This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The goal is to develop new medical therapies that reduce heavy menstrual bleeding in women. Menstrual bleeding is triggered by an acute decrease in systemic progesterone. Our hypothesis is that progesterone withdrawal triggers local inflammation coupled with the ingress of leukocytes (neutrophils and macrophages), which results in loss of blood vessel integrity, epithelial necrosis and sloughing of the upper layers of endometrium. Leukocyte infiltration is mediated by the local expression of small secreted proteins (chemokines) including interleukin 8 (IL-8;CXCL8) and monocyte chemoattractant protein (MCP-1;CCL-2). Antagonists that block the receptors for IL8 and MCP-1 (CXCR2 and CCR2b) have been developed. Rhesus macaques are menstruating nonhuman primates with menstrual cycles that are very similar to those of women and can provide a model for testing chemokine receptor antagonists (AZ01 and AZ02) on menstrual blood loss (MBL).
Our Aims are:
Aim 1 is to validate new methods for the measurement of menstrual blood loss in rhesus macaques;
Aim 2 is to test the effects of AZ01 and AZ02 on menstrual bleeding in rhesus macaques. We found that AZ01 and AZ02 (20 mg/kg) are well-tolerated, but the effect of AZ01 on MBL was variable, possibly due to the poor solubility of AZ01. Combining AZ01 and AZ02 reduced MBL. We conclude that blockade of inflammation may provide a valuable target for reducing heavy menstrual bleeding.
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