Effects of keratinocyte growth factor in the endometrium of rhesus macaques during the luteal-follicular transition

We previously reported that keratinocyte growth factor (KGF) is up-regulate d by the action of progesterone (P) in the primate endometrium, and we sugg ested that this protein is a likely mediator of P-dependent stromal-epithel ial paracrine interactions in this tissue. At the end of the menstrual cycl e, P levels fall, and the abundance of endometrial KGF transcripts decrease s approximately 9-fold. In macaques, withdrawal of P induces the luteal-fol licular transition (LFT), marked by menstrual sloughing of the functionalis zone and apoptotic regression of the basalis zone. Because KGF levels fall so dramatically during the LFT, we hypothesized that replacement with exog enous KGF during the LFT would prevent some of the endometrial changes seen after P withdrawal. Here we describe two studies of the effects of exogeno usly administered KGF during the LFT in rhesus macaques. In one experiment we administered KGF systemically to ovariectomized, juvenile rhesus macaque s during an LFT induced by hormonal manipulations. KGF had dramatic prolife rative effects on the bladder and salivary glands, known targets of KGF, bu t did not affect cell proliferation in the endometrium or block menstrual s loughing and bleeding. However, KGF strongly inhibited apoptosis in the bas alis zone, increased glandular sacculation and folding in this zone, and ha d a marked trophic effect on the spiral arteries. In the second experiment we installed oviductal catheters in ovariectomized adult rhesus macaques an d infused KGF directly into the uterine lumen during a hormonally induced L FT. Again, arteriotrophic, antiapoptotic, and basalis gland sacculation eff ects were observed in the absence of any effect on cell proliferation. We c oncluded that although KGF is mitogenic for many epithelial cell types, it does not play this role in the primate endometrium. Its most important role s may be to stimulate spiral artery growth and inhibit glandular apoptosis during the nonfertile menstrual cycle. Because its expression rises coincid ent with the time of implantation and because spiral arteries are essential to successful establishment of pregnancy, the role of KGF in the fertile m enstrual cycle deserves further study.