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



24 responses

12 04 2010

This is a wonderful article. Thank you for mentioning my blogs. I do want to point out I am not cured. I was in remission after my pituitary tumor was removed, but Cushing’s is back full force now, 3+ years later. I did so much better during the remission. I am now considering options with the help of my endocrinologist, and am taking ketoconazole to lower cortisol in the interim.

Thanks for all you do. You have a wonderful blog.

12 04 2010

Robin told me about this wonderful article. Thanks so much for discussing Cushing’s and helping to get the word out there.

I’m a 20+ year post-op survivor of pituitary Cushing’s and some of the symptoms still linger on, some nearly as badly as before surgery. But I’m considered “cured” or, as they say now, “in remission”.

Thanks again for helping get the word out to the medical community!

8 10 2012

All the Cushings Sites I have come across have been very helpful but your comment is what I have been looking for. I haven’t been able to find much help or information from Cushing sufferers ‘cured’ or ‘in remission’. I had adrenal tumour surgery 4 years ago and after a year on cortisol meds, my remaining adrenal started functioning again. Approx 1 year after that, my blood tests were regularly within the normal limits and I was considered by my GP to be cured. I don’t feel cured. I feel I am going totally crazy, I have memory problems, suffer fatigue, confusion,depression cramps, and muscle and joint pain. Because my blood tests are within the normal range now, I am getting no help or support from my Doc or Husband or anyone. Is there a site with information Post Cushings?? I really need help and feel that Cushings is going to kill me now that I’m “cured”

28 11 2012

I could not agree more. Where do we find info and support? I am also so called cured, no production of cortisol though. Take cortison tablets three times a day. However, i feel terrible. Tired, no energy, headaches, depressed. I too feel i am going crazy. An no one understands. Help help help. I can not live like this!

28 11 2012

Cecillie, contact me at and I’ll put you in touch with support groups. We care!!

12 04 2010

Great article. This really help me understand why my mind seems to be slipping away, and maybe why I had such a hard time in school. I will repost this right away!

13 04 2010
Trying to Permanently Lose Weight? Don't Ignore the Toxic Nutritional Truth! | Dr. Mom Online

[…] Irreversible Effects of Previous Cortisol Excess on Cognitive Functions in Cushing’s Disease &… […]

18 04 2010
Pissed Off Patient

Thank you! This helps explain so much. I’ve dealt with Cushing’s and am dealing with as yet undiagnosed issues as well.

Thank you for talking about Cushing’s. I am still dealing with the aftereffects almost a decade later and mine was exogenous.

Actually today I have a post up about the first time, then tomorrow I will be posting about the second time.


18 04 2010

Thanks for your wonderful comments.

I do think it is important to spread the word about rare diseases like Cushing’s disease and the effects of chronic diseases on everyday life in general. Not only to reach other people so that they can understand us a little bit more, but also for us, patients. Studies like the one summarized above and experiences from fellow patients can help to make everything fall into place.

Dear Robin, I’ve changed the text a little bit. With respect to stories of cured Cushing patients I now refer to two examples of the after effects in exogenous and endogenous Cushing, mentioned in a previous post. I do think your experiences are still relevant to the so called “cured” patients. At least I see many similarities in some respects of everyday life.

11 05 2010
What One Short Night’s Sleep does to your Glucose Metabolism « Laika's MedLibLog

[…] by the PhD student Esther Donga. Esther belongs to the study group of Romijn who also studied the previously summarized effects of previous cortisol excess on cognitive functions in Cushing’s disease […]

5 09 2011
m dombrowski

Great artilce. Has there every been any studies on the effect of Cushings on children? I had the disease when I was about 10 but it was not discovered until I was 14. It was followed by surgery and radiation. I have all the symptoms listed above and have been dealing with them for 30 years.
Did you find one of the effects to be that it was/is very diffcult to lose the weight that was gained during years before Cushings was discovered in a patient?

5 09 2011

Thanks for your comment @m.
First of all, I am not a doctor, nor am I involved in any of the studies I addressed here. I have secondary Addison’s disease and have basic medical knowledge. In addition I know how to search the biomedical literature

Thus I can’t answer the questions you raise without doing a complex search. Seems an interesting topic though and I might do a little digging later & write a post about it.

In the mean time you might like to read:
Free full text:
J Bone Miner Res. 2007 Jan;22(1):110-8.
Effects of child- and adolescent-onset endogenous Cushing syndrome on bone mass, body composition, and growth: a 7-year prospective study into young adulthood

25 10 2011

Yeah, I had cushings for about 7 years, finally had the tumors removed and the Dr. said i was fine, lost the weight, look normal now, but I have very short term memory and cant understand squat, Im glad to hear that its not all in my head lol at times I feel like I need a babysitter because I forget so much.But I do feel better now knowing its probably from having cushings for so long, thank you to whoever wrote about memory and cog. functions being off after this disease.

3 07 2012

Does anybody know if you can have cushing’s syndrome and later have it turn into Addison’s Disease?

13 10 2012
Patrick Caldwell

Thanks for the article on the long term effects of Cushings and or high levels of cortisol. I suffered from Cushings Disease for 40 years. My symptoms appeared gradually. Looking back I realize that I probably began symptoms when I was 11 or 12. Symptoms slowly worsened over time. My blood pressure became uncontrollable at 15. I had severe acne and cysts at 14. I also knew that something was wrong with my mood early. Heart rate could not be controlled. Weight gain and swelling also were prevalent. Nose bleeds were common. I was rapid cyclic manic depressive. I had temper problems. I was constantly sick. I missed 53 days of my senior year in high school. I attended college for three years after high school graduation. After numerous trips to the ER to get my nose packed for bleeding and several hospitalizations, I decided to stop attending college and try to find out what was wrong with me. I worked in a family business and with the assistance of my Family doctor, I began my research. I listed every symptom that I had and tried to determine if there was a common denominator. Soon I concluded that my problem was with my Endocrine system. to my dismay, no one would listen. I finally checked myself into a Psychiatric research facility where medical students did research on people with emotional symptoms with a suspected physical cause. It was here that a medical student told me what was wrong with me, only from observing me and spending time with me. I had surgery on September 24, 1980, followed by six weeks of radiation therapy. I returned to school in September of 1981 and graduated three years later. I went to law school one semester and then joined the workforce in the spring of 1985. I continued to experience symptoms of Cushings, though not as severe. My Endocrinologist monitored me and could not understand why I did not need replacement hormones. Elevated cortisol levels were attributed to stress. I did not see an Endocrinoligist for several years after mine retired. My health continued to deteriorate. However I continued working. Finally I found a new Endocrinologist and she discovered abnormalities immediately. After several years, a growth was found in a crevice behind my left nasal cavity. Surgery was performed. A biopsy indicated that the mass was an Adenoma with pituatary gland. This surgery occurred on January 31 2007. I continued to work even though I began having numerous problems. I was worn out. I had lived most of my life on one hour of sleep. I had severe obstructive sleep apnea. Hormone regulation was a problem. My body was in a state of shock, Blood pressure was uncontrollable. Heart rate was very fast. Poor Concentration. I was forced to go on a leave of absence. After 10 months my doctor advised me to retire on disability. He told me that I would not live long if I did not. Now I have the battle of fighting my employer’s insurance company for long term benefits. Your article may help me. I am sorry for the condensed long story but I thought it would be important if it could help someone.

Patrick Caldwell

13 10 2012

Patrick, we have a great support groups on Facebook and at the website if you are interested. I had a BLA to control my Cushing’s in 2010. I had it for many, many years, also, so I understand. (I had a pituitary surgery first.) Our group is great at helping folks figure out what to ask a doctor in terms of help to feel better. We’d love to have you.

14 10 2012
Patrick Caldwell

Thanks Robin. I plan to utilize the support groups. It’s nice to know that there are people who have had similar circumstances available. I know only one person who had Cushings.


15 10 2012

Patrick, contact me through and I’ll add you. 🙂

15 10 2012


Patrick Caldwell

25 02 2013

Reblogged this on MaryO'Medical and commented:
I know that this is currently a “heart blog” but I’ve mentioned Cushing’s a few times, and Cushing’s is my life so I’m reblogging this older post…

6 03 2014

is the e.mail still valid for help?

24 04 2014
Irreversible Effects of Previous Cortisol Excess on Cognitive Functions in Cushing’s Disease | Laika’s MedLibLog | CushieBlog

[…] Irreversible Effects of Previous Cortisol Excess on Cognitive Functions in Cushing’s Disease | Lai…. […]

6 11 2014

My name is Nicole but I’m under my sons account! I’ve just been diagnosed with cushings disease after apparently having it for many years now! I just found ought get I’ve got a adrenal gland tumor and also a tumor on my pituitary gland as well. I go on the 13th to discuss when I’ll be having my pituitary tumor removed! I am in so much pain… Does anyone know why??? It’s my lower back mainly! If I’m sitting still im ok but the second im up n moving around.. My back in the lower art is just killing me n throbbing! I’ve put on I’ve 125 pounds since I’ve had this disease n nothing I do will allow me to lose any weight! After my surgery does anyone know if the weight will come off on its own some??just taking my son to drop him off at school takes everything out of me! My family acts like they don’t believe me when I’m saying I’m hurting or I’m not feeling good of that I have no energy., I’m making my mom go with me to my visit on the 13 th., so she can hear for herself that I’m not playing or joking about any of this or the pain from it! I feel like I’m just going to give up cause I don’t no what else to do n having know one believe me or willing to be here for me or help me go threw this… It’s making everything even worse! I’m just worried mainly about the pain and if mybweight will never go away??? I’ve always been skinny n I now weigh 289’pounds!! It’s crazy!!mdoes anyone relate to this and can answer my questions about the back pain and if I’ll ever lose the wight from this.. From having cushings???

27 02 2015
Larissa Powell

I know my cognitive and social functioning is still affected by my prior cushings disease and yet my endocrinologist gave me nothing , no aftercare or even support. This disease leaves some isolated and alone. I mean who wants to be with a highly emotional irrational paranoid depressive fat looking person . 5 years later my brain is what I now call delayed . I know I am judged by my inability to think quickly I feel most often I still live this disease .

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