A survey of clinical practice patterns in diagnosis and ...

Original Articlehttp://mjiri.iums.ac.ir Medical Journal of the Islamic Republic of Iran (MJIRI)

Iran University of Medical Sciences

____________________________________________________________________________________________________________________1. MD, Professor of Endocrinology, Research Center for Prevention of Cardiovascular Disease, Institute of Endocrinology and Metabolism, IranUniversity of Medical Sciences, Tehran, Iran. [email protected]. MD, Associate Professor of Endocrinology, Department of Endocrinology, Imam Khomeini Hospital, School of Medicine, Tehran Universityof Medical Sciences, Tehran, Iran. [email protected]. MD, Assistant Professor of Endocrinology, Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti Universi-ty of Medical Sciences, Tehran, Iran. [email protected]. MD, Associate Professor of Endocrinology, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Teh-ran, Iran. [email protected]. MD, Assistant Professor of Endocrinology, Endocrine Research Center, Mashhad University of Medical Sciences, Mashhad, [email protected]. MD, Assistant Professor of Endocrinology, Endocrinology and Metabolism Research Center, Tehran University of Medical Sciences, Tehran,Iran. [email protected]. (Corresponding author) MD, Professor of Endocrinology, Endocrine Research Center, Institute of Endocrinology and Metabolism, IranUniversity of Medical Sciences, Tehran, Iran. [email protected]. MD, Assistant Professor of Endocrinology, Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medi-cal Sciences, Tehran, Iran. [email protected]. BS, Bachelor of statistics, Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Teh-ran, Iran. [email protected]

A survey of clinical practice patterns in diagnosis andmanagement of Cushing's disease in Iran

Mojtaba Malek1, Fatemeh Esfehanian2, Atieh Amouzegar3, Farzaneh Sarvghadi4Zohreh Moossavi5, Mohammad R. Mohajeri-Tehrani6, Mohammad E. Khamseh*7

Alireza Amirbaigloo8, Ameneh Ebrahim Valojerdi9

Received: 22 June 2015 Accepted: 20 September 2015 Published: 21 February 2016

AbstractBackground: Cushing's disease is the most prevalent cause of endogenous adrenocorticotrophic

hormone hypersecretion. The aim of this study was to document the current clinical practice patternin the management of Cushing's disease by Iranian Endocrinologists to determine their opinions andcompare them with the current clinical practice guidelines.

Methods: An eight-item questionnaire dealing with diagnosis, treatment and follow up of patientswith Cushing's disease was developed, piloted, and sent to the members of Iranian EndocrinologySociety.

Results: Among 90 endocrinologists invited to participate in the survey, 76 replied. Most respond-ents selected overnight dexamethasone suppression test (ONDST) and assessment of 24-hour urinaryfree cortisol (UFC) as the best screening tests followed by midnight serum cortisol and midnightsalivary cortisol. Classic high dose dexamethasone suppression test and measurement of serumACTH were selected for localization of the primary lesion by 64.5%. The primary choice of treat-ment was trans-sphenoidal pituitary surgery (86.8%). For the recurrence of Cushing's disease, thepreferred treatment modality was medical therapy followed by bilateral adrenalectomy, and pituitaryre-surgery. In case of treatment failure after the first pituitary surgery and ketoconazole treatment,51% chose bilateral adrenalectomy, while36.8% selected pasireotide only.

Conclusion: ONDST and UFC are two most common tests used to screen an index case with signsand symptoms of hypercortisolism. The primary choice of treatment in Cushing's disease is pituitarysurgery. However, medical treatment by ketokonazol is preferred for the recurrences. Pasireotide isthe second alternative after bilateral adrenalectomy in case of treatment failure after pituitary surgeryand ketoconazole.

Keywords: Cushing's disease, Diagnosis, Management, Clinical Practice.

Cite this article as: Malek M, Esfehanian F, Amouzegar A, Sarvghadi F, Moossavi Z, Mohajeri-Tehrani MR, Khamseh ME, AmirbaiglooA, Ebrahim Valojerdi A. A survey of clinical practice patterns in diagnosis and management of Cushing's disease in Iran. Med J Islam Re-pub Iran 2016 (21 February). Vol. 30:334.

Clinical practice patterns in Cushing's disease

2 Med J Islam Repub Iran 2016 (21 February). Vol. 30:334.http://mjiri.iums.ac.ir

IntroductionExcessive secretion of adrenocortico-

trophic hormone (ACTH) by a pituitarycorticotroph adenoma is the most prevalentcause of endogenous Cushing's disease.Elevated ACTH secretion plus disturbedhypothalamic-pituitary axis result in excesscortisol production from adrenal glands andsubsequent clinical features of hypercorti-solism (1).

The aim of treating Cushing's disease hasbeen to reverse clinical feature, normalizebiochemical derangement, and achievelong-term disease free survival (1).

The diagnosis and management of Cush-ing's diseaseis challenging for clinicians.The American Endocrine Society and Eu-ropean Society of Endocrinology publishedan evidence-based clinical practice guide-line in 2008 (2). Measurement of cortisol inserum, urine, or saliva is the target for di-agnosis. The main recommended investiga-tions are urinary free cortisol (UFC), over-night 1 mg and two-day 2 mg/day dexame-thasone suppression tests (DST), and late-night salivary cortisol. The optimal treat-ment for ACTH producing tumor is surgi-cal resection. However, in case of surgicalfailure or relapse, second line options in-clude medical therapy, repeated pituitarysurgery, radiotherapy, and bilateral adren-alectomy (3,4).

The aims of this survey were to documentthe current clinical practice in the diagnosisand management of Cushing's disease byIranian endocrinologist and to compare thecurrent practice with the recommendationsof the Endocrine Society Clinical PracticeGuideline.

MethodsThe survey comprised of questions in re-

lation to diagnosis, treatment, and followup of an index case with symptoms andsigns of Cushing's disease (Table 1). Somequestions required a single best response tobe selected from a list of multiple choices.Questions related to the diagnosis of etiolo-gy of Cushing's disease allowed multiple

items to be selected simultaneously. Allpossible answers were included for eachquestion in order to decrease the bias. Thequestionnaire was appraised by the mem-bers of a scientific committee and com-prised of 9 endocrinologists, expert in di-agnosis and management of Cushing's dis-ease. The target group was the clinicallyactive Iranian endocrinologists in diagnosisand management of patients with Cushing'sdisease. Survey responses were collectedanonymously.

Statistical AnalysisData were analyzed anonymously. As all

participants did not answer all questions,the valid percent was calculated individual-ly for each question. Data were expressedas frequency tables (n, %) and proportion.

ResultsResponse Rate and Respondent Charac-

teristicsNinety endocrinologists were invited to

participate in the survey; 76 (84.4%) partic-ipated, and 53 (69.7%) answered all ques-tions. Thirty eight (50%) respondents wereendocrinologists who were residing in Teh-ran (the capital city), and 38 (50%) werefrom other provinces. The majority of therespondents visited less than 10 newly di-agnosed patients with Cushing's diseaseannually. Baseline characteristics of theparticipants are presented in Table 2.

Diagnostic Evaluation of the Index CaseAssessment of 24-hour urinary free corti-

sol (UFC) and fasting serum cortisol afteran overnight dexamethasone suppressiontest (ONDST) has been obtained by 57(75%) and 66 (86.8%) of the respondents,

Table 1. The index case: A Female with cushingsyndromeA 32-yr-old woman presents with fatigue and weightgain since six months ago. She also complaints ofoligomenorhea and slowly progressive hirsutism.She is otherwise healthy and take no medicationexcept of captopril for hypertension. Her BP is135/87mmHg and has a FG score of 12, as well aspurple striae over the flanks and lower abdomen.Fasting blood glucose level is 130mg/dl.



respectively. Forty five (59%) respondentsselected both of the above screening testssimultaneously; only 9.2% of the respond-ents obtained UFC as a single screeningtest, and 22.4% selected ONDST as thebest single screening test. Moreover, meas-urement of midnight serum cortisol wasselected by 15 (19.7%) respondents. Mid-night salivary cortisol in combination with

the other tests was obtained by 7.9% of therespondents.

Figure 1-A demonstrates the percentageof respondents ordering the listed laborato-ry tests for the index case. Considering theassessment of current clinical practice forlocalizing the primary lesion, classic highdose dexamethasone suppression test maybe obtained alone by 17 (22.4%). Forty

Table 2. Baseline characteristics of the participantsAge (mean ± SD) 47.43 ± 5.36Years after graduation (mean ± SD) 8.23 ± 4.90Annual No. of visited patients (%) <10 89.2%

10-15 9.2%>15 1.5%

Location of clinical practice University clinic 80.3%Private clinic 10 %Public clinic 8.7%

Fig. 1 A.

Fig. 1 B.

Fig. 1. Percentage of respondents who would select the listed laboratory tests for screening (A) or localization (B) in apatient with clinical evidence of hypercortisolism

M. Malek, et al.

3Med J Islam Repub Iran 2016 (21 February). Vol. 30:334. http://mjiri.iums.ac.ir

nine (64.5%) respondents indicated the useof both serum ACTH and classic high dosedexamethasone suppression test, while 12(15.8%) respondents selected modifiedhigh dose dexamethasone suppression testfor localizing the primary lesion (Fig. 1-B).

The respondents were also asked to pro-vide their diagnostic approach if the prelim-inary evaluations were indicative of an ec-topic Cushing's disease. Of the respondents71 (93.4%) selected a high resolution CTscan of thorax, and 63 (82.9%) selected aspiral CT scan of the abdomen; 58 (76.3%)said they would use both tests to assess anectopic source; 53 (69.7%) of the respond-ents selected anoctreotide scan, while 9(11.8%) chose to use inferior petrosal sinussampling.

TreatmentUse of Surgical and Medical AlternativesThe participants were asked to specify

their primary choice of treatment in an in-dex case of ACTH dependent Cushing'sdisease with a 6 mm pituitary adenoma re-ported in dynamic brain MRI. Trans-sphenoidal pituitary surgery (TSS) was se-lected by 66 (86.8%)of the respondents; 4(5.3%)and 1 (1.3%) respondents preferredketoconazole, and cabergoline, respective-ly; and five of the respondents (6.6%)choselong acting somatostatinanalogues,metyrapone, mitotane, or bilateral adren-alectomy.

Recurrence of Cushing's DiseaseThe index case was operated through a

TSS approach and no evidence of hypo orhypercortisolism was found for the nexttwo years after the operation when recur-rence happened that proved to be ACTH-dependent. However, there was no evi-dence of pituitary adenoma and/or ectopicsource for the elevated ACTH in the diag-nostic evaluations.

The respondents were then asked to spec-ify their next options in treating the indexcase.

Of the respondents, 39 (51.3%) chosemedical treatment as the preferred treat-ment modality for the recurrence of Cush-ing's disease in this clinical setting, 24(31.6%) preferred bilateral adrenalectomy,and 14 (18.4%) favored pituitary re-surgery.

In the case scenario, the index case wastreated by ketoconazole. However, threemonths after the initiation of ketoconazole,liver enzymes rose to five time upper limitof the normal range. The participants werethen asked to select their choice of action.The preferred treatment for Cushing's dis-ease after pituitary surgery and ketocona-zole failure was bilateral adrenalectomy (39(51.3%)) and pasireotide (28 (36.8%)).Seven endocrinologists (9.2%) selectedcombination therapy with cabergoline andpasireotide, and only 4 (5.3%) ordered an-other pituitary surgery.

Fig. 2. Medical therapy priorities



Considering the available treatment op-tions, the respondents were asked about therate of success in the treatment of ACTHdependent Cushing's disease in Iran. Thirtyseven (48.7%) reported a success rate of30-49%, and 29 (38.2%) believed this rateseemed high (50-79%).

They were also asked to give priority to alist of drugs they would like to be availablefor treating Cushing's disease in Iran;67.9% of the respondents selected Keto-conazole as their first drug of choice while38.5% chose Pasireotide (Fig. 2).

DiscussionThis study represents the first national

survey to assess the current clinical practicein the diagnosis and management of Cush-ing's disease.

The results revealed that the majority ofIranian endocrinologists would chooseONDST and UFC as screening tests. It wasalso found that they prefer trans-sphenoidpituitary surgery for those patients whohave pituitary dependent source for hyper-cortisolism. However, when the first pitui-tary surgery fails, ketoconazole was thetreatment of choice. In the case of treatmentfailure with pituitary surgery and ketocona-zole, novel medical treatments such aspasireotide was selected by more than onethird of the participants, while bilateraladrenalectomy was preferred by a half.

The diagnostic trends identified in thisstudy are compatible with the recommenda-tions of Endocrine Society Clinical PracticeGuideline on the diagnosis of Cushing'sdiseasein 2008 (2).The guideline indicatesthat there is no single best screening test forCushing's disease. Random serum cortisolor plasma ACTH is not recommended forscreening. Moreover, 24-hour UFC, latenight salivary cortisol, 1mg ONDST, andlonger low dose DST were offered for theinitial investigation. In this survey, onlyfew participants selected random serumcortisol and plasma ACTH. Furthermore,measurement of late night salivary cortisolwas not popular as the initial investigation.Salivary cortisol represents the active form

of serum cortisol which is not affected bythe flow rate of saliva (5,6). As the salivaryglands express 11β-hydroxy steroid dehy-drogenase type 2, licorice or using tobaccomay produce a false positive result (7,8).

In this survey, the small number of partic-ipants selected late night salivary cortisolfor the initial investigation and this mayhave been due to the unavailability of thetest. More traditional tests such as ONDSTand 24-hour UFC have been available forthe past several years. Therefore, the major-ity of the endocrinologists are familiar withtheir use in clinical practice.

Considering the treatment pattern, surgi-cal removal of the pituitary adenoma by atrans-sphenoidal approach is the first linetreatment for Cushing's disease (3). Theremission rate for microadenomas was re-ported to be 65-90%, with a recurrence rateof 10-20% at 10 years (9,10).

The majority of the respondents in thissurvey selected TSS as the primary choiceof treatment in an index case with ACTHdependent Cushing's disease due to pitui-tary microadenoma. However, after a prov-en recurrence, medical treatment with keto-conazole was the preferred choice of actionby half of the participants although bilateraladrenalectomy was selected by a third.

Medical treatment has gained a signifi-cant space during recent years in treatmentof Cushing's disease. It might be performedprior to the surgery to reduce the risk ofprocedure, or control the metabolic conse-quences of high serum cortisol (11). Fur-thermore, medical treatment could reducehypercortisolism and should be consideredbefore bilateral adrenalectomy.

Bilateral adrenalectomy provides an im-mediate control of hypercortisolism. How-ever, lifelong glucocorticoid and mineralo-corticoid replacement may be necessary(12). Although the second-line treatmentfor recurrence of Cushing's diseaseshouldbe individualized, bilateral adrenalectomyis indicated when hypercortisolism persist-ed despite medical therapy (13).

Ketoconazole is an inhibitor of cortisolproduction by its action on 11β-

M. Malek, et al.

5Med J Islam Repub Iran 2016 (21 February). Vol. 30:334. http://mjiri.iums.ac.ir

hydroxylase. The average remission rate forpatients with Cushing's disease is 70%(14).The reversible elevation of liver en-zymes occurs in 5-10% of the patients andserious hepatic injury has been reported in1 out of 15000 cases (15).

In this study, pasireotide was selected bymore than a third of the respondents when apatient experiences treatment failure withpituitary surgery and ketoconazole.

Recent studies demonstrated that somato-statin receptor subtype 5 (SSt5) and dopa-mine receptor subtype 2 are frequently ex-pressed by corticotroph adenomas (16-21).Octreotide, a somatostatin analogue (SSA)with binding affinity to somatostatin type 2receptors does not have suppressive actionon ACTH (22-23). Pasireotide that binds toSSt5 was reported to normalize UFC in15% and 26% of patients with Cushing'sdisease after six months of therapy with adose of 600 µg and 900 µg, respectively.Drug induced hyperglycemia is the majoradverse event reported in the majority ofthe patients. Diarrhea, nausea, and ab-dominal pain are other most commonevents observed with pasireotide treatment(24).

This survey provided an opportunity toevaluate the current clinical practice in thediagnosis and treatment of Cushing's dis-ease in Iran. However, potential selectionbias may happen when including clinicallyactive endocrinologists in the managementof Cushing's disease.

In conclusion, our survey showed thattraditional ONDST and 24 hour UFC arestill the most popular tests for the initialinvestigation of a patient with symptomsand signs of hypercortisolism.

Considering the treatment pattern, trans-sphenoidal pituitary surgery is the treat-ment of choice in Cushing’s disease, whileketoconazole is the preferred medication incase of recurrence. Moreover, pasireotide issecond to bilateral adrenalectomy whenpituitary surgery and ketoconazole fail totreat the patient.

AcknowledgmentsAuthors wish to thank all physicians who

participated in this study. This study wasfunded and supported by Iran University ofMedical Sciences (IUMS); Grant No. 93-01-122-24527.

Conflict of interestThe authors declare that they have no

conflict of interest that could be perceivedas prejudicing the impartiality of the re-search reported.

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