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DOI: 10.1530/EJE-08-0324
European Journal of Endocrinology, Vol 159, Issue 5, 641-647
Copyright © 2008 by European Society of Endocrinology
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CLINICAL STUDY

Sex steroids in androgen-secreting adrenocortical tumors: clinical and hormonal features in comparison with non-tumoral causes of androgen excess

Catarina B d'Alva1, Gwenaelle Abiven-Lepage1,2, Vivian Viallon2,3, Lionel Groussin1,2,4, Marie Annick Dugue2,5, Xavier Bertagna1,2,4,6 and Jerôme Bertherat1,2,4,7

1 Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Service d'Endocrinologie, Paris, France2 Université Paris Descartes, Paris, France3 Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Service de Biostatistiques, Paris, France4 INSERM U 567, CNRS UMR 8104, Institut Cochin, Paris, France5 Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Service d'Hormonologie, Paris, France6 Adrenal Cancer INCa-COMETE Network, Paris, France7 Center for Rare Adrenal Diseases, Hôpital Cochin, Paris, France

(Correspondence should be addressed to J Bertherat at Service d'Endocrinologie, Hôpital Cochin, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France; Email: jerome.bertherat{at}cch.ap-hop-paris.fr)


   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 Declaration of interest
 References
 
Objective: Adrenocortical tumors (ACT) account for no more than 0.2% of the causes of androgen excess (AE). Conversely, these rare tumors have a very poor prognosis. It is difficult and important to exclude this diagnosis whenever there is AE.

Design: Retrospective investigation of androgen profiles in a large consecutive series of androgen-secreting (AS) ACT to assess their relative diagnostic value.

Methods: A total of 44 consecutive female patients with ACT-AS and a comparison group of 102 women with non-tumor causes of AE (NTAE).

Results: Patients with ACT-AS were older than the ones with NTAE (37.7 vs 24.8 years; P<0.001) and the prevalence of hirsutism, acne, and oligo/amenorrhea were not different. Free testosterone was the most commonly elevated androgen in ACT-AS (94%), followed by androstenedione (90%), DHEAS (82%), and total testosterone (76%), and all three androgens were simultaneously elevated in 56% of the cases. Androgen serum levels became subnormal in all ACT-AS patients after complete tumor removal. In NTAE, the most commonly elevated androgen was androstenedione (93%), while all three androgens were elevated in only 22% of the cases. Free testosterone values above 6.85 pg/ml (23.6 pmol/l) had the best diagnostic value for ACT-AS (sensitivity 82%, confidence interval (CI): 57–96%; specificity 97%, CI: 91–100%). Basal LH and FSH levels were significantly lower in the ACT-AS group.

Conclusion: Free testosterone was the most reliable marker of ACT-AS. However, the large overlap of androgen levels between ACT-AS and NTAE groups suggests that additional hormonal and/or imaging investigations are required to rule out ACT-AS in case of increased androgens.


   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 Declaration of interest
 References
 
Androgen excess (AE) occurs in ~7% of reproductive-aged women and is believed to be one of the most common endocrine disorders of this population (1, 2). Polycystic ovary syndrome (PCOS) and other forms of functional AE, later considered as non-tumor causes of AE (NTAE), are by far the most frequent causes, found in more than 90% of these patients (3, 4). By contrast, ovarian and adrenal androgen-secreting tumors (ACT-AS) are rare, accounting for only 0.2% of the causes of AE (3, 4). The finding of androgen secretion by an ACT is highly suggestive of malignancy. It is clearly important to identify the small proportion of patients with this potentially life-threatening condition (5).

The extent to which women with AE should be evaluated to exclude the likelihood of a neoplasm is still a matter of debate. Previously, it was suggested that a clinical presentation with rapidly progressive virilization was sufficient to identify patients requiring a more extensive investigation (6). Nevertheless, as discussed by Rosenfield (7), it is known that some ACT-AS may produce only moderate levels of androgens and have a rather indolent presentation (8, 9). In addition, high testosterone serum levels and failure of androgen suppression in response to glucocorticoid administration have also been regarded as indicators of the presence of a virilizing tumor of either the ovaries or the adrenal cortex (8, 10, 11, 12). However, this conclusion was based on relatively small series of patients.

To help identify ACT among women with AE, we have performed a retrospective analysis of 44 consecutive female patients with ACT-AS followed in a single endocrine department. The whole group was compared with 102 women with NTAE.


   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 Declaration of interest
 References
 
We retrospectively analyzed 44 consecutive women with an ACT-AS referred to the Endocrine Department of Cochin Hospital between 1989 and 2005. Tumor staging and pathological analysis were performed as described previously (13, 14, 15). The study was approved by the Institutional Review Board of Cochin Hospital and informed consent of the patients was obtained. The results of the patients with ACT-AS were compared with those of 102 consecutive women with NTAE referred to a single unit of the same department.

Hirsutism, acne, oligomenorrhea, and amenorrhea were recorded according to the physician's notes and menstrual cycles longer than 35 days were characterized as oligo/amenorrhea (16).

The NTAE group consisted of 88 women with PCOS and 14 with idiopathic hyperandrogenism (IHA) (17, 18). The ones who had received any estrogenic or anti-androgenic medication in the last 3 months were excluded from the study. All records of the patients were reevaluated by the same investigator. PCOS was classically defined by the presence of at least two of the following three abnormalities: oligomenorrhea or amenorrhea, clinical or biochemical AE, and polycystic ovaries on ultrasound (17, 18). Yet, biochemical AE was a necessary criterion for inclusion in this study. IHA was defined as the association of clinical AE and increased plasma androgen levels in the presence of normal ovulatory cycles and normal ovaries on ultrasound (18). All ultrasound records were reviewed by the same investigator. In the NTAE group, congenital adrenal hyperplasia, Cushing's syndrome, hyperprolactinemia, thyroid dysfunction, and ACT were excluded on the basis of clinical investigations, hormonal assays, and adrenal imaging by the usual routine work-up.

Hormonal determinations

Basal levels of total and free testosterone (T), androstenedione, DHEA sulfate (DHEAS), 17OHP, compound S, estradiol, estrone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were recorded in patients and controls as well as urinary-free cortisol, serum cortisol at midnight, adrenocorticotrophin (ACTH), and the results of low-dose dexamethasone suppression test in the ACT-AS group. All hormonal assays were performed at the hormone unit of Cochin Hospital as reported previously (19, 20, 21). Testosterone assays used the Testo-CT2 kit (Cis-Bio, Schering, Bagnols-sur-Ceze, France) with intra- and inter-assay coefficient of variation of 4 and 7% respectively. Free testosterone assay was done for patients investigated since 1996 with the Coat-A-count kit (DPC, Siemens, Deerfield, IL, USA) with an intra- and inter-assay coefficient of variation of 8%. Androstenedione was assayed before 2000 by an in-house RIA and thereafter with the RIA D4 androstenedione direct kit (Immunotech, Beckman, Marseilles, France) that gave similar results with an intra-assay coefficient of variation of 4% and inter-assay of 8%. DHEAS was assayed before 2000 by an in-house RIA and thereafter with the Immulite 2000 (DPC, Siemens), which gave similar results with an intra- and inter-assay coefficient of variation of 5%. 17OH-Pg was assayed with a competitive RIA using rabbit-specific antibody from M P-Biomedicals-LLC (Santa Ana, CA, USA). Compound S was assayed by competitive RIA using the IBL (Hamburg, Germany) kit. Biochemical AE in female was confirmed whenever the following androgen serum levels were increased: total testosterone (T) levels above 0.8 ng/ml (>2.77 nmol/l), free T (fT) levels above 4 pg/ml (>13.78 pmol/l), DHEAS above 2.8 µg/ml (>7.6 µmol/l), and/or androstenedione levels above 2.2 ng/ml (>7.6 nmol/l). Each of these values corresponds to the 95th percentile of healthy women. The normal range of estradiol was 20–120 pg/ml (73.4–440.4 pmol/l) and the normal range of estrone was 20–120 pg/ml (73.4–440.4 pmol/l) for women in the follicular phase.

Blood sampling for androgens and other hormonal determinations were performed without regard to the time of the menstrual cycle in the ACT-AS group. In the great majority of the NTAE, investigations were performed during the follicular phase of a spontaneous or progestin-induced menstrual cycle.

Statistical analysis

The prevalence of hirsutism, acne, and oligo/amenorrhea in the two groups (ACT-AS and NTAE) was compared with {chi}2 tests or Fisher's exact tests, when appropriate. The numeric data represented by the hormone levels were not normally distributed and the results were expressed as median values and range. Between-group comparisons were performed using the Mann–Whitney test and correlations between variables were described using Spearman's correlation coefficients (r). Results were considered statistically significant if the P value was less than 0.05. According to Youden's index (22), appropriate cut-off values for the hormone levels were selected as those maximizing the sum (specificity+sensitivity). To construct confidence interval (CI) for sensitivity and specificity, we used the normal approximation or binomial tables, when appropriate.


   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 Declaration of interest
 References
 
Clinical features

Tumor characteristics are summarized in Table 1. The group of 44 female patients was compared with the 102 female patients with NTAE. The 44 women with ACT-AS were older (median age 37.7 years, range 14.1–87.2 years) compared with the NTAE group (median 24.8 years; range 13.4–55.9 years; P<0.001). The prevalence of hirsutism, acne, and oligo/amenorrhea was not different between the two groups (Table 2).


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  		Table 1 Main characteristics of androgen-secreting adrenocortical tumors (ACT-AS).

 

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  		Table 2 Clinical characteristics and baseline hormone levels of the 44 female patients with androgen-secreting adrenocortical tumors (ACT-AS) and the 102 women of the comparison group with non-tumor causes of androgen excess (NTAE).

 
Endocrine investigation

In the ACT-AS group, seven patients (15.9%) had tumors secreting androgens alone and two (4.5%) had tumors secreting androgens and estrogens. Twenty-eight patients (63.6%) had tumors secreting both androgens and cortisol, and seven (15.9%) had tumors secreting androgens, cortisol, and estrogens (Table 1). Free testosterone was elevated in 16 of 17 patients, being the most commonly elevated androgen (94%), followed by androstenedione, which was elevated in 35 of 39 patients (90%), DHEAS elevated in 32 of 39 (82%), and total testosterone elevated in 32 of 42 patients (76%). In the NTAE group, androstenedione was elevated in 92 of 99 controls (93%), while the other androgens were elevated in less than 50% of these women; total testosterone in 44 of 102 controls (43%), free testosterone in 32 of 77 (42%), and DHEAS in 38 of 97 (39%).

Among the 38 ACT-AS patients who had all three androgen levels available (total or free testosterone, androstenedione, and DHEAS), 56% had all three values elevated, 31% had two androgens elevated, and 13% had only one androgen elevated. Conversely, among 95 NTAE patients, 40% had only one androgen elevated, 38% had two androgens elevated, and only 22% had high levels of all three androgens.

Although all androgens were significantly higher in ACT-AS than in NTAE patients, there was a great overlap between the two groups (Table 2). Basal testosterone levels superior to 1.7 ng/ml (5.9 nmol/l) distinguished ACT-AS from NTAE with 100% specificity but with a very low sensitivity (45%). Similarly, free testosterone levels superior to 11.2 pg/ml (38.6 pmol/l) had 100% specificity but only 47% sensitivity. Youden's index approach (22) depicted that free testosterone concentrations superior to 6.85 pg/ml (23.6 pmol/l) had the best sensitivity and specificity, being 82% (95% CI: 57–96%) and 97% (95% CI: 91–100%) respectively (Table 3). Thus, high free testosterone seems to be a good predictor of ACT-AS.


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  		Table 3 Sensitivity and specificity of basal hormone levels in the evaluation of female patients with androgen-secreting adrenocortical tumors (ACT-AS) and non-tumor causes of androgen excess (NTAE).

 
Compound S and 17OHP levels were also significantly higher in ACT-AS than in NTAE patients, but there was also an overlap between both groups (Table 2). Compound S was increased (≥10 ng/ml or 28.9 nmol/l) in 23 of 27 ACT-AS patients (85%); 20 of 21 patients with malignant tumors, 3 of 6 patients with apparently benign tumors. Nonetheless, it was normal and inferior to 6 ng/ml (17.3 nmol/l) in 35 of 35 NTAE (100%). Youden's index displayed that compound S level above 7 ng/ml (20.2 nmol/l) had a sensitivity of 89% (95% CI: 71–98%) and a specificity of 100% (95% CI: 90–100%) for the detection of ACT-AS (Table 3). Concerning 17OHP, it was elevated (>2 ng/ml or 6.1 nmol/l) in 24 of 36 ACT-AS patients (67%) and, among these 24 women, the median elevated level was 6 ng/ml (18.2 nmol/l; range 2–77 ng/ml or 6.1–233.3 nmol/l). In NTAE, baseline 17OHP was elevated in 10 out of 88 individuals (11%) and, among these 10 controls, the median elevated level was 2.6 ng/ml (7.9 nmol/l; range 2.1–14.8 ng/ml or 6.4–44.8 nmol/l). Nevertheless, 87 women with NTAE, including those with elevated basal 17OHP, were submitted to an ACTH stimulation test, which was normal (stimulated 17OHP <10 ng/ml or <30.3 nmol/l) in all of them. Youden's index found that a baseline 17OHP above 1.95 ng/ml (5.9 nmol/l) had a sensitivity of 67% (95% CI: 49–81%) and a specificity of 86% (95% CI: 76–93%; Table 3).

Finally, basal LH and FSH levels were significantly lower in patients with ACT-AS than with NTAE. Five menopausal ACT-AS patients who had their gonadotropins assayed all had suppressed levels of FSH (range: 0.1–2.0 U/l) and suppressed or inappropriately normal levels of LH (range: 0.1–6.0 U/l). No correlation was found between gonadotropins and testosterone, estradiol, estrone, or urinary-free cortisol in the patients with ACT-AS (data not shown). However, two of these women had extremely high estrone levels, 1900 and 9000 pg/ml (or 7030 and 33 300 pmol/l) and one had a total testosterone level of 4.2 ng/ml (14.6 nmol/l).

The post-surgical androgen concentrations were available for 36 patients with ACT-AS. All of them had subnormal androgen levels except 7 women with metastasis at diagnosis (Fig. 1). As some patients had only marginally elevated androgen levels, these post-surgical values argue against the possibility of a functional AE.


Figure 1
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  		Figure 1 Baseline steroid levels before and after surgery in female patients with androgen-secreting adrenocortical tumors (ACT-AS). The results of pre- and post-operative steroid levels obtained in 36 ACT-AS female patients are shown for total testosterone, free testosterone, androstenedione, DHEAS, 17-OH-progesterone, and compound S. The post-operative levels were subnormal for all patients, except seven presenting metastasis at diagnosis and in whom complete tumor removal could not be achieved by surgery.

 
Estrogen-secreting tumors

Among the 44 women with ACT-AS, 10 also had high estrogen levels. Estradiol was high in 6 of 34 females (18%) and the elevated estradiol levels ranged from 201 to 980 pg/ml (median 409 pg/ml or 1501 pmol/l). Estrone was high in 7 of 11 (64%) and the elevated estrone levels ranged from 204 to 9000 pg/ml (median 1900 pg/ml or 7030 pmol/l). There was a positive correlation between estradiol and free testosterone concentrations (P<0.05, r=0.5, 15 patients evaluated). However, neither did we find any correlation between estradiol and total testosterone nor between estrone and androstenedione concentrations.


   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
Declaration of interest
 References
 
Although adrenocortical masses are frequent in the general population, only a small proportion of them bear a threat due to their malignant and/or hypersecreting nature (23, 24, 25, 26). Yet, this possibility must be in mind when evaluating women with evidence of AE. Imaging approaches, mainly by computed tomography or magnetic resonance imaging (5, 27, 28), perform well but are not cost effective. Therefore, a simple tool for the screening of ACT-AS is needed.

Contrary to a frequent proposition (6), we found no clear differences in the clinical presentation of NTAE and ACT-AS in our series: the prevalence of hirsutism, acne, and oligo/amenorrhea were not sufficient to distinguish these two causes of AE. Furthermore, some tumors had a moderate AE and consequently a subtle clinical presentation.

The analysis of the basal androgen levels revealed that no single androgen had a 100% sensitivity to diagnose ACT-AS in female patients. Furthermore, free testosterone was the most commonly elevated androgen in women with ACT-AS (94%) and androstenedione in patients with NTAE (93%). On the other hand, the likelihood of having a simultaneous increase in all three androgens was much higher in ACT-AS than in NTAE group (56% vs 22%). Therefore, clinicians should be aware that half of the patients with ACT-AS have one or two androgens in the normal range.

Although androgen concentrations were higher in ACT-AS, there was an overlap between the two groups. Yet, Youden's index showed that a free testosterone level above 6.85 pg/ml (23.6 pmol/l) had a high discriminative value with a sensitivity of 82% and a specificity of 97%. In future studies, it would be interesting to analyze the diagnostic value of free testosterone derived from the assessment of the levels of total testosterone and sex-hormone binding globulin that might be more reliable than the direct method used in this study (29).

The measurement of 17OHP and compound S are of great interest considering that ACT-AS often present with defective steroid biosynthesis enzymes causing elevated levels of steroid precursors (30, 31). Baseline 17OHP was indeed high in 67% of the ACT-AS (median 6 ng/ml or 18.2 nmol/l) and 11% of the NTAE (median 2.6 ng/ml or 7.9 nmol/l), and compound S was high in 85% of ACT-AS and 0% of the NTAE. Compound S above 7 ng/ml (20.2 nmol/l) had a sensitivity of 89% and a specificity of 100% for the diagnosis of ACT-AS. Thus, among the five steroids evaluated, free testosterone and compound S seem to be the best predictors of ACT-AS.

Gonadotropins concentrations were significantly lower in patients with ACT-AS than with NTAE. Nevertheless, we did not find any correlation between gonadotropins and testosterone, estradiol, estrone, or urinary-free cortisol (data not shown). In rare cases, patients with virilizing tumors might present high gonadotropin levels and an increased LH-to-FSH ratio despite high androgens (8). In Cushing's disease, low gonadotropin levels and the menstrual irregularities result from excess cortisol rather than an increase in plasma androgens (32).

In all series of ACT, female patients clearly predominate and males account for 10–35% of the reported cases (30, 33, 34). In our series, five men with androgen-secreting tumors accounted for 10% of the ACT-AS cases (data not shown).

Elevated estrogen concentrations were found in 10 women and there was a positive correlation between estradiol and free testosterone levels, suggesting that the peripheral aromatization of testosterone could be the source of elevated estradiol concentrations.

Another interesting issue in this series of rare tumor is to clearly show that not all ACT-AS are clearly malignant, at least from a clinical perspective. Indeed, in ten cases, the Weiss score was above 4 (usually considered as the cut-off for the diagnosis of malignancy) and no tumor recurrence could be observed during follow-up. Interestingly, these tumors usually are pure androgen-secreting tumors (data not shown) by contrast with the frequent co-secretion of cortisol and androgens by the malignant tumors. This suggests the possibility that some rare ACT-AS are true benign tumors. However, one should remain cautious and long-term follow-up of ACT-AS should always be done since, as a general rule, androgen secretion by an adrenal tumor should lead to the suspicion of malignancy.

In conclusion, simultaneous increase of all three androgens is more prevalent in ACT-AS than in NTAE patients. In addition, intra-tumoral defect in steroid biosynthesis usually results in elevated steroid precursors such as 17OHP and compound S. Free testosterone and compound S would be the best markers in the initial screening of women with AE since concentrations of free testosterone superior to 6.85 ng/ml (23.6 pmol/l) and compound S superior to 7 ng/ml (20.2 nmol/l) had acceptable values of sensitivity and specificity. Conversely, we should keep in mind that a large overlap of androgen and precursor concentrations exists between ACT-AS and NTAE. Therefore, adrenal imaging is mandatory when there is any doubt about diagnosis.


   Declaration of interest
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Declaration of interest
References
 
The authors declare that there is no conflict of interest that would prejudice the impartiality of this work.


   Funding
 
This work was supported by the Plan Hospitalier de Recherche Clinique (AOM 02068) to the COMETE network.


   Acknowledgements
 
We thank Sophie Grabar for helpful discussions and Ricardo Augusto Probo for the English review. We thank the staff of the endocrine, endocrine surgery, pathology, and nuclear medicine departments of Cochin Hospital for patients' management.


   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Declaration of interest
 References
 

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Received 23 July 2008
Accepted 29 July 2008




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