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Physio Endocrinlogy Quiz 1 > Glucocorticosteroids > Flashcards

Glucocorticosteroids Flashcards

1
Q

From outer to inner the adrenal cortex produces what hormones?

A

• Salt, Sugar, Sex: Mineralcorticoids, Glucocorticoids, and Sex Hormones
• The outer zone of the Cortex is the glomerulosa (aldosterone production)
The inner zones of the cortex, the fasciculata and reticularis, produce the glucocorticoids cortisol and corticosterone, along with various androgens

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2
Q

What is the Clinical relevance of glucocorticoids?

A
  • glucocorticoids are used in massive amounts for treatment of a multitude of conditions that are unrelated to hormone deficiency.
  • autoimmune diseases, asthma, other forms of inflammation and allergy, lymphoid leukemia, and lymphomas.
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3
Q

How do the large amounts of glucocorticoids used in therapeutic does affect the HPA?

A

• Therapeutic doses in these cases are often large enough to override the normal physiological controls and functions of the glucocorticoids, with the consequence that the hypothalamic-pituitary-adrenal (HPA) system is thrown out of balance.

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4
Q

Where are glucocorticoids synthesized?
What are the natural glucocorticoids?
What are examples of synthetic glucocorticoids?

A
  • steroid hormones produced by the zona reticularis and fasciculata of the adrenal cortex.
  • Natural are: cortisol (the principal glucocorticoid in human) and corticosterone (the main glucocorticoid in rats, mice and other rodents).
  • Synthetic glucocorticoids are: dexamethasone, prednisolone, and Triamcinolone among others
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5
Q

Cortisol is derived from cholesterol. Most enzymes involved in steroid hormone biosynthesis fall into what two categories? What superfamily are the steroidogenic enzymes from?

A
  • steroid hydroxylases
  • steroid dehydrogenases.
  • Most of the steroidogenic enzymes are members of the superfamily of genes known as cytochrome P450. A series of steps lead from cholesterol through pregnenolone to cortisol.
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6
Q

Are there side reactions from the intermediates in cortisol production? Do they have clinical consequences?

A

• Reactions branching from intermediates along the path to cortisol produce adrenal androgens, which, though weak compared to testosterone, can lead to serious problems if produced in large amounts.

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7
Q

What is adrenogenital syndrome aka congenital adrenal hyperplasia (CAH)?

A

• A class of several autosomal recessive diseases resulting from mutations of enzymes that participate in the synthesis of cortisol by the adrenal glands(steroidogenesis).

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8
Q

What enzyme is most frequently missing in CAH?

A

• enzyme 21-hydroxylase is congenitally absent or dysfunctional.

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9
Q

What happens when enzyme 21-hydroxylase (or similar enzyme) is missing?
What happens in males?
What happens in females?

A

• The adrenal cortex is unable to synthesize cortisol and aldosterone.
• accumulate intermediary hormone metabolites
• the adrenal glands then overproduce adrenal androgens that have testosterone-like effects on the fetus and child, leading to so-called “virilization”.
• In males, 21-hydroxylase deficiency results in sexual precocity and acceleration of linear growth.
• Female patients have male sexual characteristics, such as masculinization of female external genitalia, thus this disease is even more important to diagnose early in females.
o There is a dramatic difference between sexual characteristics of patients where treatment started early vs. late, and if untreated, adult XX patients can exhibit male secondary sex characteristics.
o In milder cases, deepening of the voice, and developing secondary male characteristics in female patients.
o Powerpoint lecture slides show some typical features of this disease, further information can be found at http://www.endotext.org/pediatrics/pediatrics8/pediatricsframe8.htm.

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10
Q

Cortisol secretion is stimulated by the peptide hormone ACTH, which is secreted by the anterior pituitary. ACTH is produced as part of the What larger precursor protein?

A

• pro-opiomelanocortin (POMC)

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11
Q

pro-opiomelanocortin (POMC) which is the progenitor what compounds?

A
  • ACTH
  • α- and ß-MSH (melanocyte stimulating hormones)
  • ß-endorphin
  • lipoproteins.
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12
Q

Explain the cell signaling pathway that causes ACTH to intiate cortisol production

A

• ACTH acts through surface receptors MC2R on the cells of the adrenal cortex.
o The ACTH receptor (MC2R) belongs to the family of melanocortin receptors (MCRs), which are members of the rhodopsin family of 7-transmembrane G protein-coupled receptors.
• MC2R stimulates adenylate cyclase ==> cAMP ==> protein kinase A ==> steroidogenesis.
• ACTH also increases the size of the adrenal cortex.

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13
Q

What is the trophic effect of adenohypophyseal hormones?

A

• adenohypophyseal hormones increase the size, DNA, and protein synthesis of its target gland

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14
Q

What is the rate limiting step in the action of steroidogenic hormones, such as ACTH?

A

• mobilizing free cholesterol from its esterified storage form in lipid vesicles.

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15
Q

What is Steroidogenic Acute Regulatory Protein (StAR)?

A

• Mediates the transport of cholesterol from the outer to the inner mitochondrial membrane.

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16
Q

What are the steps of converting Cholesterol into corticoids (starting from within the mitochondria? (List all the steps and enzymes) (some individual step questions will follow)

A

• See Flow Chart in PPT

Enzyme lists are at the end of this deck

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17
Q

See ppt for flow chart on corticoid production

A

See ppt for flow chart on corticoid production

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17
Q

Explain the negative feedback loop of ACTH (don’t forget the synergy between CRH and ADH). How does stress (and circadian rhythm) effect the feedback loop?

A
  • ACTH is stimulated by CRH.
  • ADH/VP/AVP potentiates the actions of CRH.
  • Glucocorticoids inhibit ACTH secretion directly by suppressing POMC expression in pituitary corticotrophs, and indirectly by inhibiting secretion of CRH and ADH.
  • Superimposed on these controls, which are subject to a diurnal rhythm, is the influence of stress, which through the central nervous system stimulates CRH and ADH secretion, raising cortisol levels above those maintained by feedback.
  • Negative feedback by glucocorticoids, which prevents over-activity of the stress-induced HPA axis, is through binding to glucocorticoid receptors in the pituitary and hypothalamus
  • these receptors are present at high concentrations in the paraventricular nuclei.
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18
Q

Which nuclei in the hypothalamus have cortisol receptors that respond to negative feedback?

A

• high concentrations in the paraventricular nuclei.

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19
Q

Explain The dexamethasone suppression test. What is it used for?

A
  • Cliical method to test negative feedback of of cortisol.
  • In healthy people, a low dose of dexamethasone binds to glucocorticoid receptors in the hypothalamus and in the pituitary and inhibits the secretion of both CRH and ACTH.
  • In turn, plasma cortisol levels will decrease. Terminology: “Test posititive”
  • The main clinical use of the dexamethasone suppression test is in the differential diagnosis in patients with hypercortisolism.
  • If an adrenal tumor is present only high doses of dexamethasone will inhibit cortisol. Terminology: “Test negative”
20
Q

What time of day is plasma cortisol the highest? Lowest?

A

• Plasma levels of cortisol normally vary cyclically through the day reaching a maximum around 8 a.m. in human and falling to low levels in the late evening.

21
Q

Where is the endogenous circadian rhythm pacemaker?

A

• Endogenous pacemaker in hypothalamus (suprachiasmatic nuclei, SCN)

22
Q

What percentage of plasma cortisol is “free” at basal levels? What proteins is the rest of cortisol bound to? What happens when plasma cortisol levels increase (such as at 8 am?

A
  • At basal levels, less than 5% of the total cortisol in plasma is free, the rest is bound to CBG (corticosteroid binding globulin) and albumin.
  • At high cortisol concentrations CBG becomes saturated, and the free and albumin-bound fractions increase.
  • Only free hormone can bind to glucocorticoid receptors and exert biological activity.
23
Q

What is the plasma half life of cortisol? Where is cortisol deactivated? What does it become when deactivated

A
  • 60 min
  • kidney and liver
  • it is converted to cortisone (which can be converted back to cortisol) and to water-soluble derivatives that are excreted in the urine.
24
Q

Explain the intracelluluar receptor of ACTH and its effect on transcription. What is the is the segment of DNA called that bind ACTH-receptor complex binds to?

A
  • nuclear receptor superfamily of ligand activated transcription factors.
  • translocated to the nucleus and bind with high affinity to specific nucleotide sequences, called glucocorticoid-response elements (GRE) on the DNA, through which transcription of certain genes is stimulated or inhibited
25
Q

What are the primary (direct) and secondary (indirect) physiological actions of glucocorticoids? Are the effects of secondary actions fast or slow? What is the time frame?

A
  • inhibition of glucose transport is are primary, defined as directly effects on the cells (there are other primary actions).
  • Others are secondary to modulation — usually inhibition — of production or activity of cytokines, inflammatory agents, hormones and other mediators.
  • In general, the effects of glucocorticoids are relatively slow (hours to days).
26
Q

What are the mechanisms that glucocorticoids use raise blood glucose and counter the effects of insulin?

A
  • stimulating hepatic gluconeogenesis by activating hepatic enzymes, such as PEPCK;
  • permissively enhancing gluconeogenesis and glycogenolysis by glucagon and epinephrine (synergy)
  • inhibiting peripheral glucose utilization by reducing the uptake of glucose to cells (muscle, adipose, fibroblasts, lymphocytes)
  • mobilizing gluconeogenic substrates (amino acids) from peripheral tissues
  • promoting synthesis of liver glycogen, the substrate for acute responses to glycogenolytic agents such as glucagon and epinephrine.
27
Q

Explain the contradictory effects of cortisol stimulating both the breakdown (glycogenolysis) and synthesis of glycogen. What is adrenal diabetes?

A
  • A possible interpretation is that on the long-term, glucocorticoids increase glycogen storage thereby preparing for acute stress-induced need of increasing blood sugar.
  • During pathological conditions, the increase in blood glucose concentration can reach such high levels that the condition is called adrenal diabetes.
28
Q

Explain the acute (1-2 hr) and chronic (weeks, months) affect of glucocoriticoids on lipid metabolism

A
  • The acute effects of glucocorticoids are aimed at producing more energy
  • Acutely, as previously mentioned cortisol has a counter-regulatory effect against insulin to increase blood sugar (for the brain).
  • Glucocorticoids also stimulate free fatty acid release, by decreasing re-esterification and increasing lipolysis in adipocytes.
  • The free fatty acids serve as alternative fuel. Increased plasma free fatty acids can be observed within 1-2 hours of administration of hormone to humans.
  • Chronic high levels of glucocorticoids, such as used therapeutically or in Cushing disease lead to characteristic redistribution of fat and increase in appetite (see Powerpoint presentation).
  • These pathological changes are not well understood, but may result from normal effects acting with abnormal intensity and duration, and from interactions with other hormones.
29
Q

Explain the correlation of Glucocorticoids and Metabolic Syndrome.

A
  • Mechanism of local glucocorticoid levels
  • high cortisol in adipose tissue has been connected to obesity and the metabolic syndrome.
  • This syndrome refers to a combination of obesity, dyslipidema, hypertension and Type 2 diabetes mellitus.
  • high levels of glucocorticoids can reduce the sensitivity of skeletal muscle and adipose tissue to the stimulatory effects of insulin on glucose uptake and utilization, thereby causing insulin resistance (i.e. Type 2 diabetes mellitus).
30
Q

Explain the effects of glucocorticoids on Protein

A
  • catabolism.
  • High doses of glucocorticoids on the long-term result in massive catabolic effects on the skeletal muscle.
  • This is pathological (i.e. not physiological) change, which might result from an exaggeration of the physiological mechanism to generate gluconeogenic substrates (amino acids).
31
Q

Explain the effects of glucocorticoids on Immune and Inflammatory Reactions and also the effects of glucorticoid as a treatment of malignomas of the lymphoid system. (Long answer. Question parts broken down later)

A
  • Glucocorticoids up-regulate the expression of anti-inflammatory mediators and down-regulate the expression of pro-inflammatory mediators.
  • Most actions of glucocorticoids are due to inhibition of production of cytokines and other mediators.
  • Inhibit IL-2 and T-cell proliferation. Used in transplant rejection for immunosupression
  • Glucocorticoids also inhibit cytokine effects, such as responses of lymphocytes and eosinophils to interleukins.
  • They decrease accumulation of most of these cells at inflammatory sites.
  • Blood counts of lymphocytes, monocytes, eosinophils, and basophils DROP within 1-3 hours of glucocorticoid administration
  • neutrophil counts RISE
  • Glucocorticoids do not kill normal lymphocytes, but rather, they influence the traffic and distribution of immune cells.
  • glucocorticoids are able to kill malignant cells, and this effect is applied in treatment of lymphoid leukemias and lymphomas.
32
Q

What is the effect of corticosteroids on neutrophils? What about lymphocytes, monocytes, eosinophils, and basophils?

A
  • neutrophil counts RISE
  • Blood counts of lymphocytes, monocytes, eosinophils, and basophils DROP within 1-3 hours of glucocorticoid administration
33
Q

What is the effect of glucocorticoids on normal lymphocytes vs cancerous lymphocytes?

A
  • Glucocorticoids do not kill normal lymphocytes, but rather, they influence the traffic and distribution of immune cells.
  • glucocorticoids are able to kill malignant cells, and this effect is applied in treatment of lymphoid leukemias and lymphomas.
34
Q

Explain the Effects of glucocorticoids on bone and connective tissue. What are the direct and indirect effects?

A

• Glucocorticoids, when present in excess, cause osteoporosis and impair skeletal growth.
• Direct effects:
o 1)glucocorticoids inhibit bone formation by decreasing the number of osteoblasts and their function.
o 2) Glucocorticoids also promote the formation of osteoclasts, which results in increased bone resorption.
• Indirect effects:
o 1) decreased IGF1 synthesis
o 2) inhibition of intestinal and renal calcium resorption ==> secondary hypoparathyreodism ==> further increasing bone resorption.

35
Q

How do glucocorticoids affect connective tissue? What is a long-term effect of glucocorticoid treatment?

A
  • increase collagenase expression and inhibition of collagen synthesis, in addition to the anti-inflammatory effects discussed above.
  • are utilized in the clinic to treat degenerative joint diseases (osteoarthritis).
  • A long-term effect of glucocorticoid treatment is slow wound healing.
36
Q

Explain how Glucocorticoids influence behavior, mood, memory as well as excitability and electrical activity of neurons (ie how does they effect the CNS)

A
  • Behavioral changes with both excess glucocorticoids and glucocorticoid deficiency
  • sleep disorder is a common feature of glucocorticoid therapy.
  • High plasma levels of glucocorticoids, with little diurnal variation but few Cushing’s symptoms, are frequently observed in conjunction with clinical depression.
37
Q

Explain how excess glucocorticoids vs glucocorticoid deficiency might be detrimental for individual neurons

A
  • adrenalectomy resulted in the loss of neurons of the dentate gyrus and pyramidal neurons
  • very high glucocorticoid levels can cause death of CA3 neurons in the hippocampus and potentiate neuronal death evoked by toxic substances.
38
Q

Explain how glucocorticoids affect memory and sleep patterns

A
  • Stress and glucocorticoids impair retrieval of long-term memory and impair hippocampal long-term potentiation.
  • However they also enhance formation of the so-called “flashbulb” memories that are associated with strong emotions
  • One of the most often observed clinical adverse effect of glucocorticoid therapy is insomnia.
39
Q

Explain the complimentary effects of modest and high GLUCOCORTICOID levels AND STRESS

A

• It is generally accepted that glucocorticoids protect the body against stress.
• At Modest levels: activate some homeostatic defense mechanisms, so that these can be called into action when necessary.
o 1) enhancement of gluconeogenesis, glycogenolysis and lipolysis
o 2) enhancement of certain humoral immune reactions
o 3) enhancement of pressor activities of vasoactive agents.
o Without glucocorticoids, these mechanisms cannot respond adequately to a challenge.
• at higher, stress-induced levels: restrain or suppress various activated homeostatic defense mechanisms in order to prevent them from overshooting and damaging the organism.
o 1) counter-regulatory actions on carbohydrate metabolism that control insulin-induced hypoglycemi
o 2) immunosuppressive and anti-inflammatory actions that protect from autoimmunity and uncontrolled inflammation
o 3) suppression of potentially toxic cytokines
o 4) control of vasoactive agents like catecholamines, renin, and ADH
o 5) enhancement of water excretion that may counter excessive fluid retention after hemorrhage
o 6) suppression of neural activity
o 7) and suppression of CRH, ADH, ACTH, - endorphin, that need to be restrained both from excessive stimulation of glucocorticoid secretion and other activities they may exert.
• Substantial evidence indicates that when an impaired HPA axis cannot increase glucocorticoid activity in response to stress, unrestrained defense mechanisms do overshoot, and can damage or kill the organism.

40
Q

What are Major symptoms of adrenal insufficiency (Addison’s disease)?

A
  • Hyper-pigmentation
  • Weakness, tiredness, fatigue
  • Hypotension (<110 mmHg systolic BP)
  • Weight loss
  • GI symptoms (nausea, vomiting)
  • Anorexia (loss of appetite)
  • Fasting hypoglycemia
  • Muscle & joint pains
41
Q

What are Major symptoms of Cushing’s syndrome (Hypercortisolemia)?

A
  • Sudden weight gain, centripetal obesity
  • Moon face; facial plethora
  • Buffalo hump
  • Abdominal striae
  • Osteopenia or osteoporosis
  • Hypertension
  • Easy bruising, poor wound healing
  • Glucose intolerance or diabetes mellitus
  • Hirsutism (excessive hair in women in regions where no hair growth occurs normally)
  • Depression or psychosis
  • Recurrent infections
42
Q

Complications of glucocorticoid administration:

A
  • Osteoporosis
  • Increased susceptibility for infections
  • Poor wound healing
  • Insomnia
  • Psychological disturbances
  • Worsening of DM
  • Arrest of linear growth (children)
43
Q

Effects of Cushing Syndrome

A 
•ACTH dependent
–ACTH hypersecretion (pituitary or ectopic)
–CRH hypersecretion
•ACTH independent
–primary adrenocortical tumor
–iatrogenic (synthetic glucocorticoids)
44
Q

What is p450scc aka Cholesterol Desmolase?

A

Converts cholesterol to Pregnelone

This is a rate limiting step

45
Q

What is 3 Beta Hydroxysteroid Dehydrogenase? Name 4 reactions

A

Main: Converts pregnenolone to progesterone

2) converts 17-hydroxyprenelone to 17-hydroxyprogesterone
3) converts dehydroepiandrosterone to androsterone (androgens and estrogens synth)
4) converts androstendiol to testosterone (T and E synthesis)

46
Q

What is 21 Beta Hydroxylase aka CYP11B1?

What part of the adrenal cortex is this enzyme found?

A
  • main enzyme deficient in Congenital Adrenal Hyperplasia
    1) converts Progesterone to Deoxycorticosterone (DOC) (Corticosterone and Aldosterone pathway)
    2) converts 17-hyrdroxyprogesterone to 11-deoxycortisol (Cortisol pathway)
    Enzyme is in both the glomerulosa and the fasciculata
47
Q

What is Aldosterone synthase aka CYP11B2?

What part of the adrenal cortex is this enzyme found?

A

converts corticosterone to aldosterone
one of two rate limiting steps in aldosterone synthesis (cholesterol to pregnenelone is the other)
is only found in the Zona Glomerulosa

Physio Endocrinlogy Quiz 1 (6 decks)

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