LECTURE 12 (sex hormones + ethanol metabolism) Flashcards

1
Q

What are the three different types of oestrogen?

A
  • Estrone (E1)
  • Estradiol (E2)
  • Estriol (E3)

POTENCY: Estradiol > Estrone > Estriol

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2
Q

What is the difference between Estrone, Estradiol and Estriol?

A
  • Estrone = the only oestrogen your body makes after menopause
  • Estradiol = the most common type in women of childbearing age
  • Estriol = the main oestrogen during pregnancy
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3
Q

Estrogen synthesis happens in ___________ _________

A

Ovarian follicles

Explanation: Ovarian follicles consist of OOCYTE surrounded by THECA & GRANULOSA cella

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4
Q

What is the importance of LH and FSH in oestrogen synthesis in females?

A
  • Hypothalamus secretes GONADOTROPIN RELEASING HORMONE (GnRH) which causes the pituitary gland to release LH and FSH
  • LH acts on THECA CELLS and causes the conversion of CHOLESTEROL to ANDROSTENEDIONE via DESMOLASE
  • FSH acts on GRANULOSA CELLS and causes the conversion of ANDROSTENEDIONE to ESTROGEN via AROMATASE
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5
Q

Granulosa cells also produce ____________ which suppresses FSH

A

Inhibin

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6
Q

What does LH and FSH act on in males and females?

A

FEMALES
- Ovaries
- LH -> Theca cells
- FSH -> Granulosa cells

MALES
- Testes
- LH -> Leydig cells
- FSH -> Sertoli cells

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7
Q

What are the properties of Leydig cells?

A
  • Secrete testosterone
  • Stimulated by LH
  • Testosterone - most potent, major circulating androgen in males
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8
Q

What are the properties of Sertoli cells?

A
  • Regulate spermatogenesis
  • Support and nourish developing spermatozoa
  • Secrete inhibin -> inhibit FSH
  • Secrete androgen-binding protein -> maintain local levels of testosterone
  • Tight junctions between adjacent Sertoli cells form blood-testis barrier -> isolate gametes from auto-immune attack
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9
Q

What is Testosterone converted into in peripheral tissues?

A

Dihydrotestosterone

Explanation: Conversion by 5-ALPHA REDUCTASE -> conversion since DHT is more potent, stable and binds androgen receptors more strongly

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10
Q

What is used to treat Prostatic hyperplasia and hair loss in men?

A

5-alpha reductase inhibitor (Finasteride)

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11
Q

What is Testosterone converted into in adipose tissue and Leydig cells?

A

Estradiol

Explanation: Conversion occurs by AROMATASE

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12
Q

What are the properties of Ketoconazole?

A
  • Antifungal medication (blocks ergosterol synthesis in fungi)
  • Potent inhibitor of 17,20-lyase -> decreased androstenedione/testosterone -> GYNECOMASTIA (overdevelopment/enlargement of breasts in men)
  • Inhibits 17-alpha hydroxylase & desolate -> blocks cortisol synthesis -> treats Cushing’s syndrome
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13
Q

Describe Ethanol Metabolism

A
  • Occurs in Liver
  • Ethanol -> Acetaldehyde via ALCOHOL DEHYDROGENASE (cytosol) then Acetaldehyde -> Acetate via ALDEHYDE DEHYDROGENASE (mitochondria)
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14
Q

What are Excessive ethanol consumption consequences?

A
  • CNS depression
  • Hypoglycaemia
  • Ketosis
  • Lactic acidosis
  • Accumulation of fatty acids
  • Hyperuricemia
  • Hepatitis and cirrhosis
  • INCREASED NADH (trigger for all biochemical problems!!!)
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15
Q

What are the consequences of NADH stopping the TCA cycle?

A
  • NADH shunts oxaloacetate to malate -> Increased acetyl CoA (since citrate cannot be formed) -> increased ketone synthesis
  • Decreased gluconeogenesis -> hypoglycaemia
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16
Q

What is the link between ethanol consumption and hypoglycaemia?

A

Ethanol -> Gluconeogenesis inhibition (OAA shunted to malate) -> without gluconeogenesis, glycogen becomes the only source of fasting glucose -> danger of low glucose when glycogen is low e.g drinking without eating and drinking after running

17
Q

What is the link between Ethanol and ketones?

A
  • Liver: Acetate -> Acetyl CoA -> Ketones
  • TCA cycle stops due to high NADH -> increased acetyl CoA -> ketones
18
Q

What is the link between Ethanol and Lactic acidosis?

A
  • Body has limited supply of NAD+ inside of cells -> NAD+ regeneration is required
  • NAD+ depleted by EtOH metabolism
  • Electron transport chain converts NADH to NAD+ but increased EtOH consumptions overwhelms the ETC -> pyruvate shunted to lactate -> regenerates NAD+
19
Q

What is the link between Ethanol and Fatty acid accumulation?

A
  • High levels of NADH inhibits beta-oxidation -> beta-oxidation generates NADH & requires NAD+ -> decreased Fatty acid breakdown
  • High levels of NADH increase in Fatty acid synthesis -> inhibits TCA cycle -> increased citrate -> increased fatty acid synthesis
  • Malate accumulation -> conversion by magic enzyme -> NADPH accumulation -> increased NADPH favours fatty acid synthesis
20
Q

Why are there high levels of triglycerides in livers of alcoholic patients?

A

Since fatty acids + glycerol -> triglycerides -> results in Fatty liver

21
Q

What causes Hepatitis and Cirrhosis in alcoholics?

A

High NADH shows ethanol metabolism -> buildup of acetaldehyde -> toxic to hepatocytes -> inflammation (hepatitis) + scar tissue (cirrhosis)

22
Q

What are the properties of the Microsomal ethanol-oxidising system (MEOS)?

A
  • Alternative pathway for ethanol metabolism & metabolises small amount of ethanol
  • Becomes important with excessive consumption
  • CYP450-dependent pathway in liver
  • Consumes NADPH and Oxygen
  • Oxygen generates free radicals
  • NADPH deficiency -> glutathione cannot be regenerated -> loss of protection from oxidative stress
23
Q

Describe Urate and Lactate

A
  • Urate and lactate excreted by proximal tubule
  • Increased lactate in plasma -> decreased excretion or uric acid
  • Increased uric acid -> gout attack
24
Q

What are the properties of Alcohol dehydrogenase?

A
  • 0 order for kinetics (constant rate - no increase in rate when increased ethanol)
  • Metabolises METHANOL and ETHYLENE GLYCOL -> can lead to metabolic acidosis
  • Inhibited by Fomepizole (antizol) -> treatment for methanol/ethylene glycol intoxication
25
Q

________ can be used as a competitive inhibitor of alcohol dehydrogenase to treat methanol or ethylene glycol poisoning

A

Ethanol

26
Q

What are the properties of Aldehyde Dehydrogenase?

A
  • Inhibited by “disulfiram” (Antabuse) -> aldehyde accumulation -> Catecholamine release -> sweating, flushing, palpitations, nausea, vomiting
  • Malfunction can cause “asian flushing”
27
Q

Describe Alcohol flushing

A
  • Skin flushing when consuming alcohol
  • Due to slow metabolism of acetaldehyde
  • Common among asians due to inherited deficiency of ALDEHYDE DEHYDROGENASE
  • Possible risk of oesophageal and oropharyngeal cancer
28
Q

Why are females more susceptible than males to effects of alcohol?

A
  • Decreased activity of gastric alcohol dehydrogenase
  • Decreased body size
  • Decreased % of water in body weight
29
Q
A