Methods of Hormonal Treatment Utilizing Ascending-Dose Extended Cycle Regimens

Abstract

The present invention provides ascending-dose extended cycle regimens in which a female is administered an estrogen and a progestin for a period of greater than 30 or 31 consecutive days, optionally followed by a hormone-free period or by a period of administration of estrogen. The disclosed regimens can be administered to a female to provide contraceptive and non-contraceptive benefits.

1 . A method of contraception, the method comprising: 
 administering to a female in need thereof an estrogen and a progestin for a period of greater than 30 consecutive days,    wherein the estrogen and progestin are administered in at least three phases,    wherein a daily dosage of estrogen in a second phase is equal to or higher than a daily dosage of estrogen in a first phase,    wherein a daily dosage of estrogen in a third phase is equal to or higher than the daily dosage of estrogen in the second phase,    wherein a total daily dosage of estrogen and progestin in the second phase is higher than a total daily dosage of estrogen and progestin in the first phase, and    wherein a total daily dosage of estrogen and progestin in the third phase is higher than the total daily dosage of estrogen and progestin in the second phase.    
     
     
         2 . The method of  claim 1 , wherein the daily dosages of progestin in the first, second, and third phases are equal to each other.  
     
     
         3 . The method of  claim 1 , wherein a daily dosage of progestin in the second phase is higher than a daily dosage of progestin in the first phase, and a daily dosage of progestin in the third phase is higher than the daily dosage of progestin in the second phase.  
     
     
         4 . The method of  claim 1 , wherein a daily dosage of progestin in the second phase is equal to a daily dosage of progestin in the first phase, and a daily dosage of progestin in the third phase is higher than the daily dosage of progestin in the second phase.  
     
     
         5 . The method of  claim 1 , wherein a daily dosage of progestin in the second phase is higher than a daily dosage of progestin in the first phase, and a daily dosage of progestin in the third phase is equal to the daily dosage of progestin in the second phase.  
     
     
         6 . The method of  claim 1 , wherein a daily dosage of progestin in the second phase is less than twice a daily dosage of progestin in the first phase.  
     
     
         7 . The method of  claim 1 , wherein a daily dosage of progestin in the third phase is less than twice a daily dosage of progestin in the second phase.  
     
     
         8 . The method of  claim 2 , wherein each of the daily dosages of progestin is equivalent to 150 μg of levonorgestrel.  
     
     
         9 . The method of  claim 1 , wherein the daily dosage of progestin in the first phase is equivalent to 100 μg of levonorgestrel.  
     
     
         10 . The method of  claim 1 , wherein the daily dosage of progestin in the second phase is equivalent to 125 μg of levonorgestrel.  
     
     
         11 . The method of  claim 1 , wherein the daily dosage of progestin in the third phase is equivalent to 150 μg of levonorgestrel.  
     
     
         12 . The method of  claim 1 , wherein the daily dosages of estrogen in the first, second, and third phases are equal to each other.  
     
     
         13 . The method of  claim 1 , wherein the daily dosage of estrogen in the second phase is higher than the daily dosage of estrogen in the first phase, and the daily dosage of estrogen in the third phase is higher than the daily dosage of estrogen in the second phase.  
     
     
         14 . The method of  claim 1 , wherein the daily dosage of estrogen in the second phase is equal to the daily dosage of estrogen in the first phase, and the daily dosage of estrogen in the third phase is higher than the daily dosage of estrogen in the second phase.  
     
     
         15 . The method of  claim 1 , wherein the daily dosage of estrogen in the second phase is higher than the daily dosage of estrogen in the first phase, and the daily dosage of estrogen in the third phase is equal to the daily dosage of estrogen in the second phase.  
     
     
         16 . The method of  claim 1 , wherein the daily dosage of estrogen in the second phase is less than twice the daily dosage of estrogen in the first phase.  
     
     
         17 . The method of  claim 1 , wherein the daily dosage of estrogen in the third phase is less than twice the daily dosage of estrogen in the second phase.  
     
     
         18 . The method of  claim 1 , wherein the daily dosage of estrogen in the first phase is equivalent to 15 μg to 25 μg of ethinyl estradiol.  
     
     
         19 . The method of  claim 18 , wherein the daily dosage of estrogen in the first phase is equivalent to 20 μg of ethinyl estradiol.  
     
     
         20 . The method of  claim 1 , wherein the daily dosage of estrogen in the second phase is equivalent to 20 μg to 30 μg of ethinyl estradiol.  
     
     
         21 . The method of  claim 20 , wherein the daily dosage of estrogen in the second phase is equivalent to 25 μg of ethinyl estradiol.  
     
     
         22 . The method of  claim 1 , wherein the daily dosage of estrogen in the third phase is equivalent to 25 μg to 35 μg of ethinyl estradiol.  
     
     
         23 . The method of  claim 22 , wherein the daily dosage of estrogen in the third phase is equivalent to 30 μg of ethinyl estradiol.  
     
     
         24 - 26 . (canceled)  
     
     
         27 . The method of  claim 1 , wherein the estrogen and progestin are administered for a period of 31 to 190 consecutive days.  
     
     
         28 - 33 . (canceled)  
     
     
         34 . The method of  claim 27 , wherein the estrogen and progestin are administered for a period of 74 to 96 days.  
     
     
         35 . (canceled)  
     
     
         36 . The method of  claim 34 , wherein the estrogen and progestin are administered for a period of 84 days.  
     
     
         37 - 39 . (canceled)  
     
     
         40 . The method of  claim 36 , wherein the first phase is 21 days, the second phase is 21 days, and the third phase is 42 days.  
     
     
         41 . The method of  claim 36 , wherein the first phase is 21 days, the second phase is 42 days, and the third phase is 21 days.  
     
     
         42 . The method of  claim 36 , wherein the first phase is 42 days, the second phase is 21 days, and the third phase is 21 days.  
     
     
         43 - 57 . (canceled)  
     
     
         58 . The method of  claim 1 , further comprising a hormone-free period.  
     
     
         59 . The method of  claim 58 , wherein the hormone-free period is 2 to 10 consecutive days.  
     
     
         60 . The method of  claim 1 , further comprising administering estrogen for a period of 2 to 10 consecutive days.  
     
     
         61 . The method of  claim 60 , comprising administering estrogen for a period of 7 consecutive days.  
     
     
         62 . The method of  claim 60 , wherein the estrogen that is administered for the period of 2 to 10 consecutive days is in a daily dosage equivalent to 5 μg to 50 μg of ethinyl estradiol.  
     
     
         63 . The method of  claim 61 , wherein the estrogen that is administered for a period of 7 days is in a daily dosage equivalent to 10 μg of ethinyl estradiol.  
     
     
         64 . The method of  claim 1 , further comprising administering a second active agent.  
     
     
         65 . The method of  claim 64 , wherein the second active agent is administered (i) during a hormone-free period, (ii) in combination with an estrogen for a period of 2 to 10 consecutive days, (iii) continuously, (iv) intermittently, (v) one time, or (vi) once weekly.  
     
     
         66 . The method of  claim 64 , wherein the second active agent is selected from the group consisting of calcium, iron, and folic acid.  
     
     
         67 . The method of  claim 1 , further comprising administering an antidepressant.  
     
     
         68 . The method of  claim 67 , wherein the antidepressant is administered (i) during a hormone-free period, (ii) in combination with an estrogen for a period of 2 to 10 consecutive days, (iii) continuously, (iv) intermittently, (v) one time, or (vi) once weekly.  
     
     
         69 - 70 . (canceled)  
     
     
         71 . The method of  claim 1 , further comprising monophasically administering an estrogen and a progestin.  
     
     
         72 . The method of  claim 71 , wherein the estrogen and the progestin are monophasically administered for a period of greater than 30 consecutive days.  
     
     
         73 - 76 . (canceled)  
     
     
         77 . A method of contraception, the method comprising: 
 administering to a female in need thereof an estrogen and a progestin for a period of greater than 42 consecutive days,    wherein the estrogen and progestin are administered in at least two phases,    wherein a total daily dosage of estrogen and progestin in a second phase is higher than a total daily dosage of estrogen and progestin in a first phase, and    wherein a daily dosage of progestin in the second phase is less than twice a daily dosage of progestin in the first phase.    
     
     
         78 . The method of  claim 77 , wherein the daily dosages of progestin in the first and second phases are equal to each other.  
     
     
         79 . The method of  claim 77 , wherein the daily dosage of progestin in the second phase is higher than the daily dosage of progestin in the first phase.  
     
     
         80 . The method of  claim 78 , wherein each of the daily dosages of progestin is equivalent to 150 μg of levonorgestrel.  
     
     
         81 . The method of  claim 77 , wherein the daily dosage of progestin in the first phase is equivalent to 100 μg of levonorgestrel.  
     
     
         82 . The method of  claim 77 , wherein the daily dosage of progestin in the second phase is equivalent to 125 μg of levonorgestrel.  
     
     
         83 . The method of  claim 77 , wherein the daily dosages of estrogen in the first and second phases are equal to each other.  
     
     
         84 . The method of  claim 77 , wherein a daily dosage of estrogen in the second phase is higher than a daily dosage of estrogen in the first phase.  
     
     
         85 . The method of  claim 77 , wherein a daily dosage of estrogen in the second phase is less than twice a daily dosage of estrogen in the first place.  
     
     
         86 . The method of  claim 77 , wherein a daily dosage of estrogen in the first phase is equivalent to 15 μg to 25 μg of ethinyl estradiol.  
     
     
         87 . The method of  claim 77 , wherein a daily dosage of estrogen in the second phase is equivalent to 20 μg to 30 μg of ethinyl estradiol.  
     
     
         88 - 102 . (canceled)  
     
     
         103 . The method of  claim 77 , further comprising a hormone-free period.  
     
     
         104 . The method of  claim 103 , wherein the hormone-free period is 2 to 10 consecutive days.  
     
     
         105 . The method of  claim 77 , further comprising administering estrogen for a period of 2 to 10 consecutive days.  
     
     
         106 . The method of  claim 105 , wherein the estrogen that is administered for the period of 2 to 10 consecutive days is in a daily dosage that is equivalent to 5 μg to 50 μg of ethinyl estradiol.  
     
     
         107 . The method of  claim 77 , further comprising administering a second active agent.  
     
     
         108 . The method of  claim 107 , wherein the second active agent is administered (i) during a hormone-free period, (ii) in combination with an estrogen for a period of 2 to 10 consecutive days, (iii) continuously, (iv) intermittently, (v) one time, or (vi) once weekly.  
     
     
         109 . The method of  claim 107 , wherein the second active agent is selected from the group consisting of calcium, iron, and folic acid.  
     
     
         110 . The method of  claim 77 , further comprising administering an antidepressant.  
     
     
         111 . The method of  claim 110 , wherein the antidepressant is administered (i) during a hormone-free period, (ii) in combination with an estrogen for a period of 2 to 10 consecutive days, (iii) continuously, (iv) intermittently, (v) one time, or (vi) once weekly.  
     
     
         112 - 113 . (canceled)  
     
     
         114 . The method of  claim 77 , further comprising monophasically administering an estrogen and a progestin.  
     
     
         115 . The method of  claim 114 , wherein the estrogen and the progestin are monophasically administered for a period of greater than 30 consecutive days.  
     
     
         116 - 119 . (canceled)  
     
     
         120 . A pharmaceutical kit comprising: 
 a first vaginal ring capable of providing a daily dosage of estrogen and a daily dosage of progestin;    a second vaginal ring capable of providing a daily dosage of estrogen that is equal to or higher than that of the first vaginal ring and capable of providing a total daily dosage of estrogen and progestin that is higher than that of the first vaginal ring; and    a third vaginal ring capable of providing a daily dosage of estrogen that is equal to or higher than that of the second vaginal ring and capable of providing a total daily dosage of estrogen and progestin that is higher than that of the second vaginal ring;    wherein the vaginal rings are capable of providing estrogen and progestin for a period of greater than 30 consecutive days.    
     
     
         121 . A pharmaceutical kit comprising: 
 a first vaginal ring capable of providing a daily dosage of estrogen and a daily dosage of progestin;    a second vaginal ring capable of providing a total daily dosage of estrogen and progestin that is higher than that of the first vaginal ring and capable of providing a daily dosage of progestin that is less than twice that of the first vaginal ring;    wherein the vaginal rings are capable of providing estrogen and progestin for a period of greater than 30 consecutive days.    
     
     
         122 . The pharmaceutical kit of  claim 121 , wherein the second vaginal ring is capable of providing a daily dosage of estrogen that is equal to or higher than that of the first vaginal ring.  
     
     
         123 . A pharmaceutical kit comprising: 
 a first transdermal device capable of providing a daily dosage of estrogen and a daily dosage of progestin;    a second transdermal device capable of providing a daily dosage of estrogen that is equal to or higher than that of the first transdermal device and capable of providing a total daily dosage of estrogen and progestin that is higher than that of the first transdermal device; and    a third transdermal device capable of providing a daily dosage of estrogen that is equal to or higher than that of the second transdermal device and capable of providing a total daily dosage of estrogen and progestin that is higher than that of the second transdermal device;    wherein the transdermal devices are capable of providing estrogen and progestin for a period of greater than 30 consecutive days.    
     
     
         124 . A pharmaceutical kit comprising: 
 a first transdermal device capable of providing a daily dosage of estrogen and a daily dosage of progestin;    a second transdermal device capable of providing a total daily dosage of estrogen and progestin that is higher than that of the first transdermal device and capable of providing a daily dosage of progestin that is less than twice that of the first transdermal device;    wherein the transdermal devices are capable of providing estrogen and progestin for a period of greater than 30 consecutive days.    
     
     
         125 . The pharmaceutical kit of  claim 124 , wherein the second transdermal device is capable of providing a daily dosage of estrogen that is equal to or higher than that of the first transdermal device.  
     
     
         126 . A pharmaceutical kit comprising: 
 a first oral dosage capable of providing a daily dosage of estrogen and a daily dosage of progestin;    a second oral dosage capable of providing a daily dosage of estrogen that is equal to or higher than that of the first oral dosage and capable of providing a total daily dosage of estrogen and progestin that is higher than that of the first oral dosage; and    a third oral dosage capable of providing a daily dosage of estrogen that is equal to or higher than that of the second oral dosage and capable of providing a total daily dosage of estrogen and progestin that is higher than that of the second oral dosage;    wherein the oral dosages are capable of providing estrogen and progestin for a period of greater than 30 consecutive days.    
     
     
         127 . A pharmaceutical kit comprising: 
 a first oral dosage capable of providing a daily dosage of estrogen and a daily dosage of progestin;    a second oral dosage capable of providing a total daily dosage of estrogen and progestin that is higher than that of the first oral dosage and capable of providing a daily dosage of progestin that is less than twice that of the first oral dosage;    wherein the oral dosages are capable of providing estrogen and progestin for a period of greater than 42 consecutive days.    
     
     
         128 . The pharmaceutical kit of  claim 127 , wherein the second oral dosage is capable of providing a daily dosage of estrogen that is equal to or higher than that of the first oral dosage.  
     
     
         129 . The pharmaceutical kit of  claim 126 , comprising 21 first oral dosages, 21 second oral dosages, and 42 third oral dosages.  
     
     
         130 . The pharmaceutical kit of  claim 126 , comprising 21 first oral dosages, 42 second oral dosages, and 21 third oral dosages.  
     
     
         131 . The pharmaceutical kit of  claim 126 , comprising 42 first oral dosages, 21 second oral dosages, and 21 third oral dosages.  
     
     
         132 . The pharmaceutical kit of  claim 126 , wherein the first oral dosage is capable of providing 20 μg of ethinyl estradiol and 150 μg of levonorgestrel, the second oral dosage is capable of providing 25 μg of ethinyl estradiol and 150 μg of levonorgestrel, and the third oral dosage is capable of providing 30 μg of ethinyl estradiol and 150 μg of levonorgestrel.  
     
     
         133 . The pharmaceutical kit of  claim 126 , further comprising a fourth oral dosage capable of providing estrogen.  
     
     
         134 . The pharmaceutical kit of  claim 133 , wherein the fourth oral dosage comprises a daily equivalent of 10 μg of ethinyl estradiol.  
     
     
         135 . The pharmaceutical kit of  claim 133 , comprising 7 fourth oral dosages.  
     
     
         136 . A method of treating acne, the method comprising: 
 administering to a female in need thereof an estrogen and a progestin for a period of greater than 30 consecutive days,    wherein the estrogen and progestin are administered in at least three phases,    wherein a daily dosage of estrogen in a second phase is equal to or higher than a daily dosage of estrogen in a first phase,    wherein a daily dosage of estrogen in a third phase is equal to or higher than the daily dosage of estrogen in the second phase,    wherein a total daily dosage of estrogen and progestin in the second phase is higher than a total daily dosage of estrogen and progestin in the first phase, and    wherein a total daily dosage of estrogen and progestin in the third phase is higher than the total daily dosage of estrogen and progestin in the second phase.    
     
     
         137 . A method of treating acne, the method comprising: 
 administering to a female in need thereof an estrogen and a progestin for a period of greater than 42 consecutive days,    wherein the estrogen and progestin are administered in at least two phases,    wherein a total daily dosage of estrogen and progestin in a second phase is higher than a total daily dosage of estrogen and progestin in a first phase, and    wherein a daily dosage of progestin in the second phase is less than twice a daily dosage of progestin in the first phase.    
     
     
         138 . A method of treating headache, the method comprising: 
 administering to a female in need thereof an estrogen and a progestin for a period of greater than 30 consecutive days,    wherein the estrogen and progestin are administered in at least three phases,    wherein a daily dosage of estrogen in a second phase is equal to or higher than a daily dosage of estrogen in a first phase,    wherein a daily dosage of estrogen in a third phase is equal to or higher than the daily dosage of estrogen in the second phase,    wherein a total daily dosage of estrogen and progestin in the second phase is higher than a total daily dosage of estrogen and progestin in the first phase, and    wherein a total daily dosage of estrogen and progestin in the third phase is higher than the total daily dosage of estrogen and progestin in the second phase.    
     
     
         139 . A method of treating headache, the method comprising: 
 administering to a female in need thereof an estrogen and a progestin for a period of greater than 42 consecutive days,    wherein the estrogen and progestin are administered in at least two phases,    wherein a total daily dosage of estrogen and progestin in a second phase is higher than a total daily dosage of estrogen and progestin in a first phase, and    wherein a daily dosage of progestin in the second phase is less than twice a daily dosage of progestin in the first phase.    
     
     
         140 . A method of treating pelvic pain, the method comprising: 
 administering to a female in need thereof an estrogen and a progestin for a period of greater than 30 consecutive days,    wherein the estrogen and progestin are administered in at least three phases,    wherein a daily dosage of estrogen in a second phase is equal to or higher than a daily dosage of estrogen in a first phase,    wherein a daily dosage of estrogen in a third phase is equal to or higher than the daily dosage of estrogen in the second phase,    wherein a total daily dosage of estrogen and progestin in the second phase is higher than a total daily dosage of estrogen and progestin in the first phase, and    wherein a total daily dosage of estrogen and progestin in the third phase is higher than the total daily dosage of estrogen and progestin in the second phase.    
     
     
         141 . A method of treating pelvic pain, the method comprising: 
 administering to a female in need thereof an estrogen and a progestin for a period of greater than 42 consecutive days,    wherein the estrogen and progestin are administered in at least two phases,    wherein a total daily dosage of estrogen and progestin in a second phase is higher than a total daily dosage of estrogen and progestin in a first phase, and    wherein a daily dosage of progestin in the second phase is less than twice a daily dosage of progestin in the first phase.