So you had your surgery-

now what?
Theodore C. Friedman, M.D., Ph.D.
Professor of Medicine-Charles Drew University
Professor of Medicine-UCLA
Magic Foundation
Symposium on Cushing’s Syndrome
February 22, 2009
Las Vegas, NV
 Are you cured?
• Hard to tell
• In sustained pre-op hypercortisolism, normal
corticotrope cells are suppressed. Cure used to
be morning cortisol < 4 ug/dL
• When tumor is removed, ACTH and cortisol are
low post-op
• In episodic Cushing’s, this often doesn’t occur.
• I recommend 2 mg of dexamethasone on post-
op day 1, 1 mg on post-op day 2, no cortisol
replacement on days 3 and 4 and get a 8 am
cortisol, ACTH and electrolytes on day 5, and
start cortisol replacement right after blood draw.
 Are you cured?
• The lower the day 5 cortisol the
more likely the cure.
• Morning cortisol is often in the 10-
15 ug/dL range and patient is still
cured.
• Cortisol above 20 ug/dL or ACTH
above 30 are bad signs.
 Symptoms
• Cortisol levels drop from high to normal, leads to
relative glucocorticoid insufficiency
• Joint pains, abdominal pain, weakness, nausea,
vomiting, headache and “hit by a speeding truck”
are signs of relative low cortisol and good signs.
• Low sodium is common post-op and also gives
headache and nausea (measure sodium on day 5)
• Psychological and psychiatric symptoms
(depression, anxiety) may get worse after surgery
due to low brain CRH levels and patients (and
spouses) should be warned.
 Pathology
• Classic Cushing’s patients have clear tumors that stain for
ACTH.
• Crooke’s hyaline change occurs with sustained pre-op
hypercortisolism.
• Episodic patients may or may not be hypercortisolemic at
the time of surgery, so staining for ACTH may be negative
(tumor off)
• Tumors are often tiny and either discarded by suction or
missed by pathologist.
• I have never seen Crooke’s hyaline changes in any of my
patients
• Most of my patients have unclear or negative pathology in
spite of being cured.
• Several patients showed adrenal hyperplasia when they
went for adrenalectomy, yet had normal pituitary
pathology.
 Pathology-Hyperplasia
• Classic corticotrope hyperplasia was described in
Russia and involves the corticotrope cells in the whole
pituitary being enlarged and suggests an abundance of
CRH.
• What we see is a small pocket of ACTH-staining cells
that are larger than normal corticotrope cells, but not a
clear tumor.
• My guess is this is an early tumor.
• Often see multiple tumors connected by a barbell or an
octopus with 8 arms.
• In some cases, there is a tumor of ACTH-staining cells
on one side and hyperplasia adjacent to it.
• Patients with hyperplasia due worse, but can still be
cured with pituitary surgery.
 Cortisol replacement
• Cortisol levels go from high to either low or normal.
• If no replacement, potential for adrenal insufficiency, even if
cortisol levels are normal.
• I replace everyone, but taper off within first 3 months if no signs
of adrenal insufficiency.
• Hydrocortisone- generic, cortef- brand, many patients like
hydrocortisone better
• Body’s circadian rhythm has high cortisol in AM and low in
afternoon and evening, so want to mimic the body’s on rhythm.
• I give 15-20 mg in morning depending on size and 5 mg at
around 2 PM.
• I do not see any need for prednisone, dexamethasone or long-
lasting investigational cortisol preparations in patients on
temporary replacement.
 Cortisol replacement (2)
• I monitor 8 AM cortisol levels after holding hydrocortisone for 24
hrs (have patient skip afternoon dose the day before and take
morning dose after blood draw) every 3 months.
• Usually an AM cortisol level of > 10-12 ug/dL and no signs of
adrenal insufficiency would lead me to start a taper.
• Most cured patients can get off cortisol in 6-12 months.
• I taper HC down 2.5 mg to 5 mg every 2 weeks.
• I often get a morning cortisol level after taper, but usually don’t
restart if patient is doing well off it.
• Cosyntropin test works on adrenal cells atrophying and lags
behind serum cortisol levels- I do not find it more helpful than a
morning cortisol draw.
• I have some patients (especially those that had prior surgery) that
have undetectable morning cortisols a year after surgery, these
patients will need lifelong replacement.
 Cortisol replacement (3)
• I give subjects a script for solucortef in Act-O-vial 100
mg for IM injection, but almost never have seen
pituitary post-surgery patients need it
• I do not give adrenal bracelets.
• Double the dose of hydrocortisone if fever or
vomiting.
• If can not keep hydrocortisone down, double dose,
then give solucortef shot and go to ER
• Most patients do fine
 Other pituitary hormones
• Surgery can damage pituitary cells.
• High cortisol also suppresses pituitary function-cure
from Cushing’s can improve pituitary function
• Order of susceptibility of pituitary cells
o GH
o LH, FSH leading to low estradiol (irregular periods) and
testosterone
o TSH
o ACTH
o AVP
• At 3 months, I check IGF1, free T4, free T3, TSH,
testosterone
• If low IGF1, especially compared to pre-op, I do GH
stimulation testing- glucagon stimulation test
 Other pituitary hormones
• If low free T4 and lowish TSH, I often give
thyroid hormone replacement
• I often supplement testosterone with cream
from compounding pharmacy or enroll in my
hypopituitarism study (see end)
• If no periods after 1 year, I measure an FSH
and estradiol and replace estradiol with or
without progesterone.
 Diabetes Insipidus
• Posterior pituitary makes AVP (also
called ADH)
• Regulates free water, low AVP, DI-
polyuria and polydipsia and high serum
sodium
• High AVP-SIADH, low sodium-
headache, nausea
• 3 phases of sodium balance-1-3 days
post-op: DI, 5-10 days post-op: SIADH,
after 10 days: DI (rare)
 Diabetes Insipidus (2)

• 1st phase-in hospital often get

DDAVP, 2nd phase at home-fluid
restriction, but gets better on its own
• 3rd phase-May need DDAVP-often
given at night to prevent waking up at
night to urinate.
• Pill or nasal spray.
• Sometimes gets better on its own.
 Why would you be uncured?
• Part of the tumor left behind- a few cells or one arm of the
octopus

• Multiple tumors and only one removed.

• Incidentaloma removed, ACTH secreting tumor left behind

• Invasion outside of sella

• Misdiagnosed

• If uncured, taper off hydrocortisone, re-document

hypercortisolism and consider repeat surgery.
 Uncured-what do next
• Re-document hypercortisolism
• Reconfirm pituitary source
• Repeat pituitary MRI- “post operative changes” may
mean recurrent tumor
• If visible pituitary tumor, repeat surgery.
• If no visible tumor, consider ketoconazole (see next
lecture) to decrease cortisol synthesis.
• Consider repeat surgery, scraping the cells at the edge
of the tumor
• Consider adrenalectomy or radiation therapy
On to “Beyond pituitary surgery”
 Study
• Recruiting Women with Pituitary Problems
• Ages 18-55
• Location: Los Angeles

• To Receive Testosterone Replacement for 6 Months and

Evaluate Changes in Body Composition, Muscle Strength,
Thinking and Sexual function
• Patients May be Eligible for Growth Hormone

• Patients Will Be Compensated

• Please call Dr. Friedman or Dr. Zuckerbraun at 323-563-9385 or

email study@goodhormonehealth.com for more information or
to enroll.

• IRB approved