Circadian rhythm misalignment in people with adrenal insufficiency

[Aaron98]

It's been quiet here. Everyone must be enjoying the summer. We certainly are. My wife and I have a few big events coming up in the next few weeks - a wedding for one of my brothers, and a wedding for my best friend. My wife's parents and sister are coming over this weekend to help us paint our baby's future room. Our little one is due in October! The weeks until then can't go quickly enough.

To get on topic, I've recently been following a research study going on at the University of Chicago, which may be of interest to many of you. Its purpose is to study circadian rhythm misalignment in people with adrenal insufficiency. I don't claim to be an expert on this by any means, but as I understand it, replacement steroids do not come close to replicating the body's normal production of cortisol, which often causes fatigue and sleep problems for people with adrenal insufficiency. A healthy individual's adrenal glands typically begin producing cortisol a few hours before they wake up in the morning, which allows for a burst of energy upon waking. In a person with adrenal insufficiency, there may be great difficulty in waking up, despite receiving what should be adequate sleep. I know that sleep is typically unrefreshing for me, whether I get four hours or nine. I have to force myself to get out of bed, go downstairs, and take my hydrocortisone and fludrocortisone. It might take 45 minutes or so for me to actually feel awake. Do others with AI experience this, as well?

I've been in contact with Dr. Eve Van Cauter at the University of Chicago, and she informed me that they are still recruiting individuals with AI for this study. If you are interested, the clinical trial number is NCT03000231. It is encouraging that they are performing research that may lead to better treatment methods for AI in the future.

Below is a write-up that Dr. Van Cauter sent me regarding this study.

I hope everyone is having a lovely summer. Be well!

"Cortisol, a glucocorticoid hormone produced by the adrenal glands, is one of the few hormones that are essential for life. Patients with adrenal insufficiency (AI) do not produce cortisol and need to be on lifelong replacement therapy with synthetic glucocorticoids. Despite the fact that AI patients receive hormonal replacement, they still have a reduced life expectancy. In healthy people, the bodily production of glucocorticoids follows a large daily rhythm, with a peak around habitual wake-up time and minimal levels in the evening and early part of the night. It has been long recognized that this 24-h rhythm partly reflects the activity of a master clock in a specific area of the brain. In recent years, secondary clocks were found in most peripheral tissues, including the adrenal glands, the heart, the pancreas and the liver. When all these clocks do not tick in synchrony (referred to as “misaligned”), adverse effects on cardiovascular function, metabolism, and the immune system occur. It is now recognized that, under normal conditions, the 24-h rhythm of cortisol serves as a major synchronizing signal for the central and peripheral clocks. Patients with AI are at high risk of circadian misalignment and its adverse consequences because current regimens of glucocorticoid replacement do not mimic very well the normal rhythm of cortisol release. The present study will document for the first time the daily rhythms of sleep-wake behavior and food intake in AI patients as compared to healthy well-matched controls, and examine whether the 24-h rhythms of blood pressure and heart rate are absent or disrupted. The study will also examine whether the 24-h rhythms of other hormones are “out of sync”. Lastly, the study will determine which regimens of glucocorticoid replacement minimize the disruption of bodily rhythms.

The study is conducted at the University of Chicago Medical Center and involves 2 inpatient stays, one for 24 hours and one for 48 hours. Travel expenses are covered. The study is for research only, it does not provide diagnosis or treatment."

[monkeybus]

I don't have adrenal insufficiency, but my sleep architecture has been shot to pieces since I was about 23yo. Constantly waking up throughout the night.

Continues to this day, though Lyrica keeps me asleep all night.

I believe abnormal sleep patterns are part of our disease.

Anyone else?

I am seeing my neurologist on Monday. I'll show him the laughing gas article. Something else for him to shrug his shoulders to.

[tbird]

Thank you for this information. I've been taking prednisone and fludrocortisone for 26 years and often wonder if this really makes me as "normal" as my endocrinoligist says it does.

Do you have contact info for Dr. Van Cauter and the study?

[SongStream in reply to tbird]

All I have ever heard from my endos is that our medication is hormonal replacement therapy. And their remedy for fatigue is to increase the cortisone which is faulty reasoning.

From ClinicalTrials.gov:

United States, Illinois

The University of ChicagoRecruiting

Chicago, Illinois, United States, 60637

Contact: Eve Van Cauter, PhD 773-702-0169 [e-mail]

Contact: Susan Sam, MD 773-702-5641 [e-mail]

Principal Investigator: Eve Van Cauter, PhD

[Aaron98 in reply to SongStream]

Thanks for posting Dr. Eve Van Cauter's info, Steve. I hope this helps, tbird. Dr. Van Cauter responded to my initial email very quickly, so I would encourage you to contact her if you are interested in this study.

As I mentioned in my previous post, it has been well-established that our replacement therapy does not replicate the body's natural production of cortisol, and this contributes significantly to fatigue. Too many endocrinologists simply refer to the textbook treatment for AI, which has not changed much in forty years. I appreciate endos who are willing to go the extra mile for their patients, looking into possible different and additional treatments (DHEA supplementation, cortisol pumps, etc.) that may improve our well-being.

[bluejadedwho]

There is a new drug called Cronocort (do a search). It is being developed in the U.K. I'm in email correspondence with the developer. It is the first novel treatment for adrenal insufficiency in over 50 years. It is taken at night and therefore one would wake up on the morning feeling "normal" with the highest level of cortisol as one should. No more waking up and feeling awful having to take the hydrocortisone. This medication better mimics the normal cortisol circadian rhythm.

MONKEYBUS: I'm confused how you don't have adrenal insufficiency with a diagnoses of adrenomyeloneuropathy. As the first part of the condition is of course "adrenal". I am very envious!

[Aaron98 in reply to bluejadedwho]

This is what I'm talking about! Thanks so much for posting, bluejadedwho. Finally we're testing new and novel treatments for our adrenal insufficiency.

From Chronocort's website:

"When properly monitored and controlled there are usually no side effects of treatment, however many patients with adrenal insufficiency complain of fatigue and lack of energy. This may be due to a failure of current hydrocortisone treatment to replace the normal cortisol rhythm. In healthy individuals cortisol levels rise from around 3am in the morning and peak shortly after waking. They gradually decline over the day to low levels to about 7pm in the evening through to 3 am in morning. It is thought that the rise in cortisol levels in the early morning prepares one for the day and it is known that the loss of the circadian rhythm of cortisol is associated with fatigue, depression and metabolic abnormalities.

Cortisol has a distinctive daily rhythm. Current therapies are considered to be sub-optimal in mapping hydrocortisone release against this daily rhythm and could be superseded with more effective physiological hormonal replacement products. Chronocort® is specifically designed to replicate physiological cortisol replacement, as closely as possible, over the whole day. In clinical trials Chronocort® is being administered at bedtime and on waking with the aim to provide overnight coverage of cortisol as well as sustained replacement during the day.

Diurnal has successfully completed human volunteer studies of Chronocort® and completed a Phase 2 trial in patients. It is expected that submission of a marketing authorisation application for Chronocort® will occur by the end of 2017."

[COwithAMN Administrator AMN EASIER Volunteer in reply to bluejadedwho]

Monkeybus is not the only one who has normal adrenal functioning. I have had AMN for 30+ years but never had any adrenal insufficiency. It's one of the many peculiarities of the condition. But remember that the evidence so far is that there are 740 unique mutations of ABCD1 - see x-ald.nl/.

[bluejadedwho in reply to COwithAMN]

How bizarre isn't it? I consider those with normal adrenal function very fortunate.

[Sue95]

My son keeps his morning hydrocortisone beside the bed with a drink and takes it when the alarm goes off. He then stays in bed for half an hour so that he feels not too bad when he gets up.

It may be worth discussing the timing of your afternoon tablets and how your dosage is split over the day as this could affect whether you have any residual cortisol in the morning.