Hormone normalization therapy and uses therefor

• US 20090137478A1
• Filed: 11/12/2008
• Published: 05/28/2009
• Est. Priority Date: 05/11/2007
• Status: Active Grant

• Current Assignee: Barry M. Datlof, Lori R. Bernstein
• Original Assignee: Barry M. Datlof, Lori R. Bernstein
• Inventors: Datlof, Barry M., Bernstein, Lori R.
• Granted Patent: US 9,056,072 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/09 Luteinising hormone-releasing hormone [LHRH] , i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• CPC Class Codes: A61K 38/24 Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
• CPC Class Codes: A61P 5/24 of the sex hormones
• CPC Class Codes: G01N 2800/367 Infertility, e.g. sperm disorder, ovulatory dysfunction

Abstract

The present invention discloses a novel method of prevention of birth defects, miscarriages and infertility in women. The two therapies, disclosed herein, the hormone normalization therapy and the aromatase inhibitor-hormone normalization therapy, focus on restoring young hormonal levels in women in order to prevent female infertility and miscarriages, guide follicular and oocyte maturation, and promote correct chromosomal segregation in oocytes and early embryos.

Claims

1. A method for reducing the incidence of infertility, miscarriage and/or trisomic stillborns and liveborns in a woman in need of such treatment, comprising:

regulating levels of follicle stimulating hormone, luteinizing hormone activity, and progesterone in said woman such that said levels become similar to the levels of follicle stimulating hormone in a young and fertile woman, thereby reducing the incidence of infertility, miscarriage and/or trisomic stillborns and liveborns in said woman.

2. The method of claim 1, further comprising regulating levels of estradiol in said woman such that said levels become similar to the levels of estradiol in the young and fertile woman.

3. The method of claim 2, wherein regulation of estradiol comprises administering an inhibitor of the enzyme aromatase.

4. The method of claim 1, wherein said regulation in said woman comprises:

reducing pituitary secretion of follicle stimulating hormone and luteinizing hormone;

attenuating ovarian secretion of progesterone and estrogen; and

administering follicle stimulating hormone at various doses throughout the menstrual cycle to achieve levels of follicle stimulating hormone of a young and fertile woman;

administering luteinizing hormone and human chorionic gonadotropin to assist in oocyte and follicular maturation and to trigger ovulation, administering progesterone as needed for luteal phase support or a combination thereof.

5. The method of claim 4, wherein the pituitary secretion of follicle stimulating hormone and luteinizing hormone is reduced by administrating a gonadotropin releasing hormone or an agonist of gonadotropin releasing hormone or an antagonist of gonadotropin releasing hormone.

6. The method of claim 5, wherein said agonist of gonadotropin releasing hormone comprises Leuprolide, Buserelin, Goserelin, Histrelin, Leuprorelin, Nafarelin, Triptorelin, gonadorelin, fertirelin, or deslorelin.

7. The method of claim 5, wherein said antagonist of gonadotropin releasing hormone comprises abarelix, cetrorelix, ganirelix, antarelix, iturelix (antide), Nal-glu, or orgalutran.

8. The method of claim 4, wherein said follicle stimulating hormone is administered as human menopausal gonadotropin, purified follicle stimulating hormone, recombinant follicle stimulating hormone, or a combination thereof, with or without supplementation with luteinizing hormone activity (LH and/or hCG).

9. The method of claim 4, wherein said luteal-phase progesterone is administered as progesterone in oil for intramuscular injections, micronized progesterone vaginal suppositories in oil comprising prometrium, uterogestan, minagest or microgest, bioadhesive vaginal gels comprising crinone or prochieve, custom compounded vaginal suppositories;

with or without supplementation with an oral progesterone preparation comprised of prometrium, uterogestan, minagest or microgest capsules.

10. The method of claim 1, wherein said regulation is carried out over more than one menstrual cycle prior to attempted pregnancy.

11. The method of claim 10, wherein said regulation is carried out over at least 2 menstrual cycles, at least 3 menstrual cycles or at least 4 menstrual cycles.

12. The method of claim 1, wherein said regulation is effective in normalization of menstrual cycle length, enhancing chances of successful pregnancy in women, prevent aneuploidy in oocytes and embryos, reduce infertility by other pathways promoted by hormonal regulation or a combination thereof.

13. The method of claim 1, wherein said normalization of menstrual cycle length restores the duration of follicular phase of said woman to approximate that of a young fertile woman.

14. The method of claim 13, wherein said approximation is by administration of human menopausal gonadotropin, purified follicle stimulating hormone, and/or recombinant follicle stimulating hormone;

supplementation with luteinizing hormone and/or supplementation with urinary hCG, recombinant hCG, or highly purified hCG, triggering of ovulation with urinary hCG, recombinant hCG, highly purified hCG, or recombinant LH;

or a combination thereof.

15. The method of claim 1, wherein said infertility is due to premature ovarian failure, repeated implantation failure after in vitro fertilization, diminished ovarian reserve or idiopathic infertility.

16. The method of claim 1, wherein said woman has elevated follicle stimulating hormone level and normal estradiol level.

17. A method for reducing the incidence of infertility, miscarriage and/or trisomic stillborns and liveborns in a woman in need of such a treatment, comprising:

regulating levels of follicle stimulating hormone to approximate varying serum levels of follicle stimulating hormone that exist in a young and fertile woman, supplementing luteinizing hormone activity to support follicular and oocyte maturation and to trigger ovulation, and of progesterone to support the luteal phase, in said woman; and

co-administering an inhibitor of the enzyme aromatase such that said regulation and said administration regulates level of estradiol such that said level approximates the level of estradiol of a young and fertile woman throughout the menstrual cycle, thereby reducing the incidence of infertility, miscarriage and/or trisomic stillborns and liveborns in said woman.

18. The method of claim 17, wherein said regulation in said woman comprises:

reducing pituitary secretion of follicle stimulating hormone and luteinizing hormone;

reducing ovarian secretion of estrogen and progesterone, and

restoring follicle stimulating hormone at levels of a young and fertile woman that is specific for each stage of the menstrual cycle, restoring estradiol at a level that is specific for each stage of menstrual cycle, restoring LH activity in quantities sufficient to promote follicular and oocyte maturation and trigger ovulation in mid-cycle, and restoring progesterone in the luteal phase at levels that are adequate for luteal phase.

19. The method of claim 18, wherein the pituitary secretion of follicle stimulating hormone is reduced by administrating a gonadotropin releasing hormone, an agonist of gonadotropin stimulating hormone or an antagonist of gonadotropin stimulating hormone.

20. The method of claim 19, wherein said agonist of gonadotropin releasing hormone comprises Leuprolide, Buserelin, Goserelin, Histrelin, Leuprorel in, Nafarelin, Triptorel in, gonadorelin, fertirelin, or deslorelin.

21. The method of claim 19, wherein said antagonist of gonadotropin releasing hormone comprises abarelix, cetrorelix, ganirelix, antarelix, iturelix (antide), Nal-glu, or orgalutran.

22. The method of claim 18, wherein said follicle stimulating hormone is restored by administration of human menopausal gonadotropins or urofollitropins (partly or completely purified FSH preparations), recombinant follicle stimulating hormone, or a combination thereof, with or without supplementation with luteinizing hormone activity (LH and/or hCG).

23. The method of claim 18, wherein said progesterone is restored by administrating progesterone in oil for intramuscular injections, micronized progesterone vaginal suppositories in oil comprising prometrium, uterogestan, minagest or microgest, bioadhesive vaginal gels comprising crinone or prochieve, custom compounded vaginal suppositories, with or without supplementation with an oral progesterone preparation comprised of prometrium, uterogestan, minagest or microgest capsules.

24. The method of claim 17, wherein said aromatase inhibitor is aminogluthetimide, anastrozole, exemestane, formestane, letrozole, vorozole, 4-androstene-3,6,17-trione, 1,4,6-androstatrien-3,17-dione, or testolactone

25. The method of claim 17, wherein said regulation is carried out over at least 3 menstrual cycles

26. The method of claim 17, wherein said regulation is effective in normalization of menstrual cycle length, enhancing chances of successful pregnancy without miscarriage in women with or without elevated estradiol, preventing infertility, preventing aneuploidy in oocytes, reducing infertility by other pathways regulated by hormonal levels or a combination thereof.

27. The method of claim 26, wherein said normalization of menstrual cycle length restores the duration of follicular phase of said woman to approximate that of a young and fertile woman.

28. The method of claim 27, wherein said approximation is by administration of human menopausal gonadotropin, purified follicle stimulating hormone, recombinant follicle stimulating hormone, supplementation with luteinizing hormone, supplementation with hCG, triggering of ovulation with urinary hCG, highly purified hCG, recombinant hCG, recombinant LH or a combination thereof.

29. The method of claim 17, wherein said infertility is due to premature ovarian failure, repeated implantation failure after in vitro fertilization, ovarian aging, diminished ovarian reserve or idiopathic infertility.

30. The method of claim 17, wherein said woman has elevated follicle stimulating hormone level and elevated estradiol level or has normal follicle stimulating hormone level and elevated estradiol level.

31. A kit, comprising:

a gonadotropin releasing hormone, a gonadotropin releasing hormone agonist and/or a gonadotropin releasing hormone antagonist;

a follicle stimulating hormone preparation;

luteinizing hormone preparation and/or a human chorionic gonadotropin preparation;

a progesterone preparation; and

instructions for drug administration.

32. The kit of claim 31, further comprising an aromatase inhibitor.

33. The kit of claim 32, wherein said aromatase inhibitor is aminogluthetimide, anastrozole, exemestane, formestane, letrozole, vorozole, 4-androstene-3,6,17-trione, 1,4,6-androstatrien-3,17-dione, or testolactone.

34. The kit of claim 31, wherein said gonadotropin releasing hormone agonist comprises Leuprolide, Buserelin, Goserelin, Histrelin, Leuprorelin, Nafarelin, Triptorelin, gonadorelin, fertirelin, or deslorelin.

35. The kit of claim 31, wherein said gonadotropin releasing hormone antagonist comprises abarelix, cetrorelix, ganirelix, antarelix, iturelix (antide), Nal-glu, or orgalutran.

36. The kit of claim 31, wherein said follicle stimulating hormone preparation comprises human menopausal gonadotropin, purified follicle stimulating hormone, recombinant follicle stimulating hormone, supplementation with luteinizing hormone, supplementation with human chorionic gonadotropin or a combination thereof.

37. The kit of claim 31, wherein said luteinizing hormone activity preparation or said human chorionic gonadotropin activity preparation comprises urinary hCG, highly purified hCG, recombinant hCG or recombinant LH.

38. The kit of claim 31, wherein said progesterone preparation comprises progesterone in oil for intramuscular injections, micronized progesterone vaginal suppositories in oil comprising prometrium, uterogestan, minagest or microgest, bioadhesive vaginal gels comprising crinone or prochieve, custom compounded vaginal suppositories, with or without supplementation with an oral progesterone preparation comprised of prometrium, uterogestan, minagest or microgest capsules.