenal InsufficiencyACTH STIMULATION tests
Cushing’s SyndromeDexamethasone SUPPRESSION tests
Primary HyperaldosteronismClinical Findings
Hypertension Muscle Symptoms (due to hypokalemia)
cramping weakness periodic paralysis
Often few clinical findings at alloften just suspected after lab
abnormalities are noted
Primary HyperaldosteronismLab 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 HyperaldosteronismLaboratory Findings
CT scan of abdomen, attention adrenal glands may find solitary adenoma or carcinoma
18-OH corticosterone level 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 HyperaldosteronismKey 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 HyperaldosteronismTreatment 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 competitive inhibition):
Spironolactone has long been the drug of choice … versus
Eplerenone is a newer more expensive alternative 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)
PheochromocytomaClinical Findings
Classically: The Five P’s: Pain
Headaches Pallor
Orthostatic hypotension from impaired arterial and venous constriction responses
Palpitations Catecholamine release
Pressure (hypertension) Persipiration
PheochromocytomaClinical 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
Kronenberg, et al. Williams Textbook of Endocrinology. 2008
NEVER BIOPSY AN ADRENAL MASS WITHOUT RULING OUT PHEO FIRST!!
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
PheochromocytomaKey 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
PheochromocytomaTreatmentPharmacologic
Alpha Adrenergic-Blockade first phenoxybenzamine or shorter acting alpha blockers
Beta-blockade next if necessary Never start before alpha-blockade
Unopposed alpha-receptor stimulation can lead to worsened hypertensive crises
Calcium Channel Blockers May be better tolerated than alpha-blockade
On reserve: can inhibit catecholamine synthesis (Demser)
PheochromocytomaTreatment
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 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 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)
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? (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 SyndromeClinical 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 SyndromeDiagnosis: 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)
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.
ECTOPIC - Bronchial carcinoid. ACTH > 200.IPSS/periphery ACTH ratio < 2
ECTOPIC ACTH - Small cell lung cancer
Pituitary cases
Excess InsufficiencyACTH
Cushing’s Disease
Slow onset Classic phenotype
HTN/diabetesosteoporosisSkin thinning, ecchymoses
ACTHSalt craving,
nausea, “vague abdominal pain”,
FeverHYPOGLYCEMIA
Weight lossPubertal hair loss
GHAcromegaly
Slow OnsetSleep apneaCarpal 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
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)
Replacement for : Secondary hypothyroidism
Do not follow TSH in secondary hypothyroidism
Secondary Hypogondism
GH deficiency 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…
Aside- complications of pituitary radiation:
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
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
Excess InsufficiencyACTH
Cushing’s Disease
Slow onset Classic phenotype
HTN/diabetesosteoporosisSkin thinning, ecchymoses
ACTHSalt craving,
nausea, “vague abdominal pain”,
FeverHYPOGLYCEMIA
Weight lossPubertal hair loss
GHAcromegaly
Slow OnsetSleep apneaCarpal 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
Posterior-SIADH Posterior-DI
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) Prolactinoma, acromegaly, Cushing’s disease, other
Pancreas 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”
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
MEN 2B
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 VirilizationEtiology
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 VirilizationEtiology
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
Oligoovulation, Hyperandrogenism, Polycystic ovaries
Clinical history is important: Menstrual irregularity (oligomenorrhea/amenorrhea)/ infertility
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 long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19:41.
Hirsutism and VirilizationPCOS 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 VirilizationCongenital Adrenal HyperplasiaEnzymatic 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, β-hCG/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
Absence of ovarian oocytes and follicles
Turner syndrome 45X
46,XX and, rarely, 46,XY
Kallman syndrome
Congenital GnRH deficiency with anomsia
Radiation
Chemotherapy
Autoimmune destruction of ovaries (APS)
Secondary Hyperprolactinemia
Anorexia nervosa
Functional Hypothalamic amenorrhea
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 Check hCG, prolactin, TSH
Rule out pituitary disease or primary ovarian failure 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
25 yo man with decreased libido, decreased testicular volume, otherwise normal. AST/ALT elevated. Next Test?
Male Hypogonadism
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 Small testicles, gynecomastia, low sperm count
Women Hirsutism, small breast, enlarged clitoris,
deepening voice
Both HTN, increased CVD, acne, male-pattern
baldness, irritability, psychosis