Transcript Endocrinology II

Endocrine Board Review
LILLIAN F. LIEN, MD
DIVISION CHIEF
DIVISION OF ENDOCRINOLOGY, METABOLISM, & DIABETES
PROFESSOR OF MEDICINE, UMMC
Part II Adrenal
Pituitary
&Hypothalamus
MEN
Reproductive
Endocrine
WITH APPRECIATION TO:
SARAH E. FRENCH, MD
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
CRH
PITUITARY
Cortisol
_
feedback
+ACTH
Adrenal Glands
“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
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
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 diseaseSlow Onset:

Autoimmune Adrenalitis

Infectious Adrenalitis (see

Metastatic CA

Isolated glucocorticoid deficiency

Congenital Adrenal Hyperplasia

Adrenomyeloneuropathy
next slide)
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
Manifestations
Hyperpigmentation
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:
Etiology
Slow Onset:
Abrupt Onset:

Pituitary tumor or surgery
or radiation

Postpartum pituitary necrosis
(Sheehan’s)

Craniopharyngioma


Isolated ACTH Deficiency

Megace
Necrosis or bleeding into a
pituitary macroadenoma
(hemorrhage into a pituitary
tumor=pit apoplexy)

Long-Term
Glucocorticoid Therapy

Head trauma, lesions of the
pituitary stalk

Sarcoidosis


Hypothalamic Tumor
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 - RESULTS
INTERPRETATION 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
Cortisol
_
feedback
+ACTH
Adrenal Glands
Diagnostic Algorithm for Adrenal Insufficiency
Rule In or Out AICheck Plasma Cortisol
<3
RULES IN
Adrenal Insufficiency
Between 3 and 18
Need
Dynamic Testing
>18
RULES OUT
** NO AI **
ACTH Stim Test
NORMAL Response
Cortisol > 18
RULES OUT
** NO AI **
SUBNORMAL
RESPONSE
** RULES IN AI **
Define Type
Plasma ACTH
HIGH> 100
DIAGNOSIS
LOW or NORMAL
** PRIMARY AI **
Secondary or Tertiary
Adrenal Insufficiency
CRH STIM Test
Exaggerated
and Prolonged
ACTH
Response
Absent or Subnormal
ACTH
Response
** TERTIARY AI **
** SECONDARY AI **
TREATMENT - Adrenal Crisis
Do 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
and

10mg PO qpm
(10mg) to decrease IOP
(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!

TREATMENT
Chronic 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].”
ProphylaxisSteroids 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

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
Arafah BM.
Hypothalamic
pituitary adrenal
function during
critical illness:
limitations of
current
assessment
methods.
JCEM 2006;
91:3725-3745
Overview of Adrenal Disorders
 Adrenal
Insufficiency
ACTH STIMULATION tests
 Cushing’s
Syndrome
Dexamethasone
SUPPRESSION tests
Primary Hyperaldosteronism
Clinical Findings



Hypertension
Muscle Symptoms (due to hypokalemia)
 cramping
 weakness
 periodic paralysis
Often few clinical findings at all
 often just suspected after lab
abnormalities are noted
Primary Hyperaldosteronism
Lab 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 Hyperaldosteronism
Laboratory Findings

CT scan of abdomen, attention adrenal
glands


18-OH corticosterone level


may find solitary adenoma or carcinoma
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 Hyperaldosteronism
Key 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 Hyperaldosteronism
Treatment

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


Spironolactone has long been the drug of choice … versus
Eplerenone is a newer more expensive alternative

competitive inhibition):
 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)
Pheochromocytoma
Clinical Findings
Classically: The Five P’s:
 Pain
 Headaches

Pallor

Palpitations


Pressure (hypertension)
Persipiration
 Orthostatic
hypotension from impaired arterial
and venous constriction responses
 Catecholamine
release
Pheochromocytoma
Clinical 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
NEVER
BIOPSY AN
ADRENAL
MASS
WITHOUT
RULING OUT
PHEO FIRST!!
Kronenberg, et al. Williams Textbook of Endocrinology. 2008
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
Pheochromocytoma
Key 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
Pheochromocytoma
Treatment
Pharmacologic

Alpha Adrenergic-Blockade first


phenoxybenzamine or shorter acting alpha blockers
Beta-blockade next if necessary

Never start before alpha-blockade


Calcium Channel Blockers


Unopposed alpha-receptor stimulation can lead to worsened
hypertensive crises
May be better tolerated than alpha-blockade
On reserve: can inhibit catecholamine synthesis
(Demser)
Pheochromocytoma
Treatment

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 cases
24 yo man with resistant HTN, short stature, history of
genitourinary surgeries as a child, low potassium.
Likely diagnosis?
Congenital Adrenal Hyperplasia (17-alpha hydroxylase deficiency)
Renin low, aldosterone low, deoxycorticosterone high
45 yo farmer who dips tobacco, has resistant HTN
with hypokalemia.
Licorice (glycyrrhizic acid) inhibits conversion of hydrocortisone to cortisone
Renin low, Aldosterone low
Pituitary/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)


Growth hormone (GH)


GnRH stimulates release of LH
Follicle-stimulating hormone (FSH)


TRH stimulates release of TSH
Luteinizing hormone (LH)


GHRH stimulates release of GH
Thyroid stimulating hormone (TSH)


CRH stimulates release of ACTH
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 Syndrome
Clinical 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 Syndrome
Diagnosis: 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)
Pituitary cases
32 yo woman with Cushingoid features. Serum K 4.0.
MRI: 0.8 cm pituitary mass. IPSS/Periphery ratio >2
Cushing’s disease (PITUITARY). ACTH < 200
Next Step ----> Surgery.
42 yo woman with Cushingoid features. Serum K 3.0. CT
chest: lung nodule. Nonsmoker. MRI pituitary: normal.
IPSS/Periphery ratio <2
ECTOPIC - Bronchial carcinoid. ACTH > 200.
IPSS/periphery ACTH ratio < 2
3. 69 yo man, smoker. Weight loss, hyperpigmentation, new
onset DM and HTN. No Cushingoid features. Serum K 2.3.
CT chest: RUL mass with adenopathies IPSS/Periphery
ratio <2. ACTH >200
ECTOPIC ACTH - Small cell lung cancer
Excess
ACTH
Insufficiency
GH
GH
Slow Onset
Sleep apnea
Carpal Tunnel
HTN/Diabetes
Colon polyps
Skin tags
Salt craving,
nausea, “vague
abdominal pain”,
Fever
HYPOGLYCEMIA
Weight loss
Pubertal hair loss
Young
Short stature
FSH/LH
TSH
FSH/LH
Cushing’s Disease
Slow onset
Classic phenotype
HTN/diabetes
osteoporosis
Skin thinning,
ecchymoses
Acromegaly
TSH
Rare.
Hyperthyroidism
with “normal” or
increased TSH
ACTH
Amazingly rare
Precocious
puberty
McCune Albright
Syndrome
Rare.
Hypothyroidism
with “normal” or
decreased TSH
Older
“Decreased
Vigor”
VERY COMMON
Hypogonadism
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)
Aside- complications
of pituitary radiation:

Hypopituitarism

Replacement for :

Secondary hypothyroidism

Do not follow TSH in secondary hypothyroidism

Secondary Hypogondism

GH deficiency



Low prolactin
supports
diagnosis

Can see
hypothyroidism
and adrenal
insufficiency

Can develop
years after
radiation
treatment
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…

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
Posterior-SIADH
Excess
ACTH
Insufficiency
GH
ACTH
GH
Slow Onset
Sleep apnea
Carpal Tunnel
HTN/Diabetes
Colon polyps
Skin tags
Salt craving,
nausea, “vague
abdominal pain”,
Fever
HYPOGLYCEMIA
Weight loss
Pubertal hair loss
Young
Short stature
FSH/LH
TSH
FSH/LH
Cushing’s Disease
Slow onset
Classic phenotype
HTN/diabetes
osteoporosis
Skin thinning,
ecchymoses
Acromegaly
TSH
Rare.
Hyperthyroidism
with “normal” or
increased TSH
Posterior-DI
Amazingly rare
Precocious
puberty
McCune Albright
Syndrome
Rare.
Hypothyroidism
with “normal” or
decreased TSH
Older
“Decreased
Vigor”
VERY COMMON
Hypogonadism
with atrophic
gonads and
“normal” or low
FSH/LH
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)


Pancreas


Prolactinoma, acromegaly, Cushing’s disease, other
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”
MEN 2B

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
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 Virilization
Etiology


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 Virilization
Etiology

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


Clinical history is important:

Menstrual irregularity (oligomenorrhea/amenorrhea)/ infertility



Oligoovulation, Hyperandrogenism, Polycystic ovaries
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 longterm health risks related to polycystic ovary
syndrome (PCOS). Hum Reprod 2004; 19:41.
Hirsutism and Virilization
PCOS 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 Virilization
Congenital Adrenal Hyperplasia
Enzymatic 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, βhCG/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
Secondary

Hyperprolactinemia

Absence of ovarian oocytes
and follicles

Anorexia nervosa

Turner syndrome 45X


46,XX and, rarely, 46,XY
Functional Hypothalamic
amenorrhea
Kallman syndrome

Congenital GnRH deficiency
with anomsia

Radiation

Chemotherapy

Autoimmune destruction of
ovaries (APS)


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


Rule out pituitary disease or primary
ovarian failure


Check hCG, prolactin, TSH
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
Male Hypogonadism
25 yo man with decreased libido, decreased testicular volume,
otherwise normal. AST/ALT elevated. Next Test?
Hemochromatosis - Iron saturation > 45 is quite suggestive.
May all see arthritis, risk for Type I DM.
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


Women


Small testicles, gynecomastia, low sperm count
Hirsutism, small breast, enlarged clitoris, deepening
voice
Both

HTN, increased CVD, acne, male-pattern baldness,
irritability, psychosis