Original Article
Identification of Virilizing Adrenal Tumors in Hirsute Women
N Engl J Med 1994; 331:968-973October 13, 1994
- Abstract
Background
Hirsutism in women is usually caused by benign adrenal or ovarian disorders, but it can also be caused by adrenal carcinoma. The most effective way to identify such carcinomas is not known.
Methods
We measured serum and urinary steroids before and after the administration of 3 mg of dexamethasone per day for five days in 14 hirsute women with histologically proved adrenal tumors (12 adrenal carcinomas and 2 adrenal adenomas) and in 73 women with hirsutism of non-neoplastic origin.
Results
All the women with adrenal tumors had elevated basal serum concentrations of testosterone or dehydroepiandrosterone sulfate, as compared with 36 of the 73 women with non-neoplastic hirsutism (sensitivity, 100 percent; 95 percent confidence interval, 77 to 100; specificity, 50 percent; 95 percent confidence interval, 38 to 62). After the administration of dexamethasone, serum dehydroepiandrosterone sulfate concentrations and urinary 17-ketosteroid excretion decreased to values similar to those in normal women in all the women with non-neoplastic hirsutism, but in none of the 12 with adrenal tumors who were tested. All the women who did not have adrenal tumors had serum cortisol concentrations below 3.3 μg per deciliter (90 nmol per liter) after dexamethasone administration, whereas in all 12 patients tested who had tumors the values were higher. The suppression of serum dehydroepiandrosterone sulfate and cortisol and urinary 17-ketosteroid excretion excluded the likelihood of adrenal tumors with a sensitivity of 100 percent (95 percent confidence interval, 74 to 100) and a specificity of 100 percent (95 percent confidence interval, 89 to 100).
Conclusions
Among women with hirsutism, an adrenal tumor is unlikely if the patient has normal basal serum concentrations of testosterone and dehydroepiandrosterone sulfate. In women in whom these concentrations are elevated, a tumor is unlikely if the serum concentration of dehydroepiandrosterone sulfate and urinary 17-ketosteroid excretion are in the normal basal range and the serum cortisol concentration is less than 3.3 μg per deciliter after the administration of dexamethasone.
Media in This Article
Figure 1
Serum Concentrations of Testosterone, Androstenedione, Dehydroepiandrosterone Sulfate (DHEAS), and Dehydroepiandrosterone (DHEA) before and after the Administration of Dexamethasone for Five Days in Women with Non-Neoplastic Hirsutism and Women with Adrenal Tumors.Figure 2
Urinary 17-Ketosteroid Excretion before and after the Administration of Dexamethasone for Five Days in Women with Non-Neoplastic Hirsutism and Women with Adrenal Tumors.Article Activity
- Article
Hirsutism can be an early sign, and even the only sign, of a virilizing adrenal carcinoma or adenoma, as well as of adrenal hyperplasia and ovarian disorders, and hirsutism of neoplastic origin cannot be excluded on the basis of the history or physical examination. The extent to which hirsute women should be evaluated to exclude the likelihood of a virilizing adrenal tumor is still a matter of debate. High basal serum concentrations of testosterone and dehydroepiandrosterone sulfate -- for example, values exceeding 200 ng per deciliter (7 nmol per liter) and 700 μg per deciliter (19 μmol per liter), respectively, and urinary 17-ketosteroid excretion exceeding 50 mg (174 μmol) per 24 hours are often regarded as indicating the presence of a virilizing ovarian or adrenal tumor, and additional studies to rule out an adrenal tumor are often recommended only in women in whom the values are higher. Among women with high serum androgen or urinary 17-ketosteroid values, the failure of dexamethasone to suppress the elevations is characteristic of a virilizing tumor, whereas good suppression indicates non-neoplastic adrenal hypersecretion. However, with regard to virilizing adrenal carcinomas, this conclusion is based on results in only a few patients1-7. To determine which test is most suitable for the differentiation of hirsutism caused by a virilizing adrenal tumor from that caused by non-neoplastic disorders, we measured serum and urinary steroids in women with hirsutism as the presenting or chief symptom of histologically proved virilizing adrenal tumors, women with hirsutism of non-neoplastic origin, and normal women.
Methods
Women with Virilizing Adrenal Carcinomas or Virilizing Adrenal Adenomas
From 1980 to 1991, we studied 27 women with adrenal carcinomas and 10 women with adrenal adenomas. Their mean age was 43 years (range, 17 to 64). Hirsutism was the presenting or chief symptom in 14 of the women with adrenal carcinomas and 2 of those with adrenal adenomas. Two of the women with adrenal carcinomas underwent surgery before hormonal studies could be done. The results of the preoperative evaluation, therefore, were available for 12 women with adrenal carcinomas and both women with adrenal adenomas (Table 1Table 1
Clinical and Pathological Data on 14 Women with Virilizing Adrenal Tumors.). Five women with adrenal carcinomas and both women with adrenal adenomas presented with virilism alone. One woman with adrenal carcinoma presented with deep venous thrombosis in addition to hirsutism. The remaining six women with adrenal carcinomas had hirsutism combined with symptoms and signs of Cushing's syndrome. In the grading of hirsutism, mild denoted the presence of a few hairs on the upper lip, chin, chest, lower abdomen, or thighs; moderate, more hairs but still incompletely covering these regions; and severe, complete covering of these regions. Mild hirsutism approximates a Ferriman and Gallwey score (range, 0 to 36)9 of less than 10, moderate hirsutism a score from 10 to 20, and severe hirsutism a score of more than 20. The duration of hirsutism in all 14 patients ranged from 0.3 to 45 years (mean, 8). Four of the women with large adrenal carcinomas (Patients 2, 3, 6, and 9) reported pain in the region of the tumor, and two women (Patients 3 and 7) each had a palpable abdominal mass. The diagnosis of adrenal carcinoma was confirmed by the presence of metastases or by a histologic index above 8, as determined with the grading system of van Slooten et al.,8 on which the possible scores range from 0 to 28.4.Women with Non-Neoplastic Hirsutism
We also studied 73 consecutive women, with a mean age of 26 years (range, 14 to 44), who because of hirsutism were referred to the Department of Endocrinology and Metabolism. The duration of hirsutism in those women ranged from 1 to 28 years (mean, 10). Their mean hirsutism score, as assessed by the method of Ferriman and Gallwey,9 was 16 (range, 8 to 34). Nine women had other manifestations of virilism: frontotemporal balding in seven, deepening of the voice in three, and clitoromegaly in three. Forty of the 73 women had regular menstrual cycles, 7 had secondary amenorrhea, 15 had irregular periods, and 11 had oligomenorrhea, with menstrual cycles of more than 35 days. Forty-five women had increases in one or more serum androgens. Idiopathic hirsutism was diagnosed in the remaining 28 women. In seven women whose serum androgens after dexamethasone were suppressed into the range found in normal women after dexamethasone, the excess of androgens was attributed to the adrenal glands. In 11 women whose serum androgens remained above these ranges, the androgens were attributed to the ovaries. In 23 women whose serum androgens remained above these ranges and in whom there was also an excessive difference between the basal value and the value after dexamethasone administration, the origin was considered to be mixed ovarian and adrenal10. The origin of the androgen excess could not be established by this method in four women. Eleven women had elevated serum concentrations of luteinizing hormone (LH) and normal serum concentrations of follicle-stimulating hormone (FSH). Among 69 women who underwent ultrasonography of the ovaries, 17 had polycystic ovaries, as defined by the presence in each ovary of at least 10 cysts, 2 to 8 mm in diameter, arranged either peripherally around a dense core of stroma or scattered throughout an increased amount of stroma11. In nine women in whom the serum concentration of testosterone or androstenedione remained above the upper limit of the basal range in normal women after dexamethasone administration, adrenal tumors were excluded by adrenal computed tomography or magnetic resonance imaging and ovarian tumors were excluded by ovarian ultrasonography. Four of these women had polycystic ovaries, and three others had elevated serum LH and normal FSH concentrations. None were found to have a tumor during a follow-up period of 12 to 44 months (mean, 28).
Normal Women
The reference population comprised 31 normal women with a mean age of 28 years (range, 18 to 43). All had regular menstrual cycles. Their mean hirsutism score according to Ferriman and Gallwey9 was 2.2 (range, 0 to 6). All normal values described in this article refer to these women.
Hormonal Studies
Serum concentrations of testosterone, androstenedione, dehydroepiandrosterone sulfate, dehydroepiandrosterone, and cortisol and 24-hour urinary 17-ketosteroid excretion were measured in all the women in the three groups, with a few exceptions, as shown in Table 2Table 2
Hormone Values in 14 Women with Virilizing Adrenal Tumors.. The blood samples were obtained between 8 and 10 a.m. during the follicular phase of the menstrual cycle in women who did not have amenorrhea. Dexamethasone was administered orally, 1 mg every eight hours for five days, because it takes five days for serum androgens and urinary 17-ketosteroid excretion to be suppressed to a steady state in normal women (as compared with less than two days for the suppression of serum and urinary glucocorticoids). Urine was collected on day 5, and a blood sample was obtained between 8 and 9 a.m. on day 6.Analytic Methods
Serum concentrations of steroid, LH, and FSH were measured with commercially available assay kits, as described elsewhere12. The normal ranges were as follows: testosterone, 29 to 84 ng per deciliter (1.0 to 2.9 nmol per liter); androstenedione, 50 to 440 ng per deciliter (1.7 to 15.4 nmol per liter); dehydroepiandrosterone sulfate, 118 to 431 μg per deciliter (3.2 to 11.7 μmol per liter); dehydroepiandrosterone, 0.16 to 1.48 μg per deciliter (5.5 to 51.4 nmol per liter); cortisol, 10 to 33 μg per deciliter (276 to 911 nmol per liter); urinary 17-ketosteroids, 3.5 to 18.4 mg per 24 hours (12.1 to 63.8 μmol per 24 hours); LH, 1.5 to 9.5 U per liter; and FSH, 2.6 to 7.4 U per liter. The normal ranges after the administration of dexamethasone were as follows: testosterone, 11 to 46 ng per deciliter (0.4 to 1.6 nmol per liter); androstenedione, 6 to 130 ng per deciliter (0.2 to 4.5 nmol per liter); dehydroepiandrosterone sulfate, 7 to 74 μg per deciliter (0.2 to 2.0 μmol per liter); dehydroepiandrosterone, less than 0.01 μg per deciliter (<0.3 nmol per liter); cortisol, less than 2.5 μg per deciliter (<69 nmol per liter); and urinary 17-ketosteroids, 0.2 to 2.5 mg per 24 hours (0.7 to 8.7 μmol per 24 hours). The interassay coefficients of variation were as follows: testosterone, 6.8 percent; androstenedione, 9.0 percent; dehydroepiandrosterone sulfate, 7.1 percent; dehydroepiandrosterone, 8.2 percent; urinary 17-ketosteroids, 7.5 percent; LH, 5.0 percent; and FSH, 5.0 percent.
Statistical Analysis
Sensitivity was defined as the number of true positive results divided by the sum of true positive and false negative results. Specificity was defined as the number of true negative results divided by the sum of true negative and false positive results. Ninety-five percent confidence intervals were calculated as described by Gardner and Altman13.
Results
Basal Studies
The basal serum concentrations of all steroids and the basal 24-hour urinary 17-ketosteroid excretion in the two groups of patients overlapped (Figure 1Figure 1
Serum Concentrations of Testosterone, Androstenedione, Dehydroepiandrosterone Sulfate (DHEAS), and Dehydroepiandrosterone (DHEA) before and after the Administration of Dexamethasone for Five Days in Women with Non-Neoplastic Hirsutism and Women with Adrenal Tumors., Figure 2Figure 2Urinary 17-Ketosteroid Excretion before and after the Administration of Dexamethasone for Five Days in Women with Non-Neoplastic Hirsutism and Women with Adrenal Tumors., and Figure 3Figure 3
Serum Cortisol Concentrations before and after the Administration of Dexamethasone for Five Days in Women with Non-Neoplastic Hirsutism and Women with Adrenal Tumors. and Table 2). All 12 women with adrenal carcinomas had elevated serum testosterone concentrations, as did 1 woman with an adrenal adenoma and 30 women with non-neoplastic hirsutism. The serum testosterone concentration exceeded 200 ng per deciliter in seven women with adrenal carcinomas (three with and four without Cushing's syndrome), one woman with an adrenal adenoma, and two women with non-neoplastic hirsutism. Among the 73 women with non-neoplastic hirsutism, 36 had elevated serum concentrations of testosterone, dehydroepiandrosterone sulfate, or both.On the basis of their elevated basal serum concentrations of testosterone or dehydroepiandrosterone sulfate, all the women with adrenal carcinomas or adrenal adenomas and 36 of the women with non-neoplastic hirsutism were designated as having abnormal androgen levels. This analysis had a sensitivity of 100 percent (95 percent confidence interval, 77 to 100 percent) and a specificity of 50 percent (95 percent confidence interval, 38 to 62 percent) for the detection of adrenal tumors. By discriminant analysis of all basal values, complete discrimination between tumorous and nontumorous hirsutism could not be achieved. Four women with adrenal carcinomas (one without and three with Cushing's syndrome) and one woman with an adrenal adenoma had elevated basal serum cortisol concentrations (Figure 3).
Dexamethasone Suppression Test
Except for the values for serum dehydroepiandrosterone in two women with adrenal carcinomas, none of the women with adrenal tumors had normal suppression of any serum androgen values to within the range found in normal women after dexamethasone administration (Figure 1). In contrast, in all the women with non-neoplastic hirsutism who had elevated basal serum concentrations of dehydroepiandrosterone and dehydroepiandrosterone sulfate and urinary 17-ketosteroid excretion, the values were within the normal basal range after the administration of dexamethasone. However, serum concentrations of testosterone or androstenedione remained above the normal basal range after dexamethasone administration in nine women with non-neoplastic hirsutism (Figure 1). Serum cortisol concentrations, which were measured in 10 of the 12 women with adrenal carcinomas, were incompletely suppressed both in the women with and in those without Cushing's syndrome (Figure 3). In all the women with non-neoplastic hirsutism, the serum cortisol values after dexamethasone administration were below 3.3 μg per deciliter (90 nmol per liter).
The women with adrenal tumors were distinguished from those with non-neoplastic hirsutism on the basis of the response of serum dehydroepiandrosterone sulfate, serum cortisol, and urinary 17-ketosteroid excretion after the administration of dexamethasone (Figure 1, Figure 2, and Figure 3). After the administration of dexamethasone, neither the serum concentration of dehydroepiandrosterone sulfate nor urinary 17-ketosteroid excretion was above the normal basal range, and the serum cortisol concentration was not higher than 3.3 μg per deciliter in any of the women with non-neoplastic hirsutism, whereas in all 12 women with adrenal tumors who were tested at least one of these steroids remained above these limits. The sensitivity and specificity, respectively, of insufficient suppression of serum dehydroepiandrosterone sulfate or cortisol or of urinary 17-ketosteroid excretion after the administration of dexamethasone for the detection of adrenal tumors were 100 percent (95 percent confidence interval, 74 to 100 percent) and 100 percent (95 percent confidence interval, 89 to 100 percent).
There was no difference in the duration of hirsutism between the women with adrenal tumors and the women with non-neoplastic hirsutism (P = 0.91).
Discussion
Serum concentrations of testosterone or dehydroepiandrosterone sulfate or urinary 17-ketosteroid excretion well above the normal range are often regarded as indicators of a virilizing adrenal tumor, and additional assessment for the presence of such a tumor is generally recommended only if these values are elevated. Although all the women with adrenal tumors whom we studied had an excess of androgens, their serum concentrations of testosterone and dehydroepiandrosterone sulfate and urinary 17-ketosteroid excretion were often below the values generally accepted as indicating the presence of a tumor. Moreover, a number of the women with non-neoplastic hirsutism had similarly elevated values. Discrimination between these disorders by means of basal values alone, therefore, is not possible. On the other hand, elevated basal serum testosterone concentrations were found in all women with adrenal carcinomas, and elevated serum concentrations of dehydroepiandrosterone sulfate were found in both women with adrenal adenomas, indicating that measurements of serum testosterone and serum dehydroepiandrosterone sulfate are sensitive tests in the initial screening of hirsute women for virilizing adrenal tumors.
Failure to suppress androgen secretion with the administration of dexamethasone is generally regarded as a characteristic indication of a virilizing adrenal tumor. In reviewing the literature, we identified 9 women with virilizing adrenal carcinomas1-7 and 28 women with virilizing adrenal adenomas1,3,14-25 in whom androgen secretion was evaluated before and after dexamethasone administration. All these women had elevated serum testosterone concentrations or urinary 17-ketosteroid excretion, and in none were both these values suppressed with dexamethasone.
With the exception of serum dehydroepiandrosterone in two women with adrenal carcinomas, none of our patients with adrenal tumors who had elevated serum androgens or urinary 17-ketosteroid excretion had a decline in these values to the normal range after dexamethasone administration. In contrast, all the women with non-neoplastic hirsutism had serum concentrations of dehydroepiandrosterone sulfate and urinary 17-ketosteroid excretion that fell into the normal basal range, and their serum cortisol concentrations decreased to below 3.3 μg per deciliter (90 nmol per liter). Therefore, the fact that serum dehydroepiandrosterone sulfate or cortisol and urinary 17-ketosteroid excretion did not decline after the administration of dexamethasone differentiated the 14 women with adrenal tumors from the 73 women with non-neoplastic hirsutism with a sensitivity and specificity both of 100 percent.
The value of dexamethasone suppression tests for the identification of patients with adrenal tumors has been a matter of debate14,21. However, except for the suppression of serum testosterone in one patient21 and the suppression of urinary 17-ketosteroid excretion in three patients with virilizing adrenal adenomas,3,14,16 these reports have concerned the suppression of glucocorticoid excretion.
Virilizing ovarian tumors secrete excessive amounts of testosterone and are not suppressible by dexamethasone. The suppression of elevated serum testosterone concentrations by dexamethasone, therefore, also excludes the likelihood of a virilizing ovarian tumor.
Six of the 12 women with adrenal carcinomas in our study had symptoms of Cushing's syndrome and little suppression of serum cortisol after the administration of dexamethasone. Although the other six women with adrenal carcinomas had no manifestations of Cushing's syndrome, they also had insufficient suppression of serum cortisol. These results suggest that women with hirsutism and adrenal carcinomas, with and without Cushing's syndrome, constitute a single population that has a derangement of more than one steroidogenic pathway. Either the glucocorticoid or the androgenic pathway is predominant. The duration of the disease in the women with adrenal carcinomas who did not have Cushing's syndrome may have been too short for symptoms of the syndrome to develop.
We found that the administration of dexamethasone for five days in normal women and women with non-neoplastic hirsutism suppressed the serum cortisol concentration into the range usually considered to indicate normal suppressibility when 1 mg of dexamethasone is administered at bedtime and serum cortisol is measured the next morning. Since the serum cortisol concentrations in all 12 women with adrenal carcinomas remained well above this range, the overnight dexamethasone test is probably useful for the exclusion of a virilizing adrenal carcinoma.
We conclude that with hirsute women the measurement of serum testosterone and dehydroepiandrosterone sulfate is most suitable for an initial evaluation. Women in whom these basal values are normal are unlikely to have virilizing adrenal tumors. If serum testosterone or dehydroepiandrosterone sulfate is elevated, a virilizing tumor is unlikely if the serum dehydroepiandrosterone sulfate concentration and the urinary 17-ketosteroid excretion are within the normal basal range and the serum cortisol concentration is below 3.3 μg per deciliter after the administration of dexamethasone for five days.
We are indebted to Dr. J. Hermans for his advice on the statistical analyses.
Source Information
From the Departments of General Internal Medicine (J.D., A.E.M.), Endocrinology and Metabolism (J.D., S.K.N., H.R.H.), and Surgery (S.K.N., C.J.H.V.), University Hospital, Leiden, the Netherlands.
Address reprint requests to Dr. Derksen at the Department of General Internal Medicine, University Hospital, Bldg. 1, C1-R41, P.O. Box 9600, 2300 RC Leiden, the Netherlands.
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