Treatment of conditions relating to hormone deficiencies by administration of progestins

Abstract

The present invention includes methods for preventing endometrial hyperplasia associated with estrogen therapy through the administration of a progestin agent. The methods presented may include starting the administration of a progestin agent at a high dose, and then lowering the dose.

What is claimed is:  
     
         1 . A method of treating vasomotor symptoms comprising: 
 administering a dose of a therapeutic amount of an estrogenic compound to a subject;    administering a dose of a therapeutic amount of a progestin agent to a subject; and    administering a second dose of a therapeutic amount of a progestin agent at a later time period to the subject, said second dose comprising a lower dosage of said therapeutic amount of a progestin agent than said first dose.    
     
     
         2 . The method according to  claim 1 , wherein said progestin agent is selected from the group consisting of dl-norgestrel, norethindrone (norethisterone), norethindrone (norethisterone) acetate, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynoestrenol, quingestanol acetate, medrogestone, norgestrienone, dimethisterone, ethisterone, cyproterone acetate, desogestrel, levonorgestrel, hydroxyprogesterone caproate, 19-nortestosterone, chlormadinone acetate, megestrol acetate, norgestimate, norgestrel, trimegestone, gestodene, normegestrel acetate, progesterone, 5α-pregnan-3β, 20β-diol sulfate, 5α-pregnan-3β-ol-20-one, 16,5α-pregnen-3-ol-20-one and 4-pregnen-20β-ol-3-one-20-sulfate.  
     
     
         3 . The method according to  claim 1 , wherein said first dose comprises an equivalent of 0.5 to 40 mg of a progestin agent, based on equivalent oral doses to megestrol acetate.  
     
     
         4 . The method according to  claim 1 , wherein said first dose comprises an equivalent of 2 to 20 mg of a progestin agent, based on equivalent oral doses to megestrol acetate.  
     
     
         5 . The method according to  claim 1 , wherein said second dose comprises an equivalent of 0.025 to 10 mg of a progestin agent, based on equivalent oral doses to megestrol acetate.  
     
     
         6 . The method according to  claim 1 , wherein said estrogenic compound is a conjugated estrogen.  
     
     
         7 . The method according to  claim 1 , wherein said estrogenic compound is selected from the group consisting of estrone, 17α-estradiol, 17β-estradiol, equilin, 17α-dihydroequilin, 17β-dihydroequilin, equilenin, 17α-dihydroequilenin, 17β-dihydroequilenin, Δ 8,9 -dehydroestrone, 17α Δ 8,9 -dehydroestradiol, 17β Δ 8,9 -dehydroestradiol, 6-OH equilenin, 6-OH 17α-dihydroequilenin, ethinyl estradiol, estradiol valerate, 6-OH 17β-dihydroequilenin, and mixtures, conjugates and salts thereof.  
     
     
         8 . The method according to  claim 1 , further comprising administering an androgen compound in a daily dose.  
     
     
         9 . The method according to  claim 8 , wherein the androgenic compound is selected from the group consisting of testosterone, methyl testosterone, androsterone, androsteronediol, androsteronedione, dehydroepiandrosterone, nandrolone benzoate, 17α methyl-nortestosterone, fluoxymesterone, oxandrolone, oxymetholone, stanozolol, stanozolone, danazol, pharmaceutically acceptable esters and salts thereof, and combinations of any of the foregoing.  
     
     
         10 . The method according to  claim 1 , wherein said second dose of a progestin agent is administered after therapy of the vasomotor symptoms has been effectively established.  
     
     
         11 . The method according to  claim 1 , wherein said second dose of a progestin agent is administered between 1 week and 12 weeks after the first dose of a progestin agent.  
     
     
         12 . The method according to  claim 1 , wherein said second dose of a progestin agent is administered between 2 weeks and 8 weeks after the first dose of a progestin agent.  
     
     
         13 . The method according  claim 1 , wherein said first dose is continuously and uninterruptedly administered to said subject for a predetermined period of time and then said second dose is continuously and uninterruptedly administered to said subject.  
     
     
         14 . The method according to  claim 1 , comprising: 
 administering a third dose of a therapeutic amount of a progestin agent at a later time period to the subject than that of said second dose, said third dose comprising a lower dosage of said therapeutic amount of a progestin agent than said second dose.    
     
     
         15 . The method according to  claim 1 , wherein said subject is human.  
     
     
         16 . A method of treating menopause comprising: 
 administering a dose of a therapeutic amount of an estrogenic compound to a subject;    administering a first dose of a therapeutic amount of a progestin agent to a subject; and    administering a second dose of a therapeutic amount of a progestin agent to the subject at a later time period, said second dose comprising a lower dosage of said therapeutic amount of a progestin agent than said first dose.    
     
     
         17 . The method according to  claim 16 , wherein said first dose comprises an equivalent of 0.5 to 40 mg of a progestin agent, based on equivalent oral doses to megestrol acetate.  
     
     
         18 . The method according to  claim 16 , wherein said first dose comprises an equivalent of 2 to 20 mg of a progestin agent, based on equivalent oral doses to megestrol acetate.  
     
     
         19 . The method according to  claim 16 , wherein said second dose comprises an equivalent of 0.025 to 10 mg of a progestin agent, based on equivalent oral doses to megestrol acetate.  
     
     
         20 . The method according to  claim 16 , wherein said progestin agent is selected from the group consisting of dl-norgestrel, norethindrone (norethisterone), norethindrone (norethisterone) acetate, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynoestrenol, quingestanol acetate, medrogestone, norgestrienone, dimethisterone, ethisterone, cyproterone acetate, desogestrel, levonorgestrel, hydroxyprogesterone caproate, 19-nortestosterone, chlormadinone acetate, megestrol acetate, norgestimate, norgestrel, trimegestone, gestodene, normegestrel acetate, progesterone, 5α-pregnan-3β, 20β-diol sulfate, 5α-pregnan-3β-ol-20-one, 16,5α-pregnen-3β-ol-20-one and 4-pregnen-20β-ol-3-one-20-sulfate.  
     
     
         21 . The method according to  claim 16 , wherein said estrogenic compound is a conjugated estrogen.  
     
     
         22 . The method according to  claim 16 , wherein said estrogenic compound is selected from the group consisting of estrone, 17α-estradiol, 17β-estradiol, equilin, 17α-dihydroequilin, 17β-dihydroequilin, equilenin, 17α-dihydroequilenin, 17β-dihydroequilenin, Δ 8,9 -dehydroestrone, 17α Δ 8,9 -dehydroestradiol, 17β Δ 8,9 -dehydroestradiol, 6-OH equilenin, 6-OH 17α-dihydroequilenin, ethinyl estradiol, estradiol valerate, 6-OH 17β-dihydroequilenin, and mixtures, conjugates and salts thereof.  
     
     
         23 . The method according to  claim 16 , further comprising administering an androgen compound in a daily dose.  
     
     
         24 . The method according to  claim 23 , wherein the androgenic compound is selected from the group consisting of testosterone, methyl testosterone, androsterone, androsteronediol, androsteronedione, dehydroepiandrosterone, nandrolone benzoate, 17α methyl-nortestosterone, fluoxymesterone, oxandrolone, oxymetholone, stanozolol, stanozolone, danazol, pharmaceutically acceptable esters and salts thereof, and combinations of any of the foregoing.  
     
     
         25 . The method according to  claim 16 , wherein said second dose of a progestin agent is administered after therapy of menopause has been effectively established.  
     
     
         26 . The method according to  claim 16 , wherein said second dose of a progestin agent is administered between 1 week and 12 weeks after the first dose of a progestin agent.  
     
     
         27 . The method according to  claim 16 , wherein said second dose of a progestin agent is administered between 2 weeks and 8 weeks after the first dose of a progestin agent.  
     
     
         28 . The method according  claim 16 , wherein said first dose is continuously and uninterruptedly administered to said subject for a predetermined period of time and then said second dose is continuously and uninterruptedly administered to said subject.  
     
     
         29 . The method according to  claim 16 , wherein said subject is human.  
     
     
         30 . A method of treating hormonal deficiencies in a subject comprising: 
 administering a dose of a therapeutic amount of an estrogenic compound to a subject;    administering a first dose of a therapeutic amount of a progestin agent to a subject; and    administering a second dose of a therapeutic amount of a progestin agent to the subject at a later time period, said second dose comprising a lower dosage of said therapeutic amount of a progestin agent than said first dose.    
     
     
         31 . The method according to  claim 30 , wherein said progestin agent is selected from the group consisting of dl-norgestrel, norethindrone (norethisterone), norethindrone (norethisterone) acetate, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynoestrenol, quingestanol acetate, medrogestone, norgestrienone, dimethisterone, ethisterone, cyproterone acetate, desogestrel, levonorgestrel, hydroxyprogesterone caproate, 19-nortestosterone, chlormadinone acetate, megestrol acetate, norgestimate, norgestrel, trimegestone, gestodene, normegestrel acetate, progesterone, 5α-pregnan-3β, 20β-diol sulfate, 5α-pregnan-3β-ol-20-one, 16,5α-pregnen-3β-ol-20-one and 4-pregnen-20β-ol-3-one-20-sulfate.  
     
     
         32 . The method according to  claim 30 , wherein said first dose comprises an equivalent of 0.5 to 40 mg of a progestin agent, based on equivalent oral doses to megestrol acetate.  
     
     
         33 . The method according to  claim 30 , wherein said first dose comprises an equivalent of 2 to 20 mg of a progestin agent, based on equivalent oral doses to megestrol acetate.  
     
     
         34 . The method according to  claim 30 , wherein said second dose comprises an equivalent of 0.025 to 10 mg of a progestin agent, based on equivalent oral doses to megestrol acetate.  
     
     
         35 . The method according to  claim 30 , wherein said estrogenic compound is a conjugated estrogen.  
     
     
         36 . The method according to  claim 30 , wherein said estrogenic compound is selected from the group consisting of estrone, 17α-estradiol, 17β-estradiol, equilin, 17α-dihydroequilin, 17β-dihydroequilin, equilenin, 17α-dihydroequilenin, 17β-dihydroequilenin, Δ 8,9 -dehydroestrone, 17α Δ 8,9 -dehydroestradiol, 17β Δ 8,9 -dehydroestradiol, 6-OH equilenin, 6-OH 17α-dihydroequilenin, ethinyl estradiol, estradiol valerate, 6-OH 17β-dihydroequilenin, and mixtures, conjugates and salts thereof.  
     
     
         37 . The method according to  claim 30 , further comprising administering an androgen compound in a daily dose.  
     
     
         38 . The method according to  claim 37 , wherein the androgenic compound is selected from the group consisting of testosterone, methyl testosterone, androsterone, androsteronediol, androsteronedione, dehydroepiandrosterone, nandrolone benzoate, 17α methyl-nortestosterone, fluoxymesterone, oxandrolone, oxymetholone, stanozolol, stanozolone, danazol, pharmaceutically acceptable esters and salts thereof, and combinations of any of the foregoing.  
     
     
         39 . The method according to  claim 30 , wherein said second dose of a progestin agent is administered between 1 week and 12 weeks after the first dose of a progestin agent.  
     
     
         40 . The method according to  claim 30 , wherein said second dose of a progestin agent is administered between 2 weeks and 8 weeks after the first dose of a progestin agent.  
     
     
         41 . The method according  claim 30 , wherein said first dose is continuously and uninterruptedly administered to said subject for a predetermined period of time and then said second dose is continuously and uninterruptedly administered to said subject.  
     
     
         42 . A method of preventing endometrial hyperplasia in a subject, said method comprising: 
 administering continuously and uninterruptedly for a first predetermined time period a first dose of a progestin agent to said subject; and    administering continuously and uninterruptedly for a second predetermined time period a second dose of a progestin agent to said subject.    
     
     
         43 . The method according to  claim 42 , wherein said progestin agent is selected from the group consisting of dl-norgestrel, norethindrone (norethisterone), norethindrone (norethisterone) acetate, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynoestrenol, quingestanol acetate, medrogestone, norgestrienone, dimethisterone, ethisterone, cyproterone acetate, desogestrel, levonorgestrel, hydroxyprogesterone caproate, 19-nortestosterone, chlormadinone acetate, megestrol acetate, norgestimate, norgestrel, trimegestone, gestodene, normegestrel acetate, progesterone, 5α-pregnan-3β, 20β-diol sulfate, 5α-pregnan-3β-ol-20-one, 16,5α-pregnen-3β-ol-20-one and 4-pregnen-20β-ol-3-one-20-sulfate.  
     
     
         44 . The method according to  claim 42 , wherein said first dose comprises an equivalent of 0.5 to 40 mg of a progestin agent, based on equivalent oral doses to megestrol acetate.  
     
     
         45 . The method according to  claim 42 , wherein said first dose comprises an equivalent of 2 to 20 mg of a progestin agent, based on equivalent oral doses to megestrol acetate.  
     
     
         46 . The method according to  claim 42 , wherein said second dose comprises an equivalent of 0.025 to 10 mg of a progestin agent, based on equivalent oral doses to megestrol acetate.  
     
     
         47 . The method according to  claim 42 , further comprising administering an estrogenic compound in a daily dose.  
     
     
         48 . The method according to  claim 42 , further comprising administering an androgen compound in a daily dose.  
     
     
         49 . The method according to  claim 42 , wherein said first predetermined time period for said first dose of a progestin agent is at least two weeks before the administration of said second dose of a progestin agent.  
     
     
         50 . The method according to  claim 42 , wherein said first predetermined time period for said first dose of a progestin agent is between two to twelve weeks before the administration of said second dose of a progestin agent.  
     
     
         51 . A method for treating a patient afflicted with vasomotor symptoms, comprising administering a dose of a therapeutic amount of an estrogenic compound to a subject; administering a progestin agent to said patient for at least two cycles of a cyclical dosing schedule, wherein the first cycle comprises a dosing period of at least one week, in which the progestin agent is administered daily, at a dose of an equivalent of 8 to 40 mg/day, followed by at least one second cycle comprising a dosing period that can last for an indeterminate period of time in which a progestin agent is administered daily, at a dose of an equivalent of 4 to 20 mg/day.