- Email: [email protected]
Elevated 17-hydroxyprogesterone serum values in male patients with acne
REPORTS
Elevated 17-hydroxyprogesterone serum values in male patients with acne Marianne Placzek, MD,a Barbara Arnold, MD,a Heinrich Schmidt, MD,b Sabine Gaube, MD,a Elisabeth Keller, PhD,b Gerd Plewig, MD,a and Klaus Degitz, MDa Munich, Germany Background: Androgen excess may provoke or aggravate acne by inducing seborrhea. In women, androgen disorders are frequently suspected when acne is accompanied by hirsutism or irregularities of the menstrual cycle. In men, however, acne may be the only sign of androgen excess. Objective: Our aim was to investigate whether male patients with acne display pathologic androgen blood values. Methods: This case-control study at a university dermatology department with referred and unreferred patients investigated male acne patients (n = 82, consecutive sample) in whom the diagnosis of mild to severe acne was made, as well as a control group of men without acne (n = 38). The main outcome measures were androgen parameters including morning values of testosterone, luteinizing hormone, follicle-stimulating hormone, dehydroepiandrosterone sulfate, androstenedione, and 17-hydroxyprogesterone; as well as a corticotropin stimulation test. Results: 17-Hydroxyprogesterone levels were significantly higher (P = .01) in acne patients than in the control group, whereas the other parameters did not differ significantly. In addition, the corticotropin stimulation test revealed abnormal 17-hydroxyprogesterone induction values in 10 of 82 patients. Limitations: The analysis is limited to a selection of androgen parameters. Conclusion: The results suggest that in men irregularities of adrenal steroid metabolism may be a factor contributing to acne. ( J Am Acad Dermatol 2005;53:955-8.)
A
cne is a common skin disease. Seborrhea is recognized as a crucial pathogenic factor. Sebum production is controlled by androgens, and androgen excess may provoke or aggravate acne in susceptible persons.1 Excessive androgen production may, among other things, be due to androgen-producing tumors, polycystic ovarian syndrome, or disturbances of adrenal androgen metabolism, including congenital adrenal hyperplasia.
From the Departments of Dermatologya and Pediatrics,b LudwigMaximilian-University. Funding sources: None. Conflicts of interest: None identified. Accepted for publication July 5, 2005. Reprints not available from the authors. Correspondence to: Klaus Degitz, MD, Department of Dermatology, Ludwig-Maximilian University, Frauenlobstr 9-11, D-80337, Mu¨nchen, Germany. E-mail: [email protected]. Published online October 5, 2005. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.07.014
Abbreviations used: ACTH: DHEA-S: FSH: LH: 17-OHP: SHBG:
corticotropin dehydroepiandrosterone sulfate follicle-stimulating hormone luteinizing hormone 17-hydroxyprogesterone sex hormone-binding globulin
In women, androgen-triggered acne is frequently accompanied by other signs of hyperandrogenism (eg, hirsutism or menstrual irregularities).2 In men, however, acne may be the only symptom indicating androgen excess. To investigate the frequency and nature of androgen disorders in male patients with acne, we screened male acne patients for irregularities of androgen metabolism with endocrinologic tests and found increased levels of the 21-hydroxylase substrate, 17-hydroxyprogesterone (17-OHP). Our data suggest that acne is accompanied by hyperandrogenism not only in women but also in men and that functional 21-hydroxylase deficiency may be one underlying pathogenetic mechanism. 955
956 Placzek et al
J AM ACAD DERMATOL DECEMBER 2005
METHODS Patients. Eighty-two male patients with acne vulgaris seen consecutively in the outpatient clinic at the Department of Dermatology, LudwigMaximilian University were included. Acne severity grades were determined according to the criteria of Plewig and Kligman1 for face, chest, and back. Exclusion criteria were (1) age younger than 18 years, thereby allowing the elimination of age variations of serum levels of several hormone parameters determined in this study; (2) intake, less than 3 months before inclusion, of systemic glucocorticoids, because they would interfere with hormonal tests; and (3) known sensitivity against corticotropin (ACTH) or the injected substance tetracosactid. A control group of 38 men was recruited among hospital staff and dermatologic outpatients. Control subjects had an age distribution similar to that of the test group, no history of acne, and no current acne or acne scars on clinical inspection. The study was performed with the approval of the LudwigMaximilian University ethics commission. Participants were informed about the nature and purpose of the hormonal tests, and written consent was obtained from participants. Endocrinologic tests. Serum levels of gonadotropins (luteinizing hormone [LH], follicle-stimulating hormone [FSH]), testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and 17 OHP were determined by means of commercially available kits. Blood samples were taken between 8 and 9 AM to exclude same-day variations. In the patient group, an ACTH stimulation test was performed to detect those patients with mild forms of congenital adrenal hyperplasia with normal basal adrenal steroids.3,4 Tetracosactid, 25 IU (hormonally active ACTH fragment, Synacthen, Novartis, Nu¨rnberg, Germany), was injected. One hour after injection, another blood sample was obtained for the determination of stimulated 17-OHP serum levels. The possibility of congenital adrenal hyperplasia was entertained if basal 17-OHP levels were elevated (normal values were 32-330 ng/dL, or 0.97-9.98 nmol/L) or if ACTHstimulated 17-OHP was more than 260 ng/dL (7.87 nmol/L) above the basal level.5 Statistical analysis. The unpaired t test was used to compare hormonal parameters between study patients and control subjects. Fisher’s exact test was used to compare acne severity grades among subgroups of patients.
RESULTS The mean age of the 82 acne patients was 26.2 years (age range, 18.1-43.8 years; n = 82). All acne
severity grades were observed (Table I, group A). When acne patients were compared with a control group (mean age 28.4 years, range 18.5-41.5 years; n = 38) with regard to endocrinologic parameters, the acne patients demonstrated a significantly higher mean level of 17-OHP than the controls (P = .01; Table II). There was no significant difference in the mean levels of testosterone, LH, FSH, DHEA-S, or androstenedione. An ACTH stimulation test was performed in all 82 patients. The increase of 17-OHP in response to ACTH was 160.12 6 93.84 ng/dL (mean 6 standard deviation) and was considered abnormal in 10 of 82 patients according to the applied cut-off level for nonclassic congenital adrenal hyperplasia. In 8 of these 10 patients, the abnormal ACTH stimulation was accompanied by normal basal 17-OHP levels. Two patients displayed both increased basal 17-OHP levels and an abnormal ACTH stimulation test. Two additional patients displayed increased 17-OHP levels, but had a normal ACTH stimulation test. In the total of 12 patients demonstrating pathologic 17-OHP values, all grades of acne severity were observed (Table I, group B), and no difference was noted in acne severity when compared with patients with normal 17-OHP values (Table I, group C).
DISCUSSION We found significantly increased levels of the adrenal steroid intermediate 17-OHP in a group of male acne patients. The relevance of hyperandrogenism in male acne patients often has not been considered, whereas in women or prepubertal children suffering from acne, disorders of androgen metabolism are readily suspected. In women, acne may be accompanied by other clinical symptoms, such as hirsutism and menstrual irregularities. In children, early onset of acne would suggest a problem with androgen metabolism. Extensive investigations have documented that in women acne is accompanied by hyperandrogenemia in some patients.2 Studies addressing the relation between androgen blood levels and acne in men have produced mixed results. No difference between 11 male acne patients and 11 men without acne was noticed with regard to the 17b-hydroxysteroid mean plasma level as an overall androgen parameter.6 Mean testosterone plasma levels in 23 men with acne vulgaris or in 10 men with acne conglobata did not differ significantly from the mean testosterone level of 17 men without acne7; no differences in testosterone, sex hormonebinding globulin (SHBG), or DHEA-S values were detected between 34 male acne patients and 24 male control subjects8; the mean total or free testosterone
Placzek et al 957
J AM ACAD DERMATOL VOLUME 53, NUMBER 6
Table I. Acne severity grades of 82 male acne patients according to localization
Table II. Mean basal hormonal levels in male acne patients and control subjects
Acne severity
Ay (n = 82) Face Chest Back Bz (n = 12) Face Chest Back C§ (n = 70) Face Chest Back
None (0)
Mild (1)
Moderate (2)
Severe (3)
Average acne severity*
12 38 17
25 20 20
24 21 28
11 3 17
1.54 0.87 1.55
2 5 4
3 3 2
5 3 3
2 1 3
1.58 1.00 1.42
10 33 13
22 17 18
29 18 25
9 2 14
1.53 0.84 1.57
Data expressed in number of patients, except for average acne severity grading. *Average acne severity was semiquantitatively determined by assigning values to each acne severity grade, adding up severity values for all subjects, and dividing the sum by the number of subjects. y A, All patients. z B, Patients with abnormal 17-OHP values, either elevated basal 17-OHP or pathologic ACTH stimulation test. § C, Patients with normal 17-OHP values.
serum levels in 34 male acne patients were not significantly different from the mean total or free testosterone serum level of 12 healthy control subjects9; and serum levels of free testosterone in men with acne papulopustulosa (n = 74) did not significantly differ from age-matched male control subjects (n = 59).10 On the other hand, in a comparison of 15 men suffering from severe cystic acne with 7 male control subjects, a significantly lower SHBG serum mean value was observed in the acne patients. No differences were noted with respect to testosterone, basal, or thyrotropin-releasing hormone/luteinizing hormone-releasing hormoneestimulated LH or FSH values.11 In a study of 17 male acne patients with moderate to severe acne, increased free testosterone and free dihydrotestosterone mean plasma levels were recorded, whereas total plasma testosterone, dihydrotestosterone, androstenedione, or SHBG mean values were not significantly different from those obtained from 16 control subjects.12 Generally, most of these studies did not disclose abnormal values for gonadal androgens in acne patients, which is further supported by the lack of correlation of plasma testosterone or dihydrotestosterone levels with acne severity.13 Adrenal androgens have rarely been investigated. Thirty-two men suffering from severe cystic acne displayed higher values for DHEA-S and 17-OHP
Hormone
Free testosterone (ng/mL) LH (U/L) FSH (U/L) DHEA-S (g/dL) Androstenedione (ng/dL) 17-OHP (ng/dL)
Acne patients (n = 82)
Controls (n = 38)
P value
5.72 4.21 5.16 306.95 183.28 200.53
5.86 5.09 4.93 329.76 191.58 165.42
.70 .94 .32 .35 .45 .01
DHEA-S, dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; LH, luteinizing hormone; 17-OHP, 17-hydroxyprogesterone.
compared with 26 men without acne, whereas there were no significant differences between the groups with respect to testosterone, androstenedione, LH, FSH, or SHBG.14 In a group of 15 men suffering from severe cystic acne, 5 acne patients displayed higher than normal DHEA-S serum values, but the mean DHEA-S serum value did not significantly differ from the mean serum value of a control group.11 In a study of men with persistent acne (n = 50), significantly higher serum levels of androstenedione, testosterone, and 11-deoxycortisol were observed than in an age-matched control group (n = 50), whereas there was no difference between the groups regarding LH, FSH, 17-OHP, DHEA-S, or SHBG levels.15 The interpretation of these investigations is hampered by the heterogeneity of the androgen parameters studied and by conflicting results as to which parameters were pathologically elevated. With regard to 17OHP, one study reported elevated14 and one unchanged 17-OHP levels15 in male patients with acne compared with control subjects without acne. We report herein increased 17-OHP levels in a large group of acne patients. As opposed to previous studies, which examined patients with severe or persistent acne, our study collective contained patients with the entire spectrum of acne severity grades. Our findings support the view that a proportion of male acne patients display disturbances of androgen metabolism, especially of an increased frequency of 21-hydroxylase disturbances. This is also supported by the substantial rate of abnormal ACTH stimulation tests for 17-OHP (12.2%). Although no ACTH stimulation data were obtained from the control group, published data show a frequency of pathologic ACTH stimulation tests of only 2% of healthy adult men (n = 101).5 Defects of 21-hydroxylase activity are the major reason (approximately 95%) for congenital adrenal hyperplasia.16 The defect causes reduced cortisol biosynthesis, resulting in increased pituitary ACTH secretion. This leads to normal cortisol blood levels;
958 Placzek et al
J AM ACAD DERMATOL DECEMBER 2005
however, this occurs at the cost of an excess production of adrenal androgens, which are responsible for clinical symptoms. Severe enzyme defects cause classic forms, which manifest themselves in infancy (virilization and/or salt wasting, if the synthesis of aldosterone is also affected) or in childhood (pseudopubertas praecox, accelerated growth). In nonclassic forms, less severe symptoms occur before or after puberty (late-onset forms), including acne, hirsutism, or irregular menses. Congenital adrenal hyperplasia may even remain asymptomatic (cryptic form). The classic and nonclassic forms represent a heterogeneous spectrum of allelic variants of the 21-hydroxylase gene.17 Biochemical diagnosis relies on the determination of 17-OHP, the immediate substrate for 21-hydroxylase, before and after ACTH stimulation, and may be confirmed by genetic testing. Our finding of increased basal 17-OHP levels and pathologic ACTH stimulation tests in male acne patients emphasizes the potential to treat acne in some persons by correcting irregularities of adrenal androgen metabolism. We have previously reported successful treatment of male acne patients with biochemical signs of congenital adrenal hyperplasia.18,19 A correlation between abnormal 17-OHP values and acne severity could not be established in this study collective. This could be explained by a situation in which 21-hydroxylase deficiency fosters the development of mild acne in individuals with a lower general propensity for the development of acne and severe acne in persons with a higher propensity. We believe that endocrinologic investigations may be especially rewarding in patients with a special need for cure, for example, in patients whose disease persists beyond the usual age or who did not benefit from systemic isotretinoin, although the frequency of congenital adrenal hyperplasia under these circumstances has yet to be formally studied.
REFERENCES 1. Plewig G, Kligman AM. Acne and rosacea. 3rd ed. Berlin: Springer; 2000.
2. Lucky AW. Hormonal correlates of acne and hirsutism. Am J Med 1995;98(Suppl 1A):89S-94S. 3. New MI, Lorenzen F, Lerner AJ, Kohn B, Oberfield SE, Pollack MS, et al. Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab 1983;57:320-6. 4. White PC, New MI, Dupont B. Congenital adrenal hyperplasia. Part 1. N Engl J Med 1987;316:1519-24. 5. Knorr D, Bindlingmaier F, Ho¨ller W, Kuhnle U. Diagnosis of homozygosity and heterozygosity in congenital adrenal hyperplasia (CAH) and control of treatment. J Steroid Biochem 1983;19:645-53. 6. Lim LS, James VH. Plasma androgens in acne vulgaris. Br J Dermatol 1974;91:135-43. 7. Forstrom L, Mustakallio KK, Dessypris A, Uggeldahl PE, Adlercreutz H. Plasma testosterone levels and acne. Acta Derm Venereol 1974;54:369-71. 8. Van der Meeren HL, Thijssen JH. Circulating androgens in male acne. Br J Dermatol 1984;110:609-11. 9. Sultan C, Oliel V, Audran F, Meynadier J. Free and total plasma testosterone in men and women with acne. Acta Derm Venereol 1986;66:301-4. 10. Schmidt JB, Lindmaier A, Spona J. Endocrine parameters in acne vulgaris. Endocrinol Exp 1990;24:457-64. 11. Palatsi R, Reinilam M, Kivinen S. Pituitary function and DHEA-S in male acne and DHEA-S, prolactin and cortisol before and after oral contraceptive treatment in female acne. Acta Derm Venereol 1986;66:225-30. 12. Lawrence D, Shaw M, Katz M. Elevated free testosterone concentration in men and women with acne vulgaris. Clin Exp Dermatol 1986;11:263-73. 13. Levell MJ, Cawood ML, Burke B, Cunliffe WJ. Acne is not associated with abnormal plasma androgens. Br J Dermatol 1989;120:649-54. 14. Marynick SP, Chakmakjian ZH, McCaffree DL, Herndon JH. Androgen excess in cystic acne. N Engl J Med 1983;308:981-6. 15. Ramsay B, Alaghband Zadeh J, Carter G, Wheeler MJ, Cream JJ. Raised serum 11-deoxycortisol in men with persistent acne vulgaris. Clin Endocrinol Oxf 1995;43:305-10. 16. Merke DP, Bornstein SR, Avila NA, Chrousos GP. NIH Conference. Future directions in the study and management of congenital adrenal hyperplasia due to 21-hydroxylase. Ann Intern Med 2002;136:320-34. 17. Speiser PW, New M. Genotype and hormonal phenotype in nonclassical 21-hydroxylase deficiency. J Clin Endocrinol Metab 1987;64:86-91. 18. Placzek M, Degitz K, Schmidt H, Plewig G. Acne fulminans in a patient with late-onset congenital hyperplasia. Lancet 1999; 354:739-40. 19. Degitz K, Placzek M, Arnold B, Schmidt H, Plewig G. Congenital adrenal hyperplasia and acne in male patients. Br J Dermatol 2003;148:1263-6.
Elevated 17-hydroxyprogesterone serum values in male patients with acne Marianne Placzek, MD,a Barbara Arnold, MD,a Heinrich Schmidt, MD,b Sabine Gaube, MD,a Elisabeth Keller, PhD,b Gerd Plewig, MD,a and Klaus Degitz, MDa Munich, Germany Background: Androgen excess may provoke or aggravate acne by inducing seborrhea. In women, androgen disorders are frequently suspected when acne is accompanied by hirsutism or irregularities of the menstrual cycle. In men, however, acne may be the only sign of androgen excess. Objective: Our aim was to investigate whether male patients with acne display pathologic androgen blood values. Methods: This case-control study at a university dermatology department with referred and unreferred patients investigated male acne patients (n = 82, consecutive sample) in whom the diagnosis of mild to severe acne was made, as well as a control group of men without acne (n = 38). The main outcome measures were androgen parameters including morning values of testosterone, luteinizing hormone, follicle-stimulating hormone, dehydroepiandrosterone sulfate, androstenedione, and 17-hydroxyprogesterone; as well as a corticotropin stimulation test. Results: 17-Hydroxyprogesterone levels were significantly higher (P = .01) in acne patients than in the control group, whereas the other parameters did not differ significantly. In addition, the corticotropin stimulation test revealed abnormal 17-hydroxyprogesterone induction values in 10 of 82 patients. Limitations: The analysis is limited to a selection of androgen parameters. Conclusion: The results suggest that in men irregularities of adrenal steroid metabolism may be a factor contributing to acne. ( J Am Acad Dermatol 2005;53:955-8.)
A
cne is a common skin disease. Seborrhea is recognized as a crucial pathogenic factor. Sebum production is controlled by androgens, and androgen excess may provoke or aggravate acne in susceptible persons.1 Excessive androgen production may, among other things, be due to androgen-producing tumors, polycystic ovarian syndrome, or disturbances of adrenal androgen metabolism, including congenital adrenal hyperplasia.
From the Departments of Dermatologya and Pediatrics,b LudwigMaximilian-University. Funding sources: None. Conflicts of interest: None identified. Accepted for publication July 5, 2005. Reprints not available from the authors. Correspondence to: Klaus Degitz, MD, Department of Dermatology, Ludwig-Maximilian University, Frauenlobstr 9-11, D-80337, Mu¨nchen, Germany. E-mail: [email protected]. Published online October 5, 2005. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.07.014
Abbreviations used: ACTH: DHEA-S: FSH: LH: 17-OHP: SHBG:
corticotropin dehydroepiandrosterone sulfate follicle-stimulating hormone luteinizing hormone 17-hydroxyprogesterone sex hormone-binding globulin
In women, androgen-triggered acne is frequently accompanied by other signs of hyperandrogenism (eg, hirsutism or menstrual irregularities).2 In men, however, acne may be the only symptom indicating androgen excess. To investigate the frequency and nature of androgen disorders in male patients with acne, we screened male acne patients for irregularities of androgen metabolism with endocrinologic tests and found increased levels of the 21-hydroxylase substrate, 17-hydroxyprogesterone (17-OHP). Our data suggest that acne is accompanied by hyperandrogenism not only in women but also in men and that functional 21-hydroxylase deficiency may be one underlying pathogenetic mechanism. 955
956 Placzek et al
J AM ACAD DERMATOL DECEMBER 2005
METHODS Patients. Eighty-two male patients with acne vulgaris seen consecutively in the outpatient clinic at the Department of Dermatology, LudwigMaximilian University were included. Acne severity grades were determined according to the criteria of Plewig and Kligman1 for face, chest, and back. Exclusion criteria were (1) age younger than 18 years, thereby allowing the elimination of age variations of serum levels of several hormone parameters determined in this study; (2) intake, less than 3 months before inclusion, of systemic glucocorticoids, because they would interfere with hormonal tests; and (3) known sensitivity against corticotropin (ACTH) or the injected substance tetracosactid. A control group of 38 men was recruited among hospital staff and dermatologic outpatients. Control subjects had an age distribution similar to that of the test group, no history of acne, and no current acne or acne scars on clinical inspection. The study was performed with the approval of the LudwigMaximilian University ethics commission. Participants were informed about the nature and purpose of the hormonal tests, and written consent was obtained from participants. Endocrinologic tests. Serum levels of gonadotropins (luteinizing hormone [LH], follicle-stimulating hormone [FSH]), testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and 17 OHP were determined by means of commercially available kits. Blood samples were taken between 8 and 9 AM to exclude same-day variations. In the patient group, an ACTH stimulation test was performed to detect those patients with mild forms of congenital adrenal hyperplasia with normal basal adrenal steroids.3,4 Tetracosactid, 25 IU (hormonally active ACTH fragment, Synacthen, Novartis, Nu¨rnberg, Germany), was injected. One hour after injection, another blood sample was obtained for the determination of stimulated 17-OHP serum levels. The possibility of congenital adrenal hyperplasia was entertained if basal 17-OHP levels were elevated (normal values were 32-330 ng/dL, or 0.97-9.98 nmol/L) or if ACTHstimulated 17-OHP was more than 260 ng/dL (7.87 nmol/L) above the basal level.5 Statistical analysis. The unpaired t test was used to compare hormonal parameters between study patients and control subjects. Fisher’s exact test was used to compare acne severity grades among subgroups of patients.
RESULTS The mean age of the 82 acne patients was 26.2 years (age range, 18.1-43.8 years; n = 82). All acne
severity grades were observed (Table I, group A). When acne patients were compared with a control group (mean age 28.4 years, range 18.5-41.5 years; n = 38) with regard to endocrinologic parameters, the acne patients demonstrated a significantly higher mean level of 17-OHP than the controls (P = .01; Table II). There was no significant difference in the mean levels of testosterone, LH, FSH, DHEA-S, or androstenedione. An ACTH stimulation test was performed in all 82 patients. The increase of 17-OHP in response to ACTH was 160.12 6 93.84 ng/dL (mean 6 standard deviation) and was considered abnormal in 10 of 82 patients according to the applied cut-off level for nonclassic congenital adrenal hyperplasia. In 8 of these 10 patients, the abnormal ACTH stimulation was accompanied by normal basal 17-OHP levels. Two patients displayed both increased basal 17-OHP levels and an abnormal ACTH stimulation test. Two additional patients displayed increased 17-OHP levels, but had a normal ACTH stimulation test. In the total of 12 patients demonstrating pathologic 17-OHP values, all grades of acne severity were observed (Table I, group B), and no difference was noted in acne severity when compared with patients with normal 17-OHP values (Table I, group C).
DISCUSSION We found significantly increased levels of the adrenal steroid intermediate 17-OHP in a group of male acne patients. The relevance of hyperandrogenism in male acne patients often has not been considered, whereas in women or prepubertal children suffering from acne, disorders of androgen metabolism are readily suspected. In women, acne may be accompanied by other clinical symptoms, such as hirsutism and menstrual irregularities. In children, early onset of acne would suggest a problem with androgen metabolism. Extensive investigations have documented that in women acne is accompanied by hyperandrogenemia in some patients.2 Studies addressing the relation between androgen blood levels and acne in men have produced mixed results. No difference between 11 male acne patients and 11 men without acne was noticed with regard to the 17b-hydroxysteroid mean plasma level as an overall androgen parameter.6 Mean testosterone plasma levels in 23 men with acne vulgaris or in 10 men with acne conglobata did not differ significantly from the mean testosterone level of 17 men without acne7; no differences in testosterone, sex hormonebinding globulin (SHBG), or DHEA-S values were detected between 34 male acne patients and 24 male control subjects8; the mean total or free testosterone
Placzek et al 957
J AM ACAD DERMATOL VOLUME 53, NUMBER 6
Table I. Acne severity grades of 82 male acne patients according to localization
Table II. Mean basal hormonal levels in male acne patients and control subjects
Acne severity
Ay (n = 82) Face Chest Back Bz (n = 12) Face Chest Back C§ (n = 70) Face Chest Back
None (0)
Mild (1)
Moderate (2)
Severe (3)
Average acne severity*
12 38 17
25 20 20
24 21 28
11 3 17
1.54 0.87 1.55
2 5 4
3 3 2
5 3 3
2 1 3
1.58 1.00 1.42
10 33 13
22 17 18
29 18 25
9 2 14
1.53 0.84 1.57
Data expressed in number of patients, except for average acne severity grading. *Average acne severity was semiquantitatively determined by assigning values to each acne severity grade, adding up severity values for all subjects, and dividing the sum by the number of subjects. y A, All patients. z B, Patients with abnormal 17-OHP values, either elevated basal 17-OHP or pathologic ACTH stimulation test. § C, Patients with normal 17-OHP values.
serum levels in 34 male acne patients were not significantly different from the mean total or free testosterone serum level of 12 healthy control subjects9; and serum levels of free testosterone in men with acne papulopustulosa (n = 74) did not significantly differ from age-matched male control subjects (n = 59).10 On the other hand, in a comparison of 15 men suffering from severe cystic acne with 7 male control subjects, a significantly lower SHBG serum mean value was observed in the acne patients. No differences were noted with respect to testosterone, basal, or thyrotropin-releasing hormone/luteinizing hormone-releasing hormoneestimulated LH or FSH values.11 In a study of 17 male acne patients with moderate to severe acne, increased free testosterone and free dihydrotestosterone mean plasma levels were recorded, whereas total plasma testosterone, dihydrotestosterone, androstenedione, or SHBG mean values were not significantly different from those obtained from 16 control subjects.12 Generally, most of these studies did not disclose abnormal values for gonadal androgens in acne patients, which is further supported by the lack of correlation of plasma testosterone or dihydrotestosterone levels with acne severity.13 Adrenal androgens have rarely been investigated. Thirty-two men suffering from severe cystic acne displayed higher values for DHEA-S and 17-OHP
Hormone
Free testosterone (ng/mL) LH (U/L) FSH (U/L) DHEA-S (g/dL) Androstenedione (ng/dL) 17-OHP (ng/dL)
Acne patients (n = 82)
Controls (n = 38)
P value
5.72 4.21 5.16 306.95 183.28 200.53
5.86 5.09 4.93 329.76 191.58 165.42
.70 .94 .32 .35 .45 .01
DHEA-S, dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; LH, luteinizing hormone; 17-OHP, 17-hydroxyprogesterone.
compared with 26 men without acne, whereas there were no significant differences between the groups with respect to testosterone, androstenedione, LH, FSH, or SHBG.14 In a group of 15 men suffering from severe cystic acne, 5 acne patients displayed higher than normal DHEA-S serum values, but the mean DHEA-S serum value did not significantly differ from the mean serum value of a control group.11 In a study of men with persistent acne (n = 50), significantly higher serum levels of androstenedione, testosterone, and 11-deoxycortisol were observed than in an age-matched control group (n = 50), whereas there was no difference between the groups regarding LH, FSH, 17-OHP, DHEA-S, or SHBG levels.15 The interpretation of these investigations is hampered by the heterogeneity of the androgen parameters studied and by conflicting results as to which parameters were pathologically elevated. With regard to 17OHP, one study reported elevated14 and one unchanged 17-OHP levels15 in male patients with acne compared with control subjects without acne. We report herein increased 17-OHP levels in a large group of acne patients. As opposed to previous studies, which examined patients with severe or persistent acne, our study collective contained patients with the entire spectrum of acne severity grades. Our findings support the view that a proportion of male acne patients display disturbances of androgen metabolism, especially of an increased frequency of 21-hydroxylase disturbances. This is also supported by the substantial rate of abnormal ACTH stimulation tests for 17-OHP (12.2%). Although no ACTH stimulation data were obtained from the control group, published data show a frequency of pathologic ACTH stimulation tests of only 2% of healthy adult men (n = 101).5 Defects of 21-hydroxylase activity are the major reason (approximately 95%) for congenital adrenal hyperplasia.16 The defect causes reduced cortisol biosynthesis, resulting in increased pituitary ACTH secretion. This leads to normal cortisol blood levels;
958 Placzek et al
J AM ACAD DERMATOL DECEMBER 2005
however, this occurs at the cost of an excess production of adrenal androgens, which are responsible for clinical symptoms. Severe enzyme defects cause classic forms, which manifest themselves in infancy (virilization and/or salt wasting, if the synthesis of aldosterone is also affected) or in childhood (pseudopubertas praecox, accelerated growth). In nonclassic forms, less severe symptoms occur before or after puberty (late-onset forms), including acne, hirsutism, or irregular menses. Congenital adrenal hyperplasia may even remain asymptomatic (cryptic form). The classic and nonclassic forms represent a heterogeneous spectrum of allelic variants of the 21-hydroxylase gene.17 Biochemical diagnosis relies on the determination of 17-OHP, the immediate substrate for 21-hydroxylase, before and after ACTH stimulation, and may be confirmed by genetic testing. Our finding of increased basal 17-OHP levels and pathologic ACTH stimulation tests in male acne patients emphasizes the potential to treat acne in some persons by correcting irregularities of adrenal androgen metabolism. We have previously reported successful treatment of male acne patients with biochemical signs of congenital adrenal hyperplasia.18,19 A correlation between abnormal 17-OHP values and acne severity could not be established in this study collective. This could be explained by a situation in which 21-hydroxylase deficiency fosters the development of mild acne in individuals with a lower general propensity for the development of acne and severe acne in persons with a higher propensity. We believe that endocrinologic investigations may be especially rewarding in patients with a special need for cure, for example, in patients whose disease persists beyond the usual age or who did not benefit from systemic isotretinoin, although the frequency of congenital adrenal hyperplasia under these circumstances has yet to be formally studied.
REFERENCES 1. Plewig G, Kligman AM. Acne and rosacea. 3rd ed. Berlin: Springer; 2000.
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