Endocrinology II

Question 1

Describe the three layers of the adrenal cortex

Answer 1

1. zona glomerulosa - just under the capsule, contains aldosterone synthase (secretes aldosterone). Controlled by angio II and K+.
2. zona fasciculata - middle layer, 75% of adrenal cortex, secretes glucocorticoids, cortisol, and corticosterone and small amounts of estrogen and adrenal androgens. Controlled by ACTH.
3. zona reticularis - deep layer, secretes DHEA, androstenedione, and adrenal androgens and small amounts of glucocorticoids and estrogen Controlled by ACTH and cortical androgen-stimulating hormone (from pituitary).

Question 2

What is the beginning seq of steps in adrenal steroid synthesis?

Answer 2

1. Cholesterol is brought in via LDL. LDL attaches to membrane receptor and is endocytosed into cell.
2. Cholesterol is released from LDL via lysosomes and is brought to the mitochondria to be cleaved.
3. ACTH activates adenylyl cyclase > induces cAMP formation > activates PKA > drives desmolase.
4. Cholesterol desmolase cleaves cholesterol into pregnenolone *rate-limiting step in adrenal steroid synthesis.

Question 3

What are cytochrome P450 enzymes?

Answer 3

They are large family of iron-containing enzymes that catalyze most of the reactions in corticoid synthesis.

Question 4

Which hormones are typically bound to plasma proteins and why?

Answer 4

adrenalcortical hormones are typically bound. 90-95% of cortisol is bound, especially to cortisol-binding globin (transcortin) and albumin. ~60% of aldosterone is bound in circ. It’s thought that binding to plasma proteins smooths out fluctuations in hormone concentrations.

Question 5

What are the functions of aldosterone? What happens if too much or too little?

Answer 5

Aldosterone is released when defending fluids. It increases Na (and H2O) absorption and K secretion at renal tubular epithelial cells. Conc of extra cellular Na remains constant due to H2O absorption.
Deficiency causes loss of NaCl in urine, hyperkalmia. causes extracellular fluid loss, lower blood volume, cardiac E output, and cardiac shock. Total loss > Quick death.
Excess aldosterone elevates Na and reduces K. Na conc actually rises only a small amount since so much more H2O is also being retained. Can lead to muscle weakness, cardiac failure.

Question 6

The late segment, or second half of the distal tubule- and the subsequent collecting duct- have two distinct cell types: principle cells and intercalated cells
What is the function of the principle cells and on what do the actions of these cells depend? r
Potassium-sparing Diuretics: Na channel blockers?
Aldosterone antagonists?

Answer 6

Principle cells: reabsorb water & Na from lumen, secrete K into lumen. Na reabsorption/K secretion depends on NaK ATPase pump on basolateral membrane which keeps intracellular Na low, allows Na diffusion from lumen down gradient through Na channels. NaK pump also generates K gradient for K to flow into lumen through K channels.
Potassium-sparing Diuretics: Na channel blockers keep Na out of cell, so NaK pump can’t pull K into cell and is therefore unavailable for secretion. Used for hypertension, heart failure Aldosterone antagonists: these compete for binding to aldosterone receptors, blocks aldosterone-mediated stimulation of NaK ATPase, these drugs also have K-sparring effect.

Question 7

K+ excretion: determined by 1) rate of filtration (GFR * K+ plasma concentration), 2) rate of reabsorption, and 3) rate of secretion.
What things shift K into cells/decrease [K]o (4) and shifts K out of cells/increase[K]o (7)?
The luminal membrane of principle cells is highly permeable to K+ because of what two types of K+ channels? So, K+ secretion here is controlled by what 3 things?

Answer 7

K+ excretion: determined by 1) rate of filtration (GFR * K+ plasma concentration), 2) rate of reabsorption, and 3) rate of secretion.
Shifts K into cells/Decrease [K]o: insulin, aldosterone, beta-adrenergic stim., alkalosis.
Shifts K out of cells/Increase [K]o - diabetes mellitus, Addison’s, blocking b-adrenergic stim., acidosis, cell lysis, exercise, extracellular osmolarity.
Two types of K+ channels: 1) the renal outer medullary potassium channel (ROMK), and 2) high conductance “big” potassium channels (BK).
K+ secretion here is controlled by 1) NaK ATPase, 2) electrochemical gradient, and 3) lumen membrane permeability.

Question 8

Relationship between aldosterone and K+ secretion.

Answer 8

Excretion by late distal/collecting tubules increased by extracellular fluid K+, especially above 4.1 mEq/L.
This is by 1) stimulation of NaK pump, 2) extracellular K+ in interstitium raises gradient for K into epithelial cells, 3) high K+ stimulates aldosterone, which stimulates the NaKpump. Aldosterone, it’s sensitive to K levels, a 3mEq/L increase in K causes nearly 10X increase in aldosterone. 1) aldosterone stimulates the NaK pump. 2) also increases K permeability at lumen.

Question 9

Why does high Na intake cause no net change in K+ excretion?
Disruption of aldosterone system (adrenals removed) would cause what in regards to K concentrations?

Answer 9

High Na intake decreases plasma aldosterone, so decreased K secretion in collecting tubules. Also high Na intake (or other diuretic) increases fluid delivery to collecting tubule, as fluid flushes, lumenal K is flushed which increased gradient for K to leave cell into lumen. Net effect is that K excretion remains unchanged.
Disruption of adrenals would cause loss of ability to maintain K concentration control. In normal animals, 7X increase in K intake evokes slight increase in K concentration, but without adrenals, K levels not controlled.

Question 10

How do acidosis and alkalosis affect K excretion? Why is this?
Prolonged acidosis vs acute acidosis?

Answer 10

Acidosis- Acute increase in H+ concentration (acidosis) reduces K+ secretion, reduced H+ concentration (alkalosis) increases K secretion.
This appears to be due to effect of pH on NaK ATPase, which in turn decreases intracellular K concentration, and subsequent passive diffusion across the luminal membrane into the tubule.
Prolonged acidosis increases K excretion- probably by inhibiting NaCl and H2O reabsorption. This will increase volume delivery, stimulating K+ secretion. So, acute acidosis inhibits K+ secretion, chronic acidosis increases K+ excretion.

Question 11

A rise in distal tubular flow rate, as from volume expansion and/or high sodium intake (or diuretics) causes what changes in regards to K levels? What would a decrease cause? What are the two effects at play?

Answer 11

A rise in distal tubular flow rate results in increased K+ excretion, decrease in distal flow rate reduces K+ excretion. Two effects at play: 1) When K+ is secreted into tubular fluid, this would normally inhibit force driving K+ across the luminal membrane. With high flow, secreted K+ is flushed, so gradient pushing K+ into tubule is maintained. 2) High tubular flow rate increses BK channel number on luminal membrane. It activates these channels, increasing K+ conductance.

Question 12

Cellular Mechanism of Aldosterone? (5). This is a slow response.

Answer 12

Cellular Mechanism of Aldosterone:

1) In circulation, aldosterone is either bound to cortisol-binding globulin (CBG), to albumin, or free.
2) Aldosterone is lipid soluble, so freely diffuses across cell membrane.
3) In cell, binds to a cytoplasmic receptor, the mineralcorticoid receptor (MR). Heat-shock protein is released and two MRs form dimer.
4) Receptor dimer enters nucleus, binds to glucocorticoid response element (GRE) on DNA. Along with TFs induces transcription of mRNA.
5) mRNA translated into proteins that form: 1) several enzymes, notably the sodium potassium adenosine triphosphatase, which is critical component of Na/K pump. Also 2) membrane transport proteins, such as a sodium channel protein on luminal membrane.

Question 13

What are pressure diuresis and pressure natriuresis? This usually occur together & are referred to as pressure natriuresis.
Feedback Loop of the renal pressure naturiuresis:? (8)

Answer 13

Pressure Diuresis: increase in urinary volume from increased blood pressure. Pressure Natriuresis: increase in sodium excretion from increased blood pressure.
Acute spike in bp of 30 – 50 mmHg increases urinary output. This is demonstrable in isolated kidney so is independent of any hormone effect.
Feedback Loop: 1) increase in fluid intake above urine output accumulates fluid in the body, 2) fluid accumulation increases blood volume, 3) increased blood volume raises mean circulatory filling pressure, which 4) raises pressure gradient for venous return, which 5)elevates cardiac output, which 6)raises arterial pressure, 7) this increases urine output by pressure diuresis- note steep graph indicates slight rise in pressure has strong effect, 8) increased urine output balances increased fluid intake

Question 14

Explain “aldosterone escape”. What is the net gain of salt and water ? What is the final result for BP?

Answer 14

“aldosterone escape”- w/ excess aldosterone, there is an increase in fluids for a couple of days, plus increases in extracellular Na will increase thirst, induce drinking, but eventually the increased fluids cause an increase in arterial pressure, which will itself induce pressure natriuresis and pressure diuresis. So, an increase blood pressure will induce an increase in renal output, bring net gain of salt and water to zero, but the BP remains elevated (hypertension).

Question 15

Renin-Angeotensin system? (5)

Regulation of Aldosterone secretion? (4)

Answer 15

1. When blood pressure falls, kidneys release the enzyme renin. 2. Renin splits angiotensinogen into angiotensin I.
2. Angiotensin I is split by angiotensin-converting enzyme (ACE). One piece is angiotensin II, a strong vaso-constrictor, increasing blood pressure. 4. Angiotensin II also triggers the release of the hormone aldosterone from the adrenal glands and antidiuretic hormone from the pituitary gland. 5. Aldosterone causes the kidneys to retain salt (sodium) and excrete potassium. The sodium causes water to be retained, thus increasing blood volume and blood pressure.
   Regulation of Aldosterone secretion:
   1) increased K+ concentration in extracellular fluid greatly increases aldosterone secretion.
   2) Activation of the renin-angiotensin system, and therefore increased levels of angiotensin II strongly induces aldosterone release.
   3) increased Na+ concentration in extracellular fluid slightly decreases aldosterone secretion.
   4) ACTH is necessary for aldosterone synthesis & release, but has little effect on controlling the rate of secretion.

Question 16

95% of glucocorticoid activity is through ___ some minemal activity through __.
Carbohydrates metabolism:
Glucocorticoids stimulate gluconeogenesis (formation of carbohydrates from proteins) in liver cells by?

Answer 16

95% of activity is through Cortisol (AKA hydrocortisone), minemal activity through corticosterone.
Carbohydrates metabolism:
Glucocorticoids stimulate gluconeogenesis (formation of carbohydrates from proteins) in liver cells by:
1) Cortisol/glucocorticoids activate DNA transcription of enzymes needed to convert amino acids into glucose in liver.
2) Cortisol makes amino acids available for gluconeogensis via causing mobilization of amino acids from extraheptic tissue (esp. muscle).
3) Reduces rates of glucose utilization by cells, which results in elevated glucose levels in plasma.
4). Elevated plasma glucose levels stimulate insulin release, but the cells are less responsive. Sometimes this effect is strong enough to induce “adrenal diabetes”.

Question 17

Protein metabolism: via glucocorticoids? (2).

Fat metabolism via glucocorticoids? (2)

Answer 17

Protein metabolism: 1) protein stores reduced in all cells but hepatic cells. Due to reduced protein synthesis & increased protein catabolism, increased catabolism of protein, decreased amino acid transport. 2) Mobilization of amino acid from nonhepatic tissues, enhancement of liver proteins, increase in plasma proteins.
Fat metabolism: 1) cortisol promotes fatty acid mobilization in plasma. 2) Increased utilization of fats for energy.

Question 18

Any stress induces___ from anterior pituitary, which will induce ?
Speculated benefit are of cortisol in response to stress? Chronic response however is detrimental, may contribute to aging and disease susceptibility.

Answer 18

Any stress induces ACTH release from anterior pituitary, which will induce cortisol release: trauma, infection, extreme temperatures, sympathomimetic drugs, restraint, disease, etc.
One benefit idea is that rapid mobilization of amino acids and fats is for energy synthesis of glucose, synthesis of materials for cell survival.

Question 19

Summarize the action of cortisol in each:

Muscle- ? Vascular- ? Kidney- ? CNS- ? Fetus-?

Answer 19

Muscle- necessary for maintaining contractility.
Bone- increases reabsorption.
Vascular- needed for maintenance of BP.
Kidney- increase glomerular filtration, inhibits ADH, excretes water.
CNS- widespread receptors, modulates perceptual & emotional functions, excessive levels produce insomnia, euphoria, depression,…
Fetus- facilitates maturation of lungs, GI, CNS,…

Question 20

Elaborate on each anti-inflammatory effect of cortisol:
1. cortisol w/ prostiglandins?
2. cortisol w/ lymphocytes?
3. cortisol w/ lysosomes?
4. corisol w/ fibroblasts?
Cortisol used to suppress inflammatory response to allergens, can prevent what?

Answer 20

1. cortisol suppresses inflammation via inducing lipocortin, which inhibits phospholipase A. Phospholipase A generates arachidonic acid, which is precursor to prostaglandins. Prostaglandins mediate inflammatory response- thus, inflammation is supressed via inhibiting synthesis of prostaglandins via inhibiting arachidonic acid synthesis via inhibiting phospholipase A.
2. cortisol decreases number of T lymphocytes and their production of interleukins. This reduces fever.
3. cortisol interferes with lysosomes, reducing degradation enzymes
4. cortisol decreases fibroblasts. These are involved in extracellular matrix, wound healing, encapsulation of foreign invaders.
   Can prevent anaphylaxis shock.

Question 21

How do stressors induce the conversion of cholesterol to pregnenolone?
Cortisol has what kind of effect on CRF and ACTH release?

Answer 21

Stressors induces CRF release from hypothalamus- this induces ACTH release from anterior pituitary.
ACTH in adrenocortical cells activates adenylyl cyclase which increases cAMP- this activates protein kinase A (PKA), PKA induces conversion of cholesterol to pregnenolone, rate limiting step in adrenal hormone synthesis…
Cortisol then goes on to induce gluconeogenesis, protein mobilization, fat mobilization, anti-inflammatory actions,… these serve to relieve stress, Cortisol has inhibitory feedback effect on CRF and ACTH release
CRF, ACTH, and cortisol levels fluxuate during the day, with levels peaking in early morning, falling through the day.

Question 22

When ACTH is released by the anterior pituitary, several other hormones with similar chemical structures are also released. The gene that is transcribed to form the RNA for ACTH synthesis initially induces formation of ___ which is the precursor of _______…
___cleaves POMC, followed ___ to further process the products.

Answer 22

When ACTH is released by the anterior pituitary, several other hormones with similar chemical structures are also released. The gene that is transcribed to form the RNA for ACTH synthesis initially induces formation of POMC, which is the precursor of ACTH gamma and alpha MSH, gamma lipotropin, beta endorphin, beta MSH,…
Prohormone convertase 1 (PC1) cleaves POMC, followed by PC2 to further process the produces.

Question 23

Abnormalities of Adrenocortical Secretion: Failure of adrenal cortices, usually due to primary atrophy of adrenal cortices by autoimmunity. Also due to cancers, tuberculosis, causes what?
Mineralcortical deficiency causes what?
Glucocorticoid deficiency: causes what?

Answer 23

Abnormalities of Adrenocortical Secretion: HYPOadrenalism, Addison’s Disease = failure of adrenal cortices, usually due to primary atrophy of adrenal cortices by autoimmunity. Also due to cancers, tuberculosis,…
Mineralcortical deficiency: allows Na, Cl, water to be lost in large quantities in urine, results in loss of extracellular fluid volume. May involve hyperkalemia, acidosis. Loss of fluids will reduce plasma volume, reduce cardiac output. Untreated will cause death in days to weeks.
Glucocorticoid deficiency: Pt will not maintain normal glucose levels between meals. Less mobilization of proteins and fats depresses metabolism, causes sluggishness. Increased susceptibility to infections, deposits of melanin pigmentation in blotches, especially on lips, gums, nipples.

Question 24

Describe the effects of hyperadrenalism aka Cushing’s disease (syndrome). From what can result?

Answer 24

Hyperadrenalism- Cushing’s disease (syndrome): can result from pituitary tumors secreting ACTH, hypothalamic tumors producing CRF- results in fat being distributed from lower to upper body (buffalo torso), around face, hypertension (from Na retention) increased blood glucose, loss of proteins everywhere except liver which produces wasting and weakness, subcutaneous tissue tears easily, immune system suppressed leaving pt vulnerable to infections.

Question 25

Congenital Adrenal Hyperplasia;
Resulting from___ deficiency , results in overproduction of ___. Usually only trace amounts of __and ___produced. Explain.
Patients may also show signs of excessive ___, and inadequate __, resulting in Na-K imbalance (loss of Na, retention of K).

Answer 25

Congenital Adrenal Hyperplasia;
Resulting from 21 hydroxylase deficiency, results in overproduction of androgens. Usually only trace amounts of testosterone and estradiol produced. Substantial precursors are secreted (androstendione, DHEA, DHEA-S), converted to testosterone & estradiol in peripheral tissues. In women, these provide half of androgenic hormone requirements- maintain secondary sex characteristics. Disruptions in these pathways have significant clinical implications. Deficiency in enzyme 21-hydroxylase results in more substrate going into the androsterone pathway, rather than into the cortisol pathway. Can produce masculinization of female fetus. In the case above, patient presents with clitoromegaly (enlarged clitoris) with fused labia. Patient also showed signs of excessive cortisol, and inadequate aldosterone, resulting in Na-K imbalance (loss of Na, retention of K).

Question 26

Adrenogenital Syndrome; Adrenocortical tumors have been associated with production of excess ___. Produces what among females? Among males?

Answer 26

Adrenogenital Syndrome; Adrenocortical tumors have been associated with production of excess androgens. Among females, masculine secondary sex characteristics can develop: deepening voice, male pattern facial and body hair development, male-pattern baldness, clitoral growth, increased muscle mass.
Among males can be difficult to differentiate from ‘normal’ masculine effects of testes secretion of testosterone. In prepubescent males, can produce precocious sexual development.