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Clinical Endocrinology (1994)40,603-609

The overnight single-dose metyrapone test


is a simple and reliable index of the
hypothalamic-pituitary-adrenal axis

Tarek M. Fiad, John M. Kirby, Sean K. Cunningham and discord between these two tests was observed in 10
T. Joseph McKenna patients (53%). Nine of these patients demonstrated a
Department of Endocrinology and Diabetes Mellitus, normal response to ACTH and a subnormal response to
St Vincent’s Hospital, Elm Park, Dublin 4, Ireland metyrapone. In only one patient was an abnormal cortisol
(Received 22 July 1993; returned for revision
response to ACTH associated with a normal response to
21 September 1993; finally revised 19 October 1993; metyrapone. In contrast, in 17 patients discord between
accepted 9 November 7993) the rnetyrapone and the hypoglycaemia test was seen In
only 1patient who demonstrated a normal response to the
metyrapone test and a subnormal response to hypogly-
Summary caemia.
OBJECTIVE The ACTH stimulation test examines adrenal CONCLUSION Since the metyrapone test gives similar
responsiveness but may not examine the entire hypo- information about hypothalamic-pituitary axis function as
thalamic-pituitary-adrenal (HPA) axis and requires par- does the hypoglycaemia test, we recommend the use of
enteral administration. The cortisol response to hypo- the overnight metyrapone test as a safe, simple and
glycaemia provides an index of activity of the entire HPA reliable index of the hypothalamic-pituitary axis integrity.
axis but is demanding for patients and medical staff. The The ACTH stimulation test should not be used for patients
aim of the present study was to examine the performance suspected of having secondary adrenal insufficiency.
of the overnight single-dose metyrapone test as it pro-
vides a simple alternative test for HPA axis function.
DESIGN Audit of the overnight metyraponetest performed Current screening tests for adrenal insufficiency include
in one centre between 1979 and 1991. measurement of basal unstimulated plasma cortisol levels,
PATIENTS Three hundred and ninety-eight patients the cortisol response to adrenal stimulation with ACTH, the
underwent 576 tests. Comparisons between the re- cortisol response to hypoglycaemia, the ACTH and cortisol
sponses to metyrapone and the ACTH stimulation test and response to exogenous corticotrophin releasing hormone
of the responses to rnetyrapone and insulin induced (CRH) and the 1 1-deoxycortisol response to metyrapone.
hypoglycaemia test were possible in 87 and 17 patients Measurement of the basal cortisol level has a limited
respectively. usefulness in assessing the status of the hypothalamic-
MEASUREMENTS Following the midnight administration pituitary-adrenal axis (HPAA) because of the presence of
of metyrapone tablets, 30 mglkg orally, blood samples the normal diurnal rhythm. Furthermore there is difficulty
were obtained between 0800 and 0930 h for radioimmu- distinguishing a cortisol value in the normal range in a
noassay of both 11-deoxycortisoland cortisol. patient with normal reserve capable of responding to stress
RESULTS Five hundred and seventy-six metyrapone tests and a value in the normal range representing the maximum
were performed on 398 patients with no serious side- achievable without any reserve as occurs in partial adrenal
effects encountered. Andrenal insufficiency was diag- insufficiency. The ACTH stimulation test assesses the adre-
nosed in 105 patients. Of these, 18 had a primary adrenal nal response but not the entire HPA axis (Cunningham et al.,
disorder and 87 had a disorder of the hypothalamic- 1983). Some patients with hypothalamic-pituitary suppres-
pituitary unit. One hundred per cent concordancebetween sion maintain a normal cortisol response to ACTH. The
the metyrapone, the ACTH and the hypoglycaemia test insulin induced hypoglycaemia test is considered to be the
was seen in patients with primary adrenal insufficiency. In gold standard test as hypoglycaemia produces a major stress
19 patients with secondary adrenal insufficiency, who response which results in a maximum stimulation of the
underwent both the metyrapone and the ACTH tests, entire HPAA, via production of CRH and other stimuli of
corticotrophin secretion, e.g. vasopressin (Vale et a / . , 1983).
Correspondence: Dr T. J. McKenna, Department of
Endocrinology and Diabetes Mellitus, St Vincent’s Hospital, The usefulness of the CRH test as a tool for the assessment of
Elm Park, Dublin 4, Ireland. HPAA activity and in making the differential diagnosis

603
604 T. M. Fiad et a / . Clinical Endocrinology (1994) 40

between hypothalamic and pituitary secondary adrenal report examines our extensive experience with the overnight
failure has been evaluated over the last decade. Side-effects metyrapone test in the evaluation of possible adrenal
are minimal using CRH in doses of 100 pg or less and the test insufficiency.
is as useful as hypoglycaemia in assessing the function of the
HPAA in patients on long-term corticosteroid therapy Materials and methods
(Schlaghecke et al., 1992). However, the CRH test is costly,
requires frequent blood sampling, and the assessments of its Patients
value in differentiating hypothalamic from pituitary causes Clinical data on 398 patients with suspected HPA axis
of secondary adrenal insufficiency are conflicting (Muller et hypofunction who underwent the single-dose overnight
al., 1987; Lytras et al., 1984; Stalla et al., 1985, 1988; Taylor metyrapone test were reviewed. Side-effects of metyrapone
& Fishman, 1988).Some patients with an isolated hypothala- were recorded. Where available, comparison was made
mic defect give a normal response to CRH and this may be between the results of the metyrapone test with the results of
misleading if this diagnosis is not suspected. In contrast, the ACTH and hypoglycaemia tests.
overnight single-dose metyrapone test assesses the entire
HPA axis. Since its introduction as a test of pituitary reserve
Tests of HPA axis integrity
(Liddle et al., 1959), the metyrapone test has been performed
following several different protocols in assessing the HPAA. Metyrapone was administered at a standard dose of 30 mg/
Investigators have used variable doses, routes of administra- kg orally with a snack at midnight (Cunningham et al., 1983).
tion and measurement of plasma and urinary 1l-deoxycor- Blood was drawn between 0800 and 0930 h the following
ticosteroids, urinary 17-ketogenic steroids, plasma 1 7- morning for radioimmunoassay of 1 1-deoxycortisol and
hydroxycorticosteroids and ACTH (Buus et al., 1962; Jubiz cortisol. Using the mean less 2 standard deviations of the log
et al., 1970a Spark, 1971; Dickstein et al., 1986). The simplest transformed data from 21 normal subjects, a subnormal
of these tests is the single-dose overnight metyrapone test response to metyrapone was defined as an 11-deoxycortisol
which takes into account the observation that the ACTH and level of less than 200 nmol/l. For a test to be accepted as
1 1-deoxycortisolresponses to metyrapone follow a circadian yielding a valid subnormal response it was essential that the
rhythm (Jubiz et al., 1970b; Dolman et al., 1979). Metyra- simultaneous plasma cortisol level was less than 200 nmol/l.
pone, 30 mg/kg at midnight, induces a block in steroidogene- When additional tests of adrenal hypofunction, e.g. ACTH
sis which continues until after 0800 h (Schoneshofer et al., stimulation or hypoglycaemia, were performed they were
1977; Cunningham et al., 1988). Metyrapone inhibits 118- always undertaken at least 48 hours before the metyrapone
hydroxylase which facilitates the final step in cortisol test. ACTH was given as crl-24 ACTH, 250 pg i.v. A serum
biosynthesis, the conversion of 11-deoxycortisol to cortisol. cortisol level of greater than 500 nmol/l, one hour following
When metyrapone inhibits I la-hydroxylase, plasma cortisol ACTH administration, was considered as a normal response
levels fall which is a strong stimulus for ACTH secretion (Cunningham etal., 1983). When the hypoglycaemia test was
resulting in the accumulation of 11-deoxycortisol under performed, blood was drawn for measurement of glucose
normal conditions. When a defect exists in the hypothalamus and cortisol before and at 30, 45, 60, 90 and 120 minutes
or the pituitary or the adrenal gland, there is a subnormal 11- following the administration of short-acting insulin 0.1-0.3
deoxycortisol response to metyrapone. Although hypogly- IUjkg intravenously, with the insulin dose adjusted depend-
caemia has been promoted as providing the maximum ing on the patient’s clinical status. Satisfactory hypogly-
stimulus for cortisol production, the ACTH levels following caemia was considered to have occurred when the plasma
metyrapone have been reported to be higher than those glucose fell to less than 2.2 mmol/l. Side-effects of all tests
observed following hypoglycaemiain normal subjects (Staub were recorded.
et al., 1979). There are anecdotal reports of precipitation of
adrenal crisis by metyrapone using the 24-hour test or, more
Biochemical methods
commonly, when chronic metyrapone treatment is used in
high dosage as in Cushing’s syndrome (Verhelst et al., 1991). Serum cortisol was measured by specific radioimmunoassay
However, we know of no instance of adrenal crisis occurring without extraction of chromatographic purification using a
after overnight metyrapone. Nonetheless, because of con- ?-Coat 12SI-~ortisol kit from Clinical Assays, Travenol-
cern about precipitating adrenal crisis and the requirement Genentech Diagnostics (Cambridge, MA; catalogue no. CA-
for an 11-deoxycortisol assay which is not a conventional 529). I 1-Deoxycortisol levels were measured by
endocrine laboratory test, the metyrapone test is not used radioimmunoassay following extraction with diethyl ether
widely to assess the integrity of the HPAA. The present but without chromatographic purification (Cunningham &
Clinical Endocrinology (1994) 40 Overnight metyrapone test 605

Table 1 Diagnosis in 105 patients with abnormal responses to the Metyrapone and ACTH stimulation tests (Fig. 1)
overnight metyrapone test
Comparison of the response to ACTH with that to metyra-
pone was made in 87 pairs of tests. A 100% concordance was
Failure Number of cases
observed in patients with primary adrenal insufficiency
Primary adrenal failure (n= 12). In contrast, in the 19 patients with secondary
Acquired adrenal insufficiency, a discordance of 53% was observed
Autoimmune 16 (Table 2). Nine of these 19 patients demonstrated a normal
Tuberculosis 1 response to ACTH and a subnormal response to metyra-
Congenital pone. In only one patient was an abnormal response to
Adrenal hypoplasia 1
ACTH associated with a normal response to metyrapone.
Secondary adrenal failure This patient was treated with dexamethasone 0.5 mg nightly
Pituitary adenoma/post hypophysectomy 38 for 6 months. Dexamethasone was stopped 36 hours prior to
Post-glucocorticoid treatment 34 the ACTH stimulation test. The basal and one hour post
Idiopathic hypopituitarism 9 ACTH cortisol levels were 253 and 458 nmol/l respectively
Sheehan’ssyndrome 5
indicating mild adrenal dysfunction. A normal response to
Pituitary apoplexy 2
metyrapone test was observed 48 hours following the ACTH
test.

McK enna, 1982). Cortisol and 17-hydroxyprogesterone


cross-reacted 3.1 and 12% respectively in the 1l-deoxycorti- Metyrapone and hypoglycaemia tests (Fig. 1 )
sol assay using the 50% displacement method. Comparison of 17 paired hypoglycaemia and metyrapone
tests revealed concordance in 16 patients, being normal in 8
Results and abnormal in 8 patients. One instance of discord was
noted in a patient on long-term topical steroid treatment who
Overnight rnetyrapone test
gave a subnormal response to hypoglycaemia and a normal
Of a total of 576 metyrapone tests performed, 385 gave response to metyrapone.
normal results; these tests were carried out in 293 patients.
One hundred and fifty-five tests gave subnormal results;
Discussion
these were carried out in 105 patients. Thirty-six tests
performed in 30 subjects yielded invalid results, i.e. plasma The overnight single-dose metyrapone test is very simple to
cortisol levels greater than 200 nmol/l while the 1 I-deoxycor- perform. It requires only a single blood sample for the
tisol values were less than 200 nmol/l. The diagnoses in the measurement of 1 1-deoxycortisol and cortisol. Since there is
105 patients with adrenal insufficiency are shown in Table I. no requirement for medical supervision and because of the
Side-effects of the overnight metyrapone test were reported suitability for out-patient testing, the demand on the medical
in seven patients. One patient experienced unusual limb resources when performing the overnight metyrapone test is
sensations and complained of feeling faint, three patients minimal as is the inconvenience to patients. The recommen-
experienced nausea and vomiting, one patient complained of dation to perform the metyrapone test in hospital (Streeten et
dizziness without postural hypotension, one patient who had al., 1984; Orth et al., 1992) is based on the concern that
a repeat metyrapone test on three occasions over a period of metyrapone may precipitate significant worsening of adrenal
18 months reported no untoward effect on the first test, insufficiency symptoms. However, a serious side-effect of the
experienced dizziness and nocturnal confusion on the second overnight metyrapone test must be very rare as none was
test and complained of a sensation of being distant from the encountered in the 576 tests reviewed here and none has been
surroundings and had nightmares during the third test, and reported to our knowledge. The side-effects we reported are
one patient had nocturnal nightmares. Five of these seven not serious. Nightmares were not reported previously fol-
patients who experienced side-effects to the metyrapone test lowing metyrapone administration. Whether nightmares are
had HPAA dysfunction while one patient who had nausea related to a central effect or other metabolic effects of
and the other who had isolated nocturnal nightmares, had metyrapone is unknown.
normal HPAA function. No patient experienced significant Our results demonstrated that the ACTH test yielded
worsening of adrenal insufficiency symptoms. No significant misleading results in 47% of patients with secondary adrenal
side-effects were reported during the 17 hypoglycaemia and failure. These patients retained the ability to respond to
87 ACTH stimulation tests. exogenous ACTH; however, when the entire HPA axis was
606 T. M. Fiad et al. Clinical Endocrinology (1994) 40

Fig. 1 a, The distribution of paired results


of the ACTH stimulation and metyrapone
tests in relation to the serum cortisol cut-
off point indicated by the broken
c f * * horizontal line and the cut-off point for
r plasma 1 1-deoxycortisol values indicated
by the broken vertical line. Concordant
500 _____ ___________-- results for subnormal tests fall in the lower
7
A," A I 0 left segment and concordant normal results
I E
$ 1 2 fall in the upper right segment. Discordant
I I I I I
results appear in the other two segments. b,
200 400 600 0 200 400 6oo
The distribution of paired results for serum
Plasma Il-deoxycorlisol after rneiyrapone (nrnol/l) cortisol in response to hypoglycaemia and
the plasma 1 1-deoxycortisol response to
metyrapone related to the lower limit of
normal cut-off points, indicated by the
broken horizontal and the broken vertical
lines, respectively. Concordant subnormal
responses fall in the lower left segment
while concordant normal responses fall in
the upper right segment. There is only one
discordant response showing a normal
response to metyrapone and a subnormal
response to hypoglycaemia. A, Secondary
adrenal insufficiency; A, primary adrenai
*,
insufficiency; normal adrenal function.

Table 2 The responses of plasma 1 I-deoxycortisol to metyrapone and plasma cortisol to ACTH in 10 patients with discordant results

Diagnosis Peak cortisol 1I-Deoxycortisol


after ACTH after metyrapone
Patient Normal response z 500 nmol/l < 200 nmol/l

Unresected craniopharyngioma 883 78


Craniopharyngioma (4 months following resection) 814 64
Idiopathic hypopituitarism 510 154
Idiopathic hypopituitarism 609 74
Dexamethasone, 0.5 mg each night for 4 months 664 27
Long-term glucocorticoids treatment for asthma 51 1 170
Three-week course of prednisolone for lymphoma 1228 191
8 Two-week course of parenteral hydrocortisone injection 543 147
9 Two-week course of parenteral dexamethasone injection 552 36
10 0.5 mg dexamethasone each night for 1 month 458 256

tested by metyrapone, abnormal responses were obtained ACTH, although endogenous ACTH secretion is inadequate
indicating failure to mount a normal hypothalamic or to meet physiological requirements (Cunningham et al.,
pituitary response to hypocortisolaemia. The diagnosis of 1983). However, Clayton (1989) has stated that with the
adrenal insufficiency in these nine patients could have been exception of patients on long-term glucocorticoid treatment
missed if the ACTH test was relied upon to assess the entire where the ACTH stimulation test may not be reliable, this
HPA axis integrity. The presence of normal adrenal sensiti- test rarely misleads when assessing patients for possible
vity to ACTH in the face of subnormal HPA responsiveness adrenal insufficiency. If steroid treated patients in our study
in these patients, can be explained by partial ACTH were excluded, four patients with adrenal insufficiencywould
insufficiency rather than an absolute absence of ACTH. In have been labelled as having normal HPA axis function
this way subnormal ACTH levels may maintain the adrenal based on the results of the ACTH stimulation test. Two of
in a primed state, capable of responding to exogenous these four patients had idiopathic hypopituitarism and two
Clinical Endocrinology (1994) 40 Overnight metyrapone test 607

patients had craniopharyngioma, one of whom was assessed protocol used when assessing patients for primary adrenal
preoperatively and the second was assessed 4 months insufficiency where it gives similar information to that
following hypophysectomy. Indeed, limitations of the obtained by the metyrapone or hypoglycaemia test.
ACTH stimulation test in patients with hypothalamic- It has been generally accepted that the insulin-induced
pituitary disease have been reported previously (Borst et a/., hypoglycaemia test is the gold standard test in assessing the
198%;Cunningham et a/., 1983; Lindholm & Kehlet, 1987). It entire HPA adrenal axis. The adrenal cortisol production
has been suggested that 2 weeks following the onset of acute following hypoglycaemia exceeds that obtained following
ACTH deprivation as occurs following hypophysectomy or both the ACTH stimulation (Lindholm & Kehlet, 1987) and
pituitary apoplexy, the ACTH test is considered reliable in that following CRH (Schlaghecke et a/., 1992). Concordance
assessing the HPA axis (Kehlet et a/., 1984; Lindholm & between the results of the metyrapone test and the insulin
Kehlet, 1987). However, this has not been our experience induced hypoglycaemia were seen in all our patients on long-
even when we excluded patients on long-term glucocorticoid term steroid treatment except one who gave a subnormal
treatment since our four patients noted above who res- response to hypoglycaemia and a normal response to
ponded to ACTH but not to metyrapone, did not have acute metyrapone. A similar discord was observed previously in
ACTH deprivation. Only one patient in our series demon- one out of 19 patients on long-term glucocorticoid treat-
strated a normal result to the metyrapone test and an ment, in patients with chronic renal falure, and in three
abnormal response to ACTH. It is possible that the HPAA patients with acromegaly who had HPA axis assessment
had the opportunity to make the transition between mild following hypophysectomy for pituitary adenoma (Jasani et
insufficiency following the withdrawal of glucocorticoid al., 1967; Ramirez et a/., 1982; Delaloye et al., 1982). This
therapy 36 hours prior to the ACTH test and normal discord is unusual since both tests examine the entire HPA
function, observed following a further interval of 48 hours axis, although it is possible that different mechanisms of
when the metyrapone test was performed. If the ACTH had stimulation are activated in the two procedures. This is
been repeated at the time of the metyrapone test, a normal theoretically explained by operation of short-loop feedback
result might have been obtained, as reported in eight patients of metyrapone induced hypocortisolaemia on the pituitary
who had a subnormal response to ACTH (peak plasma to stimulate ACTH secretion in a patient with a hypothala-
cortisol ranging from 360 to 470 nmol/l), all of whom mic lesion which can be identified by a subnormal response to
demonstrated a normal cortisol response on repeating the hypoglycaemia because a normal response requires an intact
testing (May & Carey, 1985). The discrepancies between hypothalamus. In contrast, an abnormal response to metyra-
various experiences reviewed here may be related at least in pone with a normal response to hypoglycaemia has been
part to differences in cortisol assay techniques, time of reported in steroid treated patients and those with a history
plasma sampling after ACTH administration and variability ofpituitary disease (Feek et a/., 1981;Hartzband et al., 1988).
in cut-off points utilized. Lindholm and Kehlet (1987) used a Although the metyrapone and hypoglycaemia tests give
cut-off point of 500 nmol/l employing a fluorometric method similar information about the HPA axis in most instances,
which gives readings approximately 25% higher than the hypoglycaemia test requires hospital admission, constant
radioimmunoassay, for blood samples obtained 30 minutes medical supervision, involves multiple blood sampling and is
after ACTH administration; Stewart et al. (1988) recom- distressing to the patient. In addition, the induction of
mended a cut-off point of 550 nmol/l measured by radioim- profound hypoglycaemia may have unwanted consequences;
munoassay, again 30 minutes following administration of coma, seizure activity and even two deaths have recently
ACTH. However, Clayton (1989) recommended a plasma been reported in children (Shah et al., 1992). In contrast, the
cortisol cut-off point of greater than 400 nmol/l and Orth et overnight metyrapone test has the advantages of safety and
a/. (1992), in agreemeent with Burke (1985), recommended a convenience and can be performed on patients with condi-
plasma cortisol level of greater than 555 nmol/l in blood tions in which hypoglycaemia is contraindicated, e.g. epi-
samples obtained either 30 or 60 minutes following ACTH lepsy, ischaemic heart disease, old age and hypertension. In
administration. Borst et al. (1982) also recommended a cut- our experience, the metyrapone test is the procedure of
off point of 550 nmol/l in blood samples obtained 30,60 or 90 choice for patients suspected of having secondary adrenal
minutes following ACTH administration. As pointed out by insufficiency, where the ACTH test can be misleading. The
Clayton (1989), a consensus on the protocol for the ACTH metyrapone test also has advantages over the ACTH test
stirnulation test has not been achieved and this may lead to when screening for primary adrenal insufficiency since it is of
small differences in patterns of results obtained between equal sensitivity but requires only a single venipuncture in
studies. In contrast to its performance in secondary adrenal contrast to the ACTH test which requires intravenous
failure, the ACTH stimulation test is reliable irrespective of administration of the peptide and at least one additional
608 T. M. Fiad et a/. Clinical Endocrinology (1994) 40

venipuncture. Although no serious side-effect of metyrapone and metyrapone. Journal of Endocrinological Investigation, 11,
769-776.
was encountered in the 105 patients identified as having
Jasani, M.K., Boyle, J.A., Greig, W.R., Dalakos, T.G., Browning,
adrenal insufficiency, because of the theoretical risk of M.S., Thompson, A. & Buchanan, W.W. (1967) Corticosteroid-
inducing deterioration in the clinical status by further induced suppression of the hypothalamic-pituitary-adrenal axis:
compromising adrenal function, we do not recommend that observations in patients given oral corticosteroids for rheumatoid
the test is performed in an outpatient setting on patients arthritis. Quarterly Journal of Medicine, 143, 26 1-276.
exhibiting objective evidence of instability, e.g. postural Jubiz, W., Matsukura, S . , Meikle, W., Harada, G., West, C.D. &
Tyler, F.H. (1970a) Plasma metyrapone, adrenocorticotropic
hypotension, nausea or vomiting. Because of its general hormone, cortisol and deoxycortisol levels: sequential changes
performance, safety and considering its simplicity and during oral and intravenous metyrapone administration. Archives
convenience when compared to the hypoglycaemia and the of lnrernal Medicine, 125, 468-471.
ACTH tests we recommend the routine use of the overnight Jubiz, W., Meikle, W., West, C.D. &Tyler, F.H. (1970b) Single-dose
metyrapone test. Archives of Internal Medicine, 125,472-474.
metyrapone test as a sensitive index of the activity of any
Kehlet, H., Lindholm, J. & Bjerre, P. (1984) Value of the 30 minute
component of the HPAA. ACTH test in assessing hypothalamic-pituitary function after
pituitary surgery in Cushing's disease. Clinical Endocrinology, 20,
349-353.
Liddle, G.W., Estep, H.L., Kendall, J.W., Williams, W.C. &
References Townes, A.W. (1959)Clinicalapplicationofanew test ofpituitary
Borst, G.C., Michenfelder, H.J. & O.Brian, J.T. (1982) Discordant reserve. Journal of Clinical Endocrinology and Metabolism, 19,
cortisol response to exogenous ACTH and insulin-induced hypo- 875-894.
glycaemia in patients with pituitary disease. New England Journal Lindholm, J. & Kehlet, H. (1987) Re-evaluation of theclinical value
of Medicine, 306, 1462-1464. of the 30 minute ACTH test in assessing the hypothalarnic-
Burke, C.W. (1985) Adrenocortical insufficiency. Clinics in Endo- pituitary-adrenocortical function. Clinical Endocrinology, 26,53-
crinology and Metabolism, 4, 947-976. 59.
Buus, O., Binder, C. & Peterson, F. (1962) Metyrapone dosage in Lytras, N., Grossman, A., Perry, L., Tomlin, S . , Wass, J.A.H., Coy,
pituitary function tests. Lancet, i, 1040-1041. D.H., Schally, A.V., Rees, L.H. & Besser, G.M. (I 984) Cortico-
Clayton, R.N. (1989) Diagnosis of adrenal insufficiency: the short trophin releasing factor: responses in normal subjects and patients
tetracosactrin test can almost always replace the insulin stress test. with disorders of the hypothalamus and pituitary. Clinical
British Medical Journal, 298, 27 1-272. Endocrinology, 20, 7 1-84.
Cunningham, S.K., Loughlin, T., Bertagna, X., Girard, F. & May, M.E. & Carey, R.M. (1985) Rapid adrenocorticotropic
McKenna, T.J. (1988) Plasma pro-opiomelanocortin fragments hormone test in practice, retrospective review. American Journal
and adrenal steroids following administration of metyrapone to of Medicine, 19, 679-684.
normal and hirsute women. Journal of Endocrinological Investiga- Muller, O.A., Stalla, G.K. &Von Werder, K. (1987) Corticotropin-
tion, 11, 247-253. releasing factor in Humans. Hormone Research, 25, 185-198.
Cunningham, S.K. & McKenna, T.J. (1982) A system for separation Orth, D.N., Kovacs, W.J. & Debold, C.R. (1992) The adrenal
of cortisol, 1I-deoxycortisol, 17-hydroxyprogesterone and pro- cortex. In Wiiiiatns Te..xthookufEf%docrinulogy(edsJ. D. Wilson &
gesterone in a single chromatographic step and its application to D. W. Foster), pp. 585-586. W. B. Saunders, Philadelphia.
radioimmunoassay. Clinica Chernica Acta, 123, 21 1-219. Ramirez, G., Gomez-Sanchez, C., Meikle, W.A. & Jubiz, Z.W.
Cunningham, S.K., Moore, A. & McKenna, T.J. (1983) Normal (1982) Evaluation of the hypothalamic hypophysedl adrenal axis
cortisol response to corticotropin in patients with secondary in patients receiving long-term hdemodialysis. Archives oflnternal
adrenal failure. Archives of Internal Medicine, 143, 2276-2279. Medicine, 142, 1448-1452.
Delaloye, J.F., Gomez, F. & Buckhardt, P. (1982) Discordant Schlaghecke, R., Kornely, E., Santen, R.T. & Ridderskamp, P.
cortisol response in pituitary disease. New England Journal of (1992) The effect of long-term glucorticoid therapy on pituitary-
Medicine, 307, 1218. adrenal responses to exogenous corticotropin-releasing hormone.
Dickstein, G., Lahav, M. & Orr, Z.S. (1986) Single-dosemetyrapone New Englnnd Journal of Medicine, 326, 226-230.
test at 0600 h: an accurate method for assessment of pituitary- Schoneshofer, M., L'age, M. & Oelkers, W. (1977) Short term
adrenal reserve. Acta Endocrinologica, 112, 28-34. kinetics of deoxycorticosterone, deoxycortisol, corticosterone and
Dolman L.I., Nolan, G . & Jubiz, W. (1979) Metyrapone test with cortisol during single dose metyrapone test. Acta Endocrinologica,
adrenocorticotrophic levels: separating primary from secondary 85, 109-1 17.
adrenal insufficiency. Journal of the American Medical Associ- Shah, A., Stanhope, R. & Matthew, D. (1992) Hazards of pharmd-
ation, 241, 1251-1253. cological tests of growth hormone secretion in childhood. British
Feek, C.M., Bevan, J.S., Ratcliffe, J.G., Gray, C.E. & Blundell, G . Medical Journal, 304, 173-175.
(1981) The short metyrapone test: comparison of the plasma Spark, R.F. (197 1) Simplified assessment of pituitary-adrenal
ACTH response to metyrapone with the cortisol response to reserve. Measurement of serum 1I-deoxycortisol and cortisol
insulin-induced hypoglycaemia in patients with pituitary disease. after metyrapone. Annals of Internal Medicine, 75, 717-723.
Clinical Endocrinology, 15, 75-80. Stalla, G.K., Losa, M., Oeckler, R., Muller, O.A. & Von Werder, K.
Hartzband, P.I., Van Herle, A.J., Sorger, L. & Cope, D. (1988) (1985) CRF and CRF stimulation test for the differential
Assessment of hypothalamic-pituitary-adrenal (HPA) dysfunc- diagnosis of hypothalamopituitary disorders. Journal of Endocri-
tion: a comparison of ACTH stimulation, insulin-hypoglycaemia nological Investigations, 8 (Suppl. 3), 79.
Clinical Endocrinology (1994) 40 Overnight metyrapone test 609

Stalla, G.K., Losa, M., Oeckler, R., Muller, O.A. & Von Werder, K. hypothalamic-pituitary-adrenocortical system in man. Endocrine
(1988) Insulin hypoglycaemia test and releasing hormone (corti- Reviews, 5, 371-394.
cotropin-releasing hormone and growth hormone releasing hor- Taylor, A.L. & Fishman, L.M. (1988) Corticotropin-releasing
mone) stimulation in patients with pituitary failure of different hormone. New England Journal of Medicine, 319,213-222.
origin. Hormone Research 29, 191-196. Vale, W., Vaughan, J., Smith, M., Yamamoto, G., Rivier, J. &
Staub, J.J., Noelpp, B., Girard, J., Baumann, J.B., Graf, S. & Rivier, C. (1983) Effects of synthetic ovine corticotropin releasing
Ratcliffe, J.G. (1979) The short metyrapone test: comparison of factor, glucocorticoids, catecholamines, neurohypophysial pep-
the plasma ACTH response to metyrapone and insulin-induced tides, and other substances on cultured corticotropic cells.
hypoglycaemia. Clinical Endocrinology, 10,595-601. Endocrinology, 113, 1121-1 131.
Stewart, P.M., Corrie, J., Seckl, J.R., Edwards, C.R.W. and Verhelst, J.A., Trainer, P.J., Howlett, T.A., Perry, L., Rees, L.H.,
Padfield, P.L. (1988) The rational approach for assessing the Grossman, A.B., Wass, J.A.H. & Besser, G.M. (1991). Short and
hypothalamic-pituitary-adrenal axis. Lancet, i, 1208-1 210. long-term responses to metyrapone in the medical management of
Streeten, D.H.P., Anderson, G.H., Dalakos, T.G., Seeley, D., 91 patients with Cushing’s syndrome. Clinical Endocrinology, 35,
Mallov, J.S., Eusebio, R., Sunderlin, F.S., Badaway, S.Z.A. & 169-1 78.
King, R.B. (1984). Normal and abnormal function of the