Methods of treating female infertility
Further according to the present disclosure, there are methods for promoting egg maturation in assisted reproductive technologies, such as in in vitro fertilization (IVF) or in an embryo transfer (ET) process. There are also methods for decreasing the rate of ovarian hyperstimulation syndrome (OHSS), providing comparable or improved pregnancy rates, decreasing the time to pregnancy, and inhibiting premature ovulation. The methods include the step of administering a therapeutically effective amount of an active pharmaceutical ingredient of 2-(N-acetyl-D-tyrosyl-trans-4-hydroxy-L-prolyl-L-asparaginyl-L-threonyl-L-phenylalanyl) hydrazinocarbonyl-L-leucyl-Nω-methyl-L-arginyl-L-tryptophanamide or a pharmaceutically acceptable salt thereof.
1. A method of increasing endogenous luteinizing hormone (LH) level in a woman in need thereof, the method comprising: administering to the woman an initial dose of about 0.0003 mg to 0.015 mg of 2-(N-acetyl-D-tyrosyl-trans-4-hydroxy-L-prolyl-L-asparaginyl-L-threonyl-L-phenylalanyl) hydrazinocarbonyl-L-leucyl-Nω-methyl-L-arginyl-L-tryptophanamide, or a corresponding amount of a pharmaceutically acceptable salt thereof, and one or more doses of a progestogen,
wherein the maximum endogenous LH level in blood occurs between about 12 hours and about 48 hours after administration of the initial dose.
2. The method of claim 1 , wherein the maximum endogenous LH level in blood occurs between about 18 hours and about 48 hours after administration of the initial dose.
3. The method of claim 1 , wherein oocyte maturation occurs without the administration of exogenous human chorionic gonadotropin or exogenous LH.
4. The method of claim 1 , wherein the initial dose is administered when at least three ovarian follicles of at least 14 mm are visible via ultrasound.
5. The method of claim 1 , wherein the initial dose is administered when at least three ovarian follicles of at least 18 mm are visible via ultrasound.
6. The method of claim 1 , wherein the initial dose is administered when serum estradiol concentration is at least 0.49 nmol/L.
7. The method of claim 1 , wherein the method comprises administration of a GnRH antagonist about 2 days to about 10 days prior to administration of the initial dose.
8. The method of claim 7 , wherein the GnRH antagonist is selected from the group consisting of relugolix, elagolix, cetrorelix, ganirelix, abarelix, nal-blu, antide, azaline B, degarelix, D63153 (ozarelix), OBE2109, and teverelix.
9. The method of claim 1 , wherein the method comprises administering a second dose of about 0.0003 mg to 0.015 mg of 2-(N-acetyl-D-tyrosyl-trans-4-hydroxy-L-prolyl-L-asparaginyl-L-threonyl-L-phenylalanyl) hydrazinocarbonyl-L-leucyl-Nω-methyl-L-arginyl-L-tryptophanamide, or a corresponding amount of a pharmaceutically acceptable salt thereof.
10. The method of claim 1 , wherein the woman has one or more of polycystic ovarian syndrome, serum anti-Müllerian hormone greater than 15 pmol/L, total antral follicle count greater than 23 via ultrasound, serum estradiol E2 greater than 3000 pg/mL, or has experienced one or more previous episodes of ovarian hyperstimulation syndrome.
11. The method of claim 1 , wherein the woman is any one or more of anovulatory, or of advanced maternal age, or is experiencing secondary ovarian failure, oligomenorrhea, amenorrhea, endometriosis, or polycystic ovarian syndrome.
12. The method of claim 1 , wherein the woman is at risk for ovarian hyperstimulation syndrome.
13. The method of claim 1 , wherein the woman does not experience one or more symptoms of ovarian hyperstimulation syndrome after administration of the initial dose.
14. The method of claim 1 , wherein the woman has ovarian hyperstimulation syndrome and wherein after administration of the initial dose, the woman does not experience a worsening of one or more symptoms of ovarian hyperstimulation syndrome.
15. The method of claim 1 , wherein the woman's endogenous LH level in blood is elevated for at least 48 hours after administration of the initial dose of 2-(N-acetyl-D-tyrosyl-trans-4-hydroxy-L-prolyl-L-asparaginyl-L-threonyl-L-phenylalanyl) hydrazinocarbonyl-L-leucyl-Nω-methyl-L-arginyl-L-tryptophanamide, or a corresponding amount of a pharmaceutically acceptable salt thereof, compared to the woman's endogenous LH level in blood prior to administration of the initial dose.
16. The method of claim 1 , wherein the woman's endogenous LH level in blood is elevated between about 14 hours to about 84 hours after administration of the initial dose of 2-(N-acetyl-D-tyrosyl-trans-4-hydroxy-L-prolyl-L-asparaginyl-L-threonyl-L-phenylalanyl) hydrazinocarbonyl-L-leucyl-Nω-methyl-L-arginyl-L-tryptophanamide, or a corresponding amount of a pharmaceutically acceptable salt thereof, compared to the woman's endogenous LH level in blood prior to administration of the initial dose.
17. The method of claim 1 , wherein the progestogen is progesterone, dydrogesterone, or medrogesterone.
18. The method of claim 1 , wherein the progestogen is medroxyprogesterone acetate.
19. The method of claim 1 , wherein one or more doses of the one or more doses of the progestogen are administered from oocyte retrieval until up to 12 weeks after retrieval.
20. The method of claim 1 , wherein one or more doses of the one or more doses of the progestogen are administered after the initial dose.