172. DEVELOPMENT OF A NON-HORMONAL CONTRACEPTIVE: VAGINAL DELIVERY OF A LIF INHIBITOR: ITS TISSUE DISTRIBUTION AND EFFECT ON IMPLANTATION IN MICE

2009 ◽  
Vol 21 (9) ◽  
pp. 90
Author(s):  
E. M. Menkhorst ◽  
J. G. Zhang ◽  
P. O. Morgan ◽  
D. Metcalf ◽  
L. A. Salamonsen ◽  
...  
Keyword(s):  
Polyethylene Glycol ◽  
Tissue Distribution ◽  
Hormonal Contraceptive ◽  
Leukaemia Inhibitory Factor ◽  
Delivery Method ◽  
Time Points ◽  
Implantation Sites ◽  
Specific Tissue ◽  
Long Acting ◽  
Route Of Delivery

Uterine leukaemia inhibitory factor (LIF) is obligatory for fertility in mice and associated with infertility in women. Intraperitoneal injection (IPI) of a long-acting LIF inhibitor conjugated to polyethylene glycol (PEGLA) blocks endometrial LIF action preventing implantation1. Thus, PEGLA is a promising non-hormonal contraceptive. In women, vaginally applied (VA) compounds preferentially localize to the uterus suggesting a desirable delivery method for contraceptive purposes; however this has not been examined in mice. We aimed to compare the effects of VA and IPI PEGLA on tissue distribution and implantation in mice. Non-pregnant or mated female mice (Pregnant day [D] 2 [D0: day of plug], n=3/group) were given 125I-PEGLA by IPI (3x106cpm) or VA (7x105cpm). 125I-PEGLA was measured in blood and tissue at various time points. To block implantation, mated mice (n=4/group) were given PEGLA or control by IPI (500μg/injection) or VA (300μg/injection) at 1200h and 2200h on D2 and 1000h on D3 and the uterus examined for implantation sites on D6. 125 I-PEGLA accumulated in blood and uterus following IPI more rapidly (10min cf 30min), reached a higher concentration (10min, 6h and [blood] 24h; p<0.05) and remained longer (24h cf 6h) compared to VA. The percentage of protein-bound 125I in blood was higher following IPI (79.4+1.9%) than VA (47.5+6.7%) at 6h (p<0.05). Following IPI, 125I-PEGLA accumulated in the liver, gall bladder and stomach (2h) and spleen (24h) compared to control while no specific tissue accumulation was observed following VA. PEGLA prevented implantation following IPI (p<0.05) and reduced the size of implantation sites and decidualization in VA compared to controls. This study demonstrated differences in tissue distribution between VA and IPI PEGLA. It showed that VA PEGLA acted on the uterus in mice albeit to a lesser extent than IPI. It suggests that VA PEGLA is a potential route of delivery for contraceptive purposes.

414. The contraceptive potential of a long-acting IL-11 inhibitor

2008 ◽  
Vol 20 (9) ◽  
pp. 94
Author(s):  
E. Menkhorst ◽  
L. Salamonsen ◽  
L. Robb ◽  
E. Dimitriadis
Keyword(s):  
Nature Medicine ◽  
Embryo Implantation ◽  
Hormonal Contraceptive ◽  
Cyclin D3 ◽  
Human Reproduction ◽  
Luminal Epithelium ◽  
Endometrial Stromal Cells ◽  
Decidual Cells ◽  
Implantation Sites ◽  
Long Acting

Interleukin 11 (IL-11) signalling is essential for the establishment of pregnancy in mice, through its action on the differentiation of uterine endometrial stromal cells (decidualisation), a critical process during embryo implantation. IL-11Rα deficient mice are infertile due to defective decidualisation1. IL-11 expression peaks between days (D) 4.5–9.5 of pregnancy (D0: day of plug) in mouse decidua. We examined the effect of administering (intraperitoneal [IP] injection or vaginal gel) a PEGylated IL-11 antagonist (PEGIL-11A) on decidualisation and pregnancy outcome in mice. The sera half-life of PEGIL-11A (IC50 2.8nM) following IP injection was 24h, compared with <1 h for the non-PEGylated antagonist (IC50 0.26nM). Following IP injection, PEGIL-11A localised to decidual cells and blocked the IL-11 decidual target protein, cyclin D3. IP injection of 600µg/application PEGIL-11A (or PEG control) at 1000 h and 1600 h on D3 and 1000 h on D4 (n = 4/group), resulted in smaller implantation sites than controls on D6 due to retarded mesometrial decidual formation. On D10, severe decidual destruction was visible: implantation sites contained regions of haemorrhage and the uterine luminal epithelium had reformed, suggesting a return to oestrous cycling. Following vaginal application in aqueous placebo gel, PEGIL-11A localised to decidual cells. Vaginal application of 200µg/application PEGIL-11A (or control) twice daily from D2 to D5 (n = 4/group), resulted in smaller implantation sites than controls on D6 due to partial inhibition of mesometrial decidual formation. This study demonstrates that PEGIL-11A blocked IL-11 action in the uterus, resulting in total pregnancy loss, equivalent to the IL-11Rα deficient mouse. In women, IL-11 and its receptor are produced by the uterine luminal and glandular epithelium during the period of uterine receptivity2, suggesting that IL-11 may act during initial blastocyst attachment to the luminal epithelium as well as stromal decidualisation. This study provides proof-of-principle for the development of a novel, non-hormonal contraceptive for women. (1) Robb L et al. Nature Medicine 1998; 4: 303–308. (2) Dimitriadis E et al. Molecular Human Reproduction 2000; 6: 907–914.

scholarly journals Cervical and systemic concentrations of long acting hormonal contraceptive (LARC) progestins depend on delivery method: Implications for the study of HIV transmission

PLoS ONE ◽  
2019 ◽  
Vol 14 (5) ◽  
pp. e0214152 ◽  
Author(s):  
Lyndsey R. Buckner ◽  
Erma Z. Drobnis ◽  
Molly S. Augustine ◽  
Lynette K. Rogers ◽  
Jill Akers ◽  
...  
Keyword(s):  
Hiv Transmission ◽  
Hormonal Contraceptive ◽  
Delivery Method ◽  
Long Acting

152. DEVELOPMENT OF A VAGINALLY APPLIED, NON-HORMONAL CONTRACEPTIVE: THE CONTRACEPTIVE EFFICACY AND IMPACT ON BONE TURNOVER OF PEGLA, A LONG-ACTING LIF ANTAGONIST

2010 ◽  
Vol 22 (9) ◽  
pp. 70
Author(s):  
E. M. Menkhorst ◽  
J. G. Zhang ◽  
P. O. Morgan ◽  
I. J. Poulton ◽  
D. Metcalf ◽  
...  
Keyword(s):  
Bone Turnover ◽  
Embryo Implantation ◽  
Hormonal Contraceptive ◽  
Bone Volume ◽  
Leukaemia Inhibitory Factor ◽  
Hormonal Contraceptives ◽  
Contraceptive Efficacy ◽  
Sexually Transmitted ◽  
Vaginal Administration ◽  
Long Acting

The WHO has called for the urgent development of pharmacological, non-hormonal contraceptives. Leukaemia inhibitory factor (LIF) is obligatory for embryo implantation in mice and associated with infertility in women. Injection of a long-acting LIF antagonist (PEGLA) blocks uterine LIF, preventing implantation in mice, making PEGLA a promising non-hormonal contraceptive. LIF and LIFR null mice show decreased bone volume associated with increased osteoclast number and size, suggesting PEGLA may target bone. Vaginally administered PEGLA could be a ‘dual-role’ contraceptive: delivered in a microbicide which blocks the vaginal transmission of sexually transmitted infections. We aimed to establish the contraceptive efficacy of vaginally administered PEGLA and identify non-uterine targets of PEGLA in mice. PEGLA was administered to mated female mice by intraperitoneal (IP) injection or vaginally (n = 4/group) during the peri-implantation period to determine its effect on implantation and bone turnover. The tissue and blood accumulation of 125I-PEGLA or control was identified at various time-points following IP injection (≤120 h) or vaginal administration (≤24 h) (n = 3/group). PEGLA administered via vaginal gel blocked implantation (0.0+0.0 vs 8.5+0.5) at a lower dose (500 μg) than IP injection (1500 μg). PEGLA administered by IP injection resulted in fewer (4.0+0.3% vs 7.7+1.5%; P < 0.05) but larger (20.9+0.9 μm vs 18.1+0.5 μm; P < 0.05) osteoclasts and increased trabecular bone volume (6.8+0.9% vs 3.1+1.1%; P < 0.05) but vaginally administered PEGLA had no effect on bone (P > 0.05). 125 I-PEGLA accumulated more quickly (10 min vs 30 min) and was retained longer (96 h vs 24 h) in blood and tissue following IP injection compared to vaginal administration. This is the first study to show the contraceptive efficacy of a PEGylated compound following vaginal delivery. Local delivery of PEGLA decreased the required dose and eliminated the effect on bone, suggesting that local administration would minimise the non-target effects of PEGLA. Contraceptive trials are now required in non-human primates to progress PEGLA towards human clinical trials.

The cell adhesion molecule M-cadherin is specifically expressed in developing and regenerating, but not denervated skeletal muscle

Development ◽  
1993 ◽  
Vol 117 (4) ◽  
pp. 1409-1420 ◽  
Author(s):  
R. Moore ◽  
F.S. Walsh
Keyword(s):  
Skeletal Muscle ◽  
Tissue Distribution ◽  
Cell Adhesion Molecule ◽  
Muscle Denervation ◽  
Regulatory Factor ◽  
Myogenic Regulatory Factor ◽  
Adult Skeletal Muscle ◽  
Specific Tissue ◽  
Alpha Actin

The spatiotemporal distribution of M-cadherin mRNA has been determined by in situ hybridization in the mouse embryo and in adult skeletal muscle following experimental regeneration and denervation. M-cadherin mRNA is highly tissue specific and is found only in developing skeletal muscle. In contrast, N-cadherin mRNA has a broader tissue distribution in the embryo, being found on both neural elements and skeletal and cardiac muscle. M-cadherin is expressed in the myotomes shortly after they form, along with the myogenic regulatory factor myogenin. M-cadherin is expressed in muscles derived from the myotomes and is detected in forelimb bud precursor cells at embryonic day 11.5. In the latter case M-cadherin expression appears co-ordinately with that of myogenin and cardiac alpha-actin. Shortly before birth, M-cadherin expression is down regulated. M-cadherin can, however, be re-expressed following experimental regeneration of skeletal muscle. Here M-cadherin is transiently expressed on regenerating myoblasts but not myotubes. Following muscle denervation no evidence was found for re-expression of M-cadherin under conditions where there was strong expression of the nicotinic acetylcholine receptor on myofibres. The highly specific tissue distribution and unique developmental profile distinguishes M-cadherin from other cadherins and suggests a role in cell surface events during early myogenesis.

TissueDistributionDBs: a repository of organism-specific tissue-distribution profiles

2009 ◽  
Vol 125 (3-6) ◽  
pp. 651-658 ◽  
Author(s):  
Sunitha Kogenaru ◽  
Coral del Val ◽  
Agnes Hotz-Wagenblatt ◽  
Karl-Heinz Glatting
Keyword(s):  
Tissue Distribution ◽  
Specific Tissue

Corrigendum to: Condom use among young women in Australia using long-acting reversible contraceptives or other hormonal contraceptives

Sexual Health ◽  
2020 ◽  
Vol 17 (4) ◽  
pp. 395
Author(s):  
Julie Nguyen ◽  
Henrietta Williams ◽  
Kathleen McNamee ◽  
Nabreesa Shafeeu ◽  
Alaina Vaisey ◽  
...  
Keyword(s):  
Condom Use ◽  
Contraceptive Use ◽  
Health Centre ◽  
Unwanted Pregnancy ◽  
Hormonal Contraceptive ◽  
Sexual Practices ◽  
Hormonal Contraceptives ◽  
Relationship Length ◽  
Sexually Transmissible Infections ◽  
Long Acting

Background:Dual condom and long-acting reversible contraceptive (LARC) or non-LARC hormonal contraceptive use is the most effective way to protect against unwanted pregnancy and sexually transmissible infections (STIs). This study aimed to determine whether condom use varied between users of LARC and non-LARC hormonal contraceptives and explore their motivations for condom use. Methods: Women aged 16–24 years attending a sexual and reproductive health centre in Melbourne, Australia, completed a survey about contraceptives and sexual practices. The proportion of LARC and non-LARC hormonal contraceptive users using condoms was calculated and logistic regression compared condom use between the two groups. Condom use was based on frequency of use and coded as a binary variable ‘never, not usually or sometimes’ versus ‘usually or always’. Results: In all, 294 (97%) women participated in the study; 23.8% (95% confidence interval (CI) 19.0–29.1%) used LARC and 41.7% (95% CI 36.0–47.6%) used non-LARC hormonal contraceptives. Condom use was reported by 26.1% (95% CI 16.3–38.1%) of LARC users and by 27.8% (95% CI 19.9–37.0%) of non-LARC hormonal contraceptive users. There was no difference in condom use between groups (odds ratio (OR) 0.9; 95% CI 0.4–1.9). Condom use reduced with increasing relationship length (≥6 months vs no relationship: OR 0.2; 95% CI 0.1–0.6). Non-LARC hormonal contraceptive users were more motivated to use condoms if worried about pregnancy than LARC users (62.8% vs 47.8%; P = 0.04). Conclusion: Condom use was low and similar between users of LARC and non-LARC hormonal contraceptives, and was associated with the length of the relationship. These results highlight the need to promote condom use when prescribing LARCs and non-LARC hormonal contraceptives to reduce the risk of STIs.

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