CA2321406A1 - Restoration of perturbed barrier function by application of antiandrogens - Google Patents

Abstract

Disorders of the skin and mucous membranes that have a disrupted or dysfunctional epidermal barrier are treated or prevented by the administration of antiandrogens, including antagonists of the androgen receptor, inhibitors of the conversion of testosterone to dihydrotestosterone, and agents that suppress androgen production at the level of the hypothalamic-pituitary axis.

Description

P A TFTvIT
Attornev_ Docket No.: 23072-l 14100US
UC Case No. 2000-294-1 RESTORATION OF PERTURBED BARRIER
FUNCTION BY APPLICATION OF
ANTIANDROGENS
STATEMENT AS TO R(GHTS TO INVENTIONS MADE UNDER
FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
This invention was made with Government support by the Veterans Administration Gram: Nos. HD 29706 and AR 19098. awarded by the National Institutes of Health. The Government has certain rights in this invention.
BACKGROUND OF THE INVENTION
1. Field of the Invention This invention resides in the technical field of formulations for the treatment of skin conditions, and relates in particular to the treatment of subjects suffering from skin or mucous membrane diseases or disorders that display disruptions of the barrier function.

2. Description of the Prior Art The cutaneous permeability barrier resides in the outermost layer of the epidermis, the stratum corneum (SC). The SC is a highly resilient tissue organized into a unique two-compartment system of nucleated corneoc~~tes embedded in a lipid-enriched, intercellular matrix. ~,~~hich is enriched in ceramides, cholesterol. and free fatty acids. This hydrophobic mixture is organized into stacks of broad lamellar bilayers, which mediate both 2(1 transcutaneous water loss and the l7ercutaneous absorption of xenobiotics.
Acute and chronic perturbations in the permeability ban-ier stimulate a coordinated lipid synthetic and secretory response in the underlying epidernais that leads to rapid restoration of barrier homeostasis.
Yet. little is known about the reguiation of epidermal lipid metabolism by circulating hormones or other biological response modifiers. Both male primates and rodents exhibit more robust cutaneous lipid synthesis than age-matched females. Moreover, epidermis/keratinoc~~tes express androgen receptors and possess the enzymatic apparatus to convert testosterone to dihydrotestosterone. Yet, priior studies failed to discern gender-related differences in human barrier function (Reed, .1.T., et al., Archiv. Dermatol.
131:1134-1 I38 (1995)).

In contrast, sex hormones exert important influences on the latest stages of development of the permeability barrier in utero (Williams, M.L., et al., J.
Invest Dermatol.
Symposium Proceedings 3:75-79 (19!8)). Whereas exogenous estrogens accelerate barrier ontogenesis both in utero and in grovr~th-factor-free explant cultures, androgens retard the kinetics of barrier ont:ogenesis (Hanle;y, K., et al., J. Clin. Invest.
97:2576-2584 (1996)).
Moreover, male fetuses display a delay in barrier development vs. female littermates, an effect that is reversible when pregnant mothers are treated with the testosterone receptor antagonist, flutamide (Hanley, K., et .al., J. Clin. Invest. 97:2576-2584 (1996)). Although decreased survival rates in male premature infants have been ascribed to increased respiratory distress rates (Khoury, M.J., et al., ,Arn. J. Obstet. Gynecol. 151:772-782 (1985)), a negative influence of androgens on skin development could explain ongoing differences in premature human male vs. female infants, even when treated with surfactant replacement therapy (Allen, M.C., et al., l~~ Engl. J. Mee:f. :329:1597-1601 (1993); La Pine, T.R., et al., Pediatrics 96:479-483 (1995)).
SUMMARY OF THE INVENTION
It has now been discovered that the formation of a functional epidermal barrier is accelerated by the administration of antiandrogens. While the prior art has addressed the administration of antiandrogens to pregnant female rats to observe its effect on the skin of the fetal rat, this invention resides in the discovery that antiandrogens are effective on mammalian subjects i.n general, and also that they arcs effective as topical treatments.
Included among the definition of anti~androgens are (i) antagonists of the androgen receptor, (ii) agents that suppress androgen production at the level of the hypothalamic-pituitary axis, and (iii) inhibitors of the conversion of testosterone to dihydrotestosterone.
The invention thus resides in the use of antiandrogens the treatment of mammalian skin suffering from a deficient or perturbed barrier function. The invention is particularly useful in the treatment of premature infants, as well as various forms of dermatitis, inflammation to mucous membranes, ulcers and erosions, and any physiological condition or disease in which a perturbed barrier function is present.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graphical representation of a study showing the improvement of barrier recovery after surgical castration of male mice.

FIG. 2 is a graphical representation of a study showing the worsening of barrier recovery in castrated male rnic.e after systemic testosterone replacement.
FIG. 3 is a graphical representation of a study showing the improvement of barrier recovery in male mice after systemic flutamide treatment.
FIG. 4 is a graphical representation of a study showing the improvement of barrier recovery in male mice after topical flutamide treatment.
FIG. 5 is a graphical representation of a study showing that barrier recovery is faster in pre-pubertal mice than it is in young adult male mice.
FIG. 6 is a graphical representation of a study showing the changes in barrier recovery in relation to testosterone therapy in a hypogonadal human male.
DETAILED DESCRIPTION OF T'HE INVENTION AND
PREFERRED EMBODIMENTS
Antagonists of the androgen receptor are well known in the pharmaceutical industry for uses other that those provided by the present invention. Included among these antagonists are those of the formula O
R~-_ ~ ~ N , _R3 in which:
R' is a. CZ-Cb alkyl, CS-C~ cycloalkyl, CS-C~ cycloalkyl substituted with C1-alkyl, or C2-C6 alkyl substituted with one or more of the following:
halogen, hydroxyl, phenylsulfonyl, and halogen-substituted phenylsulfonyl, and RZ and R3 are either the same or different, and being either nitro, trifluoromethyll, halogen, cyano, C1-C3 alkyl, or C1-C3 alkoxy.
Certain subgenera within the scope of this formula are preferred. For example, R' is preferably CZ-C6 alkyl or CZ-C6 alkyl substituted with one or more of halogen, hydroxyl, phenylsulfonyl, and halogen-substituted phenylsulfo:nyl. More preferably, R' is CZ-C6 alkyl or CZ-C6 alkyl substituted with hydroxyl, phenylsulfonyl, halogen-substituted phenylsulfonyl, or a combination of hydroxyl and halogen-substituted phenylsulfonyl.
Antiandrogens of these structures are disclosed in United States Patent No. 3,847,988 and United States Patent No. 4,636,505. The disclosures of both of these patents are incorporated by reference.
Examples of specific antiandrogens within this formula are flutamide, whose scientific name is 2-methyl-N-[4-nitro-3-(trifluorome;thyl)phenyl]propanamide and whose molecular formula is CF, O

CH-~~ N O

and bicalutamide, whose scientific name is (~)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl propanamide and whose structural formula is H
S. , N \ CF3 O
F CN
Antiandrogens that are inhibitors of the conversion of testosterone to dihydrotestosterone are exemplified by certain substituted androstenones and certain pregnadienediones. One example is megestrol acetate, whose scientific name is 17a-hydroxy-6-methylpregna-4,6-dime-3,20-dione acetate and whose structural formula is C O O

O
Another example is finasteride, whose scientific name is (Sa,, 17(3)-N-(1,1-dimethylethyl)-3-oxo-4-azaandrost-1-ene-17-carboxarr~ide, and whose structural formula is H
C/N\C CH
( z)z Disclosures of compounds of this general structure are found in United States Patents Nos.

3,356,573 and 3,400,137, the disclosures of both of which are incorporated herein by reference for all legal purposes capable of being served thereby.
Antiandrogens that are, agents that suppress androgen production at the level of the hypothalamic-pituitary axis are exemplified by LHRH (leutinizing hormone releasing hormone) and its analogues, whose structures are known to those skilled in the art.
In the practice of this invention, the antiandrogens will be administered as active ingredients in a formulation thief is pharmaceutically acceptable for the particular means of administration desired. In certain embodiments of this invention, the formulation is intended for topical administration, while in others the formulation is intended for systemic administration or for intralesional administration. These formulations may or may not contain a vehicle, although the use of a vehicle is preferred. Preferred vehicles are non-lipid vehicles, particular water-miscible liquids or mixtures of water-miscible liquids. Examples of such liquids are methanol, ethanol., isopropanol, ethylene glycol, propylene glycol, and butylene glycol. The most appropriate vehicle will depend on the particular type of administration that the formulation is designed for.
The concentration of active ingredient in the formulation is not critical to the invention and can vary widely, depending on the vehicle, the type and stage of condition being treated, the site where treatment is being administered, and similar considerations. In most applications, the optimum concentration will range from about 10 p.g/mL
to about 100 pg/mL. In general, however, the optimum amounts for any given application or active agent will be readily determinable by routine experimentation.
The formulation can be a lotion, a solution, a gel, a cream, an emollient cream, an unguent, a spray, or any other .form that will permit topical application.
The formulation H
H

may also contain one or more agents that promote the spreading of the formulation over the affected area, but are otherwise biologically inactive. Examples of these agents are surfactants, humectants, wetting agents, emulsifiers and propellants.
Examples of skin conditions that are susceptible to treatment by the practice of this invention are:
Barrier Abnormality Representing Primary Process Chronological aging (epidermis) Photoaging (epidermis) Atopic; dermatitis The skin of premature infants of gestational age less than 33 weeks Cheilitis RXLI, Gaucher's (I:f); Neimann-Pick (I) Burns Ulcers (ischemic, vascular, diabetic) Blisters/bullous disorders (friction, keratin abnormalities) Diabetes Barrier Abnormality Triggers Imrrmnologic Abnormality Psoriasis (plaque type) Irritant contact derrrcatitis (acute) Occupational dermatitis (acute) Diaper dermatitis Allergic contact dermatitis Barrier Abnormality Sustains Pathophysiology Atopic: dermatitis Irritant contact dermatitis (chronic) Occupational dermatitis (chronic) Psoriasis Hypertrophic scars and keloids Cheilitis Lamellar ichthyoses; >=?pidermolytic hyperkeratosis; Harlequin ichthyosis Immunologic Abnormality Triggers Barrier Abnormality Phytotoxic reactions Bullou.s allergic reactions Erythrodermic, pust.ular, and guttate psoriasis Optimal methods and frequency of administration will be readily apparent to those skilled in the art or are capable of determination by routine experimentation. Effective results in most cases are achieved by topical application of a thin layer over the affected area, or the area where ones seeks to achieve the desired effect. Depending on the condition being addressed, its stage or degree, and whether application is done for therapeutic or preventive reasons, effective results are achieved with application rates ranging from one application every two or three days to four or more applications per day.
The invention is generally applicable to the treatment of the skin of terrestrial mammals, including for example humans, domestic pets, and livestock and other farm animals.
The following examples are offered for purposes of illustration, and are not intended to limit or to define the invention. All literature citations in these examples and throughout this speci:frcation are incorporated herein by reference for all legal purposes capable of being served thereby.
EXAMPLES
Materials:
Castrated, sham-operated, and normal hairless male mice (Sk:hl) were purchased from Charles River Laboratories (Philadelphia, PA). Adult mice, age weeks, were used for all experiments. Serum testosterone levels were >1500 pg/mL in control animals and less than 20 in castrated animals. Prepubertal male mice were utilized between four and five: weeks of age. Testosterone propionate and flutamide was purchased from Sigma Chemical Co. (St. Louis, MO). Subcutaneous testosterone and flutamide were solubilized in peanut oil. Topical testosterone and flutamide were solubilized in propylene glycol:ethanol (7:3 vols) at the final concentrations, volumes, areas and routes of administration described in the results and figure legends for each experiment. Peanut oil and propylene glycol:ethanol were used as vehicles, respectively.
A single 58-year old, hypogonadal male subject (post-transphenoidal hypophysectomy in 1984) was studied at various points before and after testosterone replacement (testosterone cyprionate 200 mg IM at three-week intervals).

Measurements of Barrier Recovery and Stratum Corneum Integrity:
Trans-epidermal wader loss (TEWL) was measured with an electrolytic water analyzer (Meeco, Warrington, PA). Barrier function was disrupted by sequential cellophane tape stripping until TEWL levels reached 3 to 8 mg/c:m2/h. TEWL was measured immediately after barrier disruption a.nd at various time intervals after acute disruption, usually at one, three, six, and 12 hours after barrier disruption. Stratum corneum integrity was defined as the mean number o:F tape strippings required to abrogate the barrier to >3 mg/cm2/h.
Lipid Synthesis Studies:
For the in vitro studies, animals were killed one hour after barrier disruption and skin samples of approximately 1 cm2 were incubated for two hours at 37°C in a 2-mL
solution of 10 mM ethylene diamine tetraacetic acid (EDTA) in Dulbecco's PBS, calcium and magnesium free, containing 40 pci [14C] acetate. After stopping the reaction by immersion in iced phosphate-buffered saline (PBS), the epidermis was separated from the dermis and the quantities of labeled fatty acids and cholesterol were determined in the epidermis after saponification, extraction, and thin layer chromatography (Grubauer, G., et al., J. Ljpid Res. 28:746-752 (1987); :Mao-Qiang, M., et al., J. Clin. Invest.
92:791-798 (1993)). Results were expressed as nanomoles incorporated per hour per gram of epidermis.
Light Microscopy, Ultrastructural and Quantitative Morphometric Studies:
Skin biopsy samples vvere taken immediately before and three hours after tape stripping of castrated mice, treated with either subcutaneous testosterone or vehicle (n = three from each group), and processed for Might and electron microscopy. Samples were minced to <0.5 mm3, fixed in modified Kaxnovsky's fixative overnight, and post-fixed in either 0.5%
ruthenium tetroxide or 2% aqueous osmium tetroxide, both containing 1.5%
potassium ferrocyanide, as described by Hou, S..Y.E., et al., J. Invest. Dermatol.
96:215-223 (1991).
After fixation, all samples were dehydrated in graded ethanol solutions, and embedded in an Epon-epoxy mixture. One-half micron sections, stained with toluidine blue, were used for light microscopic studies. Ultrathin ~cections were ea;amined, with or without further contrasting with lead citrate, in an electron microscope (Zeiss 10A, Carl Zeiss, Thornwood, NY) operated at 60 kV.
For quantitative studies, 10-15 pictures of the outer stratum granulosum (SG) and the SG-SC interface at a constant original magnification of 1 S,OOOx were selected at random from each sample group. l.,a~mellar body (LB) density was calculated using a point-count intersect method (Elias, H., e;t al., Guide to Practical Stereology, Basel:Karger (1983)).
A grid of test points was superimposed over non-overlapping regions of each picture.
Intersect points over lamellar bodies vs. cytosol were totaled per cell and for each experimental group as a whole. Assignment of organelles as lamellar bodies required the presence of a trilaminar limiting merrcbrane; characteristic ellipsoidal shape; and a 0.4-0.6-~m long axis. The nucleus was excluded from calculations of cytosolic volume. The volume ratio of lamellar bodies in the outer SG layer comprises the number of LB
intersects/number of cytosolic intersects x 100. The extent of lamellar body secretion was quantified as the cross-sectional area of the intercellular domain at the SG-SC junction/the measured length in p,m of the measured area. The cross-sectional area was determined by two unrelated methods: (a) by weighing paper overlays of the region (Rassner, U., et al., Tissue & Cell 31:489-498 ( 1999)); and (b) by integrating area measurement on the scanned pictures with NIH image software.
Statistical Analysis:
For statistical analyses, two-tailed Student's t Test and SPSS software (SPSS
Inc., Chicago, IL) were used. Data are expressed as mean ~ SEM with p<0.05 considered significant.
RESULTS
To assess the impact of androgens on permeability barrier homeostasis, the kinetics of barrier recovery in castrated vs. sham-operated hairless mice were compared, with barrier recovery studies performed eight weeks after castration or sham operation. Barrier recovery was assessed one, three, six, and 12 hours after acute disruption by sequential tape stripping. The results, expressed as mean ~ SEM, are shown in FIG. 1, which indicates that the kinetics of barrier recovery was accelerated significantly at all time points in castrated mice, with the greatest differences apparent at one and three bouts (FIG. 1; p < 001 and <
0.05, respectively). Moreover, castrated animals displayed significantly greater stratum corneum integrity than testosterone-rc;plete, castrated and control animals.
The results are shown in Table I.

TABLE I: STRATUM CORNEI1M INTEGRITY IN CASTRATED, TESTOSTERONE
REPLETE VS. CONTROL MICE
ANIMALS TAPE STRIPPINGS f SEMa Non-Castrated 3.29 + 0.18b (n = 7) Castrated + Vehicle 4.27 + 0.14h (n=11) Castrated + Testosterone 2.27 ~ 0.14h (n = 11;) a Number of stripping,s required to abrogate barrier to TEWL >3 mg/cm2/h b Differences between all groups are significant at p <0.001 These results show that surgically-induced hypogonadism leads to accelerated barrier recovery and enhanced stratum corneum intei;rity in male mice.
To ascertain further wlhether accelerated barrier recovery after castration is due to androgen depletion, the effects of testosterone-repletion vs. vehicle-repletion in castrated mice were assessed by injecting castrated mice simultaneously with either testosterone propionate (5 mg/kg) diluted in peanut oil or peanut ;ail alone daily for seven days, followed by measurement of barrier recovery after tape stripping over a distant site on the eighth day.
Whereas vehicle treatment did not influence barrier recovery rates, testosterone administration slowed barrier recovery at all time points (FIG. 2, showing mean ~ SEM), with the greatest difference at three hours (p< 0.001 ). These results show that testosterone reverses the acceleration in barrier recovery that occurs in castrated mice.
To determine whether the castration-induced acceleration of barrier recovery is specific for surgical castration, or a more general attribute of testosterone deficiency, the effects of medical castration on barrier recovery in normal (non-castrated) male mice were assessed. For these studies, either the androgen-receptor antagonist, flutamide (50 mg/kg), or vehicle alone subcutaneously were administered once daily for seven days, followed by measurement of barrier recovery on the eighth day. ,4s seen in FIG. 3 (again showing mean ~
SEM), barrier recovery accelerated at all time points in systemic flutamide-treated animals.
In fact, the absolute recovery rates at each time point were virtually identical for medical castration to those in surgically-castraited animals. These results show that testosterone depletion has positive effects on perrrieability barrier homeostasis, independent of the method of production of hypogonadism.

To determine whether the negative effects of testosterone on the barrier are due to systemic or cutaneous alterations produced by the hormone, a study was performed to determine whether the effects of testosterone are due to a direct effect of the hormone on the skin itself, measuring; barrier recovery after seven, once-daily applications of flutamide (30 ~,g/mL) to a 2.5 cm2 area on one flank of normal, non-castrated mice. The contralateral flank was treated daily with an equal volume of the propylene glycol:ethanol vehicle alone.
Flutamide accelerated barrier recovery, while the vehicle applied to the contralateral flank did not alter barrier recovery rates relative to vehicle applied to non-flutamide-treated mice (FIG.

4, showing mean ~ S EM)). Since flutamide-treatment only affected the treated flank (the contralateral flank did not change significantly), these results show that the effects of testosterone are due to local, rather than distant effects of the hormone.
A study was then performed to determine whether variations in endogenous androgen levels are associated with pre- vs. post-pubertal differences in barrier homeostasis.
Mice display low androgen levels while they are still pre-pubertal, i.e., less than six weeks old, with a post-pube~rtal increase in hormone levels ;zfter eight weeks of age. As seen in FIG.

5, prepubertal mice (~E-5 weeks old) display more rapid barrier recovery rates than do young adult male mice (11-week-old) at botlh three and six hours after acute disruption (p < 0.02).
Recovery rates in the eleven week-old mice again we're comparable to those in the somewhat older (12-14 week), non-castrated adults described above (see FIGS. 1-4).
These results show that differences in male gonadal status are associated with post-natal, developmental changes in barrier function.
A study was then performed to ascertain whether the negative effects of androgens are of potential relevance for humans. Barrier recovery kinetics were assessed in one hypogonadal subject receiving intermittent testosterone replacement.
Barrier recovery measurements taken at times of the high testosterone period (two or three days after muscular injections of testosterone cyprionate, 200 mg) and low (immediately prior to next injection).
Serum testosterone levels were taken at the same time. As seen in FIG. 6, barrier recovery rates were highest when serum testosl:erone levels approached their nadir, while conversely, the kinetics of recovery slowed in conjunction with high testosterone blood levels. Although all observations were from a single subject, they achieved statistical significance (p = 0.011;
Student's t test applied to multiple me;asurements). These results indicate that permeability barrier homeostasis in humans also changes with alterations in serum testosterone.

A series of studies was then conducted to identify potential mechanisms by which androgens might compromise barrier homeostasis. These results are shown in Table II.
TABLE II: LIPID SYNTHESIS IN TESTOSTERONE- vs. VEHICLE-TREATED
('AST RATED l~rIICE
ANIMALS SYNTHESIS (nmoUg epidermal weight/h) Castrated Chol BA TNS
+ Testosterone 3.40 i O.SSa 17.12 t 1.9b 4.56 ~ 0.82°
<0.01 <0.001 <0.02 + Vehicle 1.37 ~ 0.23 6.72 t 0.60 1.59 t 0.29 Sham-Operated +Testosterone 3.49 ~ 0.92a IS.66~4.336 4.31 ~ 1.260 <0.05 NS <0.05 + Vehicle 1.21 t 0.25 6.95 ~ 0.85 1.40 ~ 0.30 a.b.c Differences are not significant; ZNS = total non-saponifiable lipids The syntheses of both non-saponifiable epidermal lipids (primarily cholesterol) and saponifiable epidermal lipids (fatty acids) were comparable in castrated and non-castrated animals. However, testosterone administration caused a significant, but equivalent increase in. epidermal lipid synthesis in both castrated and non-castrated animals.
Since these results show that testosterone repletion stimulates epidermal lipid synthesis, modulations in lipid synthesis alone cannot explain the decline in barrier homeostasis in testosterone-replete animals.
Three ultrastructural rr~arkers of the lamellar body secretory system were then assessed as potential mechanisms that could explain the testosterone-induced decline in barrier recovery rates.. Both visual assessment in coded micrographs (observer-blinded) and quantitative stereological (morphornetric) measures were employed. Because the morphology of castrated epidermis was comparable to that of untreated skin, both assessments were focused on baseline: morphology in testosterone-replete vs.
vehicle-treated castrated mice, when TEWL rates were comparable, and on the morphology of castrated, testosterone-replete vs. vehicle-treated epidermis three hours after acute barrier disruption (when functional differences were maximal). Under basal conditions, a reduction was observed in the number of lamellae bodies (LB) in the cytosol of the cells in SG layer in testosterone-replete animals. These observations were supported by quantitative (stereological) measurements, which showed a significant reduction in the volume fraction of LB in the cytosol of outermost SG cells (Table II). Presumably as a result of decreased LB
production, the amount of secreted contents at the stratum granulosum (SG)-SC
interface was also reduced in testosterone-replete animals (Table I:f ). Further evidence of reduced secretion included the frequent presence of entombed LB within the cytosol of testosterone-replete, but not vehicle-treated.corneocytes. Furthermore, the processing of secreted LB
contents into mature lamellar bilayers appeared to be delayed, as indicated by the persistence of partially-processed lamellar contents at the level of the SC 2-3 interface. Finally, as a result of decreased LB formation and secretion, the absolute quantities of extracellular lamellae in the SC interstices also appeared to be reduced, as evidence by decreased lamellae between SC 1 and SC2.
The reductions in LB iEormation and secretion in testosterone-replete animals were even more striking three hours after barrier disruption, observations that were again validated by quantitative studies (T'able II). Decreased LB secretion was evidenced by a diminution in the quantities of extracellular lamellae in testosterone-replete animals, as well as increased, intercellular lacunae in the SC interstice°s, which displayed decreased lamellar contents. Together, t:~hese results demonstrate a decrease in LB formation, resulting in both decreased secretion and a diminution in extracellular lamellar bilayers in testosterone-replete animals.
The foregoing is offered primarily for purposes of illustration. It will be readily apparent to those skilled in the art that the concentrations, operating conditions, materials, procedural steps, and other parameters and protocols described herein may be further modified or substituted in various ways without departing from the spirit and scope of the invention.

Claims (11)

1. A method for treating the epidermis of a terrestrial mammalian subject suffering from a perturbed epidermal barrier function, said method comprising topically administering to said epidermis a topical composition comprising an antiandrogen.

2. A method for treating the epidermis of an adult human subject suffering from a perturbed epidermal barrier function, said method comprising administering to said subject a composition comprising an antiandrogen.

3. A method in accordance with claim 2 comprising topically administering said composition to said subject.

4. A method in accordance with claims 1 or 2 in which said antiandrogen is an antagonist of the androgen receptor.

5. A method in accordance with claims 1 or 2 in which said antiandrogen is an antagonist of the androgen receptor, said antagonist having the formula in which:
R1 is a member selected from the group consisting of:
C2-C6 alkyl, C5-C7 cycloalkyl, C5-C7 cycloalkyl substituted with C1-C6 alkyl, and C2-C6 alkyl substituted with a member selected from the group consisting of halogen, hydroxyl, phenylsulfonyl, and halogen-substituted phenylsulfonyl, R2 and R3 are members independently selected from the group consisting of nitro, trifluoromethyl, halogen, cyano, C1-C3 alkyl, and C1-C3 alkoxy.

6. A method in accordance with claims 1 or 2 in which said antiandrogen is a member selected from the group consisting of flutamide and bicalutamide.

7. A method in accordance with claims 1 or 2 in which said antiandrogen is flutamide.

8. A method in accordance with claims 1 or 2 in which said antiandrogen is an inhibitor of the conversion of testosterone to dihydrotestosterone.

9. A method in accordance with claims 1 or 2 in which said antiandrogen is a member selected from the group consisting of megestrol acetate and finasteride.

10. A method in accordance with claims 1 or 2 in which said antiandrogen is an agent that suppresses androgen production at the level of the hypothalamic-pituitary axis.

11. A method in accordance with claims 1 or 2 in which said antiandrogen is a member selected from the group consisting of LHRH and analogues of LHRH.