The prognostic value of acute adrenal suppression and stimulation tests in hyperandrogenic women

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1 FERTUJTY AND STERILITY Copyright c 1982 The American Fertility Society Vol. 37, No.2, February 198~ Printed in U.SA. The prognostic value of acute adrenal suppression and stimulation tests in hyperandrogenic women Emil Steinberger, M.D.* Luis J. Rodriguez-Rigau, M.D. Keith D. Smith, M.D. Department of Reproductive Medicine and Biology, University of Texas Medical School at Houston, Houston, Texas A group of 106 consecutively seen hyperandrogenic women were subjected to an acute adrenal suppression and stimulation test. The results of these tests were analyzed with respect to androgen suppression achieved after chronic glucocorticoid therapy in the same patients. The data suggested that an acute dexamethasone test may identify the group of hyperandrogenic women who respond poorly to chronic glucocorticoid therapy. This group of patients were found to have elevated luteinizing hormone (LH) levels and LHlfollicle-stimulating hormone (FSH) ratios, suggesting the possibility of an LH-related hyperandrogenism. In patients whose elevated testosterone levels were suppressed by dexamethasone, adrenocorticotropic hormone (ACTH) induced a prompt return of the testosterone levels to baseline, suggesting an ACTH -dependent hyperandrogenism. In these patients, the degree of testosterone suppression after dexamethasone was not quantitatively related to the degree of testosterone suppression after chronic glucocorticoid therapy. In all cases chronic therapy resulted in a greater suppression of androgen levels than the acute. dexamethasone test. In conclusion, an acute dexamethasone suppression test appears to be of clinical value in the management of the hyperandrogenic female, particularly in identification of women who will not respond to chronic glucocorticoid suppression therapy. Fertil Steril 37:187, 1982 Literature has accumulated suggesting the presence of elevated circulating androgen levels in a large segment of patients with hirsutism, acne, ovarian dysfunction, and infertility.1-9 A suppressive effect of glucocorticoid administration on the elevated androgen levels in some of these patients has also been reported. 1, 5; 6, 8, 10, 11 The criteria for selection of the appropriate patient population to receive glucocorticoid therapy have not been defined. A number ofinvestiga- Received May 7,1981; revised and accepted September 21, *Reprint requests: Emil Steinberger, M.D., Department of Reproductive Medicine and Biology, University of Texas Medical School at Houston, P.O. Box 20708, Houston, Texas tors suggested one form or another of adrenai stimulation or suppression tests to identify this patient population. 1, In some studies only glucocorticoid suppression was employed, while in others both glucocorticoid suppression and adrenocorticotropic hormone (ACTH) stimulation were utilized. In most instances the studies involved only a small number of subjects. Although most noted that plasma androgens frequently suppressed after glucocorticoid administration, the incidence and degree of suppression were variable. Generally,each author reported a variant of adrenal suppression and/or stimulation test and compared their results with similar published tests that employed different protocols. Rarely were the results of these tests compared with the results of chronic glucocorticoid therapy in the same patients. Consequently, there is a Vol. 37, No.2, February 1982 Steinberger et ai. Adrenal tests in hyperandrogenic women 187

paucity of information regarding the prognostic value of these, tests. In the present study a large number of hyper androgenic women was subjected to an acute adrenal suppression and stimulation test.

2 paucity of information regarding the prognostic value of these, tests. In the present study a large number of hyper androgenic women was subjected to an acute adrenal suppression and stimulation test. The results were correlated with the response of the same patients to chronic glucocorticoid therapy. MATERIALS AND METHODS The study population was composed of 106 consecutively seen women with clinical signs of hyperandrogenism (hirsutism, acne, and/or clitoral hypertrophy). Patients receiving hormonal therapy, including oral contraceptives, as well as menopausal or castrated women were not included. Baseline circulating levels of testosterone, cortisol, luteinizing hormone (LH), and folliclestimulating hormone (FSH) were measured between 8:00 A.M. and 10:00 A.M. on days 7 to 10 of the menstrual cycle. Dexamethasone, 1 mg, was administered at midnight, and plasma testosterone and cortisol levels were measured at 9:00 A.M. the following morning. Immediately after this blood sample was obtained, an intravenous bolus of 250 j.lg of synthetic ACTH (Cortrosyn, Organon, aminoacids 1-24 of ACTH) was given, and subsequent blood samples were taken at 30, 60, and 90 minutes. Testosterone and cortisol were measured in each sample. Each patient was then placed on prednisone therapy, 7.5 mg daily (2.5 mg in the morning and 5 mg in the evening). Blood samples for measurement of plasma testosterone were obtained between 8:00 A.M. and 10:00 A.M. on days 7 to 10 of the menstrual cycle after 2 to 3 months of prednisone treatment. An additional randomly selected group of 26 women had the ACTH stimulation test immediately after the baseline sample and the dexamethasone suppression test following the ACTH stimulation. Testosterone, FSH, and LH were measured by radioimmunoassay as previously described Cortisol was determined by radioimmunoassay with the use of similar methodology. Inter- and intra-assay coefficients of variation of these assays do not exceed 10% and 8%, respectively. RESULTS Mean baseline levels of testosterone, cortisol, LH, and FSH, as well as LH/FSH ratios, are shown in Table 1. Plasma testosterone levels were significantly elevated (P < 0.01; normal Table 1. Baseline Circulating Levels of Testosterone, Cortisol, LH, FSH, and LH/FSH Ratios in 106 Women with Clinical Signs of Hyperandrogenism a Hormone Testosterone Cortisol Luteinizing hormone Follicle-stimulating hormone LHiFSH Mean level 63.1 ± 2.3 ng% 11.5 ± 0.5 fj.g% 16.0 ± 1.2 mlu/ml 8.0 ± 1.6 mlu/ml 2.5 ± 0.2 a All samples were obtained in the morning between days 7 and 10 of the menstrual cycle. Values are mean ± standard error. level in the early follicular phase 29.3 ± 1.5 ng%7). Cortisol levels were within the normal range in all patients (4-20 j.lg% in the morning). The mean LHIFSH ratio was higher than that reported for normal women on days 7 to 10 ofthe menstrual cycle. 17 Figure 1 illustrates the changes in plasma cortisol and testosterone levels following acute dexamethasone suppression and ACTH stimulation. The cortisol response was within the normal range. The mean suppression of plasma testosterone after dexamethasone was 30% (P < 0.001). ACTH stimulation resulted in a return of the mean plasma testosterone level to baseline within 60 minutes and a slight, statistically not significant, elevation over baseline by 90 minutes. The mean plasma testosterone level after chronic prednisone therapy was 35.9 ± 2.4 ng% (mean ± standard error). This value is significantly lower than the baseline (63.1 ± 2.3, P < 0.001) and the dexamethasone-suppressed value (45.3 ± 2.2, P < 0.01). Figure 2 illustrates the changes in mean plasma cortisol and testosterone levels in the 26 ~....3 c; 25 :E 1 o u.. E '" ~ Cortisol T,sto,te,one 3~' 50' go' BL OX ACTH BL OX PR Figure 1 Plasma cortisol and testosterone levels after acute dexamethasone suppression followed by ACTH stimulation in 106 women with clinical signs of hyperandrogenism (for details see text). BL, baseline; DX, dexamethasone; PR, prednisone. 188 SteiniJerger et ai. Adrenal tests in hyperandrogenic women Fertility and Sterility

3 25 - '#. => 20.5 Ci... i 15 c.:i E :: 10 A: 5 caruso! T, :s< 3~' 60' 90' Bl ACTH OX Testosterone ll~.l 1, 3~' 60' go' Bl ACTH OX. 100 Figure 2 Plasma cortisol and testosterone levels after acute ACTH stimulation followed by dexamethasone suppression in 26 women with clinical signs of hyperandrogenism. BL, baseline; DX, dexamethasone. women evaluated by the reversed testing procedure (ACTH stimulation followed by dexamethasone suppression). The quantitative response of plasma cortisol to ACTH and dexamethasone was similar to that described in Figure 1. Mean plasma testosterone showed a slight, statistically not significant, rise after ACTH. Dexamethasone administration resulted in an average suppression of plasma testosterone of 25.3% (P < 0.05). The study population of 106 women was grouped by their baseline testosterone levels into 6 groups (Fig. 3). Plasma testosterone levels in group 1 «40 ng%) were not significantly different from normal (29.3 ± 1.5 ng%); all other groups had significant elevated testosterone levels. The responses of plasma testosterone to acute dexamethasone suppression and chronic prednisone therapy were compared. Dexamethasone suppression resulted in a similar percentage of suppression in each group (27.2% to 33.1%). Thus, the degree of suppression was not related to the baseline testosterone level. Chronic prednis~ne therapy resulted in suppression of mean plasma testosterone levels below 34 ng% in all groups except in the group with the highest mean baseline testosterone level (above 80 ng%). Except for this latter group, mean plasma testosterone levels after prednisone treatment were similar in all groups. To evaluate the possible relationships between the results of the acute dexamethasone suppression test, the LHIFSH ratio, the cortisol levels, and the response to chronic prednisone therapy, 20 the study population was grouped on the basis of ' the percentage of suppression of plasma testosterone after dexamethasone administration (Table 2). No statistically significant differences could be detected between the baseline mean plasma testosterone and cortisol levels in these groups. Chronic prednisone therapy resulted in approximately 50% suppression of plasma testosterone in all groups except in the group that totally failed to be suppressed after dexamethasone. In the latter group, prednisone therapy resulted in an average testosterone suppression of only 18.2%. This group also showed a significantly higher LH/FSH ratio than any of the other groups. Consequently, no correlation between acute dexamethasone suppression, chronic prednisone therapy, and LHIFSH ratio was demonstrated except for the findings in the group of patients that totally failed to respond to the acute dexamethasone suppression test. Data presented in Table 3 illustrate the relationship between baseline hormone levels and plasma testosterone levels after prednisone treatment. There was no relationship to cortisol or FSH levels. Baseline testosterone levels correlated significantly with testosterone levels after prednisone treatment (linear regression analysis: r = 0.5, P < 0.001). One-way analysis of variance showed significant differences in baseline testosterone levels between the groups. The comparison of LH/FSH ratios between the various groups showed significantly higher ratios in patients with plasma testosterone levels above 40 ng/dl during prednisone treatment. This increased ratio was due to LH elevation rather than changes in FSH levels. In Table 4 the study population was grouped on the basis of maximum stimulation of plasma cor- 100 nz17 n.13 BL OX PH IL DX PI ~70 111% > 10 II" B.slllnl Plasma Tlstosteronl Llvel Figure 3 Effect of acute dexamethasone suppression and chronic prednisone therapy or plasma testosterone levels in the study population (n = 106) grouped by baseline testosterone levels. BL, baseline; DX, dexamethasone; PR, prednisone. Vol. 37, No.2, February 1982 Steinberger et ai. Adrenal tests in hyperandrogenic women 189

4 Table 2. Circulating Hormone Levels in the Study Population Grouped on the Basis of Percentage of Suppression of Plasma Testosterone After Acute Dexamethasone Suppression % Suppression of testosterone after dexamethasone > 60.0 Baseline testos ± ± ± ± ± ± ± ± 8.4 terone (ng/dl) Baseline cortisol 10.3 ± ± ± ± ± ± ± ± 1.3 (fj.g/dl) LHiFSH ratio 4.1 ± 0.9" 2.9 ± ± ± ± ± ± ± 0.4 % Suppression of 18.2 ± 5.4 b 50.2 ± ± ± ± ± ± ± 10.7 testosterone by prednisone % Women ap < bp < 0.01 (one-way analysis of variance). tisollevels after ACTH stimulation. There was no relationship to baseline testosterone, testosterone levels after acute dexamethasone suppression or chronic prednisone treatment, or to LHIFSH ratio. Baseline cortisol levels were directly related to the maximum stimulation of cortisol after ACTH. DISCUSSION Abnormally high circulating androgen levels have been reported in patients with clinical signs of hyperandrogenism, disturbed ovarian function, and infertility.i-9 Beneficial effects of glucocorticoid therapy in women with hyperandrogenism and ovarian dysfunction were first reported by Jones et al. in Subsequently, glucocorticoid therapy was shown to be effective in patients with hirsutism, menstrual" irregularities, and infertility.5, 6, 8,10,11,19-21 Unfortunately, not all patients respond to this form of therapy. 5, 8, 21, 22 It was suggested that the success of glucocorticoid therapy was related to the origin of the elevated androgens, i.e., a good response in patients with predominantly adrenal androgens and poor response in those with predominantly ovarian androgens. Various protocols for adre:p.al suppres- sion and stimulation testing were proposed to differentiate between ovarian and adrenal androgen production. 1, 11-14, 23 The validity of these tests to identify the origin of elevated androgen levels has been questioned, since it has been suggested that glucocorticoids may also suppress ovarian androgens.24,25 The question of the origin of the elevated androgens may be academic from the clinician's viewpoint. It has been demonstrated that the beneficial effect of chronic glucocorticoid therapy on ovarian dysfunction and infertility of patients with hyperandrogenism is directly related to the suppression of the elevated androgen levels.5, 8 Thus, regardless of the origin of the excessive androgens, glucocorticoid therapy is beneficial if the androgen levels are suppressed. From a pragmatic viewpoint, a test that could identify those patients who may respond to glucocorticoid therapy would be of prognostic value.- The results of the present study suggest that an acute dexamethasone suppression test may accomplish this purpose. In this study, a large group of unselected hyperandrogenic women were subjected to an acute dexamethasone suppression test. All patients whose elevated testosterone levels were suppres- Table 3. Circulating Hormone Levels in the Study PopuLation Grouped on the Basis of Plasma Testosterone Level After Chronic Prednisone Treatment Plasma testosterone (ng%) during prednisone treatment < > 50.0 Baseline testosterone (ng%) 54.2 ± ± ± ± 9.9a 83.0 ± 5.1b Baseline cortisol (fj.g%) 13.3 ± ± ± ± ± 0.9 FSH (mlu/ml) 6.8 ± ± ± ± ± 0.5 LH (miulml) 10.2 ± ± ± ± 2.2a 22.1 ± 3.3b LHIFSH ratio 1.5 ± ± ± ± 0.6a 3.7 ± 0.5b % Women ap < bp < 0.01 (one-way analysis of variance). 190 Steinberger et al. Adrenal tests in hyperandrogenic women Fertility and Sterility

Table 4. Circulating Hormone Levels in the Study Population Grouped on the Basis of Maximum Stimulation of Plasma Cortisol After ACTH Administration Maximum stimulation <.

5 Table 4. Circulating Hormone Levels in the Study Population Grouped on the Basis of Maximum Stimulation of Plasma Cortisol After ACTH Administration Maximum stimulation <... 1%) of plasma cortisol after ACTH ~lo.t >25.0 Baseline cortisol (... g%) 6.5 ± 1.3" 10.7 ± 0.7 b 10.7 ± 0.8 c 14.9 ± LId 14.1 ± 1.5d Baseline testosterone (ng%) 54.4 ± ± ± ± ± 4.8 Testosterone after dexa ± ± ± ± ± 4.8 methasone (ng%) Testosterone during pred ± ± ± ± ± 3.9 nisone (ng%) LH/FSH ratio 3.3 ± ± ± ± ± 0.6 % Women n9 "< c, dp < 0.01; " < b < dp < 0.05; c < dp < 0.01 (one-way analysis of variance). sible, regardless of degree, responded to chronic prednisone therapy with essentially a normalization of testosterone levels. On the other hand, those patients whose plasma testosterone levels remained unchanged after dexamethasone responded poorly to chronic prednisone therapy. Some patients with poor dexamethasone response «10% suppression of testosterone) nevertheless responded to chronic prednisone therapy. It is of interest to note that the nonresponders, as a group, also had significantly elevated LH levels and LHIFSH ratios, suggesting that in these patients the elevated testosterone levels may have been LH-related. The administration of ACTH failed to induce significant elevation of testosterone levels above baseline. This observation is in agreement with previous reports. 23 However, when ACTH was administered after dexamethasone, the suppressed testosterone levels were returned to baseline rapidly (within 60 minutes). This suggests that dexamethasone administration probably suppressed ACTH-dependent testosterone production. Despite this apparent ACTH-dependence of testosterone levels in this group of patients, an adrenal origin of testosterone cannot be established conclusively. It has been suggested that in some patients with ACTH-dependent hyperandrogenism, the etiology of the disorder may be a "partial" congenital or acquired adrenal hyperplasia.26,27 In the present study, there was no relation between cortisol levels or their response to ACTH and baseline testosterone levels or the response of testosterone to glucocorticoid administration. Extensive investigation of intermediary adrenal steroid metabolites would have been necessary to rule out a congenital or acquired adrenal hyperplasia in this group of patients. In conclusion, it appears. that an acute dexamethasone suppression test has a prognostic value in identifying those hyperandrogenic women who will respond poorly to chronic glucocorticoid therapy. This approach eliminates the necessity for a time-consuming therapeutic trial of glucocorticoid therapy and leads to a rapid institution of alternative diagnostic and therapeutic measures in this group of patients. REFERENCES 1. Bardin CW, Hembree WC, Lipsett MB: Suppression of testosterone and androstenedione production rates with dexamethasone in women with idiopathic hirsutism and polycystic ovaries. J Clin Endocrinol Metab 28:1300, Abraham GE, Chakmakjian ZH, Buster JE, Marshall JR: Ovarian and adrenal contributions to peripheral androgens in hirsute women. Obstet Gyneco146:169, Hosseinian AM, Kim MH, Rosenfield RL: Obesity and oligomenorrhea are associated with hyperandrogenism independent of hirsutism. J Clin Endocrinol Metab. 42:765, Paulson JD, Keller DW, Wiest WG, Warren JC: Free testosterone concentrations in serum: elevation is the hallmark of hirsutism. Am J Obstet Gynecol 128:851, Steinberger E, Smith KD, Tcholakian RK, Rodriguez-Rigau LJ: Testosterone levels in female partners of infertile couples: relationship between androgen levels in the woman, the male factor and the incidence of pregnancy. Am J Obstet Gyneco1133:133, Radwanska E, Sloan C: Serum testosterone levels in infertile women. Int J Fertil 24:176, Smith KD, Rodriguez-Rigau LJ, Tcholakian RK, Steinberger E: The relation between plasma testosterone levels and the lengths of phases of the menstrual cycle. Fertil Steril 32:403, Rodriguez-Rigau LJ, Smith KD, Tcholakian RK, Steinberger E: Effect of prednisone on plasma testosterone levels and on duration of phases of the menstrual cycle in hyperandrogenic women. Fertil Steril 32:408, Steinberger E, Rodriguez-Rigau LJ, Smith KD, Held B: the menstrual cycle and plasma testosterone levels in women with acne. J Am Acad Dermatol 4:54, Horton R, Neisler J: Plasma androgens in patients with the polycystic ovary syndrome. J Clin Endocrinol Metab 28:479,1968 Vol. 37, No.2, February 1982 Steinberger et al. Adrenal tests in hyperandrogenic women 191

6 11. Abraham GE, Maroulis GB, Buster JE, Chang RJ, Marshall JR: Effect of dexamethasone on serum cortisol and androgen levels in hirsute patients. Obstet Gynecol 47: 395, Ettinger B, Von Werder K, Thenaers GC, Forsham PH: Plasma testosterone stimulation-suppression dynamics in hirsute women. Am J Med 51:170, Givens JR: Hirsutism and hyperandrogenism. In Advances in Internal Medicine, Volume 21, Edited by GH Stollerman. Year Book Medical Publishers, 1976, p Gibson M, Lackritz R, Schiff I, Tulchinsky D: Abnormal adrenal responses to adrenocorticotropic hormone in hyperandrogenic women. Fertil Steril 33:43, Smith KD, Tcholakian RK, Chowdhury M, Steinberger E: Rapid oscillations in plasma levels of testosterone, LH and FSH in men. Fertil Steril 25:965, Rao PN, Moore PH, Peterson DM, Tcholakian RK: Synthesis of new steroid haptens for radioimmunoassay. Part V carboxymethyl ether derivative of testosterone: a highly specific antiserum for immunoassay of testosterone from both male and female plasma without chromatography. J Steroid Biochem 9:539, Lobo RA, Granger L, Goebelsmann V, Mishell DR: Elevations in unbound serum estradiol as a possible mechanism for inappropriate gonadotropin secretion in women with PCO. J Clin Endocrinol Metab 52:156, Jones GES, Howard JE, Langford H: The use of cortisone in follicular phase disturbances. Fertil Steril 4:49, PerloffWH, Channick BJ: Effect of prednisone on abnormal menstrual function. Am J Obstet Gynecol 77:138, Perloff WH, Smith KD, Steinberger E: Effect of prednisone on female infertility. Int J Fertil 10:31, Smith KD, Steinberger E, PerloffWH: Polycystic ovarian disease: a report of 301 patients. Am J Obstet Gynecol 93:994, Yen SSC: The polycystic ovary syndrome. Clin Endocrinol 12:177, Givens JR, Andersen RN, Ragland JB, Wiser WL, Umstot ES: Adrenal function in hirsutism. I. Diurnal change and response of plasma androstenedione, testosterone, 17 -hydroxyprogesterone, cortisol, LH and FSH to dexamethasone and 1f. unit of ACTH. J Clin Endocrinol Metab 40:988, Janata J, Starka L: Effect of cortisol on the production of ovarian androgens. J Endocrinol 29:93, Kirschner MA, Zucker R, Jespersen D: Idiopathic hirsutism-an ovarian abnormality. N Engl J Med 294:637, New MI, Lorenzen F, Pang S, Gunczler P, Dupont B, Levine LS: "Acquired" adrenal hyperplasia with 21-hydroxylase deficiency is not the same genetic disorder as congenital adrenal hyperplasia. J Clin Endocrinol Metab 48:356, Levine LS, Dupont B, Lorenzen F, Pang S, Pollack M, Oberfield S, Kohn B, Lerner A, Cacciari E, Mantero F, Cassio A, Scaroni C, Chiumello G, Rondanini GF, Gargantini L, Giovanelli G, Virdis R, Bartolotta E, Migliori C, Pintor C, Tato L, Barboni F, New MI: Cryptic 21-hydroxylase deficiency in families of patients with classical congenital adrenal hyperplasia. J Clin Endocrinol Metab 51:1316, Steinberger et al. Adrenal tests in hyperandrogenic women Fertility and Sterility

THE RELATION BETWEEN PLASMA TESTOSTERONE LEVELS AND THE LENGTHS OF PHASES OF THE MENSTRUAL CYCLE*

FERTILITY AND STERILITY Copyright 1979 The American Fertility Society Vol. 32, No.4, October 1979 Printed in U.s.A. THE RELATION BETWEEN PLASMA TESTOSTERONE LEVELS AND THE LENGTHS OF PHASES OF THE MENSTRUAL