Management of Cushing Disease After Transsphenoidal Surgery

Radiation therapy can be administered if there is a clear target on imaging that is not surgically approachable. However, radiation therapy is unsuccessful in a significant portion of cases and it may take up to 10 years for success to be achieved.6 In addition, bilateral adrenalectomy may be used, but this is often utilized in patients with more advanced disease or with significant illness such as severe infections or malignancy.  

Dr Fleseriu: Recurrence after surgery poses a diagnostic challenge, especially early in the course of returning hypercortisolemia. The first test to reveal abnormal results is usually a late-night salivary cortisol measure. However, there are limitations related to assay performance as well as individual patient variability. Dexamethasone suppression tests and 24-hour urine free cortisol results are next to reveal abnormal results. Once confirmed, there are several second-line treatments: medical therapy, repeat surgery, radiation, and bilateral adrenalectomy.

Radiation therapy is used when pituitary surgery is unsuccessful, in invasive adenomas, or in poor surgical candidates, mostly after medical therapy fails. However, while awaiting radiation effects, which may take several years, patients should receive medication to decrease cortisol.

Bilateral adrenalectomy is usually reserved as a third-line treatment option in patients with uncontrolled hypercortisolemia despite pituitary surgery, medical therapy, and/or pituitary radiation. It can be lifesaving in patients with severe and prolonged Cushing syndrome who require rapid and permanent control of hypercortisolism. Furthermore, it is of interest in patients desiring fertility in whom pituitary irradiation or surgery is likely to result in irreversible hypogonadism.

Endocrinology Advisor: What are additional recommendations for clinicians regarding the management of these patients? 

Dr Tritos: Early recognition of Cushing disease and appropriate, prompt referral of these patients to experienced neurosurgeons in specialist centers are very important aspects of care. In addition, it is critical to address and manage comorbidities associated with Cushing disease, such as hypertension, diabetes mellitus, depression, osteoporosis, cardiovascular disease, infection, and others, in consultation with appropriate specialists.

Dr Katznelson: The best first step for therapy is to choose a neurosurgeon who is experienced in pituitary surgery, as surgical outcomes are clearly better with more experienced pituitary neurosurgeons. Probably the best recommendation is to be aware of appropriate biochemical testing to confirm the initial diagnosis of Cushing disease, as many patients undergo unnecessary surgery. An initial clear-cut diagnosis, as well as an appropriate postoperative assessment, are essential for the care of these patients.

Dr Fleseriu: Over the last decade, there has been renewed focus on complications of Cushing disease, including hypercoagulability, hypertension, and decreased quality of life. We have shown in a metanalysis this year that Cushing is associated with significantly increased odds of venous thromboembolism — almost 18 times higher — compared with the general population.7 How to prevent these events is still unclear.

As many ACTH-secreting pituitary adenomas are small and not visible on regular gadolinium magnetic resonance imaging (MRI), other options, including 11C-methionine positron emission tomography-computed tomography (PET-CT)/spoiled gradient recalled (SPGR) MRI, could be potentially important additions to the clinician’s armamentarium. Utility of Gallium-68 Dotatate scan in localizing ectopic tumors is helpful in some, but not all, cases.8

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Management of Cushing disease often requires multiple treatment modalities to achieve rapid and durable remission, which has been shown to improve morbidity, mortality, and quality of life. Treatment should be individualized based on type of tumor, availability of each therapeutic option, and patient preference.

Endocrinology Advisor: What are the remaining needs in this area in terms of research or otherwise? 

Dr Tritos: Cushing disease is still associated with substantial long-term morbidity and mortality. Although there have been remarkable advances in the care of these patients, there is a lot that remains to be done. Our diagnostic and imaging studies have improved but are still imperfect and need to be further refined. Recurrence of hypercortisolism is common and often presents a difficult management problem. Even patients who are in remission frequently experience residual symptoms and comorbidities requiring close collaboration between appropriate subspecialists. The evolving concept and eventual establishment of Pituitary Tumor Centers of Excellence may help to advance patient care and outcomes.9

Dr Katznelson: Although we have several medications available for use, there is a need for novel therapies with enhanced targeting of the underlying tumor, resulting in higher rates of tumor control. There is a clear need for more research in this area. There is also a need for more education on the general approach to the diagnosis and management of Cushing disease. The clinical approach is often complex, and education on a clear approach to these patients is paramount.


1. National Institutes of Health: US National Library of Medicine. Cushing disease. Accessed November 6, 2019.

2. Tritos NA, Biller BMK. Current management of Cushing’s disease. J Intern Med. 2019;286(5):526-541.

3. Ritzel K, Beuschlein F, Mickisch A, et al. Outcome of bilateral adrenalectomy in Cushing’s syndrome: a systematic review. J Clin Endocrinol Metab. 2013;98(10):3939-3948.

4. Asuzu D, Chatain GP, Hayes C, et al. Normalized early postoperative cortisol and ACTH values predict nonremission after surgery for Cushing disease. J Clin Endocrinol Metab. 2017;102(7):2179-2187.

5. Bastos RVS, Silva CMDM, Tagliarini JV, et al. Endoscopic versus microscopic transsphenoidal surgery in the treatment of pituitary tumors: systematic review and meta-analysis of randomized and non-randomized controlled trials. Arch Endocrinol Metab. 2016;60(5):411-419.

6. The Pituitary Society. Cushing’s syndrome & disease – treatments. Accessed November 6, 2019.

7. Wagner J, Langlois F, Lim DST, McCartney S, Fleseriu M. Hypercoagulability and risk of venous thromboembolic events in endogenous Cushing’s syndrome: a systematic meta-analysis. Front Endocrinol (Lausanne). 2019;9:805.

8. Varlamov E, Hinojosa-Amaya JM, Stack M, Fleseriu M. Diagnostic utility of Gallium-68-somatostatin receptor PET/CT in ectopic ACTH-secreting tumors: a systematic literature review and single-center clinical experience. Pituitary. 2019;22(5):445-455.

9. Casanueva FF, Barkan AL, Buchfelder M, et al. Criteria for the definition of Pituitary Tumor Centers of Excellence (PTCOE): a Pituitary Society Statement. Pituitary. 2017;20(5):489-498.

This article originally appeared on Endocrinology Advisor