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Medical Management of Cushing's
Syndrome
Farah H Morgan, Marc Laufgraben
Expert Rev Endocrinol Metab. 2013;8(2):183-193.

Abstract and Introduction
Abstract

Cushing's syndrome is a debilitating endocrine disorder which results from
hypercortisolemia. While endogenous Cushing's syndrome can be caused by an
adrenocorticotrophic hormone (ACTH)-dependent or ACTH-independent
mechanism, it is most often a result of excess secretion of ACTH by a
corticotroph adenoma (Cushing's disease). Untreated hypercortisolemia causes
significant morbidity and increased mortality due to its metabolic effects including
hypertension, osteoporosis, obesity, dyslipidemia, osteoporosis and glucose
intolerance. Although primary therapy is surgical, a substantial portion of patients
will go on to require second-line therapies including repeat surgery, radiotherapy
or drug therapy. While medical therapy for Cushing's syndrome has been limited,
several new agents are being investigated. This aim of this review is to analyze
and present the available options for medical management of Cushing's
syndrome as well as review potential new therapies and their role in the
treatment of this disorder.
Introduction

Endogenous Cushing's syndrome is a debilitating endocrine disorder which
results from excess circulating cortisol. Eighty percent of the cases are a result of
excess adrenocorticotrophic hormone (ACTH) secretion, usually by a corticotroph
pituitary adenoma, also called Cushing's disease. [1,2] Other causes of ACTHdependent Cushing's syndrome include extrapituitary tumors that secrete ACTH
(ectopic Cushing's syndrome) and, rarely, corticotroph-releasing hormonesecreting tumors. Twenty percent of the patients with endogenous Cushing's
syndrome will have ACTH-independent Cushing's syndrome caused by an
adrenocortical tumor or adrenal hyperplasia. [1] While a rare disease with an
estimated incidence of two to three cases per million population per year, [3] the
metabolic effects of hypercortisolemia may result in hyperglycemia, osteoporosis,
hypertension, dyslipidemia, obesity, muscle weakness, depression, hirsutism,
acne, cognitive impairment, menstrual disturbances and fatigue. [1,4–6] These
effects cause significant morbidity and decreased quality of life. The overall
mortality in patients with active Cushing's syndrome may be up to four-times
higher than the general population. [7,8]

Treatment Options for Cushing's Syndrome
The goal of the treatment of Cushing's syndrome is rapid normalization of the
negative metabolic effects and biochemical abnormalities associated with the
disorder. Treatment is ultimately directed at the source of the disorder. Patients
with cortisol-producing adrenal adenomas will be cured by unilateral
adrenalectomy, while those with adrenal carcinomas will often have residual or
metastatic disease after surgery that requires second-line treatment. The
preferred treatment for patients with ACTH-independent bilateral adrenal
hyperplasia is bilateral adrenalectomy. While treatment for ectopic tumors targets
the underlying neoplasm, patients often require second-line therapy for persistent
hypercortisolemia.
In patients with Cushing's disease, the primary treatment modality is
transsphenoidal surgery, which results in variable remission rates of 50–80%. [1,9–
12]
Second-line therapies (after recurrence or failure to attain remission after initial
surgery) include repeat transsphenoidal surgery, radiotherapy, bilateral
adrenalectomy or medical therapy. In an experienced center, repeat
transsphenoidal surgery is often the preferred second-line treatment. Fifty
percent of patients will attain remission after a second transsphenoidal
surgery. [1,11,13,14] While relatively effective, repeat transsphenoidal surgery does
carry a higher risk of hypopituitarism. [13,15] Radiotherapy has up to an 83% longterm remission rate, although time to remission is delayed by 12–48 months or
more, requiring patients to be placed on medical therapy as a bridge during this
time period to control effects of hypercortisolism. [1,4,16,17] The risk of new pituitary
deficiency following radiotherapy ranges from 50 to 60%, [4,15,18] and these
deficiencies often appear many years after treatment.
While bilateral adrenalectomy is a permanent cure for hypercortisolemia in
Cushing's disease, patients then have adrenal insufficiency requiring life long
replacement therapy with glucocorticoids and mineralocorticoids. Occasionally,
patients can have continued hypercortisolemia following bilateral adrenalectomy
as a result of cortisol secretion from adrenal rests. Patients with Cushing's
disease treated with bilateral adrenalectomy are also at risk for Nelson's
syndrome (corticotroph tumor progression) which occurs in up to 50% of the
patients. [1,11,19] The risk of Nelson's syndrome may be higher in patients with a
shorter duration of Cushing's syndrome prior to adrenalectomy, higher plasma
ACTH concentrations the year after adrenalectomy, and those with visible
adenoma on MRI. [19] The major advantage to adrenalectomy is the rapid control
of hypercortisolemia. Bilateral adrenalectomy is often considered in patients who
have failed repeat transsphenoidal surgery or radiotherapy, and in women who
do not want to risk the possibility of hypogonadism and infertility from other
treatment modalities. [1]

Medical Therapy
Medical therapy of hypercortisolemia is typically reserved for patients who are
unable to undergo surgery, for patients who have failed to achieve remission with
other treatment modalities, as a bridge to radiotherapy or surgery, or as a

palliative option (Figure 1). A number of potential targets exist for medical therapy
including inhibition of steroidogenesis, inhibition of ACTH secretion and
glucocorticoid receptor antagonism (). The most commonly used agents have
been steroidogenesis inhibitors although other classes of medications are being
actively investigated.
Table 1. Medical therapy for the treatment of Cushing's syndrome.
Drug

Initial dose

Maximum
dose

Major limitations

Steroidogenesis inhibitors
Ketoconazol
e

200 mg
b.i.d.

400 mg t.i.d.

Elevated LFTs, hypogonadism

Metyrapone

250 mg
q.i.d.

1500 mg
q.i.d.

Hirsutism, edema, HTN,
hypokalemia

Mitotane

500 mg
b.i.d.

3000 mg t.i.d. GI upset, ataxia, confusion, vertigo

Etomidate

0.1 mg/kg/h 0.3 mg/kg/h

iv. administration, sedation

Glucocorticoid receptor antagonism
Mifepristone

300 mg daily 1200 mg daily Hypokalemia, nausea

ACTH modulators
Pasireotide

600 μg bid

900 μg b.i.d.

Hyperglycemia, nausea, diarrhea

Cabergoline

1 mg/week

7 mg/week

Nausea, dizziness, hypotension

ACTH: Adrenocorticotrophic hormone; b.i.d.: Twice daily; GI: Gastrointestinal;
HTN: Hypertension; iv.: Intravenous; LFTs: Liver function tests; q.i.d.: Four-times
daily; t.i.d.: Three-times daily.
Data taken from [1,39,43,49,58].

Figure 1.
Algorithm for appropriate use of medical therapy in Cushing's disease. TSS:
Trans-sphenoidal surgery.

Steroidogenesis Inhibitors
Steroidogenesis inhibitors control cortisol production by decreasing steroid
hormone production in the adrenal gland through inhibition of one or more
enzymes involved in steroid synthesis. Steroidogenesis inhibitors can be used for
either partial or complete blockade of cortisol production. When used for partial
blockade, the doses of these medications are adjusted to achieve normal urine
cortisol levels. When used for complete blockade, a 'block and replace' strategy
involves steroidogenesis inhibitors at doses that will achieve complete inhibition
of cortisol synthesis, and glucocorticoids to replace physiologic needs.
Ketoconazole

Ketoconazole, an antifungal agent, is the most commonly used steroidogenesis
inhibitor in the USA because of its availability and relatively rapid onset of action.
It is an imidazole derivative that inhibits steroid synthesis through inhibition of
cytochrome P450 enzymes 17,20-lyase, 11-B hydroxylase, 17-hydroxylase and

side chain cleavage. [15,20] These effects are dose dependent and completely and
rapidly reversible upon drug discontinuation.
In 1982, Pont et al. evaluated the effects of ketoconazole on steroid synthesis in
healthy subjects. The investigators demonstrated a blunted cortisol response to
synthetic ACTH (Cortrosyn) 4–6 h after administration of 400–600 mg of
ketoconazole. [21] This blunted cortisol response persisted for up to 8 h and was
resolved by 16 h. [21] This was one of the first reports to demonstrate the adrenal
effects of ketoconazole and suggest the potential use of ketoconazole in the
treatment of Cushing's syndrome. A number of small case series using
ketoconazole in the treatment of Cushing's syndrome ensued. [22]In 1991,
Sonino et al. evaluated a larger series of 34 patients with Cushing's syndrome
who were treated with ketoconazole as a palliative measure in preparation for
surgery, before or after radiation treatment or in patients not suitable for surgery.
The patient population consisted of 28 patients with Cushing's disease, one with
an adrenal adenoma, two with adrenal hyperplasia, one with adrenal carcinoma
and two with ectopic ACTH production. Doses ranged from 400 to 800 mg/day
divided into two doses. The patient with adrenal carcinoma received a dose of
1000–1200 mg/day for 3 months. Doses were adjusted periodically based on
clinical response. Urine-free cortisol decreased from 1296 ± 176 to 270 ± 69
nmol/day (normal range: 55–331 nmol/day; p < 0.001). Urine-free cortisol
remained in the normal range throughout treatment in 30 out of 34 patients while
on therapy. [23] Two of the 34 patients developed increased cortisol levels after 6
months of treatment and another two had continued elevated cortisol levels. [23] A
meta-analysis of eight trials involving patients with Cushing's syndrome treated
with ketoconazole as monotherapy reported an average remission rate of 70%
(25–93%). [15,18,24]
In 2008, Castinetti et al. published a study evaluating a total of 38 patients with
Cushing's disease between 1995 and 2008 treated with ketoconazole for a mean
duration of 23 months. Initial dosing was 200–400 mg/day with dose increases of
200 mg/day every 10–15 days up to a maximum dose of 1200 mg/day. Of the
patients included in the study, 17 had previous unsuccessful pituitary surgery, 15
had no visible tumor on MRI, one refused surgery, one had a contraindication to
surgery and four were awaiting the effect of gamma knife radiosurgery. Five
patients discontinued treatment in the first week because of nausea and diarrhea.
One of the five patients also had a fivefold increase in GGT despite normal ALT
and AST. [2] Seventeen patients (44.7%) achieved biochemical control of disease
with normalization of urine-free cortisol within the first 3 months on therapy. [2] In
five patients with diabetes, glycosylated hemoglobin (HbA1c) was improved by
0.5–3.5%. This study differed from others in having a large proportion of patients
treated with ketoconazole as a primary treatment modality. There was no
difference in study parameters between patients treated with ketoconazole as
primary verse secondary therapy. [2]
The most common side effects of ketoconazole when used as an antifungal at
lower doses of 200–400 mg daily are gastrointestinal side effects and pruritis
occurring in 2–5% of the patients. [18,20,25] A major limiting side effect is elevated
liver function enzymes. Ketoconazole carries a black box warning for

hepatotoxicity associated with fatalities. Idiosyncratic liver dysfunction occurs in
1:10,000 exposed patients. [25] Liver enzymes should be monitored closely during
treatment and titration: biweekly for the first 2 months of treatment and then
monthly thereafter. Elevation in liver enzymes is dose dependent occurring in
10% of the patients but is reversible with discontinuation of the drug. [18,20] If liver
enzymes become elevated greater than threefold the normal level, ketoconazole
should be discontinued. [1] Adrenal insufficiency is rare. Hypogonadism occurs
commonly in men because of inhibition of sex steroid synthesis. [15,18,23,26] There is
some evidence to suggest inhibition of 1,25 vitamin D synthesis although this
effect has not been completely elucidated. [22]
Ketoconazole does have a number of drug interactions because of its strong
inhibition of CYP3A4. This results in potentiation of drugs that are metabolized by
CYP3A4, such as oral anticoagulants, mifepristone, statins, cyclosporine and
tacrolimus. Combination with CYP3A inducers such as phenytoin may reduce
ketoconazole levels. [18,20]
Administering ketoconazole with food decreases its concentrations. In addition,
gastric acid is required for adequate absorption therefore it should not be
administered with a proton pump inhibitor or histamine 2 receptor blocker. [20] The
initial dosing of ketoconazole is 200 mg twice daily. Urine-free cortisol can be
monitored for effectiveness and the dose can be titrated up to a maximum of 400
mg three-times daily for control of hypercortisolism. [1]
Metyrapone

Metyrapone was first introduced in 1956 and was shown to block the production
of cortisol through the inhibition of 11B-hydroxylase, resulting in a dramatic rise in
11-deoxycortisol, a precursor steroid with mineralocorticoid activity formed
immediately proximal to cortisol in the steroid biosynthesis pathway. [18,27] It was
initially used as a diagnostic test of ACTH reserve as well as in the differential
diagnosis of Cushing's syndrome, [27] but it was eventually shown to be effective in
the treatment of Cushing's syndrome.
In 1977, Jeffcoate et al. treated 13 patients with Cushing's disease with
metyrapone for 2–66 months. The dose varied from 250 mg twice daily to 1000
mg four times daily. Clinical features of Cushing's syndrome rapidly improved.
Although this study was limited by the small number of patients as well as the fact
that urine-free cortisol levels were not reported, it did demonstrate the usefulness
of this agent in the treatment of Cushing's syndrome. [27,28] In a larger study,
Verherst et al. evaluated 91 patients, 57 with Cushing's disease, ten with adrenal
adenomas, six with adrenocortical carcinoma and 18 with ectopic Cushing's
syndrome [29]. Short- and long-term responses to metyrapone were evaluated.
Test dosing with 750 mg demonstrated a decrease in cortisol levels within 2 h of
administration of metyrapone. Fifty three patients with Cushing's disease were
followed on treatment with metyrapone short term for 1–16 weeks prior to
definitive therapy. Patients were initiated on 250–750 mg of metyrapone every 8
h. This dose was titrated after 48–72 h based on cortisol levels to a minimum of
250 mg twice daily and a maximum of 1.5 g four times daily. Target cortisol levels
were <400 nmol/l given that levels of 300–400 nmol/l reflect normal cortisol

production and were associated with clinical remission from previous
studies. [27,29]Mean cortisol levels dropped from 654 to <400 nmol/l in 75% of the
patients on a median dose of 2250 mg/day. Metyrapone was then administered
for a median of 27 months in 24 patients with Cushing's disease after pituitary
irradiation. Adequate control of hypercortisolemia occurred in 83% of the
patients. [29] It is thus reported to be effective for primary therapy for Cushing's
disease, at least in the short term, in 75% of the patients and also effective in
combination with radiotherapy.[15,18,29] Metyrapone was found to be similarly
effective at controlling hypercortisolemia in patients with adrenal tumors (81% of
the 16 patients achieved mean cortisol levels of <400 nmol/l) and ectopic ACTH
production (70% of the 18 patients achieved mean cortisol levels of <400
nmol/l). [29]
Gastrointestinal side effects and dizziness frequently occur. As noted previously,
the inhibition of 11B-hydroxylase results in a dramatic rise in the mineralocorticoid
11-deoxycortisol. Despite this, hypokalemia, edema and hypertension are
relatively infrequent side effects. Verhelst et al. reported new hypokalemia in 6%
of the patients and edema in 8%. [29] Metyrapone also results in an increase in
androgen levels causing the undesirable effect of hirsutism in up to 52% of
women. [29]
Initial dosing is 250 mg four-times daily with a maximum dose of 1500 mg fourtimes daily. [1] Metyrapone was previously only available in the USA for
compassionate use but has recently become commercially available in the USA
and parts of Europe through a specialty pharmacy (HRA Pharma). [101]
Mitotane

Mitotane reduces cortisol synthesis through the inhibition of 11B-hydroxylase, 18hydroxylase, 3-α hydroxylase, hydroxysteroid dehydrogenase and several
cholesterol side chain cleavage enzymes. [18] It is also an adrenolytic agent at
doses greater than 4 g per day, and is used most often for the treatment of
adrenocortical carcinoma.
Mitotane has been studied for the management of Cushing's syndrome from both
ACTH-dependent and ACTH-independent causes. In 1979, Luton et al. studied
62 patients with Cushing's disease treated with mitotane (4–12 gm/day divided
three-times daily) for an average duration of 8 months [30]. In most cases, the
initial daily dose was 12 g per day for 3 months and then 8 g per day. Forty six
patients received mitotane alone and 16 patients received mitotane in addition to
pituitary irradiation. Remission was achieved in 38 of the 46 patients given
mitotane alone and in all patients who received drug therapy plus
radiation. [30] During long-term follow-up, 20 patients relapsed and required further
treatment. Overall remission rates of Cushing's disease with mitotane are up to
83% short term. [15,18,30] In addition, Luton et al. demonstrated clinical effectiveness
of mitotane in controlling hormonal secretion of adrenocortical carcinoma.
Seventy five percent of the 59 patients with adrenocortical carcinoma receiving
mitotane therapy had control of hormonal secretion. [31] More recent studies have
demonstrated the effective use of combination chemotherapy with mitotane for
the treatment of adrenocortical carcinoma. [32]

Gastrointestinal side effects include nausea, anorexia and vomiting. These side
effects are often dose limiting. Other side effects observed include gynecomastia,
hypercholesterolemia and hyperuricemia. [18,30] More serious neurologic side
effects include ataxia, lethargy, vertigo and confusion. Side effects often limit the
tolerability of mitotane. In addition, mitotane is teratogenic and should be used
with extreme caution in women of childbearing potential. Mitotane also has a slow
(weeks to months) onset of effect as adipose tissue accumulation delays
achievement of therapeutic serum levels. [33] Therefore, it has been advocated to
be used in combination with another drug to attain more rapid control of
hypercortisolism. [1,18,34] In patients with Cushing's disease, if pituitary irradiation is
not used in combination with mitotane, there may be risk of Nelson's syndrome
as the reductions in cortisol achieved by mitotane mimic effects of
adrenalectomy. [18,24] Adrenal insufficiency is an expected side effect due to the
adrenolytic effect of the drug particularly at higher doses. Mitotane increases
cortisol binding globulin, resulting in an overestimation of serum-free cortisol,
making this an unreliable measure of steroidogenesis. Therefore, patients should
be monitored for reduction in steroidogenesis with serum ACTH, plasma renin,
sodium, potassium and urine-free cortisol. Once urine-free cortisol levels are
normalized, replacement glucocorticoids should be initiated. Initiation of
hydrocortisone should start at a dose of 25–30 mg/day with titration of
hydrocortisone based on urine-free cortisol and plasma ACTH levels.
Hydrocortisone requirements increase two- to three-fold on mitotane therapy
because mitotane increases its metabolism. [35] An alternative glucocorticoid
replacement is prednisone, as its metabolism is not effected by
mitotane. [15,18]Replacement mineralocorticoids are often not required immediately
as the zona glomerulosa is more resistant to mitotane's adrenolytic effects. [35]
Initial dosing of mitotane in Cushing's syndrome is 0.5–1 g daily in divided doses
with titration up to a maximum of 3000 mg three-times daily. [1] Dosing of mitotane
for adrenocortical carcinoma begins at 1–2 g/day with titration by 1–2 g every 1–2
weeks up to a maximum of 10 g/day. Serum levels of mitotane should be
measured by a gas chromatography-flame ionization detection assay at 4–8week intervals initially with goal serum levels of 10–14 mg/l. [33] Once appropriate
serum levels are achieved, they should be followed every 3 months. [33] When
using mitotane for adjuvant therapy in patients with adrenocortical carcinoma with
normal urine-free cortisol levels, glucocorticoid replacement should occur with the
start of mitotane therapy or when the dose reaches 2 g/day. [35] In patients started
on mitotane for residual adrenocortical carcinoma with continued
hypercortisolemia, glucocorticoids should be initiated when hypercortisolemia is
controlled as indicated by normalization of urine-free cortisol. [35]
Aminoglutethimide

Aminoglutethimide was first introduced in 1959 as an anticonvulsant and was
subsequently found to inhibit steroidogenesis through inhibition of side chain
cleavage and therefore the conversion of cholesterol to pregnenolone, [18,24,36] the
first step in steroid hormone biosynthesis. Because of this mechanism, it also
inhibits estrogen and aldosterone production, [18] and has been investigated in the
treatment of breast cancer. [37]

Inhibition of steroidogenesis with aminoglutethimide results in a compensatory
increase in ACTH, which subsequently causes cortisol to rise again (the 'escape
phenomenon'). [37] In patients with Cushing's disease, the effect of
aminoglutethimide on cortisol levels lasts 3–7 days before the escape
phenomenon occurs. Because of this, studies have shown aminoglutethimide to
have limited efficacy in Cushing's disease. Initial reports demonstrated a roughly
30% reduction in cortisol synthesis. [37] A large study of 66 patients with Cushing's
syndrome demonstrated clinical efficacy in 14 of the 33 patients with Cushing's
disease. [24] Aminoglutethimide is no longer used in the treatment of Cushing's
syndrome because of lack of availability.
Etomidate

Etomidate, an intravenous medication used for anesthesia induction, inhibits
cholesterol side chain cleavage and 11-B hydroxylase. Etomidate was initially
developed as a nonopioid anesthetic, but because of an association with
increased mortality in critically ill patients, it was discovered to have an inhibitory
effect on adrenal steroid synthesis. [38] Studies in healthy subjects revealed that
the infusion of etomidate resulted in significant suppression of cortisol levels after
5 h with maximal effects at 11 h. [38,39] Etomidate has been successfully used as a
short-term treatment in critically ill patients with Cushing's syndrome unable to
take oral medications. [38] Krakoff et al. used etomidate successfully as long-term
treatment for 5.5 months in a critically ill patient unable to take oral medications.
Initial dosing was 0.03 mg/kg/h with titration to a goal cortisol concentration of
15–30 µg/dl. This cortisol target was chosen to mimic cortisol values that would
be appropriate for stress in the intensive care unit. Etomidate resulted in the
adequate control of hypercortisolemia as defined by target serum cortisol.
Adrenal insufficiency was a reversible side effect which was treated successfully
with hydrocortisone. [38]
The major limitation is its availability only as an intravenous preparation. While
sedation occurs at higher doses (induction anesthesia doses are typically 0.2–0.4
mg/kg/h), doses as low as 0.04–0.05 mg/kg/h have been shown to adequately
inhibit cortisol production without causing sedation. [40] Thus, etomidate can be a
safe and effective treatment for Cushing's syndrome in patients requiring rapid
control of hypercortisolemia. [40] Transient myoclonus is a common but short-lived
effect, and adrenal insufficiency, should it occur, is reversible. The effect of
adrenal suppression has been reported to last between 1 and 4 days with shortterm use of the drug but up to 14 days when etomidate is used for longer
durations. [38]
Because of its availability as an intravenous preparation only, it has been used
primarily in the emergent setting for rapid control of hypercortisolemia. [15,18,38] It is
administered with an initial bolus of 0.03 mg/kg/h followed by an infusion of 0.1
mg/kg/h with a maximum dose of 0.3 mg/kg/h. [1] Etomidate should be titrated to a
goal serum cortisol level of 500–800 nmol/l in a physiologically stressed patient
and 150–300 nmol/l in a nonphysiologically stressed patient. [40] Sedation scoring
should be performed every 2 h for the first 24 h, and then every 12 h until the
infusion is stable. [40]

ACTH Modulators
Agents that directly lower ACTH secretion by a pituitary adenoma represent an
attractive option for the treatment of Cushing's disease, as these drugs directly
target the pathogenesis of disease. Among these are dopamine agonists and
somatostatin analogs. While one would hope that the ACTH modulators would
reduce tumor volume (of particular concern in patients with pituitary
macroadenomas), there is very limited data on effects of these medications on
tumor size.
Dopamine Agonists

Bromocriptine was introduced in 1968 as a dopamine receptor agonist with rapid
inhibitory effects on pituitary prolactin secretion. [36] Dopamine agonists are widely
available and used clinically for the treatment of prolactinomas and occasionally
for acromegaly. However, use in Cushing's syndrome has shown variable results
possibly with better short-term than long-term results. Boscaro et al. reported no
acute change in ACTH after a single dose of bromocriptine but a reduction in
ACTH in two of the five patients after 2 days of drug therapy. [41] Other series have
reported response rates of 4–23% after acute or chronic administration. [39]
Pivonello et al. studied D2 receptor expression on corticotroph pituitary tumors,
the effects of in vitro dopamine agonist on ACTH secretion and the effect of in
vivo dopamine agonist therapy in 20 patients who underwent transsphenoidal
resection for Cushing's disease. [42] Functional D2 expression was found in 80% of
the pituitary corticotroph tumors. In vitro suppression of ACTH in response to
dopamine agonist therapy occurred in 100% of the D2-positive tumors. [43] Threemonth treatment with cabergoline (doses ranging from 1 mg/week to 3 mg/week)
suppressed cortisol in 60% of the patients with remission rates reported in four of
the ten patients (40%). Initial dosing was 1 mg/week. Monthly increases of 1
mg/week were made until normalization of daily urinary cortisol excretion
occurred, up to a maximum dose was 3 mg/week. All cabergoline responsive
patients had tumors with D2 expression. All nonresponders, with the exception of
one patient, had D2-negative tumors. [42] An extension of this trial with 20 subjects
treated with doses of cabergoline of 1–7 mg/week (initiation at 1 mg/week with
titration of 1 mg monthly until normalization of urine-free cortisol was attained or a
maximal dose of 7 mg/week was reached) again demonstrated a 40% remission
rate with tumor shrinkage in 20% of the patients. [43]
More recently, Godbout et al. performed a retrospective analysis of 30 patients
with Cushing's disease treated with 0.5–6 mg/week of
cabergoline. [44] Cabergoline was initiated at a dose of 0.5–1 mg/week and was
increased by 0.5–1.0 mg/week at 1 or 2 month intervals until normalization of
urine-free cortisol or maximal dose of 6 mg/week. Twenty seven patients were
placed on therapy for persistent or recurrent disease after initial pituitary surgery
and three patients were started on cabergoline as primary therapy. Within 3–6
months, complete remission (defined by normalization of urine-free cortisol) was
achieved in 36.6% of the patients and partial remission, defined as urine-free
cortisol <125% of the upper limit of normal, was achieved in 13.3% of the

patients. Average time to remission was 4.2 months. Long-term treatment
resulted in complete remission in 30% of the patients with average doses of 2.1
mg/week and average treatment duration of 37 months. [44]
Specifically desirable is the potential for improvement in plasma glucose and
insulin resistance with the use of these agents. [7,11,15,43,45] In the study by
Pivonello et al., the prevalence of diabetes and impairment of glucose tolerance
was reduced from 25 and 37% at baseline to 10 and 20% after 24 months of
treatment. [43] Side effects of dopamine agonist therapy include hypotension,
asthenia, dizziness, nausea and dry mouth. [11] While cardiac valve dysfunction is
a concern with high-dose therapy (which is used in patients with Parkinson's
disease), this was not observed in the reported studies likely because
cabergoline is used at much lower doses in patients with
hyperprolactinemia. [39,42,44]
Although there are no head-to-head trials, available data cited above suggest that
cabergoline may be more effective than bromocriptine in patients with Cushing's
disease with a 30–40% response rate versus 4–23% response rate. Cabergoline
for Cushing's disease is typically initiated at 0.5 mg per week, with titration to a
maximal dose of 7 mg/week.
Somatostatin Analogues

Somatostatin analogues are clinically used for the treatment of acromegaly and
have the benefit of both reduction of tumor size and hormonal control of this
disease. Because pituitary corticotroph adenomas express somatostatin
receptors, somatostatin analogues have been investigated as a potential targeted
therapy for the treatment of Cushing's disease.
Octreotide, a somatostatin analogue, which predominantly acts on somatostatin
type 2 receptors (sst2 receptors), has been shown, in vitro, to lower ACTH levels
but is largely ineffective in lowering ACTH levels in vivo in patients with
hypercortisolemia secondary to Cushing's disease. [11,15] This may be a result of
relatively low levels of expression of sst2 in patients with Cushing's disease. [39] By
contrast, somatostatin analogs have been shown to be effective in reducing
pathologic ACTH levels in patients with Nelson's syndrome. The fact that patients
with Nelson's syndrome show an increased uptake of the radiolabeled
somatostatin analog pentetreotide and respond to somatostatin with a reduction
in pathologic ACTH production indicates that the downregulation of sst2 receptors
in patients with Cushing's disease may be a result of hypercortisolemia. [46] A
newer multiligand somatostatin analog, pasireotide, which acts on type 1, 2, 3
and 5 somatostatin receptors (sst receptors) with highest affinity for sst5
receptors, which are highly expressed in corticotroph pituitary adenomas, [39] has
been demonstrated to inhibit ACTH release in human corticotroph
cells. [7,15,47] Pasireotide has a 40-fold higher affinity for sst5 receptors than
octreotide. [39]
In 2006, Batista et al. evaluated fresh tumor tissue from 13 patients with
Cushing's disease who underwent transsphenoidal resection of their pituitary
tumor. [47] Sst5 was highly expressed in 83% of the tumors. Changes in cell

proliferation and ACTH secretion as a result of pasireotide were measured as
percent suppression. Pasireotide resulted in 10–70% suppression of cell
proliferation and 23–56% suppression of ACTH secretion. Pasireotide
suppressed cell proliferation in all tumors and suppressed ACTH secretion in five
of six tumors. [47]
Boscaro et al. evaluated 39 patients in a Phase II, open-label, single arm
multicenter center study [48]. Patients either had de novo Cushing's disease
(newly diagnosed without previous treatment) and were candidates for pituitary
surgery or had persistent or recurrent Cushing's disease after surgery. No
patients had received prior radiation therapy. Patients self-administered 600 µg
subcutaneously twice daily for 15 days. The primary efficacy outcome was
normalization of urine-free cortisol at 15 days. Twenty nine patients were in the
primary efficacy analysis. The other ten patients were excluded because of
discontinuation of drug (one), inadequate urine-free cortisol measurements (five)
and normal baseline urine-free cortisol (four). The investigators reported that 76%
of the patients treated with pasireotide had reduction in urine-free cortisol and
17% had normalization of urine-free cortisol. [48] Mean urine-free cortisol
decreased from baseline by 44.5% (p = 0.021). Serum ACTH did not differ at the
start or end of the study between responders and nonresponders. [48]
Most recently, Colao et al. performed a double-blind, Phase III trial of 162 adults
with Cushing's syndrome treated with 600 or 900 µg of pasireotide administered
subcutaneously twice daily. The primary end point was reduction of urine-free
cortisol to or below the normal range at 6 months with an open-label extension
through 12 months. [49] Median urine-free cortisol decreased by 50% by month 2
and remained stable but only 12 of the 82 patients (15%) in the 600 µg group and
21 of the 80 (26%) patients in the 900 µg group had normal cortisol levels at
month 6. At month 12, 13% of those in the 600 µg group and 25% of the patients
in the 900 µg group had normalization of urine-free cortisol. [49] Pasireotide
received recent EU approval as well as recent US FDA approval in the US and
will be marketed as Signifor® (Novartis Pharmaceuticals).
Boscaro et al. reported adverse effects of pasireotide in up to 93% of the patients
most commonly diarrhea (53%), nausea (43.6%), hyperglycemia (35.9%),
headache (17.9%) and abdominal pain (17.9%). The most common side effects
reported in the most recent Phase III trial were diarrhea (58%), nausea (52%),
hyperglycemia (40%), cholelithiasis (30%), headache (28%), abdominal pain
(24%), fatigue (19%) and diabetes (18%). In fact, hyperglycemia-related effects
occurred in up to 73% of the patients. [49] Forty eight percent of the nondiabetic
patients had a glycated hemoglobin >6.5% at study end. [49]Hypothyroidism is
also a well-recognized side effect due to inhibition of TSH secretion.
Retinoic Acid

Retinoic acid has been shown to inhibit proliferation, invasion and tumor
growth in vivo. It also induces apoptosis in different cell types (human and animal
cancer cells) mediated by reduction in the binding of transcription factors which
are thought to be essential in the control of the POMC gene, which is crucial in

ACTH production. [50] Animal studies have shown reduction in ACTH, cortisol and
tumor size in dogs with Cushing's disease treated with retinoic acid. [50]
More recently, a prospective, multicenter pilot study evaluated the effectiveness
of retinoic acid in the treatment of Cushing's syndrome. Seven patients with
Cushing's disease were initiated on 10 mg of retinoic acid daily with doubling
every 2 weeks with a maximum dose of 80 mg daily. Urine-free cortisol was
evaluated at 6 months for response. Responders (those with an at least 50%
reduction in urine-free cortisol) continued treatment for a total of 12 months. Five
patients experienced reduction in urine-free cortisol values; of these, three
patients achieved normal urine-free cortisol. [51]
Although this pilot study is intriguing, larger studies are needed to further
evaluate the effectiveness and side effects of treatment with retinoic acid in
Cushing's syndrome. This medication is teratogenic and is not currently approved
for use in the treatment of Cushing's syndrome. [51]

Glucocorticoid Receptor Antagonism
Mifepristone

Mifepristone (RU486) was originally developed as an antiglucocorticoid. It binds
the glucocorticoid receptor with a fourfold higher affinity than dexamethasone and
18-fold higher affinity than cortisol resulting in inhibition of activation of the
glucocorticoid receptor. [52] During investigations for its antiglucocorticoid effect, it
was quickly recognized as an antiprogestin and was subsequently developed and
marketed as an abortifacient. [52] Despite its main use as an abortifacient,
mifepristone was reported in several case reports since the 1980s for the
treatment of refractory Cushing's syndrome. [53–56]
A larger series evaluating the effectiveness of mifepristone was published in 2009
by Castinetti et al. [57]. The investigators reported a retrospective study of 20
patients with Cushing's syndrome due to malignant or benign causes. Patients
were treated with mifepristone at oral doses of 400–2000 mg for 5 days to 24
months. Initial dosing was 200–1000 mg/day based on the decision of the
investigator with a maximal dose of 2000 mg. Improvement in clinical symptoms
occurred in 15 of the 20 patients along with improvement in blood glucose levels
in four of the seven patients with hyperglycemia. [57]
Most recently, a large open-label, 24-week multicenter study demonstrated a
reduction in glucose and improvement in a number of other parameters in 50
Cushing's patients treated with mifepristone. Forty three patients had Cushing's
disease, four had ectopic ACTH tumors, and three had adrenal carcinoma.
Treatment with mifepristone was initiated at 300 mg per day and could be
increased incrementally to a maximum dose of 900–1200 mg daily based on
weight. Dose adjustments of 300 mg per day were allowed at day 14 and weeks
6 and 10. Patients were separated into a diabetes cohort (29 patients) and a
hypertension cohort (21 patients). The primary end point in the diabetes cohort
was a reduction in area under the curve for glucose on oral glucose tolerance test
of at least 25% from baseline. Sixty percent of subjects met this primary end point

(p < 0.001). Average reduction in HbA1c was 1.1% (p < 0.001). [58] The
primary end point in the hypertension cohort was a 5 mmHg reduction in diastolic
blood pressure. This end point was met in 38% of the patients though mean
diastolic and systolic blood pressure were unchanged. Other benefits observed
were a 3.6% decline in percent total body fat (p < 0.001) and reduction in waist
circumference. Mood, cognition and quality-of-life scores were also improved. [58]
In addition to blocking the peripheral actions of cortisol, mifepristone blocks
central activity as well causing upregulation of the hypothalamic–pituitary–adrenal
axis, resulting in increased ACTH and cortisol in a proportion of patients with
Cushing's disease. [52] Seventy two percent of the patients with Cushing's disease
treated with mifepristone had at least a twofold increase in ACTH, cortisol or
both. [52] This is not seen in patients with nonpituitary causes of Cushing's
syndrome. [52]Because of this, there is currently no biochemical test to measure its
antiglucocorticoid efficacy and practitioners must rely on the clinical response.
Doses should be titrated based on the symptoms (mood and cognition), clinical
features (bodyweight and composition and blood pressure) and biochemical
parameters such as glucose and HbA1c.
Adverse reactions occurring in ≥20% of the patients include nausea, fatigue,
headache, hypokalemia, arthralgia, vomiting, peripheral edema, hypertension,
dizziness, decreased appetite and endometrial hyperplasia. Other laboratory
abnormalities found were a reduction in high-density lipoprotein levels and
asymptomatic elevations in thyroid stimulating hormone. Recommended
monitoring should include measurement of serum potassium, clinical assessment
of adrenal insufficiency and yearly vaginal ultrasound in women to evaluate for
endometrial hyperplasia. [58,59] Because of the inability to biochemically monitor
cortisol levels, patients must be monitored closely for clinical evidence of adrenal
insufficiency. When observed, this should be treated with cessation of
mifepristone and high-dose dexamethasone to overcome glucocorticoid blockade
for 2 weeks given the long half-life of mifepristone. [59]
In addition, mifepristone effects a number of cytochrome P450 enzymes.
CYP3A4 is involved in the metabolism of mifepristone and mifepristone also both
inhibits and induces CYP3A4. Therefore, drugs that are metabolized by CYP3A4
should be avoided or used with caution. Other enzymes affected by mifepristone
are CYP2C8/2C9 and CYP2B6. Drugs metabolized by these pathways should be
used with caution. [59]
Mifepristone was recently approved by the FDA for use in patients with
hyperglycemia secondary to Cushing's syndrome who have either failed to
achieve remission with surgery or are not surgical candidates. Initial dosing is
300 mg/day with titration up to a maximal dose of 1200 mg/day or 20 mg/kg/day.
It is being marketed as Korlym™ (Corcept Therapeutics Inc., CA, USA) and is
currently available through a central distribution pharmacy. Prescribers must
complete and submit a patient enrollment form to Support Program for Access
and Reimbursement of Korlym (SPARK). SPARK will determine insurance
eligibility and assistance. [102] The cost of Korlym is approximately US$186 per 300
mg pill. Co-pay assistance and patient assistance programs will be available

through Corcept pharmaceuticals and further assistance is available through
National Organization for Rare Disorders. Korlym is not currently available or
approved for use in Cushing's syndrome in the UK or Europe.

Combination Therapy
While each drug available for the treatment of Cushing's syndrome has
limitations, combining agents may limit the side effects of each while improving
treatment efficacy, although there are very few systematic studies of combination
therapy. Aminoglutethimide has often been used in combination with another
agent [18,24] due to its limited efficacy and escape phenomenon. Mitotane is also
often used in combination with another agent due to its delayed onset of action,
while the combination of metyrapone with another steroidogenesis inhibitor would
be expected to reduce the accumulation of cortisol precursors with
mineralocorticoid or androgenic properties that is seen with metyrapone alone.
Kamenicky et al. reported successful combination of mitotane (3–5 g/day),
metyrapone (3–4.5 g/day) and ketoconazole (400–1200 mg/day) in 11 patients
with Cushing's syndrome. Initial dosing was 2.25 g/day of metyrapone, 800
mg/day of ketoconazole and 3 g/day of mitotane. [37] These doses were adjusted
based on the clinical severity, urine-free cortisol excretion and tolerance. All
patients experienced a marked clinical improvement as well as a rapid decrease
in urine-free cortisol from 2737 at baseline to 50 µg/24 h (normal range: 10–65
µg/24 h; p < 0.001) within 24–48 h of treatment. [34] After 3.5 months, seven
patients remained on mitotane alone with control of urine-free cortisol. The most
common side effects were nausea and vomiting occurring in 63% of the patients
although this did not require drug discontinuation and was manageable with
antiemetics. Hypercholesterolemia, hypokalemia and elevated LFTs were also
observed. [34]
Following Boscaro et al. pilot study of pasireotide, [48] Feelders et al. evaluated the
usefulness of stepwise combination therapy with pasireotide, cabergoline and
ketoconazole hypothesizing a synergistic effect. [60] This prospective, open-label
multicenter trial enrolled 17 patients with Cushing's disease in an 80 day trial. The
primary outcome was normalization of urine-free cortisol levels. [60] All patients
were started on pasireotide 100 µg three-times daily. This dose was increased to
250 µg three-times daily at day 15 if urine-free cortisol was not normalized.
Cabergoline, 0.5 mg every other day, was added on day 28 if urine-free cortisol
had not normalized on pasireotide alone. This dose was increased to 1.0 mg
every other day after 5 days and 1.5 mg every other day after 10 days if urinefree cortisol was not normalized. Ketoconazole, 200 mg three-times daily, was
then added on day 60 if urine-free cortisol had not normalized on the combination
of pasireotide and cabergoline therapy. [60] Pasireotide alone induced remission in
29% of patients, the addition of cabergoline induced remission in an additional
24% and adding ketoconazole induced remission in an additional 35% of
patients. [60] Clinical features of Cushing's syndrome also improved. The most
significant adverse event was hyperglycemia with HbA1c increasing from 5.8 ±
0.2 to 6.7 ± 0.3% (p < 0.01). [60]

To date, there are no clinical studies evaluating the combination of mifepristone
with other available agents. As treatment with mifepristone results in an increase
in ACTH in patients with Cushing's disease, pairing it with an ACTH modulator
may prove useful. Ketoconazole may also represent a logical choice for
combination with mifepristone, particularly because it is often well tolerated and is
widely available, though caution would need to be taken because of its interaction
with CYP3A. For now, combination therapy with mifepristone remains speculative
and studies are needed to evaluate effectiveness and side effects.

Expert Commentary
The management of Cushing's syndrome continues to be challenging. Primary
treatment is surgery for the majority of patients with both ACTH-dependent and
ACTH-independent causes of Cushing's syndrome, but a substantial proportion
of patients with Cushing's disease, adrenocortical carcinoma and the ectopic
ACTH syndrome will have residual or recurrent hypercortisolemia.
Pharmacological treatment continues to be an important adjunctive therapy in
these patients. Although mitotane remains the treatment of choice in patients with
adrenocortical carcinoma due to its cytotoxic effects, in most cases of Cushing's
syndrome with residual hypercortisolemia, ketoconazole has been used as firstline medical therapy. Ketoconazole is inexpensive, often effective and generally
well-tolerated, although LFT abnormalities and male hypogonadism can be
problematic. Metyrapone has typically been used in combination with
ketoconazole or in patients who cannot tolerate ketoconazole. In addition to the
above strategies, pasireotide (available in the EU and recently approved by the
FDA in the USA) and cabergoline can be used as tumor-directed therapy in
patients with Cushing's disease. Etomidate is rarely used due to its limitations.
While combination therapy remains common and has the potential advantage of
improved efficacy with reduced side effects, it is important to keep in mind that
knowledge of combination therapy comes largely from case reports and small
open-label studies.

Five-year View
The recent approval of mifepristone in the US represents an exciting
development in the management of residual or recurrent hypercortisolemia in
patients with Cushing's syndrome. On the other hand, mifepristone is very
expensive and monitoring of therapy is difficult due to the lack of biochemical
markers of treatment efficacy. Furthermore, most physicians presently lack
experience with its use. Because of this, mifepristone will likely be used as
second- or third-line medical therapy, alone or in combination with other agents.
Pasireotide, recently approved in the EU and in the USA, could represent an
attractive tumor-directed medical therapy, although the increased incidence of
hyperglycemia seen with this agent is potentially problematic.

Sidebar
Key Issues

ï‚· Cushing's syndrome is a debilitating disorder which requires rapid reversal
of hypercortisolemia to limit morbidity.
ï‚· The primary treatment for Cushing's syndrome remains surgical although
residual or recurrent disease is common.
ï‚· Medical therapy should be considered in patients who have failed to
achieve remission with initial surgery, as a bridge to radiation therapy, or in
patients who are not surgical candidates.
ï‚· Ketoconazole is typically the first-line option for medical therapy of
hypercortisolemia in Cushing's syndrome.
ï‚· The efficacy of cabergoline is limited but the potential for improvement in
glucose control is desirable.
ï‚· Glucocorticoid receptor antagonists (mifepristone) and somatostatin
receptor antagonists (pasireotide) represent exciting new developments.
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Papers of special note have been highlighted as:
* of interest
** of considerable interest
Websites
101 Metopirone Order Form. www.metopirone.us (Accessed 14 August
2012)
102 Support Program for Access and Reimbursement of Korlym.
www.korlymspark.com (Accessed 18 May 2012)
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with the
subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.
Expert Rev Endocrinol Metab. 2013;8(2):183-193. © 2013 Expert Reviews Ltd.

www.medscape.com

Mineralocorticoid Resistance
David S. Geller
Clin Endocrinol. 2005;62(5):513-520.

The mineralocorticoid aldosterone plays a crucial role in regulation of volume and
electrolyte homeostasis. In recent years there has been considerable progress in
deciphering the role of aldosterone in human physiology by the study of
monogenic disorders exhibiting mineralocorticoid resistance. Although these
disorders are rare, the elucidation of their molecular basis has yielded many
insights into aldosterone biology that are proving relevant to the care of patients
with a wide variety ofcardiovascular diseases. Recent advances in understanding
the molecular basis of syndromes of mineralocorticoid resistance are reviewed
with a view towards an improved understanding of the role of aldosterone in renal
sodium transport and its relationship to cardiovascular disease.
Since its original isolation by Simpson and Tait, [1] aldosterone has occupied a
prominent place in our understanding of physiological mechanisms by which the
kidney regulates salt and electrolyte balance. As the final effector molecule in the
renin—angiotensin—aldosterone pathway, aldosterone plays a crucial role in the
regulation of blood pressure and potassium homeostasis. Secreted in response
to hypotension or hyperkalaemia, aldosterone binds to the mineralocorticoid
receptor (MR ) in the distal nephron, triggering increased sodium reabsorption via
the epithelial sodium channel (ENaC) to restore intravascular volume. The
electrical gradient created by sodium reabsorption provides a driving force for
potassium and proton secretion, giving aldosterone a prominent role in electrolyte
homeostasis as well. Although the importance of aldosterone to human
physiology has never been questioned, aldosterone has been largely overlooked
in clinical practice for some time, noted only in those rare patients exhibiting
hypertension and hypokalaemia. Recent years, however, have witnessed an
upsurge in interest in aldosterone biology, driven primarily by clinical findings
implicating aldosterone as an important culprit in cardiovascular disease. Studies
have shown important benefits of aldosterone antagonism in a variety of
important clinical conditions, including heart failure [2,3] and renal disease. [4—
6]
Similarly, the realization that excess aldosterone effect maycause
hypertension in the absence of hypokalaemia has led to the suggestion that
aldosteronism may underlie a significant proportion of what has previously been
considered to be essential hypertension; [7] specific measures to decrease
aldosterone effect in these patients may be highly effective in reducing blood
pressure. These findings have triggered a marked upsurge in the use of
antimineralocorticoid agents. [8]
Although the benefits of mineralocorticoid antagonism in these and other clinical
conditions are clear, the mechanism by which antimineralocorticoid agents exert
their beneficial effects remains in question. It has been proposed that
mineralocorticoid antagonism exerts beneficial effects via blockade of MR
specific effects in the heart and vascular tissue itself, [9—11] but others argue that
the principal benefit of mineralocorticoid blockade is alteration of renal sodium
reabsorption. Clarifying this issue is of great importance, as it will suggest
mechanisms by which outcomes may be further improved in these patients. In all
likelihood, further insights will require improved understanding of aldosterone
biology and physiology.
One avenue for clarification of aldosterone biology in humans has involved the
study of patients resistant to the effects of aldosterone. Mineralocorticoid

resistance occurs in a variety of clinical conditions, both genetic and acquired,
and recent years have witnessed significant advances in our understanding of
mechanisms by which aldosterone resistance occurs. Here, we review a variety
of clinical conditions featuring mineralocorticoid resistance and use insights
gained from these states in an attempt to clarify underlying mechanisms of
aldosterone biology.
First described in 1958 by Cheek and Perry, [12] pseudohypoaldosteronism type 1
(PHA1) is a rare condition characterized by renal resistance to the actions of
aldosterone; patients exhibit salt wasting, hyperkalaemia and metabolic acidosis
despite elevated serum aldosterone levels. Early attempts to determine the
molecular basis of PHA1 led to conflicting results. Armanini and colleagues
suggested that PHA1 is caused by a genetic absence of the MR , as they were
unable detect functional receptors in lymphocytes of PHA1 patients. [13] However,
multiple attempts to identify disease-causing mutations in the MR gene proved
unsuccessful, [14—16] leaving the underlying disease mechanism in doubt. The
situation was clarified somewhat with the realization that the term PHA1 refers to
two similar but easily distinguishable forms, an autosomal recessive form and an
autosomal dominant form. [17] Each is described in detail below.
Patients with autosomal recessive PHA1 (arPHA1) suffer from life-threatening
salt wasting and hyperkalaemia, and they require massive doses of sodium
coupled with the chronic use of potassium binding resins to maintain electrolyte
homeostasis and stay alive. This form of the disorder has sometimes been called
generalized PHA1, as there is evidence of salt wasting not only from the kidney
but also from the colon, sweat glands and salivary glands. Although Armanini's
initial studies had hinted that MR mutations might underlie arPHA1, no mutations
in MR could be identified in affected kindreds. Progress eventually came with the
realization that mutations anywhere in the aldosterone effector pathway could
cause clinical mineralocorticoid resistance. As ENaC was known to be the
primary mediator of aldosterone-dependent sodium transport in the distal
nephron, the subunits of ENaC became logical candidate genes, and it was soon
demonstrated that homozygous mutations in either the alpha, beta or gamma
subunit of ENaC cause arPHA1. [18,19] A variety of mutations, including missense,
nonsense, frameshift and splice-site mutations, have been identified in these
genes (Fig. 1). Included in this list are a number of N-terminal stop codons and
frameshift mutations, suggesting that these mutations bring about a complete
loss of function. The mutations identified are located primarily in exonic regions of
the genes, but this is likely to reflect an observational bias, and indeed, a large
homozygous deletion in the promoter region of β-ENAC has also been
demonstrated to cause arPHA1. [20] To date, there are no reports of patients with
recessive PHA1 with mutations in any other gene, and so this phenotype is
believed to be restricted to mutations in the ENaC subunits. While homozygous
loss-of-function mutations in the MR lead to a PHA1 phenotype in mice, [21] this
mutation has never been identified in humans.

arPHA1 is caused by mutations in subunits of ENaC. The identity and location of
all published mutations in the α, β and γ subunits of the epithelial sodium
channel causing arPHA1 are depicted. For each gene, mutations are dispersed
throughout the gene. fr, frameshift; spl, splice-site mutation; X, stop codon.
Clinical phenotypes in arPHA1 are not limited to the kidney; patients have
evidence of salt-wasting from the sweat and salivary glands and colon as
well. [17] Young arPHA1 patients suffer from a novel pulmonary syndrome
characterized by recurrent episodes of chest congestion, coughing and wheezing
in the absence of airway infection with Staphylococcus aureus orPseudomonas
aeruginosa , which stems from a decreased ability to absorb liquid from airway
surfaces and consequent increased lung water. [22] Consistent with this, mice
lacking α - or β-ENaC die at birth from respiratory failure due to an inability to
resorb lung water, [23,24] and γ -ENaC-deficient mice have a mild respiratory
phenotype reminiscent of what is observed in human arPHA1 patients. [25]
Two clinical disorders feature similar phenotypes to arPHA1 and must be
distinguished. The first is autosomal dominant PHA1 (adPHA1, described below),
which, like arPHA1, features renal salt wasting, hyperkalaemia and increased
aldosterone levels. However, arPHA1 has a much more severe
course. [17] Patients with arPHA1 typically present in the first 2 weeks of life with
weakness, failure to thrive, and the electrolyte disturbances described above,
while adPHA1 patients may present much later or not at all. A history of parental
consanguinity argues strongly for recessive disease, as do elevated sweat and
salivary sodium levels. [17] Finally, while parents of a child with arPHA1 generally
have normal serum aldosterone levels, a parent of a child with adPHA1 may have
markedly elevated aldosterone levels in the absence of hypertension, indicating
that he or she is an asymptomatic carrier of the disease gene.
Autosomal recessive PHA1 must also be distinguished from Bartter's syndrome
type 2, caused by homozygous loss-of-function mutations in the ROMK2

potassium channel. [26] Unlike patients with other forms of Bartter's syndrome, who
present with hypokalaemia and metabolic alkalosis, patients with this form of
Bartter's syndrome often present with a clinical picture similar to PHA1, with the
neonatal onset of salt wasting, hyperkalaemia and acidosis. However, the
hyperkalaemia and acidosis present at birth in patients with Bartter's syndrome
type 2 disappears with sodium resuscitation, and the more characteristic clinical
picture of Bartter's syndrome, including hypokalaemia and metabolic alkalosis,
becomes apparent. [27]The transient hyperkalaemia these patients experience at
birth suggests the crucial role of ROMK in aldosterone-dependent potassium
secretion at birth and suggests that other distal nephron aldosterone-dependent
potassium secretory channels develop postnatally.
In the kidney, ENaC is expressed in the distal nephron, localizing primarily to the
cortical collecting tubule's principal cell. Electrogenic sodium reabsorption via
ENaC into the principal cell results in a net negative charge in the tubular lumen,
creating a powerful charge stimulus for the distal nephron either to resorb a
negatively charged chloride ion via paracellular transport pathways or
alternatively to secrete a positively charged potassium or hydrogen ion into the
tubular lumen. The absence of a functional ENaC in PHA1 patients prevents
principal cell sodium reabsorption, resulting in salt wasting and, furthermore, an
inability of the distal nephron to appropriately secrete potassium and hydrogen
ions. Thus, the characteristic hyperkalaemia, metabolic acidosis, elevated renin
and aldosterone levels and salt wasting of PHA1 can all be explained on the
basis of the loss of function in the epithelial sodium channel. The remarkable
inability of arPHA1 patients to regulate potassium and hydrogen ion balance
highlights the crucial role of ENaC-mediated sodium reabsorption for electrolyte
homeostasis.
The severe phenotype of patients with arPHA1 comes perhaps as a bit of a
surprise, as primers on kidney function have long suggested a relatively minor
role of the collecting duct in the reclamation of the filtered sodium load.
Traditional estimates have suggested that two-thirds of filtered sodium is
reclaimed in the proximal tubule, a further 20—25% is reabsorbed in the loop of
Henle, via the Na-K-2Cl cotransporter (NKCC2), 7% is reclaimed in the distal
convoluted tubule via the thiazide-sensitive cotransporter (TSC), and only 2% is
reabsorbed via ENaC in the collecting duct. It is thus somewhat surprising to note
that although patients who lack NKCC2 (Bartter's syndrome) [28] or TSC
(Gitelman's syndrome) [29] do indeed have reduced arterial blood pressure, the
primary clinical sequelae are more often caused by electrolyte disturbances
related to potassium, calcium and magnesium handling; these patients do not die
of salt wasting. [30] Similarly, mice deficient in NHE3, believed to be the principal
sodium transport pathway in the proximal tubule, have low blood pressure, but
again, their principal problems stem from altered electrolyte balance. [31,32] In
contrast to humans lacking these more proximal sodium transport systems,
humans lacking ENaC function have a catastrophic course, with frequent
neonatal death from volume depletion and hyperkalaemia. The severity of
disease in these individuals makes it clear that aldosterone-mediated sodium
transport through ENaC plays a much more important role in sodium and

electrolyte homeostasis than is suggested by reports claiming it is responsible for
reabsorbing only 2% of the filtered sodium load.
How is it that humans lacking NCCT or NKCC2, transporters responsible for large
amounts of the filtered sodium load, maintain volume homeostasis, while humans
lacking ENaC have significant haemodynamic compromise when stressed?
Tubuloglomerular feedback, the process by which the kidney regulates
glomerular filtration in response to alterations in tubular flow, probably plays a
role; [33] in the setting of volume depletion, the kidney reduces filtration at the
glomerulus, thereby decreasing the work of tubular sodium reabsorption to a
more manageable level. Another mechanism by which Bartter's and Gitelman's
syndrome patients maintain volume homeostasis is via the activation of the renin
—angiotensin—aldosterone system, which markedly upregulates sodium
transport in the distal nephron. Although the collecting duct resorbs only 2% of
the filtered sodium load at baseline conditions, recent data suggest that
aldosterone induces amiloride-sensitive sodium currents via ENaC in the
adjacent connecting tubule. Sodium transport in this region, largely undetectable
at baseline, rises to roughly 10% of the filtered sodium load, making the
connecting tubule an important and perhaps somewhat overlooked region for
maintenance of sodium homeostasis. [34] Supporting the important role of the
connecting tubule in renal sodium reabsorption is the finding that whereas mice
lacking ENaC have massive life-threatening salt wasting, mice lacking ENaC
specifically in the collecting duct are phenotypically normal, suggesting strongly
that aldosterone-sensitive ENaC-mediated sodium transport outside the
collecting tubule (and presumably also in the connecting tubule) contributes
significantly to sodium homeostasis. [35] This activity is absent in arPHA1 patients,
rendering them more or less defenceless against volume challenges and forcing
them to maintain high sodium intake for survival. Importantly, the potency of this
activity suggests that the efficacy of loop and thiazide diuretics for the treatment
of hypertension and oedematous states can be markedly enhanced by the
concurrent use of agents that inhibit ENaC, such as amiloride or spironolactone.
Autosomal dominant PHA1 shares many of the same clinical features as the
recessive form of the disease, including salt wasting, hyperkalaemia and acidosis
despite elevated aldosterone levels, but it is generally much milder in its course.
adPHA1 patients may either be asymptomatic or have evidence of significant salt
wasting during the neonatal period, but symptoms generally subside after early
childhood. Unlike patients with arPHA1, patients with adPHA1 do not have
elevated sweat or salivary sodium levels, and there is no described pulmonary
component. adPHA1 is caused by heterozygyous loss-of-function mutations in
the MR. [36] As with loss-of-function mutations in ENaC, loss-of-function mutations
in the MR lead to salt wasting and volume depletion, resulting in elevated serum
renin and aldosterone levels in affected individuals. Elevated aldosterone levels
are not sufficient to normalize sodium and potassium balance early in life, and
patients normally require salt supplementation and perhaps potassium binding
resins. After childhood years, however, adPHA1 patients maintain electrolyte
homeostasis without salt supplementation. This is in marked contrast to arPHA1
patients, who require lifelong sodium supplementation and potassium binding
resins.

To date, 16 different PHA1-causing mutations in MR have been identified (Fig. 2),
including nonsense, frameshift, missense and splice-site mutations distributed
throughout the gene. The question has been raised as to whether mutations in
genes other than MR may cause adPHA1. It has been proposed that adPHA1 is
a genetically heterogeneous disorder based on the failure to identify diseasecausing mutations in MR after the sequencing of all exonic sequences in adPHA1
patients. [37,38]However, linkage analysis, which could have definitively excluded
the gene, was not performed in either of these studies, and therefore nonexonic
disease-causing mutations, such as promoter, intronic or a 3' untranslated region
mutations, may have been missed. In this vein, Sartorato et al . performed
linkage analysis in a kindred in whom no exonic MR defect was identified by
exonic sequence analysis, and they identified a large deletion in the MR gene
locus. [39] In our experience, we have identified MR mutations in six of seven
kindreds with clear evidence of dominant disease transmission, and we could not
exclude linkage to MR in the remaining kindred. As such, we believe that
mutation in the MR remains the principal, if not the only, cause of adPHA1.

adPHA1 is caused by mutations in MR. The identity and location of all published
mutations in the mineralocorticoid receptor causing arPHA1 are depicted. fr,
frameshift; spl, splice-site mutation; X, stop codon.
It is perhaps surprising that heterozygous loss-of-function mutations in the MR
result in a clinical phenotype, as one functional MR copy is still present and would
presumably make up for the missing allele. As the MR is known to function as a
dimer, we therefore wondered whether mutant MR peptides might be produced
by PHA1 patients that could interfere with the function of the wild-type allele,
either by forming an inactive heterodimer or perhaps by binding to and
inactivating necessary transcription factors. We answered this question by the
study of kindred PHA30, a large dominant French kindred that has been well
described in the literature. [17] We identified a disease-causing mutation in MR in
an individual in this kindred, a C

T substitution that converts Arg594 to a stop codon, resulting in termination of
translation prior to the DNA binding and hormone binding domains of the
receptor. We screened MR cDNA prepared from peripheral blood lymphocytes
from a PHA30 kindred member bearing this mutation. Interestingly, we
demonstrated that although genomic DNA shows evidence of the heterozygous
mutation, the mutation is absent in cDNA prepared from RNA derived from
peripheral blood lymphocytes (Gelleret al. , manuscript in preparation). This
suggests that the mutant RNA has been degraded, most likely via nonsense-

mediated decay, [40] and that it is therefore not expressed. It is thus clear that
haploinsufficiency of MR is sufficient to cause the adPHA1 phenotype.
The ability to assign affection status on the basis of genotype rather than
phenotype allowed us recently to perform genotype—phenotype correlation
studies. We extended two large kindreds from a small village in the north-west of
Spain by recruiting all first-degree relatives of genotypically affected individuals.
Although not known to be related, these two kindreds share the same R537X
mutation. [36] In all, we studied 14 affected and 22 unaffected adult kindred
members. We found no difference among all indices of aldosterone function we
could measure — the groups were clinically indistinguishable from each other in
terms of systolic blood pressure, diastolic blood pressure, serum sodium, serum
potassium, fractional excretion of sodium, and trans-tubular potassium gradient.
The only significant difference between the two groups was in serum aldosterone
level. Adult family members with PHA1 had serum aldosterone levels
approximately 15-fold higher than their unaffected brethren, indicating that they
were able to maintain salt homeostasis by markedly up-regulating aldosterone
synthesis (Geller et al. , manuscript in preparation).
Pregnancy and infancy are two periods of intrinsic aldosterone resistance, and so
we were curious to determine whether patients with PHA1 would be at risk during
these two phases of life. Although we noted a number of spontaneous
miscarriages in pregnant women with adPHA1, the incidence of miscarriage did
not differ from that in the general population, and so we cannot assert that PHA1
played a role in antepartum difficulties. On the other hand, we identified four
deaths in neonates at risk for adPHA1, and others have noted this as
well. [41] Although genotypic data are not available on the deceased infants, the
high infant mortality rate coupled with the known importance of aldosterone in the
neonatal period makes it reasonable to wonder whether PHA1 may have played
a role in these infants' deaths, and we therefore recommend prophylactic salt
supplementation and early definitive diagnosis for infants known to be at risk for
adPHA1 (Geller et al. , manuscript in preparation).
The clinical severity of disease in adPHA1 patients early in life highlights the
essential role of aldosterone-sensitive sodium transport in the neonate and raises
the question as to the reasons underlying the apparently diminished requirement
for this system in later years. One possibility relates to the low sodium content of
human breast milk, [42,43] which may render neonates particularly sensitive to renal
salt wasting; this sensitivity lessens as the infant transitions to the high salt intake
characteristic in the industrialized world. This suggests a gene-by-environment
interaction, in that, on a low-sodium diet, humans are dependent on maximal
activation of the renin—angiotensin—aldosterone system, and MR
haploinsufficiency results in volume depletion and hyperkalaemia, but on a highsalt diet, adPHA1 is clinically silent. An alternate explanation for the improvement
in the adPHA1 phenotype after the neonatal years involves the development of
the renal tubule. Aldosterone-mediated sodium transport through ENaC in the
cortical collecting duct (CCD) is coupled to K + secretion via a potassium
secretory channel ROMK. ROMK is expressed postnatally, [44] potentially allowing
improved efficiency of the renin—angiotensin—aldosterone system, and possibly

providing a physiological mechanism for enhanced mineralocorticoid-sensitive
sodium and potassium transport after the perinatal period.
Pseudohypoaldosteronism type 2 (PHA2) is a rare Mendelian disorder
characterized by the autosomal dominant transmission of hypertension,
hyperkalaemia and metabolic acidosis with normal renal function, with the salient
finding that thiazide diuretics rapidly ameliorate all clinical findings. In contrast to
PHA1, serum aldosterone levels are either low or normal, and thus the term
'pseudohypoaldosteronism' is somewhat of a misnomer. Nevertheless, the failure
of the kidney to appropriately secrete potassium in this condition suggests a
degree of aldosterone resistance, and recent data on cellular mechanisms
underlying PHA2 are instructive for the understanding of clinical syndromes of
aldosterone resistance.
Some years ago, two loci for PHA2 were identified on chromosomes 1 and 17 by
linkage analysis but the precise molecular defect remained unknown. Recently,
however, a novel form of the disorder linking to chromosome 12p13 was
identified, [45,46]and Wilson et al . demonstrated that affected members in these
kindreds carry large deletions in the first intron of a serine—threonine kinase
called WNK1. [46] The mutation results in an upregulation of WNK1 mRNA
expression, although the mechanism by which this results in hypertension and
hyperkalaemia is not entirely clear. [46] Wilson et al . further identified a family of
novel WNK1 paralogues and demonstrated that mutations in one of these,
WNK4, cause PHA2 in kindreds linking to chromosome 16. The disease-causing
mutations in WNK4 are missense mutations that alter a highly conserved 10amino-acid sequence of the encoded protein.
The WNK kinases are so named because they lack a conserved lysine residue
seen in the catalytic domain of the kinase domain of all other serine kinases
(WNK = with no lysine [K]). WNK1 is expressed widely throughout the body,
whereas WNK4 is limited to the distal nephron. Recently, there has been
remarkable progress in understanding the mechanism by which mutations in
WNK1 and WNK4 cause hyperkalaemia and hypertension. In vitro , WNK4 acts
as a negative regulator of the thiazide-sensitive cotransporter NCCT, and
furthermore, mutant WNK4 molecules identified in patients with PHA2 lose their
ability to inhibit NCCT. [47,48] Further evidence suggests that WNK1 acts as a
negative regulator of WNK4. [48] These activities of WNK1 and WNK4 suggest a
straightforward mechanism for the hypertension observed in PHA2 patients,
through the loss of regulation of distal nephron sodium reabsorption. However,
the mechanism by which these mutations result in hyperkalaemia would not be
explained by these findings. Kahle et al. , [49] however, recently demonstrated that
WNK4 also inhibits the renal K + channel ROMK used in distal nephron potassium
secretion, and that the same WNK4 mutations that relieve NCCT inhibition
increase inhibition of ROMK. These data support the hypothesis that WNK4
functions as a molecular switch that regulates the balance between sodium
reabsorption and potassium secretion necessary for integrated homeostasis and
is probably a key regulator of the aldosterone effector pathway. [49] Moreover, they
provide a compelling explanation for the underlying pathophysiology of PHA2,
and provide a novel mechanism for mineralocorticoid resistance in the distal

nephron. As WNK4-mediated regulation of sodium transport in the kidney relies
on a mechanism distinct from the mechanism regulating potassium balance, it
seems plausible that natriuretic agents lacking the often dose-limiting side-effects
of hypokalaemia (thiazide diuretics) or hyperkalaemia (antimineralocorticoids)
could one day be developed.
As the above examples show, mineralocorticoid resistance can be caused by the
loss of function of any gene product involved in the MR effector pathway. Work in
recent years has identified the serum- and glucocorticoid-regulated kinase (sgk1)
as a gene activated by aldosterone that, in turn, may upregulate heterologously
expressed epithelial sodium channels. [50] To investigate the potential role of sgk1
mutations in mediating mineralocorticoid resistance, Wulff et al . generated a
mouse genetically deficient in sgk1. [51] Although a variety of preliminary studies
suggested an important role of SGK1 in aldosterone action, mice deficient in
SGK1 are able to maintain normal sodium homeostasis on a standard NaCl
intake. However, they are unable to appropriately decrease urinary sodium
excretion in response to a low-salt diet and similarly demonstrate a defect in renal
potassium excretion. These data confirm that sgk1 plays a role in the aldosterone
signalling pathway. However, in contrast to the necessary roles of the MR and
ENaC in aldosterone function, sgk1 appears to play only a modulatory role
necessary for fine-tuning of salt and potassium homeostasis, at least in mice.
Importantly, this implies that there are other crucial regulatory pathways in the
aldosterone signalling cascade that remain to be described, each of which could
provide a useful pharmaceutical target.
Although the genetic examples of mineralocorticoid resistance cited above shed
light on the mechanisms by which aldosterone regulates extracellular volume in
the kidney, these are indications rarely encountered in clinical practice. There are
some clinical situations in which mineralocorticoid resistance is encountered in
the absence of an underlying genetic defect. Transient pseudohypoaldosteronism
has been described in infants with urinary tract obstruction [52] or urinary tract
infection,[53] and is reversible with treatment of the primary problem. A PHA1-like
picture, with hypovolaemia, hyperkalaemia and elevated aldosterone levels, has
been reported in patients following small bowel resection, but these patients
probably have intestinal salt wasting and an appropriate renal response to the
actions of aldosterone. The most common clinical scenario of aldosterone
resistance occurs in patients receiving a calcineurin inhibitor, such as cyclosporin
or tacrolimus, for immunosuppression. Hyperkalaemia is a common side-effect of
these medications, but the mechanism(s) underlying resistance to aldosteroneinduced kaliuresis remain poorly understood. These medications inhibit renin
(and presumably aldosterone) secretion but also result in tubular insensitivity to
aldosterone effect. [54,55] Recent studies suggest that aldosterone resistance may
be mediated by a reduction in mineralocorticoid receptor expression, perhaps
mediated through transcriptional mechanisms. [56—58] Further understanding of the
mechanisms of aldosterone resistance induced by these agents may help us to
prevent this common and dose-limiting side-effect.
A wide variety of clinical and experimental evidence suggests an important role of
aldosterone in mediating cardiovascular disease. Of particular interest, a number

of studies have focused on extrarenal roles of aldosterone, stemming from the
finding that the MR is expressed in diverse tissues including the myocardium and
the vascular endothelium. Recent progress has taught us much about
mechanisms of aldosterone action, but it is clear that we have more to
understand. Nevertheless, the insights gained from these studies have taught us
much about aldosterone biology.
One interesting finding stemming from the study of these monogenic disorders of
mineralocorticoid resistance is the uncertain correlation between aldosterone
levels and cardiovascular disease. A wide variety of studies have suggested
pathological effects of angiotensin II and aldosterone on cardiovascular tissue,
mediating such effects as cardiac fibrosis and left ventricular
hypertrophy. [9,11,59] The example of arPHA1 and adPHA1 make it clear that
angiotensin II and aldosterone are not in and of themselves the primary
mediators of the pathology observed. Patients with arPHA1 have lifelong
elevation of renin, angiotensin II, and aldosterone levels many times above the
norm (with a normal MR pathway in extrarenal tissues), and yet, left ventricular
hypertrophy and cardiac fibrosis have never been observed in humans or in mice
lacking ENaC. By contrast, patients with Liddle's syndrome, which is
characterized by constitutive activation of ENaC, leading to hypertension and
hypokalaemia despite lifelong suppression of renin, angiotensin II and
aldosterone, have a high incidence of left ventricular hypertrophy and renal
failure. Stated simply, excess renal sodium reabsorption is necessary and
sufficient to produce cardiovascular disease, whereas angiotensin II and
aldosterone are neither necessary nor sufficient. Whether aldosterone worsens
cardiovascular pathology above and beyond its effect on renal sodium
reabsorption remains an open question. Nevertheless, these findings lend
support to the proposition that the principal culprit mediating cardiovascular
disease in many of the widely cited experimental systems of cardiovascular
disease is not angiotensin II or aldosterone, but the excess renal sodium
reabsorption induced by these hormones. Similarly, while there has been much
interest in so-called nongenomic effects of aldosterone on cardiovascular
parameters, [60] the finding that arPHA1 patients have low blood pressure and no
cardiovascular disease suggests that the proposed nongenomic effects of
aldosterone have only a limited role on cardiovascular health independent of salt
balance as well.
Can this notion that the principal effects of aldosterone in cardiac disease relate
to salt balance be supported by the wide variety of studies suggesting a role of
aldosterone itself in cardiovascular disease? Among the widely cited examples of
aldosterone-mediated toxicity is the finding that mineralocorticoid antagonists
such as spironolactone or eplerenone, given at doses that do not noticeably alter
salt balance or blood pressure, markedly decrease the incidence of stroke and
renal injury in stroke-prone spontaneously hypertensive rats; [61—63] the absence of
a blood pressure lowering effect has been cited as evidence that aldosterone
blockade must have an effect above and beyond its effect on renal salt
reabsorption. However, recent studies have demonstrated that amiloride, an
inhibitor of ENaC, also reduces the incidence of stroke in this model system,
again in the absence of a change in blood pressure. [64] Importantly, it should be

noted that amiloride, unlike spironolactone, is thought to work exclusively in the
renal tubular lumen, because only there is the concentration of the drug sufficient
for ENaC inhibition. Similarly, the demonstration that aldosterone administration
leads to hypertrophy and fibrosis not only in the high-pressure left heart
circulation but also in the low-pressure circulation encountered in the right heart
circulation has been used to suggest that aldosterone must have direct effects on
the heart independent of renal salt reabsorption. [10,11]Again, however, the
replication of these data in a high-salt (and therefore low-aldosterone) model
again suggests strongly that the true culprit is excess salt, not
aldosterone. [65] Clarification of the true pathological effects will require further
investigation, but given the importance of the renin—angiotensin—aldosterone
pathway to sodium homeostasis and cardiovascular disease, it is clear that an
improved understanding of aldosterone biology is likely to lead to improved
treatment of cardiovascular disease.
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Funding information
The research by Dr Geller is supported by K08-DK02765 and NHLBI P50HL55007.
Reprint Address
David S. Geller, Tel.: (203) 737 5298; Fax: (203) 785 4904; Email: [email protected]
Clin Endocrinol. 2005;62(5):513-520. © 2005 Blackwell Publishing
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Current Practice of Glucocorticoid
Replacement Therapy and Patient-Perceived
Health Outcomes in Adrenal Insufficiency
A Worldwide Patient Survey
M Forss, G Batcheller, S Skrtic, G Johannsson
BMC Endocr Disord. 2012;12(8)

Abstract
Background
The aim was to survey current practice in glucocorticoid replacement therapy and
self-perceived health outcomes in patients with adrenal insufficiency.
Methods
Participants were recruited via patient organizations to respond anonymously to a
web-based survey developed by clinical experts. Unique entries were set up for
each patient organization enabling geographical localization of the entries.
Results
1245 participants responded (primary adrenal insufficiency: 84%; secondary
adrenal insufficiency: 11%; unsure: 5%). Therapies included hydrocortisone
(75%), prednisone/prednisolone (11%), cortisone acetate (6%) and
dexamethasone (4%). Dosing regimens were once daily (10%), twice daily
(42%), thrice daily (32%) or other (17%). Compromised subjective health
necessitating changes to physical activity or social-, work- or family life was
reported by 64% of the participants. 40% of the participants reported absence
from work/school in the last 3 months. Irrespective of diagnosis, 76% were
concerned about long-term side-effects of therapy, mainly osteoporosis (78%),
obesity (64%) and cardiovascular morbidity (46%). 38% of the participants had
been hospitalized in the last year.
Conclusions
Glucocorticoid replacement therapy among the respondents consisted primarily
of hydrocortisone administered twice or thrice daily. A majority reported impact of
their disease or treatment on subjective health requiring alterations in e.g.
physical activity or family life. Three quarters reported concerns about long-term
side-effects of the treatment. These data demonstrate — from the patients'
perspective — a need for improvement in the management of adrenal
insufficiency.

Background
In the two largest registry-based studies on mortality in patients with Addison's
disease, the relative risk of death was more than 2-fold compared to the

background population despite treatment. [1,2] Patients with hypopituitarism and
secondary AI also have increased relative risk of death. [3] Based on the increase
in cardiovascular risk factors [4,5] and reduced bone mineral density (mainly in
female AI patients), [6-10] overly high glucocorticoid exposure is likely to occur at
least during parts of the day/night. This is supported by data showing an inverse
relationship between dose exposure and bone mineral density.[7] Due to the short
half-life of hydrocortisone, each oral dose is followed by a rapid increase and
often an overly high peak in serum cortisol concentration followed by a rapid
decline. Multiple doses of immediate-release hydrocortisone tablets are needed
in order to cover the active part of the day but result in a peak after each dose
and a trough between doses. It has been estimated that AI patients are on
average over-substituted by 6-7mg hydrocortisone/day based on an ideal body
mass area-dose ratio of 11mg/m 2. [11] Besides symptoms indicating over-exposure
to glucocorticoids, e.g. a tendency to gain weight, symptoms indicating
underexposure, e.g. salt craving, were also commonly reported in a previous
survey. [12]
The subjective health-related quality of life (QoL) of AI patients is impaired on a
group level [13-16] with health scores inferior to those of the background population.
General health and vitality have been found to be consistently impaired, [13] with
fatigue being the most characteristic subjective health feature of AI. [12,13] Working
ability is reduced to various degrees in different countries. [11-14] Attempts to reestablish the normal cortisol exposure-time profile have in an open study
demonstrated improvement in well-being, [17] and improved QoL was observed in
another study when changing from a twice daily (BID) to a thrice daily (TID)
regimen. [18] These data suggest that the peaks and troughs between doses may
to some extent explain the poor self-perceived well-being reported by patients.
The aim of this patient survey was to investigate current practice in glucocorticoid
replacement therapy (therapy and dosage regimen) in patients with primary or
secondary AI in different countries and the participants’ self-perceived health
status and outcomes by type of disease and therapy.

Methods
This was an open cross-sectional survey. Participants were recruited via patient
organizations (e-mail contact lists and newsletters) to respond anonymously to
the web-based survey. The following patient organizations actively approached
their members to participate in the survey and had links to the survey on their
home page: National Adrenal Diseases Foundation (NADF) in the US, Australian
Addison’s Disease Foundation, Addison’s Disease Self Help Group (ADSHG) in
the UK and Cushing’s Support and Research Foundation (CSRF) in the US.
Some additional patient organizations also had information about and/or links to
the survey on their respective websites: CARES foundation in the US,
Association Surrénales in France, two Swedish associations (The Swedish
Addison Association and Hypofysis), two Danish associations (Addisonforeningen
in Denmark and Danish Morbus Addison Site), the Dutch Addison & Cushing
Society (NVACP) and Associazioni Italiana Pazienti Addison in Italy. A link was
also set up on the sponsor’s website for other patients wanting to complete the
survey.

The questionnaire covered a range of questions (39 questions in total), including
patient demographics (country, type of disease, etc.), medication and satisfaction
with the current medication. It also covered impact of the disease on selfperceived subjective health, the prevalence and impact of fatigue, views on longterm side effects related to treatment, hospitalizations and absenteeism from
work or school. The questionnaire consisted of a mix of single select, multiple
select and open questions. A pilot survey was conducted with four members from
different patient organizations to ensure the validity of the questions in the
questionnaire. Revisions were then made to the questionnaire before the survey
was conducted. In order to ensure the privacy of the participants’ contact details,
it was agreed that each patient organization should send out alerts via e-mail and
newsletters to inform its members about the survey and its objectives. Although
no research ethics committee approval is needed for the conduct of this kind of
patient survey, [19] a research application had to be completed for the UK patient
organization ADSHG, in order to be able to recruit volunteers from their
membership registry. No remuneration was given to the participants. No data on
age and gender were collected in order to further protect the individual identity of
the participants.
Unique links for each patient organization were set up in the web survey tool
Easyresearch (by QuestBack, Oslo, Norway), the technical platform used for
administration and analysis of the survey. The unique entries enabled
geographical localization of the entries. The intention was to have the survey
open for approximately 6 weeks, but the survey opening time was extended as a
result of the high degree of interest from individual patients and additional patient
organizations. The survey was open from September 12th to December 19th
2008.
The data were analyzed descriptively (frequency analysis) by disease type
(primary or secondary AI), treatment and dosing regimen. The country-specific
analyses included only countries with more than 20 participants. The
denominator for the calculation of frequency varied between the questions since
not all participants answered all questions. The asking of some of the questions,
such as on subjective general health, was dependent on previous answers (e.g.
degree of impact on QoL was only asked if the participant had answered that the
disease affected their QoL). No statistical tests were performed.

Results
A total of 1281 persons visited the webpage of the survey whereof 1245
responded to at least the first question (“In which country do you live?”). The
respondents were from (by number of participants): US (801), Australia (90),
France (81), UK (80), Canada (37), Sweden (35), Denmark (19), the Netherlands
(8), Germany (7), Belgium (6), New Zealand (5), Mexico (4), Ecuador (3), Ireland
(3), Spain (3), Chile (2), Dominican Republic (2), India (2), Norway (2),
Philippines (2), Poland (2), South Africa (2), Switzerland (2), Argentina (1), Dubai
(1), Greece (1), Hungary (1), Israel (1), Italy (1), Jamaica (1), Martinique (1),
Portugal (1), Serbia (1) and Uruguay (1).

When asked “What type of cortisol deficiency are you suffering from?”, 939
participants (84%) defined their AI as primary (Addison’s disease, congenital
adrenal hyperplasia, adrenal disease causing dysfunction of adrenal glands or
removed glands) and 125 (11%) as secondary (pituitary or hypothalamic disease)
while 51 (5%) were unsure.
Glucocorticoid Treatment Regimen

Overall, hydrocortisone was used by 75% of the participants,
prednisone/prednisolone by 11%, cortisone acetate by 6% and dexamethasone
by 4% of the participants, . A high proportion of participants (40%) in Australia
reported using cortisone acetate. Among the countries with at least 20
respondents, the use of prednisone/prednisolone was most common in Canada
(27%), the US (14%) and Australia (11%) and dexamethasone was most
commonly used in Australia (5%) and the US (4%). The distribution of therapies
was similar between patients with primary and secondary AI. The majority of the
patients were on BID (42%), or TID (32%), while 10% were on an OD regimen, .
Of the patients on a BID regimen, 58% took their medication in the morning and
afternoon and 42% in the morning and evening. Patients with secondary AI took
their BID dosing in the morning and afternoon (39%) rather than in the morning
and evening (9%). 53% of the patients on prednisone/prednisolone were on BID
and 5% on TID. For treatment regimen by therapy, please see .
Table 1. Therapy and dosing regimen, by type of adrenal insufficiency,
reported in an international patient survey

Table 1. Therapy and dosing regimen, by type of adrenal insufficiency,
reported in an international patient survey

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Table 2. Dosing regimen, by therapy, reported in an international patient
survey

One quarter (23%) of the participants were dissatisfied or very dissatisfied with
their current treatment, 18% were indifferent and 59% were satisfied or very
satisfied. Patients with secondary AI reported less satisfaction with their current
therapy than patients with primary AI. The ratings of satisfaction were similar
among the different therapies.
Multiple daily dosing was reported as a problem by 38% of the participants
whereof 15% were on OD, 35% on BID, 32% on TID and 17% on another
regimen. Of those who did not find multiple daily dosing to be a problem 7% were
on OD, 45% on BID, 32% on TID and 16% on another regimen. Among
respondents answering that multiple daily dosing was a problem 94% reported
one or more of the following: difficulties to remember/forgetting doses (particularly
the midday and afternoon doses), difficulties in taking the medication at a specific
time every day and/or difficulties to remember to bring the medication. Many
reported that their days are planned according to their dose intake and for those
who lead a busy life and are working, this was found to be challenging as some
also reported that they do not want to be seen by their colleagues when taking
their medication. Several reported that multiple daily dosing becomes very
restrictive to an active life and that multiple daily dosing is a reminder several
times per day that they have this disease. Many also reported health issues such
as being fatigue and exhausted in the day, evening and the following day(s) if
missing a dose. In addition, many reported that taking a missed dose too late
disrupts their sleep and causes issues with insomnia. Some reported instability of

physical and mental well-being with mood swings and ups and downs in energy
levels. The patients who reported multiple daily dosing to be a problem also
reported higher frequencies of impacted QoL, more fatigue and more activities
altered due to their disease (data not shown).
Enduring efficacy over 24 hours was considered the most important feature of an
optimal replacement medication (29%) followed by few side effects (25%) and
low risk of adrenal crisis (22%). Similar responses were obtained from patients
with primary and secondary AI.
Health-Related Questions and Hospitalizations

A majority of the patients (648 of 1026 [64%]) reported impacted quality of life
(QoL) due to their illness, 87% (99 of 114) of patients with secondary AI and 60%
(515 of 857) of the patients with primary AI. Approximately three quarters (73 of
99 [74%]) of the patients with secondary AI graded the impact on QoL as “quite a
lot” or “very much”, . The proportion of patients who reported impaired QoL varied
with dosing regimen (OD > BID > TID). However, the level of impairment did not
differ between the dosing regimens. A lower proportion of patients treated with
hydrocortisone reported impaired QoL compared with patients receiving cortisone
acetate or prednisone/prednisolone but the level of impairment did not differ
between the therapies (data not country-adjusted).
Table 3. Impact of adrenal insufficiency on quality of life (QoL) captured in an
international survey

All patients were asked “What activities do you need to alter due to your AI?”,
regardless of whether they had answered that their QoL was impaired or not. A
large percentage of the participants reported that they had had to alter their
physical activity (56%), social life (40%), work life (39%) or family life (31%) due
to their illness (the participants were allowed to choose more than one
alternative). A higher proportion of patients with secondary AI (90%) than with
primary AI (68%) reported that they had had to alter work life, social life, physical
activity or family life, Figure 1.

Figure 1.
Change in activities due to adrenal insufficiency. Responses to the question
“What activities do you need to alter due to your adrenal insufficiency”? in an
international patient survey. A total of 1001 subjects responded to this question.
A majority of the participants reported fatigue in the morning (57%) and during the
day (65%) to be a problem. Fatigue was more pronounced in patients with
secondary AI than in patients with primary AI, . Of those reporting morning fatigue
to be a problem, 75% also reported fatigue during the day to be a problem.
Similarly, of those reporting fatigue during the day to be a problem, 85% also
reported morning fatigue to be a problem.
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Table 4. Fatigue in the morning and during the day reported by patients with
adrenal insufficiency in an international patient survey

In this survey, 61% of the respondents considered themselves fit to work while
17% did not. Additionally 5% of the respondents both considered themselves unfit
to work and were on sick leave, 10% were retired and 7% were unemployed. Of
those considering themselves fit to work, 72% considered themselves fit to work
full-time, while 18% could work 75%, 9% could work 50% and 1% could work <
50%. Overall, 40% of the participants had been absent from work in the last 3
months and, again, this was more common among patients suffering from
secondary AI (50%) than for patients with primary AI (38%). Almost one third
(28%) of those being away from work or school reported more than 3 weeks’
absence in the 3 months preceding their participation in the survey, . A higher
percentage of patients treated with prednisone/prednisolone reported
absenteeism compared with patients on hydrocortisone and they also reported
more lengthy absenteeism (data not shown).
Table 5. Absenteeism from work or school due to adrenal insufficiency in the
last 3 months reported in an international patient survey

A majority of the participants were worried about long-term side effects. The
participants were most worried about osteoporosis (79%), followed by obesity
(64%), fatigue (52%) and cardiovascular problems (46%) (more than one
alternative could be chosen), . A higher proportion of those treated with
prednisone/prednisolone were worried about long-term side effects than those
treated with hydrocortisone (data not shown).
Table 6. Worries about long-term effects reported by patients with adrenal
insufficiency in an international patient survey

Overall, 32% of the participants reported that they increased their dose due to
physical activity at least once per week (primary AI patients: 30%; secondary AI
patients: 49%) and 66% increased their dose due to illness at least once per
month (primary AI patients: 65%; secondary AI patients: 76%).
Overall, 38% of the participants responding to the question about hospitalizations
(N=977) answered that they had been hospitalized at least once during the last
12 months (37% of patients with primary AI and 43% of patients with secondary
AI). One third of the patients (32%) had been hospitalized more than once during
the last 12 months. The reported reason for hospitalization was adrenal crisis,
vomiting or an acute infection for 17% of the patients who had been hospitalized.

Discussion
The conduct of this survey was similar to previous cross-sectional surveys with
participants recruited via patient organizations. [5,11,12] The current survey of 1245

respondents is to our knowledge the largest patient survey to date in patients with
AI. Previous studies have shown that outcomes in patients with AI are
compromised. [12-14] The responses from this survey provide more information on
the impact of the disease and its treatment on patient-perceived outcomes, and
support previous data showing a large impact of the disease and its treatment on
the daily life of these patients.
Therapy traditions differ to some extent between countries but hydrocortisone
was the most commonly used therapy in this survey (75%), irrespectively of
country, which is also in line with previous studies from Europe. [4,20] The
distribution of therapies, i.e. type of glucocorticoid, was similar between patients
with primary and secondary AI. Three quarters of the patients were on a BID or
TID regimen. One unexpected observation in this survey was the high
percentage (58%) of patients on prednisone/prednisolone who were on a BID or
TID regimen.
That multiple daily dosing is a problem from a compliance point of view is well
known from other therapies. [21] The free-text answers to the open questions of
this survey confirmed that multiple daily dosing is not optimal in AI and has an
impact on patients’ social life and work life. More specifically, 4 of 10 patients in
this survey found multiple daily dosing to be a problem. The impact on leading a
normal life was attributed both to multiple dosing and to fluctuations in
mental/physical energy over the day as multiple daily dosing with
hydrocortisone/cortisone acetate causes peaks and low trough values in-between
dosing occasions. When asked about the most important features of an optimal
replacement medication, the patients ranked efficacy over 24 hours first and few
side effects second. More patients on TID were satisfied with their treatment
compared to those on BID or OD treatment. This might be attributable to the
better cortisol coverage of TID during the active part of the day [22,23]over the
convenience of fewer dosing times.
The results from this survey are in line with a recently published clinical
study [24] which showed that a majority of the patients preferred the four-daily
dosing regimen to twice daily when comparing equal doses of hydrocortisone
given either twice daily or four times daily. The reasons reported were less
fatigue, more alertness during the day, less headache and a feeling that the
treatment effect was less varying during the day. The patients had complaints
after the study that a four-dose regimen may be difficult to manage in the long
run. [24] Another study has shown that a thrice-daily administration with weightadjusted doses provides a better PK profile within the constraints of immediaterelease hydrocortisone formulations. [25] 85% of the patients opted to remain on
the TID regimen given in that study. These data suggest that patients experience
benefits of having increased cortisol coverage during the active part of the day.
One caveat of the above studies is that the total exposure of cortisol is higher
when the same daily dose of hydrocortisone is administered divided into three or
four daily doses than at BID administration. This is due to the fact that increasing
the dose of hydrocortisone at one dose occasion does not result in a proportional
increase in total exposure of cortisol due to the non-linear bioavailability of orally
administered hydrocortisone. [26]Thus, there might be a short-term perceived

benefit of the increased cortisol exposure whereas the long-term risk may
increase.
It is difficult to mimic physiological cortisol profiles with immediate release
hydrocortisone replacement therapies. [22,25]Therefore, attempts to better mimic the
normal cortisol profiles have been made by developing new treatment regimens
using the concept of chronotherapy, i.e. considering circadian rhythms in
determining the timing and amount of the medication to optimize the desired
effects and minimize the undesired ones. [17,27] A once-daily treatment with dual
action, combining immediate release and extended release hydrocortisone has
shown benefit over immediate release hydrocortisone with the same daily dosing
administered thrice daily in patients with adrenal insufficiency. [28]
Two thirds of the participants reported impacted QoL from their illness. In line with
this being a patient survey (capturing the patient’s general perception of their
subjective health at only one time point) and not a clinical trial, the questionnaire
used in this survey did not include validated QoL questions from specific QoL
questionnaires. Instead, the included questions were focused on the patients’
general perception of how and to what degree their disease and/or treatment
affected their QoL. This survey showed that patients with secondary AI perceived
their QoL as more impaired than patients with primary AI, which is in agreement
with a previous study using validated QoL questionnaires showing that patients
with AI have compromised QoL and that the impairment of QoL is worse in
patients with secondary AI. [14] The current survey did not collect data on comorbidities. Patients with secondary adrenal insufficiency may have other
hormone deficiencies which could impact on QoL. However, data from previous
studies are inconsistent and while some impact was observed in a Norwegian
study of patients with Addison’s disease, [13] another study [14] showed that the
impairment in health-related subjective health status in AI patients is largely
independent of concomitant diseases.
More than half of the AI patients needed to alter their physical activity and many
needed to change their social life, work life or family life due to their illness. The
level of impact on social life is in line with data from another international survey,
conducted in 2003, in which one-third reported that their condition impacted on
their ability to participate in social activities. [29] A Dutch patient survey reports
similar impact on lifestyle. [5] Detailed questions on fatigue were included in the
current survey as fatigue is the most commonly reported subjective health-related
problem in AI. [5,11-13,29,30] This survey showed that 57% of the participants
experienced fatigue in the morning as a problem and 65% reported fatigue during
the day to be a problem. This response is in some contrast to the general
perception that morning fatigue is a much larger clinical problem than fatigue
during the day in patients with AI who have low or undetectable serum morning
cortisol levels when using hydrocortisone BID or TID. Fatigue was more common
in secondary AI than in primary AI and often necessitated changes in daily
activities or changes in dose or the timing of dosing.
The current survey demonstrated a high absenteeism from work or school. More
specifically, 4 of 10 patients reported absenteeism from work or school due to AI

in the last 3 months and one third of those reported more than 3 weeks’ absence.
Furthermore, 17% of the participants did not consider themselves to be fit to
work. Among those who considered themselves fit to work, 28% worked part-time
instead of full-time. These data are similar to those of a survey conducted across
the UK, Canada, Australia and New Zealand (n=850), [29] in which over 10% of the
respondents reported that they were unable to work compared with 1% in the
matched control group. Moreover, in the study by Hahner et al., [14] 18% of the AI
patients (primary and secondary) did not work vs. 4% in the general population.
In a Norwegian study, working disability amounted to 26% among patients with
primary AI vs. 10% in the general population. [13]
Patients with AI are educated to increase their glucocorticoid dose in stressful
situations and in association with other illnesses. This survey showed that 6075% of the patients increased their replacement dose due to illness every month.
The high rate of hospitalizations in this survey (38% of the patients had been
hospitalized at least once in the last year) is in line with the Dutch survey in which
3 of 10 patients had been hospitalized. [5] The reported reason for hospitalization
was adrenal crisis, vomiting or an acute infection in 17% of the patients. As a
comparison, the incidence rate of adrenal crises was 6.3 per 100 patient years in
a study by Hahner et al. [31] The reason for this discrepancy is most likely the
differences in methods of collecting data and that the definition of adrenal crisis is
not the same, e.g. only cases of hospitalization necessitating i.v. glucocorticoid
administration were counted as adrenal crises in the study by Hahner.
Because of the relatively small disease population, age and gender were not
included in the questionnaire in order to protect personal integrity and anonymity.
Internet use and behaviours linked to it are hypothetical confounding factors in
the interpretation of the survey results. Patients who seek information about their
disease usually tend to be more active than other patients, which can also affect
the results. Despite the fact that congenital adrenal hyperplasia (CAH) constitutes
one form of primary AI, it would have been interesting to analyse data on this
patient group separately as recent data published by Arlt et al. (2010) showed
significantly impaired health status and adverse metabolic and skeletal health in
adult CAH patients,[32] however, data were not separately collected for patients
with CAH in this survey.

Conclusions
This international survey showed that the glucocorticoid replacement regimens in
AI differ to some degree between countries. Three quarters of the AI patients
participating in the survey received hydrocortisone administered two or three
times daily. A large majority of the participants reported that their disease and the
current treatment have an impact on QoL leading to alterations in physical
activity, social life, work life and family life. Furthermore, 76% of the participants
reported concerns of long-term side-effects of their treatment. These data
demonstrate — from the AI patients' perspective — an obvious need for
improvement in the management of AI including the regimen of glucocorticoid
replacement therapy.

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Acknowledgments
We thank the participants in the survey and the patient organizations supporting
their members to participate and share their experience. We also thank Karin
Gewert, Writewise, who provided medical writing services on behalf of DuoCort
Pharma.
Competing Interests
This survey was funded by DuoCort Pharma. MF works for DuoCort Pharma AB.
GB, SS and GJ have equity interests in DuoCort AB.
Authors’ Contributions
All authors contributed to the design of the survey and writing/review of the
manuscript. All authors read and approved the final manuscript.
BMC Endocr Disord. 2012;12(8) © 2012 BioMed Central, Ltd.
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