Best Practice & Research Clinical Endocrinology & Metabolism xxx (2014) 1e8

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Best Practice & Research Clinical

Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem

Mineralocorticoid substitution and monitoring

in primary adrenal insufficiency
Marcus Quinkler, MD, Prof. Dr. med. a, b, **,
Wolgang Oelkers, MD, Prof. Dr. med. c,
Hanna Remde, cand. med. b,
Bruno Allolio, MD, Prof. Dr. med. d, *
a
Endocrinology in Charlottenburg, Berlin, Germany
b
Charit

e University Medicine, Berlin, Germany
c
Endokrinologikum, Berlin, Germany
d
Endocrinology and Diabetes Unit, Department of Internal Medicine I, University Hospital of Wuerzburg,
Germany

Keywords:
Patients with primary adrenal insufficiency usually show pro-
hypotension nounced impairment of aldosterone secretion and, therefore,
salt craving require also mineralocorticoid replacement for full recovery.
hyperkalemia Clinical signs of mineralocorticoid deficiency comprise hypoten-
plasma renin activity sion, weakness, salt craving and electrolyte disturbances (hyper-
9a-fluorocortisol kalemia, hyponatremia). Mineralocorticoid deficiency is confirmed
fludrocortisone by demonstration of profoundly decreased aldosterone and highly
elevated plasma renin activity (PRA). Standard replacement con-
sists of 9a-fluorocortisol (fludrocortisone) given once daily as a
single oral dose (0.05e0.2 mg). Monitoring of mineralocorticoid
replacement consists of clinical assessment (well-being, physical
examination, blood pressure, electrolyte measurements) and
measurement of PRA aiming at a PRA level in the upper normal
range. Current replacement regimens may often be associated
with mild hypovolemia. Dose adjustments are frequently needed
in pregnancy to compensate for the anti-mineralocorticoid activity
of progesterone and in high ambient temperature to avoid sodium
depletion. In arterial hypertension a dose reduction is usually
recommended, but monitoring for hyperkalemia is required.
© 2014 Published by Elsevier Ltd.

* Corresponding author. Endocrinology and Diabetes Unit, Department of Internal Medicine I, University Hospital of
Wuerzburg, Oberduerrbacher Strasse 6, D-97080 Wuerzburg, Germany.
** Corresponding author. Endocrinology in Charlottenburg, Stuttgarter Platz 1, D-10627 Berlin, Germany.
E-mail addresses: marcusquinkler@t-online.de (M. Quinkler), allolio_b@medizin.uni-wuerzburg.de (B. Allolio).

http://dx.doi.org/10.1016/j.beem.2014.08.008
1521-690X/© 2014 Published by Elsevier Ltd.

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primary adrenal insufficiency, Best Practice & Research Clinical Endocrinology & Metabolism (2014),
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Introduction

In secondary adrenal insufficiency (SAI), caused by ACTH deficiency, aldosterone secretion remains
largely intact, as it is mainly under the control of the renin angiotensin system. In contrast, in primary
adrenal insufficiency (PAI) aldosterone secretion is usually severely impaired due to destruction (e.g. by
an autoimmune adrenalitis) or removal (bilateral adrenalectomy) of the zona glomerulosa. Thus
mineralocorticoid replacement is required to compensate for the loss of aldosterone secretion causing
electrolyte imbalance, hypovolemia and hypotension. Intriguingly, optimal mineralocorticoid
replacement has received little attention in the last two decades, certainly much less than glucocor-
ticoid substitution. This may indicate that mineralocorticoid replacement in PAI poses no or little
problems for these patients. However, it is also conceivable that neglecting optimal mineralocorticoid
substitution contributes to the well-known failure to fully restore the quality of life [3,11,19] to normal
in these patients.

Clinical presentation and diagnosis of mineralocorticoid deficiency

Fatigue and loss of energy are mentioned most often in patients with PAI, e.g. Addison's disease, as
well as unspecific symptoms like weight loss, a loss of appetite, diarrhea, vomiting and nausea [4]. These
unspecific symptoms and complaints quite often lead to the false diagnosis of psychiatric or gastroin-
testinal diseases [1]. In a German cohort, the more specific PAI symptoms like hypotension (55%), hy-
perpigmentation of patient's skin (41%) and salt craving (38%) were less frequently present [4]. Other
studies, however, showed higher percentages of hypotension (80%) and hyperpigmentation (90%)
[31,41]. Aldosterone deficit leads to natriuresis and initially isosmotic dehydration resulting in arterial
hypotension, in particular orthostatic hypotension [28]. Furthermore, volume deficit stimulates ADH
secretion which may be further enhanced by glucocorticoid deficiency leading to a more pronounced
loss of sodium than water and worsening hyponatremia. However, the classical combination of hypo-
natremia and hyperkalemia, resulting from impaired potassium excretion, is not always reliable, because
hyponatremia is often only mild and also hyperkalemia is found in only in 50% of PAI patients. The latter
is not only caused by aldosterone deficiency, but also by reduced glomerular filtration rate. Salt craving is
also related to aldosterone deficiency, but is reported in only 15% [2,45]. However, it is our experience
that salt craving is not reported spontaneously, but only after specific questioning.
A universally used diagnostic test to confirm PAI, is the rapid ACTH-test with 1e24 ACTH (250 mg
synacthen intravenously) demonstrating a failure of the adrenal to adequately respond to exogenous
ACTH in the presence of clearly elevated baseline ACTH levels [33]. To evaluate the mineralocorticoid
axis in PAI patients combined measurement (8:00e0:00 h) of basal aldosterone and PRA should be
performed and has high diagnostic accuracy typically demonstrating strongly elevated PRA together
with a decreased aldosterone concentration. For example, in a series of patients with zona glomerulosa
insufficiency plasma renin activity (PRA) showed levels higher than 3.08 ng/L*s (11.1 ng/mL*h), and
aldosterone levels below 216 pmol/l [33]. The PRA/aldosterone ratio clearly differentiates between PAI
patients (range 18.9e1287.9) and healthy subjects (range 0.19e2.79). As measurement of PRA is time
consuming and demanding, it has largely been replaced in clinical practice by determination of PRC.
While elevated levels of PRC have been demonstrated in Addison's disease and have also been used for
monitoring of replacement therapy [8], a formal comparison of the respective clinical utility of PRA and
PRC in PAI remains lacking.

Mineralocorticoid substitution

Desoxycorticosterone (DOC), a mineralocorticoid precursor in aldosterone synthesis, was identified

in 1937 [29] and used since 1939 in oil and pellets in the treatment of Addison's disease [44]. Aldo-
sterone itself is not suitable for replacement therapy because of its short half-life and rapid hepatic
inactivation after oral ingestion. In 1954 9a-fluor-11b,17a,21-trihydroxy-pregnen-(4)-dion-(3,20),
called 9a-fluorohydrocortison or 9a-fluorocortisol or fludrocortisone, was discovered and patented in

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1958 [13,14]. It exhibits 200 to 400-fold higher mineralocorticoid potency than hydrocortisone.
However, it binds with similar affinity to the isolated human mineralocorticoid receptor (hMR). The
mineralocorticoid potency is mainly due to the fact that the fluor atom on carbon 9 of the steroid
molecule protects from rapid conversion by 11b-hydroxysteroid dehydrogenase type 2, the gatekeeper
of the hMR, and guarantees the steroid free access to the hMR [32]. Transactivation studies with hMR in
CV-1 cells revealed that the mineralocorticoid potency of 9a-fluorocortisol is 10-times higher than that
of aldosterone [17]. Binding of 9a-fluorocortisol to the hMR leads to full mineralocorticoid action
including sodium retention, potassium elimination, and water reabsorption. Since the availability of
9a-fluorocortisol, DOC is not used any more for mineralocorticoid therapy in PAI.
The absorption of 9a-fluorocortisol is rapid and virtually complete [46]. It occurs in blood 20 min
after oral ingestion and peaks 90 mine120 min after intake. Newer studies showed that a patient in
septic shock treated with one 50 mg dose of 9a-fluorocortisol acetate reached a maximal plasma
concentration of 0.36 ng/mL after 2 h as measured with liquid chromatographyemass spectrometry
(LC-MS) [40]. 9a-fluorocortisol acetate is hydrolyzed in human serum rapidly to 9a-fluorocortisol, the
active molecule. Elimination from plasma has been reported to occur in two or three phases with
half-lives of 2e3 h, 4.5 and 10.2 h respectively [46,47]. However, newer studies with LC-MS mea-
surements revealed that there are only two different phases of elimination, the first 2e4 h, and the
second 4e6 h after 9a-fluorocortisol acetate administration [40]. The mean half-time was 4.9 h
resulting in 9a-fluorocortisol levels below 20% 16 h after administration. When dosing 9a-fluo-
rocortisol every 12 h the limit maximum is reached after 25 h, amounting to the 1.3-fold of the
maximum obtained after a single oral application [46]. Nearly 80% of 9a-fluorocortisol is eliminated
via the urine [46].
Oelkers et al. described the titration of 9a-fluorocortisol in 15 Addison's patients [33]. To avoid
overtreatment they aimed at a PRA level between 3 and 10 ng/mL*h. In combination with hydrocor-
tisone doses between 15 and 25 mg/day, this goal was obtained with 0.075 mg in 3 patients, 0.1 mg in 7
patients, 0.15 mg in 2 and 0.2 mg in 3 patients. Based on this data, 9a-fluorocortisol is usually rec-
ommended for mineralocorticoid replacement as a single morning dose of 0.05e0.20 mg upon
awakening. Children and younger adults may require higher doses [22]. The currently available forms
of 9a-fluorocortisol preparation include 0.1 and 0.05 mg tablets.
The new formulation instructions (e.g. for Florinef™) require patients to keep the medication
refrigerated. The actual decay rate is, however, only 0.1% in the first 6 months at room temperature [21].
Patients should be advised to take salt and salty foods without restrictions. However, it should be
sodium chloride salt and not potassium chloride salt to avoid hyperkalemia.
The dose of mineralocorticoid may be as critical as the dose of glucocorticoid in the management of
congenital adrenal hyperplasia (CAH), and regular determination of PRA should be made, particularly if
clinical control is difficult [16]. The inclusion of 9a-fluorocortisol in the therapy of patients with salt-
wasting CAH resulted in a significant lowering of PRA [27]. Interestingly this was seen also in part of
CAH patients with the simple-virilizing form. These findings resulted in recognition that treatment
with mineralocorticoid should be continued indefinitely in salt-wasting CAH. Although stopping 9a-
fluorocortisol may not always produce a salt losing crisis, it may be more difficult to achieve adequate
androgen suppression even with larger doses of glucocorticoids [15,20]. This might be due to the fact
that high 17-hydroxy-progesterone levels in poorly controlled CAH patients might have a direct impact
on PRA and natriuresis, because 17-hydroxy-progesterone possesses an anti-mineralocorticoid po-
tency [37e39]. Therefore it might be reasonable to increase 9a-fluorocortisol dose in salt-wasting CAH
patients with high 17-hydroxy-progesterone levels and to avoid too high hydrocortisone dosages [27].
Secondly, it was shown that administration of 9a-fluorocortisol at doses of 0.5 mg, significantly
reduced hormonal levels during the nocturnal nadir of HPA axis [6]. However, such a dose is clearly
above the replacement needs in patients with mineralocorticoid deficiency. Yet another study showed
that systemic administration of 9a-fluorocortisol in doses between 0.1 and 0.3 mg significantly
inhibited the HPA response to the hypophysial stimulus CRH [23]. One explanation might be that 9a-
fluorocortisol, which possesses a 10-times higher glucocorticoid activity than cortisol, displays its
potency at the glucocorticoid receptor [17].
On the other hand it is important to note that hydrocortisone, the most frequently used gluco-
corticoid for substitution therapy, possesses significant mineralocorticoid activity. It has been

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primary adrenal insufficiency, Best Practice & Research Clinical Endocrinology & Metabolism (2014),
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estimated that the mineralocorticoid potency of hydrocortisone, given by the oral route, is about 1/
400th that of 9a-fluorocortisol. If the mineralocorticoid potency of 1 mg 9a-fluorocortisol is defined as
1 mineralocorticoid unit (MCU), 0.4 mg hydrocortisone may also be regarded as 1 MCU. If this is
correct, the standard dose of 20 mg hydrocortisone for glucocorticoid replacement equals in its
mineralocorticoid activity 0.05 mg of 9a-fluorocortisol [33]. Although the relationship between hy-
drocortisone dose and mineralocorticoid activity may not be fully linear, this concept is highly useful
and gives a good explanation, why high intravenous doses of hydrocortisone in adrenal crisis cover
the mineralocorticoid needs making additional administration of 9a-fluorocortisol unnecessary.
Accordingly, patients with adrenal insufficiency on dexamethasone (e.g. in CAH), which has no
mineralocorticoid activity, show higher PRA values than patients on hydrocortisone [35]. Therefore
those patients require higher 9a-fluorocortisol doses. Prednisolone has an approximately 4-times
lower MR-potency than hydrocortisone in vitro (but a still 10-times higher MR-potency than dexa-
methasone) [17]. This is the reason, why it is recommended in PAI patients on prednisolone therapy to
slightly increase 9a-fluorocortisol doses.

Monitoring of mineralocorticoid replacement

Mineralocorticoid replacement is evaluated clinically by asking the patient about salt craving or
lightheadedness, measuring blood pressure in the supine and standing positions to assess orthostatic
dysregulation, and by identifying the presence of peripheral edema [21]. General well-being, elec-
trolytes within the normal range and normal blood pressure without evidence of postural hypo-
tension indicate adequate mineralocorticoid replacement. Furthermore, a PRA in the upper normal
range has been found to be a useful marker for a correct mineralocorticoid dose [12,33] (Fig. 1).
However, such a PRA in the upper normal range has not been uniformly accepted as proof of a correct
replacement dose. Accordingly, it has been suggested that the dose titration should not necessarily
attempt to normalize PRA levels because this might result in a higher incidence of arterial hyper-
tension [22]. In addition, some patients may develop mild signs of over-replacement (e.g. edema)
with a PRA in the upper normal range. On the other hand, it has been suggested that many patients
with mineralocorticoid deficiency are under-replaced and higher doses were recommended [42]
leading to PRA levels clearly below the upper normal range. However, in this study the initial in-
crease from 0.1 to 0.3 mg 9a-fluorocortisol had later to be reduced to 0.2 mg, as six of the ten patients
had developed ankle edema and five had low potassium. The initially slightly subnormal plasma
volume (89%) in patients on 0.1 mg 9a-fluorocortisol increased to 105% at the end of the study and
the blood pressure was significantly higher raising questions on the long term safety of this strategy.
However, eight out of ten patients felt better on the higher final dose than on their initial dose prior

Fig. 1. Flow-chart for dose adjustment of 9a-fluorocortisol in primary adrenal insufficiency. * Look for alternative explanations of
abnormalities prior to dose change.

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the dose adjustment and were reluctant to reduce their dose. Significantly increased fatigue has been
reported in patients interrupting their mineralocorticoid replacement while their glucocorticoid
therapy remained unchanged [22].
The time of day of blood sampling for PRA is not critical in the evaluation of mineralocorticoid
replacement therapy [12]. Importantly, PRA and angiotensin II measurements reflected better the
mineralocorticoid dose being more sensitive than serum sodium or potassium, total plasma proteins,
heart rate, or orthostatic blood pressure [35]. However, in female PAI patients who are taking oral
contraceptives, a higher PRA level should be taken into account due to stimulation of plasma renin
substrate [35]. In PAI patients PRA correlates negatively with plasma volume [42]. However in PAI
patients who have not yet received glucocorticoid replacement therapy, PRA levels underestimate
volume deficiency due to the fact that concentration of plasma renin substrate are low due to gluco-
corticoid deficiency [43]. PRA was tested for usefulness in the assessment of mineralocorticoid
replacement on 14 patients with Addison's disease and showed to correctly determine mineralocor-
ticoid under-replacement [8], although the authors suggested that atrial natriuretic peptide (ANP) is a
more sensitive parameter of 9a-fluorocortisol over-replacement. However, in this study both PRA and
ANP showed high variability indicating that the clinical utility of both measurements for the individual
patient should not be overestimated.
The feedback of 9a-fluorocortisol on PRA is mediated via changes in extracellular fluid volume and
blood pressure. This is the reason why changes in the PRA occur only days or even weeks after changing
the 9a-fluorocortisol dose [25]. It is, therefore, recommended that PRA should be monitored not earlier
than two weeks after changing the dose of 9a-fluorocortisol [33,35] and an even longer interval of 4
weeks has been suggested [42].
Studies assessing the volume status of patients with PAI consistently found some hypovolemia
with standard replacement therapy [22,42]. In fact, under-replacement with 9a-fluorocortisol
seems to be quite common, and is sometimes compensated for by over-replacement of glucocor-
ticoids [21].
This may predispose to adrenal crisis, which occurs more frequently in PAI than in SAI [18]. Adrenal
crisis could be triggered by further volume reduction, if salt depletion occurs either due to dietary
restriction or by enhanced loss (e.g. via sweating) or if vomiting and diarrhea further lead to acute
volume loss [18].
Slight puffiness of the face and hands and a PRA in the lower normal range are possible early signs
for over-substitution with 9a-fluorocortisol [35]. Rapid weight gain, high blood pressure and hypo-
kalemia clearly indicate a too high dose of 9a-fluorocortisol.

Special therapeutic conditions

Pregnancy

Progesterone has anti-mineralocorticoid potency in vitro [38] and in vivo [39], and is competing
with aldosterone or 9a-fluorocortisol for binding to the hMR. During pregnancy progesterone levels
steadily increase and the 9a-fluorocortisol dose may need to be increased depending on blood pressure
and potassium levels. PRA concentrations are not informative during pregnancy due to the pregnancy
induced increase in renin substrate [10]. Oelkers and other investigators reported increasing re-
quirements of 9a-fluorocortisol substitution in Addisonian women during pregnancy [9,36] reaching
doses of 0.3e0.6 mg (up to six-fold increase) to maintain normal potassium levels. After delivery the
dosage has to be lowered to the pre-pregnancy level without delay, as progesterone rapidly declines
after removal of the placenta [36]. Intriguingly, the need to increase 9a-fluorocortisol substitution in
pregnancy seems to be not generally accepted [7,26] and more well documented pregnancies in pa-
tients with PAI are probably needed to settle this issue. However, we strongly recommend to closely
monitor blood pressure and potassium levels during pregnancy and to early consider the need of
increasing doses of 9a-fluorocortisol in the care of these women with PAI.
At delivery, hydrocortisone 100e150 mg/day intravenously during the first 24e48 h is recom-
mended followed by rapid tapering and oral administration.

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Concomitant hypertension

In hypertensive patients, the 9a-fluorocortisol dose may be reduced as a first therapeutic measure
under monitoring of serum potassium levels to avoid hyperkalemia. However, it should not be entirely
stopped, as this may facilitate the occurrence of hyperkalemia. As patients with PAI receiving standard
replacement are often slightly hypovolemic (see above), diuretics are less useful and should be avoided.
Obviously, also other medications such as carbenoxolone, liquorice, and NSAID are interacting and
should not be given [30]. A direct vasodilator, e.g. calcium antagonist, is probably the best choice of
anti-hypertensive treatment in patients with PAI. Again, more data on hypertensive patients with PAI
are needed to better guide treatment.

Interfering drugs

Phenytoin has been reported to have adverse effects (hyponatremia, hyperkalemia and hypoten-
sion) on mineralocorticoid replacement with 9a-fluorocortisol in two patients with Addison disease
[24]. Their 9a-fluorocortisol doses needed to be increased up to 0.4 mg daily. Phenytoin induces hepatic
6-hydroxylation, one of the major 9a-fluorocortisol metabolic pathways. Compared to cortisol itself,
9a-fluorocortisol has a strongly reduced Ring A metabolic clearance rate due to its fluor at position 9
[5]. Therefore, drugs which induce 6-hydroxylation, such as phenobarbital and rifampicin, might also
enhance the metabolism of 9a-fluorocortisol.

Salt deficiency

Many patients note problems during hot weather, as it often leads to increased salt loss by sweating.
In case of hot climate or strong perspiration it is, therefore, useful to transiently increase the 9a-flu-
orocortisol dose (by 0.1e0.2 mg/d) and/or the salt intake.

Adrenal crisis

PAI patients with acute adrenal crisis who receive 100 mg or more hydrocortisone per day do not
need 9a-fluorocortisol medication on those days, because the increased dosage of hydrocortisone
covers not only the glucocorticoid requirements but also provides sufficient mineralocorticoid activity
[34], as has been outlined above. Administration of 0.9% NaCl is generally recommended in adrenal
crisis to provide sufficient sodium and to correct hypovolemia.

Practice points

 Clinical signs of aldosterone deficiency are hypotension, salt craving, weakness, often
combined with hyponatremia and hyperkalemia.
 The diagnosis is based on the demonstration of decreased basal serum aldosterone and
elevated PRA.
 9a-fluorocortisol is the standard therapy with doses of 0.05e0.2 mg once daily.
 Patients should take sodium salt without restrictions.
 Signs for adequate replacement therapy are general well-being, electrolytes within the
normal range, normal blood pressure, and a PRA in the upper normal range.
 Doses often need to be increased during pregnancy (in case of hyperkalemia, hypotension),
and in hot weather with increased sweating, and should be reduced in patients developing
hypertension.

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primary adrenal insufficiency, Best Practice & Research Clinical Endocrinology & Metabolism (2014),
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Research agenda

 More data including meaningful endpoints (well-being, blood pressure) is needed to estab-
lish improved monitoring strategies in mineralocorticoid deficiency.
 The role of mild volume deficit with current mineralocorticoid replacement regimens for
fatigue should be investigated.
 More pregnant patients with primary adrenal insufficiency need to be analyzed to establish
correct dose adjustments during pregnancy.
 Once versus twice daily dosing of 9a-fluorocortisol has not been investigated.
 PRC has not been evaluated and compared to PRA in patients with primary adrenal insuffi-
ciency, but is probably as good as PRA measurement.

Conflict of interest

None.

Acknowledgments

None.

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Please cite this article in press as: Quinkler M, et al., Mineralocorticoid substitution and monitoring in
primary adrenal insufficiency, Best Practice & Research Clinical Endocrinology & Metabolism (2014),
http://dx.doi.org/10.1016/j.beem.2014.08.008