Method of treating atrophic vulvar dystrophy
This application is a continuation of copending application Ser. No. 666,930 filed Mar. 15, 1976 (now abandoned). 
    
    
     This invention pertains to the treatment of vulvar dystrophy. More particularly, the invention is related to the treatment of chronic vulvar dystrophies with progestin compounds. 
     As used herein the term &#34;vulvar dystrophies&#34; includes several related disorders afflicting the skin in the area of the vulva which have, in the past, been known as leukoplakia, leukoplakic vulvitis, lichen sclerosis et atrophicus, kraurosis vulvae, primary vulvar atrophy, sclerotic dermatoses, atrophic and hypertrophic vulvitis, and lichen simplex chronicus (localized neurodermatitis) of the vulva. The aforementioned vulvar dystrophic lesions may be segregated into three separate classifications: 
     The first category includes hyperplastic dystrophies which are generally characterized by a thickening of the epithelial layers and hyperkeratosis. These lesions frequently involve the hood of the clitoris, the labia majora, the interlabial sulci and may extend onto the lateral surface of the labia majora and even the adjacent thighs. Lichen simplex chronicus (neurodermatitis) and leukoplakia are usually classified as hyperplastic dystrophies. 
     A second category of vulvar disorders are the atrophic dystrophies, or those conditions associated with shrinkage or contracture of the vulvar skin which may also include a sclerosing progressive atrophy of the mucocutaneous teguments of the vulva leading gradually to stenosis of the vaginal orifice. The atrophic dystrophies include lichen sclerosus et atrophicus, kraurosis vulvae and atrophic vulvitis. 
     A third classification, mixed dystrophy, refers to those conditions in which an atrophic affliction is associated with a hyperplastic change. For example, lichen sclerosus et atrophicus is often associated with both hyperplastic epithelium and atrophic vulvar changes. This condition also includes areas of hyperplasia which develop adjacent to an otherwise atrophic lesion and which may therefore represent a form of neurodermatitis, in contrast to hyperplastic nodes mixed with the atrophic areas within the lesion per se. Microscopic evaluation of biopsied vulvar lesions has verified the coexistence of both hyperplastic and atrophic changes. 
     All of the preceding conditions are extensively discussed in the prior art, although it is generally acknowledged that none has a specific known cause or remedy, and because their macroscopic and microscopic appearances are so variable and interchangeable, their precise diagnosis by clinical or histological techniques is extremely difficult. While the vulvar dystrophies in themselves are responsible for a considerable degree of patient discomfort, usually being accompanied by pruritis and scaling, of greater importance is recent evidence that the associated lesions may ultimately become malignant conditions, if untreated. 
     Treatment of vulvar dystrophies has become largely confined to the control of symptoms, primarily pruritus. In this respect, local application of corticosteroids has been sed with some degree of success to alleviate pruritus and swelling. However, control of pruritus and burning does not assure that the lesions will regress. 
     More recently, investigators have found that topical application of testosterone has been successful in controlling the symptoms associated with lichen sclerosus et atrophicus. However, testosterone has been of little value for either controlling symptoms or altering the gross and histopathologic changes in vulvar tissues which accompany hyperplastic lesions. An important drawback to the use of testosterone is that it often stimulates libido, hirsutism, and causes enlargement of the clitoris. 
     A different treatment involves oral administration of chloroquine to treat lichen sclerosus et atrophicus. However, as this drug may induce corneal and retinal changes, it is seldom utilized. 
     Other investigators have advocated the use of high dosages of vitamin A and dilute hydrochloric acids to treat vulvar dystrophies. Although this treatment has occasionally provided symptomatic remission and regression of vulvar lesions, the results are unpredictable. 
     Finally, surgical treatment ranging from wide excision of a localized lesion to vulvectomy is utilized for those patients with uncontrollable disease. However, the high recurrence rate of the lesions associated with vulvar dystrophy requires regular observation of the patient for an extended period after surgery. 
     It has now been unexpectedly discovered that vulvar dystrophies may be treated successfully by topical application of a progestin, preferably progesterone, to the afflicted area. This discovery is particularly surprising in view of the limited utility of the androgen hormones in treating vulvar dystrophies. In a particularly preferred aspect of the present invention, a pharmaceutical formulation comprising a pharmaceutically acceptable hydrophilic ointment base containing a suspension of progesterone (Pregn-4-ene, 3, 20-dione) dissolved in vegetable oil is topically applied to an area afflicted with vulvar dystrophy. 
     As used herein the term &#34;progestin&#34; refers to the natural progestational hormones secreted by the corpus luteum and their synthetic equivalents. The progestins found to be useful in the present invention are those which are capable of producing progestational changes in the uterus and include, for example, progesterone (Pregn-4-ene, 3, 20-dione), 17 hydroxy progesterone, 17 alpha hydroxy progesterone caproate, pregnenolone, 17 hydroxy pregnenolone, medoxy progesterone, megesterol acetate, and 6-fluoro progesterone. 
     Progesterone, the preferred progestin for use in the present invention is a white or creamy white crystalline powder which is odorless and stable in air. Progesterone is practically insoluble in water, slightly soluble in vegetable oils and soluble in alcohol. 
     According to the present invention, one or a combination of progestins is topically applied to the afflicted vulvar area, preferably in the form of a vegetable oil solution carried in a hydrophilic ointment to treat vulvar dystrophies. In most instances the progestin agent (preferably progesterone) is dissolved in a co-solvent solution consisting of a small (about 2 to 20% by weight) quantity of a pharmaceutically acceptable alcohol (e.g., benzyl alcohol) and a major amount (20 to 98% by weight) of vegetable oil. Effective vegetable oils for use in the present invention include sesame oil, peanut oil, linseed oil, corn oil, olive oil, tung oil and the like. 
     The progestin in oil solution is then incorporated into a clinically acceptable carrier vehicle, preferably a hydrophilic salve, cream or ointment as for example those based on lanolin, petrolatum, white ointment (white wax and white petrolatum), or anhydrous lanolin. The progestin in oil solution is admixed with the hydrophilic carrier by conventional mixing techniques in a bowl or other suitable mixing receptacle. One carrier vehicle preferred for use in the present invention is a hydrophilic ointment prepared according to the following Example. 
    
    
     EXAMPLE I 
     
         ______________________________________                                    
Methylparaben         2.25 grams                                          
Propylparaben         0.15 grams                                          
Sodium lauryl sulfate 10 grams                                            
Propylene glycol      120 grams                                           
Stearyl alcohol       250 grams                                           
White petrolatum      250 grams                                           
Purified water Q.S. to                                                    
                      1000 grams                                          
______________________________________                                    
 
    
     The ointment is prepared by melting the stearyl alcohol and the white petrolatum on a steam bath. The melt is warmed to about 75 degrees. Thereafter the other ingredients, previously dissolved in the water and warmed to 75 degrees are added. The mixture is stirred until it congeals. 
     A commercially available hydrophilic carrier suitable for use in the present invention is available under the trademark UNIBASE from Parke-Davis &amp; Company. 
     Preferably, the progestin in oil solution is suspended in the hydrophilic carrier by simply admixing the two ingredients in an open receptacle with the use of glass stirring rod. In the preferred embodiment of the invention, an oil solution of progesterone (Pregn-4-ene, 3, 20-dione) in which each ml of solution contains 25 milligrams of progesterone, 4% benzyl alcohol, 0.5% chlorbutanol (chloral derivatives) as preservatives and sesame oil (to make one ml) is admixed with 7.5 grams of a hydrophilic ointment prepared according to Example I. After the progesterone in oil has been thoroughly admixed to form a substantially uniform suspension in the carrier vehicle, the ointment is transferred to a container which is sealed and then stored. Especially good results have been obtained using this formulation in the treatment of kraurosis vulvae and leukoplakia. 
     Bases suitable for use as carrier vehicles in the present invention include hydrophilic materials, e.g., white ointment (simple ointment), hydrophilic petrolatum, white petrolatum, lanolin, anhydrous lanolin and similar hydrophilic salves, creams and ointments in which progesterone can be carried for topical application to the skin. 
     The pharmaceutical formulations of the present invention usually contain from between about 0.1 to about 5% by weight of the total formulation of the active progestin ingredient. In most instances, from about 0.25 to about 0.75% by weight, and preferably 0.35% by weight of the total formulation of a progestin, preferably progesterone, is employed. The effective dosage of the formulation of this invention required to treat vulvar dystrophy depends upon the severity of condition, stage and individual characteristics of the subject being treated. The exact dosage applied in each treatment is not critical since the effective amount may be administered in one or a plurality of treatments. 
     While the progestin is preferably applied to the afflicted area in the form of an ointment, as exemplified above, it may also be applied directly to the wound by spraying or swabbing it on the wound. Both the powder and the ointment may be applied first to an absorbent medium which is then applied to the afflicted area and held on by a bandage, adhesive tape or occlusive dressing. In a similar fashion, the active ingredient may be incorporated into tablets, capsules or suppositories for topical application to the afflicted vulvar passages. 
     The pharmaceutical formulations of the invention are preferably administered to the afflicted areas in the form of a viscous hydrophilic ointment, twice each day, in the morning and in the evening. 
     The progestins of the present invention may be applied alone or along with therapeutically effective agents such as ascorbic acid, ascorbyl palmitate, pharmaceutically acceptable zinc salts, e.g., zinc oxide, zince stearate, zinc citrate; antiseptics such as lydocaine, procaine, etc. and antibiotics such as neomycin, chloramphenicol, sulfanilamide, tetracycline and the like. 
     The effectiveness of the pharmaceutical formulations of this invention in treating vulvar dystrophies has been confirmed by clinical tests in humans. In order to provide a basis for comparison the pharmaceutical preparation used in all cases contained 25 milligrams of progesterone (Pregn-4-ene-3, 20-dione admixed with 7.5 grams of a relatively viscous hydrophilic ointment of the type disclosed in Example I herein. Each patient was instructed to apply the medication topically to the afflicted area twice a day (morning and evening). The following table summarizes the results of the clinical trials. 
     
         __________________________________________________________________________
PATIENT                                                                   
NO.   AGE DIAGNOSIS       TREATMENT      RESULTS                          
__________________________________________________________________________
1     56  Kraurosis vulvae - prior treat-                                 
                          Progesterone hydrophilic oint-                  
                                         Whitish depigmentation           
          ments with estrogenic vaginal                                   
                          ment (prepared as above) applied                
                                         almost completely dis-           
          creams and steroids ineffective                                 
                          topically to the afflicted area                 
                                         appeared and relief              
          and discontinued - the patient                                  
                          twice a day for 3 months                        
                                         from dyspareunia and             
          reported dyspareunia and       burning sensation after          
          localized burning - observed   2 weeks treatment.               
          stenosis of the vaginal orifice -                               
                                         Discontinuance of the            
          vulvar skin thin, dry, shiny and                                
                                         ointment led to a recur-         
          whitish in appearance - biopsy rence of the disease             
          confirmed diagnosis of kraurosis                                
                                         both subjectively and            
          vulvae                         objectively. Re-use of           
                                         the ointment promptly            
                                         reversed the process             
                                         and even once a day              
                                         application was found            
                                         sufficient.                      
                                         As a control progesterone        
                                         was omitted from the             
                                         preparation for 1 month.         
                                         This modification of the         
                                         formula was accompanied          
                                         by a gradual reapperance         
                                         of all symptons. Sub-            
                                         sequent treatment with           
                                         a progesterone in oil            
                                         suspension (UNIBASE -            
                                         Park-Davis - substituted         
                                         for the hydrophilic oint-        
                                         ment of Example I) was           
                                         equally effective in             
                                         treating the disease.            
2     54  Biopsied early leukoplakia.                                     
                          Progesterone in oil hydrophilic                 
                                         Dyspareunia alleviated -         
                          ointment (as in Example I)                      
                                         marked decrease in whitish       
                          applied topicaly to the afflicted               
                                         appearance of vulvar             
                          area at least once a day for 3                  
                                         tissues - biopsy conformed       
                          months.        remission and disappearance      
                                         of symptoms.                     
3     47  Pathological report of                                          
                          Estrogen creams and cortisone                   
                                         After 1 month&#39;s treatment        
          vulvar biopsy confirmed                                         
                          employed with no response.                      
                                         dyspareunia markedly             
          presence of cystic hyper-                                       
                          Progesterone hydrophilic oint-                  
                                         decreased - whitish lesions      
          plasia and kraurosis                                            
                          ment (as in Example I) applied                  
                                         decreased in size and            
          vulvae.         topically to the afflicted area                 
                                         intensity. Tissues appear        
                          twice a ay for 6 months.                        
                                         healthier and more pliable.      
4     54  Biopsy confirmed kraurosis                                      
                          Progesterone in oil hydrophilic                 
                                         Decrease in size and             
          vulvae.         ointment (as in Example I)                      
                                         number of whitish lesions        
                          applied topically twice a day                   
                                         on the introitus.                
                          to the afflicted area for 1                     
                          month.                                          
5     42  Biopsy confirmed kraurosis                                      
                          Progesterone in oil hydrophilic                 
                                         Marked relief from dryness       
          vulvae.         ointment (as in Example I)                      
                                         and dyspareunia. Almost          
                          applied topically to the                        
                                         complte disappearance of         
                          afflicted area twice a day for                  
                                         whitist plaques.                 
                          2 weeks.                                        
                                         No systemic side effects         
                                         were noted in any of the         
                                         above cases as confirmed         
                                         by laboratory blood and          
                                         urine tests.                     
__________________________________________________________________________
 
    
     It should be noted that the progestin treatment of the present invention does not provide a cure for vulvar dystrophies, but rather is used to secure temporary remission and palliation of the symptoms associated with such disorders. Although application of progestin may be halted during periods of remission, treatment can be reinstituted upon recurrence or development of a new outbreak of vulvar dystrophy to provide a subsequent remission period.