challenging pituitary cases -...

Challenging Pituitary Cases

Sue Samson, MD, PhD, FRCPC, FACE

Associate Professor of Medicine and Neurosurgery Medical Director Pituitary Center

Baylor College of Medicine, Houston TX

Tom Blevins, MD, FNLA, FACE, ECNU Texas Diabetes and Endocrinology

Austin, TX

42 y/o male In 2005 presented with facial “swelling” 24 hour ufc was 853 ug/day,

ACTH 187 and random cortisol was 44 ug/dl ◦ Chest CT and Octroscan-neg and 8mg overnight dex suppression-cortisol was 25 ug/dl ◦ Pituitary MRI unremarkable- ? Fullness on the L and IPSS lateralized to the L (MDA)

11/05 TPS, removal of L sided adenoma, cortisol to 1.2 ug/dl post op ◦ Post op MRI clear ◦ 4/07 ufc 317 ug/day and asymptomatic and 5/07—repeat TPS followed by persistent

hypercortisolism

8/07—stereotactic radiosurgery followed by ketoconazole ◦ 8/08- off ketoconazole and cortisols normal

2012-gradual recurrence of hypercortisolism (ufg 123 ug/day) and restarted ketoconazole ◦ LFT elevation on ketoconazole ◦ Trial of cabergoline --nausea and headache

What next?

Case of Recurrent Cushings Disease

Transsphenoidal surgery is the primary therapy in most patients, with remission rates of 65 to 90%

Relapse occurs in up to 30% of patients. ◦ Second-line options include the following: Repeat pituitary surgery Radiation therapy Bilateral adrenalectomy Medical therapy

Cushings Disease

Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline

Nieman et al, J Clin Endocrinol Metab, August 2015, 100(8):2807–2831

Somatostatin analog indicated for the treatment of adult

patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative

Pasireotide Indication

Glucocorticoid receptor blocker indicated to control

hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing’s syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery

Mifepristone Indication

2013-started Pasireotide 0.3mg bid and UFC was 12.7 ug/day ◦ 12/16 -On 0.5mg bid-no Cushing's sx. Ufc 35 ug/day. ◦ Glucose pre-pasireotide was 80-92 mg/dl and since then has ranged between 94

and 105 mg/dl fasting ◦ 4/17 -fbs was 105 with an A1c of 6.0%

Igf-1 was has ranged between 46 and 82 ng/ml on rx (55-177 ng/ml)

Recurrent Cushings Back to our patient

Binds with high affinity to 4 of the 5 somatostatin receptor subtypes (sst)- particularly high affinity for sst5

Pituitary corticotroph adenomas primarily express sst5

Pasireotide

Sst2-preferential somatostatin analogs (octreotide and lanreotide)-not effective in treating ACTH dependent hypercortisolism

sst1, sst2, and sst5 expressed on ◦ 100, 44, and 87% of Beta cells ◦ 26, 89, and 35% of Alpha cells

Double-blind, phase 3 study, 162 adults with Cushing’s disease and a UFC of at least 1.5 times ULN to receive subcutaneous pasireotide at a dose of 600 μg (82 patients)or 900 μg (80 patients) twice daily.

NEJM 366;10 March 8, 2012

Colao, et al. NEJM 366;10 March 8, 2012

Hyperglycemia-related events. ◦ Hyperglycemia (40%), diabetes mellitus (18%), increased HbA1c (11%), and type 2

diabetes mellitus (9%).

Increases in fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) were seen soon after initiation and were sustained during the treatment period.

A new antidiabetic medication was initiated in 74 of the 162 patients. ◦ In patients not receiving glucose-lowering medications at baseline, at least one

medication was started during the study in 53 of 129 patients (41%); 21 of 33 patients (64%) receiving antidiabetic medication at baseline received at least one additional agent

At one-month follow-up visits following discontinuation, mean FPG

and HbA1c levels decreased but remained above baseline values.

Pasireotide-Hyperglycemia and Diabetes

Colao, et al. NEJM 366;10 March 8, 2012

Hyperglycemia Associated With Pasireotide: Results From a Mechanistic Study in Healthy Volunteers

Henry et al, J Clin Endocrinol Metab, August 2013, 98(8):3446–3453

45 healthy male volunteers randomized to pasireotide 600 (n 19), 900 (n 19) sc twice a day for 7 days. An OGTT, a hyperglycemic clamp test, a hyperinsulinemic-euglycemic clamp test were performed on 3 consecutive days at baseline and treatment end

Henry et al, J Clin Endocrinol Metab, August 2013, 98(8):3446–3453

Back to our patient What would you do if his fbs was 134mg/dl and A1c was 7.5%

after starting pasireotide? A. Stop the med as having diabetes is worse than having

Cushing’s

B. Change to mifepristone

C. Suggest seeing a dietitian and exercising and starting a medication if necessary


Which med would you start for the hyperglycemia? a. Metformin and then an SGLT-2 if needed

b. A TZD since pasireotide causes insulin resistance

c. Metformin and then a DPP 4 inhibitor or GLP-RA

d. Insulin since oral meds have been proven to be

ineffective in this setting


Breitschaft et al. 2014. Diabetes Res Clinical Practice 103: 458-65

1 dose Pasireotide

Baseline

7 days Pasireotide

Metformin

Liraglutide

Vildigliptin

Nateglinide

Management of hyperglycemia associated with pasireotide: Healthy volunteer study

Vildagliptin and liraglutide were most effective in minimizing pasireotide-associated hyperglycemia in healthy volunteers

Managing hyperglycemia in patients with Cushing’s disease treated with pasireotide: medical expert recommendations

Colao et al, Pituitary (2014) 17:180–186

56 y/o female has a hx of Cushing's disease dxed in 2001--two TPS surgeries in 2002 and in 2006.

After a petrosal sinus sampling in 2014 which was not directional, she had repeat TPS in 5/14 and an adenoma was removed. Pre surgery UFC was high at 92.0 ug/day and total cortisol was 24.2, ACTH was 40.

Post op her 24 hour ufc was 54 ug/day (slightly elevated) and her am cortisol was 16.2.

Her 7/14- 24 hour ufc was 63.9 with an am cortisol of 25.4. Her 10/14 lab showed a 24 hour ufc of 66.7 mcg/24 hours and an ACTH of 26 and am cortisol of 22.4

She declined XRT and was placed on Pasireotide 0.6 mcg bid since late May 2015. (had h/a with cabergoline)

She had a 24 hour ufc of 16.2 in 11/16 and her am cortisol was 15.4. Her 24 hour ufc was 18.7 in 3/17

Her pre-pasireotide fbs was 98 mg/dl and her A1c was 5.8%. Her fbs rose to 128 mg/dl (SMBG 105-140mg/dl) and A1c to 7.2% after 6 months of pasireotide

She didn’t tolerate metformin and she had a minimal response to a DPP 4 med. She was placed on a GLP-1 RA in 2016 and her 3/17 fbs was 104mg/dl and her A1c was 6.4%.

Recurrent Cushings: Case 2

Would mifepristone have been a better choice for her?


Progesterone receptor antagonist that has glucocorticoid receptor antagonist activity at higher concentrations

More than three times the binding affinity for the glucocorticoid receptor than dexamethasone

It does not bind to the mineralocorticoid receptor

Mifepristone

Adrenal insufficiency: Monitor for signs and symptoms of AI Hypokalemia: Correct prior and monitor for during

treatment Vaginal bleeding and endometrial changes ◦ Use with caution if patient also has a hemorrhagic disorder or is on anti-

coagulant therapy QT interval prolongation: Avoid use with QT interval-

prolonging drugs Use of Strong CYP3A Inhibitors: Concomitant use can

increase mifepristone plasma levels ◦ Use only when necessary and limit mifepristone dose to 600 mg

Mifepristone-Warnings and Precautions

Fleseriu et al. J Clin Endocrinol Metab, June 2012, 97(6):2039–2049

24-wk multicenter, open-label trial after failed multimodality therapy 50 adults with endogenous CS associated with type 2 diabetes

mellitus/impaired glucose tolerance (C-DM) or a diagnosis of hypertension alone (C-HT).

Mifepristone was administered at doses of 300-1200 mg daily

Main Outcome Measures: ◦ Change in area under the curve for glucose on 2-h oral glucose test for C-DM ◦ Change in diastolic blood pressure from baseline to wk 24 for C-HT


During treatment, 72% of the 43 patients had at least a 2-fold increase in ACTH, cortisol, or both. ◦ These changes were observed early (by d 14), plateaued from wk 10–24, and declined to

baseline levels at the follow-up visit 6 wk after discontinuation of mifepristone. ◦ Late-night salivary cortisol increased 7.92-fold (1.43) at wk 16, and urinary free cortisol

increased 7.70-fold (15.29) at wk 24. ◦ At the 6-wk follow-up visit, ACTH and cortisol (serum and urine) declined to near baseline

levels. Twenty-two patients had a serum potassium level less than 3.5 mEq/liter,

but only three experienced severe hypokalemia <2.5 mEq/liter Mifepristone does not decrease cortisol production, measurement of this

hormone should not be performed during treatment


Significant decreases in plasma and fasting plasma glucose (P 0.03), as measured by OGTT from baseline to wk 24. The OGTT response curves at each visit were statistically different compared with baseline

AEs were reported in 88% of patients during mifepristone

treatment, ◦ Nausea (48%) ◦ fatigue (48%) ◦ headache (44%) ◦ decreased blood potassium (34%) ◦ arthralgia (30%) ◦ vomiting (26%) ◦ Peripheral edema (26%) ◦ HTN (24%) ◦ dizziness (22%) ◦ Decreased appetite (20%) ◦ endometrial thickening (20%)

Mifepristone-safety


Pituitary MRIs were obtained in 41patients; 17 had visible tumors, 10 of which were macroadenomas, and the remaining 24 did not have visible tumors after surgery.

MRIs were stable at wk 10 and 24 in all cases except one. This patient’s adenoma increased in size at wk 10, leading to treatment discontinuation.

Mifepristone


The Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing’s Syndrome (SEISMIC) was a 24-week, open-label study of mifepristone,

Long-term extension (LTE) is a multicenter U.S. study.

43 CD patients were enrolled in SEISMIC with 27 continuing into the LTE study.

Fleseriu et al. J Clin Endocrinol Metab, October 2014, 99(10):3718–3727

Changes in ACTH Levels and Corticotroph Tumor Size – LTE Mifepristone

Fleseriu et al. J Clin Endocrinol Metab, October 2014, 99(10):3718–3727

35 y/o with Cushings disease diagnosed in 2009. She had transphenoidal resection in 2009, 2013 and most recently again in 2016. Her first 2 surgeries were performed in Austin, her most recent surgery UTSW in Dallas.

Labs in 2017 show biochemical evidence for persistent Cushing's (UFC and salivary cortisol)

Radiation is being considered.

She takes desmopressin for DI and T4 hypothyroidism.

Baseline weight was 175 lbs, she is now 380 lbs

She has IGT, a recent HgA1C was 6.1%--acanthosis nigricans on exam. Her recent fasting glucose was 96 mg/dl ◦ She is on metformin

She has infertility. She is seeing a Reproductive Endocrinologist and has findings consistent with secondary hypogonadism. She is interested in fertility and is currently on an OCP


a) Start cabergoline b) Start mifepristone c) Start pasireotide d) IPSS and consider another surgery e) Send her to see Dr Samsom

What is the next step?

Challenging Pituitary cases Susan L Samson MD PhD FRCPC FACE

Associate Professor of Medicine and Neurosurgery Medical Director Pituitary Center

Baylor College of Medicine, Houston TX

Cushing’s: When all else fails…

• 64 yo female – Presented Jan 2017 to outside clinic to establish

care – Had had mild weight gain (went on Weight

watchers and lost 10 lbs) – Increased BP and started on lisinopril – “No specific complaints” – Routine bloodwork

• Na 145/K 3.1/Glucose 154 mg/dl

Cushing’s: When all else fails… • Repeat blood work 4 weeks later

– Na 145 – K+ <2 – Glucose 242 mg/dl – Cortisol 110 mcg/dl, ACTH 162 pg/ml – Started on spironolactone 50 mg, KCL 40 meq twice a day,

metformin • Referred to Endocrinologist who documented

– No history of rapid weight gain – Muscle weakness and easy bruising – Mild facial rounding, mildly increased dorsal cervical and supraclavicular

fat pads – No abdominal striae – Bruise on leg from a fall – Bilateral pedal edema, 2+ – Normal mood and affect

Cushing’s: When all else fails… • Repeat blood work 4 weeks later

– Na 145/K <2/Glucose 242 mg/dl – Cortisol 110 mcg/dl, ACTH 162 pg/ml – Started on spironolactone 50 mg, KCL 40 meq twice a day,

metformin • Referred to Endocrinologist who documented

– No history of rapid weight gain – Muscle weakness and easy bruising – Mild facial rounding, mildly increased dorsal cervical and

supraclavicular fat pads – No abdominal striae – Bruise on leg from a fall – Bilateral pedal edema, 2+ – Normal mood and affect

• UFC 13000

Pituitary MRI

Suspected right-sided subtle pituitary microadenoma maximal transverse dimension 4 mm seen only on dynamic

Cushing’s: When all else fails…

• Referred to the Pituitary Center

IPSS Minutes post-CRH

ACTH -5 0 1 3 5 10 15 20

Peripheral pg/mL 84 109 167 106 115 44 108 78

Right pg/mL 185 119 124 188 201 223 112 141

Left pg/mL 113 167 162 151 156 158 131 170

What next?

• The search for ectopic sources

Chest CT

• 1 x 1.3 cm nodule is seen in the left lung base • 7 mm calcified granuloma is seen in the right lower lobe

1.6 cm hypodense lesion in pancreatic tail

Abdominal CT

Octreotide Scan

Tracer distribution is physiological. Bilateral pleural effusions.

PET Scan

• Chest: – Within the right upper lobe there is a

hypermetabolic nodule measuring 18 x 9 mm with maximal SUV of 3.31

– Within the right lung apex there is a somewhat nodular area measuring 13 x 6 mm, with maximal SUV of 1.63

Work-up interrupted….

• 4/7 to 4/26/2017 – Perforated bowel from diverticulitis – Sigmoid colectomy with colostomy

• 5/2/2017 – Readmitted from SNF for shortness of breath – Required intubation and ICU care – Trach

PET Scan

• Chest: – Within the right upper lobe there is a

hypermetabolic nodule measuring 18 x 9 mm with maximal SUV of 3.31

– Within the right lung apex there is a somewhat nodular area measuring 13 x 6 mm, with maximal SUV of 1.63

Still looking….

• FNA by bronchoscopy – Small fragments of bronchial epithelium – Negative for malignancy – Addendum: rare fungal hyphae elements

• 1 out of 4 media Aspergillus fumigatus

1.6 cm hypodense lesion in pancreatic tail

Steroidogenesis inhibitors (adrenostatic) • Ketoconazole

• Multiple steps in cortisol synthesis • EMA/FDA 2013 black box warning

re: liver failure • Cushing’s is off-label

• Etomidate • Multiple steps in cortisol synthesis • ICU monitoring

• Metyrapone • 11-β-hydroxylase inhibitor • approved as a “diagnostic agent” • Have to contact the distributer for

special allocation • Cushing’s is off-label

• Mitotane (adrenolytic) • Multiple steps in cortisol

synthesis Adrenalectomy risk of Nelson’s

Radiation • fractionated external beam or

stereotactic radiosurgery • cure in 50-60% of good candidates but

requires years for full effect

Cabergoline • Targeting ACTH secretion at the level of

the adenoma • Not FDA approved for this indication • A subset of patients with mild-moderate

CD

Cushing’s: When all else fails….

Ketoconazole 200 mg BID

Voriconazole

Metyrapone 250 mg q6h

Intubation Ketoconazole 200 mg BID

Ketoconazole 400 mg BID

Ketoconazole Etomidate 3 mg/h





CT Abdomen

April 10, 2017 Feb 22, 2017

Pathology

• "right adrenal" consists of a 35 gm adrenalectomy measuring 6.6 x 4.5 x 1.5 cm.

• "left adrenal" consists of a 47 gm adrenalectomy measuring 7 x 4 x 2 cm.

• adrenal gland to be mottled, red-brown, green-yellow discoloration with no distinct mass seen.

• Scattered extramedullary hematopoiesis is seen in the adrenal parenchyma.

• Focal nuclear atypia are seen in the hyperplastic adrenocortical tissue.

• No definitive mass or malignancy is seen.

Cushing’s: when all else fails

• 6/26/2017 – Discharged to rehabilitation at SNF – Currently on maintenance dose hydrocortisone

and fludrocortisone.

Where do we go from here? • Could normalization of cortisol

help to manifest an elusive ectopic tumor? – 7-27% are remain occult after all

imaging modalities explored – Cortisol effects on SSTR

expression? – Removal of cortisol “feedback”

on tumor?

Tyrrell et al. 1975. JCEM 40: 1125-1127. Lamberts et al. 1989. Acta Endocrinologica 120: 760-766 De Bruins et al. 2012. Mifepristone effects on Tumor somatostatin receptor expression….. JCEM 97:455-462 %

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Where do we go from here?

• 68Ga-DOTATATE (DOTA-DPhe1,Tyr3-octreotate) approval by the U.S. Food and Drug in 2016 – NETSPOT® (SSTR Gallium 68 DOTATATE PET/CT

imaging) now included in the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology version 2017 update for the evaluation of neuroendocrine tumors

• Meta-analysis of 14 studies – SSTR PET/CT after Octreotide scanning led to a

change in management in 39% of patients

Barrio et al. 2017 . J. Nucl. Med. 58(5):756-761.

Isidori et al. 2015. Conventional and Nuclear Medicine Imaging in Ectopic Cushing's Syndrome: A Systematic Review.J Clin Endocrinol Metab. 2015;100(9):3231-3244..2015-158

68Gallium-SSTR-PET/CT had 100% sensitivity among covert cases

• Octreotide is

ineffective for patients with Cushing’s disease (known since the ‘90s)

Tyrrell et al. 1975. JCEM 40: 1125-1127. Lamberts et al. 1989. Acta Endocrinologica 120: 760-766.

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Refractory Acromegaly • 53 yo teacher from Colorado

– Increased ring size (up by 5 sizes)---prior to dx, now stable – Increased shoe size 8 >>> 11--prior to dx, now stable – Carpal Tunnel Syndrome- stable – Skin Tags – Hair Loss – Snoring and diagnosis of sleep apnea – Enlarged tongue and difficulty with speech – Loss of menstrual cycles 6 years previous. – Knee pain – Uncontrolled diabetes on 180 units insulin per day (HbA1C

9%)

• 53 yo teacher from Colorado – Increased ring size (up by 2 sizes)---prior to dx, now stable – Increased shoe size 8 >>> 11--prior to dx, now stable – Carpal Tunnel Syndrome- stable – Skin Tags – Hair Loss – Snoring and diagnosis of sleep apnea – Enlarged tongue and difficulty with speech – Loss of menstrual cycles 6 years previous. – Knee pain – Uncontrolled diabetes on 180 units insulin per day (HbA1C

9%)

Pre-op

Very Vascular tumor

MRI FINDINGS: There is a lobulated, noncystic, diffusion restricted sellar based mass with negligible peripheral enhancement that measures 3.2 cm AP x 2.9 cm transverse x 3.5 cm craniocaudal. The mass extends superiorly to splay and thin the optic chiasm. The mass invades the left cavernous sinus. The mass remodels the floor of the sella turcica, with encroachment into the left greater than right sphenoid sinuses. The mass extends posteriorly to contact the left mammillary body and partially efface the interpeduncular and superior prepontine cisterns. The mass encircles, but does not compress, the left carotid siphon and P1 segment left posterior cerebral artery, which has a fetal origin. The mass partially encircles, but does not compress, the supraclinoid right internal carotid and distal basilar arteries. The native pituitary gland is displaced to the right, lying over the superior margin of the cavernous segment right internal carotid artery. The infundibulum is thinned and draped over the right superolateral margin of the tumor.

• Dr. Yoshor (NSx) conveyed that there was a lot of involvement of the tumor around vascular structures including a posterior communicating artery which required caution rather than an aggressive resection. The pathology also was unique and with co-staining for GH and PRL and there was neuronal metaplasia.

MICROSCOPIC DIAGNOSIS: PITUITARY GLAND, TRANSSPHENOIDAL HYPOPHYSECTOMY (SPECIMEN #1): MIXED SOMATOTROPHIC AND PROLACTIN CELL ADENOMA WITH NEURONAL METAPLASIA PITUITARY GLAND, TRANSSPHENOIDAL HYPOPHYSECTOMY (SPECIMEN #3): MIXED SOMATOTROPHIC AND PROLACTIN CELL ADENOMA WITH NEURONAL METAPLASIA SMALL FRAGMENT OF ADENOHYPOPHYSIS Comment: The tumor cells are positive for growth hormone and prolactin, including the metaplastic neuronal component. Some of the neuronal component is also positive for epithelial markers (Cam 5.2 and pan-cytokeratin). Tumor is negative for GFAP and EMA. Stains for TSH, LH, FSH, p53, and ACTH are negative in tumor. Both neuropil and neurons are strongly positive for neurofilament. MIB-1 labeling index is less than 1%.

Post-op 1 month

Sandret L et al. JCEM 2011;96:1327-1335

Cabergoline and Acromegaly: a Meta-analysis

• IGF-I levels during treatment with somatostatin analogs alone and after cabergoline addition

• 5 studies • 52% achieved normal IGF-I

levels • The change in IGF-I was

related to – baseline IGF-I level – not to the dose of

cabergoline, the duration of treatment, or the baseline prolactin concentration.

1 month 6 months

Post-op

1 month 6 months

1 month 3 years

3 years 1 month

3 years

• Pasireotide increases hyperglycemic evens or worsens glycemic control for patients without diabetes/IGT/diabetes on oral medications

• BUT….for insulin dependent patients, decreased insulin requirements over time (down from 180 units to 40 units per day with episodes of hypoglycemia and improved HbA1C).

Ref. Range 3/4/2014 11:12

6/3/2014 11:40

9/16/2014 11:44

11/3/2015 15:00

6/7/2016 11:32

HbA1C Latest Ref Range: 4.0 - 5.6 %

9.0 (H) 8.1 (H) 7.5 (H) 7.9 (H) 7.6 (H)

Cushing’s Recurrence

• 38 yo presented with weight gain, diabetes and hypertension and found to have ACTH dependent CS in 2005

• 6 mm adenoma left gland

Case: EG

• TSR 2006 and went into remission • HbA1C normalized off of medication • Did not require BP meds

Case: EG

• 2011 had increased BP and re-diagnosed with Dm2 • described similar symptoms to her initial

presentation • Second TSR 2012 of 5 mm area on left side

Case: EG

• Post-op, mild decrease in ACTH/cortisol but not in remission

• Worsening symptoms and cortisol levels over the next 6 months

Case: EG

• MRI of the sella at 3 months did not reveal any visible disease treatable by surgery or radiosurgery

• Ketoconazole resulted in elevated liver enzymes which normalized off of the medication

Case: EG

• MRI of the sella at 3 months did not reveal any visible disease treatable by surgery or radiosurgery

• Ketoconazole resulted in elevated liver enzymes which normalized off of the medication

What are our Medical options for her?

Case: EG

• Started on 300 mg Mifepristone • K+ 3.9 at 2 weeks, 3.5 at 4 weeks • Added PO K+ and titrated up to 600 mg • Patient called to say her legs were swollen….

And she had a dark rash….

• Peripheral edema • Hypokalemia /Alkalosis

– K+ usually 2.5-3.5 (occasionally <2.5)

• Increased BP (12/40 of all with HTN baseline)

SEISMIC: AEs


• Peripheral edema • Hypokalemia /Alkalosis

– K+ usually 2.5-3.5 (occasionally <2.5)

• Increased BP (12/40 of all with HTN baseline) • Action of cortisol at the aldosterone receptor

as it overwhelms 11-β-HSD • Treated with spironolactone • Titrated to 900 mg

SEISMIC: AEs


Case: EG

Baseline 1 month 6 months

Cortisol (mcg/dl) 15.3 23.6 30.7

ACTH (pg.ml) 62 117 178

SEISMIC LTE: Tumor Size Baseline Progressed

>2 mm Stable (not visible or same size)

Regressed

Non-visible 20 1 (4 mm) 19 --

Micro 9 0 8 1

Macro 7 3* 3 1

Fleseriu et al. J Clin Endocrinol Metab, 2014, 99:3718-27.

N = 36, 12 to >30 months of therapy *Cavernous sinus invasion, 2 with radiation In the core, one patient discontinued due to growth which manifested at 10 weeks

Case:EG

• Call from ER that patient is there with nausea and vomiting and fever….

SEISMIC: AEs • 88% of patients

– Nausea (48%) – Fatigue (48%) – Headache (44%) – Low BP (34%) – Arthralgia (30%) – Vomiting (26%) – Peripheral edema (26%) – HTN (24%) – Dizziness (22%) – Decreased appetite (20% – Endometrial thickening (20%)

SEISMIC: AEs • 88% of patients

– Nausea (48%) – Fatigue (48%) – Headache (44%) – Low BP (34%) – Arthralgia (30%) – Vomiting (26%) – Peripheral edema (26%) – HTN (24%) – Dizziness (22%) – Decreased appetite (20%) – Endometrial thickening (20%)

• Clinical adrenal insufficiency – reported in two patients and symptoms consistent

with AI in five instances • Withdraw mifepristone • Administer moderate dose dexamethasone (2-4 mg q6-

12h) because need to overcome the high affinity of M for the receptor (hydrocortisone won’t help you).

SEISMIC: AEs


Case: EG

• Call from ER that patient is there with nausea and vomiting and fever….

• Mifepristone stopped and Dex 2 mg BID administered for 5 days

• Rapid flu test positive • Mifepristone re-instated

Case:EG

• Weight loss • Increased exercise tolerance • HbA1C 8.3% to 7.2% • Improved “wellness”

• Endometrial effects – Vaginal bleeding in premenopausal women (5) – Endometrial thickening was reported as an AE in

10 women – Three women underwent dilatation and curettage

for unresolved endometrial thickening. – Prolonged metrorrhagia in two of them after

discontinuing mifepristone

• Not thought to be a precancerous condition

SEISMIC: AEs


Why E.G? Mifepristone

Positive Considerations – Is a fast clinical

response needed? (e.g. surgery, procedure)

– Hyperglycemia/Dm2

Negative considerations – Reproductive/menstrual

status? – Adherence to

medications/visits (K+, etc.)

– Tumor volume/aggressiveness

Acknowledgements Daniel Yoshor MD Mas Takashima MD Steve Carpenter MD Sherly Sebastian NP Baylor St. Luke’s Medical Center

challenging pituitary cases -...

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