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European Journal of (2008) 159 641–647 ISSN 0804-4643

CLINICAL STUDY Sex 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 Jeroˆme Bertherat1,2,4,7 1Assistance Publique-Hoˆpitaux de Paris, Hoˆpital Cochin, Service d’Endocrinologie, Paris, France, 2Universite´ Paris Descartes, Paris, France, 3Assistance Publique-Hoˆpitaux de Paris, Hoˆpital Cochin, Service de Biostatistiques, Paris, France, 4INSERM U 567, CNRS UMR 8104, Institut Cochin, Paris, France, 5Assistance Publique-Hoˆpitaux de Paris, Hoˆpital Cochin, Service d’Hormonologie, Paris, France, 6Adrenal Cancer INCa-COMETE Network, Paris, France and 7Center for Rare Adrenal Diseases, Hoˆpital Cochin, Paris, France (Correspondence should be addressed to J Bertherat at Service d’Endocrinologie, Hoˆpital Cochin, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France; Email: [email protected])

Abstract 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 , , and oligo/ were not different. Free was the most commonly elevated androgen in ACT-AS (94%), followed by (90%), DHEAS (82%), and total testosterone (76%), and all three androgens were simultaneouslyelevated 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.

European Journal of Endocrinology 159 641–647

Introduction debate. Previously, it was suggested that a clinical presentation with rapidly progressive was Androgen excess (AE) occurs in w7% of reproductive- sufficient to identify patients requiring a more extensive aged women and is believed to be one of the most investigation (6). Nevertheless, as discussed by Rosenfield common endocrine disorders of this population (1, 2). (7), it is known that some ACT-AS may produce only Polycystic syndrome (PCOS) and other forms of moderate levels of androgens and have a rather indolent functional AE, later considered as non-tumor causes of presentation (8, 9). In addition, high testosterone serum AE (NTAE), are by far the most frequent causes, found in levels and failure of androgen suppression in response to more than 90% of these patients (3, 4). By contrast, administration have also been regarded as ovarian and adrenal androgen-secreting tumors (ACT- indicators of the presence of a virilizing tumor of either the AS) are rare, accounting for only 0.2% of the causes of or the (8, 10–12). However, this AE (3, 4). The finding of androgen secretion by an ACT conclusion was based on relatively small series of patients. is highly suggestive of malignancy. It is clearly To help identify ACT among women with AE, we have important to identify the small proportion of patients performed a retrospective analysis of 44 consecutive with this potentially life-threatening condition (5). female patients with ACT-AS followed in a single The extent to which women with AE should be evaluated endocrine department. The whole group was compared to exclude the likelihood of a neoplasm is still a matter of with 102 women with NTAE.

q 2008 European Society of Endocrinology DOI: 10.1530/EJE-08-0324 Online version via www.eje-online.org

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Subjects and methods Marseilles, France) that gave similar results with an intra-assay coefficient of variation of 4% and inter-assay We retrospectively analyzed 44 consecutive women of 8%. DHEAS was assayed before 2000 by an in-house with an ACT-AS referred to the Endocrine Department RIA and thereafter with the Immulite 2000 (DPC, of Cochin Hospital between 1989 and 2005. Tumor Siemens), which gave similar results with an intra- and staging and pathological analysis were performed as inter-assay coefficient of variation of 5%. 17OH-Pg was described previously (13–15). The study was approved assayed with a competitive RIA using rabbit-specific by the Institutional Review Board of Cochin Hospital antibody from M P-Biomedicals-LLC (Santa Ana, CA, and informed consent of the patients was obtained. The USA). Compound S was assayed by competitive RIA results of the patients with ACT-AS were compared with using the IBL (Hamburg, Germany) kit. Biochemical AE those of 102 consecutive women with NTAE referred to in female was confirmed whenever the following a single unit of the same department. androgen serum levels were increased: total testoster- Hirsutism, acne, oligomenorrhea, and amenorrhea one (T) levels above 0.8 ng/ml (O2.77 nmol/l), free were recorded according to the physician’s notes and T (fT) levels above 4 pg/ml (O13.78 pmol/l), DHEAS menstrual cycles longer than 35 days were charac- above 2.8 mg/ml (O7.6 mmol/l), and/or androstene- terized as oligo/amenorrhea (16). dione levels above 2.2 ng/ml (O7.6 nmol/l). Each of The NTAE group consisted of 88 women with PCOS these values corresponds to the 95th percentile of and 14 with idiopathic (IHA) (17, healthy women. The normal range of was 18). The ones who had received any estrogenic or anti- 20–120 pg/ml (73.4–440.4 pmol/l) and the normal androgenic in the last 3 months were range of was 20–120 pg/ml (73.4– excluded from the study. All records of the patients 440.4 pmol/l) for women in the . were reevaluated by the same investigator. PCOS was Blood sampling for androgens and other hormonal classically defined by the presence of at least two of the determinations were performed without regard to the following three abnormalities: oligomenorrhea or time of the menstrual cycle in the ACT-AS group. In the amenorrhea, clinical or biochemical AE, and polycystic great majority of the NTAE, investigations were ovaries on ultrasound (17, 18). Yet, biochemical AE was performed during the follicular phase of a spontaneous a necessary criterion for inclusion in this study. IHA was or progestin-induced menstrual cycle. defined as the association of clinical AE and increased plasma androgen levels in the presence of normal ovulatory cycles and normal ovaries on ultrasound Statistical analysis (18). All ultrasound records were reviewed by the same The prevalence of hirsutism, acne, and oligo/amenor- investigator. In the NTAE group, congenital adrenal rhea in the two groups (ACT-AS and NTAE) was hyperplasia, Cushing’s syndrome, hyperprolactinemia, compared with c2 tests or Fisher’s exact tests, when thyroid dysfunction, and ACT were excluded on the appropriate. The numeric data represented by the basis of clinical investigations, hormonal assays, and levels were not normally distributed and the adrenal imaging by the usual routine work-up. results were expressed as median values and range. Between-group comparisons were performed using the Mann–Whitney test and correlations between variables Hormonal determinations were described using Spearman’s correlation coeffi- Basal levels of total and free testosterone (T), androste- cients (r). Results were considered statistically signi- nedione, DHEA sulfate (DHEAS), 17OHP, compound S, ficant if the P value was less than 0.05. According to estradiol, estrone, follicle-stimulating hormone (FSH), Youden’s index (22), appropriate cut-off values for the and (LH) were recorded in patients hormone levels were selected as those maximizing the and controls as well as urinary-free , serum sum (specificityCsensitivity). To construct confidence cortisol at midnight, adrenocorticotrophin (ACTH), and interval (CI) for sensitivity and specificity, we used the the results of low-dose dexamethasone suppression test normal approximation or binomial tables, when in the ACT-AS group. All hormonal assays were appropriate. performed at the hormone unit of Cochin Hospital as reported previously (19–21). Testosterone assays used the Testo-CT2 kit (Cis-Bio, Schering, Bagnols-sur-Ceze, France) with intra- and inter-assay coefficient of Results variation of 4 and 7% respectively. Free testosterone Clinical features assay was done for patients investigated since 1996 with the Coat-A-count kit (DPC, Siemens, Deerfield, IL, Tumor characteristics are summarized in Table 1. The USA) with an intra- and inter-assay coefficient of group of 44 female patients was compared with the 102 variation of 8%. Androstenedione was assayed before female patients with NTAE. The 44 women with ACT- 2000 by an in-house RIA and thereafter with the RIA AS were older (median age 37.7 years, range 14.1–87.2 D4 androstenedione direct kit (Immunotech, Beckman, years) compared with the NTAE group (median 24.8

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Table 1 Main characteristics of androgen-secreting adrenocortical Table 2 Clinical characteristics and baseline hormone levels of the tumors (ACT-AS). 44 female patients with androgen-secreting adrenocortical tumors (ACT-AS) and the 102 women of the comparison group with non- Tumor characteristics Results tumor causes of androgen excess (NTAE).

Tumor size (cm) 9.5 (4–27) ACT-AS NTAE P value Tumor weight (g) 265.5 (22–2718) Tumor extension n (%) Age (years) 37.7 (14.1–87.2) 24.8 (13.4–55.9) !0.001 Localized 17 (38.6) Hirsutism n (%) 33/42 (78.6) 86/97 (88.6) 0.19 Regional extension 14 (31.8) Acne n (%) 14/36 (38.9) 35/77 (45.5) 0.65 Metastatic 23 (52.3) Oligo/amenorrhea 22/24 (91.6)a 77/79 (97.4)b 0.49 Undetermined 1 (2.3) n (%) secretion profile n (%) Total testosterone 1.5 (0.3–7.8) 0.8 (0.2–1.6) !0.0001 Androgen and cortisol 28 (63.6) (ng/ml) Androgen, cortisol, and 7 (15.9) Free testosterone 8.8 (2.2–35.2) 3.2 (0.1–10.4) !0.0001 Androgen and estrogen 2 (4.5) (pg/ml) Androgen 7 (15.9) Androstenedione 6.1 (1.7–49) 3.2 (1.4–9.3) !0.0001 Histological grade n (%) (ng/ml) Weiss criteria %3 9 (20.5) DHEAS (mg/ml) 5.8 (0.4–15) 2.6 (0.6–6.4) !0.0001 Weiss criteria R4 35 (79.5) Compound S 15.0 (4–150) 2.9 (0.9–5.7) !0.0001 Follow-up (years) 2.1 (0.2–10.9) (ng/ml) Death n 19 (43.1) 17OHP (ng/ml) 2.9 (0.4–77) 1.0 (0.1–14.8) !0.0001 Estradiol (pg/ml) 59.5 (2.1–980) 52.0 (5–413) 0.62 The table shows, for the 44 female patients with ACT-AS, the tumor size Estrone (pg/ml) 225 (88–9000) – – (expressed in cm), the tumor weight determined for the operated patients LH (U/l) 1.3 (0–27) 13.2 (2.9–44) !0.0001 (expressed in g), the tumor extension at initial staging, the main results of FSH (U/l) 2.0 (0–7.9) 5.6 (1–11) !0.0001 steroid secretion investigations, the diagnosis of malignancy (based on the Weiss score and clinical follow-up), the duration of follow-up, and the death Age and hormone levels are expressed in median (range). Conversion factors: rate of the series during follow-up. Results are given as median (range) or total T (ng/ml; to convert to nmol/l multiply by 3467), free T (pg/ml; to convert to number of cases and (%) as indicated. pmol/l multiply by 3446), androstenedione (ng/ml; to convert to nmol/l multiply by 3492), DHEAS (mg/ml; to convert to mmol/l multiply by 2714), 17OHP (ng/ml; years; range 13.4–55.9 years; P!0.001). The to convert to nmol/l multiply by 303), compound S (ng/ml; to convert to nmol/l prevalence of hirsutism, acne, and oligo/amenorrhea multiply by 2887), estradiol (pg/ml; to convert to pmol/l multiply by 367), and estrone (pg/ml; to convert to pmol/l multiply by 37). was not different between the two groups (Table 2). aThe eight menopaused patients as well as the nine women taking estrogen therapy and three other patients for which the menstrual pattern was not recorded were excluded from this analysis. bThe 14 NTAE with idiopathic hyperandrogenism were excluded from this Endocrine investigation analysis. In the ACT-AS group, seven patients (15.9%) had tumors secreting androgens alone and two (4.5%) had tumors testosterone levels superior to 1.7 ng/ml (5.9 nmol/l) secreting androgens and . Twenty-eight patients distinguished ACT-AS from NTAE with 100% specificity (63.6%) had tumors secreting both androgens and but with a very low sensitivity (45%). Similarly, free cortisol, and seven (15.9%) had tumors secreting testosterone levels superior to 11.2 pg/ml (38.6 pmol/l) androgens, cortisol, and estrogens (Table 1). Free had 100% specificity but only 47% sensitivity. Youden’s testosterone was elevated in 16 of 17 patients, being the index approach (22) depicted that free testosterone most commonly elevated androgen (94%), followed by concentrations superior to 6.85 pg/ml (23.6 pmol/l) androstenedione, which was elevated in 35 of 39 patients had the best sensitivity and specificity, being 82% (95% (90%), DHEAS elevated in 32 of 39 (82%), and total CI: 57–96%) and 97% (95% CI: 91–100%) respectively testosterone elevated in 32 of 42 patients (76%). In the (Table 3). Thus, high free testosterone seems to be a NTAE group, androstenedione was elevated in 92 of 99 good predictor of ACT-AS. controls (93%), while the other androgens were elevated Compound S and 17OHP levels were also significantly in less than 50% of these women; total testosterone in 44 higher in ACT-AS than in NTAE patients, but there was of 102 controls (43%), free testosterone in 32 of 77 (42%), also an overlap between both groups (Table 2). and DHEAS in 38 of 97 (39%). Compound S was increased (R10 ng/ml or Among the 38 ACT-AS patients who had all three 28.9 nmol/l) in 23 of 27 ACT-AS patients (85%); 20 androgen levels available (total or free testosterone, of 21 patients with malignant tumors, 3 of 6 patients androstenedione, and DHEAS), 56% had all three with apparently benign tumors. Nonetheless, it was values elevated, 31% had two androgens elevated, and normal and inferior to 6 ng/ml (17.3 nmol/l) in 35 of 13% had only one androgen elevated. Conversely, 35 NTAE (100%). Youden’s index displayed that among 95 NTAE patients, 40% had only one androgen compound S level above 7 ng/ml (20.2 nmol/l) had a elevated, 38% had two androgens elevated, and only sensitivity of 89% (95% CI: 71–98%) and a specificity of 22% had high levels of all three androgens. 100% (95% CI: 90–100%) for the detection of ACT-AS Although all androgens were significantly higher in (Table 3). Concerning 17OHP, it was elevated ACT-AS than in NTAE patients, there was a great (O2 ng/ml or 6.1 nmol/l) in 24 of 36 ACT-AS patients overlap between the two groups (Table 2). Basal (67%) and, among these 24 women, the median

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Table 3 Sensitivity and specificity of basal hormone levels in the to 980 pg/ml (median 409 pg/ml or 1501 pmol/l). evaluation of female patients with androgen-secreting adrenocor- Estrone was high in 7 of 11 (64%) and the elevated tical tumors (ACT-AS) and non-tumor causes of androgen excess estrone levels ranged from 204 to 9000 pg/ml (median (NTAE). 1900 pg/ml or 7030 pmol/l). There was a positive ACT-AS NTAE Sensitivity Specificity correlation between estradiol and free testosterone (n) (n) % (CIa) % (CIa) concentrations (P!0.05, rZ0.5, 15 patients evalu- ated). However, neither did we find any correlation Total testosterone 42 102 60 (45–74) 94 (90–99) between estradiol and total testosterone nor between O1.25 ng/ml Free testosterone 17 77 82 (57–96) 97 (91–100) estrone and androstenedione concentrations. O6.85 pg/ml Androstenedione 38 99 66 (49–80) 80 (71–87) O4.65 ng/ml DHEAS O 39 97 79 (64–91) 79 (70–87) Discussion 3.6 mg/ml 17OHP O 36 79 67 (49–81) 86 (76–93) Although adrenocortical masses are frequent in the 1.95 ng/ml general population, only a small proportion of them Compound S O 27 35 89 (71–98) 100 (90–100) 7 ng/ml bear a threat due to their malignant and/or hyperse- creting nature (23–26). Yet, this possibility must be in Thresholds were selected using Youden’s index, as described in the methods. a mind when evaluating women with evidence of AE. CI: 95% confidence intervals. Imaging approaches, mainly by computed tomography or magnetic resonance imaging (5, 27, 28), perform elevated level was 6 ng/ml (18.2 nmol/l; range 2– well but are not cost effective. Therefore, a simple tool 77 ng/ml or 6.1–233.3 nmol/l). In NTAE, baseline for the screening of ACT-AS is needed. 17OHP was elevated in 10 out of 88 individuals Contrary to a frequent proposition (6), we found no (11%) and, among these 10 controls, the median clear differences in the clinical presentation of NTAE elevated level was 2.6 ng/ml (7.9 nmol/l; range 2.1– and ACT-AS in our series: the prevalence of hirsutism, 14.8 ng/ml or 6.4–44.8 nmol/l). Nevertheless, 87 acne, and oligo/amenorrhea were not sufficient to women with NTAE, including those with elevated distinguish these two causes of AE. Furthermore, some basal 17OHP, were submitted to an ACTH stimulation tumors had a moderate AE and consequently a subtle test, which was normal (stimulated 17OHP !10 ng/ml clinical presentation. or !30.3 nmol/l) in all of them. Youden’s index found The analysis of the basal androgen levels revealed that a baseline 17OHP above 1.95 ng/ml (5.9 nmol/l) that no single androgen had a 100% sensitivity to had a sensitivity of 67% (95% CI: 49–81%) and a diagnose ACT-AS in female patients. Furthermore, free specificity of 86% (95% CI: 76–93%; Table 3). testosterone was the most commonly elevated androgen Finally, basal LH and FSH levels were significantly in women with ACT-AS (94%) and androstenedione in lower in patients with ACT-AS than with NTAE. Five patients with NTAE (93%). On the other hand, the menopausal ACT-AS patients who had their gonado- likelihood of having a simultaneous increase in all three tropins assayed all had suppressed levels of FSH (range: androgens was much higher in ACT-AS than in NTAE 0.1–2.0 U/l) and suppressed or inappropriately normal group (56% vs 22%). Therefore, clinicians should be levels of LH (range: 0.1–6.0 U/l). No correlation was aware that half of the patients with ACT-AS have one or found between and testosterone, estra- two androgens in the normal range. diol, estrone, or urinary-free cortisol in the patients with Although androgen concentrations were higher in ACT-AS (data not shown). However, two of these ACT-AS, there was an overlap between the two groups. women had extremely high estrone levels, 1900 and Yet, Youden’s index showed that a free testosterone level 9000 pg/ml (or 7030 and 33 300 pmol/l) and one had above 6.85 pg/ml (23.6 pmol/l) had a high discrimina- a total testosterone level of 4.2 ng/ml (14.6 nmol/l). tive value with a sensitivity of 82% and a specificity of The post-surgical androgen concentrations were 97%. In future studies, it would be interesting to analyze available for 36 patients with ACT-AS. All of them the diagnostic value of free testosterone derived from the had subnormal androgen levels except 7 women with assessment of the levels of total testosterone and sex- metastasis at diagnosis (Fig. 1). As some patients had hormone binding globulin that might be more reliable only marginally elevated androgen levels, these post- than the direct method used in this study (29). surgical values argue against the possibility of a The measurement of 17OHP and compound S are of functional AE. great interest considering that ACT-AS often present with defective steroid enzymes causing elevated Estrogen-secreting tumors levels of steroid precursors (30, 31). Baseline 17OHP was indeed high in 67% of the ACT-AS (median 6 ng/ml or Among the 44 women with ACT-AS, 10 also had high 18.2 nmol/l) and 11% of the NTAE (median 2.6 ng/ml or estrogen levels. Estradiol was high in 6 of 34 females 7.9 nmol/l), and compound S was high in 85% of ACT-AS (18%) and the elevated estradiol levels ranged from 201 and 0% of the NTAE. Compound S above 7 ng/ml

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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-, 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.

(20.2 nmol/l) had a sensitivity of 89% and a specificity of In all series of ACT, female patients clearly pre- 100% for the diagnosis of ACT-AS. Thus, among the five dominate and males account for 10–35% of the steroids evaluated, free testosterone and compound S reported cases (30, 33, 34). In our series, five men seem to be the best predictors of ACT-AS. with androgen-secreting tumors accounted for 10% of Gonadotropins concentrations were significantly lower the ACT-AS cases (data not shown). in patients with ACT-AS than with NTAE. Nevertheless, Elevated estrogen concentrations were found in 10 we did not find any correlation between gonadotropins women and there was a positive correlation between and testosterone, estradiol, estrone, or urinary-free estradiol and free testosterone levels, suggesting that the cortisol (data not shown). In rare cases, patients with peripheral aromatization of testosterone could be the virilizing tumors might present high levels source of elevated estradiol concentrations. and an increased LH-to-FSH ratio despite high androgens Another interesting issue in this series of rare tumor is (8). In Cushing’s disease, low gonadotropin levels and the to clearly show that not all ACT-AS are clearly malignant, menstrual irregularities result from excess cortisol rather at least from a clinical perspective. Indeed, in ten cases, the than an increase in plasma androgens (32). Weiss score was above 4 (usually considered as the cut-off

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Downloaded from Bioscientifica.com at 09/30/2021 01:57:32AM via free access 646 C B d’Alva and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159 for the diagnosis of malignancy) and no tumor recurrence disorders in 950 women referred because of clinical hyperan- could be observed during follow-up. Interestingly, these drogenism. Journal of Clinical Endocrinology and 2006 tumors usually are pure androgen-secreting tumors (data 91 2–6. 5 Libe R, Fratticci A & Bertherat J. Adrenocortical cancer: not shown) by contrast with the frequent co-secretion of pathophysiology and clinical management. Endocrine-Related cortisol and androgens by the malignant tumors. This Cancer 2007 14 13–28. suggests the possibility that some rare ACT-AS are true 6 Management of hirsutism. Drug and Therapeutics Bulletin 1989 27 benign tumors. However,one should remain cautious and 49–51. long-term follow-up of ACT-AS should always be done 7 Rosenfield RL. Clinical practice. Hirsutism. New England Journal of Medicine 2005 353 2578–2588. since, as a general rule, androgen secretion by an adrenal 8 Kaltsas GA, Isidori AM, Kola BP, Skelly RH, Chew SL, Jenkins PJ, tumor should lead to the suspicion of malignancy. Monson JP, Grossman AB & Besser GM. The value of the low-dose In conclusion, simultaneous increase of all three dexamethasone suppression test in the differential diagnosis of androgens is more prevalent in ACT-AS than in NTAE hyperandrogenism in women. Journal of Clinical Endocrinology and patients. In addition, intra-tumoral defect in steroid Metabolism 2003 88 2634–2643. biosynthesis usually results in elevated steroid pre- 9 Rosenfield RL, Cohen RM & Talerman A. cell tumor of the ovary in reference to adult-onset congenital adrenal hyperplasia cursors such as 17OHP and compound S. Free and polycystic ovary syndrome. A case report. Journal of testosterone and compound S would be the best markers Reproductive Medicine 1987 32 363–369. in the initial screening of women with AE since 10 Waggoner W, Boots LR & Azziz R. Total testosterone and DHEAS concentrations of free testosterone superior to levels as predictors of androgen-secreting neoplasms: a popula- 6.85 ng/ml (23.6 pmol/l) and compound S superior to tional study. Gynecological Endocrinology 1999 13 394–400. 11 O’Driscoll JB, Mamtora H, Higginson J, Pollock A, Kane J & 7 ng/ml (20.2 nmol/l) had acceptable values of sensi- Anderson DC. A prospective study of the prevalence of clear-cut tivity and specificity. Conversely, we should keep in mind endocrine disorders and polycystic ovaries in 350 patients that a large overlap of androgen and precursor presenting with hirsutism or androgenic alopecia. Clinical concentrations exists between ACT-AS and NTAE. Endocrinology 1994 41 231–236. Therefore, adrenal imaging is mandatory when there 12 Derksen J, Nagesser SK, Meinders AE, Haak HR & van de Velde CJ. is any doubt about diagnosis. Identification of virilizing adrenal tumors in hirsute women. New England Journal of Medicine 1994 331 968–973. 13 Tissier F, Louvel A, Grabar S, Hagnere AM, Bertherat J, Vacher- Declaration of interest Lavenu MC, Dousset B, Chapuis Y, Bertagna X & Gicquel C. Cyclin E correlates with malignancy and adverse prognosis in adreno- The authors declare that there is no conflict of interest that would cortical tumors. European Journal of Endocrinology 2004 150 prejudice the impartiality of this work. 809–817. 14 Tissier F, Cavard C, Groussin L, Perlemoine K, Fumey G, Hagnere AM, Rene-Corail F, Jullian E, Gicquel C, Bertagna X, Funding Vacher-Lavenu MC, Perret C & Bertherat J. Mutations of beta- catenin in adrenocortical tumors: activation of the Wnt signaling This work was supported by the Plan Hospitalier de Recherche Clinique (AOM 02068) to the COMETE network. pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Research 2005 65 7622–7627. 15 Libe R, Groussin L, Tissier F, Elie C, Rene-Corail F, Fratticci A, Acknowledgements Jullian E, Beck-Peccoz P, Bertagna X, Gicquel C & Bertherat J. Somatic TP53 mutations are relatively rare among adrenocortical We thank Sophie Grabar for helpful discussions and Ricardo Augusto cancers with the frequent 17p13 loss of heterozygosity. Clinical Probo for the English review. We thank the staff of the endocrine, Cancer Research 2007 13 844–850. endocrine surgery, pathology, and nuclear medicine departments of 16 Speroff L. Dysfunctional uterine bleeding. In Clinical Gynecologic Cochin Hospital for patients’ management. 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