3/4 adrenal gland hormones and regulations

Pheochromocytoma

An uncommon tumor caused by hyperplasia of adrenal medulla or other chromaffin tissue. Excessive, unregulated production of catecholamines Symptoms; Sudden outburst of hypertension, headaches, episodes of sweating, anxiousness, tremor and glucose intolerance Laboratory detection of urinary catecholamines and their metabolites is critical for diagnosis and treatment, adrenalectomy and subsequent glucocorticoid and mineralocorticoid replacement therapy may be necessary

Androgenic steroids produced by adrenal cortex can be converted by peripheral tissue to

Testosterone

Development of the AG

The adrenal cortex develops from mesodermal cells into steroidogenic cells that produce mineralocorticoids, glucocorticoids, and adrenal androgens but neural crest-derived chromaffin cells migrate into the cortical cells to form the medulla Influence of Cortisol: Chromaffin cells have the potential of developing into postganglionic sympathetic neurons and synthesize the norepinephrine from tyrosine, however, the cells of the adrenal medulla are exposed to high local concentrations of cortisol (from the cortex) which inhibits neuronal differentiation. Additionally, cortisol induces the expression of phenylethanolamine-N-methyl transferase (PNMT) in chromaffin cells, which converts norepinephrine to epinephrine - the primary hormonal product of the adrenal medulla. The Adrenal medulla (AM) bridges the endocrine and sympathetic NS; similar to a sympathetic ganglion without postganglionic processes. Instead of being secreted near a target organ, adrenomedullary catecholamines are secreted into the blood and act as hormones.

Degradation of catecholamines

The biological response of catecholamines is very brief ~ 10 sec, circulating catecholamines are degraded There are two primary enzymes involved in the degradation of catecholamines: monoamine oxidase (MAO) - the predominant enzyme in neuronal mitochondria catechol-O-methyltransferase (COMT)

suprachiasmatic nucleus

a cluster of neurons in the hypothalamus in the brain that governs the timing of circadian rhythms

Addison disease

a rare, chronic endocrine disorder in which the adrenal glands do not produce sufficient steroid hormones (glucocorticoids and often mineralocorticoids). Symptoms Overproduction of ACTH due to decreased negative feedback by cortisol Skin hyperpigmentation (excessive ACTH as well as other products of the parent precursor, POMC, lead to increases in a and g forms of melanocyte-stimulating hormone, MSH) Glucocorticoid deficiency symptoms: predisposition to hypoglycemia, hypotension, changes in mood and personality, muscle weakness, anemia, decreased GI motility and appetite (weight loss), decreased water clearance Mineralocorticoid deficiency symptoms: loss of Na (craving for salt) and fluids and retention of K (hyperkalemia), hypotension, muscle fatigue and pain ( due to increased extracellular K)

Desmolase

cholesterol to pregnenolone

Cushing syndrome

is hypercorticism (increased glucocorticoid production) caused by a pituitary basophilic adenoma. Cushing's syndrome refers to the consequences of increased plasma glucocorticoid concentration from any source. ACTH and cortisol measurements discriminate between ACTH-dependent and independent causes. Two primary consequences 1. Salt and water-retention with renal loss of K+ results in "moon face". The fluid-retention eventually leads to cardiac hypertrophy due to prolonged hypertension. There is often peripheral oedema, due to the glucocorticoid-induced diabetes. This type of diabetes is typically resistant even to large doses of insulin. 2. Catabolism causes muscle wasting, fat accumulation, osteoporosis with kyphosis, buffalo hump, and fractures. The skin is thin with ulcers and red stirrer, and there is poor wound healing. There is impaired fibrocyte formation and capillary resistance.

ACTH (adrenocorticotropic hormone) rapid effects: long term effects: trophic effects:

rapid effects: StAR, HSL, SCC(desmolase) long term effects: enzymes necessary for cholesterol synthesis and LDL receptor trophic effects: health of z. fasciculata and reticularis

CRH (corticotropin releasing hormone)

stimulates release of ACTH

Metabolic effect of cortisol

the action of glucocorticoids is essential for gluconeogenesis, vascular responsiveness to catecholamines, for supression of inflamatory and immune responses, and for modulation of CNS function: catabolic and diabetogenic qualities - stimulates protein and tryglycerine production - stimulates gluconeogenesis in liver - inhibition of glucose uptake by body (insulin antagonism) but not brain. Elevates blood glucose levels, diabetogenic effect. Nervous system becomes primary user of glucose during stress - inhibits bone formation - inhibition of non-essential functions (reproduction, growth) - cortisol tames immune response ( prescribed to suppress inflammation and the immune system. Analogs of glucocorticoids are frequently used pharmacological( e.g. immunosuppressants in organ transplantations. when cortisol lvls are high, many of the body defense mechanisms against infection are inhibited.

regulation of glucocorticoid secretion by HPA axis

the suprachiasmatic nucleus and retina impose a circadian rhythm on CRH secretion, therefore ACTH, therefore cortisol.

aldosterone

governs the extracellular volume (ECV) due to its action on Na retention/absorption by the kidney. Arginine vasopressin (AVP) - also known as antidiuretic hormone (ADH) - regulates osmolality because of its effect on free water balance (and indirectly affects Na concentration)

glucocorticoid levels regulation

1. Imbalance - hypothalamus perceives low blood concentration of glucocorticoids via sensors in the blood 2. hormone release - hypothalamus releases corticotropin-releasing hormone CRH - CRH triggers the adrenal glands to release glucocorticoid into the blood 3. Correction - blood concentration of glucocorticoids increases 4. negative feedback - hypothalamus perceives normal concentration of glucocorticoid and stops releasing CRH - HOMEOSTASIS - 1. Imbalance

Cortisol is:

A glucocorticoid and increases plasma glucose levels; deficiency can result in hypoglycaemia. Bc of the antiflamatory and immunosuppressive actions of adrenal corticosteroids, synthetic analogs are widely used to treat disorders like skin rashes and arthritis

The adrenal gland is

A hybrid gland consisting of a cortex and a medula. The hormones of the ADrenal gland are important regulators of metabolism and serve an important role in adaption to stress

Synthesis of aldosterone

As with cortisol, the adrenal cortex synthesizes aldosterone from cholesterol. Because glomerulosa cells are the only ones that contain aldosterone synthase, these cells are the exclusive site of aldosterone synthesis. As with cortisol, no storage pool of presynthesized aldosterone so secretion of aldosterone by the adrenal is limited by the rate at which the glomerulosa cells can synthesize the hormone. ACTH, extracellular [K+] [Na+], and the peptide hormone ANG II stimulate the production of aldosterone in the glomerulosa cell. They enhance secretion by increasing the activity of enzymes acting at rate-limiting steps in aldosterone synthesis. These include the SCC enzyme (common to all steroid-producing cells) and aldosterone synthase (unique to glomerulosa cells and involved in the final steps of formation). Once secreted, ∼37% of circulating aldosterone remains free in plasma. The rest weakly binds to CBG (∼21%) and albumin (∼42%). The major action of aldosterone is to stimulate the kidney to reabsorb Na+ and water and to enhance K+ secretion. Aldosterone has similar actions in the colon, salivary glands, and sweat glands. Mineralocorticoid receptors (MRs) are also present in the myocardium, liver, brain, and other tissues, but the physiological role in these tissues is unclear. Like all the other steroid hormones, it acts by modulating gene transcription after binding to the MR. Surprisingly, MR in the kidney has a similar affinity for aldosterone and cortisol but cortisol normally circulates at much higher concentrations than does aldosterone (5 to 20 μg/dL versus 2 to 8 ng/dL).

Physiologic actions of catecholamines

Because the adrenal medulla is directly innervated by the autonomic nervous system, adrenomedullary responses are very rapid. Because of the involvement of several centers in the CNS adrenomedullary responses can precede onset of the actual stress (i.e., responses can be anticipated). For example, consider the sympathoadrenal response to exercise. Exercise is similar to the fight-or-flight response, but without the subjective element of fear. It increases circulating levels of both norepinephrine and epinephrine. The overall goal of the sympathoadrenal system during exercise is to meet the increased energy demands of skeletal and cardiac muscle while maintaining sufficient oxygen and glucose supply to the brain. The response to exercise includes three of the following major physiologic actions of norepinephrine and epinephrine - When you run from a predator, you want to keep glucose in the blood so the brain can get the glucose. The brain needs to think of a way to escape, and thinking burns glucose. Fatty acids are broken down as another source of ATP. Heart rate and force increases. Digestion slows, respiratory passages open, bronchiole dilation occurs. BP goes up from vasoconstriction in less needed organs. - Epinephrine is antagonistic to insulin - Consider the sympathoadrenal response to exercise. Exercise is similar to the fight-or-flight response, but without the subjective element of fear. It increases circulating levels of both norepinephrine and epinephrine. The overall goal of the sympathoadrenal system during exercise is to meet the increased energy demands of skeletal and cardiac muscle while maintaining sufficient oxygen and glucose supply to the brain. The response to exercise includes three of the following major physiologic actions of norepinephrine and epinephrine - Increased blood flow to the muscles Norepinephrine and epinephrine (β1) act on the heart to increase the rate (chronotropy) and strength (inotropy) of contractions, induce vasoconstriction (α) of veins and lymphatics. All these effects increase cardiac output. - Increased glucose availability Epinephrine promotes glycogenolysis in muscle (β2). Exercising muscle can also use free fatty acids (FFAs), and epinephrine and norepinephrine (β2 and β3) promote lipolysis in adipose tissue. This increases circulating levels of lactate and glycerol, which can be used by the liver as gluconeogenic substrates to increase glucose. Epinephrine increases blood glucose by increasing hepatic glycogenolysis and gluconeogenesis (β2). - decreased energy demand by visceral smooth muscle. In general, a sympathoadrenal response decreases overall motility of the smooth muscle in the GI tract and urinary tract, thereby conserving energy where it is not needed.

Mechanism of action of catecholmines

Catecholamines act through adrenergic GPCRs The α receptors and β3 receptors respond better to norepinephrine than epinephrine. The β1 receptor responds equally to the two catecholamines, whereas epinephrine is more potent than norepinephrine for the β2 receptor. A large number of synthetic selective and nonselective adrenergic agonists and antagonists now exist. A single catecholamine may thus evoke multiple different responses as a consequence of circulating concentration e.g., epinephrine may evoke both vasodilation and vasoconstriction

The primary production of chromatic cell in the medulla is

Epinephrine, it also produces epinephrine precursor norepinephrine. These catecholamines are structurally and functionally distinct from the steroid hormones

effects of altered glucocorticoid/steroid lvls

In hypocortisolism (e.g., primary adrenal insufficiency, Addison's disease), there is hypoglycemia. In hypercortisolism (e.g., Cushing's syndrome), there is hyperglycemia

Mechanism of action of aldosterone

In the target cells of the renal tubule, aldosterone increases the activity of several key proteins involved in Na+ transport. - increases transcription of the Na-K pump, so augmenting distal Na+ reabsorption. - increases expression of apical Na+ channels and an Na/K/Cl cotransporter so increasing Na+ reabsorption and K+ secretion. ROMK = renal outer medullary potassium channel ENaC = epithelial sodium channel SGK = Serine/threonine-protein kinase Aldosterone regulates only that small fraction of renal Na+ reabsorption that occurs in the distal tubule and collecting duct. Most Na+ reabsorption occurs in the proximal tubule by aldosterone-independent mechanisms, but loss of aldosterone-mediated Na+ reabsorption can result in significant electrolyte abnormalities, including life-threatening hyperkalemia and hypotension. Conversely, excess aldosterone secretion produces hypokalemia and hypertension. 2% change in excretion of Na 3 L change in ECV

Aldosterone is a

Mineralocorticoid, promotes salt and water retention by the kidney, Kristi cal for the normal salt/water balance.

Regulation of catecholamines

Secretion of epinephrine and norepinephrine from the adrenal medulla is regulated primarily by descending sympathetic signals in response to various forms of stress, including exercise, hypoglycemia, and surgery. The primary autonomic centers that initiate sympathetic responses reside in the hypothalamus and brainstem, and they receive inputs from the cerebral cortex, the limbic system, and other regions of the hypothalamus and brainstem. The chemical signal for catecholamine secretion from the adrenal medulla is acetylcholine (ACh), which is secreted from preganglionic sympathetic neurons and binds to nicotinic receptors on chromaffin cells. ACh increases the activity of the rate-limiting enzyme, tyrosine hydroxylase, and of dopamine β-hydroxylase and stimulates exocytosis of the chromaffin granules. Synthesis of epinephrine and norepinephrine is closely coupled to secretion so that the levels of intracellular catecholamines do not change significantly, even in the face of changing sympathetic activity. Cortisol regulates epinephrine production by maintaining adequate expression of the PNMT gene in chromaffin cells

StAR

Steroidogenic acute regulatory protein

How then do the renal tubule cells avoid sensing cortisol as a mineralocorticoid?

The presence of 11β-HSD2 effectively confers aldosterone specificity on the MR.

Synthesis of Catecholamines

epinephrine, some norepinephrine, are stored in the chromaffin granule complexed with adenosine triphosphate (ATP), Ca2+, and proteins called chromogranins. Note: synergy between CRH/ACTH/cortisol and sympathetic epinephrine axis i.e., stress resulting in cortisol release sustains the epinephrine response About 70-80% of the cells of the adrenal medulla secrete epinephrine, and the remaining 20-30% secrete norepinephrine. Circulating epinephrine is derived entirely from the AM but only about 30% of the circulating norepinephrine comes from it, the rest from postganglionic sympathetic nerve terminals. Because the adrenal medulla is not the sole source of catecholamine production, this tissue is not essential for life.

adrenal hyperplasia

excessive growth of the adrenal gland 21-hydroxylase deficiency symptoms: varying degree of virilism in females including hirsutism and clitoral hyperplasia; precocious puberty in boys Also, when the HPA axis is over-stimulated because of stress, and if the body cannot keep up with the demand for cortisol, or if there is any other steroidogenic enzyme block, excess ACTH might be shunted into the androgen production pathway.