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