Novel hormone replacement therapy trial demonstrates improved memory function in adrenal patients

Better timing for
cortisol replacement therapies, to more closely replicate the secretion
patterns of people with normal levels of the hormone, has shown a significant
improvement in patients’ cognitive function. This is the striking finding from
a new trial led by University of Bristol scientists including Professor
Stafford Lightman and published in the Proceedings
of the National Academy of Science (PNAS). The findings are potentially
important and underline the case for novel therapeutic approaches, as patients
on cortisol replacement therapy often have side effects that make it difficult
for them to lead normal lives.

Cortisol is a key
hormone that is critical for the maintenance of life. It regulates a wide range
of physiological functions from metabolism and immune responses through to
blood pressure and blood sugar levels. It plays an important role in memory
formation and other cognitive processes, and helps the body respond to
stress. Low levels of cortisol are associated with debilitating fatigue,
muscle weakness, dangerously low blood pressure and depression.

Cortisol-deficient
patients who are diagnosed with adrenal insufficiency and placed on treatment
recover from their worse symptoms with daily hydrocortisone replacement therapy.
However, the condition is life-long and even with current optimal regimes of
cortisol replacement this oral therapy is associated with impaired quality of
life affecting cognitive function, mood, sleep and immune response.

In people with
normal levels of the hormone, cortisol is secreted in an oscillating pattern
with pulses of hormone released at multiple times throughout a 24-hour day. In
this study, the authors recruited 15 male volunteers between 20 and 33-years.
Participants were provided with cortisol replacement therapy either via a
continuous infusion replicating normal human secretion frequencies, or received
the same level of cortisol without these oscillating patterns via either oral
tablets or a continuous infusion. The study then assessed the effect on
participants’ memory, emotional responsiveness and brain activity across the
three treatment methods.

The team found
significant variation in the response patterns of certain
glucocorticoid-sensitive brain regions to emotional images of facial
expression, when they compared outcomes across the three treatment methods that
study participants undertook.

Compared with the
other treatments, oscillating pulsed hydrocortisone dosing most closely
replicates normal human patterns of cortisol secretion. Study
participants performed significantly better across the range of cognitive tasks
they were assigned, during this treatment and were observed to have improved
working memory capacity under high-cognitive demands.

Participants
reported poorer sleep quality during a constant non-pulsatile hydrocortisone
infusion over 24 hours, compared with the two other treatments they undertook
during this trial. This finding is consistent with outcomes in a previous
international study of continuous hydrocortisone infusion outcomes, but remains
unexplained.

Stafford Lightman,
Professor of Medicine and a neuroendocrinology expert at Bristol Medical
School, said:

“The pharmaceutical industry has invested heavily in providing
new and more potent drugs. However, our findings suggest that rather than
needing any new drugs, it is the timing of cortisol delivery- in line with the
body’s own rhythmic pattern of cortisol secretion – that is important for
normal cognition and behaviour. This has major implications for the use of
chronobiology (timing biology) to improve therapies by taking account of the
importance of the pattern of drug presentation to the tissues of the body. This
could be important not only for improving cortisol replacement therapy but also
has major implications understanding the role of glucocorticoid dynamics in
stress and psychiatric disease.”

Katherine
White, Chair of Addison’s Disease Self-Help Group (the charity for adrenal
patients in UK and Ireland) said:

“This is an ambitious study and its findings
offer a welcome insight into the quality of life impairments experienced by
many adrenal patients. The study’s reported conclusions suggest an exciting
potential for chronobiological approaches in endocrine replacement therapy to
improve cognitive function and sleep quality for adrenal patients.”

The study was funded by the Medical Research Council and Wellcome.