6. Adrenal cortex - hormones and physiology Flashcards
Anatomy of the adrenal gland
Adrenal glands lie on top of the kidneys
Divided into inner adrenal medulla (10%) and the outer adrenal cortex (90%)
What does the medulla do?
Medulla is concerned with stress response (fight or flight) but not essential for life
What is the cortex associated with?
The cortex is concerned with stress, sodium and glucose homeostasis. A functioning adrenal cortex is essential for life.
What does the adrenal cortex synthesise?
The adrenal cortex synthesises many different hormones of a similar chemical structure (steroid hormones) which are derived from cholesterol from the diet or synthesised within the gland itself.
Testosterone, cortisol, eostrogen and progesterone are all steroids
What are the three layers of the adrenal cortex?
Outer: zona glomerulosa
Middle: zona fasciculata
Inner: zona reticularis
Cells within the different areas possess different enzymes and therefore synthesise different adrenocortical hormones
What are the effects of steroid hormones
Classified according to their predominant action:
glucocorticoids e.g. cortisol control sugars
mineralocorticoids e.g. aldosterone control minerals Na+ and K+
What hormones are made in which layers of the adrenal cortex?
Aldosterone: in the zona glomerulosa because it has 18-hydroxylase enzyme
17a-hydroxypregnalone and 17a-hydroxyprogesterone and hormones derived from them: zona fasciculata and zona reticularis because have 17a-hydroxylase
cortisol - zona fasciculata
androgens - zona reticularis
Does the adrenal cortex secrete sex hormones?
Under normal circumstances, the adrenal cortex secretes small quantities of male sex hormones (androgens) such as dehydroepiandrosterone, androstenedione and testosterone, and the femal eostregens e.g. oestradiol. Only significant in adrenal disorders
Are mineralocorticoids and glucocorticoids synthesis, secretion and actions controlled together?
They are controlled independently
How is glucocorticoid secretion controlled?
The hypothalamus releases CRH which stimulates the anterior pituitary to release ACTH
ACTH stimulates the adrenal cortex to releases cortisol
Cortisol has a negative feedback effect on CRH release from the hypothalamus
What are the patterns of ACTH and cortisol secretion?
The secretion of ACTH is pulsatile, it peaks in the early morning and at the time of waking, and nadirs in the middle of the night.
There is also increased secretion at times of prolonged stress.
Cortisol secretion shows the same pattern but the peak and nadir occurs approx 2 hours later than those of ACTH
This pattern is related to sleep- wake patterns: disrupted by shift work and long-haul travel
Transport of glucocorticoids
- 10% of cortisol is transported in a free, active form
- 75% bound to corticosteroid binding globulin (CBG or transcortin)
- 15% albumin-bound
the same proteins also transport the other glucocorticoids and progesterone
How does pregnancy affect glucocorticoid transport
Pregnancy associated with an increase in CBG which results in a compensatory increase in circulating plasma cortisol concentrations
The amount of free cortisol remains stable
Describe the metabolism of the adrenal steroids
Steroid hormones are glucoronidated in the liver to make them water soluble then excreted in the urine
How do steroid hormones including glucocorticoids produce their effects?
By acting on intracellular receptors and alterations in gene expression: inevitably results in a delay of hours to days, but in some cases cortisol has rapid effects e.g. feedback inhibition of ACTH secretion
Negative feedback isn’t based on gene expression but on membrane effects so doesn’t take days and can be instantaneous
Describe the effects of cortisol on carbohydrate metabolism
The most important actions of cortisol at normal physiological concentrations are those on carbohydrate metabolism. These are opposite to insulin i.e.:
- antagonises the effects of insulin on the cellular uptake of glucose
- stimulates glycogenolysis
- stimulates hepatic gluconeogenesis
What are the effects of cortisol on fatty acids?
Cortisol stimulates lipolysis and fatty acid mobilisation, partially by potentiating the effects of growth hormone and catecholamines
In excessive concentrations, cortisol causes fat synthesis and deposition in novel anatomical sites, most notably the face, the trunk and the intrascapular region of the shoulder
What are the effects of cortisol on amino acids?
In the liver, cortisol stimulates amino acid uptake leads to enhanced gluconeogenesis
In the periphery, it inhibits amino acid uptake and protein synthesis, resulting in a net loss of skeletal protein
What is the effect of glucocorticoids on aldosterone?
Glucocorticoids are also able to stimulate aldosterone receptors
although aldosterone-sensitive tissues possess an enzyme, 11b-hydroxysteroid dehydrogenase, which converts cortisol to inactive cortisone
Do mineralocorticoids and glucocorticoids have the same effect?
Mineralocorticoid actions of glucocorticoids are apparent at high concentrations of mineralocorticoid
What is the effect of cortisol on blood vessels?
Excess cortisol can cause an enhanced vasoconstrictor response to catecholamines which results in increased blood pressure
What are some psychological effects of glucocorticoids?
Glucocorticoids can also produce psychological effects with possible feelings of elation or sedation
What effect does psychological and physiological stress have on corticosteroids
Trauma, infection and hypoglycaemia and other times of psychological and physiological stress causes rapid secretion of ACTH and corticosteroids
At these raised concentrations, additional effects of these hormones become apparent
How do glucocorticoids affect the body’s defence systems?
- suppress lymphoid tissues, reduce antibody production and inhibit cellular immune system
- stabilise leukocyte membranes and reduce release of proteolytic enzymes
- inhibit phospholipase A2 and reduce synthesis of inflammatory mediators
- immunosuppressant
What is the most important role of glucocorticoids?
Their most important role is in the response to stress
in absence of corticosteroids, even mild stress can be fatal
At times of prolonged stress, glucocorticoids maintain enhanced supply of glucose which may be needed for prolonged response to the stressor, but also suppress inflammatory response
At times of injury:
pain alerts the sufferer to damage
Oedema dilutes toxic substances that may be present and immobilises/stabilises joints
Leukocyte infiltrationdestroys any invading cells whilst antibodies inactivate the foreign proteins
Tissue repair is enhanced by prostaglandins
What effect do glucocorticoids have on injury and tissue repair?
Glucocorticoids appear to potentiate adverse effects of injury and delay tissue repair, so steroids can appear to be acting contrary to the individual’s best interests.
- Adrenocortical stress response decreases the inflammatory response
- Removes pain and decreases immobilisation induced by the oedema
- steroid-induced sedation also causes a lack of awareness of severity of situation
- overall effect is that individual is able to perform despite presence of injury or infection
How is mineralocorticoid secretion controlled?
Aldosterone and 11-deoxycorticosterone are physiologically important mineralocorticoids.
ACTH doesn’t really influence aldosterone secretion, but ACTH stimulates initial conversion of cholesterol to pregnenolone
RAAS controls the secretion of aldosterone - not negative feedback through ACTH
The secretion of aldosterone is also directly stimulated by trauma, anxiety, hyperkalaemia and hyponatraemia, and inhibited by atrial natriuretic peptide (ANP)
How does aldosterone act on a cellular level?
Aldosterone is only 50% protein bound within circulation.
Aldosterone has specific intracellular receptors which cause expression of ion channels that transport sodium and potassium ions across the cell membrane
Where does aldosterone act in the body?
Aldosterone stimulates the reabsorption of sodium ions in:
- the distal tubule of the kidney (most effect),
- the collecting duct,
- the proximal tubule
- the ascending loop of Henle
and in the colon, sweat and salivary glands
What effect does aldosterone have?
Sodium and reabsorption occurs in exchange for either potassium or hydrogen ions
By controlling reabsorption of sodium ions, aldosterone influences plasma sodium concentration, which in turn influences water reabsorption in the collecting duct via an effect on ADH secretion
The interaction of the RAAS system, aldosterone and ADH therefore controls blood volume and influences blood pressure
What are the pharmacological uses of glucocorticoids
Glucocorticoids (eg hydrocortisone = cortisol) are used in:
- for replacement therapy
- for their immunosuppressive or anti-inflammatory effects in conditions such as arthritis, asthma or allergies
- for the treatment of proliferative conditions such as leukaemia.
Mineralocorticoids pharmacological therapy
Mineralocorticoids are used only for replacement therapy.
The short plasma half-life of aldosterone renders it unsuitable for mineralocorticoid replacement therapy thus the drug of choice is fludrocortisol.
What influences the selection of glucocorticoid?
In most cases the selection of the glucocorticoid is dependent upon the pharmacokinetics of the available agents and the predominant effect required.
Most glucocorticoids are orally active but their absorption through the skin varies as does their plasma half-life.
What are the adverse effects of glucocorticoids
- Steroid usage may suppress wound healing and may exacerbate infections due to their immunosuppresant effects.
- Long term use in children may cause inhibition of growth, and in adults may result in osteoporosis.
- The development of diabetes mellitus and other symptoms of Cushing’s syndrome also often accompanies steroid therapy.
Probably the most important adverse effect, however, is suppression of the hypothalamic-pituitary axis.
Chronic administration of exogenous glucocorticoids results in suppression of ACTH secretion leading to atrophy of the adrenal cortex.
Other consequences of suppression of the anterior pituitary may include disturbances of sex hormone secretion resulting in symptoms such as menstrual disturbances.
What happens if steroid therapy stops abruptly?
If steroid therapy is then stopped abruptly, the adrenal cortex is unable to secrete endogenous hormones and the patient suffers an Addisonian crisis, which may be fatal.
This consequence overcome by the gradual reduction of the dose of the exogenous steroid
What advantages does local administration of corticosteroids have over systemic?
Local drug administration overcomes these problems, but systemic steroids cause these problems. You can’t become addicted to steroids, but can’t come off them immediately, have to get off them over a few weeks.
What do anti-inflammatory corticosteroids do?
Anti-inflammatory corticosteroids remove the symptoms without affecting the cause of the underlying disorder, which may worsen.
