1. THE ADRENAL GLANDS

2. 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

3. Regulation of the adrenal secretion
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 this
hormone 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
CRH
ACTH
CORTISOL

5. 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.

6. ADRENOCORTICAL INSUFFICIENCY (ADDISON’S DISEASE)

7. 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

8. 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

9. 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

10. 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

11. 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)

12. GLUCOCORTICOID DEFICIENCY
DIAGNOSIS OF ACI
1. 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

13. mild acidosis, mild hypercalcemia
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 lymphocitosis
azotemia with ↑concentration of blood urea nitrogen and serum creatinine (←volume depletion and dehydration)
mild acidosis, mild hypercalcemia

14. DIAGNOSIS OF ACI 2. DIAGNOSIS OF PRIMARY AND SECONDARY FORMS OF ACI
If adrenal insufficiency is present, plasma ACTH levels are used to 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)

15. DIAGNOSIS OF ACI 3. 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

16. 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 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)

17. 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 mg/day during periods of major stress, such as a surgical procedure; the usual maintenance dosage may be resumed in h if improvement occurs
ETIOLOGIC TREATEMENT
when it is possible

18. 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

19. CUSHING’S SYNDROME

20. 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

21. Cushing’s syndrome: differential diagnosis
ACTH-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 syndrome
Adrenal adenoma and carcinoma
Iatrogenic (e.g. pharmacologic doses of prednisolone, dexamethasone)
Nodular adrenal hyperplasia

22. CUSHING’S SYNDROME
CRH
CRH
ACTH
ACTH  
CORTISOL
CORTISOL 

23. CUSHING’ SYNDROME
ACTH-LIKE
CRH 
ACTH 
CORTISOL  

24. CRH  CRH  ACTH  ACTH  CORTISOL   CORTISOL 
CUSHING’ SYNDROME
CRH 
CRH 
ACTH 
ACTH 
CORTISOL  
CORTISOL 

25. 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

26. 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 dysfunction
In 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)

27. LABORATORY FINDINGS CUSHING’s syndrom- DIAGNOSIS
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

28. GLUCOCORTICOID EXCESS
CUSHING’S SYNDROME
GLUCOCORTICOID EXCESS
a. Plasma cortisol 8 a.m. i (V.N.: 8 a.m ng/ml; nmol/l; 4-6 p.m.: 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

29. +/- ANDROGEN EXCESS b. Diurnal rhytm of cortisol (8ºº, 18ºº)
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)

30. 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)

31. 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

32. ACTH-independent forms
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 (-)

33. Iatrogenic: remove source if possible CUSHING’S DISEASE
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

34. 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)

35. POSTTERAPEUTHYC SPECIFIC COMPLICATIONS NELSON SYNDROME
CUSHING’ SYNDROME
POSTTERAPEUTHYC SPECIFIC COMPLICATIONS
NELSON SYNDROME
ADRENOCORTICAL INUFFICIENCY