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 Cushing’s 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 < 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.

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 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.

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 • 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.

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 > 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.

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 Cushing’s 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”

17. 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