Irreversible Effects of Previous Cortisol Excess on Cognitive Functions in Cushing’s Disease

10 04 2010

ResearchBlogging.orgApril 8th is Cushing’s Awareness Day. This day has been chosen as a day of awareness as it is the birthday of Dr. Harvey Cushing, a neurosurgeon, who discovered this illness.

Cushing’s disease is a rare hormone disease caused by prolonged exposure to high levels of the stress hormone cortisol in the blood, whereas Addison’s disease is caused by the opposite: the lack of cortisol. For more background information on both see this previous post. Ramona Bates MD, of Suture for a Living, has written an excellent review (in plain language) about Cushing’s Disease on occasion of Cushing Awareness Day at EmaxHealth.

From this you can learn that Cushing’s disease can be due to the patient taking cortisol-like glucocorticoids, such as prednisone for asthma (exogenous cause), but can also arise because people’s bodies make too much of cortisol itself.  This may be due to a tumor on the pituitary gland, the adrenal gland, or elsewhere in the body.

Symptoms of Cushing’s disease are related to the effects of high levels of cortisol or other glucocorticoids on the immune system, the metabolism and  the brain. Symptoms include rapid weight gain, particularly of the trunk and face (central obesity, “moon face” and buffalo neck), thinning of the skin and easy bruising, excessive hair growth, opportunistic infections, osteoporosis and high blood pressure.

Less emphasized than the clinical features are the often very disabling cognitive deficits and emotional symptoms that accompany Cushing’s disease. Cushing patients may suffer from various psychological disturbances, like insomnia, mood swings, depression and manic depression, and from cognitive decline. Several studies have shown that these glucocorticoid induced changes are accompanied by atrophy of the brain, and in particular of the  hippocampal region, leading to hippocampal volume loss and a profound loss of synapses [2]. This hippocampal loss seems reversible [2], but are neurological and psychological defects also restored? This is far more important to the patient than anatomic changes.

If we listen to Cushing patients, who are “cured” and have traded Cushing’s disease for Addison’s disease, we notice that they feel better after their high levels of cortisol have normalized, but not fully cured (see two examples of ex-Cushing patients with longlasting if not irreversible health) problems in my previous post here. [added 2010-04-17)
To realize how this affects daily life, I recommend to read the photo-blog 365 days with Cushing by Robin (also author of Survive the Journey). Quite a few of her posts deal with the continuous weakness (tag muscle atrophy), tiredness (tag fatigue), problems with (short-term) memory (see tag memory)  or both (like here and here).

Scientifically the question is to which extent ex-Cushing patients score worse than other healthy individuals or chronically ill people and, if so, whether this can be attributed to the previous high levels of glucocorticoids.

A recent study by endocrinologists (and one neurologists) from the Leiden University Medical Center assessed the cognitive functioning of patients  after long-term cure of their Cushing’s disease (caused by a ACTH producing pituitary adenoma, that induces overproduction of cortisol (hypercortisolism) by the adrenals [1]. Previous studies had contradictory outcomes and/or were too small to draw conclusions.

The authors first compared a group of 74 Cushing patients (with a previous pituitary tumor) with matched healthy controls (selected by the patients themselves). Matched means that these controls had the same characteristics as the Cushing patients with respect to gender (male/female: 13/61), age (52 yr) and education.
Cushing patients were on average 13 years in remission and were followed for another 3 years (total 16 yrs follow-up). Cushing’s disease  had been established by clinical signs and symptoms and by appropriate biochemical tests. All patients were treated by transsphenoidal surgery (surgery via the nostrils), if necessary followed by repeat surgery and/or radiotherapy (27%). Cure of Cushing’s disease was defined by normal overnight suppression of plasma cortisol levels after administration of dexamethasone and normal 24-h urinary excretion rates of cortisol. 58% of the patients had at least one form of hypopituitarism (deficiency of one or more hormones) and half of the patients needed hydrocortisone replacement therapy.

Long after their cure, 62% of the Cushing patients reported memory problems, and 47% reported problems in executive functioning. The Hospital Anxiety and Depression Scale (HADS)-score (10.5)  indicated no clinical depression or anxiety. Patients with long-term cure of Cushing’s disease did not perform worse on measures of global cognitive functioning. However, these patients had several other cognitive impairments, mainly in the memory domain.
Only a single test result (FAS, measures verbal mental flexibility and fluency) was significantly different between patients with short and long-term remission.

From direct comparison with healthy controls it is not clear what causes these cognitive alterations in Cushing patients.

Therefore the cognitive function of Cushing patients was compared to that of patients previously treated for non-functioning pituitary macroadenomas (NFMA).
NFMA patients were chosen, because they have undergone similar treatments (transsphenoidal surgery (100%), with repeat surgery and/or radiotherapy (44%) as the Cushing patients. They also shared hypopituitarism and the need for hydrocortisone substitution in half of the cases. NFMA patients, however, have never been exposed to prolonged excess of cortisol.

Cushing patients could not be directly compared to NFMA-patients, because these patient groups differed with regard to age and gender.

Thus Cushing patients were compared to matched healthy controls and NFMA to another set of healthy controls, matched to these NFMA patients (Male/Female: 30/24  and mean age: 61 yr).

To compare Cushing patients with NFMA patients the Z-scores* were calculated for each patient group in relation to their appropriate control group. A general linear model was used to compare the Z-scores.

Overall Cushing patients performed worse than NFMA patients. In the memory domain, patients cured from Cushing’s disease had a significantly lower MQ measured with the Wechsler Memory Scale compared with patients with NFMA in the subscales concentration and visual memory. On the Verbal Learning Test of Rey, patients cured from Cushing’s disease recalled fewer words in the imprinting, the immediate and delayed recall trials. Furthermore, on the Rey Complex Figure, patients with cured Cushing’s disease scored worse on both trials when compared with NFMA patients. In tests measuring executive function, patients cured from Cushing’s disease made fewer correct substitutions on the Letter-Digit Substitution Test and came up with fewer correct patterns on the Figure Fluency Test compared with treated NFMA patients.

These impairments were not merely related to pituitary disease in general and/or its treatment, because these patients with long-term cure of Cushing’s disease also revealed subtle impairments in cognitive function compared with patients previously treated for NFMA. These are most likely caused by the irreversible effects of previous glucocorticoid excess on the central nervous system (because this is the main difference between the two).

Sub-analysis indicated that hypopituitarism was associated with mildly impaired executive functioning** and hydrocortisone dependency** and additional radiotherapy were negatively associated with memory and executive functioning, whereas the duration of remission positively influenced memory and executive functioning.

The main point of criticism, apparently raised during the review process and discussed by the authors, is the presentation of the data without adjustments for multiple comparisons. When more than one test is used, the chance of finding at least one test statistically significant due to chance increases. As the authors point out, however, the positive significant results were not randomly distributed among the different variables. Furthermore, the findings are plausible given the irreversible effects of cortisol excess on the central nervous system in experimental animal and clinical studies.

Although not addressed in this study, similar cognitive impairments would be expected in patients having continuous overexposure to exogenous glucocorticosteroids, like prednison.

* Z-scores: The z score for an item, indicates how far and in what direction, that item deviates from its distribution’s mean, expressed in units of its distribution’s standard deviation. The z score transformation is especially useful when seeking to compare the relative standings of items from distributions with different means and/or different standard deviations (see:

** This makes me wonder whether Addison patients with panhypopituitarism have lower cognitive functions compared to healthy controls as well.

Hattip: Hersenschade door stresshormoon lijkt onomkeerbaar (2010/04/08/) (


  1. Tiemensma J, Kokshoorn NE, Biermasz NR, Keijser BJ, Wassenaar MJ, Middelkoop HA, Pereira AM, & Romijn JA (2010). Subtle Cognitive Impairments in Patients with Long-Term Cure of Cushing’s Disease. The Journal of clinical endocrinology and metabolism PMID: 20371667
  2. Patil CG, Lad SP, Katznelson L, & Laws ER Jr (2007). Brain atrophy and cognitive deficits in Cushing’s disease. Neurosurgical focus, 23 (3) PMID: 17961025 Freely available PDF, also published at Medscape

Invisible Chronic Illness: Addison’s Disease

17 08 2009

This week the Grand Round will be hosted by Invisible Illness Week, a blog dedicated to the National Invisible  Ilness Week, which runs September 14 -20, 2009. The purpose:

National Invisible Chronic Illness Awareness Week  (..) is a worldwide effort to bring together people who live with invisible chronic illness and those who love them. Organizations are encouraged to educate the general public, churches, healthcare professionals and government officials about the impact of living with a chronic illness that is not visually apparent.

The theme of the Grand Round is, not very surprisingly: Invisible chronic Illness.

I won’t write about this professionally -being a librarian-, but I will speak from my own experience.

As many of you know, I’ve the chronic illness Addison’s Disease. Not that I feel ill. It doesn’t affect me, really… Not anymore.. I think.

But many people with Addison’s disease suffer silently from this disease. And like many other diseases this disease is seldomly understood by partners, colleagues, friends ….. and doctors.

Before I explain more about Addison’s disease, first let me say that almost every disease is “invisible” to others. People can never fully understand what an illness means to someone suffering from it.

Ball-and-stick model of the cortisol (hydrocor...

Cortisol, Image via Wikipedia

Patients with Addison’s disease make no or too small amounts of cortisol, a hormone made by the adrenal cortex. Cortisol has a bad reputation as the stress hormone among many people. It doesn’t deserve this reputation as this hormone is vital to life. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior (Wikipedia)

Too much of this hormone causes Cushing’s disease, too little causes Addison’s disease. If you want to know what Cushing does to your body and mind, then please read the letter of Kate when she was first diagnosed with Cushing’s, at Robin’s “Survive the Journey”.

Here, I will confine myself to Addison’s disease. It is a very good example of an invisible yet serious disease.

There are 3 forms of Addison: primary (defect in the adrenal cortex itself, often also leading to a defect in aldosteron production), secondary Addison (by a defect in the hypophysis or hypothalamus) and iatrogenic Addison (caused by overtreatment with corticosteroids)

Here some reasons why the illness, although “invisible”, can have great impact on your live.

1. Diagnosis.

Diagnosis is often a challenge, especially in patients with primary Addison, most of whom look healthy because of their pigmented skin. Nowadays, the main cause of primary Addison’s disease is immune destruction of the adrenal cortex. This has often a slow onset and in 50% of the patients the diagnosis takes more than 2, sometimes even more than 10 years [1]. 38% of the patients even experience vague complaints, that can later be attributed to Addison, during 11->30 years before diagnosis [1].

Before the diagnosis is made, people with Addison’s Disease often feel extremely tired and miserable. Even when the disease fully manifests itself the symptoms are largely vague and aspecific. The most common symptoms are fatigue, dizziness, muscle weakness, weight loss, difficulty in standing up, vomiting, anxiety, diarrhea, headache, sweating, changes in mood and personality, and joint and muscle pains. Often the symptoms aren’t taken seriously (enough) or the illness is mistaken for anorexia or depression.

My secondary Addison was the consequence of an injury to the pituitary gland as result of heavy blood loss during complicated childbirth (see previous post). The week between the cause and the diagnosis of the disease, was the most terrible week of my life. I felt awful, weak, (well I lost >3 liters of blood to start with), couldn’t give breast milk (no prolactin), and I disgusted food so much, you can’t imagine. I couldn’t get anything down my throat, only the look of it made me vomit. And I felt so bad not being able to care for the baby, but I just couldn’t. I couldn’t even stand for more then a few minutes, couldn’t walk.  And then there was unstoppable diarrhea, dizzyness, and speaking with double tongue. And practically no one took it seriously, not the gynaecologists, not the nurses, not the paediatricians, nor my friends or family.

But this was only one week. How would it have been if it durated 5 or 10 years?

2. Grieve and adaptation.

Once the disease is diagnosed you have to learn to live with a body that has let you down (grieve) and you have to learn to become confident again (adapt). You also have to find a new balance. I’ve lost a few hormones overnight (ACTH, cortisol, thyroid hormone, growth hormone, prolactin, gonadotrope hormones) and believe me, it took me a few years to feel reasonable normal again. It is quite surprising how badly I was informed. Very little information about the risk of an Addisonian crises, the dosing of cortisol under various conditions.
It was also confronting how little people wanted to know about the disease or what I had been through. Visitors after the birth wanted me to be euphoric and didn’t want me to go into any detail of what had happened. They cut me short by saying: “But you have a lovely baby”. Somebody cried that she didn’t want to hear it. So I stopped trying to speak about it.

I took no sick leave, immediately went back to work. My boss – a nephrologist, never asked after my health, not once.

As I said it took a few years before my “come-back”. I didn’t feel myself. It was as if I couldn’t think, as if my head was filled with cottonwool. Afterwards I think the main reason for improval was the reduction of the cortisol from 30 mg to 12.5 per day and the use of DHEAs plus that I regained confidence in myself.

3. Comorbidity

With cortisol I lost some other hormones which are also essential. Patients with primary Addison often miss aldosteron as well, which makes them more liable for an Addisonian crisis. Primary Addisonians may also have other immune diseases, like autoimmune thyroid disease, gonadal failure, type 1 diabetes and vitiligo.

4. Addisonian crisis

An addisonian crisis is an emergency situation, with possible fatal outcome, associated mainly with an acute deficiency of the glucocorticoid cortisol. This occurs in (extremely) stressful situations. Some Addisonpatients are more prone to it than others. You can -and should – take precautions, like wearing alert bracelets or necklaces, so that emergency personnel can identify adrenal insufficiency and provide stress doses of steroids in the event of trauma, surgery, or hospitalization.

Some Addisonians fear these crises so much that they dear not walk or run alone. Many Addison patients don’t go to a country far away, some don’t even pass the border (and you know the Netherlands aren’t that big).

5. Addison’s disease can be treated but not cured.

Addison patients are treated with corticosteroids like hydrocortisone and are substituted with other hormones that they may lack. Without treatment, the disease is lethal, with treatment the disease is not cured. I do feel all right now, but many of my fellow patients don’t. I think that the following excerpt from a Seminar of Wiebke Arlt and Bruno Allolio about adrenal insufficiency [2] makes this very clear.

Despite adequate glucocorticoid and mineralocorticoid replacement, health-related quality of life is greatly impaired in patients with primary and secondary adrenal insufficiency. Predominant complaints are fatigue, lack of energy, depression, and anxiety. In addition, affected women frequently complain about impaired libido. In a survey of 91 individuals, 50% of patients with primary adrenal insufficiency considered themselves unfit to work and 30% needed household help. In another survey of 88 individuals the number of patients who received disablility pensions was two to three times higher than in the general population. The adverse effect of chronic adrenal insufficiency on health-related quality of life is comparable to that of congestive heart failure. However, fine-tuning of glucocorticoid replacement leaves only a narrow margin for improvement, and changes in timing or dose do not result in improved wellbeing.


  1. Zelissen PM. Addison patients in the Netherlands: medical report of the survey. The Hague: Dutch Addison Society, 1994.
  2. Wiebke Arlt, Bruno Allolio. Adrenal Insufficiency, Lancet 2003; 361: 1881–93 , full text on

Earlier posts on the subject:

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