L3: Hypothalamic-Pituitary Adrenal Axis

Two functional divisions of the adrenal glands

1. Inner medulla

2. Outer cortex

Medulla: origin

• neural crest origin

Medulla: upon stimulation by sympathetic preganglionic fibres…

• Chromaffin (chromium stain affinity) cells

• release catecholamine hormones in circulation

  • e.g Adrenaline

What is adrenaline made from

• noradrenaline by the enzyme PNMT

  • pehtylethanolamine N-methyltransferase)

Does the medulla also secrete noradrenaline?

• A SMALL amount

• but too low to be significant in the blood

  • → mainly works as a neurotransmitter

Cortex: strucutre in the adrenal gland and origin

• makes up 85% of the adult adrenal gland

• derived from embryonic mesoderm

What does the adrenal cortex secrete

• wide range of steroid hormones

  • synthesised from cholesterol

What does it secrete in the human fetus?

• LARGE fetal zone of the inner cortex

• synthesizes the androgen DHEA

What happens to the fetal zone after birth?

• degenerates and disappears after birth

• outer cortex expands to form three zones in the adult gland

Three zones of the adult adrenal gland

1. Zona glomerulosa

2. Zona reticularis

3. Zona Fasciculata

1. zone glomerulosa

• outermost zone

1. What does it secrete

• hormone aldosterone

  • → mineralcorticoid

  • effects plasma electrolytes

1. Where does aldosterone act

• on distal tubule of the kidney

• AND: on sweat glands and salivary glands and gut

1. What does aldoesterone do

Promotes:

1. reabsorption of Na+ 

2. secretion of K+

3. proton section by type-A intercalated cells of the kidney

1. Important factors increasing aldoestone secretion

1. increased plasma potassium ion concentration

2. angiotensin II

1. Role of ACTH?

• DOES NOT influence secretion rate of aldosterone 

but

• ACTH is needed as permissive factor

  • allows secretion to occur

1. What does loss of ACTH or destruction of adrenal glands cause?

→ mineralcorticoid deficiency

2. Zona reticularis

• innermost zone

2. What does it secrete

• weak androgens

• importantly→ DHEA (dehydroepiandrosterone)

2. effect on men vs women?

Men→ no significant effect

• coz the testes secrete large amounts of ‘strong’ androgen testosterone

Women→ around half of circulating androgens are from adrenal gland

• Also→ promote sexual behaviour in female primates and libido in women

2. What are these androgens converted into?

• converted peripherally to the moore potenent testosterone and 5alpha-DHT

  • → responsible for pubic and axillary hair

2. Weak anddrogens may alternatively be converted to…

• Oestrogens

  • WHERE?: Both within the cortec and elsewhere in the body

• → becomes an important source after the menopause

3. Zona fasciculata

• the middle and largest zone of the adrenal cortex

3. What is it secrete/make?

• makes steroid hormones→ glucocorticoids

  • → thse increase glucose levels

3. Important glucocorticoids

1. Cortisol→ most important

2. Corticosterone→ secreted in place of cortisol in some other animals including rates

3. What are corticosteroids

Collective term for:

1. Mineral corticoids

and

2. Glucocorticoids

Control of the adrenal cortex: what is pro-opiomelanocortin (POMC)

• protein precursor

  • from which a number of polypeptide hormones are cleaved

• WHERE: within corticotrophs of the anterior pituitary

Products of POMC include

1. beta-endorphin

2. melanocyte-stimulating hormone (MSH)

   • → associated with colour changes in vertebrates

What is the most important POMC derivative

• Adrenocorticotrophic hormone (ACTH)

  • 39 amino acid polypeptide

What is the Hypothalamic-pituitary adrenal axis (HPA)

• hierarchical control structure

• within which ACTH plays a role

HPA axis:

1. releases corticotropin-releasing hormone (CRH)

2. stimulates corticotrophs

   1. (forms 20% of the anterior pituitary)

3. release ACTH

   1. (ADH may augment ACTH release in times of stress)

ACTH effect

General stimulatory effect on adrenal cortex

1. increases the size of cortical cells

2. needed for normal adrenal cortical function

3. simulates synthesis and secretion of cortisol

Negative feedback effect by cortisol on the HPA axis, demonstrated by…

1. Demonstrated by adrenal gland ablation on one side:

   • Slow enlargement of contralateral adrenal cortex

2. repeated injections of exogenous cortisol

   • → cause atrophy of adrenal cortex

Cortisol: how is it released

• in pulses

• following the pulsatile release of ACTH

Cortisol pronounced circadian rhythm

• large surge in the hours just before wakng in the morning

Cortisol: how is it transported?

• 95% of plasma cortisol is bound to protein→ cortisol binding globulin

  • (CBG= transcortin)

Cortisol half-life

• LONG half-life

• 70 mins

How does cortisol work

As a typical steroid hormone:

1. binds to cytoplasmic receptor 

2. moves to the nucleus and regulates gene expression

Therefore, the timing of effect…

• may take hours→ days

What is stress?

• an adverse circumstance that disturbs, or is likely to disturb, the normal physiological or psychological functioning of an individual

What is pschological stress

• anticipation, justified or not, that a challenge to homeostasis looms

What situations are stressful?

• unpredictable situations

• and those out of our control

Stressors are met by responses:

1. Physiological→ met by specific endocrine response

   • e.g PTH in response to hypocalcaemia

2. Other stressors→ induce ‘general adaptation syndrome’

What is the General Adaptation Syndrome

1. Alarm reaction

2. stage of resistance

3. stage of exhaustion (inappropriately named)

1. Alarm reaction

Involves:

• sympathetic nervous response → instant

• Hypothalamic-pituitary adrenal axis→ glucocorticoids released after a few mins

2. Stage of resistance

• new dynamic state 

• whereby homeostais is restored

  • although perhaps with different set points

• lasts days or weeks

3. Stage of exhaustion

• detrimental effects of chronic stress

• Selye thought→ the body was running out of stress hormones

• BUT: we now know that it is chronically elevnated levels of

  • glucocorticoids

  • → responsible for many of these effects

Selye’s concept used today?

• still useful

• specific phyiologcical responses can be seen as superimposed onto this specific general response

Important note about what stress is referring to

Can also be

• strenuous exercise

• sex

• animal courtship

→ also increase cortisol release

THERFORE: must be cautious in interpreting any iinstance of elevated cortisol as being unpleasant ‘stressful’ situation, without additional evidence

Cortisol glucocorticoid role: when is cortisol released

• in response to hypoglycerimia

• helps to raise blood sugar levels

  • → glucocorticoid role

Long -term or short term effects?

• more important in the long-term

Specific role of cortisol

1. promotes breakdown of muscle and plasma proteins to provide amino acids for gluconeogenesis

2. stimulates liver enzymes to convert amino acids to glucose

3. inhibits glucose uptake by muscle adipose tissue to preserve it for tissues such as brain

   1. An insulin resistance effect similar to that of GH~

4. Promotes FFA release from adipose tissue

   1. indirectly and

   2. As a permissive factor→ allow GH and adrenaline to have this effect

What does the nocturnal surge of cortisol do?

• help protect liver glycogen stores

• so remain available for emergencies

What happens to humans with deficiency of both GH and ACTH during strenous exercise or starvation?

• precipitate fatal hypoglycaemia

see chicken experiment

Cortisol importance

• it is essential for life

What is acute inflammation

• local reaction to injury involving:

  1. increased local blood flow

  2. increased capillary permeability

  3. exudation of white blood cells

How are these responses mediated?

• chemical mediators

  • released from damaged cells

What does cortisol do?

inhibits many components of the inflammatory process

The HPA axis and immune system

• interact closely with the immune system

High levels of glucocorticoids results in…

Immunosuppression

• and stress can exacerbate certain diseases

How is this adaptive?

How is it adaptive?

• Under normal circumstances→ immune system becomes activated at the  onset of stressful challenege

• Cortisol’s role may be to restrain this elevated immune response

  • returning things to normal later on

Compared to pharmacological doses of glucocorticoids (or chronic stress)

Different

• immune response is suppressed to levels below the baseline

Other actions of cortisol: where does cortisol act

• surprising number of tissues

• some are seen as permissive or have generalized functions

Examples of other effects of cortisol

1. Secreted by fetal adrenal gland in late gestation

   1. number of roles in fetal maturation and preparations for birth

2. Allows arteriolar smooth muscle to respond to noradrenaline, adrenaline and angiotensin II

   1. vital in maintaining BP (another reason why cortisol is essential)

3. Change your mood

   1. sensory acuity

   2. jet-lag due to circadian rhythm of cortisol being out of step

4. Inihibits bone formation and collagen synthesis in the skin

5. suppress reproductive function

6. Some mineral corticoid activity

6. How does cortisol have some mineral corticoid activity?

• receptor of aldosterone has some affinity for cortisol

6. But because cortisol is secreted in much larger quantities than aldosterone

Need to prevent the aldosterone receptor in the kidney from being overwhelmed by cortisol:

1. distal tubule cells express enzyme→ degrades cortisol

2. enzyme is inhibited by glycyrrhetinic acid

What happens if you have too much glycrrhetinic acid?

• you reabsoard too much Na+

→ Hypertension

Essay questions

1. Why do we have adrenal glands? (NST 1B 1993)

2. Compare and contrast the metabolic roles of growth hormone and cortisol.

3. Discuss the role of cortisol in times of stress.