Physiology of adrenal hormones

This chapter is related to Section U1(vi) from the 2017 CICM Primary Syllabus, which asks the exam candidate to  "describe the control, secretions and functions of renal and adrenal hormones". Without trying to be lazy, and only out of mild interest in the SEO-destroying effects of duplicate content, the author needs to point out that much of this material has had to be scattered across Deranged Physiology because it would have been more logical to have it positioned there. For example, the chapter on the endocrine functions of the kidney coveres all things related to the functions of renal hormones, as that is a whole separate syllabus item (Section H1(iv), "outline the endocrine functions of the kidney"). The chapter on the humoral regulation of blood volume and flow covers much of the content concerning the regulation and end-organ effects of adrenal hormones like aldosterone and the catecholamines. Catecholamine receptors and their many clinical effects are discussed in the pages dealing with the autonomic nervous system, and the steroids and catecholamines themselves are important enough to have whole monographs dedicated to them alone.

What's left for this page, then? The remaining aspects left uncovered are the functional anatomy of the adrenal glands, their physiological behaviour (i.e. how they synthesise, store and secrete their hormones) and most of the regulatory influences on their function are not really discussed anywhere else. Plus it was probably worthwhile to bring all the material together in one spot. Thus:

In terms of peer-reviewed resources, one good find was Considine (2003), a chapter from an obsolete 2003 physiology textbook which is mentioned here because it is actually pretty good, and because it is somehow available for free (though if the reader is resorting to reading textbook chapters, as a well-resourced member of the medical fraternity they may instead prefer to pay for modern editions of the actual official college-recommended books). For the reader who requires a lot of detail, Young & Landsberg (2010) can be recommended for adrenal medullary physiology, and 

Functional anatomy of the adrenal gland

Anatomy of the adrenal gland

Grossly, these are small pyramidal organs in the retroperitoneum weighing about 6 grams each. You have two of them; each of your kidneys wears one as a hat. The reader looking for a more professional description of their anatomy would be satisfied with this excellent paper by Avisse et al (2000), and Dobbie & Symington (1964) specifically for the vascular supply. For the CICM trainee, the following series of crude approximations will probably suffice:

• Surface landmarks: Epigastrium, opposite the 11th intercostal end of the vertebral space and the 12th rib 
• Basic structural anatomy: small (50 × 30 × 10 mm) irregular shaped yellowish glands:
  • Right adrenal is pyramidal in shape
  • Left adrenal is wedge-shaped or crescentic
• Relations: 
  • Right adrenal:
    • Lies between the inferior vena cava and the right crus of the diaphragm
    • Right border projects to the right of the vena cava
    • Inferiorly, bordered by the right kidney
    • Superiorly, in contact with the bare area of the liver
    • Medially, near the right inferior phrenic vessels
    • Lower half has a peritoneal covering (hepatorenal pouch, greater sac) - the rest does not
  • Left adrenal:
    • Over the medial border of the left kidney and its hilum
    • Anteriorly, lower pole is covered by the body of the pancreas and the splenic artery
    • Upper pole is covered with peritoneum of the lesser sac and forms part of the stomach bed
    • Superiorly, lies on the left crus of the diaphragm with the left inferior phrenic artery adjacent
    • Inferiorly, 
    • Medially, borders the coeliac ganglion and is overlapped by the left gastric vessels
    • Posteriorly, covers the left greater splanchnic nerve.
  • Separated from the thalamus by the the hypothalamic sulcus of Monro
  • Anterior limits: Lamina terminalis
  • Superior limits: inferolateral wall of the 3rd ventricle
  • Posteriorly,limited by the periaqueductal gray substance and tegmentum of the brainstem
  • Inferiorly, connected to the pituitary by the infundibulum (hypophyseal stalk)
  • Laterally, surrounded by the basal ganglia
• Blood supply: 
  • Multiple arteries supply each adrenal gland:
    • inferior phrenic artery
    • renal arteries
    • branches of the abdominal aorta
• Venous drainage:
  • Drained by a single vein:
    • Right adrenal vein enters the IVC directly
    • Left adrenal vein drains into the left renal vein
• Innervation: 
  • Myelinated preganglionic fibres from splanchnic nerve plexuses (aortic and renal), directly innervating the adrenal medulla
  • Also adrenal blood vessels receive normal postganglionic sympathetic innervation
• Function:
  • Secretion of catecholamines (medulla), corticosteroids (cortex) and androgens (also cortex)

Fine structure of the adrenal glands

It would be fair to say that, like the pancreas, each adrenal gland is really two distinct glands co-located in one organ. The cortex and the medulla are quite separate, in the sense that they develop from different embryonic precursors and perform totally different roles:

Adrenal stratum	Secreted hormone product
Cortex: Zona glomerulosa	Aldosterone
Cortex: Zona fasciculata	Cortisol
Cortex: Zona reticularis	Androgens
Medulla	Catecholamines

These layers are well separated morphologically, such that the untrained eye can easily see their boundaries on the cut surface of a fresh specimen:

Well, those are not exactly fresh, as they were fixed in buffered formalin by Iizuka et al (2015), but the reader should be able to derive from this image the correct impression that different adrenal gland cell populations are organised in distinct layers and are clearly separate from each other. Instead of producing a pink-and-purple histological section, the best way to remind the revising exam candidate about this concept is probably with this sort of hand-drawn diagram, such as this one from the 1984 Illustrated Encyclopedia of Human Histology by Radivoj V. Krstić:

The arterial supply of each gland is highly variable but generally consists of several feeding vessels. These tend to penetrate from the capsule in, and each gland has a single draining vein in its centre.  There are also penetrating vessels which bypass arterial blood though the cortex to directly feed the medulla. The logic behind this from-the-outside-in traffic of blood seems to be the paracrine influence of cortical hormonal products on medullary function: it appears that corticosteroids stimulate the biosynthesis of catecholamines by increasing the activity of phenylethanolamine N-methyltransferase, a unique enzyme which converts noradrenaline to adrenaline.

Unimaginatively, we settled on "adrenal", "medulla" and "cortex" to name these structures, even after Bartolomeo Eustachi named them Glandlulae Renibus Incumbentes. That, reader, is the sort of nomenclature that belongs in the papal library - you can almost see the dust on the embossed gold lettering. Unfortunately the discussion of the newly described glands fell in the middle of the challenging period known as the era of anatomici contentiosi, a period of the sixteenth century that was characterised by vicious verbal duels between warring anatomists, during which nobody could agree on anything (and as the result for about two hundred years everybody was for some reason convinced that these organs were hollow). Only after these professors and their students had died or retired were we able to make some progress, finally arriving at modern terminology with Nagel in 1836.

The adrenal medulla

This inner portion of each gland is basically a weaponised sympathetic ganglion. It is composed of chromaffin cells, which are described as "neuroendocrine" to account for the fact that they are neural tissue that secretes systemically available hormones. These really are nerve endings, but the venous blood is their synaptic cleft. They receive innervation from the preganglionic neurons of the sympathetic nervous system, and respond to the release of acetylcholine. Diaz-Flores et al (2008) describe their histological characteristics with a lot more detail than could possibly be required from the CICM trainee. In summary:

• Chromaffin cells derive from the neural crest, i.e. the same tissue as peripheral and autonomic nerves.
• They resemble nerves, in the sense that they are excitable, synapsed with other nerves (preganglionic sympathetic fibres), and secrete neurotransmitter molecules. In fact the very first synaptic junction described in electron microscopy literature was the splanchnicoadrenomedullary synapse (by Coupland, in 1965)
• These are large (20 μm) polygonal cells, and their cytoplasm contains the species-defining chromaffin granules, which are small (~0.2 μm) electron-dense inclusion bodies scattered throughout the cell:
  
• They are referred to as "chromaffin" because they stain brown when fixed with chrome salts. This is distinct from the chromophil cells of the pituitary, which are so called because they love all kinds of pigment, and stain readily into different colours. Chromaffin cells were first named by Alfred Kohn who noted that they stain green with ferric chloride and brown with chromium salts, a reaction they have directly with the adrenaline and noradrenaline in the granules (Carmichael & Winkler, 1985).
• Chromaffin granules are protein-rich subcellular organelles that contain the secretory and synthetic apparatus for making catecholamines, and they appear to have catecholamine specificity, i.e. some granules are clearly specialised to produce noradrenaline and stain differently to the other granules which produce adrenaline. This separates the population of chromaffin cells into adrenergic and noradrenergic.
• Normally, about 20% of the chromaffin cells are noradrenergic, and the rest are adrenergic.

These cells have excitable neuron-like properties, and if they are properly motivated with the right kind of neurotrophic growth factors they can actually differentiate into morphologically normal neurons (with dendrites and everything). They are not exactly myelinated, but they do surround themselves with a retinue of "sustentacular cells", which are a relative of the Schwann cell and which seem to perform Schwann-like roles. Surrounding clusters of adrenergic and noradrenergic chromaffin cells is a highly vascular connective tissue that is organised into loose collagen baskets, penetrated with medullary capillaries. Like all the blood in the adrenal glands, these drainage vessels all collect into a single draining vein which carries catecholamine-rich blood back into the central circulation. The adrenal vein is therefore exposed to truly monstrous concentrations of catecholamines, which suggests that it must be completely unresponsive to their effects. Whether it lacks receptors is not reported in the literature, but it does have some peculiar anatomical features: for example, there is no circumferential smooth muscle here (it's all longitudinal), which means it is probably incapable of vasoconstriction.

The adrenal cortex

This is the area that secretes steroid hormones, putting the "cort" into  "corticosteroids" and "glucocorticoids". It is completely distinct from the adrenal medulla embryologically: this tissue arises from the intermediate mesoderm, the origins of the kidneys and the reproductive system. The cortex takes up about 85% of the total mass of the gland, and of that whole, the vast majority is occupied by the zona fasciculata, which is responsible for the synthesis of corticosteroids.

The cells here are arranged in cords or columns. They are rich in mitochondria and endoplasmic reticulum, and well supplied with blood. All zones use cholesterol as a substrate, so there is plenty of it around, which makes the cortex fatty and yellow (whereas the medulla is reddy-brown). Here, in an image from kumc.edu, the lipid droplets in the zona fasciculata cells of a mouse adrenal gland can be plainly seen.

The cholesterol in these droplets is acquired from the bloodstream LDL by endocytosis, where both the lipid molecules and their carrier lipoprotein (apoprotein B100) are captured and internalised by the adrenal cortical cells. It remains in these vesicles as esterified cholesterol (bound to a fatty acid), which is the way you would normally store cholesterol inside cells (for example this is the same thing that happens inside foam cells of atheromae). The main reason for the esterification is that free cholesterol is actually a rather toxic chemical; it is rather fond of lipid structures, and tends to get in the way by forming rafts and crystals in cell membranes, thereby interfering with the traffic of other molecules and the function of embedded proteins. You can liberate some free cholesterol at any time by the action of cholesterol ester hydrolase, which is what happens on demand, whenever the synthesis of more steroids is called for.

Apart from these features the adrenal cortex is an unsexy layer of tissue; it has nothing especially interesting about it, and no critical care trainee will ever be asked a detailed question about its fine structure. The mechanisms of hormone synthesis are really where the money is, in terms of marks and questions. 

Synthesis and storage of adrenal hormones

From the CICM exam perspective, the catecholamine synthesis pathway is probably more important than the steroid pathway, mainly because it has attractive connections to anihypertesives and Parkinson disease drugs. On the other hand, the biosynthesis of steroids is not something the intensivist is ever expected to manipulate, and is therefore unlikely to ever appear in an exam question.

Synthesis and storage of catecholamines

Synthesis of catecholamine molecules is described in some detail elsewhere. Briefly, it consists of the following steps:

• Tyrosine, a non-essential amino acid, is the precursor molecule that gets taken up into the adrenal medullary cells. 
• Tyrosine hydroxylase then catalyses the synthesis of L-dihydroxyphenylalanine (DOPA, which was scubaed into dopa),  and this seems to be the rate-limiting step for catecholamine synthesis. 
• Dopa is then decarboxylated into dopamine by dopa decarboxylase, the enzyme targeted by anti-Parkinsons drugs, and also the one that uses vitamin B6 as a cofactor (which is where isoniazid interferes with it, causing seizures and lactic acidosis)
• Dopamine is metabolised into noradrenaline by dopamine β-hydroxylase, which is expressed throughout the central and peripheral nervous system
• Noradrenaline is converted into adrenaline by phenylethanolamine N-methyltransferase, which is an enzyme only really found in the adrenal medulla (as other sympathetic nerve endings do not secrete any adrenaline). For this reason, an adrenal phaeochromocytoma will secrete adrenaline, whereas a paraganglioma (arising from other sympathetic tissues) will typically secrete only noradrenaline. 

In case a picture is still worth a thousand words in this economy, here's a visual version of the same catecholamine biosynthesis pathway:

This tends to mainly occur in the rough endoplasmic reticulum of the chromaffin cells, and it finishes the final stages in the granules themselves. The reactions described above are probably rather important from the perspective of answering exam questions,  but the rest of the heavily industrialised process of making chromaffin granules probably is not. Still, here it is:

• Formation:
  • Catecholamine prohormones are synthesised in the rough endoplasmic reticulum of the chromaffin cells
  • These are transferred to the Golgi apparatus and aggregate together with chromogranins, which are soluble proteins that aggregate under the influence of pH and calcium changes.
  • Those proteins are then re-sorted, and any non-secretory proteins are extracted
  • The granules then undergo various maturation steps which further concentrate their contents and acidify it. The acidification is essential, as the low pH environment increases the water solubility of the catecholamines, causing them to become trapped in the granules. This is identical to the process of trapping catecholamines in the acidic presynaptic vesicles of the sympathetic neurons. 
• Traffic:
  • Mature chromaffin granules are stored in two compartments, with one group "docked" to the cell membrane, ready for release.
  • The reserve pool is not ready for exocytosis but can be recruited. 
• Exocytosis:
  • With an appropriate signal, the chromaffin granules fuse with the external cell membrane and release their contents. They don't have to release their entire contents, however, and some is often held in reserve. Under low-intensity stimulation, the membrane pore that opens between the granule and the outside world may be quite small - perhaps 4nm, according to Diaz-Flores et al (2008). Only a few noradrenaline molecules would sneak through.
  • What gets released is not only pure catecholamine molecules, but a whole mess of granule content, something Winkler et al (1997) referred to as the "secretory cocktail". The ingredients include obviously adrenaline and noradrenaline, but also chromogranins A and B, secretogranin II, enkephalin precursors, as well as various random neuropeptides, ATP and calcium. 
• Recapture and endocytosis
  • Granules which have emptied to some extent are recycled and returned to the Golgi apparatus for repackaging and enrichment with catecholamines.

None of this is especially relevant for the casual reader, and it is hoped that the small font and the neutral grey of the blockquote has made it easier to skip that section. The bottom line is that these granules generally only release a very small fraction of their content. This means the adrenal medulla is a rich source of catecholamine molecules, which remains largely untapped during normal daily life, and the rate of secretion from this organ can scale massively as required. For example, in haemorrhagic shock or other major physiological stress, adrenaline secretion can suddenly increase by over sixty times. 

In case anyone ever needs to know this for any reason, the normal secretion rate of adrenaline is said to be about 150 μg per day (Feher, 2012), which ends up being about 6-7 μg/hr, or 6-7ml/hr of the standard 6mg/100ml dilution. Working from the finding that (according to Langemann, 1951) the adrenal medulla is approximately 10% catecholamines by weight, and taking that the medulla occupies about 15% of a normal 6g gland, and there are two medullas, one comes to the conclusion that an average adult's adrenal medulla tissue contains a total of about 180mg of raw catecholamine, of which about 80% is probably adrenaline.

Synthesis of steroid hormones in the adrenal cortex

Unlike the catecholamines, steroid hormones are not stored in any meaningful sense. Minimal stored cortisol exists in the zona fasciculata because the cells there tend to make it on demand, rather than storing it for quickly triggered release.  They are fortunately well supplied from whole warehouses of esterified cholesterol, which means that on-demand biosynthesis can launch immediately without being rate-limited by long supply lines. 

Four CYP enzymes and cholesterol ester hydrolase are the key players involved in making corticosteroids from cholesterol. It would seem pointless to explain each individual step, considering especially that vast fields of text wave at the reader from professional endocrine literature. Instead of trying to recreate the diligence of authors like Payne & Hales (2004),  it would be better to leave the reference here for the interested reader, and link to a molecular pathway flowchart from Rhoades & Tanner (2003) without intruding it into the flow of text. The important features can be oversimplified into this list of bullet points:

• The synthesis of steroids requires adrenal mitochondria, which contain many of the enzymes required to start and finish the process. 
• The precursor for all these steroids is pregnenolone, which is the direct product of cholesterol. 
• The cells of the different zones of the cortex perform different molecular manipulations of this precursor: 
  • Zona glomerulosa lacks a key enzyme (17α-hydroxylase) and is therefore unable to make androgens or cortisol, so it ends up making aldosterone
  • Zona fasciculata and zona reticularis can both make androgens and cortisol, but lack aldosterone synthase, and so cannot make aldosterone.
  • Adrenal androgen synthesis is relatively unimportant in the male, as the main androgen product of the adrenal glands (dehydroepiandrosterone) is weaker than what the testes manufacture. On the other hand, in the female, these adrenal glands are a major source of androgens.

Release and regulation of adrenal hormones

You could summarise this entire section with the words "stress response", and this would be at least partially accurate. To borrow a turn of phrase from an excellent 1954 lecture by Marthe Vogt, the adrenal gland has a large share in maintaining the constancy of the "milieu interieur", and is an important lever your body can pull to defend itself from "stress", loosely defined as any perturbation of the homeostatic setpoints for vital signs and electrolytes. Specifically, adrenal hormone secretion is stimulated strongly by haemodynamic stress such as hypovolemia, low cardiac output, or anything else that stimulates the activity of renin and angiotensin. Angiotensin II acts as a potent independent stimulator of cortisol catecholamine and aldosterone release, and all of those end up released by other independent mechanisms as well. 

Release and regulation of catecholamines

To cut a long story short, the main stimulus for the release of catecholamines from the adrenal medulla is the direct stimulation of chromaffin cells by the preganglionic sympathetic nerve endings:

• Acetylcholine is released from the preganglionic synapse
• The chromaffin cells have nicotinic acetylcholine receptors
• Activating these nicotinic receptors leads to the depolarisation of the chromaffin cells (remember that these are an excitable tissue)
• This depolarisation leads to an increase in intracellular calcium
• Intracellular calcium influx leads to the membrane fusion of granules and exocytosis of granule content, much as it would lead to the release of noradrenaline from synaptic vesicles if these chromaffin cells were normal sympathetic neurons.

Those sympathetic nerve endings are in turn stimulated by any generic factor that might activate the sympathetic nervous system centrally, ranging from hypotension to psychological distress. Apart from this (single most important) stimulus factor, catecholamine release can be stimulated by ACTH, histamine, angiotensin II, VIP, neuropeptide Y, enkephalins, substance P,  and many others. 

Release and regulation of cortisol

ACTH is the main regulatory influence on the release of cortisol. It is a large peptide released from the pituitary under the influence of multiple factors, including:

• Hypothalamic CRH release
• Circadian cycle
• Glucocorticoid feedback to the hypothalamus and pituitary
• Angiotensin-II
• Vasopressin
• Catecholamines
• Descending neural pathways from the cortex

Basically, if it is a signal sent during a stress response, it will probably stimulate the release of ACTH. Then:

• ACTH binds to its receptor, which G_s-protein-coupled
• This stimulates the production of cAMP
• cAMP stimulates both the enzymes required for steroidogenesis, and the enzymes required to retrieve and de-esterify the stored cholesterol in the cortical cells

Additionally, several different cytokines (IL-1, IL-6, TNF) neuropeptides and catecholamines can all influence the rate of cortisol synthesis and the responsiveness of adrenal cortical cells. 

This sounds like a laborious process (to make a bunch of steroid molecules from raw materials) but is in fact quite rapid because all the enzymes and reagents are immediately available in the cells, i.e. no genetic transcription is required at any stage. As anyone who has ever performed a short synacthen test will know, a sizeable increase in cortisol should be expected within the first 30 minutes. 

Cortisol secretion in response to this sort of stimulation is graded, in the sense that more stimulation leads to more cortisol, but only up to a point. When Dorin et al  (2012) pumped ACTH into their healthy volunteers, they found the cortisol response began to plateau at a certain maximum stimulatory ACTH concentration. It is generally said that the maximum daily cortisol output is about 300mg. It is possible that this maximum is insufficient for stressors of truly life-threatening proportions (in fact it would be logical to expect that they wouldn't be), which has given rise to the concept of "relative adrenal insufficiency".

Release and regulation of aldosterone

Aldosterone secretion and feedback control are already well covered in the section on the humoral regulation of blood volume, and it would be pointless to reproduce all that material here. A summary such as this will suffice:

• Stimulus: hypovolemia, sodium depletion, hyperkalemia
• Sensor:  zona glomerulosa cells of the adrenal cortex
• Afferent: RAAS (via angiotensin), pituitary (via ACTH) and directly (potassium)
• Efferent: aldosterone secretion and binding to widespread intracellular receptors
• Effectors: Numerous targets, but mainly vessel smooth muscle and renal tubule
• Effect: vasoconstriction, salt and water retention, potassium excretion

It would be fair to say that the activity of aldosterone and cortisol are peripherally related, as they are both required to manage the sort of stress that an intensivist would find recognisable (for example, shock, hypovolemia, electrolyte derangement, etc). Some of the same stimuli affect the release of both hormones, and aldosterone and cortisol have a certain amount of overlap in their affinity for each other's receptors (in fact the mineralocorticoid receptor has the same affinity for both). However under normal physiological conditions neither are secreted in enough concentration to make themselves a major influence on the receptor system of the other. 

Now that we are on the topic of receptors:

Receptors for adrenal hormone ligands

Because of how central catecholamines and steroids are to critical care medicine, long-form discussions of their mechanisms and functions exist all over this site. These are pleiotropic hormones, their effects are beyond counting, and it would make no sense to list them all again on this page, as it would be a pointless duplication. At the same time, it would also be pointless to list only some of their effects, but not others (because how do you choose which ones?) So: only the molecular mechanisms and second messenger systems will be mentioned here.

Catecholamine receptor physiology

The behaviour of catecholamines at the synapse and the effects of catecholamine receptor activation are discussed elsewhere.

• Catecholamine receptors are G-protein coupled
• α-1 receptors are G_q-protein coupled
  • Their activation increases the ionised calcium content of the cell via the activity of IP₃ as the secondary messenger
• α-2 receptors are G_i-protein coupled
  • Their activation inactivates adenylyl cyclase, which means they reduce the availability of cyclic AMP, and have a generally inhibitory effect.
  • Their clinical effects are
• β receptors are G_s-protein coupled 
  • Their activation increases the synthesis of cAMP. The increased cAMP leads to, among other things, increased availability of intracellular calcium, which means increased contractility and heart rate. 

Glucocorticoid and mineralocorticoid receptor physiology

The physiological effects of activating corticosteroid receptors are discussed elsewhere. The cellular mechanisms involved are complex, and best discussed by experts, such as Oakley & Cidowski (2013) or Nicolaides et al (2020). A quick oversimplification of their work would probably still be a

The glucocorticoid and mineralocorticoid receptors are very similar structurally: both are large proteins with four main functional regions, belonging to the nuclear receptor superfamily of ligand-dependent transcription factors. Both receptors seem to have arisen from the same ancestral gene; they split from some kind of ancient omni-receptor very early in the evolution of the vertebrates, apparently about 450 million years ago (Baker, 2019). Lampreys and hagfish have a single common ancestral corticoid receptor, but teleosts and gnasthosomes (sharks, etc) have distinct steroid receptors for their glucocorticoids and mineralocorticoids. These receptors remain very similar structurally and are strongly conserved from an evolutionary standpoint, probably because their activity is so critical for survival. For example, the disruption of glucocorticoid receptor signalling in knockout mouse models results in death shortly after birth, mainly due to the failure of lung maturation but also with numerous other developmental catastrophes (for example, the congenital absence of an adrenal medulla).

The glucocorticoid receptor has affinity for only glucocorticoids, whereas the mineralocorticoid receptor has equal affinity for glucocorticoids and mineralocorticoids, but is usually co-located with the 11β-HSD2 enzyme which converts cortisol to inactive cortisone, decreasing its mineralocorticoid effect. This co-location is pretty normal for the nuclear transcription factor receptors - they generally tend to hang around surrounded by a posse of chaperone proteins. Upon binding their ligand, steroid receptors are freed from this retinue, and undergo a conformational change that exposes localisation sequences and results in their translocation to the nucleus. These receptors are of course capable of much more than that; it appears that they can sit in the membrane and influence second messenger signalling, or they can lurk in the cytosol, influencing protein function.

In the nucleus the steroid-receptor complex activate numerous transcription mechanisms, leading to the modulation of protein synthesis activity (up or down, depending on the "chromatin landscape", i.e. what binding sites are available). After performing its duties the activated receptor is degraded by the ubiquitin-proteasome pathway, which stops the steroid activity by clearing it from the nucleus. This nuclear process - binding the ligand, localisation, transfer to the nucleus through nuclear pores, activation of transcription machinery, transciprion and protein synthesis (or its suppression), etc - takes time (let's say, hours), and accounts for the delay seen with many of the effects of corticosteroids.

Apart from this genomic/transcriptional effect, steroids have more immediate nongenomic effects (Song & Buttgereit, 2006):

• By altering cell membrane properties, which occurs over the timeframe of seconds, and which may be responsible for some of the immediate effects of steroids on immune cell metabolism
• By binding to membrane-bound receptors,. which may be responsible for lymphocyte and neutrophil apoptosis due to high dose glucocorticoids
• By rapidly interaction with intracellular signalling pathways through cytosolic steroid receptors, which may be responsible for some of the anti-inflammatory effects, for example where arachidonic acid metabolite production is suppressed