Methods for treating FSH related conditions with GnRH antagonists

1. A method for treating hormone refractory prostate cancer in a male subject, comprising administering to a subject a gonadotropin releasing hormone (GnRH) antagonist suitable for in vivo administration and able to reduce both plasma follicle stimulating hormone (FSH) and luteinizing hormone (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, 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, thereby treating an FSH related condition in the subject.

2. The method of claim 1 , wherein the symptom alleviating level is about 1-4 mIU/ml.

3. The method of claim 1 , wherein the symptom alleviating level is about 1 mIU/ml or less.

4. The method of claim 1 , wherein the symptom alleviating level is about 2 mIU/ml or less.

5. The method of claim 1 , wherein the symptom alleviating level is about 3 mIU/ml or less.

6. The method of claim 1 , wherein the symptom alleviating level is about 4 mIU/ml or less.

7. A method for reducing follicle stimulating hormone (FSH) levels in a male subject to treat hormone refractory prostate cancer comprising administering to the subject a gonadotropin releasing hormone (GnRH) antagonist suitable for in vivo administration and able to reduce both FSH and luteinizing hormone (LH) levels in a subject in an amount or in a formulation effective to reduce plasma FSH in the levels subject, 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, thereby reducing FSH levels in the subject.

8. The method of claim 1 , or claim 7 , wherein in the GnRH antagonist has an ED 50 for histamine release in a standard in vitro histamine release assay of at least 3 μg/ml.

9. The method of claim 1 or claim 7 , 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.

10. The method of claim 1 or claim 7 , 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.

11. The method of claim 1 or 7 , wherein the GnRH antagonist is a decapeptide.

12. The method of claim 1 or 7 , wherein the GnRH antagonist is a nonapeptide.

13. The method of claim 1 or 7 , 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-Tip, 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 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.

14. The method of claim 1 or 7 , 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, Mer, 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.

15. The method of claims 1 or 7 , 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 pharmaceutically acceptable salt thereof.

16. The method of claim 1 or 7 , 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.

17. The method of claim 1 or 7 , wherein the GnRH antagonist is administered to the subject using a sustained-release formulation.

18. The method of claim 17 , 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.

19. The method of claim 1 or 7 , wherein the GnRH antagonist is administered at a dosage of about 5-500 μg/kg/day.

20. The method of claim 1 or 7 , wherein the GnRH antagonist is administered at a dosage of about 10-400 μg/kg/day.

21. The method of claims 1 or 7 , wherein the GnRH antagonist is administered at a dosage of about 10-100 μg/kg/day.

22. The method of claim 1 or 7 , wherein the subject is a mammal.

23. The method of claim 22 , wherein the mammal is a human.

24. A method for treating hormone refractory prostate cancer in a male subject, comprising administering to a subject a gonadotropin releasing hormone (GnRH) antagonist comprising Ac-D-Nal-4-Cl-D-Phe-D-Pal-Ser-Tyr-D-Asn-Leu-Lys(iPr)-Pro-D-Ala-NH 2 in an amount or in a formulation effective to reduce plasma follicle stimulating hormone (FSH) levels in the subject to a symptom alleviating level, thereby treating hormone refractory prostate cancer in the subject.

25. A method for treating hormone refractory prostate cancer in a male subject, comprising administering to a subject a gonadotrophin releasing hormone (GnRH) antagonist comprising Ac-D-Nal-4-Cl-D-Phe-D-Pal-Ser-N-Me-Tyr-D-Asn-Leu-Lys(iPr)-Pro-D-Ala-NH 2 in an amount or in a formulation effective to reduce plasma follicle stimulating hormone (FSH) levels in the subject to a symptom alleviating lelvel, thereby treating hormone refractory prostate cancer in the subject.

26. The method of anyone of claim 24 or 25 wherein said plasma FSH level is 2 mIU/ml or less for a period of at least 29 days.

27. The method of anyone of claim 24 or 25 wherein said plasma FSH level is 2 mIU/ml or less for a period of at least 57 days.

28. A method for treating hormone refractory prostate cancer in a male subject, comprising administering to a subject a gonadotropin releasing hormone (GnRH) antagonist suitable for in vivo administration and able to reduce both plasma follicle stimulating hormone (FSH) and luteinizing hormone (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, 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, Mer, 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, thereby treating hormone refractory prostate cancer in the male subject.

29. A method for reducing follicle stimulating hormone (FSH) levels in a male subject to treat hormone refractory prostate cancer comprising administering to the subject a gonadotropin releasing hormone (GnRH) antagonist suitable for in vivo administration and able to reduce both FSH and luteinizing hormone (LH) levels in a subject in an amount or in a formulation effective to reduce plasma FSH levels in the subject, 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, Mer, 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, thereby reducing FSH levels in the male subject.