title: Vaginally administered PEGylated LIF antagonist blocked embryo implantation and eliminated non-target effects on bone in mice.
abstract: Female-controlled contraception/HIV prevention is critical to address health issues associated with gender inequality. Therefore, a contraceptive which can be administered in tandem with a microbicide to inhibit sexually transmitted infections, is desirable. Uterine leukemia inhibitory factor (LIF) is obligatory for blastocyst implantation in mice and associated with infertility in women. We aimed to determine whether a PEGylated LIF inhibitor (PEGLA) was an effective contraceptive following vaginal delivery and to identify non-uterine targets of PEGLA in mice.Vaginally-applied (125)I-PEGLA accumulated in blood more slowly (30 min vs 10 min) and showed reduced tissue and blood retention (24 h vs 96 h) compared to intraperitoneal injection in mice. Vaginally-applied PEGLA blocked implantation. PEGLA administered by intraperitoneal injection inhibited bone remodelling whereas vaginally-applied PEGLA had no effect on bone. Further, PEGLA had no effect in an animal model of multiple sclerosis, experimental auto-immune encephalomyelitis, suggesting PEGLA cannot target the central nervous system.Vaginally-administered PEGLA is a promising non-hormonal contraceptive, one which could be delivered alone, or in tandem with a microbicide. Vaginal application reduced the total dose of PEGLA required to block implantation and eliminated the systemic effect on bone, showing the vagina is a promising site of administration for larger drugs which target organs within the reproductive tract.
authors: Embryo Implantation, Prince Henry's Institute, Clayton, Australia. ellen.menkhorst@princehenrys.org
authors: Ellen
authors: E
authors: Menkhorst
authors: Jian-Guo
authors: JG
authors: Zhang
authors: Natalie A
authors: NA
authors: Sims
authors: Phillip O
authors: PO
authors: Morgan
authors: Priscilla
authors: P
authors: Soo
authors: Ingrid J
authors: IJ
authors: Poulton
authors: Donald
authors: D
authors: Metcalf
authors: Estella
authors: E
authors: Alexandrou
authors: Melissa
authors: M
authors: Gresle
authors: Lois A
authors: LA
authors: Salamonsen
authors: Helmut
authors: H
authors: Butzkueven
authors: Nicos A
authors: NA
authors: Nicola
authors: Evdokia
authors: E
authors: Dimitriadis
references: Nature. 1992 Sep 3;359(6390):76-9
references: 1522892
references: J Assist Reprod Genet. 2000 Sep;17(8):415-8
references: 11062850
references: Development. 1995 May;121(5):1283-99
references: 7789261
references: Am J Reprod Immunol. 2007 Jul;58(1):65-74
references: 17565549
references: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19357-62
references: 18042698
references: Fertil Steril. 2001 Dec;76(6):1108-12
references: 11730735
references: Obstet Gynecol. 2000 Mar;95(3):403-6
references: 10711552
references: Science. 2010 Sep 3;329(5996):1168-74
references: 20643915
references: Autoimmunity. 1998;28(2):109-20
references: 9771980
references: Contraception. 2007 Aug;76(2):111-6
references: 17656180
references: Hum Reprod. 2006 May;21(5):1316-9
references: 16373404
references: Endocrinology. 1993 Mar;132(3):1359-66
references: 8440191
references: Biol Reprod. 2009 May;80(5):920-7
references: 19144959
references: Science. 2010 Jul 9;329(5988):145-7
references: 20616253
references: Biol Reprod. 1994 Apr;50(4):882-7
references: 7515287
references: Fertil Steril. 2005 Jul;84(1):46-51
references: 16009156
references: Reprod Biol Endocrinol. 2007 Nov 29;5:44
references: 18047677
references: J Reprod Fertil. 1994 Jul;101(2):421-6
references: 7932378
references: Nature. 2008 Jul 10;454(7201):221-5
references: 18548006
references: Cytokine Growth Factor Rev. 2009 Aug;20(4):319-28
references: 19647472
references: Soc Reprod Fertil Suppl. 2007;63:421-31
references: 17566288
references: Lancet. 2009 Sep 19;374(9694):949
references: 19766868
references: Philos Trans R Soc Lond B Biol Sci. 2009 Oct 27;364(1532):3093-9
references: 19770158
references: J Biol Chem. 2004 Jan 16;279(3):2125-34
references: 14585833
references: J Bone Miner Res. 2008 Dec;23(12):2025-32
references: 18665789
references: J Clin Invest. 2010 Feb;120(2):582-92
references: 20051625
references: Hum Reprod Update. 1999 Jul-Aug;5(4):365-72
references: 10465526
references: J Reprod Immunol. 2006 Feb;69(1):53-64
references: 16310857
references: J Cell Physiol. 1991 Sep;148(3):430-9
references: 1918172
references: Ann N Y Acad Sci. 1997 Sep 26;828:291-9
references: 9329850
references: Glia. 2006 May;53(7):696-703
references: 16498619
references: Biochem Biophys Res Commun. 2005 Nov 4;336(4):1268-77
references: 16176808
references: Gynecol Endocrinol. 2004 May;18(5):240-3
references: 15346659
references: Endocr Rev. 1997 Dec;18(6):832-72
references: 9408745
references: Expert Rev Med Devices. 2008 Sep;5(5):639-54
references: 18803474
references: Nat Med. 2002 Jun;8(6):620-4
references: 12042814
references: Nat Med. 2002 Jun;8(6):613-9
references: 12042813
references: Clin Sci (Lond). 2007 Jan;112(2):77-91
references: 17155930
references: Fertil Steril. 2004 May;81(5):1414-6
references: 15136116
references: Am J Physiol Endocrinol Metab. 2006 Mar;290(3):E456-62
references: 16204337
references: J Clin Invest. 2008 Apr;118(4):1330-43
references: 18382745
references: Clin Endocrinol (Oxf). 2010 May;72(5):571-83
references: 19740118
references: Tohoku J Exp Med. 1985 Nov;147(3):261-5
references: 3911492
references: Curr Opin HIV AIDS. 2009 Jul;4(4):240-6
references: 19532059
references: J Endocrinol. 1996 Jan;148(1):95-102
references: 8568476
references: Mol Hum Reprod. 2006 Aug;12(8):491-5
references: 16621928
references: J Control Release. 2005 Mar 21;103(2):301-13
references: 15763615
references: Endocrinology. 2009 Jun;150(6):2915-23
references: 19213836