Publications

BACKGROUND

The efficacy of emergency contraceptive pills (ECPs) is currently uncertain. The best way to obtain a robust efficacy estimate would be to conduct a placebo-controlled randomized trial. We aimed to assess the feasibility of identifying women eligible for such a trial.

STUDY DESIGN

We conducted a survey of women aged 18-35 years in five sexually transmitted disease clinics and urgent care centers in Kenya and the United States in 2006.

RESULTS

Of 177 women surveyed, only 10 (6%) reported no reasons for exclusion from a potential efficacy trial. Of the rest, 149 (83%) had not recently had sex that conferred a substantial risk of pregnancy. At all sites combined, the rate of identification of potentially eligible women was 0.6 per day of interviewing.

CONCLUSION

A placebo-controlled efficacy trial of ECPs would likely require several thousand participants. Recruitment for such a trial in these types of sites would be prolonged.

Stratum corneum comprises corneocytes, derived from outer stratum granulosum during terminal differentiation, embedded in a lipid-enriched extracellular matrix, secreted from epidermal lamellar bodies. Permeability barrier insults stimulate rapid secretion of preformed lamellar bodies from the outer stratum granulosum, regulated through modulations in ionic gradients and serine protease (SP)/protease-activated receptor type 2 (PAR2) signaling. Because corneocytes are also required for barrier function, we hypothesized that corneocyte formation could also be regulated by barrier function. Barrier abrogation by two unrelated methods initiated a wave of cornification, assessed as TdT-mediated dUTP nick end-labeling-positive cells in stratum granulosum and newly cornified cells by electron microscopy. Because cornification was blocked by occlusion, corneocytes formed specifically in response to barrier, rather than injury or cell replacement, requirements. SP inhibitors and hyperacidification (which decreases SP activity) blocked cornification after barrier disruption. Similarly, cornification was delayed in PAR2(-/-) mice. Although classical markers of apoptosis [poly(ADP-ribose)polymerase and caspase (Casp)-3] remained unchanged, barrier disruption activated Casp-14. Moreover, the pan-Casp inhibitor Z-VAD-FMK delayed cornification, and corneocytes were structurally aberrant in Casp14(-/-) mice. Thus, permeability barrier requirements coordinately drive both the generation of the stratum corneum lipid-enriched extracellular matrix and the transformation of granular cells into corneocytes, in an SP- and Casp-14-dependent manner, signaled by PAR2.