Cushing’s is a weird, scary, complicated disease and as such it can be tough to get your head around it. I thought I’d have a go at an easy to understand, basic guide to try and help those going through this or just curious about it. It’s based around my own experiences and research but I have not gone through every test or procedure so some information might be less useful than others. I am not a medical professional by any means and medical science is constantly being updated so please take this article with a pinch of salt. It is to give a rough overview only and not to replace medical advice given to you by your own medical professionals.
What is Cushing’s?
The most basic definition of Cushing’s is a high amount of cortisol or steroids within your body. The scientific name is hypercortisolism. This excess cortisol can come from either an internal source, usually a tumour, or an external source, such as taking steroids for another condition. This stops your HPA (hypothalamic-pituitary-adrenal) axis working correctly. Cushing’s is named after Harvey Cushing, the neurosurgeon who was the first one to describe Cushing’s disease. It’s a very rare disease, only affecting 1-2 people in a million each year. I won’t address symptoms here as they can be very individual and none of them are required for a Cushing’s diagnosis. I have included a diagram with some of the more common ones though.
How does a healthy HPA axis work?
In a healthy person the hypothalamus (part of your brain) secretes a hormone called CRH (corticotropin-releasing hormone) which tells your pituitary gland (just under the brain) to secrete ACTH (adrenocorticotrophic hormone) which in turn tells your adrenal glands (just on top of your kidneys) to secrete cortisol. When you have enough cortisol, the cortisol itself feeds back into the pituitary gland to tell it no more is needed and CRH and ACTH production is switched off. When your levels drop too low the cycle starts again. This axis gets disrupted with Cushing’s as tumours don’t listen to these commands and just do what they want. If it’s caused by taking steroids your own axis is often suppressed as your body is seeing you as having plenty of cortisol all the time and therefore stops bothering to produce any.
A normal cortisol level is higher in the morning to help us wake up. It then slowly drops throughout the day, spiking again slightly at noon, though not as high as it did to wake us, and is low overnight to let us sleep. Production starts up again around 4am to help us reach the high waking level.
There are a lot of different terms that get thrown around for Cushing’s. What do they all mean?
Cushing’s Syndrome – technically, all Cushing’s is Cushing’s Syndrome. This is the umbrella term for Cushing’s/hypercortisolism. However there are a lot of subcategories and alternative names as listed below.
Cushing’s Disease – this is specifically Cushing’s caused by a pituitary tumour. The tumours are usually benign, meaning not cancerous themselves, but the effects of excess cortisol are every bit as devastating as cancer.
Endogenous Cushing’s – this is a term used to mean the source of the excess steroids is coming from within the body.
Exogenous Cushing’s – the source of the excess steroids is outside of the body, in other words you’re taking steroids for another condition.
Ectopic Cushing’s – a rare form of a rare condition, this is Cushing’s caused by a tumour not in the adrenals or pituitary. The most common place is in the lung and these tumours can be cancerous.
Iatragenic Cushing’s – another way of saying exogenous, caused by taking steroids for another condition.
ACTH Dependant Cushing’s – this means your ACTH is also high. It usually indicates a pituitary tumour, but can rarely be an ectopic tumour (see above).
ACTH Independant Cushing’s – your ACTH is normal or possibly even low. This would indicate an adrenal tumour or would also be if you are taking steroids for other conditions.
Pseudo Cushing’s – an exceptionally rare type of Cushing’s, this is where the patient will get Cushing’s syndrome from other conditions, for example extreme alcoholism or severe depression.
Cyclical Cushing’s – many medical professionals aren’t very aware of this. It’s a form of Cushing’s where the symptoms come and go. There is no obvious timeframe to the cycle, it doesn’t seem to follow the menstrual cycle and differs between individuals. Some have reported only weeks between cycles, others as much as years! Often, someone who gets Cushing’s for a second time apparently get’s it starting up as cyclical. My personal theory is that cyclical is the tumour starting to wake up but not working full time yet; perhaps we all start out as cyclical but so mildly we don’t realise we’re ill until we’re past the cyclical phase.
Adenoma – this is what the tumours are often called. Pituitary adenoma, adrenal adenoma, it means a benign tumour. You will also see incidental adenoma which means a tumour that isn’t secreting.
ACTH – Adrenocorticotrophic hormone. This is produced by your pituitary gland to stimulate your adrenals to make cortisol.
CRH – corticotrophin-releasing hormone. This is produced by your hypothalamus to stimulate your pituitary gland to make ACTH.
No one test can rule Cushing’s in or out. You need many different tests running and multiple highs as performing surgery can lead to further complications such as full hormone replacement that may not have been necessary.
Early morning blood serum cortisol – ideally taken between 8am and 9am, as this is when it should be highest naturally. However it can sometimes appear normal in someone with Cushing’s but then not drop throughout the rest of the day, so this can’t be used on its own to rule out Cushing’s. Mine, for example, was always above the normal range though so probably could have been used to diagnose on its own, provided I had multiple high samples.
Early morning blood serum ACTH – the same idea as above. This one must be done at a hospital as ACTH degrades quickly and must be put on ice immediately. It’s not always done at this stage as it indicates the source of Cushing’s more than whether you have Cushing’s or not, but is easily done at the same time as the above test.
24 hour urinary free cortisol – this is a fun test that involves you collecting all your urine for 24 hours in a jug. In theory, a healthy body only ever creates cortisol when it is required, so there should be no excess in your urine. In reality, no body is perfect so there will usually be a little excess. However this should still be minimal so this is often considered a gold standard test for high levels. 2 or 3 tests should be done, not just 1.
Midnight saliva cortisol – not one I ever had the pleasure of doing. Cortisol should be low over night, particularly around midnight and in your saliva, so this is one test that can be done to catch a high. It consists of chewing on a swab at midnight. It seems to be one that is used quite commonly when checking for cyclical Cushing’s, I assume because it’s a relatively easy test to carry out for multiple days or weeks at home.
Dexamethasone Suppression Test (Dex test) – there are two forms of this, the low and the high versions. The differences are the amount of dexamethasone taken I believe. I’ve only done the low dose version. Check out this video for a good explanation. This test shouldn’t really be used as a diagnostic test, but more to look for the source of your Cushing’s, as many people have suppressed on this test but gone on to have Cushing’s. Dexamethasone is a steroid that is very similar to cortisol. The idea is that you take the tablet at midnight, when your natural cortisol levels are low. When your HPA axis starts to gear up for the morning cortisol levels, it will see the dexamethasone in your blood and think it doesn’t need to make any cortisol. However, once again, a tumour would not listen to this and would still be spitting out cortisol. You need to have a blood test taken around 8am or 9am following taking the tablet to see if your natural levels are low (suppressed) or not (unsuppressed).
Once a mixture of the above tests have been done, odds are you are now diagnosed with Cushing’s Syndrome but the source still needs to be discovered. As I mentioned, the dex test is more of a source finding one but is also used diagnostically to an extent. For me it was used as both, as I did not suppress and they took ACTH at the same time which indicated a pituitary tumour as it was high. The next steps may include the following scans or tests. The scans should not be done unless you have the biochemical evidence to prove you have Cushing’s; as previously mentioned a large percentage of the population have incidental tumours so simply seeing one on a scan will not prove you have Cushing’s or that the tumour is the source of your Cushing’s.
MRI Scan – if you have high ACTH, odds are you have a pituitary tumour. An MRI scan will be ordered of your pituitary to see if a tumour shows up. Many tumours do not show up on an MRI though as they are so small, around 30% don’t show. Also, even if one does show up, it doesn’t mean it is the source of your Cushing’s. Somewhere between 10% – 20% of the population have pituitary tumours but they’re not secreting anything. To increase chances of a tumour showing you should ideally have a specific MRI scan done on the pituitary (not a general brain scan), preferably on a 3T strength machine (gives a better picture than a 1.5T) and with dynamic contrast protocal (the contrast is slowly injected via IV whilst you’re still in the machine, rather than taking you out of the machine, injecting it, then putting you back in). This is because both the pituitary and the tumour light up on the MRI but the speed at which they light up is different, so by injecting the contrast whilst you’re still being scanned, the radiologist is more likely to be able to spot this difference.
CT Scan – this is usually to check for a tumour on your adrenals. I’ve not had one done for adrenals, only on my lungs, but it was fairly similar to an MRI scan from what I remember. Again, contrast is often used, although I’m not sure if it’s easier to see adrenal adenomas than pituitary ones.
CRH Test – the CRH test is used to see if it’s likely to be a pituitary tumour. I had to do one of these as my tumour didn’t show on MRI scans. I often refer to it as a less invasive IPSS as it’s the same principle but with only an arm cannula involved. It may also be used to ensure a tumour that has shown on an MRI is actually secreting. CRH is acquired and you need to go in for a few hours. A cannula will be put in your arm and a baseline blood sample taken for cortisol and ACTH. The CRH will then be injected and multiple vials are taken at very specific time intervals for a couple of hours, both cortisol and ACTH. It’s a tough one to find information about online so I’m not 100% certain on how the results are interpreted but it’s something to do with the rate at which your cortisol increases that will indicate if you have a pituitary tumour or not.
IPSS – the IPSS (Inferior Petrosal Sinus Sampling) is often the final test to find the source and for many people won’t be needed. My hospital, a centre of excellence for pituitary issues that deals with a relatively large number of Cushing’s patients, hadn’t done one for 6 months prior to when I had mine. I had to do this due to my MRI not showing a tumour but the CRH results ‘strongly suggesting’ it was a pituitary tumour. I believe there is a similar procedure for adrenals as well but I’m not sure what that’s called and think it’s used even more rarely. It is a day case procedure but does carry risks, including stroke, so it is not done unless required. It sounds far worse than it actually is. You will have a cannula put in your arm, as with the CRH test, but you will also need to have catheters snaked from your groin directly into the blood vessels next to your pituitary gland, one either side of it. Due to this it can also help to pinpoint which side of the gland a tumour is on. As with the CRH test, baseline blood cortisol and ACTH is taken then CRH is injected and again, specifically timed intervals to see how your levels do or don’t rise, from both the arm and the pituitary catheters.
Generally speaking, you’re never cured of Cushing’s. It’s like cancer in that it can always come back so we’re considered in remission. It is more likely to recur if it’s from a pituitary source; it’s much rarer for an adrenal patient to get it again unless all the tumour is not removed, which is less likely as they usually remove the entire adrenal gland. The exception to this is if you have a BLA as it’s almost impossible for it to come back then other than in very rare situations. Treatment will depend on the source of your Cushing’s.
Steroid induced Cushing’s – If your Cushing’s is due to taking steroids, the logical step is to stop taking them. However, odds are you need those steroids so you will either need to work with your medical team to find an alternative treatment or, if none are available, wean down to the lowest possible dose you can survive on and hope that’s low enough to get rid of the Cushing’s symptoms. Sometimes it may mean finding a fine balance between controlling the condition that requires steroids and minimising Cushing’s symptoms as much as possible.
Cortisol lowering medications – Prior to surgery you may be put on cortisol lowering medication. In the UK this is often Metyrapone. In the US it’s often Ketaconazole. These are rarely a long term solution and is used as a stop gap to slow down, stop or even reverse symptoms. Sometimes however they will need to be used for the long term, for example if the tumour is not possible to fully remove with surgery or if radiation hasn’t worked. It must be closely monitored to ensure your cortisol doesn’t drop too low and also to keep on top of your symptoms. Doses may need to be increased over time and eventually it may not be able to fully keep the Cushing’s under control.
Adrenal tumours – usually the gland that has the tumour on will be removed completely. This is called an adrenalectomy. They’re often performed as keyhole surgery where possible but may need to be done as open surgery. Your stomach needs to be pumped full of gas to enable the surgeon to operate successfully which can lead to pain and discomfort after the surgery until it dissipates.
Pituitary tumours – the tumour will be removed via transsphenoidal surgery and requires a very experienced surgeon to perform this surgery in order to damage as little of the gland as possible. This is a procedure that requires the surgeon to access the pituitary gland via the sinuses, usually through the nose but sometimes through a cut in the upper lip by the top teeth. It takes a very skilled surgeon to carry out this surgery and does risk disrupting other pituitary hormones. The surgeon will usually be a neurosurgeon but can sometimes have an ENT surgeon to guide them if there has been previous nasal surgery, or in a couple of centres in the UK (including where mine was done) the ENT surgeon will be the lead surgeon. As with any surgery it does carry risks and particularly as it’s so close to the brain but it’s a relatively easy one to recover from. Personally I only had a very mild headache for a few days after and as there’s no obvious entry wound, you don’t risk knocking it or opening it quite so much as a more conventional surgical site. The surgeon will try to remove all the tumour whilst leaving as much of the pituitary intact as possible.
Sometimes surgery isn’t possible. A pituitary tumour may be just too small, or too close to a major vein. In these cases there are radiation therapies available. The radiotherapies are all very targeted doses to the tumour and can take a few years to know if they have been successful. I don’t have experience of these myself so the information below has come from the experiences of some of my friends.
Linac (Linear Accelerator) Radiotherapy – the friend who had this had 25 doses over 5 weeks. Linac is considered low risk and has been proven to work; it has indeed worked for my friend who still has remaining tumour but it is dormant and her cortisol levels are slightly low but close to normal range.
Gamma Knife Radiotherapy – this is done with just one dose. You will have a frame screwed to your head to keep you still and ensure precision targeting.
Cyber Knife Radiotherapy – there are very few centres able to carry this out in the UK. This radiotherapy is carried out over a maximum of 5 treatments and is, like the previous radiation therapies, a very targeted therapy straight into the tumour. A mask is used on your head which is bolted to the bed to keep you still. For my friend it worked within a year and she was declared in remission. Following treatment she had a bad headache that one night and felt very unwell for 3 or 4 days after.
Ectopic tumours – these again require surgery at the site of the tumour and, if cancerous, probably the usual run of chemotherapy as well.
Bilateral Adrenalectomy (BLA) – When all other alternatives have been ruled out, or if a tumour persistently comes back, the final option is a bilateral adrenalectomy, or BLA. This is where both adrenal glands are removed. You are now considered cured of Cushing’s as you can no longer produce any cortisol yourself. There are however very rare circumstances where Cushing’s can recur, for example if you develop Nelson’s Syndrome.
Recovery from the surgery is like any other but from Cushing’s itself is not easy. You’ve often had years of cortisol destroying every cell in your body so it can take a long time to heal. I tend to liken it to getting a paper cut; it only takes a second to get the cut but it takes days to heal. With Cushing’s we’ve been getting ‘cut’ for years so it will take years to fully heal. Not only that but the withdrawal from cortisol is horrible. Your body gets used to having so much cortisol sloshing around that when you take that excess away you crash hard. It has often been likened to heroin withdrawal, it can be that painful and tough. But it’s important to remember that as hard as it is, you are slowly recovering and in the long run it’s worth it.
Following surgery you should be put on a cortisol replacement and monitored regularly. Due to the tumour constantly spitting out cortisol your own HPA axis will often have been disrupted and temporarily be unable to produce any itself. We need cortisol to live so this needs replacing until your body figures out how to do it again by itself. This is known as adrenal insufficiency. Some people never regain the ability to make their own cortisol and will remain steroid dependent for life.
Whilst adrenal insufficient you will need to take a regular, daily dose of a cortisol replacement. The most common is Hydrocortisone (HC) although there are others. These doses will usually be spread out across 2 or 3 times a day and the total amount will vary for every individual as HC only lasts between 4 – 6 hours in the body. You also need to be prepared to take extra doses if you come under stress; this doesn’t just mean work stress but includes being ill, losing someone, the excitement of getting married, having a surgical or dental procedure, or even stubbing your toe. If your cortisol drops extremely low you’re at risk of an adrenal crisis which can lead to multiple organ failures and death quite quickly, so everyone who is steroid dependent should also be given an emergency injection kit (or multiple) to keep on them at all times. This is a big booster dose, akin to a diabetic having an insulin injection.
Following surgery we should be monitored by our endocrinology teams. Tests can be run to see if we are producing our own cortisol. The most basic of these is an early morning blood test just like the one done for diagnosis, taken after not taking your replacements for part of the day before. Another common one is the Short Syncathen Test (SST) which tests the whole HPA axis by taking a baseline blood cortisol (again after withholding replacements usually), injecting you with syncathen (a synthetic ACTH) and then taking another cortisol reading after 30 minutes to see how your body has responded to the request for more cortisol.
If you’re found to be making enough cortisol on your own to come off replacements you should taper down slowly. Many endocrinologists think you just need to come off it quickly or even cold turkey. This can however still put you at risk of an adrenal crisis and will generally make you feel awful as you’re basically going through cortisol withdrawal again. Take your time and only drop by a small amount when you feel comfortable at the previous dose. You also need to continue carrying some replacements plus an emergency injection with you for up to 6 months or more after you come off the replacements as although you may be making enough for day to day life, your body may still not be able to produce enough in a sudden stressful situation. Once off the replacements you should still be monitored as there is the chance of the Cushing’s returning.
The Pituitary Foundation – despite the name they’re good for all things Cushing’s, including adrenal, and are a great source of information with booklets on the sick day rules, how to take your emergency injection, what to expect following surgery etc.
Cushing’s UK Facebook group – a closed group filled with knowledgeable and wonderful people. We are patients, not medical professionals, but our collective experience can help with understanding tests and results and it’s great for support from people going through the same things. We’re part of The Pituitary Foundation as well.
Addison’s Disease Self-Help Group – a charity with lots of information regarding Addison’s Disease and adrenal insufficiency in general.
UK Addison’s Disease & AI Facebook group – another closed group like the Cushing’s one for all people with some form of adrenal insufficiency. Again, they are not medical professionals but it is a collective group with lots of experience of being patients.
Cushing’s Resources – my previous post with various resources I’ve found useful.