TWI396542B - 激素補充調配物 - Google Patents
激素補充調配物 Download PDFInfo
- Publication number
- TWI396542B TWI396542B TW096131421A TW96131421A TWI396542B TW I396542 B TWI396542 B TW I396542B TW 096131421 A TW096131421 A TW 096131421A TW 96131421 A TW96131421 A TW 96131421A TW I396542 B TWI396542 B TW I396542B
- Authority
- TW
- Taiwan
- Prior art keywords
- formulation
- estrogen
- estradiol
- estrogens
- hydroxyestrone
- Prior art date
Links
- 238000009472 formulation Methods 0.000 title claims description 46
- 239000000203 mixture Substances 0.000 title claims description 46
- 229940088597 hormone Drugs 0.000 title claims description 7
- 239000005556 hormone Substances 0.000 title claims description 7
- 229940011871 estrogen Drugs 0.000 claims description 95
- 239000000262 estrogen Substances 0.000 claims description 95
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 65
- 229960005309 estradiol Drugs 0.000 claims description 38
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims description 25
- PROQIPRRNZUXQM-UHFFFAOYSA-N (16alpha,17betaOH)-Estra-1,3,5(10)-triene-3,16,17-triol Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)O)C4C3CCC2=C1 PROQIPRRNZUXQM-UHFFFAOYSA-N 0.000 claims description 22
- 229960001348 estriol Drugs 0.000 claims description 22
- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 claims description 22
- SWINWPBPEKHUOD-UHFFFAOYSA-N 2-hydroxyestron Natural products OC1=C(O)C=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 SWINWPBPEKHUOD-UHFFFAOYSA-N 0.000 claims description 19
- SWINWPBPEKHUOD-JPVZDGGYSA-N 2-hydroxyestrone Chemical compound OC1=C(O)C=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 SWINWPBPEKHUOD-JPVZDGGYSA-N 0.000 claims description 19
- CQOQDQWUFQDJMK-SSTWWWIQSA-N 2-methoxy-17beta-estradiol Chemical compound C([C@@H]12)C[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CCC1=C2C=C(OC)C(O)=C1 CQOQDQWUFQDJMK-SSTWWWIQSA-N 0.000 claims description 19
- DILDHNKDVHLEQB-XSSYPUMDSA-N 2-hydroxy-17beta-estradiol Chemical compound OC1=C(O)C=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 DILDHNKDVHLEQB-XSSYPUMDSA-N 0.000 claims description 14
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 13
- 229940011671 vitamin b6 Drugs 0.000 claims description 13
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 claims description 10
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims description 10
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 claims description 8
- 230000009469 supplementation Effects 0.000 claims description 8
- 238000002560 therapeutic procedure Methods 0.000 claims description 8
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 7
- 229960000304 folic acid Drugs 0.000 claims description 7
- 235000019152 folic acid Nutrition 0.000 claims description 7
- 239000011724 folic acid Substances 0.000 claims description 7
- 238000002657 hormone replacement therapy Methods 0.000 claims description 7
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 claims description 6
- 229910017052 cobalt Inorganic materials 0.000 claims description 6
- 239000010941 cobalt Substances 0.000 claims description 6
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 6
- 229960003987 melatonin Drugs 0.000 claims description 6
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 claims description 6
- INBDPOJZYZJUDA-UHFFFAOYSA-N methanedithiol Chemical compound SCS INBDPOJZYZJUDA-UHFFFAOYSA-N 0.000 claims description 5
- 239000000186 progesterone Substances 0.000 claims description 5
- 229960003387 progesterone Drugs 0.000 claims description 5
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 claims description 5
- 229960003604 testosterone Drugs 0.000 claims description 5
- 239000011726 vitamin B6 Substances 0.000 claims description 5
- 235000019158 vitamin B6 Nutrition 0.000 claims description 5
- 229910052711 selenium Inorganic materials 0.000 claims description 4
- 239000011669 selenium Substances 0.000 claims description 4
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims 1
- 150000003431 steroids Chemical class 0.000 claims 1
- 239000002207 metabolite Substances 0.000 description 25
- 239000013589 supplement Substances 0.000 description 19
- 230000000711 cancerogenic effect Effects 0.000 description 15
- 231100000315 carcinogenic Toxicity 0.000 description 12
- 241000283073 Equus caballus Species 0.000 description 11
- 229930182833 estradiol Natural products 0.000 description 11
- 230000001681 protective effect Effects 0.000 description 11
- 230000000694 effects Effects 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 8
- 235000008160 pyridoxine Nutrition 0.000 description 8
- 239000011677 pyridoxine Substances 0.000 description 8
- 201000011510 cancer Diseases 0.000 description 7
- 239000004615 ingredient Substances 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 230000009245 menopause Effects 0.000 description 6
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 5
- 206010006187 Breast cancer Diseases 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 5
- 229960003399 estrone Drugs 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108010085330 Estradiol Receptors Proteins 0.000 description 3
- 102100038595 Estrogen receptor Human genes 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000003054 hormonal effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- WPOCIZJTELRQMF-UHFFFAOYSA-N 16alpha-Hydroxyestrone Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)=O)C4C3CCC2=C1 WPOCIZJTELRQMF-UHFFFAOYSA-N 0.000 description 2
- 150000000307 17β-estradiols Chemical class 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000003907 kidney function Effects 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229940094984 other estrogen in atc Drugs 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- FDFNTZDUOBCJMD-DMHIMHRUSA-N 15alpha-hydroxyestrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(C[C@@H]4O)=O)[C@@H]4[C@@H]3CCC2=C1 FDFNTZDUOBCJMD-DMHIMHRUSA-N 0.000 description 1
- KJDGFQJCHFJTRH-UHFFFAOYSA-N 16-Ketoestradiol Natural products OC1=CC=C2C3CCC(C)(C(C(=O)C4)O)C4C3CCC2=C1 KJDGFQJCHFJTRH-UHFFFAOYSA-N 0.000 description 1
- KJDGFQJCHFJTRH-YONAWACDSA-N 16-Ketoestradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](C(=O)C4)O)[C@@H]4[C@@H]3CCC2=C1 KJDGFQJCHFJTRH-YONAWACDSA-N 0.000 description 1
- WPOCIZJTELRQMF-QFXBJFAPSA-N 16alpha-hydroxyestrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C([C@H](O)C4)=O)[C@@H]4[C@@H]3CCC2=C1 WPOCIZJTELRQMF-QFXBJFAPSA-N 0.000 description 1
- PROQIPRRNZUXQM-ZMSHIADSSA-N 16beta-hydroxyestradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZMSHIADSSA-N 0.000 description 1
- WPOCIZJTELRQMF-LFRCEIEQSA-N 16beta-hydroxyestrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C([C@@H](O)C4)=O)[C@@H]4[C@@H]3CCC2=C1 WPOCIZJTELRQMF-LFRCEIEQSA-N 0.000 description 1
- WHEUWNKSCXYKBU-UHFFFAOYSA-N 2-Methoxyestron Natural products C12CCC3(C)C(=O)CCC3C2CCC2=C1C=C(OC)C(O)=C2 WHEUWNKSCXYKBU-UHFFFAOYSA-N 0.000 description 1
- WHEUWNKSCXYKBU-QPWUGHHJSA-N 2-methoxyestrone Chemical compound C([C@@H]12)C[C@]3(C)C(=O)CC[C@H]3[C@@H]1CCC1=C2C=C(OC)C(O)=C1 WHEUWNKSCXYKBU-QPWUGHHJSA-N 0.000 description 1
- XQZVQQZZOVBNLU-UHFFFAOYSA-N 4-Hydroxyestrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1O XQZVQQZZOVBNLU-UHFFFAOYSA-N 0.000 description 1
- QOZFCKXEVSGWGS-ZHIYBZGJSA-N 4-hydroxy-17beta-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1O QOZFCKXEVSGWGS-ZHIYBZGJSA-N 0.000 description 1
- XQZVQQZZOVBNLU-QDTBLXIISA-N 4-hydroxyestrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O XQZVQQZZOVBNLU-QDTBLXIISA-N 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 229940035811 conjugated estrogen Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- QTTMOCOWZLSYSV-QWAPEVOJSA-M equilin sodium sulfate Chemical compound [Na+].[O-]S(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4C3=CCC2=C1 QTTMOCOWZLSYSV-QWAPEVOJSA-M 0.000 description 1
- 150000002159 estradiols Chemical class 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- 125000003929 folic acid group Chemical group 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000007407 health benefit Effects 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 231100001223 noncarcinogenic Toxicity 0.000 description 1
- 230000004783 oxidative metabolism Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000002181 pyridoxine group Chemical group 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 125000003748 selenium group Chemical group *[Se]* 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- -1 sulfated M-MeO Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 150000004072 triols Chemical class 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4415—Pyridoxine, i.e. Vitamin B6
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本發明大體上係關於激素補充治療法,且具體地係有關一種新穎的雌激素補充調配物。
激素補充治療法已問世一些時日。激素補充治療法之一特殊方面(一般稱為雌激素補充劑)已用於更年期期間或更年期後的婦女超過30年。使用雌激素補充劑(通常係通過經皮吸收或口服予以完成)的理由,係為了補足身體製造之雌激素的下降或低水平。典型地,更年期期間及更年期後雌激素產量減少,隨後急遽下降。在此期間,醫師通常會開立雌激素補充劑。不過,在其中其他原因造成雌激素產量下降或若雌激素產量低於所需的其他情況中,亦可開立雌激素補充劑。此可能發生於未達更年期之婦女。
使用雌激素補充劑的理由(業已經許多年的科學研究證實)包括預防及/或治療骨質疏鬆症及心血管疾病,以及預防與老化有關的心智功能衰減。雌激素補充劑亦已被用於減少外貌因老化引起之變化。
最常被開立作為雌激素補充劑的雌激素,實際上係由馬尿濃縮得來,其通常稱為馬結合性雌激素(equine-conjugated estrogen)或純粹稱為馬雌激素。此外,單一天然生成之人類雌激素代謝物(典型為17-β-雌二醇,呈「貼片」形式)已被且目前正被開立。許多醫生以及其他人已反對認為馬雌激素不宜用於人類且甚至可能具危險性,因為有許多獨特的馬雌激素不存於人體,且(因此)在馬雌激素與欲代替的人類雌激素間缺乏關聯性。亦有某些證據顯示馬雌激素具致癌作用。
如上所陳,天然的17-β-雌二醇(單一的雌激素)典型係以雌激素貼片的劑型予以使用。雖然此單一雌激素顯然比馬雌激素更適合用於雌激素補充劑,咸相信其對於雌激素治療法並不完全,因為正常有許多不同的雌激素及其代謝物在人體(特別是於婦女)血流中循環。
就此點而論,有許多特定的人類雌激素(有時稱為「典型的」人類雌激素)已為補充治療法中廣泛研究的主題。此等典型的雌激素包括雌甾酮、雌二醇(17-β-雌二醇)及雌三醇。已發現雌三醇的治療果效相當微弱,而17-β-雌二醇被認為最有效,但一般卻公認其具有些微致癌性。雌甾酮亦具有致癌作用,雖然雌甾酮及17-β-雌二醇兩者的致癌性皆低於馬雌激素。關於雌三醇的致癌作用,有從不具致癌性或甚至具抗致癌性到輕微的致癌性的爭論。
為嘗試藉由補充治療法複製或模擬人體中所含的天然雌激素,某些醫生於1980年代開始以三種典型人類雌激素之組合(亦即雌甾酮、17-β-雌二醇及雌三醇的組合)。典型地,該組合中含有80%雌三醇、10%雌甾酮及10%雌二醇,不過此等百分比在不同調配物間略有不同。
然而,即便使用天然雌激素補充劑,仍有關於其致癌作用及其他不欲的可能結果之關切。考慮到有文獻顯示雌激素補充劑對健康相當有益之事實,開發一種不僅適當、天然且有效,並且被設計以防止或最小化不良副作用(包括致癌性副作用)的雌激素補充劑明顯係所欲的。
據此,本發明係一種於激素補充治療法中使用之雌激素調配物,其包括:某量之2-羥基雌甾酮(2-hydroxyestrone)、某量之17-β-雌二醇、某量之雌三醇、以及某量之2-甲氧基雌二醇的組合,其中各組成部分之量約略如下:其中2-羥基雌甾酮及雌三醇各約構成該等雌激素的35-45重量%,其中17-β-雌二醇約構成該等雌激素的10-30重量%,而其中2-甲氧基雌二醇構成該等雌激素的1/2-2重量%。
如上所指出,由馬尿製得之馬雌激素在歷史上且迄今仍有很大的程度被用作為人類雌激素補充治療法。不過,於使用天然雌激素中之優點已致使許多醫師開立特殊之單一天然生成的雌激素代謝物(例如17-β-雌二醇)或是近來之三種「典型」人類雌激素(亦即雌甾酮、17-β-雌二醇及雌三醇)之組合。
然而,長期以來的研究已揭露人體中有許多雌激素。此等額外的雌激素基本上包括(但不限於)雌甾酮、2-羥基雌甾酮、2-甲氧基雌甾酮、4-羥基雌甾酮、15-α-羥基雌甾酮、16-α-羥基雌甾酮、16-β-羥基雌甾酮、雌二醇(17-β-雌二醇)、2-羥基雌二醇、2-甲氧基雌二醇、4-羥基雌二醇、16-氧代雌二醇、雌三醇、16-表雌三醇(16-epistriol)及17-表雌三醇。此並非打算為明細表,因為仍有其他雌激素及其等的代謝產物存於人體中。不過,其確實包括大多數目前認為在正常情形下存在之雌激素。
在較佳具體實例中,本發明是一種包括數種正常於人體中循環的雌激素結合數種其他成分之新穎調配物;該等成分之目的係用於補足所選出之雌激素並與之共同作用以增強並增加其等的治療效果,並減少其等的反治療作用/缺點。
此新穎調配物係基於最接近於體中實際雌激素存在與發揮作用的雌激素水平。血流中最豐富的兩種雌激素為雌三醇及2-羥基雌甾酮,二者量大約相等。由於17-β-雌二醇最具治療效果,故亦包括於本發明調配物中。已證實2-羥基雌甾酮對癌為保護性,而雌三醇則非致癌性或者可能甚至為些微的抗癌性。17-β-雌二醇因已被指出為些許致癌性,故此組成部分之量被嚴格限制。於本調配物中,對於此三種雌激素,2-羥基雌甾酮及雌三醇約為38-44重量%的範圍,而17-β-雌二醇可在10-20重量%間作變化。於一僅包括2-羥基雌甾酮及17-β-雌二醇的具體實例中,該調配物為80-90%的2-羥基雌甾酮及10-20%的17-β-雌二醇。在極大量的可能之雌激素組合中,已發現以上組合甚具果效。
更具體地,關於三種雌激素的調配物,17-β-雌二醇(雖為三者中量最少者)一般被相信是所有雌激素中最有效者並提供了最大的治療效果,但亦提供最大的致癌風險。2-羥基雌甾酮的癌症風險較低,尤其是量高時。2-羥基雌甾酮有時也被稱為「好雌激素」。不過,其被視為是一種弱的雌激素,僅具有輕微程度的雌激素防護性活性。然而,此非致癌性弱雌激素可藉由占據可能否則會被更具致癌性的17-β-雌二醇刺激之所選定受體位點,而有助於保護抵抗雌激素相關型癌症。2-羥基雌甾酮已被發現為人體血流中數一數二豐富的雌激素。
雌三醇(雖為另一種弱雌激素)一般被認為係具抗癌性或與癌症的關係不明。其亦藉由占據受體位點保護抵抗致癌性雌激素,且是其他各種雌激素之去毒化產物。此外,雌三醇也是血流中數一數二豐富的天然雌激素。
以上三種雌激素(於所揭示的一般量)為一種新穎的且治療有效的雌激素組合,其同時最小化任何所導致的癌症的可能性。
本發明調配物之較佳形式包括數種其他成分。一種成分為吡哆醇(pyridoxine)(維生素B6)。添加吡哆醇的目的是幫助憂鬱症及液體保留(其有時肇因於雌激素干擾各種有賴於吡哆醇以保持適切功能的各種酵素系統)。
第二種添加成分為葉酸,其已通常被發現在更年期後之婦女中量為低的,且亦已被發現對於維持正常腦功能為重要的。雌激素補充劑可能會干擾天然葉酸之代謝。
另一種添加成分為硒,其可降低乳癌的風險。最後,已發現鈷有益,因為無足夠的鈷,雌激素補充治療法的效果可明顯降低(若不是被消滅)。添加鈷防止酵素將所補充的雌激素太快自身體清除,其有助於保持雌激素補充治療攝生法之效用。
吡哆醇及其他成分之量當然可變化,只要提供對正常的治療效果為足夠的量即可。不過,大體上,在2-羥基雌甾酮與雌三醇約為1000-2500微克的範圍(雖然較佳的範圍為1000-1125微克)的情況中,吡哆醇會約為20毫克,而葉酸為400-800微克的範圍,而硒及鈷係200-300微克的範圍。此等成分之每一者確保組成部分的有效水平。
上述調配物不僅提供呈天然形式的雌激素補充劑之明顯助益,且亦包括其他成分,其等特別被設計以減少或消除潛在地由補充雌激素造成,或是呈其副作用的某些問題或缺點。因此,本發明調配物是一種有效但安全的激素治療法,其維持雌激素補充劑的優點但不具前述缺點。
上述調配物的防護作用可藉由添加所選出的雌激素代謝物及其他成分而改善。已發現將某些代謝物添加至上述調配物(並非迄今為止用於於激素補充治療法)會降低此治療法(特別包括上述調配物)潛在的心血管及致癌作用。該等經選出的代謝物為特定雌二醇之雌激素代謝物。
雌二醇本身在各種組織及/或器官中誘發各種不同的生物作用,其係藉由雌二醇與雌二醇受體(ER)的直接交互作用,其隨即活化對該等組織及/或器官具有專一作用及防護性生物作用之特定基因之群組。亦已知雌二醇能藉由獨立於ER的方式誘發防護性生物作用。雌二醇藉由不同途徑轉化成各種代謝物,轉化成雌激素的與雌激素的代謝物兩者,某些其中被選出者具有防護性生物作用。
以下的雌二醇代謝物當添加至以上調配物時具有功效以產生改善的調配物:2-甲氧基雌二醇及2-羥基雌二醇。2-羥基雌二醇及2-甲氧基雌二醇(2-MeO)為親本激素(17-β-雌二醇,為上述調配物之一部分)的下游代謝物。雌二醇一般係藉由氧化代謝作用代謝以形成所需的羥基化代謝物,2-羥基雌二醇。17-β-雌二醇係藉由第1及第2階段肝酵素代謝成2-甲氧基雌二醇,其為此經改良的調配物中較佳的代謝物。
以上代謝物(尤其是2-甲氧基雌二醇,但2-羥基雌二醇也是)一般被視為安全的且會產生關於心臟健康以及對抗可能的乳癌(其等為與慣用的HRT治療法相關的風險)以及血癌及多發性骨髓癌、與其他者的防護作用。2-MeO亦有助於維持良好的腎功能,且能降低高血壓。該等代謝物因此能提供激素支持,同時亦提供對不欲的作用之保護。
一般而言,隨著女人老化,肝臟產生較少的防護性代謝物。因此,以雌激素的天然組合(如以上調配物中所陳者)納入所選定的代謝物係有益的。上文論及的特殊代謝物,2-甲氧基雌二醇(以及其硫酸化代謝物)及2-羥基雌二醇迄今未曾被用作為或是被考慮作為激素補充治療法調配物之部分,而已於本文由眾多可能的代謝物中選出。迄今未有人提出納入特定雌激素的代謝物作為HRT調配物之部分的觀念。如上指出,17-β-雌二醇為一種強效的治療性雌激素,但稍具致癌性。因此,典型地不會考慮且事實上迄今未曾考慮所選出之17-β-雌二醇之代謝物於防護及治療的價值之用途。
2-甲氧基雌二醇係藉由酵素性O-甲基化步驟(其接著雌三醇之羥基化)而生成,亦即,其為17-β-雌二醇的下游代謝物。雌二醇及其羥基化代謝物可被進一步代謝以生成硫酸化物,如硫酸化之M-MeO,其亦為HRT中之有效代謝物。大體上,2-甲氧基雌二醇及2-羥基雌二醇對組織及器官最具生物活性與防護性,其提供對心臟及腎臟功能與對抗否則可能由激素補充治療法調配物誘發的癌症的防護作用,其中2-甲氧基雌二醇為目前較佳的代謝物。
除了上述代謝物以外,亦可將其他成分/藥劑添加至調配物中,該等成分/藥劑包括維生素B6(吡哆醇,作為催化劑)、以及DHEA(其改善葡萄糖耐受性、減少體脂肪及增加骨質)。婦女需雄激素來防止雌激素的有害謝性分解。當DHEA與雌激素同時存在時,乳細胞癌生長受抑制。因此,DHEA有關於乳癌之保護性功效。此外,睪固酮、黃體酮(progesterone)及褪黑激素亦為所欲之添加劑。褪黑激素(一種天然的抗氧化劑)保護抵抗乳癌,且增進乳細胞健康。其他成分包括葉酸、鈷及硒。
另一種有效藥劑為二吲哚基甲烷(Di-Indolyl Mathane,DIM),其可調節雌激素之代謝。其傾向將雌激素之代謝轉向為防護性雌激素並遠離有害的雌激素。有效量為60-300毫克。
據此,所欲之激素補充治療法計畫可包括以下者之調配物:2-羥基雌甾酮、17-β-雌二醇、雌三醇、及2-MeO雌激素、以及可能的2-羥基雌二醇、以及選定量之添加劑如睪固酮、葉酸、二-吲哚基甲烷及吡哆醇(於早晨(AM)使用),而黃體酮、DHEA及褪黑激素的調配物可於夜晚使用。該等添加劑之量為:黃體酮1毫克-100毫克;睪固酮1/2毫克-5毫克;DHEA 1毫克-50毫克;葉酸100微克-2毫克;維生素B6(吡哆醇)1毫克-100毫克;及二吲哚基甲烷60-300毫克。
較佳的包含該等關鍵雌激素組成部分的基底調配物與其等相對重量百分比為:2-羥基雌甾酮.........35-45%雌三醇.........35-45% 17-β-雌二醇.........10-30% 2-甲氧基雌二醇.........1/2-2% 2-羥基雌二醇(添加時).........2-10%
調配物中之明確量包括:600-1200微克的2-羥基雌甾酮、1000-1500微克的雌三醇、200-500微克的17-β-雌二醇及15-50微克的甲氧基雌二醇。當2-羥基雌二醇為該調配物之部分時,使用15-50微克的2-羥基雌二醇。
該等調配物可使用已知技術(包括口服),以各種形式(例如呈膠囊或錠劑、呈各種局部形式)投藥於口腔或皮膚、直腸、非經腸、或陰道。該等調配物可方便地呈單位劑量形式或亞劑(sub-dose),且可藉習用製藥技術製備。
雖然本發明的較佳具體實例已為了明之目的揭露於本文,應瞭解在不背離本發明之精神(其由以下申請專利範圍定義)下,可將各種改變、修改及取代併入。尤其,各成分之量可作些許變化,只要能維持治療效果即可。
Claims (13)
- 一種於激素補充治療法中使用之雌激素調配物,其包含:某量之2-羥基雌甾酮(2-hydroxyestrone)、某量之17-β-雌二醇、某量之雌三醇、以及某量之2-甲氧基雌二醇的組合,其中各組成部分含量約略如下:其中2-羥基雌甾酮及雌三醇各約構成該等雌激素的35-45重量%,其中17-β-雌二醇約構成該等雌激素的10-30重量%,而其中2-甲氧基雌二醇構成該等雌激素的½-2重量%。
- 如申請專利範圍第1項之調配物,其包括2-羥基雌二醇,約雌激素的2-10重量%。
- 如申請專利範圍第1項之調配物,其包括維生素B6。
- 如申請專利範圍第1項之調配物,其包括DHEA。
- 如申請專利範圍第1項之調配物,其包括二吲哚基甲烷。
- 如申請專利範圍第1項之調配物,其包括睪固酮,及褪黑激素。
- 如申請專利範圍第6項之調配物,其包括黃體酮(progesterone)。
- 如申請專利範圍第1項之調配物,其包括鈷及硒。
- 如申請專利範圍第1項之調配物,其中該調配物包含600-1200微克的2-羥基雌甾酮、200-500微克的17-β-雌二醇、1000-1500微克的雌三醇及15-50微克的2-甲氧基雌二醇。
- 如申請專利範圍第8項之調配物,其包括15-50微克之2-羥基雌二醇。
- 如申請專利範圍第9項之調配物,其包括5-25毫克的DHEA、0.5-5.0毫克的睪固酮、褪黑激素及60-300毫克的二吲哚基甲烷。
- 一種包含:17-β-雌二醇、雌三醇、2-羥基雌甾酮及2-甲氧基雌二醇、睪固酮、維生素B6、葉酸及二-吲哚基甲烷之調配物;以及包含:黃體酮、DHEA、及褪黑激素之另一種調配物於製備用於激素補充治療之醫藥品的用途,其中前者的調配物係於早晨使用,而後者的調配物係於晚間使用。
- 如申請專利範圍第12項之用途,其中該在早晨使用之調配物包括2-羥基雌二醇。
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US11/371,580 US9446049B2 (en) | 2006-03-09 | 2006-03-09 | Hormone replacement formulation |
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CA (1) | CA2645320C (zh) |
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CN106176765A (zh) * | 2016-06-17 | 2016-12-07 | 南京精全生物医药科技有限公司 | 2‑羟基雌激素在制备用于治疗与雌激素相关疾病的药物中的应用 |
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US20040180866A1 (en) * | 2003-03-14 | 2004-09-16 | Mamchur Stephen A. | Hormone concentrate pharmaceutical composition |
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US4835147A (en) * | 1987-05-06 | 1989-05-30 | City Of Hope | Dehydroepiandrosterone therapy for ameleoration of prostate hypertrophy and sexual dysfunction |
IN170311B (zh) * | 1989-01-17 | 1992-03-14 | Cohen Michael | |
US6708822B1 (en) * | 1999-11-30 | 2004-03-23 | Cutispharma, Inc. | Compositions and kits for compounding pharmaceuticals |
US6299896B1 (en) * | 2000-04-13 | 2001-10-09 | Cooper Concepts, Inc. | Multi-vitamin and mineral supplement |
WO2002030355A2 (en) * | 2000-10-11 | 2002-04-18 | Laura Kragie | Composition and method of alleviating adverse side effects and/or enhancing efficacy of agents that inhibit aromatase |
US6911438B2 (en) * | 2001-09-12 | 2005-06-28 | Jonathan V. Wright | Hormone replacement formulation |
US8404272B2 (en) * | 2003-06-26 | 2013-03-26 | Poly-Med, Inc. | Fiber-reinforced composite rings for intravaginal controlled drug delivery |
WO2005051357A1 (en) * | 2003-11-19 | 2005-06-09 | Entremed, Inc. | Antiangiogenic agents |
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WO2007103638A2 (en) | 2007-09-13 |
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GB2451360B (en) | 2011-10-05 |
CA2645320C (en) | 2016-08-30 |
US9446049B2 (en) | 2016-09-20 |
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TW200908985A (en) | 2009-03-01 |
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