Medical Management of Cushing’s Disease · Medical Management of Cushing’s Disease Dr S. Ali Imran MBBS, FRCP (Edin), FRCPC Professor of Medicine Division of Endocrinology & Metabolism

Medical Management of Cushing’s Disease

Dr S. Ali Imran MBBS, FRCP (Edin), FRCPC Professor of Medicine

Division of Endocrinology & Metabolism Dalhousie University, Halifax, NS

List of topics that we will cover

The pertinent pituitary physiology

An update on the medical management of ACTH producing pituitary tumours

Details of surgical management will not be covered during the talk but you are welcome to ask about it in the Q&A session

Amy’s case

-  Gained 50 lbs in 1 year -  Amenorrhea for 10

months -  New-onset hypertension -  Proximal muscle

weakness -  Depression

Amy’s case

- Gained 50 lbs in 1 year -  Amenorrhea for 10

months -  New onset hypertension -  Seen by psychiatry for ‘psychosis’

Hypothalamo-pituitary system

Hypothalamic pituitary hormones

Goals of therapy for functioning sellar tumors

Remove (or shrink) the tumour

Normalize hormone levels

Pituitary Adrenal Axis

Surgery PaseriotideCabergoline

SurgeryKetoconazoleMetyraponeEtomidateLCI699

MifepristoneY

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Y1150Y1146

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Y

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Y9

Y1

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Y

Y

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Insulin

SSS

S

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Insulin

SSS

S

SS

PI3K

JAK2

Ins Ins-R

GHRs

IGF-I

During co-treatment with SSAs, PEG (being a competitive GHR blocker) has less GH to compete with, and less GHRs to block on the liver. Moreover, SSAs inhibit IGF-1 generation by liver directly

Leung et al. JCEM 2000

Murray RD et al. JCI 2004

SSAs, decreasing portal insulin concentration, may reduce the number of GHRs expressed in the liver, and may also directly inhibit liver IGF-1 generation

Cortisol Synthesis

Pregnenolone

11-deoxycortisol

Cortisol

17-OH pregnenolone

17-OH progesterone

Cholesterol

ACTH

Aldosterone

Corticosterone

18-OH corticosterone

Feedback loop malfunctioning in Cushing’s

Progesterone

Dehydroepiandrosterone

Androstenedione

Testosterone

11-deoxycorticosterone

Estradiol

Estrone

11-deoxycortisol

ACTH

Testosterone


First-line therapy: Transsphenoidal adenomectomy

First-line therapy for patients with Cushing’s disease is transsphenoidal adenomectomy to remove the ACTH-secreting pituitary adenoma

Treatment goals

Normalization of cortisol levels

Reversal of clinical features

Long-term biochemical control

Removal of tumor mass

Preservation of normal pituitary function

Biochemical remission

• Post-operative biochemical assessment is used to: – Evaluate whether patients are in remission – Inform decisions about the need for further therapy, such as repeat

surgery or medical therapy – Provide an idea of overall surgical success

• There are three possible outcomes of pituitary surgery:

ACTH +++

Cortisol +++ Adrenal

ACTH �ve

Failure

Adrenal No cortisol

ACTH �ve

No ACTH

Success

Adrenal Cortisol +

ACTH+ ACTH �ve

Partial success

Post-operative remission rates and long-term recurrence rates vary widely

Remission

Recurrence

0

Swearingen 1999 (n=161)

Invitti 1999 (n=236)

Sonino 1996 (n=103)

Knappe 1996 (n=310)

Bakiri 1996 (n=50)

Favia 1994 (n=110)

Trainer 1993 (n=45)

McCance 1993 (n=57)

Lindholm 1992 (n=48)

Robert 1991 (n=78)

Burke 1990 (n=41)

Guilhaume 1988 (n=64)

Mampalam 1988 (n=216)

Nakane 1987 (n=93)

Fahlbusch 1986 (n=101)

Lüdecke 1985 (n=100)

Boggan 1983 (n=100)

10 20 30 40 50 60 70 80 90 100 Patients (%)

Newell-Price J. IPC 2011;abst P13

Post-operative remission rates and long-term recurrence rates vary widely

Remission

Recurrence

0

Swearingen 1999 (n=161)

Invitti 1999 (n=236)

Sonino 1996 (n=103)

Knappe 1996 (n=310)

Bakiri 1996 (n=50)

Favia 1994 (n=110)

Trainer 1993 (n=45)

McCance 1993 (n=57)

Lindholm 1992 (n=48)

Robert 1991 (n=78)

Burke 1990 (n=41)

Guilhaume 1988 (n=64)

Mampalam 1988 (n=216)

Nakane 1987 (n=93)

Fahlbusch 1986 (n=101)

Lüdecke 1985 (n=100)

Boggan 1983 (n=100)

10 20 30 40 50 60 70 80 90 100 Patients (%)

In 17 studies published from 1983 to 1999, remission rates ranged from 46–93% recurrence rates ranged from 0–28%


Similar rates reported in more recent studies

Remission

Recurrence

Valassi 2010 (n=620) Alwani 2010 (n=79)

Jagannathan 2009 (n=261) Fomekong 2009 (n=40)

Atkinson 2008 (n=42)

Hammer 2004 (n=289) Rollin 2004 (n=41)

Pereira 2003 (n=78) Chen 2003 (n=174)

Flitsch 2003 (n=147) Shimon 2002 (n=82)

Rees 2002 (n=54) Barbetta 2001 (n=68)

Chee 2001 (n=61) Imaki 2001 (n=49)

Patients (%)

Jehle 2008 (n=193) Prevedello 2008 (n=167)

Xing 2008 (n=266) Carrasco 2008 (n=68)

Romanholi 2008 (n=57) Patil 2008 (n=215)

Rollin 2007 (n=108) Pouratian 2007 (n=111)

Acebes 2007 (n=44) Shah 2006 (n=65)

Hoffmann 2006 (n=100) Esposito 2006 (n=40) Atkinson 2005 (n=63)

10 20 30 40 50 60 70 80 90 100 0


Currently used medical therapies in Cushing’s disease

Steroido- genesis inhibitors

• Mitotane, metyrapone, ketoconazole, etomidate

• Reduce cortisol levels via inhibition of steroid synthesis in the adrenal gland

• Temporary, palliative treatment

Biller BMK et al. J Clin Endocrinol Metab 2008;93:2454–2462




MifepristoneY

GrowthHormone

Y

Y

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Fn II

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Fn III

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Insulin

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Ketoconazole

• Efficacy as monotherapy (200–1200 mg/day):1

– Retrospective study of 38 patients with active Cushing’s disease

– Treatment was stopped in first week in 5 patients due to clinical or biological intolerance

– 17 (51%) had normalized UFC at follow-up (mean: 23 months) – Clinical regression of signs of hypercortisolism – 5 patients with no visible adenoma at baseline developed a visible

tumor during follow-up

• Adverse events associated with ketoconazole include:2 – GI events – Pruritus and rash – Liver toxicity – Gynecomastia – Impairment of testicular function – Adrenal insufficiency

1. Castinetti F et al. Eur J Endocrinol 2008;158:91–99 2. Dang CN & Trainer P. Arq Bras Endocrinol Metabol 2007,51:1339–1348




MifepristoneY

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Cabergoline

• Potent dopamine type 2 receptor (DR2) agonist

• Approximately 80% of ACTH-secreting adenomas express the dopamine D2 receptor1

• Studies (n=20–27) have demonstrated the effective use of cabergoline in persistent or recurrent Cushing’s disease2,3

• The phenomenon of escape has been described

• Studies in larger patient populations are required to establish efficacy and safety

1. Pivonello R et al. J Clin Endocrinol Metab 2004;89:2452–2462

2. Pivonello R et al. J Clin Endocrinol Metab 2009;94:223–230 3. Godbout A et al. Eur J Endocrinol 2010;163:709–716

N

NH

NH

N

N H

O

O

The Medical Treatment of Cushing’s Disease:Effectiveness of Chronic Treatment with theDopamine Agonist Cabergoline in PatientsUnsuccessfully Treated by Surgery

Rosario Pivonello, Maria Cristina De Martino, Paolo Cappabianca, Monica De Leo,Antongiulio Faggiano, Gaetano Lombardi, Leo J. Hofland, Steven W. J. Lamberts,and Annamaria Colao

Departments of Molecular and Clinical Endocrinology and Oncology (R.P., M.C.D.M., M.D.L., A.F., G.L., A.C.),and Neurosurgery (P.C.), “Federico II” University, 80131 Naples, Italy; and Department of Internal Medicine(R.P., L.J.H., S.W.J.L.), Erasmus Medical Center, Rotterdam 3015 CE, The Netherlands

Background: The role of dopamine agonists in the treatment of Cushing’s disease (CD) has beenpreviously debated.

Aim: The aim of this study was to evaluate the effectiveness of short-term (3 months) and long-term(12–24 months) treatment with cabergoline in patients with CD.

Patients and Methods: 20 patients with CD unsuccessfully treated by surgery entered the study.Cabergoline was administered at an initial dose of 1 mg/wk, with a monthly increase of 1 mg, untilurinary cortisol levels normalized or the maximal dose of 7 mg/wk was achieved. The responsivenessto treatment was evaluated according to changes in urinary cortisol excretion. A decrease greaterthan 25% was considered as a partial response, whereas complete normalization was consideredas a full response at short-term evaluation; persistence of normal cortisol excretion was the onlycriterion to evaluate the response at long-term evaluation.

Results: After short-term treatment, 15 (75%) patients were responsive to cabergoline treatment.Among these, normalization of cortisol excretion was maintained in 10, whereas treatment escapewas observed in five patients after 6–18 months. Among the 10 long-term responsive patients,eight were followed for 24 months, whereas the remaining two were followed for 12–18 months,due to cabergoline withdrawal for intolerance. A sustained control of cortisol secretion for 24month cabergoline treatment at the maximal dose ranging from 1-7 mg/wk (median: 3.5) withoutsignificant side effects, was obtained in eight of 20 (40%) patients.

Conclusions: The results of this study demonstrated that cabergoline treatment is effective incontrolling cortisol secretion for at least 1–2 yr in more than one third of a limited population ofpatients with CD. If this evidence is confirmed by additional studies, this agent may be consideredas a useful treatment option in patients with CD who are unsuccessfully treated by neurosurgery.(J Clin Endocrinol Metab 94: 223–230, 2009)

Cushing’s disease (CD) is the most common form of Cushing’ssyndrome, caused by a corticotroph pituitary tumor, and

often complicated by hypertension and impaired glucose toler-ance and associated with increased morbidity and mortality for

cardiovascular diseases (1–3). The first-line treatment of CD issurgery, with the objective of removing the pituitary tumor, al-though it is effective in inducing immediate disease remission inaround 70% and late disease remission in around 50% of pa-

ISSN Print 0021-972X ISSN Online 1945-7197Printed in U.S.A.Copyright © 2009 by The Endocrine Societydoi: 10.1210/jc.2008-1533 Received July 16, 2008. Accepted October 17, 2008.First Published Online October 28, 2008

Abbreviations: CD, Cushing’s disease; HOMA-B, homeostasis model of assessment-!-cellfunction; HOMA-IR, homeostasis model of assessment-insulin resistance; MRI, magneticresonance imaging; PRL, prolactin.

O R I G I N A L A R T I C L E

E n d o c r i n e R e s e a r c h — B r i e f R e p o r t

J Clin Endocrinol Metab, January 2009, 94(1):223–230 jcem.endojournals.org 223

















































ysis calculating the Pearson’s coefficient. Data are expressed as mean ! SE.Significance was set at 5%.

Results

Responsiveness to treatment with cabergolineAt short-term treatment, 15 (75%) patients were responsive

[eight (40%) partial and seven (35%) full responders], whereasfive (25%) were resistant. Cabergoline was withdrawn in allresistant patients, except in one, who continued treatment for 12months. Among the 15 responsive patients, six of the eight (75%)partial responders normalized cortisol levels after 6–12 monthtreatment with increasing cabergoline dose. However, two of theseven (28.6%) full responders and three of the eight (37.5%)partial responders experienced a treatment escape after 12–18month treatment, and stopped treatment. At the 12-month fol-low-up, 10 (50%) patients were persistently controlled at themedian cabergoline dose of 6 mg/wk (1–7 mg/wk). Cabergo-line was discontinued during the second year of follow-up intwo (10%) patients who did not tolerate the treatment be-cause of severe asthenia associated with hypotension. At the24-month follow-up, eight (40%) patients were persistentlycontrolled at a median cabergoline dose of 3.5 mg/wk (1–7mg/wk) (Figs. 1 and 2). In these patients, all multiple urinarycortisol levels were within the normal range, or very close tothe upper limit of the normal range. A flowchart explaining thedisposition of the different patients during the short-term and long-term study and the corresponding outcome of the treatment isshown in Fig. 3. The presence of hyperprolactinemia was signifi-

cantlyassociatedwiththeresponsiveness toshort-term(!2"5.455;P " 0.038), but not long-term (!2 " 5.051; P " 0.070), treatment.

Effectiveness of treatment with cabergoline

Short-term treatment (Table 2)The clinical picture improved in the majority of responsive

patients, whereas it mildly improved, remained stable, ormildly worsened in resistant patients. Despite a mild increaseof body mass index, waist to hip ratio significantly decreased,as well as blood pressure, serum glucose and insulin, HOMA-IR, and tumor volume. Systolic and diastolic blood pressuresignificantly decreased in resistant patients as well, whereasHOMA-B did not change both in responsive and resistancepatients. PRL levels were lower than the normal range in allpatients.

Long-term treatmentResponsive patients (Table 3). The clinical picture further im-proved during treatment. Body mass index slightly increasedduring the first 3–6 months, but significantly decreased there-after, whereas waist to hip ratio progressively decreased. Theprevalence of overweight or obesity decreased from 87.5% atbaseline to 62.5% at the 24-month treatment. The distributionof fat mass was modified from an abdominal to a generalizedpattern in the majority of patients. Muscle mass and strength aswell as skin features slightly or significantly improved in themajority of patients. Systolic and diastolic blood pressure valuessignificantly decreased, becoming stable after 6–12 month treat-ment. The prevalence of hypertension decreased from 50% at

0 3 6 9 12 15 18 21 24

0

250

500

750

1000

months

urin

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cort

isol

leve

ls( µ

g/da

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FIG. 1. Urinary cortisol levels during the entire period of treatment in all 20 patients treated with cabergoline. The patients long-term response to cabergolinetreatment are shown with black lines, those with early response and late escape are shown with purple lines, and those nonresponders to the treatment areshown with red lines. The shaded area indicates the normal range of urinary cortisol levels (35–135 "g/d). Urinary cortisol levels represent the mean of threedifferent urine collections performed on three different nonconsecutive days of the same week.

226 Pivonello et al. Cabergoline Treatment in CD J Clin Endocrinol Metab, January 2009, 94(1):223–230

Eight out of 20 patients normalized their cortisol

Effectiveness of cabergoline in monotherapy and combinedwith ketoconazole in the management of Cushing’s disease

Lucio Vilar • Luciana A. Naves • Monalisa F. Azevedo • Maria Juliana Arruda •

Carla M. Arahata • Lidiane Moura e Silva • Rodrigo Agra • Lisete Pontes •

Larissa Montenegro • Jose Luciano Albuquerque • Viviane Canadas

Published online: 27 November 2009! Springer Science+Business Media, LLC 2009

Abstract The expression of dopamine receptor subtypeshas been reported in corticotroph adenomas, and this

finding support the possibility for medical treatment of

Cushing’s disease (CD) with dopamine agonists whenconventional treatment has failed. The aim of this study

was to evaluate the effectiveness of cabergoline (at doses

of up 3 mg/week), alone or combined with relatively lowdoses of ketoconazole (up to 400 mg/day), in 12 patients

with CD unsuccessfully treated by transsphenoidal surgery.

After 6 months of cabergoline therapy, normalization of24 h urinary free cortisol (UFC) levels occurred in three

patients (25%) at doses ranging from 2–3 mg/week,

whereas reductions ranging from 15.0 to 48.4% were foundin the remaining. The addition of ketonocazole to the nine

patients without an adequate response to cabergoline was

able to normalize UFC excretion in six patients (66.7%) atdoses of 200 mg/day (three patients), 300 mg/day (two

patients) and 400 mg/day (one patient). In the remaining

patients UFC levels did not normalize but a significant

reduction ranging from to 44.4 to 51.7% was achieved. Intwo of the six responsive patients to combination therapy,

the weekly dose of cabergoline could be later reduced from

3 to 2 mg. Our findings demonstrated that cabergolinemonotherapy was able to reverse hypercortisolism in 25%

of patients with CD unsuccessfully treated by surgery.

Moreover, the addition of relatively low doses of keto-conazole led to normalization of UFC in about two-thirds

of patients not achieving a full response to cabergoline.

Keywords Cushing’s disease ! Cabergoline !Ketoconazole

Introduction

Cushing’s disease (CD), the most common form of

endogenous Cushing’s syndrome, is caused by an ACTH-secreting pituitary tumor and is associated with increased

morbidity and mortality particularly due to metabolic and

cardiovascular complications [1–3]. The treatment ofchoice for CD is transsphenoidal surgery (TSS) which

yields immediate disease remission in about 70% ofpatients but the late disease remission rate is around 50%

[4, 5]. Pituitary irradiation [6] and bilateral adrenalectomy

[7] are alternative treatment approaches but they can beassociated with serious complications, such as hypopitu-

itarism and Nelson’s syndrome, respectively [4, 5].

There is currently no medical therapy for CD that targetsthe pituitary adenoma. Pharmacotherapy, particularly

ketoconazole (an adrenal blocking drug), is rather used

before surgery or as a transient palliative treatment beforedefinitive cure in patients submitted to pituitary radio-

therapy [4, 8]. There are also few reports of successful

primary therapy with ketoconazole in patients that refused

L. Vilar ! M. J. Arruda ! C. M. Arahata ! L. Moura e Silva !R. Agra ! L. Pontes ! L. Montenegro ! J. L. Albuquerque !V. CanadasDivision of Endocrinology, Hospital das Clınicas, FederalUniversity of Pernambuco, Recife, Brazil

L. VilarPernambuco Center for Diabetes and Endocrinology, FederalUniversity of Pernambuco, Recife, Brazil

L. A. Naves ! M. F. AzevedoDivision of Endocrinology, Hospital Universitario de Brasilia,Brasilia, Brazil

L. Vilar (&)Rua Clovis Silveira Barros, 84/1202, Boa Vista, Recife CEP50.050-270, Brazile-mail: [email protected]

123

Pituitary (2010) 13:123–129

DOI 10.1007/s11102-009-0209-8

Cabergoline alone

Statistical analysis

In the analysis of qualitative variables, the v2 test or theFisher exact test (when necessary) was used. The Student

t-test was performed for the comparative analysis of

quantitative variables. Results are expressed as percent-ages and mean values ± SD unless otherwise indicated.

P values\0.05 were considered statistically significant.

Results

Responsiveness to treatment with cabergoline

Comparing the last value during cabergoline monotherapywith baseline (Table 1), mean ± SD UFC levels decreased

from 637.8 ± 245.7 (range 226–991) lg/day to 434.1 ±

256.8 (range 82–791) lg/day (P\ 0.001). Normalizationof UFC levels occurred in three patients (25%) at caberg-

oline doses ranging from 2 to 3 mg/week (mean ± SD,

2.5 ± 0.5), whereas reductions ranging from 15.0 to 48.4%were found in the remaining. Three patients were labeled

as resistant to cabergoline (UFC decrease\25%). In two

patients, the normalization of UFC excretion was achievedat the dose of 2 mg/week (Table 1) (Fig. 1).

Regardless the UFC normalization, all patients reported

improvement of clinical symptoms during the treatmentwith cabergoline.

Responsiveness to treatment with cabergolineand ketoconazole

The addition of ketonocazole, at doses ranging from 200

to 400 mg/day (mean ± SD, 325 ± 103.5), to the nineTable

1Characteristicsofthepatients

andtheirresponse

tothetreatm

entwithcabergoline(CAB)

Patients

Age/

sex

IHC

CABdose

(mg/week)

Durationoftreatm

ent

(months)

UFC

norm

alization

UFC

reduction(%

)UFCbefore

CAB(lg/d)

UFCafter

CAB(lg/d)

Baseline

PRL

No.1

34/F

ACTH

(?)

2.0

6Yes

66.7

226

82

Nl

No.2

37/F

ACTH

(?)

2.0

6Yes

68.6

280

88

Nl

No.3

40/F

ACTH

(?)

3.0

6Yes

77.6

368

82.5

Nl

No.4

47/M

ACTH

(?)

3.0

6No

34.6

523

342

Nl

No.5

43/M

ACTH

(?)

3.0

6No

37.4

591

370

Nl

No.6

44/M

ACTH

(?)

3.0

6No

48.4

680

351

Nl

No.7

52/M

ACTH

(?)

3.0

6No

26.4

735

541

Nl

No.8

38/F

ACTH

(?)

3.0

6No

26.1

720

532

Nl

No.9

51/F

ACTH

(?)

3.0

6No

26.5

792

582

Nl

No.10

48/F

ACTH

(?)

3.0

6No

19.2

882

712

Nl

No.11

46/F

ACTH

(?)

3.0

6No

15.0

866

736

Nl

No.12

34/F

ACTH

(?)

3.0

6No

20.2

991

791

Nl

IHC

immunohystochemistry,PRLprolactin,Nlnorm

al

Urinary

freecortisol(U

FC)norm

alrange=

10–90lg/day

Fig. 1 Changes in 24 h urinary free cortisol levels after treatmentwith cabergoline. The number on each arrow indicates the maximaldose of cabergoline expressed in mg/week administered to eachpatient

Pituitary (2010) 13:123–129 125

123

patients without a full response to cabergoline yielded a

mean ± SD UFC levels decrease from 520.7 ± 156.1(range 342–791) lg/day to 149.6 ± 124.1 (range 72–385)

lg/day (P\ 0.001). Normalization of UFC levels were

achieved at doses of 200 mg/day in three patients, 300 mg/day in two patients and 400 mg/day in one patient. In the

remaining patients UFC levels could not be normalized but

a significant reduction ranging from to 44.4 to 51.7% wasachieved (Table 2) (Fig. 2). As shown in Table 2, UFC

levels in patients that did not respond to combinationtherapy was significantly higher than those of responsive

patients: 746.3 ± 40.5 (range 712–791) lg/day versus

453 ± 109.7 (range 342–582) lg/day (P\ 0.001). Bycontrast, there was no correlation between the response to

treatment and PRL levels (normal in all patients) or the

expression of PRL by immunohystochemistry (negative inall subjects). In two out of the six responsive patients to

combined therapy, the weekly dose of CAB could be later

reduced from 3 to 2 mg without elevation UFC levelsbeyond the upper limit of the normal range.

Overall, normalization of daily UFC excretion could be

obtained in nine patients (75%), three (25%) submitted tocabergoline monotherapy and in six (66.7%) undergoing

the combination of cabergoline with ketoconazole. The

response was not infleuTreatment escape, manifested asrelapse of hypercortisolism and elevation of UFC levels

during the use of cabergoline alone or combination therapy,

was not observed in any patient.

Tolerability

Cabergoline and ketoconazole were well tolerated and

none of the patients had to interrupt the treatment. Tran-

sient moderate dizziness and/or nausea were reported bythree patients treated with cabergoline. After the addition

of ketoconazole, mild transient elevation of transaminaseswas found in one out of nine patients (11.1%). No patients

developed symptoms of hypoglycemia while on cabergo-

line or combined therapy. Moreover, none of the patientsexperienced any significant symptom or sign related to

cardiac disease; particularly, no patients developed cardiac

valve regurgitation.

Discussion

Unlike prolactinomas and acromegaly, currently there is

not an effective medication to treat Cushing’s disease thatacts at the level of the pituitary gland inhibiting ACTH

secretion by the corticotroph tumor [1, 2]. Some neuro-

modulatory drugs were used in the past, however, due to

Table 2 Characteristics of the patients and their response to the treatment with cabergoline (CAB) ? ketoconazole (KTCZ)

Patients CAB dose(mg/wk)

KTCZ dose(mg/d)

Duration oftreatment(months)

UFCnormalization

UFCreduction(%)

UFC beforeKTCZ (lg/d)

UFC afterKTCZ (lg/d)

No. 4 3.0 200 6 Yes 75.1 342 85

No. 5 3.0 200 6 Yes 76 370 89

No. 6 3.0 200 6 Yes 74.3 351 90

No. 7 3.0 300 6 Yes 86.7 541 72

No. 8 3.0* 300 6 Yes 85.3 532 78

No. 9 3.0* 400 6 Yes 85.2 582 86

No. 10 3.0 400 6 No 44.4 712 316

No. 11 3.0 400 6 No 51.7 736 381

No. 12 3.0 400 6 No 48.7 791 385

In patients No. 8 and 9 the dose of cabergoline could be later reduced to 2 mg/week

Urinary free cortisol (UFC) normal range = 10–90 lg/day

Fig. 2 Changes in 24 h urinary free cortisol levels after treatmentwith cabergoline and ketoconazole. The number on each arrowindicates the maximal dose of ketoconazole expressed in mg/dayadministered to each patient

126 Pituitary (2010) 13:123–129

123

Cabergoline plus KetoconazoleEffectiveness of cabergoline in monotherapy and combinedwith ketoconazole in the management of Cushing’s disease

Lucio Vilar • Luciana A. Naves • Monalisa F. Azevedo • Maria Juliana Arruda •

Carla M. Arahata • Lidiane Moura e Silva • Rodrigo Agra • Lisete Pontes •

Larissa Montenegro • Jose Luciano Albuquerque • Viviane Canadas

Published online: 27 November 2009! Springer Science+Business Media, LLC 2009

Abstract The expression of dopamine receptor subtypeshas been reported in corticotroph adenomas, and this

finding support the possibility for medical treatment of

Cushing’s disease (CD) with dopamine agonists whenconventional treatment has failed. The aim of this study

was to evaluate the effectiveness of cabergoline (at doses

of up 3 mg/week), alone or combined with relatively lowdoses of ketoconazole (up to 400 mg/day), in 12 patients

with CD unsuccessfully treated by transsphenoidal surgery.

After 6 months of cabergoline therapy, normalization of24 h urinary free cortisol (UFC) levels occurred in three

patients (25%) at doses ranging from 2–3 mg/week,

whereas reductions ranging from 15.0 to 48.4% were foundin the remaining. The addition of ketonocazole to the nine

patients without an adequate response to cabergoline was

able to normalize UFC excretion in six patients (66.7%) atdoses of 200 mg/day (three patients), 300 mg/day (two

patients) and 400 mg/day (one patient). In the remaining

patients UFC levels did not normalize but a significant

reduction ranging from to 44.4 to 51.7% was achieved. Intwo of the six responsive patients to combination therapy,

the weekly dose of cabergoline could be later reduced from

3 to 2 mg. Our findings demonstrated that cabergolinemonotherapy was able to reverse hypercortisolism in 25%

of patients with CD unsuccessfully treated by surgery.

Moreover, the addition of relatively low doses of keto-conazole led to normalization of UFC in about two-thirds

of patients not achieving a full response to cabergoline.

Keywords Cushing’s disease ! Cabergoline !Ketoconazole

Introduction

Cushing’s disease (CD), the most common form of

endogenous Cushing’s syndrome, is caused by an ACTH-secreting pituitary tumor and is associated with increased

morbidity and mortality particularly due to metabolic and

cardiovascular complications [1–3]. The treatment ofchoice for CD is transsphenoidal surgery (TSS) which

yields immediate disease remission in about 70% ofpatients but the late disease remission rate is around 50%

[4, 5]. Pituitary irradiation [6] and bilateral adrenalectomy

[7] are alternative treatment approaches but they can beassociated with serious complications, such as hypopitu-

itarism and Nelson’s syndrome, respectively [4, 5].

There is currently no medical therapy for CD that targetsthe pituitary adenoma. Pharmacotherapy, particularly

ketoconazole (an adrenal blocking drug), is rather used

before surgery or as a transient palliative treatment beforedefinitive cure in patients submitted to pituitary radio-

therapy [4, 8]. There are also few reports of successful

primary therapy with ketoconazole in patients that refused

L. Vilar ! M. J. Arruda ! C. M. Arahata ! L. Moura e Silva !R. Agra ! L. Pontes ! L. Montenegro ! J. L. Albuquerque !V. CanadasDivision of Endocrinology, Hospital das Clınicas, FederalUniversity of Pernambuco, Recife, Brazil

L. VilarPernambuco Center for Diabetes and Endocrinology, FederalUniversity of Pernambuco, Recife, Brazil

L. A. Naves ! M. F. AzevedoDivision of Endocrinology, Hospital Universitario de Brasilia,Brasilia, Brazil

L. Vilar (&)Rua Clovis Silveira Barros, 84/1202, Boa Vista, Recife CEP50.050-270, Brazile-mail: [email protected]

123

Pituitary (2010) 13:123–129

DOI 10.1007/s11102-009-0209-8




MifepristoneY

GrowthHormone

Y

Y

Y

Y

PP

Fn II

I

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Y

GrowthHormone

Y

Y

Y

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PPPP

Fn II

I

Fn III

Fn II

I

Fn III

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Y

Y

Y

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Fn III

Fn III

Y

Y

Y

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Fn III

Fn III

Fn III

Y

GrowthHormone

Y

Y

Y

Y

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GrowthHormone

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Y

Y

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I

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Y

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Y

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Fn III

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Fn III

Fn III

Fn III

Y

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Y

Y

Y

Y

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Fn III

Fn III

Y

GrowthHormone

Y

Y

Y

Y

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Fn III

Fn III

Fn III

Y

Y

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Y

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Fn III

Y

Y

Y

Y

Y

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Fn III

Fn III

Fn III

Y

Growth

Hormone

Y

Y

Y

Y

PP

Fn III

Fn III

Y

Growth

Hormone

Y

Y

Y

Y

PPPP

Fn III

Fn III

Fn III

Fn III

Y

Y

Y

Y

Y

PP

Fn III

Fn III

Y

Y

Y

Y

Y

PPPP

Fn III

Fn IIIFn III

Fn III

Y1146

Y1151

Y960

Y1316

Y1322

Kinase

Y1150Y1146

Y1151

Y960

Y1316

Y1322

Kinase

Y1150

Y

Y

Y9

Y1

Y1

Kina

se

Y1150

Y

Y

Y9

Y1

Y1

Kina

se

Y1150

Insulin

SSS

S

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Insulin

SSS

S

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PI3K

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IGF-I





Mifepristone

• Glucocorticoid receptor (GR) antagonist blocks the action of cortisol by binding to the GR-II (cortisol) receptor – 3–4-fold higher affinity than dexamethasone – 18-fold higher affinity than cortisol

• In Phase III clinical development as a treatment for endogenous Cushing’s syndrome Screening

42 days 24-week treatment

Day 1 Week 6 Week 10 Week 16 Week 24

n=50 enrolled

n=84 screened

Dose escalation until week 10

n=34 completed

Fleseriu M et al. Endocr Rev 2011;32:OR09-5

Mifepristone in Cushing’s disease: Conclusions

• Mifepristone treatment was associated with clinical improvements in patients with refractory Cushing’s syndrome – Glucose tolerance and hypertension improved in 60% and 38%,

respectively – Body weight decreased by an average of 5.7 kg – Waist circumference decreased by an average of 7 cm

in women and 8 cm in men

• However, mifepristone blocks the glucocorticoid receptor rather than targeting the underlying cause of Cushing’s disease

• Increases in ACTH and UFC levels were observed on mifepristone treatment




MifepristoneY

GrowthHormone

Y

Y

Y

Y

PP

Fn II

I

Fn III

Y

GrowthHormone

Y

Y

Y

Y

PPPP

Fn II

I

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Fn II

I

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Y

Y

Y

Y

Y

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Fn III

Y

Y

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Y

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Y

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Y

Y

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Y

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Y

Y

Y

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Y

Y

Y

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Y

GrowthHormone

Y

Y

Y

Y

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Fn II

I

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Fn II

I

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Y

Y

Y

Y

Y

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Fn III

Fn III

Y

Y

Y

Y

Y

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Fn III

Fn III

Fn III

Fn III

Y

GrowthHormone

Y

Y

Y

Y

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Fn III

Fn III

Y

GrowthHormone

Y

Y

Y

Y

PPPP

Fn III

Fn III

Fn III

Fn III

Y

Y

Y

Y

Y

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Fn III

Fn III

Y

Y

Y

Y

Y

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Fn III

Fn III

Fn III

Fn III

Y

GrowthHormone

Y

Y

Y

Y

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Fn II

I

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Y

GrowthHormone

Y

Y

Y

Y

PPPP

Fn II

I

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Fn II

I

Fn III

Y

Y

Y

Y

Y

PP

Fn III

Fn III

Y

Y

Y

Y

Y

PPPP

Fn III

Fn III

Fn III

Fn III

Y

GrowthHormone

Y

Y

Y

Y

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Fn III

Fn III

Y

GrowthHormone

Y

Y

Y

Y

PPPP

Fn III

Fn III

Fn III

Fn III

Y

Y

Y

Y

Y

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Fn III

Fn III

Y

Y

Y

Y

Y

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Fn III

Fn III

Fn III

Fn III

Y

Growth

Hormone

Y

Y

Y

Y

PP

Fn III

Fn III

Y

Growth

Hormone

Y

Y

Y

Y

PPPP

Fn III

Fn III

Fn III

Fn III

Y

Y

Y

Y

Y

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Fn III

Fn III

Y

Y

Y

Y

Y

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Fn III

Fn IIIFn III

Fn III

Y1146

Y1151

Y960

Y1316

Y1322

Kinase

Y1150Y1146

Y1151

Y960

Y1316

Y1322

Kinase

Y1150

Y

Y

Y9

Y1

Y1

Kina

se

Y1150

Y

Y

Y9

Y1

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se

Y1150

Insulin

SSS

S

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Insulin

SSS

S

SS

PI3K

JAK2

Ins Ins-R

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Pasireotide

• Multireceptor-targeted somatostatin analogue – 30-, 5- and 39-fold higher affinity for sst1, sst3 and

sst5 than octreotide, and similar affinity for sst21

• Expression of sst5 predominates in ACTH-secreting pituitary adenomas2,3

– sst1, sst2 and sst3 are also expressed

• Broad binding profile means that pasireotide may be an effective treatment for Cushing’s disease

N H

O

N H

O N

O

O N H

N H

N H

N H N H

O

O

O O

N H 2

O

N H 2

1. Bruns C et al. Eur J Endocrinol 2002;146:707–716 2. Strowski MZ et al. Neuroendocrinology 2002;75:339–346

3. Sharma K et al. Mol Endocrinol 1999;13:82–90

2500

Change in UFC from baseline to month 6 in the 103 patients with baseline and month-6 UFC measurements

Individual patients sorted by baseline UFC

UFC

(�g/

24 h

)

0

180

360

540

720

1400

600 µg bid

900 µg bid

ULN†

Baseline UFC Month-6 UFC Month-6 UFC �ULN *

†Reference line is the upper limit normal UFC, which is 52.5 �g/24 h (145 nmol/24 h)

Median percentage UFC change from baseline was –47.9% in both groups

Response status

600 µg bid (n=82)

900 µg bid (n=80)

Overall (n=162)

6-month response, n (%)* 12 (14.6) 21 (26.3) 33 (20.4)

95% confidence interval (7.0, 22.3) (16.6, 35.9) (14.2, 26.6)

12-month response, n (%)† 11 (13.4) 20 (25.0) 31 (19.1)

Primary efficacy results

Predetermined criterion for the primary efficacy endpoint: lower bound of the 95% CI >15% for either of the dose groups;

this was met for the 900 µg group

*NOTE: Responder was a patient with UFC �� uptitration

†NOTE: Responder was a patient with UFC ��irrespective of uptitration

LCI699

1Menard J et al. J Am Coll Cardiol 2010;55:A61.E583

Highly potent inhibitor of 11β-hydroxylase (Three times more potent then metyrapone for inhibiting 11β-hydroxylase Also inhibits aldosterone synthase

LCI699 mechanism of action

Pregnenolone

11-deoxycortisol

Cortisol

17-OH pregnenolone

17-OH progesterone

Cholesterol

ACTH

Aldosterone

CYP11B

2

Corticosterone

18-OH corticosterone

LCI699

CYP11B1 LCI699

Feedback loop malfunctioning in Cushing’s

Progesterone

Dehydroepiandrosterone

Androstenedione

Testosterone


Estradiol

Estrone

Potent inhibitor of 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2)Blocks last steps in cortisol and aldosterone production

•  It is administered orally and it displays a half-life longer than metyrapone, allowing twice-daily dosing

•  It has a three times higher potency (in vitro IC50 for CYP11B1 ��of 2.5 nM vs 7.5 nM) than metyraponeIC50, half maximal inhibitory concentration

X

X

11-deoxycortisol

ACTH

Testosterone


Pivonello R. et al. Oral presentation OR17-4 ENDO 2014, Chicago, IL, USA, June 22, 2014 14MDL160E July 5th, 2014

LCI699 early study Inclusion

Male or female patients aged 18–75 years Confirmed Cushing’s disease UFC >1.5x ULN (mean of three 24-hour urine samples) No other current medical treatment for Cushing’s disease

Exclusion Tumour with chiasmal compression Poorly controlled diabetes (HbA1c >9%)

HbA, hemoglobin A; ULN, upper limit of normal

Pivonello R et al. Endocr Rev 2012;33:abst OR49-1 14MDL160E July 5th, 2014

Demographics and baseline characteristics

Patients (N=12)

Mean age ± SD, years (range) 39.0 ± 10.3 (22–55)

Females: males 8:4

Caucasian, n (%) 12 (100)

Mean BMI ± SD, kg/m2 (range) 33.8 ± 8.5 (23.8–48.7)

Prior pituitary surgery, n (%) 10 (83)

Mean UFC ± SEM, µg/24h (range) 345.8 ± 111.0 (115.0–1530.7)

Mean UFC ± SEM, fold ULN (range) 4.7 ± 1.3 (1.6–17.0)

Pivonello R et al. Endocr Rev 2012;33:abst OR49-1

BMI, body mass index; SD, standard deviation; SEM, standard error of the mean

14MDL160E July 5th, 2014

Urinary cortisol over time in all patients

Mea

n U

FC ±

SEM

(fol

d U

LN)

0

1

2

3

4

5

6

7

1 14 28 42 56 70 84

Day

LCI699 dose escalation Washout

All 12 patients had normalized UFC or >50% reduction in UFC by day 70 –  11/12 (92%) had normal 24-hour UFC at day 70 –  Urinary cortisol normalized at least once in all 12 patients


LCI699 doses required to normalize UFC

The doses most frequently associated with 24-hour UFC normalization were 10 and 20 mg/day

0

1

2

3

4

5

6

<10 10 20 30 40 100Dose (mg/day)

Patie

nts

(n)

Pivonello R et al. Endocr Rev 2012;33:abst OR49-1 14MDL160E July 5th, 2014

Changes in clinical and laboratory features during LCI699 treatment

Baseline (n=12)

Day 70 (n=12)

Change from baseline (n=12)

SBP, mmHg 139.3 ± 4.4 129.3 ± 5.5 –10.0 ± 4.3

DBP, mmHg 88.8 ± 3.8 82.8 ± 3.0 –6.0 ± 4.3

Weight, kg 96.8 ± 8.8 100.3 ± 9.5 3.5 ± 1.4

Glucose, mmol/L 5.4 ± 0.5 5.7 ± 0.4 0.3 ± 0.3

Potassium, mEq/L 4.1 ± 0.1 3.8 ± 0.2 –0.3 ± 0.2

Sodium, mEq/L 140.3 ± 1.1 140.8 ± 1.0 0.5 ± 1.1


NOTE: Data presented as mean ± SEM DBP, diastolic blood pressure; SBP, systolic blood pressure

14MDL160E July 5th, 2014

LINC 1: Most common AEs* during treatment with LCI699 (occurring in at least two patients)

Patients, n (%) Fatigue 7 (58.3) Nausea 5 (41.6) Diarrhea 3 (25.0) Headache 3 (25.0) Hypokalemia 3 (25.0) Muscle spasms 3 (25.0) Vomiting 3 (25.0) Abdominal discomfort 2 (16.6) Abdominal pain 2 (16.6) Arthralgia 2 (16.6) Arthropod bite 2 (16.6) Dizziness 2 (16.6) Lipase increased 2 (16.6) Pruritus 2 (16.6)

*Assessed based on MedDRA definitions Pivonello R et al. Endocr Rev 2012;33:abst OR49-1 14MDL160E July 5th, 2014

Mitotane, Etomidate and Metyrapone

These drugs are only used in malignant cortisol producing tumours of the adrenal gland Long-term use of these agents in ACTH producing pituitary tumours is NOT indicated.

Amy’s case

-  Underwent surgery -  In remission since then -  Lost over 75 lbs -  BP normal -  Working as a nurse

Watercolor – Fall River, NS S. Ali Imran, 2011

Documents

Medical Management of Cushing’s Disease · Medical Management of Cushing’s Disease Dr S. Ali Imran MBBS, FRCP (Edin), FRCPC Professor of Medicine Division of Endocrinology & Metabolism