Adrenal gland

From Iusmphysiology

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

Contents 1 Adrenal glands 1.1 Objectives 1.2 Anatomy 1.3 Histology 1.4 Cortex 1.4.1 Corticotropin releasing hormone 1.4.2 ACTH 1.4.3 Cortex regulation by renin-angiotensin and acth 1.5 Zones of the adrenal gland 1.6 Zone histology 1.7 Stress and the adrenals 1.8 Steroidogenesis 1.8.1 Glucocorticoids (cortisol) 1.8.2 Cortisol effects on various systems 1.8.3 Mineralocorticoids (aldosterone) 1.8.3.1 Regulation 1.8.3.2 Pathway 1.8.3.3 Metabolism of adrenal steroids 1.8.3.4 A non-receptor mechanism... 1.8.4 Adnrogens 1.8.4.1 Adrenarch 1.9 Adrenal diseases 1.9.1 Addison's disease 1.9.2 Adrenal insufficiency 1.9.3 Cushing's syndrome 1.9.4 Cushing's disease 1.9.5 Other 1.9.6 Hypoaldosteronism 1.9.7 Primary aldosteronism 1.9.8 Congenital adrenal hyperplasia 1.9.8.1 21-hydroxylase deficiency 1.9.8.2 11-beta hydroxylase deficiency 1.9.8.3 17-hydroxylase defciency 1.9.8.4 3-hydroxysteroid dehydrogenase II 1.9.9 Catecholamine deficiencies 1.9.9.1 Signaliing

Adrenal glands

Objectives

Anatomy

• Next to the kidneys = "ad" "renal"
• Have great blood supply.
  • Plumbing is different on the left and right sides.

Histology

• Two basic parts: cortex and medulla.
• cortex:
  • mesodermal orgin
    • This 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 in th emidul
  • Ectodermal origin
    • This 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

Cortex

• Part of the HPA axis (hypo, pit, adrenal)
• Hypo makes CRH which is a positive secretory portal hormone
• corticotropes in pit makes acth
• ACTh has several roles on adrenal
  • Causes growth in addition to changes in synthesis at adrenal
  • Causes overgrowth in disease states
• ACTH can be high when feedback loops are broken
  • I.e. cortisol not feedbinb back on hypo or pit, perhaps.

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

Corticotropin releasing hormone

• CRF = CRH
• small peptide, hits receptor on pit cells
• Promotes POMC production in corticotropes of pit
• ACTH generated
  • 39 aa peptide
  • AKA corticotropin
  • Affects steroidogenic cells of adrenal
    • Especially fasciculata and reticularis
    • Less role in glomerulosa

ACTH

• Hits target in cortex of adrenal.
• Binds to an MC2R (receptor)
• Activates cAMP pathways

Cortex regulation by renin-angiotensin and acth

• Glomerula makes aldosterone
  • Responds to reinin-angiotensin
• Fasciculata makes cortisol
  • Resonds to ACTH
• Reticularis makes DHEA
  • Responds to ACTH
• Reticularis and fasciculata will atrophy if pit is removed.
• All these products of these three zones are steroids.
• Will not be tested on structure of steroids versus sterol.

Zones of the adrenal gland

• Glomerulosa
  • Makes adlosterone and deoxycorticosterone
• Fasciculata
  • Makes cortisol and corticosterone
• Reticularis
  • Makes Adrostendione and DHEA
• Medulla
  • CATS, mostly epi (adrenaline), some NE

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.

what?

Stress and the adrenals

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

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.

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 cortosol 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.

Cortisol effects on various systems

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

Mineralocorticoids (aldosterone)

• Made by zona glomerulosa
• Aldosterone is the major one
• Effects:
  • Increases interstitial Na (at the kidney); increases water retention
  • Decreases K+ and H+ (at the kidney)

Regulation

• Read this

Pathway

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

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

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.

Adnrogens

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

Adrenarch

• Important for driving adrenarch.
• 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

Adrenal diseases

• Can be of excess or of insufficiency.

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

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.

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

Cushing's disease

• A specific form of Cushing's syndrome.
  • Secondary cushing's syndrome
• Tumor of the pit htat 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.

Read it yourself

• • Recall that these are all caused by high levels of cortisols

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.

Hypoaldosteronism

• These pts usually present with hyperkalemia and hyponatremia.
  • Also have orthostatic hypotension.
• He won't test us on enzyme names in the flow chart of steroid production.

Primary aldosteronism

• Conn syndrome
  • Production of aldosterone-producing adenoma.

See slide

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)
• 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
  • Excess mineralocoriticoids
    • Hypertension
  • Get the others.

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

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

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.

3-hydroxysteroid dehydrogenase II

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

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.

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.