Gynecology-endocrinology

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1 Gynecology-endocrinology FERTILITY AND STERILITY Copyright (fj 1991 The American Fertility Society Vol. 55, No, 5, May 1991 Printed on acid-free paper in U.S.A. Serum androsterone conjugates differentiate between acne and hirsutism in hyperandrogenic women* Enrico Carmina, M,D,t Frank Z. Stanczyk, Ph.D,:!: Robert K Matteri, M.D, Rogerio A. Lobo, M,D,:!:II Universita di Palermo, Palermo, Italy, and University of Southern California School of Medicine, Los Angeles, California Objective: To determine if among hyperandrogenic women acne may be differentiated from hirsutism by markers of peripheral androgen metabolism. Design: Prospective outpatient study of 36 hyperandrogenic women and controls divided into groups based on the presence or absence of significant hirsutism and the presence or absence of moderate to severe acne. Serum levels of adrenal and ovarian derived androgens were elevated but similar in all patient groups. Interventions: Measurement of serum androgens including metabolites of 5a-reductase activity: 3a-androstanediol glucuronide and sulfate and androsterone (A) glucuronide and sulfate. Results: 3a-androstanediol glucuronide and sulfate were elevated in all groups (P < 0.05) and could differentiate between hirsute and non hirsute patients but were similar in patients with and without acne. Serum A glucuronide and sulfate were only significantly elevated in patients with acne (P < 0.01) and were higher than levels in controls and hirsute patients without acne. Ratios of precursor androgens to A glucuronide and sulfate were significantly higher in patients with acne compared with patients without acne (P < 0.05). Conclusions: Altered peripheral metabolism in acne may favor the formation of A conjugates, which may help differentiate acne from hirsutism among hyperandrogenic women. Fertil Steril 55:872, 1991 Androgens are well known to stimulate sebaceous gland activity, largely by increasing cell division,! and to increase sebum production. 2 In women with acne, this androgenic effect may be accounted for by an increase in either ovarian or adrenal androgen Received October 4, 1990; revised and accepted January 22, * This work was presented, in part, at the 37th Annual Meeting of the Society for Gynecologic Investigation, St. Louis, Missouri, March 21 to 24, t Cattedra di Endocrinologia, Universita di Palermo. :j: Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Southern California School of Medicine. Present address: Good Samaritan Hospital, Portland, Oregon. II Reprint requests: Rogerio A. Lobo, M.D., Department of Obstetrics and Gynecology, Women's Hospital, Room 1M2, LAC+USC Medical Center, 1240 North Mission Road, Los Angeles, California production. 3,4 There is also evidence implicating enhanced peripheral androgen metabolism in some patients with acne. 5 This has been shown to be the result of increased 5a-reductase activity, at least in part, and may be reflected by elevated levels of serum 3a-androstanediol glucuronide (3a-diol G).6,7 A similar situation has long been recognized to exist in women with hirsutism. 8,9 In our studies of hyperandrogenic women, we have been impressed that some women do not manifest both acne and hirsutism and that these two disorders may occur separately. We therefore pondered what characterizes hyperandrogenic patients with acne and postulated that differences in peripheral (skin) androgen metabolism may explain the different manifestations. To this end, we have studied a group of hyperandrogenic women with hirsutism, who either have or do not have acne, and have also com- 872 Carmina et at. Elevated androsterone conjugates in acne

2 pared these patients with others who have acne but no hirsutism. We specifically wished to compare in these patients those androgens produced by the adrenal and ovary as well as those 5a-reduced conjugates known to reflect peripheral androgen metabolism. Subjects MATERIALS AND METHODS Thirty-six hyperandrogenic women, 17 to 29 years of age, were studied and compared with 8 normal ovulatory controls, 18 to 25 years of age (group 1). The hyperandrogenic patients had all presented for the first time with complaints of either hirsutism and/or acne and were found to be hyperandrogenic. Hyperandrogenism was defined as an elevation in serum testosterone (T) and/or dehydroepiandrosterone sulfate (DHEAS). Fifty percent of the patients had oligomenorrhea. For the purpose of this study, menstrual aberrations were not a specific differentiating criterion. Women were either studied in the early follicular phase of a spontaneous cycle or after a progesterone-induced menses. Hirsutism was graded by a modification of the method of Ferriman-Gallweylo and the severity of acne was scored 0 to 3 according to a modification of the method of Lookingbill et al. 7 Absence of lesions was scored as grade O. Grade 1 (mild) lesions were characterized by comedones with either no or only a few inflammatory papules or pustules. Grade 2 (moderate) lesions were so classified if they were numerous and inflammatory but with rare cystic activity. Grade 3 (severe) lesions were the worst lesions and were so graded when there were innumerable inflammatory papules and pustules as well as cysts. For the purpose of this study, we only included patients who had significant grades of moderate and severe acne (grades 2 [n = 10] and grades 3 [n = 7]) and patients who had Ferriman-Gallwey scores> 8. The hyperandrogenic patients were divided into three groups as follows: Eleven women (group 2) were not hirsute and had Ferriman-Gallwey scores < 8 but had acne, mean (TSE) score of 2.4 ±.2. Group 3 was composed of 6 hirsute patients (Ferriman-Gallwey scores of 16 ± 2) who also had acne and had lesion scores of 2.5 ±.2. Group 4 consisted of 19 hirsute patients who did not have acne. In these patients, the Ferriman-Gallwey score was 12 ± 2.4. No patient had adrenal or thyroid disease. There was no evidence of masculinization or clitoromegaly and patients had never received any medications or systemic treatment for either hirsutism or acne. Protocol All patients had fasting bloods obtained between 8:00 and 10:00 A.M. after at least a half hour of recumbent rest. Sera were separated and stored at -20 C until assayed for total T, androstenedione (4A) and DHEAS by established radioimmunoassay (RIA) techniquesy-13 Unbound T was measured by a specific RIA using reagents purchased from Diagnostic Products Corporation (Los Angeles, CA). In addition, the following 5a-reduced androgen conjugates were measured: 3a-diol G, 3a-diol sulfate, androsterone (A) glucuronide, and A sulfate. These assays employed specific hydrolysis of the conjugates, followed by extraction, celite column chromatography, and RIA as previously described.14,15 In all cases intra-assay and interassay coefficients of variation did not exceed 12%. Statistical Analyses Comparisons between groups were carried out using the Kruskal-Wallis test as well as ANOV A. Regression analysis was employed using the method of least squares. RESULTS Table 1 depicts the characteristics of the hyperandrogenic patients and controls together with their levels of T, unbound T, 4A, and DHEAS. There were no differences in ages or weights between the groups. Hirsutism scores in hirsute patients and acne scores in patients with acne were also similar. Although all three groups had higher androgen levels when compared with controls, there were no differences between any of the groups. Compared with controls, all hyperandrogenic groups had higher levels of serum 3a-diol G and 3adiol sulfate (Fig. 1). However, both hirsute groups had higher levels of 3a-diol G compared with the nonhirsute group (P < 0.05), regardless ofthe presence of acne. Serum 3a-diol G did not differentiate between hirsute patients with and without acne. For serum 3a-diol sulfate, levels in the three groups were similar and could not differentiate between those patients with hirsutism or acne. Although menstrual irregularity was not a criterion for assessment in this study, mean levels of serum ovarian and adrenal androgens (Table 1) were not different between patients who reported spon- VoL 55, No.5, May 1991 Carmina et al. Elevated androsterone conjugates in acne 873

3 Table 1 Hirsute and Acne Status of Patients and Serum Levels of Ovarian and Adrenal Androgens Ferriman-Gallwey score Acne Total T Unbound T DHEAS Group 1 (n = 8) Group 2 (n = 11) Group 3 (n = 6) Group 4 (n = 19) <8 <8 16 ± 2 12 ± 2.4 o 2.4 ± ± 0.2 o 29.8±4 a 92 ± 9 b 97 ± 7 b 89.2 ± 8 b ng/dl 1.64 ± ± 0.5 b 3.45 ± 0.5 b 4.2 ± 0.3 b ng/ml 1.77 ± ± O.4 b 3.9 ± 0.3 b 4.1 ± 0.3 b p.g/ml 1.56 ± ± 0.3 b 2.37 ± 0.6 b 2.38 ± 0.3 b a Values are means ± SE. b P < 0.01 study groups versus controls. taneous menses and those with oligomenorrhea. In those patients who reported cyclic menses, ovulatory status was not determined. In Figure 2, the A conjugates are depicted. When comparing groups on the basis of hirsutism (group 2 versus group 3), serum A glucuronide was not significantly different. However, both these groups had moderate to severe acne lesions. In comparing the hirsute patients with and without acne, the patients with acne (group 3) had significantly higher values (P < 0.05). For A sulfate (Fig. 2), only patients with acne had elevated levels when compared with controls or the hirsute patients without acne. In this latter group (group 4), values of A sulfate were similar to controls. There were, however, no differences in values between nonhirsute and hirsute patients with acne (group 2 versus group 3). Among the patients with acne, 12 of 17 (70.6%) had elevations in A sulfate compared with normal controls (>1,155 ng/ml) and 17 of 17 (100%) had elevations in A glucuronide (>46 ng/ml). Because of the elevations in A conjugates in patients with acne, we attempted to correlate levels of the A conjugates with their presumed precursor androgens (T, unbound T, /1 4 A, and D HEAS) in all the hyperandrogenic patients. No correlations were found between A sulfate and these precursors except between A sulfate and DHEAS in the hyperandrogenic patients without acne (n = 19) (r = 0.63, P < 0.01). In acne patients (n = 17), this correlation (r = 0.34) was not significant. For A glucuronide, only /1 4 A correlated (r = 0.68, P < 0.01), but again only in patients without acne (n = 9). In acne patients (n = 17), the correlation was not significant (r = 0.24). Figure 3 depicts ratios of precursors to the A conjugates in all hyperandrogenic patients with and without acne. Hyperandrogenic patients without acne had similar ratios of A sulfate/dheas, A glucuronide/ /1 4 A, and A glucuronide/unbound T when compared with controls. However, when compared with either hyperandrogenic patients without acne or with controls, patients with acne had significantly increased ratios (P < 0.05, P < 0.01, and P < 0.02, respectively). DISCUSSION It remains clear that hyperandrogenism is prevalent among women with acne. Although investi :J". :J" S. 9 S. 60 :2 c:: e Jg a 6 In c;, :g 30 " Figure 1 Serum levels (means ± SE) of 3a-diol G and 3a-diol sulfate in normal controls (group 1), hyperandrogenic patients with acne but no hirsutism (group 2), hirsute hyperandrogenic patients with acne (group 3), and hyperandrogenic patients with hirsutism but without acne (group 4). *, signifies differences from controls (P < 0.02, P < 0.01). The D signifies significant differences between group 2 and group 3 (P < 0.05) :J" i S. s. :g 100 c:: Jg 1000 e a «.2 C> « Figure 2 Serum levels (means ± SE) of A sulfate and A glucuronide in normal controls (group 1), hyperandrogenic patients with acne but no hirsutism (group 2), hirsute hyperandrogenic patients with acne (group 3), and hyperandrogenic patients with hirsutism but without acne (group 4). *, indicates differences from controls (P < 0.05, P < 0.01). The + indicates differences between group 4 and the other groups (P < 0.05). 874 Carmina et al. Elevated androsterone conjugates in acne

4 BOO " { 40 i 40 :!: I j 1400 " 200 ;;. ".. Lo nl 20 n Figure 3 Ratios of A sulfate/dheas, A glucuronide/114a, and A glucuronide/unbound T in Group 1 (open bars) and all hyperandrogenic patients (shaded bars) without acne and with acne. The parallel shading indicates hyperandrogenic patients without acne and those with cross hatching, those patients with acne. 6, signifies differences between patients with and without acne: P < 0.05, P < 0.01, P < 0.02, respectively. Ratios of A glucuronide/ 114A and A glucuronide/unbound T are different from group 1 (P < 0.01). gators have previously reported elevations in ovarian, adrenal, and/or peripheral androgen levels, to our knowledge no data exist specifically differentiating acne from hirsutism in hyperandrogenic women. Here we have divided patients on the basis of the presence or absence of acne (moderate or severe) and have also only studied those hirsute patients with a significant complaint. For this reason, we have not attempted to show direct correlations between acne lesion scores and serum androgen levels because only grades 2 and 3 lesions for acne were considered. We have found that although precursor androgen levels from both the ovary and adrenal are elevated in hirsute and acne patients, these levels, including unbound T, could not distinguish between patients with these complaints. Markers of peripheral androgen production, such as serum 3a-diol G, were found to be elevated in the presence of hirsutism, and this confirms previous data. 9,15,16 Of importance, we have demonstrated here that only A conjugates can significantly differentiate between patients with and without acne. Because we wished to differentiate acne from hirsutism, the numbers of subjects studied are small. The results of this study, although convincing to us, have therefore to be interpreted with some caution. Serum 3a-diol G has been found to be elevated in patients with acne.6,7 In this study, we have confirmed that serum 3a-diol G is a useful marker in hirsutism, but that it is unable to distinguish between patients with and without acne. Serum 3adiol sulfate was even less useful in this regard. Compared with these findings, both A glucuronide and A sulfate were elevated in hyperandrogenic acne patients regardless of the presence or absence of hir- sutism. Indeed, significant differences in these levels occurred according to the presence or absence of acne, suggesting a major role of A metabolism in acne patients. In patients without acne, A sulfate and DHEAS correlated and, as expected,!:l4a, the principal substrate for 5a-reductase in women,17 also correlated. Our finding that serum androgen levels from the ovary and adrenal did not correlate with A conjugate levels in hyperandrogenic acne patients suggests that local (skin) factors other than substrate dependency determines, at least in part, the production of these conjugate levels. In evaluating ratios of the ovarian and adrenal precursors, significant elevations occurred only in hyperandrogenic patients with acne. We suggest therefore, that in acne, skin sebaceous activity is shifted toward A metabolism. Although we are cognizant that skin and peripheral tissues are not the exclusive sites of A metabolism and that A may also be produced by the liver, we have shown previously that A and CI9 conjugates may be produced directly by skin.8.18 Indeed, in this study, hirsute patients with equally elevated levels of ovarian and adrenal steroids but who did not have acne had essentially normal levels of A glucuronide and A sulfate, suggesting that hepatic metabolism alone cannot explain the elevations in hyperandrogenic women. Nevertheless, awaiting further investigation is the comparison of A metabolism in the sebaceous glands of acne patients with that of other metabolites of 5a-reductase activities. Although we have previously found A conjugates to be as valuable as 3a-diol G for the assessment of peripheral androgen action in hirsutism,15 we had never distinguished between patients on the basis of the presence or absence of acne. Here we suggest that A metabolism may play a more major role in patients with acne. However, we do not suggest that A metabolites should be measured at this time to distinguish between patients with acne and hirsutism. Our data, however, strongly suggest that it is increased A metabolism in patients with acne that results in elevated levels of serum A conjugates in hyperandrogenic patients. Our own data would suggest further that both ovarian and adrenal androgens are important precursors for this metabolism. REFERENCES 1. Ebling FJ: The effects of cyproterone acetate and oestradiol upon testosterone stimulated sebaceous activity in the rat. Acta Endocrinol (Copenh) 72:361, Strauss JS, Pochi PE, Downing DT: The sebaceous glands: twenty-five years of progress. J Invest DermatoI67:90, 1976 Vol. 55, No.5, May 1991 Carmina et al. Elevated androsterone conjugates in acne 875

5 3. Scholl GM, Wu CH, Leyden J: Androgen excess in women with acne. Obstet Gynecol 64:683, Marynick SP, Chakmakjian ZH, McCaffree DL, Herndo JH: Androgen excess in cystic acne. N Engl J Med 308:981, Luderschmidt CHR: Pathogenesis of acne vulgaris. In Androgenization in Women, Edited by J Hammerstein, D Lachnit-Fixson, F Neumann, G Plewig. Amsterdam, Excerpta Medica, 1980, p Lookingbill DP, Horton R, Demers LM, Egan N, Marks JG, Santen RJ: Tissue production of androgens in women with acne. J Am Acad Dermatol 12:481, Lookingbill DP, Egan N, Santen RJ, Demers LM: Correlation of serum 3a-androstanediol glucuronide with acne and chest hair density in men. J Clin Endocrinol Metab 67:986, Serafini P, Ablan F, Lobo RA: 5a-Reductase activity in the genital skin of hirsute women. J Clin Endocrinol Metab 60: 349, Lobo RA, Goebelsmann D, Horton R: Evidence for the importance of peripheral tissue events in the development of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab 57:393, Hatch R, Rosenfield RL, Kim MH, Tredway D: Hirsutism: implications, etiology and treatment. Am J Obstet Gynecol 140:815, Lobo RA, Granger L, Goebelsmann D, Mishell DR, Jr: Elevations in unbound serum estradiol as a possible mechanism for inappropriate gonadotropin secretion in women with PCO. J Clin Endocrinol Metab 52:156, Lobo RA, Kletzky OA, Kaptein EM, Goebelsmann D: Prolactin modulation of dehydroepiandrosterone sulfate secretion. Am J Obstet Gynecol 138:632, Stumpf PG, Nakamura RM, Mishell DR, Jr: Changes in physiologically free circulating estradiol and testosterone during exposure to levonorgestrel. J Clin Endocrinol Metab 52:138, Morimoto I, Edmiston A, Hawks D, Horton R: Studies on the origin of androstanediol and androstanediol glucuronide in young and elderly men. J Clin Endocrinol Metab 52:772, Matteri RK, Stanczyk FZ, Gentzschein EE, Delgado C, Lobo RA: Androgen sulfate and glucuronide conjugates in nonhirsute and hirsute women with polycystic ovarian syndrome. Am J Obstet Gynecol 161:1704, Horton R, Hawks D, Lobo R: 3a,17-Androstanediol glucuronide in plasma: a marker of androgen action in idiopathic hirsutism. J Clin Invest 69:1203, Silva PD, Gentzschein EEK, Lobo RA: Androstenedione may be a more important precursor of tissue dihydrotestosterone than testosterone in women. Fertil Steril 48:419, Lobo RA, Paul WL, Gentzschein E, Serafini PC, Catalino JA, Paulson RJ, Horton R: Production of 3a-androstanediol glucuronide in human genital skin. J Clin Endocrinol Metab 65:711, Carmina et ai. Elevated androsterone conjugates in acne

Prolactin modulates peripheral androgen metabolism*

FERTILITY AND STERILITY Copyright 1986 The American Fertility Society Printed in USA, Prolactin modulates peripheral androgen metabolism* Paulo Serafini, M,D, t Rogerio A, Lobo, M,D,:j: Department of Obstetrics