Address for correspondence: Robert M. Brenner, Oregon Regional Primate Research Center, 505 NW 185th Avenue, Beaverton, OR 97006. Voice: 503-690-5331; fax: 503-690-5563.
BrennerR{at}OHSU.edu
According to current theory, endometriosis is initiated during
retrograde menstruation when menstrual fragments flow out of
the fimbriated end of the fallopian tubes and become established
on the ovarian surface or other sites in the peritoneal cavity.
In recent years, new data have accumulated on the properties
of menstruating tissue itself, and several laboratories agree
that this tissue is rich in matrix metalloproteinases (MMPs)
that may facilitate endometriotic implantation. Recently, we
found that vascular endothelial growth factor (VEGF) and its
receptor VEGFR-2 (KDR) were dramatically upregulated in the
stromal cells of the superficial endometrial zones by progesterone
(P) withdrawal during the premenstrual phase. A unique role
of VEGF at this stage of the cycle may be to stimulate MMP expression
in stromal cells because VEGF, KDR, and MMPs were all coordinately
induced in these cells in the superficial zone of the primate
endometrium by P withdrawal. The rich content of MMPs and VEGF
in the menstrual fragments could facilitate attachment and angiogenesis
of menstrual fragments in ectopic sites. In addition, a variety
of chemokines, cytokines, and cellular regulators are induced
by P withdrawal in the premenstrual human endometrium. These
include NF
B, prostaglandins, interleukin-8 (IL-8), cyclooxygenase-2
(COX-2), and monocyte chemotactic peptide-1 (MCP-1), among others.
The perivascular expression of several of these factors may
facilitate the rapid invasion of leukocytes into the endometrium,
especially in the superficial zones. Consequently, menstrual
fragments may be rich in IL-8 and MCP-1, both of which would
add to the angiogenic potential of such fragments in ectopic
sites. In sum, menstrual tissue is rich in VEGF, KDR, MMPs,
leukocytes, chemokines, cytokines, and prostaglandins, all factors
that may facilitate attachment and angiogenesis when menstrual
fragments exit from the tubes and implant on pelvic sites. Additional
research on these and other factors in premenstrual and menstrual
endometrium may deepen our understanding of both the establishment
and progression of this debilitating disease.
