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The Treatment of Acne with Tace1
THE TREATMENT OF ACNE WITH TACE* Ror L. Kxr, MD. Although many factors have been cited as the cause of acne, it has become apparent that hormonal inIfuences play a major role in its development. Hamilton (1) presented convincing evidence that testosterone propionate would pro-
duce acne in susceptible individuals and pointed out the absence of acne in eunuchs. It has been found, too, that the administration of ACTH and cortisone, both of which have androgenic qualities, is followed in some cases by the development of acne (2). While a preponderance of androgenic hormones is
often followed by acneform eruptions, it cannot be stated categorically that such excesses in themselves account for the disturbance because there is a concomitant alteration of the estrogen—androgen ratio. In a number of patients suffering from acne, it was found (3) that there was a moderate increase in the urinary excretion of androgen and a moderate decrease in the urinary excretion of estrogen which resulted in altered ratio. On the other hand, Lawrence and Werthessen (4) noted a decrease in urinary estrogen with no significant change in the excretion of urinary androgen, but they felt that the resulting increased ratio of androgen to estrogen was the responsible inciting factor. The occurrence of premenstrual exacerbation of acne is well known and has been ascribed to
the fact that at this period during the menstrual cycle, estrogen levels are at their lowest and, as a result, the androgen—estrogen ratio is elevated (5—7).
In an effort to restore the endocrine balance, estrogens have been administered to patients suffering from acne, with varying results. Sulzberger (2), reporting on the therapeutic effect of female sex hormones in refractory cases of acne, stated that in one-third of these patients such hormones were a valuable adjuvant, but untoward reactions occurred in a large number of cases. Nausea, delayed menses, prolonged flow and "spotting" were often so severe that it became necessary to stop the treatment. In a small series of cases, others reported good (8, 9) and bad (10, 11) results following estrogen therapy. A new synthetic estrogen, TACE, has been given therapeutic trial in a number of patients suffering from acne. TACE differs from other commonly used estrogens
in several respects. After oral administration it is stored in the body fat from which it is released slowly over a period of time (12, 13). In experimental animals, the administration of other estrogens has been shown to produce hyperplasia of the adrenals, but following TACE this effect is minimal (13, 14). This is of some importance in the treatment of acne, a condition in which a relative excess of androgenic steroids is considered to be an important causal factor. In addition, the use of TACE is reported to produce very few undesirable side effects (15). * TACE (chlorotrianisene(tri-p-anisylohloroethylene)) kindly furnished by The William S. Merrell Co. Received for publication April 17, 1953. 79
80
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY EXPERIMENTAL
Forty patients were given the drug (see Table I). All of these cases were young females except for three males. Nearly all were given 12 mgs. per day. Since there may be storage in fat with gradual release, a few of the patients were given the remedy throughout the cycle as well as just during the postovulatory phase. The chart shows the effects of its administration. Many of these patients were given topical applications simultaneously, and some of them had x-ray therapy. TABLE I WHEN GWEN
EPECT ON MENSES
NO. C4SS
40 RESULTS
Marked Improve.
Flare Premenstrually, 20
1
20
Same
19
Other Reactions
Worse
0
Discontinued due to marked irregularity of menses
Discontinued due to dysmenorrhea, 3 cases Had to have D and C, 1 case Increased sexual activity and spotting between periods in 1 case Missed two periods, 2 cases Given to three males who were unimproved DISCUSSION
Certainly this is not a cure for acne. Lynch (11) has demonstrated that many with acne improve with no therapy. Of course, there are many factors involved. Concommitant therapy, the age group observed, and even the temperature and
humidity are factors. Even with adequate controls, it is difficult to appraise such a therapeutic agent in this disease. Many patients seemed to improve while under observation. The effect on the menses was less when the drug was given during the post-
ovulatory phase of the menstrual cycle than through the entire cycle. Then, too, this effect seemed less after the drug had been taken for several months than for the first few months. These young females seem to adapt to the added estrogen. Perhaps the dose was too large. Maybe smaller doses would have had as good or better effect on their acne with less effect on the menstrual cycle. Several girls who developed tender breasts while on other estrogens did not do so on TACE. Reactions certainly were no higher on this estrogen than on previ-
TACE IN TREATMENT OF ACNE
81
ously tried chemicals; as a matter of fact, they were somewhat less, but still occur. The three males taking the drug showed no improvement. The exact approach to acne is still to be found. It appears likely that more than one factor is at work (16). REFERENCES 1. HAMILTON, JAMES B.: Male hormone substance; A prime factor in acne. J. Clin. Endocrinol., 1: 570—592, 1941. 2. SULZBEEGER, MARION B. AND WITTEN, VICTOR H.: Hormones and acne vulgaris. Med.
Clin. North America, 35: 373—390, 1951. 3. WILE, U. J., SNow, J. S. AND BEADBIJRY, J. T.: Stndies of sex hormones in acne: II. Urinary excretion of androgenic and estrogenic substances. Arch. Dermat. & Syph., 39: 200—210, 1939.
4. LAWRENCE, CHARLES H. AND WERTHESSEN, NICHOLAS T.: The endocrine dyscrasia of
acne vulgaris in women. Endocrinology, 27: 755—758, 1940. 5. NATHANSON, IRA T., TOWNE, Lois E. AND AUB, JOSEPH C.: The daily excretion of urinary androgens in normal children. Endocrinology, 24: 335—338, 1939. 6. SMITH, GEOROE VAN S., SMITH, 0. WATKINS, AND PINCUS, GREGORY: Total urinary
estrogen, estrone and estriol during a menstrual cycle and a pregnancy. Am. J. Physiol., 121: 98—106, 1938.
7. WAY, STUART C.: Discussion of Paper by William C. Goeckerman: Hormonal therapy
of acne vulgaris in the female; A clinical attempt at its evaluation. Arch. Dermat. & Syph., 61: 241—242, 1950.
8. LAWRENCE, CHARLES H. AND WERTHESSEN, NICHOLAS T.: Treatment of acne with
orally adlninistered estrogens. J. Clin. Endocrinol., 2: 636—638, 1942. 9. GOECKERMAN, WILLIAM C.: Hormonal therapy of acne vulgaris in the female; A clinical
attempt at its evaluation. Arch. Dermat. & Syph., 61: 237—243, 1950. 10. BIRNBRRG, CHARLES H. AND REIN, CHARLES P.: Treatment of acne vulgaris; A pre-
liminary study on the value of pregnant-mare serum. J. Clin. Endocrinol., 4: 65—70, 1944.
11. (a) LYNCH, F.: Acne in university students. J.A.M.A., 113: 1792, 1939. (b) LYNCH, F. W.: Acne vulgaris; Review of histologic changes observed in early lesions. Arch. Dermat. & Syph. 42: 593—606, 1940. 12. GREENBLATT, ROBERT B. AND BROWN, NELSON 11.: The storage of estrogen in human fat after estrogen administration. Am. J. Obst. & Gynec., 63: 1361—1363, 1952. 13 THOMPSON, C. H. AND WaRNEH, H. W.: Studies on estrogen, tri-p-anisylchloroethylene. Proc. Soc. Exper. Biol. & Med., 77: 494—497, 1951.
14. TRUNNELL, J. B.: Effects of TACE in the male rat. Read at TACE Symposium, Cincinnati, Ohio, January 17, 1952. 15. BICKERS, WILLIAM: Clinical report on the oral depot effect of TACE in the menopause.
Ibid. 16. BECKER, F. T.: The acne problem. Arch. Dermat. & Syph., 67: 173, 1953.
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
94
linolenic acid extract. Arch. This pdf is a scanned copy UV of irradiated a printed document.
24. Wynn, C. H. and Iqbal, M.: Isolation of rat
skin lysosomes and a comparison with liver Path., 80: 91, 1965. and spleen lysosomes. Biochem. J., 98: lOP, 37. Nicolaides, N.: Lipids, membranes, and the 1966.
human epidermis, p. 511, The Epidermis
Eds., Montagna, W. and Lobitz, W. C. Acascopic localization of acid phosphatase in demic Press, New York. human epidermis. J. Invest. Derm., 46: 431, 38. Wills, E. D. and Wilkinson, A. E.: Release of 1966. enzymes from lysosomes by irradiation and 26. Rowden, C.: Ultrastructural studies of kerathe relation of lipid peroxide formation to tinized epithelia of the mouse. I. Combined enzyme release. Biochem. J., 99: 657, 1966. electron microscope and cytochemical study 39. Lane, N. I. and Novikoff, A. B.: Effects of of lysosomes in mouse epidermis and esoarginine deprivation, ultraviolet radiation and X-radiation on cultured KB cells. J. phageal epithelium. J. Invest. Derm., 49: 181, 25. Olson, R. L. and Nordquist, R. E.: Ultramicro-
No warranty is given about the accuracy of the copy.
Users should refer to the original published dermal cells. Nature, 216: 1031, 1967. version of1965. the material. vest. Derm., 45: 448, 28. Hall, J. H., Smith, J. G., Jr. and Burnett, S. 41. Daniels, F., Jr. and Johnson, B. E.: In prepa1967.
Cell Biol., 27: 603, 1965.
27. Prose, P. H., Sedlis, E. and Bigelow, M.: The 40. Fukuyama, K., Epstein, W. L. and Epstein, demonstration of lysosomes in the diseased J. H.: Effect of ultraviolet light on RNA skin of infants with infantile eczema. J. Inand protein synthesis in differentiated epi-
C.: The lysosome in contact dermatitis: A ration. histochemical study. J. Invest. Derm., 49: 42. Ito, M.: Histochemical investigations of Unna's oxygen and reduction areas by means of 590, 1967. 29. Pearse, A. C. E.: p. 882, Histochemistry Theoultraviolet irradiation, Studies on Melanin, retical and Applied, 2nd ed., Churchill, London, 1960.
30. Pearse, A. C. E.: p. 910, Histacheini.stry Thearetscal and Applied, 2nd ed., Churchill, London, 1960.
31. Daniels, F., Jr., Brophy, D. and Lobitz, W. C.: Histochemical responses of human skin fol-
lowing ultraviolet irradiation. J. Invest. Derm.,37: 351, 1961.
32. Bitensky, L.: The demonstration of lysosomes by the controlled temperature freezing section method. Quart. J. Micr. Sci., 103: 205, 1952.
33. Diengdoh, J. V.: The demonstration of lysosomes in mouse skin. Quart. J. Micr. Sci., 105: 73, 1964.
34. Jarret, A., Spearman, R. I. C. and Hardy, J. A.:
Tohoku, J. Exp. Med., 65: Supplement V, 10, 1957.
43. Bitcnsky, L.: Lysosomes in normal and pathological cells, pp. 362—375, Lysasames Eds., de Reuck, A. V. S. and Cameron, M. Churchill, London, 1953.
44. Janoff, A. and Zweifach, B. W.: Production of inflammatory changes in the microcirculation by cationic proteins extracted from lysosomes. J. Exp. Med., 120: 747, 1964.
45. Herion, J. C., Spitznagel, J. K., Walker, R. I. and Zeya, H. I.: Pyrogenicity of granulocyte lysosomes. Amer. J. Physiol., 211: 693, 1966.
46. Baden, H. P. and Pearlman, C.: The effect of ultraviolet light on protein and nucleic acid synthesis in the epidermis. J. Invest. Derm.,
Histochemistry of keratinization. Brit. J. 43: 71, 1964. Derm., 71: 277, 1959. 35. De Duve, C. and Wattiaux, R.: Functions of 47. Bullough, W. S. and Laurence, E. B.: Mitotic control by internal secretion: the role of lysosomes. Ann. Rev. Physiol., 28: 435, 1966. the chalone-adrenalin complex. Exp. Cell. 36. Waravdekar, V. S., Saclaw, L. D., Jones, W. A. and Kuhns, J. C.: Skin changes induced by
Res., 33: 176, 1964.
duce acne in susceptible individuals and pointed out the absence of acne in eunuchs. It has been found, too, that the administration of ACTH and cortisone, both of which have androgenic qualities, is followed in some cases by the development of acne (2). While a preponderance of androgenic hormones is
often followed by acneform eruptions, it cannot be stated categorically that such excesses in themselves account for the disturbance because there is a concomitant alteration of the estrogen—androgen ratio. In a number of patients suffering from acne, it was found (3) that there was a moderate increase in the urinary excretion of androgen and a moderate decrease in the urinary excretion of estrogen which resulted in altered ratio. On the other hand, Lawrence and Werthessen (4) noted a decrease in urinary estrogen with no significant change in the excretion of urinary androgen, but they felt that the resulting increased ratio of androgen to estrogen was the responsible inciting factor. The occurrence of premenstrual exacerbation of acne is well known and has been ascribed to
the fact that at this period during the menstrual cycle, estrogen levels are at their lowest and, as a result, the androgen—estrogen ratio is elevated (5—7).
In an effort to restore the endocrine balance, estrogens have been administered to patients suffering from acne, with varying results. Sulzberger (2), reporting on the therapeutic effect of female sex hormones in refractory cases of acne, stated that in one-third of these patients such hormones were a valuable adjuvant, but untoward reactions occurred in a large number of cases. Nausea, delayed menses, prolonged flow and "spotting" were often so severe that it became necessary to stop the treatment. In a small series of cases, others reported good (8, 9) and bad (10, 11) results following estrogen therapy. A new synthetic estrogen, TACE, has been given therapeutic trial in a number of patients suffering from acne. TACE differs from other commonly used estrogens
in several respects. After oral administration it is stored in the body fat from which it is released slowly over a period of time (12, 13). In experimental animals, the administration of other estrogens has been shown to produce hyperplasia of the adrenals, but following TACE this effect is minimal (13, 14). This is of some importance in the treatment of acne, a condition in which a relative excess of androgenic steroids is considered to be an important causal factor. In addition, the use of TACE is reported to produce very few undesirable side effects (15). * TACE (chlorotrianisene(tri-p-anisylohloroethylene)) kindly furnished by The William S. Merrell Co. Received for publication April 17, 1953. 79
80
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY EXPERIMENTAL
Forty patients were given the drug (see Table I). All of these cases were young females except for three males. Nearly all were given 12 mgs. per day. Since there may be storage in fat with gradual release, a few of the patients were given the remedy throughout the cycle as well as just during the postovulatory phase. The chart shows the effects of its administration. Many of these patients were given topical applications simultaneously, and some of them had x-ray therapy. TABLE I WHEN GWEN
EPECT ON MENSES
NO. C4SS
40 RESULTS
Marked Improve.
Flare Premenstrually, 20
1
20
Same
19
Other Reactions
Worse
0
Discontinued due to marked irregularity of menses
Discontinued due to dysmenorrhea, 3 cases Had to have D and C, 1 case Increased sexual activity and spotting between periods in 1 case Missed two periods, 2 cases Given to three males who were unimproved DISCUSSION
Certainly this is not a cure for acne. Lynch (11) has demonstrated that many with acne improve with no therapy. Of course, there are many factors involved. Concommitant therapy, the age group observed, and even the temperature and
humidity are factors. Even with adequate controls, it is difficult to appraise such a therapeutic agent in this disease. Many patients seemed to improve while under observation. The effect on the menses was less when the drug was given during the post-
ovulatory phase of the menstrual cycle than through the entire cycle. Then, too, this effect seemed less after the drug had been taken for several months than for the first few months. These young females seem to adapt to the added estrogen. Perhaps the dose was too large. Maybe smaller doses would have had as good or better effect on their acne with less effect on the menstrual cycle. Several girls who developed tender breasts while on other estrogens did not do so on TACE. Reactions certainly were no higher on this estrogen than on previ-
TACE IN TREATMENT OF ACNE
81
ously tried chemicals; as a matter of fact, they were somewhat less, but still occur. The three males taking the drug showed no improvement. The exact approach to acne is still to be found. It appears likely that more than one factor is at work (16). REFERENCES 1. HAMILTON, JAMES B.: Male hormone substance; A prime factor in acne. J. Clin. Endocrinol., 1: 570—592, 1941. 2. SULZBEEGER, MARION B. AND WITTEN, VICTOR H.: Hormones and acne vulgaris. Med.
Clin. North America, 35: 373—390, 1951. 3. WILE, U. J., SNow, J. S. AND BEADBIJRY, J. T.: Stndies of sex hormones in acne: II. Urinary excretion of androgenic and estrogenic substances. Arch. Dermat. & Syph., 39: 200—210, 1939.
4. LAWRENCE, CHARLES H. AND WERTHESSEN, NICHOLAS T.: The endocrine dyscrasia of
acne vulgaris in women. Endocrinology, 27: 755—758, 1940. 5. NATHANSON, IRA T., TOWNE, Lois E. AND AUB, JOSEPH C.: The daily excretion of urinary androgens in normal children. Endocrinology, 24: 335—338, 1939. 6. SMITH, GEOROE VAN S., SMITH, 0. WATKINS, AND PINCUS, GREGORY: Total urinary
estrogen, estrone and estriol during a menstrual cycle and a pregnancy. Am. J. Physiol., 121: 98—106, 1938.
7. WAY, STUART C.: Discussion of Paper by William C. Goeckerman: Hormonal therapy
of acne vulgaris in the female; A clinical attempt at its evaluation. Arch. Dermat. & Syph., 61: 241—242, 1950.
8. LAWRENCE, CHARLES H. AND WERTHESSEN, NICHOLAS T.: Treatment of acne with
orally adlninistered estrogens. J. Clin. Endocrinol., 2: 636—638, 1942. 9. GOECKERMAN, WILLIAM C.: Hormonal therapy of acne vulgaris in the female; A clinical
attempt at its evaluation. Arch. Dermat. & Syph., 61: 237—243, 1950. 10. BIRNBRRG, CHARLES H. AND REIN, CHARLES P.: Treatment of acne vulgaris; A pre-
liminary study on the value of pregnant-mare serum. J. Clin. Endocrinol., 4: 65—70, 1944.
11. (a) LYNCH, F.: Acne in university students. J.A.M.A., 113: 1792, 1939. (b) LYNCH, F. W.: Acne vulgaris; Review of histologic changes observed in early lesions. Arch. Dermat. & Syph. 42: 593—606, 1940. 12. GREENBLATT, ROBERT B. AND BROWN, NELSON 11.: The storage of estrogen in human fat after estrogen administration. Am. J. Obst. & Gynec., 63: 1361—1363, 1952. 13 THOMPSON, C. H. AND WaRNEH, H. W.: Studies on estrogen, tri-p-anisylchloroethylene. Proc. Soc. Exper. Biol. & Med., 77: 494—497, 1951.
14. TRUNNELL, J. B.: Effects of TACE in the male rat. Read at TACE Symposium, Cincinnati, Ohio, January 17, 1952. 15. BICKERS, WILLIAM: Clinical report on the oral depot effect of TACE in the menopause.
Ibid. 16. BECKER, F. T.: The acne problem. Arch. Dermat. & Syph., 67: 173, 1953.
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
94
linolenic acid extract. Arch. This pdf is a scanned copy UV of irradiated a printed document.
24. Wynn, C. H. and Iqbal, M.: Isolation of rat
skin lysosomes and a comparison with liver Path., 80: 91, 1965. and spleen lysosomes. Biochem. J., 98: lOP, 37. Nicolaides, N.: Lipids, membranes, and the 1966.
human epidermis, p. 511, The Epidermis
Eds., Montagna, W. and Lobitz, W. C. Acascopic localization of acid phosphatase in demic Press, New York. human epidermis. J. Invest. Derm., 46: 431, 38. Wills, E. D. and Wilkinson, A. E.: Release of 1966. enzymes from lysosomes by irradiation and 26. Rowden, C.: Ultrastructural studies of kerathe relation of lipid peroxide formation to tinized epithelia of the mouse. I. Combined enzyme release. Biochem. J., 99: 657, 1966. electron microscope and cytochemical study 39. Lane, N. I. and Novikoff, A. B.: Effects of of lysosomes in mouse epidermis and esoarginine deprivation, ultraviolet radiation and X-radiation on cultured KB cells. J. phageal epithelium. J. Invest. Derm., 49: 181, 25. Olson, R. L. and Nordquist, R. E.: Ultramicro-
No warranty is given about the accuracy of the copy.
Users should refer to the original published dermal cells. Nature, 216: 1031, 1967. version of1965. the material. vest. Derm., 45: 448, 28. Hall, J. H., Smith, J. G., Jr. and Burnett, S. 41. Daniels, F., Jr. and Johnson, B. E.: In prepa1967.
Cell Biol., 27: 603, 1965.
27. Prose, P. H., Sedlis, E. and Bigelow, M.: The 40. Fukuyama, K., Epstein, W. L. and Epstein, demonstration of lysosomes in the diseased J. H.: Effect of ultraviolet light on RNA skin of infants with infantile eczema. J. Inand protein synthesis in differentiated epi-
C.: The lysosome in contact dermatitis: A ration. histochemical study. J. Invest. Derm., 49: 42. Ito, M.: Histochemical investigations of Unna's oxygen and reduction areas by means of 590, 1967. 29. Pearse, A. C. E.: p. 882, Histochemistry Theoultraviolet irradiation, Studies on Melanin, retical and Applied, 2nd ed., Churchill, London, 1960.
30. Pearse, A. C. E.: p. 910, Histacheini.stry Thearetscal and Applied, 2nd ed., Churchill, London, 1960.
31. Daniels, F., Jr., Brophy, D. and Lobitz, W. C.: Histochemical responses of human skin fol-
lowing ultraviolet irradiation. J. Invest. Derm.,37: 351, 1961.
32. Bitensky, L.: The demonstration of lysosomes by the controlled temperature freezing section method. Quart. J. Micr. Sci., 103: 205, 1952.
33. Diengdoh, J. V.: The demonstration of lysosomes in mouse skin. Quart. J. Micr. Sci., 105: 73, 1964.
34. Jarret, A., Spearman, R. I. C. and Hardy, J. A.:
Tohoku, J. Exp. Med., 65: Supplement V, 10, 1957.
43. Bitcnsky, L.: Lysosomes in normal and pathological cells, pp. 362—375, Lysasames Eds., de Reuck, A. V. S. and Cameron, M. Churchill, London, 1953.
44. Janoff, A. and Zweifach, B. W.: Production of inflammatory changes in the microcirculation by cationic proteins extracted from lysosomes. J. Exp. Med., 120: 747, 1964.
45. Herion, J. C., Spitznagel, J. K., Walker, R. I. and Zeya, H. I.: Pyrogenicity of granulocyte lysosomes. Amer. J. Physiol., 211: 693, 1966.
46. Baden, H. P. and Pearlman, C.: The effect of ultraviolet light on protein and nucleic acid synthesis in the epidermis. J. Invest. Derm.,
Histochemistry of keratinization. Brit. J. 43: 71, 1964. Derm., 71: 277, 1959. 35. De Duve, C. and Wattiaux, R.: Functions of 47. Bullough, W. S. and Laurence, E. B.: Mitotic control by internal secretion: the role of lysosomes. Ann. Rev. Physiol., 28: 435, 1966. the chalone-adrenalin complex. Exp. Cell. 36. Waravdekar, V. S., Saclaw, L. D., Jones, W. A. and Kuhns, J. C.: Skin changes induced by
Res., 33: 176, 1964.