This Article  • Abstract  • PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on Web of Science (39)  • Contact me when this article is cited  Related Content  • Related articles  • Similar articles in this journal  Topic Collections  • Acne  • Dermatology, Other  • Alert me on articles by topic  Social Bookmarking   What's this?

Diane Thiboutot, MD; Kathryn Gilliland, BS; Jan Light, LPN; Donald Lookingbill, MD

Arch Dermatol. 1999;135:1041-1045.

ABSTRACT
Objective  To determine if there are differences in the activity of 17-hydroxysteroid dehydrogenase and 5-reductase (responsible for the production of testosterone and dihydrotestosterone, respectively) in sebaceous glands obtained from men and women with and without acne.

Design  Single-center examination of androgen levels and sebaceous gland enzyme activity in a cohort of volunteers.

Setting  Academic referral center.

Patients  Thirty-four subjects, consisting of 8 women with acne, 10 women without acne, 8 men with acne, and 8 men without acne.

Interventions  Single visit for blood sampling and 2 biopsies of forehead skin.

Main Outcome Measures  Serum levels of androgens were determined and compared with the activity of 5-reductase and 17-hydroxysteroid dehydrogenase in sebaceous glands microdissected from skin samples.

Results  No significant differences in the activity of 5-reductase or 17-hydroxysteroid dehydrogenase in sebaceous glands according to the presence of acne were noted in either men or women. The activity of 5-reductase and 17-hydroxysteroid dehydrogenase was significantly greater in sebaceous glands from men (n=16) than women (n=17). The oxidative activity of 17-hydroxysteroid dehydrogenase was 2-fold higher in men than women. Serum levels of dehydroepiandrosterone sulfate, androstenedione, testosterone, and dihydrotestosterone were significantly higher in women with acne than in women without acne. No differences in serum androgen levels were noted in men on the basis of the presence of acne.

Conclusions  Higher serum androgen levels are associated with the presence of acne in women. A role for locally produced androgens in this process, however, cannot be excluded.

INTRODUCTION

Jump to Section  • Top  • Introduction  • Subjects and methods  • Results  • Comment  • Conclusions  • Author information  • References

SEBUM PRODUCTION is stimulated by androgens and is key in the development of acne vulgaris.^1-4 Several investigators have looked for direct relationships between serum androgen levels, sebum secretion rate, and the presence of acne.⁵ The presence of acne in prepubertal girls and sebum production in both sexes correlate with serum dehydroepiandrosterone sulfate (DHEAS) levels.^6-7 Dehydroepiandrosterone sulfate is an adrenal precursor for synthesis of more potent androgens, such as testosterone and dihydrotestosterone (DHT). Although increased serum androgen levels correlate with the presence of severe nodular acne in men and women, these levels are often within the normal range in mild to moderate acne.⁸ This raises the question of whether there is an increased local production of androgens within the sebaceous gland (SG) of patients with acne vulgaris that leads to increased sebum secretion.^9-10

The SG possesses each of the steroid metabolizing enzymes needed to convert DHEAS to DHT^11-13 (Figure 1). 3-Hydroxysteroid dehydrogenase (3-HSD) reduces dehydroepiandrosterone to androstenedione. Two isozymes have been identified.¹⁴ 17-Hydroxysteroid dehydrogenase (17-HSD) is a reversible enzyme that can use different nucleotide cofactors and act either as an oxidase (to produce androstenedione from testosterone) or as a reductase (to produce testosterone from androstenedione). Recent-ly, 6 isozymes of 17-HSD have been described.^15-16 The type 2 isozyme is biochemically active in human SGs.¹⁷ Two isozymes of 5-reductase (5-R) (type 1 and type 2) have been identified.^18-20 The type 1 isozyme of 5-R is predominant in SGs and is present in higher levels in acne-prone skin than in skin obtained from regions not prone to acne.^21-22

View larger version (6K): [in this window] [in a new window] Figure 1. Androgen metabolism in the skin. Dehydroepiandrosterone sulfate (DHEAS) can be converted within the skin to testosterone and dihydrotestosterone (DHT) by means of the following enzymes: sulfotransferase, 3-hydroxysteroid dehydrogenase (3-HSD), 17-hydroxysteroid dehydrogenase (17-HSD), and 5-reductase (5-R). DHEA indicates dehydroepiandrosterone.

To date, no studies have been done to determine if there are sex-related differences in the activity of 17-HSD and 5-R in human sebaceous glands. Furthermore, it is not known if the activity of these enzymes is greater in SGs isolated from subjects with acne than in SGs from subjects without acne. The goal of this study was to determine if there are differences in the activity of 17-HSD and 5-R in SGs based on sex or the presence of acne. Serum androgen levels were determined and compared with tissue enzyme activity.

SUBJECTS AND METHODS

Jump to Section  • Top  • Introduction  • Subjects and methods  • Results  • Comment  • Conclusions  • Author information  • References

SUBJECTS

The study was approved by the institutional review board of Pennsylvania State University College of Medicine, Hershey. Men and women aged 18 to 45 years with and without acne were recruited especially for this study. Subjects with acne were defined as having a minimum of 15 comedones and 10 inflammatory papules on the face. Subjects were excluded if they had received oral antibiotics within 1 month before the study; used topical acne medications such as antibiotics, benzoyl peroxide, or tretinoin within 2 weeks before the study; received treatment in the past with oral retinoids; had known underlying endocrine disease, such as congenital adrenal hyperplasia, polycystic ovary syndrome, or adrenal or ovarian tumor; or were currently using oral contraceptives, contraceptive injection, implantable contraceptives, estrogens, prednisone, other corticosteroids, or finasteride.

PROCEDURES

All women were studied in the luteal phase of their menstrual cycle. Blood samples were taken for serum DHEAS, androstenedione, total and free testosterone, DHT, and 3-androstanediol glucuronide. Skin biopsies of the forehead were performed as follows. A 12-mm elliptical excision (4 mm at its widest point) was made from each side of the forehead, approximately 6 mm from the hairline. Skin was excised in the subcutaneous layer and a layered closure was performed. Skin specimens were transported on ice to the dermatology laboratory, where microdissections were performed according to previously described techniques.²²

Biochemical assays for the activities of 17-HSD and 5-R were performed on isolated SG as previously described.^22-23 Samples were incubated at 37°C at pH 5 and 7. Incubations for 5-R were carried out for 30 minutes, and those for 17-HSD were carried out for 60 minutes. The substrate for the 5-R reaction was tritiated testosterone (10⁶ disintegrations per minute) in the presence of 10-µmol/L cold testosterone and 500-µmol/L nicotinamide adenine dinucleotide phosphate as a cofactor. The same isotope was used as the substrate for the oxidative reaction of 17-HSD, but nicotinamide adenine dinucleotide (1 µmol/L) was used as the cofactor. Tritiated androstenedione (10⁶ disintegrations per minute) in the presence of 10-µmol/L cold androstenedione was used as the substrate for the reductive activity of 17-HSD, and nicotinamide adenine dinucleotide reduced (1 µmol/L) was used as the cofactor.

Enzyme activity was calculated by means of the net percentage conversion of substrate, the molar concentration of substrate, and the incubation volume. To account for potential differences in the sizes of SG assayed and, hence, differences in enzyme activity, data were normalized to SG protein concentration. Data are expressed as picomoles of product per minute per milligram of protein.

SERUM ANDROGENS

Serum levels of DHEAS, testosterone, DHT, and 3-androstanediol glucuronide were determined by means of radioimmunoassay methods previously described.¹¹

DATA ANALYSIS

Unpaired t tests on log base 10 transformed data were used to compare enzyme activity between men and women and subjects with and without acne. The same test was used to compare serum androgens between groups. A paired t test using log transformed data was used to compare activity of different enzymes within the same groups. Correlation coefficients between enzyme activities in the SG and serum androgen levels were determined on the basis of sex and the presence of acne. Significance of the correlation was tested at a 95% confidence interval with Fisher r to z test.

RESULTS

Jump to Section  • Top  • Introduction  • Subjects and methods  • Results  • Comment  • Conclusions  • Author information  • References

A total of 34 subjects were studied: 8 women with acne (mean±SD age, 31±5 years), 10 women without acne (mean age, 33±7 years), 8 men with acne (mean age, 26±7 years), and 8 men without acne (mean age, 34±7 years). The acne grade was mild in all subjects examined. The mean (±SEM) total lesion counts in men and women with acne were 41±9 and 44±7, respectively.

TISSUE ENZYME ACTIVITIES

Activities of 5-R and of 17-HSD in SG from the forehead were compared in men and women with and without acne (Table 1). No significant differences were noted in enzyme activity based on the presence of acne in either men or women. Although the mean activities of 5-R and 17-HSD were higher in SG from women with acne than women without acne, these differences did not achieve statistical significance (P=.08 and .19, respectively).

View this table: [in this window] [in a new window] Table 1. Activity of 5-R and 17-HSD in Sebaceous Glands*

The mean tissue enzyme activities of 5-R, reductive 17-HSD, and oxidative 17-HSD were significantly greater in men than women, with respective P values of .05, less than .001, and .004 (unpaired t test) (Figure 2).

View larger version (17K): [in this window] [in a new window] Figure 2. Mean±SEM activity of 5-reductase (5-R) and reductive and oxidative 17-hydroxysteroid dehydrogenase (17-HSD) in sebaceous glands from men and women. Activity of all 3 enzymes was significantly greater in men than women, with respective P values of .05 (asterisk), <.001 (dagger), and .004 (double dagger) (unpaired t test). In addition, the activity of 5-R was significantly greater than both the reductive and oxidative activity of 17-HSD in sebaceous glands from both men and women.

The mean activity (±SEM) of 5-R in SG was significantly greater than both the reductive and oxidative activity of 17-HSD in all groups of subjects studied. Corresponding P values are given in Table 1.

SERUM ANDROGENS

Mean serum levels (±SEM) of DHEAS, androstenedione, testosterone, free testosterone, and DHT (but not 3-androstanediol glucuronide) were significantly greater in women with acne than women without acne, by unpaired t test (Table 2). No differences in serum androgen levels were noted in men on the basis of the presence of acne.

View this table: [in this window] [in a new window] Table 2. Serum Androgen Levels in Subjects With and Without Acne*

CORRELATION OF TISSUE ENZYME ACTIVITY AND SERUM ANDROGEN LEVELS

Tissue enzyme activity correlated with serum androgen levels only in women without acne. Reductive activity of 17-HSD correlated with serum androstenedione level (r=0.948, P<.001) and total testosterone level (r=0.673, P=.04). Activity of 5-R in SG correlated with serum androstenedione level (r=0.658, P=.04) and DHT level (r=0.671, P=.03). No correlation was noted between tissue enzyme activity and serum androgens in women with acne or in men with or without acne.

COMMENT

Jump to Section  • Top  • Introduction  • Subjects and methods  • Results  • Comment  • Conclusions  • Author information  • References

The relationship between serum androgen concentrations and the local production of androgens within sebaceous glands is not clear. Acne is associated with elevated serum androgen levels in women with virilizing tumors and with elevated serum DHEAS levels in both men and women with partial adrenal hydroxylase deficiencies.⁸ Whether androgens from the systemic circulation act directly to stimulate the sebaceous glands or whether they act indirectly to stimulate enzymes involved in androgen production within the sebaceous gland itself is not known.

TISSUE ENZYME ACTIVITIES IN SUBJECTS WITH AND WITHOUT ACNE

Our data fail to demonstrate any significant difference in tissue enzyme activity based on the presence of acne. Although a trend toward higher 5-R activity and reductive activity of 17-HSD was noted in SG from women with acne compared with women without acne, the power to detect such a difference in this study may have been limited by the small sample size.

TISSUE ENZYME ACTIVITIES IN MEN COMPARED WITH WOMEN

The activity of 5-R was significantly greater in SGs from men compared with glands from women. In addition, the oxidative activity of 17-HSD was 2- to 3-fold higher in SGs from men compared with women. As a reversible enzyme, 17-HSD can either produce the potent androgen testosterone (via reduction) or, in effect, "inactivate" it by converting it back to androstenedione (via oxidation). The type 2 isozyme of 17-HSD is active in human SGs. This isozyme prefers to oxidize testosterone to its less active precursor. In this regard, it has been suggested that the oxidative activity of the type 2 isozyme may protect target tissues (such as the SG) from the effects of potent androgens.²⁴ In this study, there was not much difference between the oxidative and reductive activities of 17-HSD. This is an artifact of the assay system, which uses homogenized glands that were provided with excess amounts of cofactors. In studies of intact SGs without added cofactors, the oxidative activity of 17-HSD predominates over its reductive activity by a much wider margin than in homogenized SGs.¹⁷

COMPARISON OF 5-R AND 17-HSD ACTIVITY IN SG

Few large studies have compared the activities of 17-HSD and 5-R in the same SG samples obtained from facial skin of both men and women. Our data demonstrate that 5-R is 2- to 4-fold more active than 17-HSD in sebaceous glands from both men and women. Both 5-R and the oxidative 17-HSD enzymes compete for testosterone as a substrate. With predominance of 5-R activity, the net effect within SGs is the conversion of testosterone to the more potent androgen DHT, which in turn is thought to mediate sebum production. Interestingly, the opposite is true in keratinocytes cultured from the infrainfundibulum of vellus follicles of forehead skin.²³ In these cells, the activity of 17-HSD is 2.5- to 8-fold greater than the activity of 5-R. Hence, vellus follicles from the face may be better protected from the effects of potent androgens than SGs because of predominance of 17-HSD oxidative activity over activity of 5-R.

THE ROLE OF SERUM ANDROGENS

Serum androgen levels were significantly higher in women with acne than in those without acne. Interestingly, these values were still within the normal range. No differences in serum androgen levels were noted in men on the basis of the presence of acne. Our data demonstrate that the highest specific activity of 17-HSD and 5-R was found in groups with the highest serum androgen levels. For example, enzyme activity was significantly greater in SGs from men than in those from women. Therefore, tissue enzyme activity may be proportional to serum androgen levels. Tissue enzyme activity correlated directly with serum androgen levels only in women without acne.

Possible interpretations of these data include the following: (1) Serum levels of androgens may play a role in the development of acne in women by acting directly on SGs, by stimulating local tissue enzyme activity, or both. (2) Serum androgens are less important than nonhormonal factors in the pathogenesis of acne in men. (3) Tissue enzyme activity in men may be maximally stimulated by their serum levels of androgens.

The effects of androgens on acne are most evident in women. If serum androgens serve as substrates for sebaceous gland enzymes, women with acne may have greater tissue production of androgens than women without acne if the activity of 5-R is increased within their SGs. Alternatively, serum levels of androgens may be more important than locally produced androgens in modulating sebum production.

CONCLUSIONS

Jump to Section  • Top  • Introduction  • Subjects and methods  • Results  • Comment  • Conclusions  • Author information  • References

It is clear that acne is a multifactorial disease. Sebum is one part of the equation. Many men do not have acne despite their high levels of androgens compared with women. Furthermore, many individuals have high sebum production, yet they do not develop acne. Currently available hormonal therapies for acne act either to reduce the production of androgens by the adrenal gland or ovary or to inhibit the action of androgens at the target site (SG) by blocking the androgen receptor. This in turn leads to decreased sebum production. There are no hormonal therapies available that specifically block androgen-metabolizing enzymes within the SG. Such therapies may be beneficial in treating acne if sebum production is mediated by locally produced androgens. Whether sebum production is modulated by systemic androgens, locally produced androgens, or a combination of both still remains to be determined. This is one research question that will most likely be answered in the clinical setting as specific inhibitors of androgen-metabolizing enzymes become available.

AUTHOR INFORMATION

Jump to Section  • Top  • Introduction  • Subjects and methods  • Results  • Comment  • Conclusions  • Author information  • References

Accepted for publication October 27, 1998.

This work was supported by a Leaders Society Dermatology Foundation Clinical Career Development Award, Evanston, Ill; the Pennsylvania State University Dermatology Research Endowment Fund, Hershey; a grant from Unilever Research US, Inc, Edgewater, NJ; and grant K08AR02018 from the National Institutes of Health, Bethesda, Md.

Corresponding author: Diane Thiboutot, MD, Section of Dermatology, Pennsylvania State University College of Medicine, 500 University Dr, Hershey, PA 17033 (e-mail: dthibout{at}med.hmc.psghs.edu).

From the Section of Dermatology, Division of Internal Medicine, Pennsylvania State University College of Medicine, Hershey (Dr Thiboutot and Mss Gilliland and Light); and Department of Dermatology, The Mayo Clinic at Jacksonville, Jacksonville, Fla (Dr Lookingbill).

REFERENCES

Jump to Section  • Top  • Introduction  • Subjects and methods  • Results  • Comment  • Conclusions  • Author information  • References

1. Strauss JS, Kligman AM, Pochi PE. The effect of androgens and estrogens on human sebaceous glands. J Invest Dermatol. 1962;39:139-155. ISI | PUBMED 2. Pochi PE, Strauss JS. Sebaceous gland response in man to the administration of testosterone, D4-androstenedione, and dehydroisoandrosterone. J Invest Dermatol. 1969;52:32-36. ISI | PUBMED 3. Pochi PE, Strauss JS. Endocrinologic control of the development and activity of the human sebaceous gland. J Invest Dermatol. 1974;62:191-201. FULL TEXT | ISI | PUBMED 4. Thody AJ, Shuster S. Control and function of sebaceous glands. Physiol Rev. 1989;69:383-385. FREE FULL TEXT 5. Lucky A, McGuire J, Rosenfield R, Lucky P, Rich B. Plasma androgens in women with acne vulgaris. J Invest Dermatol. 1983;81:70-74. FULL TEXT | ISI | PUBMED 6. Lucky AW, Biro FM, Huster GA, Leach AD, Morrison JA, Ratterman J. Acne vulgaris in premenarchal girls: an early sign of puberty associated with rising levels of dehydroepiandrosterone. Arch Dermatol. 1994;130:308-314. FREE FULL TEXT 7. Stewart ME, Downing DT, Cook JS, Hansen JR, Strauss JS. Sebaceous glandactivity and serum dehydroepiandrosterone sulfate levels in boys and girls. Arch Dermatol. 1992;128:1345-1348. FREE FULL TEXT 8. Marynick SP, Chakmajian ZH, McCaffree DL, Herdon JH. Androgen excess in cystic acne. N Engl J Med. 1983;308:981-986. ABSTRACT 9. Sansone G, Reisner RM. Differential rates of conversion of testosterone to dihydrotestosterone in acne and in normal human skin: a possible pathogenic factor in acne. J Invest Dermatol. 1971;56:366-372. FULL TEXT | ISI | PUBMED 10. Lookingbill DP, Horton R, Demers LM, Egan N, Marks JG, Santen RJ. Tissue production of androgens in women with acne. J Am Acad Dermatol. 1985;12:481-487. ISI | PUBMED 11. Simpson NB, Cunliffe WJ, Hodgins MB. The relationship between the in vitro activity of 3-hydroxysteroid dehydrogenase ^4-5-isomerase in human sebaceous glands and their secretory activity in vivo. J Invest Dermatol. 1983;81:139-144. FULL TEXT | ISI | PUBMED 12. Hay JB, Hodgins MB. Metabolism of androgens by human skin in acne. Br J Dermatol. 1974;91:123-133. FULL TEXT | ISI | PUBMED 13. Hay JB, Hodgins MB. Distribution of androgen metabolizing enzymes in isolated tissues of human forehead and axillary skin. J Endocrinol. 1978;79:29-39. FREE FULL TEXT 14. Morel Y, Mebarki F, Rheaume E, Sanchez R, Forest MG, Simard J. Structure-function relationships of 3-beta-hydroxysteroid dehydrogenase: contribution made by molecular genetics of 3-beta-hydroxysteroid dehydrogenase deficiency. Steroids. 1997;62:176-184. FULL TEXT | ISI | PUBMED 15. Andersson S, Moghrabi N. Physiology and molecular genetics of 17-hydroxysteroid dehydrogenases. Steroids. 1997;62:143-147. FULL TEXT | ISI | PUBMED 16. Biswas MG, Russell DW. Expression cloning and characterization of oxidative 17- and 3-hydroxysteroid dehydrogenases from rat and human prostate. J Biol Chem. 1997;272:15959-15966. FREE FULL TEXT 17. Thiboutot D, Martin P, Volikas L, Gilliland K. Oxidative activity of 17-hydroxysteroid dehydrogenase predominates in human sebaceous glands. J Invest Dermatol. 1998;111:390-395. FULL TEXT | ISI | PUBMED 18. Andersson S, Berman DM, Jenkins EP, Russell DW. Deletion of steroid 5-reductase 2 gene in male pseudohermaphroditism. Nature. 1991;354:159-161. FULL TEXT | PUBMED 19. Andersson S, Russell DW. Structural and biochemical properties of cloned and expressed human and rat steroid 5-reductase. Biochemistry. 1990;87:3640-3644. 20. Jenkins EP, Andersson S, Imperato-McGinley J, Wilson JD, Russell DW. Genetic and pharmacological evidence for more than one human steroid 5-reductase. J Clin Invest. 1992;89:293-300. ISI | PUBMED 21. Harris G. Identification and selective inhibition of an isozyme of steroid 5-reductase in human scalp. Proc Natl Acad Sci U S A. 1992;89:10787-10791. FREE FULL TEXT 22. Thiboutot D, Harris G, Iles V, Cimis G, Gilliland K, Hagari S. Activity of the type 1 5-reductase exhibits regional differences in isolated sebaceous glands and whole skin. J Invest Dermatol. 1995;105:209-214. FULL TEXT | ISI | PUBMED 23. Thiboutot D, Knaggs H, Gilliland K, Lin G. Activity of 5-alpha-reductase and 17-beta-hydroxysteroid dehydrogenase in the infrainfundibulum of subjects with and without acne vulgaris. Dermatology. 1998;196:38-42. FULL TEXT | ISI | PUBMED 24. Wu L, Einstein M, Geissler W, Chan HK, Elliston KO, Andersson S. Expression cloning and characterization of human 17-hydroxysteroid dehydrogenase type 2, a microsomal enzyme possessing 20-hydroxysteroid dehydrogenase activity. J Biol Chem. 1993;268:12964-12969. FREE FULL TEXT

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

RELATED ARTICLES

Acne Vulgaris: State of the Science
Guy F. Webster
Arch Dermatol. 1999;135(9):1101-1102.
EXTRACT | FULL TEXT  

Archives of Dermatology Reader's Choice: Continuing Medical Education
Arch Dermatol. 1999;135(9):1139-1140.
FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Acne in Adolescence and Cause-specific Mortality: Lower Coronary Heart Disease but Higher Prostate Cancer Mortality: The Glasgow Alumni Cohort Study
Galobardes et al.
Am J Epidemiol 2005;161:1094-1101.
ABSTRACT | FULL TEXT  

Correlation Between Serum Levels of Insulin-like Growth Factor 1, Dehydroepiandrosterone Sulfate, and Dihydrotestosterone and Acne Lesion Counts in Adult Women
Cappel et al.
Arch Dermatol 2005;141:333-338.
ABSTRACT | FULL TEXT  

A systematic review of the evidence for 'myths and misconceptions' in acne management: diet, face-washing and sunlight
Magin et al.
Fam Pract 2005;22:62-70.
ABSTRACT | FULL TEXT  

Treatment of Acne Vulgaris
Haider and Shaw
JAMA 2004;292:726-735.
ABSTRACT | FULL TEXT  

Metformin or Antiandrogen in the Treatment of Hirsutism in Polycystic Ovary Syndrome
Harborne et al.
J. Clin. Endocrinol. Metab. 2003;88:4116-4123.
ABSTRACT | FULL TEXT  

17{beta}-Hydroxysteroid Dehydrogenase Type XI Localizes to Human Steroidogenic Cells
Chai et al.
Endocrinology 2003;144:2084-2091.
ABSTRACT | FULL TEXT  

Acne Vulgaris: A Disease of Western Civilization
Cordain et al.
Arch Dermatol 2002;138:1584-1590.
ABSTRACT | FULL TEXT  

Immunolocalization of 5{alpha}-Reductase Isozymes in Acne Lesions and Normal Skin
Thiboutot et al.
Arch Dermatol 2000;136:1125-1129.
ABSTRACT | FULL TEXT  

Role of Hormones in Pilosebaceous Unit Development
Deplewski and Rosenfield
Endocr. Rev. 2000;21:363-392.
ABSTRACT | FULL TEXT  

Acne Vulgaris: State of the Science
Webster
Arch Dermatol 1999;135:1101-1102.
FULL TEXT