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

During exercise, epinephrine and norepinephrine act to:

a. Increase muscle glycogenolysis

b. Increase hepatic glycolysis

c. Decrease adipocyte lipolysis

d. Decrease hepatic ketogenesis

a. Increase muscle glycogenolysis

A congenital null mutation of 11- hydroxylase would result in:

a. Sodium wasting

b. Hyperglycemia

c. Masculinization of a female fetus

d. Atrophy of adrenal cortex

c. Masculinization of a female fetus

One treatment for hypertension is the use of aldosterone receptor antagonists. A side effect of this treatment can be:

a. Cardiac hypertrophy

b. Hyperkalemia

c. Metabolic alkalosis

d. Edema

b. Hyperkalemia

Glucocorticoid analogs are used at high levels to suppress inflammation. A side effect of this treatment can be:

a. Adrenocortical hypertrophy

b. Hypoglycemia

c. Hyperpigmentation of the skin

d. Osteoporosis

d. Osteoporosis

Cortisol is prevented from interacting with the mineralocorticoid receptor in the distal nephron through the action of:

a. Cortisol-binding protein

b. 11B-hydroxysteroid dehydrogenase type 2

c. 17B-hydroxysteroid dehydrogenase type 1

d. Serum and glucocorticoid-regulated kinase (SGK)

b. 11B-hydroxysteroid dehydrogenase type 2

1. What is Lily’s diagnosis?

2. Which of the following agents should be administered first to control Lily’s blood pressure prior to surgery?

1. Pheochromocytomas

2. An α1-adrenergic antagonist

(Don’t want to give Beta-adrenergic antagonist first because if someone is constricted, you run the risk of hypoperfusion and death of tissues.)

Predict how the following serum values will be altered in this case compared to normal based on a deficiency of 21-hydroxylase (Aldosterone, K, Na, Renin).

Aldosterone will be decreased

K will be increased

Na will be decreased

Renin will be increased

The most likely enzyme deficiency is:

17α-hydroxylase

Causes of Cushing’s Syndrome

ACTH-dependent

ACTH-independent

Factitious

1. The results from Corti are most consistent with an overproduction of THIS from THIS:

2. Why was Corti’s response to the dexamethasone suppression test abnormal?

1. Cortisol from an adrenal tumor

2. There’s unregulated secretion of ACTH/Cortisol from the adrenal tumor

Corti had increased central obesity, muscle wasting, and striae. What are the biological effects of cortisol that are responsible for each of these physical findings?

Hyperlipidemia, lipolysis, adipose deposition changes, proteolysis too (muscle wasting).

1. What might you expect to see upon a bone scan?

2. Corti’s blood pressure was 165/105. Explain the hypertension.

3. Why was Corti’s blood glucose 160 mg/dL?

1. Chronic = decrease in bone density

2. Cortisol increases cardiac output via Alpha 1 Receptors!

3. Increased Cortisol = decrease in glucose uptake and insulin secretion. Decrease in GLUT 4 receptor expression.

Some cases of marked hypercortisolemia are associated with a hypokalemic alkalosis. What is the physiologic basis for the hypokalemia in these cases?

Oversaturation of 11β-hydroxysteroid-dehydrogenase (11β-HSD2 enzyme).

(Found in mineralocorticoid receptor tissues like the kidney!

Oversaturation of this enzyme results in cross reaction of it with mineral and glucocorticoids.)

Corti had his left adrenal gland removed and was subsequently placed on exogenous glucocorticoids. What is the rationale for replacement of glucocorticoids at this time?

The pituitary corticotrophs have atrophied over the course of Corti’s disease.

(One adrenal gland is more than adequate!

What we see in this case is Corti has high cortisol levels, he’s not making CRH from hypothalamus or ACTH from pituitary.)

Main findings in primary aldosteronism

Hypertension

Hypokalemia

Metabolic alkalosis

Hypomagnesemia

1. What condition does Dawn have?

2. An appropriate screening test in this case is (initial step in documenting excess hormone):

1. primary aldosteronism

2. Ratio of aldosterone to plasma renin activity

(Plasma aldosterone has 90% sensitivity and specificity for the diagnosis of primary hyperaldosteronism)

An appropriate confirmatory test in this case is (second step-suppression):

Infusion of normal saline and assay aldosterone levels

(We need to test if aldosterone is working the way that it should.

Test this via increasing blood volume.

Increase blood volume -> inhibit renin -> inhibit aldosterone. If this doesn’t happen, aldosterone regulation isn’t working right.)

How would you expect Dawn’s acid-base status to change?

Lots of hydrogen ion which causes metabolic alkalosis

Conn’s Syndrome

AKA Primary Hyperaldosteronism

• As this condition of hyperaldosteronism from a tumor continues on, there’s Na Escape Phenomenon (Na levels are returned to the high end of the normal range).

Addison’s Disease

AKA Primary Adrenal Insufficiency

Caused by:

• Autoimmune

• Metastatic disease

• Adrenalectomy

• Infectious adrenalitis

• Adrenoleukodystrophy

• Hemorrhagic infarction

• Infiltrative

• Drugs

• Congenital adrenal hyperplasia

Debra’s clinical presentation, laboratory values, and lack of a response to the rapid ACTH test indicate her deficiency is in the:

Adrenal Gland

1. Absence of which hormone accounts for Debra’s relative hyponatremia, hyperkalemia?

2. Give an explanation for Debra’s hypotension. Why is Debra hypoglycemic?

1. ACTH

2. No, Cortisol means decreased BP (no stress) and more insulin present (less glucose).

(Primary adrenal deficiency = indicates issue in the adrenal gland = we lose aldosterone!)

The presentation of primary adrenal insufficiency is distinct from secondary adrenal insufficiency in that:

Primary adrenal insufficiency usually presents with hyperpigmentation

What hormones need to be replaced in primary adrenal insufficiency? Secondary adrenal insufficiency?

Primary – need cortisol and aldosterone

Secondary – don’t need to replace aldosterone but depending on what’s happening in pituitary, you may need to replace other hormones there. Depends on the true cause of this!

What hormone may be replaced but is not necessary in primary adrenal insufficiency?

Primary, adrenal androgens (especially if female). Adrenal gland is main source for androgens for females

How do doses of corticosteroids need to be adjusted during periods of stress in primary adrenal insufficiency? (for example, illness or surgery)

Increase it! You need more of it during stressful times because cortisol is the stress hormone.

1. What endocrine disorder should you consider in this patient?

2. Which other symptoms would you expect to see in Jennifer?

3. What test would you run first?

1. Hypercorisolism

2. Hypercortisolism: fatigue, weight gain, central adiposity, easy brusing.

3. 24 hr urine free cortisol & Dexamethasone suppression test

1. What additional test would you like to order?

2. What do you suspect is the cause of Jennifer’s condition?

3. How will elevated androgen levels effect Jennifer?

1. Urine free 24 hour cortisol → Jennifer’s levels were 300 µg/dL levels (nl, < 90-100 µg/day)

   Dexamethasone suppression test and 8 am cortisol sampling→ Jennifer’s levels were 25 µg/dL (nl, < 5 µg/dl)

   ACTH → Jennifer’s levels were 120 pg/ml (nl, 6-76 pg/ml)

2. Cushing’s Disease

3. Menstrual irregularities and hirsutism (male pattern hair)

1. What medication was Jennifer likely prescribed?

2. What is the cause of her new symptoms?

3. What will the following lab values look like in Jennifer at this time?

1. Synthetic Glucocorticoid (to allow tissue to recover)

2. Adrenal Insufficiency

3. Cortisol = low, ACTH = low, Potassium = normal

(Cortisol will be low, ACTH will be low (due to lack of response of the normal tissue) and potassium will be normal (aldosterone levels will be normal in this case since aldosterone is not under primary control of ACTH))

1. What diagnosis should be suspected in John?

2. What is the basis for this diagnosis and why would this condition develop now?

3. What tests should be done to evaluate endocrine function?

1. Adrenal Insufficiency after an illness (because cortisol is low).

2. His dose of glucocorticoids was tapered to allow the corticotrophs to start producing ACTH. He was doing fine until a stressful event (illness) precipitated a need for additional cortisol which he was unable to response to adequately.

3. Cortrosyn (synthetic ACTH) stimulation test

Explain the mechanism that could result in hyponatremia in this case of adrenal insufficiency.

Elevations in CRH can also trigger ADH secretion, leading to water retention and hyponatremia (see next slide for diagram)