title: Kaempferol Exhibits Progestogenic Effects in Ovariectomized Rats.
abstract: OBJECTIVE
  Progesterone (P4) plays a central role in women's health. Synthetic progestins are used clinically in hormone replacement therapy (HRT), oral contraceptives, and for the treatment of endometriosis and infertility. Unfortunately, synthetic progestins are associated with side effects, including cardiovascular disease and breast cancer. Botanical dietary supplements are widely consumed for the alleviation of a variety of gynecological issues, but very few studies have characterized natural compounds in terms of their ability to bind to and activate progesterone receptors (PR). Kaempferol is a flavonoid that functions as a non-steroidal selective progesterone receptor modulator (SPRM)in vitro. This study investigated the molecular and physiological effects of kaempferol in the ovariectomized rat uteri.
  
  
  METHODS
  Since genistein is a phytoestrogen that was previously demonstrated to increase uterine weight and proliferation, the ability of kaempferol to block genistein action in the uterus was investigated. Analyses of proliferation, steroid receptor expression, and induction of well-established PR-regulated targetsAregandHand2were completed using histological analysis and qPCR gene induction experiments. In addition, kaempferolin silicobinding analysis was completed for PR. The activation of estrogen and androgen receptor signalling was determinedin vitro.
  
  
  RESULTS
  Molecular docking analysis confirmed that kaempferol adopts poses that are consistent with occupying the ligand-binding pocket of PRA. Kaempferol induced expression of PR regulated transcriptional targets in the ovariectomized rat uteri, includingHand2andAreg. Consistent with progesterone-l ke activity, kaempferol attenuated genistein-induced uterine luminal epithelial proliferation without increasing uterine weight. Kaempferol signalled without down regulating PR expressionin vitroandin vivoand without activating estrogen and androgen receptors.
  
  
  CONCLUSIONS
  Taken together, these data suggest that kaempferol is a unique natural PR modulator that activates PR signalingin vitroandin vivowithout triggering PR degradation.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: May Fern
authors.initials: MF
authors.lastname: Toh
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Mendonca
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Eddie
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Endsley
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Lantvit
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Pavel A
authors.initials: PA
authors.lastname: Petukhov
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Burdette
keywords: Botanicals; Genistein; Hormone replacement therapy; Kaempferol; Progesterone receptor; Progestin
references.citation: Nutr Cancer. 1997;27(1):31-40
references.pmid: 8970179
references.citation: J Biol Chem. 2001 Oct 19;276(42):38472-9
references.pmid: 11504717
references.citation: Arch Pharm Res. 2006 May;29(5):354-62
references.pmid: 16756079
references.citation: J Ethnopharmacol. 2012 Aug 30;143(1):14-23
references.pmid: 22771317
references.citation: Endocrinology. 2004 Mar;145(3):1314-21
references.pmid: 14617569
references.citation: Mol Endocrinol. 2007 May;21(5):1066-81
references.pmid: 17356170
references.citation: J Comput Chem. 2002 Dec;23(16):1623-41
references.pmid: 12395429
references.citation: Nutr Cancer. 2008;60(6):800-9
references.pmid: 19005980
references.citation: Oncol Rep. 2012 Jan;27(1):87-93
references.pmid: 21922150
references.citation: J Biol Chem. 1989 Apr 15;264(11):6520-8
references.pmid: 2703504
references.citation: Mol Cell Endocrinol. 2008 Jul 16;289(1-2):85-93
references.pmid: 18400372
references.citation: J Endocrinol. 1970 Sep;48(1):109-15
references.pmid: 5472392
references.citation: Clin Cancer Res. 2009 Sep 15;15(18):5784-93
references.pmid: 19737954
references.citation: J Mol Biol. 1995 Jan 6;245(1):43-53
references.pmid: 7823319
references.citation: FEBS Lett. 2009 Feb 18;583(4):643-7
references.pmid: 19171140
references.citation: J Biol Chem. 1996 Mar 15;271(11):6379-88
references.pmid: 8626436
references.citation: Nature. 1998 May 28;393(6683):392-6
references.pmid: 9620806
references.citation: Breast Cancer Res. 2012 Feb 03;14(1):R21
references.pmid: 22305057
references.citation: J Nutr. 2003 Jun;133(6):1937-42
references.pmid: 12771342
references.citation: Mol Endocrinol. 1995 Jun;9(6):691-705
references.pmid: 8592515
references.citation: Br Med J. 1980 Mar 22;280(6217):825-7
references.pmid: 7370683
references.citation: Mol Cell Endocrinol. 2006 Mar 27;248(1-2):94-103
references.pmid: 16406281
references.citation: Food Chem. 2011 Sep 15;128(2):513-519
references.pmid: 21625365
references.citation: Oncol Lett. 2013 Jan;5(1):139-144
references.pmid: 23255909
references.citation: J Womens Health (Larchmt). 2005 Sep;14(7):634-49
references.pmid: 16181020
references.citation: Eur J Clin Nutr. 2004 Jun;58(6):947-54
references.pmid: 15164116
references.citation: J Steroid Biochem Mol Biol. 2004 Feb;88(2):113-22
references.pmid: 15084343
references.citation: J Endocrinol. 1973 Jun;57(3):549-54
references.pmid: 4715727
references.citation: Arch Intern Med. 2005 Feb 14;165(3):281-6
references.pmid: 15710790
references.citation: Reprod Toxicol. 2003 Jul-Aug;17(4):421-32
references.pmid: 12849853
references.citation: Science. 2011 Feb 18;331(6019):912-6
references.pmid: 21330545
references.citation: J Nutr. 2002 Jan;132(1):27-30
references.pmid: 11773503
references.citation: Steroids. 2000 Oct-Nov;65(10-11):659-64
references.pmid: 11108873
references.citation: Steroids. 2003 Nov;68(10-13):761-70
references.pmid: 14667966
references.citation: Carcinogenesis. 2010 Aug;31(8):1392-9
references.pmid: 20547493
references.citation: Climacteric. 2012 Apr;15 Suppl 1:18-25
references.pmid: 22432812
references.citation: Fen Zi Xi Bao Sheng Wu Xue Bao. 2007 Apr;40(2):103-12
references.pmid: 17580663
references.citation: Int J Cancer. 2007 Nov 15;121(10):2225-32
references.pmid: 17471564
references.citation: Drugs Aging. 2004;21(13):865-83
references.pmid: 15493951
references.citation: Biol Reprod. 1998 Nov;59(5):1143-52
references.pmid: 9780321
references.citation: J Agric Food Chem. 2005 Aug 10;53(16):6246-53
references.pmid: 16076101
references.citation: J Ovarian Res. 2013 Feb 07;6(1):12
references.pmid: 23388061
references.citation: Cancer Epidemiol Biomarkers Prev. 2005 Jan;14(1):98-107
references.pmid: 15668482
references.citation: Mediators Inflamm. 2007;2007:45673
references.pmid: 18274639
references.citation: Prog Mol Biol Transl Sci. 2009;87:53-85
references.pmid: 20374701
references.citation: J Nutr. 1997 Feb;127(2):263-9
references.pmid: 9039826
references.citation: Cancer Res. 2012 Apr 15;72(8):2028-35
references.pmid: 22369929
references.citation: Endocr Rev. 2005 May;26(3):423-38
references.pmid: 15857972
references.citation: Chin Med. 2012 Apr 30;7:10
references.pmid: 22546174
references.citation: Nucl Recept Signal. 2009 Dec 31;7:e009
references.pmid: 20087430
references.citation: Biol Reprod. 2000 Jan;62(1):168-77
references.pmid: 10611082
references.citation: Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1032-7
references.pmid: 10655479
references.citation: Breast Cancer Res Treat. 2000 Jul;62(1):35-49
references.pmid: 10989984
references.citation: EMBO J. 1990 May;9(5):1603-14
references.pmid: 2328727
references.citation: Steroids. 2000 Oct-Nov;65(10-11):763-71
references.pmid: 11108887
references.citation: J Natl Cancer Inst. 1998 Dec 2;90(23):1774-86
references.pmid: 9839517
references.citation: Reproduction. 2004 Aug;128(2):139-46
references.pmid: 15280552
references.citation: Maturitas. 2003 Dec 10;46 Suppl 1:S59-69
references.pmid: 14670647
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Nov 1;877(29):3595-600
references.pmid: 19748328
references.citation: Mini Rev Med Chem. 2011 Apr;11(4):298-344
references.pmid: 21428901
references.citation: Proc Soc Exp Biol Med. 1998 Mar;217(3):369-78
references.pmid: 9492350
references.citation: J Endocrinol. 1973 Oct;59(1):205-6
references.pmid: 4748527
references.citation: Mol Endocrinol. 2005 Aug;19(8):1978-90
references.pmid: 15845746
references.citation: J Endocrinol. 2004 Apr;181(1):157-67
references.pmid: 15072576
references.citation: Semin Cell Dev Biol. 2008 Apr;19(2):178-86
references.pmid: 18280760
references.citation: Arch Pharm Res. 2008 Apr;31(4):424-8
references.pmid: 18449498
references.citation: Breast Cancer Res. 2005;7(6):R1036-50
references.pmid: 16457685
references.citation: Chem Biol Interact. 2008 Oct 22;176(1):30-9
references.pmid: 18619951
references.citation: Am J Physiol Heart Circ Physiol. 2008 Apr;294(4):H1630-7
references.pmid: 18281378
references.citation: J Comput Aided Mol Des. 2012 Jun;26(6):775-86
references.pmid: 22566074
references.citation: Food Chem Toxicol. 2000 Jul;38(7):555-64
references.pmid: 10942316
references.citation: Steroids. 2012 Jun;77(7):765-73
references.pmid: 22484153
references.citation: Ernst Schering Res Found Workshop. 2005;(52):19-37
references.pmid: 15704466
references.citation: Endocr Rev. 2013 Feb;34(1):130-62
references.pmid: 23303565