Adrenal gland

From Iusmphysiology

Current revision as of 21:06, 21 March 2011

• continued here from Endocrine control mechanism on 03/02/11 at 11:11AM.

[edit] Adrenal glands

[edit] Objectives

[edit] Anatomy

• Next to the kidneys = "ad" "renal"
• Have great blood supply so they can be signaled and release their signals.
  • Plumbing is different on the left and right sides.

[edit] Histology

• Two basic parts: cortex and medulla.
• Cortex:
  • mesodermal orgin which makes sense because the mesoderm is generally found on the outside of the internal organs and the cortex is the outside part of the adrenal gland
  • Zona glomerulosa
  • Zona fasciculata
  • Zona reticularis
  • GoFaRM = glomerulosa, fasciculata, reticularis, medulla
• Medulla is in the middle of the organ
  • Ectodermal origin which makes sense because it controls the catecholamines which are kind of nervous system like in the way they signal and the ectoderm makes the nervous system.
  • Cats: epi, NE
• Cortex on the outside of the whole organ

[edit] Cortex

• Part of the HPA axis (hypo, pit, adrenal)
• Hypo makes CRH which is a positive secretory portal hormone
• Corticotropes in pit make ACTH
• ACTh has several roles on adrenal:
  • Causes growth
  • Causes changes in what the adrenal cells synthesize
  • Causes overgrowth in disease states
• ACTH can be high when feedback loops are broken
  • I.e. cortisol not feeding back on hypo or pit, perhaps.

• Separate types of feedback loops
  • More when we talk about growth hormone.

[edit] Corticotropin releasing hormone

• CRF = CRH
• CRF is a small peptide that binds receptors on pituitary cells, namely the corticotropes.
• Promotes POMC production in corticotropes of pit
• ACTH generated from the POMC gene
  • ACTH is a 39 aa peptide
  • ACTH is also known as corticotropin
  • ACTH affects the steroidogenic cells of the adrenal gland, especially the fasciculata and the reticularis.
  • NOTE: ACTH has less affect on the glomerulosa than the other two layers of the cortex.

[edit] ACTH

• Hits target in cortex of adrenal.
• Binds to an MC2R (receptor) on the cells of the cortex layers.
• ACTH activates cAMP pathways via the MC2R receptor.

[edit] Zones of the adrenal gland

• Glomerulosa
  • Makes adlosterone and deoxycorticosterone
  • Responds to reinin-angiotensin
• Fasciculata
  • Makes cortisol and corticosterone
  • Resonds to ACTH
• Reticularis
  • Makes Adrostendione and DHEA
  • Responds to ACTH
• Reticularis and fasciculata will atrophy if pit is removed (because they respond to ACTH!).
• All these products of these three zones are steroids.
• Will not be tested on structure of steroids versus sterol.

• Medulla
  • Makes CATS, mostly epi (adrenaline), some NE

[edit] Zone histology

• There is discrete histology
• Think of things as flowing stuff through the area
  • If an enzyme is missing, things flow in the other direction.

[edit] Stress and the adrenals

• Short term stress: Cats
• Long term stress: Corticosteroids via ACTH and the mineralocorticoids (glomerulosa, not via ACTH)

[edit] Steroidogenesis

• Structures are for help, not tested.
• He likes this diagram b/c it is layered with the layers: glomerulosa, fasciculata, and reticularis. ("layerd version")
• Estradiol and test are not made at significant amounts in the adrenal.
  • Mostly DHEA is made and put in blood
  • Test and est made elsewhere.

[edit] Glucocorticoids (cortisol)

• Cortisol is the major glucocorticoid made in humans.
  • Released in circadian rhythm
• Go example of thinking about cycles when measuring hormones in pts.
• Stress is a major player in cortisol release
  • via CRH-ACTH axis
• A hormone carried in blood by binding proteins.
  • Corticoseteroid binding globulin (CBG)
  • Albumin
  • Transcortin
• Glucocorticoids bind on glucocorticoid receptors, then HSPs then homodimerize to go into the nucleus to be a txn factor.
  • Txn factors work with partner prots to affect txn.
  • for cortisol, GR does not work direclty with partner proteins.

[edit] Cortisol effects on various systems

• Acts on many, many tissues.
• Read this, know this.
• Most effects are "permissive"

[edit] Mineralocorticoids (aldosterone)

• Made by zona glomerulosa
  • This makes sense because aldosterone acts at the kidney and the kidney has glomerula.
• Aldosterone is the major one
• Effects:
  • Increases interstitial Na (at the kidney); increases water retention
  • Decreases K+ and H+ (at the kidney)

[edit] Regulation

• Read this

[edit] Pathway

• Study this, he went really fast.
• Aldosterone binds to cytoplasmic minteralocorticoid recetpors, uses HSPs, homodimersizes, etc.
• Causes Na to be retained.

[edit] Metabolism of adrenal steroids

• You have to make hormone action discrete so we control half-life and such.
• Body has two mechanisms:
  • Modifications to inactivate
  • Modifications to increase solubility
    • Allows loss at urine
  • Done by adding sugar groups, etc.
• Metabolites can be key diagnositic tools
  • Can help identify tumors

[edit] A non-receptor mechanism...

• Enzymes that convert excessive glucocorticoids into non-responsive, non-MR binders gives us a way to control signaling if there's too much aldosterone.

[edit] Androgens

• Major forms are adrostendione and DHEA
• These are not present much in the adrenals b/c they are produced where blood flow in the adrenal exits.

[edit] Adrenarche

• Androgens (and therfore the reticularis) are important for driving adrenarche.
• This helps develop: pubic hair, auxillary hair, acne, and adult body odor.
• one disease term is virulization; means that there is an excess of androgens and this axis is elevated

[edit] Adrenal diseases

• Can be of excess or of insufficiency.

[edit] Addison's disease

• JFK had Addison's disease.
• Adrenocortico insufficiency:
  • Too little cortisol being produced
• Primary Cause:
  • Autoimmune
  • Infectious
• Secondary cause
  • Pit doesn't make enough ACTH
  • 1 in 100K so rare
• Presentation:
  • Low cortisol
  • hypoglycemia
  • high ACTH
    • b/c no feedback:
      • could lead to adrenal hypertrophy,
      • could lead to odd coloring b/c it increases ACTH which has the sequence of the MSH hormone so it can activate the MSHr
  • high sex hormone precursors like ADHEA.
  • Loss of the aldosterone axis

[edit] Adrenal insufficiency

• This diagram explains how to differentially diagnose adrenal issues.
• It's a function of the ACTH and Cortisol levels
  • When ACTH is low...
  • If cortisol is low...
• Adrenal insufficiency occurs in pit in the 2nd and 3rd from the left.

[edit] Cushing's syndrome

• Diseases of excess of cortisol
• Could be an adrenal tumor making too much cortisol.
• Causes really low ACTH b/c lots of feedback on the Pit
• An umbrella term for overproduction of cortisol
  • If it is a pit ACTH-producing tumor, then it is the disease.
• Primary is adrenocorticol carcinoma or adenoma
• Can also be caused by excessive exogenous glucocorticoids
  • And when stopped suddenly can cause an acute form of Addison's disease

[edit] Cushing's disease

• A specific form of Cushing's syndrome.
  • Also known as Secondary cushing's syndrome
• Tumor of the pit that makes ACTH
• Similar outcome to syndrome (too much cortisol)
• Can tell the diff b/c ACTH is high.
• Presentation:
  • Key are high bp and high blood sugar.
  • Recall that these are all caused by high levels of cortisols

[edit] Other

• Other tumors (in other parts of the body) that make ACTH or something that mimics ACTH.
  • "Ectopic ACTH secretion"
  • A certain rare type of lung cancer does this.

[edit] Hypoaldosteronism

• These pts usually present with hyperkalemia and hyponatremia.
  • Recall that aldosterone acts at the kidneys to cause Na (and H20) retention and to excrete K and H+.
  • Also have orthostatic hypotension.
    • This makes sense because if they don't retain enough Na and H20 then they will become hypovolemic and thus when they stand their cerebral blood pressure will drop.
• He won't test us on enzyme names in the flow chart of steroid production.

[edit] Primary aldosteronism

• Conn syndrome
  • Production of aldosterone-producing adenoma.

See slide

[edit] Congenital adrenal hyperplasia

• Babies tested at birth.
• Deficiency of certain steroid synthesis enzymes
• Low cortisol
• High ACTH b/c of low feedback
• Can be high androgens (not always though)
• 1:16k, thus tested
• Enzymes:
  • The enzyme missing affects the outcome
  • He named four major classes
• Outcomes by outcome of deficiency:
  • Low mineralocorticoids
    • Vomiting due to salt wasting, dehydration, death
    • Na is not retained, water is lost.

Why would vomitting occur because of salt wasting?

• • Excess mineralocoriticoids
    • Hypertension (Na retained, water retained)
  • Get the others.

[edit] 21-hydroxylase deficiency

• 90% of CAH cases are this.
• Prevalent in Askanazi jews.
• Salt wasting
• Low cortisols
• High levels of androgen precursors
  • Leads to virulization

[edit] 11-beta hydroxylase deficiency

• Stops cortisol
• build up of DHEA
• You can make DOC, though, which can have corticosteroid affects.
  • Causes low-renin hypertension.
• more rare

[edit] 17-hydroxylase defciency

• Got confused, read about it, see email.
  • "I mislabeled the diagram – 17 hydroxylase is enzyme 3a not 3b – therefore low androgens and cortisol result. You can get high levels of DOC and therefore hypertension and hypokalemia. Due to the renin control system, aldosterone levels are not high."
• The most rare.

[edit] 3-hydroxysteroid dehydrogenase II

• Low androgen, cortisol, and mineralocorticoids
• Causes....

[edit] Catecholamine deficiencies

• Adrenal medulla can be seen as modified part of autonomic nervous system.
  • Fight or flight.
• Cells are anlogous to autonomic postganglionic symp fibers.
• main homrons are adrenaline and nor-adrenaline
  • From tyrosine
  • Main ring is a catechol
• Which is made is determined by which enzymes are present.
  • Cells usually make one or the other, not both.
  • The enzyemes are methyl-transferases.
    • Use folate?
• Made by chromaffin cells
  • Granules are produced that hold the cats
  • Can be released rapidly.
• 80% adrenaline, 20% noradrenaline.

[edit] Signaliing

• Adrennergic receptors
  • Alpha
    • Interact with epi and norepi
  • Beta
    • More specific for epi
    • Beta blockers

• Pathways:
  • Alpha 1 is main positive signal
  • alpha 2 is a feedback and has some negative actions
  • Major actions; read them.

• Metabolism:
  • We look for vanillic acid
    • A biproduct is vanillymandelic acid
    • found in urine for "certain diseases"

• medullary dysfunction
  • Hypofunction: orthostatic hypotnesion, low blood pressure, etc.
    • Often due to surgery to remove entire adrenal
  • Hyperfucntion:
    • Could be due to tumors or ectomic tumors (phaeochromocytomas)
      • Produces too much catecolamines
      • Often given blockers of adrenergic receptors
      • Elevated HR, bp, palpitations, sweating, headaches, psychiatric symptoms (religious delusions), et cetera.
      • Manic symptoms

• stopped here on 03/02/11 at 12PM.