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BIOCHEMISTRY > ME04 - Adrenal Androgens > Flashcards

ME04 - Adrenal Androgens Flashcards

1
Q

Central 20% of Adrenal Gland
Neuroectodermal origin
Functionally related to sympathetic nervous system
An enlarged specialized sympathetic ganglion

A

Adrenal Medulla

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2
Q

What does Adrenal Medulla secretes in response to sympathetic stimulation

A

CATECHOLAMINES |? Discharge catecholamines into the bloodstream
? Composed of Chromaffin cells

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3
Q

What innervates Adrenal Medulla?

A

Cholinergic preganglionic sympathetic neurons

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4
Q

Components of Chromaffin cells

A

Has granules that contains: epinephrine and norepinephrine (20% by weight), adenosine triphosphate and other nucleotides (15%), proteins (35%), and lipids (20%).

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5
Q

Main functions of Adrenal Medulla

A

Catecholamines are secreted into the blood to act as hormones
? Source of all circulating epinephrine (80%) and ~30% of circulating norepinephrine (20%)

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6
Q

Describe Adrenal Medulla Vascularity

A

Blood is carried from cortex to medulla ; Few medullary arterioles (oxygen- and nutrient-rich blood)
Numerous cortical sinusoids (rich with cortical hormones)

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7
Q

Flow to the suprarenal vein

A

Medullary arterioles and cortical sinusoids fuse ? medullary plexus of vessels ? single suprarenal vein

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8
Q

Consequence of the Adrenal Medulla Vascularity

A

high concentration of cortisol from cortex bathe chromaffin cells

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9
Q

Action of Cortisol to the Adrenal Medulla Vascularity

A

Cortisol inhibits neuronal differentiation of the medullary cells
Cortisol induces expression of PNMT (converts NE to epinephrine)

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10
Q

? Outer 80% of Adrenal Gland
? Mesodermal in origin
? Secretes corticosteroids which are all synthesized from cholesterol.

A

Adrenal Cortex

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11
Q

Three Distinct layers of Adrenal Cortex

A

? Zona glomerulosa: Mineralocorticoids (Aldosterone)
? Zona fasciculata: Glucocorticoids (Cortisol)
? Zona reticularis: Adrenal androgens (Androgen)

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12
Q

Thin layer underneath the capsule of Adrenal Cortex

A

Zona Glomerulosa

? Secretes ALDOSTERONE because it contains ALDOSTERONE SYNTHASE
? Controlled mainly by ANGIOTENSIN II & POTASSIUM
Both stimulate aldosterone secretion

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13
Q

? Middle and widest of the Adrenal Cortex
? Has Straight cords of large cells with “foamy” cytoplasm
filled with lipid droplets

A

Zona Fasciculata

? Secretes CORTISOL & CORTICOSTERONE, and small amounts of androgen and estrogen
? Controlled by ACTH (Adrenocorticotropichormone)

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14
Q

Deep layer OF Adrenal Cortex

A

Zona Reticularis

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15
Q

Hormones secreted by the Zona Reticularis

A 
Secretes DHEA (Dehydroepiandrosteione) and Androstenedione, and small amounts of estrogen and glucocorticoids
? Controlled by ACTH & Cortical androgen stimulating hormone.
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16
Q

What are the 2 principal Corticosteroids?

A

Aldosterone & Cortisol

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17
Q

Principal Mineralocorticoid

A

Aldosterone (principal mineralocorticoid)

o Affect the electrolyes (?minerals?) of the ECF ? Sodium & Potassium

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18
Q

Principal Glucocorticoid

A

Cortisol (principal glucocorticoid)
o Exhibit important effects that increase blood glucose concentration
o Protein and fat metabolism

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19
Q

Formation of Catecholamines

A

Tyrosine&raquo_space; (Tyrosine Hydroxylase)» DOPA&raquo_space; Dopamine&raquo_space; (Dopamine B-hydroxylase)» NE&raquo_space; (PMNT)&raquo_space; Epinephrine

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20
Q

Rate limiting step in the formation of catecholamines

A

Tyrosine Hydroxylase

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21
Q

Dopamine B Hydroxylase is induced by what factor?

A

Sympathetic stimulation

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22
Q

PMNT is done by what type of transport?

A

Facilitated Diffusion

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23
Q

What are adrenocortical Hormones

A

Progesterone, Glucocorticoids, Mineralocorticoids

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24
Q

Structure of Adrenocortical Hormone

A

? All are chemical modifications of CHOLESTEROL -
4 rings with 21 carbons
? Progesterone, GLUCOCORTICOID, and MINERALOCORTICOID are 21-carbon steroids
? ANDROGEN are 19-carbon steroids | ESTROGEN (produced primarily in the ovaries) are 18-carbon steroid

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25
Q

Synthesis of Adrenocortical Hormones

A

Each layer is specialized to synthesize particular hormones
? Depending on the presence or absence of enzymes
17,20- lyase in zona fasciculata: androgenic steroid
Aldosterone synthase in zona glomerulosa: aldosterone

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26
Q

Rate limiting reaction in the Synthesis of Adrenocortical Hormones

A

Transfer of cholesterol from the outer to the inner mitochondrial membrane

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27
Q

First step in conversion STAR (stereodogenic acute regulatory protein)

A 
Cholesterol desmolase (CYP 11A1) - first step in conversion
STAR (stereodogenic acute regulatory protein) - facilitates entry of free cholesterol
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28
Q

? Principal mineralocorticoid
? Synthesized only by the zona glomerulosa | Due to presence of aldosterone synthase
Cannot synthesize glucocorticoids

A

Aldosterone

29
Q

What regulates Aldosterone

A

Regulated primarily by __________________________

Minimally influenced by ACTH

30
Q

Transport and Metabolism of Aldosterone

A

? Only ~60% bind to plasma proteins, 40% in free form
? half-life: ~20 mins
? Almost all inactivated by the liver in one pass
Conjugated especially to glucuronic acid and to a lesser extent sulfates
? Excretion
Bile then feces: ~25%
Urine: remaining

31
Q

Physiologic Action of Aldosterone on DCT and CD

A

Three actions on the late distal tubule and collecting ducts of the kidney:
increases Na+ reabsorption (principal cells)
increases K+ secretion (principal cells)
increases H+ secretion (?-intercalated cells)

32
Q

EFFECTS OF INCREASE IN ALDOSTERONE

A

??Excess increases ECF Volume and arterial pressure but has only small effect on plasma sodium concentration.
simultaneous osmotic absorption of almost equivalent amounts of water
stimulate thirst and increased water intake

??Excess causes hypokalemia and muscle weakness; Too Little causes hyperkalemia and cardiac toxicity.
Stimulates transport of potassium into ICF
Alters the electrical excitability of the nerve and muscle fiber membranes
weakness of heart contraction, development of arrhythmia, heart failure

33
Q

EFFECT OF ALDOSTERONE IN SALIVARY AND SWEAT GLANDS

A

Effect on salivary glands: for conservation of salt when excessive quantities of saliva are lost
Effect on sweat glands: for conservation of salt in hot environments

34
Q

Aldosterone has a proinflammatory, profibrotic effect on the cardiovascular system, causes LVH and remodeling. True or False?

A

True. Aldosterone binds to mineralocorticoid receptor, an intracellular receptor. Similar to cortisol that alters gene expression

35
Q

What is the Cellular mechanism of Aldosterone

A

? Aldosterone diffuses readily to the interior of the tubular epithelial cells.
? Combines with __________________________
Has a stereomolecular configuration that allows only aldosterone or very similar compounds to combine with it.
? Aldosterone-receptor complex diffuses into the nucleus
? mRNA, in conjunction with the ribosomes, causes protein formation.
one or more enzymes
membrane transport proteins required for sodium, potassium, and hydrogen transport through the cell membrane

36
Q

Aldosterone is almost entirely independent of regulation of cortisol and androgens by zona fasciculata and reticularis. True or False?

A

True.

37
Q

Major stimuli for aldosterone production

A

INC Angiotensin and Serum potassium

38
Q

INC Na ion concentration very slightly decreases aldosterone secretion. True or False?

A

True.

39
Q

ACTH is necessary for aldosterone secretion. True or false?

A

True, but has little effect in controlling the rate of secretion in most physiological conditions

40
Q

Major actions of angiotensin II on the adrenal cortex

A

Specifically increase output of ALDOSTERONE
increased growth (HYPERTROPHY) and Vascularity of the zona glomerulosa;
NO EFFECT on other two zones
increased StAR and ALDOSTERONE SYNTHASE activity

41
Q

? Major glucocorticoid (STRESS HORMONE)
? Synthesized in zona fasciculata/ reticularis
? ? 95% of glucocorticoid activity of the adrenocortical secretions

A

CORTISOL

42
Q

Small but significant portion of Cortisol

A

Corticosterone

43
Q

Transport and Metabolism of Cortisol

A

? Cortisol is bound predominantly (>90%) when in circulation
cortisol-binding globulin (i.e. transcortin)
Albumin (5-7%)
? Circulating half-life of cortisol: 60-90 minutes
? Liver - predominant site of steroid inactivation inactivates cortisol and conjugates them so that they can be excreted more readily by the kidney

44
Q

Mechanism of Action of Cortisol

A

??Acts through glucocorticoid receptor (GR)

??Increased gene transcription:

  1. Rapid translocation of the cortisol-GR complex into the nucleus
  2. Cortisol-GR complex interacts with glucocorticoid response elements (GREs) in the DNA
  3. Recruitment of coactivator proteins
  4. Assembly of general transcription factors

??Reduced gene transcription

  1. Rapid translocation of the cortisol-GR complex into the nucleus
  2. Interaction with negative glucocorticoid response elements (GREs)
  3. Recruitment of corepressor proteins; OR interference with ability of transcription factors to activate gene expression
45
Q

Cortisol’s Effect on Metabolism

A

o Catabolic and diabetogenic

o ? blood glucose
??Stimulates GLUCONEOGENESIS in liver
??Inhibit PROTEIN SYNTHESIS, ? proteolysis in muscle
??INCREASE lipolysis

o Promotes glucose sparing
??Decreases glucose utilization by tissues
??Decreases insulin sensitivity of adipose tissue
??? Glut4-mediated glucose uptake
??Potentiates effects of catecholamines on lipolysis

46
Q

Cortisol’s Cardiovascular Actions

A

o Permissive actions on Catecholamines
o Good cardiac output and blood pressure
o Stimulates EPO synthesis

47
Q

Cortisol’s Anti-inflammatory and immunosuppressive actions

A

o DECREASE production of proinflammatory cytokines

o INCREASE production of anti-inflammatory cytokines

48
Q

Cortisol results to Decrease or Inhibition as Anti-Inflammatory and Immunosuppressive Actions

A

o INHIBIT leucocyte migration to site
o INHIBIT phagocytic activity of neutrophils
o ? circulating T-lymphocytes
o ? ability of T-lymphocytes to migrate to site of antigenic stimulation
o Promote atrophy of thymus and other lymphoid tissue
o Inhibit cell-mediated immunity

49
Q

When CORTISOL stabilizes lysozomal membranes, it results to:

A

Stabilizes lysozomal membranes ? ? release of proteolytic enzymes that augment local swelling

50
Q

Cortisol’s action on Reproductive System

A

dampen reproductive behavior and function

? ? the function of the reproductive axis at the hypothalamic, pituitary and gonadal levels

51
Q

Cortisol’s action on the bone

A

o ? bone resorption
? ?intestinal Ca+2 absorption
? ? renal Ca+2 reabsorption
o Inhibit osteoblast bone-forming functions

52
Q

Cortisol’s action on the kidney

A

o Inhibit secretion and action of ADH
o ? GFR by increasing cardiac output and acting directly on the kidney
? Vasodilation of the afferent arteriole

53
Q

Cortisol’s action on the CNS

A

Glucocorticoid receptor in the limbic system
? Decreases REM sleep
? Increases slow-wave sleep
? Increases awake time

54
Q

Cortisol’s action on FETAL DEVELOPMENT

A

o Required for normal development of CNS, retina, skin, GI tract and lungs
o In the lungs, induces differentiation and maturation of TYPE II Alveolar Cells

55
Q

Other actions of Cortisol

A

? Connective tissue:
Inhibit fibroblast proliferation and collagen formation
? Gastrointestinal tract:
Trophic effect on GI mucosa
Stimulates appetite
Stimulates gastric acid and pepsin secretion

56
Q

How is the Secretion of Cortisol regulated

A

? Regulated by hypothalamus-pituitary-adrenal axis
Hypothalamus: CORTICOTROPIN RELEASING HORMONE (CRH)
Pituitary gland: ADRENOCORTICOTROPIC HORMONE
? Almost entirely controlled by ACTH from anterior pituitary
? Norigenic and systemic stress

57
Q

Strong diurnal rhythmic regulation from suprachiasmatic nucleus. True or False?

A

True, Cortisol surges early predawn and morning hours then decline continually throughout the day and night

58
Q

CRH chronically increases _______________________________ gene expression

A

Prooplomelanocortin (POMC)

59
Q

precursor of ACTH and other peptides such as melanocyte-stimulating hormone (MSH)

A

POMC

60
Q

What does Adrenal Androgen produces

A

? Produces DHEAS & DHEA and androstenedione

? Only small amounts of potent androgens are normally produced by adrenal cortex

61
Q

In females, adrenal androgens are major androgens:

A

For pubic and axillary hair

For libido

62
Q

What is the main product of Adrenal Androgen?

A

DHEAS: main product
Become detectable at ~6 years old: adrenarche
Continually increase, peak during mid-twenties and progressively decline with age (DHEA exhibit same pattern)
Most abundant circulating hormone in young adults

63
Q

Formation of DHEAS and DHEA

A

? Zona reticularis expresses cofactors or conditions that enhance the 17,20-lyase function, generating DHEA from 17-hydroxypregnenolone
? Expresses DHEA SULFOTRANSFERASE (SULT2A1 gene), which converts DHEA into DHEAS
? 3?-HSD is expressed at much lower levels
? Androstenedione is a minor product compared to DHEAS and DHEA

64
Q

Metabolism of DHEAS and DHEA

A

? DHEAS can be converted back to DHEA by peripheral sulfatases
? DHEA and androstenedione can be converted to active androgens (testosterone and dihydrotestosterone) peripherally in both sexes
? DHEA binds to albumin and other globulins in blood with LOW affinity.
? half-life: 15-30 mins
? DHEAS binds to albumin with high affinity
? half-life: 7-10 hours

65
Q

Physiologic Actions OF Adrenal Androgens

A

? Contribution of adrenal androgens to active androgens
Men: negligible
Women: for the growth of axillary and pubic hair and for libido

66
Q

Regulation of Secretion OF ADRENAL ANDROGEN

A

??ACTH: primary regulator
zona reticularis shows the same atrophic changes as the zona fasciculata in conditions with little or no ACTH

DHEA and androstenedione display same diurnal pattern as cortisol

DHEA: does not follow diurnal pattern because of long half-life

67
Q

Other unknown factors regulate zona reticularis function

A

Adrenarche occurs in the face of constant ACTH and cortisol levels
Rise and decline of DHEAS is not associated with a similar pattern of ACTH and cortisol production

68
Q

SUMMARY:

A

The adrenal cortex secretes an entirely different group of hormones, called corticosteroids. These hormones are all synthesized from the steroid cholesterol, and they all have similar chemical formulas. However, slight differences in their molecular structures give them several different but very important functions.

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