Suppression of Adrenal Function by Low-dose Prednisone: Assessment with 24-hour Urinary Steroid Hormone Profiles - A Review of Five Cases
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Adrenal Suppression Case Study
Suppression of Adrenal Function by
Low-dose Prednisone:
Assessment with 24-hour Urinary Steroid
Hormone Profiles - A Review of Five Cases
Patrick N. Friel, BS; Thomas Alexander MD;
Jonathan V. Wright, MD
Abstract significant adverse consequences in terms of sex
The impact of the synthetic glucocorticoid hormone production, bone health, endocrine and
prednjsone on adrenal steroid hormone immune system function, and neuropsychiatric
production was examined using 24-hour urinary status. Studies of DHEA replacement in patients
steroid hormone profiling. Five women, who taking prednisone for lupus demonstrate
were chronically taking low-dose prednisone, amelioration of some of these adverse effects.
were tested, and the relevant literature was {Altern Med Rev 2006;11 (1 ):40-46)
reviewed. As expected, adrenal glucocorticoid
production, measured by urinary terminal Introduction
cortisol and cortisone metabolites, was markedly The synthetic glucocorticoid prednisone is
suppressed compared to reference range values used for its anti-inflammatory properties in the treat-
(p=0.03). Urinary cortisol and cortisone, reflecting ment of many different conditions, including rheu-
circulating gtucocorticoids, were decreased to matologic, hormonal, allergic, respiratory, and other
a lesser extent than their terminal metabolites. disorders. Prednisone administration results in nu-
Urinary dehydroepiandrosterone{DHEA)excretion merous side effects., a number of which are the result
was dramatically suppressed (p=0.03), while the of its suppression of adrenal cortex function. After
downstream androgen metabolites androsterone prednisone administration, adrenal production of the
and etiocholanolone were suppressed to a lesser endogenous glucocorticoids, cortisol and cortisone,
extent. Aldosterone and tetrahydrocorticosterone declines. This can result in marked hypocortisolism
production demonstrated modest suppression after discontinuation of high dose prednisone thera-
after prednisone administration, but allo- py, especially in seriously ill patients.'
tetrahydrocorticosterone, which is highly
Because prednisone suppresses adrenal
sensitive to adrenocorticotropic hormone (ACTH)
function by reducing adrenocorticotropic hormone
secretion, was suppressed to a greater extent.
(ACTH) secretion by the anterior pituitary gland.
Prednisone administration results in a decrease
in ACTH secretion by the anterior pituitary,
suppressing synthesis of glucocorticoids, DHEA,
and DHEA metabolites. Decreased glucocorticoid Patrick N. Friel, BS - Forensic Toxicologist, Washington State Toxicology
synthesis is adaptive, because prednisone is active Laboratory.
Correspondence address: 2203 Airport Way South, Seattle. WA 98134
at the glucocorticoid receptor, but suppression of E-mail: Pat.Friel@wsp,wa.gov
DHEA synthesis is not mitigated by prednisone. Thomas Alexander, MD - Private practice, Tahoma Clinic, Renton, WA; Clinical
DHEA is an important sex hormone precursor, Consultant. Meridian Valley Laboratory, Renton, WA.
neurosterold, and endocrine and immune Jonathan V. Wright, MD - Medical Director, Tahoma Clinic, Renton, WA; Medical
modulator; therefore, DHEA depletion may have Director, Meridian Valley Laboratory, Renton, WA.
Page 40 Alternative Medicine Review • Volume 11, Number 1 • 2006
Case Study Adrenal Suppression
other adrenal hormones normally produeed after standard addition. The ethyl acetate extract was evap-
ACTH sthnulation are also vulnerable as a conse- orated to dryness. and the MOX/TMS derivatives of
quence of prednisone therapy.' After ACTH adminis- the steroids were prepared. The final derivatized ex-
tration to healthy adults, plasma and urinary concen- tracts were dissolved in hexane. washed with de-ion-
trations of glucocorticoids. dehydroepiandrosterone ized water, and an aliquot of the hexane phase was
(DHEA). and aldosterone all increase.- This suggests injected into the gas chromatograph-mass spectrom-
that patients treated with prednisone may experience eter (GC-MS).
not only declines in glucocorticoids but also declines The GC-MS system included an Agilent
in aldosterone and DHEA and its metabolites. The 6890 GC with a 7683 Autosampler. an Agilent 5973N
limited data available in the literature suggest DHEA MSD. and an Enhanced MSD Chemstation data sys-
may be even more sensitive to suppression by pred- tem. A 30 m X 0.25 mm ID. 0.25-micron film thick-
nisone than the glucocorticoids.' while aldosterone is ness dimethylpolysiloxane column was used, with
somewhat less sensitive, probably because its secre- helium (1.9 mL/min) as the carrier gas. Analytes were
tion is mediated by multiple mechanisms. separated during a 32-minute temperature program,
in the course of reviewing routine urinary and the steroids were identified and quantified using
steroid hormone profiles conducted on a large number selected ion monitoring. Calibration was performed
of patients for diverse clinical purposes, the authors with derivatized standards prepared from pure ana-
noticed a striking and consistent pattern in the results lytical reference materials (Steraloids; Newport. RI).
for the small number of patients tested who were tak- Chromatograms for all five cases were re-
ing prednisone. This article describes this pattern, re- viewed for accuracy as follows. Prednisone is a syn-
views its mechanisms and the relevant literature, and thetic analog of cortisone that differs from cortisone
discusses its clinical and research implications. only by the presence of a double-bond rather than a
single-bond between carbons I and 2 in the A-ring.
Methods Similarly, prednisone's metabolite prednisolone dif-
Five women who were chronically taking fers from cortisol only in the presence of the same
prednisone had 24-hour urinary steroid hormone double-bond in the same location. Thus, the molecu-
profiles conducted at Meridian Valley Laboratory be- lar ions for prednisone and prednisolone have a mass
tween February and June 2005. Patients submitted a number two less than those of cortisone and cortisol.
questionnaire on the use of hormones, other medica- Prednisone and prednisolone were not fully resolved
tions, and symptoms, with their urine specimens. The chromatographically from cortisone and cortisol. but
questionnaires were used as part of the laboratory cortisone and cortisol analysis was possible because
quality assurance program, for review of test results, of the mass difference of the molecular ions.
and for consultation with physicians who ordered the Aldosterone was analyzed by radioimmuno-
tests. The median age was 41 years (span 32-60); one assay (Diagnostic Products Corporation; Los Ange-
woman had regular menstrual cycles, two had irregu- les, CA).
lar cycles, and two were postmenopausal. Prednisone The completeness of 24-hour urine collec-
dose was 5 mg/day for two patients. 10 mg/day for tion was assessed by measurement of creatinine (ref-
one. and not known for two. although use of predni- erence range 0.5-2.0 g/24 hours).
sone was confirmed on the questionnaire. Reference ranges for the majority of analytes
Steroid analysis was performed as described were taken from the literature."* Reference ranges for
previously.^ Steroids were isolated from urine by cortisol. cortisone, and DHEA were determined by an
solid phase extraction (C18 columns: United Chemi- in-house study of 30 healthy young adults. Reference
cal Technologies: Bristol. PA), eluted with methanol. ranges for cortisol and cortisone are similar to those
and the methanolic extract was evaporated to dry- in other studies using similar methodology.^ Urinary
ness. The residue was reconstituted in acetate buffer, DHEA excretion declines with age; the lower limit
hydrolyzed overnight with sulfatase/beta-glucuroni- for the DHEA reference range in this report is higher
dase. and extracted with ethyl acetate after internal than some others reported in the literature, primarily
Alternative Medicine Review • Volume 11, Number 1 • 2006 Page 41
Adrenal Suppression Case Study
Figure 1. Metabolic Pathways for Adrenal Steroids
Mineralocorticoid Corticosteroid Sex Hormone
Pathway Pathway Pathway
Pregnenolone 17-OH Pregnenolone DHEA
3-(i dehydrogenase
Progesterone 17-OH Progesterone Androstenedione
21-hydroxylase
11 -Deoxy-Corticosterone 11[i-Deoxycortisol Testosterone
11-hydroxylase
Corticosterone Cortisol Estradiol
Aldosterone Cortisone Androsterone
Etiocholanolone
Tetrahydrocorticosterone Tetrahydrocortisol
+
allo-Tetrahydrocorticosterone allo-Tetrahydrocortisol
Tetrahydrocorttsone
Compounds measured for this study are In bold type, and synthetic enzymes are in italics
because this laboratory's reference range reflects val- Urinary adrenal steroid hormones arc uni-
ues found in young adults. The reference range for formly lower in women taking prednisone than in un-
aldosterone was taken from the radioimmunoassay medicated patients of similar age. Steroid hormone
kit package insert and is specific for individuals with data for the patients taking prednisone were organized
a normal sodium intake. Statistical analysis was con- into three groups: glucocorticoids. sex hormones, and
ducted using the sign test. mineralocorticoids (Figure 1). As expected, glucocorti-
coid production was suppressed, as shown in Table 1.
Results Results for prcgnanetriol. which is elevated
All five patients had normal creatinine excre- in adrenal hyperplasia. were within the reference
tion (median 1.1 g/24 hours, span 0.8-1.8 g/24 hours; range (100-1500 pi^l2A hours) in three patients and
reference range 0.5-2.0 g/24 hours). below the lower limit in two.
Page 42 Alternative Medicine Review • Volume 11, Number 1 • 2006
Case Study Adrenal Suppression
Table 1. Glucocorticoid Levels in Subjects on Prednisone
Glucocorticoid Reference Range Women taking
(Mg/24 hr) Prednisone (median, span)
Cortisol 30-170 25 (8-38)
Cortisone 31-209 18 9-56
Tetrahydrocortisone 1700-4200 191 (24-1628)*
Tetrahydrocortisol 900-2600 116(17-579)*
'p=0.03 (patient values compared to lower limit of reference range)
DHEA was excreted at remarkably low lev- Steroids derived from corticosterone demon-
els: two terminal DHEA metabolites, androsterone strated a milder pattern of suppression after predni-
and etiocholanolone. were consistently below reter- sone administration (Table 3). Results for aldo.sterone
enee range values as well, as summarized in Table and tetrahydrocorticosterone were within the refer-
2. Androsterone and etiocholanolone results for one ence range for a majority of patients, but results for
patient were excluded from Table 2 because she was allo tetrahydrocorticosterone were below the lower
taking testosterone. In this ease, urinary testcster- limit of the reference range for all but one patient.
one excretion was 66 /^g/24 hr (reference range 5-35 The results in the tables are summarized in
//g/24 hr). DHEA I /Yg/24 hr. androsterone 456 /(g/24 Figure 2. in which a vertical bar represents the span
hr. and etiocholanolone 530 /(g/24 hr. Androsterone of values for each steroid: a horizontal bar intersect-
and etiocholanolone are metabolites of testosterone ing the span represents the median.
as well as DHEA. Because of the exclusion of one
patient's values for androsterone and etiocholano-
lone. statistical comparisons of patient values and the
lower limit of the reference range were significant at
the p=0.06 level.
Table 2. DHEA and Metabolites in Subjects on Prednisone
Androgen Reference Range Women taking
(Mg/24 hr) Prednisone (median, span)
DHEA 100-2000 7 1-8*
Androsterone 500-3200 160(30-333)
Etiocholanolone 500-5000 177(70-384)
'p=0.03 (patient values compared to lower limit of reference range)
Alternative Medicine Review • Volume 11, Number 1 • 2006 Page 43
Adrenal Suppression Case Study
Table 3. Corticosterone Metabolites in Subjects on Prednisone
Corticosterone Metabolite Reference Range Women taking
(|jg/24 hr) Prednisone (median, span)
Aldosterone 6-25 6(4-18)
Tetrahydrocorticosterone 30-240 66(6-111)
allo-Tetrahydrocorticosterone 130-600 38(6-218)
*p=0.03 (patient values compared to lower limit of reference range)
1
Discussion A second potential confounding factor is that
The suppression of ACTH secretion after depressed DHEA synthesis in the women studied
prednisone administration has a profound Impact on could have been caused by their medical condition,
adrenal steroid production. The cortisol metabolites rather than prednisone administration. The medi-
tetrahydrocortisone. letrahydrocortisol. and allo-tetra- cal complaints included a diagnosis of fibromyalgia
hydrocortisol account for approximately 5i) percent in two patients and "severe aches and pains" in two
of daily cortisol biosynthesis.^ The marked decline of patients. Four patients also complained of headaches
these metabolites in these women taking prednisone - two severe, one moderate, and one mild. However,
reflects the decrease in cortisol production that results other studies of prednisone administration have also
from prednisone administration. Urinary cortisol and demonstrated the same decline in DHEA production.
cortisone, which reflect circulating glucocorticoids. For example, a study of daily versus alternate-day,
were also diminished after prednisone. but not to the low-dose prednisone in hirsute women found that.
same extent as the terminal metabolites (Figure 2). after both regimens, basal serum DHEA and DHBA-
DHEA excretion was very low in this group sulfate concentrations were suppressed to a greater
of women, which is consistent with the ACTH media- degree than serum cortisol concentrations.^ Studies
tion of DHEA production. One potential confounding in adolescents and adults, but not young children,
factor is that DHEA production declines with age. demonstrate marked suppression of DHEA synthesis
The subjects ranged in age from 32-60 years, and the after prednisone administration.'^ The prednisone-as-
laboratory reference range lower limit in this report sociated reduction in ACTH release by the anterior
(100 //g/24 hr) reflects values for young adults. A pituitary offers a compelling mechanism for the de-
comprehensive study by Weykamp et al determined cline in DHEA production.
urinary DHEA excretion rates across the lifespan in The mineralocorticoid steroids aldosterone
males and females." They reported a reference range and tetrahydrocorticosterone demonstrated modest
lower limit of 58 ;/g/24 hr for women ages 17-50 suppression after prednisone administration. This is
years and the same lower limit for women ages 51-70 consistent with the reports that aldosterone produc-
years. Even if this somewhat lower reference range tion is mediated by multiple mechanisms, with ACTH
limit is used, the urinary DHEA values for subjects stimulation responsible for approximately one-half of
in this study are remarkably low (1-8 //g/24 hr). The aldosterone output.' The results suggest that suppres-
downstream DHEA metabolites androsterone and sion of aldosterone synthesis after prednisone admin-
etiocholanolone were also consistently below the ref- istration may only be of concern in patients consum-
erence range lower limit, although not to the same ing a low-salt diet, when demands for aldosterone
degree as DHEA values (Figure 2). synthesis are high. Allo-tetrahydrocorticosterone
production was suppressed to a greater extent than
Page 44 Alternative Medicine Review • Volume 11, Number 1 • 2006
Case Study Adrenal Suppression
Figure 2. Urinary Steroids in Patients on Prednisone
the other corticosterone metabolites (Table 3; Figure (although prednisone has Iower relative mineralocor-
2). This is consistent with results from studies iden- ticoid potency'). In contrast, the marked suppression
tifying allo-tetrahydrocortieosterone as a sensitive of DHEA synthesis after prednisone administration
stress marker."'" The role of allo-tetrahydrocortico- results in an uncompensated loss of a key sex ste-
sterone as a stress marker is supported by the authors' roid precursor, neurosteroid (produced in the CNS,
experience that, after ACTH stimulation (250 //g IM), independent of the adrenals), and endocrine- and im-
allo-tetrahydrocortieosterone consistently exhibits mune-system modulator." '' Decreased sex hormone
the greatest percentage increase of any adrenal ste- production may be a factor in the development of os-
roid measured. teoporosis. Low DHEA concentrations are found in
The suppression of glucocorticoid synthe- patients with depression."^'- and may also be associat-
sis after prednisone administration is an appropriate ed with the development of insulin resistance, hyper-
adaptive response, because prednisone binds to the lipidemia. and age-related declines in immune sys-
glucocorticoid receptor and elicits physiological ef- tem function.'-" This raises the question of whether
fects that are qualitatively similar to those of cortisol DHEA supplementation might benefit patients who
Alternative Medicine Review • Volume 11, Number 1 • 2006 Page 45
Adrenal Suppression Case Study
take prednisone chronically. Two studies in women 4. Friel PN. Hinchcliffe C. Wright JV. Hormone
with lupus who were taking prednisone have shown replacement with estradiol: conventional oral doses
result in excessive exposure to estrone. Altern Med
DHEA supplementation often allows patients to re-
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bone loss associated with chronic prednisone admin- Steroid profile for urine: reference values. Clin
istration.'""^ In another study, women with adrenal Chem 1989:35:2281-2284.
insufficiency treated with 50 mg/day DHEA expe- 6. Palermo M. Gomez-Sanehez C. Roitman E.
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related 3-oxo-4-enc steroids in urine using gas
and sexuality."'
chromatography/mas^ speclrometry wiih stable
The subjects described in this article repre- isotope-labeled internal standards. Steroids
sent a small sample of women taking prednisone. 1996:61:583-589.
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dehydrogenase activity in patients with unipc)lar
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