Pasireotide after Surgery for Persistent Cushing’s Disease

1 IIIrd Department of General Surgery and Emergency, Emergency University Hospital, Bucharest, Romania 2 „Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 3 Department of Endocrinology, County Clinical Emergency Hospital, Cluj-Napoca, Romania 4 Clinical Hospital of Infectious Diseases, Cluj-Napoca, Romania 5 „C.I. Parhon” National Institute of Endocrinology, Bucharest, Romania 6 „Iuliu Hatieganu” University of Medicine and Pharmacy & County Clinical Hospital, Cluj-Napoca, Romania 7 „Sf. Pantelimon” Clinical Emergency Hospital, Bucharest, Romania 8 „Dr. Carol Davila” Centtral Military Emergency University Hospital, Bucharest, Romania Corresponding author: Mara CARSOTE, „C.I. Parhon” National Institute of Endocrinology, Bucharest, Romania. E-mail: carsote_m@hotmail.com Abstract


INTRODUCTION
Although it is a rare disease, the increased morbidity associated with CD requires multiple therapeutic approaches, especially in case of persistent hypercortisolism. Th e fi rst-line treatment is represented by transsphenoidal surgery, but medical therapy is a sustainable option in case of recurrent or persistent CD, when surgery is contraindicated or until radiation therapy has taken full eff ect 1 . Pasireotide is a new-generation multi-receptor-targeted somatostatin receptor ligand used in the treatment of CD, but its eff ect on glucose metabolism should be taken into consideration when choosing the best treatment option for each patient 2 .

CASE PRESENTATION
A 27-year-old female was referred to our clinic for weight gain (50 kg in 8 years), occipital headache with frontal and retro-orbital radiation, fatigue, dyspnea, perspiration, mood swings corresponding to recurrent depressive episodes, worsening of hirsutism and the appearance of purple-red striae on the lower abdomen, thighs and under the breasts.
Her medical history revealed high blood pressure diagnosed 2 years prior and primary hypothyroidism.
Biochemical workup revealed polycythemia, leukocytosis, fasting hyperglycemia, hypercholesterolemia and hypertriglyceridemia (  (Figure 2). Abdominal Computer tomography (CT) showed bilateral adrenal hyperplasia. Th e diagnosis of Cushing's disease was established and transsphenoidal adenomectomy was recommended. Because the patient initially refused surgery, treatment with pasireotide was initiated at a dose of 0.6 mg twice daily. After 18 months she experienced spectacular weight loss of 32 kg, her blood pressure normalized, requi-  a higher frequency of hyperglycemia 2,6-8 . In a metaanalysis, mild side eff ects were observed in 39.3% of patients and severe side eff ects were observed in 15.2% of patients, respectively 1 . Concerning the hyperglycemic eff ect associated with pasireotide treatment, 73% of patients in a 12-month trial and 68.4% of patients in a 6-month trial developed hyperglycemia as a side eff ect [9][10][11] . Our patient also developed hyperglycemia related to pasireotide, partially controlled by insulin and oral antidiabetic drugs. Moreover, treatment with Pasireotide was interrupted 18 months later due to partial control of hypercortisolism and the patient underwent transsphenoidal adenomectomy. After surgery, the glycemic parameters were restored to normal levels, but the persistence of glucocorticoid hypersecretion required further medical therapy. Th e same side eff ect, impaired glucose metabolism, reappeared and specifi c hypoglycemic therapy was resumed.
Regarding the mechanisms of Pasireotide-induced hyperglycemia, it has been reported that glucose metabolism is associated with the disease pathophysiology 2. Pasireotide binds both to SST2 (somatostatin receptor type 2) and SST5 (somatostatin receptor type 5), but with higher affi nity to SST5. Insulin secretion is also mediated by SST2 and SST5 12 . As a result, the hyperglycemic eff ects of Pasireotide in Cushing's disease are mainly due to its tendency to decrease incretin and insulin secretion 13 . Moreover, uncontrolled hypercortisolism in CD causes reduced insulin sensitivity which cannot be counterbalanced by reduced insulin levels associated with Pasireotide 14 .
Nonetheless, the hyperglycemic eff ect of Pasireotide is transient and can be explained by its absent eff ect on insulin sensitivity and minimal eff ects on glucagon secretion 13 .
In this case, a possible therapeutic approach would be the association of dopaminergic agonists, even if hyperprolactinemia has resolved postoperatively.

CONCLUSION
In conclusion, in case of persistent Cushing's disease the challenge lies in identifying the optimal therapeutic methods in order to achieve a cure while, at the ring the cessation of antihypertensive therapy, but no signifi cant reduction of ACTH and cortisol levels was reported. Moreover, the patient developed type 2 diabetes mellitus that was progressively treated with three antidiabetic drugs and insulin. After three months the patient underwent transsphenoidal adenomectomy, complicated with central diabetes insipidus which remitted 2 months later and multiple pituitary hormone insuffi ciency: thyroid stimulating hormone (TSH) defi ciency (of <0.004 μUI/mL, normal: 0.4-4μUI/mL), gonadotropin insuffi ciency (FSH-follicular stimulating hormone of 3.76 U/L, normal: 3.85-8.78U/L, LHluteinizing hormone of 1.84 U/L, normal: 2.12-10.9 U/L), somatotropin insuffi ciency (IGF1-insulin-like growth factor 1 of 91.9 ng/mL, normal: 117-329ng/ mL). Consequently, thyroxine dose was increased and combined oral contraceptive treatment was started. Because no signifi cant remission of hypercortisolism was achieved, treatment with pasireotide 0.6 mg twice daily was resumed three months later. Altered glycemic profi le with high glycosylated hemoglobin of 7.6% (normal:4.8-5.6%) were reported after resumption of treatment, suggesting the recurrence of type 2 diabetes mellitus. In this case, a combination of the available drug therapies may be an alternative for optimal disease control, in order to limit the side eff ects.

DISCUSSIONS
Chronic elevation of cortisol levels leads to increased morbidity by altering the metabolic profi le and body composition, inducing insulin resistance, muscle wasting, hypertension, fat maldistribution and neuropsychiatric disorders 1,3 . As a result, hypercortisolism must be treated eff ectively and, if possible, defi nitively.
Even though transsphenoidal pituitary adenomectomy provides adequate control of cortisol levels in 65-90% of patients with CD, there are still patients who need medical therapy. In recent years, there has been increasing experience with fi rst-line medical therapy, such as pasireotide 2 .
Th ere are studies showing a normalization of UFC levels in 41.3% of 150 patients treated with various dosages of pasireotide over a 12-month period, establishing a direct link between the lowering of the UFC and the improvement of systolic and diastolic blood pressure and tumor volume reduction 4,5 .
Nevertheless, pasireotide has its adverse eff ects related to gastrointestinal symptoms and cholelitiasis, consistent with other somatostatin analogs (SSA), and authors declare that all the procedures and experiments of this study respect the ethical standards in the Helsinki Declaration of 1975, as revised in 2008(5), as well as the national law. Informed consent was obtained from all the patients included in the study. same time, limiting the side eff ects. Careful long-term follow-up by a multidisciplinary team is required for each patient.
Compliance with ethics requirements: Th e authors declare no confl ict of interest regarding this article. Th e