2. Steroid hormone biosynthesis

Question 1

Where is cholesterol found in the body?

Answer 1

Distribution:

• Membrane lipid (regulator of membrane fluidity)
• In plasma associated with apoproteins, triacylglycerols and phospholipids in various types of micellular structures called lipoproteins
• Cytosolic lipid droplets as cholesterol esters (mainly in steroid-secreting endocrine cells)

Question 2

What is the precursory for all steroids?

Answer 2

Cholesterol

Question 3

What is the process of cholesterol biosynthesis?

Answer 3

The liver synthesises cholesterol de novo from acetyl CoA in a multi-step process that occurs in the SER and cytosol. The rate-limiting step is the conversation of HMG-CoA to mevalonate by HMG-CoA reductase.

Question 4

Which major classes of plasma lipoproteins contain the highest % if cholesteryl esters (core)?

Answer 4

IDL

LDL

Question 5

Cholesterol metabolism, exogenous and endogenous pathway?

Answer 5

Exogenous pathway for lipid metabolism:
Dietary cholesterol and fatty acids are absorbed.
Triglycerides are formed in the intestinal cell from free fatty acids and glycerol and cholesterol is esterified.
Triglycerides and cholesterol combine to form chylomicrons.
Chylomicrons enter the circulation and travel to peripheral sites.
In peripheral tissues, free fatty acids are released from the chylomicrons to be used as energy, converted to triglyceride or stored in adipose.
Remnants are used in the formation of HDL.

Endogenous pathway for lipid metabolism:
VLDL is formed in the liver from triglycerides and cholesterol esters.
These can be hydrolyzed by lipoprotein lipase to form IDL or VLDL remnants.
VLDL remnants are cleared from the circulation or incorporated into LDL.
LDL particles contain a core of cholesterol esters and a smaller amount of triglyceride.
LDL is internalized by hepatic and nonhepatic tissues.
In the liver, LDL is converted into bile acids and secreted into the intestines.
In non hepatic tissues, LDL is used in hormone production, cell membrane synthesis, or stored.
LDL is also taken up by macrophages and other cells which can lead to excess accumulation and the formation of foam cells which are important in plaque formation.

Question 6

Uptake of cholesterol by receptor mediated endocytosis and synthesis of steroid hormones

Answer 6

Binding of LDL to receptors (receptor mediated endocytosis) of cells aggregates Clathrin to binding site on inside of cell. These form sphere vesicle coating around LDL inside the cell.

The receptors and clathrins break down leaving the lipoprotein to split into AAs, cholesterol and FFAs. Cholesterol then going onto form pregnenolone

Question 7

3 main physiological roles of cholesterol?

Answer 7

1. Component of call (plasma) membranes
   - Decreases membrane fluidity
   - Decreases physical permeability to charged/polar compounds associated with the formation of lipid rafts
2. Precursor for the production of bile salts
   - Uptake of fats and fat-soluble vitamins in GIT
3. Precursory for all steroid hormones
   - e.g. Glucocorticoids, mineralocorticoids and sex steroids

Question 8

Describe the biosynthesis of steroid hormones?

Answer 8

Cholesterol esters (catalysed by chol. ester hydrolase) –> cholesterol.

Cholesterol forms pregnenolone which then forms hormones via enzymatic processing in mitochondria, SER, etc

Steroid hormones: Progesterone, estradiol, testosterone, cortisol, aldosterone

Question 9

HMG-CoA inhibitor?

Answer 9

Statin

Question 10

Role of LCAT and CETP?

Answer 10

LCAT: Lecithin-cholesterol acyltransferase
CETP: Cholesteryl ester transfer protein

Cholesterol + lecithin – (LCAT)–> Chol. esters + lysolecithin

CETP transfers cholesterol esters from HDLs to VLDLs, LDLs and IDLs

Question 11

Structure of cholesterol

Answer 11

Cyclopentano- perhydro- phenanthrene nucleus
8-carbon aliphatic side chain

with OH and 2 x CH3

Question 12

What is the synonym and gene for Cholesterol side chain cleavage, a cytochrome p-450 enzyme involved in steroidogenesis?

Answer 12

Synonym: P-450 SSC
Gene: CYP11A1

Question 13

The enzymes required for the biosynthesis of adrenal steroids (aldosterone and cortisol), where are they found?

Answer 13

The SER and mitochondria.

Question 14

What are the different layers of the adrenal gland, from top to bottom?

Answer 14

Capsule
(Zona glomerulosa
Zona fasciculata
Zona reticularis) CORTEX
Medulla

Question 15

What is the name of the side chain cleavage enzyme that catalyses the reaction of mitochondria to pregnenolone?

Answer 15

20,22 desmolase

Question 16

What the hormones released from the following layers of the adrenal gland cells:
Zona glomerulosa?
Zona fasciculata?
Zona reticularis?
Medulla?

Answer 16

Zona glomerulosa: Mineralocorticoid e.g. aldosterone
Zona fasciculata: Glucocorticoids e.g. cortisol
Zona reticularis: Glucocorticoids e.g. Androgens (DHEA and androstenedione)
Medulla: Epinephrine from chromaffin cells

Question 17

Structure of the adrenal gland?

Answer 17

Made up of 2 glands, the cortex and the medulla

Adrenal cortex in 3 layers (zona glomerulosa, zona fasciculata, zona reticularis)

Question 18

Blood supply of the adrenal gland?

Answer 18

Capsular artery and medullary vein.
The blood supply enters the cortex in the subcapsular region and flows through anastomotic capillary beds while coursing through both the cortex and the medulla.

Question 19

What is the preferred pathways in humans for testosterone production from pregnenolone?

Answer 19

Pregnenolone

• -> 17-alpha-hydroxypregnenolone
• -> DHEA
• -> Androstenediol
• -> via oxidation of the A ring to TESTOSTERONE

Question 20

What is the relationship of Leydig and Sertoli cell physiology?

Answer 20

There is crosstalk between Leydig cells and Sertoli cells. The Leydig cells make testosterone, which acts on Sertoli cells. Conversely, the Sertoli cells convert some of this testosterone to estradiol (because of the presence of aromatase), which can act on the Leydig cells. Sertoli cells also generate growth factors that act on the Leydig cells. ATP, adenosine triphosphate;
cAMP, cyclic adenosine monophosphate; FSH, follicle stimulating hormone; PKA, protein kinase A.

Question 21

What hormone do Leydig and Sertoli cells detect?

Answer 21

Leydig= LH has receptors
Sertoli = FSH has receptors

Useful mnemonics: “L” for LH and Leydig, “S” for FSH and Sertoli.

Question 22

What hormones do Leydig and Sertoli cells detect and what is the main consequence of detection?

Answer 22

The Leydig cell has receptors for LH. The binding of LH increases testosterone synthesis.
The Sertoli cell has receptors for FSH. FSH promotes the synthesis of androgen-binding protein (ABP), aromatase, growth factors, and inhibin.

Question 23

How do the ovaries produce steroids?

Answer 23

The ovary differs from the testis in having aromatase, which converts androgens to estrogens

Question 24

What is are the main hormonal products of ovaries in the follicular and luteal phase?

Answer 24

During the follicular phase,
the major product of the follicle is estradiol
During the luteal phase, the major products of the corpus luteum are the progestins, although estradiol synthesis is still substantial.

Question 25

In the follicular phase, __ primes the theca cell to convert cholesterol to ____________. Because the theca cell lacks aromatase, it cannot generate ______ from this androstenedione. Instead, the androstenedione diffuses to the ______ cell, whose aromatase activity has been stimulated by ___. The aromatase converts the androstenedione to estradiol. In the luteal phase, the vascularization of the corpus luteum makes ___ available to the granulosa-lutein cells. Thus, both the theca-lutein and the granulosa-lutein cells can produce ______, the major product of the corpus luteum.

Answer 25

In the follicular phase, LH primes the theca cell to convert cholesterol to androstenedione. Because the theca cell lacks aromatase, it cannot generate estradiol from this androstenedione. Instead, the androstenedione diffuses to the granulosa cell, whose aromatase activity has been stimulated by FSH. The aromatase converts the androstenedione to estradiol. In the luteal phase, the vascularization of the corpus luteum makes LDL available to the granulosa-lutein cells. Thus, both the theca-lutein and the granulosa-lutein cells can produce progesterone, the major product of the corpus luteum

Question 26

Estrogen and progestosterone production by ovarian theca and granulosa cells

Answer 26

1. In the follicular phase, LH primes the theca cell to convert cholesterol to androstenedione. (Because the theca cell lacks aromatase, it cannot generate estradiol from this androstenedione.)
2. The androstenedione diffuses to the granulosa cell, whose aromatase activity has been stimulated by FSH.
3. The aromatase converts the androstenedione to estradiol. In the luteal phase, the vascularization of the corpus luteum makes LDL available to the granulosa-lutein cells. Thus, both the theca-lutein and the granulosa-lutein cells can produce progesterone (but only thecal cells can produce androstenedione), the major product of the corpus luteum

Question 27

Why are both thecal and granulosa cells require to produce oestrogen and progesterone?

Answer 27

As thecal cells lack aromatase to convert testosterone to estradiol

As granulosa cells lack 17,20-desmolase to convert progesterone to androstenedione

Question 28

LDL –> ________ –> Pregnenolone –> ________ –> Androstenedione –> _________ –> Estradiol

Answer 28

LDL –> Cholesterol –> Pregnenolone –> Progesterone –> Androstenedione –> Testosterone –> Estradiol

Question 29

All steroids derived from cholesterol by…

Answer 29

Intracellular enzymatic processing of cytochrome P450 class of mixed functional oxidases (CYP genes)

Question 30

Where are the major sits of steroid hormone biosynthesis?

Answer 30

Adrenal cortex:
Z.glomerulosa = aldosterone
Z.fasciculata= cortisol
Z reticularis = cortisol + androgens

Gonads:
Leydig cells in testes = Androgens
Thecal/granulosa cells= Estrogens and progestins