Category: Pituitary Disorders/Neuroendocrinology

Monitor: 4

4 - SECONDARY ADRENAL INSUFFICIENCY DUE TO THE IMMUNE CHECKPOINT INHIBITOR PEMBROLIZUMAB

Saturday, Apr 27
10:00 AM – 10:30 AM

Objective :

A 53 year old male received pembrolizumab (Keytruda), an immune checkpoint inhibitor, for metastatic melanoma.  He tolerated eleven cycles of treatment well but experienced unusual fatigue, anorexia, and unintentional weight loss after the twelfth treatment cycle.  An 8 AM cortisol level was marginal at 4 mg/dL, prompting a standard ACTH stimulation test that was notable for 30 and 60 min cortisol levels of 12.2 μg/dL and 14.1 μg/dL, respectively (expected ≥ 18 μg/dL).  Given the patient’s symptoms, ACTH stimulation test results, and treatment with pembrolizumab, a diagnosis of secondary adrenal insufficiency was made.  Evaluation for other anterior pituitary deficits was unremarkable, and no anatomic abnormalities of the pituitary gland were observed on MRI.  The patient’s symptoms completely resolved after starting prednisone 5 mg daily.


Methods : NA


Results : NA


Discussion :

Pembrolizumab is a monoclonal antibody that inhibits the programmed cell death receptor 1 (PD-1) and augments T-cell antitumor activity.  The other class of immune checkpoint inhibitors, monoclonal antibodies to cytotoxic T-lymphocyte antigen 4 (CTLA-4), cause hypophysitis and anterior pituitary dysfunction in approximately 10% of patients, but hypophysitis during treatment with anti-PD-1 receptor antibodies is rare and occurs in < 1% of patients.  In the 15 cases of anti-PD-1 receptor antibody induced pituitary injury published to date, most patients experienced isolated secondary adrenal insufficiency with no abnormalities on pituitary imaging as in this patient’s case.  The presumed mechanism of corticotroph injury is lymphocytic hypophysitis; however, unlike spontaneous and anti-CTLA-4 induced hypophysitis, pituitary enlargement on MRI is uncommon.  There is a male predominance to hypophysitis occurring in patients treated with anti-PD-1 antibodies or anti-CTLA-4 antibodies, while spontaneous lymphocytic hypophysitis has a strong female predominance.  Unfortunately, loss of corticotroph function persists after stopping pembrolizumab.  Treatment with glucocorticoids is indicated and should result in prompt symptomatic relief.     


Conclusion : Though it is rare, secondary adrenal insufficiency should be investigated in patients treated with anti-PD-1 receptor antibodies who develop provocative symptoms.  Evaluation for panhypopituitarism and pituitary imaging are indicated, but the majority of patients will have isolated loss of corticotroph function and no anatomic pituitary abnormalities.  Prompt diagnosis is key to timely treatment with exogenous glucocorticoids.

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Mohammad J. Ansari

Endocrinology Fellow
Division of Endocrinology, SIU School of Medicine
Springfield, Illinois

I am a graduate of Frontier Medical and Dental College in Pakistan. I completed internal medicine residency at Jersey Shore University Medical Center (Perth Amboy, NJ). I am currently a first year fellow in the SIU School of Medicine Division of Endocrinology (Springfield, IL).

Ula Tarabichi

Internal Medicine Resident Physician
Department of Medicine, SIU School of Medicine

Dr. Ula Tarabichi is is a third year internal medicine resident at the SIU School of Medicine, and she intends to apply for fellowship training in endocrinology.

Hadoun Jabri

Assistant Professor of Medicine
Division of Endocrinology, SIU School of Medicine

Dr. Jabri is an Assistant Professor of Medicine and Associate Fellowship Program Director in the SIU Division of Endocrinology.

Qiang Nai

Associate Professor
Massachusetts General Cancer Center

Dr. Nai is a an associate professor who works at Massachusetts General Cancer Center.

Anis Rehman

Assistant Professor of Medicine
Division of Endocrinology, SIU School of Medicine

Dr. Anis Rehman is an Assistant Professor of Medicine in the SIU School of Medicine Division of Endocrinology.

Michael Jakoby

Associate Professor of Medicine and Chief
Division of Endocrinology, SIU School of Medicine
Springfield, Illinois

Dr. Jakoby is the Division Chief and an Associate Professor of Medicine in the SIU School of Medicine Division of Endocrinology.

Mohammad J. Ansari

Endocrinology Fellow
Division of Endocrinology, SIU School of Medicine
Springfield, Illinois

I am a graduate of Frontier Medical and Dental College in Pakistan. I completed internal medicine residency at Jersey Shore University Medical Center (Perth Amboy, NJ). I am currently a first year fellow in the SIU School of Medicine Division of Endocrinology (Springfield, IL).