TOPICAL ANDROGEN TREATMENT FOR ACNE a review by A. J. M. Vermorken and J. J. G. Houben

What is Acne? ACNE VULGARIS IS A DISORDER OF THE SKIN w h i c h begins

ABSTRACT

Acne results from the increased production of sebum and the accumulation of sebum in the sebaceous duct. Androgens have a direct influence on this condition as they stimulate both the formation of sebum and the hyperkeratinisation of the upper part of the duct which leads eventually to its obstruction. Clinical tests have demonstrated that most acne patients do not have an increased level of androgen in the blood. They do, however, show an increased conversion of testosterone to 5-alpha-dihydrotestosterone (5-alpha-DHT) in the skin. This latter hormone is responsible for the stimulation of the sebaceous gland. The enzymic conversion of testosterone to 5-alpha-DHT can be inhibited by progesterone. Progesterone, when applied topically in an alcohol/water solution, is 80 percent metabolized in the skin and is not converted into androgens in the body. It may therefore be expected that the topical application of progesterone will not give rise to side effects in either men or women. Preliminary trials are in agreement with this expectation. Extensive clinical investigations of an alcohol/ water solution of progesterone are therefore recommended, as this may be the first clinically useful, locally active, antiandrogen to be effective in the treatment of acne. Drug Intelligence and Clinical Pharmacy

VOL 12

with the accumulation of sebum in the sebaceous duct. This accumulation results from obstruction of the duct together with an increased sebum secretion. The pressure built up by the accumulated sebum can rupture the duct. Diffusion of the sebum, particularly of its fatty acids, into the skin brings about an inflammatory reaction which is often accompanied by an infection. More Corynebacterium acnes have been found on the surface and in the pilosebaceous duct of patients with acne than of controls.1'2 Besides causing infection, bacteria produce lipases that stimulate the inflammatory processes by hydrolyzing the sebum into fatty acids. Bacteria also produce other enzymes and antigens that seem to play a role in the formation of acne lesions. These effects can be attributed to both Corynebacterium acnes and Staphylococcus epidermis.2 The first clinical sign of acne is a hyperkeratosis of the opening of the sebaceous duct, which blocks the upper part of the follicle.3»4 As this hyperkeratosis can be produced in test animals by large doses of androgens, A. J. M. VERMORKEN is a member of the Departments of Biochemistry, Human Genetics and Pharmacology of the University of Nijmegen and J. J. G. HOUBEN is a member of the Department of Pharmacology of the University of Nijmegen, Geert Grooteplein Noord 21, Nijmegen, The Netherlands. T h e authors wish to thank Prof. E. J. Ariens and Prof. H. Bloemendal (Departments of Pharmacology and Biochemistry, University of Nijmegen) for critically reading the manuscript. T h e authors also wish to thank Mr. A. M. Vermorken for valuable and stimulating discussions.

MAR 78

151

and as acne in humans generally occurs in puberty and never in castrates, it is highly likely that androgens are involved in this process.5 It has also been observed that androgens stimulate sebum secretion. They increase the number of lobes of the sebaceous glands and of the cells of the follicles by stimulating the rate of mitosis.6·7 The involvement of androgens in the formation of acne is further suggested by the fact that serious cases of acne are often observed in women that suffer from polycystic ovaries and virilizing tumors.8

The Mechanism of Androgen Action

Figure 1. a) Flank organ of a 10-week-old male hamster b) Flank organ of a 10-week-old female hamster c) Flank organ of a 10-week-old female hamster; the left organ has been treated with 4 /ig of testosterone propionate daily for 3 weeks, while the right organ has not been treated (From Voigt and Hsia,84 with permission)

152

Although the adrenals and normal ovaries produce a small amount of the most important male hormone, testosterone, it is mainly produced by the Leydig cells in the testes. From the testes, testosterone diffuses to the seminal tubes and also into the circulation, thereby reaching all the peripheral organs. A feed-back mechanism involving the hypothalamus maintains a constant concentration of testosterone in the blood. The mechanism of testosterone's action can best be studied at its most important target organ, the prostate. Testosterone causes this organ to grow more intensely and to increase its secretion. The action of the hormone in the prostate cell was studied by injecting radioactive testosterone into castrated test animals. The retention of testosterone in the prostate and in nontarget tissues was compared. It appeared that the radioactivity per wet weight of tissue was much higher in the prostate than in blood, spleen, lung, thymus and diaphragm.9 It was also demonstrated by biochemical and autoradiographic studies that the major part of the radioactivity was concentrated in the cellular nuclei,10»11 which justifies the conclusion that the hormonal activity is occurring in the cell nucleus. Isolation of the prostate cellular nuclei from test animals treated with radioactive labeled testosterone revealed that it was primarily 5-alpha-DHT and not testosterone that was bound in the nuclei.9«12·13 The retention of 5-alpha-DHT by prostate cell nuclei was also reproduced in vitro by incubating minced prostrate gland with radioactive testosterone. About 80 percent of the radioactivity associated with the isolated nuclei could be identified as 5-alpha-DHT. These results show that 5-alpha-DHT and not testosterone is the active hormone. This is further sustained by the observation that 5-alpha-DHT is a more potent androgen in biological assays than is testosterone.14·15·16

Androgens in the Skin Following the discovery of the rçle of testosterone metabolism in the prostate, it was necessary to determine whether 5-alpha-DHT was also formed in the skin. In 1968, Gomez and Hsia were able to demonstrate that this was so by incubating human skin with testosterone.17 Their findings were confirmed by Wilson and Walker in 1969.18 The next question posed was whether 5-alpha-DHT was also formed in the sebaceous gland and, if so,

ANDROGENS AND ACNE whether the activity of the gland was stimulated by this metabolite. For this investigation hamsters were used as test animals. These animals possess flank organs, a pair of pigmented nodules that consist of large sebaceous glands. The flank organs in the male hamster are much larger than those in the female (Figures la and l b ) . However, female flank organs can be enormously enlarged by local treatment with testosterone (Figure l c ) 19,20 Normal sebaceous glands are very small, so these large organs were very suitable for experimental purposes. In 1972, Takayasu and Adachi were able to show that testosterone is indeed converted into 5-alpha-DHT by flank-organ tissue.21 Also, when radioactive testosterone was injected into the hamster, radioactive 5-alpha-DHT could be found in the flank-organ and, as has been demonstrated in the human prostate, the amount of 5-alpha-DHT bound in the nuclei was much greater than that of testosterone. It was therefore concluded that 5-alpha-DHT is the active hormone in the sebaceous gland. These results led Sansone and Reisner to compare the formation of 5-alpha-DHT in the skin of patients with acne with its formation in the skin of control persons.22 They found that the production of this metabolite in diseased skin is 2 to 20 times greater than that in healthy skin (Figure 2). Moreover, they confirmed the results of Wilson and Walker, who had previously shown that the rate of production of 5-alpha-DHT is strongly dependent upon the area from which the biopsy is taken. In the skin of the forehead, for instance, 5alpha-DHT is formed more rapidly than in the skin of the chin or the back (Figure 2). 2 2 These facts gave rise to a completely new view of the hereditary disease acne. This disease is obviously not due to a changed hormone-level in the blood, but to the hormone levels in the skin itself. This justifies the conclusion that local treatment may be effective, a concept that could represent a break-through in the treatment of acne.

dihydrore&roaterone f o r m a t i o n (μμ moles /mg t i s s u e /3 h )

70-] o normal • acne

605040-

• 3020-

8

° o

chin

*

1 ?

back forehead WOMEN

chin

back forehead MEN

Figure 2. Formation of 5-alpha-dihydrotestosterone in the skin of the chin, back and forehead of acne-patients and control persons (Data has been taken from Sansone and Reisner-)

In order to prevent the action of testosterone in the sebaceous gland, testosterone antagonists, i.e., substances that abolish the action of testosterone in target organs, have been sought. In 1962, Strauss et al.23 investigated whether estrogens act as testosterone antagonists. For this purpose sebum secretion was measured at the two sides of the forehead by determining the increase in weight of a piece of blotting paper which had been attached to the skin for a certain period of time. When one side of the forehead was rubbed with a solution of estrogen, a decreased sebum-secretion was observed. However, this decrease was also found at the controlsite. Moreover, in males, loss of libido and feminization phenomena were observed after prolonged treatment. These systemic phenomena indicated that a local antagonism did not occur, but that the absorption of estrogens into the blood probably decreased the secretion of testosterone from the testes. VOL 12

•

10-

How to Inhibit the Activity of the Sebaceous Gland

Drug Intelligence and Clinical Pharmacy

• •

MAR 78

During the development of the oral contraceptives, a number of the preparations tested turned out to be androgen-antagonists. Cyproterone acetate, for instance, is a very potent androgen-antagonist. When acne-patients were treated orally with this hormone, there was a rapid and significant improvement in their condition. 24 ' 26 There were disadvantages to the oral use of such preparations, however. Males suffered a loss of libido and potency,27 while the drugs could not be given to pregnant females as they caused feminization of the fetus.28»29 Topical treatment of the human skin with cyproterone acetate did not inhibit the activity of the sebaceous glands.30·31 The drug had no topical activity towards the flank-organ of the hamster either.

Figure 3. a) Flank organs of female hamsters treated topically with 4 ßg of testosterone propionate daily for 3 weeks b) Flank organs of female hamsters treated simultaneously with 4 ßg of testosterone propionate plus 400 ßg of 4-androsten3-one-17j3-carboxylic acid daily for 3 weeks. (From Voigt and Hsia," with permission)

Table 2. 5a-Reduction of Radioactive Testosterone Incubated with Pubic Skin of Normal Men: Inhibition by Topically Applied Progesterone. 38 PERCENTAGE OF 5»-REDUCED METABOLITES

Casel Case2 Case 3 Case 4 Case 5 Average value

154

BEFORE PROGESTERONE APPLICATION

AFTER PROGESTERONE APPLICATION

INHIBITION (PERCENT)

11 13 20 17 11

3 5 2 5 2

73 61 90 70 82

14.4±4

3.4±1.5

75.2±11.1

When it was found that 5-alpha-DHT (and not testosterone) stimulated the sebaceous glands, and that the active form of the androgen is mainly formed in the skin,21 it was expected that substances which were able to inhibit 5-alpha-reductase would also function as testosterone antagonists. Therefore, Voigt et al.33 tested a great number of steroids for their capacity to inhibit the conversion of testosterone to 5-alpha-DHT in microsomal suspensions of the skin. Four of the substances tested had a considerable inhibitory capacity. These were androstenedione, deoxycorticosterone, progesterone and 4-androsten-3-one-170-carboxylic acid (4A-17/Î-CA). Voigt and Hsia34 doubted the usefulness of androstenedione, deoxycorticosterone and progesterone for therapy, since these substances had intrinsic hormonal activity. They therefore proposed to investigate the antiandrogenic activity of 4A-17ß-CA, since this substance was not known to possess any hormonal activity. In 1973 they described the action of this steroid on the flank-organ of the hamster.34 Figure 1 shows the difference between the flank-organ of an adult male and an adult female. When the organ of the female is rubbed daily for three weeks with 4/