Definisi

• adalah kondisi klinik sebagai akibat dari paparan

kronik glukokortikoid menyebabkan kadar
glukokortikoid dlm sirkulasi berlebihan.
disebut juga sebagai
• hiperadrenokortikalisme
• Hiperadrenalkortikalisme
• Hiperkortisolisme
• Penyebab paling umum : sekresi berlebih ACTH dari
kelenjar hipofisis anterior (Cushing’s disease)
ETIOLOGI

A. Cushing’s disease :
Dapat tjd :
• secara spontan  cushing’s syndrome
spontaneous atau , merupakan penyebab
terbesar, kejadian kira2 2 – 4 kasus / juta populasi
dan pd wanita 9 X lebih banyak drpd laki-laki
• sebagai hasil pemberian kronik (jangka panjang)
kortikosteroid  Cushing’s syndrome iatrogenic
Spontaneous cushing’s syndrome / Cushing’s disease
bisa tjd akibat :
• Adenoma hipofisis sekresi berlebih ACTH (> 90%)
• Hiperplasia difuse / pituitary corticotroph cells yg
bertanggung jawab thdp hipersekresi ACTH
Hiperplasia kmk krn hipersekresi CRH oleh hipotalamus
atau tumor pensekresi CRH (CRH-secreting tumors)
Hipersekresi kronik CRH tidak menyebabkan adenoma
hipofisis
B. Ectopic ACTH Syndrome
Tumor non hipofisis mensintesis & mensekresikan secara berlebih
(hipersekresi) ACTH yg aktif secara biologi atau peptida menyerupai
ACTH (ACTH-like peptide)
Biasanya karsinoma sel kecil dari paru atau tumor karsinoid dari
bronkhial
Lebih banyak menyerang laki-laki
C. ECTOPIC CRH Syndrome
• Sangat jarang menyebabkan Cushing’s Syndrome
• Sebagian besar kasus berhub dg tumor karsinoid bronkhial
D. Functioning Adrenocortical Tumors
Baik adrenocortical adenoma dan carcinoma menyebabkan Cushing’s
syndrome melalui pengeluaran kortisol secara autonom
Adenoma memp vaskuler yang tinggi, dengan area nekrosis,
perdarahan, degenerasi kista dan kalsifikasi bisa metastase ke ginjal,
retroperitoneum, liver dan paru
E. Adrenal Micronodular Hyperplasia
Jarang menyebabkan Cushing’s Syndrome
Sekitar separuh kasus timbul secara mendadak pada anak2 dan dewasa
muda
F. Adrenal Macronodular Hyperplasia
Jarang menyebabkan Cushing’s Syndrome
Beberapa pasien dg macronodular hyperplasia tidak menunjukkan
gambaran cushingoid tipikal
Patofisiologi
Patofisiologi

Penyebab dapat dibagi 2 kategori :

ACTH-dependent peningkatan kadar kortisol tergantung pada
ACTH dan tidak dapat menekan sekresi ACTH dari hipofisis
ACTH-independent peningkatan kadar kortisol tidak tergantung
ACTH (autonom) dan dapat menekan sekresi ACTH dari hipofisis
Klasifikasi

ACTH dependent
Cushing’s disease
Ectopic ACTH syndrome
Ectopic corticotropin-releasing hormone syndrome*
ACTH independent
Iatrogenic
Adrenal adenoma
Micronodular hyperplasia*
Macronodular hyperplasia*

Ket : ACTH : Adrenocorticotropin hormone

* : accounts per 1 percent or less of cases
(Adapted with permission from Orth DN Cushing’s Syndrome. N Engl. J.
Med, 1995 ; 332 : 791 – 803)
• ACTH-dependent Cushing’s syndrome :
~ Cushing’s disease 80% kasus ACTH-dependent
~ Ectopic ACTH hypersecretion 20%
~ Ectopic CRH secretion jarang
Dimana kesemuanya ditandai dg hipersekresi ACTH kronik dan
peningkatan sekresi kortisol
• ACTH-independent Cushing’s syndrome :
~ Glucocorticoid-secreting adrenocortical adenoma dan carcinoma
~ Adrenal micronodular dan macronodular hyperplasia
Kesemuanya ditandai dg sekresi secara autonom kortisol dan penekanan
ACTH hipofisis
Adrenal tumor

• Carcinoma dan adrenal

adenoma primer tidak di
bawah kendali hipotalamus-
hipofisis dan kmd secara
autonom mensekresikan
lebih kortisol
• Hiperkortisol menekan
produksi ACTH hipofisis
menyebabkan atrofi
korteks adrenal
Manifestasi Klinik
FUNGSI KORTISOL

Memelihara tekanan darah dan fungsi kardiovaskuler.

Menurunkan respon inflamasi sistem imun.
Menyeimbangkan efek insulin dalam memecah glukosa
untuk energi.
Mengatur metabolisme protein, karbohidrat, dan lemak.
Fungsi terpenting : membantu tubuh terhadap respon
stress.
(kadar kortisol wanita pada kehamilan 3 bln terakhir
dan atlit secara normal tinggi).
dmk juga pada orang2 dg depresi, alkoholisme,
malnutrisi dan gangguan panik.
GEJALA

Obesitas tubuh bagian atas, muka bulat, peningkatan lemak sekitar

leher, lengan dan kaki kurus, pada anak-anak pertumbuhan lambat.
Gejala lain : kulit fragile, kurus, memar dan tidak sehat, kulit warna
ungu pink pada perut, paha, lengan dan payudara.(striae)
Tulang rapuh dan bengkok, patah tulang (fraktur) pada tulang rusuk
(iga) dan tulang belakang.
Sangat lelah, otot lemah, tek. darah dan kadar gula darah tinggi,
irritabilitas, ansietas, depresi.
Pertumbuhan rambut pada muka, leher, dada, perut dan paha (pada
wanita)
Periode menstruasi tidak teratur/ terhenti.
Penurunan libido sex pada laki-laki
Penderita Cushing’s Syndrome
Penderita Cushing’s Syndrome anak
Gejala Cushing’s Syndrome
Striae pada abdomen dan payudara
Moonface
Moonface
Striae pada stomach
Striae
Pertumbuhan rambut pada dada
Striae pada lengan
Striae pada siku
Buffalohump (punggung menebal)
Buffalohump (punggung menebal)
Exogenous Cushing
Syndromme
DIAGNOSIS

Berdasarkan tinjauan riwayat medis pasien,

pemeriksaan fisik, dan test lab.
X ray : utk menentukan lokasi tumor.
24 urin 24 jam bebas kortisol
paling spesifik, kadar > 50 – 100 µg / hari utk
dewasa cushing’s syndrome
Test Supresi Dexametason
utk membedakan peningkatan ACTH karena
adenoma hipofisis dan tumor ektopik.
Test Stimulasi CRH
utk membedakan antara adenoma hipofisis dengan
sindroma ACTH ektopik atau tumor adrenal penghasil
kortisol
DIAGNOSIS

Visualisasi langsung Kelenjar Endokrin (Imaging

Radiologi)
- melihat ukuran dan bentuk kelenjar hipofisis dan
adrenal serta menentukan jika ada tumor.
- dengan CT ( Computerized Tomography) scan dan
MRI (Magnetic Resonance Imaging).
Sampling Sinus Petrosal
- test terbaik utk membedakan penyebab Cushing’s
syndrome antara hipofisis dengan ektopik.
Test Dexametason – CRH
- membedakan Cushing’s syndrome dengan Pseudo
Cushing’s Syndrome secara cepat.
- Peningkatan kadar kortisol selama test menunjukkan
adanya Cushing’s Syndrome
• Pseudo-Cushing's syndrome is a medical condition in which patients
display the signs, symptoms, and abnormal hormone levels seen in
Cushing's syndrome. Pseudo-Cushing's syndrome, however, is not
caused by a problem with the hypothalamic-pituitary-adrenal axis as
Cushing's is. It is an idiopathic condition.
Pemeriksaan lab Pseudo
Cushing Syndromme
• Levels of cortisol and ACTH are both high
• 24-hour urinary cortisol levels are high
• Dexamethasone suppression test fails to suppress
serum cortisol
• Loss of diurnal variation in cortisol levels- Loss of
Diurnal Variation is seen only in true Cushing's
Syndrome or Disease.
• High mean corpuscular volume and gamma-
glutamyl transferase may be clues to alcoholism
• Polycystic Ovarian Syndrome should be ruled out,
since PCOS has similar symptoms.
Diagnosis
banding=Differential
diagnosis
• Differentiation from Cushing's is extremely difficult
• Causes of Cushing's should be excluded with
imaging of the lungs, adrenal glands, and pituitary
gland - but these often appear normal in Cushing's
anyway
• In the alcoholic patient with pseudo-Cushing's,
admission to hospital (and avoidance of alcohol) will
result in normal midnight cortisol levels within 5
days, excluding Cushing's[1]
Diagnosa kerja utk menegakkan
Cushing’s Syndrome
MRI pada adrenal tumor
Test utk mendiagnosa Cushing’s
syndrome
Test Normal Hyperplasia Adenoma Carcinoma

Plasma

Kortisol 17/8 /  /   /

(μg/dL, 
AM/PM)
After low-  Normal Normal Normal
dose DST
After high-   / Normal Normal Normal
dose DST
ACTH 10 - 80   
(pg/mL)
Urine

Kortisol 20 - 90   
(μg/24 h)
Sasaran terapi

Karena terjadi hiperkortisolisme maka sasaran terapinya adl

menurunkan kadar kortisol plasma

TERAPI tergantung etiologi / penyebab

Terapi farmakologi obat
Terapi non farmakologitindakan bedah / operasi dan radiasi
 TERAPI
Treatment

Dosing
Etiology Non drug Drug Initial Usual Max
Ectopic Surgery Metyrapone 1 – 1, 5 g/d, 1 – 6 g/d, 6 g/d
ACTH syndrome Chemotherapy tabs divided q4-6 h divided q4-6
Irradiation 250 mg h
Aminoglutethi 0,5-1 g/d, 1 g/d, 2 g/d
mide tabs, 250 divided 96 bid – divided q6
mg qid x 2 weeks

Pituitary Surgery Cyproheptadin 4 mg bid 24 – 32 32 mg/d

dependent Irradiation e, 2 mg/5 mL mg/d.,
syrup or 4 mg divided qid
tabs
Mitotane tabs
500 mg 1-6 g/d, 16 g/d
increased by 1-2 9 – 10 g/d,
g/d q3-7d divided tid –
Metyrapone qid
See above See above
See above

Adrenal Surgery + Ketokonazole, 200 mg qd - bid 600 – 800 1200 mg/d

adenoma postoperative tabs 200 mg mg/d,
replacement divided bid
Adrenal Surgery Mitotane See above See above See above
Terapi farmakologi

• Steroid inhibitor
• Adrenolitik agent
mitotan
• Neuromodulator agent
• Antagonis reseptor
glukokortikoid
Steroid Inhibitor

Inhibitor steroid : metyrapone, aminogluthetimide,

ketokonazole
Metyrapone dan aminogluthetimide bila tdk kontinu,
mempunyai efikasi terbatas → shg digunakan sesudah
operasi.
Metyrapone : menghambat aktivitas 11 – hydroxylase,
sehingga sintesis kortisol terhambat.
Setelah terapi akan diikuti dg peningkatan kadar ACTH
plasma, karena tjd penurunan mendadak kortisol.
ES : mual, muntah, vertigo, sakit kepala, bingung, sakit perut,
rash.
Ketokonazole

• Antifungal derival imidazole

• Mempunyai efektivitas tinggi menurunkan kortisol
• Mek kerja : menghambat enzim sit P450 (11 –
hydroxylase dan 17- hydroxylase)
• ES : ginekomastia & penurunan kadar testoterone
plasma
• ES umum : peningkatan transaminase hepatik
(reversibel), ginekomastia, gangguan GI
Aminoglutethimide
Pertama digunakan utk epilepsi, kmd sbg inhibitor
sintesis kortisol yg poten
Mek. Kerja : menghambat konversi kolesterol mjd
pregnenolon. Penurunan kortisol plasma sampai dg
50%
ES : sedasi, mual, ataksia, dan skin rash.
Interaksi : dg warfarin akan menurunkan efek
antikoagulan.
Indikasi : penggunaan jangka pendek Cushing’s
disease dg sindrom ACTH ektopik, digunakan sbg
kombinasi dg metyrapone → efektif pd cushing yg
tdk dpt dioperasi.
Adrenolytic agent mitotane (orto-para-
dichlorodiphenyl dichloroethane)

Menghambat 11-hidroksilasi dari 11-desoksikortisol dan

11-desoksikortikosteron pada korteks.
Menurunkan sekresi kortisol plasma, urin, 17-substitued
kortisol.
Mitotane secara selektif menghambat fs adrenokortikal
tanpa menyebabkan destruksi seluler.
Karena tjd penurunan besar kortisol, perlu monitoring
penurunan kortisol di RS.
ES : 80% pasien mengalami lethargi dan somnolen, 40%
pasien dg ES CNS lainnya, hiperkolesterolemia.
Neuromodulator agent

• Cyproheptadine
• Bromocriptine
• Valproic acid
• Octreotide
Cyproheptadine

• Menurunkan sekresi ACTH

• Perlu monitoring kadar kortisol pada urin 24 jam bebas kortisol
• ES : sedasi & hiperfagia
• Respon Rate (RR) tidak lebih 30%, jadi perlu dipantau
kekambuhannya
Antagonis reseptor glukokortikoid

RU-486 (mifepristone) adl antagonis reseptor progesteron dan

glukokortikoid menghambat supresi deksametason dan
kortisol endogen.
Spironolactoneantagonis kompetitif aldosteron, memperbaiki
hipertensi & hipokalemia pada Cushing’s syndrome
Terapi adenoma hipofisis

1. Dg pembedahan →transsphenoidal adenomectomy (tkt

keberhasilan 80%), penurunan ACTH sampai 2 tingkat di
bwh Normal
Jk tjd penurunan drastis →suplai kortisol sintetik
(hidrokortison/prednison)
Jika pembedahan gagal → radioterapi (> 6 mgu), tkt
keberhasilan 40 – 50% pada dws, > 80% pada anak.
2. Kombinasi radiasi dg Mitotane (Lysodren)
Mitotane menekan produksi kortisol & menurun kadarnya
dlm plasma dan urine, 30 – 40 % pasien berhasil
3. Aminoglutethimide, Metyrapone, Trilostane &
Ketokonazole → ada ES
Terapi sindroma ACTH ektopik

Prinsip terapi : eliminasi semua jaringan kanker

penghasil ACTH (misal sel kanker paru)
Pembedahan
Radioterapi
Kemoterapi
Imunoterapi
Kombinasi →tgt tipe dan luas kanker
Tumor adrenal
Dg :
Pembedahan
adrenolectomy
Pada Primary
Pigmented
Micronodular Adrenal
Disease dan Carney’s
Complex dg
pembedahan kel.
Adrenal.
Learn How to Treat Cushing's
Syndrome

• 1Cushing's syndrome may be caused in different ways and categorized

accordingly. Long-term use of steroids (such as prednisone) or adrenal
abnormalities can cause the disease to surface. However, pituitary
adenomas (benign tumors) are to blame in most cases, and this
condition is referred to as Cushing's disease. In other cases, ectopic
ACTH syndrome is at work, which means malignant tumors have formed
on the pituitary, causing a domino reaction of ACTH and cortisol release.
• 2The exact reason your body is producing too much cortisol will
determine how to treat the disease. Conventional treatments include
radiation, chemotherapy, administration of cortisol-inhibiting drugs
and/or surgery.
• 3Pituitary adenomas are usually treated by a surgical procedure called a
transsphenoidal adenomectomy, which has a better than 80 percent
success rate. The pituitary gland is accessed through the nose via a thin
tube containing a microscope, and tiny instruments are used to remove
the tumor.
Cont’d

• 4Be aware that surgery on the pituitary may cause ACTH levels to fall
below normal, which is typical. Therefore, it may become necessary to
follow up with administration of a synthetic form of cortisol, such as
hydrocortisone or prednisone.
• 5Expect that radiotherapy or a combination of radiation therapy and
medication may be necessary if you're not a good candidate for surgery.
While radiation works to shrink tumors, drugs such as mitotane
(Lysodren) help to inhibit cortisol production.
• 6Know that there are several medications used to control cortisone
secretion, including mitotane, aminoglutethimide, metyrapone,
trilostane and ketoconazole.
•
Read more: How to Treat Cushing's Syndrome | eHow.com
http://www.ehow.com/how_2048201_treat-cushings-
syndrome.html#ixzz12pFKoNXq
Monitoring terapi

• Kadar kortisol serum pada pemeriksaan urin 24 jam bebas kortisol

• Perbaikan gejala & manifestasi klinik Cushing’syndrome
• Risiko kekambuhan terutama utk obat2 dg RR yg rendah
Penderita Cushing’s sebelum pembedahan
Penderita Cushing’s sesudah pembedahan
Sesudah pembedahan & sebelum pembedahan
Adrenocortical carcinoma in
infant
• The patient is a Caucasian female born at term with a birth
weight of 3.06 kg; pregnancy and delivery were
uncomplicated. At six months of age, she was referred to
pediatric endocrine clinic due to features of Cushing
syndrome. She had a three month history of progressive
Cushingoid facies, acne and irritability. Her linear growth
apparently had been arrested between three and six months
of age, although she gained weight at an accelerated rate.
Prior to referral, laboratory evaluation by her primary care
physician revealed serum cortisol of 240 mcg/dl (normal,
4.5–22.7 mcg/dl); total testosterone of 185 ng/dl (normal,
6–77ng/dl), and DHEA-S of 401 mcg/dl (normal, 16–96 
mcg/dl). Serum ACTH was less than 5 pg/ml (normal, 10–60 
pg/ml).
• Her weight at initial evaluation in our clinic at six months of age was 7.52 kg (60–
75th percentile) and length was 59.1 cm (< 5th percentile). Blood pressure was
110/70 mmHg. Physical examination showed Cushingoid facies, buffalo hump,
facial acne, and poor muscle tone (Figure 2). There were no signs of virilization.
Family history was noncontributory.
• Physical examination of the patient revealed features of Cushing Syndrome
including round facies, acne, plethora, central obesity, and poor muscle tone; she
lacked clitoromegaly, hirsutism or other signs of virilization.
• An MRI of the abdomen showed a heterogeneous right adrenal mass measuring
3.6×5.4×3.8 cm; this mass was found to extend as a tumor thrombus into the
inferior vena cava. The tumor thrombus appeared to extend to approximately 2 
cm from the right atrium. There were no metastases seen in the liver or lungs on
MRI. A Doppler ultrasound showed minimal, but present flow around the IVC
tumor thrombus which measured 2.5×0.9×1 cm. Laboratory evaluation showed
serum cortisol 70.8 mcg/dl (normal, 4.5–22.7 mcg/dl); aldosterone 4.2 ng/dl
(normal 6.5–86.0 ng/dl); testosterone 59 ng/dl (normal, 6–77 ng/dl); ACTH <5
(normal, 10–60 pg/ml).