Lecture 9 - Steroid hormones

Question 1

What are the 3 types of adrenocortical steroid hormones and give an example of each

Answer 1

Mineralocorticoids - aldosterone, progesterone
Glucocorticoids - cortisol
Androgens - testosterone, estradiol, DHEA

Question 2

Where are steroid hormones synthesised?

Answer 2

Usually in peripheral endocrine organs such as the adrenal cortex and gonads, however can also be synthesised in the brain

Question 3

How are steroid hormones transported in the blood?

And how does this affect their activity

Answer 3

Bound to either globulin proteins or albumin.
When bound = inactive
Only the free form is biologically active
Only 1-2% are circulating in active form

Question 4

Where in the body do steroid hormones act?

Answer 4

In the periphery and in the CNS

Lipid soluble so can pass through cell membranes and the blood brain barrier

Question 5

What are steroid hormones derived from?

Answer 5

Cholesterol

Question 6

What can happen to steroid hormones in the brain that affects their activity? And give an example

Answer 6

Converted into other metabolites that act on different receptors
Testosterone can be converted into estradiol by the enzyme aromatase

Question 7

Name two other enzymes that convert hormones into other hormones in the brain

Answer 7

5-alpha-reductase

3-beta-HSD

Question 8

What is the name given to steroid hormones that are synthesised within the CNS?

Answer 8

Neurosteroids

Question 9

Describe neurosteroid synthesis

Answer 9

Mainly synthesised by glial cells
The mitochondria converts cholesterol into pregnanolone
Pregnanolone a neurosteroid itself or can be converted into other steroids

Question 10

Name 3 examples of neurosteroids

Answer 10

Pregnanolone
DHEA
Pheromones

Question 11

How is the production of sex hormones and glucocorticoids regulated?

Answer 11

Hypothalamic-pituitary-adrenal/gonadal axis

Question 12

What are the two types of steroid hormone signalling? Describe the differences

• where are the receptors
• regulatory or neuromodulatory?
• speed
• consequence

Answer 12

Genomic - mediated by hormonal steroids acting on nuclear receptors, regulatory, slow (hours-days), receptor binds to DNA response element, regulates gene transcription
Non genomic - neuroactive steroids bind to membrane receptors, neuromodulatory, fast (seconds to minutes), activation of second messengers

Question 13

What are the 5 parts of the generic steroid hormone receptor structure? and function of each

Answer 13

N terminus (AF1) - binds transcription factors, determines where receptor binds to DNA
Core DNA binding domain - binds DNA response element
Hinge region - regulates dimerisation
Ligand binding domain (AF2) - binds ligand, highly specific
C terminus

Question 14

Which sections of the steroid hormone receptor are conserved between different types and which are variable?

Answer 14

AF1 and AF2 highly variable

CBD, hinge region, N terminus conserved

Question 15

Whats the proper name for when a steroid hormone activates gene transcription?

Answer 15

Transactivation

Question 16

What are the 4 types of glucocorticoid DNA response elements and how do they affect gene transcription?

Answer 16

Positive response element - transactivation
Negative response element - repression
Composite response element (receptor binds to gene AND transcription factors) - activation or repression
Tethering response element (receptor binds only transcription factors, NOT gene) - activation or repression

Question 17

What is steric hinderance?

Answer 17

Steroid receptor binds DNA response element, prevents transcription factors or machinery from binding, so represses expression

Question 18

What is CREB?

Answer 18

cAMP response element binding protein
Cellular transcription factor
Activated by cAMP, binds cAMP response elements in DNA

Question 19

What are the 3 ways in which steroid hormones can affect changes in genomic expression?

Answer 19

1. Classic genomic pathway
2. Steroid hormone binds to GPCR, increased cAMP, activation of CREB
3. Steroid hormones binds membrane receptor, activation of neighbouring GPCR or ion channel, increased cAMP, activation of CREB

Question 20

Example of a membrane bound steroid receptor

Answer 20

GPER = G-protein coupled estrogen receptor

Question 21

Name 4 signalling mechanisms of steroid receptors that do not result in genomic changes
e.g. that are used by androgens such as testosterone

Answer 21

1. Bind to GPCRs, activation of second messengers
2. Bind to GPCRs that are coupled to ion channels, ion influx activates second messengers
3. Metabolites of the steroid hormone modulate activity of a neurotransmitter receptor
4. Steroid hormone binds to phospholipids, impacts membrane flexibility and ATPases function

Question 22

What is allopregnanolone?

Answer 22

Neurosteroid
Positive allosteric modulator of the GABAa receptor
In clinical trials for anti anxiety medication

Question 23

Describe the processes in the hypothalamic-pituitary-adrenal axis

Answer 23

Neurons in the hypothalamus contain corticotropin releasing hormone (CRH) and arginine vasopressin (AVP)
These project onto the pituitary which releases ACTH
ACTH acts on adrenal gland which releases cortisol and noradrenaline

Question 24

Describe how cortisol release is regulated

Answer 24

Cortisol passes BBB and acts on hypothalamus and pituitary gland to suppress CRH and ACTH production, negative feedback

Adrenaline acts on the pituitary gland to increase ACTH production - positive feedback

Question 25

What are the two types of corticosteroid hormone receptors in the CNS and what are the differences between them

Answer 25

Type 1 - mineralocorticoid receptor, binds mineralocorticoids and glucocorticoids equally. Saturated at basal levels of glucocorticoids. Determines basal HPA activity

Type II - glucocorticoid receptor. Greater affinity for glucocorticoids than mineralocorticoids. Determines maximal HPA response to stress

Question 26

What are the effects of cortisol?

Answer 26

Binds to glucocorticoid receptors which are present all throughout the body. 20% of genome mRNA expression influenced by glucocorticoids. so has many effects including weight gain, depression, immune system suppression

Question 27

Where are corticotropin releasing hormone neurons found in the brain?

Answer 27

Paraventricular nucleus of hypothalamus
Amygdala
Hippocampus
and many other regions

Question 28

How does oestrogen and progesterone modulate sexual behaviour?

Answer 28

Exposure to estradiol during maturation affects adult sexual behaviour in rats
Oestrogen modulates sexual motivation acutely throughout the day via membrane receptors (neuromodulatory)
Also chronically over the year (affects breeding patterns), via nuclear receptors (regulatory)

Question 29

Why does chronic stress impact memory and mood?

Answer 29

Cortisol bind to glucocorticoid receptors in the hippocampus (affects memory) and amygdala (affects fear). Prolonged activation of these receptors modulates structure of synapses and dendritic spines, through use of brain derived neurotrophic factor (BDNF)

Question 30

By what 3 ways can glucocorticoids affect glutamatergic synapses?

Answer 30

1. GR receptor activation causes glutamate release
2. GR receptor activation stimulates endocannabinoid production, which regulates glutamate release
3. Increase glutamate gene transcription

Excessive glutamate release leads to excitotoxicity and cell death.

Question 31

Why does stress in early life leads to an inability to cope with stress later in life?

Answer 31

Chronic early life stress causes downregulation of glucocorticoid receptors. Cortisol less able to exert negative feedback on the HPA axis

Question 32

What is nandrolone?

Answer 32

Synthetic androgen and anabolic steroid. Agonist of androgen receptor