Steroid Hormone Metabolism

Question 1

Describe the primary effect of cortisol

Answer 1

• Liver: long term gluconeogenesis
• Fat tissue: degradation of TAGs and release of fatty acids
• Skeletal muscle: degradation of muscle proteins
• Modulation of the inflammatory response: inhibition of stimulated PLA and eicosanoid synthesis

Question 2

Describe the synthesis and release of adrenal androgen

Answer 2

• The synthesis of adrenal androgen is stimulated by ACTH
• The weak androgens DHEA and androstenedione are released into the blood and can be converted in peripheral tissues to testosterone or estrogen
  
  • Adipose tissue -> estrogen
  • Extra-adrenal tissue -> testosterone

Question 3

Describe the function of StAR

Answer 3

• Brings free cholesterol into the mitochondrial; it is an important regulatory step of Steroid hormone synthesis
  
  • ACTH leads via PKA to activation of both cholesteryl esterase and StAR
    
    • The generated free cholesterol is transported into the mitochondrial matrix

Question 4

describe the rate limiting step of hormone synthesis

Answer 4

• Catalyzed by the cholesterol side-chain cleavage enzyme (desmolase, or 11a)
• The side chain cleavage of cholesterol (C27) forms pregnenolone (21C) which is an intermediate of all steroid hormones
  
  • Pregnenolone is formed from cholesterol inside the mt

Question 5

describe 3-B hydroxysteroid DH

Answer 5

leads to severe deficiency of all mineralocorticoids and glucocorticoids and to salt excretion in urine

the synthesis of DHEA in adrenals is stimulated but sex hormone synthesis in testes and ovaries is reduced

Question 6

CYP 21 deficiency

Answer 6

• no synthesis of aldosterone
• no synthesis of cortisol
• INCREASED synthesis of DHEA and androstenedione

the stimulated adrenal cortex now forms more androgens = masculinization

hypotension and possible “salt crisis”

Question 7

CYP 11B deficiency

Answer 7

• no synthesis of aldosterone
• no synthesis of cortisol

the stimulated adrenal cortext now forms more androgens = masculinization

mild hypertension possible (since deoxycorticosterone still overproduced)

Question 8

describe synthesis of testosterone

Answer 8

• the Leydig cells of the testes ave receptors for LH which activates synthesis of testosterone
• Pregnenalone -> DHEA -> adrostenedione -> testosterone
  
  • via CYP 17

Question 9

describe formation of dihydrotestosterone (DHT)

Answer 9

• testosterone can be activated by 5-alpha-reductase in Sertoli cells and other target cells to the more potent DHT

Question 10

describe theca cells

Answer 10

• located in ovaries, theca cells have receptors for LH which activates synthesis and secretion of primarily androgens

Question 11

describe follicle granulosa cells

Answer 11

• located in the ovaries, follicle granulosa cells have receptors for FSH and use androgens to synthesize estrogen and serete primarily estradiol

Question 12

describe aromatase

Answer 12

• aromatase frms the aromatic ring of estrogens which will bend ring A in an upward configuration which is needed for recognition by the estrogen receptor
• Treatment of estrogen-responsive breast cancer includes drugs which
  
  • interfere with receptor binding
  • inhibit aromatase (CYP 19)

Question 13

describe causes of Cushing syndrome

Answer 13

• characterized by high levels of cortisol in blood caused by:
  
  • adrenal adenoma or carcinoma
    
    • tumor in z. fasiculata leads to release of cortisol and androgens in higher quantity than normal which also leads to low levels of ACTH
    • ACTH-producing pituitary tumor (Cushing DISEASE)
    • prolonged administration of high doses of corticosteroidal drugs

Question 14

describe characteristics of Cusing syndrome

Answer 14

• characteristic fat distribution
  
  • increased upper body fat
  • fatty hump between shoulders
  • red round face
• thin arms and legs (cortisol increases muscle degradation)
• elevated blood glucose
• reduced inflammatory response
• hirsutism

Question 15

describe causes of Addison disease

Answer 15

• insufficiency and atrophy of adrenal cortex
  
  • autoimmne destruction or tumors
  • infections like HIV, TB
• low levels of cortisol
  
  • hypoglycemia
  • high levels of ACTH which does not lead to overstimulation because of atrophy of the adrenal cortex
• low levels of aldosterone causes:
  
  • low BP
  • high K levels
  • low Na levels
    
    • salt cravings

Question 16

describe symptoms of Addison Disease

Answer 16

• bronze pigmentation of skin and ugm due to increased synthesis of CRH and increased synthesis of a large precursor protein that is cleaved to: ACTH and MSH
• failure to thrive
• weight loss
• muscle weakness and salt craving
• abdominal pain