ME04 - Adrenal Androgens

Question 1

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

Answer 1

Adrenal Medulla

Question 2

What does Adrenal Medulla secretes in response to sympathetic stimulation

Answer 2

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

Question 3

What innervates Adrenal Medulla?

Answer 3

Cholinergic preganglionic sympathetic neurons

Question 4

Components of Chromaffin cells

Answer 4

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

Question 5

Main functions of Adrenal Medulla

Answer 5

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

Question 6

Describe Adrenal Medulla Vascularity

Answer 6

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

Question 7

Flow to the suprarenal vein

Answer 7

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

Question 8

Consequence of the Adrenal Medulla Vascularity

Answer 8

high concentration of cortisol from cortex bathe chromaffin cells

Question 9

Action of Cortisol to the Adrenal Medulla Vascularity

Answer 9

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

Question 10

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

Answer 10

Adrenal Cortex

Question 11

Three Distinct layers of Adrenal Cortex

Answer 11

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

Question 12

Thin layer underneath the capsule of Adrenal Cortex

Answer 12

Zona Glomerulosa

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

Question 13

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

Answer 13

Zona Fasciculata

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

Question 14

Deep layer OF Adrenal Cortex

Answer 14

Zona Reticularis

Question 15

Hormones secreted by the Zona Reticularis

Answer 15

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

Question 16

What are the 2 principal Corticosteroids?

Answer 16

Aldosterone & Cortisol

Question 17

Principal Mineralocorticoid

Answer 17

Aldosterone (principal mineralocorticoid)

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

Question 18

Principal Glucocorticoid

Answer 18

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

Question 19

Formation of Catecholamines

Answer 19

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

Question 20

Rate limiting step in the formation of catecholamines

Answer 20

Tyrosine Hydroxylase

Question 21

Dopamine B Hydroxylase is induced by what factor?

Answer 21

Sympathetic stimulation

Question 22

PMNT is done by what type of transport?

Answer 22

Facilitated Diffusion

Question 23

What are adrenocortical Hormones

Answer 23

Progesterone, Glucocorticoids, Mineralocorticoids

Question 24

Structure of Adrenocortical Hormone

Answer 24

? 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

Question 25

Synthesis of Adrenocortical Hormones

Answer 25

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

Question 26

Rate limiting reaction in the Synthesis of Adrenocortical Hormones

Answer 26

Transfer of cholesterol from the outer to the inner mitochondrial membrane

Question 27

First step in conversion STAR (stereodogenic acute regulatory protein)

Answer 27

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

Question 28

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

Answer 28

Aldosterone

Question 29

What regulates Aldosterone

Answer 29

Regulated primarily by __________________________ | Minimally influenced by ACTH

Question 30

Transport and Metabolism of Aldosterone

Answer 30

? 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

Question 31

Physiologic Action of Aldosterone on DCT and CD

Answer 31

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)

Question 32

EFFECTS OF INCREASE IN ALDOSTERONE

Answer 32

??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

Question 33

EFFECT OF ALDOSTERONE IN SALIVARY AND SWEAT GLANDS

Answer 33

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

Question 34

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

Answer 34

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

Question 35

What is the Cellular mechanism of Aldosterone

Answer 35

? 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

Question 36

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

Answer 36

True.

Question 37

Major stimuli for aldosterone production

Answer 37

INC Angiotensin and Serum potassium

Question 38

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

Answer 38

True.

Question 39

ACTH is necessary for aldosterone secretion. True or false?

Answer 39

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

Question 40

Major actions of angiotensin II on the adrenal cortex

Answer 40

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

Question 41

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

Answer 41

CORTISOL

Question 42

Small but significant portion of Cortisol

Answer 42

Corticosterone

Question 43

Transport and Metabolism of Cortisol

Answer 43

? 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

Question 44

Mechanism of Action of Cortisol

Answer 44

??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

Question 45

Cortisol's Effect on Metabolism

Answer 45

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

Question 46

Cortisol's Cardiovascular Actions

Answer 46

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

Question 47

Cortisol's Anti-inflammatory and immunosuppressive actions

Answer 47

o DECREASE production of proinflammatory cytokines | o INCREASE production of anti-inflammatory cytokines

Question 48

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

Answer 48

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

Question 49

When CORTISOL stabilizes lysozomal membranes, it results to:

Answer 49

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

Question 50

Cortisol's action on Reproductive System

Answer 50

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

Question 51

Cortisol's action on the bone

Answer 51

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

Question 52

Cortisol's action on the kidney

Answer 52

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

Question 53

Cortisol's action on the CNS

Answer 53

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

Question 54

Cortisol's action on FETAL DEVELOPMENT

Answer 54

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

Question 55

Other actions of Cortisol

Answer 55

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

Question 56

How is the Secretion of Cortisol regulated

Answer 56

? 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

Question 57

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

Answer 57

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

Question 58

CRH chronically increases _______________________________ gene expression

Answer 58

Prooplomelanocortin (POMC)

Question 59

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

Answer 59

POMC

Question 60

What does Adrenal Androgen produces

Answer 60

? Produces DHEAS & DHEA and androstenedione | ? Only small amounts of potent androgens are normally produced by adrenal cortex

Question 61

In females, adrenal androgens are major androgens:

Answer 61

For pubic and axillary hair | For libido

Question 62

What is the main product of Adrenal Androgen?

Answer 62

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

Question 63

Formation of DHEAS and DHEA

Answer 63

? 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

Question 64

Metabolism of DHEAS and DHEA

Answer 64

? 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

Question 65

Physiologic Actions OF Adrenal Androgens

Answer 65

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

Question 66

Regulation of Secretion OF ADRENAL ANDROGEN

Answer 66

??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

Question 67

Other unknown factors regulate zona reticularis function

Answer 67

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

Question 68

SUMMARY:

Answer 68

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.