THE ADRENAL GLANDS

Anatomy -paired organs adjacent to the kidneys, containing:a cortex a medulla→epinephrine (E), norepinephrine (NE), small amounts

of dopamine The adrenal cortex – 3 functional and morphological different

zones: - glomerulosa secreting mineralocorticoids-Aldosterone,

DOC(deoxycorticosterone) - fasciculata secreting glucocorticoids(cortisol) and androgens -reticularis secreting adrenal androgens

( dehydroepiandrostenedione (DHEA), DHEA sulfate and androstendione ) and cortisol

Glucocorticoid and androgen production ( the zonae fasciculata and reticularis) are under the control of

ACTH, which regulates both steroid synthesis and also

adrenal growth; excess or deficiency of thishormone alters their structure and function→ ↑ ACTH: hyperplasia and hypertrophy of these

zones occur+ ↑production of cortisol and androgens

→ ↓ ACTH:both zones atrophy +↓production of

cortisol and androgens

!!! Only cortisol is responsible of the negative FB on the CRH and ACTH secretion

CRHCRH

ACTHACTH

CORTISOLCORTISOL

Regulation of the adrenal secretion

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C O R TIZ O L

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C R H , A V P

R eglarea secretie i de a ldosteron

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A L D O S TE R O N

S R A A

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REGULATION OF THE ADRENAL SECRETION

The adrenal androgens, DHEA, DHEA-sulfate, androstendione have minimal intrinsic androgenic activity, and they contribute to androgenity by their peripheral conversion to the more potent androgens testosterone(T) and DHT.

The synthesis of aldosterone by the zona glomerulosa is primarily regulated by- the renin-angitensin system (RAS)

- potassium - (lesser extent ACTH ) → in ACTH deficiency- aldosterone secretion remains normal except in a few

cases.

ADRENOCORTICAL ADRENOCORTICAL INSUFFICIENCYINSUFFICIENCY

(ADDISON’S DISEASE)(ADDISON’S DISEASE)

ADRENOCORTICAL INSUFFICIENCY

= deficient adrenal production of glucocorticoids or mineralocoricoids results in adrenocortical insufficiency (ACI)

CLASSIFICATIONS

According to the location of lesion Primary ACI← either the consequence of destruction or

dysfunction of the cortex Central ACI ←secondary to deficient pituitary ACTH secretion! Glucocorticoid therapy is the most common cause of secondary

adrenocortical insufficiency

According to evolution Chronic ACI Acute ACI

ACI ETIOLOGY PRIMARY ADRENOCORTICAL DISEASE (ADDION’S DISEASE)

TUBERCULOSIS ( prior to 1920, was the major cause )

AUTOIMMUNE • Sporadic

• APS, type I: hypoparathyroidism, chronic mucocutaneous candidiasis, adrenal insufficiency, gondal failure, hypothyroidism, DM type 1, DI+ nonendocrine diseases: alopecia, pernicious anemia, chronic active hepatitis

• APS type II: adrenal insufficiency, autoimmune thyroid disease, gonadal failure, DM type1, DI+ celiac sprue, vitiligo, pernicious anemia, myastenia gravis (also known as Schmidt’s syndrome)

RARE CAUSES Metastatic adrenal disease (lung cancer, non-Hodgkin’s and Hodgkin’s

lymphoma) Other infections – fungi, CMV, HIV Infiltrations: amyloidosis, hemochromatosis Intra-adrenal hemorrhage ( when Addison’s disease is caused by

meningococcus, the association with adrenal insufficiency is known as Waterhouse-Friderichsen syndrome) after menngococcal septicemia

Bilateral adrenalectomy or drugs : ketoconazole, mitotane

ACI ETIOLOGY

CENTRAL (SECONDARY) ADRENOCORTICAL INSUFFICIENCY ( see hypotalamus-pituitary section)

ACUTE ADRENOCORTICL INSUFFICIENCY ( INFANTS

CONGENITAL ADRENAL HYPOPLASIA CONGENITAL ADRENAL HYPERPLASIA (←defects in several

enzymes implicated in the steroid biosynthetic pathways e.g 21 hydroxylase deficiency)

ADRENAL HEMORRHAGE ADRENAL VEIN TROMBOSIS BILATERAL ADRENALECTOMY

CLINICAL FEATURES IN ADDISON’S DISEASE PRIMARY ADRENOCORTICAL INSUFFICIENCY

1.Hyperpigmentation (=the classic physical finding) of the skin and mucous membranes

2.weakness and fatigue

3.gastrontestinal disturbances: nausea, vomiting, diarrhea or constipation, abdominal pain, salt craving

4.anorexia, weight loss

5.hypotension, postural hypotension; + orthostatic symptoms: dizziness and ocasionally syncope

6.hypoglycemia (sweats, tremor, headache

7.irritability, emotional instability, depression 8.loss of axillary and pubic hair-in women (← ↓ secretion of adrenal androgens) 9.associated conditions: vitiligo, features of other autoimmune

endocrinopathies

SECONDARY ADRENOCORTICAL INSUFFICIENCY

hyperpigmentation is not present; the skin is pale!

+ /- complex clinical features (panhypopituitarism), features of underlying cause( e.g. headache, visual field defects if pituitary tumor)

DIAGNOSIS OF ACI 1. ESTABLISHING THE DIAGNOSIS OF ACI1. ESTABLISHING THE DIAGNOSIS OF ACI

GLUCOCORTICOID DEFICIENCY

Cortisol (basal) 8a.m. <70 ng/ml; since basal levels of adrenocortical steroids in either urine or plasma may be normal in partial adrenal insufficiency ( low-normal), tests of adrenocortical reserve are necessary to establish the diagnosis.

urine free cortisol ( measured in a 24-h urine collection)↓ Urinary 17-hydroxycorticosteroids ( the urinary metabolites of

cortisol) (should no longer be used)

< 3 mg/24h women si < 5 mg/24h in men

Serum glucose ↓< 70mg/dl

DIAGNOSIS OF ACI

MiNERALOCORTICOID DEFICIENCY Plasma aldosterone↓or low-normal (in primary form!!!) Plasma renin activity↑(in primary form!!!) Hyponatremia and hyperkalemia are classic manifestations of glucocorticoid and

mineralocorticoid deficiency and should suggest the diagnosis – K ↑ (acute adrenal crisis)

ADRENAL ANDROGENS DEFICIT Plasma levels of DHEA, DHEA sulfate, androstendione ↓ Urinary 17-ketosteroids ( urinary androgen metabolites) ↓(should no longer be

used) women < 7mg/24h, men <10 mg/24 h)

Others ECG: low voltage, vertical QRS axis, nonspecific ST-T wave abnormalities

secondary to abnormal electrolytes FBC - normocytic, normochromic anemia (← altered androgen

metabolism) neutropenia, eosinophilia and a relative neutropenia, eosinophilia and a relative lymphocitosislymphocitosis

azotemia with azotemia with ↑concentration of blood urea nitrogen and serum ↑concentration of blood urea nitrogen and serum creatinine (←volume depletion and dehydration)creatinine (←volume depletion and dehydration)

mild acidosis, mild hypercalcemiamild acidosis, mild hypercalcemia

DIAGNOSIS OF ACI

2. DIAGNOSIS OF PRIMARY AND SECONDARY FORMS OF ACI2. DIAGNOSIS OF PRIMARY AND SECONDARY FORMS OF ACI

If adrenal insufficiency is presentIf adrenal insufficiency is present, , plasma ACTH levelsplasma ACTH levels are used to are used to differentiate primary and secondary forms; differentiate primary and secondary forms;

ACTH plasmatic – primary ACI ACTH plasmatic / “low-normal”– central ACI The rapid ACTH stimulation test (250µg tetracosactide

(synacthen)) / The ACTH (Synacthen) test (1 mg)

DIAGNOSIS OF ACI 3. TESTS FOR ETIOLOGY3. TESTS FOR ETIOLOGY

→ TUBERCULOSIS Chest radiograph, tuberculin testing, and early morning urine samples

cultured for Mycobacterium tuberculosis – abdominal radiograph: calcifictions of the adrenals - CT scan : may reveal enalrged or calcified glands ( this aspect is also

suggestive for hemorrhagic or malignant diagnosis) → AUTOIMMUNE Test (radioimmunoassays) for autoantibodies such as those against the 21-

hydroxylase antigen ( indirect information ← testing for thyroid autoantibodies)

CT: small, atrophic adrenal glands → CENTRAL FORM CT/MRI of the hypotalamus –pituitary can identify the lesion

TREATMENT OF ADRENOCORTICAL INSUFFICIENCY replacement treatment (life-long gluco- and mineralo-corticoid

therapy) !the aim = to produce levels of glucocorticoids and

mineralocorticoids equivalent to those achieved in an individual with normal HPA function under similar circumstances.

MAINTENANCE THERAPY GLUCOCORTICOIDS

CORTISOL ( HYDROCORTISON) is the glucocorticoid preparation of first choice. 15-25 mg/day in 2 doses (10-20mg/5-10mg)

PREDNISONE 5-7,5(10 )mg/day

MINERALOCORTICOIDS 9--fluorocortisol (fludrocortisone) (ASTONIN H) 0.1 mg/tb ½-2

tb/day

ANDROGENS DECANOFORT 1 f/2 weeks i.m. or DHEA 50mg/day→ an

improvement in well-being and sexual function in F

LIFESTYLE ADVICE – ↑ in proteins, vitamine, adequate dietary sodium intake (!!!not restriction)

TREATMENT OF THE CHRONIC ADRENOCORTICAL INSUFFICIENCY

GENERAL MEASURES –PREVENTION OF ADRENAL CRISIS The essential elements are patient education and increased

glucocorticoid dosages during illness! The replacement therapy will not be interrupted for any cause!!! It is generally expected that the daily dose of hydrocortisone should

be doubled (or 3*) during period of minor stress and the dose needs to be increased to as much as 200-300 mg/day during periods of major stress, such as a surgical procedure; the usual maintenance dosage may be resumed in 24-48 h if improvement occurs

ETIOLOGIC TREATEMENT when it is possible

ACUTE ADRENAL CRISIS

CLINIC: a state of acute ACI and occurs in patients with Addison’s disease who are exposed to stress of infection, trauma, surgery, or dehydration due to salt deprivation, vomiting or diarrhea. Abdominal pain, tenderness ( mimic an acute abdominal emergency) ( abdominal

distention, rigidity and rebound tenderness are less frequent) nausea, vomiting, anorexia

Fever (← infection or hypoadrenalism per se) Weakness, apathy, depressed mentation Hypoglycemia Hypotension and shock

LABORATORY FINDINGS hipoNa,hiperK, hypoglycemia, urea, creatinin , hematocrit , metabolic acidosis

TREATMENT Iv glucose and saline are administered to corect volume depletion, hypotenion and

hypoglycemia HHC 100mg iv every 6 h for 24 h; when the patient is stable, reduce the dosage to 50 mg

every 6 h; taper to maintenance therapy by day 4 or 5 and add mineralocorticoid as required

CUSHING’S SYNDROMECUSHING’S SYNDROME

CUSHING’ SYNDROME

= the constellation of symptoms and physical features caused by chronic glucocorticoid excess

it is most commonly iatrogenic, resulting from chronic glucocorticoid therapy

“spontaneous” Cushing’s syndrome is caused by abnormalities of the pituitary or adrenal or may occur as a consequence of ACTH or CRH secretion by nonpituitary tumors ( ectopic ACTH sdr, ectopic CRH sdr)

! Cushing’s disease is defined as the specific type of Cushing’ s syndrome due to excessive pituitary ACTH secretion from a pituitary tumor

Cushing’s syndrome: differential diagnosisCushing’s syndrome: differential diagnosis

ACTH-DEPENDENT Cushing’s syndromeACTH-DEPENDENT Cushing’s syndrome

Pituitary adenoma (Cushing’s disease )

Nonpituitary neoplasm ( ectopic ACTH, CRH syndrome) Tumors causing the ectopic ACTH syndrome: small cell carcinoma of the lung

(50% of cases), carcinoid tumors (lung, thymus, gut pancreas, ovary), pancreatic islet cell tumors, medullary carcinoma of the thyroid, pheocromocytoma

Iatrogenic ( treatment with ACTH 1-24)

ACTH-INDEPENDENT Cushing/s syndromeACTH-INDEPENDENT Cushing/s syndrome Adrenal adenoma and carcinoma Iatrogenic (e.g. pharmacologic doses of prednisolone, dexamethasone) Nodular adrenal hyperplasia

CUSHING’S SYNDROME

CRH

ACTH

CORTISOL CORTISOL

ACTH

CRH

CUSHING’ SYNDROME

CRH

ACTH

CORTISOL

ACTH-LIKE

CUSHING’ SYNDROME

CRH

ACTH

CORTISOL CORTISOL

ACTH

CRH

CUSHING’S SYNDROME –CLINICAL FEATURES OBESITY : weight and obesity are the commonest sign, →centripetal in

nature; + patients develop fat depots over the thoracocervical spine (“buffalo hump”), in the supraclavicular region, and over the cheeks and temporal regions, giving rise to the rounded “moon-like” facies ( accompanied by facial plethora in most patients)

SKIN : →thin and atrophic; easy bruisability following minimal trauma; red striae- abdominal, over the breast, hips, buttocks, thighs and axillae; acne and papular lesions. Opportunistic bacterial and fungal infections may occur; hyperpigmentation is rare in Cushing’s disease but common in the ectopic ACTH sdr (← overstimulation of melanocyte receptors by ACTH)

MUSCLE : muscle weakness is more often proximal and is usually most prominent in the lower extremities (myopathy)

BONE : significant osteopenia and osteoporosis → fractures, typically of the feet, ribs or vertebrae; in chilhood the commonest presentation is with poor linear growth and weight gain( !generalized obesity)

CARDIOVASCULAR: hypertension is a classic feature of spontaneous Cushing’s syndrome( dBP>100mmHg ); this, togheter with the established metabolic consequences of the disease ( diabetes, hyperlipidemi..), is thought to explain the ↑ cardiovascular mortality in untreated cases; + thromboembolic events

CUSHING’S SYNDROME –CLINICAL FEATURES

Metabolic: IGT and overt DM; ↑circulating cholesterol and triglycerides; renali calculi secondary to glucocorticoid induced hypercalciuria;

CNS and psychologic disturbances: emotional lability, irritability, anxiety, depression, poor concentration, poor memory; euphoria

Reproductive dysfunctionIn women: menstrual irregularities: oligomenorrhea,

amenorrhea, hypertricosis on the face; signs of masculinization (virilization): hirsutism, alopecia, acne, amenorrhea (← usually signifies concomitent androgen excess as may occur secondary ACTH-mediated adrenal androgen secretion)

In men: ↓libido, impotence+/- some degree of gynecomastia (← cortisol suppression of LH secretion →↓testosterone secretion by the testis)

CUSHING’s syndrom- DIAGNOSIS

LABORATORY FINDINGS high normal hemoglobin, hematocrit and red cell counts total white count –usually normal

Lymphocites, eosinophils ↓

Serum electrolytes : hyper Na+, hypo K+

fasting hyperglycemia/ clinical diabetes/ abnormal glucose tolerance test

metabolic alkalosis

cholesterol and triglicerides=↑

Serum calcium= normal, hypercalciuria

ECG← hypertensive, ischemic and electrolyte-induced changes

Abdominal ultrasound : renal stones

X-ray: vertebral compression fractures, rib fractures, cardiomegaly due to hypertensive or atherosclerotic heart disease

CUSHING’S SYNDROME

GLUCOCORTICOID EXCESS a. Plasma cortisol 8 a.m. i (V.N.: 8 a.m. -70-220 ng/ml; 171-

536nmol/l; 4-6 p.m.:64-340 nmol/l)

Circadian rhytm: - is superimposed on episodic secretion; it is the result of CNS events that regulate both the number and magnitude of CRH and ACTH secretory episodes; the absence of diurnal rhytm has been considered a hallmark of the diagnosis of Cushing’ s syndrome; normally cortisol is secreted episodically with a diurnal rhytm paralleling the secretion of ACTH; levels are usually highest early in the morning and ↓ gradually throughout the day, reaching a nadir in the late evening.

Disrupted (abnormal) circadian rhytm: is carachterized by failure to ↓ cortisol secretion during the evening

SINDROMUL CUSHING

b. Diurnal rhytm of cortisol (8ºº, 18ºº)

c. Urinary 17-hydroxycorticosteroids ( the urinary metabolites of cortisol) (should no longer be used) ↑

d. Urinary free cortisol- the assay of unbound cortisol excreted in the urine is an excellent method for the diagnosis of Cushing’s sdr (24h urine collection)→ the method is particularly useful in differentiating simple obesity from Cushing’s sdr

+/- ANDROGEN EXCESS Plasma levels of DHEA, DHEA sulfate, androstendione ↑ Urinary 17-ketosteroids ( urinary androgen metabolites)

↑(should no longer be used) women < 7mg/24h, men <10 mg/24 h)

DIAGNOSIS-DYNAMIC TESTS ! The clinical suspicion of Cushing’s sdr

must be confirmed with biochemical studies.

A. Dexamethasone(DXM) suppression test(overnight DXM suppression test)(Bricaire test)= the best screening test

B The 48-hour low-dose DXM test (Liddle test-2*2)

DIFFERENTIAL DIAGNOSIS OF CUSHING’S SYNDROM

C. Plasma ACTH (vn :9-52 pg/ml)

=the best way to distinguish between ACTH-dependent Cushung’s sdr (pituitary or nonpituitary ACTH-secreting neoplasm) and ACTH-independent hypercortisolism

ACTH ↓ (<10 pg/ml) in ACTH- independent Cushing’s sdr ACTH normal or ↑ (> 10pg/ml and frequently >52pg/ml)= ACTH secreting neoplasm

D. High-dose DXM suppression test (Liddle test -2*8) → distinguish pituitary causes from ectopic ACTH production

E. Morphological investigations

Pituitary MRI : when ACTH-dependent Cushing’s sdr is present, MRI of the pituitary gland with gadolinium enhancement should be performed.

Adrenal localizing procedures: abdominal CT scan =the best (or MRI- adrenal carcinoma); abdominal ultrasonography

CT of the chest → nonpituitary ACTH-secreting tumor ((! Majority of these lesions are in the thorax)); then CT of abdomen pelvis

CUSHING’S SYNDROME

ACTH-independent forms

cortisol + ACTH + test 2x2 (-) + test 2x8 (-)

ACTH-dependent forms

Pituitary form cortisol + ACTH n/ + test 2x2 (-) + test 2x8 (+)

Paraneoplstic form cortisol + ACTH + test 2x2 (-) + test 2x8 (-)

CUSHING’S SDR TREATMENT

DEPENDS ON THE CAUSE Iatrogenic: remove source if possible

CUSHING’S DISEASE Selective removal of a pituitary adenoma( transsfenoidal approach)/+/-

pituitary radiotherapy (when no response to pituitary surgery or incomplete removal )

Bilateral adrenalectomy – when pituitary surgery has failed or when the condition has recurred (+ pituitary radiation at the time of bilateral adrenalectomy- to avoid subsequent development of Nelson’s sdr =postadrenalectomy hyperpigmentation with a locally aggressive pituitary tumor) + replacement therapy

CUSHING’ S SYNDROME TREATMENT

ECTOPIC ACTH SYNDROME Removal of the primary tumor ( when it is possible- ! ) Bilateral adrenalectomy if the primary tumor is not found (+ replacement

therapy)

ADRENAL CAUSES Adrenal adenomas unilateral (laparoscopic) adrenalectomy Adrenal carcinoma – try to remove the primary tumor

- medical treatment:

mitotane= the drug of choice (an adrenolytic drug)

ketoconzole (blocks a variety steroidogenic enzymes and thus ↓ plasma cortisol levels)

CUSHING’ SYNDROME

POSTTERAPEUTHYC SPECIFIC COMPLICATIONS

NELSON SYNDROME

ADRENOCORTICAL INUFFICIENCY