CUSHINGS SYNDROME 1 to present - Qatar University

Maryam Khaja, Rihab Kaissi, BSc(pharm)

Doctor of Pharmacy Students

College of Pharmacy

19 th of January 2012

CUSHING’S SYNDROME

1

� Introduction

� Epidemiology

� Causes

� Pathophysiology

� Clinical presentation

� Diagnosis

� Complications

� Goals of therapy

� Treatment

� Prognosis

Outline

2

� In 1932, Cushing first described a syndrome of pituitary basophilism

� Until this time patients with:

� Unexplained central obesity

� Cutaneous striae

� Osteoporosis, weakness

� Hypertension

� Diabetes mellitus

� No definite diagnosis

� Cushing emphasized that the disease was of pituitary origin

Introduction

3

DiPiro JT. Pharmacotherapy: A pathophysiologic approach. New York: McGraw Hill; 2008.

� Ten years later, after the development of the method for measuring urinary steroids

� Daughaday discovered ↑↑ steroids in the urine of patients

with cushing’s disease

� Finally, the end product was identified

� Cushing’s syndrome was correctly explained

� An excess of cortisol in the plasma (hypercortisolism)

Introduction

4


� Most cases of Cushing syndrome are due to

� Exogenous glucocorticoids

� Incidence of endogenous Cushing syndrome has been estimated at 13 cases per million individuals

� 70% � a pituitary ACTH-producing tumor

� 15% � ectopic ACTH

� 15% � a primary adrenal tumor

� Female-to-male incidence ratio is approximately 5:1

� Adrenal or pituitary tumor

Epidemiology

5DiPiro JT. Pharmacotherapy: A pathophysiologic approach. New York: McGraw Hill; 2008.Brown RJ, Kelly MH, Collins MT. Cushing Syndrome in the McCune-Albright Syndrome. J ClinEndocrinol Metab. Feb 15 2010

� Ectopic Adrenocorticotropic hormone (ACTH) production men >women

� The increased incidence of lung tumors

� The peak incidence of Cushing syndrome due to

� An adrenal or pituitary adenoma is in persons aged 25-40 years

� Ectopic ACTH production due to lung cancer occurs later in life

Epidemiology

6


� Cushing syndrome is caused by prolonged exposure to elevated levels of either endogenous glucocorticoids or exogenous glucocorticoids

� Co r t i co t r op i n - r e l eas ing ho rmone

(CRH)

Pathophysiology

7


� Exogenous steroid administration

� Injections of steroids into joints and the use of steroid inhalers

� Patients with diseases that respond to steroid therapy are especially likely to receive steroids and thus develop Cushing syndrome

� Rheumatologic, pulmonary, neurological, and nephrologicdiseases

Causes

8


� Endogenous glucocorticoid overproduction (ACTH-dependent)� causing adrenal hyperplasia

� (≈70% of Cushing’s cases)

� OR abnormal adrenocortical tissues (ACTH-independent)� Adenoma

� Ectopic ACTH syndrome refers to excessive ACTH production resulting from an endocrine or nonendocrine tumor

� Usually of the pancreas, thyroid, or lung

� Small-cell carcinoma of the lung will lead to ectopic ACTH secretion in 0.5% to 2% of cases,

� Whereas bronchial carcinoid tumors are usually the most common

Causes

9


� To distinguish between the various etiologies

Causes

10


� 90% of patients:

� Central obesity and facial rounding (moon face)

� 50% of patients will exhibit:

� Peripheral obesity and fat accumulation (buffalo hump)

� Striae are usually present along the lower abdomen and take on a red to purple color

� Hypertensive (morbidity and mortality of Cushing’s syndrome 75% to 85% of patients)

� Glucose intolerance is present in 60% of patients

Clinical Presentation

11


12


� Central obesity, hypertension, and glucose intolerance are components of metabolic syndrome and can increase the risk of coronary heart disease (CHD) and stroke threefold


13


� Infer ior petrosals inus sampl ing (IPSS)

� Jugular venous sampl ing (JVS)

Diagnosis

14


Differential diseases

15


� Bone loss (osteoporosis), which can result in unusual bone fractures, such as rib fractures and fractures of the bones in the feet

� High blood pressure (hypertension)

� Diabetes

� Frequent or unusual infections

� Loss of muscle mass and strength

Complications

www.mayoclinic.com

� Reverse the clinical manifestations by reducing cortisol secretion to normal

� Eradicate any tumor threatening the health of the patient

� Avoid permanent dependence upon medications

� Avoid permanent hormone deficiency

Goals of Therapy

www.uptodate.om

� Surgery

� Transsphenoidal resection of the pituitary microadenoma

� Preservation of pituitary function

� Low complication rate

� High clinical improvement rate

Non-pharmacological Therapy

Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM. Pharmacotherapy: A pathophysiologic approach. 7th edc

� Surgery

� Irradiation of the pituitary has provided clinical improvement

in approximately 50% of patients

� Improvement is usually not seen until 6 to 12 months

� Can create pituitary-dependent hormone deficiencies

� Reserved for patients with persistent hypercortisolemia after transsphenoidal surgery



� Surgery

� Bilateral adrenalectomy surgery

� Rapidly reverses hypercortisolism, but patients can develop Nelson syndrome



� Surgery

� Adrenal Adenoma

� Surgical resection is associated with relatively few side effects and a high cure rate

� Steroid replacement is needed both perioperatively and postoperatively

� Therapy should be continued for 6 to 12 months following surgery

� Ectopic ACTH syndrome

� Multiple sites of tumors exist

� Locating the ectopic sites are essential but often difficult

� Surgical excision remains optimal in these patients



� Surgery

� Adrenal Carcinoma

� Patients have an unpredictable and unfavorable outcome with surgical resection

� Complete tumor cannot be excised, leaving the patient with some degree of symptomatology and extra-adrenal involvement

� Radiotherapy can be used if metastases are discovered

� Palliative pharmacologic intervention(e.g.mitotane) for patients not candidate for a surgery




www.uptodate.com

General Principals


Hormone Production and Metabolism


� The main indications for medical therapy

� Management of hypercortisolism when surgery is contraindicated

� Control of hypercortisolism in preparation for surgery

� Persistence or recurrence of hypercortisolism after surgery

� Control of hypercortisolism while waiting for the effect of pituitary radiation in patients with ACTH-secreting pituitary tumors

� Treatment of occult ectopic ACTH syndrome

Pharmacological Therapy

www.uptodate.com

� Pharmacotherapy of Cushing’s syndrome can be divided into 4 categories

� Steroidogenic inhibitors

� Adrenolytic agents

� Neuromodulators of ACTH release

� Glucocorticoid receptor blocking agents



� Steroidogenic inhibitors

� Metyrapone

� Aminoglutethimide

� Ketoconazole

� Etomidate

� Fluconazole

� Trilostane

� Should not be used after successful surgery!

� Combinations have additive or synergistic therapeutic effects


ACTH dependent

Cushing's syndrome

www.uptodate.com

� Metyrapone

� Inhibits 11-hydroxylase activity

� Initial ACTH concentrations can cause an in androgenic and mineralocorticoid hormones

� Side effects include nausea, vomiting, vertigo, headache, dizziness, abdominal discomfort, and allergic rash




www.uptodate.com

� Aminoglutethimide

� Blocks the conversion of cholesterol to pregnenolone

� Alone is indicated for short-term use in inoperable Cushing’s disease with ectopic ACTH syndrome

� Has limited efficacy as a single agent, with relapse occurring after discontinuation of therapy

� Side effects include severe sedation, nausea, ataxia, and skin rashes




www.uptodate.com

� Ketoconazole

� Inhibits 11- hydroxylase and 17-hydroxylase

� Is highly effective in lowering cortisol in Cushing’s disease

� Its side effects include reversible elevation in LFT, sedation, nausea, vomiting, gynecomastia, decreased libido, and impotence

� It also decreases estradiol and testosterone production in women

� Liver function should be monitored at regular intervals !




www.uptodate.com

� Etomidate

� An anesthetic drug that blocks 11-beta-hydroxylation

� Useful in hospitalized patients when infused intravenously in a low, nonhypnotic dose

� It lowers serum cortisol to normal within about 10 hours

� ACTH secretion might rise and overcome the etomidateblockade with more chronic administration

� Sedation is a theoretical side effect




www.uptodate.com

� Adrenolytic agents

�Mitotane



�Mitotane

� Used primarily for the treatment of adrenal carcinoma

� It can also be used to achieve medical adrenalectomy or as an adjunctive medication in patients with ectopic ACTH secretion

� The usual duration of adjunctive mitotane is 6 to 9months

� It is taken up by fatty tissues and persists in plasma long after the drug is discontinued

� The major side effects are nausea, vomiting, and anorexia



� Neuromodulators of ACTH release

� Cyproheptadine

� Ritanserin

� Bromocriptine

� Cabergoline

� Valproic acid

� Octreotide

� Lanreotide

� Rosiglitazone

� Tretinoin


No Consistent clinical

efficacy !


� Glucocorticoid receptor blocking agents

�Mifepristone



� Mifepristone

� Is an anti-progestational drug

� Competes with glucocorticoids for binding to their receptor, thereby blocking their action

� It appears to be effective, although cortisol secretion increased in some

� It blocks the action of exogenous glucocorticoid



Sites of Action of Adrenal Enzyme Inhibitors

Sites of Action of Adrenal Enzyme Inhibitors


� Suggested approach

� Block and replace

� Normalization strategy

� Hydrocortisone

� Prednisone

� Dexamethasone


www.uptodate.com

Medical Management Algorithm

� Untreated Cushing's syndrome is often fatal

� Most deaths being due to

� Cardiovascular, thromboembolic, or hypertensive complications or bacterial or fungal infections

� Cushing's disease is virtually always curable

� No patient with Cushing's syndrome of any cause should die from persistent hypercortisolism

Prognosis

www.uptodate.com

47

Documents

CUSHINGS SYNDROME 1 to present - Qatar University