1. Adrenal Glands
Part 3

2. Adrenal Medulla
The adrenal medulla accounts for about 10% of the mass of the adrenal gland
Distinct embryologically and physiologically from the cortex, although cortical and medullary hormones often act in a complementary manner
Cells of the adrenal medulla have an affinity for chromium salts in histological preparations and hence are called chromaffin cells
Chromaffin cells are innervated by neurons from the spinal cord

3. Secretory Products The principal secretory products:
epinephrine and norepinephrine,
are derivatives of the amino acid tyrosine
and belong to a class of compounds called catecholamines
are stored in membrane-bound granules within chromaffin cells
The adrenal medulla also produces and secretes several neuropeptides but their physiological role is incompletely understood

4. Biosynthesis of Medullary Catecholamines
Hydroxylation of tyrosine to form dihydroxyphenylalanine (DOPA) is the rate determining reaction and is catalyzed by the enzyme tyrosine hydroxylase
Activity of this enzyme is inhibited by catecholamines (product inhibition) and stimulated by phosphorylation
The enzyme phenylethanolamine-N-methyltransferase (PNMT) is at least partly inducible by cortisol
determine the ratio of epinephrine to norepinephrine production

5. Storage, Release, and Metabolism of Medullary Hormones
All the epinephrine in blood originates in the adrenal glands
However, norepinephrine may reach the blood either by adrenal secretion or by diffusion from sympathetic synapses
Catecholamines are stored in secretory granules Acetylcholine released during neuronal stimulation increases the influx of sodium ions which depolarizes the plasma membrane
This leads to an influx of calcium through voltage-sensitive channels triggering the secretion of catecholamines

6. Storage, Release, and Metabolism of Medullary Hormones
The half-lives of medullary hormones in the peripheral circulation have been estimated to be less than 10 seconds for epinephrine and less than 15 seconds for norepinephrine
Epinephrine and norepinephrine that are cleared from the circulation are either stored or degraded

7. Physiological Actions of Medullary Hormones
The sympathetic nervous system and adrenal medullary hormones, like the cortical hormones, act on a wide variety of tissues to maintain the integrity of the internal environment
Catecholamines enable us to cope with emergencies and equip us for “fright, fight, or flight”

8. Physiological Actions of Medullary Hormones
Epinephrine
Norepinephrine
Cells in virtually all tissues of the body express G-protein coupled receptors for epinephrine and norepinephrine on their surface membranes
They are called adrenergic receptors originally were divided into two categories, α and β

9. Physiological Actions of Medullary Hormones
Cardiovascular effects:
maximize cardiac output and ensure perfusion of the brain and working muscles
Metabolic effects:
ensure an adequate supply of energy-rich substrate
Respiratory System:
Relaxation of bronchial muscles facilitates pulmonary ventilation.
Ocular effects:
increase visual acuity
Effects on skeletal muscle:
increase muscular performance,
and quiescence of the gut permits diversion of blood flow, oxygen, and fuel to reinforce these effects

10. Regulation of Adrenal Medullary Function
The sympathetic nervous system, including its adrenal medullary component, is activated by any actual or threatened change in the internal or external environment
Input reaches the adrenal medulla through its sympathetic innervation
Signals arising in the hypothalamus and other integrating centers activate both the neural and hormonal components of the sympathetic nervous system

11. Regulation of Adrenal Medullary Function
Norepinephrine- or epinephrine-secreting cells can be preferentially and independently stimulated
In response to hypoglycemia detected by glucose monitoring cells in the central nervous system:
the concentration of norepinephrine in blood may increase threefold
whereas that of epinephrine, which tends to be a more effective hyperglycemic agent, may increase 50-fold

12. Disorders of Adrenocortical Insufficiency

13. Adrenocortical Insufficiency
Decreased hormonal secretion is indicated by a dotted line and increased secretion by a dark solid line

14. Adrenocortical Insufficiency
Deficient adrenal production of glucocorticoids or mineralocorticoids results in adrenocortical insufficiency which is either the consequence of:
Primary adrenocortical insufficiency
Destruction or dysfunction of the cortex (Addison’s disease )
Autoimmune disease
deficiency in both cortisol and aldosterone production
As a consequence of metastatic infiltration
Infectious
Congenital unresponsiveness to ACTH
 A rare defect in the adrenal ACTH receptor protein
Congenital adrenal hyperplasia

15. Adrenocortical Insufficiency
Congenital (virilizing) adrenal hyperplasia, 
Inherited enzymatic defects in cortisol biosynthesis
any of the steroidogenic enzymes may be affected
Deficiency of 21β-hydroxylase, one of the key enzymes in the cortisol (and aldosterone) synthetic pathway, leads to:
a reduction in cortisol secretion
with a compensatory rise in plasma ACTH
and a build up of adrenal androgenic steroid precursors (androstenedione and ultimately testosterone)
The excess production of ACTH leads to an excessive growth (hyperplasia) of the adrenal cortex

16. Female infants may show symptoms of:
There are general symptoms of glucocorticoid/mineralo-corticoid deficiency
Female infants may show symptoms of:
abnormal sexual organs
or later in life (precocious puberty, hirsutism or amenorrhoea in adulthood)

17. Disorders of Adrenocortical Insufficiency
Secondary adrenocortical insufficiency
Secondary to deficient pituitary ACTH secretion
Glucocorticoid therapy is the most common cause of secondary adrenocortical insufficiency

18. Boxes enclose clinical decisions, Circles enclose diagnostic tests
Metyrapone blocks the synthesis of cortisol & rapid fall of cortisol
Evaluation of suspected primary or secondary adrenocortical insufficiency.
Boxes enclose clinical decisions,
Circles enclose diagnostic tests
Hypoglycemia induces a central nervous system stress response, increases CRH release, and in this way increases ACTH and cortisol secretion

19. Thus, in healthy individuals, the fall in serum cortisol conc
Thus, in healthy individuals, the fall in serum cortisol conc. leads sequentially to decreased negative feedback at hypothalamic and pituitary levels,
This increases CRH and ACTH secretion and adrenal steroidogenesis; the resultant secretion of cortisol precursors, in particular,
11-deoxycortisol, can be measured by different techniques in blood or its metabolites in urine
Metyrapone 

20. Treatment
In patients with chronic adrenal insufficiency combination replacement therapy with both glucocorticoid and mineralocorticoid compounds is necessary
A combination of hydrocortisone  and fludrocortisone (a synthetic mineralocorticoid) administered by mouth, is recommended

21. Hypersecretion

22. Hypersecretion of Glucocorticoids
The resultant condition of hypercortisolism is called Cushing’s syndrome
More prevalent in women
Its symptoms may also be induced after long-term therapy with glucocorticoids
(e.g. for asthma, rheumatoid arthritis or inflammatory bowel disease)
The condition of excess pituitary ACTH secretion is traditionally referred to as Cushing’s disease

23. Cushing’s Syndrome ACTH-dependent ACTH-independent
Pituitary adenoma (Cushing’s disease)
Nonpituitary neoplasm
ACTH-independent
Adrenal neoplasm (adenoma, carcinoma)
Nodular adrenal hyperplasia

24. small cell carcinoma of the lung causes ectopic ACTH secretion

25. Cushing’s Syndrome The classical features of Cushing’s syndrome are:
Muscle weakness and wasting
thin arms and legs- due to increased protein breakdown
Back pain (due to osteoporosis)
Excess cortisol (or glucocorticoid treatment) interferes with bone metabolism
Redistribution of body fat tissue
rounded (moon) face

26. Treatment
This is usually by removal of the pituitary, ectopic (usually in lung) or adrenal tumor if possible, coupled with corticosteroid replacement therapy
When tumors are not easily located or inoperable, patients may undergo therapy with a steroid synthesis inhibitor
Metyrapone is a competitive inhibitor of the enzyme involved in the final step of cortisol synthesis in the adrenal cortex;
this drug may also be used in the treatment of Cushing’s syndrome arising from an ectopic ACTH-secreting tumor

27. Mineralocorticoid Hyposecretion
Isolated deficiency in aldosterone production (hypoaldosteronism) may be due to adrenal enzyme defects (very rare)
It may occur for example, as a consequence of renal disease due to diabetes mellitus 
The general symptoms of mineralocorticoid deficiency:
i.e. increased Na+/H2O excretion,
hyperkalaemia (high plasma K+),
hypotension and metabolic acidosis would also be seen in conjunction with those of glucocorticoid lack in cases of adrenal insufficiency (e.g. Addison’s disease)

28. Mineralocorticoid Hypersecretion
Aldosterone excess (hyperaldosteronism) may be divided into two types:
Primary Hyperaldosteronism (Conn’s Syndrome):
caused by a bilateral adrenal hyperplasia (abnormal enlargement)
or small tumour (adenoma) of the adrenal zona glomerulosa. 
Patients exhibit hypertension (due to Na+ and H2O retention)
and a low plasma K+ level
Plasma renin levels are characteristically low in this condition
Diagnosis is made by demonstration of:
a high plasma or urine aldosterone level, 
in conjunction with a low level of plasma renin
blood volume expansion by saline loading, would fail to suppress the high aldosterone level

29. Mineralocorticoid Hypersecretion
Secondary Hyperaldosteronism:
This is caused by an abnormally increased renin release, and therefore raised levels of angiotensin II
Some possible causes include:
Poor renal perfusion e.g. in renal artery stenosis;
Malignant hypertension (i.e. hypertension associated with progressive renal failure due to renal arteriolar necrosis);
Renal tumour of the juxtaglomerular cells;
Excessive Na+ and H2O loss during diuretic therapy (most common cause) or dietary Na+ deprivation;
Congestive heart failure

30. Treatment Hypoaldosteronism Hyperaldosteronism
treated by replacement therapy
Hyperaldosteronism
should involve the treatment of the underlying cause of the abnormal renin/angiotensin system activation
This is coupled with administration of Spironolactone (antagonist  of the mineralocorticoid , aldosterone, and androgen receptors ) for long-term management

31. DISORDERS OF ADRENAL MEDULLARY FUNCTION

32. Adrenal Medullary Hypofunction (Epinephrine Deficiency)
Epinephrine is the major catecholamine secreted by the normal adrenal medulla and its secretion is unique to the adrenal medulla
Epinephrine deficiency is caused by:
bilateral adrenalectomies,
tuberculosis,
Hemorrhage
autonomic insufficiency
autonomic nervous system (ANS) malfunctions
Or Cortisol deficiency

33. Adrenal Medullary Hyperfunction
The adrenal medulla is not known to play a significant role in essential hypertension
Norepinephrine can increase blood pressure by increasing:
increasing cardiac output,
increasing peripheral resistance through their vasoconstrictive action on the arteriole,
and increasing renin release from the kidney leading to increased circulating levels of angiotensin II

34. Pheochromocytoma
Rare, usually noncancerous (benign) tumor that develops in cells in the center of an adrenal gland
Are usually unilateral
Symptoms include:
Headaches
Palpitations
Diaphoresis
Severe hypertension
Treatment of malignant tumors consists of surgery, chemotherapy, external beam radiation to skeletal metastases, and high-dose 131I-MIBG (metaiodobenzylguanidine) therapy for patients with MIBG-avid tumors
Diaphoresis: تعرق غزير