Methods for treating FSH related conditions with GnRH antagonists

Abstract

Methods for treating FSH related conditions, such as prostatic intraepithelial neoplasia, pedophilia, infertility, or vaginal bleeding, with GnRH antagonists are disclosed. The methods of the invention generally feature administering to a subject a GnRH antagonist suitable for in vivo administration and able to reduce both plasma FSH and LH levels in a subject, in an amount or in a formulation effective to reduce plasma FSH levels in the subject to a symptom alleviating level. In vitro fertilization and male contraceptive methods are also provided.

1 . A method for treating an FSH related condition in a subject, comprising administering to a subject a GnRH antagonist suitable for in vivo administration and able to reduce both plasma FSH and LH levels in a subject, in an amount or in a formulation effective to reduce plasma FSH levels in the subject to a symptom alleviating level, thereby treating an FSH related condition in the subject.  
   
   
       2 . The method of  claim 1 , wherein the symptom alleviating level is about 1 mIU/ml or less.  
   
   
       3 . The method of  claim 1 , wherein the symptom alleviating level is about 2 mIU/ml or less.  
   
   
       4 . The method of  claim 1 , wherein the symptom alleviating level is about 3 mIU/ml or less.  
   
   
       5 . The method of  claim 1 , wherein the symptom alleviating level is about 4 mIU/ml or less.  
   
   
       6 . The method of  claim 1 , wherein the symptom alleviating level is about 1-4 mIU/ml.  
   
   
       7 . The method of  claim 1 , wherein the FSH related condition is selected from the group consisting of prostatic intraepithelial neoplasia, vaginal bleeding, infertility, pedophilia, precocious puberty, prostate cancer, ovarian cancer, benign prostatic hypertrophy, endometriosis, uterine fibroids, breast cancer, premenstrual syndrome, polycystic ovary syndrome, pituitary gonadotropin tumors, testicular cancer, ovarian cysts, disorders related to an LH/FSH ratio imbalance, and thyroid related disorders.  
   
   
       8 . The method of  claim 1 , wherein the FSH related condition is selected from the group consisting of prostatic intraepithelial neoplasia, vaginal bleeding, infertility, pedophilia, and pituitary gonadotropin tumors.  
   
   
       9 .- 15 . (canceled)  
   
   
       16 . The method of  claim 7 , wherein the vaginal bleeding is due to thrombocytopenia.  
   
   
       17 . The method of  claim 16 , wherein the thrombocytopenia is caused by chemotherapy treatment.  
   
   
       18 . The method of  claim 7 , wherein the subject is suffering from a proliferative disorder and the condition is vaginal bleeding.  
   
   
       19 . The method of  claim 18 , wherein the proliferative disorder is acute myeloid leukemia.  
   
   
       20 . The method of  claim 7 , wherein the subject is a transplant recipient and the condition is vaginal bleeding.  
   
   
       21 .- 25 . (canceled)  
   
   
       26 . A method for contraception in a male subject comprising: 
 administering to a male subject a GnRH antagonist suitable for in vivo administration and able to reduce both plasma FSH and LH levels in a male subject, in an amount or in a formulation effective to reduce plasma FSH levels in the male subject to a symptom alleviating level; and    administering testosterone to the male subject in an amount or in a formulation effective to restore libido and potency in the male subject.    
   
   
       27 .- 34 . (canceled)  
   
   
       35 . The method of  claim 1 , wherein the GnRH antagonist has an ED 50  for histamine release in a standard in vitro histamine release assay of at least 3 μg/ml.  
   
   
       36 . The method of  claim 1 , wherein the GnRH antagonist has an ED 50  for histamine release in a standard in vitro histamine release assay of at least 5 μg/ml.  
   
   
       37 . The method of  claim 1 , wherein the GnRH antagonist has an ED 50  for histamine release in a standard in vitro histamine release assay of at least 10 μg/ml.  
   
   
       38 . The method of  claim 1 , wherein the GnRH antagonist is a decapeptide or a nonapeptide compound having a D-asparagine, an L-asparagine, a D-glutamine, or an L-glutamine at a position corresponding to position 6 of naturally occurring GnRH, or a pharmaceutically acceptable salt thereof.  
   
   
       39 . The method of  claim 38 , wherein the GnRH antagonist is a decapeptide.  
   
   
       40 . The method of  claim 38 , wherein the GnRH antagonist is a nonapeptide.  
   
   
       41 . The method of  claim 1 , wherein the GnRH antagonist is a peptide compound comprising a structure: 
 A-B—C-D-E-F-G-H—I-J    wherein    A is pyro-Glu, Ac-D-Nal, Ac-D-Qal, Ac-Sar, or Ac-D-Pal, or an analogue thereof;    B is His or 4-Cl- D-Phe, or an analogue thereof;    C is Trp, D-Pal, D-Nal, L-Nal-D-Pal(N—O), or D-Trp, or an analogue thereof;    D is Ser, or an analogue thereof;    E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or Ile, or an analogue thereof;    F is D-Asn or D-Gln;    G is Leu or Trp, or an analogue thereof;    H is Lys(iPr), Gln, Met, or Arg, or an analogue thereof;    I is Pro, or an analogue thereof; and    J is Gly-NH 2  or D-Ala-NH 2 , or an analogue thereof;    or a pharmaceutically acceptable salt thereof.    
   
   
       42 . The method of  claim 1 , wherein the GnRH antagonist is a peptide compound comprising a structure: 
 A-B—C-D-E-F-G-H—I-J    wherein    A is pyro-Glu, Ac-D-Nal, Ac-D-Qal, Ac-Sar, or Ac-D-Pal, or an analogue thereof,    B is His or 4-Cl-D-Phe, or an analogue thereof;    C is Trp, D-Pal, D-Nal, L-Nal-D-Pal(N—O), or Trp, or an analogue thereof;    D is Ser, or an analogue thereof;    E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or Ile, or an analogue thereof;    F is D-Asn;    G is Leu or Trp, or an analogue thereof;    H is Lys(iPr), Gln, Met, or Arg, or an analogue thereof;    I is Pro, or an analogue thereof; and    J is Gly-NH 2  or D-Ala-NH 2 , or an analogue thereof; or a pharmaceutically acceptable salt thereof.    
   
   
       43 . The method of  claim 1 , wherein the GnRH antagonist is a peptide compound comprising a structure: 
 Ac-D-Nal-4-Cl-D-Phe-D-Pal-Ser-N-Me-Tyr-D-Asn-Leu-Lys(iPr)-Pro-D-Ala-NH 2 ;    or a pharmaceutically acceptable salt thereof.    
   
   
       44 . The method of  claim 1 , wherein the GnRH antagonist is a peptide compound comprising a structure: 
 Ac-D-Nal-4-Cl-D-Phe-D-Pal-Ser-Tyr-D-Asn-Leu-Lys(iPr)-Pro-D-Ala-NH 2 ;    or a pharmaceutically acceptable salt thereof.    
   
   
       45 . The method of  claim 1 , wherein the GnRH antagonist is administered to the subject using a sustained-release formulation  
   
   
       46 . The method of  claim 44 , wherein the sustained-release formulation of GnRH antagonist comprises a solid ionic complex of a GnRH antagonist and a carrier macromolecule, wherein the carrier and GnRH antagonist used to form the complex are combined at a weight ratio of carrier:antagonist of 0.5:1 to 0.1:1.  
   
   
       47 . The method of  claim 1 , wherein the GnRH antagonist is administered at a dosage of about 5-500 μg/kg/day.  
   
   
       48 . The method of  claim 1 , wherein the GnRH antagonist is administered at a dosage of about 10-400 μg/kg/day.  
   
   
       49 . The method of  claim 1 , wherein the GnRH antagonist is administered at a dosage of about 10-100 μg/kg/day.  
   
   
       50 . The method of  claim 1 , wherein the subject is a mammal.  
   
   
       51 . The method of  claim 50 , wherein the mammal is a human.  
   
   
       52 . The method of  claim 51 , wherein the mammal is a female human.  
   
   
       53 . The method of  claim 51 , wherein the mammal is a male human.  
   
   
       54 . A method for treating infertility in a female subject comprising: 
 administering to a female subject a GnRH antagonist suitable for in vivo administration and able to reduce both plasma FSH and LH levels in a female subject, in an amount or in a formulation effective to reduce plasma FSH levels in the female subject to a symptom alleviating level;    harvesting an ovum from the female subject before the effect of the GnRH antagonist has dissipated;    combining the ovum with a spermatozoon in vitro, thereby fertilizing the ovum; and    transferring the fertilized ovum into the uterus of the female subject, thereby treating infertility in the female subject.    
   
   
       55 . (canceled)  
   
   
       56 . A method for in vitro fertilization of an ovum comprising: 
 administering to a female subject a GnRH antagonist suitable for in vivo administration and able to reduce both plasma FSH and LH levels in a female subject, in an amount or in a formulation effective to reduce plasma FSH levels in the female subject to a symptom alleviating level;    harvesting an ovum from the female subject before the effect of the GnRH antagonist has dissipated; and    combining the ovum with a spermatozoon in vitro, to thereby fertilize the ovum.    
   
   
       57 .- 59 . (canceled)