Lecture 9 - Steroid hormones Flashcards
What are the 3 types of adrenocortical steroid hormones and give an example of each
Mineralocorticoids - aldosterone, progesterone
Glucocorticoids - cortisol
Androgens - testosterone, estradiol, DHEA
Where are steroid hormones synthesised?
Usually in peripheral endocrine organs such as the adrenal cortex and gonads, however can also be synthesised in the brain
How are steroid hormones transported in the blood?
And how does this affect their activity
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
Where in the body do steroid hormones act?
In the periphery and in the CNS
Lipid soluble so can pass through cell membranes and the blood brain barrier
What are steroid hormones derived from?
Cholesterol
What can happen to steroid hormones in the brain that affects their activity? And give an example
Converted into other metabolites that act on different receptors
Testosterone can be converted into estradiol by the enzyme aromatase
Name two other enzymes that convert hormones into other hormones in the brain
5-alpha-reductase
3-beta-HSD
What is the name given to steroid hormones that are synthesised within the CNS?
Neurosteroids
Describe neurosteroid synthesis
Mainly synthesised by glial cells
The mitochondria converts cholesterol into pregnanolone
Pregnanolone a neurosteroid itself or can be converted into other steroids
Name 3 examples of neurosteroids
Pregnanolone
DHEA
Pheromones
How is the production of sex hormones and glucocorticoids regulated?
Hypothalamic-pituitary-adrenal/gonadal axis
What are the two types of steroid hormone signalling? Describe the differences
- where are the receptors
- regulatory or neuromodulatory?
- speed
- consequence
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
What are the 5 parts of the generic steroid hormone receptor structure? and function of each
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
Which sections of the steroid hormone receptor are conserved between different types and which are variable?
AF1 and AF2 highly variable
CBD, hinge region, N terminus conserved
Whats the proper name for when a steroid hormone activates gene transcription?
Transactivation
What are the 4 types of glucocorticoid DNA response elements and how do they affect gene transcription?
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
What is steric hinderance?
Steroid receptor binds DNA response element, prevents transcription factors or machinery from binding, so represses expression
What is CREB?
cAMP response element binding protein
Cellular transcription factor
Activated by cAMP, binds cAMP response elements in DNA
What are the 3 ways in which steroid hormones can affect changes in genomic expression?
- Classic genomic pathway
- Steroid hormone binds to GPCR, increased cAMP, activation of CREB
- Steroid hormones binds membrane receptor, activation of neighbouring GPCR or ion channel, increased cAMP, activation of CREB
Example of a membrane bound steroid receptor
GPER = G-protein coupled estrogen receptor
Name 4 signalling mechanisms of steroid receptors that do not result in genomic changes
e.g. that are used by androgens such as testosterone
- Bind to GPCRs, activation of second messengers
- Bind to GPCRs that are coupled to ion channels, ion influx activates second messengers
- Metabolites of the steroid hormone modulate activity of a neurotransmitter receptor
- Steroid hormone binds to phospholipids, impacts membrane flexibility and ATPases function
What is allopregnanolone?
Neurosteroid
Positive allosteric modulator of the GABAa receptor
In clinical trials for anti anxiety medication
Describe the processes in the hypothalamic-pituitary-adrenal axis
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
Describe how cortisol release is regulated
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
What are the two types of corticosteroid hormone receptors in the CNS and what are the differences between them
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
What are the effects of cortisol?
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
Where are corticotropin releasing hormone neurons found in the brain?
Paraventricular nucleus of hypothalamus
Amygdala
Hippocampus
and many other regions
How does oestrogen and progesterone modulate sexual behaviour?
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)
Why does chronic stress impact memory and mood?
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)
By what 3 ways can glucocorticoids affect glutamatergic synapses?
- GR receptor activation causes glutamate release
- GR receptor activation stimulates endocannabinoid production, which regulates glutamate release
- Increase glutamate gene transcription
Excessive glutamate release leads to excitotoxicity and cell death.
Why does stress in early life leads to an inability to cope with stress later in life?
Chronic early life stress causes downregulation of glucocorticoid receptors. Cortisol less able to exert negative feedback on the HPA axis
What is nandrolone?
Synthetic androgen and anabolic steroid. Agonist of androgen receptor
