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24 hour profiles

THE VALUE OF 24 HOUR PROFILES IN CONGENITAL ADRENAL Kathy Geertsma and Peter Hindmarsh

Having participated in discussions on several message boards regarding what I have
learnt through my son having 24 hour profiles, many people have contacted me with
questions. This prompted me to ask his Professor, Peter Hindmarsh of Great
Ormond Street Hospital, London, to explain the benefits of having a full 24 hour
profile. As parents, we hate to see our children having blood tests. Yet, from the
knowledge we have gained from these, it really seems that the minor discomfort of
having a profile, far outweigh the problems and upset that can be caused by both
over-treatment and under-treatment, (especially weight/growth issues). Although my
son has always had blood tests and blood spot profiles, it was not until we changed
to Professor Hindmarsh did he have a full 24 hour profile done. It was only when
studying these results were we able to really discover how his body handles the
different steroids and adjust his medication.
The data showed that my son’s body metabolises hydrocortisone quickly and he was
often without any cortisol which caused him tiredness and headaches. In previous
years he had never had his cortisol levels checked, only his 17OHP. Based on this
17OHP result, his previous specialist kept increasing his hydrocortisone dose, which
caused weight gain. What my son really needed and the 24 hour profile showed, was
smaller, more regular doses throughout the day. Dosing four times a day can be
considered a nuisance. However having seen the difference, as many parents have,
especially those who follow the circadian rhythm dosing with early morning doses, it
is well worth the effort in achieving optimal control allowing good health, growth and
less weight problems.
In this article we think through the biology behind profiles and consider how they are
undertaken. We look at how to analyse them and point out problems that can arise
when samples are taken too far apart. The article is lengthy so take it in chunks.
Some of it you may know already, so skip those bits if you want.
ASSESSING HYDROCORTISONE REPLACEMENT IN CONGENITAL
ADRENAL HYPERPLASIA

Cortisol is the hormone that is not produced in people with CAH. In children it is replaced using hydrocortisone which is a synthetic form of cortisol. When we replace with hydrocortisone we try to mimic the way in which the body normally produces cortisol. Cortisol is made by the adrenal gland and the levels in the blood vary during the day. This is called the Circadian Rhythm of cortisol. Values are high in the morning and early afternoon and low in the evening. You might like to think of cortisol therefore as a get up and go hormone. The graph below (Fig.1) shows the cortisol levels during a 24 hour period in a person without CAH. rtis
o 300

08:0009:0010:0011:0012:0013:0014:0015:0016:0017:0018:0019:0020:0021:0022:0023:0000:0001:0002:0003:0004:0005:0006:0007:00
Clock Time

Fig.1

This diagram tells us that cortisol levels vary during the day and is a useful reference
when we start to think about treating children and young people with hydrocortisone.

WHAT DOES CORTISOL DO?

The quick answer is lots. It is important for many things the body does such as
maintaining blood pressure and blood glucose levels. This is one of the reasons why
we worry when people become ill and cannot take their hydrocortisone as blood
glucose levels can go low. Cortisol is also important for helping fight infections and
mobilising the body to deal with stress.

SO WHAT IS HYDROCORTISONE?

Hydrocortisone is a synthetic form of cortisol. There are other similar drugs such as
prednisolone and dexamethasone. Prednisolone and dexamethasone differ
structurally from hydrocortisone and last longer in the blood: – prednisolone for 6-8
hours, dexamethasone 12 hours.
You might think the longer the better but this is not simply the case as prednisolone
and dexamethasone have a tendency to suppress growth which is why we use
hydrocortisone in children. A further advantage is that we can measure hydrocortisone in the blood but not prednisolone or dexamethasone As prednisolone and dexamethasone are far more potent than hydrocortisone their use should be avoided in children because of the risk of growth suppression and weight gain. The table below (Fig.2) shows the equivalent doses for these two glucocorticoids against hydrocortisone: Duration
Mineralocorticoid
of Action Action
Suppressing
on Effect
The figures in the table show us that compared to hydrocortisone, prednisolone and dexamethasone are 5 and 80 times more likely on a dose for dose basis to suppress growth. Note also that the duration of action and peak of action for the steroids differ. Dexamethasone does not peak in its action like the other two steroids, and so is likely to give a more constant exposure over time than the up and down profile of hydrocortisone and prednisolone. It is also important to consider the impact of 9α-fludrocortisone which is used as a replacement of Aldosterone in salt-losers. Fludrocortisone has not only mineralocorticoid but also potent glucocorticoid activity (a bit like dexamethasone) as shown in the table and it is important to remember this when calculating the total daily glucocorticoid dosing: i.e. the contribution of 9α-fludrocortisone needs to be included in the total.

WHAT HAPPENS WHEN YOU TAKE A HYDROCORTISONE TABLET?

Hydrocortisone is absorbed very quickly from the gut. In fact the absorption is very
efficient and nearly 100% is absorbed. If we measure cortisol in the blood after
taking hydrocortisone then it looks like this: (Fig.3)
Hydrocortisone Over 6 hours
CORTISOL
mnol/ls

l/L
o
m 400

00:00 00:20 00:40 01:00 01:20 01:40 02:00 02:20 02:40 03:00 03:20 03:40 04:00 04:20 04:40 05:00 05:20 05:40 06:00
Time Minutes/Hours
Fig.3

This shows that it takes about 1-2 hours for hydrocortisone to reach a peak and
about 6 hours before the dose wears off.

HOW DO HYDROCORTISONE AND 17OHP INTERACT?

In people without CAH there is no real interaction between cortisol and 17OHP
because 17OHP levels are low compared to cortisol. Remember the pathway of how
cortisol is produced from cholesterol? It looks like this: (Fig.4)
ACTH (from Pituitary Gland)

CHOLESTEROL

17-OH Progesterone

21-hydroxylase

11-deoxycortisol

Cortisol

Fig.4


Remember that the block is in making cortisol, so you get an increase in ACTH to
compensate, which raises 17OHP as it is before the block.
SO HOW DO CORTISOL AND 17OHP RELATE TO EACH OTHER?

This gets a bit technical but bear with us.
As you can see in the hydrocortisone profile the cortisol peaks around 1-2 hours after
a dose. But because the cortisol has to tell ACTH to dampen down, this takes a bit of
time before we see a change in ACTH and a bit more time as the adrenal gland
switches off the production of 17OHP.
This switch off takes about 1 hour after the peak of cortisol.

WHAT ARE WE TRYING TO DO WITH PROFILES?

With a 24 hour profile you test not only the 17OHP but the cortisol at two hourly
intervals during the night and early morning. This allows us to answer three
questions:
Is the CAH under control – the 17OHP measure Am I having too much hydrocortisone – the cortisol measure Am I having too little hydrocortisone – how long does the hydrocortisone last The 24 hour profile would not normally be achievable in out-patients and therefore an admission would be required. BUT CAN WE GET THIS INFORMATION FROM BLOOD SPOT TESTS?
The blood spots show a ‘snap shot picture’ of only the 17OHP at that moment. They are very valuable to do because at that time, just before the dose, if the 17OHP is too high, you know that you either need more hydrocortisone or take it more frequently and if the 17OHP were too low the dose may need reducing but by how much? This method does not show the peaks after the cortisol is taken and the troughs as the cortisol is metabolised and therefore does not give a full picture of what is happening between doses. What you would need to do here is to carefully time samples pre and about 3 hours post dose to get a feel for the effect of hydrocortisone. Unless the samples are taken with respect to dosing then it is very hard to interpret and results can be misleading. SO HOW DO YOU MAKE A PROFILE?
You need an intravenous cannula that is put in under local anaesthetic cream so that lots of small samples can be taken every 2 hours. If the cannula is working well, there is no pain and even if the patient is upset it doesn't really affect the 17OHP, so you get more accurate readings. You measure cortisol and 17OHP but you can also measure lots of other things (hormones) on the same sample such as ACTH, androstenedione and measures of how well the testes or ovaries are working and at times that you would not normally be able to achieve in out-patients, i.e. early morning when the ACTH starts to rise. It may seem that a lot of samples are taken but in reality the amount of blood is not excessive – about an egg-cup full. It is important to realise that if you take too few samples and/or do not relate them to the dose then you may get falsely reassuring information. This is particularly relevant in ‘one off’ blood tests; it is essential to know the cortisol value, 17OHP and the time the tablet was taken as without considering all this vital information you could get false information suggesting poor control because you hit an odd occasion when 17OHP is high or too low. A common example of this is a sample taken, or blood spot done pre breakfast when the hydrocortisone given at 22.00 hours the previous evening is out of the system by the next morning causing the 17OHP value to be high, however after the morning dose, the 17OHP comes down within range again as the cortisol rises. An example of this can be seen in the graph below (Fig.5) 24 Hour Profile (20 minute samples)

Fig.5

Here you can see the high 17OHP in the morning which settles once the
hydrocortisone tablet is taken first thing after waking. Notice the effect of the evening
dose which has high peak at 22.00h but notice the 17OHP was low anyway.
However, when you want the hydrocortisone to suppress the 17OHP, early hours of
the morning (04.00h onwards) the hydrocortisone is wearing off. This tells you that
the best way to deal with the problem is to have the hydrocortisone as late as
possible the previous evening and preferably about 01.00 - 02.00h!!
WHAT INFORMATION DO YOU GET?
We have an actual patient plot here of cortisol and 17OHP in the graph below (Fig.6) This person has hydrocortisone at 08.00 h, 15.00 h and 22.00h. You can see the height of the cortisol peaks and judge if too high or too low. This is important as hydrocortisone peaks two hours after taking it, so a sample taken at this time, will show how high the cortisol peaks:- a). If the peak is too high, this will over suppress the 17OHP which will then drop too low. This would show the dose is too high and could be lowered (evening plot in yellow). If the cortisol is too low, the 17OHP will be higher than it should be so the dose needs to be increased (morning at 06.00h) Cortisol
l/L
o
n
m
P 300

H
O
7
1
d
n 200

rtis
o
C 100

Time (hours)
Fig.6

Then by studying the graph as a whole, you would see how long the cortisol is lasting
in the system, which can be used to establish the best time to take doses.
1. Fast metabolism: in this scenario the cortisol would clear the system very quickly and although you would achieve a high peak of cortisol, it would rapidly fall and therefore not suppress the 17OHP sufficiently. What would then occur is a peak of 17OHP and a dip of cortisol way before the next dose of hydrocortisone is due to be taken. Almost like the situation at 15.00h in the graph. This could mean that in order to gain better control, smaller doses taken more frequently would be better suited. 2. Slow metabolism: in this scenario, the cortisol remains in the system for a longer period of time and therefore doses can be taken less frequently.
Blood Tests and Blood Spots

Let’s just think again on those single blood tests or tests taken at infrequent time
intervals. We are using a different set of data now from another patient.
If a one off blood test was taken just after 12.00h in clinic and we plot the result on a
graph, (Fig.7) this is the information we would get.
One off blood test in clinic
17OHP nmol/l
04:00 06:00 08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:00 02:00 04:00

Fig.7

You would say based on this 17 OHP result that we are doing well and no changes
are required. However we have no idea of the exact time the tablet was taken in
relation to the dose, it might have been taken earlier or later than usual, we have no
idea of the cortisol level, and no idea what is happening the rest of the day to the 17
OHP or cortisol.

BLOOD SPOTS

These certainly let us do more tests. If we plot the results of pre-dose blood spots in
the chart below, (Fig.8) this is the information we would get from the data which does
not show the peaks and troughs of 17OHP or the cortisol. If we were to join these
dots we do not see a true picture of what is happening to the 17 OHP.
Pre-dose Blood Spots
17OHP nmol/l
l/L
o
m
n 200

The problem with this is that it is not possible to be sure what needs to be changed. Increasing the evening dose will not help the 22.00h 17OHP as it is low anyway and is unlikely to make much difference to the early morning sample as the time course of hydrocortisone is such that the system will not be suppressed much after 03.00h. The afternoon result says maybe alright. What is not clear is how this is achieved. Is the hydrocortisone dose just right or perhaps too high? Is the timing of the doses alright as they could easily have run out of hydrocortisone earlier and about to escape from control? Remember what we said about 17OHP not changing much until about 1 hour or so after a cortisol is high. However if we add the cortisol results to this as in the chart below, (Fig.9) you will see that this patient is experiencing high peaks of cortisol, however the cortisol is not lasting until the next dose. This is often apparent when children feel tired or get headaches at lunchtime. The 17OHP looks fine but it is the cortisol that matters at this point from the symptoms standpoint. This is why a full profile would be informative, as the balance between control (17OHP) and over/under treatment (cortisol) can be determined. Blood spots with cortisol profile
17OHP nmol/l
Cortisol
Fig.9

In the graph below (Fig.10) when we add the full 17 OHP results from this profile we
can see the following:
1. There are periods where the cortisol is dropping too low pre dose and is not lasting until the next dose is due to be taken, even though the 17 OHP level is within range. The symptoms a patient could suffer as previously described, are tiredness and headaches. 2. There are periods where the cortisol levels peak too high which causes the 17 OHP levels to drop too low. This could lead to weight gain and other side effects you get with over treatment. Add in the full 17 OHP results
The results of both the 17 OHP blood sample taken in clinic, and the afternoon and evening pre-dose 17 OHP blood spots, show good control. The early morning, pre-dose 17 OHP blood spot would show an out of range 17 OHP result, however there is a great difference of opinion on what the optimal 17 OHP level at this time should be. If the early morning dose was increased based on this, it would only give an
even higher morning cortisol peak and cause the 17 OHP level to drop even lower,
but the 17 OHP would rise again as soon the cortisol drops well before the next dose
is due. This would increase the side effects. If the evening dose was increased you
would get the same scenario. Studying the graph above this patient’s medication
could be fine tuned by changing the timing of the doses and giving 4 smaller doses a
day.

WHY GET CORTISOL RIGHT?
The main things to avoid are over and under treatment. Over treatment leads to
weight gain, high blood pressure and potentially high blood glucose levels. In
addition over time high cortisol leads to poor bone strength.
Under treatment not only means that the CAH goes out of control so that androgen
levels increase but it leaves the person at risk of low blood glucose concentrations
particularly during times of illness
OUR CONCLUSIONS

After looking at lots of these types of profiles and checking out what our changes
have done for people we have come up with the following thoughts:
1. In trying to achieve optimal control, it is important to consider the high peaks and low drops of cortisol. When studying all the data that a full 24 hour profile provides, the hydrocortisone dose and timing can be manipulated/adjusted to avoid excessive peaks and troughs of both 17OHP and cortisol levels, therefore causing less side effects. 2. Often these profiles will show that better control is gained by having smaller doses taken more frequently throughout the 24 hour period, which also ensures the patient is not cortisol deficient due to the relatively short half life of hydrocortisone. The data obtained from a 24 hour profile allows fine tuning of the dose in congenital adrenal hyperplasia.

Source: http://congenitaladrenalhyperplasia.org/Final_24_Hour_Profile_Article.pdf

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