Metabolism of steroid hormones Flashcards
What are steroids?
Lipophilic molecules that are derived from cholesterol
What is the lipophilic property of steroids due to?
- The non-polar fused ring structure
- The hydrocarbon side chains
- The minimal presence of polar functional groups
How many major classes of steroid hormones are there?
5 major steorid classes
What are the major classes of steroid hormones?
- Progesterone
- Testosterone
- Estradiol
- Aldosterone
- Cortisol
What is the function of progesterones?
Prepares the uterus for implantation and supports pregnancy
What is an example of testosterone?
DHEA, a metabolite of testosterone, supports the embryonic development of the male phenotype
What is the function of estradiol?
Promotes development of female sex characteristics
What is the function of aldosterone?
Regulates salt balance and the volume and pressure of blood
What is the function of cortisol?
Stimulates glucose and glycogen synthesis and inhibits the inflammatory response
How do all steroid hormones operate?
Operate in a similar fashion: they bind to specific intracellular receptor proteins that subsequently regulate gene expression
Where do all steroid hormones originate from?
Cholesterol, which is transported into the mitochondria for the first step of synthesis
What is the steroidogenesis pathway like?
Cholesterol is converted into pregnenolone by CYP11A1, making it the rate-limiting step of steroidgenesis
What is pregnenolone metabolised into?
Metabolized into three main pathways leading to the production of Glucocorticoids, mineralocorticoids, androgens and estrogens
Which enzymes determine the direction of pregnenolone’s conversion into different steroid classes?
CYP17A1
CYP21A2
What do enzyme mutations or deficiencies in CYP17A1 and CYP21A2 lead to?
Congenital adrenal hyperplasia
What is the CYP17A1 inhibitor?
Abiraterone acetate
What is abiraterone acetate?
CYP17A1 inhibitor and an inhibitor of androgen biosynthesis prolonged overall survival among patients with metastatic prostate cancer
What are tissue-specific modifications?
Peripheral tissue can further metabolize these steroids, modifying their activity
What does 5a-reductase do?
Converts testosterone to dihydrotestosterone, a more potent androgen
What is the function of tissue-specific modifications?
This local metabolism modifies the activity, potency, or function of the hormones to meet the needs of the specific tissue
What are the enzyme families that are involved in steroidogenesis?
CYP450 enzymes like CYP17A1, which catalyzes hydroxylation reactions
Hydroxysteroid dehydrogenases, or HSDs, which modify hydroxyketone groups
What are the structural characteristics of steroid hormones?
They all share a structure, a series of four fused rings called cyclospentaperhydrophenantherene ring
The functional groups attached to this core determine what kind of adrenal cortex hormone it will be
How can steroid hormones enter the cell?
Only the unbound, free fraction is active and can enter the cells
What is the metabolism of steroid hormones like?
Biphasic
What are the phases of the metabolism of the steroid hormones?
Phase 1: CYP3A4 in the liver adds hydroxyl groups, making the molecules slightly more water-soluble
Phase 2: involves conjugation reaction like sulfation or glucuronidation
What is the purpose of the functions that occur during the metabolism of steroid hormones?
They fully solubilize the steroids, preparing them for excretion
What are the excretion pathways of the steroid hormones?
Conjugated steroid metabolites are excreted through urine or bile
Measuring these metabolites in urine is a common diagnostic tool for endocrine disorders
What is the transport and metabolism of steroid hormones like?
It is a tightly regulated process to ensure hormonal balance
What is the general mechanism of steroid actions: genomic?
Unlike protein hormones, steroids diffuse across the cell membrane because they are lipophilic
Inside the cell, they bind to specific receptors
What are the different parts of the receptors that the steroid hormones bind to inside the cell?
- Hormone binding site
- DNA binding site
- A site that activates transcription machinery to regulate gene expression
What is the general mechanism of steroid actions (glucocorticoids)?
Cortisol increases anti-inflammatory proteins and decreases inflammatory gene expression. That is why it is used to treat conditions like asthma and arthritis
What is the general mechanism of steroid actions (testosterone)?
An androgen that promotes muscle growth and male secondary sexual characteristics
Estradiol: an estrogen, that regulates female reprodcution
When are the genomic effects seen?
Within minutes, hours or days
What is the general mechanism of steroid actions: nongenomic?
The nongenomic effects are believed to involve the direct binding of the extracellular GC-CBG complex to cell membrane receptors
WHat is the effect of elevated levels of cortisol and the synthesis of GCs?
Known to exert rapid-onset, nongenomic effects that are seen within seconds or minutes and do not involve the GR or a change in the gene expression
What are examples of nongenomic effects?
- The rapid suppression of ACTH release
- The inhibition of exocytosis in inflammatory cell types
- The strong inhibition of growth hormone release
What are disorders of steroidogenesis?
When steroid synthesis is disrupted, it leads to diseases like congenital adrenal hyperplasia, where enzyme defects cause hormone imbalances
When does Addison’s disease occur?
When cortisol levels are too low
What type of synthetic glucocorticoids are widely used to treat inflammation?
Dexamethasone
What does long term use of dexamethasone lead to?
Side effects like immune suppression
