detail regarding hpa axis and its relation

detail regarding hpa axis and its relation

1.  

 

Physiology of HPA axis
Dr
Parul jain

2. INTRODUCTION
The
adrenal glands are part of an adaptive system involved

in the maintenance of a homeostatic biological balance in
response
to stress.
The
adrenal glands release cortisol, epinephrine, and
norepinephrine
to preserve a healthy, but dynamic equilibrium.
Specific
brain nuclei control adrenal gland function either
through
the actions of the hypothalamic-pituitary-adrenal
(HPA)
axis, initiated by traditional HPA drivers like
corticotrophin
releasing factor (CRF) from the hypothalamus,
or
through direct innervation by stimulated preganglionic
sympathetic
nerves.

4. CRH (Corticotropin-releasing hormone)
Corticotropin-releasing hormone (CRH) is a part of corticotropin
releasing factor.

Three homologus neuropeptides – Urocortin I, Urocortin II, and
Urocortin III

A 41-amino acid peptide derived from a 196-amino acid preprohormone.
Parvocellular neuroendocrine cells within the paraventricular nucleus of
the hypothalamus
Regulates basal and stress-induced release of pituitary ACTH

Detected in cerebral cortex, hypothalamus, anterior pituitary, adrenal
glands, testis, ovary, gut, heart, lungs and placenta

CRF gene expression can be altered (catecholamines, serotonin,
cytokines, glucocorticoids)

5. CRH-continued

CRF R1

Corticotrophs
of the anterior pituitary

Mediates
actions of the HPA axis and anxiety-related behavior

CRF R2

Brain
and periphery

Regulation
of feeding behavior and cardiovascular function

ACTIONS OF CRH

Initiate HPA
 Axis

Role in parturition

DHEA

PROSTAGLANDINS

6. APPLIED ASPECTS
CRH-1 receptor antagonist pexacerfont is

currently
under investigation for the treatment
of
generalized anxiety disorder.

CRH-1 antagonist antalarmin has
been
researched
in animal studies for the
treatment
of anxiety, depression but no
human
trials with this compound have been
carried
out.

7. POMC (Proopiomelanocortin)
241
Amino acids
Constitute
about 10 percent of the gland
Binding
of CRF with CRF R1 on corticotrophs
Simulation
of  POMC mRNA
Synthesis
 and ACTH release

8. CLEAVAGE OF POMC INTO ACTH

9. NPP    
27–102
melanotropin
gamma
 
γ-MSH 77–87
potential
peptide
   
105–134
corticotropin adrenocorticotropic
hormone
ACTH 138–176
melanotropin
alpha
melanocyte-stimulating
hormone
α-MSH 138–150
corticotropin-like
intermediate peptide
 
CLIP 156–176
lipotropin
beta
 
β-LPH 179–267
lipotropin
gamma
 
γ-LPH 179–234
melanotropin
beta
 
β-MSH 217–234
beta-endorphin    
237–267
met-enkephalin    
237–241
 

10. ACTH
consists
of 39 amino acids.
stimulates
secretion of glucocorticoids from adrenal
cortex.
ACTH receptor
is
a seven-membrane-spanning G protein-coupled
receptor.
upon
ligand binding, the receptor undergoes
conformation
changes that stimulate the enzyme
adenylyl
cyclase which leads to an increase in
intracellular
cAMP and subsequent activation of
protein
kinase A.

11. Actions of ACTH include-

Immediate actions
include StAR mediated increase in
cholesterol
delivery to the
mitochondria
where the P450scc
(CYP11A1)
enzyme is located.

P450scc
catalyzes the first step of steroidogenesis that is
cleavage
of the side-chain of cholesterol.

stimulates lipoprotein uptake into
cortical cells. This increases
the
bio-availability of cholesterol in the cells of the adrenal cortex.

The

long term actions (24 – 26 HRS) of
ACTH include
stimulation
of the transcription of the genes coding for
steroidogenic
enzymes, especially P450scc, steroid 11β-
hydroxylase,
adrenodoxin

12. ADRENAL GLANDS

13. Basal secretions
Group Hormone Daily
secretions
Glucocorticoids
 Cortisol
 Corticosterone
5 – 30 mg
2 – 5 mg
Mineralocorticoids
 Aldosterone
 11-
deoxycorticosterone
5 – 150 μg
Trace
Sex Hormones
Androgen
Progestogen
Oestrogen
 DHEA
 Progesterone
 Oestradiol
15 – 30 mg
0.4 – 0.8 mg
Trace

14. Regulation of cortisol
(ROLE OF STRESS)
Stress
can greatly affect levels of cortisol in
the
blood. It can override the hypothalamic-
pituitary
axis of negative feedback. The
magnitude
of the increase of blood cortisol is
proportional
to the intensity of the stressful
stimulation.
More stress – more cortisol. Less
stress-
less cortisol.

15. STRESSORS
(HYPOGLYCEMIA, FEVER)
CYTOKINES
Activation of vagus nerve
NTS/ Amygdala
PVN

17. Circadian rhythm of ACTH & Cortisol
Controlled
by hypothalamic SCN,
(central
circadian oscillator (pacemaker) or
central
clock)

Levels
highest on wakening and declining
throughout
reaching nadir in evening
Dependent
on day night and sleep wake
cycle.
Takes
2 weeks for circardian rhythm to reset
to
an altered day night cycle.

19. NEGATIVE FEEDBACK
Glucocorticoids
themselves exert negative feedback
Mainly
mediated by two receptors-
Glucocorticoid receptor (GR)-
Patients
having mutations in GR or in chronic stress states have
high
ACTH and cortisol levels.
More
affinity to synthetic corticosteroids.
Inhibition
of CRH and AVP mRNA synthesis and secretion.
Inhibition
of POMC gene transcription
Mineralocorticoid receptor (MR)

20. NEGATIVE FEEDBACK

21. ACTIVATION OF GRs

22. HPA AXIS SUPPRESSION BY CS
THERAPY
Exert
negative feedback mechanism through GR
Depends
on dose, potency, half life and duration of
administration.
(Dexamethasone has maximum
potential)
Less
than 3 weeks HPA suppression unlikely.
Dose
of >=15 mg prednisolone will invariably
suppress
HPA axis.
Night
doses cause more HPA axis suppression.
Gradual
withdrawal should be done.
Recovery
can be assessed by SST or ITT.

23. ADRENAL ANDROGEN
REGULATION
•DHEA,
androstenedione stimulated by ACTH
•Similar
circadian rhythm to cortisol.
•Additional
stimulatory factors (CASH) are present as
evident
by-
Dexamethasone studies-
complete cortisol
suppression,
only 20% for DHEA.
Adrenarche-
6-8 years, cortisol production
unaltered
Aging-
Reduction in DHEA, no change in cortisol
Anorexia nervosa and illness-
Fall in DHEA, no
change
in cortisol

24. REGULATION OF MINERALOCORTICOIDS
Aldosterone
is released due to:
1)
Activation of the renin-angiotensin system
in
the kidneys by increasing the transcription
of
CYP11B2.

2)
Direct stimulation of the adrenal cortex by
increase
in blood K+ concentration
This
zone is relatively independent of ACTH.
It
may have a weak effect in releasing
aldosterone
(10%-20%)

25. STATES ASSOCIATED WITH HYPERACTIVATION OR
HYPOACTIVATION OF HPA AXIS

26. THANK YOU