16-Adrenal Glands

Adrenal Glands

These are located in the retroperitoneal cavity above each kidney and the hormone secretions are essential for life

The adrenal cortex and adrenal medulla are two separate glands that have different origins

Adrenal Cortex

Mesodermal origin with three distinct layers (80% of tissue)

3 Layers:

• Zona Glomerulosa (Aldosterone by ANG II)

• Zona Fasciculata (Cortisol by ACTH)

• Zona Reticularis (Androgens by ACTH)

Adrenal Medulla

Neuroectodermal origin and represents 20% of the tissue

Makes Epi by ANS (sometimes NE too)

Blood Supply for Adrenal Glands

Superior, middle, and inferior suprarenal arteries

• Branches from the arteries form a network of capillaries that flow from the adrenal cortex to the medulla

Directionality in blood flow results in a high concentration of steroid hormones being delivered to the adrenal medulla

• Cortisol influences the biosynthetic pathway of catecholamines

Venous Drainage Adrenal Glands

Venous drainage is via a single renal vein on each side (right→inferior vena cava and left→left renal artery)

Synthesis of Catecholamines (based on, controlled by, released by)

Based on a tyrosine derivative!

Under control of the CRH-ACTH-cortisol axis

• ACTH stimulates synthesis of DOPA

• Cortisol increases PNMT (upregulates NE→Epi)

Release is triggered by ANS control

Neurons and Adrenal Medulla

Synthesis of catecholamines happening in these 2 locations:

Norepinephrine and Epinephrine

THESE are Synthesized in Different Cellular Compartments

• NE in chromatin granules

• Once in cytosol, PMNT can act on NE to make Epi!

Catecholamine Receptors

Adrenergic receptors

Types:

• Alpha 1

• Alpha 2

• Beta 1

• Beta 2

• Beta 3

Alpha 1 Receptor

• Tissue Distribution: Sympathetic postsynaptic nerve terminals

• Action: Increase vascular smooth muscle contraction

Alpha 2 Receptor

• Tissue Distribution: Sympathetic presynaptic nerve terminals; beta cells of pancreatic islets

• Action: Inhibit norepinephrine release; inhibit insulin release

Beta 1 Receptor

• Tissue Distribution: Heart

• Action: Increase cardiac output

Beta 2 Receptor

• Tissue Distribution: Liver; smooth muscle of vasculature, bronchioles, and uterus

• Action: Increase hepatic glucose output; decrease contraction of blood vessels, bronchioles, and uterus

EPI has a higher affinity for this!

Integrated Catecholamine Response to Exercise

• Increased CO, venous return, & blood flow to skel muscle

• Alpha receptors simultaneously decrease blood flow to GI

• Bronchioles (via Beta 2 receptors) dilate!

  • Increases exchange of O2 and CO2

• Overall, Catecholamines stimulate increase in blood glucose and mobilization of other energy stores (increasing nutrient supply to mm.)

  • lipolysis

  • gluconeogenesis

  • ketogenesis

  • decreasing glucose uptake

• Beta Cells- decrease in insulin secretion

• Alpha Cells- increase in glucagon secretion

Degradation of Catecholamines

• They’re only active for 10 seconds

• Degradation happens via 2 enzymes:

  • COMT: catecholamine-O-methyltransferase

  • MAO: monoamine oxidase

At the end of degradation of NE/Epi, we see Metanephrine 7 Vanillymandelic Acid (found in urine).

Determining total catecholamine production

Catecholamines, metanephrines, and

vanillylmandelic acid (VMA) can be measured

Pheochromocytoma

Tumor of chromaffin tissue

Produces excess catecholamines

Symptoms sporadic

• Headaches

• Sweating

• Palpitations

Adrenal Cortex Hormones

• Aldosterone

• Cortisol

• Androgens

Aldosterone

(mineralocorticoid- regulates salt and water retention)

Functions in salt and water homeostasis

Cortisol

(glucocorticoid- increases plasma glucose)

Released in response to stress

Influences glucose utilization, immune and inflammatory homeostasis

Androgens

dehydroepiandrosterone (DHEA)

Primary androgenic hormone in females

Biosynthetic Pathway for Adrenal Hormones: Enzymes

We start out with cholesterol and then numerous enzymes are involved in taking that cholesterol and turning it into adrenal hormones:

17-Alpha Hydroxylase

21-Alpha Hydroxylase

11-Beta Hydroxylase

Aldosterone Synthase

Cholesterol

What all adrenal hormones are derivatives of

That Zone

Each zone of the adrenal cortex contains a specific set of enzymes that controls hormone production for _.

Aldosterone

Converts glucocorticoids into mineralocorticoids in the biosynthetic pathway.

Gluc and Mineral corticoids can have overlapping activity on the receptors of each particular hormone.

Thus, our body has put only Gluc or Mineral corticoid receptors in specific areas so it only receives the one it’s supposed to.

Cortisol (what is it, stimulating factors, inhibiting factors, pathway)

Hormone from the adrenal cortex:

Stimulatory Factors:

• Stress

• Sleep-wake transition

• Decreased blood cortisol levels

Inhibitory Factors:

• Increased blood cortisol levels (it inhibits itself)

• Somatostatin

Pathway:

• Stress helps regulate CRH from hypothalamus

• CRH stimulates ACTH production in pituitary gland

• When ACTH is release, it can work on adrenal cortex to induce synthesis of glucocorticoids/cortisol

• Cortisol feedback loops:

  • Negative- inhibits ACTH & CRH

Actions of Cortisol

1. Increases gluconeogenesis, protein catabolism, lipolysis, and decreases glucose utilization and insulin sensitivity

2. Anti-inflammatory effects

3. Suppresses immune responses

   1. T cell suppression (IL-2)

   2. Lyses eosinophils

4. Maintain vascular responsiveness to catecholamines

   1. Maintains normal blood pressure

   2. ↓ cortisol → hypotension

5. Inhibition of bone formation

   1. Decreases type I collagen

   2. Decreases osteoblast activity

   3. Decreases gut Ca2+ absorption

6. Increases glomerular filtration rate (GFR)

7. Decreases REM sleep (psychosis)

Acute Release of Cortisol

Cortisol Increases

Insulin/Glucagon Ratio Decreases

Epi and NE Increases

Using our energy stores, increase in glucose production

Metabolic response to stress ensures there’s enough energy to meet increased demands (aka enough glucose for brain).

• Cortisol is increasing energy

• Cortisol is limiting immune response to stress

Chronic Release of Cortisol

Cortisol Increased

Insulin/Glucagon Ratio Increased

Epi & NE Decreased

Increased appetite, increased glycogen synthesis, increased protein synthesis, decreased GLUT-4 glucose intake (Cortisol is antagonizing insulin)! Decreased lipolysis and increased TAG synthesis.

Metabolic responses: localized obesity & muscle weakening. Decreased glucose uptake due to cortisol antagonizing insulin. See both hyperglycemia and hyperinsulinemia.

Steroid Cushing Syndrome

• overreplacing glucocorticoids/cortisol to treat their chronic inflammatory condition → Cushing Syndrome (too much cortisol) and Adrenal Atrophy (body isn’t making its own anymore)

Cushing Disease

• Tumor in anterior pituitary (overproducing ACTH) → too much cortisol → adrenal hyperplasia

Adrenal Cushing Syndrome

• Tumor in adrenal cortex or nodular hyperplasia → too much cortisol

Paraneoplastic syndrome

• tumor in location other than anterior pituitary that’s overproducing ACTH → too much cortisol

Why do we see Adrenal Atrophy in the Presence of Exogenous Glucocorticoids?

Normal:

• Hypothalamus → CRH → Pituitary → ACTH → Zona Fasciculata → Cortisol

Too many exogenous glucocorticoids:

• Too much corticosteroid present → feeds back to inhibit CRH from hypothalamus & ACTH from pituitary

• No stimulation of hypothalamus & pituitary = no hormones produced (CRH and ACTH) = Zona Fasciculata atrophies

• This is why we have taper doses of steroids, to allow adrenal gland to build back up and make its own again!

Aldosterone

Renin-Angiotensin (Major Regulatory Pathway)

• Liver: Angiotensinogen

• Kidney: Renin production

Pathway

• Angiotensinogen (Liver) → via Renin (in kidney)→ Angiotensin I (ANGI) → via ACE (in lung)→ Angiotensin II (ANGII)

ANGII

• Triggers aldosterone synthesis by acting on adrenal cortex

• Aldosterone then works on our kidneys to decrease Na/Water excretion (but increases K secretion)

Renin Expression

• Induced by decreased blood pressure (lower blood volume)

When BP increases (thanks to aldosterone), it shuts renin down!

Note: High K levels will promote synthesis of aldosterone & decrease K retention!

Actions of Aldosterone (what it controls, vs ADH, receptors, lack, excess)

• Controls Na+ resorption in the extracellular space

  • Increases Na+ resorption, increases K+ and H+ secretion

• Contrast THIS to ADH which regulates water balance and hence plasma osmolality

  • ADH doesn’t impact Na absorption, THIS does

• Receptors

  • Kidney- target cells have 11β-HSD2 (11B-hydroxysteroid dehydrogenase II) that converts cortisol to cortisone which has low affinity for the mineralocorticoid receptor (MR)

  • Colon

  • Salivary glands

  • Sweat glands

• Lack of aldosterone

  • Hyperkalemia, hypotension, metabolic acidosis

• Excess aldosterone

  • Hypokalemia, hypertension, metabolic alkalosis

Interconversion of Cortisol to Cortisone

11β-hydroxysteroid dehydrogenase type II is for mineralocorticoid cells (Cortisol → Cortisone)

11β-hydroxysteroid dehydrogenase type I is for glucocorticoid cells (Cortisone → Cortisol)

Primary Hyperaldosteronism (causes & what happens)

Most common cause:

• Idiopathic (generalized increase in the zona glomerulus)

Second most common cause:

• Adenoma in adrenal cortex

What happens:

• too much aldosterone

• Na is reabsorbed, water follows (develops HTN)

• K is excreted (hypokalemia)

• H loss (metabolic alkalosis)

Actions of Adrenal Androgens

Females

• Presence of pubic and axillary hair, libido

• In females the only primary of androgens is from the adrenal cortex

Males

• Same as testosterone

• Men do not need adrenal androgens as they are synthesized in the testes

Adrenal Pathophysiology

Cortisol:

• Excess = Cushing's syndrome

• Deficiency = Addison's disease and hypocortisolism

Aldosterone:

• Excess = Hyperaldosteronism (Conn's syndrome)

• Deficiency = Addison's disease and hypoadrenalism.

Sex steroids:

• Excess = Hirsutism or virilization.

Congenital Adrenal Hyperplasia

A group of autosomal recessive disorders that involve a deficiency in either cortisol, aldosterone, or both due to impaired synthesis.

Enzyme Deficiency: 21-hydroxylase

Glucocorticoid Effect: Low

Mineralocorticoid Effect: Low; salt-wasting

Androgenic Effect: High; virilizing

Buildup of precursors but we DON’T get cortisol or any other corticosteroids. We’re left with excess androgens.

Caused by:

• Mutation in CYP21A2 gene!

• Can have total loss or partial loss

• Total loss:

  • Salt-wasting

  • Hyponatremia

  • Hyperkalemia

  • Hypotension

  • Cardiovascular collapse and possibly death

  • Virilization- recognizable in females at birth but more difficult in males

Enzyme Deficiency: 11β-hydroxylase

Glucocorticoid Effect: Low

Mineralocorticoid Effect: Moderate; hypertensive effect from excess deoxycorticosterone (DOC)

Androgenic Effect: High; virilizing

We lose cortisol and aldosterone BUT deoxycorticosterone is produced (it has some mineralocorticoid activity). We still produce our androgens!

Caused by:

• Gene mutation in CYP11B1

  • Loss of negative feedback inhibition and ACTH-mediated adrenal androgen excess is observed

  • Mineralocorticoid activity is attributed to deoxycorticosterone (DOC) and increased secretion is postulated to be responsible for the observed hypertension in these patients

Enzyme Deficiency: 17-α-hydroxylase

Glucocorticoid Effect: Low

Mineralocorticoid Effect: Excess; hypertensive

Androgenic Effect: Low; feminizing

ACTH will be high, cortisol is gone, and we’ve lost adrenal androgens. BUT we have a build-up of DOC (thus overload of mineralocorticoids).

Caused by:

• Mutation in gene CYP17

  • Impaired sex steroid and cortisol biosynthesis

  • Excess intermediary steroids with mineralocorticoid activity leads to varying degrees of hypertension and hypokalemia

  • No androgen activity

    • Females fail to develop secondary sexual characteristics

    • Males develop ambiguous external genitalia