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 125I-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.
Highlights
The World Health Organization has called for the urgent development of pharmacological, non-hormonal contraceptives [1]
There was no difference in the number of corpora lutea (CL) between the PEGylated LIF inhibitor (PEGLA) and PEGMSA control treatment groups indicating that normal ovulations had occurred (PEGLA 6.560.6; PEGMSA 8.560.9 CL/mouse; P = 0.1367)
This study suggests that the vagina may be a suitable route of administration of a leukemia inhibitory factor (LIF) antagonist for contraceptive purposes in women, providing an option for a non-steroidal contraceptive that can be combined with a microbicidal drug for inhibition of sexually transmitted infections (STI), including HIV
Summary
The World Health Organization has called for the urgent development of pharmacological, non-hormonal contraceptives [1]. Affordable and reliable contraception improves maternal and child health and reduces population growth [3], which will help to reduce the consequences of climate change [4]. Female controlled contraception/HIV prevention is critical to address health issues associated with gender inequality [5]. Progress in the contraceptive development arena has been so poor that a recent report by the United Kingdom All Party Parliamentary Group on Population, Development and Reproductive Health [6] concluded that the Millennium Development Goals of the United Nations cannot be met given the levels of population growth in the poorest countries
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