Interim results of a non-interventional, observational study evaluating the long-term safety and efficacy of pasireotide sc in Cushing's disease

Summary We report the use of pasireotide in a rare and unusual case of pituitary macroadenoma co-secreting GH, prolactin and ACTH. A 62-year-old Caucasian man presented with impotence. Clinically, he appeared acromegalic and subsequent investigations confirmed GH excess and hyperprolactinaemia. Magnetic resonance imaging (MRI) of pituitary revealed a large pituitary macroadenoma. He underwent trans-sphenoidal surgery and histology confirmed an adenoma with immunohistochemistry positive for ACTH, GH and prolactin. Acromegaly was not cured following surgery and inadequately controlled despite subsequent octreotide therapy. He underwent further debulking pituitary surgery, following which IGF1 levels improved but still high. This time adenoma cells showed immunohistochemistry positivity for ACTH only, following which subsequent investigations confirmed intermittent hypercortisolaemia compatible with pituitary Cushing's disease. We recommended radiotherapy, but in view of the pluripotential nature of the tumour, we proceeded with a trial of s.c. pasireotide therapy on the basis that it may control both his acromegaly and Cushing's disease. After 3 months of pasireotide therapy, his mean GH and IGF1 levels improved significantly, with improvement in his symptoms but intermittent hypercortisolaemia persists. His glycaemic control deteriorated requiring addition of new anti-diabetic medication. MRI imaging showed loss of contrast uptake within the tumour following pasireotide therapy but no change in size. We conclude that our patient has had a partial response to pasireotide therapy. Long-term follow-up studies are needed to establish its safety and efficacy in patients with acromegaly and/or Cushing's disease. Learning points Plurihormonal pituitary adenomas are rare and unusual. Patients with pituitary adenomas co-secreting ACTH and GH are more likely to present with acromegaly because GH excess can mask hypercortisolaemia. Pasireotide holds potential where conventional somatostatin analogues are not effective in acromegaly due to higher affinity for somatostatin receptor subtypes 1, 2, 3 and 5. Significant deterioration in glycaemic control remains a concern in the use of pasireotide. Currently, long-term safety and efficacy of pasireotide in patients with acromegaly and/or Cushing's disease are not fully clear.

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Endocrinological long-term follow-up study of patients bilaterally adrenalectomized for Cushing's disease

Acta Endocrinologica ◽

10.1530/acta.0.114s107a ◽

1987 ◽

Vol 116 (3_Suppl) ◽

pp. S107-S108

Author(s):

A. EDELMANN ◽

L. RADBRUCH ◽

L. NOCKE-FINCK

Keyword(s):

Cushing’S Disease ◽

Cushing's Disease ◽

Follow Up Study ◽

Long Term Follow Up

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Favorable long-term outcome of bilateral adrenalectomy in Cushing's disease

Endocrine Abstracts ◽

10.1530/endoabs.35.p7 ◽

2014 ◽

Author(s):

Andrea Osswald ◽

Eva Plomer ◽

Christina Dimopoulou ◽

Monika Milian ◽

Rainer Blaser ◽

...

Keyword(s):

Cushing’S Disease ◽

Bilateral Adrenalectomy ◽

Cushing's Disease ◽

Term Outcome ◽

Long Term Outcome

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Long-term remission and recurrence rates after transsphenoidal surgery for cushing's disease

Endocrine Abstracts ◽

10.1530/endoabs.35.p716 ◽

2014 ◽

Author(s):

Paloma Moreno Moreno ◽

Julia Silva Fernandez ◽

Maria Rosa Alhambra Exposito ◽

Maria angeles Galvez Moreno

Keyword(s):

Cushing’S Disease ◽

Transsphenoidal Surgery ◽

Cushing's Disease ◽

Recurrence Rates

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Faculty Opinions recommendation of Cabergoline monotherapy in the long-term treatment of Cushing's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718270049.793490682 ◽

2014 ◽

Author(s):

Maria Fleseriu ◽

Shirley McCartney

Keyword(s):

Cushing’S Disease ◽

Term Treatment ◽

Cushing's Disease ◽

Long Term Treatment

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Diagnosis and Multimodality Management of Cushing’s Disease: A Practical Review

International Journal of Endocrinology ◽

10.1155/2013/893781 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 10

Author(s):

Gabriel Zada

Keyword(s):

Pituitary Adenoma ◽

Cushing’S Disease ◽

Patient Survival ◽

Clinical Laboratory ◽

Management Strategies ◽

Serum Cortisol ◽

Cushing's Disease ◽

First Line ◽

Stepwise Approach

Cushing’s Disease is caused by oversecretion of ACTH from a pituitary adenoma and results in subsequent elevations of systemic cortisol, ultimately contributing to reduced patient survival. The diagnosis of Cushing’s Disease frequently involves a stepwise approach including clinical, laboratory, neuroimaging, and sometimes interventional radiology techniques, often mandating multidisciplinary collaboration from numerous specialty practitioners. Pituitary microadenomas that do not appear on designated pituitary MRI or dynamic contrast protocols may pose a particularly challenging subset of this disease. The treatment of Cushing’s Disease typically involves transsphenoidal surgical resection of the pituitary adenoma as a first-line option, yet may require the addition of adjunctive measures such as stereotactic radiosurgery or medical management to achieve normalization of serum cortisol levels. Vigilant long-term serial endocrine monitoring of patients is imperative in order to detect any recurrence that may occur, even years following initial remission. In this paper, a stepwise approach to the diagnosis, and various management strategies and associated outcomes in patients with Cushing’s Disease are discussed.

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Endogenous ACTH Concentration-Cortisol Secretion Dose Analysis Unmasks Decreased ACTH Potency in Cushing's Disease with Restoration after Successful Pituitary Adenomectomy

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2011-1878 ◽

2011 ◽

Vol 96 (12) ◽

pp. 3768-3774 ◽

Cited By ~ 8

Author(s):

Ferdinand Roelfsema ◽

Daniel M. Keenan ◽

Johannes D. Veldhuis

Keyword(s):

Surgical Treatment ◽

Cushing’S Disease ◽

Pituitary Surgery ◽

Pulse Frequency ◽

Cushing's Disease ◽

P Value ◽

Cortisol Secretion ◽

Acth Concentration ◽

Active Disease

Background: The relationship between circulating ACTH levels and cortisol secretion in Cushing's disease is not precisely known. Hypothesis: Chronic ACTH hyperstimulation leads to decreased adrenal potency and is restored after normalization of ACTH secretion. Subjects: Subjects included 20 patients with Cushing's disease, eight patients in long-term remission, and 36 healthy controls. Outcomes: ACTH and cortisol secretion rates and analytical dose-response estimates of endogenous ACTH efficacy (maximal cortisol secretion), dynamic ACTH potency, and adrenal sensitivity (slope term) from 24-h ACTH-cortisol profiles were evaluated. Results: Both basal and pulsatile secretion of ACTH and cortisol were increased in patients with active disease but normal in cured patients. ACTH, but not cortisol pulse frequency, was amplified in patients and restored after successful surgical treatment. ACTH EC50, an inverse measure of potency, was higher during pulse onset in Cushing's disease (59 ± 7.4 ng/liter) than in controls (20 ± 3.7 ng/liter) (P < 0.0001) and remitted patients after surgery [15 ± 3.2 ng/liter, P value not significant (NS) vs. controls] and during pulse recovery phases [128 ± 18 (P <0.0001), 70 ± 8.4, and 67 ± 17 ng/liter (NS vs. controls), respectively]. Efficacy was increased in active disease and normalized after surgical treatment [patients, 38 ± 8.3 nmol/liter · min, vs. controls, 21 ± 2.3 nmol/liter · min (P <0.0001), and cured patients, 15 ± 3.2 nmol/liter · min (NS vs. controls)]. Sensitivity to endogenous ACTH did not differ among the three groups. Conclusion: The adrenal gland in Cushing's disease exhibits decreased responsiveness to submaximal ACTH drive and amplified efficacy, with unchanged sensitivity. These target-gland abnormalities are reversible in long-term remission after pituitary surgery.

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