Plasma dehydroepiandrosterone sulfate levels in patients with hyperfunctioning and non-hyperfunctioning adrenal tumors before and after adrenal surgery
Miklós Tóth, Károly Rácz, Ibolya Varga, Vilmos Adleff, Csilla Jakab, László Fűtő, Róbert Kiss and Edit Gláz Gastroenterological and Endocrinological Research Group, 2nd Department of Medicine, Semmelweis University Medical School. Budapest, Hungary (Correspondence should be addressed to M Tóth, Second Department of Medicine, Semmelweis University Medical School, H-1088, Budapest, Szentkirályi u. 46, Hungary)
Abstract
To investigate the clinical significance of plasma dehydroepiandrosterone sulfate (DHEAS) measure- ments, 175 patients with histologically confirmed adrenal tumors, 10 cortisol-producing adenomas, 59 aldosterone-producing adenomas, 56 non-hyperfunctioning adenomas, 13 adrenocortical carci- nomas, 13 adrenal cysts, and 24 adrenomedullary tumors were studied. Plasma DHEAS levels were expressed as percentage of the mean of sex- and age-matched groups of healthy, normal subjects (DHEAS %). We found that before adrenal surgery, DHEAS % values were significantly reduced in patients with cortisol-producing (mean, 15.2% of control; 95% confidence interval (CI), 9.4-24.7%), non-hyperfunctioning (28.4%; 22-4-36.0%) as well as aldosterone-producing adrenocortical adeno- mas (55.4%; 47.1-65.1%) compared with controls, while values were normal in patients with adrenal cysts and in those with adrenomedullary tumors. Plasma DHEAS % values exhibited a great variability in adrenocortical carcinomas (mean, 84.0%; 95% CI, 33-2-212.5%). Death from adrenocortical carcinoma was more frequent in patients with high plasma DHEAS % values compared with those with low DHEAS %. During long-term postoperative monitoring, we found that plasma DHEAS levels of patients with aldosterone-producing and non-hyperfunctioning adenomas returned to normal in the second and fourth postoperative year respectively. In patients with cortisol-producing adenomas, plasma DHEAS remained suppressed for as long as 8 years after the operation. These findings show that except in adrenocortical carcinomas and cysts, plasma DHEAS levels are significantly decreased in all groups of adrenocortical tumors, including non-hyperfunctioning and aldosterone- producing tumors. The extent of this decrease and the postoperative persistence of suppressed plasma DHEAS levels may be related to the glucocorticoid production of adrenocortical tumors.
European Journal of Endocrinology 136 290-295
Introduction
Dehydroepiandrosterone sulfate (DHEAS), the most abundant steroid circulating in blood, originates mainly, if not entirely, from the adrenal cortex. The evaluation of the clinical significance of plasma DHEAS measurements in various clinical conditions is compli- cated by the fact that plasma DHEAS levels are sex- dependent and that they exhibit an age-related decrease of about 75% throughout the life span of healthy subjects (1).
Earlier studies suggested an important diagnostic role for plasma DHEAS measurements in patients with malignant adrenocortical tumors, which often showed elevated levels (2, 3). Patients with benign adrenocor- tical adenomas causing Cushing’s syndrome, on the other hand, usually had decreased plasma DHEAS levels (4, 5). Recently, the frequent occurrence of incidentally discovered adrenocortical adenomas led to a renewed
interest in plasma DHEAS measurements (3, 6, 7). It seems that this interest is supported by observations showing that if salt-wasting 21-hydroxylase deficiency is excluded (8), suppressed plasma DHEAS may be one of the most sensitive indicators of suppressed adreno- corticotropin (ACTH) secretion in patients with benign adrenocortical adenomas. Thus, it has been proposed that an occult cortisol overproduction, present in at least some incidentally discovered adrenocortical ade- nomas, leads to suppressed ACTH secretion, which results in a substantial decrease of plasma DHEAS levels.
In this study, we wanted to determine whether plasma DHEAS determinations could have diagnostic and/or prognostic roles in patients with different adrenal tumors. For this purpose, we determined plasma DHEAS levels in a large series of patients with surgically proven adrenocortical and adrenomedullary tumors both before adrenal surgery and during a long postsurgical period which lasted up to 8 years. In
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addition to patients with adrenocortical carcinomas, cortisol-producing adenomas and non-hyperfunction- ing adrenocortical adenomas, the studies included patients with several types of other adrenal tumors whose plasma DHEAS levels have not been previously reported, such as aldosterone-producing adenomas causing primary hyperaldosteronism, pheochromocy- tomas as well as those with adrenal cysts.
Subjects and methods
The charts of 327 patients with unilateral adrenal masses who were evaluated between 1987 and 1994 in this Endocrine Unit were reviewed. Surgery was performed in cases with hormonal overactivity and those with suspected adrenal malignancy. The study included 170 patients who underwent unilateral adrenalectomy and five patients with typical adrenal cysts without surgery.
Clinical evaluation included routine clinical labora- tory methods, 24-h urinary excretion of vanillylman- delic acid, abdominal ultrasonography, adrenal computed tomography and, if indicated, selective adrenal blood sampling and MIBG scintigraphy.
A detailed hormonal evaluation was performed both before and 2 weeks after adrenal surgery; this included measurements of plasma cortisol, 11-deoxycorticoster- one, 18-OH-11-deoxycorticosterone, dehydroepiandro- sterone, DHEAS, 17-OH-progesterone, androstenedione, testosterone and dihydrotestosterone at 0800 h under resting conditions. An overnight low-dose dexametha- sone test was performed before and 2 weeks after adrenal surgery. Suppression by dexamethasone was considered normal when morning plasma cortisol fell below 3.6 µg/dl (100 nmol/l) (9, 10). Plasma renin activity, aldosterone and 18-OH-corticosterone in the supine position and after upright posture plus furose- mide administration were also determined in all patients, both before and 2 weeks after adrenal surgery.
Plasma cortisol, 11-deoxycorticosterone, 18-OH-11- deoxycorticosterone, dehydroepiandrosterone, DHEAS, 17-OH-progesterone, androstenedione, testosterone, dihydrotestosterone, aldosterone and 18-OH-corticos- terone were measured with previously published RIA methods, using highly specific antisera (11-13). The intra-assay coefficient of variation for these assays was between 6 and 10%, while the interassay coefficient of variation was between 5 and 9%. Plasma renin activity and ACTH were determined using commercially avail- able kits (Rianen, DuPont and CIS Bio International respectively).
Plasma DHEAS levels are expressed as percentage (DHEAS %) of the logarithmic mean of sex- and age- matched groups of endocrinologically normal subjects (981 men and 481 women) reportedly recruited from a New York dermatological practice (1). The mean plasma DHEAS levels obtained from this report as well
as the plasma DHEAS values of 89 healthy normal Hungarian subjects (20 men; 69 women; aged between 16 and 82 years) plotted versus age are shown in Fig. 1. The absolute plasma DHEAS levels as well as the age- and sex-matched DHEAS % values (mean, 87.1%; 95% confidence interval (CI), 73·6-103.8%) in our control subjects were similar to those reported (1). Based on these data, the normal plasma DHEAS % was considered to be between 40 and 230%.
The sex and age distribution and the sizes of tumors are summarized in Table 1. Based on clinical and histological findings, the adrenal tumors were classified as cortisol-producing adenomas, incidentally discovered non-hyperfunctioning adrenocortical adenomas, aldos- terone-producing adenomas causing primary aldoster- onism, adrenocortical carcinomas, adrenal cysts and adrenomedullary tumors (pheochromocytoma, 22; ganglioneuroma, 2) (Table 1). For long-term follow-up lasting up to 8 years after surgery, plasma DHEAS levels
450
8
· Men
o Women
400
00
300
Plasma DHEAS (µg/dl)
200
8
100
00
00
0
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
>70
Age groups (years)
| Patient groups | No. of patients | Male/ female | Age (years) | Tumor diameter (mm) | DHEAS % | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Mean | Range | Mean | Range | Mean | Range | 95% CI | ||||
| Adrenocortical adenomas | ||||||||||
| Cortisol-producing | 10 | 2/8 | 40-7 | 24-55 | 39-4 | 10-70 | 15.2* | 7-66 | 9-4-24-7 | Downloaded |
| Non-hyperfunctioning | 56 | 13/43 | 51.0 | 28-69 | 38.7 | 12-100 | 28-4* | 3-151 | 22-4-36-0 | |
| Aldosterone-producing | 59 | 25/34 | 45.3 | 32-64 | 18.7 | 5-40 | 55.4* | 18-192 | 47-1-65-1 | |
| Adrenocortical carcinomas | 13 | 1/12 | 55.8 | 36-73 | 60-1 | 12-100 | 84.0 | 4-878 | 33.2-212.5 | |
| Adrenal cysts ** | 13 | 2/11 | 42.2 | 20-61 | 42.6 | 15-60 | 53-7 | 5-240 | 27-7-104.3 | |
| Adrenomedullary tumors | 24 | 10/14 | 47-4 | 15-74 | 48.5 | 15-115 | 75.1 | 13-298 | from https://academic.oup.com/ejendo/article/136/3/290/6754488 by WT Cox Information Services user on 02 April 2026 55-4-101.8 | |
*P < 0-001 vs normal subjects. ** Five patients were not subjected to adrenal surgery.
were determined 2 weeks after surgery and then every 6 months in those patients in whom the tumors had been removed. The mean period of follow-up was 4.4 years (range 0.5-8 years). None of these patients received long-term postoperative hydrocortisone medication.
Plasma DHEAS % values were log-transformed and expressed as the geometric mean and 95% CI. Group differences were analyzed by ANOVA, and a paired comparison was performed by Tukey’s method. Simple linear regression was used to analyze the relationship between logarithmic DHEAS % values and post-dex- amethasone plasma cortisol concentrations. The criter- ion for significance was set at P < 0.05.
Results
Adrenocortical adenomas
Table 1 shows that before adrenal surgery patients with cortisol-producing, non-hyperfunctioning and aldoster- one-producing adrenocortical adenomas had signifi- cantly reduced plasma DHEAS % values. Table 1 also shows that the lowest plasma DHEAS % values were observed in patients with cortisol-producing adenomas. In addition, all but one patient with cortisol-producing adenomas had plasma DHEAS % values which were
below the lowest limit of normal values determined in sex- and age-matched healthy subjects (Table 2). In contrast, patients with aldosterone-producing adeno- mas showed moderately although still significantly decreased mean plasma DHEAS % values and most, although not all, patients had DHEAS % values which were within the normal range (Table 2). It is interesting that plasma DHEAS % values in patients with non- hyperfunctioning adrenocortical adenomas were largely reduced, although the decrease in mean values was less pronounced compared with that found in cortisol- producing adenomas.
Twelve patients in the non-hyperfunctioning adrenal adenoma group (12/56; 21%) and three patients in the aldosterone-producing adenoma group (3/59; 5%) showed incompletely suppressible plasma cortisol during the low-dose overnight dexamethasone test. Interestingly, plasma DHEAS % values of the non- hyperfunctioning adenoma group tended to be lower in patients with incompletely suppressible plasma cortisol levels (mean, 23.4; range, 7.1-44.7%; vs mean, 32-4; range, 3.0-151.4% in patients with completely sup- pressible plasma cortisol), although the difference between the two subgroups was not significant.
After surgical removal of the adrenal adenomas, plasma DHEAS % values were monitored in several patients with cortisol-producing adenomas (n = 7),
| Patient groups | DHEAS % No. of No. of patients with: patients Decreased Normal Increased | |||
|---|---|---|---|---|
| Adrenocortical adenomas | ||||
| Cortisol-producing | 10 | 9 | 1 | 0 |
| Non-hyperfunctioning | 56 | 32 | 24 | 0 |
| Aldosterone-producing | 59 | 17 | 42 | 0 |
| Adrenocortical carcinomas | 13 | 4 | 5 | 4 |
| Adrenal cysts | 13 | 5 | 7 | 1 |
| Adrenomedullary tumors | 24 | 6 | 16 | 2 |
140
☐ Cortisol-producing adenomas ( n=7)
☒ Non-hyperfunctioning adenomas ( n=15 )
120
☒ Aldosterone-producing adenomas ( n=26 )
Plasma DHEAS % values
100
80
60
40
T
20
T
T
0
0-12
13-24
25-36
37-48
>49
Months after adrenal surgery
aldosterone-producing adenomas (n = 26), and non- hyperfunctioning adrenocortical adenomas (n = 15) for a period of up to 8 years, with an average follow- up of 4-4 years. Postoperative plasma DHEAS levels were lowest 2 weeks after surgery (mean, 15.0%; 95% CI, 14.0-17.0%). Figure 2 shows that in patients with aldosterone-producing adenomas, the moderately reduced plasma DHEAS % values returned to normal in the second postoperative year whereas the marke- dly reduced values in patients with non-hyperfunction- ing adrenocortical adenomas were normalized only
after the fourth postoperative year. In contrast, the very low plasma DHEAS % values in patients with cortisol- producing adenomas remained low as long as 8 years after operation.
Adrenocortical carcinomas
Table 2 shows that in patients with adrenocortical carcinomas, plasma DHEAS % values exhibited a great variability. In contrast to adrenocortical adenomas in which none of the patients had increased plasma DHEAS
| Patients | Tumor size (mm) | Steroids produced in excess | Presence of metastasis | Follow-up period (months) | Death from adrenal cancer | Preoperative plasma DHEAS (%) | ||
|---|---|---|---|---|---|---|---|---|
| No. | Age (years) | Sex | ||||||
| 1 | 58 | F | 60 | DOC | No | 68 | Alive | 15 |
| 2 | 66 | F | 100 | F | Yes | 8 | Yes | 61 |
| 3 | 70 | F | 80 | T, AD | Yes | 20 | Yes | 304 |
| 4 | 36 | F | 70 | F, DOC | Yes | 3 | Yes | 670 |
| 5 | 62 | F | 15 | F, T | Yes | 3 | Yes | 878 |
| 6 | 49 | F | 45 | None | No | 21 | Alive | 88 |
| 7 | 36 | F | 80 | F, DOC, 17-OH-P | Yes | 1 | Yes | 807 |
| 8 | 43 | F | 34 | None | No | 98 | Unrelated1 | 7 |
| 9 | 63 | F | 120 | DOC, 17-OH-P | Yes | 30 | Yes | 157 |
| 10 | 70 | M | 80 | None | No | 10 | Not known | 4 |
| 11 | 73 | F | 80 | F, DOC | No | 1 | Unrelated 2 | 38 |
| 12 | 63 | F | 70 | None | No | 2 | Not known | 150 |
| 13 | 56 | F | 90 | DOC | No | 60 | Alive | 123 |
1Breast cancer death; 2intraoperative death.
F, cortisol; DOC, 11-deoxycorticosterone; 17-OH-P, 17-hydroxyprogesterone; T, testosterone; AD, androstenedione.
% values, about one-third of adrenocortical carcinomas showed increased DHEAS % values (Table 2).
As shown in Table 3, which summarizes the individual plasma DHEAS % values and the main clinical findings in adrenocortical carcinomas, death from adrenal tumor was more frequent in patients with high plasma DHEAS % values (four out of four) compared with those with low or normal DHEAS % (two out of five).
Adrenal cysts and adrenomedullary tumors
As shown in Table 1, patients with adrenomedullary tumors as well as those with adrenal cysts had plasma DHEAS % values which were not significantly different from those found in sex- and age-matched healthy, normal subjects. Moreover, analysis of the individual data revealed that most patients with these two types of adrenal disorder had plasma DHEAS % values which were within the normal range measured in healthy subjects.
Discussion
Yamaji & Ibayashi (4) were the first to report significantly suppressed plasma DHEAS levels in patients with adrenal adenoma causing Cushing’s syndrome. This finding was confirmed by Kleiber et al. (5), who showed that in three patients with cortisol- producing adenoma, the low plasma DHEAS failed to return to normal for up to 15 months of the follow-up period (5). In our study, nine of the ten patients with cortisol-producing adenoma had low plasma DHEAS % values and these low values persisted for as long as 8 years after adrenal surgery. In addition to patients with cortisol-producing adenomas, we also found signifi- cantly reduced plasma DHEAS % values in patients with non-hyperfunctioning and aldosterone-producing ade- nomas.
The mechanism(s) responsible for low plasma DHEAS levels in these patients with adrenocortical adenomas is not entirely understood. The most reasonable explana- tion is that cortisol overproduction of the adenomas leads to suppressed ACTH secretion, which causes a reduction of adrenal DHEAS production. In this respect it seems important that patients with non-hyperfunc- tioning adrenocortical adenomas may exhibit several subtle abnormalities in the activity of the hypothalamic- pituitary-adrenal axis, such as increased 24-h mean plasma cortisol levels in 7% of cases (3), a blunted day/ night amplitude of cortisol rhythm in 14% of cases (3), an impaired suppressibility of plasma cortisol with dexamethasone in 14-17% of cases (3, 6, 14), a blunted ACTH response to corticotropin-releasing hor- mone in 22-33% of cases (3, 10, 14), an elevated urinary cortisol excretion in 21% of cases (6), and a
decreased plasma ACTH level in 25% of cases (6). Decreased plasma DHEAS levels were also found in the rare non-tumorous primary hypercortisolism, and in pigmented nodular adrenal dysplasia (15). It is also possible that the low plasma DHEAS values found in about 30% of patients with aldosterone-producing adenomas in our study may be due to a subtle- glucocorticoid excess. Thus, there may be a spectrum of cortisol excess syndromes (16-19) ranging from the classical Cushing’s syndrome due to cortisol- producing adenomas to a subtle glucocorticoid excess (10, 20, 21) caused by non-hyperfunctioning adreno- cortical adenomas and, perhaps, by aldosterone- producing adenomas.
In addition to suppressed ACTH secretion due to glucocorticoid excess, decreased plasma DHEAS levels in patients with adrenocortical adenomas could involves several other mechanisms. First, there are proposals for- the existence of a specific pituitary factor regulatings DHEAS production (5), which may be a non-ACTH: fragment of pro-opiomelanocortin (22). Secondly, adre- nocortical adenomas may have decreased activity of 17,20-lyase, perhaps as a consequence of suppressed ACTH secretion (23). Thirdly, a recent study (24) showed that the attached adrenal glands of adrenocor- tical adenomas causing Cushing’s and ‘pre-Cushing’s’ syndromes exhibited markedly decreased dehydroepian- drosterone sulfotransferase immunoreactivity, which may be due to the suppressed ACTH secretion and may, therefore, contribute to decreased DHEAS produc- tion.
Our study showed that decreased plasma DHEAS values were fairly common in patients with adrenocor- tical adenomas not only before surgery but also during a long-term postsurgical follow-up period. It seemedo particularly interesting that decreased plasma DHEAS levels continued to persist for several years, with the longest duration in patients with overt cortisol excess causing classical Cushing’s syndrome. In contrast, the postsurgical persistence of low plasma DHEAS levels, was shorter in patients who had a presumably mild” cortisol excess. These findings indicate that both the? severity and the postsurgical duration of suppressed plasma DHEAS values are indicative of the presence of cortisol overproduction in these adrenocortical tumors.º
Our study also showed that in contrast to patients- with adrenocortical adenomas who never had increased> plasma DHEAS values, about one-third of patients with- adrenocortical carcinomas showed increased plasma DHEAS levels. It was also remarkable that patients with” carcinomas and decreased plasma DHEAS values seemed to have a better prognosis and a longer survival period compared with those with increased plasma DHEAS levels.
Finally, our study indicated that patients with adrenal cysts and those with adrenomedullary tumors had normal plasma DHEAS values. This observation is in agreement with previous reports suggesting that the
activity of the hypothalamic-pituitary-adrenal axis may be normal in these adrenal disorders (25, 26).
Acknowledgements
The authors thank Mr Péter Vargha (Biometric Unit of Semmelweis University Medical School) for his help in statistical analysis. This work was supported in part by grants T5458 and T013193 from the National Scientific Research Foundation of Hungary.
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