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Neuroendocrine and Pituitary
Tumor Clinical Center (NEPTCC) Bulletin

Winter 2020/2021 | Volume 26, Issue 1

Journal Club: Review of Levoketoconazole and Osilodrostat in the Treatment of Cushing’s Syndrome

Dr. Allison Kimball

Cushing’s syndrome is a serious condition characterized by cortisol excess and associated with increased mortality, primarily related to cardiovascular disease (1, 2). The most common source of cortisol overproduction is a pituitary adenoma (Cushing’s disease). Medical treatment is indicated for persistent or recurrent hypercortisolism following surgery, estimated to occur in one third of patients (3), or when surgery or radiation are contraindicated. Although several medications with different mechanisms of action are available, Cushing’s syndrome is difficult to treat. Additional effective and well-tolerated medications are needed.

Results from phase 3 trials studying the efficacy and safety of two new pharmacologic treatments for Cushing’s syndrome, levoketoconazole and osilodrostat, were recently published (4, 5), and a review of these studies follows.

SONICS (levoketoconazole)

Ketoconazole (a racemic mixture of the enantiomers 2S,4R-ketoconazole and 2R,4S-ketoconazole) inhibits several enzymes involved in adrenal steroidogenesis, leading to decreased cortisol production. It is not FDA-approved for the treatment of Cushing’s syndrome in the US, although it is used off-label for this purpose. Important considerations are drug-drug interactions and side effects, and there is a black box warning for rare liver toxicity, which advises monitoring of liver function tests. While efficacy of ketoconazole has been established by retrospective and observational data, it has never been studied in a prospective clinical trial. The 2S,4R enantiomer of ketoconazole, levoketoconazole, is about twice as potent in vitro in inhibiting enzymes such as 17α-hydroxylase and 11β-hydroxylase, which makes it a promising pharmacologic treatment option (6).

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Role of Growth Hormone in Nonalcoholic Fatty Liver Disease (NAFLD)

Lindsay T. Fourman, MDNonalcoholic fatty liver disease (NAFLD) is a common disorder.

Characterized by hepatocellular triglyceride accumulation in the absence of significant alcohol consumption, NAFLD is the most common liver disease in the U.S., with an estimated prevalence of 30% (1). NAFLD is associated with obesity and metabolic syndrome, and is an independent risk factor for coronary artery disease. NAFLD also may progress to cirrhosis or hepatocellular carcinoma, and is expected to surpass hepatitis C as the principal indication for liver transplantation within the next decade (2). Despite its growing threat to public health, the pathogenesis and effective management of NAFLD remain poorly understood. There also is no approved pharmacologic intervention for NAFLD with treatment recommendations focused on lifestyle modification, which may be difficult to achieve (3).

Growth hormone deficiency plays a role in NAFLD pathogenesis.

Pituitary growth hormone (GH) deficiency is characterized by enhanced visceral adiposity, reduced lean body mass, and dyslipidemia. Recent evidence also suggests that GH deficiency is a risk factor for NAFLD. In one case-control study, the prevalence of NAFLD was a striking 77% among consecutive patients with GH deficiency, which constituted a 6.4-fold increase compared to controls matched for age, sex, and BMI. Notably, in this study, treatment of a small subset of these individuals with GH led to a reduction in steatosis and fibrosis on liver biopsy (4). Relatedly, mice with liver-specific knockout of the GH receptor demonstrated increased liver fat and inflammation. These mice further demonstrated significant perturbations in lipid metabolism as characterized by upregulation of genes involved in hepatic lipid uptake and de novo lipogenesis. In this prior study, restoration of hepatic insulin-like growth factor 1 (IGF-1) expression only partially reversed the NAFLD phenotype, suggesting contributions of both components of the GH/IGF-1 axis to the pathogenesis of this disease (5).

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Announcement on Zervas Lectureship

Save the Date
Special Lecture

22nd Annual Nicholas T. Zervas, M.D. Lectureship Massachusetts General Hospital

*Virtual Event*
Tuesday, May 19, 2021 at 12pm

Maria Fleseriu, M.D, FACE
Professor of Medicine and Neurological Surgery and Director of the Northwest Pituitary Center at Oregon Health and Science University in Portland, Oregon

For further information call Philip at 617-726-3870


Maria Fleseriu

Clinical Endocrinology: 2022

Save the Date!



April 6 – April 10, 2022

For nearly 50 years this course has provided practicing endocrinologists and other healthcare providers with a comprehensive review and update of recent literature in clinical endocrinology. The faculty consists of staff endocrinologists at the Massachusetts General Hospital and Harvard Medical School as well as nationally-renowned guest lecturers, all selected for their teaching and clinical skills. A comprehensive syllabus is provided.

For additional information contact
Harvard Medical School
Department of Continuing Education

By mail
Harvard MED-CME
P.O. Box 825
Boston, MA 02117-0825

By telephone

On-line registration and program information will be available fall 2021; to be added to the mailing list before that, send a message to Course Administrator Melissa Machado at and 617-726-3270.

Potts Mentoring Award Announcement

Dr. Karen K. MillerDr. Karen K. Miller

On January 26th, 2021, Dr. Karen K. Miller, Chief of the MGH Neuroendocrine Unit, was honored with the MGH John T. Potts, Jr., MD Faculty Mentoring Award at the MGH Celebration of Mentoring event. The MGH Center for Faculty Development created the annual Award in 2011 to recognize a senior faculty member who has contributed to the success of junior faculty members and trainees. In accepting the award, Dr. Miller thanked those who had nominated her and her mentor, Dr. Anne Klibanski, former Chief of the MGH Neuroendocrine Unit and current President and CEO of Mass General Brigham, “who modeled mentoring so beautifully.” She added, “The real gift is to have had the honor to mentor and co-mentor so many talented and hardworking individuals…to be a part, however small, of their great work and to be entrusted with their careers.”

Research Studies Available

The Neuroendocrine and Pituitary Tumor Clinical Center is involved in many different research studies. Types of studies and enrollment status changes frequently, so please call our office (617-726-3870) or search from a list of clinical studies (

Welcoming Our New Staff Members

Dr. Allison Kimball Dr. Allison Kimball

Dr. Allison Kimball earned her medical degree at Boston University School of Medicine. She completed her Internal Medicine residency training at Beth Israel Deaconess Medical Center and her Endocrinology fellowship training at Massachusetts General Hospital. Dr. Kimball is the Assistant Clinical Director of the MGH Neuroendocrine and Pituitary Tumor Clinical Center, where she sees patients with neuroendocrine and pituitary disorders. She also sees patients with diabetes at the MGH Diabetes Center and provides endocrine consultations on patients hospitalized at MGH. She has a focus in medical education, teaching medical students at Harvard Medical School and residents and other trainees at MGH. Dr. Kimball additionally performs clinical research in the MGH Neuroendocrine Unit.



Dr. Armen YerevanianDr. Armen Yerevanian

Dr. Armen Yerevanian earned his medical degree at Case Western Reserve University School of Medicine. He completed internal medicine residency at Harbor-UCLA Medical Center where he also served as chief resident. His fellowship in Endocrinology, Diabetes and Metabolism was conducted at Massachusetts General Hospital. He currently sees patients in the MGH Neuroendocrine and Pituitary Tumor Clinical Center as well as the MGH Diabetes Center. His research interests involve the hormonal regulation of adipose tissue and metabolism.