Well, it’s been a busy week. Wednesday saw me at the Royal Institution taking my 13-year-old daughter to a Maths Masterclass, where we learnt about vectors, followed by a wander through Green and St James Parks and then an hour in the National Gallery; Thursday I was at the Wellcome Collection for one of the Exchanges at the Frontier series with Brian Greene; and then on Friday evening it was back to the Royal Institution for the Friday Evening Discourse Rhythms of the Body.
These are traditionally formal events, so I was uncomfortably attired in evening dress, but the quality of the speaker soon made me forget that I was not in my usual sloppy clothing. It wasn’t a subject that I am particularly interested in, but the delight of the lectures at the Ri is the variety of the subjects: and the enthusiasm of the lecturer usually makes for interested audiences.
The discourse was given by Stafford Lightman, Professor of Medicine at the University of Bristol, and Director of the Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, the subject was the hormonal hypothalamic-pituitary-adrenal axis, but to start us off he discussed rhythmic physiological processes, which was the subject of an earlier Ri FED, Seasons of Life (I was stuffed into evening dress for that, too).
Starting with the magicicada (13-17-year cycle); the green sea turtle (male annual, female 2-4 years); red-tailed godwit (11000km migration each year); sheep (short day breeder); ringtailed lemur (long day breeder); oysters (and women) under a tidal/lunar monthly cycle; into daily cycles – heliotrope, nitrogen fixation in cyanobacteria; to the general day/night cycles in humans: core body temperature, melatonin, urine volume, growth hormone, prolactin, heart rate, liver metabolism, and cortisol, to name but a few. These cycles can be affected by jet lag, working shift hours, or stress.
But this discourse was about ultradian rhythms – ones which are more rapid than daily. It has been khown that there is a circadian rhythm in the production of cortisol in the body, with a maximum in the morning, and the level showing a roughly bell-shaped curve with the minimum at night; recent research has shown that there is a much faster ultradian rhythm of pulses which summate to give the circadian rhythm. It’s a negative feedback cycle, causing an oscillation, although the mean is normal.
The paraventricular nucleus of the hypothalamus produces CRH; this then causes the pituitary gland to produce adrenocorticotropic hormone (ACTH); ACTH causes the adrenal gland to produce glucocorticoids (mainly cortisol [CORT]); the glucocorticoids then suppress the production of CRH and ACTH.
The mechanism works like this: CORT enters the cell, binds to receptors in the cytoplasm, then is carried into the nucleus where it binds to the DNA for two seconds or so, and which then sends out messenger RNA to whichever organ it’s aimed at.
CORT can’t be stored, so it is only available in the body in spikes of production, and it’s been shown that this is vitally important for many body functions: CORT is very soluble in fat, so can get anywhere in the body.
If rats are given a pulsatile infusion of cortical their brain activation is normal: they respond to stress and then return to normal; if they are given a flat infusion they don’t respond to stress and behave like a depressed rat.
CORT is immensely important for well-being. There are cortisol receptors in the hippocampus which are used in memory function, for example, but an abnormal pattern of cortisol can be implicated in an awful lot of conditions: eating disorders; hives; acne; acid reflux disease; diarrhoea/constipation; depression; chronic fatigue; sleep deprivation; hypotension; migraines; sleep apnoea; abnormal memory function; and diabetes (although all these conditions have multiple causality). CORT pulsatility affects these body systems: musculoskeletal; respiratory; cardiovascular; endocrine; gastrointestinal; and reproductive.
There are also changes in CORT pulsatility with age: episodic secretion of CORT decreases with age, to very flat levels in the aged; this may go some way to explaining some of the problems of ageing.
The hope is that there therapies may be produced that takes account of this pulsing: an example already found is that in Addison’s Disease patients feel much better if they’re given their medication in pulses; an idea for the future is that if cancer medication is given in the right pattern lower doses can be used, which will give less side effects and a lower likelihood of resistance developing; another is that in asthma and rheumatoid arthritis the symptoms are worse in the morning but the first steroids are given when the patient has woken up rather than before waking. If the drugs can be administered chronologically then it may be possible to give lower doses.
The cortisol abnormality seems to be implicated in many conditions: in the severely depressed there is often abnormal CORT levels, and when the depression improves so does the CORT levels; and abnormally high CORT levels changes synaptic function, and so may have a relationship with Alzheimer’s Disease.
One of the last questions in the Q&A was about exercise and cortisol levels. Apparently exercise has a major affect on CORT levels, it causes higher levels but without the bad side effects; and regular exercise causes the body to produce an anticipatory surge of cortisol before the exercise.
A fascinating discourse about some very important science: let’s hope the research funding doesn’t dry up.