Original Article
ACTH Stimulation Tests and Plasma Dehydroepiandrosterone Sulfate Levels in Women with Hirsutism
N Engl J Med 1990; 323:849-854September 27, 1990
- Abstract
- Abstract
Background.
Hirsutism in women is a clinical manifestation of excessive production of androgens. The source of the excess androgen may be either the ovaries or the adrenal glands, and distinguishing between these sources may be difficult.
Methods.
To determine whether measurements of plasma dehydroepiandrosterone (DHEA) sulfate and ACTH stimulation tests, both widely used in the evaluation of hirsutism in women, provide useful information, we performed both tests in 22 normal women and 31 female patients with hirsutism. The hormones measured in plasma during the ACTH stimulation tests were progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, DHEA, androstenedione, 11-deoxycortisol, and cortisol.
Results.
The women with hirsutism were divided into four groups based on their individual responses to ACTH stimulation: patients with a possible 3β-hydroxy-
5-steroid dehydrogenase deficiency, those with a possible 21-hydroxylase deficiency, those with a possible 11 β-hydroxylase deficiency, and those with no apparent defect in steroidogenesis. The results in 19 patients (61 percent) suggested subtle defects in adrenal steroidogenesis. There was no significant correlation between the basal plasma DHEA sulfate levels and the hormonal response to ACTH, nor were the basal levels of hormones predictive of the levels after ACTH stimulation. Eleven patients had significantly elevated basal levels of plasma DHEA sulfate; only 5 of these 11 had responses to ACTH suggestive of compromised steroidogenesis. Thirteen patients who had responses suggestive of defective steroidogenesis had DHEA sulfate levels within the normal range.Conclusions.
A substantial proportion of women with hirsutism have mild defects in adrenal steroidogenesis, revealed by an ACTH stimulation test, that are indicative of late-onset (nonclassic) congenital adrenal hyperplasia. Measurements of basal steroid levels are not helpful in differentiating among the causes of increased androgen production in such patients and may be misleading. (N Engl J Med 1990; 323:849–54.)
Media in This Article
Figure 1
Mean (±SE) Incremental Increases in Plasma Hormone Levels 30 Minutes after ACTH Stimulation, According to Study Group.Figure 2
Mean (±SD) Ratios of Plasma Hormone Levels before and 30 Minutes after ACTH Stimulation, According to Study Group.Article Activity
- Article
HIRSUTISM is one of the clinical manifestations of increased circulating levels of androgens in women. The increase in the androgen levels may be due to exogenous sources, increased adrenal or ovarian secretion, or increased peripheral conversion of weak androgenic hormones such as dehydroepiandrosterone (DHEA) or androstenedione to more potent androgens.1 Distinguishing among the causes of androgen excess may be difficult, but it is important because appropriate treatment depends on the diagnosis of the underlying disorder.
DHEA sulfate is an easily measured, slowly metabolized steroid conjugate that is produced primarily by the adrenal glands.2 3 4 Measurements of this hormone should therefore be helpful in distinguishing excessive adrenal production of androgens from excessive ovarian production, and indeed, plasma DHEA sulfate is often measured during the evaluation of women with hirsutism.5 6 7
Among the causes of hirsutism are several forms of late-onset (or nonclassic) congenital adrenal hyperplasia. They are 3β-hydroxy-
5-steroid dehydrogenase deficiency, 21-hydroxylase deficiency, and 11β-hydroxylase deficiency.8 9 10 11 The prevalence of these adrenal disorders as causes of hirsutism is unknown. Since basal hormone levels may be normal in patients with mild defects of adrenal steroidogenesis, ACTH stimulation tests are often performed to evaluate patients in whom these metabolic defects are suspected.12 Although there is debate about the overall value of such testing,13 14 15 16 17 18 19 20 there is agreement that the magnitude of the rise in plasma 17-hydroxyprogesterone levels after the administration of ACTH is the most discriminating laboratory test for adrenal 21-hydroxylase deficiency.21 We undertook this study to evaluate the diagnostic usefulness of the measurement of plasma DHEA sulfate levels and ACTH stimulation tests in women with hirsutism and to determine the frequency of the various forms of late-onset congenital adrenal hyperplasia among these patients.
Methods
Patients
ACTH stimulation tests were performed in 22 normal women and 31 patients referred to an endocrinologist for the evaluation of hirsutism. The normal women were 21 to 35 years old, had regular menstrual cycles, and were tested during the follicular phase of their cycles. The patients were 15 to 29 years old; although many had irregular menses, none had amenorrhea, and all were tested when their plasma progesterone levels were less than 3.2 nmol per liter (100 ng per deciliter) — i.e., not during the luteal phase of their cycles.
Virilization was limited to hirsutism and acne. Hirsutism in four areas — the face (including the sideburns, upper lip, and chin), the chest, the upper and lower abdomen, and the thighs — was assigned a score of 0 to 4 for each area, with the use of a modification of the method of Ferriman and Gallwey.22 Hirsutism was considered to be present if two or more of these four areas were assigned a score of 2 or more. Most patients had a total score of 4 to 8; the highest score was 12, found in about one fifth of the patients. Neither the normal women nor the patients were taking oral contraceptives or glucocorticoids. None of the patients were taking medications associated with hirsutism, and none had Cushing's syndrome, acanthosis nigricans, hyperprolactinemia, or a family history of congenital adrenal hyperplasia.
The protocol was approved by the Human Rights Committee of Children's Hospital of Pittsburgh, and informed consent was obtained from all subjects.
ACTH Testing and Hormone Assays
Blood samples were obtained before and 30 minutes after the administration of 100 units of ACTH (cosyntropin) by intravenous bolus injection over a 1-minute period. Samples also were obtained after 60 minutes in some subjects. The tests were performed between 8 and 10 a.m. Plasma levels of progesterone, 17-hydroxyprogesterone, androstenedione, and cortisol were determined according to previously described methods; the respective interassay coefficients of variation were 13.1 percent, 9.5 percent, 11.2 percent, and 14.1 percent.23 , 24 Plasma DHEA was assayed with a commercial kit (ICN Biomedicals, Carson, Calif.); the interassay coefficient of variation was 14.4 percent. Reagents from the same manufacturer were used to measure 17-hydroxypregnenolone (after extraction and chromatography as recommended by the manufacturer) and DHEA sulfate; the interassay coefficients of variation for these assays were 11.4 percent and 18.4 percent, respectively. Plasma 11-deoxycortisol was measured by a commercial firm (Endocrine Sciences, Tarzana, Calif.). All hormone measurements in each subject were performed in triplicate within single assays.
The rise in hormone levels was calculated by subtracting the value 30 minutes after ACTH administration from the value at time zero. (To convert values in nanomoles per liter to nanograms per deciliter, multiply the molar concentrations of the respective hormones by the following factors: progesterone, 31.5; 17-hydroxypregnenolone, 33.3; 17-hydroxyprogesterone, 33.1; DHEA, 28.8; androstenedione, 28.6; 11-deoxycortisol, 34.6; cortisol, 36,600; and DHEA sulfate, 36.81.)
Categorization of Patients and Statistical Analysis
The results of ACTH stimulation tests in each patient were compared with the results in the normal women. This analysis allowed the patients to be divided into four groups on the basis of the responses of the hormone levels to ACTH. The incremental response (hormone level at 30 minutes) was considered to be increased when the increment was greater than the mean ±2 SD of the increment in the normal women. An increased incremental response of plasma 17-hydroxypregnenolone was considered to indicate decreased activity of 3β-hydroxy-
5-steroid dehydrogenase12 (group 1), an increased incremental response of plasma 17-hydroxyprogesterone was considered to indicate decreased activity of 21-hydroxylase21 , 25 (group 2), and an increased incremental response of plasma 11-deoxycortisol was considered to indicate decreased activity of 11β-hydroxylase (group 3). A normal response in a patient was considered to indicate the absence of a detectable defect in steroidogenesis (group 4).The differences between the levels in the blood sample obtained at time zero and that obtained at 30 minutes were determined by paired t-tests. For measurements obtained at 0, 30, and 60 minutes, we used analysis of variance for repeated measures; differences between groups were examined for statistical significance with Scheffé's test. Differences between group means were evaluated with analysis of variance and Scheffé's test. Differences between patients in group 4 and the normal women were determined with independent two-tailed t-tests. All statistical analyses were performed with ABstat statistical software (Anderson-Bell, Canon City, Colo.).
Results
The hormone responses to stimulation with ACTH were used to separate the patients with hirsutism into four groups as previously defined: those with decreased 3β-hydroxy-
5-steroid dehydrogenase activity, those with decreased 21-hydroxylase activity, those with decreased 11β-hydroxylase activity, and those with normal hormone activity (Fig. 1Figure 1Mean (±SE) Incremental Increases in Plasma Hormone Levels 30 Minutes after ACTH Stimulation, According to Study Group. and Table 1Table 1
Plasma Hormone Levels in Normal Women and Patients with Hirsutism, before and after ACTH Stimulation.*). There was no correlation between the score for hirsutism and basal or ACTH-stimulated hormone levels.The 13 patients in group 1 had responses considered to indicate decreased activity of 3β-hydroxy-
5-steroid dehydrogenase, in that all had an increased incremental response of plasma 17-hydroxypregnenolone. Eight of these 13 patients had an incremental rise in plasma DHEA of more than 2 SD above the mean for the normal women. In 11 patients the ratio of 17-hydroxypregnenolone to 17-hydroxyprogesterone at 30 minutes was more than 2 SD above the mean for the normal women; in all 13 patients in group 1, the mean value for this ratio at 30 and 60 minutes was significantly higher than the mean for the normal women and for the three other groups of patients (P<0.005 for the comparison of values at 0, 30, and 60 minutes) (Fig. 2Figure 2Mean (±SD) Ratios of Plasma Hormone Levels before and 30 Minutes after ACTH Stimulation, According to Study Group.).The five patients in group 2 had responses considered to indicate decreased 21-hydroxylase activity. In addition to their increased plasma 17-hydroxyprogesterone responses to ACTH, all had a rise in the sum of the incremental increases in progesterone and 17-hydroxyprogesterone over a period of 30 minutes, a criterion used by other investigators to identify abnormal responses.26 This sum (mean ±SD, 0.4±0.15 nmol per liter [11.8±4.8 ng per deciliter]; range, 0.3 to 0.59 nmol [8.4 to 19.7 ng]) was more than 2.5 SD above the sum for the normal women (mean, 0.13± 0.05 nmol per liter [4.4±1.6 ng per deciliter]; range, 0.05 to 0.20 nmol [1.5 to 6.7 ng]; P<0.05). The increase was significantly higher in group 2 than in the other groups of patients (P<0.0001), as were the plasma progesterone level at 30 minutes (P<0.01) and the ratios of 17-hydroxyprogesterone to androstenedione at 30 and 60 minutes (P<0.05).
The single patient in group 3 had an increased incremental response of plasma 11-deoxycortisol and therefore was considered to have decreased 11β-hydroxylase activity.
The 12 patients in group 4 had dynamic hormonal responses to ACTH stimulation that were within normal limits and therefore were considered to have normal steroidogenesis. When their responses were compared with those of the normal women by means of t-tests, however, they had higher mean plasma levels of progesterone at 0 and 60 minutes (2.8±0.5 vs. 1.8±0.5 nmol per liter), 17-hydroxyprogesterone at 0 and 60 minutes (6.1±1.6 vs. 4.0±1.6 nmol per liter, P<0.05), DHEA at 0 and 30 minutes (Table 1) and 60 minutes (data not shown), androstenedione at 0 and 30 minutes (Table 1) and at 60 minutes (data not shown), and DHEA sulfate at 0 and 30 minutes (Table 1).
A comparison of the hormone ratios (Fig. 2) in the normal women and the patients in group 4 showed that the ratios of 17-hydroxypregnenolone to 17-hydroxyprogesterone and of DHEA to androstenedione at 0 and 30 minutes were similar in both groups. The 17-hydroxypregnenolone:DHEA ratio at 0 minutes was similar in both groups; the ratio at 30 minutes was slightly but not significantly lower in group 4. The ratio of 17-hydroxyprogesterone to androstenedione was similar in both groups at 0 minutes but significantly lower in group 4 at 30 minutes (P<0.05).
An analysis of all five groups showed that basal plasma levels of progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, DHEA, and 11-deoxycortisol were similar. Within each group, there was no difference between the hormone levels at 30 minutes and those at 60 minutes. Among all groups, the ratios of basal hormone levels were similar (Fig. 2).
The mean plasma DHEA sulfate levels were not increased significantly in any groups 30 or 60 minutes after ACTH administration. The mean basal level of DHEA sulfate was highest in group 4 and lowest in the normal women. However, because of the wide individual variation in basal plasma DHEA sulfate levels (Fig. 3Figure 3
Distribution Frequency of Basal Plasma DHEA Sulfate Levels among the Study Groups.), there were no significant differences between groups. Thirteen of the 19 patients considered to have defects in steroidogenesis had basal plasma DHEA sulfate levels within the normal range (9 patients in group 1, 3 patients in group 2, and the 1 patient in group 3). Conversely, six patients in group 4 and one normal woman had elevated basal plasma DHEA sulfate levels.Among the 53 subjects studied, there was no significant correlation between the basal plasma DHEA sulfate level and the incremental increase in the level of progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, DHEA, androstenedione, or 11-deoxycortisol, or between the DHEA sulfate level at 0 minutes and the sum of the incremental increases in plasma progesterone and 17-hydroxyprogesterone at 30 minutes. Similarly, there was no significant correlation between the plasma level of 17-hydroxyprogesterone, 17-hydroxypregnenolone, and 11-deoxycortisol at 0 minutes and the incremental increases in these hormones at 30 minutes.
Discussion
We measured plasma DHEA sulfate levels and performed ACTH stimulation tests in 31 patients referred for the evaluation of hirsutism, and divided them into four groups on the basis of increases in levels of precursor hormones in response to ACTH.27 Thirteen patients had increased incremental responses of plasma 17-hydroxypregnenolone and plasma DHEA as well as an elevated ratio of 17-hydroxypregnenolone to 17-hydroxyprogesterone at 30 minutes — findings typical of decreased 3β-hydroxy-
5-steroid dehydrogenase activity.12 Five patients were considered to have decreased activity of 21-hydroxylase on the basis of measurement of the incremental increase in plasma 17-hydroxyprogesterone, which is considered the most discriminating test for the diagnosis of 21-hydroxylase deficiency.21 The increase in the value for the combined levels of 17-hydroxyprogesterone and progesterone further supports the diagnosis of decreased activity of 21-hydroxylase.26 One patient had an increased incremental response of 11-deoxycortisol and thus was considered to have decreased 11β-hydroxylase activity. Her androgen levels were lower than those in the other patients with hirsutism, perhaps reflecting individual variation in sensitivity to androgens.28 Twelve patients had no evidence of defects in steroidogenesis, although they had hirsutism and elevated mean plasma levels of androstenedione, DHEA, and DHEA sulfate. All hormone ratios except the ratio of 17-hydroxyprogesterone to androstenedione after ACTH stimulation were similar in these patients and the normal women. These findings are consistent with an abnormality in C-17,20-lyase activity, as has previously been suggested.29 30 31
Ten of the 13 patients in group 1 had normal basal plasma 17-hydroxypregnenolone levels; the 3 with elevated levels had normal basal plasma DHEA sulfate levels. Hence, since only three patients had elevated basal plasma DHEA sulfate levels, seven in group 1 would not have been further evaluated if only basal blood samples had been obtained. Four patients (two in group 2 and two in group 4) as well as three normal women had elevated basal plasma 17-hydroxyprogesterone levels. Thus, three of five patients considered to have 21-hydroxylase deficiency would not have been identified if only basal plasma 17-hydroxyprogesterone levels had been measured.
Eleven of the 31 patients with hirsutism had significantly elevated plasma levels of DHEA sulfate; only 5 of these patients had responses to ACTH that were suggestive of compromised steroidogenesis (3 patients in group 1 and 2 in group 2). The other six patients were classified as members of group 4, in which the mean basal plasma DHEA sulfate level was highest. One normal woman also had a high level (10,297 nmol per liter). Thirteen patients with responses to ACTH stimulation that were suggestive of defects of steroidogenesis had basal plasma DHEA sulfate levels within the normal range. As in a previous study,32 plasma DHEA sulfate did not increase in response to ACTH. Thus, nine patients in group 1, three patients in group 2, and the patient in group 3 would not have been evaluated further if the measurement of basal plasma DHEA sulfate levels had been deemed an adequate screening test. These findings indicate that the measurement of plasma DHEA sulfate is of limited value in the evaluation of women with hirsutism. Extremely elevated levels are suggestive of an autonomously functioning adrenal tumor, and moderately elevated levels confirm the presence of increased adrenal androgen secretion without indicating the pathophysiologic cause. However, some women with excessive secretion of adrenal androgen due to incomplete defects in steroidogenesis would not have been identified if measurement of plasma DHEA sulfate levels had been relied on.
The usefulness of the ACTH stimulation test in the evaluation of hirsutism in women has been questioned. Chetkowski13 and Cobin14 and their colleagues reported that ACTH stimulation tests were not cost effective in such evaluations. Other groups have suggested that only women with elevated basal plasma levels of 17-hydroxyprogesterone or testosterone should undergo ACTH stimulation testing.15 16 17 18 However, measurement of plasma 17-hydroxypregnenolone or 11-deoxycortisol to exclude other forms of congenital adrenal hyperplasia was not performed in any of these studies. Among our 31 patients, more patients had findings suggestive of decreased 3β-hydroxy-
5-steroid dehydrogenase activity than of decreased 21-hydroxylase activity. Our patients may not be representative of the general population in that they were referred to us for the specific clinical problem of hirsutism. Therefore, we cannot comment on the prevalence of defects in steroidogenesis as a cause of hirsutism.Elevated basal levels of hormones were not predictive of the individual response to ACTH. Three patients in group 4 had elevated basal levels of DHEA sulfate and other hormones. The hormone levels at 30 and 60 minutes as well as the incremental increases were normal in these three patients. Since the heterogeneous causes of hirsutism have no distinguishing clinical features, our data illustrate and confirm the findings of previous reports about the need for ACTH stimulation tests to determine whether mild defects in steroidogenesis are present.19 , 20 , 33
In summary, basal measurements of plasma DHEA sulfate and 17-hydroxyprogesterone levels do not discriminate among the causes of increased androgen levels and may be misleading in the evaluation of women with hirsutism. Our results reaffirm the importance of ACTH stimulation tests in the diagnostic evaluation of women with this disorder and suggest that abnormalities in adrenal enzyme activity may be more common among such women than has previously been thought.
Supported in part by a General Clinical Research Center grant (RR-00084) from the National Institutes of Health and by the Renziehausen Trust Fund of Children's Hospital of Pittsburgh.
Source Information
From the Department of Pediatrics, University of Pittsburgh School of Medicine and the Children's Hospital of Pittsburgh, Pittsburgh (S.F.S., D.N.F., P.A.L.), and the Department of Endocrinology, Hospital Central, Barrio Union, San Martin, Caracas, Venezuela (R.L.). Address reprint requests to Dr. Lee at Children's Hospital of Pittsburgh, One Children's Place, 3705 Fifth Ave., Pittsburgh, PA 15213–3417.
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