Original Article
Detection of Functional Ovarian Hyperandrogenism in Women with Androgen Excess
N Engl J Med 1992; 327:157-162July 16, 1992
- Abstract
- Abstract
Background.
Distinguishing between ovarian and adrenal causes of androgen excess may be difficult. We have found that women with the polycystic ovary syndrome have supranormal plasma 17-hydroxyprogesterone responses to the gonadotropin-releasing hormone agonist nafarelin. We determined the usefulness of testing with nafarelin to distinguish ovarian causes of hyperandrogenism in women.
Methods.
We studied 40 consecutive women with hyperandrogenism who had oligomenorrhea, hirsutism, or acne. All 40 underwent testing with nafarelin, dexamethasone, and corticotropin with measurement of circulating concentrations of gonadotropins and steroid hormones, and 19 underwent ovarian ultrasonography.
Results.
The plasma 17-hydroxyprogesterone response to nafarelin was supranormal in 23 of the 40 women (58 percent), and the plasma androgen response to corticotropin was elevated in 23; 13 women had both abnormalities. Only one woman had conclusive evidence of a steroidogenic block; she had nonclassic adrenal 21-hydroxylase deficiency. Of the 23 women with abnormal responses to nafarelin, only 11 (48 percent) had elevated base-line serum luteinizing hormone concentrations. Of the 13 women with abnormal responses to nafarelin who underwent ultrasonography, 7 (54 percent) had polycystic ovaries. Peak plasma 17-hydroxyprogesterone concentrations after nafarelin administration correlated closely with plasma free testosterone concentrations after dexamethasone administration (r = 0.75, P<0.001).
Conclusions.
Approximately half of women with oligomenorrhea, hirsutism, or acne have an abnormal response to the gonadotropin-releasing hormone agonist nafarelin, suggesting an ovarian cause of their androgen excess. (N Engl J Med 1992;327:157–62.)
Article Activity
- Article
THE association of polycystic ovaries, amenorrhea, hirsutism, and obesity was reported by Stein and Leventhal in 1935.1 Abnormalities subsequently found to be characteristic of what is now called the polycystic ovary syndrome include hyperandrogenemia and increased concentrations of serum luteinizing hormone (LH) or an increase in the ratio of LH to follicle-stimulating hormone (FSH) in serum.2 3 4 5 However, the syndrome is clinically, histologically, and biochemically heterogeneous6; some women have the clinical syndrome but not polycystic ovaries or abnormalities of gonadotropin secretion.7 8 9 10 11 12 13
Several lines of evidence suggest that the polycystic ovary syndrome is a form of functional ovarian hyperandrogenism.14 Typically, androgen secretion is not normalized by the administration of dexamethasone to suppress adrenal function,2 but normalization can be accomplished by the long-term administration of an oral contraceptive agent or a gonadotropin-releasing hormone (GnRH) agonist.9 , 15 In addition, ovarian-vein—catheterization studies indicate that ovarian overproduction of androgens occurs in the majority of women with hirsutism, not just in those with the polycystic ovary syndrome.16 We recently reported that women with well-defined polycystic ovary syndrome have a supranormal plasma 17-hydroxyprogesterone response to stimulation with nafarelin, a GnRH agonist.17 The proximate cause of this response appears to be abnormal regulation of the androgen-forming enzyme cytochrome P450c17, with increased 17α-hydroxylase activity and high but relatively inefficient 17,20-lyase activity, rather than a steroidogenic block.17 18 19
We undertook the present study to determine the frequency of abnormal responses to nafarelin in unselected women with androgen excess and to determine whether the response to the test could be used as a marker for the type of ovarian hyperandrogenism characteristic of the polycystic ovary syndrome. Because adrenal abnormalities are frequent in these women and the relation between the polycystic ovary syndrome and nonclassic congenital adrenal hyperplasia is uncertain,15 , 18 19 20 21 22 we also evaluated adrenal steroidogenic function in these women.
Methods
Selection and Classification of Patients
We studied 40 consecutive women 17 to 39 years old with evidence of androgen excess (oligomenorrhea, hirsutism, or acne) and an initial plasma free testosterone concentration of at least 1 ng per deciliter (35 pmol per liter) who sought care at the medicine, obstetrics and gynecology, and pediatric endocrinology clinics of the University of Chicago Hospitals. None of the women had thyroid dysfunction, Cushing's syndrome, or hyperprolactinemia. Hirsutism was indicated by a score of 8 or more on the Ferriman—Gallwey scale (maximal possible score, 36).2 Healthy women 17 to 34 years old with a mean (±SD) body-mass index of 21.4±2.3 (the weight in kilograms divided by the square of the height in meters) were studied on days 3 to 10 of their menstrual cycles (13 women for the nafarelin test and 17 for the corticotropin test). The racial or ethnic composition of the two groups was representative of that of women attending these clinics: 67 percent were white, 23 percent were black, 7 percent were Hispanic, and 3 percent were Asian. The study protocol was approved by the institutional review board of the University of Chicago, and informed consent was obtained from each woman.
The women with hyperandrogenism were assigned diagnoses as follows: functional ovarian hyperandrogenism, defined by an abnormal response to nafarelin or dexamethasone suppression; polycystic ovary syndrome, defined as hyperandrogenism with an elevated base-line serum LH concentration with or without polycystic ovaries on ultrasonography; and adrenal hyperandrogenism, defined as hyperresponsiveness of plasma 17-ketosteroid concentrations (dehydroepiandrosterone or androstenedione) to corticotropin. The diagnoses were not mutually exclusive.
Study Protocol
Oral contraceptive agents were discontinued at least two months before the study began. Plasma levels of total and free testosterone, sex hormone—binding globulin, and dehydroepiandrosterone sulfate and serum levels of LH and FSH were measured at the time of initial evaluation. The women underwent nafarelin, corticotropin, and dexamethasone tests at the University of Chicago Clinical Research Center. The nafarelin and corticotropin stimulation tests were performed in the early follicular phase of the menstrual cycle or after at least two months of amenorrhea.
Ultrasonography
Transvaginal ultrasonography was performed with a 5-MHz 90-degree phased-array sector vaginal probe (GE RT 3000, General Electric, Milwaukee) in an unselected subgroup of 19 of the 40 women with hyperandrogenism, who did not differ significantly from the remainder. Ovaries were defined as polycystic if each contained four or more immature follicles measuring 10 mm or less that were aligned near the surface, with a prominent capsular echo in the absence of a corpus luteum.23 Although most patients had enlarged ovaries, enlargement was not a diagnostic criterion. All studies were analyzed by the same sonographer.
Nafarelin Test
Dexamethasone was given in a dose of 0.5 mg four times daily for four days. Starting 8 hours after the last dose, blood samples were collected every 20 minutes for 1 hour for base-line measurement of serum gonadotropins and once for base-line measurement of plasma steroid hormones. Then, the GnRH agonist nafarelin ([6-D-(2-naphthyl) alanine] GnRH acetate; Syntex, Palo Alto, Calif.) was given as a single 100-μg subcutaneous injection at 8 a.m. Blood samples were collected at intervals of 30 minutes to 4 hours for 24 hours thereafter for gonadotropin measurements and at 16, 20, and 24 hours for steroid-hormone measurements.17 Dexamethasone was continued during the 24-hour sampling period after the administration of nafarelin. The response to nafarelin was considered supranormal (positive) if the peak plasma 17-hydroxyprogesterone concentration was greater than 259 ng per deciliter (7.8 nmol per liter). The base-line serum LH concentration (mean of four samples) was considered abnormal if greater than 15.7 IU per liter. These values represent 2 SD above the mean values in 13 normal women, in whom the peak plasma 17-hydroxyprogesterone concentration was 168±45 ng per deciliter (5.1±1.4 nmol per liter) after nafarelin administration and the base-line serum LH concentration was 10.3±2.7 IU per liter.
Corticotropin Stimulation Test
Corticotropin ( 10 μg per square meter of body-surface area) was administered at 8 a.m., 10 hours after the administration of dexamethasone (1.0 mg per square meter).24 Plasma cortisol and steroids were measured 0, 30, and 60 minutes after corticotropin administration. The response to the corticotropin test was considered abnormal if the increase (mean of the 30-minute and 60-minute values minus the base-line value) in the dehydroepiandrosterone or androstenedione concentration was more than 2 SD above the mean in 17 similarly tested normal women or if the plasma 17-hydroxyprogesterone concentration was more than 1000 ng per deciliter (30.3 nmol per liter). The latter is an established criterion for the diagnosis of nonclassic congenital adrenal hyperplasia caused by 21-hydroxylase deficiency.25
Dexamethasone Androgen-Suppression Test
Plasma concentrations of total and free testosterone, dehydroepiandrosterone sulfate, and cortisol were measured before and after the administration of dexamethasone (0.5 mg four times daily for four days); the second blood sample was obtained at 8 a.m., 8 to 10 hours after the last dose of dexamethasone. Dexamethasone suppression of androgen was considered to be abnormal if in the presence of normal adrenocortical suppression, the plasma free testosterone concentration remained elevated (≥0.8 ng per deciliter [28 pmol per liter]).2 The mean (±SD) plasma free testosterone concentration in the 13 normal women who had nafarelin tests was 0.3±0.2 ng per deciliter (12±7 pmol per liter) after dexamethasone administration.
Hormone Assays
Serum LH and FSH were measured with the use of antiserums and standards provided by the National Hormone and Pituitary Program, in radioimmunoassays with enhanced specificity for bioactive species.17 The results were expressed in terms of highly purified standards: 1.0 ng of LH I-2 in our assay is equivalent to 7.8 IU and 1.0 ng of FSH I-3 is equivalent to 3.9 IU as determined in a multilaboratory quality-control program. Plasma concentrations of testosterone, cortisol, dehydroepiandrosterone, and sex hormone—binding globulin were measured with commercial kits (Diagnostic Products, Los Angeles, and Diagnostic Sciences, Webster, Tex.). The free fraction of plasma testosterone was measured by competitive protein binding.18 Plasma levels of 17-hydroxyprogesterone, androstenedione, 17-hydroxypregnenolone, dehydroepiandrosterone, and 11-deoxycortisol were determined by radioimmunoassay after these steroids had been chromatographically purified as previously reported.17 The precision of these assays averaged 7 percent (intraassay coefficient of variation) and 12 percent (interassay coefficient).
Statistical Analysis
The results were compared by the chi-square test or paired or unpaired t-test, with the Bonferroni correction for multiple comparisons when appropriate. Analysis of variance was used to identify group differences in the plasma concentrations of free testosterone and base-line concentrations of LH and the area under the curve for the LH response, which were then evaluated with Tukey's studentized range test.
Results
The clinical and hormonal characteristics of the 40 women with hyperandrogenemia are shown in Table 1Table 1
Clinical Features and Hormone Levels of Women with Androgen Excess at the Time of Initial Evaluation, According to Their Response to the Nafarelin Test.* according to their response to nafarelin. Thirty-five women (88 percent) had hirsutism. Twenty-three women (58 percent; 95 percent confidence interval, 42 percent to 73 percent) had supranormal plasma 17-hydroxyprogesterone responses to nafarelin. The values were supranormal at all three evaluations (at 16, 20, and 24 hours) in 20 of these 23 women. Except for a greater incidence of oligomenorrhea (87 percent vs. 59 percent; P<0.05), there were no historical, physical, or hormonal findings that distinguished the women with supranormal responses to nafarelin from those with normal responses.Transvaginal ovarian ultrasonography was performed in 19 women, of whom 10 (53 percent) had polycystic ovaries (Table 1). Seven of these 10 women had a supranormal response to nafarelin. Of the nine women without polycystic ovaries, six had a supranormal response. There was no significant difference in mean (±SD) age between the women with polycystic ovaries and those with normal ovaries (24±5 vs. 23±5 years). In comparison with the nafarelin test, ultrasonography had a sensitivity and specificity for ovarian hyperandrogenism of 54 percent and 50 percent, respectively.
Thirteen of the 23 women with a supranormal response to nafarelin (57 percent) had an abnormal response to corticotropin, as did 10 of the 17 women with a normal response to nafarelin (59 percent) (Table 2Table 2
Responses to Nafarelin in Relation to Responses to Corticotropin in Women with Androgen Excess.). The responses to both tests were abnormal in 13 women, the response to nafarelin alone was abnormal in 10 women, and the response to corticotropin alone was abnormal in 10 women. In 7 women, the responses to both tests were normal. The mean base-line concentrations of plasma free testosterone in these four groups were similar. Conclusive evidence of a steroidogenic block was evident in only one woman; she had a peak plasma 17-hydroxyprogesterone concentration of 4758 ng per deciliter (144 nmol per liter) 60 minutes after the administration of corticotropin. Her response to nafarelin was normal. Otherwise, the women who had normal responses to nafarelin had a pattern of adrenal-steroid responses similar to that in the women who had abnormal responses to nafarelin.The relation between the peak plasma 17-hydroxyprogesterone concentration after nafarelin administration and the base-line serum LH concentration was significant only when the values for the women with hyperandrogenism and the normal women were analyzed together (Fig. 1Figure 1
Base-Line Serum LH Concentration in Relation to the Peak Plasma 17-Hydroxyprogesterone Concentration in Response to Nafarelin.). The correlation between the mean of the plasma 17-hydroxyprogesterone values 16, 20, and 24 hours after nafarelin administration and the base-line LH level was also significant. There was no significant correlation between the base-line LH:FSH ratio and the plasma 17-hydroxyprogesterone response to nafarelin (r = 0.24). The relation between the value for 24-hour LH secretion in response to nafarelin (represented by the area under the curve for LH) and the peak plasma 17-hydroxyprogesterone concentration was significant (r = 0.27, P<0.05) only when the mean base-line serum LH value was not subtracted.The relation between abnormalities of the base-line serum LH concentration and the peak plasma 17-hydroxyprogesterone concentration after nafarelin administration is summarized in Table 3Table 3
Responses to Nafarelin in Women with Androgen Excess, According to Base-Line Serum LH Concentration.. Among the 23 women with abnormal responses to the nafarelin test, the base-line serum LH concentration was elevated in 11 (48 percent; group A, Table 3) and normal in 12 (52 percent; group B). Among the 17 women with normal responses to nafarelin, the base-line LH concentration was elevated in 5 (29 percent; group C) and normal in 12 (71 percent; group D). The area under the LH-response curve did not differ significantly between any of these four groups and the normal women (P>0.05 by analysis of variance).The correlation between the plasma free testosterone concentration measured after dexamethasone administration and the plasma 17-hydroxyprogesterone response to nafarelin was significant in the 40 women with hyperandrogenism (P<0.001) (Fig. 2Figure 2
Plasma Free Testosterone Concentration (after the Administration of Dexamethasone) in Relation to the Peak Plasma 17-Hydroxyprogesterone Concentration in Response to Nafarelin.). The close correlation between the results of these two tests supports the concept that the findings on both tests reflect related aspects of ovarian androgen production. Of the 27 women with an abnormal plasma free testosterone concentration after dexamethasone administration, 22 (81 percent) had supranormal responses to nafarelin (Table 4Table 4
Responses to Nafarelin in Relation to Responses to Dexamethasone in Women with Androgen Excess.). One woman with an abnormal response to nafarelin had a normal response to dexamethasone. The responses to either the dexamethasone or nafarelin test were abnormal in 28 of the 40 women (70 percent). The sensitivity and specificity of the dexamethasone suppression test with respect to the results of the nafarelin test were 96 percent and 71 percent, respectively; the dexamethasone suppression test predicted the result of the nafarelin test in 81 percent of women when it was positive and 92 percent when it was negative.Discussion
We found that 58 percent of women with androgen excess had abnormal responses to nafarelin and 58 percent had abnormal responses to corticotropin. According to these tests, hyperandrogenism was caused by ovarian dysfunction alone in 25 percent of the women, by ovarian and adrenal dysfunction combined in another 33 percent, and by adrenal dysfunction alone in 25 percent, including the one woman who had nonclassic (late onset) adrenal 21-hydroxylase deficiency. The remainder (17 percent) had normal responses to both tests.
The plasma free testosterone concentrations were similar in the women with an abnormal response to nafarelin and in those with an abnormal response to corticotropin alone, suggesting that the abnormal response to nafarelin was not due to increased adrenal androgen secretion. This concept is supported by the finding of a normal response to nafarelin in the one woman with late-onset adrenal 21-hydroxylase deficiency in this study (and in another woman studied later). Likewise, an abnormal response to nafarelin was not a function of adiposity; the mean body-mass index was similar among the women with hyperandrogenism whether their responses to nafarelin were normal or abnormal.
Our results are consistent with earlier observations, based on the results of ovarian-vein catheterization,16 dexamethasone suppression testing,2 , 12 , 13 and long-term administration of GnRH agonists,9 , 15 that the majority of women with androgen excess have ovarian hyperandrogenism. The results go further, however, indicating that over half of women with hyperandrogenism have the type of biochemical dysfunction of the ovaries that characterizes the polycystic ovary syndrome.17 Furthermore, they indicate that such women are more alike in this respect than they are alike in ovarian structure. Of the women who underwent ovarian ultrasonography, 54 percent of those who had abnormal responses to nafarelin had polycystic ovaries. The ultrasonographic criteria used to identify polycystic ovaries are variable; investigators using criteria26 more conservative than ours found that 23 percent of normal women in one study had polycystic ovaries.27 Ultrasonographic findings seem therefore not only relatively insensitive but also nonspecific for the diagnosis of ovarian hyperandrogenism. These data support the argument of many investigators that polycystic ovaries need not be present for the polycystic ovary syndrome to be diagnosed.4 , 5 , 8 9 10 11 12 13 14
Likewise, our results support the contention that an elevation of the serum LH concentration or LH:FSH ratio is not required for diagnosis of an ovarian disorder in women with androgen excess.7 , 9 , 11 12 13 14 Approximately half the women with abnormal responses to the nafarelin test had elevated base-line serum LH concentrations (group A, Table 3). Such women may have a primary hypothalamic—pituitary abnormality.3 , 4 , 14 However, other women had ovarian hyperandrogenism that was independent of LH excess (group B).
These results are compatible with a model in which functional ovarian hyperandrogenism can result either from LH excess or from abnormal modulation of ovarian androgen responsiveness to LH.18 , 19 Androgen synthesis by theca cells is normally coordinated with estrogen synthesis by granulosa cells to prevent over secretion of either hormone (Fig. 3Figure 3
Major Factors Regulating Ovarian Androgen and Estrogen Biosynthesis.). The synthesis of 17-hydroxyprogesterone and androstenedione in response to LH appears to be modulated at the level of 17α-hydroxylase and 17,20-lyase activity, both of which are activities of cytochrome P450c17 in theca cells. The stimulation of this enzyme by LH is augmented by specific intraovarian and hormonal factors, such as those shown in Figure 3.28 29 30 31 The process of up-regulation of P450c17 activities is counterbalanced by a process of desensitization to LH, which sets in as LH stimulation increases and which involves down-regulation of P450c17 activities by other intraovarian factors18 , 19 , 32 33 34 (some of which are illustrated in Figure 3). An imbalance between these up-regulating and down-regulating factors may cause ovarian hyperandrogenism despite normal LH secretion. Alternatively, an LH molecule with enhanced bioactivity may explain some of these findings,35 although our assay for LH minimizes this possibility.A small group of five women had elevated base-line serum LH concentrations but normal responses to nafarelin (group C, Table 3). Although their condition met standard diagnostic criteria for the polycystic ovary syndrome, three of them also did not have ovarian hyperandrogenism according to the criteria of the dexamethasone test. Thus, through an unknown mechanism, their ovarian function seems to have compensated for the elevated LH secretion to some degree. Twelve women with hyperandrogenism (group D) had both normal LH secretion and a normal response to nafarelin. Seven of these women had adrenal hyperandrogenism; one of them and two others had evidence of ovarian hyperandrogenism as indicated by an abnormal response to the dexamethasone suppression test. Three women had normal responses to all tests.
Considerable evidence suggests that the dexamethasone suppression test can be used to diagnose ovarian hyperandrogenism,2 , 12 13 14 but it has not been widely used for this purpose. This is partly because its results are indirect and are best based on the measurement of plasma free testosterone concentrations, a procedure not widely available or well standardized. Concern has also been raised that the administration of dexamethasone may suppress ovarian function.16 Nevertheless, the high degree of correlation and high concordance (approximately 85 percent) between the nafarelin and the dexamethasone suppression tests indicate that their results reflect related aspects of ovarian androgenic function. The nafarelin test has the advantage of being a short, direct, and specific test of pituitary—ovarian function that reveals the exact nature of ovarian steroidogenesis.17 18 19 In addition, its end point is the measurement of plasma 17-hydroxyprogesterone, for which there is a well-standardized assay.
The failure of this battery of tests to delineate a source of excess androgen secretion in all women may be due to the insensitivity of the tests. Alternatively, it is possible that in some women, androgen excess results from increased peripheral conversion of secreted precursors.
We conclude that the majority of women with androgen excess have functional ovarian hyperandrogenism. The results of nafarelin testing indicate that much of what is considered idiopathic hirsutism or amenorrhea in women with hyperandrogenism in whom the results of serum LH measurement or ovarian ultrasonography are normal is a form of ovarian hyperandrogenism that is closely related functionally to the polycystic ovary syndrome.
Supported in part by grants (HD-06308, RR-00055, DK-07011–17, and RR-00055–28SL) from the U.S. Public Health Service, and in part by Syntex Research.
Presented in part at the 73rd annual meeting of the Endocrine Society, Washington, D.C., June 21, 1991.
Source Information
From the Departments of Medicine (D.A.E., R.L.R., D.F.B.), Pediatrics (R.L.R.), and Obstetrics/Gynecology (R.B.B., Z.S.), University of Chicago, Pritzker School of Medicine, Chicago. Address reprint requests to Dr. Ehrmann at the Department of Medicine, Section of Endocrinology, University of Chicago, Pritzker School of Medicine, 5841 S. Maryland Ave., MC 1027, Chicago, IL 60637.
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