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Replication of cortisol circadian rhythm: New advances in hydrocortisone replacement therapy

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Cortisol has one of the most distinct and fascinating circadian rhythms in human physiology. This is regulated by the central clock located in the suprachiasmatic nucleus of the hypothalamus. It has been suggested that cortisol acts as a secondary messenger between central and peripheral clocks, hence its importance in the synchronization of body circadian rhythms. Conventional immediate-release hydrocortisone, either at twice- or thrice-daily doses, is not capable of replicating physiological cortisol circadian rhythm and patients with adrenal insufficiency or congenital adrenal hyperplasia still suffer from a poor quality of life and increased mortality. Novel treatments for replacement therapy are therefore essential. Proof-of-concept studies using hydrocortisone infusions suggest that the circadian delivery of hydrocortisone may improve biochemical control and life quality in patients lacking cortisol with an impaired cortisol rhythm. Recently oral formulations of modified-release hydrocortisone are being developed and it has been shown that it is possible to replicate cortisol circadian rhythm and also achieve better control of morning androgen levels. These new drug therapies are promising and potentially offer a more effective treatment with less adverse effects. Definite improvements clearly need to be established in future clinical trials.
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Metabolism
Therapeutic Advances in Endocrinology and
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DOI: 10.1177/2042018810380214
2010 1: 129 originally published online 10 August 2010Therapeutic Advances in Endocrinology and Metabolism
Sharon Chan and Miguel Debono
Review: Replication of cortisol circadian rhythm: new advances in hydrocortisone replacement therapy
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Replication of cortisol circadian rhythm:
new advances in hydrocortisone
replacement therapy
Sharon Chan and Miguel Debono
Abstract:Cortisol has one of the most distinct and fascinating circadian rhythms in human
physiology. This is regulated by the central clock located in the suprachiasmatic nucleus of the
hypothalamus. It has been suggested that cortisol acts as a secondary messenger between
central and peripheral clocks, hence its importance in the synchronization of body circadian
rhythms. Conventional immediate-release hydrocortisone, either at twice- or thrice-daily
doses, is not capable of replicating physiological cortisol circadian rhythm and patients with
adrenal insufficiency or congenital adrenal hyperplasia still suffer from a poor quality of life
and increased mortality. Novel treatments for replacement therapy are therefore essential.
Proof-of-concept studies using hydrocortisone infusions suggest that the circadian delivery of
hydrocortisone may improve biochemical control and life quality in patients lacking cortisol
with an impaired cortisol rhythm. Recently oral formulations of modified-release hydrocorti-
sone are being developed and it has been shown that it is possible to replicate cortisol
circadian rhythm and also achieve better control of morning androgen levels. These new drug
therapies are promising and potentially offer a more effective treatment with less adverse
effects. Definite improvements clearly need to be established in future clinical trials.
Keywords:central clock, circadian rhythm, cortisol, hypothalamopituitaryadrenal axis,
modified release hydrocortisone
Introduction
Cortisol is an essential steroid hormone secreted
by the adrenal gland and like many other physi-
ological processes in the body has a circadian
rhythm. This rhythm is distinct and is regulated
by the main circadian oscillator (pacemaker) in
the suprachiasmatic nucleus (SCN) which is
located in the hypothalamus. Normal individuals,
without disease of the hypothalamopitui-
taryadrenal (HPA) axis, at midnight, have very
low or undetectable cortisol levels that build up
overnight to peak first thing in the morning.
Cortisol levels then decline slowly throughout
the day [Debono et al. 2009; Krieger et al.
1971; Weitzman et al. 1971].
Patients who are deficient in cortisol are known
to suffer from adrenal insufficiency. The condi-
tion typically presents insidiously and may be
easily overlooked. Patients will die if adrenal
insufficiency is not diagnosed promptly and trea-
ted effectively [Oelkers, 1996] and longevity may
be reduced as a consequence of stress-induced
crises [Arlt and Allolio, 2003]. All patients need
to be on life-long glucocorticoid replacement
treatment [Arlt and Allolio, 2003].
Management of adrenal insufficiency is one of
the challenges that face every endocrinologist.
Hydrocortisone, the generic pharmaceutical
name of cortisol and the most commonly used
drug for adrenal insufficiency, has a short
plasma half-life and patients taking this tablet
wake with undetectable cortisol levels only
achieving peak cortisol levels an hour after
taking their dose of hydrocortisone [Mah et al.
2004]. The pharmacokinetics of immediate-
release hydrocortisone makes it impossible for
physicians to replicate physiological cortisol
release. A number of research studies have
explored different hydrocortisone regimes to try
and identify the best doses and patterns of treat-
ment [Mah et al. 2004; Howlett, 1997; Groves
et al. 1988]. Unfortunately, notwithstanding
http://tae.sagepub.com 129
Therapeutic Advances in Endocrinology and Metabolism Review
Ther Adv Endocrinol
Metab
(2010) 1(3) 129138
DOI: 10.1177/
2042018810380214
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Correspondence to:
Dr Miguel Debono, MD,
MRCP
M Floor, Room 110,
Academic Unit of
Endocrinology,
Department of Human
Metabolism, University of
Sheffield, Beech Hill Road,
Sheffield S10 2RX, UK
M.debono@
sheffield.ac.uk
Dr Sharon Chan, MBChB
Department of Medicine,
Royal Hallamshire
Hospital, Glossop Road,
Sheffield, S10 2JF, UK
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doctors’ efforts, these regimens inevitably result
in steroid over-replacement or under-replace-
ment [Peacey et al. 1997]. Impaired general
health and vitality perception [Bergthorsdottir
et al. 2006; Mills et al. 2004], bone loss
[Wichers et al. 1999] and abnormal glucose
levels [al-Shoumer et al. 1995] are some of the
consequences of these regimes.
Whilst adrenal insufficiency typically presents
insidiously, there is a risk of death if it is not diag-
nosed and treated appropriately [Oelkers, 1996].
Patients with primary adrenal insufficiency,
although on full replacement therapy, have a
mortality rate which is twofold greater than that
of the background population the greatest
number of deaths occurring from cardiovascular,
malignant, endocrine, respiratory and infectious
diseases [Bergthorsdottir et al. 2006]. In a cohort
of 6107 patients on pituitary-derived growth hor-
mone providing 105,797 person-years of follow
up the overall risk of death was four times the
normal population. Importantly, one of the
most striking risk factors was adrenal insuffi-
ciency. Eighty six per cent of subjects found
dead or comatose by relatives probably died
from adrenal insufficiency which was either mis-
treated or overlooked [Mills et al. 2004].
New formulations of hydrocortisone bearing
modified-release characteristics with the aim of
imitating the physiological cortisol circadian
rhythm can hopefully reduce morbidity and mor-
tality rates.
Synchronization of circadian rhythms
Humans exhibit daily physiological and beha-
vioural rhythms with nearly all body functions
showing significant daily variations; these include
sleep, body temperature, plasma concentrations
of cortisol and growth hormone, and urinary
excretion of potassium [Moore-Ede et al. 1983].
These circadian rhythms are produced by endog-
enous processes referred to as circadian oscilla-
tors which coordinate and orchestrate molecular
and physiological rhythms with changes in the
environment [Dunlap, 1999]. The autonomic
nervous system and endocrine signals are the
principal mediators of this internal rhythmicity
[Buijs and Kalsbeek, 2001].
Central and peripheral circadian oscillators
In the early 1970s, brain lesion experiments and
metabolic and electrophysiologic studies indi-
cated that in mammals, in the hypothalamic
SCN, existed a central circadian oscillator (pace-
maker) or central clock [Moore and Lenn, 1972].
The SCN, a cluster of around 10,000 neurones
located on either side of the midline above the
optic chiasma [Hastings, 1997], is subdivided
into a ventral ‘core’ region, that receives informa-
tion from the retina and brain stem and is respon-
sible for entrainment, and a dorsal ‘shell’ region,
which appears to be a primary pacemaker whose
output drives behavioural and other rhythms.
The phase of a circadian rhythm can be synchro-
nized to the phase of the daynight cycle to
which it is exposed. This process is initiated by
light stimulating a specialized group of retinal
ganglion cells [Rollag et al. 2003]. Their unmy-
elinated axons form the retinohypothalamic
tracts in the optic nerves and their transmitters
synaptically affect the SCN clock cells, harbour-
ing CLOCK genes. This leads to activation of
proteins that reset the circadian pacemaker’s
core autoregulatory transcriptiontranslation
loop [Meijer and Schwartz, 2003].
In the early 1980s, CLOCK genes were identified
in Drosophila, whilst homologue genes were
identified in mammals, 10 years later [Vitaterna
et al. 1994; Reddy et al. 1984]. Pacemaking neu-
rons express clock-controlled genes and these
cells within the shell region are postulated to
synchronize with each other and communi-
cate rhythmicity to distinct target tissues.
Transcription of five clock genes Period (Per 1, 2),
Cryptochrome (Cry 1, 2), and Reverbare
activated during the day when CLOCK and
BMAL1 proteins bind to promoter sequences.
Transcription of these genes continues until
PER and CRY proteins accumulate to sufficient
levels in the nucleus to repress CLOCK/
BMAL1 activation. This occurs in the night.
Transcription of the five daytime genes begins
again in the early morning hours when PER/
CRY protein levels begin to fall [Reppert and
Weaver, 2001]. The pacemaking cells within
the core synchronize with each other, communi-
cate with pacemakers in the shell region, and
drive rhythms outside the SCN [Hastings and
Herzog, 2004]. These output pathways are
likely to involve both humoral and nervous sig-
nals [Silver et al. 1996], which act as secondary
messengers relaying information between clock
cells in central and also peripheral oscillators;
manifesting itself in circadian physiology and
behaviour.
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CLOCK genes have also been found to be
expressed peripherally in different tissues in a cir-
cadian fashion. In several peripheral tissues cir-
cadian rhythms in RNA are evident for each of
the PER genes [Zylka et al. 1998]. In these tis-
sues, the oscillation of each PER gene is delayed
by 39 h to the oscillation in the central pace-
maker, suggesting that peripheral pacemakers
are synchronized and regulated by the SCN.
Circadian cycles can be entrained by serum com-
ponents, highlighting the importance of chemical
signal transduction for the coordination of circa-
dian gene expression [Balsalobre et al. 1998].
Given that glucocorticoids do exhibit a circadian
rhythm and glucocorticoid receptors are found in
most peripheral cells and tissues but not in the
SCN [Rosenfeld et al. 1993], glucocorticoids are
highly likely candidates to act as secondary mes-
sengers or entraining signals [Balsalobre et al.
2000].
Physiology of cortisol circadian rhythm
Regulation of cortisol circadian rhythm
Cortisol has one of the most distinct and inter-
esting circadian rhythms in the body. It is well
established and has been analysed in fine detail
[Weitzman et al. 1971], and is characterized by a
constant and reproducible pattern under stable
physiological conditions [Selmaoui and Touitou,
2003]. In 33 normal individuals who had
20-minute cortisol profiling over 24 h we have
shown that cortisol levels reach lowest levels at
around midnight, levels start to rise at around
02:00 to 03:00 and reach a peak at around
08:30. Cortisol levels then slowly decrease back
to the nadir to complete the cycle over 24 h.
The peak cortisol level attained was approxi-
mately 399 nmol/l, whilst the nadir cortisol was
<50 nmol/l [Debono et al. 2009] (Figure 1).
The regulation of glucocorticoid, or cortisol
release, is critically determined by the activity of
the HPA axis. The HPA axis receives input from
the central pacemaker which controls the circa-
dian release of corticotrophin-releasing hormone
(CRH) in the paraventricular nucleus, this also
stimulated by physical and emotional stressors.
CRH in turn stimulates release of adrenocortico-
trophic hormones (ACTH) from the cortico-
troph cells in the anterior pituitary, and thence
the glucocorticoid cortisol from the adrenal
cortex. In turn, cortisol exerts inhibitory effects
at pituitary and hypothalamic levels, in a classical
negative feedback loop although there is no feed-
back on the SCN [Oster et al. 2006b].
The adrenal gland contains a circadian clock that
sets specific time intervals during which the adre-
nal most effectively responds to ACTH. This is
regulated via the splanchnic nerve [Jasper and
Engeland, 1997]. Clock genes are expressed
rhythmically in the zona glomerulosa and zona
fasciculata, and entire pathways characteristic
for the adrenal gland, such as steroid metabolism
or catecholamine production, are transcription-
ally regulated by the circadian clock [Oster
et al. 2006a]. Expression of clock genes in the
adrenal gland shows a 6-h phase delay relative
to the SCN which is mainly induced via the
SCNsympathetic nervous system without
accompanying activation of the HPA axis
[Fahrenkrug et al. 2008; Ishida et al. 2005].
This gene expression accompanies the rhythmic
secretion of plasma and brain cortisol.
Cortisol production rate
A number of cortisol secretory episodes occur
during the 24 h of the day making it possible to
describe four different unequal temporal phases.
These phases are represented by a period of min-
imal secretory activity, during which cortisol
secretion is negligible, and occurs 4 h prior to
and 2 h after sleep onset, a preliminary nocturnal
secretory episode at the third through fifth hours
of sleep, a main secretory phase of a series of
three to five episodes occurring during the sixth
to eighth hours of sleep and continuing through
the first hour of wakefulness and an intermittent
waking secretory activity of four to nine secretory
episodes found in the 212-h waking period
[Weitzman et al. 1971]. Advances in the measure-
ment of the total amount of cortisol produced in
a day shows that this is around 5.77.4 mg/m
2
/
day or 9.59.9 mg/day [Kerrigan et al. 1993;
Esteban and Yergey, 1990; Linder et al. 1990]
which is much less than previous estimates.
Cortisol production rates in children and adoles-
cents are very similar. These findings support
regimes with lower oral daily hydrocortisone
doses of 1525 mg [Peacey et al. 1997].
Current hydrocortisone therapy in
adrenal insufficiency
The importance of cortisol is especially evident
when it becomes deficient, a state known as adre-
nal insufficiency. Thomas Addison described
Addison’s disease in 1855 recognizing the impor-
tance of the adrenal cortex for life and Brown
S Chan and M Debono
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Sequard in 1856 performed the first adrenalec-
tomies to highlight this finding. Notwithstanding,
it took years to confirm this theory in view of
conflicting ideas especially when epinephrine
was discovered in 1900. It was not until the
1930s that a good amount of work was done on
cortical extracts. In 1936 Pfiffner, Reichstein and
Kendall showed that a large number of steroids
could be crystallized from the extract. A few years
later ACTH was discovered by Li, Evans and
Simpson in 1943 and cortisone by Sarett in
1946 [Savage, 1951]. Since the first published
report of the efficacy of cortisone in the treatment
of rheumatoid arthritis in 1949 [Rubin, 2007]
and Hench, Kendall and Reichstein were
awarded the Nobel prize in medicine, patients
with adrenal insufficiency have been treated
with glucocorticoid replacement, and apart
from the introduction of fludrocortisone in the
1950s, replacement therapy has not changed
[Lovas and Husebye, 2008]. Hydrocortisone is
now used in most centres around the world
although only cortisone acetate or synthetic glu-
cocorticoids such as prednisolone are available in
some European countries, and elsewhere such as
Brazil.
Management of adrenal insufficiency is not so
straightforward. This is because hydrocortisone
has a short plasma half-life and patients taking
this tablet wake with undetectable cortisol levels
achieving peak cortisol levels an hour after taking
their dose of hydrocortisone [Mah et al. 2004;
Derendorf et al. 1991]. Low levels of cortisol
are then present by mid-afternoon. The pharma-
cokinetics of immediate release hydrocortisone
makes it impossible for physicians to replicate
physiological cortisol release.
Identifying an optimal regime
A number of research studies have explored dif-
ferent hydrocortisone regimes to try and identify
the best doses and patterns of treatment. Patients
on a thrice-daily regimen, monitored using corti-
sol day curves, showed a much more constant
level then when compared with those on a
twice-daily regimen, who had plasma cortisol
levels falling to very low levels by 16:00 [Groves
et al. 1988]. In 20 cortisol insufficient patients
given oral immediate-release hydrocortisone in
the fasted or fed state it was shown that weight-
adjusted dosing decreased interpatient variability
in maximum cortisol concentration from 31%
to 7% when compared with the fixed dose, and
reduced overexposure to <5%. Thrice-daily
dosing before food was recommended as the pre-
ferred hydrocortisone regime [Mah et al. 2004]
but although better this still was far from repli-
cating physiological cortisol rhythm (Figure 2).
24.0
20.0
16.0
12.0
8.0
4.0
Clock time
MESOR: 5.2 mcg/dL
(4.7 – 5.7)
Cortisol (mcg/dL)
Acrophase: 0832h
(0759h – 0905 h)
Nadir: 0018h
(2339h – 0058 h)
222324 1 2 3 4 5 6 7 8 9 101112131415161718192021
Figure 1. Circadian rhythm of cortisol in 33 individuals with 20-minute cortisol profiling. Peak cortisol
levels are reached at around 08:30 and nadir cortisol levels at around midnight. The peaks of cortisol at
noon and around 18:00 represent meal-induced cortisol stimulation. (Reproduced with permission from The
Endocrine Society and Debono et al. [2009]).
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Limitations of current hydrocortisone
replacement therapy
In general, inadequate replacement of glucocor-
ticoids may lead to malaise, postural hypoten-
sion, diarrhoea, abdominal pain, weight loss,
poor response to stress and electrolyte abnormal-
ities. Conversely, excessive replacement may lead
to Cushingoid features, glucose intolerance,
hypertension and cardiovascular disease, neuro-
psychiatric illness such as mania and depression,
protein catabolism and osteoporosis [Arlt et al.
2006; Arlt and Allolio, 2003].
The subjective health status of patients with
Addison’s disease has been shown to be low
when compared with normal individuals and
one quarter of patients are out of work due to
disability [Lovas et al. 2002]. A poor quality of
life has also been revealed in patients with sec-
ondary adrenal insufficiency [Hahner et al.
2007]. Groves and colleagues revealed that
well-being is lowest just before the first dose of
steroid is taken in the morning, it then rises to a
maximum at lunch time, and falls gradually
toward evening [Groves et al. 1988]. When inves-
tigating the effects of different hydrocortisone
regimes on quality of life, doses above 30 mg/
day were associated with a worse health status
and thrice-daily intake of hydrocortisone was
not superior to twice-daily intake [Bleicken
et al. 2010]. An explanation for such a signifi-
cantly impaired quality of life may be related to
the nonphysiological replacement of cortisol
using conventional treatments. This highlights
the benefits patients with cortisol deficiency
may potentially receive from physiological corti-
sol replacement.
A bidirectional relationship exists between corti-
sol rhythmic activity and the sleepwake cycle
(SWC) although both systems have two separate
generators in the SCN [Spath-Schwalbe et al.
1992]. Sleep disturbances associated with
increased daytime fatigue have been reported
for patients with adrenal insufficiency [Lovas
et al. 2003]. Rapid eye movement (REM) sleep
latency and time may vary in patients with adre-
nal insufficiency on conventional treatment this
interrupting sleep continuity [Garcia-Borreguero
et al. 2000]. Effects on the SWC are variable and
may also be related to the dose of corticosteroids
[Buckley and Schatzberg, 2005]. Physiological
cortisol replacement could potentially achieve
sleep indices closer to normal values in patients
with adrenal insufficiency.
Bone loss secondary to depression of osteoblastic
function, evident by lower osteocalcin levels, may
also occur with increasing hydrocortisone doses
[Peacey et al. 1997]. Whether effects on bone
density do occur is debatable [Arlt et al. 2006;
Zelissen et al. 1994]. The circadian variation in
osteocalcin is under the control of the endoge-
nous circadian variation in serum cortisol
[Heshmati et al. 1998]. Replacement of conven-
tional hydrocortisone by circadian cortisol ther-
apy could possibly provide a treatment which
interacts with bone physiology more effectively.
Patients with hypopituitarism on hydrocortisone
equivalent doses greater than 20 mg/day have a
higher body mass index (BMI), total cholesterol,
low-density lipoprotein cholesterol (LDL-C)
and triglycerides [Filipsson et al. 2006]. Large
cortisol peaks, as may occur with conventional
NightDay
6 10141822 2 6
0
150
300
450
600
750
Serum cortisol (nmol/L)
Figure 2. Simulated cortisol profile for a patient (broken line) following thrice-daily hydrocortisone adminis-
tration (10 mg at 06:00, 5mg at 12:00 and 2.5 mg at 18:00, shown as solid arrows). (Reproduced with permission
from John Wiley & Sons Ltd. and Mah et al. [2004]).
S Chan and M Debono
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hydrocortisone, may be associated with a reduc-
tion in insulin sensitivity that manifests itself
46 h after the cortisol elevation and may persist
for more than 16 h [Plat et al. 1996]. It is unlikely
that patients on low-dose conventional therapy or
those on physiological replacement develop ster-
oid-induced diabetes, as very high peaks of cor-
tisol should not occur, but clearly the risk
increases with higher doses.
Conventional hydrocortisone replacement ther-
apy has made it possible for patients with adrenal
insufficiency to live a relatively normal life but it
is evident that mortality and morbidity risks are
higher than in the normal population.
Circadian hydrocortisone therapy:
moving to improved replacement
The management of patients with adrenal
insufficiency should be improved to ameliorate
health-related quality of life, improve biochemi-
cal control and to reduce long-term adverse
effects. Physiological hormone replacement,
using sustained formulations of hydrocortisone,
should be the safest and most effective and prac-
tical solution. Over the past few years interven-
tions introducing circadian cortisol therapy,
using hydrocortisone infusions and modified-
release oral formulations, have shown that these
treatments could potentially imitate physiological
cortisol rhythm and hence result in more valuable
options for patients with adrenal insufficiency.
Circadian hydrocortisone infusions
In two proof-of-concept studies using circadian
intravenous and subcutaneous infusions of
hydrocortisone, replicating the physiological cor-
tisol circadian rhythm, it was shown that morning
ACTH and 17OHP levels improved when com-
pared with conventional hydrocortisone therapy
[Lovas and Husebye, 2007; Merza et al. 2006]
(Figure 3). These data support the notion that
delivering physiological hydrocortisone replace-
ment is likely to improve control in these patients.
The problem with hydrocortisone infusions
are their lack of practicality. An alternative
regime is waking to take immediate-release
hydrocortisone dose at 03:00, and such an
approach resulted in a significant improvement
in 17OHP, testosterone and individual urinary
17-ketosteroids in five patients with congenital
adrenal hyperplasia. This was not achieved by giv-
ing doses which were either higher or taken later
on in the evening [Moeller, 1985]. Although
effective this strategy is not practical as this
would mean interrupting patients’ sleep and
only extremely cooperative patients would bene-
fit. Further, daytime fatigue may result from
sleep fragmentation.
A more practical solution is the develop-
ment of oral modified-release formulations of
hydrocortisone.
Delayed and sustained release oral
formulations of hydrocortisone
One approach is a modified-release hydrocorti-
sone (MR-HC) tablet that can be taken late at
night and then allow a delayed and then sus-
tained release that can then simulate the cortisol
circadian rhythm, by allowing a rise in circulating
cortisol starting in the early hours of the morning
and peaking at approximately 08:00. This
consists of an insoluble barrier coat covering all
but the upper surface of the tablet, where a layer
dissolving slowly retards release from an inner
drug-containing layer. When giving a once-daily
MR-HC at different doses at 22:00 in dexa-
methasone-suppressed individuals, the 24-h cor-
tisol profile at this once-daily dose showed an
earlier peak level at 06:00 compared with the
physiological peak at 08:32, and only maintained
a physiological cortisol level for less than 12 h
(Figure 4). By pharmacokinetic modelling
we showed that taking 1520 mg of MR-HC
at 23:00 and 10 mg at 07:00 the drug could
potentially reproduce physiological circadian
cortisol levels [Debono et al. 2009] over 24 h.
Time (hour)
Infusion
Conventional
07:0005:0003:0023:0021:0019:0017:0015:0013:0011:0009:00
ACTH (ng/l)
350
300
250
200
150
100
50
0
01:00
Figure 3. Comparison of mean serum ACTH levels
in Addison’s and congenital adrenal hyperplasia
patients during conventional replacement therapy
and during circadian infusion of hydrocortisone
(to convert values from ng/l to pmol/l 0.22).
(Reproduced with permission from John Wiley &
Sons Ltd. and Merza et al. [2006]).
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When compared with immediate-release hydro-
cortisone in patients with congenital adrenal
hyperplasia those on MR-HC 30 mg at 22:00
had significantly lower 17OHP levels; highlight-
ing this formulation’s advantageous characteris-
tics [Verma et al. 2010].
Another formulation with combined immediate-
and extended-release characteristics has also
been developed. In a study to determine single
dose pharmacokinetics and dose proportionality
it was shown that the time to reach a serum con-
centration of cortisol (>200 nmol/l) of clinical
significance was within 25 minutes and a peak
of 400450 nmol/l was obtained within 50 min-
utes after the 20 mg tablet. Serum cortisol per-
sisted above 200 nmol/l for around 6 h thereafter
whereas all serum concentrations 1824 h after
intake were below 50 nmol/l [Johannsson et al.
2009]. This formulation was unable to fully rep-
licate the physiological cortisol rhythm as taking
the tablet at 07:00 misses the 03:00 cortisol rise.
For this tablet to achieve near-normal circadian
cortisol levels, it would have to be taken earlier as
a once-daily dose raising compliance issues and
causing sleep problems.
The hope is that these new drug-delivery
technologies should improve and simplify
glucocorticoid replacement therapy by being
more effective, have less adverse effects and
improve compliance. Despite these breakthrough
discoveries of modified-release hydrocortisone
that aim to replicate the 24-h physiological corti-
sol profile, further studies in patients with
adrenal insufficiency are still needed. Further,
these recommended regimens are not necessarily
without adverse affects and their effects on symp-
toms, including quality of life, still need to be
addressed.
Conclusion
The adrenal glucocorticoid, cortisol, is an essen-
tial stress hormone and deficiency leads to death.
Cortisol levels are high early in the morning
and low at time of sleep onset and loss of the
cortisol circadian rhythm is associated with adre-
nal insufficiency. Unfortunately, conventional
hydrocortisone replacement cannot reproduce
this physiological rhythm so patients inadver-
tently are under- or over-replaced. This could
possibly explain why patients with adrenal insuf-
ficiency suffer from a poor health-related quality
of life, with an increased mortality risk, sleep dis-
turbances, impaired psychological well being and
also, at high doses, worsening of cardiovascular
risk factors and defects in bone turnover.
Physiological cortisol replacement with improve-
ments in biochemical control and quality of life
has offered new prospects for patients on hydro-
cortisone replacement. Studies using hydrocorti-
sone infusions have highlighted the efficacy of
this therapy and oral formulations of modified
24.0
20.0
16.0
12.0
8.0
4.0
0
Clock time
MR-HC 5mg MR-HC 10mg MR-HC 15mg MR-HC 30mg IR-HC 10mg
Cortisol (mcg/dL)
221242322 23456789101112131415161718192021
Figure 4. Concentration-time profiles for modified-release hydrocortisone (MR-HC) 5 mg, 10 mg, 15 mg and
30 mg compared with immediate-release hydrocortisone (IRHC). Graph showing delayed and sustained release
characteristics of MR-HC (to convert values from mcg/dl to nmol/l 27.59). (Reproduced with permission from
The Endocrine Society and Debono et al. [2009]).
S Chan and M Debono
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release hydrocortisone are at advanced stages of
development with initial data showing optimistic
results. The future of hydrocortisone replace-
ment lies in the use of physiological therapy for
patients with adrenal insufficiency and congenital
adrenal hyperplasia. Hopefully this should reduce
adverse effects and improve quality of life.
Funding
This article received no specific grant from
any funding agency in the public, commercial,
or not-for-profit sectors.
Conflict of interest statement
The authors have no conflicts of interest to
declare.
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Background Adrenal insufficiency can result in significant patient morbidity and mortality, but due to the range of symptoms and variable clinical course and etiologies, it can be a challenging condition to diagnose and manage. Objective This narrative review will discuss the evaluation of an adult patient at risk for a new diagnosis of adrenal insufficiency and the management of a patient with known or suspected adrenal insufficiency. Discussion A new presentation of adrenal insufficiency can range from nonspecific, minor symptoms including fatigue, to a life-threatening adrenal crisis with hemodynamic instability. Due to the variety of signs and symptoms, the diagnosis is often missed. Those with known adrenal insufficiency are at risk for adrenal crisis, which may occur due to a variety of triggers. Initial evaluation includes assessment for the underlying etiology or concomitant condition, laboratory analysis, and imaging, when clinically indicated. Although not necessary for evaluation in the emergency department setting, the diagnosis is confirmed by specific testing such as the cosyntropin stimulation test. The mainstay of treatment in adrenal crisis is hydrocortisone, intravenous fluid, glucose repletion, and treatment of the underlying acute trigger. Conclusions Emergency clinicians must be prepared to recognize, evaluate, and manage those with known or suspected adrenal insufficiency or adrenal crisis.
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Various in vitro model systems have been established over the last decades, to understand physiological processes, the causalities of diseases and the response of humans to environmental and industrial chemicals or therapeutic drugs. Common to all is a limited biological significance due to the impairment of functionality, for instance by the lack of physiological 3D tissue architecture or the loss of fundamental regulatory mechanisms including the circadian rhythm. The circadian rhythm is an adaption of living organisms to rhythmic environmental changes of the day-night cycle and coordinates behavior as well as various crucial physiological processes in a 24-hour pattern. Here, we discuss the impact of integrating circadian regulation in experimental approaches and toxicological assessments to improve the biological relevance of the obtained results. In particular, it is known for some time that an ongoing disruption of the circadian rhythmicity is associated with an increased risk for cardiovascular disease, metabolic dysfunction or cancer. In the context of health recovery, the importance of circadian control mechanism is recognized by chronopharmacological concepts to increase the efficiency of pharmacological treatment strategies. Despite the undeniable circadian dependency and the biological relevance of manifold cellular and molecular processes, the impact of circadian regulation is hardly considered in a wide range of biomedical and toxicological research areas. Reactivating the circadian regulation holds the promise to enhance the biological relevance and reliability of in vitro approaches. In the context of human health protection the implementation of a circadian regulation will subsequently generate advanced physiologically relevant in vitro approaches and allows an improved toxicological assessment of health risks. In addition, the establishment of circadian disruption as a novel toxicological endpoint will provide a better understanding of toxicological mode of actions of environmental and industrial chemicals or drugs and enlarge the knowledge of disease development.
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Cells and tissues are routinely cultured in vitro for biological research with findings being extrapolated to their host organ and tissue function. However, most samples are cultured and studied in unphysiological environments, without temporal variation in the biochemical cues that are ubiquitous in vivo. The artificiality of these conditions undermines the predictive value of cell culture studies. We ascribe the prevalence of this suboptimal culture methodology to the lack of practical continuous flow systems that are economical and robust. Here, we design and implement an expandable multiplexed flow system for cell culture superfusion. By expanding on the concept of the planar peristaltic pump, we fabricated a highly compact and multiplexed pump head with up to 48 active pump lines. The pump is incorporated into a custom, open-top superfusion system configured for conventional multi-well culture plates. We then demonstrated the utility of the system for in vitro circadian entrainment using a daily cortisol pulse, generating a sustained circadian amplitude that is essential for physiological emulation and chrono-pharmacological studies. The multiplexed pump is complemented by a package of fluidic interconnection and management methods enabling user-friendly and scalable operation. Collectively, the suite of technologies provides a much-needed improvement in physiological emulation to support the predictive value of in vitro biomedical and biological research.
Article
To study the influence of glucocorticoid replacement therapy on bone mineral density. Cross-sectional. University hospital in the Netherlands. 91 patients with Addison disease who had been receiving glucocorticoid replacement therapy for a mean of 10.6 years (range, 0.5 to 36.5 years). Bone mineral density of the lumbar spine and both femoral necks using a dual-energy x-ray absorptiometer and basal serum concentrations of adrenocorticotropin, gonadal hormones, and adrenal androgens. Decreased bone mineral density (less than 2 standard deviations [SD] of the mean value of an age-matched reference population) was found in 10 of 31 men (32%; 95% Cl, 17% to 51%) and in 4 of 60 women (7%; Cl, 2% to 16%). No statistically significant differences were found between men and women with regard to age, duration of glucocorticoid substitution, or glucocorticoid dose, either in absolute quantities or when expressed per kilogram of body weight. However, in men with decreased bone mineral density, the daily hydrocortisone dose per kilogram of body weight (0.43 +/- 0.08 mg/kg; mean +/- SD) was significantly (P = 0.032) higher than in men with normal bone mineral density (0.35 +/- 0.10 mg/kg). After correction for possible confounding variables, a significant linear correlation was found between hydrocortisone dose per kilogram of body weight and bone mineral density of the lumbar spine in the men (regression coefficient, -0.86; Cl, -1.60 to -0.13; P = 0.029) but not in the women. Long-term treatment with standard replacement doses of glucocorticoids may induce bone loss in men with Addison disease. Adjustment of glucocorticoid therapy to the lowest acceptable dose is mandatory in Addison disease, and regular measurement of bone mineral density may be helpful in identifying men at risk for the development of osteoporosis.
Article
Nine clinically healthy men, 41–47 yr of age, served as subjects in a 24-hr study conducted at the Edward Hines Jr Veterans Administration Hospital in the Chicago area in May 1988. Physiologic measurements, and blood and urine samples were collected at 3-hr intervals over a single 24-hr period beginning at 1900. The number of variables measured or calculated (total = 98) included: 6 vital signs (oral temperature, pulse, blood- and intraocular pressures); 16 in whole blood (counts and differentials); 50 in serum (SMAC-24, lipids, hormones, electrophoresis of LDH and proteins); and 26 in urine (solids, proteins, creatinine, catecholamines, melatonin, Cortisol, electrolytes and metals). Data were analyzed for time effect by analysis of variance (ANO VA) and for circadian rhythm by single cosinor. Individual rhythm characteristics for each variable were summarized for the group by population mean cosinor. The vast majority of variables revealed statistically significant within-day changes in values as validated by one-way ANOVA. All vital signs (except for intraocular pressures) and all serum hormones displayed a prominent circadian rhythm for the group, as did most variables in whole blood, while only about half of the variables in urine demonstrated a significant group rhythm. The results obtained are meant to: (a) document the circadian time structure; and (b) serve as reference values for circadian rhythm characteristics (range of change, mesor, amplitude and acrophase) for a defined group of individuals: clinically-healthy adult men in the prime of life.
Article
The conventional treatment of CAH with hydrocortisone (16–19 mg/m2 per day) and 9α-F-cortisol (just enough to normalise renin concentrations, started at 07:00 h) was inffective in suppressing the early morning rise of 17-OH-progesterone and in turn androgens in about 20% of our patients. The present work explored the effect of a modified dosage regimen of the drug in five patients. The schedule was: 03:00 h F 33%+9α-F-F 33%; 07:00 h F 30%; 12:00 h F 22%+9α-F-F 33%; 17:30 h F 15%+9α-F-F 33%. Monitored levels of circulating 17-OH-progesterone, testosterone, and individual urinary 17-ketosteroids showed significant improvement, which was not achieved by giving higher or later evening doses. Menarche was induced in two girls (bone age 15 years). The modified dosage schedule offers on the one hand the possibility of better management of CAH, and on the other, cuts down the risk of enhanced Cushing-like effects, which in animal models have been related frequently to dosage schedules not corresponding to the circadian rhythm. The difficulty of administering the drugs at 03:00 h should be overcome by the development of a late-releasing preparation.
Article
The authors and the journal apologize for an error in the above paper which appeared in 157 (1) ( 109–112 ). In this paper on page 110, the hydrocortisone doses given in Fig. 1A were incorrect. The correct hydrocortisone doses were 0.5 (08–12 h), 0.2 (12–20 h), 0.05 (20–02 h) and 1.0 mg/m ² body surface area/hour (02–08 h).
Article
BACKGROUND AND OBJECTIVES Excess Impaired glucose tolerance and diabetes mellitus have been reported in hypopituitary adults on conventional replacement therapy Including glucocorticoids. We investigated the effect of the glucocorticoid component on glucose tolerance and intermediary metabolites in hypopituitary adults. DESIGN A 3-hour 75-g oral glucose tolerance test (OGTT) was performed on two study days, at least one week apart. On one study day, the glucocorticoid replacement morning dose was taken 60 minutes before the OGTT, and on the other it was left until after the OGTT. All other pituitary replacement therapies were kept unchanged on the two study days. PATIENTS Eight hypopituitary adults (3 males and 5 females; aged 46–76 years) on conventional replacement therapy were studied. Their duration of hypopituitarism was mean (range) 15 (5–31) years. Their mean body mass index (BMI) was 28·4 (24·1–35·1) kg/m2. Their total daily cortisol dose was 26 (15–30) mg. MEASUREMENTS Plasma glucose, insulin, non-esterified fatty acids (NEFA), glycerol and 3-hydroxybutyrate were measured at 30-minute intervals and plasma cortisol levels were measured hourly. RESULTS Fasting glucose and insulin concentrations were similar on the glucocorticoid day (GD) and the non-glucocorticoid day (NGD) (glucose (mean ± SD) 4·9 ± 0·9 vs 4·4 ± 0·5 mmol/l, insulin (median (range) 5 (1-17) vs 2 (1-15) mU/l, respectively). Post-glucose glycaemia was higher on the GD than on the NGD with a significantly higher glucose area under the curve (AUC) (45·0 ± 82 vs 38·9 ± 11·7 mmol/l h, P < 0·05). Post-glucose insulinaemia was also higher on the GD than on the NGD with significantly higher insulin AUC (270 (47-909) vs 207 (46-687)mU/l h, P < 0·02). Impaired glucose tolerance was found in three patients on the GD, one of whom continued to have impaired glucose tolerance on the NGD. The areas under the curves of NEFA, glycerol and 3-hydroxybutyrate were not significantly different on the two days. On the NGD, plasma cortisol levels were undetectable (<50nmol/l) in all patients and on the GD the median (range) peak was 500 (330–740) nmol/l dropping to 125 (60-330) nmol/l at 180 minutes. The difference in glucose AUC between the two days correlated with the maximal plasma cortisol levels (Spearman's p= 0·83, P < 0·01). CONCLUSIONS Glucocorticoid replacement therapy taken pre-prandially In hypopituitary adults induces mild elevations In circulating glucose and insulin levels even with acceptable plasma cortisol concentrations. Optimal regimens for glucocorticoid replacement require more study.
Article
The mean 24-hour plasma level of cortisol with plasma sampling every 20–30 minutes was determined in 32 normal women aged 12–73, 40 normal men aged 10–55, 21 depressed women aged 20–61, and 11 depressed men aged 22–66. The mean levels of cortisol were higher in the group of depressives compared with the controls. Cortisol levels showed a significant linear correlation with age in normal women but not in normal men. Both depressed women and men had a significant linear increase of cortisol levels with age. The finding that age substantially contributes to increased levels of cortisol calls for cautious interpretation of any data concerning that hormone when the variable of age is not adequately controlled. Furthermore, aging and depression may have some underlying mechanisms whose elucidation may contribute to the understanding of the pathophysiology of vulnerability to affective disorders.
Article
Bone turnover has a circadian pattern, with bone resorption and, to a lesser extent, bone formation increasing at night. Serum cortisol also has a circadian pattern and is a potential candidate for mediating the circadian changes in bone turnover. Thus, we measured bone formation and resorption markers before (study A) and after (study B) elimination of the morning peak of cortisol. We also assessed effects of the circadian cortisol pattern on serum calcium, PTH, and urinary calcium excretion. Ten normal postmenopausal women, aged 63-75 yr (mean, 69 yr), were studied. Metyrapone was administered to block endogenous cortisol synthesis and either a variable (study A) or a constant (study B) infusion of cortisol was given to reproduce and then abolish the morning cortisol peak. Blood was sampled every 2 h for serum cortisol, ionized calcium, PTH, and bone formation markers [osteocalcin and carboxyl-terminal propeptide of type I collagen (PICP)], and timed 4-h urine samples were collected for measurement of calcium, phosphorus, sodium, potassium, and bone resorption markers (N-telopeptide of type I collagen and free deoxypyridinoline). During study A, serum osteocalcin had a circadian pattern, with a peak at 0400 h and a nadir at 1400 h. During study B, however, the afternoon nadir of serum osteocalcin was eliminated (P < 0.001 and P < 0.005 for the difference in the patterns of peak and nadir, respectively, on the 2 study days). In contrast, the circadian patterns of serum PICP and urinary N-telopeptide of type I collagen and free deoxypyridinoline were virtually identical during the two studies. Urinary calcium excretion declined after the cortisol peak, without differences between the 2 study days in phosphorus or sodium excretion or in serum PTH. We conclude that the circadian variation in serum cortisol is responsible for the circadian pattern of serum osteocalcin, but not that of PICP or bone resorption markers. The physiological variation in serum cortisol may also reduce urinary calcium excretion.