So you had your surgery-now what?

1
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 Cushings Syndrome
• February 22, 2009
• Las Vegas, NV

2
Are you cured?

• Hard to tell
• In sustained pre-op hypercortisolism, normal
  corticotrope cells are suppressed. Cure used to
  be morning cortisol lt 4 ug/dL
• When tumor is removed, ACTH and cortisol are low
  post-op
• In episodic Cushings, this often doesnt 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.

3
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.

4
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.

5
Pathology

• Classic Cushings patients have clear tumors that
  stain for ACTH.
• Crookes 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 Crookes 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.

6
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.

7
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
• Bodys circadian rhythm has high cortisol in AM
  and low in afternoon and evening, so want to
  mimic the bodys 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.

8
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 gt 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 dont 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.

9
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

10
Other pituitary hormones

• Surgery can damage pituitary cells.
• High cortisol also suppresses pituitary
  function-cure from Cushings can improve
  pituitary function
• Order of susceptibility of pituitary cells
• GH
• LH, FSH leading to low estradiol (irregular
  periods) and testosterone
• TSH
• ACTH
• AVP
• At 3 months, I check IGF1, freet4, free T3, TSH,
  testosterone
• If low IGF1, especially compared to pre-op, I do
  GH stimulation testing- glucagon stimulation test

11
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.

12
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)

13
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.

14
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 of hydrocortisone, re-document
  hypercortisolism and consider repeat surgery.

15
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, scrapping the cells at
  the edge of the tumor
• Consider adrenalectomy or radiation therapy

16
On to Beyond pituitary surgery

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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_at_goodhormonehealth.com
  for more information or to enroll.
• IRB approved