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 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 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 > 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 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

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 of 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, scrapping 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 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 or for more information or to enroll. IRB approved