Method of hormonal treatment for menopausal or post-menopausal disorders involving continuous administration of progestogens and estrogens

Abstract

A method of hormonally treating menopausal (including perimenopausal and post-menopausal) disorders in women, a composition, and a multi-preparation pack therefor. The administrative regimen to which the pack is particularly adapted comprises continuously and uninterruptedly administering a progestogen to a woman while cyclically administering an estrogen by using a repetitive dosage regimen. This regimen calls for administering the estrogen continuously for a period of time between about 20 and about 120 days, followed by terminating administering the estrogen for a period of time between about 3 and about 7 days. Alternatively, both the progestogen and estrogen may be administered for the full treatment period without interruption. The regimen avoids many of the problems associated with the administration of estrogen alone or with progestogen administered according to conventional regimens, and also avoids problems associated with such conventional regimens by maintaining the estrogen and progestogen at low daily dosage levels of between 0.005 mg and 2.5 mg estrogen and 0.25 mg and 30 mg progestogen.

We claim: . . 
     
       1.  A method of hormonally treating menopausal or post-menopausal disorders in a woman, comprising administering to said woman continuously and uninterrupted both progestogen and estrogen in daily dosage units of progestogen equivalent to laevo-norgestrel dosages of from about 0.025 mg to about 0.075 mg, and of estrogen equivalent to estradiol dosages of about 0.5 mg to about 2.0 mg..!.. .2. The method of claim 1 wherein said estrogen is 17 β-estradiol and said progestogen is dl-norgestrel or laevo-norgestrel, the daily dosage level of said 17 β-estradiol being about 1 mg, the daily dosage level of said dl-norgestrel (where present) being about 100 micrograms, and the daily dosage of said laevo-norgestrel 
     
     
        (where present being about 50 micrograms..!.3. A method of hormonally treating perimenopausal, menopausal or post-menopausal disorders in a woman, comprising: A. continuously and uninterruptedly administering a progestogen to said woman in daily dosage units of progestogen equivalent to laevo-norgestrel dosages of from about 0.025 mg to about 0.075 mg, and   B. cyclically administering an estrogen to said woman by repetitively using a dosage regimen comprising: (i) administering said estrogen continuously for a period of time between about 20 and about 120 days in daily dosage units of estrogen equivalent to estradiol dosages of from about 0.500 mg to about 2 mg, followed by   (ii) terminating administering said estrogen for a period of time between     
     
     
        about 3 and about 7 days. 4. The method of claim 3 wherein said progestogen is selected from the following group, with respective maximum and minimum daily dosage levels as follows:   ______________________________________
                 Dosage   (mg/day)
                 Minimum  Maximum
______________________________________
Laeve-norgestrel   about 0.025
                              about 0.075
dl-norgestrel      about 0.050
                              about 0.150
Norethindrone (norethisterone)
                   about 0.15 about 1.0
Norethindrone (norethisterone)
                   about 0.10 about 1.0
acetate
Ethynodiol diacetate
                   about 0.10 about 1.0
Dydrogesterone     about 5    about 30
Medroxyprogesterone acetate
                   about 1    abou 15
Norethynodrel      about 0.203
                              about 5
Allylestrenol      about 1    about 10
Lynoestrenol       about 0.300
                              about 2
Quingestanol acetate
                   about 0.050
                              about 1
Medrogestone       about 1    about 10
Norgestrienone     about 0.020
                              about 0.200
Dimethisterone     about 0.500
                              about 15
Ethisterone        about 1    about 25
Cyproterone acetate
                   about 0.300
                              about 10.Iadd...Iaddend.
______________________________________
     
     
     
        5. The method of claim 3 wherein said estrogen is selected from the following group, with respective maximum and minimum daily dosage levels as follows:   ______________________________________
                Dosage   (mg/day)
                Minimum  Maximum
______________________________________
Estradiol         about 0.500
                             about 2
Estradiol-17β
                  about 0.500
                             about 2
Estradiol valerate
                  about 0.500
                             about 2
Conjugated equine estrogens
                  about 0.300
                             about 2.5
Estrone           about 0.300
                             about 2.5
Piperazine estrone sulphate
                  about 0.250
                             about 2.5
(estropipate)
Ethinyl estrodiol about 0.005
                             about 0.020
Mestranol         about 0.005
                             about 0.030
. .Quinestranol.!. .Iadd.Quinestrol.Iaddend.
                  about 0.005
                             about 0.020.Iadd...Iaddend.
______________________________________
     
     
     
        6. The method of claim 5 or claim 4 wherein said estrogen is selected from the following group, with respective daily dosage levels as follows:   ______________________________________
                     Dosage (mg/day)
______________________________________
Estradiol              about 1
Estradiol-17β     about 1
Estradiol valerate     about 1
Conjugated equine estrogens
                       about 0.600
Estrone                about 0.600
Piperazine estrone sulphate (estropipate)
                       about 0.500
Ethinyl estradiol      about 0.010
Mestranol              about 0.015
. .Quinestranol.!. .Iadd.Quinestrol.Iaddend.
                       about 0.010.Iadd...Iaddend.
______________________________________
     
     
     
        7. The method of claim 5 wherein said progestogen is selected from the following group, with respective daily dosage levels as follows:   ______________________________________
                     Dosage (mg/day)
______________________________________
Laevo-norgestrel       about 0.050
dl-norgestrel          about 0.100
Norethindrone (norethisterone)
                       about 0.30
Norethindrone (norethisterone)
                       abour 0.30
Ethynodiol diacetate   about 0.30
Dydrogestrone          about 10
Medroxyprogesterone acetate
                       about 2.5
Norethynodrel          about 1
Allylestrenol          about 2
Lynoestrenol           about 0.200
Quingestanol acetate   about 0.200
Medrogestone           about 2
Norgestrienone         about 0.050
Dimethisterone         about 1
Ethisterone            about 2.5.Iadd...Iaddend.
______________________________________
     
     
     
        8. The method of . .any of claims.!. .Iadd.claim .Iaddend.5 wherein said estrogen and said progestogen are selected from the following combination: Estradiol/Laevo-norgestrel   Estradiol 17β/Laevo-norgestrel   Conjugated equine estrogens/Laevo-norgestrel   Estradiol/dl-norgestrel   Estradiol 17β/dl-norgestrel   Estradiol valerate/Laevonorgestrel   Estradiol valerate/dl-norgestrel   Conjugated equine estrogens/dl-norgestrel   Estradiol/Norethindrone (norethisteron)   Estradiol 17β/Norethindrone (norethisterone)   Estradiol valerate/Norethindrone (norethisterone)   Conjugated equine estrogens/Norethindrone (norethisterone)   Estradiol/Norethindrone (norethisterone) acetate   Estradiol 17β/Norethindrone (norethisterone) acetate   Estradiol valerate/Norethindrone (norethisterone) acetate   Conjugated equine estrogen/Norethindrone (norethisterone) acetate   Estradiol/Medroxyprogesterone acetate   Estradiol 17β/Medroxyprogesterone acetate   Estradiol valerate/Medroxyprogesterone acetate   
     
     
       Conjugated equine estrogen/Medroxyprogesterone acetate. 9. The method of claim 8 wherein said estrogen is 17β-estradiol and said progestogen 
     
     
        is dl-norgestrel or laevo-norgestrel. 10. The method of claim 9 wherein the daily dosage level of said 17β-estradiol is between about 0.5 mg and about 2 mg, the daily dosage level of said dl-norgestrel, where present, is between about 50 and about 150 micrograms and the daily dosage level of said laevo-norgestrel, where present, is between about 25 and 
     
     
        about 75 micrograms. 11. The method of claim 10 wherein the daily dosage level of said dl-norgestrel is about 75 micrograms. . .12. The method of claim 1 or 3 wherein said estrogen is a synthetic estrogen..!.. .13. The method of claim 12 wherein said synthetic estrogen is selected from the group consisting of ethinyl estradiol, mestranol and quinestranol..!.. .14. The method of claim 1 or 3 wherein said estrogen is a natural estrogen..!.. .15. The method of claim 14 wherein said natural estrogen is selected from the group consisting of conjugated equine estrogens, estradiol, estradiol-17β estradiol valerate, estrone, piperazine estrone sulphate, estriol, estriol succinate and polyestrol phosphate..!.. .16. The method of claim 1 or 3, wherein said progestogen is selected from the group consisting of laevo-norgestrel, dl-norge, trel, norethindrone (norethisterone), norethindrone (norethisteron) acetate, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynoestrenol, quingestanol acetate, medrogestone, norgestrienone, dimethisterone, ethisterone, and cyprotecone acetate..!.. .17. A pharmaceutical composition for the hormonal treatment of perimenopausal, menopausal and post-menopausal disorders in a woman, said composition being in implantable or intramuscularly injectable form and comprising, in association with a pharmaceutically acceptable barrier, sufficient progestogen and estrogen to provide dosage levels to said woman equivalent to orally administered daily dosages of progestogen equivalent to laevo-norgestrel dosages of from about 0.025 mg to about 0.075 mg and of estrogen equivalent to estradiol dosages of about 0.5 mg to about 2 mg..!.. .18. The pharmaceutical composition of claim 17 in implantable form, wherein said estrogen is selected from the group consisting of estradiol, estradiol-17β, and estradiol valerate..!.. .19. The pharmaceutical composition of claim 18 or 17 in implantable form, wherein said progestogen is selected from the group consisting of laevo-norgestrel, dl-norgestrel, norgestrienone, and norethindrone acetate..!.. .20. The pharmaceutical composition of claim 17 in injectable form, wherein said progestogen is selected from the group consisting of medroxyprogesterone acetate, norethindrone enanthate, gestronol hexanoate, 
     
     
        and algestone acetophenide..!..Iadd.21.  A method of hormonally treating menopausal or postmenopausal disorders in a woman to prevent or retard the demineralization of bone, comprising administering continuously and uninterruptedly over the treatment period, in fixed daily dosages and at dosages and a duration sufficient to effectively retard or prevent the demineralization of bone while minimizing spotting and/or bleeding, both progestogen and estrogen in daily dosage units of progestogen equivalent to laevo-norgestrel dosages of from about 0.025 mg to about 0.05 mg, and of estrogen equivalent to estradiol dosages of about 0.5 mg to about 2.0 mg. .Iaddend..Iadd.22. A method of hormonally treating menopausal or postmenopausal disorders in a woman to prevent or retard the demineralization of bone, comprising administering continuously and uninterruptedly over the treatment period, in fixed daily dosages and at dosages and a duration sufficient to effectively retard or prevent the demineralization of bone while minimizing spotting and/or bleeding, both progestogen and estrogen in daily dosage units of progestogen equivalent to laevo-norgestrel dosages of from about 0.025 mg to about 0.075 mg, and of estrogen equivalent to estradiol dosages of about 0.5 mg to about 2.0 mg, wherein the progestogen and the estrogen are combined in a single dosage form. .Iaddend..Iadd.23. A method of hormonally treating menopausal or postmenopausal disorders in a woman, comprising administering continuously and uninterruptedly over the treatment period, in fixed daily dosages which minimize spotting and/or bleeding, both progestogen and estrogen in daily dosage units of progestogen equivalent to laevo-norgestrel dosages of from about 0.025 mg to about 0.05 mg, and of estrogen equivalent to estradiol dosages of about 0.5 mg to about 0.25 mg. 
     
     
        .Iaddend..Iadd.24.  A method of hormonally treating menopausal or postmenopausal disorders in a woman, comprising administering continuously and uninterruptedly over the treatment period, in fixed daily dosages which minimize spotting and/or bleeding, both progestogen and estrogen in daily dosage units of progestogen equivalent to laevo-norgestrel dosages of from about 0.025 mg to about 0.075 mg, and of estrogen equivalent to estradiol dosages of about 0.5 mg to about 2.0 mg, wherein the progestogen and the estrogen are combined in a single dose form. .Iaddend..Iadd.25. The method of claim 21 or 23, wherein the progestogen and the estrogen are combined in a single dosage form. .Iaddend..Iadd.26. The method of claim 21, 22, 23, 24 or 25, wherein the estrogen consists essentially of a bone-sparing estrogen. .Iaddend..Iadd.27. The method of claim 21, 22, 23, 24 or 25, wherein the fixed daily dosages are administered over a treatment period of greater than 120 days. .Iaddend..Iadd.28. The method of claim 21 or 22, wherein the dosages and duration of treatment are effective to prevent or retard osteoporosis. .Iaddend..Iadd.29. The method of claim 21, 22, 23, 24 or 25, wherein the dosages and duration of treatment are sufficient to prevent or retard changes in blood lipids which might otherwise predispose the woman to cardiovascular disease. .Iaddend..Iadd.30. The method of claim 21, 22, 23, 24 or 25, wherein said progestogen is selected from the group consisting of laevo-norgestrel, dl-norgestrel, ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel, allylestrenol, lynoestrenol, quingestanol acetate, medrogestone, norgestrienone, dimethisterone, ethisterone, and cyproterone acetate. .Iaddend..Iadd.31. The method of claim 22 or 24, wherein said progestogen is selected from the following group, with respective minimum and maximum daily dosage levels as follows:   ______________________________________
              .Iadd.Dosage(mg/day)
                         Dosage (mg/day)
              Minimum    Maximum
______________________________________
Laevo-norgestrel
                about 0.025  about 0.075
dl-norgestrel   about 0.050  about 0.150
Ethynodiol diacetate
                about 0.10   about 1.0
Dydrogesterone  about 5      about 30
Medroxyprogesterone acetate
                about 1      about 15
Norethynodrel   about 0.200  about 5
Allylestrenol   about 1      about 10
Lynoestrenol    about 0.100  about 2
Quingestanol acetate
                about 0.050  about 1
Medrogestone    about 1      about 10
Norgestrienone  about 0.020  about 0.200
Dimethisterone  about 0.500  about 15
Ethisterone     about 1      about 25
Cyproterone acetate
                about 0.100  about 10..Iaddend.
______________________________________
     
     
     
       .Iadd.32.  The method of claim 21, 23, 25, wherein said progestogen is selected from the following group, with respective minimum and maximum daily dosage levels as follows:   ______________________________________
              .Iadd.Dosage(mg/day)
                         Dosage (mg/day)
              Minimum    Maximum
______________________________________
Laevo-norgestrel
                about 0.025  about 0.050
dl-norgestrel   about 0.050  about 0.100
Ethynodiol diacetate
                about 0.10   about 0.30
Dydrogesterone  about 5      about 10
Medroxyprogesterone acetate
                about 1      about 2.5
Norethynodrel   about 0.200  about 1
Allylestrenol   about 1      about 2
Lynoestrenol    about 0.100  about 0.200
Quingestanol acetate
                about 0.050  about 0.200
Medrogestone    about 1      about 2
Norgestrienone  about 0.020  about 0.050
Dimethisterone  about 0.500  about 1
Ethisterone     about 1      about 2.5
Cyproterone acetate
                about 0.100  about 0.500..Iaddend.
______________________________________
     .Iadd.33. The method of claim 21, 22, 23, 24 or 25, wherein said estrogen is selected from the group consisting of estradiol, estradiol-17β, conjugated equine estrogens, estradiol valerate, estrone, piperazine estrone sulphate, ethinyl estradiol, mestranol, and quinestrol. .Iaddend..Iadd.34. The method of claim 33, wherein said estrogen is selected from the following group, with respective minimum and maximum daily dosage levels as follows:     ______________________________________
              .Iadd.Dosage(mg/day)
                         Dosage (mg/day)
              Minimum    Maximum
______________________________________
Estradiol       about 0.500  about 2
Estradiol-17β
                about 0.500  about 2
Estradiol valerate
                about 0.500  about 2
Conjugated equine estrogens
                about 0.300  about 2.5
Estrone         about 0.300  about 2.5
Piperazine estrone sulphate
                about 0.250  about 2.5
(estropipate)
Ethinyl estrodiol
                about 0.005  about 0.020
Mestranol       about 0.005  about 0.040
Quinestrol      about 0.005  about 0.030..Iaddend.
______________________________________
     .Iadd.35. The method of claim 34, wherein said estrogen is selected from the following group, with respective minimum and maximum daily dosage levels as follows:     ______________________________________
              .Iadd.Dosage(mg/day)
                         Dosage (mg/day)
              Minimum    Maximum
______________________________________
Estradiol       about 0.500  about 1
Estradiol-17β
                about 0.500  about 1
Estradiol valerate
                about 0.500  about 1
Conjugated equine estrogens
                about 0.300  about 0.600
Estrone         about 0.300  about 0.600
Piperazine estrone sulphate
                about 0.250  about 0.500
(estropipate)
Ethinyl estrodiol
                about 0.005  about 0.010
Mestranol       about 0.005  about 0.015
Quinestrol      about 0.005  about 0.010..Iaddend.tz,1/32
     
     
     
       .Iadd.36.  The method of claim 30, 31, 32, 33, 34 or 35, wherein the fixed daily dosages are administered over a treatment period of greater than 120 days. .Iaddend..Iadd.37. The method of claim 21, 23 or 25, wherein the progestogen is medroxyprogesterone acetate in an amount of from about 1 mg to about 2.5 mg. .Iaddend..Iadd.38. The method of claim 21, 22, 23, 24 or 25, wherein the estrogen is conjugated equine estrogens in an amount of from about 0.300 mg to about 2.5 mg. .Iaddend..Iadd.39. The method of claim 21, 23 or 25, wherein the progestogen is medroxyprogesterone acetate in an amount of from about 1 mg to about 2.5 mg, and the estrogen is conjugated equine estrogens in an amount of from about 0.300 mg to about 2.5 mg. .Iadd.40. The method of claim 39, wherein the estrogen is conjugated equine estrogens in an amount of from about 0.300 to about 0.600. .Iaddend..Iadd.41. The method of claim 39, wherein the progestogen is medroxyprogesterone acetate in an amount of about 2.5 mg and the estrogen is conjugated equine estrogens in an amount of about 0.600 mg. .Iaddend..Iadd.42. The method of claim 39, wherein the progestogen is medroxyprogesterone acetate in an amount of about 2.5 mg and the estrogen is conjugated equine estrogens in an amount of about 0.300 mg. .Iaddend..Iadd.43. The method of claim 37, 38, 39, 40, 41 or 42, wherein the fixed daily dosages are administered over a treatment period of greater than 120 days. .Iaddend..Iadd.44. The method of claim 37, 38, 39, 40, 41 or 42, wherein the dosages and duration of treatment are sufficient to prevent or retard changes in blood lipids which might otherwise predispose the woman to cardiovascular disease. .Iaddend..Iadd.45. The method of claim 21, 23 or 25, wherein said progestogen is norethindrone (norethisterone) acetate in an amount of from about 0.10 mg to about 0.20 mg. .Iaddend..Iadd.46. The method of claim 21, 22, 23, 24 or 25, wherein said estrogen is selected from the group consisting of estradiol, estradiol 17-β, or estradiol valerate and is in an amount of from about 0.500 to about 1 mg. .Iaddend..Iadd.47. The method of claims 22 or 24, wherein the estrogen is estradiol-17β administered in fixed daily dosages of between about 0.500 and about 1 mg and the progestogen is norethindrone acetate. .Iaddend..Iadd.48. The method of claim 47, wherein the fixed daily dosages are administered over a treatment period of greater than 120 days. .Iaddend..Iadd.49. The method of claim 47, wherein the dosages and duration of treatment are sufficient to prevent or retard changes in blood lipids which might otherwise predispose the woman to cardiovascular disease. .Iaddend..Iadd.50. The method of claim 21, 23, 25 or 27, wherein said estrogen is piperazine estrone sulphate (estropipate). .Iaddend..Iadd.51. The method of claim 21, 23, 25 or 27, wherein said estrogen is 17β-estradiol and said progestogen is dl-norgestrel or laevo-norgestrel, the daily dosage level of said 17β-estradiol being about 1 mg, the daily dosage level of said dl-norgestrel (where present) being about 100 micrograms, and the daily dosage of said laevo-norgestrel (where present) being about 50 micrograms. .Iaddend..Iadd.52. The method of claim 21, 22, 23, 24 or 25 wherein the selected dosages are the minimum effective quantities of progestogen and estrogen. .Iaddend..Iadd.53. The method of claim 21 or 23, wherein said daily dosages of progestogen and estrogen are administered once daily. .Iaddend..Iadd.54. The method of claim 22, 24 or 25, wherein said single dosage form is a tablet. .Iaddend..Iadd.55. The method of claim 21, 22, 23 or 24, wherein said progestogen is in micronized form. .Iaddend..Iadd.56. The method of claim 21, 22, 23 or 24, wherein said estrogen is a synthetic estrogen. .Iaddend..Iadd.57. The method of claim 21, 22, 23 or 24, wherein the estrogen is a natural estrogen. .Iaddend.