3. INTRODUCTION
● External environmental
changes > human brain
interprets as dangerous or
stressful
○ these changes under the
influence of the adrenal
glands, also known as
the suprarenal glands
● asymmetrical organs
● located suprarenally N
bilaterally in the
retroabdominal cavity
● responsible for secreting
stress hormones >
physiological adaptations
5. Location and relations
● The left and right suprarenal
glands differ slightly in Shape
and location of their respective
kidneys
○ The right gland is more
pyramidal N sits on top
of the upper pole of the
kidney
○ left gland is more
crescenteric N hangs
more over the medial side
of the left kidney
6. Cortex of suprarenal gland
● The cortex can be subdivided into :
○ zona glomerulosa
■ comprised of small rounded cells
■ responsible for secreting mineralocorticoids such as aldosterone
■ Aldosterone regulates the uptake of water in the distal convoluted tubules,
alters the body’s blood pressure
○ zona fasciculata
■ significantly thicker than the other two cortical layers
■ made up of pale staining vacuolated cells
■ responsible for secreting glucocorticoids > increase the overall blood glucose level
> more energy for a system under stress
7. Cortex of suprarenal gland
○ zona reticularis
■ consists of smaller cells
■ suprarenal androgens are produced
■ precursors for testosterone
8. Medulla of suprarenal gland
● At the center of the organ is a thin, grey medulla
○ hromaffin cells, splanchnic nerves and dilated capillaries
● The chromaffin cells are responsible for the production of catecholamines
○ namely epinephrine (adrenaline), norepinephrine (noradrenaline) and
dopamine
○ Epinephrine is released directly into the medullary capillaries and
carried to their site of action via systemic circulation
11. Innervation
● The action of the suprarenal gland is regulated both by neuronal and
hormonal stimulation
● The cortex is activated by adrenocorticotropic hormone (ACTH)
● ACTH stimulates cortical zones to produce corticosteroids
● suprarenal medulla is innervated by type B (medium diameter,
myelinated) preganglionic nerve fibers
○ hese nerve fibers leave the lateral horn of the spinal cord from the T5
– T8 segments
● The fibers converge after bypassing the sympathetic trunk, forming the
greater splanchnic nerve
13. Blood supply and lymphatic drainage
● The suprarenal glands receive arterial supply directly from the
abdominal aorta as well as from the inferior phrenic arteries and the
renal arteries
15. INTRODUCTION
● The adrenal cortex produces three classes of corticosteroid hormones:
○ glucocorticoids (e.g., cortisol)
○ Mineralocorticoids (e.g., aldosterone)
○ adrenal androgen precursors (e.g., dehydroepiandrosterone, DHEA)
● Glucocorticoids and mineralocorticoids
○ act through specifi c nuclear receptors
○ regulating aspects of the physiologic stress
● Adrenal androgen precursors
○ converted in the gonads, to sex steroids
○ act via nuclear androgen and estrogen receptors
16. INTRODUCTION
○ Disorders of the adrenal cortex
■ deficiency or excess? of one or several of the three major corticosteroid classes
○ Caused ?
■ Inherited glandular
■ Enzymatic disorder ( autoimmune disorders, infection, infarction, iatrogenic event
such as surgey)
○ neoplasia, leading to increased production of adrenocorticotropic hormone (ACTH)
○ increased production of glucocorticoid or mineral corticoids or mineral corticoid by
adrenal noduls
17. REGULATORY CONTROL OF
STEROIDOGENESIS
● Production of glucocorticoids and adrenal androgens is under the control of the
hypothalamic-pituitary- adrenal (HPA) axis
● mineralocorticoids are regulated by the renin-angiotensin-aldosterone (RAA) system
● Hypothalamic release of corticotropin-releasing hormone (CRH)
○ Response to endogenous or exogenous stress
○ CRH stimulates the cleavage of the 241– amino acid polypeptide pro
opiomelanocortin (POMC) by pituitary-specifi c prohormone convertase
○ Yielding ACTH
● ACTH
○ released by the corticotrope cells of the anterior pituitary
○ pivotal regulator of cortisol synthesis
○ short-term effects on mineralocorticoid and adrenal androgen synthesis
18. REGULATORY CONTROL OF
STEROIDOGENESIS
● CRH and ACTH follows a circadian rhythm under the control of the hypothalamus
(chiasmatic nucleus (SCN))
○ peak levels in the morning and low levels in the evening
● Glucocorticoid excess is diagnosed by employing dexsametasone suppression test
○ Dexamethasone suppresses CRH/ACTH
○ If cortisol production is autonomous (e.g., adrenal nodule) > ACTH is already
suppressed
○ ACTH-producing pituitary adenoma > induces suppression at high doses
○ the tumors are usually resistant to dexamethasone suppression
○ useful to establish the diagnosis of Cushing’s syndrome and to assist with the
differential diagnosis of cortisol excess
19. REGULATORY CONTROL OF
STEROIDOGENESIS
● to assess glucocorticoid deficiency, ACTH stimulation of cortisol production is used
○ The ACTH peptide contain 39 amino acids (the frist 24 can make physiologic respons)
○ The standard ACTH stimulation test involves administration of cosyntropin (ACTH
1-24), 0.25 mg IM or IV, collection of blood samples at 0, 30, and 60 minute for
cortisol
○ normal response cortisol level >20 μg/dL or an increment of >10 μg/dL over baseline
● Alternatively, an insulin tolerance test (ITT) can be used to assess adrenal insufficiency
○ injection of insulin to induce hypoglycemia > represents a strong stress signal >
triggers hypothalamic CRH release and activation of the entire HPA axis
○ administration of regular insulin 0.1 U/kg IV
21. REGULATORY CONTROL OF
STEROIDOGENESIS
● Mineralocorticoid production is controlled by the
RAA regulatory cycle
● initiated by the release of renin from the
juxtaglomerular cells in the kidney
● cleavage of angiotensinogen to angiotensin I in the
liver
○ (Angiotensin-converting enzyme (ACE) cleaves
angiotensin I to angiotensin II)
○ binds and activates the angiotensin II receptor
type 1 (AT1 receptor)
● Increased aldosterone production and vasocontriction
○ Aldosterone enhances sodium retention and
potassium excretion, and increases arterial
perfusion pressure
22. STEROID HORMONE SYNTHESIS,
METABOLISM, AND ACTION
● ACTH stimulation is required > steroidogenesis
● The ACTH receptor MC2R (melanocortin 2 receptor) interacts
with the MC2R-accessory protein MRAP > the complex is
transported to the adrenocortical cell membrane
● ACTH stimulation generates cyclic AMP (cAMP)
○ upregulates the protein kinase A (PKA) signaling pathway
● PKA activation impacts steroidogenesis in three district ways:
○ increases the import of cholesterol esters
○ increases the activity of hormone-sensitive lipase >
cleaves cholesterol esters to cholesterol for import into
the mitochondrion
○ increases the availability and phosphorylation of CREB
(cAMP response element binding)
26. Cushing’S Syndrome
Cushing’s syndrome reflects a constellation
of clinical features that result from chronic
exposure to excess glucocorticoids of any
etiology
27. CLASIFICATION
● The disorder can be
○ ACTH dependent
■ (e.g., pituitary corticotrope adenoma, ectopic secretion of ACTH by nonpituitary
tumor)
○ ACTH independent
■ (e.g., adrenocortical adenoma, adrenocortical carcinoma, nodular adrenal
hyperplasia)
○ Iatrogenic
■ (e.g., administration of glucocorticoids to treat various inflammatory condition)
29. Epidemiology
● Cushing’s syndrome is generally considered a
rare disease
○ incidence of 1–2 per 100,000
population per year
● several features of Cushing’s such as
centripetal obesity, type 2 diabetes, and
osteoporotic vertebral fracture
● majority of patients, Cushing’s syndrome is
caused by an ACTH-producing corticotrope
adenoma of the pituitary (described by
Harvey Cushing in 1912)
● medical use of glucocorticoids for
immunosuppression
31. ETIOLOGY & PATHOPHYSIOLOGY
● 90% of patients with Cushing’s disease, ACTH excess is caused by a corticotrope pituitary
microadenoma, a few millimeters in diameter
○ Pituitary macroadenomas (i.e., tumors >1 cm in size)
● Ectopic ACTH production is predominantly caused by occult carcinoid tumors (frequently
in the lung, but also in thymus or pancreas)
○ originate from medullary thyroid carcinoma or pheochromocytoma
● The majority of patients with ACTH-independent cortisol escess > cortisol-producing
adrenal adenoma
● Adrenocortical carcinomas may also cause ACTH independent disease and are often large
> excess several corticosteroid classes
33. Clinical manifestations
● Glucocorticoids affect almost all cells of the body > cortisol excess impact multiple
physiologic systems > upregulation of gluconeogenesis, lipolysis, and protein catabolism
● excess glucocorticoid secretion overcomes the ability of 11β-HSD2 > rapidly inactivate
cortisol to cortisone in the kidney n exerting mineralcorticoid action > diastolic
hypertention, hypocalemia, and edema
● Excess glucocorticoids also interfere central regulatory system > suppression of
gonadotropins > hypogonadism and amenorrhea, and suppression of the hypothalamic-
pituitary-thyroid axis > decreased TSH (thyroid-stimulating hormone) secretion
● clinical signs and symptoms observed in Cushing’s syndrome are relatively nonspecific
○ obesity, diabetes, diastolic hypertension, hirsutism, and depression
● more specific features Clinical manifestations :
○ fragility of the skin, with easy bruising and broad
○ purplish striae
○ signs of proximal myopathy
34. Clinical manifestations
● In ectopic ACTH
syndrome,
hyperpigmentation
knuckles, scars, or
● skin areas exposed
to increased
friction can be
observed
● The majority of
patients also
experience
psychiatric
symptoms, mostly
in the form of
anxiety or
depression A. Note central obesity and broad, purple stretch marks (B, close-up). C.
Note thin and brittle skin in an elderly patient with Cushing’s. D.
Hyperpigmentation of the knuckles in a patient with ectopic ACTH excess
38. SUPPORTING TEST
● Screening/confirmation of diagnosis
○ • 24-h urinary free cortisol excretion increased above normal (3x)
○ Dexamethasone overnight test (Plasma cortisol >50 nmol/L at 8-9 a.m. after 1 mg
dexamethasone at 11 p.m.)
○ Midnight plasma (or salivary) cortisol >130 nmol/L
○ Low dose DEX test (Plasma cortisol >50 nmol/L after 0.5 mg dexamethasone q6h for
2 days)
● Differential diagnosis 1: Plasma ACTH
○ ACTH normal or high >15 pg/Ml
■ MRI pituitary
■ CRH test (ACTH increase >40% at 15-30 min + cortisol increase >20% at 45-
60 min after CRH 100 µg IV)
■ High dose DEX test (Cortisol suppression >50% after q6h 2 mg DEX for 2
days)
43. MANAGEMENT
● Cushing's overt is associated with a poor prognosis if left untreated
● In ACTH-independent disease, treatment consists of surgical removal of the adrenal
tumor
○ For smaller tumors, a minimally invasive approach can be employed
○ arger tumors and those suspected of malignancy > pen approach is preferred
○ the treatment of choice is selective removal of the pituitary corticotrope tumor
● This results in an initial cure rate of 70–80% when performed by a highly experienced
surgeon
● If pituitary disease recurs, there are several options, including second surgery,
radiotherapy, stereotactic radiosurgery, and bilateral adrenalectomy
● Oral agents for ushing’s syndrome are metyrapone and ketoconazole
● Metyrapone inhibits cortisol synthesis at the level of 11βhydroxylase
● ntimycotic drug ketoconazole inhibits the early steps of steroidogenesis
● Typical starting doses are 500 mg tid for metyrapone (maximum dose, 6 g) and 200 mg tid
for ketoconazole (maximum dose, 1200 mg)
45. PROGNOSIS
● earliest studies of Cushing syndrome reported a median survival of 4.6 years and five-
year survival of only 50%
● The morbidity and mortality of Cushing syndrome are primarily due to :
○ iabetes,hypertension, heart disease, obesity, and osteoporosis with fractures
49. Deterrence and Patient Education
● Cushing syndrome should be treated by an interprofessional team lead by an
endocrinologist
● The patient should be educated about the complication of Cushing syndrome due to
impaired quality
51. DAFTAR PUSTAKA
● Harrison's Principles of Internal Medicine. New York :McGraw-Hill, Health Professions
Division, 1998.
● Jameson, J. Larry., & Harrison, T. R. (2013). Harrison’s endocrinology. 549.
https://books.google.com/books/about/Harrison_s_Endocrinology_3E.html?hl=id&id=yF
zFQMCMOGYC
● Longmore, Murray, et al. Oxford Handbook of Clinical Medicine. 8th ed., Oxford
University Press, 2010.
● Kumar, P. J. (Parveen J., & Clark, M. L. (2005). Kumar & Clark clinical medicine. 1508.
https://books.google.com/books/about/Kumar_Clark_Clinical_Medicine.html?hl=id&id=
03BrAAAAMAAJ
● Hirsch D, Shimon I, Manisterski Y, Aviran-Barak N, Amitai O, Nadler V, Alboim S, Kopel
V, Tsvetov G. Cushing's syndrome: comparison between Cushing's disease and adrenal
Cushing's. Endocrine. 2018 Dec;62(3):712-720.
● Lodish MB, Keil MF, Stratakis CA. Cushing's Syndrome in Pediatrics: An Update.
Endocrinol Metab Clin North Am. 2018 Jun;47(2):451-462.
