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Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica (R.R., L.T., A.L., M.D.M., C.B., V.N., G.L.), Dipartimento di Scienze Biomorfologiche e Funzionali (L.D.V.), Università di Napoli "Federico II", Napoli, 80131 Italy
Address correspondence and requests for reprints to: Rossi Riccardo, M.D., piazza degli Artisti n.17, 80129 Napoli, Italy.
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Abstract |
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6.21 mmol/L, low-density lipoprotein
cholesterol 4.14 mmol/L and/or triglycerides 1.8
mmol/L). Compared with a healthy population, bone mineral density
Z-score, determined by the DEXA technique, tended to be slightly (but
not significantly) lower in patients with adrenal adenoma (-0.41
SD). Endocrine data were compared with 107 sex- and
age-matched controls, and patients with adenomas were found to have
heterogeneous hormonal abnormalities. In particular, significantly
higher serum cortisol values (P < 0.001), lower
ACTH concentration (P < 0.05), and impaired
cortisol suppression by dexamethasone (P < 0.001)
were observed. Moreover, in patients with adenomas, cortisol, 17-OH
progesterone, and androstenedione responses to corticotropin were
significantly increased (P < 0.001, all), whereas
dehydroepiandrosterone sulfate levels were significantly lower at
baseline, with blunted response to corticotropin (P
< 0.001, both). However, the criteria for subclinical CS were met by
12 of 50 (24%) patients. Of these, 6 (50%) were diffusely obese, 11
(91.6%) had mild-to-severe hypertension, 5 (41.6%) had type-2
diabetes mellitus, and 6 (50%) had abnormal serum lipids. The clinical
and hormonal features improved in all patients treated by
adrenalectomy, but seemed unchanged in all those who did not undergo
surgery (follow-up, 9 to 73 months), except for one, who was previously
found as having nonfunctioning adenoma and then revealed to have
subclinical CS. In conclusion, an unexpectedly high prevalence of
subtle autonomous cortisol secretion, associated with high occurrence
of hypertension, diabetes mellitus, elevated lipids, and diffuse
obesity, was found in incidentally discovered adrenal adenomas.
Although the pathological entity of a subclinical hypercortisolism
state remained mostly stable in time during follow-up, hypertension,
metabolic disorders, and hormonal abnormalities improved in all
patients treated by adrenalectomy. These findings support the
hypothesis that clinically silent hypercortisolism is probably not
completely asymptomatic. |
Introduction |
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Several years ago, Ross and Aron (6) suggested that endocrine screening procedures, including urinary cortisol measurement and dexamethasone (DXM) testing, were not justified in patients with incidentalomas, given the low probability of cortisol production in such tumors. However, since 1990, an increasing body of evidence has emerged showing that subtle cortisol production and subsequent abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are more frequent than previously thought. In the early 1990s, several authors have reported abnormalities in the HPA axis in 5–6% of adrenal incidentalomas (7, 8); but since 1992, the occurrence reported has increased to 12–16% of patients with incidentalomas (9, 10, 11, 12, 13). This entity has been defined as subclinical or preclinical Cushing’s syndrome (CS). "Subclinical CS" is likely a more adequate definition, because the rate of progression to overt CS is unclear and probably is very low (10, 14).
The true prevalence of autonomous cortisol production by incidentally discovered adrenal tumors is unknown and likely is underestimated because of the infrequent use of careful endocrine evaluation of incidentalomas in the older studies. However, different criteria have been adopted to define autonomous cortisol secretion in more recent studies (14, 15). The lack of both standard endocrine tests and criteria for the definition of subclinical CS limits the possibility of a correct evaluation and management of these patients. Moreover, recent evidence has shown a growing prevalence of autonomous cortisol production, emphasizing the importance of careful endocrine evaluation in all patients with apparently nonfunctional adrenal tumors such as incidentalomas.
The purpose of the present study was to evaluate the presence of subclinical CS attributable to autonomous cortisol production in a group of consecutive patients with incidentally discovered adrenal adenomas and to follow the natural history of this pathological entity.
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Subjects and Methods |
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From 1992 to 1998, 65 consecutive patients (41 women and 24 men; age range, 27–78 yr; mean, 54) with incidentally detected adrenal masses were prospectively evaluated. They were part of a group of 106 patients referred to the Department of Molecular and Clinical Endocrinology and Oncology of the "Federico II University", in Naples, for the evaluation of adrenal masses. All the incidentalomas were discovered by abdominal ultrasound or CT scan, performed for the evaluation of unrelated diseases, such as urinary tract infection, renal colic, or biliary colic, nonspecific abdominal pain, or during a common check-up. Patients with known extraadrenal malignancies or those with hypertension of possible endocrine origin (i.e. paroxysmal hypertension, hypertension resistant to treatment or associated with hypokaliemia) were excluded. None of the patients showed specific signs or symptoms of hormone production excess, nor were they on hormonal treatment. A group of 107 healthy subjects and patients with multinodular euthyroid goiter and TSH concentration within the normal range (0.8–3.2 mU/L) also entered the study as controls (65 women and 42 men; age range, 29–75 yr; mean, 52.2). All of them were normal at the physical examination, had a negative medical history, and were not taking any medication. The study was designed in accordance with the Declaration of Helsinki; all subjects and patients gave their informed consent to enter the study.
The 65 patients of the study group were all hospitalized. All standard blood analytes were determined by routine clinical laboratory methods. In patients who had previously undergone only abdominal ultrasound, a CT scan was also performed. All CT scans were reviewed by the same radiologist. Fifty patients with adrenocortical adenoma were selected from those with adrenal incidentalomas. The selection was performed on the basis of an initial endocrine evaluation plus CT criteria suggesting the presence of a benign mass (16, 17), as follows: tumor size less than 3.5 cm with a round or oval shape, hypodense and homogeneous pattern with well-defined margins, and no or mild enhancement after iv contrast medium administration. Patients with pheochromocitoma (n = 5), ganglioneuroma (n = 2), carcinoma (n = 2), schwanoma (n = 1), cysts (n = 3), and asymptomatic metastasis of other tumors (n = 2) were excluded. The diagnosis of adenoma was then confirmed by histological findings in 19 patients. When the histological examination was not available, as in patients who had not undergone surgery, the diagnosis of adenoma was confirmed by follow-up data.
At entry, all patients underwent the following endocrine evaluation:
baseline serum cortisol and plasma ACTH at 0800; 1600, and 2400 h
(mean of at least two samples taken on different days); measurement of
24-h excretion of urinary free cortisol (UFF), serum basal
17-hydroxyprogesterone (17-OHP), 
4-androstenedione, testosterone,
and dehydroepiandrosterone sulfate (DHEAS); and a low-dose 2-mg DXM
suppression test (orally, 0.5 mg, four times a day for 2 days, with
measurement of serum cortisol and other steroids at 0800 h the
following morning; UFF was also determined). In addition, 24-h urinary
excretion of catecholamines and vanillylmandelic acid was determined,
to exclude the presence of pheochromocytoma; and measurement of renin
plasma activity and aldosterone in the upright posture was always
performed to exclude an aldosterone-producing adenoma. Nevertheless,
serum potassium values were normal in all patients in a salt-repleted
state.
To better assess steroid biosynthesis, a long ACTH test was performed
(250 µg of 1,24-ACTH; Synacthen, Ciba, Basel, Switzerland) in iv 5-h
infusion, with blood sampling at time 0, 5, and 6 h for F, 17-OHP,
4-androstenedione, and DHEAS. In patients who failed to achieve
serum cortisol suppression to below 3 µg/dL (83 nmol/L) after the
administration of 2-mg DXM (9), a high-dose DXM test was performed (2
mg, four times a day for 2 days).
Two more parameters were considered for the assessment of F secretion rates in adenomas: the daily average cortisol, calculated as (F0800 + F1600 + F2400 h)/3; and the cortisol percent ratio (F% ratio), expressing F circadian rhythm abnormalities, calculated as (F 2400/F 0800) x 100.
To define the reference range for each variable determined, means
± 2 SD were calculated in the control group. The ACTH test
was performed in 78 healthy subjects (41 women and 37 men; mean age, 49
yr), and means ± 3 SD were considered as cut off
values for abnormal responses of each variable, given the great
variability of steroid responses to ACTH stimulus. The results of
adrenal adenomas are compared with those of the control group in Table 1
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Corticoadrenal scintigraphy was performed using
[75Se]selenio-6
-methyl-19-nor-cholesterol
(Scintadren; Amersham Pharmacia Biotech, Amersham,
The Netherlands) in 33 patients. Scintigrams were obtained by crystal
-camera on days 3 and 7 after radiotracer injection. All scintiscans
were reviewed by the same operator.
Bone mineral density (BMD) was evaluated in 18 patients, by dual-energy x-ray absorptiometry (DEXA), using a QDR 1000 densitometer (Hologic, Inc., Waltham, MA). BMD was measured on the lumbar spine in patients under 65 yr and at the right femoral neck in those older than 65 yr. Because of budget restrictions, only 1 measurement site per person was chosen, i.e. the spine district, known to experience a greater damage with excess cortisol administration, was substituted by the femoral neck district in elderly subjects. The substitution was done on the basis of epidemiological data in Southern Italy, indicating that this region is generally more sensitive in the elderly than the lumbar spine, likely because of frequent rheumatological pathologies, such as ostheoarthritis, at the latter site (18). Individual BMD values were expressed as Z-score, which represents the difference between individual value and mean of the reference age- and sex- matched population, expressed as SD. The reference population adopted was the international pooled sample provided by the densitometer manufacturer (19); their data, in fact, did not differ significantly from those obtained on a local sample in a prestudy performed when the machine was set (18).
All the patients were followed up at regular intervals at 6 and 12 months and then every year for a median period of 34 months (range, 6–85 months). The same endocrine and clinical evaluation and abdominal CT scan were performed at least twice in all patients, at 6-month intervals. A 2-yr follow-up period was completed in 29 patients. None of the patients developed clinical signs of hormonal excess during follow-up. Women of reproductive age were studied in the early follicular phase of the menstrual cycle (days 3–6).
Endocrine assessment
All hormone assays were performed in the same laboratory using
commercially available kits. F, UFF, T, and DHEAS were tested by
Immulite, solid-phase chemiluminescent enzyme immunoassay (DPC; Los
Angeles, CA ) and 4-androstenedione, 17-OHP by RIA (Diagnostic Systems Laboratories, Inc., Webster, TX). ACTH was tested by
double-antibody 125I RIA (DPC).
Statistical analysis
The results are expressed as mean ± SD. The statistical analysis was performed by the Wilcoxon test for unpaired data. The ANOVA was used for comparison of mean hormone levels between groups. The nonparametric method (Mann-Whitney U-test) was used when Wilk-Shapiro’s test was not consistent with the Gaussian distribution of the data, i.e. for the evaluation of 17-OHP and DHEAS values. Significance was considered to be at P < 0.05.
Subclinical hypercortisolism was considered in accordance with the recommendations of the National Italian Study Group on Adrenal Tumors (4, 20) (some authors of this study participated in that multicentric study, and their data were included in the papers): no clinical sign of hormone excess (including truncal obesity, thin extremities with muscular hypotrophy, moon face, nuchal gibbous, and cutaneous purple striae) in the presence of at least two abnormalities in HPA function, assessed by routine endocrine tests. A necessary condition was failure to achieve serum cortisol suppression to below 83 nmol/L (3 µg/dL) by 2-mg DXM. Other abnormalities included: 1) UFF exceeding mean + 2 SD of the control group; 2) average daily cortisol exceeding mean + 2 SD of controls; 3) F% ratio above mean ± 2 SD of controls F% ratio; and 4) reduced ACTH levels.
No patient with bilateral mass had TC scan evidence of pituitary adenoma or endocrine pattern suggesting Cushing’s disease (lack of F response to 2 mg DXM test but responsiveness to 8 mg DXM test).
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Results |
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A diagnosis of adrenocortical adenoma was made in 50 patients [21
men and 29 women, 32–73 yr old (mean, 56.3 yr)]. In 19, the tumors
were located on the left side; in 28, they were on the right side; 3
patients presented bilateral masses. The size, obtained by CT ranged
from 1–6.5 cm (mean, 3.26 cm). In patients with a bilateral pathology,
the size of the largest adenoma was considered. Twenty-four patients
(48%) had mild-to-severe hypertension (21), 12 (24%) had type-2
diabetes with fasting hyperglycemia (>126 mg/dL)(22), 6 patients had
glucose intolerance (22), and 18 (36%) were diffusely obese [body
mass index (BMI) determined as weight/height2,
BMI > 25]. Moreover, 14 patients (28%) had abnormal serum lipid
concentrations (cholesterol 240 mg/dL (6.21 mmol/L),
low-density lipoprotein cholesterol 160 mg/dL (4.14 mmol/L),
and/or triglycerides 160 mg/dL (1.8 mmol/L). Compared with a
sex- and age- matched healthy population, mean BMD Z-score was not
significantly different (-0.41 SD, 95% CI: -1.127 to
0.3115).
Corticoadrenal scintigraphy
The mapping showed an early (3 days) [75Se-19] nor-cholesterol uptake by all adenomas; in 14 of 33 patients, it was unilateral and concordant with the side of the lesion, suggesting an inhibited function of the other adrenal gland. The uptake was bilateral and symmetrical in 1 patient and bilateral, asymmetrical and prevalent on the side of the lesion in the remaining 18.
Endocrine data
The results of hormonal evaluation are summarized in Table 1
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Compared with controls, patients with adenomas had significantly higher
morning serum F, average F, and F% ratio (P < 0.001).
In adenomas, a statistically significant difference was found also in
morning ACTH levels, which were lower (P < 0.05) and
in the degree of F suppression by 2 mg DXM, which was impaired
(P < 0.001). Moreover, F, 17-OHP, and
4-androstenedione responses to corticotropin were also significantly
increased (P < 0.001), whereas DHEAS was significantly
lower at baseline and showed a blunted response to corticotropin
(P < 0.001). Considering each single patient, 19 of
them had average serum cortisol levels that exceeded the normal range,
8 had high F% ratios, and 11 patients had an increased UFF. DXM failed
to suppress serum F levels in 16 patients; 15 subjects had low ACTH
basal values. Frequent abnormalities were also observed in response to
corticotropin administration: F and 17-OHP responses exceeded the
normal range in 22 and 33 patients, respectively. On the other hand,
DHEAS values ranged from normal to very low and were below control
ranges in 24 patients; this was always associated with a blunted
response to ACTH. A good correlation was found between the
suppressibility of serum and urinary F by 2- and 8-mg DXM test.
Subclinical CS patients
Twelve (9 women, 3 men) of the overall series of 50 patients with
adenoma were considered as having subclinical CS. The clinical and
hormonal features are shown in Table 2.
Six adenomas were located on the right side and 3 on the left; 3
patients had bilateral adenomas. The diameter ranged from 1.5–6.0 cm
(mean, 3.4 cm). The patients’ ages ranged between 47 and 72 yr (mean,
60.7yr). Six patients (50%) were diffusely obese; mild-to-severe
systolic-diastolic hypertension (21) was found in 11 patients (91.8%),
type-2 diabetes mellitus (22) in 5 (41.8%), glucose intolerance with
fasting hyperinsulinism (22) in 2, and abnormal lipids values in six
(50%). No significant difference was found in BMD Z-score between
subclinical CS and the remaining adenomas (data not shown).
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. When considering the patients affected
by subclinical CS and those by nonfunctioning adenomas as 2 separate
groups, a significant difference was found in serum and urinary
post-DXM F suppressibility, albeit to a lesser degree in subclinical CS
(P < 0.001 and P < 0,005
respectively), and in morning ACTH values (Fig. 2a), also lower in the same group
(P < 0,05). DHEAS also showed a more important
impairment of the response to corticotropin stimulation in subclinical
CS, compared with nonfunctioning adenomas (P < 0,05)
(Fig. 2b). Nevertheless, no significant difference was found in 17-OHP
and 4-androstenedione values between the 2 groups, who were
comparable in terms of age (60.75 ± 10.5 yr vs.
59.4 ± 9.7 yr).
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Treatment and follow-up. Five of 12 patients with subclinical CS were treated by adrenalectomy, and the histological diagnosis was adenoma in all the cases. Median postoperative follow-up was 38 months (range, 12–63). In 2 patients (nos. 5 and 10), a transient adrenocortical insufficiency occurred that was treated by oral replacement therapy with cortone acetate. Patient no.1 was affected by transient dynamic adrenal insufficiency, defined as normal basal cortisol levels with blunted response (<500 nmol/L) (23) to corticotropin administration and was treated by replacement therapy only in situations of stress for a period of 12 months.
Three patients (nos. 5, 9, and 12), previously affected by arterial hypertension, became normotensive after surgery; and treatment was withdrawn. Normal arterial pressure persisted after the recovery of residual adrenal function in patient no. 5. A partial improvement in arterial pressure values was also present in patients 1 and 4, who thus required a smaller daily dose of antihypertensive therapy. A partial improvement in the initial glucose and lipid values was also found in patients treated by surgery. Two patients (nos. 9 and 10) were able to reduce their oral antidiabetic medications, and one (no. 1) was able to reduce the insulin daily dose. All these improvements persisted during the follow-up period.
Seven patients with subclinical CS did not undergo surgical treatment but were prescribed medical treatment for hypertension, diabetes, dislipidemia, and osteopenia, as appropriate. The clinical and hormonal features did not change substantially in six of them after a median follow-up of 28 months (range, 9–73 months). Patient no. 7 was initially diagnosed as having so-called nonfunctional adenoma; 6 months later, using the same endocrine investigation, the hormonal pattern fulfilled the criteria for the diagnosis of subclinical CS, despite an unchanged tumor size of 4.3 cm. The same endocrine pattern suggestive of autonomous F secretion was confirmed after 6 other months. Tumor size increased by about 0.3 cm in patient numbers 3 and 5, over a period of 24 and 12 months, respectively, and by about 0.5 cm in patient no. 9; it did not change in others. The increase in tumor size was not associated with any significant modification in steroid secretion pattern.
Among the 13 patients in the group with nonfunctioning adenomas treated by adrenalectomy because of the large tumor size, 2 presented adrenocortical insufficiency, lasting 6 and 15 months, respectively; and 2 others, a dynamic insufficiency lasting 6 and 38 months, respectively. Before surgery, all of these patients presented some abnormalities in F, DHEAS, and 17-OHP secretion; and 2 of them had a scintigraphic pattern of unilateral uptake (1 patient with overt insufficiency and another with dynamic insufficiency), whereas a bilateral asymmetrical concordant pattern was present in 2 other patients (1 with overt and 1 with dynamic insufficiency). Improvement in clinical features was also observed in these patients after surgical treatment, to the extent that antihypertensive and antidiabetic therapy could be reduced in more than half of them; 2 patients even became normotensive. All the improvements persisted during the follow-up period.
Concerning endocrine data, normalization of most abnormalities
(including baseline F, UFF, average daily F and F% ratio, post-DXM F
suppressibility and 1,24-stimulated F, and 17-OHP values) were observed
in all patients treated surgically who did not suffer from adrenal
insufficiency, independent of whether they had subclinical CS or a
nonfunctioning adenoma; DHEAS values, instead, continued to be low. In
all but one patient affected by adrenal insufficiency, 17-OHP response
to 1,24-ACTH became normal after recovery of the adrenal function. Only
patient no. 1, who had a bilateral lesion (Table 2), after the first
period of dynamic insufficiency subsequent to a unilateral
adrenalectomy that removed only the larger tumor, showed again an
increased response of 17-OHP to 1,24-ACTH in the absence of other
hormonal abnormalities.
During the median follow-up of 26 months, no substantial changes in clinical and endocrine features were observed in those patients with nonfunctioning adenoma who were not treated by surgery. Tumor size increased from 0.2–0.9 cm in four of them over the period from 6–22 months and was unchanged in others. One patient underwent surgical treatment because of an increase in tumor size, by about 0.9 cm, that exceeded 3.5 cm in diameter. No increase in tumor size was associated with any significant steroid secretion change.
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Discussion |
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The diagnosis of adenoma in patients not treated surgically, made on the basis of CT criteria, was confirmed by scintigraphic uptake pattern (25) and by follow-up data.
Fifty patients with incidentally discovered adrenal adenomas evaluated in this study presented a wide spectrum of abnormalities in steroid secretion and HPA axis function. Nevertheless, in only several of them, the biochemical findings consistently pointed to a subtle functional autonomy of cortisol production, defined as subclinical CS. Previous studies had used variable criteria for such definition, reporting an occurrence of subclinical CS that ranged from 5–19% (8, 9, 12, 13, 26, 27). The criteria for the diagnosis of subclinical CS suggested by the National Italian Group of Study on Adrenal Tumors were used in the present study (20); two abnormal HPA axis routine tests were required to reduce the possibility of such classification on the basis of a false positive result. A necessary condition was repeated failure in adequate cortisol suppression by DXM, considered as the hallmark of abnormal steroid secretion with high negative predictive value when the suppression is normal (10, 28). Impaired F suppression was revealed at least twice in all patients considered to be affected by subclinical CS; the initial findings were confirmed after a 6-month interval. Although quite strict criteria were used for the definition of subclinical CS, an unexpectedly high prevalence (24%) was observed in our patients affected by adrenal adenoma. The degree of autonomous cortisol production ranged from slightly abnormal to completely pathological and was biochemically similar to the pattern of overt CS caused by adrenal adenoma in two patients (nos. 3 and 12).
Steroid abnormalities may be an expression of a partial autonomous
cortisol production and/or dysregulation of intratumoral and
intraadrenal enzymes. Variable expression of functional ACTH receptors
and cytochrome P450 activities were described (29, 30). However, the
most common endocrine abnormalities in this study were found in 17-OHP
and DHEAS values. The opposite behavior observed for 17-OHP (increased
accumulation) and DHEAS (decreased accumulation) seems to be
attributable to a dysregulation of cytochrome P450C17 with
17-hydroxylase and 17,20-lyase activities. The impaired activity of the
latter may perhaps be an intrinsic intraadrenal adaptory mechanism,
limiting the overproduction of androgens (31, 32). Cytochrome P450c17,
common to adrenal gland and gonads, is likely to be regulated mainly on
the 5-pathway in adrenals and on the 4-pathway in gonads (31).
Whereas DHEAS and 17-OHP secretion abnormalities similar to those found
by us have been reported in other studies (3, 4, 13, 20, 27), a
significant reduction in basal 4-androstenedione concentrations was
reported in a study on 32 incidentally discovered adenomas that
included 4 subclinical CS patients, compared with 14 controls
(13). The difference disappeared after a short corticotropin test (30
min). Contrarily, we did not find any difference in baseline
A4-androstenedione values between adenomas and controls, but only in
peak response to a long ACTH test, which is considered to be the most
effective stimulus on adrenal steroidogenesis, especially on androgens
(33). Moreover, the 2 groups of patients considered were not comparable
at all: our group of patients with adenomas was characterized by a
male-to-female ratio of 0.72; whereas the smaller group in Ambrosi’s
study (13) was composed prevalently of women (M/F ratio, 0.39), and the
men studied were older. However, further data are needed to elucidate
whether abnormalities in 4-androstenedione secretion ratio are
frequent and have some pathological meaning in adrenal adenomas.
Moreover, concentrations of other precursors of the glucocorticoid and
mineralocorticoid pathways (such as progesterone, 11-deoxycortisol, and
11-deoxycorticosterone) have also been studied, had their accumulation
described in incidentalomas (34, 35, 36), and may have a possible role in
determining hypertension and metabolic abnormalities (37).
Hypertension, diabetes, hyperlipidemia, and diffuse obesity have frequently been observed in patients with adrenal adenomas, the prevalence being even higher in those with subclinical CS. Incidentalomas are frequently seen in patients with other diseases, which accounts for their higher prevalence, compared with the general population. In spite of similar BMI in patients with subclinical CS and nonfunctioning adenomas (26.5 ± 6.8 vs. 25.6 ± 5.9), the occurrence of diabetes and abnormal lipids levels was higher in the group of subclinical CS patients (50% vs. 26% and 50% vs. 21%, respectively). The difference was even greater for hypertension, which occurred in 91.8% of patients with subclinical CS and in 34% of the remaining patients. The high prevalence of hypertension and metabolic disorders in patients with subclinical CS suggests that the clinically silent hypercortisolism is probably not completely asymptomatic. Variable extent and duration of subtle cortisol autonomous secretion may influence the clinical features. This hypothesis is supported by the fact that hormonal and clinical features improved in all patients after surgical treatment. This improvement, described also by other authors (9), was persistent during the follow-up period, even after resolution of the biochemical adrenal insufficiency.
With regard to the scintigraphic pattern, unilateral concordant or bilateral asymmetrical concordant uptake of radiocholesterol in this study predicted neither degree of endocrine abnormalities nor adrenocortical insufficiency after surgical treatment. This is in agreement with some previous studies (14, 30), although several others have found some degree of relationship between radiocholesterol uptake and the functional characteristics of adrenocortical lesions (3, 8, 25). In a recent study, adrenal scintiscans were performed in 136 patients affected by adrenal incidentaloma, indicating a significant positive correlation between cortisol secretion rate abnormalities and radiotracer uptake (38). Such correlation was not sought in our study, our study population being relatively small; however, unilateral concordant uptake was present in both patients with subclinical CS and postsurgical insufficiency, and in those without significant steroidogenic abnormalities or with no insufficiency after surgical approach. Furthermore, adrenal insufficiency was present in 1 woman with a unilateral adenoma associated with subclinical CS (patient no. 5) and a scintigraphic pattern of bilateral symmetrical radiocholesterol uptake. The follow-up data confirmed that the concordant uptake, however, provided the classification of adrenal mass as benign (25, 38). Moreover, none of the abnormalities in cortisol production were reliable in predicting which patient will need glucocorticoid replacement therapy after surgical treatment of the adenoma. Thus, all patients who undergo adrenalectomy should be screened for residual adrenal function.
There are several facts suggesting that the entity of subclinical CS remains mostly stable in time: first, unchanged clinical and endocrine features in patients with subclinical CS not treated surgically over the follow-up period; second, their age (60.75 + 10.5 yr), which differed significantly from those of the 8 patients with overt CS caused by adrenal adenoma and who were a part of the initial series of 106 patients admitted to our department for the evaluation of adrenal mass (33 ± 6.4 yr, data not shown). The hypothesis that the majority of patients with subtle hypercortisolism will never develop a clinically overt disease is also supported by the relatively infrequent occurrence of CS (10). Because the previous data about the effects of subtle hypercortisolism and its natural history are still unclear and the follow-up periods of such patients in various studies are relatively short, there was insufficient evidence of surgical treatment usefulness in such patients to recommend it for all of them. For this reason, in our study, surgical treatment was restricted to patients with large tumors (diameter > 3.5cm) and to those with recent, severe hypertension. All patients, whether treated surgically or not, are in follow-up under conservative treatment for their current symptoms.
On the other hand, hypertension, insulin resistance, unfavorable lipid profile, and abdominal/visceral obesity are well-known symptoms of overt CS and are related to increased risk of cardiovascular disease. Metabolic consequences of more subtle but likely, prolonged effects of hypercortisolism on the cardiovascular system in subclinical CS might also be present. The groups of patients with subclinical CS are still too small, dishomogeneous, and studied in different ways, making it impossible to draw any reasonable conclusion about the risk. If the high prevalence of hypertension and metabolic disorders found in our study is to be confirmed by others, surgical treatment should possibly be recommended to almost all patients with a subclinical CS.
Despite the abnormal biochemical markers of bone turnover in patients with adrenal incidentalomas documented by previous studies (39, 40), our BMD data are consistent with the lack of significant bone loss in patients with adrenal adenoma, even when associated with subclinical CS.
In conclusion, abdominal CT scans and at least a minimal biochemical evaluation, including determination of serum electrolytes, lipids, glycemia, catecholamines urinary excretion, baseline ACTH and steroids (F, 17-OHP, DHEAS, UFF), and DXM suppression test (low-dose, 2-mg test), should be performed in all patients with adrenal incidentalomas to determine the functional autonomy and biological behavior of the lesion. As to the surgical treatment of incidentalomas, this should still be reserved for patients with large tumors, imaging characteristics suggestive of malignancy, recent severe hypertension, evidence of increase in tumor size, or overt hypersecretion during follow-up, until the discrepancy between the clear improvement in clinical and endocrine features in surgically treated patients and apparent stability of those treated pharmacologically is elucidated. However, all patients treated by surgery should be screened for adrenal insufficiency.
Received March 9, 1999.
Revised September 30, 1999.
Accepted December 28, 1999.
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M. Sereg, A. Szappanos, J. Toke, K. Karlinger, K. Feldman, E. Kaszper, I. Varga, E. Glaz, K. Racz, and M. Toth Atherosclerotic risk factors and complications in patients with non-functioning adrenal adenomas treated with or without adrenalectomy: a long-term follow-up study Eur. J. Endocrinol., April 1, 2009; 160(4): 647 - 655. [Abstract] [Full Text] [PDF]
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C. Fagour, S. Bardet, V. Rohmer, Y. Arimone, P. Lecomte, N. Valli, and A. Tabarin Usefulness of adrenal scintigraphy in the follow-up of adrenocortical incidentalomas: a prospective multicenter study Eur. J. Endocrinol., February 1, 2009; 160(2): 257 - 264. [Abstract] [Full Text] [PDF]
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M.-L. Nunes, S. Vattaut, J.-B. Corcuff, A. Rault, H. Loiseau, B. Gatta, N. Valli, L. Letenneur, and A. Tabarin Late-Night Salivary Cortisol for Diagnosis of Overt and Subclinical Cushing's Syndrome in Hospitalized and Ambulatory Patients J. Clin. Endocrinol. Metab., February 1, 2009; 94(2): 456 - 462. [Abstract] [Full Text] [PDF]
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B. Masserini, V. Morelli, S. Bergamaschi, F. Ermetici, C. Eller-Vainicher, A. M. Barbieri, M. A. Maffini, A. Scillitani, B. Ambrosi, P. Beck-Peccoz, et al. The limited role of midnight salivary cortisol levels in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentaloma Eur. J. Endocrinol., January 1, 2009; 160(1): 87 - 92. [Abstract] [Full Text] [PDF]
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 P K Singh and H N Buch Adrenal incidentaloma: evaluation and management J. Clin. Pathol., November 1, 2008; 61(11): 1168 - 1173. [Abstract] [Full Text] [PDF]
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 I. Chiodini, M. L. Mascia, S. Muscarella, C. Battista, S. Minisola, M. Arosio, S. A. Santini, G. Guglielmi, V. Carnevale, and A. Scillitani Subclinical Hypercortisolism among Outpatients Referred for Osteoporosis Ann Intern Med, October 16, 2007; 147(8): 541 - 548. [Abstract] [Full Text] [PDF]
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L. K. Nieman Screening for Reversible Osteoporosis: Is Cortisol a Culprit? Ann Intern Med, October 16, 2007; 147(8): 582 - 584. [Full Text] [PDF]
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J R Meinardi, B H R Wolffenbuttel, and R P F Dullaart Cyclic Cushing's syndrome: a clinical challenge Eur. J. Endocrinol., September 1, 2007; 157(3): 245 - 254. [Abstract] [Full Text] [PDF]
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L. Tauchmanova, R. Pivonello, M. C. De Martino, A. Rusciano, M. De Leo, C. Ruosi, C. Mainolfi, G. Lombardi, M. Salvatore, and A. Colao Effects of sex steroids on bone in women with subclinical or overt endogenous hypercortisolism Eur. J. Endocrinol., September 1, 2007; 157(3): 359 - 366. [Abstract] [Full Text] [PDF]
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S. H. Golden, S. Malhotra, G. S. Wand, F. L. Brancati, D. Ford, and K. Horton Adrenal Gland Volume and Dexamethasone-Suppressed Cortisol Correlate with Total Daily Salivary Cortisol in African-American Women J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1358 - 1363. [Abstract] [Full Text] [PDF]
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 W. F. Young Jr. The Incidentally Discovered Adrenal Mass N. Engl. J. Med., February 8, 2007; 356(6): 601 - 610. [Full Text] [PDF]
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D Vezzosi, D Cartier, C Regnier, P Otal, A Bennet, F Parmentier, M Plantavid, A Lacroix, H Lefebvre, and P Caron Familial adrenocorticotropin-independent macronodular adrenal hyperplasia with aberrant serotonin and vasopressin adrenal receptors Eur. J. Endocrinol., January 1, 2007; 156(1): 21 - 31. [Abstract] [Full Text] [PDF]
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J. Majnik, A. Patocs, K. Balogh, M. Toth, P. Gergics, A. Szappanos, A. Mondok, G. Borgulya, P. Panczel, Z. Prohaszka, et al. Overrepresentation of the N363S Variant of the Glucocorticoid Receptor Gene in Patients with Bilateral Adrenal Incidentalomas J. Clin. Endocrinol. Metab., July 1, 2006; 91(7): 2796 - 2799. [Abstract] [Full Text] [PDF]
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B. Bulow, S. Jansson, C. Juhlin, L. Steen, M. Thoren, H. Wahrenberg, S. Valdemarsson, B. Wangberg, B. Ahreen, and on behalf of the Swedish Research Council Study Gr Adrenal incidentaloma - follow-up results from a Swedish prospective study. Eur. J. Endocrinol., March 1, 2006; 154(3): 419 - 423. [Abstract] [Full Text] [PDF]
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I. Chiodini, M. Torlontano, A. Scillitani, M. Arosio, S. Bacci, S. Di Lembo, P. Epaminonda, G. Augello, R. Enrini, B. Ambrosi, et al. Association of subclinical hypercortisolism with type 2 diabetes mellitus: a case-control study in hospitalized patients Eur. J. Endocrinol., December 1, 2005; 153(6): 837 - 844. [Abstract] [Full Text] [PDF]
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 R Nawar and D Aron Adrenal incidentalomas -- a continuing management dilemma Endocr. Relat. Cancer, September 1, 2005; 12(3): 585 - 598. [Abstract] [Full Text] [PDF]
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S. M. Gold, I. Dziobek, K. Rogers, A. Bayoumy, P. F. McHugh, and A. Convit Hypertension and Hypothalamo-Pituitary-Adrenal Axis Hyperactivity Affect Frontal Lobe Integrity J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3262 - 3267. [Abstract] [Full Text] [PDF]
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R. G. Dluhy, M. M. Maher, and C.-L. Wu Case 7-2005 - A 59-Year-Old Woman with an Incidentally Discovered Adrenal Nodule N. Engl. J. Med., March 10, 2005; 352(10): 1025 - 1032. [Full Text] [PDF]
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 P. J. Hornsby Aging of the Human Adrenal Cortex Sci. Aging Knowl. Environ., September 1, 2004; 2004(35): re6 - re6. [Abstract] [Full Text] [PDF]
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I. Chiodini, G. Guglielmi, C. Battista, V. Carnevale, M. Torlontano, M. Cammisa, V. Trischitta, and A. Scillitani Spinal Volumetric Bone Mineral Density and Vertebral Fractures in Female Patients with Adrenal Incidentalomas: The Effects of Subclinical Hypercortisolism and Gonadal Status J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2237 - 2241. [Abstract] [Full Text] [PDF]
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 G. Mansmann, J. Lau, E. Balk, M. Rothberg, Y. Miyachi, and S. R. Bornstein The Clinically Inapparent Adrenal Mass: Update in Diagnosis and Management Endocr. Rev., April 1, 2004; 25(2): 309 - 340. [Abstract] [Full Text] [PDF]
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 D. A. Scheuer, A. G. Bechtold, S. S. Shank, and S. F. Akana Glucocorticoids act in the dorsal hindbrain to increase arterial pressure Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H458 - H467. [Abstract] [Full Text] [PDF]
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B. Catargi, V. Rigalleau, A. Poussin, N. Ronci-Chaix, V. Bex, V. Vergnot, H. Gin, P. Roger, and A. Tabarin Occult Cushing's Syndrome in Type-2 Diabetes J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5808 - 5813. [Abstract] [Full Text] [PDF]
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 G. La Cava, A. Imperiale, C. Olianti, G. R. Gheri, C. Ladu, M. Mannelli, and A. Pupi SPECT Semiquantitative Analysis of Adrenocortical 131I-6{beta}-Iodomethyl-Norcholesterol Uptake to Discriminate Subclinical and Preclinical Functioning Adrenal Incidentaloma J. Nucl. Med., July 1, 2003; 44(7): 1057 - 1064. [Abstract] [Full Text] [PDF]
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 T. Dimitriou, C. Maser-Gluth, and T. Remer Adrenocortical activity in healthy children is associated with fat mass Am. J. Clinical Nutrition, March 1, 2003; 77(3): 731 - 736. [Abstract] [Full Text] [PDF]
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I. Chiodini, L. Tauchmanova, M. Torlontano, C. Battista, G. Guglielmi, M. Cammisa, A. Colao, V. Carnevale, R. Rossi, S. Di Lembo, et al. Bone Involvement in Eugonadal Male Patients with Adrenal Incidentaloma and Subclinical Hypercortisolism J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5491 - 5494. [Abstract] [Full Text] [PDF]
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L. Tauchmanova, R. Rossi, B. Biondi, M. Pulcrano, V. Nuzzo, E.-A. Palmieri, S. Fazio, and G. Lombardi Patients with Subclinical Cushing's Syndrome due to Adrenal Adenoma Have Increased Cardiovascular Risk J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 4872 - 4878. [Abstract] [Full Text] [PDF]
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G. G. M. Garrapa, P. Pantanetti, G. Arnaldi, F. Mantero, and E. Faloia Body Composition and Metabolic Features in Women with Adrenal Incidentaloma or Cushing's Syndrome J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5301 - 5306. [Abstract] [Full Text] [PDF]
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I. Chiodini, M. Torlontano, V. Carnevale, G. Guglielmi, M. Cammisa, V. Trischitta, and A. Scillitani Bone Loss Rate in Adrenal Incidentalomas: A Longitudinal Study J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5337 - 5341. [Abstract] [Full Text] [PDF]
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G. Osella, G. Reimondo, P. Peretti, A. Alì, P. Paccotti, A. Angeli, and M. Terzolo The Patients with Incidentally Discovered Adrenal Adenoma (Incidentaloma) Are Not at Increased Risk of Osteoporosis J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 604 - 607. [Abstract] [Full Text]
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R. Rosse and L. Tauchmanovà Authors' Response: Metabolic Abnormalities in Patients with Adrenal Incidentaloma J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 951 - 952. [Full Text]
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J.-M. Fernández-Real, J. Gonzalbez, and W. Ricart Metabolic Abnormalities in Patients with Adrenal Incidentaloma J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 950b - 951. [Full Text]
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