62 Steroid hormone biosynthesis Flashcards
What is the precursor of all steroids?
Cholesterol
What is the distribution of cholesterol?
- Membrane lipid:
• Regulator of membrane fluidity - Plasma:
• Associated with apoproteins, triacylglycerols and phospholipids in various types of micellular structures called lipoproteins - Steroid-secreting endocrine cells:
• Cytosolic lipid droplets as cholesterol esters
Cholesterol biosynthesis?
- Liver synthesises cholesterol de novo from acetyl CoA in a multi-step process that occurs in SER and cytosol
- Rate-limiting step is conversion of HMG-CoA –> mevalonate by HMG-Coa reductase
Which major classes of plasma lipoproteins contain the highest % if cholesteryl esters (core)?
IDL (30%)
LDL (35-40%)
Where are the plasma lipoproteins made?
- Chylomicrons - gut
* VLDL, IDL, LDL, HDL - liver
Cholesterol metabolism - exogenous pathway?
- 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 (taken up by liver)
Cholesterol metabolism - endogenous pathway?
- 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
Uptake of cholesterol by receptor mediated endocytosis and synthesis of steroid hormones
- 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 on to form pregnenolone (aldosterone, cortisol, estradiol, testosterone)
The cholesterol needed as the starting material in the synthesis of steroid hormones come from which 2 sources?
- ~80% taken up as LDL particles via receptor-mediated endocytosis
- Cell synthesis the remaining (20%) cholesterol de novo from Acetyl CoA
3 main physiological roles of cholesterol?
- Component of cell (plasma) membranes
• Decreases membrane fluidity
• Decreases physical permeability to charged/polar compounds associated with the formation of lipid rafts - Precursor for the production of bile salts
• Uptake of fats and fat-soluble vitamins in GIT - Precursory for all steroid hormones
• e.g. Glucocorticoids, mineralocorticoids and sex steroids
Describe the biosynthesis of steroid hormones?
- Cholesterol esters (catalysed by chol. ester hydrolase) –> cholesterol
- Cholesterol forms pregnenolone (side chain cleavage by desmolase) which then forms hormones via enzymatic processing in mitochondria, SER
- Steroid hormones: Progesterone, estradiol, testosterone, cortisol, aldosterone
Describe the biosynthesis of adrenal steroids?
- Synthesis of adrenal steroids (mineralocorticoid aldosterone and glucocorticoid cortisol) from cholesterol
- Enzymes located in SER or mitochondria
- Side-chain cleavage enzyme that produces pregnenolone is 20, 22 desmolase
- If the synthesis of cortisol is prevented by any one of several dysfunctional enzymes, other steroid products might be produced in excess
- e.g. A block in the 21 alpha-hydroxylase will diminish production of both cortisol and aldosterone and increase production of the sex steroids
Examples of cytochrome P-450 enzymes involved in steroidogenesis?
- Cholesterol side chain cleavage
- 11-Beta-Hydroxylase
- 17-Alpha-Hydroxylase
- 17, 20- Desmolase
- 21-Alpha-Hydroxylase
- Aldosterone synthase
- Aromatase
• 57 different P-450 enzymes in human genome
What does aromatase (P-450arom) do?
Catalyses a reaction essential fort eh production of oestrogens
The enzymes required for the biosynthesis of adrenal steroids (aldosterone and cortisol), where are they found?
SER and mitochondria
What are the different layers of the adrenal gland, from outer to inner?
- Capsule
- Cortex
• Zona glomerulosa
• Zona fasciculata
• Zona reticularis - Medulla
Structure of the adrenal gland?
- Sits upon each kidney
- 2 glands - cortex and medulla
- Adrenal cortex has 3 layers that surround the medulla
- Adrenal medulla contains chromatin cells
Blood supply of the adrenal gland?
Blood supply enters the cortex in the subscapular region and flows through anastomotic capillary beds while coursing through both the cortex and the medulla
What are the hormones released from the following layers of the adrenal gland cells: • Cortex: - Zona glomerulosa? - Zona fasciculata? - Zona reticularis? • Medulla?
• Cortex:
- 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
What does zona glomerulosa of adrenal gland secrete?
Aldosterone
What does zona fasciculata and reicularis synthesise?
Cortisol and sex steroids
What does the adrenal medulla contain and secrete?
- Contains chromatin cells
* Secrete epinephrine and small amount of norepinephrine
Describe the biosynthesis of testosterone?
- Synthesis of androgens from cholesterol
- Enzymes locates in SER or mitochondria
- Side-chain cleavage enzyme that produces pregnenolone is 20,22 desmolase
- 4 possible pathways from pregnenolone –> testosterone
- Preferred pathway in the human testis is the one to androstenediol, followed by oxidation of the A ring to testosterone
- Some of these pathways are shared in the biosynthesis of the glucocorticoids, mineralocorticoids and estrogens
What is the name of the side chain cleavage enzyme that catalyses the reaction of cholesterol to pregnenolone?
20,22 desmolase
What is the relationship of Leydig and Sertoli cell physiology?
- Leydig cell:
• Receptors for LH
• Binding of LH increases testosterone synthesis - Sertoli cell:
• Receptors for FSH (promotes synthesis of androgen-binding protein (ABP), aromatase, growth factors, and inhibin) - 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
What hormones do Leydig and Sertoli cells detect? What does it do?
- Leydig:
• LH - increases testosterone synthesis - Sertoli:
• FSH - promotes synthesis of androgen-binding protein (ABP), aromatase, growth factors and inhibin
Biosynthesis of ovarian steroids?
- Synthesis of progestins and oestrogen from cholesterol
- Enzymes located in SER or mitochondria
- Side-chain cleavage enzymes that produces pregenolone - 20,22 desmolase
- Ovary differs from the testis in having aromatase - converts androgens –> oestrogens
What cells produce oestrogen and progesterone?
Ovarian thecal and granulose cells
Oestrogen and progesterone production by ovarian thecal and granulose cells physiology
• The final steroid products of the ovaries depend on the different phases of the menstrual cycle
• During the follicular phase,
the major product of the follicle is estradiol, whereas during the luteal phase, the major products of the corpus luteum are the
progestins, although estradiol synthesis is still substantial
• In the follicular phase, LH primes the theca cell to convert
cholesterol to androstenedione
• Because the thecal 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 vascularisation 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
What are the main hormonal products of ovaries in the follicular phase?
- Follicular phase:
• Estradiol - Luteal phase:
• Progestins
In the follicular phase, LH primes the theca cell to convert what substance?
Cholesterol –> androstenedione
Which cell, ovarian thecal or granulosa, lacks aromatase? Consequence?
- Theca cells lacks aromatase
* Can’t generate estradiol from androstenedione
What happens to the androstenedione formed in ovarian thecal cells?
Diffuses to granulosa cell, whose aromatase activity has been stimulated by FSH
The aromatase activity in ovarian granulosa cells is stimulated by what?
FSH
What is the function of aromatase in ovarian granulosa cells?
Converts androstenedione –> estradiol
In the luteal phase, what does the vascularisation of the corpus luteum result in?
Makes LDL available to the granulosa-lutein cells
What is the major product of the corpus luteum?
Progesterone (via theca-lutein and granulose-lutein cells)
All steroids (including hormones) derived from ____ by ____?
From cholesterol by intracellular enzymatic processing by various membranes of the cytochrome P450 class of mixed functional oxidases (CYP genes)
Cholesterol:
• Derived from?
• Synthesised in? Transported to? Taken up by? Stored?
- Derived from diet
- Synthesised in the liver transported to steroidogenic tissues primarily in the form of LDL, taken up by RME and stored esterified to fatty acids in cytosolic lipid droplets
How is cholesterol made into the final steroid product?
- Removal of the side chain by desmolase (point of regulation of steroid hormone production)
- Various other Cyt P450 enzymes situated within the mitochondria and SER process pregnenolone –> the final steroid product (glucocorticoids, mineralocorticoids and sex steroids)
Where are the major sites of steroid hormone biosynthesis?
• Adrenal cortex
- Zona glomerulosa: aldosterone
- Zona fasciculata: cortisol
- Zona reticularis: cortisol and androgens
• Gonads
- Leydig cells in testes: androgens
- Thecal/ granulosa cells: oestrogens and progestins
