Endocrinology - Exam 2 & 3 (Aldosterone & Cortisol)

What are the adrenal glands derived from? (2)

Neuronal & epithelial tissue

What part of the adrenal cortex develops form mesodermal cells which form cords of epithelial endocrine cells and develop into steroidogenic cells? What does this result in?

Outer portion of the adrenal cortex

-- results in 3 zones

After the cortex forms, the inner portion of teh adrenal gland is formed by neural crest derived cells associated with sympathetic ganglia, called what?

Chromaffin cells

What is the inner poriton of the adrenal gland called?

Adrenal medulla

What are the three layers of the outer layer of the adrenal cortex?

1) Zona glomerulosa

2) Zona fasciculata

3) Zona reticularis

What hormone form the Hypothalamus stimulates corticotrophs?

Corticotrophin Releasing Hormone (CRH)

What nucelus of the hypothalamus releases CRH? What mechanism does it use?

Paraventricular nucelus

(Adenylyl cyclase mechanism)

What type of hormone is Adrenocorticotrophic hormone (ACTH)? What mechanism does it use?

Peptide hormone

- Adenylyl cyclase

What do corticotrophs secrete?

Adrenocorticotrophic Hormone (ACTH)

What is the target of ACTH? What does it function to do?

Adrenal gland (cortex)

-- stimulates the three layers to produce their hormones (Aldosterone, Cortisol, & Androgens)

What mechanism do Aldosterone, Cortisol, and Androgens (Adrenal cortex hormones) use?

Steroid hormone mechanism

What is the function of the adrenal cortex hormones (Aldosterone, Cortisol, & Androgens)?

Metabolism of glucose, proteins & fat, regulating salt and water (BP)

Which of the Adrenal cortex hormones is a mineralocorticoid? Glucocorticoid?

Mineralocorticoid = Aldosterone

Glucocorticoid = Cortisol

T/F: All human steroids including adrenocortical steroids are derived from cholesterol (LDL)?

TRUE

T/F: Adrenocortical hormones are not bound to plasma proteins in blood

FALSE

- bound to cortisol-binding globulin or trasncortin (since steroid)

What are the 7 steps of the Steroid Hormone mechanism that Adrenocortical hormones undergo?

1) Steroid hormone diffuses across cell membrane to enter target cell in cytosol or nucleus

2) Steroid hormone binds to the E domain

3) Hormone-receptor dimerizes and binds C domain (specific DNA sequence SRE, steroid response elements)

4) Hormone-receptor complex becomes trasncription actor regulating transcription of gene

5) new mRNA trasncribed

6) Leaves nucleus

7) Translated to new proteins which are specific to the hormone

ACTH is a _____ stimulator to the zona glomerulosa?

WEAK

(there are two other things that are far more potent in their effect to make aldosterone)

What is the zona glomerulosa (ZG) regulated/stimulated primarily by what two things (aka the two things far more potent than ACTH stimulation)?

1) RAAS --> (Renin Angiotensin Aldosterone System; goal to make ATII which stimulates aldosterone; driven by decrease in BP)

2) Plasma [K+] --> (& decreased [Na]; increasing concentration stimulates aldosterone to fix it)

What is the zona glomerulosa regulated/inhibited primarily by? What two other conditions can decrease Aldosterone secretion?

ANP

Other:

- increase Na/decrease K in ECF

- Normal BP

First step for the conversion of cholesterol to mineralocorticoids (aldosterone):

Pregnenolone oxidized by _______________ to form progesterone

3-beta-hydroxysteroid dehydrogenase (3B-HDS)

Second step for the conversion of cholesterol to mineralocorticoids (aldosterone):

Progesterone converted by _______________ to form 11-deoxycortisterone (DOC)

21 alpha/beta-hydroxylase

NOTE: DOC is a weak mineralcorticoid

Third step for the conversion of cholesterol to mineralocorticoids (aldosterone):

11-deoxycortisterone (DOC) converted by _______________ to form corticosterone

11 beta-hydroxylase

Fourth/Final step for the conversion of cholesterol to mineralocorticoids (aldosterone):

Corticosterone converted by _______________ to form aldosterone

Aldosterone synthase

What enzyme ONLY exists in the zona glomerulosa for the conversation form cholesterol to aldosterone?

Aldosterone synthase (4th/final step)

T/F: The primary regulation of aldosterone secretion occurs by ACTH

FALSE

- NOT by ACTH, but through changes in extracellular fluid (ECF) volume via RAAS and through changes in K levels

What is RAAS (Renin-Angiotensin-Aldosterone System)? (6 steps)

KNOW THIS FOR QUIZ TOMORROW;

1) Decrease in extracellular fluid volume/decrease in BP

2) Decrease renal perfusion pressure

3) Increased RENIN secretion by juxtaglomerular cells (jg or granular cells) of kidney

4) RENIN (angiotensinogenase) catalyzes conversion of angiotensinogen to angiotensin I (ATI; inactive)

5) Angiotensin-converting enzyme (ACE) catalyzes conversion of ATI to ATII (Angiotensin II)

6) Acts on zona glomerulosa to stimulate ALDOSTERONE synthesis

SUMMARY of RAAS system (on quiz!)

Low renal perfusion pressure -->

increase secretion of Renin -->

increased angiotensin II and aldosterone -->

Increase Na reabsorption & increase serum pH -->

Increases H2O reabsorption and BP

What is the main goal of mineralcorticoids (aldosterone)?

Increase renal tubular reabsorption of sodium (into ECF) and secretion of potassium (into urine)

-- physiological role to preserve vascular volume

The reabsorption of sodium is accompanies by the reabsorption of what? What affect does this have on blood pressure?

Water

-- Increases blood pressure (& BV)

Aldosterone has what three actions in the late distal tubule and collecting ducts of the kidney?

1) Increase Na reabsorption

2) Increase K secretion

3) Increase H secretion

Na reabsorption and K secretion are on ______ cells of the distal convoluted tubules of the kidney nephron, while H secretion is on _________ cells of the collecting ducts of the kidneys?

Na & K on Principal cells

H on alpha-intercalated cells

Elevated levels of aldosterone (such as with an aldosterone-secreting tumor) cause what changes? (2)

1) Na reabsorption, K & H secretion all INCREASED

2) ECF volume expansion and hypertension, hypokalemia, and metabolic alkalosis

Decreased levels of Aldosterone (such as from Addison's disease) causes what changes? (2)

1) Na reabsorption, K & H secretion all DECREASED

2) ECF volume contraction and hypotension, hyperkalemia, and metabolic acidosis

What hormone from the hypothalamus will act on the corticotropes of the anterior pituitary? What does this stimulate the corticotropes to release?

CRH

ACTH

The ACTH will act on what layer of the adrenal cortex to release cortisol?

Zona fasiculata

The major glucocorticoid produced in humans is cortisol; when its used in medications what is it called?

Hydrocortisone

T/F: ACTH is a strong stimulator to the zona fasiculata

TRUE

What enzymes are only found in the zona fasciculata for the conversion of cholesterol to cortisol?

17-alpha-hydroxylase & 3 beta-hydroxysteroid dehydrogenase

In the conversion of cholesterol to cortisol:

Pregnenolone is oxidized by ______ to form progesterone

3B-HDS (3-beta-hydroxysteroid)

In the conversion of cholesterol to cortisol:

Progesterone is converted by __________ to 17-hydroxyprogesterone

17 alpha-hydroxylase

In the conversion of cholesterol to cortisol:

Another pathway to form 17-hydroxyprogesterone =

Pregnenolone is converted by __________ to 17-hydroxypregnonlone and then converted by ___________ into 17-hydroxyprogesterone

17-alpha-hydroxylase

3 beta-hydroxysteroid dehydrogenase

In the conversion of cholesterol to cortisol:

17-hydroxyprogesterone is converted by ___________ to 11-deoxycortisol

21 alpha/beta - hydroxylase

In the conversion of cholesterol to cortisol:

11-deoxycortisol has a hydroxyl added to it by _______ to produce cortisol

11 beta-hydroxylase

What is the stress managing hormone?

Cortisol

T/F: Cortisol is secreted in a pulsatile sequence throughout the day.

TRUE

-- 10 secretory bursts during a 24 hour period

What is the time where cortisol secretion is the lowest? Highest?

Lowest = evening hours and just after falling asleep

Highest = major burst right before waking (accounts for 1/2 of total/daily cortisol secretion)

The "internal clock" that drives the diurnal pattern can be shifted by altering what?

Sleep-wake cycle

-- such as coma, blindness, constant exposure to either light/dark

What does Cortisol help our body with?

Regulate blood pressure, electrolyte balance, blood sugar, fat storage, immune response, digestion, & more

What feedback cycle does Cortisol use?

Negative feedback loop!

Cortisol directly and indirectly inhibit secretion of ______ form the hypothalamus

CRH

-- inhibits secretion from hypothalamus, effects hilppocampal neurons, or action on the anterior pitutary which inhibits ACTH

Stress (long-term) increases the release of what? What does this lead to?

CRH & ACTH --> Leads to MORE CORTISOL

Proper cortisol in circulation maintains homeostasis according to the body's accumulative stress and physiologic needs every _______ seconds

3-6 seconds

What is the inactive form of Cortisol

Cortisone

What are some drivers for the conversion of Cortisol to Cortisone? (5)

1) Glucocorticoids (steroids)

2) Progesterone

3) Increase TH

4) PCOS

5) Curcumin

What are some accelerated metabolite conversion form cortisol to alpha-THF & B-THF? (5)

1) Insulin resistance

2) Obesity

3) Inflammation

4) Decrease TH

5) Leptin resistance

NOTE: These are the same factors the drive the conversion of cortisone to cortisol

What are the functions of Cortisol? (7)

Many effects (almost every cell in body has receptors)

-- in stressful situations, cortisol helps us respond and survive quickly and then return to normal state quickly

1) Stimulation of gluconeogenesis

2) Anti-inflammatory and immunosuppressive action

3) Maintenance of vascular responsiveness to catecholamines

4) Inhibition of bone formation

5) ADH antagonist

6) Trophic effects on GI mucosa

7) Stimulates erythropoietin

Cortisol release is controlled by what?

HPA axis (Hypothalamic-pituitary-adrenal)

What mechanism of action does cortisol use?

Steroid hormone mechanism

T/F: Cortisol is bound to transcortin in the blood.

TRUE

Where and what cortisol effects SUMMARY:

1) Brain --> stress reactivity regulation (control of sleep-wake, appetite, memory)

2) Heart --> Enhancement of vascular reactivity to vasoactive agents

3) Kidney --> Increased Na reabsorption and K secretion

4) Immune --> anti-inflammatory and immunosuppressive actions

5) Bone --> increased bone reabsorption (increase osteoclast & increase osteoblast; to release AA)

6) Adipose --> increased lypolysis & free FA, decreased glucose transports, decreased Leptin action

7) Muscle --> increase proteolysis; decrease glucose transport

8) Pancreas --> decrease insulin secretion

9) Liver --> increased neoglucogenesis & glycogen storage (potentiation of glucagon and epinephrine effects)

What effect does Glucocorticoids (Cortisol) have on glucose/glycogen?

1) Simulates gluconeogenesis & Glycogen storage/synthesis

-- cortisol increases protein catabolism in muscle to decrease new protein synthesis; provide AA to liver for gluconeogenesis; increase lipolysis; increase expression of glycogen synthase

2) Decrease glucose utilization by tissues and decrease insulin sensitivity of adipose

NOTE: ELEVATES Glucose blood level!!

Glucocorticoids are essential for survival during ______ because they stimulate gluconeogenic routes. What does this mean for hypocortisolism (Addison's) or hypercortisolism (Cushing syndrome)?

Fasting state

Hypercortisolism = Hypoglycemia

Hypercortisolism = Hyperglycemia

What effect does Glucocorticoids (Cortisol) cause an inhibitory inflammatory immune response? (3)

1) Cortisol induces synthesis of LIPOCORTIN (inhibitor of phospholipase A2)

-- component of anti-inflammatory effect is based on inhibiting synthesis of precursor for prostaglandins and leukotrienes form basophils

2) Cortisol inhibits production of interleukin-2 (IL-2) from lymphocytes and the proliferation of T lymphocytes

3) Cortisol inhibits release of histamine (basophils) and serotinin form mast cells and platelets

T/F: Cortisol can be used in diseases involving inflammatory processes such as autoimmune conditions

TRUE

How does cortisol maintain normal blood pressure? How is this affected with hypocorticolism & hypercorticolism?

Cortisol required for vasoconstrictive response of arterioles to catecholamines

-- Hypocorticolism = hypotension

-- Hypercorticolism = hypertension

How does cortisol inhibit bone formation (increase bone resorption)?

1) synthesis of type 1 collagen

2) formation of new bone by osteoblasts

3) intestinal Ca absorption

How does cortisol affect the kidney?

increase glomerular filtration rate

-- causes vasodilation of afferent arterioles, thereby increasing renal blood flow and GFR

What are the effects of cortisol on the CNS/

Glucocorticoid receptors found particularly in limbic system, affecting changes of behavior, mood, decreased memory

-- cortisol decreases REM sleep, increases slow-wave & awake time

What gland is considered the anti-stress glands?

Adrenal glands

What are the 4 major types of stress?

Physical

Chemical

Thermal

Emotional/Mental

T/F: Cortisol is not always present in the body, but it does pulsate in its arrival

FALSE

-- always present; but does peak/pulsate in levels

T/F: The short term effects of stress are negative, but the long-term effects are positive

FALSE

- short term effects positive (bursts of energy, heightened memory, decrease pain sensitivity, increased immunity)

-- PERSISTENTLY HIGH LEVELS PROBLEMATIC (blood sugar imbalance, HBP, lowered immunity, decreased bone density/muscle mass, abdominal fat, lowered sex drive, impaired concentration, anxiety, depression, irregular menstrual cycles)

T/F: All our organs (and immunity) are negatively impacted by high levels of cortisol

TRUE

What is the condition when chronic stress puts adrenal into overdrive and continues to flood body with cortisol; eventually adrenals can no longer keep up with the constant demand?

Adrenal Fatigue

What is stage 1 of the Hans Selye's General Adaptation Syndrome?

General alarm reaction

-- first rxn to stress; body releases stress hormones (including cortisol)

What is stage 2 of the Hans Selye's General Adaptation Syndrome?

Resistance

-- after period of chronic stress, body adapts to ongoing threat and tried to return to normal functions; glucose levels increase to sustain energy and blood pressure increase

What is stage 3 of the Hans Selye's General Adaptation Syndrome?

Exhaustion

-- body run out of reserves of energy and immunity; blood sugar decreases, leading to decreased stress tolerance, progressive mental and physicals exhaustion, illness, and collapse; body organs begin to fail and eventually illness/death

What are some symptoms of Adrenal Fatigue/Insufficiency/Exhaustion?

Decreased cortisol; fatigue; poor stress response; poor mood regulation; brain fog; craving slaty/sweet foods; compromised immunity; insomnia; frequent urination; decreases muscle tone; depression; weight gain; low libido

How do you test for adrenal fatigue?

Measure fluctuating levels of cortisol using at-home urine/saliva tests

What is the DUTCH test?

measure of free cortisol, free cortisomea nd their metabolites (help to better understand cortisol production and the metabolites (alpha-THF; B-THF; THE)

Sum of metabolites help determine total adrenal output

How is Adrenal fatigue treated?

No pharmaceutical method; many patients who are put on thyroid meds w/o adrenal support get worse

-- Adjust them often (occiput/C1/C2, C5/C7 (Thyroid), T4-T7 (Detox), T9/T12 (Adrenal/Diaphragm), Sacrum)

-- Adaptogens (ex: licorice root (+) & Phosphatidylserine (-/calming) reduces cortisol

What are herbal medicines that are specifically restorative to the hypothalamic pituitary adrenal axis to help the body adapt and cope with stress?

Adaptogens

If free cortisol is truly low and symptomatic, do not give them what two medications? What should we do instead?

Hydrocortisone or prednisone

(Synthetic cortisol)

-- only gibe in TRUE distress (Addisonian crisis)

Instead we want to address what is driving it C-->c or C-->metabolites such as lifestyle (insulin, obesity, inflammation, hypothyroid, leptin resistance)

How long does mild adrenal fatigue last? Moderate? Severe?

Mild = 6 months

Moderate = 1yr - 18 months

Severe = 2 years