Histology Adrenal Gland

- Ada korteks dan medulla, dan dibungkus oleh capsule perinephric (Perinephric fat) dan juga Gerota fascia
- Korteks ada 3 layer :
o Zona glomerulosa (lapisan terluar dari korteks)
 Beneath the capsule
 Slightly basophilic cells with lipid droplets
 Secresi Mineralocortikoids  Aldosterone
o Zona Fasciculata (lapisan dibawah glomerulosa)
 Zona terbesar dari korteks
 cells arranged in columns around sinusoidal capillaries
 Cells mengandung banyak lipid droplets  Foamy appearances (spongiocytes)
 Secretes Glucocorticoid  Cortisol
o Zona Retikularis (zona terdalam korteks, berbatasan dengan medulla)
 Cells mengandung banyak Lipofuscin
 Sekresi sex hormone  DHEA
- Medulla
o Mengandung chromaffin cells (mirip nerve cells, tapi modified)
o Cell2 bulat dan oval, stain dengan Chrome salts
o Secretes Epinephrine, dan sedikit Norepinephrine

Anatomy Adrenal Gland

- Terdiri dari capsule, cortex, medulla
- Terletak diatas ginjal, dibungkus bersama ginjal oleh Gerota fascia, yang isinya adalah perinephric fat (fat
capsule)
- Arteries :
o A. Suprarenalis superior
 Berasal dari A. phrenica inferior
o A. Suprarenalis mediae
 Dari aorta
o A. Suprarenalis inferior
 Berasal dari A. Renalis
- Vein : V. suprarenalis langsung ke aorta
- Innervation : Sympathetic nerve dari Nervus
Sphlanchnicus
Physiology Adrenal Cortex
- Synthesis Adrenal Hormones
o Zona glomerulosa
 Satu2nya bagian yg bisa sekresi aldosterone karena punya aldosterone synthase
 Diatur oleh Angiotensin 2 dan potassium
o Zona Fasciculata
 Secrete Cortisol dan corticosterone + small amount of androgen dan estrogen
 Diatur oleh ACTH (adrenocorticotropin Hormone) dari pituitary
o Zona reticularis
 Secrete Adrenal Androgen (Dehydroepiandrosterone / DHEA dan Androstenedione)
 Diatur oleh ACTH dan cortical androgen-stimulating hormone dari pituitary
- Adrenal hormone dibentuk dari cholesterol
o Cholesterol yang diambil untuk membuat hormone sebagian besar berasal dari LDL (karena banyak
cholesterol)
o LDL akan diffuse dari plasma ke interstitial fluid dan mengikat di receptor di adrenocorticoid
membrane pada “coated pits”
o Coated pits akan diendocitosis dan cholesterol released untuk dipakai menjadi hormone
o Cholesterol akan diantar ke mitochondria dan dicleaved oleh enzim cholesterol desmolase menjadi
pregnolone (fase control synthesis hormone ditingkatkan atau direndahkan)

- Adrenal hormones terikat pada plasma proteins

o Cortisol di plasma terikat pada Cortisol-Binding-Globulin (transcortin)
 90-95% cortisol terikat pada protein, makanya half-lifenya panjang bisa 60-90menit)
o Aldosterone sekitar 60% terikat pada plasma protein, makanya half-lifenya ga lama sekitar 20 menit
- Aldosterone effects :
o Aldo increases renal tubular reabsorption of sodium and secretion of potassium (kerja utama di
principal cells of the collecting tubules).
o excess Aldo increases ECF volume and arterial pressure
o Excess Aldosterone causes hypokalemia and muscle weakness, while deficiency of Aldo
menyebabkan hyperkalemia and cardiac toxicity.
o Excess Aldo increases tubular hydrogen ion secretion and causes alkalosis (karena salah satu
pathwaynya adalah Natrium diambil ditukar dengan H ion).
 o Aldo stimulates sodium, potassium transport in sweat glands, salivary glands, and intestinal
epithelial cells (sama intinya Na diambil sama Chloride tapi dibuang nya Potassium dan bicarbonate
ions.
- Effect of Cortisol:
o Carbo:
 Stimulation of gluconeogenesis (best-known metabolic effect of cortisol). Bisa meningkatkan
gluconeo sampe 10 kali lipat dengan cara seperti : increases enzyme yang diperlukan untuk
gluconeo, causes mobilization dari amino acids ke liver, meng antagonize insulin effects
(insulin fungsinya hambat gluconeo).
 decrease glucose utilization by cells (dia decrease GLUT 4 dimana diperlukan untuk masukin
gula ke dalam cells  insulin resistance), lalu juga menekan kerja cascade di dalam sel
sehingga gula tidak jadi dipecah).
 elevated blood glucose concentration and “Adrenal Diabetes”  karena sangat tingginya
gluconeo dan tidak dipakainya glucose dalam darah  hyperglycemia diatas 50% normal 
called Adrenal Diabetes.
o Protein:
 Reduction in protein stores in cells (karena kurangnya synthesis protein di dalam sel, dan
meningkatnya catabolism protein di cells)  lemahnya muscle
 Increase liver and plasma protein (protein di cell tubuh lain berkurang, namun tinggi di liver
dan protein bebas di plasma
 Transport protein ke extrahepatic cell berkurang  increased blood amino acids
o Fat:
 mobilization of fatty acids  Dengan begitu maka konsentrasi fatty acids dalam darah tinggi
dan increase penggunaannya sebagai energy. Cortisol juga mempunyai effect enhance the
oxidation dari fatty acids in the cells.
 excess cortisol causes obesity. Bisa terbentuk “moon face” dan buffalo-like torso walaupun
mekanisme nya belum jelas tapi di hipotesiskan bahwa fat dari makanan lebih cepat
diendapkan daripada di oxidized dan mobilized.
o Anti inflammatory: (mengurangi inflamasi)
 cortisol prevents the development of inflammation by stabilizing lysosomes, decreases
permeability of the capillaries, decrease migration of WBC into the inflamed area, decrease
phagocytosis of the damaged cells, lymphocyte production dikurangi, reduces the release of
IL-1 dari WBC (cortisol mencegah inflamasi sebelum terjadi).
 cortisol causes resolution of inflammation, intinya dia bisa tetap block proses inflam dan
mempercepat proses penyembuhan.
- Regulation Of Cortisol
o Secresi Cortisol dipengaruhi oleh ACTH (Adrenocorticotropic Hormone) yang disekresi dari pituitary
o ACTH dipengaruhi oleh Corticotropin-Releasing Factor dari hypothalamus
 - Adrenal Androgen
o Several moderately active male sex hormones called adrenal androgens (the most important DHEA)
are continually secreted by the adrenal cortex, especially during fetal life. Also progesterone and
estrogens are secreted in minute quantities.
o Normally adrenal androgens only weak effects in humans. It is possible bahwa dulunya waktu
childhood sex hormones itu dihasilkan oleh adrenal.
o Begitu pula dengan wanita, misalnya pertumbuhan pubic and axillary hair itu results from the action
of these hormones. Pada tissue dia lebih converted ke testosterone dimana mempunyai effect
sexual yang lebih kuat.

- Cortisol levels may be high in people with psychiatric disorders, alcoholism, anorexia nervosa, pregnancy, or
morbid obesity. This may be called “pseudo-Cushing state”.

CUSHING SYNDROME
- Clinical Features:
o Most patients with Cushing’s syndrome present because of rapid weight gain, which is the most
striking feature of this disorder, resulting in central adiposity, round or “moon” facies, and a
dorsocervical fat pad, or “buffalo hump”
o Skin :
 violaceous striae, ecchymoses,
 karena kekurangan collagen synthesis  thin and fragile skin
 hyperpigmentation,
 oily skin,
 acne, and
 facial plethora
o Musculoskeletal
 Excess glucocorticoids can suppress muscle protein synthesis, which atrophies the muscles
 Weakness karena proximal myopathy
 Osteoporosis
o Gonadal Dysfunction
 Inhibitory effect of Gonadotropin releasing hormone (GnRH), FSH, LH karena tingginya
cortisol
 Tingginya androgen buat :
 Hirsutism (Unwanted men hair pattern on women’s face, back, and chest)
 Oily skin
 Acne
 Menstrual irregularities (amenorrhea, oligorrhea)
  Loss of libido and impotence

o Psychiatric
 Emotional changes
 Irritability, anxiety, depression
 Endogenous Cushing syndrome
 Depression
 Exogenous Cushing Syndrome
 Mania
o Common comorbidities
 Increased hepatic gluconeogenesis, insulin resistance  DM
 Hypertension (karena increased extracellular volume)
 Obesity, hypertension, osteoporosis, DM  non-specific findings of Cushing Syndrome
- Diagnosis
DEXAMETHASONE SUPPRESION TEST
Ada 2 tipe :

- Low Dose Dexamethasone suppression test (LDDST)

- High Dose Dexamethasone suppression test (HDDST)

Cara pengumpulan urine bisa :

- Overnight method (dalam 1 malam)

- Standard 3 day method (hari pertama Cuma pengumpulan urin 24 jam dan cek cortisol, hari kedua dan
ketiga mulai pemberian dexamethasone)

LDDST:

- Low-dose overnight -- You will get 1 milligram (mg) of dexamethasone at 11 p.m., and a health care provider
will draw your blood the next morning at 8 a.m. for a cortisol measurement.
- Standard low-dose -- Urine is collected over 3 days (stored in 24-hour collection containers) to measure
cortisol. On day 2, you will get a low dose (0.5 mg) of dexamethasone by mouth every 6 hours for 48 hours.
- The reference ranges for the low-dose dexamethasone suppression tests are as follows:
o Overnight dexamethasone suppression test: Serum cortisol less than 1.8 mcg/dL (< 50 nmol/L)
o Standard 2-day dexamethasone suppression test: Serum cortisol less than 1.8 mcg/dL (< 50 nmol/L)
- Pemberian glucocorticoid akan merendahkan ACTH dari pituitary, jika LDDST tidak menurunkan Cortisol,
Cushing syndrome is suspected
- Orang “Pseudo Cushing State” tidak akan terpengaruh LDDST

Dexamethasone – Corticotropin Releasing Hormone (CRH) Test :

- Pemberian CRH akan stimulasi pituitary untuk sekresi ACTH

- Namun karena pemberian dexamethasone sebelumnya, pemberian CRH akan mencegah meningkatnya
Cortisol
- Jika pasien hanya Pseudo-Cushing State, cortisol tidak akan naik
- Jika pasien Cushing Syndrome, cortisol naik

HDDST :

- Serupa dengan LDDST tapi menggunakan high dose

 - High-dose overnight -- The provider will measure your cortisol on the morning of the test. Then you will
receive 8 mg of dexamethasone at 11 p.m. Your blood is drawn the next morning at 8 a.m. for a cortisol
measurement.
- Standard high-dose -- Urine is collected over 3 days (stored in 24-hour collection containers) for
measurement of cortisol. On day 2, you will receive a high dose (2 mg) of dexamethasone by mouth every 6
hours for 48 hours.
- The reference ranges for the high-dose dexamethasone suppression tests are as follows:
o Overnight dexamethasone suppression test: Decrease of more than 50% in serum cortisol
o Standard two-day dexamethasone suppression test: Decrease of more than 50% in serum cortisol or
a decrease of more than 50% in 24-hour urinary free cortisol
- Bisa membedakan ACTH production karena pituitary adenoma, atau ectopic ACTH producing tumour
o Cortisol akan turun ketika HDDST diberikan pada pasien dengan pituitary adenoma
o Cortisol tidak turun ketika HDDST diberikan pada pasien ectopic ACTH producing tumour

Imaging :

- CT SCAN adrenal / MRI Pituitary / CT chest, abdomen, pelvis

Petrosal Sinus Sampling :

- Pengambilan darah dari petrosal sinus veins (vena yang drain pituitary) dengan masukkan tube dari thigh or
groin areas
- Dibandingkan dengan Forearm vein
- Jika ACTH meningkat pada petrosal veins  Pituitary Adenoma
- Jika ACTH sama pada petrosal vein dengan forearm vein  ectopic ACTH syndrome

ADRENAL CRYSIS
- Is a life-threatening situation resulting from insufficient levels of cortisol
- When adrenal crisis can occurs?
o Patients with known Addison’s disease or secondary (hypothalamic or pituitary) adrenal failure
o Patients with congenital adrenal hyperplasia
o Patient dalam pharmacological doses of prednisolone or other glucocorticoids, including dexa
dengan dosis >5 mg daily for longer than one month
o Patients on long term inhaled steroids treatment
o Patients on long term topical steroids treatment
 - Diagnosis : AC should be suspected if a patient had two or more of the following :
o nausea or vomiting,
o severe fatigue,
o severe headache,
o mental confusion,
o hypotension (SBP <100 mmHg) causing postural dizziness,
o hyponatremia,
o hyperkalemia, and
o hypoglycemia.
- Treatment. Including :
- Intravenous fluids  0.9% saline
o infusion rate 1 L per hour until SBP > 100 mmHg, then reduced rate according to clinical state
- Intravenous Hydrocortisone
o 100 mg IV stat then 100 mg IV qds for 24-48 hours
o If unable to gain IV access give same dose as IM injection
- If hypoglycemic (blood glucose <4.0 mmol/L)
o 100 ml 20% dextrose over 10-15 minutes stat
o IV infusion 10% dextrose at 100 ml/hr if hypoglycemic persists
o Monitor blood glucose hourly

MANAGEMENT OF CUSHING
- ACTH independent dz (primary)
o Surgical removal of adrenal tumour (kalo small bisa minimal invasive, kalo gede open surgery)
- Cushing Disease
o Selective removal of pituitary corticotrope tumour (via endoscopic trans-sphenoidal surgery)
o BIASA ADA RELAPSE  harus long-term followup
o Kalau relapse  second surgery, radiotherapy, stereotactic radiosurgery, bilateral adrenalectomy
- Oral agent yg berfungsi:
o Metyrapone
 Inhibit cortisol synthesis pada 11β-Hydroxylase
 Starting dose 500mg max 6g
o Ketoconazole
 Inhibit early steps of steroidogenesis
 Starting dose 200mg max 1200mg
o
o Mitotane (turunan dari pestisida)
 Ada efek adrenolytic  hanya dipakai pada adrenocortical carcinoma
o Etomidate