Introduction

This article explains the production and effects of adrenal products. For more information on mechanisms of blood pressure regulation, secretion of ions, and other effects related to the action of mineralocorticoids, please see this article.

  • The adrenal glands are also sometimes known as suprarenal glands
  • They sit on top of the kidneys. They weight about 4g, and have a medulla and a cortex, like the kidneys themselves.
  • The medulla – is directly connected to the sympathetic nervous system, and will secrete adrenaline and noradrenaline in response to sympathetic stimulation.
  • These two hormones cause almost the exact same effects on body tissues as direct sympathetic stimulation itself does.
  • The cortex secretes an entirely different type of hormone – corticosteroids. The corticosteroids are all synthesised from cholesterol, and have similar chemical formulas.
  • There are three types of corticosteroid:
    • Mineralcorticoids – e.g. aldosterone – these are so called because they effect the ‘minerals’ (electrolytes) of the blood. They particularly effect sodium and potassium.
    • Glucocorticoids – e.g. cortisol – so called due to their effects on glucose metabolism – however they also have important effects on protein and fat metabolism.
    • Androgens – these are sex hormones that exhibit similar effects to testosterone. They are not particularly important, except in disease of the adrenal glands where their hypersecretion can result in masculization.

Anatomy

  • The zona glomerulosa – this constitutes about 25% of the adrenal cortex, and it is where aldosterone is produced – this region contains the enzyme aldosterone synthase. The production of aldosterone is controlled by extracellular fluid concentrations of angiotensin II and potassium. Both these two chemicals will increase the synthesis of aldosterone. Prolonged stimulation of this zone can lead to its hypertrophy.
  • The zona fasciculata – this constitutes about 75% of the adrenal cortex, and secretes glucocorticoids as well as small amounts of androgens and oestrogens. The secretion of these hormones is largely controlled by the hypothalamic-pituitary axis – and the release of ACTH (adrenocorticotropic hormone).
  • The zona reticularis – this is responsilbe for most of the androgen output of the adrenal galnd and it also secretes some oestrogens and glucocorticoids.
  • The mechanisms of androgen secretion are not well understood in comparison with the mechanisms of mineralcorticoid and glucocorticoid secretion.
 
 

Corticosteroids

The term ‘corticosteroid’ can actually refer to both mineralocorticoids (i.e. aldosterone) and to glucocorticoids, i.e. to the hormones produced in the adrenal cortex.
Often a ‘mineralocorticoid’ will also have some glucocorticoid activity, and vice-versa.
 
All corticosteroids are synthesised from cholesterol. The adrenal cortex is capable of synthesising its own cholesterol from acetate, however, >80% of the cholesterol it uses comes from LDL’s circulating in the blood. LDL’s have high concentrations of cholesterol and are absorbed from coated pits by endocytosis into adrenal cells.
  • ACTH will cause an increase in corticosteroid synthesis by both increasing the number of surface receptors for LDL’s and it will also increase the number of enzymes used to liberate cholesterol from endocytosed LDL’s.
  • Note that stress also causes an increase in cortisol production.
  • The rate limiting step in to production of adrenal hormones is the first step in cholesterol breakdown, which occurs in the mitochondria by the enzyme cholesterol desmolase.
  • ACTH and angiotensin II will both increase the rate of this reaction.
  • There are then a series of reactions in the mitochondria, and then later on the ER that lead to the production of hormones. Obviously, some of these reactions differ depending on which region of the cortex you are in.
Corticosteroids are transported in the blood bound to plasma proteins. Aldosterone tends to bind to albumin. About 40% of aldosterone remains free, giving it a half-life of about 20 minutes. Cortisol ion the other hand binds to cortisol binding globulin (aka transcortin) as well as to albumin. This means there is much less free cortisol in the blood and as a result, cortisol has a half-life of 60-90 minutes.
The general effect of these binding globulins is that it helps buffer sudden changes in concentration of the corticosteroids, such as in brief periods of stress, or when ACTH is released. Binding proteins also ensure that there is a uniform distribution of corticosteroids to the peripheral tissues.
Corticosteroids are metabolised by the liver. They are converted mainly into glucuronic acid and to a lesser extent sulphates. These metabolites are inactive and have no glucocorticoid or mineralocorticoid activity. 25% of the metabolites are removed by the liver, whilst the rest enter general circulation and remain unbound in plasma, and they are then removed by the kidneys.
Diseases of the liver directly reduce the excretion of these products.
 

Mineralocorticoids 

e.g. aldosterone, cortisol, cortisone
Many mineralocorticoids also have glucocorticoid activity!
Aldosterone is responsible for over 90% of the activity of mineralocorticoids. Cortisol is only responsible for a very small amount of activity, but it is secreted in very large amounts (it is responsible for a LOT of glucocorticoid activity!)
Cortisone is a synthetic corticoid, with lots of glucocorticoid activity, but not much mineralocorticoid activity. Generally, the synthetic glucocorticoids (e.g. cortisone and dexamethasone) have no or very little mineralocorticoid activity.
Cortisol is particularly relevant in pathological instances – it has relatively little mineralocorticoid activity, but in excess this can become noticeable – however it will also cause significant glucocorticoid issues!
Without mineralocorticoids, potassium concentration in the extracellular fluid rises rapidly, sodium and chloride are rapidly lost from the body, as is a lot of fluid. The individual will develop diminished cardiac output, and will enter a shock like state, before death occurs, if no treatment is administered.
 

Effects of aldosterone

  • Aldosterone causes increased absorption of sodium, and increased secretion of potassium by the renal tubules. Therefore, in the extracellular fluid, aldosterone causes an increase in sodium and a decrease in potassium levels.
  • Conversely, a lack of aldosterone can result in high extracellular potassium levels and low sodium levels.
  • Despite these effects, the actual amount of sodium retained is very small, and thus excess sodium retention is rarely an issue. However, the sodium retention causes secondary fluid retention and thus increases arterial pressure significantly. It also causes a sensation of thirst.
  • Any excess fluid and sodium will then be removed by normal kidney function – due to pressure diuresis. This method of maintaining normal fluid and salt levels despite high levels of aldosterone is known as the aldosterone escape. Once this level is reached, the level amount of salt and water gain by the body is zero. However, by this stage, the individual will be in a state of hypertension.
  • Excess aldosterone will cause hypokalaemia which will lead to muscle weakness as a result of altered cell permeability. It also leads to alkalosis; because aldosterone causes retention of sodium – and this occurs by two mechanisms. The first (already discussed) is where potassium is exchanged for sodium in the renal tubules, but another mechanism involves the exchange of sodium for hydrogen, thus resulting in mild alkalosis. Lack of aldosterone can lead to cardiac failure as a result of high potassium levels.
  • Aldosterone also has effect on the GIt and on sweat glands.
  • Sweating – normally, we secrete sodium chloride, potassium and bicarbonate in our sweat. The bicarbonate and potassium tend to be subsequently lost, but the sodium chloride can be re-absorbed along the sweat gland. In the presence of aldosterone, this process is enhanced.
  • GIt – aldosterone enhances the absorption of sodium from the diet. This effect mainly occurs in the colon. Without aldosterone, this sort of sodium absorption can be poor. This also means that fewer chloride ions and less water is absorbed, which can in turn cause diarrhoea, exaggerating the effect.
 

Mechanism of action

This mechanism is described for tubular cells:
Aldosterone is lipid soluble, and thus it will diffuse into the cell. From here, it binds to a specific receptor in the cytoplasm, that transports it to the nucleus, where it alters RNA transcription, causing the production of extra sodium channels. Thus, the effect of aldosterone on sodium retention is not immediate – it takes about 45 minutes after a cell receives aldosterone for sodium retention to increase.
 
The two most important factors in regulation of aldosterone secretion are:
  • Potassium ion concentration
  • Renin-angiotensin system
Sodium ion concentration and ACTH also regulate secretion but to a much lesser extent.
 

Glucocorticoids

The main endogenous glucocorticoid is cortisol (aka hydrocortisone). This account for over 95% of glucocorticoid activity. Corticosterone is the other main endogenous glucocorticoid. All other glucocorticoids that you come across are probably synthetic!!
The main effect of glucocorticoids is to stimulate gluconeogenesis!! (production of glucose of carbohydrate and protein in the liver). They can increases this process up to 10x. This extra glucose is then stored as glycogen in the liver and muscle cells. Some of it also ends up being released into the blood, and combine this with decreased utilization of glucose by cells, you end up with an increase in circulating glucose.  This is sometimes referred to as adrenal diabetes. The unusual conditions present with adrenal diabetes reduce the cells sensitivity to insulin, and thus carbohydrate metabolism is affected by glucocorticoids. The reason why insulin sensitivity is affected is unclear, but one theory suggests that high levels of fatty acids in the blood (mobilised by the increase in gluconeogenesis) impair the effect of insulin.
 

Mechanism

These products enter cells passively via diffusion, and will then bind with cytoplasmic receptors, causing a conformational changes in the receptor, which exposes a DNA binding site. This new complex will then migrate to the nucleus, and bind to a receptor and will cause a change in gene transcription.
About 1% of genes can be regulated in this fashion.
As well as their DNA effects, glucocorticoids cause transduction effects one they have bound to their ligand, but are still floating around in the cytoplasm. The effects caused through this pathway are thought to be those involved in the anti-inflammatory property of steroids.
An activated glucocorticoid receptor will cause release of the protein annexin-1 which has potent effects on the movement of leukocytes.
 
The effects on inflammation happen very quickly (within minutes) as opposed to the effects on DNA transcription which occur over a much longer time frame.
 

Metabolic actions

  • Carbohydrates – Glucocorticoids cause a decrease in the utilization of circulating glucose (mechanism unknown – thought o involve modification of enzymes involved with glucose breakdown within a cell), and an increase in gluconeogenesis. This leads to a tendency for hyperglycaemia. There is also an increase in glucose storage, which is probably a result of increased secreted insulin as a response to the hyperglycaemia.
  • Proteins – causes increased catabolism and decreased anabolism – i.e. they cause an overall increase in ‘metabolism’ – breakdown of products to release energy, but a decrease in ‘growth’. Overall there is an increase in protein breakdown, and a decrease in protein synthesis – which can lead to muscle ‘wasting’. However, there is an increase in synthesis of liver proteins. This effect is thought to result from an enhanced transport of amino acid into liver cells (whereas with most other cells, amino acid transport into cells in decreased – but catabolism carries on as normal, and thus over time, proteins are removed from peripheral cells).
  • Fats –Initially it causes mobilisation of fat from adipose tissue into the blood, allowing their utilisation for energy needs. This effect probably results from reduced glucose transport into adipose cells, thus they think that glucose levels are low, and so they release fats.
  • Later, it has an effect on lypolitic hormones, and causes a redistribution of fat, like that seen in Cushing’s syndrome (e.g. Moon face and buffalo hump). This peculiar type of obesity results from the deposition of fat on the torso and around the head.
  • Electrolytes – glucocorticoids tend to reduce the amount of calcium in the body by reducing its uptake from the GIt, and increasing its excretion by the kidneys. This can induce osteoporosis. Glucocorticoids are also likely to cause sodium retention and potassium loss.
Basically, all these effects involve a conservation of glucose, at the cost of other mechanisms.
 

Regulatory actions

Hypothalamus and anterior pituitary – causes a feedback effect resulting in reduced release of endogenous glucocorticoids
Cardiovascular system – reduced vasodilation and decreased fluid exudation (oozing)
Musculoskeletal system – decreased osteoblast, and decreased osteoclast activity
Inflammation and immunity

  • Acute inflammation – decreased influx and activity of leukocytes
  • Chronic inflammation – decreased activity of mononuclear cells, decreased angiogenesis (development of new blood vessels)
  • Lymphoid tissues – decreased action of B and T cells, and decreased release of inflammatory mediators by T cells.
  • Decreased production of cytokines
  • Decreased expression of COX-2 and thus decreased prostaglandin synthesis
  • Decreased generation of nitric oxide
  • Decreased histamine release from basophils
  • Decreased production of IgG     
  • Decreased complement components in the blood
  • Increased anti-inflammatory factors such as IL-10 and annexin-1
  • Overall, this results in decreased immune response – both to acquired auto-immune problems, but also to the protective role of the immune system.
 

Cortisol and stress

Stress will cause a rapid (within minutes) secretion of ACTH, which results in a rapid secretion of cortisol. Types of ‘stress’ that induce this include:
  • Trauma
  • Infection
  • Extreme temperature
  • Surgery
  • Almost any debilitating disease!
  • Environmental / social factors – feeling ‘stressed’!

However, it is not always certain why cortisol and its effects are useful in stressful situations. The most obvious thing is that glucose is made available for utilisation, although its actual utilisation is slowed and impeded. Also it is thought that the proteins released in catabolism can, in the very short term, be used by cells to create proteins that are essential to life (such as in the case of trauma). This is possible due to the fact that the most important proteins in a cell are affected last by cortisol – i.e. the ones you need to least are the ones that are broken down first.

 

Anti-inflammatory effects

When tissues are damaged (such as in situations that may lead to stress), then inflammation almost always results, however, cortisol will counteract this effect.
Cortisol will not only block inflammation from occurring, but it will also reduce inflammation once it has begun. The mechanisms by which this occurs are as follows:
  1. Stabilisation of lysosomal membranes – this makes it much more difficult for membranes of lysosomes to rupture, and thus the inflammatory proteins often released in the first stages of inflammation are much less likely to be released.
  2. Decreased capillary permeability – this is probably secondary to the first effect.
  3. Decreased migration and activity of white blood cells – this is a result of reduced release of inflammatory proteins.
  4. General immune system suppression – especially that of T cells. This reduces inflammation, due to the inflammatory actions of T cells on affected areas.
  5. Reduction of fever – this is mainly a result of reduced secretion of IL-1 from white blood cells. The reduced temperature will also reduce the amount of vasodilation, and thus reduce oedema.
The resolution of inflammation is also affected by these factors, but also probably results from the other mechanisms of cortisol – such as mobilisation of fat, glucose and protein reserves – which allows for rapid healing.
It is also important to remember that this increase in the inflammatory reaction, and general suppression of the immune system makes a person more vulnerable to pathogens. A continued administration of steroids can lead to atrophy of lymphoid tissue. This can ultimately lead to death from diseases that would otherwise not normally be fatal.
One final effect is that cortisol increases the number of RBC’s. Conversely a lack of cortisol can result in anaemia.
 

Regulation of secretion

Corticotrophic-releasing hormone is released by the hypothalamus in response to circadian rhythm, stress and other stimuli. This then travels down the portal system, and stimulates the release of ACTH from the anterior pituitary.
As well as the pattern shown above, secretion of ACTH also follows a circadian rhythm – levels are highest in the morning and lowest in the late evening.
ACTh is produced from a massive molecule, that when cleaved produces other active products, such as endorphins and melanocytre stimulating hormone are also released. This massive precursor molecule is known as POMC. Under normal conditions, the levels of these other products are too low to have any noticeable effect, however, in diseases that affect ACTH secretion, such as Addison’s disease, then other POMC products may also be produced in abundance, and exhibit physiological effects. In particular, melanocyte stimulating hormone will produce a darker skin colour, particularly in those individuals with naturally darker skin to begin with. 
 

Glucocorticoids as treatments

Common synthetic examples include; prednisolone and dexamethasone.
These can be given orally, IV, or by enema.
They are often used to obtain a remission phase of a disease, but usually cannot be used to maintain this phase.
They have many side effects, and this is the main reason why they are not used long-term to maintain the remission. Steroids are very effective at what they do, but the side effects can be nasty.
 
They are produced naturally by the body in small amounts, and are synthesised as required by the pituitary gland in response to circulating ACTH levels. They are released in a definite circadian rhythm, with the highest levels of secretion in the morning, that gradually reduce throughout the day, until the very low levels at night.
 
Glucocorticoids are the ‘Holy grail’ of treating inflammation. They act on both the late and early stage reactions – and thus are effective in chronic inflammation. They will reverse virtually any type of inflammation, whatever the cause.
They are also useful after graft surgery – because they can suppress the response against the ‘foreign’ tissue.
It is interesting to note that natural levels of glucocorticoids actually rise when our immune system is more active. It is thought this occurs to prevent our immune system from ‘getting out of control’ and threatening homeostasis. Cortisone is a glucocorticoid – its levels have been shown to be high when we are stressed – thus reducing the immune response in times of stress. Note that cortisone and prednisone are inactive until they are converted into hydrocortisone and prednisolone in vivo.
Corticosteroids are inactive in the liver and elsewhere in the body.
 

Unwanted effects

These are most likely to occur with large and/or prolonged doses.
  • Poor wound healing
  • Peptic ulceration
  • Cushing’s syndromewhich is basically a manifestation of all the metabolic and systemic effects described above.
  • Diabetes – as a result of the hyperglycaemia
  • Weakness and muscle wasting
  • Stunted growth in children – particularly if the treatment is continued for more than 6 months – even if the dose is low.
  • CNS effects – often the patient may experience euphoris, but it can also manifest as depression. In depressed patients, the depression may be due to a disruption of the circadian rhythm secretion of the steroids.
  • Oral thrush (candidasis) often occurs when the drugs are taken orally, as a result of suppression of local inflammatory processes.
 
Sudden withdrawal after treatment can result in adrenal insufficiency as a result of the patient’s inability to synthesis corticosteroids. Phased withdrawal patterns should always be followed.
 

Pharmacokinetics

Corticosteroids can be taken by pretty much any route imaginable! Usually, when they are not given orally, this is to avoid systemic effects.
When systemic therapy is necessary, taking the drug on alternate days has been shown to reduce the risk of side effects.
 
Endogenous corticosteroids are carried in the blood by corticosteroid-binding globulin (CBG) and albumin. About 77% is carried by CBG. However, when the drug is administered, much of it travels unbound. Bound steroids are inactive – so I guess this means the binding, in normal circumstances – acts as a storage and buffer system.
 
Hydrocortisone has a half life on 90 minutes, but its effects are present for 2-8 hours after administration.

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